Real-World Event-Free Survival and Real-World Pathological Complete Response in Early-Stage Triple-Negative Breast Cancer: Concordance with Estimates from the control arm of the KEYNOTE-522 Trial

Real-World Event-Free Survival and Real-World Pathological Complete Response in Early-Stage Triple-Negative Breast Cancer: Concordance with Estimates from the control arm of the KEYNOTE-522 Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Real-World Event-Free Survival and Real-World Pathological Complete Response in Early-Stage Triple-Negative Breast Cancer: Concordance with Estimates from the control arm of the KEYNOTE-522 Trial Carole R. Berini, Jessica K. Paulus, Malcolm Charles, Zhaohui Su, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8098549/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 : Clinical outcomes such as event-free survival (EFS) and pathological complete response (pCR) have the potential to support medical product development for early-stage breast cancer. Replicability of trial estimates for these endpoints in the real world is needed. Objective : To assess the concordance of real-world (RW) EFS and pCR for early-stage triple negative breast cancer (eTNBC) with estimates from the KEYNOTE-522 clinical trial control arm. Methods : This retrospective observational cohort study used electronic health record data from US community oncology practices within The US Oncology Network. The RW cohort was developed using eligibility criteria aligned with KEYNOTE-522, with eligibility determined at the date of neoadjuvant treatment initiation. Patients newly diagnosed with eTNBC between 1/1/2020 and 3/30/2022 were followed through 7/18/2023. To balance baseline characteristics between the RW and clinical trial populations, a matching-adjusted indirect comparison (MAIC) was implemented using inverse probability of treatment weighting (IPTW). Relative risks (RRs) for rwpCR and hazard ratios (HRs) for rwEFS were calculated, before and after MAIC-weighting. Results : A total of 311 patients in the RW cohort met eligibility criteria aligned with the KEYNOTE-522 clinical trial. The adjusted HR for rwEFS and RR for rwpCR were 1.00 (95% CI: 0.72, 1.38; p=0.980) and 0.96 (95% CI 0.80, 1.14; p=0.627), respectively. A sensitivity analysis for rwEFS that censored RW patients at the time of immunotherapy treatment gave consistent results. Conclusion : EFS and pCR were concordant between the RW cohort and the KEYNOTE-522 control arm. RW results can reflect clinical trial outcomes in a matched real-world population. These findings increase confidence in the replicability of early-stage trial estimates in RW settings. Biological sciences/Cancer Health sciences/Medical research Health sciences/Oncology Figures Figure 1 Figure 2 Figure 3 INTRODUCTION In oncology, primary endpoints used to evaluate therapy often include response rate (RR), overall survival (OS), and progression-free survival (PFS). 1 Previous studies evaluating the alignment between cancer progression endpoints from randomized controlled trials (RCT) and their real-world data (RWD) counterparts have focused on advanced-stage cancers, including non-small cell lung cancer, melanoma, breast cancer, and thyroid cancer. 2 – 4 With advances in therapy and better outcomes for patients, intermediate assessments of clinical outcomes for progression and recurrence are also needed in real-world (RW) settings. 2 This may be especially important in cancers with high survival rates, such as breast cancer, which in the United States has a 5-year relative survival of almost 92%. 5 Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer for which intermediate endpoints such as event-free survival (EFS) and pathological complete response (pCR) can provide timely insights into treatment outcomes. 6 For instance, in 2013, the FDA recognized the utility of pCR as an endpoint to support accelerated approval of therapy in breast cancer in neoadjuvant settings and released guidelines for its use in industry in July 2020. 7 Population-based studies have supported the use of pCR as a surrogate survival endpoint in real-world settings, especially in aggressive tumor subtypes such as triple-negative early breast cancer. 8 , 9 Nonetheless, the validity of pCR as a surrogate survival endpoint remains to be confirmed. 10 , 11 EFS has been identified by the FDA as a surrogate endpoint for OS, but its concordance with RW settings has not been evaluated. 12 , 13 The Phase 3 KEYNOTE-522 trial demonstrated that the addition of pembrolizumab to a carboplatin-based chemotherapy regimen significantly improved EFS and pCR for patients with early-stage TNBC. 14 , 15 Reliable early-stage real-world endpoints, such as rwEFS and rwpCR for breast cancer, can help bridge the gap between clinical trial efficacy and real-world effectiveness, accelerate product development, inform regulatory decisions and post-approval needs, and improve clinical practice. Studies are needed to evaluate the extent to which real-world endpoints can replicate RCT-based estimates, and to validate estimates generated using equivalent real-world definitions for specific trial endpoints. 2 , 4 None to date have reported replicability of these clinical endpoints among early-stage TNBC patients. This study adopted a trial emulation framework 16 – 19 to evaluate RW estimates of EFS and pCR in early-stage TNBC and compare them with published clinical trial results from the KEYNOTE-522 trial control arm as a benchmark. The goal of this study was to evaluate concordance between the RW and clinical trial findings to advance our understanding of data quality and readiness to support product development. METHODS Study Design This retrospective observational cohort study used iKnowMed® (iKM) EHR data from US community oncology practices within The US Oncology Network. The design followed seven key features of a trial emulation framework to establish eligibility, treatment strategy, assignment procedure, follow-up period, outcomes, causal contract, and analysis plan (Fig. 1 ). The US Oncology Network includes over 2,700 affiliated physicians operating in over 600 sites of care across states. Approximately 1.2 million US cancer patients are treated annually in The US Oncology Network. 20 In addition to the de-identified data available in structured fields, a custom chart abstraction was conducted to gather additional information about clinical trial-based eligibility criteria. The study was approved as exempt by the Castle IRB. Since this study is based on retrospective observational data along with published data, human consent to participate and a clinical trial number are not applicable. Population The real-world cohort was developed using eligibility criteria that aligned with the KEYNOTE-522 trial (Table 1 ). Eligibility was determined at the date of neoadjuvant treatment initiation (index date) to align with the trial’s randomization time point. Table 1 KEYNOTE-522 and Real-world Eligibility Criteria of Patients with eTNBC KEYNOTE-522 Trial Eligibility Criteria Corresponding Real-World Eligibility Criteria Inclusion criteria from KEYNOTE-522 Newly diagnosed, locally advanced, centrally confirmed TNBC, as defined by the most recent American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines. Documentation of all the following: - Pathology report available at the time of initial breast cancer diagnosis - Disease stage II or III at diagnosis - Negative results for biomarkers ER, PR, and HER2 Patients were ineligible if disease stage was IA, IB, I, IV for breast cancer during the study identification period. Previously untreated locally advanced non-metastatic (M0) TNBC defined as the following combined primary tumor (T) and regional lymph node (N) staging per current American Joint Committee of Cancer (AJCC) staging criteria for breast cancer as assessed by the investigator based on radiological and/or clinical assessment: • T1c, N1-N2 • T2, N0-N2 • T3, N0-N2 • T4a-d, N0-N2 Documentation of T1c, N1-N2, T2, N0-N2, T3, N0-N2 or T4a-d, N0-N2 closest to diagnosis. Core needle biopsy consisting of at least 2 separate tumor cores from the primary tumor at screening to the central laboratory. Not Applicable 1 Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 10 days of treatment initiation. Documentation of performance status ECOG (or Karnofsky converted to ECOG) score of 0 or 1 closest to index date. Adequate organ function. Not Applicable 1 Males and female participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 12 months after the last dose of study treatment for participants who have received cyclophosphamide, and 6 months after the last dose of study treatment for participants who did not. Not Applicable 1 Exclusion criteria from KEYNOTE-522 History of invasive malignancy ≤ 5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. Excluded patients diagnosed with or who received treatment for another primary cancer following initial diagnosis through the index date Received prior chemotherapy, targeted