Stromal tumor-infiltrating lymphocytes and pathologic response to neoadjuvant chemotherapy with the addition of platinum and pembrolizumab in TNBC: A single-center real-world study

Stromal tumor-infiltrating lymphocytes and pathologic response to neoadjuvant chemotherapy with the addition of platinum and pembrolizumab in TNBC: A single-center real-world study | 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 Research Article Stromal tumor-infiltrating lymphocytes and pathologic response to neoadjuvant chemotherapy with the addition of platinum and pembrolizumab in TNBC: A single-center real-world study Soong June Bae, Jee Hung Kim, Min Ji Kim, Yoonwon Kook, Seung Ho Baek, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4342102/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Immunochemotherapy with pembrolizumab has been integrated into clinical practice as part of the standard-of-care for non-metastatic triple-negative breast cancer (TNBC) with high risk. We conducted a real-world study in TNBC patients treated with neoadjuvant chemotherapy to compare pathologic complete response (pCR) rates relative to stromal tumor-infiltrating lymphocytes (sTIL) across different regimens: non-carboplatin, carboplatin-, and pembrolizumab-chemotherapy. Methods We analyzed a cohort of 450 patients with TNBC who underwent surgery following neoadjuvant chemotherapy between March 2007 and February 2024. Treatment groups included 247 non-carboplatin, 120 carboplatin, and 83 pembrolizumab-chemotherapy recipients. sTIL was evaluated in biopsied samples. Lymphocyte-predominant breast cancer (LPBC) was defined as tumors with high sTIL (≥ 50%). Results The pCR rates were 32% in the non-carboplatin-, 57% in the carboplatin-, and 64% in the pembrolizumab-chemotherapy group. Ninety-two patients (20.4%) had LPBC. In LPBC, the pCR rates did not increase with the addition of carboplatin (50.0% in the non-carboplatin and 41.7% in carboplatin) but reached 83.3% with the addition of pembrolizumab and carboplatin. Among the non-LPBC, the pCR rate increased from 26.7% to 61.1% with the addition of carboplatin, but there was no difference in the pCR rate between the carboplatin and pembrolizumab groups (61.1% and 61.2%, respectively). Conclusions In LPBC patients, the addition of carboplatin did not result in an elevated pCR rate; however, the addition of pembrolizumab tended to raise the pCR rate. In non-LPBC, the addition of carboplatin significantly increased the pCR rate, while the addition of pembrolizumab did not have the same effect. Figures Figure 1 Figure 2 Figure 3 Introduction Since neoadjuvant pembrolizumab combined with chemotherapy has been shown to increase pathologic complete response (pCR) rates [1], and subsequent administration of adjuvant pembrolizumab post-surgery has extended event-free survival (EFS) compared to neoadjuvant chemotherapy alone in patients with early triple-negative breast cancer (TNBC) [2], immunochemotherapy including pembrolizumab has become the standard of care for managing early TNBC patients at high risk. Prior to the era of immunochemotherapy with pembrolizumab, anthracycline- and taxane-based (A-T) chemotherapy regimens were the preferred treatment approach in TNBC [3]. Furthermore, investigators endeavored to enhance clinical outcomes by incorporating carboplatin into the A-T regimen. Previous trials have commonly shown that the addition of carboplatin to A-T increases the rate of pCR [4-6], although improvements in EFS were inconsistent [6-8]. Despite the controversy surrounding the addition of carboplatin to A-T, carboplatin-containing chemotherapy has been the most preferred polychemotherapy regimen for TNBC with high risk [1]. In addition, robust evidence suggests that a high level of stromal tumor-infiltrating lymphocytes (sTILs) in pre-treatment biopsied samples correlates with an increased rate of pCR in TNBC patients undergoing neoadjuvant chemotherapy [9-14]. However, there has been limited data regarding the impact of sTILs on response to different neoadjuvant chemotherapy regimens with or without pembrolizumab in TNBC patients. In this study, we conducted a real-world study in TNBC patients treated with neoadjuvant chemotherapy compare pCR rates relative to sTIL levels across different neoadjuvant chemotherapy regimens: i) non-carboplatin-chemotherapy ii) carboplatin-chemotherapy, and iii) pembrolizumab-chemotherapy. Methods Study population In this retrospective cohort study, we included 450 non-metastatic TNBC patients treated with neoadjuvant chemotherapy at Gangnam Severance Hospital, Seoul, Republic of Korea. All patients underwent curative surgery after neoadjuvant chemotherapy between March 2007 and February 2024. Chemotherapy regimen was chosen as per local guidelines at the time of diagnosis. We excluded the patients diagnosed with recurrent or metachronous BC. This study included the patients at clinical stage IIIC. Staging was performed according to the 8 th edition of the American Joint Committee on Cancer system, and histologic grading was conducted using the Elston-Ellis modification of the Scarff-Bloom-Richardson grade. TNBC was defined as estrogen receptor (ER)-negative and progesterone receptor (PR)–negative according to the guidelines of the American Society of Clinical Oncology and the College of American Pathologists using immunohistochemistry results of tumor. HER2 negativity was determined by IHC (score 0 or 1+) or by fluorescent silver in situ hybridization for cases with an IHC score of 2+. Clinical stage information was determined through physical examination and imaging studies, including mammography, breast ultrasonography, and breast magnetic resonance imaging. To rule out distant metastasis, abdominal and chest computed tomography scans, and bone scans, with/without PET-CT, were performed. Information regarding ER, PR, HER2 status, histologic grade, and sTILs was collected using biopsied samples before neoadjuvant chemotherapy. Germline BRCA1/2 mutation status was assessed in whole blood samples. Unknown information was treated as missing values. Pathological complete response (pCR) was defined as ypT0/is N0. The study was approved by the Institutional Review Board, adhering to good clinical practice guidelines under the Declaration of Helsinki. Chemotherapy regimen Among the study population, 247 (54.9%) patients received the non-carboplatin-chemotherapy, 120 (26.7%) received the carboplatin-chemotherapy, and 83 (18.4%) received the pembrolizumab-chemotherapy [1]. The non-carboplatin group included anthracycline-cyclophosphamide followed by taxane regimen (AC/T), and concurrent anthracycline plus taxane regimen, or anthracycline alone or taxane alone regimen. The carboplatin-chemotherapy group included patients with anthracycline-cyclophosphamide followed by taxane-carboplatin regimen or taxane-carboplatin followed by anthracycline-cyclophosphamide regimen. Patients in the pembrolizumab-chemotherapy group were all treated with the KN-522 regimen (8 cycles of pembrolizumab 200mg, given with 12 cycles of 1 week (W) paclitaxel and 4 cycles of 3W carboplatin, followed by 4 cycles of 3W doxorubicin and cyclophosphamide. Five patients were unable to complete 8 cycles of chemotherapy due to adverse effects. In this study, patients who received at least one dose of pembrolizumab were included in the pembrolizumab-chemotherapy group for analysis. Our study population was summarized in Supplementary Figure 1 . Stromal tumor-infiltrating lymphocytes sTILs were evaluated in biopsied samples before neoadjuvant chemotherapy based on hematoxylin and eosin-stained slides following the protocol by the TIL international working group [15]. We previously reported that sTILs of biopsied samples were correlated with that of surgical specimens, allowing evaluation in biopsied samples [16]. The average sTIL levels was counted from all available tumor area for each case, and the average percentage score was reported. In this study, lymphocyte-predominant breast cancer (LPBC) was defined as tumors having high sTIL levels (≥ 50%) [17, 18]. Non-LPBC tumors were classified into two groups; i) low sTIL (≤ 10%) and ii) intermediate sTILs (11%-49%) [10]. Statistics Continuous variables were compared using the Mann–Whitney U test and Student’s t -test. Kolmogorov–Smirnov tests were used to assess the normal distribution of the continuous variables. Nominal variables were compared using χ 2 or Fisher’s exact tests. Multivariable binary logistic regression analysis was performed to identify predictive factors for pCR. The variables with p -value < 0.05 were included in the multivariable model, and the stepwise backward Wald method was used to arrive at the final model. All statistical analyses were performed using SPSS program version 27.0 (SPSS Inc., Chicago, USA) and R software (https://www.r-projet.org; version 3.6.1). A p -value < 0.05 was considered statistically significant. Results Study population We identified 450 patients with TNBC who underwent neoadjuvant chemotherapy followed by curative surgery. Baseline demographics and tumor characteristics are described in Table 1 . Among these patients, 185 (41.4%) were aged ≥ 50 years, and 188 (41.8%) had with histologic grade III tumors. Of these, germline BRCA1/2 mutation testing was conducted in 264 patients, with mutations identified in 58 (22.0%) of them. Most of the patients had clinical T2 or T3 (399/450 [88.6%]) or clinically node-positive tumors (367/450 [81.6%]). Evaluation of stromal Tumor-Infiltrating Lymphocytes (sTILs) in biopsy specimens was conducted in 369 patients (82.0%), revealing a median sTILs level