Neoadjuvant pembrolizumab plus chemotherapy in germline BRCA mutated triple negative breast cancer cohort

Neoadjuvant pembrolizumab plus chemotherapy in germline BRCA mutated triple negative breast cancer cohort | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Neoadjuvant pembrolizumab plus chemotherapy in germline BRCA mutated triple negative breast cancer cohort Monique Celeste Tavares, Flávia C. Balint, Romualdo Barroso-Sousa Barroso-Sousa, and 34 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8929138/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Neoadjuvant pembrolizumab plus chemotherapy improves outcomes in early triple negative breast cancer, but real world evidence in germline BRCA carriers remains limited. We analyzed 726 consecutively treated patients from the Neo Real GBECAM 0123 multicenter cohort who received at least one cycle of neoadjuvant pembrolizumab with chemotherapy and underwent surgery. Pathologic complete response was higher among pathogenic or likely pathogenic BRCA1 or BRCA2 carriers than in wild type or untested patients (74.0% vs 61.7%). With a median follow up of 20.3 months, event free and overall survival were favorable in both groups, with a non significant trend toward improved event free survival in BRCA carriers, most apparent among patients with residual disease. Biological sciences/Cancer Health sciences/Oncology triple-negative breast cancer pembrolizumab BRCA neoadjuvant therapy pathologic complete response event-free survival real-world study Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 INTRODUCTION Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor (ER) and progesterone receptor (PR) expression and by lack of HER2 overexpression or gene amplification. This receptor profile limits established targeted treatment options and is generally associated with more aggressive tumor biology, higher early recurrence risk, and poorer prognosis compared with hormone receptor–positive disease. TNBC accounts for approximately 10–15% of all breast cancers, is diagnosed more frequently in younger patients, and is overrepresented in some populations (e.g., African American and Hispanic women), contributing to substantial psychosocial and economic burden. Biologically, TNBC is heterogeneous and comprises distinct molecular subtypes with potential therapeutic relevance; however, broadly effective, universally applicable targeted strategies remain limited. [ 1 – 2 ]. KEYNOTE-522 established pembrolizumab combined with neoadjuvant chemotherapy (paclitaxel–carboplatin followed by anthracycline/cyclophosphamide) and continued adjuvant pembrolizumab as a standard for high-risk early-stage TNBC, improving pCR, event-free survival, and overall survival versus chemotherapy alone [ 3 – 4 ]. In parallel, 10–15% of TNBC tumors harbor germline BRCA 1/2 pathogenic variants and frequently exhibit homologous recombination deficiency (HRD), identifiable by genomic scars and mutational signature [ 3 – 2 – 5 – 7 ]. HRD is associated with enhanced sensitivity to DNA-damaging agents (including platinum) and to PARP inhibitors in metastatic disease (OlympiAD, EMBRACA) and in the adjuvant setting (OlympiA) [ 8 – 13 ]. Mechanistically, HRD may also modulate immunogenicity and the tumor microenvironment, potentially influencing response to immune checkpoint blockade [ 2 , 14 ]. Because pCR correlates with long-term outcomes at the trial level, pCR and residual disease metrics can serve as clinically meaningful intermediate endpoints [ 15 – 16 ]. Real-world evidence (RWE) complements clinical trials by characterizing outcomes, treatment patterns, and resource use in routine practice, thereby informing clinical decision-making and implementation. Given the limited data evaluating the KEYNOTE-522 regimen in patients with g BRCA , we aimed to assess clinical characteristics, pathologic response, survival outcomes, and safety in a multicenter real-world cohort of patients with TNBC and g BRCA treated according to the KEYNOTE-522 regimen [ 1 , 17 ]. RESULTS Germline BRCA testing Overall, 600 (82.64%) underwent germline BRCA 1/ BRCA 2 mutation testing and had the testing results available. A hundred twenty-six patients (17.4%) were not tested or had the testing status unavailable. Among those tested, germline BRCA pathogenic/likely pathogenic variants (m BRCA ) were identified in 105/600 (17.5%), corresponding to 105/726 (14.5%) of the overall cohort. BRCA 1 variants were observed in 82 patients (78.1%) and BRCA 2 variants in 22 (21%). The control group comprised 621 patients (wt/unk BRCA ) (Table 1). Table 1. Germline BRCA Testing Overview Measure n % of total cohort (N=726) % among tested (N=600) % among mBRCA (N=105) Total cohort 726 100.0% - - Tested with results available 600 82.6% 100.0% - Not tested / testing status unavailable 126 17.4% - - mBRCA (pathogenic/likely pathogenic) 105 14.5% 17.5% 100.0% wtBRCA among tested 495 68.2% 82.5% - Control group (wt/unkBRCA) 621 85.5% - - - BRCA1 82 11.3% 13.7% 78.1% - BRCA2 22 3.0% 3.7% 21.0% - BRCA subtype not specified 1 0.1% 0.2% 1.0% Patients characteristics m BRCA patients were younger than wt/unk BRCA (median 40.2 vs 45.3 years; p<0.0001) and more frequently premenopausal; BMI did not differ between groups. Initial clinical stage distribution was similar (stage II 72.3% and stage III 27.7% in both; p=0.96). High histologic grade (grade 3) was more frequent in m BRCA , although not statistically significant (80.2% vs 74.2%; p=0.25). Ki-67 was higher in m BRCA (median 80% vs 70%; p=0.01). Invasive carcinoma of no special type predominated in both groups (95% vs 88%). Neoadjuvant treatment completion and tolerance were comparable. Mastectomy was more common in m BRCA (88.3% vs 34.7%; p<0.001). Adjuvant chemotherapy was less frequent in m BRCA (3.3% vs 22.2%; p<0.001), while adjuvant immunotherapy use was similar (83.3% vs 78.2%; p=0.98). Adjuvant radiotherapy was less frequent in m BRCA (64.4% vs 87.1%, p<0.001%) (Table 2). Table 2. Comparative Clinical and Treatment Characteristics: m BRCA vs wt/unk BRCA Cohorts. Characteristic m BRCA (n=105) wt/unk BRCA (n=621) p-value Median age (years) 40.2 45.3 <0.001 Premenopausal status 61.1% 51.6% 0.029 Clinical stage Stage II: 72.0% / Stage III: 27.7% Stage II: 73.0% / Stage III: 27.7% 0.96 Histologic grade 3 80.2% 74.2% 0.25 Median Ki-67 80% 70% 0.01 Histology: NST 95% 88% — TILs ≥ 30% 40.7% 26.2% 0.117 Mastectomy 88.3% 34.7% <0.001 Adjuvant chemotherapy 3.3% 22.2% <0.001 Adjuvant immunotherapy (pembrolizumab) 83.3% 78.2% 0.98 Adjuvant radiotherapy 64.4% 87.1% <0.001 Abbreviations: NST, invasive carcinoma of no special type; TILs, tumor infiltrating lymphocytes Pathologic complete response rates Patients with m BRCA had higher pCR rates compared to patients with wt/unk BRCA (74.0% vs 61.7% ; OR 1.78, 95% CI 1.10 – 2.87, P = 0.0244). Progression during neoadjuvant therapy occurred in 1.2% of m BRCA vs 4.4% of wt/unk BRCA (p=0.23) (Figure 1). In the multivariable logistic regression model including BRCA status, disease stage, tumor grade, Ki-67 index, and number of neoadjuvant pembrolizumab cycles, BRCA status remained significantly associated with pCR (OR 1.70, 95% CI 1.01 – 2.89, P = 0.048). Additionally, Ki-67 ≥ 50% was independently associated with a higher likelihood of achieving pCR, whereas patients with stage III disease and those who received fewer than six cycles of neoadjuvant pembrolizumab had a lower probability of pCR (Table 3). TILs were not included in the multivariable analysis due to the high proportion of missing data. Most patients in both groups (82.2% in m BRCA and 87.7% in wt/unk BRCA , P=0.252) continued adjuvant pembrolizumab after a pathologic complete response. For those with m BRCA and residual disease (n=26), a combined strategy of pembrolizumab plus olaparib was used in 57.7%, 19.2% received pembrolizumab without olaparib, and 11.5% received olaparib without pembrolizumab. The remaining 11.6% received adjuvant capecitabine (with or without pembrolizumab). For those with wt/unk and residual disease, the most used regimen was pembrolizumab plus capecitabine (57.5%), followed by pembrolizumab alone (26.1%), and capecitabine alone (12.6%). Table 3. Univariate and multivariable analysis of factors associated with pathologic complete response. Univariate analysis Multivariable analysis OR 95% CI P-value OR 95% CI P-value BRCA 1/2 (mutated vs wild-type/unknown) 1.78 1.10 – 2.87 0.017 1.70 1.01 – 2.89 0.048 Ki67 index (≥ 50% vs < 50%) 2.67 1.85 – 3.86 < 0.001 2.36 1.56 – 3.58 <0.001 TILs (≥ 30% vs < 30%) 2.70 1.39 – 5.27 0.026 - - - Tumor grade (3 vs 1-2) 1.82 1.25 – 2.65 0.002 1.45 0.95 - 2.22 0.080 Disease stage (III vs II) 0.54 0.38 - 0.78 0.001 0.52 0.35 - 0.78 0.002 AC regimen (dose-dense vs every 3-week) 1.14 0.83 – 1.58 0.399 - - - Number of neoadjuvant pembrolizumab cycles (< 6 versus ≥ 6) 0.52 0.34 – 0.80 0.003 0.48 0.30 - 0.76 0.002 Abbreviations: OR, odds ratio; CI, confidence interval; TILs, tumor infiltrating lymphocytes; AC, anthracycline and cyclophosphamide. Survival outcomes With a median follow-up of 22 months , patients harboring germline m BRCA showed a trend toward improved EFS compared with wt/unk BRCA counterparts, with 2-year EFS rates of 92.3% and 86.2%, respectively (HR: 0.51, 95% CI 0.23 – 1.11, P = 0.091). Although not statistically significant, this pattern suggests a clinically meaningful benefit (Figure 2). Median EFS was not reached in either cohort. For patients whose tumors achieved a pathologic complete response, favorable EFS was observed regardless of the BRCA status, with 2-year EFS rates greater than 94% in both groups (HR 1.10, 95% CI 0.31 – 3.88, P=0.875). For those whose tumors had residual disease, the 2-year EFS rates were 85.9% in m BRCA and 74.4% in wt/unk BRCA (HR 0.59, 95% CI 0.21- 1.63, P=0.311). EFS for each BRCA group according to pathologic response is shown in Figure 3. As shown in Figure 4, patients with germline m BRCA also exhibited a trend toward improved OS compared with wt/unk BRCA , with 2-year OS rates of 98.9% versus 95.1%, respectively (HR 0.17, 95% CI 0.02 – 1.26, P = 0.083) (Figure 4). Kaplan–Meier curves showing overall survival (OS) in patients with germline BRCA mutations (m BRCA , red line) and BRCA wild-type (wt/unk BRCA , blue dashed line). Median OS was not reached in either cohort. At 2 years, OS rates were 98.9% versus 95.1%, respectively (HR 0.17, 95% CI 0.02 – 1.26, P = 0.083). Safety Use of G-CSF tended to be higher in m BRCA (74% vs 65.5%; p=0.122). Notably, G-CSF is routinely administered as part of primary prophylaxis for patients receiving dose-dense AC in routine practice; therefore, in this real-world dataset, G-CSF use likely reflects both protocol-driven prophylaxis and clinical indications, and we did not systematically distinguish primary from secondary prophylaxis. Overall, the safety patterns were similar in patients with m BRCA and wt/unk BRCA . Rates of febrile neutropenia were similar (8.7% vs 10.2%; p=0.85). Dose reductions (15.5% vs 12.8%; p=0.65), treatment delays (25.7% vs 25.3%; p=1.00), and discontinuations (24.4% vs 22.9%; p=0.88) were comparable between the two groups. (Figure 5). DISCUSSION In this real-world Latin American cohort (n=726) treated according to the KEYNOTE-522 protocol, we observed that patients with mBRCA had higher pCR rates and a trend toward improved long-term outcomes compared with those with wt/unkBRCA . In the pivotal trial, BRCA status was not reported [3-4]. In our cohort, approximately one in seven patients carried a mBRCA , with a predominance of BRCA 1. These patients were younger and exhibited more proliferative disease (higher Ki-67, higher histological grade) and a trend toward higher TILs. The addition of pembrolizumab to taxane–carboplatin followed by anthracycline/cyclophosphamide resulted in substantially higher pCR in mBRCA compared with wt/unkBRCA (74.0% vs. 61.7%), translating into excellent EFS and OS. Biologically, germline BRCA 1/2 pathogenic variants are a hallmark of HRD, which is common in TNBC and can be characterized by genomic scars Loss of Heterozygosity (LOH), Telomeric Allelic Imbalance ( TAI), Large-Scale State Transitions (LST) and mutational signature [5-7]. This biology underpins sensitivity to platinum-based chemotherapy (e.g., TNT; GeparSixto) and synthetic lethality with PARP inhibition, with demonstrated clinical benefit in metastatic disease (OlympiAD, EMBRACA) and in high-risk early-stage disease (OlympiA) [8-13]. HRD may also increase tumor immunogenicity through DNA-sensing pathways, contributing to higher TILs in BRCA1 -mutated tumors in some cohorts, although results are heterogeneous [2,14]. Our findings are broadly consistent with smaller real-world series that specifically evaluated gBRCA -mutated TNBC treated with anthracycline–taxane–platinum regimens plus pembrolizumab [24-27]. In a multicenter Italian cohort of 184 patients, Fedele et al. reported pCR rates of 80.0% in BRCA1- mutated, 75.0% in BRCA2 -mutated, and 61.1% in wild-type tumors; pooled BRCA1/2 carriers had a higher probability of pCR than wild-type patients (78.4% vs 61.1%; OR 2.17; 95% CI 1.01–4.97), survival data remain immature [24]. A Korean series of 199 patients treated with a KEYNOTE-522–like regimen with or without pembrolizumab similarly found numerically higher pCR in mBRCA (73.5% vs 59.3%; p = 0.075) and comparable absolute pCR gains with pembrolizumab in mutated and non-mutated groups, suggesting that mBRCA behaves primarily as a chemosensitivity/HRD marker rather than a specific predictor of incremental immunotherapy benefit [25]. Etan et al. reported analogous findings in an Israeli cohort of 100 stage II–III TNBC patients treated with anthracycline, taxane and carboplatin (ACTC) or a KEYNOTE-522 based chemo-immunotherapy regimen: one-third were mBRCA and attained higher pCR irrespective of regimen, with pCR reaching 100% among mBRCA treated with KN522. At 50 months, KN522 was associated with improved OS/EFS versus ACTC, and pCR, rather than mBRCA status, was the main driver of long-term outcomes [26]. A larger Korean cohort of 316 patients uniformly treated with KN522-based regimens also showed significantly higher pCR in mBRCA vs wild-type tumors (73.9% vs 59.3%; p = 0.040) but no independent effect of mBRCA on DFS after adjusting for stage, PD-L1, adjuvant therapy, and pCR [27]. Taken together, these real-world data, including the present Neo-Real cohort, consistently show that mBRCA TNBC derives higher pCR rates, typically in the 70–80% range, representing an absolute gain of 10–15 percentage points compared with BRCA wild-type tumors under KEYNOTE-522–like regimens. However, a distinct survival advantage attributable to BRCA status alone has not been robustly demonstrated; in multivariable models, mBRCA per se has not emerged as an independent prognostic factor for DFS/OS once pCR and standard clinicopathologic variables are accounted for [23-26]. Current evidence therefore supports germline mBRCA1/2 as a marker of enhanced platinum-based chemosensitivity/HRD, while long-term benefit from KEYNOTE-522, like chemo-immunotherapy seems to be driven predominantly by achieving pCR (table 4). At the trial level, pCR and residual disease burden are associated with long-term outcomes, supporting their use as intermediate endpoints while recognizing imperfect surrogacy for EFS/OS [15-16,18-22]. From a post-neoadjuvant perspective, RCB