therapy, and radiation therapy within the past 12 months. Excluded patients who received systemic anticancer treatment or radiation for breast cancer within 12 months prior to index Received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti-programmed death - ligand 1 (anti-PD-L1), or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated antigen-4 [CTLA-4], OX-40, CD137 [tumor necrosis factor receptor superfamily member 9 (TNFRSF9)]) or previously participated in a pembrolizumab (MK-3475) clinical study. Excluded patients who received neo-adjuvant or adjuvant immunotherapy at any time before and including the index date Currently participating in or has participated in an interventional clinical study with an investigational compound or device within 4 weeks of the first dose of treatment in this current study. Excluded patients who participated in an interventional clinical trial following diagnosis and through index date Received a live vaccine within 30 days of the first dose of study treatment. Not Applicable 1 Active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Excluded patients with documentation of any of the following autoimmune diseases during the 2 years prior to index: rheumatoid arthritis, psoriasis, multiple sclerosis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosus, Hashimoto’s autoimmune thyroiditis, sarcoidosis, polymyalgia rheumatica, scleroderma, psoriatic arthritis, Sjogren’s syndrome, Guillain-Barre syndrome, Graves’ disease, Addison’s disease, Idiopathic thrombocytopenia, Myasthenia gravis, Ankylosing spondylitis Diagnosis of immunodeficiency or is receiving systemic steroid therapy (i.e., dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. Not Applicable 1 Known history of Human Immunodeficiency Virus (HIV). Excluded patients with documentation of AIDS/HIV within 6 months prior to or on index. Known active Hepatitis B or Hepatitis C. Excluded patients with documentation of hepatitis B or hepatitis C infection within 6 months prior to or on index. History of (non-infectious) pneumonitis that required steroids or current pneumonitis. Excluded patients with documentation of pneumonitis any time prior to index, on index date, or 30 days post index. Active infection requiring systemic therapy. Excluded patients with documentation of active infection requiring systemic therapy 30 days pre or post and including index. Significant cardiovascular disease, such as: history of myocardial infarction, acute coronary syndrome or coronary angioplasty/stenting/bypass grafting within the last 6 months OR congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA Class III or IV. Excluded patients with documentation of congestive heart failure (CHF), acute myocardial infarction (MI) or history of myocardial infarction within 6 months prior to or on index. Pregnant or breastfeeding or expecting to conceive children within the projected duration of the study, starting with the screening visit through 12 months after the last dose of study treatment for participants who have received cyclophosphamide, and for 6 months after the last dose of study treatment for participants who have not. Not Applicable 1 Known hypersensitivity to the components of the study treatment or its analogs. Not Applicable 1 Known history of active tuberculosis (TB, Bacillus Tuberculosis). Excluded patients with documentation of tuberculosis within 6 months prior to or on index 1 Not applicable to real-world settings as these are not reliably documented in the EHR. Eligible patients were ≥ 18 years and had received a diagnosis of HER2-negative disease with a pathology report available for the initial breast cancer diagnosis (Stage II-III). All patients were diagnosed during the study identification period, 1 January 2020 to 31 March 2022. Patients were excluded if they were diagnosed with or received treatment for another primary cancer before the study observation period, or if they participated in an interventional clinical trial before the study observation period (18 July 2023). Endpoints EFS was defined as the time interval from initiation of neoadjuvant therapy until the first of the following events: 1) progression of disease, if the patient did not have surgery for breast cancer before the end of follow-up, 2) locoregional or metastatic recurrence, 3) additional primary cancer diagnosis, or 4) death due to any cause. Additional criteria defining EFS are shown in Table 2 . Table 2 Real-World Elements to Define Pathologic Complete Response (pCR) and Event-Free Survival (EFS) Based on the KEYNOTE-522 Clinical Trial Definitions KEYNOTE-522 Endpoint Elements Corresponding Real-World Endpoint Elements pCR Time of definitive surgery Date of first surgery for breast cancer after initiation of neoadjuvant treatment (index date) (ypT0/Tis) No invasive cancer in the breast irrespective of ductal carcinoma in situ or nodal involvement following completion of neoadjuvant systemic therapy by the American Joint Committee on Cancer (AJCC) staging criteria (7th edition) assessed by the local pathologist at the time of definitive surgery. Documentation of pathological complete response with no documentation of residual tumor in breast (ypT0 ypN0) No residual invasive and in situ cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sample regional lymph nodes following completion of neoadjuvant systemic therapy by AJCC staging criteria (7th edition) assessed by the local pathologist at the time of definitive surgery. Documentation of pathological complete response with no documentation of residual tumor in breast and lymph nodes EFS Randomization date Initiation of neoadjuvant treatment (index date) Progression of disease that precludes definitive surgery Earliest date of documented disease progression or recurrence that occurs during neoadjuvant therapy and results in no surgery for breast cancer prior to the end of follow-up Date of progression of disease (Subjects who had locoregional progressive disease (PD) - as assessed radiologically during the neoadjuvant treatment phase, but underwent definitive surgery and had clear margins, will not be classified as having an EFS event. If the subject had pCR, then the PD will be considered pseudoprogression. Subjects who did not have PD during the neoadjuvant treatment phase, but had positive margins at their last surgery, will be classified as having an EFS event at surgery.) Date of documented disease progression If patients had surgery for breast cancer during the study observation period with no mention of positive margins, they were not classified as having an EFS event. If patients did not have disease progression during the study observation period but had resection with positive margins, they were classified as having an EFS event at the time of surgery. Local or distant recurrence (Subjects who had locoregional PD - as assessed radiologically - during the neoadjuvant treatment phase, but went to surgery and ended up with positive margins at their last surgery, will be classified as having an EFS event at the time of diagnosis of locoregional PD. Subjects who had distant PD (metastasis, confirmed by biopsy or 2 imaging studies at least 4 weeks apart, if a biopsy was not feasible) during the neoadjuvant treatment phase had an EFS event at the time of diagnosis of distant PD, even if the subjects had palliative breast surgery. Subjects who had cytological, histological, and/or radiological evidence of local or distant recurrence during the adjuvant phase had an EFS event at the time recurrence was diagnosed.) Date and type (locoregional or metastatic) of recurrence If patients had locoregional recurrence during the study observation period but underwent resection with positive margins, they were classified as having an EFS event at the time of diagnosis of locoregional recurrence. If patients had metastatic recurrence, they were classified as having an EFS event. Date of surgery Date of surgery Margins Extent of surgical resection (complete resection with no mention of positive margins, resection with positive margins, not documented) Second primary malignancy Record of diagnosis and/or treatment for another primary cancer and date. Death due to any cause Date of death due to any cause pCR was met if there was no evidence of tumor in the resected specimen following initiation of neoadjuvant therapy. Timing of surgery was defined as the first surgery for breast cancer after initiation of neoadjuvant treatment. While documentation of residual tumor was assessed by a local pathologist for the clinical trial, in the RWD, this criterion relied on physician documentation within the patients' charts. Additional criteria defining pCR are shown in Table 2 . KEYNOTE-522 Data EFS data for the control arm of KEYNOTE-522 were extracted from the published paper 14 using digitizing methods 21 , 22 and Web Plot Digitizer 23 . pCR results from the first interim analysis of KEYNOTE-522 control arm 15 were used to assess concordance with the RW population, as