of 20% (interquartile range [IQR], 3-40%). Based on the treatment regimen, the patients were divided as follows: non-carboplatin-chemotherapy group (247 patients [54.9%]), carboplatin-chemotherapy group (120 patients [26.7%]), and pembrolizumab-chemotherapy group (83 patients [18.4%]). The prevalence of LPBC (sTILs ≥ 50%) varied across three groups, with higher frequencies observed sequentially in the non-carboplatin (56/247 [31.8%]), carboplatin (24/114 [21.1%]), and pembrolizumab groups (12 /89 [15.2%]). Other clinicopathological factors did not significantly differ among the three groups. In addition, among patients with available sTILs data, baseline features were comparable across treatment regimens ( Supplementary Table 1 ). Pathologic complete response rates according to the regimens Of 450 patients, 201 (44.7%) achieved pCR after neoadjuvant systemic treatments. Specifically, pCR rates were 32.4% (79/247) in the non-carboplatin chemotherapy group, 57.5% (69/120) in the carboplatin-chemotherapy group, and 63.9% (53/83) in the pembrolizumab-chemotherapy group ( Figure 1A ). The pCR rate of the non-carboplatin-chemotherapy group was significantly lower than those of the carboplatin- and pembrolizumab-chemotherapy groups, respectively. However, no statistical difference in pCR rate was noted between the carboplatin- and pembrolizumab-chemotherapy group ( P = 0.293). These outcomes of pCR according to the regimens were consistent in the subset of 369 patients evaluated for sTILs: pCR rates were 34.1% (60/176) in the non-carboplatin-chemotherapy group, 57.0% (65/114) in the carboplatin regimen group, and 64.6% (51/79) in the pembrolizumab-chemotherapy group ( Figure 1B ). Multivariable analysis showed that the neoadjuvant chemotherapy regimen was an independent factor for pCR. Compared to the non-carboplatin regimen, the carboplatin (adjusted odds ratio [OR], 2.73; 95% CI, 1.64–4.57; P < 0.001) and pembrolizumab (adjusted OR, 4.00; 95% CI, 2.20–7.16; P < 0.001) regimens were significantly associated with increased odds of achieving pCR ( Table 2 ). However, in this analysis, high TILs (³ 50%) was not demonstrated as an independent factor for pCR ( Table 2 ). Pathologic complete response rates of the regimen groups in relation to sTILs In the cohort with available sTILs data, 24.9% (92/369) were classified as LPBC (sTILs ≥ 50%), and 75.1% (277/369) were classified as non-LPBC (sTILs < 50%). Within the patients with LPBC, the pCR rates for the non-carboplatin- (28/56 [50.0%]) and carboplatin- (10/24 [41.7%]) chemotherapy groups were similar, whereas the pCR rate for the pembrolizumab-chemotherapy group (10/12 [83.3%]) was significantly higher compared to the other two groups (Figure 2A). In the multivariable analysis ( Table 3 ), the pembrolizumab-chemotherapy group (adjusted OR, 6.40; 95% CI, 1.09–37.47; P = 0.040) showed a significant increase in the pCR rate compared to those in the non-carboplatin group, whereas the carboplatin group showed no difference from the non-carboplatin group (adjusted OR, 1.01; 95% CI, 0.31–3.26; P = 0.986). Among the patients with non-LPBC, the non-carboplatin-chemotherapy group (32/120 [26.7%]) had a significantly lower pCR rate compared to the other groups, while the carboplatin- (55/90 [61.1%]) and pembrolizumab- (41 of 67 [62.5%]) chemotherapy groups had similar pCR rates ( Figure 2B ). The multivariable analysis showed that both the carboplatin (adjusted OR, 4.36; 95% CI, 2.17–8.78; p < 0.001) and pembrolizumab (adjusted OR, 3.94; 95% CI, 1.91–8.13; p < 0.001) groups significantly increased pCR rate compared the non-carboplatin group ( Table 3 ). Consistent outcomes were noted in the subset of 295 clinically node-positive disease. Among LPBC patients, the pembrolizumab-chemotherapy group demonstrated a significantly higher pCR rate (9/10 [90.0%]) than the other groups. In non-LPBC patients, the non-carboplatin-chemotherapy group exhibited a lower pCR rate compared to the carboplatin- and pembrolizumab-chemotherapy groups ( Supplementary Figure 2 ). The multivariable analysis confirmed these findings, indicating that the pembrolizumab-chemotherapy regimen was associated with a higher likelihood of pCR in LPBC compared to the other two groups ( Table 3 ). However, the probability of pCR did not differ between the carboplatin- and pembrolizumab-chemotherapy groups in non-LPBC. Lastly, we divided the non-LPBC group into two subgroups based on TIL levels (low [sTIL≤ 10%] and intermediate [sTIL, 11-49%]) and compared the pCR rates of each regimen among the three groups defined by sTILs. In this analysis, the pCR rate for the pembrolizumab-chemotherapy group showed a consistent increase across the TILs subgroups: 57.7% in the low-, 73.3% in the intermediate-, and 83.3% in the high ( Figure 3 ). However, the pCR rates for the carboplatin-chemotherapy group were 57.4% and 66.7% in the low and intermediate groups, respectively, but dropped to 41.7% in the high group. The pCR rates for the non-carboplatin chemotherapy group were low at 24.2% and 29.6% in the low and intermediate groups, respectively, but increased to 51.8% in the high group. Discussion In this study, we conducted a real-world study in TNBC patients treated with neoadjuvant chemotherapy to compare pCR rates relative to sTIL level across different neoadjuvant chemotherapy regimens: i) non-carboplatin-chemotherapy, ii) carboplatin- chemotherapy, and iii) pembrolizumab- chemotherapy. While our real-world data represent the early experiences following the introduction of pembrolizumab, we observed a numerical increase in pCR rates across different regimens, consistent with the results of the KeyNote-522 study: non-carboplatin-chemotherapy, 32.4%; carboplatin- chemotherapy, 57.5%; pembrolizumab- chemotherapy, 67.8%. Furthermore, in TNBC cases with high sTILs, referred as to LPBC, the addition of pembrolizumab to chemotherapy resulted in a pCR rate exceeding 80%, whereas the incorporation of carboplatin into AC/T chemotherapy did not enhance the response. Conversely, in non-LPBC, the inclusion of carboplatin in AC/T significantly enhanced the pCR rate. However, the introduction of pembrolizumab did not demonstrate additional efficacy in this subgroup. When the patients were classified into three groups by sTIL level ( Figure 3 ), the pembrolizumab-chemotherapy group correlated with increased pCR rates in higher TILs subgroups, whereas carboplatin-chemotherapy group did not show this positive trend. In addition, the non-carboplatin-chemotherapy group exhibited a trend of rising pCR rates corresponding to increasing TILs; however, these rates remained noticeably lower than those observed in the pembrolizumab-chemotherapy group. The analysis demonstrates that pembrolizumab-chemotherapy is particularly effective, and its efficacy appears to be related to sTIL levels, suggesting a potential immunological synergy. When the patients were classified into three groups based on sTILs, the pembrolizumab-chemotherapy group showed elevated pCR rates correlated with the sTIL groups, whereas the carboplatin-chemotherapy group did not exhibit this phenomenon ( Figure 3 ). Additionally, the non-carboplatin-chemotherapy group tended to have increasing pCR rates in relation to increasing sTILs; however, the absolute pCR rate was just above 50% even in the high TIL group. These findings suggest that only pembrolizumab-chemotherapy may enhance responses relative to sTILs. It is well established that TNBC tumors exhibit a tumor microenvironment (TME) enriched with immune cells, characterized by high levels of sTILs, PD-L1-positivity and up-regulated immune gene signatures [13, 14, 19, 20]. These immune biomarkers exhibit correlations [13, 20]. Presently, in advanced TNBC, pembrolizumab is exclusively indicated for patients with high PD-L1 expression, as identified by the 22C3 pharmDx assay with a cutoff of a combined positive score (CPS) of 10 [21, 22]. However, in early TNBC, pembrolizumab is administered to all patients regardless of PD-L1 status [1, 2]. Nevertheless, pembrolizumab-based immunochemotherapy achieved a pCR rate of 68.9% in the PD-L1-positive group compared to 45.3% in the PD-L1-negative group [1]. Considering positive correlation between PD-L1 status and TILs level [20, 23], these findings suggest that pembrolizumab-based immunochemotherapy may enhance response in TNBC with a more immunogenic TME. Additionally, in the Neo-PACT trial, which evaluated pembrolizumab-containing immunochemotherapy without anthracyclines in early TNBC, high sTIL as biomarkers for the degree of immune enrichment was predictive of pCR [13]. These findings suggest that the efficacy of pembrolizumab in TNBC is positively correlated with sTIL levels and may reach its maximum in cases classified as LPBC [17, 18, 24], as observed in our study. Currently, ongoing trials are exploring immunochemotherapy with de-escalation of backbone chemotherapy, such as anthracyclines-free regimen or 4 cycles taxane-platinum [25, 26], based on sTIL levels. Intriguingly, we noted that carboplatin increased pCR rate in non-LPBC (sTIL<50%). While high sTIL levels were associated with pCR in neoadjuvant chemotherapy trials with carboplatin in TNBC, it remains unknown whether carboplatin addition can elevate pCR in non-LPBC. Among previous trials, the GeparSixto study demonstrated a pCR rate of 74% with carboplatin compared to 43% without carboplatin in LPBC (sTIL ≥60%), while in non-LPBC cases, the rates were 46% with carboplatin and 34% without carboplatin, respectively [4]. In contrast, the study by Dieci MV et al. showed that carboplatin significantly increased the pCR