provides granularity beyond binary pCR and has been validated as a prognostic tool across breast cancer subtypes; higher RCB is associated with worse long-term outcomes and can guide escalation strategies [18–22]. In TNBC with residual invasive disease after standard neoadjuvant chemotherapy, adjuvant capecitabine improved disease-free and overall survival (CREATE-X) and remains a relevant option alongside immunotherapy-based regimens [27]. For mBRCA with high-risk early disease, adjuvant olaparib improved invasive and distant disease-free survival and overall survival in OlympiA, supporting consideration of PARP inhibition in eligible patients after completion of local therapy and standard systemic treatment [12–13]. In our cohort, the EFS separation was more apparent among patients with residual disease, a setting in which adjuvant management is typically risk-adapted. While higher pCR rates may contribute to cohort-level EFS differences, the non-significant EFS trend among patients with residual disease may also have been influenced by differential use of post-neoadjuvant escalation strategies, including olaparib in eligible mBRCA and capecitabine-based approaches in residual TNBC. Given the observational design and heterogeneity/coverage limitations in post-neoadjuvant therapy delivery, these findings should be interpreted as hypothesis-generating. TILs are a robust prognostic biomarker in early TNBC and are supported by standardized scoring recommendations from the International TILs Working Group [28-29]. Recent cohorts suggest that selected patients with stage I TNBC and very high stromal TILs may achieve excellent long-term outcomes with locoregional therapy alone, prompting interest in prospective de-escalation trials [30-31]. Early-phase studies are exploring immunotherapy-only or reduced-chemotherapy approaches in immunologically ‘hot’ TNBC, including the BELLINI trial [32] and ongoing TIL-guided programs such as ETNA, OPTImaL, and DespaTIL (ClinicalTrials.gov identifiers: NCT06078384, NCT06476119, NCT07074106) [33–35].Complementary immune features, including the CD8/FOXP3 ratio, may further refine risk stratification [36]. Beyond systemic therapy, comprehensive survivorship planning for young gBRCA includes genetic counseling and consideration of risk-reducing surgeries, which have been associated with improved survival in international cohorts [37]. This retrospective multicenter study has inherent limitations, including missing data (TILs, RCB), inter-center heterogeneity, variability in AE reporting, and the absence of standardized auditing. Approximately 17% of patients did not undergo BRCA testing. These individuals were pragmatically grouped with the wild-type cohort for analysis; however, we acknowledge that this approach may dilute observed differences. Nevertheless, to the best of our knowledge, this represents the largest cohort evaluating the KEYNOTE-522 regimen in mBRCA patients and provides valuable insights to guide future research. Importantly, it also contributes data from a Latin American population, which remains underrepresented in prospective clinical trials. Table 4. pCR and survival according to germline mBRCA status in TNBC treated with KEYNOTE-522–based regimens Study / year Total N BRCA status distribution pCR mBRCA vs wt BRCA (%) p-value (pCR) Survival signal ( mBRCA vs wtBRCA) Fedele et al., 2025 184 mBRCA: 37 (20.1%); wtBRCA: 147 (79.9%) 78.4 vs 61.1 0.05 Higher pCR in mBRCA; survival data immature/not reported. Bae / Kim et al., 2024 199 mBRCA: 49 (24.6%); wtBRCA: 150 (75.4%) 73.5 vs 59.3 0.075 No clear DFS difference by mBRCA; no significant interaction with pembrolizumab. Etan et al., 2025 ≈100 mBRCA: 32 (≈32%); wtBRCA: 68 (≈68%) 100 vs 64.7 NR KN522 improves OS/EFS vs ACTC overall; outcomes mainly driven by pCR, not mBRCA status alone. Park et al., 2025 316 mBRCA : 46 (14.6%); wtBRCA: 270 (85.4%) 73.9 vs 59.3 0.040 mBRCA not independent for DFS (HR 1.71; 95% CI 0.63–4.65); pCR strongly prognostic. Tavares et al., 2025 (Neo-Real) 726 mBRCA : 105 (14.5%); wtBRCA: 621 (85.5%) 74.0 vs 61.7 0.0244 Trend to better EFS in mBRCA; survival predominantly driven by achievement of pCR. Abbreviations: TNBC, triple-negative breast cancer; mBRCA, germline BRCA1/2-mutated; wtBRCA, BRCA wild-type; pCR, pathologic complete response; DFS, disease-free survival; OS, overall survival; EFS, event-free survival; NR, not reported; KN522, KEYNOTE-522 regimen; ACTC, anthracycline–taxane–carboplatin. Emerging evidence suggests that BRCA1/2 alterations may modulate the tumor microenvironment and influence response to immune checkpoint blockade [14]; moreover, breast cancers arising in germline BRCA1 versus BRCA2 carriers may represent distinct biological and clinical entities with potentially divergent therapeutic opportunities [2] . This real-world study supports that TNBC patients with germline BRCA mutations represent a biologically distinct subgroup, achieving higher pCR rates and showing a trend toward improved EFS with a KEYNOTE-522 based regimen. The 12.3% absolute increase in pCR was accompanied by favorable EFS trajectories. Collectively, these findings have meaningful clinical implications and support the development of risk-adapted strategies, including more individualized treatment approaches for patients with mBRCA. METHODS Study design and setting We performed a multicenter, observational cohort study of patients with early-stage TNBC treated with neoadjuvant chemotherapy plus pembrolizumab across 14 cancer centers in Brazil and 16 centers in Argentina from July 2020 to July 2025. Data was collected from electronic medical records using a standardized case-report form and independently verified. Participants Eligible patients had histologically confirmed TNBC (any histologic subtype) and received ≥1 cycle of neoadjuvant pembrolizumab with chemotherapy. Baseline disease stage mirrored the KEYNOTE-522 population (cT2N0 and/or cT1 with node-positive disease; M0). Patients who underwent definitive breast surgery after the neoadjuvant therapy were included in the primary analyses of pCR. All consecutively treated patients were included, regardless of the availability of germline testing. Germline BRCA1/2 testing was universally recommended for patients with early-stage TNBC across participating centers; however, test uptake was contingent on local availability and insurance/health system authorization , which varied over time and across sites. When performed, BRCA1/2 testing used one or more of the following platforms, with validated clinical assays: multigene next-generation sequencing (NGS) panels; targeted NGS for BRCA1/2 ; multiplex ligation-dependent probe amplification (MLPA) for large genomic rearrangements; and/or targeted qPCR or digital PCR for specific variants. According to the results, patients were categorized as: mBRCA : carriers of pathogenic or likely pathogenic germline BRCA1/2 variants; variants of uncertain significance (VUS) were not classified as mBRCA ; or wt/unkBRCA : germline BRCA1/2 wild-type/negative results or unknown/unavailable status (including untested patients), analyzed together. The study was approved by the Research Ethics Committees/Institutional Review Boards of all participating centers: A.C.Camargo Cancer Center Research Ethics Committee (São Paulo, Brazil); Grupo Brasileiro de Estudos em Câncer de Mama (GBECAM) Research Committee (São Paulo, Brazil); Hospital Brasília – Américas Oncologia Ethics Committee (Brasília, Brazil); Instituto D’Or de Pesquisa e Ensino (IDOR) Research Ethics Committees (São Paulo, Rio de Janeiro, and Recife, Brazil); Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo Research Ethics Committee (São Paulo, Brazil); SUMA (Grupo Cooperativa Argentino para el estudio y la investigación del Cáncer de Mama) Ethics Committee (Buenos Aires, Argentina); Instituto Américas Ethics Committee (Rio de Janeiro, Brazil); Hospital 9 de Julho (Américas Oncologia) Ethics Committee (São Paulo, Brazil); Hospital Moinhos de Vento Ethics Committee (Porto Alegre, Brazil); Hospital Samaritano (Américas Oncologia) Ethics Committee (São Paulo, Brazil); Hospital Sírio-Libanês Ethics Committees (Brasília and São Paulo, Brazil); Hospital Beneficência Portuguesa Ethics Committee (São Paulo, Brazil); Hospital Santa Paula (Américas Oncologia) Ethics Committee (São Paulo, Brazil); Clínica AMO Ethics Committee (Salvador, Brazil); Instituto do Câncer do Ceará Ethics Committee (Fortaleza, Brazil); Centro Integrado de Pesquisa da Amazônia (CINPAM) Ethics Committee (Manaus, Brazil); and Hospital São Domingos Ethics Committee (São Luís, Brazil). The study was conducted in accordance with the Declaration of Helsinki; consent procedures followed local regulations. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors The study was approved by the Research Ethics Committees/Institutional Review Boards of all participating centers: A.C.Camargo Cancer Center Research Ethics Committee (São Paulo, Brazil); Grupo Brasileiro de Estudos em Câncer de Mama (GBECAM) Research Committee (São Paulo, Brazil); Hospital Brasília – Américas Oncologia Ethics Committee (Brasília, Brazil); Instituto D’Or de Pesquisa e Ensino (IDOR) Research Ethics Committees (São Paulo, Rio de Janeiro, and Recife, Brazil); Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo Research Ethics Committee (São Paulo, Brazil); SUMA (Grupo Cooperativa Argentino para el estudio y la investigación del Cáncer de Mama) Ethics Committee (Buenos Aires, Argentina); Instituto Américas Ethics Committee (Rio de Janeiro, Brazil); Hospital 9 de Julho (Américas Oncologia) Ethics Committee (São Paulo, Brazil); Hospital Moinhos de Vento Ethics Committee (Porto Alegre, Brazil); Hospital Samaritano (Américas Oncologia) Ethics Committee (São Paulo, Brazil); Hospital Sírio-Libanês Ethics Committees (Brasília and São Paulo, Brazil); Hospital Beneficência Portuguesa Ethics Committee (São Paulo, Brazil); Hospital Santa Paula (Américas Oncologia) Ethics Committee (São Paulo, Brazil); Clínica AMO Ethics Committee (Salvador, Brazil); Instituto do Câncer do Ceará Ethics Committee (Fortaleza, Brazil); Centro Integrado de Pesquisa da Amazônia (CINPAM) Ethics Committee (Manaus, Brazil); and Hospital São Domingos Ethics Committee (São Luís, Brazil). The study was conducted in accordance with the Declaration of Helsinki; consent procedures followed local regulations. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors Statistical analysis The primary outcomes were pathologic complete response (pCR), defined as ypT0/Tis ypN0 at surgery. The wt/unk BRCA category was analyzed as a control group per the prespecified plan. Univariate and multivariable logistic regression were used to evaluate factors associated with pCR. Variables were selected for the multivariable regression based on their clinical relevance and the association with pCR in the univariate analysis. Residual disease was categorized using the Residual Cancer Burden (RCB) index when available [18-22]. Secondary outcomes included event-free survival (EFS) and overall survival (OS). EFS was defined as the time from the first neoadjuvant dose to any of the following events: disease progression precluding surgery, local, regional, or distant recurrence, development of a second invasive cancer, or death from any cause. OS was calculated from the date of first neoadjuvant dose until the date of death from any cause. OS was analyzed descriptively given the low number of events. Patients without events were censored at the date of last contact. Median follow-up was estimated using the reverse Kaplan–Meier method. Additional secondary outcomes comprised progression during neoadjuvant therapy and safety, assessed by the incidence of grade ≥3 adverse events (AEs). Continuous variables are reported as median (IQR) and were compared with the Mann–Whitney U test, as appropriate. Categorical variables are summarized as counts (percentages) and compared using χ² or Fisher’s exact tests. Time-to-event endpoints were estimated with the Kaplan–Meier method and compared by the log-rank test; hazard ratios (HRs) with 95% confidence intervals (CIs) were derived from Cox proportional-hazards models. Two-sided p <0.05 was considered statistically significant. Missing data were handled by complete-case analysis for each endpoint. Declarations Data availability De-identified individual participant data that support the findings of this study are available from the corresponding author upon reasonable request. Access is subject to institutional policies, ethics approval, and data-sharing agreements due to patient privacy and confidentiality requirements. Code availability Statistical analysis code is available from the corresponding author upon reasonable request. Acknowledgements Partial results of this manuscript have been presented as a poster at the San Antonio Breast Cancer Symposium 2025. Author contributions R.C.B., M.C.T., J.B., D.D.R., D.A.S., D.M.G., C.H.A., B.M.Z., A.F., M.L.B., P.M.H., L.T., and R.B.S. contributed to the study conception and design. R.C.B., F.C.B, I.M.S, M.O.A, M.G, F.M, R.D.P.F, C.L.S, M.R.M, Z.S.S, A.M.U.G, M.M.F.M., N.J.B.G, M.V.C., D.M.G., N.C.C.N, P.M ,M.R , G.R, and R.B.S. contributed to the conduct or collection, data analysis and interpretation. R.C.B., M.C.T., J.B., D.D.R., D.A.S., D.M.G., C.H.A., B.M.Z., A.F., F.B.M, M.L.B., S.A.M, M.D.P.E.D, S.M.S, V.C.C.L, J.C.C.R, E.S.S, G.R., L.T., M.R., M.V.C, and R.B.S. contributed to the drafting of the manuscript and critical revisions. All authors gave their final approval of the manuscript to be submitted. Competing interests The Authors declare no Competing Non-Financial Interests but the following Competing Financial Interests: RBS: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Eli Lilly, Gilead, Libbs, Pfizer, Novartis, MSD, and Roche. Financial support for educational programs and symposia: AstraZeneca, Daiichi-Sankyo, Gilead, Eli Lilly, and MSD. Institutional Research grant: AstraZeneca, Daiichi-Sankyo. LL: Speaker fees and/or honoraria for consulting or advisory functions: Adium. Travel grants: MSD, Gador. PM: Speaker fees and/or honoraria for consulting or advisory functions: MSD, AstraZeneca, Roche, Pfizer, Novartis, ADIUM, GSK, Gador. Institutional Research grant: Novartis, AstraZeneca, Roche, GSK. Travel grants: Astra Zeneca, Novartis, ADIUM, Roche. SAM: Tavel grants ADIUM, AstraZeneca, Novartis, MSD, Elea. MR: Travel grants: Novartis, AstraZeneca, ADIUM, Elea, MVC: Speaker fees and/or honoraria for consulting or advisory functions: MSD, AstraZeneca, Roche, Pfizer, Novartis, ADIUM, Gador. Institutional Research grant: Novartis, AstraZeneca, Roche. Travel grants: Astra Zeneca, Novartis, ADIUM, Roche. JB: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Lilly, Gilead, Pfizer, Novartis, MSD, Roche, Knight Pharmaceuticals. Financial support for educational programs and symposia: Roche, Daiichi-Sankyo. DDR: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Lilly, Libbs, Pfizer, Novartis, Roche, GSK, Sanofi, Amgen, Zodiac Pharma. Financial support for educational programs and symposia: Roche. DAS: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo. Financial support for educational programs and symposia: AstraZeneca. JAPA: Speaker fees and/or honoraria for consulting or advisory functions: Novartis, AstraZeneca, MSD, Lilly. DMG: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo, Teva, Roche, AstraZeneca, Pfizer, Lilly, Novartis. Financial