this was the prespecified time point to statistically evaluate pCR in the clinical trial. Patients in the control arm of KEYNOTE-522 received neoadjuvant placebo plus chemotherapy. After definitive surgery, they received adjuvant placebo plus chemotherapy. EFS Unadjusted and MAIC-adjusted Kaplan-Meier (KM) curves were produced for the control arm of the trial and the RW cohort. Since KEYNOTE-522 followed an intention-to-treat (ITT) approach, this was used as the primary analysis. For this analysis, patients were censored at the time of an event, death, or the end of the study period. An as-treated (AT) analysis was also conducted in which patients were censored when they initiated immunotherapy to further align the real-world treatment journey for eligible patients with that of trial control arm. Unadjusted and MAIC-adjusted hazard ratios (HRs), 95% confidence intervals (CIs), and p-values were calculated using Cox modeling, with the trial control arm as the reference group. pCR Relative risks (RRs) were calculated from a generalized linear model with a log-link function and a binomial distribution. As pCR is a proportion, it was analyzed using generalized linear models with a log link function and a binomial distribution. Risk ratios (RRs), 95% CIs, and p-values were reported, with the trial comparator arm as the reference group. Statistical Analysis To balance the clinical trial and RW patient populations on available baseline characteristics, a matching adjusted indirect comparison (MAIC) was implemented (Signorovitch 2010 & 2012), which adjusted for age group, sex, race, ethnicity, and ECOG score. As individual patient data were not available for KEYNOTE-522, the average treatment effect on the treated (ATT) was estimated. 24 Concordance between the estimates from the control arm of KEYNOTE-522 and RW endpoints was assessed by: (1) visually describing outcomes in each population using Kaplan Meier curves, (2) comparing outcomes by study design using Cox proportional hazard models and generalized linear models, setting the KEYNOTE-522 control arm as the reference group, to generate effect estimates, and their associated 95% CIs and p values. RESULTS Baseline Characteristics A total of 311 patients met RW eligibility criteria aligned with the KEYNOTE-522 clinical trial. Compared to the KEYNOTE-522 control arm, patients in the RW cohort were older (24% were aged ≥ 65 years vs. 12%) and included a greater proportion of patients with stage III (45% vs. 25%) and ECOG ≥ 1 (41% vs. 13%). After MAIC adjustment, the baseline characteristics of the RW cohort were similar to the KEYNOTE-522 control arm (Table 3 ). Table 3 Baseline Characteristics of the KEYNOTE-522 Control Arm and Real-World Cohort Variable KEYNOTE-522 control arm (N = 390) Unadjusted RW Cohort (N = 311) MAIC-Adjusted RW Cohort (N = 311) Age group (years), N (%) <65 342 (88%) 237 (76%) 88.4% ≥65 48 (12%) 74 (24%) 11.6% Race, N (%) White/Caucasian 242 (62%) 184 (59%) 68.2% Other 117 (30%) 86 (28%) 22.5% Not documented 31 (8%) 41 (13%) 9.3% Ethnicity, N (%) Hispanic 39 (10%) 24 (8%) 7.7% Not Hispanic 307 (79%) 43 (14%) 80.1% Not documented 44 (11%) 244 (78%) 12.2% Clinical Cancer Stage at Initial Diagnosis, N (%) Stage I, Stage II 292 (75%) 173 (56%) 77.5% Stage III 98 (25%) 138 (44%) 22.5% ECOG, N (%) 0 341 (87%) 185 (59%) 88.4% 1 49 (13%) 126 (41%) 11.6% Endpoint Concordance Concordance was achieved between the rw cohort and the KEYNOTE-522 control arm in all analyses, with the strongest concordance achieved after MAIC adjustment and in the ITT analysis. EFS Figure 2 shows the unadjusted and MAIC-adjusted Kaplan-Meier EFS curves for both the ITT and AT analyses. In the primary (ITT) analysis of EFS, the unadjusted and MAIC-adjusted HRs were 0.84 (95% CI 0.62, 1.16; p = 0.289) and 1.00 (95% CI 0.72, 1.38; p = 0.980), respectively. Median follow-up time in the ITT analysis was 24.6 months. In the AT analysis, the unadjusted and MAIC-adjusted HRs were 0.86 (95% CI 0.61, 1.21; p = 0.387) and 1.02 (95% CI 0.72, 1.44; p = 0.918), respectively. Median follow-up time in the AT analysis was 19.8 months. pCR For pCR, the unadjusted and MAIC-adjusted RRs were 0.88 (95% CI: 0.73, 1.05; p = 0.156) and 0.96 (95% CI: 0.80, 1.14; p = 0.627), respectively (Table 4 ). Table 4 Unadjusted and MAIC-Adjusted Estimates of Pathologic Complete Response (pCR) Pathologic Complete Response (pCR) Total N Number of events Unadjusted Risk Ratio 95% Confidence Interval p-value MAIC-Adjusted Risk Ratio 95% Confidence Interval p-value KEYNOTE-522 (reference) 201 103 0.88 0.73, 1.05 0.1559 0.96 0.80, 1.14 0.627 Real-world Cohort 301* 135 *10 patients did not have recorded pCR results and were excluded from this analysis A forest plot illustrating the unadjusted and MAIC-adjusted estimates for pCR and EFS is provided in Fig. 3 . It shows how confounding is statistically adjusted through MAIC for both endpoints, as well as the impact of the sensitivity analysis (intention-to-treat vs. as-treated approach) for EFS. DISCUSSION This study of real-world data from community oncology demonstrated that, with the application of the trial emulation framework, real-world endpoints can approximate clinical trial estimates in eTNBC patients in a matching population. The current findings increase confidence in the reliability and replicability of rwEFS and rwpCR in eTNBC. After applying eligibility criteria that aligned with the KEYNOTE-522 clinical trial, real-world patients were slightly older, with marginally higher disease burden and lower performance status. This points to the greater heterogeneity of patients in the RW setting. Other studies have also observed that patients in community settings are generally older, more racially diverse, and from lower socioeconomic status than those enrolled in cancer clinical trials. 25 – 29 The greater heterogeneity of patients in RW practice highlights the importance of estimating clinical outcomes in this setting in addition to estimates from RCTs. MAIC adjustment improved the balance of baseline characteristics across the clinical trial and RW populations. Median observed follow-up was shorter in the ITT analysis of EFS compared to the AT analysis (24.6 months versus 19.8 months) as patients who received subsequent IO therapy in the adjuvant setting were censored. Nonetheless, the AT analysis did not appreciably change the survival estimates, suggesting that censoring was non-informative, and that receipt of IO was not confounded by disease progression and did not distort the RW survival estimates. In KEYNOTE-522, median EFS was not reached 14 , and pCR was 51.2% in the control arm 15 . These results are comparable to those of the BrighTNess, NeoSTOP, and CALGB40603 clinical trials, supporting the choice of KEYNOTE-522 as a benchmark trial for evaluating the concordance of real-world endpoints in TNBC. 30 – 32 The replication of early-stage cancer endpoints using RW evidence is a rapidly evolving area of research to better understand treatment effectiveness outside the clinical trial setting. 33 Despite guidance from the Food and Drug Administration (FDA) and other regulatory bodies, as well as ongoing initiatives to validate RW response from groups such as Friends of Cancer Research, no consensus exists on the specific methods for demonstrating concordance with trial endpoints in RW settings. 34 – 36 This study used a trial emulation framework to ensure a robust methodological approach, minimizing potential sources of bias. 37 , 38 Previous studies have replicated clinical trial results for late-stage endpoints with mixed results. For instance, Ton et al. showed that overall survival can be replicated with RWD in NSCLC. 4 Chesang et al. broadly emulated survival outcomes from a prostate cancer trial and highlighted challenges like the timing of treatment. 39 Tan et al . identified variability in endpoint concordance, emphasizing the importance of analytic decisions. 