rate in non-LPBC (sTIL < 60%) [27]. The discrepancy between the two studies may be partly explained by differences in backbone chemotherapy regimens; the GeparSixto study utilized weekly paclitaxel and liposomal doxorubicin for 18 weeks, whereas the study by Dieci MV et al. employed AC followed by weekly paclitaxel for 24 weeks. Further investigations are necessary to fully understand the distinct response patterns to incorporation of carboplatin based on TIL levels in TNBC. Additionally, ongoing trials could assess the potential of novel agents, such as TROP2-targeting antibody-drug conjugates, to enhance response rates in non-LPBC cases [28]. Our study has several limitations. Firstly, our study represents early-phase real-world outcomes following the implementation of pembrolizumab-based immunochemotherapy for early-stage TNBC, which has led to a relatively small cohort in the pembrolizumab group, with an even smaller subset of high TILs cases. Additionally, important immune biomarkers, such as PD-L1 CPS score, were not fully evaluated in relation to TILs. Despite these limitations, our study leveraged sTILs and addressed differential responses across three different regimens: carboplatin-based and non-carboplatin-based, as well as pembrolizumab immunochemotherapy. Our findings may provide a foundation for tailoring immunochemotherapy based on stromal TILs in TNBC. Conclusion In conclusion, our real-world data consistently demonstrates an increased pCR rate with the addition of carboplatin and pembrolizumab. In LPBC, the addition of carboplatin did not result in an elevated pCR rate. 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Neoadjuvant TIL- and Response-Adapted Chemoimmunotherapy for TNBC (NeoTract). Accessed October 24, 2023. https://clinicaltrials. gov/study/NCT05645380 Dieci MV, Carbognin L, Miglietta F et al (2023) Incorporating weekly carboplatin in anthracycline and paclitaxel-containing neoadjuvant chemotherapy for triple-negative breast cancer: propensity-score matching analysis and TIL evaluation. Br J Cancer 128:266-274. https://doi.org/10.1038/s41416-022-02050-8 A Phase III Randomised Study to Evaluate Dato-DXd and Durvalumab for Neoadjuvant/Adjuvant Treatment of Triple-Negative or Hormone Receptor-low/HER2-negative Breast Cancer. Accessed February 25, 2024. https://clinicaltrials. gov/study/NCT06112379. Tables Table 1. Baseline characteristics of patients according to neoadjuvant chemotherapy regimen (n = 450). Non-carboplatin (N = 247) Carboplatin (N = 120) Pembrolizumab (N = 83) Total (N =450) P Age, n (%) 0.630 ≤ 50 143 (57.9) 75 (62.5) 47 (56.6) 265 (58.9) > 50 104 (42.1) 45 (37.5) 36 (43.4) 185 (41.4) Germline BRCA1/2 mutation * 0.090 No 86 (81.9) 64 (70.3) 56 (82.4) 206 (78.0) Yes 19 (18.1) 27 (29.7) 12 (17.6) 58 (22.0) Clinical tumor stage 0.156 1 14 (5.7) 7 (5.8) 6 (7.2) 27 (6.0) 2 163 (66.0) 91 (75.8) 62 (74.7) 316 (70.2) 3 51 (20.6) 18 (15.0) 14 (16.9) 83 (18.4) 4 19 (7.7) 4 (3.3) 1 (1.2) 24 (5.3) Clinical nodal stage 0.280 0 47 (19.0) 25 (20.8) 11 (13.3) 83 (18.4) 1 100 (40.5) 51 (42.5) 43 (51.8) 194 (43.1) 2 87 (35.2) 36 (30.0) 21 (25.3) 144 (32.0) 3 13 (5.3) 8 (6.7) 8 (9.6) 29 (6.4) Clinical Stage, n (%) 0.133 I,IIA 49 (19.8) 24 (20.0) 13 (15.7) 86 (19.1) IIB 75 (30.4) 41 (34.2) 37 (44.6) 153 (34.0) IIIA 93 (37.7) 43 (35.8) 24 (28.9) 160 (35.6) IIIB 17 (6.9) 4 (3.3) 1 (1.2) 22 (4.9) IIIC 13 (5.3) 8 (6.7) 8 (9.6) 29 (6.4) Histologic grade * , n (%) 0.369 † 1 4 (2.2) 0 1 (1.3) 5 (1.3) 2 85 (47.0) 53 (46.5) 44 (55.0) 182 (48.5) 3 92 (50.8) 61 (53.5) 35 (43.8) 188 (48.5) sTILs, median (range) 20 (10-60) 20 (3-40) 10 (3-25) 20 (3-40) <0.001 sTILs * , % 0.009 <50 120 (68.2) 90 (78.9) 67 (84.8) 277 (75.1) ≥50 56 (31.8) 24 (21.1) 12 (15.2) 92 (24.9) Surgery type 0.512 Lumpectomy 137 (55.5) 74 (61.7) 49 (59.0) 260 (57.8) Mastectomy 110 (44.5) 46 (38.3) 34 (41.0) 190 (42.2) * Missing values † P -values were obtained with the Fisher’s exact test. sTILs, stromal tumor-infiltrating lymphocytes. Table 2. Odds ratio (OR) and 95% confidence interval (CI) for pathologic complete response i n 369 patients with available sTILs. Univariable analysis Multivariable analysis OR 95% CI P adjusted OR 95% CI P Age ≤ 50 Ref. Ref. > 50 0.69 0.46-1.04 0.079 0.80 0.51-1.26 0.341 Histologic grade 0.074 0.175 1 Ref. Ref. 2 3.01 0.33-27.48 0.329 2.17 0.21-22.13 0.512 3 4.55 0.50-41.50 0.179 3.20 0.31-32.78 0.327 Clinical tumor stage 0.126 0.578 1 Ref. Ref. 2 0.94 0.41-2.13 0.876 0.83 0.35-1.96 0.666 3 0.62 0.25-1.59 0.322 0.67 0.25-1.78 0.417 4 0.25 0.06-1.13 0.071 0.37 0.08-1.81 0.220 Clinical nodal stage 0.555 0 Ref. Ref. 1 1.15 0.66-2.01 0.612 0.90 0.50-1.64 0.730 2 0.78 0.43-1.40 0.399 0.67 0.35-1.28 0.227 3 0.73 0.30-1.77 0.482 0.64 0.241.72 0.379 sTILs < 50% Ref. Ref. ≥50% 1.27 0.79-2.04 0.322 1.60 0.95-2.69 0.079 Regimen < 0.001 Non-carboplatin Ref. Ref. Carboplatin 2.57 1.58-4.16 < 0.001 2.73 1.64-4.53 < 0.001 Pembrolizumab 3.52 2.02-6.14 < 0.001 4.00 2.20-7.16 < 0.001 sTILs, stromal tumor-infiltrating lymphocytes. Table 3. Odds ratio (OR) and 95% confidence interval (CI) of treatment regimen for pathologic complete response stratified by stromal tumor-infiltrating lymphocytes. Cohort Regimen Multivariable analysis adjusted OR * 95% CI P All patients with sTILs LPBC Non-carboplatin Ref. Carboplatin 1.01 0.31-3.26 0.986 Pembrolizumab 6.40 1.09-37.47 0.040 Non-LPBC Non-carboplatin Ref. Carboplatin 4.09 2.24-7.48 <0.001 Pembrolizumab 4.47 2.30-8.67 <0.001 Cohort Regimen Multivariable analysis adjusted OR † 95% CI P cN+ patients with sTILs LPBC Non-carboplatin Ref. Carboplatin 0.98 0.30-3.23 0.977 Pembrolizumab 11.45 1.17-112.43 0.036 Non-LPBC Non-carboplatin Ref. Carboplatin 4.36 2.17-8.78 <0.001 Pembrolizumab 3.94 1.91-8.13 50), histologic grade (1 vs. 2 vs. 3), clinical tumor stage (1 vs. 2 vs. 3 vs. 4), and clinical nodal stage (0 vs. 1 vs. 2 vs. 3). † Adjusted for age (≤ 50 vs. > 50), histologic grade (1 vs. 2 vs. 3), clinical tumor stage (1 vs. 2 vs. 3 vs. 4), and clinical nodal stage (1 vs. 2 vs. 3). sTILs, stromal tumor-infiltrating lymphocytes; LPBC, lymphocyte-predominant breast cancer. Additional Declarations No competing interests reported. Supplementary Files SupplementalTable1.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4342102","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":298693183,"identity":"f66a57dd-ad21-42a1-a8f6-adc3ec0a2ddc","order_by":0,"name":"Soong June Bae","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Soong","middleName":"June","lastName":"Bae","suffix":""},{"id":298693190,"identity":"ac14eca9-c706-4807-a624-50e5a57b1d02","order_by":1,"name":"Jee Hung Kim","email":"","orcid":"","institution":"Yonsei University College of 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Ahn","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAz0lEQVRIiWNgGAWjYHACxgcJBmxyDAw8xGthNvhQwWdMkhY2yRln5BIbiNbC33/8gjRvm1n6hhu5hz8w1NgR1iJxI6fAmLctLXfDjbw0CYZjyURYc4MnIZm37RhQS44Z0JEHCOuQP38m4TBv2/90gxs5xh8Y/hGhxeBA+sHGGWfYEoBaDCQY24jQYngjh5nhQwWb4cwzb8wkEvuI8Ivc+ePPfwCjUp7vONBhH74REWLAGDQAUwogJyUQo4GBgf0BmJJvIE75KBgFo2AUjEAAALqHPsS5ce5eAAAAAElFTkSuQmCC","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Sung","middleName":"Gwe","lastName":"Ahn","suffix":""}],"badges":[],"createdAt":"2024-04-29 10:24:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4342102/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4342102/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":56039900,"identity":"4a85c8f5-fd69-4942-8cb9-9d7f5fd4454c","added_by":"auto","created_at":"2024-05-07 19:13:24","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":134434,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePathologic complete response (pCR) rate according to neoadjuvant treatment regimens (A) in all patients and (B) patients with available stromal tumor-infiltrating lymphocytes (sTILs) data.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4342102/v1/f7f66e41e55ff6c92612a0a0.png"},{"id":56039901,"identity":"a070063a-fefb-4af0-b7e1-79f1dc255451","added_by":"auto","created_at":"2024-05-07 19:13:24","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":138408,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePathologic complete response (pCR) rate according to neoadjuvant treatment regimens stratified by stromal tumor-infiltrating lymphocytes (sTILs): \u003c/strong\u003e(A) in lymphocyte-predominant breast cancer (LPBC) with high sTILs (≥ 50%), and (B) in non-LPBC with low sTILs (\u0026lt; 50%).\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4342102/v1/34795f2e85a8a6d8983a376b.png"},{"id":56039907,"identity":"e3ea6575-1715-475a-b4bf-38b6aa981a0b","added_by":"auto","created_at":"2024-05-07 19:13:24","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":80742,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChanges in pathologic complete response (pCR) rate according to stromal tumor-infiltrating lymphocytes (sTILs) level in each neoadjuvant treatment regimen.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4342102/v1/14e95e62688f76712054e649.png"},{"id":61665462,"identity":"b298f3cd-9a6f-44bf-9fc7-b951dc69d9de","added_by":"auto","created_at":"2024-08-02 15:57:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1186735,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4342102/v1/bfbe5c35-5f0d-4989-a816-4d5a2969fa65.pdf"},{"id":56039903,"identity":"538f4fdb-3c40-4ee4-9b34-c6365785b866","added_by":"auto","created_at":"2024-05-07 19:13:24","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":19755,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4342102/v1/7a9004eee5acd97d3008e3bf.