support for educational programs and symposia: AstraZeneca, Libbs, Roche. Research grant: Novartis. MS: Speaker fees and/or honoraria for consulting or advisory functions: Adium, GSK, Travel Grants: Roche, AstraZeneca, MSD. MRM: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Pfizer, Novartis, Roche, MSD, Knight. Financial support for educational programs and symposia: MSD, AstraZeneca, Knight, Novartis. BMZ: AstraZeneca, Daiichi-Sankyo, Eli Lilly, Gilead, Pfizer, Novartis, MSD, Roche, Addium. AF: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo, Novartis, Gilead, MSD, BMS, AstraZeneca, Pfizer. Financial support for educational programs and symposia: AstraZeneca, Daiichi-Sankyo, MSD, Novartis. GC: Speaker fees and/or honoraria for consulting or advisory functions: Amgen, AstraZeneca. Travel grants: Roche. CHA: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo, Gilead AstraZeneca, Novartis, MSD. Financial support for educational programs and symposia: AstraZeneca, Daiichi-Sankyo, MSD, Lilly, Roche, Novartis, Gilead, Medscape. RC: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Eli Lilly, Gilead, MSD, and GSK. MMFM: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Eli Lilly, Gilead, Addium, Novartis, MSD, and Roche. Financial support for educational programs and symposia: AstraZeneca, Daiichi-Sankyo, Gilead, Eli Lilly, Roche, MSD and Novartis. PMH: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo. LT: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo, MSD, AstraZeneca, Pfizer, Lilly, Novartis. Financial support for educational programs and symposia: AstraZeneca, Roche, Gilead. Institutional Research grant: Novartis. CP: Speaker fees and/or honoraria for consulting or advisory functions: Knight. Travel grants: Astra Zeneca, Gador, Novartis, Pfizer, Raffo, Roche. RCB: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo, Nestle Health Science, Addium, Gilead, MSD, BMS, AstraZeneca, Ache, Pfizer, Roche, Libbs, Lilly, Novartis, and GSK. Financial support for educational programs and symposia: AstraZeneca, Daiichi-Sankyo, MSD. Institutional Research grant: Novartis, AstraZeneca. IMS, FCB, MCT, FM, RPF, GR, CLS, and ZSS declare no conflict of interest. References Orlandini LF, et al. Epidemiological analyses reveal a high incidence of breast cancer in young women in Brazil. JCO Glob Oncol. 2021;7:81–88. doi: 10.1200/GO.20.00440 . Zattarin E, et al. Breast cancers arising in subjects with germline BRCA1 or BRCA2 mutations: different biological and clinical entities with potentially diverse therapeutic opportunities. Crit Rev Oncol Hematol. 2023;190:104109. doi: 10.1016/j.critrevonc.2023.104109 . Schmid P, et al. Overall survival with pembrolizumab in early-stage triple-negative breast cancer. N Engl J Med. 2024;391(21):1981–1991. doi: 10.1056/NEJMoa2402605 . Schmid P, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2022;386(6):556–567. doi: 10.1056/NEJMoa2112651 . Li J, et al. DNA damage response in breast cancer and its role in guiding precise therapies: a comprehensive review. Biomark Res. 2024;12:111. doi: 10.1186/s40364-024-00609-5 . Lenz L, et al. Identifying homologous recombination deficiency in breast cancer: genomic instability score distributions differ among breast cancer subtypes. Breast Cancer Res Treat. 2023;202(1):191–201. doi: 10.1007/s10549-023-07046-3 . Polak P, et al. A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer. Nat Genet. 2017;49(10):1476–1486. doi: 10.1038/ng.3934 . Tutt A, et al. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer: the TNT Trial. Nat Med. 2018;24(5):628–637. doi: 10.1038/s41591-018-0009-7 . Hahnen E, et al. Germline mutation status, pathological complete response, and disease-free survival in triple-negative breast cancer: secondary analysis of a randomized clinical trial. JAMA Oncol. 2017;3(10):1378–1385. doi: 10.1001/jamaoncol.2017.1007 . Litton JK, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379(8):753–763. doi: 10.1056/NEJMoa1802905 . Robson M, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523–533. doi: 10.1056/NEJMoa1706450 . Tutt ANJ, et al. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med. 2021;384(25):2394–2405. doi: 10.1056/NEJMoa2105215 . Geyer CE, et al. Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline BRCA1/2 mutations and high-risk early breast cancer. Ann Oncol. 2022;33(12):1250–1268. Samstein RM, et al. Mutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy. Nat Cancer. 2021;1(12):1188–1203. doi: 10.1038/s43018-020-00139-8 . Cortazar P, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384(9938):164–172. doi: 10.1016/S0140-6736(13)62422-8 . Spring LM, et al. Pathologic complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and survival: a comprehensive meta-analysis. npj Breast Cancer. 2020;6:22. doi: 10.1038/s41523-020-00159-6 . Bonadio RC, et al. Real-world treatment patterns and outcomes in stage I-III triple-negative breast cancer treated with a KEYNOTE-522 regimen: Neo-Real/GBECAM-0123 Study. JCO Glob Oncol. 2025;In press. Symmans WF, et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 2007;25(28):4414–4422. doi: 10.1200/JCO.2007.10.6823 . Symmans WF, et al. Residual cancer burden class and long-term survival following neoadjuvant chemotherapy. J Clin Oncol. 2017;35(10):1049–1060. doi: 10.1200/JCO.2015.63.1010 . Symmans WF, et al. Long-term prognostic value of residual cancer burden after neoadjuvant chemotherapy in the I-SPY2 trial. JAMA Oncol. 2021;7(11):1654–1663. doi: 10.1001/jamaoncol.2021.4006 . Yau C, et al. Residual cancer burden after neoadjuvant therapy and long-term survival outcomes in breast cancer. Lancet Oncol. 2022;23(2):235–244. doi: 10.1016/S1470-2045(21)00689-1 . Pusztai L, et al. Relationship of residual cancer burden and event-free survival in KEYNOTE-522. Ann Oncol. 2024;35(4):429–436. doi: 10.1016/j.annonc.2023.12.014 . Fedele P, et al. Germline BRCA status and pathologic complete response in triple-negative breast cancer patients treated with neoadjuvant chemo-immunotherapy: a real-world multicenter analysis. J Clin Med. 2025;14(24):8854. doi: 10.3390/jcm14248854 . Bae SJ, et al. Efficacy of neoadjuvant pembrolizumab combined with chemotherapy in patients with early-stage triple-negative breast cancer: a real-world study from South Korea. Ann Oncol. 2024;35(Suppl 7):S1406. doi: 10.1016/j.annonc.2024.10.023 . Etan T, et al. Efficacy and toxicity of pembrolizumab in addition to neoadjuvant platinum-based chemotherapy in TNBC patients with and without germline BRCA mutations. J Clin Oncol. 2025;43(16_suppl):e12611. Park HS, et al. Efficacy and safety of neoadjuvant pembrolizumab plus chemotherapy for triple-negative breast cancer: a multicenter retrospective study. Eur J Surg Oncol. 2025;51(5):109215. doi: 10.1016/j.ejso.2025.109215 . Masuda N, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017;376(22):2147–2159. doi: 10.1056/NEJMoa1612645 . Salgado R, et al. The evaluation of tumor-infiltrating lymphocytes in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26(2):259–271. doi: 10.1093/annonc/mdu450 . Loi S, et al. Tumor-infiltrating lymphocytes and prognosis: a pooled individual patient analysis of early-stage triple-negative breast cancers. J Clin Oncol. 2019;37(7):559–569. doi: 10.1200/JCO.18.01010 . Geurts VCM, et al. Outcomes by tumor-infiltrating lymphocytes in stage I triple-negative breast cancer treated with surgery with or without radiotherapy, without chemotherapy: a cohort study. JAMA Oncol . 2024;10(8):1077–1086. doi: 10.1001/jamaoncol.2024.1917 . Leon-Ferre RA, et al. Tumor-infiltrating lymphocytes in triple-negative breast cancer. JAMA. 2024;331(13):1135–1144. doi: 10.1001/jama.2024.3056 . Nederlof I, et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in early-stage triple-negative breast cancer: a phase 2 adaptive trial. Nat Med. 2024;30(11):3223–3235. doi: 10.1038/s41591-024-03249-3 . ClinicalTrials.gov. ETNA Trial (NCT06078384). Accessed 2026 Jan 18. ClinicalTrials.gov. OPTImaL Trial (NCT06476119). Accessed 2026 Jan 18. ClinicalTrials.gov. DespaTIL Study: TIL-Driven De-escalated Chemotherapy in Stage I–II TNBC (NCT07074106). Accessed 2026 Jan 18. Tavares MC, et al. CD8/FOXP3 ratio and tumor microenvironment exhibit different immunological profiles and clinical impact in triple negative breast cancer treated with neoadjuvant chemotherapy in a Latin American cohort. Breast Cancer Res Treat. 2021;187(2):553–565. doi: 10.1007/s10549-021-06196-8 . Blondeaux E, et al. Association between risk-reducing surgeries and survival in young BRCA mutation carriers: an international prospective cohort study. Lancet Oncol. 2025;26(6):940–951. Additional Declarations Competing interest reported. The Authors declare no Competing Non-Financial Interests but the following Competing Financial Interests: RBS: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Eli Lilly, Gilead, Libbs, Pfizer, Novartis, MSD, and Roche. Financial support for educational programs and symposia: AstraZeneca, Daiichi-Sankyo, Gilead, Eli Lilly, and MSD. Institutional Research grant: AstraZeneca, Daiichi-Sankyo. LL: Speaker fees and/or honoraria for consulting or advisory functions: Adium. Travel grants: MSD, Gador. PM: Speaker fees and/or honoraria for consulting or advisory functions: MSD, AstraZeneca, Roche, Pfizer, Novartis, ADIUM, GSK, Gador. Institutional Research grant: Novartis, AstraZeneca, Roche, GSK. Travel grants: Astra Zeneca, Novartis, ADIUM, Roche. SAM: Tavel grants ADIUM, AstraZeneca, Novartis, MSD, Elea. MR: Travel grants: Novartis, AstraZeneca, ADIUM, Elea, MVC: Speaker fees and/or honoraria for consulting or advisory functions: MSD, AstraZeneca, Roche, Pfizer, Novartis, ADIUM, Gador. Institutional Research grant: Novartis, AstraZeneca, Roche. Travel grants: Astra Zeneca, Novartis, ADIUM, Roche. JB: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Lilly, Gilead, Pfizer, Novartis, MSD, Roche, Knight Pharmaceuticals. Financial support for educational programs and symposia: Roche, Daiichi-Sankyo. DDR: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Lilly, Libbs, Pfizer, Novartis, Roche, GSK, Sanofi, Amgen, Zodiac Pharma. Financial support for educational programs and symposia: Roche. DAS: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo. Financial support for educational programs and symposia: AstraZeneca. JAPA: Speaker fees and/or honoraria for consulting or advisory functions: Novartis, AstraZeneca, MSD, Lilly. DMG: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo, Teva, Roche, AstraZeneca, Pfizer, Lilly, Novartis. Financial support for educational programs and symposia: AstraZeneca, Libbs, Roche. Research grant: Novartis. MS: Speaker fees and/or honoraria for consulting or advisory functions: Adium, GSK, Travel Grants: Roche, AstraZeneca, MSD. MRM: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Pfizer, Novartis, Roche, MSD, Knight. Financial support for educational programs and symposia: MSD, AstraZeneca, Knight, Novartis. BMZ: AstraZeneca, Daiichi-Sankyo, Eli Lilly, Gilead, Pfizer, Novartis, MSD, Roche, Addium. AF: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo, Novartis, Gilead, MSD, BMS, AstraZeneca, Pfizer. Financial support for educational programs and symposia: AstraZeneca, Daiichi-Sankyo, MSD, Novartis. GC: Speaker fees and/or honoraria for consulting or advisory functions: Amgen, AstraZeneca. Travel grants: Roche. CHA: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo, Gilead AstraZeneca, Novartis, MSD. Financial support for educational programs and symposia: AstraZeneca, Daiichi-Sankyo, MSD, Lilly, Roche, Novartis, Gilead, Medscape. RC: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Eli Lilly, Gilead, MSD, and GSK. MMFM: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Eli Lilly, Gilead, Addium, Novartis, MSD, and Roche. Financial support for educational programs and symposia: AstraZeneca, Daiichi-Sankyo, Gilead, Eli Lilly, Roche, MSD and Novartis. PMH: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo. LT: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo, MSD, AstraZeneca, Pfizer, Lilly, Novartis. Financial support for educational programs and symposia: AstraZeneca, Roche, Gilead. Institutional Research grant: Novartis. CP: Speaker fees and/or honoraria for consulting or advisory functions: Knight. Travel grants: Astra Zeneca, Gador, Novartis, Pfizer, Raffo, Roche. RCB: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo, Nestle Health Science, Addium, Gilead, MSD, BMS, AstraZeneca, Ache, Pfizer, Roche, Libbs, Lilly, Novartis, and GSK. Financial support for educational programs and symposia: AstraZeneca, Daiichi-Sankyo, MSD. Institutional Research grant: Novartis, AstraZeneca. IMS, FCB, MCT, FM, RPF, GR, CLS, and ZSS declare no conflict of interest. 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Gagliato","email":"","orcid":"","institution":"Grupo Brasileiro de Estudos em Câncer de Mama (GBECAM),","correspondingAuthor":false,"prefix":"","firstName":"Débora","middleName":"M.","lastName":"Gagliato","suffix":""},{"id":602794126,"identity":"b7213e31-9af6-4d6e-80a0-a8db3a662600","order_by":21,"name":"Ana Maria U. Gomes","email":"","orcid":"","institution":"Beneficência Portuguesa de São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Ana","middleName":"Maria U.","lastName":"Gomes","suffix":""},{"id":602794128,"identity":"48104a7e-5091-4e11-a2ec-1fa01a1b79a9","order_by":22,"name":"Bruna M. Zucchetti","email":"","orcid":"","institution":"Grupo Brasileiro de Estudos em Câncer de Mama (GBECAM),","correspondingAuthor":false,"prefix":"","firstName":"Bruna","middleName":"M.","lastName":"Zucchetti","suffix":""},{"id":602794130,"identity":"c1b41a21-f95a-403f-bab4-69708828037e","order_by":23,"name":"Anezka Ferrari","email":"","orcid":"","institution":"Hospital Santa Paula (Américas Oncologia)","correspondingAuthor":false,"prefix":"","firstName":"Anezka","middleName":"","lastName":"Ferrari","suffix":""},{"id":602794132,"identity":"0a7ca413-082e-4038-b0df-d1705f27f39c","order_by":24,"name":"Mayana L. Brito","email":"","orcid":"","institution":"Clínica AMO","correspondingAuthor":false,"prefix":"","firstName":"Mayana","middleName":"L.","lastName":"Brito","suffix":""},{"id":602794133,"identity":"af655155-c671-406b-bf32-6392f352fede","order_by":25,"name":"Maria Marcela F. Monteiro","email":"","orcid":"","institution":"Instituto do Câncer do Ceará","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Marcela F.","lastName":"Monteiro","suffix":""},{"id":602794136,"identity":"9f440c5e-251a-4885-80ef-d64fc0c046db","order_by":26,"name":"Gilmara Resende","email":"","orcid":"","institution":"Centro Integrado de Pesquisa da Amazônia (CINPAM)","correspondingAuthor":false,"prefix":"","firstName":"Gilmara","middleName":"","lastName":"Resende","suffix":""},{"id":602794137,"identity":"a8f08b8d-7295-4e7a-ac7c-d433029d22e7","order_by":27,"name":"Noele J.B. Gomes","email":"","orcid":"","institution":"Grupo Brasileiro de Estudos em Câncer de Mama (GBECAM),","correspondingAuthor":false,"prefix":"","firstName":"Noele","middleName":"J.B.","lastName":"Gomes","suffix":""},{"id":602794138,"identity":"b25fdb07-686f-4846-aa12-2ae40c232dc1","order_by":28,"name":"Maria Victoria Costanzo","email":"","orcid":"","institution":"SUMA (Grupo Cooperativa Argentino para el estudio y la investigación del Cáncer de