40 The current study is among the first to contribute to the validation of rwEFS and rwpCR in early-stage TNBC. Reliable early-stage endpoints are needed for timely, actionable insights into treatment effectiveness. Limitations Although a trial emulation framework and MAIC adjustment address confounding by balancing baseline characteristics between the RW cohort and clinical trial arm, adjustment was limited to data available for both populations, and residual and unmeasured confounding may remain. For example, based on KEYNOTE-522 reporting, ten potential confounders were available for adjustment. BMI, BRCA status, and Ki-67 expression are potential confounders that could not be included in the MAIC. Nonetheless, the impact of the MAIC adjustments was relatively small on the unadjusted versus adjusted hazard ratios and risk ratios, indicating that residual confounding may be minimal, so that their impact on endpoint estimates is likely minor. This study may be limited by differences in the timing of assessments, particularly as the RW cohort was not evaluated on a fixed schedule, as patients in the trial were. Misclassification bias is possible as the study used iKM EHR data, which are collected for clinical practice and subject to missingness and coding errors. This may introduce some level of misclassification of diagnoses, events, or procedures of interest in the study. Likewise, some variables of interest may not be complete across the entire population. For instance, patients missing key matching variables were not included in the RW cohort (e.g., ECOG was poorly documented, and patients missing ECOG performance status were excluded). Finally, results from this study may be most generalizable to other community oncology practices and those using the iKM EHR, as data collection varies across health systems. Conclusion Real-world endpoints rwEFS and rwpCR for eTNBC are concordant with clinical trial estimates when key study design aspects are aligned and high-quality EHR data are leveraged. These findings increase confidence in the replicability of trial estimates in a matched RW population for clinical decision-making. Declarations AUTHOR CONTRIBUTIONS All authors (CB, JP, MC, ZS, PC, JRE, AH, KD) made substantial contributions to the conception and design of the study. MC and ZS performed statistical analyses. All authors (CB, JP, MC, ZS, PC, JRE, AH, KD) participated in the interpretation of results and reviewed and approved the final manuscript. FUNDING This study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. COMPETING INTERESTS All authors declare no financial or non-financial competing interests. DATA AND CODE AVAILABILITY The datasets generated and analyzed during the current study are not publicly available as they are subject to a contractual agreement with Ontada. This is legally required in order to safeguard patient information and follow compliance rules under HIPAA. The underlying code for this study is not publicly available for proprietary reasons. References Delgado, A. & Guddati, A. K. Clinical endpoints in oncology - a primer. Am J Cancer Res 11 , 1121-1131 (2021). Griffith, S. D. et al. 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Annals of Oncology 33 , 384-394 (2022). https://doi.org/10.1016/j.annonc.2022.01.009 Sharma, P. et al. Randomized Phase II Trial of Anthracycline-free and Anthracycline-containing Neoadjuvant Carboplatin Chemotherapy Regimens in Stage I-III Triple-negative Breast Cancer (NeoSTOP). Clinical cancer research : an official journal of the American Association for Cancer Research 27 , 975-982 (2021). https://doi.org/10.1158/1078-0432.ccr-20-3646 Sikov, W. M. et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 33 , 13-21 (2015). https://doi.org/10.1200/jco.2014.57.0572 McKelvey, B. A. et al. Evaluation of Real-World Tumor Response Derived From Electronic Health Record Data Sources: A Feasibility Analysis in Patients With Metastatic Non–Small Cell Lung Cancer Treated With Chemotherapy. JCO clinical cancer informatics , e2400091 (2024). https://doi.org/10.1200/cci.24.00091 (FDA), U. S. F. a. D. A. Real-World Data: Assessing Electronic Health Records and Medical Claims Data To Support Regulatory Decision-Making for Drug and Biological Products , (2024). Firends of Cancer Research. What is the best approach for evaluating real-world data to generate real-world evidence to identify drugs that benefit patients? , ( Purpura, C. A., Garry, E. M., Honig, N., Case, A. & Rassen, J. A. The Role of Real-World Evidence in FDA-Approved New Drug and Biologics License Applications. Clinical pharmacology and therapeutics 111 , 135-144 (2022). https://doi.org/10.1002/cpt.2474 Fu, E. L. Target Trial Emulation to Improve Causal Inference from Observational Data: What, Why, and How? J Am Soc Nephrol 34 , 1305-1314 (2023). https://doi.org/10.1681/asn.0000000000000152 Gini, R. et al. Describing diversity of real world data sources in pharmacoepidemiologic studies: The DIVERSE scoping review. Pharmacoepidemiology and Drug Safety 33 , e5787 (2024). https://doi.org/https://doi.org/10.1002/pds.5787 Chesang, C. et al. Emulating an existing trial of treatments for prostate cancer using real-world data: challenges and lessons learned. Journal of clinical epidemiology 182 , 111767 (2025). https://doi.org/10.1016/j.jclinepi.2025.111767 Tan, K. et al. Emulating Control Arms for Cancer Clinical Trials Using External Cohorts Created From Electronic Health Record-Derived Real-World Data. Clinical pharmacology and therapeutics 111 , 168-178 (2022). https://doi.org/10.1002/cpt.2351 Additional Declarations No competing interests reported. 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1","display":"","copyAsset":false,"role":"figure","size":198423,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy Design following steps from a trial emulation framework\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8098549/v1/26ebbb95510518be502498aa.png"},{"id":97127504,"identity":"aa8c45fa-54b6-429d-9f03-0a6a862cb627","added_by":"auto","created_at":"2025-12-01 08:30:01","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":72185,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier Curves of Event-Free Survival for the KEYNOTE-522 Control Arm and RW Cohort\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8098549/v1/891a8e1f25cc5b63b96b5b32.png"},{"id":97142493,"identity":"9b2d1339-c845-45cf-bba3-c7f64b2eda49","added_by":"auto","created_at":"2025-12-01 10:07:38","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":46855,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest Plot of Endpoints Comparing the Real-World Cohort and KEYNOTE-522 Control Arm\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8098549/v1/766bc9f9c907c756e6f394ec.png"},{"id":99313911,"identity":"9d6ba224-d69d-4050-aeec-9206b7f5b608","added_by":"auto","created_at":"2025-12-31 16:20:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1395704,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8098549/v1/db201253-7eff-4de8-a013-9bb8029c9e84.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eReal-World Event-Free Survival and Real-World Pathological Complete Response in Early-Stage Triple-Negative Breast Cancer: Concordance with Estimates from the control arm of the KEYNOTE-522 Trial\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eIn oncology, primary endpoints used to evaluate therapy often include response rate (RR), overall survival (OS), and progression-free survival (PFS).\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Previous studies evaluating the alignment between cancer progression endpoints from randomized controlled trials (RCT) and their real-world data (RWD) counterparts have focused on advanced-stage cancers, including non-small cell lung cancer, melanoma, breast cancer, and thyroid cancer.\u003csup\u003e\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e With advances in therapy and better outcomes for patients, intermediate assessments of clinical outcomes for progression and recurrence are also needed in real-world (RW) settings.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e This may be especially important in cancers with high survival rates, such as breast cancer, which in the United States has a 5-year relative survival of almost 92%.\u003csup\u003e5\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eTriple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer for which intermediate endpoints such as event-free survival (EFS) and pathological complete response (pCR) can provide timely insights into treatment outcomes.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e For instance, in 2013, the FDA recognized the utility of pCR as an endpoint to support accelerated approval of therapy in breast cancer in neoadjuvant settings and released guidelines for its use in industry in July 2020.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Population-based studies have supported the use of pCR as a surrogate survival endpoint in real-world settings, especially in aggressive tumor subtypes such as triple-negative early breast cancer.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Nonetheless, the validity of pCR as a surrogate survival endpoint remains to be confirmed.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e EFS has been identified by the FDA as a surrogate endpoint for OS, but its concordance with RW settings has not been evaluated.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e The Phase 3 KEYNOTE-522 trial demonstrated that the addition of pembrolizumab to a carboplatin-based chemotherapy regimen significantly improved EFS and pCR for patients with early-stage TNBC.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eReliable early-stage real-world endpoints, such as rwEFS and rwpCR for breast cancer, can help bridge the gap between clinical trial efficacy and real-world effectiveness, accelerate product development, inform regulatory decisions and post-approval needs, and improve clinical practice. Studies are needed to evaluate the extent to which real-world endpoints can replicate RCT-based estimates, and to validate estimates generated using equivalent real-world definitions for specific trial endpoints.