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Stromal tumor-infiltrating lymphocytes and pathologic response to neoadjuvant chemotherapy with the addition of platinum and pembrolizumab in TNBC: A single-center real-world study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSince neoadjuvant pembrolizumab combined with chemotherapy has been shown to increase pathologic complete\u0026nbsp;response (pCR) rates\u0026nbsp;[1], and subsequent administration of adjuvant pembrolizumab post-surgery has extended event-free survival (EFS) compared to neoadjuvant chemotherapy alone in patients with early triple-negative breast cancer (TNBC)\u0026nbsp;[2], immunochemotherapy including pembrolizumab has become the standard of care for managing early TNBC patients at high risk.\u003c/p\u003e\n\u003cp\u003ePrior to the era of immunochemotherapy with pembrolizumab, anthracycline- and taxane-based (A-T) chemotherapy regimens\u0026nbsp;were the preferred treatment approach in TNBC\u0026nbsp;[3]. Furthermore, investigators endeavored to enhance clinical outcomes by incorporating carboplatin into the A-T regimen. Previous trials have commonly shown that the addition of carboplatin to A-T increases the rate of pCR\u0026nbsp;[4-6], although improvements in EFS were inconsistent\u0026nbsp;[6-8]. Despite the controversy surrounding the addition of carboplatin to A-T, carboplatin-containing chemotherapy has been the most preferred polychemotherapy regimen for TNBC with high risk\u0026nbsp;[1].\u003c/p\u003e\n\u003cp\u003eIn addition, robust evidence suggests that a high level of stromal tumor-infiltrating lymphocytes (sTILs) in pre-treatment biopsied samples correlates with an increased rate of pCR in TNBC patients undergoing neoadjuvant chemotherapy\u0026nbsp;[9-14]. However, there has been limited data regarding the impact of sTILs on response to different neoadjuvant chemotherapy regimens with or without pembrolizumab in TNBC patients.\u003c/p\u003e\n\u003cp\u003eIn this study, we conducted a real-world study in TNBC patients treated with neoadjuvant chemotherapy compare pCR rates relative to sTIL levels across different neoadjuvant chemotherapy regimens: i) non-carboplatin-chemotherapy ii) carboplatin-chemotherapy, and iii) pembrolizumab-chemotherapy.\u0026nbsp;\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this retrospective cohort study, we included 450 non-metastatic TNBC patients treated with neoadjuvant chemotherapy at Gangnam Severance Hospital, Seoul, Republic of Korea. All patients underwent curative surgery after neoadjuvant chemotherapy between March 2007 and February 2024. Chemotherapy regimen was chosen as per local guidelines at the time of diagnosis. We excluded the patients diagnosed with recurrent or metachronous BC. This study included the patients at clinical stage IIIC. Staging was performed according to the 8\u003csup\u003eth\u003c/sup\u003e edition of the American Joint Committee on Cancer system, and histologic grading was conducted using the Elston-Ellis modification of the Scarff-Bloom-Richardson grade.\u003c/p\u003e\n\u003cp\u003eTNBC was defined as estrogen receptor (ER)-negative and progesterone receptor (PR)–negative according to the guidelines of the American Society of Clinical Oncology and the College of American Pathologists using immunohistochemistry results of tumor. HER2 negativity was determined by IHC (score 0 or 1+) or by fluorescent silver in situ hybridization for cases with an IHC score of 2+. Clinical stage information was determined through physical examination and imaging studies, including mammography, breast ultrasonography, and breast magnetic resonance imaging. To rule out distant metastasis, abdominal and chest computed tomography scans, and bone scans, with/without PET-CT, were performed. Information regarding ER, PR, HER2 status, histologic grade, and sTILs was collected using biopsied samples before neoadjuvant chemotherapy. Germline BRCA1/2 mutation status was assessed in whole blood samples. Unknown information was treated as missing values. Pathological complete response (pCR) was defined as ypT0/is N0. The study was approved by the Institutional Review Board, adhering to good clinical practice guidelines under the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eChemotherapy regimen\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the study population, 247 (54.9%) patients received the\u0026nbsp;non-carboplatin-chemotherapy,\u0026nbsp;120 (26.7%) received the\u0026nbsp;carboplatin-chemotherapy,\u0026nbsp;and 83 (18.4%) received the\u0026nbsp;pembrolizumab-chemotherapy\u0026nbsp;[1].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe non-carboplatin group included anthracycline-cyclophosphamide followed by taxane regimen (AC/T), and concurrent anthracycline plus taxane regimen, or anthracycline alone or taxane alone regimen. The carboplatin-chemotherapy group included patients with anthracycline-cyclophosphamide followed by taxane-carboplatin regimen or taxane-carboplatin followed by anthracycline-cyclophosphamide regimen. Patients in the pembrolizumab-chemotherapy group were all treated with the KN-522 regimen (8 cycles of pembrolizumab 200mg, given with 12 cycles of 1 week (W) paclitaxel and 4 cycles of 3W carboplatin, followed by 4 cycles of 3W doxorubicin and cyclophosphamide. Five patients were unable to complete 8 cycles of chemotherapy due to adverse effects. In this study, patients who received at least one dose of pembrolizumab were included in the pembrolizumab-chemotherapy group for analysis. Our study population was summarized in \u003cstrong\u003eSupplementary Figure 1\u003c/strong\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStromal tumor-infiltrating lymphocytes\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003esTILs were evaluated in biopsied samples before neoadjuvant chemotherapy based on hematoxylin and eosin-stained slides following the protocol by the TIL international working group \u0026nbsp;[15]. We previously reported that sTILs of biopsied samples were correlated with that of surgical specimens, allowing evaluation in biopsied samples \u0026nbsp;[16].\u0026nbsp;The average sTIL levels was counted from all available tumor area for each case, and the average percentage score was reported. In this study, lymphocyte-predominant breast cancer (LPBC) was defined as tumors having high sTIL levels (≥ 50%) \u0026nbsp;[17, 18].\u0026nbsp;Non-LPBC tumors were classified into two groups; i) low sTIL (≤\u0026nbsp;10%) and ii) intermediate sTILs (11%-49%) \u0026nbsp;[10].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eContinuous variables were compared using the Mann–Whitney U test and Student’s \u003cem\u003et\u003c/em\u003e-test. Kolmogorov–Smirnov tests were used to assess the normal distribution of the continuous variables. Nominal variables were compared using \u003cem\u003eχ\u003c/em\u003e\u003csup\u003e2\u0026nbsp;\u003c/sup\u003eor Fisher’s exact tests. Multivariable binary logistic regression analysis was performed to identify predictive factors for pCR. The variables with \u003cem\u003ep\u003c/em\u003e-value \u0026lt; 0.05 were included in the multivariable model, and the stepwise backward Wald method was used to arrive at the final model. All statistical analyses were performed using SPSS program version 27.0 (SPSS Inc., Chicago, USA) and R software (https://www.r-projet.org; version 3.6.1). A \u003cem\u003ep\u003c/em\u003e-value \u0026lt; 0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eStudy population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe identified 450 patients with TNBC who underwent neoadjuvant chemotherapy followed by curative surgery. Baseline demographics and tumor characteristics are described in \u003cstrong\u003eTable 1\u003c/strong\u003e. Among these patients, 185 (41.4%) were aged ≥ 50 years, and 188 (41.8%) had with histologic grade III tumors. Of these, germline BRCA1/2 mutation testing was conducted in 264 patients, with mutations identified in 58 (22.0%) of them. Most of the patients had clinical T2 or T3 (399/450 [88.6%]) or clinically node-positive tumors (367/450 [81.6%]). Evaluation of stromal Tumor-Infiltrating Lymphocytes (sTILs) in biopsy specimens was conducted in 369 patients (82.0%), revealing a median sTILs level of 20% (interquartile range [IQR], 3-40%).\u003c/p\u003e\n\u003cp\u003eBased on the treatment regimen, the patients\u0026nbsp;were divided as follows: non-carboplatin-chemotherapy group (247 patients [54.9%]), carboplatin-chemotherapy group (120 patients [26.7%]), and pembrolizumab-chemotherapy group (83 patients [18.4%]). The prevalence of LPBC (sTILs ≥ 50%) varied across three groups, with higher frequencies observed sequentially in the non-carboplatin (56/247 [31.8%]), carboplatin (24/114 [21.1%]), and pembrolizumab groups (12 /89 [15.2%]). Other clinicopathological factors did not significantly differ among the three groups. In addition, among patients with available sTILs data, baseline features were comparable across treatment regimens (\u003cstrong\u003eSupplementary Table 1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePathologic complete response rates according to the regimens\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf 450 patients, 201 (44.7%) achieved pCR after neoadjuvant systemic treatments. Specifically, pCR rates were 32.4% (79/247) in the non-carboplatin chemotherapy group, 57.5% (69/120) in the carboplatin-chemotherapy group, and 63.9% (53/83) in the pembrolizumab-chemotherapy group (\u003cstrong\u003eFigure 1A\u003c/strong\u003e). The pCR rate of the non-carboplatin-chemotherapy group was significantly lower than those of the carboplatin- and pembrolizumab-chemotherapy groups, respectively. However, no statistical difference in pCR rate was noted between the carboplatin- and pembrolizumab-chemotherapy group (\u003cem\u003eP\u003c/em\u003e = 0.293).