Mama)","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Victoria","lastName":"Costanzo","suffix":""},{"id":602794139,"identity":"7254526e-402a-47d0-8b6a-3f3e4a4c3c39","order_by":29,"name":"Solange Moraes Sanches","email":"","orcid":"","institution":"AC Camargo Hospital","correspondingAuthor":false,"prefix":"","firstName":"Solange","middleName":"Moraes","lastName":"Sanches","suffix":""},{"id":602794140,"identity":"09ce6601-7567-4c51-b992-c5176632c696","order_by":30,"name":"Vladmir Claudio C. de Lima","email":"","orcid":"","institution":"AC Camargo Hospital","correspondingAuthor":false,"prefix":"","firstName":"Vladmir","middleName":"Claudio C.","lastName":"de Lima","suffix":""},{"id":602794141,"identity":"eefc1f6e-297b-424e-90e6-a09760a334ee","order_by":31,"name":"Jose C. Casali Rocha","email":"","orcid":"","institution":"AC Camargo Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jose","middleName":"C. Casali","lastName":"Rocha","suffix":""},{"id":602794142,"identity":"92337eeb-deab-49d1-ae42-2bb6af60f4e4","order_by":32,"name":"Elizabeth Santana dos Santos","email":"","orcid":"","institution":"AC Camargo Hospital","correspondingAuthor":false,"prefix":"","firstName":"Elizabeth","middleName":"Santana dos","lastName":"Santos","suffix":""},{"id":602794143,"identity":"c5166795-1ca6-4488-817a-9a7b368f87f2","order_by":33,"name":"Paulo M. Hoff","email":"","orcid":"","institution":"Instituto do Câncer do Estado de São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Paulo","middleName":"M.","lastName":"Hoff","suffix":""},{"id":602794144,"identity":"98601c38-012a-4eda-bc44-d1deb56c732e","order_by":34,"name":"Maria del Pilar Estevez-Diz","email":"","orcid":"","institution":"Instituto do Câncer do Estado de São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"del Pilar","lastName":"Estevez-Diz","suffix":""},{"id":602794145,"identity":"23e08803-51a8-4e6a-bf1e-654ec2990a13","order_by":35,"name":"Fabiana B. Makdissi","email":"","orcid":"","institution":"AC Camargo Hospital","correspondingAuthor":false,"prefix":"","firstName":"Fabiana","middleName":"B.","lastName":"Makdissi","suffix":""},{"id":602794146,"identity":"cef46514-f4e9-4ffc-9ead-c383bee53fdf","order_by":36,"name":"Renata Colombo Bonadio","email":"","orcid":"","institution":"Grupo Brasileiro de Estudos em Câncer de Mama (GBECAM),","correspondingAuthor":false,"prefix":"","firstName":"Renata","middleName":"Colombo","lastName":"Bonadio","suffix":""}],"badges":[],"createdAt":"2026-02-20 21:23:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8929138/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8929138/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104396345,"identity":"c9413490-113b-4055-aa8f-3408d9db66fa","added_by":"auto","created_at":"2026-03-11 11:11:46","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":300462,"visible":true,"origin":"","legend":"\u003cp\u003ePathologic complete response (pCR) rates by germline \u003cem\u003eBRCA\u003c/em\u003e status. Bars show the proportion of patients achieving pCR in the m\u003cem\u003eBRCA\u003c/em\u003e group (pathogenic/likely pathogenic germline \u003cem\u003eBRCA\u003c/em\u003e variant; n=105) and the wt/unk\u003cem\u003eBRCA\u003c/em\u003e group (germline \u003cem\u003eBRCA\u003c/em\u003ewild-type; n=621). Observed pCR rates were 74.0% in m\u003cem\u003eBRCA\u003c/em\u003e and 61.7% in wt/unk\u003cem\u003eBRCA\u003c/em\u003e; p=0.0244 for the between-group comparison.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-8929138/v1/5f6a2919471eaaf18892efee.png"},{"id":104396546,"identity":"df575bf6-2254-439a-a810-b3eb322abae6","added_by":"auto","created_at":"2026-03-11 11:12:24","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":181924,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eEvent-free survival according to germline BRCA status.\u003c/em\u003e Kaplan–Meier curves showing event-free survival (EFS) in patients with germline \u003cem\u003eBRCA\u003c/em\u003e mutations (m\u003cem\u003eBRCA\u003c/em\u003e) versus wild-type/ unknown \u003cem\u003eBRCA\u003c/em\u003e (wt/unk\u003cem\u003eBRCA\u003c/em\u003e). Median EFS was not reached in either cohort. At 2 years, EFS rates were 92.3% for m\u003cem\u003eBRCA\u003c/em\u003eversus 86.2% for wt/unk\u003cem\u003eBRCA\u003c/em\u003e, respectively (HR: 0.51, 95% CI 0.23 – 1.11, P = 0.091).\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-8929138/v1/8ff3fec7e06d694c865d5e06.png"},{"id":104396450,"identity":"dd7fe956-4a53-4509-8adc-f53a27d8432c","added_by":"auto","created_at":"2026-03-11 11:12:03","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":285977,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eEvent-free survival for patients with a pathologic complete response or residual disease according to germline BRCA status.\u003c/em\u003eKaplan–Meier curves showing: A) event-free survival (EFS) in patients with germline \u003cem\u003eBRCA\u003c/em\u003e mutations (m\u003cem\u003eBRCA\u003c/em\u003e) versus wild-type/ unknown \u003cem\u003eBRCA\u003c/em\u003e(wt/unk\u003cem\u003eBRCA\u003c/em\u003e) among patients whose tumors achieved a pathologic complete response (HR 1.10, 95% CI 0.31 – 3.88, P=0.875). B) EFS in patients with m\u003cem\u003eBRCA\u003c/em\u003eversus wt/unk\u003cem\u003eBRCA\u003c/em\u003e among those with residual disease (HR 0.59, 95% CI 0.21- 1.63, P=0.311).\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-8929138/v1/0a1ad9ff5741e0ee98037e90.png"},{"id":104396468,"identity":"e9665a1c-3d7c-4f23-ae01-21aa58fc3138","added_by":"auto","created_at":"2026-03-11 11:12:09","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":178247,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eOverall survival according to germline BRCA status.\u003c/em\u003e\u003cbr\u003e\nKaplan–Meier curves showing overall survival (OS) in patients with germline \u003cem\u003eBRCA\u003c/em\u003emutations (m\u003cem\u003eBRCA\u003c/em\u003e, red line) and \u003cem\u003eBRCA\u003c/em\u003e wild-type (wt/unk\u003cem\u003eBRCA\u003c/em\u003e, blue dashed line). Median OS was not reached in either cohort. At 2 years, OS rates were 98.9% versus 95.1%, respectively (HR 0.17, 95% CI 0.02 – 1.26, P = 0.083).\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-8929138/v1/83112b7d7b06807b1893bb5b.png"},{"id":104396339,"identity":"30512f7f-4541-4b3e-8d23-f05793626c2c","added_by":"auto","created_at":"2026-03-11 11:11:43","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":254768,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eAdverse events according to germline BRCA status.\u003c/em\u003e\u003cbr\u003e\nBar chart comparing adverse event rates between patients with germline \u003cem\u003eBRCA\u003c/em\u003emutations (m\u003cem\u003eBRCA\u003c/em\u003e, red bars) and wild-type/ unknown \u003cem\u003eBRCA\u003c/em\u003e (wt/unk\u003cem\u003eBRCA\u003c/em\u003e, blue bars). The frequency of treatment discontinuation (22.9% vs 24.6%), treatment delay (23.2% vs 25.7%), and dose reduction (12.5% vs 15.5%) was similar across groups. Febrile neutropenia occurred in 10.2% versus 8.7% of patients, respectively (p=0.83). No statistically significant differences in toxicity profiles were observed between groups.\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-8929138/v1/9cf071da5a155e2b7995949b.png"},{"id":104396596,"identity":"dda6205b-e112-4e8c-acc4-b9a60a6fbadb","added_by":"auto","created_at":"2026-03-11 11:12:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2490588,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8929138/v1/41a42374-f68f-4ff3-a949-aa4cd3549455.pdf"},{"id":104396332,"identity":"5f28b77e-9848-4203-b3cd-d50da2ab9243","added_by":"auto","created_at":"2026-03-11 11:11:36","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":93045,"visible":true,"origin":"","legend":"","description":"","filename":"NeoRealnpJBCTablesonly.docx","url":"https://assets-eu.researchsquare.com/files/rs-8929138/v1/b45f337997a2a0cf934a3a65.docx"}],"financialInterests":"Competing interest reported. The Authors declare no Competing Non-Financial Interests but the following Competing Financial Interests: RBS: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Eli Lilly, Gilead, Libbs, Pfizer, Novartis, MSD, and Roche. Financial support for educational programs and symposia: AstraZeneca, Daiichi-Sankyo, Gilead, Eli Lilly, and MSD. Institutional Research grant: AstraZeneca, Daiichi-Sankyo. LL: Speaker fees and/or honoraria for consulting or advisory functions: Adium. Travel grants: MSD, Gador. PM: Speaker fees and/or honoraria for consulting or advisory functions: MSD, AstraZeneca, Roche, Pfizer, Novartis, ADIUM, GSK, Gador. Institutional Research grant: Novartis, AstraZeneca, Roche, GSK. Travel grants: Astra Zeneca, Novartis, ADIUM, Roche. SAM: Tavel grants ADIUM, AstraZeneca, Novartis, MSD, Elea. MR: Travel grants: Novartis, AstraZeneca, ADIUM, Elea, \nMVC: Speaker fees and/or honoraria for consulting or advisory functions: MSD, AstraZeneca, Roche, Pfizer, Novartis, ADIUM, Gador. Institutional Research grant: Novartis, AstraZeneca, Roche. Travel grants: Astra Zeneca, Novartis, ADIUM, Roche. JB: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Lilly, Gilead, Pfizer, Novartis, MSD, Roche, Knight Pharmaceuticals. Financial support for educational programs and symposia: Roche, Daiichi-Sankyo. DDR: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Lilly, Libbs, Pfizer, Novartis, Roche, GSK, Sanofi, Amgen, Zodiac Pharma. Financial support for educational programs and symposia: Roche. DAS: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo. Financial support for educational programs and symposia: AstraZeneca. JAPA: Speaker fees and/or honoraria for consulting or advisory functions: Novartis, AstraZeneca, MSD, Lilly. DMG: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo, Teva, Roche, AstraZeneca, Pfizer, Lilly, Novartis. Financial support for educational programs and symposia: AstraZeneca, Libbs, Roche. Research grant: Novartis. MS: Speaker fees and/or honoraria for consulting or advisory functions: Adium, GSK, Travel Grants: Roche, AstraZeneca, MSD. MRM: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Pfizer, Novartis, Roche, MSD, Knight. Financial support for educational programs and symposia: MSD, AstraZeneca, Knight, Novartis. BMZ: AstraZeneca, Daiichi-Sankyo, Eli Lilly, Gilead, Pfizer, Novartis, MSD, Roche, Addium. AF: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo, Novartis, Gilead, MSD, BMS, AstraZeneca, Pfizer. Financial support for educational programs and symposia: AstraZeneca, Daiichi-Sankyo, MSD, Novartis. GC: Speaker fees and/or honoraria for consulting or advisory functions: Amgen, AstraZeneca. Travel grants: Roche. CHA: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo, Gilead AstraZeneca, Novartis, MSD. Financial support for educational programs and symposia: AstraZeneca, Daiichi-Sankyo, MSD, Lilly, Roche, Novartis, Gilead, Medscape. RC: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Eli Lilly, Gilead, MSD, and GSK. MMFM: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Eli Lilly, Gilead, Addium, Novartis, MSD, and Roche. Financial support for educational programs and symposia: AstraZeneca, Daiichi-Sankyo, Gilead, Eli Lilly, Roche, MSD and Novartis. PMH: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo. LT: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo, MSD, AstraZeneca, Pfizer, Lilly, Novartis. Financial support for educational programs and symposia: AstraZeneca, Roche, Gilead. Institutional Research grant: Novartis. CP: Speaker fees and/or honoraria for consulting or advisory functions: Knight. Travel grants: Astra Zeneca, Gador, Novartis, Pfizer, Raffo, Roche. RCB: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo, Nestle Health Science, Addium, Gilead, MSD, BMS, AstraZeneca, Ache, Pfizer, Roche, Libbs, Lilly, Novartis, and GSK. Financial support for educational programs and symposia: AstraZeneca, Daiichi-Sankyo, MSD. Institutional Research grant: Novartis, AstraZeneca. IMS, FCB, MCT, FM, RPF, GR, CLS, and ZSS declare no conflict of interest.","formattedTitle":"Neoadjuvant pembrolizumab plus chemotherapy in germline BRCA mutated triple negative breast cancer cohort","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eTriple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor (ER) and progesterone receptor (PR) expression and by lack of HER2 overexpression or gene amplification. This receptor profile limits established targeted treatment options and is generally associated with more aggressive tumor biology, higher early recurrence risk, and poorer prognosis compared with hormone receptor\u0026ndash;positive disease. TNBC accounts for approximately 10\u0026ndash;15% of all breast cancers, is diagnosed more frequently in younger patients, and is overrepresented in some populations (e.g., African American and Hispanic women), contributing to substantial psychosocial and economic burden. Biologically, TNBC is heterogeneous and comprises distinct molecular subtypes with potential therapeutic relevance; however, broadly effective, universally applicable targeted strategies remain limited. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eKEYNOTE-522 established pembrolizumab combined with neoadjuvant chemotherapy (paclitaxel\u0026ndash;carboplatin followed by anthracycline/cyclophosphamide) and continued adjuvant pembrolizumab as a standard for high-risk early-stage TNBC, improving pCR, event-free survival, and overall survival versus chemotherapy alone [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In parallel, 10\u0026ndash;15% of TNBC tumors harbor germline \u003cem\u003eBRCA\u003c/em\u003e1/2 pathogenic variants and frequently exhibit homologous recombination deficiency (HRD), identifiable by genomic scars and mutational signature [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. HRD is associated with enhanced sensitivity to DNA-damaging agents (including platinum) and to PARP inhibitors in metastatic disease (OlympiAD, EMBRACA) and in the adjuvant setting (OlympiA) [\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Mechanistically, HRD may also modulate immunogenicity and the tumor microenvironment, potentially influencing response to immune checkpoint blockade [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Because pCR correlates with long-term outcomes at the trial level, pCR and residual disease metrics can serve as clinically meaningful intermediate endpoints [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eReal-world evidence (RWE) complements clinical trials by characterizing outcomes, treatment patterns, and resource use in routine practice, thereby informing clinical decision-making and implementation. Given the limited data evaluating the KEYNOTE-522 regimen in patients with g\u003cem\u003eBRCA\u003c/em\u003e, we aimed to assess clinical characteristics, pathologic response, survival outcomes, and safety in a multicenter real-world cohort of patients with TNBC and g\u003cem\u003eBRCA\u003c/em\u003e treated according to the KEYNOTE-522 regimen [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e"},{"header":"RESULTS","content":"\u003ch2\u003e\u003cstrong\u003eGermline \u003cem\u003eBRCA\u003c/em\u003e testing\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eOverall, 600 (82.64%) underwent germline \u003cem\u003eBRCA\u003c/em\u003e1/\u003cem\u003eBRCA\u003c/em\u003e2 mutation testing and had the testing results available. A hundred twenty-six patients (17.4%) were not tested or had the testing status unavailable. \u003cstrong\u003eAmong those tested, germline \u003cem\u003eBRCA\u003c/em\u003e pathogenic/likely pathogenic variants (m\u003cem\u003eBRCA\u003c/em\u003e) were identified in 105/600 (17.5%), corresponding to 105/726 (14.5%) of the overall cohort.