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e None to date have reported replicability of these clinical endpoints among early-stage TNBC patients. This study adopted a trial emulation framework\u003csup\u003e\u003cspan additionalcitationids=\"CR17 CR18\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e to evaluate RW estimates of EFS and pCR in early-stage TNBC and compare them with published clinical trial results from the KEYNOTE-522 trial control arm as a benchmark. The goal of this study was to evaluate concordance between the RW and clinical trial findings to advance our understanding of data quality and readiness to support product development.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy Design\u003c/h2\u003e\u003cp\u003eThis retrospective observational cohort study used iKnowMed\u0026reg; (iKM) EHR data from US community oncology practices within The US Oncology Network. The design followed seven key features of a trial emulation framework to establish eligibility, treatment strategy, assignment procedure, follow-up period, outcomes, causal contract, and analysis plan (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe US Oncology Network includes over 2,700 affiliated physicians operating in over 600 sites of care across states. Approximately 1.2\u0026nbsp;million US cancer patients are treated annually in The US Oncology Network.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e In addition to the de-identified data available in structured fields, a custom chart abstraction was conducted to gather additional information about clinical trial-based eligibility criteria. The study was approved as exempt by the Castle IRB. Since this study is based on retrospective observational data along with published data, human consent to participate and a clinical trial number are not applicable.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003ePopulation\u003c/h3\u003e\n\u003cp\u003eThe real-world cohort was developed using eligibility criteria that aligned with the KEYNOTE-522 trial (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Eligibility was determined at the date of neoadjuvant treatment initiation (index date) to align with the trial\u0026rsquo;s randomization time point.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eKEYNOTE-522 and Real-world Eligibility Criteria of Patients with eTNBC\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKEYNOTE-522 Trial\u003c/p\u003e\u003cp\u003eEligibility Criteria\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCorresponding Real-World\u003c/p\u003e\u003cp\u003eEligibility Criteria\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eInclusion criteria from KEYNOTE-522\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNewly diagnosed, locally advanced, centrally confirmed TNBC, as defined by the most recent American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDocumentation of all the following:\u003c/p\u003e\u003cp\u003e- Pathology report available at the time of initial breast cancer diagnosis\u003c/p\u003e\u003cp\u003e- Disease stage II or III at diagnosis\u003c/p\u003e\u003cp\u003e- Negative results for biomarkers ER, PR, and HER2\u003c/p\u003e\u003cp\u003ePatients were ineligible if disease stage was IA, IB, I, IV for breast cancer during the study identification period.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePreviously untreated locally advanced non-metastatic (M0) TNBC defined as the following combined primary tumor (T) and regional lymph node (N) staging per current American Joint Committee of Cancer (AJCC) staging criteria for breast cancer as assessed by the investigator based on radiological and/or clinical assessment:\u003c/p\u003e\u003cp\u003e\u0026bull; T1c, N1-N2\u003c/p\u003e\u003cp\u003e\u0026bull; T2, N0-N2\u003c/p\u003e\u003cp\u003e\u0026bull; T3, N0-N2\u003c/p\u003e\u003cp\u003e\u0026bull; T4a-d, N0-N2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDocumentation of T1c, N1-N2, T2, N0-N2, T3, N0-N2 or T4a-d, N0-N2 closest to diagnosis.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCore needle biopsy consisting of at least 2 separate tumor cores from the primary tumor at screening to the central laboratory.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNot Applicable\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 10 days of treatment initiation.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDocumentation of performance status ECOG (or Karnofsky converted to ECOG) score of 0 or 1 closest to index date.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdequate organ function.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNot Applicable\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMales and female participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 12 months after the last dose of study treatment for participants who have received cyclophosphamide, and 6 months after the last dose of study treatment for participants who did not.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNot Applicable\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eExclusion criteria from KEYNOTE-522\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHistory of invasive malignancy\u0026thinsp;\u0026le;\u0026thinsp;5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eExcluded patients diagnosed with or who received treatment for another primary cancer following initial diagnosis through the index date\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReceived prior chemotherapy, targeted therapy, and radiation therapy within the past 12 months.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eExcluded patients who received systemic anticancer treatment or radiation for breast cancer within 12 months prior to index\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReceived prior therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti-programmed death - ligand 1 (anti-PD-L1), or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated antigen-4 [CTLA-4], OX-40, CD137 [tumor necrosis factor receptor superfamily member 9 (TNFRSF9)]) or previously participated in a pembrolizumab (MK-3475) clinical study.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eExcluded patients who received neo-adjuvant or adjuvant immunotherapy at any time before and including the index date\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCurrently participating in or has participated in an interventional clinical study with an investigational compound or device within 4 weeks of the first dose of treatment in this current study.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eExcluded patients who participated in an interventional clinical trial following diagnosis and through index date\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReceived a live vaccine within 30 days of the first dose of study treatment.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNot Applicable\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eActive autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs).\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eExcluded patients with documentation of any of the following autoimmune diseases during the 2 years prior to index: rheumatoid arthritis, psoriasis, multiple sclerosis, Crohn\u0026rsquo;s disease, ulcerative colitis, systemic lupus erythematosus, Hashimoto\u0026rsquo;s autoimmune thyroiditis, sarcoidosis, polymyalgia rheumatica, scleroderma, psoriatic arthritis, Sjogren\u0026rsquo;s syndrome, Guillain-Barre syndrome, Graves\u0026rsquo; disease, Addison\u0026rsquo;s disease, Idiopathic thrombocytopenia, Myasthenia gravis, Ankylosing spondylitis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiagnosis of immunodeficiency or is receiving systemic steroid therapy (i.e., dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNot Applicable\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKnown history of Human Immunodeficiency Virus (HIV).\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eExcluded patients with documentation of AIDS/HIV within 6 months prior to or on index.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKnown active Hepatitis B or Hepatitis C.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eExcluded patients with documentation of hepatitis B or hepatitis C infection within 6 months prior to or on index.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHistory of (non-infectious) pneumonitis that required steroids or current pneumonitis.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eExcluded patients with documentation of pneumonitis any time prior to index, on index date, or 30 days post index.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eActive infection requiring systemic therapy.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eExcluded patients with documentation of active infection requiring systemic therapy 30 days pre or post and including index.