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThese outcomes of pCR according to the regimens were consistent in the subset of 369 patients evaluated for sTILs: pCR rates were 34.1% (60/176) in the non-carboplatin-chemotherapy group, 57.0% (65/114) in the carboplatin regimen group, and 64.6% (51/79) in the pembrolizumab-chemotherapy group (\u003cstrong\u003eFigure 1B\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMultivariable analysis showed that the neoadjuvant chemotherapy regimen was an independent factor for pCR. Compared to the non-carboplatin regimen, the carboplatin\u0026nbsp;(adjusted odds ratio [OR], 2.73; 95% CI, 1.64–4.57; \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001)\u0026nbsp;and pembrolizumab\u0026nbsp;(adjusted OR, 4.00; 95% CI, 2.20–7.16; \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001) regimens\u0026nbsp;were significantly associated with increased odds of achieving pCR (\u003cstrong\u003eTable 2\u003c/strong\u003e). However, in this analysis, high TILs (³\u0026nbsp;50%) was not demonstrated as an independent factor for pCR (\u003cstrong\u003eTable 2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePathologic complete response rates of the regimen groups in relation to sTILs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the cohort with available sTILs data, 24.9% (92/369) were classified as LPBC (sTILs ≥ 50%), and 75.1% (277/369) were classified as non-LPBC (sTILs \u0026lt; 50%). Within the patients with LPBC, the pCR rates for the non-carboplatin- (28/56 [50.0%]) and carboplatin- (10/24 [41.7%]) chemotherapy groups were similar, whereas the pCR rate for the pembrolizumab-chemotherapy group (10/12 [83.3%]) was significantly higher compared to the other two groups (Figure 2A). In the multivariable analysis (\u003cstrong\u003eTable 3\u003c/strong\u003e), the pembrolizumab-chemotherapy group\u0026nbsp;(adjusted OR, 6.40; 95% CI, 1.09–37.47; \u003cem\u003eP\u003c/em\u003e = 0.040)\u0026nbsp;showed a significant increase in the pCR rate compared to those in the non-carboplatin group, whereas the carboplatin group showed no difference from the non-carboplatin group\u0026nbsp;(adjusted OR, 1.01; 95% CI, 0.31–3.26; \u003cem\u003eP\u003c/em\u003e = 0.986).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAmong the patients with non-LPBC, the non-carboplatin-chemotherapy group (32/120 [26.7%]) had a significantly lower pCR rate compared to the other groups, while the carboplatin- (55/90 [61.1%]) and pembrolizumab- (41 of 67 [62.5%]) chemotherapy groups had similar pCR rates (\u003cstrong\u003eFigure 2B\u003c/strong\u003e). The multivariable analysis showed that both the carboplatin\u0026nbsp;(adjusted OR, 4.36; 95% CI, 2.17–8.78; \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001)\u0026nbsp;and pembrolizumab\u0026nbsp;(adjusted OR, 3.94; 95% CI, 1.91–8.13; \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001)\u0026nbsp;groups significantly increased pCR rate compared the non-carboplatin group (\u003cstrong\u003eTable 3\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsistent outcomes were noted in the subset of 295 clinically node-positive disease. Among LPBC patients, the pembrolizumab-chemotherapy group demonstrated a significantly higher pCR rate (9/10 [90.0%]) than the other groups. In non-LPBC patients, the non-carboplatin-chemotherapy group exhibited a lower pCR rate compared to the carboplatin- and pembrolizumab-chemotherapy groups (\u003cstrong\u003eSupplementary Figure 2\u003c/strong\u003e). The multivariable analysis confirmed these findings, indicating that the pembrolizumab-chemotherapy regimen was associated with a higher likelihood of pCR in LPBC compared to the other two groups (\u003cstrong\u003eTable 3\u003c/strong\u003e). However, the probability of pCR did not differ between the carboplatin- and pembrolizumab-chemotherapy groups in non-LPBC.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLastly, we divided the non-LPBC group into two subgroups based on TIL levels (low [sTIL≤ 10%] and intermediate [sTIL, 11-49%]) and compared the pCR rates of each regimen among the three groups defined by sTILs. In this analysis, the pCR rate for the pembrolizumab-chemotherapy group showed a consistent increase across the TILs subgroups: 57.7% in the low-, 73.3% in the intermediate-, and 83.3% in the high (\u003cstrong\u003eFigure 3\u003c/strong\u003e). However, the pCR rates for the carboplatin-chemotherapy group were 57.4% and 66.7% in the low and intermediate groups, respectively, but dropped to 41.7% in the high group. The pCR rates for the non-carboplatin chemotherapy group were low at 24.2% and 29.6% in the low and intermediate groups, respectively, but increased to 51.8% in the high group.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we conducted a real-world study in TNBC patients treated with neoadjuvant chemotherapy to compare pCR rates relative to sTIL level across different neoadjuvant chemotherapy regimens: i) non-carboplatin-chemotherapy, ii) carboplatin- chemotherapy, and iii) pembrolizumab- chemotherapy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhile our real-world data represent the early experiences following the introduction of pembrolizumab, we observed a numerical increase in pCR rates across different regimens, consistent with the results of the KeyNote-522 study: non-carboplatin-chemotherapy, 32.4%; carboplatin- chemotherapy, 57.5%; pembrolizumab- chemotherapy, 67.8%. Furthermore, in TNBC cases with high sTILs, referred as to LPBC, the addition of pembrolizumab to chemotherapy resulted in a pCR rate exceeding 80%, whereas the incorporation of carboplatin into AC/T chemotherapy did not enhance the response. Conversely, in non-LPBC, the inclusion of carboplatin in AC/T significantly enhanced the pCR rate. However, the introduction of pembrolizumab did not demonstrate additional efficacy in this subgroup.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhen the patients were classified into three groups by sTIL level (\u003cstrong\u003eFigure 3\u003c/strong\u003e), the pembrolizumab-chemotherapy group correlated with increased pCR rates in higher TILs subgroups, whereas carboplatin-chemotherapy group did not show this positive trend. In addition, the non-carboplatin-chemotherapy group exhibited a trend of rising pCR rates corresponding to increasing TILs; however, these rates remained noticeably lower than those observed in the pembrolizumab-chemotherapy group. The analysis demonstrates that pembrolizumab-chemotherapy is particularly effective, and its efficacy appears to be related to sTIL levels, suggesting a potential immunological synergy.\u003c/p\u003e\n\u003cp\u003eWhen the patients were classified into three groups based on sTILs, the pembrolizumab-chemotherapy group showed elevated pCR rates correlated with the sTIL groups, whereas the carboplatin-chemotherapy group did not exhibit this phenomenon (\u003cstrong\u003eFigure 3\u003c/strong\u003e). Additionally, the non-carboplatin-chemotherapy group tended to have increasing pCR rates in relation to increasing sTILs; however, the absolute pCR rate was just above 50% even in the high TIL group. These findings suggest that only pembrolizumab-chemotherapy may enhance responses relative to sTILs.\u003c/p\u003e\n\u003cp\u003eIt is well established that TNBC tumors exhibit a tumor microenvironment (TME) enriched with immune cells, characterized by high levels of sTILs, PD-L1-positivity and up-regulated immune gene signatures [13, 14, 19, 20]. These immune biomarkers exhibit correlations [13, 20]. Presently, in advanced TNBC, pembrolizumab is exclusively indicated for patients with high PD-L1 expression, as identified by the 22C3 pharmDx assay with a cutoff of a combined positive score (CPS) of 10 [21, 22]. However, in early TNBC, pembrolizumab is administered to all patients regardless of PD-L1 status \u0026nbsp;[1, 2]. Nevertheless, pembrolizumab-based immunochemotherapy achieved a pCR rate of 68.9% in the PD-L1-positive group compared to 45.3% in the PD-L1-negative group [1]. Considering positive correlation between PD-L1 status and TILs level [20, 23], these findings suggest that pembrolizumab-based immunochemotherapy may enhance response in TNBC with a more immunogenic TME.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAdditionally, in the Neo-PACT trial, which evaluated pembrolizumab-containing immunochemotherapy without anthracyclines in early TNBC, high sTIL as biomarkers for the degree of immune enrichment was predictive of pCR\u0026nbsp;[13]. These findings suggest that the efficacy of pembrolizumab in TNBC is positively correlated with sTIL levels and may reach its maximum in cases classified as LPBC\u0026nbsp;[17, 18, 24], as observed in our study. Currently, ongoing trials are exploring immunochemotherapy with de-escalation of backbone chemotherapy, such as anthracyclines-free regimen or 4 cycles taxane-platinum [25, 26], based on sTIL levels.\u003c/p\u003e\n\u003cp\u003eIntriguingly, we noted that carboplatin increased pCR rate in non-LPBC (sTIL\u0026lt;50%). While high sTIL levels were associated with pCR in neoadjuvant chemotherapy trials with carboplatin in TNBC, it remains unknown whether carboplatin addition can elevate pCR in non-LPBC.