\u003c/strong\u003e \u003cem\u003eBRCA\u003c/em\u003e1 variants were observed in 82 patients (78.1%) and \u003cem\u003eBRCA\u003c/em\u003e2 variants in 22 (21%). The control group comprised 621 patients (wt/unk\u003cem\u003eBRCA\u003c/em\u003e) (Table 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Germline \u003cem\u003eBRCA\u003c/em\u003e Testing Overview\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 269px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMeasure\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e% of total cohort\u003cbr\u003e\u0026nbsp;(N=726)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e% among tested\u003cbr\u003e\u0026nbsp;(N=600)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e% among mBRCA\u003cbr\u003e\u0026nbsp;(N=105)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 269px;\"\u003e\n \u003cp\u003eTotal cohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e726\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e100.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 269px;\"\u003e\n \u003cp\u003eTested with results available\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e600\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e82.6%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e100.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 269px;\"\u003e\n \u003cp\u003eNot tested / testing status unavailable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e126\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e17.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 269px;\"\u003e\n \u003cp\u003e\u003cem\u003emBRCA\u0026nbsp;\u003c/em\u003e(pathogenic/likely pathogenic)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e14.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e17.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e100.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 269px;\"\u003e\n \u003cp\u003e\u003cem\u003ewtBRCA\u003c/em\u003e among tested\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e495\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e68.2%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e82.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 269px;\"\u003e\n \u003cp\u003eControl group (wt/unkBRCA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e621\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e85.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 269px;\"\u003e\n \u003cp\u003e\u003cem\u003e- BRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e11.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e13.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e78.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 269px;\"\u003e\n \u003cp\u003e\u003cem\u003e- BRCA2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e3.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e3.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e21.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 269px;\"\u003e\n \u003cp\u003e- \u003cem\u003eBRCA\u003c/em\u003e subtype not specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e0.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e0.2%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e1.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003ch2\u003e\u003cstrong\u003ePatients \u0026nbsp;characteristics\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003em\u003cem\u003eBRCA\u003c/em\u003e patients were younger than wt/unk\u003cem\u003eBRCA\u003c/em\u003e (median 40.2 vs 45.3 years; p\u0026lt;0.0001) and more frequently premenopausal; BMI did not differ between groups. Initial clinical stage distribution was similar (stage II 72.3% and stage III 27.7% in both; p=0.96). High histologic grade (grade 3) was more frequent in m\u003cem\u003eBRCA\u003c/em\u003e, although not statistically significant (80.2% vs 74.2%; p=0.25). Ki-67 was higher in m\u003cem\u003eBRCA\u003c/em\u003e (median 80% vs 70%; p=0.01). Invasive carcinoma of no special type predominated in both groups (95% vs 88%).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNeoadjuvant treatment completion and tolerance were comparable. Mastectomy was more common in m\u003cem\u003eBRCA\u003c/em\u003e (88.3% vs 34.7%; p\u0026lt;0.001). Adjuvant chemotherapy was less frequent in m\u003cem\u003eBRCA\u003c/em\u003e (3.3% vs 22.2%; p\u0026lt;0.001), while adjuvant immunotherapy use was similar (83.3% vs 78.2%; p=0.98). Adjuvant radiotherapy was less frequent in m\u003cem\u003eBRCA\u003c/em\u003e (64.4% vs 87.1%, p\u0026lt;0.001%) (Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Comparative Clinical and Treatment Characteristics: m\u003cem\u003eBRCA\u003c/em\u003e vs wt/unk\u003cem\u003eBRCA\u003c/em\u003e Cohorts.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"576\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003em\u003cem\u003eBRCA\u003c/em\u003e (n=105)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ewt/unk\u003cem\u003eBRCA\u003c/em\u003e (n=621)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eMedian age (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e40.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e45.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003ePremenopausal status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u0026nbsp;61.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e51.6%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e0.029\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eClinical stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eStage II: 72.0% / Stage III: 27.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eStage II: 73.0% / Stage III: 27.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eHistologic grade 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e80.2%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e74.2%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eMedian Ki-67\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e80%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e70%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eHistology: NST\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e95%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e88%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eTILs \u0026ge; 30%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e40.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e26.2%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e0.117\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eMastectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e88.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e34.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eAdjuvant chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e3.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e22.2%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eAdjuvant immunotherapy (pembrolizumab)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e83.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e78.2%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e0.98\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eAdjuvant radiotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e64.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e87.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003ch3\u003eAbbreviations: NST, invasive carcinoma of no special type; TILs, tumor infiltrating lymphocytes\u003c/h3\u003e\n\u003ch3\u003e\u0026nbsp;\u003c/h3\u003e\n\u003ch3\u003ePathologic complete response rates\u003c/h3\u003e\n\u003cp\u003ePatients with m\u003cem\u003eBRCA\u003c/em\u003e had higher pCR rates compared to patients with wt/unk\u003cem\u003eBRCA\u003c/em\u003e (74.0% vs 61.7% ; OR 1.78, 95% CI 1.10 \u0026ndash; 2.87, P = 0.0244). Progression during neoadjuvant therapy occurred in 1.2% of m\u003cem\u003eBRCA\u003c/em\u003e vs 4.4% of wt/unk\u003cem\u003eBRCA\u003c/em\u003e (p=0.23) (Figure 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the multivariable logistic regression model including \u003cem\u003eBRCA\u003c/em\u003e status, disease stage, tumor grade, Ki-67 index, and number of neoadjuvant pembrolizumab cycles, \u003cem\u003eBRCA\u003c/em\u003e status remained significantly associated with pCR (OR 1.70, 95% CI 1.01 \u0026ndash; 2.89, P = 0.048). Additionally, Ki-67 \u0026ge; 50% was independently associated with a higher likelihood of achieving pCR, whereas patients with stage III disease and those who received fewer than six cycles of neoadjuvant pembrolizumab had a lower probability of pCR (Table 3). TILs were not included in the multivariable analysis due to the high proportion of missing data. Most patients in both groups (82.2% in m\u003cem\u003eBRCA\u003c/em\u003e and 87.7% in wt/unk\u003cem\u003eBRCA\u003c/em\u003e, P=0.252) continued adjuvant pembrolizumab after a pathologic complete response.\u0026nbsp;For those with m\u003cem\u003eBRCA\u003c/em\u003e and residual disease (n=26), a combined strategy of pembrolizumab plus olaparib was used in 57.7%, 19.2% received pembrolizumab without olaparib, and 11.5% received olaparib without pembrolizumab. \u003cstrong\u003eThe remaining 11.6% received adjuvant capecitabine (with or without pembrolizumab).\u003c/strong\u003e For those with wt/unk and residual disease, the most used regimen was pembrolizumab plus capecitabine (57.5%), followed by pembrolizumab alone (26.1%), and capecitabine alone (12.6%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Univariate and multivariable analysis of factors associated with pathologic complete response.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"639\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3436%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 27.9477%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnivariate analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 21.5364%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMultivariable analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3436%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.4712%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4835%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.1314%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.3013%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4835%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.3643%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3436%;\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA\u003c/em\u003e1/2 (mutated vs wild-type/unknown)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.4712%;\"\u003e\n \u003cp\u003e1.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4835%;\"\u003e\n \u003cp\u003e1.10 \u0026ndash; 2.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.1314%;\"\u003e\n \u003cp\u003e0.017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.3013%;\"\u003e\n \u003cp\u003e1.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4835%;\"\u003e\n \u003cp\u003e1.01 \u0026ndash; 2.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.3643%;\"\u003e\n \u003cp\u003e0.048\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3436%;\"\u003e\n \u003cp\u003eKi67 index (\u0026ge; 50% vs \u0026lt; 50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.4712%;\"\u003e\n \u003cp\u003e2.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4835%;\"\u003e\n \u003cp\u003e1.85 \u0026ndash; 3.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.1314%;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.3013%;\"\u003e\n \u003cp\u003e2.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4835%;\"\u003e\n \u003cp\u003e1.56 \u0026ndash; 3.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.3643%;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3436%;\"\u003e\n \u003cp\u003eTILs (\u0026ge;\u0026nbsp;30% vs \u0026lt; 30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.4712%;\"\u003e\n \u003cp\u003e2.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4835%;\"\u003e\n \u003cp\u003e1.39 \u0026ndash; 5.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.1314%;\"\u003e\n \u003cp\u003e0.026\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.3013%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4835%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.3643%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3436%;\"\u003e\n \u003cp\u003eTumor grade (3 vs 1-2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.4712%;\"\u003e\n \u003cp\u003e1.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4835%;\"\u003e\n \u003cp\u003e1.25 \u0026ndash; 2.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.1314%;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.3013%;\"\u003e\n \u003cp\u003e1.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4835%;\"\u003e\n \u003cp\u003e0.95 - 2.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.3643%;\"\u003e\n \u003cp\u003e0.080\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3436%;\"\u003e\n \u003cp\u003eDisease stage (III vs II)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.4712%;\"\u003e\n \u003cp\u003e0.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4835%;\"\u003e\n \u003cp\u003e0.38 - 0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.1314%;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.3013%;\"\u003e\n \u003cp\u003e0.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4835%;\"\u003e\n \u003cp\u003e0.35 - 0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.3643%;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3436%;\"\u003e\n \u003cp\u003eAC regimen (dose-dense vs every 3-week)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.4712%;\"\u003e\n \u003cp\u003e1.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4835%;\"\u003e\n \u003cp\u003e0.83 \u0026ndash; 1.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.1314%;\"\u003e\n \u003cp\u003e0.399\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.3013%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4835%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.1945%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3436%;\"\u003e\n \u003cp\u003eNumber of neoadjuvant pembrolizumab cycles (\u0026lt; 6 versus\u0026nbsp;\u0026ge; 6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.4712%;\"\u003e\n \u003cp\u003e0.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4835%;\"\u003e\n \u003cp\u003e0.34 \u0026ndash; 0.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.1314%;\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.3013%;\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4835%;\"\u003e\n \u003cp\u003e0.30 - 0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.1945%;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: OR, odds ratio; CI, confidence interval; TILs, tumor infiltrating lymphocytes; AC, anthracycline and cyclophosphamide.\u003c/p\u003e\n\u003ch3\u003eSurvival outcomes\u003c/h3\u003e\n\u003cp\u003eWith a \u003cstrong\u003emedian follow-up of 22 months\u003c/strong\u003e, patients harboring germline m\u003cem\u003eBRCA\u003c/em\u003e showed a trend toward improved EFS compared with wt/unk\u003cem\u003eBRCA\u003c/em\u003e counterparts, with 2-year EFS rates of 92.3% and 86.2%, respectively (HR: 0.51, 95% CI 0.23 \u0026ndash; 1.11, P = 0.091). Although not statistically significant, this pattern suggests a clinically meaningful benefit (Figure 2). Median EFS was not reached in either cohort.