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSignificant cardiovascular disease, such as: history of myocardial infarction, acute coronary syndrome or coronary angioplasty/stenting/bypass grafting within the last 6 months OR congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA Class III or IV.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eExcluded patients with documentation of congestive heart failure (CHF), acute myocardial infarction (MI) or history of myocardial infarction within 6 months prior to or on index.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePregnant or breastfeeding or expecting to conceive children within the projected duration of the study, starting with the screening visit through 12 months after the last dose of study treatment for participants who have received cyclophosphamide, and for 6 months after the last dose of study treatment for participants who have not.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNot Applicable\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKnown hypersensitivity to the components of the study treatment or its analogs.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNot Applicable\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKnown history of active tuberculosis (TB, Bacillus Tuberculosis).\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eExcluded patients with documentation of tuberculosis within 6 months prior to or on index\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003csup\u003e1\u003c/sup\u003eNot applicable to real-world settings as these are not reliably documented in the EHR.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eEligible patients were \u0026ge;\u0026thinsp;18 years and had received a diagnosis of HER2-negative disease with a pathology report available for the initial breast cancer diagnosis (Stage II-III). All patients were diagnosed during the study identification period, 1 January 2020 to 31 March 2022.\u003c/p\u003e\u003cp\u003ePatients were excluded if they were diagnosed with or received treatment for another primary cancer before the study observation period, or if they participated in an interventional clinical trial before the study observation period (18 July 2023).\u003c/p\u003e\n\u003ch3\u003eEndpoints\u003c/h3\u003e\n\u003cp\u003eEFS was defined as the time interval from initiation of neoadjuvant therapy until the first of the following events: 1) progression of disease, if the patient did not have surgery for breast cancer before the end of follow-up, 2) locoregional or metastatic recurrence, 3) additional primary cancer diagnosis, or 4) death due to any cause. Additional criteria defining EFS are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eReal-World Elements to Define Pathologic Complete Response (pCR) and Event-Free Survival (EFS) Based on the KEYNOTE-522 Clinical Trial Definitions\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKEYNOTE-522 Endpoint Elements\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCorresponding Real-World Endpoint Elements\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003epCR\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTime of definitive surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDate of first surgery for breast cancer after initiation of neoadjuvant treatment (index date)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e(ypT0/Tis) No invasive cancer in the breast irrespective of ductal carcinoma in situ or nodal involvement following completion of neoadjuvant systemic therapy by the American Joint Committee on Cancer (AJCC) staging criteria (7th edition) assessed by the local pathologist at the time of definitive surgery.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDocumentation of pathological complete response with no documentation of residual tumor in breast\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e(ypT0 ypN0) No residual invasive and in situ cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sample regional lymph nodes following completion of neoadjuvant systemic therapy by AJCC staging criteria (7th edition) assessed by the local pathologist at the time of definitive surgery.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDocumentation of pathological complete response with no documentation of residual tumor in breast and lymph nodes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eEFS\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRandomization date\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eInitiation of neoadjuvant treatment (index date)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProgression of disease that precludes definitive surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEarliest date of documented disease progression or recurrence that occurs during neoadjuvant therapy and results in no surgery for breast cancer prior to the end of follow-up\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDate of progression of disease (Subjects who had locoregional progressive disease (PD) - as assessed radiologically during the neoadjuvant treatment phase, but underwent definitive surgery and had clear margins, will not be classified as having an EFS event. If the subject had pCR, then the PD will be considered pseudoprogression. Subjects who did not have PD during the neoadjuvant treatment phase, but had positive margins at their last surgery, will be classified as having an EFS event at surgery.)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDate of documented disease progression\u003c/p\u003e\u003cp\u003eIf patients had surgery for breast cancer during the study observation period with no mention of positive margins, they were not classified as having an EFS event.\u003c/p\u003e\u003cp\u003eIf patients did not have disease progression during the study observation period but had resection with positive margins, they were classified as having an EFS event at the time of surgery.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLocal or distant recurrence (Subjects who had locoregional PD - as assessed radiologically - during the neoadjuvant treatment phase, but went to surgery and ended up with positive margins at their last surgery, will be classified as having an EFS event at the time of diagnosis of locoregional PD. Subjects who had distant PD (metastasis, confirmed by biopsy or 2 imaging studies at least 4 weeks apart, if a biopsy was not feasible) during the neoadjuvant treatment phase had an EFS event at the time of diagnosis of distant PD, even if the subjects had palliative breast surgery. Subjects who had cytological, histological, and/or radiological evidence of local or distant recurrence during the adjuvant phase had an EFS event at the time recurrence was diagnosed.)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDate and type (locoregional or metastatic) of recurrence\u003c/p\u003e\u003cp\u003eIf patients had locoregional recurrence during the study observation period but underwent resection with positive margins, they were classified as having an EFS event at the time of diagnosis of locoregional recurrence.\u003c/p\u003e\u003cp\u003eIf patients had metastatic recurrence, they were classified as having an EFS event.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDate of surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDate of surgery\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMargins\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eExtent of surgical resection (complete resection with no mention of positive margins, resection with positive margins, not documented)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSecond primary malignancy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRecord of diagnosis and/or treatment for another primary cancer and date.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDeath due to any cause\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDate of death due to any cause\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003epCR was met if there was no evidence of tumor in the resected specimen following initiation of neoadjuvant therapy. Timing of surgery was defined as the first surgery for breast cancer after initiation of neoadjuvant treatment. While documentation of residual tumor was assessed by a local pathologist for the clinical trial, in the RWD, this criterion relied on physician documentation within the patients' charts. Additional criteria defining pCR are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003ch3\u003eKEYNOTE-522 Data\u003c/h3\u003e\n\u003cp\u003eEFS data for the control arm of KEYNOTE-522 were extracted from the published paper\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e using digitizing methods\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e and Web Plot Digitizer\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. pCR results from the first interim analysis of KEYNOTE-522 control arm\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e were used to assess concordance with the RW population, as this was the prespecified time point to statistically evaluate pCR in the clinical trial.