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAmong previous trials, the GeparSixto study demonstrated a pCR rate of 74% with carboplatin compared to 43% without carboplatin in LPBC (sTIL \u0026ge;60%), while in non-LPBC cases, the rates were 46% with carboplatin and 34% without carboplatin, respectively \u0026nbsp;[4]. In contrast, the study by Dieci MV et al. showed that carboplatin significantly increased the pCR rate in non-LPBC (sTIL \u0026lt; 60%) [27]. The discrepancy between the two studies may be partly explained by differences in backbone chemotherapy regimens; the GeparSixto study utilized weekly paclitaxel and liposomal doxorubicin for 18 weeks, whereas the study by Dieci MV et al. employed AC followed by weekly paclitaxel for 24 weeks. Further investigations are necessary to fully understand the distinct response patterns to incorporation of carboplatin based on TIL levels in TNBC. Additionally, ongoing trials could assess the potential of novel agents, such as TROP2-targeting antibody-drug conjugates, to enhance response rates in non-LPBC cases [28].\u003c/p\u003e\n\u003cp\u003eOur study has several limitations. Firstly, our study represents early-phase real-world outcomes following the implementation of pembrolizumab-based immunochemotherapy for early-stage TNBC, which has led to a relatively small cohort in the pembrolizumab group, with an even smaller subset of high TILs cases. Additionally, important immune biomarkers, such as PD-L1 CPS score, were not fully evaluated in relation to TILs. Despite these limitations, our study leveraged sTILs and addressed differential responses across three different regimens: carboplatin-based and non-carboplatin-based, as well as pembrolizumab immunochemotherapy. Our findings may provide a foundation for tailoring immunochemotherapy based on stromal TILs in TNBC. \u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, our real-world data consistently demonstrates an increased pCR rate with the addition of carboplatin and pembrolizumab. In LPBC, the addition of carboplatin did not result in an elevated pCR rate. However, the addition of pembrolizumab tended to boost the pCR rate, surpassing 80%. On the other hand, among patients with non-LPBC, the addition of carboplatin significantly increased the pCR rate, while the addition of pembrolizumab did not have the same effect. Further efforts should be made to improve the response to pembrolizumab-chemotherapy for patients with low baseline sTIL levels.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSchmid P, Cortes J, Pusztai L et al (2020) Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med 382:810-821. https://doi.org/10.1056/NEJMoa1910549\u003c/li\u003e\n \u003cli\u003eSchmid P, Cortes J, Dent R et al (2022) Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer. N Engl J Med 386:556-567. https://doi.org/10.1056/NEJMoa2112651\u003c/li\u003e\n \u003cli\u003eBurstein HJ, Curigliano G, Loibl S, Dubsky P, Gnant M, Poortmans P, Colleoni M, Denkert C, Piccart-Gebhart M, Regan M, Senn HJ, Winer EP, Thurlimann B (2019) Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019. 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Breast Cancer Res Treat 171:295-302. https://doi.org/10.1007/s10549-018-4842-7\u003c/li\u003e\n \u003cli\u003eLoi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, Rouas G, Francis P, Crown JP, Hitre E, de Azambuja E, Quinaux E, Di Leo A, Michiels S, Piccart MJ, Sotiriou C (2013) Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol 31:860-867. https://doi.org/10.1200/jco.2011.41.0902\u003c/li\u003e\n \u003cli\u003eDieci MV, Mathieu MC, Guarneri V, Conte P, Delaloge S, Andre F, Goubar A (2015) Prognostic and predictive value of tumor-infiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials. 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N Engl J Med 387:217-226. https://doi.org/10.1056/NEJMoa2202809\u003c/li\u003e\n \u003cli\u003eEmens LA, Molinero L, Loi S, Rugo HS, Schneeweiss A, Di\u0026eacute;ras V, Iwata H, Barrios CH, Nechaeva M, Nguyen-Duc A, Chui SY, Husain A, Winer EP, Adams S, Schmid P (2021) Atezolizumab and nab-Paclitaxel in Advanced Triple-Negative Breast Cancer: Biomarker Evaluation of the IMpassion130 Study. J Natl Cancer Inst 113:1005-1016. https://doi.org/10.1093/jnci/djab004\u003c/li\u003e\n \u003cli\u003eStanton SE, Adams S, Disis ML (2016) Variation in the Incidence and Magnitude of Tumor-Infiltrating Lymphocytes in Breast Cancer Subtypes: A Systematic Review. JAMA Oncol 2:1354-1360. https://doi.org/10.1001/jamaoncol.2016.1061\u003c/li\u003e\n \u003cli\u003eUS National Cancer Institute, Cancer Therapy Evaluation Program. Shorter Anthracycline-Free Chemoimmunotherapy Adapted to Pathological Response in Early TNBC (SCARLET); SWOG S2212. Accessed October 24, 2023. https://www.swog. org/our-network.\u003c/li\u003e\n \u003cli\u003eUniversity of Kansas Medical Center. Neoadjuvant TIL- and Response-Adapted Chemoimmunotherapy for TNBC (NeoTract). Accessed October 24, 2023. https://clinicaltrials. gov/study/NCT05645380\u003c/li\u003e\n \u003cli\u003eDieci MV, Carbognin L, Miglietta F et al (2023) Incorporating weekly carboplatin in anthracycline and paclitaxel-containing neoadjuvant chemotherapy for triple-negative breast cancer: propensity-score matching analysis and TIL evaluation. Br J Cancer 128:266-274. https://doi.org/10.1038/s41416-022-02050-8\u003c/li\u003e\n \u003cli\u003eA Phase III Randomised Study to Evaluate Dato-DXd and Durvalumab for Neoadjuvant/Adjuvant Treatment of Triple-Negative or Hormone Receptor-low/HER2-negative Breast Cancer. Accessed February 25, 2024. https://clinicaltrials. gov/study/NCT06112379.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Baseline characteristics of patients according to neoadjuvant chemotherapy regimen (n = 450).\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003eNon-carboplatin (N = 247)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003eCarboplatin (N = 120)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003ePembrolizumab (N = 83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003eTotal (N =450)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003eAge, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e0.630\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e\u0026le; 50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e143 (57.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e75 (62.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e47 (56.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e265 (58.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e\u0026gt; 50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e104 (42.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e45 (37.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e36 (43.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e185 (41.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003eGermline BRCA1/2 mutation\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e0.090\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e86 (81.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e64 (70.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e56 (82.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e206 (78.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e19 (18.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e27 (29.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e12 (17.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e58 (22.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003eClinical tumor stage\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e0.156\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e14 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e7 (5.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e6 (7.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e27 (6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e163 (66.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e91 (75.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e62 (74.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e316 (70.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e51 (20.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e18 (15.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e14 (16.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e83 (18.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e19 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e4 (3.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e1 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e24 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003eClinical nodal stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e0.280\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e47 (19.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e25 (20.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e11 (13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e83 (18.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e100 (40.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e51 (42.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e43 (51.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e194 (43.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e87 (35.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e36 (30.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e21 (25.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e144 (32.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e13 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e8 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e8 (9.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e29 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003eClinical Stage, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e0.133\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003eI,IIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e49 (19.