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor patients whose tumors achieved a pathologic complete response, favorable EFS was observed regardless of the \u003cem\u003eBRCA\u003c/em\u003e status, with 2-year EFS rates greater than 94% in both groups (HR 1.10, 95% CI 0.31 \u0026ndash; 3.88, P=0.875). For those whose tumors had residual disease, the 2-year EFS rates were 85.9% in m\u003cem\u003eBRCA\u003c/em\u003e and 74.4% in wt/unk\u003cem\u003eBRCA\u003c/em\u003e (HR 0.59, 95% CI 0.21- 1.63, P=0.311). EFS for each \u003cem\u003eBRCA\u003c/em\u003e group according to pathologic response is shown in Figure 3.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs shown in Figure 4, patients with germline m\u003cem\u003eBRCA\u003c/em\u003e also exhibited a trend toward improved OS compared with wt/unk\u003cem\u003eBRCA\u003c/em\u003e, with 2-year OS rates of 98.9% versus 95.1%, respectively (HR 0.17, 95% CI 0.02 \u0026ndash; 1.26, P = 0.083) (Figure 4).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eKaplan\u0026ndash;Meier curves showing overall survival (OS) in patients with germline \u003cem\u003eBRCA\u003c/em\u003e mutations (m\u003cem\u003eBRCA\u003c/em\u003e, red line) and \u003cem\u003eBRCA\u003c/em\u003e wild-type (wt/unk\u003cem\u003eBRCA\u003c/em\u003e, blue dashed line). Median OS was not reached in either cohort. At 2 years, OS rates were 98.9% versus 95.1%, respectively (HR 0.17, 95% CI 0.02 \u0026ndash; 1.26, P = 0.083). \u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eSafety\u003c/h3\u003e\n\u003cp\u003eUse of G-CSF tended to be higher in m\u003cem\u003eBRCA\u003c/em\u003e (74% vs 65.5%; p=0.122). Notably, G-CSF is routinely administered as part of primary prophylaxis for patients receiving dose-dense AC in routine practice; therefore, in this real-world dataset, G-CSF use likely reflects both protocol-driven prophylaxis and clinical indications, and we did not systematically distinguish primary from secondary prophylaxis. Overall, the safety patterns were similar in patients with m\u003cem\u003eBRCA\u003c/em\u003e and wt/unk\u003cem\u003eBRCA\u003c/em\u003e. Rates of febrile neutropenia were similar (8.7% vs 10.2%; p=0.85). Dose reductions (15.5% vs 12.8%; p=0.65), treatment delays (25.7% vs 25.3%; p=1.00), and discontinuations (24.4% vs 22.9%; p=0.88) were comparable between the two groups. (Figure 5).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this real-world Latin American cohort (n=726) treated according to the KEYNOTE-522 protocol, we observed that patients with \u003cem\u003emBRCA\u0026nbsp;\u003c/em\u003ehad higher pCR rates and a trend toward improved long-term outcomes compared with those with \u003cem\u003ewt/unkBRCA\u003c/em\u003e. In the pivotal trial, \u003cem\u003eBRCA\u003c/em\u003e status was not reported [3-4]. In our cohort, approximately one in seven patients carried a \u003cem\u003emBRCA\u003c/em\u003e, with a predominance of \u003cem\u003eBRCA\u003c/em\u003e1. These patients were younger and exhibited more proliferative disease (higher Ki-67, higher histological grade) and a trend toward higher TILs. The addition of pembrolizumab to taxane–carboplatin followed by anthracycline/cyclophosphamide resulted in substantially higher pCR in \u003cem\u003emBRCA\u0026nbsp;\u003c/em\u003ecompared with \u003cem\u003ewt/unkBRCA\u003c/em\u003e (74.0% vs. 61.7%), translating into excellent EFS and OS.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBiologically, germline \u003cem\u003eBRCA\u003c/em\u003e1/2 pathogenic variants are a hallmark of HRD, which is common in TNBC and can be characterized by genomic scars Loss of Heterozygosity (LOH), \u003cem\u003eTelomeric Allelic Imbalance (\u003c/em\u003eTAI), Large-Scale State Transitions (LST) and mutational signature [5-7]. This biology underpins sensitivity to platinum-based chemotherapy (e.g., TNT; GeparSixto) and synthetic lethality with PARP inhibition, with demonstrated clinical benefit in metastatic disease (OlympiAD, EMBRACA) and in high-risk early-stage disease (OlympiA) [8-13]. HRD may also increase tumor immunogenicity through DNA-sensing pathways, contributing to higher TILs in \u003cem\u003eBRCA1\u003c/em\u003e-mutated tumors in some cohorts, although results are heterogeneous [2,14].\u003c/p\u003e\n\u003cp\u003eOur findings are broadly consistent with smaller real-world series that specifically evaluated \u003cem\u003egBRCA\u003c/em\u003e-mutated TNBC treated with anthracycline–taxane–platinum regimens plus pembrolizumab [24-27]. In a multicenter Italian cohort of 184 patients, Fedele et al. reported pCR rates of 80.0% in \u003cem\u003eBRCA1-\u003c/em\u003emutated, 75.0% in \u003cem\u003eBRCA2\u003c/em\u003e-mutated, and 61.1% in wild-type tumors; pooled \u003cem\u003eBRCA1/2\u003c/em\u003e carriers had a higher probability of pCR than wild-type patients (78.4% vs 61.1%; OR 2.17; 95% CI 1.01–4.97), survival data remain immature [24]. A Korean series of 199 patients treated with a KEYNOTE-522–like regimen with or without pembrolizumab similarly found numerically higher pCR in \u003cem\u003emBRCA\u0026nbsp;\u003c/em\u003e (73.5% vs 59.3%; p = 0.075) and comparable absolute pCR gains with pembrolizumab in mutated and non-mutated groups, suggesting that \u003cem\u003emBRCA\u0026nbsp;\u003c/em\u003ebehaves primarily as a chemosensitivity/HRD marker rather than a specific predictor of incremental immunotherapy benefit [25]. Etan et al. reported analogous findings in an Israeli cohort of 100 stage II–III TNBC patients treated with anthracycline, taxane and carboplatin (ACTC) or a KEYNOTE-522 based chemo-immunotherapy regimen: one-third were \u003cem\u003emBRCA\u0026nbsp;\u003c/em\u003e and attained higher pCR irrespective of regimen, with pCR reaching 100% among \u003cem\u003emBRCA\u003c/em\u003e\u0026nbsp; treated with KN522. At 50 months, KN522 was associated with improved OS/EFS versus ACTC, and pCR, rather than \u003cem\u003emBRCA\u003c/em\u003e status, was the main driver of long-term outcomes [26]. A larger Korean cohort of 316 patients uniformly treated with KN522-based regimens also showed significantly higher pCR in \u003cem\u003emBRCA\u003c/em\u003e vs wild-type tumors (73.9% vs 59.3%; p = 0.040) but no independent effect of \u003cem\u003emBRCA\u0026nbsp;\u003c/em\u003eon DFS after adjusting for stage, PD-L1, adjuvant therapy, and pCR [27].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTaken together, these real-world data, including the present Neo-Real cohort, consistently show that \u003cem\u003emBRCA\u003c/em\u003e TNBC derives higher pCR rates, typically in the 70–80% range, representing an absolute gain of 10–15 percentage points compared with \u003cem\u003eBRCA\u003c/em\u003e wild-type tumors under KEYNOTE-522–like regimens. However, a distinct survival advantage attributable to \u003cem\u003eBRCA\u003c/em\u003e status alone has not been robustly demonstrated; in multivariable models, \u003cem\u003emBRCA\u003c/em\u003e per se has not emerged as an independent prognostic factor for DFS/OS once pCR and standard clinicopathologic variables are accounted for [23-26]. Current evidence therefore supports germline \u003cem\u003emBRCA1/2\u003c/em\u003e as a marker of enhanced platinum-based chemosensitivity/HRD, while long-term benefit from KEYNOTE-522, like chemo-immunotherapy seems to be driven predominantly by achieving pCR (table 4). At the trial level, pCR and residual disease burden are associated with long-term outcomes, supporting their use as intermediate endpoints while recognizing imperfect surrogacy for EFS/OS [15-16,18-22].\u003c/p\u003e\n\u003cp\u003eFrom a post-neoadjuvant perspective, RCB provides granularity beyond binary pCR and has been validated as a prognostic tool across breast cancer subtypes; higher RCB is associated with worse long-term outcomes and can guide escalation strategies [18–22]. In TNBC with residual invasive disease after standard neoadjuvant chemotherapy, adjuvant capecitabine improved disease-free and overall survival (CREATE-X) and remains a relevant option alongside immunotherapy-based regimens [27]. For \u003cem\u003emBRCA\u0026nbsp;\u003c/em\u003ewith high-risk early disease, adjuvant olaparib improved invasive and distant disease-free survival and overall survival in OlympiA, supporting consideration of PARP inhibition in eligible patients after completion of local therapy and standard systemic treatment [12–13].\u003c/p\u003e\n\u003cp\u003eIn our cohort, the EFS separation was more apparent among patients with residual disease, a setting in which adjuvant management is typically risk-adapted. While higher pCR rates may contribute to cohort-level EFS differences, the non-significant EFS trend among patients with residual disease may also have been influenced by differential use of post-neoadjuvant escalation strategies, including olaparib in eligible \u003cem\u003emBRCA\u0026nbsp;\u003c/em\u003eand capecitabine-based approaches in residual TNBC. Given the observational design and heterogeneity/coverage limitations in post-neoadjuvant therapy delivery, these findings should be interpreted as hypothesis-generating.\u003c/p\u003e\n\u003cp\u003eTILs are a robust prognostic biomarker in early TNBC and are supported by standardized scoring recommendations from the International TILs Working Group [28-29]. Recent cohorts suggest that selected patients with stage I TNBC and very high stromal TILs may achieve excellent long-term outcomes with locoregional therapy alone, prompting interest in prospective de-escalation trials [30-31]. Early-phase studies are exploring immunotherapy-only or reduced-chemotherapy approaches in immunologically ‘hot’ TNBC, including the BELLINI trial [32] and ongoing TIL-guided programs such as ETNA, OPTImaL, and DespaTIL (ClinicalTrials.gov identifiers: NCT06078384, NCT06476119, NCT07074106) [33–35].Complementary immune features, including the CD8/FOXP3 ratio, may further refine risk stratification [36].\u003c/p\u003e\n\u003cp\u003eBeyond systemic therapy, comprehensive survivorship planning for young \u003cem\u003egBRCA\u0026nbsp;\u003c/em\u003eincludes genetic counseling and consideration of risk-reducing surgeries, which have been associated with improved survival in international cohorts [37].\u003c/p\u003e\n\u003cp\u003eThis retrospective multicenter study has inherent limitations, including missing data (TILs, RCB), inter-center heterogeneity, variability in AE reporting, and the absence of standardized auditing. Approximately 17% of patients did not undergo \u003cem\u003eBRCA\u003c/em\u003e testing. These individuals were pragmatically grouped with the wild-type cohort for analysis; however, we acknowledge that this approach may dilute observed differences. Nevertheless, to the best of our knowledge, this represents the largest cohort evaluating the KEYNOTE-522 regimen in \u003cem\u003emBRCA\u003c/em\u003e patients and provides valuable insights to guide future research. Importantly, it also contributes data from a Latin American population, which remains underrepresented in prospective clinical trials.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003epCR and survival according to germline \u003cem\u003emBRCA\u003c/em\u003e status in TNBC treated with KEYNOTE-522–based regimens\u003c/strong\u003e\u003c/p\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eStudy / year\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eTotal N\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eBRCA\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;status distribution\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003epCR \u003cem\u003emBRCA\u003c/em\u003e vs wt\u003cem\u003eBRCA\u003c/em\u003e (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ep-value (pCR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSurvival signal (\u003cem\u003emBRCA\u003c/em\u003e vs \u003cem\u003ewtBRCA)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eFedele et al., 2025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e184\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cem\u003emBRCA:\u003c/em\u003e 37 (20.1%); \u003cem\u003ewtBRCA:\u003c/em\u003e 147 (79.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e78.4 vs 61.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eHigher pCR in \u003cem\u003emBRCA;\u003c/em\u003e survival data immature/not reported.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eBae / Kim et al., 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e199\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cem\u003emBRCA:\u003c/em\u003e 49 (24.6%); \u003cem\u003ewtBRCA:\u003c/em\u003e 150 (75.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e73.5 vs 59.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.075\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo clear DFS difference by \u003cem\u003emBRCA;\u003c/em\u003e no significant interaction with pembrolizumab.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eEtan et al., 2025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e≈100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cem\u003emBRCA:\u003c/em\u003e 32 (≈32%); \u003cem\u003ewtBRCA:\u003c/em\u003e 68 (≈68%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e100 vs 64.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eKN522 improves OS/EFS vs ACTC overall; outcomes mainly driven by pCR, not \u003cem\u003emBRCA\u003c/em\u003e status alone.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePark et al., 2025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e316\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cem\u003emBRCA\u003c/em\u003e: 46 (14.6%); \u003cem\u003ewtBRCA:\u003c/em\u003e 270 (85.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e73.9 vs 59.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.040\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cem\u003emBRCA\u0026nbsp;\u003c/em\u003enot independent for DFS (HR 1.71; 95% CI 0.63–4.65); pCR strongly prognostic.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTavares et al., 2025 (Neo-Real)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e726\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cem\u003emBRCA\u003c/em\u003e: 105 (14.5%); \u003cem\u003ewtBRCA:\u003c/em\u003e 621 (85.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e74.0 vs 61.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.0244\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eTrend to better EFS in \u003cem\u003emBRCA;\u003c/em\u003e survival predominantly driven by achievement of pCR.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAbbreviations: TNBC, triple-negative breast cancer; mBRCA, germline BRCA1/2-mutated; wtBRCA, BRCA wild-type; pCR, pathologic complete response; DFS, disease-free survival; OS, overall survival; EFS, event-free survival; NR, not reported; KN522, KEYNOTE-522 regimen; ACTC, anthracycline–taxane–carboplatin.