\u003c/p\u003e\u003cp\u003ePatients in the control arm of KEYNOTE-522 received neoadjuvant placebo plus chemotherapy. After definitive surgery, they received adjuvant placebo plus chemotherapy.\u003c/p\u003e\n\u003ch3\u003eEFS\u003c/h3\u003e\n\u003cp\u003eUnadjusted and MAIC-adjusted Kaplan-Meier (KM) curves were produced for the control arm of the trial and the RW cohort. Since KEYNOTE-522 followed an intention-to-treat (ITT) approach, this was used as the primary analysis. For this analysis, patients were censored at the time of an event, death, or the end of the study period. An as-treated (AT) analysis was also conducted in which patients were censored when they initiated immunotherapy to further align the real-world treatment journey for eligible patients with that of trial control arm. Unadjusted and MAIC-adjusted hazard ratios (HRs), 95% confidence intervals (CIs), and p-values were calculated using Cox modeling, with the trial control arm as the reference group.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003epCR\u003c/h2\u003e\u003cp\u003eRelative risks (RRs) were calculated from a generalized linear model with a log-link function and a binomial distribution. As pCR is a proportion, it was analyzed using generalized linear models with a log link function and a binomial distribution. Risk ratios (RRs), 95% CIs, and p-values were reported, with the trial comparator arm as the reference group.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eTo balance the clinical trial and RW patient populations on available baseline characteristics, a matching adjusted indirect comparison (MAIC) was implemented (Signorovitch 2010 \u0026amp; 2012), which adjusted for age group, sex, race, ethnicity, and ECOG score. As individual patient data were not available for KEYNOTE-522, the average treatment effect on the treated (ATT) was estimated.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eConcordance between the estimates from the control arm of KEYNOTE-522 and RW endpoints was assessed by: (1) visually describing outcomes in each population using Kaplan Meier curves, (2) comparing outcomes by study design using Cox proportional hazard models and generalized linear models, setting the KEYNOTE-522 control arm as the reference group, to generate effect estimates, and their associated 95% CIs and p values.\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eBaseline Characteristics\u003c/h2\u003e\n \u003cp\u003eA total of 311 patients met RW eligibility criteria aligned with the KEYNOTE-522 clinical trial. Compared to the KEYNOTE-522 control arm, patients in the RW cohort were older (24% were aged\u0026thinsp;\u0026ge;\u0026thinsp;65 years vs. 12%) and included a greater proportion of patients with stage III (45% vs. 25%) and ECOG\u0026thinsp;\u0026ge;\u0026thinsp;1 (41% vs. 13%). After MAIC adjustment, the baseline characteristics of the RW cohort were similar to the KEYNOTE-522 control arm (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline Characteristics of the KEYNOTE-522 Control Arm and Real-World Cohort\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eKEYNOTE-522 control arm (N\u0026thinsp;=\u0026thinsp;390)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eUnadjusted RW Cohort\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;311)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMAIC-Adjusted RW Cohort\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;311)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eAge group (years), N (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e342 (88%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e237 (76%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e88.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e48 (12%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e74 (24%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.6%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eRace, N (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWhite/Caucasian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e242 (62%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e184 (59%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68.2%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOther\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e117 (30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e86 (28%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot documented\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31 (8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eEthnicity, N (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHispanic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot Hispanic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e307 (79%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e80.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot documented\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44 (11%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e244 (78%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.2%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical Cancer Stage at Initial Diagnosis, N (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStage I, Stage II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e292 (75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e173 (56%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e77.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStage III\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e98 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e138 (44%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eECOG, N (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e341 (87%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e185 (59%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e88.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e126 (41%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.6%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eEndpoint Concordance\u003c/h2\u003e\n \u003cp\u003eConcordance was achieved between the rw cohort and the KEYNOTE-522 control arm in all analyses, with the strongest concordance achieved after MAIC adjustment and in the ITT analysis.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003eEFS\u003c/h2\u003e\n \u003cp\u003eFigure 2 shows the unadjusted and MAIC-adjusted Kaplan-Meier EFS curves for both the ITT and AT analyses.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n \u003cp\u003eIn the primary (ITT) analysis of EFS, the unadjusted and MAIC-adjusted HRs were 0.84 (95% CI 0.62, 1.16; p\u0026thinsp;=\u0026thinsp;0.289) and 1.00 (95% CI 0.72, 1.38; p\u0026thinsp;=\u0026thinsp;0.980), respectively. Median follow-up time in the ITT analysis was 24.6 months. In the AT analysis, the unadjusted and MAIC-adjusted HRs were 0.86 (95% CI 0.61, 1.21; p\u0026thinsp;=\u0026thinsp;0.387) and 1.02 (95% CI 0.72, 1.44; p\u0026thinsp;=\u0026thinsp;0.918), respectively. Median follow-up time in the AT analysis was 19.8 months.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\n \u003ch2\u003epCR\u003c/h2\u003e\n \u003cp\u003eFor pCR, the unadjusted and MAIC-adjusted RRs were 0.88 (95% CI: 0.73, 1.05; p\u0026thinsp;=\u0026thinsp;0.156) and 0.96 (95% CI: 0.80, 1.14; p\u0026thinsp;=\u0026thinsp;0.627), respectively (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eUnadjusted and MAIC-Adjusted Estimates of Pathologic Complete Response (pCR)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePathologic Complete Response (pCR)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal N\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNumber of events\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eUnadjusted Risk Ratio\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95% Confidence Interval\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMAIC-Adjusted Risk Ratio\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95% Confidence Interval\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKEYNOTE-522 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e201\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e103\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" rowspan=\"2\"\u003e\n \u003cp\u003e0.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" rowspan=\"2\"\u003e\n \u003cp\u003e0.73, 1.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" rowspan=\"2\"\u003e\n \u003cp\u003e0.1559\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" rowspan=\"2\"\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" rowspan=\"2\"\u003e\n \u003cp\u003e0.80, 1.