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e24 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e13 (15.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e86 (19.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003eIIB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e75 (30.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e41 (34.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e37 (44.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e153 (34.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003eIIIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e93 (37.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e43 (35.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e24 (28.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e160 (35.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003eIIIB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e17 (6.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e4 (3.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e1 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e22 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e\u0026nbsp; IIIC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e13 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e8 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e8 (9.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e29 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003eHistologic grade\u003csup\u003e*\u003c/sup\u003e, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e0.369\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e1\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e4 (2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e1 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e5 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e85 (47.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e53 (46.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e44 (55.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e182 (48.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e92 (50.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e61 (53.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e35 (43.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e188 (48.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003esTILs, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e20 (10-60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e20 (3-40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e10 (3-25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e20 (3-40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003esTILs\u003csup\u003e*\u003c/sup\u003e, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e\u0026lt;50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e120 (68.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e90 (78.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e67 (84.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e277 (75.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e\u0026ge;50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e56 (31.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e24 (21.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e12 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e92 (24.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003eSurgery type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e0.512\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003eLumpectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e137 (55.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e74 (61.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e49 (59.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e260 (57.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003eMastectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e110 (44.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e46 (38.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e34 (41.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e190 (42.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003e*\u003c/sup\u003eMissing values\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e-values were obtained with the Fisher\u0026rsquo;s exact test.\u003c/p\u003e\n\u003cp\u003esTILs, stromal tumor-infiltrating lymphocytes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eOdds ratio (OR) and 95% confidence interval (CI) for pathologic complete response\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ei\u003c/strong\u003e\u003cstrong\u003en 369 patients with available sTILs.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.131313131313131%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.42424242424242%\" colspan=\"3\"\u003e\n \u003cp\u003eUnivariable analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.44444444444444%\" colspan=\"4\"\u003e\n \u003cp\u003eMultivariable analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003eadjusted OR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e95% CI\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003e\u0026le; 50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003e\u0026gt; 50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.46-1.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\n \u003cp\u003e0.079\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.80\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.51-1.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.341\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003eHistologic grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\n \u003cp\u003e0.074\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.175\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e3.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.33-27.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\n \u003cp\u003e0.329\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e2.17\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.21-22.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.512\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e4.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.50-41.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\n \u003cp\u003e0.179\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e3.20\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.31-32.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.327\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003eClinical tumor stage\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\n \u003cp\u003e0.126\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.578\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.41-2.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\n \u003cp\u003e0.876\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.83\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.35-1.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.666\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.25-1.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\n \u003cp\u003e0.322\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.67\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.25-1.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.417\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.06-1.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\n \u003cp\u003e0.071\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.37\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.08-1.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.220\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003eClinical nodal stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.555\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e1.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.66-2.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\n \u003cp\u003e0.612\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.90\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.50-1.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.730\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.43-1.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\n \u003cp\u003e0.399\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.67\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.35-1.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.227\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.30-1.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\n \u003cp\u003e0.482\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.64\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.241.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.379\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003esTILs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003e\u0026lt; 50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003e\u0026ge;50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e1.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.79-2.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\n \u003cp\u003e0.322\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e1.60\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.95-2.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e0.079\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003eRegimen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003eNon-carboplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003eCarboplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e2.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e1.58-4.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e2.73\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e1.64-4.