\u003c/p\u003e\n\u003cp\u003eEmerging evidence suggests that \u003cem\u003eBRCA1/2\u003c/em\u003e alterations may modulate the tumor microenvironment and influence response to immune checkpoint blockade\u0026nbsp;[14]; moreover, breast cancers arising in germline \u003cem\u003eBRCA1\u0026nbsp;\u003c/em\u003eversus \u003cem\u003eBRCA2\u0026nbsp;\u003c/em\u003ecarriers may represent distinct biological and clinical entities with potentially divergent therapeutic opportunities \u003cstrong\u003e[2]\u003c/strong\u003e\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis real-world study supports that TNBC patients with germline \u003cem\u003eBRCA\u003c/em\u003e mutations represent a biologically distinct subgroup, achieving higher pCR rates and showing a trend toward improved EFS with a KEYNOTE-522 based regimen. The 12.3% absolute increase in pCR was accompanied by favorable EFS trajectories. Collectively, these findings have meaningful clinical implications and support the development of risk-adapted strategies, including more individualized treatment approaches for patients with \u003cem\u003emBRCA.\u003c/em\u003e\u003c/p\u003e"},{"header":"METHODS","content":"\u003ch2\u003e\u003cstrong\u003eStudy design and setting\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eWe performed a multicenter, observational cohort study of patients with early-stage TNBC treated with neoadjuvant chemotherapy plus pembrolizumab across 14 cancer centers in Brazil and 16 centers in Argentina from July 2020 to July 2025. Data was collected from electronic medical records using a standardized case-report form and independently verified.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eParticipants\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eEligible patients had histologically confirmed TNBC (any histologic subtype) and received ≥1 cycle of neoadjuvant pembrolizumab with chemotherapy. Baseline disease stage mirrored the KEYNOTE-522 population (cT2N0 and/or cT1 with node-positive disease; M0). Patients who underwent definitive breast surgery after the neoadjuvant therapy were included in the primary analyses of pCR.\u003c/p\u003e\n\u003cp\u003eAll consecutively treated patients were included, regardless of the availability of germline testing.\u0026nbsp;Germline BRCA1/2 testing was \u003cstrong\u003euniversally recommended\u003c/strong\u003e for patients with early-stage TNBC across participating centers; however, \u003cstrong\u003etest uptake was contingent on local availability and insurance/health system authorization\u003c/strong\u003e, which varied over time and across sites. When performed, \u003cstrong\u003e\u003cem\u003eBRCA1/2\u003c/em\u003e\u003c/strong\u003e testing used one or more of the following platforms, with\u0026nbsp;validated clinical assays: multigene next-generation sequencing (NGS) panels; targeted NGS for\u0026nbsp;\u003cem\u003eBRCA1/2\u003c/em\u003e; multiplex ligation-dependent probe amplification (MLPA) for large genomic rearrangements; and/or targeted qPCR or digital PCR for specific variants.\u003cbr\u003eAccording to the results, patients were categorized as:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003e\u003cem\u003emBRCA\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e:\u003c/em\u003e\u003c/strong\u003e carriers of\u003cstrong\u003e\u0026nbsp;\u003cstrong\u003epathogenic or likely pathogenic\u003c/strong\u003e\u003c/strong\u003e germline \u003cem\u003eBRCA1/2\u003c/em\u003e variants; \u003cstrong\u003evariants of uncertain significance (VUS) were not classified as \u003cem\u003emBRCA\u003c/em\u003e\u003c/strong\u003e;\u0026nbsp;or\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003e\u003cem\u003ewt/unkBRCA\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e:\u003c/em\u003e\u003c/strong\u003e germline \u003cem\u003eBRCA1/2\u003c/em\u003e wild-type/negative results or \u003cstrong\u003eunknown/unavailable status\u003c/strong\u003e (including untested patients), analyzed together.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThe study was approved by the Research Ethics Committees/Institutional Review Boards of all participating centers: A.C.Camargo Cancer Center Research Ethics Committee (São Paulo, Brazil); Grupo Brasileiro de Estudos em Câncer de Mama (GBECAM) Research Committee (São Paulo, Brazil); Hospital Brasília – Américas Oncologia Ethics Committee (Brasília, Brazil); Instituto D’Or de Pesquisa e Ensino (IDOR) Research Ethics Committees (São Paulo, Rio de Janeiro, and Recife, Brazil); Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo Research Ethics Committee (São Paulo, Brazil); SUMA (Grupo Cooperativa Argentino para el estudio y la investigación del Cáncer de Mama) Ethics Committee (Buenos Aires, Argentina); Instituto Américas Ethics Committee (Rio de Janeiro, Brazil); Hospital 9 de Julho (Américas Oncologia) Ethics Committee (São Paulo, Brazil); Hospital Moinhos de Vento Ethics Committee (Porto Alegre, Brazil); Hospital Samaritano (Américas Oncologia) Ethics Committee (São Paulo, Brazil); Hospital Sírio-Libanês Ethics Committees (Brasília and São Paulo, Brazil); Hospital Beneficência Portuguesa Ethics Committee (São Paulo, Brazil); Hospital Santa Paula (Américas Oncologia) Ethics Committee (São Paulo, Brazil); Clínica AMO Ethics Committee (Salvador, Brazil); Instituto do Câncer do Ceará Ethics Committee (Fortaleza, Brazil); Centro Integrado de Pesquisa da Amazônia (CINPAM) Ethics Committee (Manaus, Brazil); and Hospital São Domingos Ethics Committee (São Luís, Brazil). The study was conducted in accordance with the Declaration of Helsinki; consent procedures followed local regulations. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Research Ethics Committees/Institutional Review Boards of all participating centers: A.C.Camargo Cancer Center Research Ethics Committee (São Paulo, Brazil); Grupo Brasileiro de Estudos em Câncer de Mama (GBECAM) Research Committee (São Paulo, Brazil); Hospital Brasília – Américas Oncologia Ethics Committee (Brasília, Brazil); Instituto D’Or de Pesquisa e Ensino (IDOR) Research Ethics Committees (São Paulo, Rio de Janeiro, and Recife, Brazil); Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo Research Ethics Committee (São Paulo, Brazil); SUMA (Grupo Cooperativa Argentino para el estudio y la investigación del Cáncer de Mama) Ethics Committee (Buenos Aires, Argentina); Instituto Américas Ethics Committee (Rio de Janeiro, Brazil); Hospital 9 de Julho (Américas Oncologia) Ethics Committee (São Paulo, Brazil); Hospital Moinhos de Vento Ethics Committee (Porto Alegre, Brazil); Hospital Samaritano (Américas Oncologia) Ethics Committee (São Paulo, Brazil); Hospital Sírio-Libanês Ethics Committees (Brasília and São Paulo, Brazil); Hospital Beneficência Portuguesa Ethics Committee (São Paulo, Brazil); Hospital Santa Paula (Américas Oncologia) Ethics Committee (São Paulo, Brazil); Clínica AMO Ethics Committee (Salvador, Brazil); Instituto do Câncer do Ceará Ethics Committee (Fortaleza, Brazil); Centro Integrado de Pesquisa da Amazônia (CINPAM) Ethics Committee (Manaus, Brazil); and Hospital São Domingos Ethics Committee (São Luís, Brazil). The study was conducted in accordance with the Declaration of Helsinki; consent procedures followed local regulations. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe primary outcomes were pathologic complete response (pCR), defined as ypT0/Tis ypN0 at surgery. The wt/unk\u003cem\u003eBRCA\u003c/em\u003e category was analyzed as a control group per the prespecified plan. Univariate and multivariable logistic regression were used to evaluate factors associated with pCR. Variables were selected for the multivariable regression based on their clinical relevance and the association with pCR in the univariate analysis. Residual disease was categorized using the Residual Cancer Burden (RCB) index when available [18-22].\u003c/p\u003e\n\u003cp\u003eSecondary outcomes included event-free survival (EFS) and overall survival (OS). EFS was defined as the time from the first neoadjuvant dose to any of the following events: disease progression precluding surgery, local, regional, or distant recurrence, development of a second invasive cancer, or death from any cause. OS was calculated from the date of first neoadjuvant dose until the date of death from any cause.\u0026nbsp;OS was analyzed descriptively given the low number of events. Patients without events were censored at the date of last contact. Median follow-up was estimated using the reverse Kaplan–Meier method. Additional secondary outcomes comprised progression during neoadjuvant therapy and safety, assessed by the incidence of grade ≥3 adverse events (AEs).\u003c/p\u003e\n\u003cp\u003eContinuous variables are reported as median (IQR) and were compared with the Mann–Whitney U test, as appropriate. Categorical variables are summarized as counts (percentages) and compared using χ² or Fisher’s exact tests. Time-to-event endpoints were estimated with the Kaplan–Meier method and compared by the log-rank test; hazard ratios (HRs) with 95% confidence intervals (CIs) were derived from Cox proportional-hazards models. Two-sided \u003cstrong\u003ep \u0026lt;0.05\u003c/strong\u003e was considered statistically significant. Missing data were handled by complete-case analysis for each endpoint.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eDe-identified individual participant data that support the findings of this study are available from the corresponding author upon reasonable request. Access is subject to institutional policies, ethics approval, and data-sharing agreements due to patient privacy and confidentiality requirements.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eCode availability\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eStatistical analysis code is available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003ePartial results of this manuscript have been presented as a poster at the San Antonio Breast Cancer Symposium 2025.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eR.C.B., M.C.T., J.B., D.D.R., D.A.S., D.M.G., C.H.A., B.M.Z., A.F., M.L.B., P.M.H., L.T., and R.B.S. contributed to the study conception and design. R.C.B., F.C.B, I.M.S, M.O.A, M.G, F.M, R.D.P.F, \u0026nbsp;C.L.S, \u0026nbsp;M.R.M, Z.S.S, A.M.U.G, M.M.F.M., N.J.B.G, M.V.C., D.M.G., N.C.C.N, P.M ,M.R , G.R, and R.B.S. contributed to the conduct or collection, data analysis and interpretation. R.C.B., M.C.T., J.B., D.D.R., D.A.S., D.M.G., C.H.A., B.M.Z., A.F., F.B.M, M.L.B., S.A.M, M.D.P.E.D, S.M.S, V.C.C.L, J.C.C.R, E.S.S, G.R., L.T., M.R., M.V.C, and R.B.S. contributed to the drafting of the manuscript and critical revisions. All authors gave their final approval of the manuscript to be submitted.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe Authors declare no Competing Non-Financial Interests but the following Competing Financial Interests: RBS: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Eli Lilly, Gilead, Libbs, Pfizer, Novartis, MSD, and Roche. Financial support for educational programs and symposia: AstraZeneca, Daiichi-Sankyo, Gilead, Eli Lilly, and MSD. Institutional Research grant: AstraZeneca, Daiichi-Sankyo. LL: Speaker fees and/or honoraria for consulting or advisory functions: Adium. Travel grants: MSD, Gador. PM: Speaker fees and/or honoraria for consulting or advisory functions: MSD, AstraZeneca, Roche, Pfizer, Novartis, ADIUM, GSK, Gador. Institutional Research grant: Novartis, AstraZeneca, Roche, GSK. Travel grants: Astra Zeneca, Novartis, ADIUM, Roche. SAM: Tavel grants ADIUM, AstraZeneca, Novartis, MSD, Elea. MR: Travel grants: Novartis, AstraZeneca, ADIUM, Elea,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMVC: Speaker fees and/or honoraria for consulting or advisory functions: MSD, AstraZeneca, Roche, Pfizer, Novartis, ADIUM, Gador. Institutional Research grant: Novartis, AstraZeneca, Roche. Travel grants: Astra Zeneca, Novartis, ADIUM, Roche. JB: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Lilly, Gilead, Pfizer, Novartis, MSD, Roche, Knight Pharmaceuticals. Financial support for educational programs and symposia: Roche, Daiichi-Sankyo. DDR: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Lilly, Libbs, Pfizer, Novartis, Roche, GSK, Sanofi, Amgen, Zodiac Pharma. Financial support for educational programs and symposia: Roche. DAS: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo. Financial support for educational programs and symposia: AstraZeneca. JAPA: Speaker fees and/or honoraria for consulting or advisory functions: Novartis, AstraZeneca, MSD, Lilly. DMG: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo, Teva, Roche, AstraZeneca, Pfizer, Lilly, Novartis. Financial support for educational programs and symposia: AstraZeneca, Libbs, Roche. Research grant: Novartis. MS: Speaker fees and/or honoraria for consulting or advisory functions: Adium, GSK, Travel Grants: Roche, AstraZeneca, MSD. MRM: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Pfizer, Novartis, Roche, MSD, Knight. Financial support for educational programs and symposia: MSD, AstraZeneca, Knight, Novartis. BMZ: \u0026nbsp;AstraZeneca, Daiichi-Sankyo, Eli Lilly, Gilead, Pfizer, Novartis, MSD, Roche, Addium. AF: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo, Novartis, Gilead, MSD, BMS, AstraZeneca, Pfizer. Financial support for educational programs and symposia: AstraZeneca, Daiichi-Sankyo, MSD, Novartis. GC: Speaker fees and/or honoraria for consulting or advisory functions: Amgen, AstraZeneca. Travel grants: Roche. CHA: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo, Gilead AstraZeneca, Novartis, MSD. Financial support for educational programs and symposia: AstraZeneca, Daiichi-Sankyo, MSD, Lilly, Roche, Novartis, Gilead, Medscape. RC: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Eli Lilly, Gilead, MSD, and GSK. MMFM: Speaker fees and/or honoraria for consulting or advisory functions: AstraZeneca, Daiichi-Sankyo, Eli Lilly, Gilead, Addium, Novartis, MSD, and Roche. Financial support for educational programs and symposia: AstraZeneca, Daiichi-Sankyo, Gilead, Eli Lilly, Roche, MSD and Novartis. PMH: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo. LT: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo, MSD, AstraZeneca, Pfizer, Lilly, Novartis. Financial support for educational programs and symposia: AstraZeneca, Roche, Gilead. Institutional Research grant: Novartis. CP: Speaker fees and/or honoraria for consulting or advisory functions: Knight. Travel grants: Astra Zeneca, Gador, Novartis, Pfizer, Raffo, Roche. RCB: Speaker fees and/or honoraria for consulting or advisory functions: Daiichi-Sankyo, Nestle Health Science, Addium, Gilead, MSD, BMS, AstraZeneca, Ache, Pfizer, Roche, Libbs, Lilly, Novartis, and GSK. Financial support for educational programs and symposia: AstraZeneca, Daiichi-Sankyo, MSD. Institutional Research grant: Novartis, AstraZeneca. IMS, FCB, MCT, FM, RPF, GR, CLS, and ZSS declare no conflict of interest.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOrlandini LF, et al. Epidemiological analyses reveal a high incidence of breast cancer in young women in Brazil. \u003cem\u003eJCO Glob Oncol.\u003c/em\u003e 2021;7:81\u0026ndash;88. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/GO.20.00440\u003c/span\u003e\u003cspan address=\"10.1200/GO.20.00440\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZattarin E, et al. Breast cancers arising in subjects with germline BRCA1 or BRCA2 mutations: different biological and clinical entities with potentially diverse therapeutic opportunities. \u003cem\u003eCrit Rev Oncol Hematol.\u003c/em\u003e 2023;190:104109. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.critrevonc.2023.104109\u003c/span\u003e\u003cspan address=\"10.1016/j.critrevonc.2023.104109\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchmid P, et al. Overall survival with pembrolizumab in early-stage triple-negative breast cancer. \u003cem\u003eN Engl J Med.\u003c/em\u003e 2024;391(21):1981\u0026ndash;1991. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa2402605\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2402605\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchmid P, et al. Pembrolizumab for early triple-negative breast cancer. \u003cem\u003eN Engl J Med.\u003c/em\u003e 2022;386(6):556\u0026ndash;567. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa2112651\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2112651\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi J, et al. DNA damage response in breast cancer and its role in guiding precise therapies: a comprehensive review. \u003cem\u003eBiomark Res.\u003c/em\u003e 2024;12:111. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s40364-024-00609-5\u003c/span\u003e\u003cspan address=\"10.1186/s40364-024-00609-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLenz L, et al. Identifying homologous recombination deficiency in breast cancer: genomic instability score distributions differ among breast cancer subtypes. \u003cem\u003eBreast Cancer Res Treat.\u003c/em\u003e 2023;202(1):191\u0026ndash;201. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s10549-023-07046-3\u003c/span\u003e\u003cspan address=\"10.1007/s10549-023-07046-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePolak P, et al. A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer. \u003cem\u003eNat Genet.\u003c/em\u003e 2017;49(10):1476\u0026ndash;1486. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/ng.3934\u003c/span\u003e\u003cspan address=\"10.1038/ng.3934\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTutt A, et al. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer: the TNT Trial. \u003cem\u003eNat Med.\u003c/em\u003e 2018;24(5):628\u0026ndash;637. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41591-018-0009-7\u003c/span\u003e\u003cspan address=\"10.1038/s41591-018-0009-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHahnen E, et al. Germline mutation status, pathological complete response, and disease-free survival in triple-negative breast cancer: secondary analysis of a randomized clinical trial. \u003cem\u003eJAMA Oncol.\u003c/em\u003e 2017;3(10):1378\u0026ndash;1385. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jamaoncol.2017.1007\u003c/span\u003e\u003cspan address=\"10.1001/jamaoncol.2017.1007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLitton JK, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. \u003cem\u003eN Engl J Med.\u003c/em\u003e 2018;379(8):753\u0026ndash;763. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa1802905\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa1802905\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRobson M, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. \u003cem\u003eN Engl J Med.\u003c/em\u003e 2017;377(6):523\u0026ndash;533. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa1706450\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa1706450\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTutt ANJ, et al. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. \u003cem\u003eN Engl J Med.\u003c/em\u003e 2021;384(25):2394\u0026ndash;2405. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa2105215\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2105215\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGeyer CE, et al. Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline BRCA1/2 mutations and high-risk early breast cancer. \u003cem\u003eAnn Oncol.\u003c/em\u003e 2022;33(12):1250\u0026ndash;1268.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSamstein RM, et al. Mutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy. \u003cem\u003eNat Cancer.\u003c/em\u003e 2021;1(12):1188\u0026ndash;1203. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s43018-020-00139-8\u003c/span\u003e\u003cspan address=\"10.1038/s43018-020-00139-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCortazar P, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. \u003cem\u003eLancet.\u003c/em\u003e 2014;384(9938):164\u0026ndash;172. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S0140-6736(13)62422-8\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(13)62422-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpring LM, et al. Pathologic complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and survival: a comprehensive meta-analysis. \u003cem\u003enpj Breast Cancer.\u003c/em\u003e 2020;6:22. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41523-020-00159-6\u003c/span\u003e\u003cspan address=\"10.1038/s41523-020-00159-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBonadio RC, et al. Real-world treatment patterns and outcomes in stage I-III triple-negative breast cancer treated with a KEYNOTE-522 regimen: Neo-Real/GBECAM-0123 Study. \u003cem\u003eJCO Glob Oncol.\u003c/em\u003e 2025;In press.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSymmans WF, et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. \u003cem\u003eJ Clin Oncol.\u003c/em\u003e 2007;25(28):4414\u0026ndash;4422. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.2007.10.6823\u003c/span\u003e\u003cspan address=\"10.1200/JCO.2007.10.6823\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSymmans WF, et al. Residual cancer burden class and long-term survival following neoadjuvant chemotherapy. \u003cem\u003eJ Clin Oncol.\u003c/em\u003e 2017;35(10):1049\u0026ndash;1060. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.2015.63.1010\u003c/span\u003e\u003cspan address=\"10.1200/JCO.2015.63.1010\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSymmans WF, et al. Long-term prognostic value of residual cancer burden after neoadjuvant chemotherapy in the I-SPY2 trial. \u003cem\u003eJAMA Oncol.\u003c/em\u003e 2021;7(11):1654\u0026ndash;1663. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jamaoncol.2021.4006\u003c/span\u003e\u003cspan address=\"10.1001/jamaoncol.2021.4006\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYau C, et al. Residual cancer burden after neoadjuvant therapy and long-term survival outcomes in breast cancer. \u003cem\u003eLancet Oncol.\u003c/em\u003e 2022;23(2):235\u0026ndash;244. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S1470-2045(21)00689-1\u003c/span\u003e\u003cspan address=\"10.1016/S1470-2045(21)00689-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePusztai L, et al. Relationship of residual cancer burden and event-free survival in KEYNOTE-522. \u003cem\u003eAnn Oncol.\u003c/em\u003e 2024;35(4):429\u0026ndash;436. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.annonc.2023.12.014\u003c/span\u003e\u003cspan address=\"10.1016/j.annonc.2023.12.014\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFedele P, et al. Germline BRCA status and pathologic complete response in triple-negative breast cancer patients treated with neoadjuvant chemo-immunotherapy: a real-world multicenter analysis. \u003cem\u003eJ Clin Med.\u003c/em\u003e 2025;14(24):8854. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/jcm14248854\u003c/span\u003e\u003cspan address=\"10.3390/jcm14248854\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBae SJ, et al. Efficacy of neoadjuvant pembrolizumab combined with chemotherapy in patients with early-stage triple-negative breast cancer: a real-world study from South Korea. \u003cem\u003eAnn Oncol.\u003c/em\u003e 2024;35(Suppl 7):S1406. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.annonc.2024.10.023\u003c/span\u003e\u003cspan address=\"10.1016/j.annonc.2024.10.023\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEtan T, et al. Efficacy and toxicity of pembrolizumab in addition to neoadjuvant platinum-based chemotherapy in TNBC patients with and without germline BRCA mutations. \u003cem\u003eJ Clin Oncol.\u003c/em\u003e 2025;43(16_suppl):e12611.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePark HS, et al. Efficacy and safety of neoadjuvant pembrolizumab plus chemotherapy for triple-negative breast cancer: a multicenter retrospective study. \u003cem\u003eEur J Surg Oncol.\u003c/em\u003e 2025;51(5):109215. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ejso.2025.109215\u003c/span\u003e\u003cspan address=\"10.1016/j.ejso.2025.109215\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMasuda N, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. \u003cem\u003eN Engl J Med.\u003c/em\u003e 2017;376(22):2147\u0026ndash;2159. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa1612645\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa1612645\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSalgado R, et al. The evaluation of tumor-infiltrating lymphocytes in breast cancer: recommendations by an International TILs Working Group 2014. \u003cem\u003eAnn Oncol.\u003c/em\u003e 2015;26(2):259\u0026ndash;271. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/annonc/mdu450\u003c/span\u003e\u003cspan address=\"10.1093/annonc/mdu450\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLoi S, et al. Tumor-infiltrating lymphocytes and prognosis: a pooled individual patient analysis of early-stage triple-negative breast cancers. \u003cem\u003eJ Clin Oncol.\u003c/em\u003e 2019;37(7):559\u0026ndash;569. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.18.01010\u003c/span\u003e\u003cspan address=\"10.1200/JCO.18.01010\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGeurts VCM, et al. Outcomes by tumor-infiltrating lymphocytes in stage I triple-negative breast cancer treated with surgery with or without radiotherapy, without chemotherapy: a cohort study. \u003cem\u003eJAMA Oncol\u003c/em\u003e. 2024;10(8):1077\u0026ndash;1086. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jamaoncol.2024.1917\u003c/span\u003e\u003cspan address=\"10.1001/jamaoncol.2024.1917\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeon-Ferre RA, et al. Tumor-infiltrating lymphocytes in triple-negative breast cancer. \u003cem\u003eJAMA.\u003c/em\u003e 2024;331(13):1135\u0026ndash;1144. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jama.2024.3056\u003c/span\u003e\u003cspan address=\"10.1001/jama.2024.3056\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNederlof I, et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in early-stage triple-negative breast cancer: a phase 2 adaptive trial. \u003cem\u003eNat Med.\u003c/em\u003e 2024;30(11):3223\u0026ndash;3235. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41591-024-03249-3\u003c/span\u003e\u003cspan address=\"10.1038/s41591-024-03249-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eClinicalTrials.gov. ETNA Trial (NCT06078384). Accessed 2026 Jan 18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eClinicalTrials.gov. OPTImaL Trial (NCT06476119). Accessed 2026 Jan 18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eClinicalTrials.gov. DespaTIL Study: TIL-Driven De-escalated Chemotherapy in Stage I\u0026ndash;II TNBC (NCT07074106). Accessed 2026 Jan 18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTavares MC, et al. CD8/FOXP3 ratio and tumor microenvironment exhibit different immunological profiles and clinical impact in triple negative breast cancer treated with neoadjuvant chemotherapy in a Latin American cohort. \u003cem\u003eBreast Cancer Res Treat.\u003c/em\u003e 2021;187(2):553\u0026ndash;565. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s10549-021-06196-8\u003c/span\u003e\u003cspan address=\"10.1007/s10549-021-06196-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBlondeaux E, et al. Association between risk-reducing surgeries and survival in young BRCA mutation carriers: an international prospective cohort study. \u003cem\u003eLancet Oncol.\u003c/em\u003e 2025;26(6):940\u0026ndash;951.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"npj-breast-cancer","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"npjbcancer","sideBox":"Learn more about [npj Breast Cancer](http://www.nature.com/npjbcancer/)","snPcode":"41523","submissionUrl":"https://mts-npjbcancer.nature.com/","title":"npj Breast Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"triple-negative breast cancer, pembrolizumab, BRCA, neoadjuvant therapy, pathologic complete response, event-free survival, real-world study","lastPublishedDoi":"10.21203/rs.3.rs-8929138/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8929138/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eNeoadjuvant pembrolizumab plus chemotherapy improves outcomes in early triple negative breast cancer, but real world evidence in germline BRCA carriers remains limited. We analyzed 726 consecutively treated patients from the Neo Real GBECAM 0123 multicenter cohort who received at least one cycle of neoadjuvant pembrolizumab with chemotherapy and underwent surgery. Pathologic complete response was higher among pathogenic or likely pathogenic BRCA1 or BRCA2 carriers than in wild type or untested patients (74.0% vs 61.7%). With a median follow up of 20.3 months, event free and overall survival were favorable in both groups, with a non significant trend toward improved event free survival in BRCA carriers, most apparent among patients with residual disease.\u003c/p\u003e","manuscriptTitle":"Neoadjuvant pembrolizumab plus chemotherapy in germline BRCA mutated triple negative breast cancer cohort","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-11 11:09:00","doi":"10.21203/rs.3.rs-8929138/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-20T23:14:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-17T01:21:10+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-15T15:10:02+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-13T15:24:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"197108740590585024738989139208552668955","date":"2026-03-08T23:31:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"267993074763011381617036805412876837931","date":"2026-03-06T13:38:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"205883189181048703208036704918411055401","date":"2026-03-06T13:38:01+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-06T06:07:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-25T23:40:19+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-25T01:07:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Breast Cancer","date":"2026-02-20T21:18:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-breast-cancer","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"npjbcancer","sideBox":"Learn more about [npj Breast Cancer](http://www.nature.com/npjbcancer/)","snPcode":"41523","submissionUrl":"https://mts-npjbcancer.nature.com/","title":"npj Breast Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"695fc7d4-1025-4af5-9ff9-99666a611092","owner":[],"postedDate":"March 11th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":64138946,"name":"Biological sciences/Cancer"},{"id":64138947,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2026-05-05T00:38:56+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-11 11:09:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8929138","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8929138","identity":"rs-8929138","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}