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003ePembrolizumab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e3.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e2.02-6.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e4.00\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e2.20-7.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.231638418079097%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"13.841807909604519%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"13.841807909604519%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.994350282485875%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"0.423728813559322%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"13.841807909604519%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"13.841807909604519%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"13.983050847457626%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003esTILs, stromal tumor-infiltrating lymphocytes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eOdds ratio (OR) and 95% confidence interval (CI) of treatment regimen for pathologic complete response stratified by stromal tumor-infiltrating lymphocytes.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.6530612244898%\" colspan=\"2\" rowspan=\"2\"\u003e\n \u003cp\u003eCohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.306122448979592%\" rowspan=\"2\"\u003e\n \u003cp\u003eRegimen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.04081632653061%\" colspan=\"3\"\u003e\n \u003cp\u003eMultivariable analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\"\u003e\n \u003cp\u003eadjusted OR\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.489795918367346%\" rowspan=\"6\"\u003e\n \u003cp\u003eAll patients with sTILs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.16326530612245%\" rowspan=\"3\"\u003e\n \u003cp\u003eLPBC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.306122448979592%\"\u003e\n \u003cp\u003eNon-carboplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.346938775510203%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.346938775510203%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"17.346938775510203%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.727272727272727%\"\u003e\n \u003cp\u003eCarboplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e1.01\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e0.31-3.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e0.986\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.727272727272727%\"\u003e\n \u003cp\u003ePembrolizumab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e6.40\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e1.09-37.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e0.040\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.81081081081081%\" rowspan=\"3\"\u003e\n \u003cp\u003eNon-LPBC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.27027027027027%\"\u003e\n \u003cp\u003eNon-carboplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.972972972972972%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.972972972972972%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"22.972972972972972%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.727272727272727%\"\u003e\n \u003cp\u003eCarboplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e4.09\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e2.24-7.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.727272727272727%\"\u003e\n \u003cp\u003ePembrolizumab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e4.47\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e2.30-8.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.6530612244898%\" colspan=\"2\" rowspan=\"2\"\u003e\n \u003cp\u003eCohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.306122448979592%\" rowspan=\"2\"\u003e\n \u003cp\u003eRegimen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.04081632653061%\" colspan=\"3\"\u003e\n \u003cp\u003eMultivariable analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\"\u003e\n \u003cp\u003eadjusted OR\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.489795918367346%\" rowspan=\"6\"\u003e\n \u003cp\u003ecN+ patients with sTILs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.16326530612245%\" rowspan=\"3\"\u003e\n \u003cp\u003eLPBC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.306122448979592%\"\u003e\n \u003cp\u003eNon-carboplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.346938775510203%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.346938775510203%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"17.346938775510203%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.727272727272727%\"\u003e\n \u003cp\u003eCarboplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e0.98\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e0.30-3.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e0.977\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.727272727272727%\"\u003e\n \u003cp\u003ePembrolizumab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e11.45\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e1.17-112.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e0.036\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.81081081081081%\" rowspan=\"3\"\u003e\n \u003cp\u003eNon-LPBC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.27027027027027%\"\u003e\n \u003cp\u003eNon-carboplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.972972972972972%\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.972972972972972%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"22.972972972972972%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.727272727272727%\"\u003e\n \u003cp\u003eCarboplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e4.36\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e2.17-8.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.727272727272727%\"\u003e\n \u003cp\u003ePembrolizumab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e3.94\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e1.91-8.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\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\u003cp\u003e\u003csup\u003e*\u003c/sup\u003eAdjusted for age (\u0026le;\u0026nbsp;50 vs. \u0026gt; 50), histologic grade (1 vs. 2 vs. 3), clinical tumor stage (1 vs. 2 vs. 3 vs. 4), and clinical nodal stage (0 vs. 1 vs. 2 vs. 3).\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003eAdjusted for age (\u0026le;\u0026nbsp;50 vs. \u0026gt; 50), histologic grade (1 vs. 2 vs. 3), clinical tumor stage (1 vs. 2 vs. 3 vs. 4), and clinical nodal stage (1 vs. 2 vs. 3).\u003c/p\u003e\n\u003cp\u003esTILs, stromal tumor-infiltrating lymphocytes; LPBC, lymphocyte-predominant breast cancer.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4342102/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4342102/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eImmunochemotherapy with pembrolizumab has been integrated into clinical practice as part of the standard-of-care for non-metastatic triple-negative breast cancer (TNBC) with high risk. We conducted a real-world study in TNBC patients treated with neoadjuvant chemotherapy to compare pathologic complete response (pCR) rates relative to stromal tumor-infiltrating lymphocytes (sTIL) across different regimens: non-carboplatin, carboplatin-, and pembrolizumab-chemotherapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe analyzed a cohort of 450 patients with TNBC who underwent surgery following neoadjuvant chemotherapy between March 2007 and February 2024. Treatment groups included 247 non-carboplatin, 120 carboplatin, and 83 pembrolizumab-chemotherapy recipients. sTIL was evaluated in biopsied samples. Lymphocyte-predominant breast cancer (LPBC) was defined as tumors with high sTIL (≥ 50%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe pCR rates were 32% in the non-carboplatin-, 57% in the carboplatin-, and 64% in the pembrolizumab-chemotherapy group. Ninety-two patients (20.4%) had LPBC. In LPBC, the pCR rates did not increase with the addition of carboplatin (50.0% in the non-carboplatin and 41.7% in carboplatin) but reached 83.3% with the addition of pembrolizumab and carboplatin. Among the non-LPBC, the pCR rate increased from 26.7% to 61.1% with the addition of carboplatin, but there was no difference in the pCR rate between the carboplatin and pembrolizumab groups (61.1% and 61.2%, respectively).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn LPBC patients, the addition of carboplatin did not result in an elevated pCR rate; however, the addition of pembrolizumab tended to raise the pCR rate. In non-LPBC, the addition of carboplatin significantly increased the pCR rate, while the addition of pembrolizumab did not have the same effect.\u003c/p\u003e","manuscriptTitle":"Stromal tumor-infiltrating lymphocytes and pathologic response to neoadjuvant chemotherapy with the addition of platinum and pembrolizumab in TNBC: A single-center real-world study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-07 19:13:17","doi":"10.21203/rs.3.rs-4342102/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c10cdeac-38e4-4548-a753-cd1f3cf1654e","owner":[],"postedDate":"May 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-02T15:49:33+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-07 19:13:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4342102","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4342102","identity":"rs-4342102","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}