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" rowspan=\"2\"\u003e\n \u003cp\u003e0.627\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReal-world Cohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e301*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e135\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\"\u003e*10 patients did not have recorded pCR results and were excluded from this analysis\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eA forest plot illustrating the unadjusted and MAIC-adjusted estimates for pCR and EFS is provided in Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\n \u003cp\u003eIt shows how confounding is statistically adjusted through MAIC for both endpoints, as well as the impact of the sensitivity analysis (intention-to-treat vs. as-treated approach) for EFS.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis study of real-world data from community oncology demonstrated that, with the application of the trial emulation framework, real-world endpoints can approximate clinical trial estimates in eTNBC patients in a matching population. The current findings increase confidence in the reliability and replicability of rwEFS and rwpCR in eTNBC.\u003c/p\u003e\u003cp\u003eAfter applying eligibility criteria that aligned with the KEYNOTE-522 clinical trial, real-world patients were slightly older, with marginally higher disease burden and lower performance status. This points to the greater heterogeneity of patients in the RW setting. Other studies have also observed that patients in community settings are generally older, more racially diverse, and from lower socioeconomic status than those enrolled in cancer clinical trials.\u003csup\u003e\u003cspan additionalcitationids=\"CR26 CR27 CR28\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e The greater heterogeneity of patients in RW practice highlights the importance of estimating clinical outcomes in this setting in addition to estimates from RCTs.\u003c/p\u003e\u003cp\u003eMAIC adjustment improved the balance of baseline characteristics across the clinical trial and RW populations. Median observed follow-up was shorter in the ITT analysis of EFS compared to the AT analysis (24.6 months versus 19.8 months) as patients who received subsequent IO therapy in the adjuvant setting were censored. Nonetheless, the AT analysis did not appreciably change the survival estimates, suggesting that censoring was non-informative, and that receipt of IO was not confounded by disease progression and did not distort the RW survival estimates.\u003c/p\u003e\u003cp\u003eIn KEYNOTE-522, median EFS was not reached\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, and pCR was 51.2% in the control arm\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. These results are comparable to those of the BrighTNess, NeoSTOP, and CALGB40603 clinical trials, supporting the choice of KEYNOTE-522 as a benchmark trial for evaluating the concordance of real-world endpoints in TNBC.\u003csup\u003e\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThe replication of early-stage cancer endpoints using RW evidence is a rapidly evolving area of research to better understand treatment effectiveness outside the clinical trial setting.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e Despite guidance from the Food and Drug Administration (FDA) and other regulatory bodies, as well as ongoing initiatives to validate RW response from groups such as Friends of Cancer Research, no consensus exists on the specific methods for demonstrating concordance with trial endpoints in RW settings.\u003csup\u003e\u003cspan additionalcitationids=\"CR35\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e This study used a trial emulation framework to ensure a robust methodological approach, minimizing potential sources of bias.\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003ePrevious studies have replicated clinical trial results for late-stage endpoints with mixed results. For instance, Ton \u003cem\u003eet al.\u003c/em\u003e showed that overall survival can be replicated with RWD in NSCLC.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Chesang \u003cem\u003eet al.\u003c/em\u003e broadly emulated survival outcomes from a prostate cancer trial and highlighted challenges like the timing of treatment.\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e Tan \u003cem\u003eet al\u003c/em\u003e. identified variability in endpoint concordance, emphasizing the importance of analytic decisions. \u003csup\u003e40\u003c/sup\u003e The current study is among the first to contribute to the validation of rwEFS and rwpCR in early-stage TNBC. Reliable early-stage endpoints are needed for timely, actionable insights into treatment effectiveness.\u003c/p\u003e\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\u003ch2\u003eLimitations\u003c/h2\u003e\u003cp\u003eAlthough a trial emulation framework and MAIC adjustment address confounding by balancing baseline characteristics between the RW cohort and clinical trial arm, adjustment was limited to data available for both populations, and residual and unmeasured confounding may remain. For example, based on KEYNOTE-522 reporting, ten potential confounders were available for adjustment. BMI, BRCA status, and Ki-67 expression are potential confounders that could not be included in the MAIC. Nonetheless, the impact of the MAIC adjustments was relatively small on the unadjusted versus adjusted hazard ratios and risk ratios, indicating that residual confounding may be minimal, so that their impact on endpoint estimates is likely minor.\u003c/p\u003e\u003cp\u003eThis study may be limited by differences in the timing of assessments, particularly as the RW cohort was not evaluated on a fixed schedule, as patients in the trial were. Misclassification bias is possible as the study used iKM EHR data, which are collected for clinical practice and subject to missingness and coding errors. This may introduce some level of misclassification of diagnoses, events, or procedures of interest in the study. Likewise, some variables of interest may not be complete across the entire population. For instance, patients missing key matching variables were not included in the RW cohort (e.g., ECOG was poorly documented, and patients missing ECOG performance status were excluded).\u003c/p\u003e\u003cp\u003eFinally, results from this study may be most generalizable to other community oncology practices and those using the iKM EHR, as data collection varies across health systems.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eReal-world endpoints rwEFS and rwpCR for eTNBC are concordant with clinical trial estimates when key study design aspects are aligned and high-quality EHR data are leveraged. These findings increase confidence in the replicability of trial estimates in a matched RW population for clinical decision-making.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors (CB, JP, MC, ZS, PC, JRE, AH, KD) made substantial contributions to the conception and design of the study. MC and ZS performed statistical analyses. All authors (CB, JP, MC, ZS, PC, JRE, AH, KD) participated in the interpretation of results and reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by Merck Sharp \u0026amp; Dohme LLC, a subsidiary of Merck \u0026amp; Co., Inc., Rahway, NJ, USA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOMPETING INTERESTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no financial or non-financial competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AND CODE AVAILABILITY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analyzed during the current study are not publicly available as they are subject to a contractual agreement with Ontada. This is legally required in order to safeguard patient information and follow compliance rules under HIPAA. The underlying code for this study is not publicly available for proprietary reasons.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDelgado, A. \u0026amp; Guddati, A. K. Clinical endpoints in oncology - a primer. \u003cem\u003eAm J Cancer Res\u003c/em\u003e \u003cstrong\u003e11\u003c/strong\u003e, 1121-1131 (2021).\u003c/li\u003e\n\u003cli\u003eGriffith, S. 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Replicability of trial estimates for these endpoints in the real world is needed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e: To assess the concordance of real-world (RW) EFS and pCR for early-stage triple negative breast cancer (eTNBC) with estimates from the KEYNOTE-522 clinical trial control arm.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: This retrospective observational cohort study used electronic health record data from US community oncology practices within The US Oncology Network. The RW cohort was developed using eligibility criteria aligned with KEYNOTE-522, with eligibility determined at the date of neoadjuvant treatment initiation. Patients newly diagnosed with eTNBC between 1/1/2020 and 3/30/2022 were followed through 7/18/2023. To balance baseline characteristics between the RW and clinical trial populations, a matching-adjusted indirect comparison (MAIC) was implemented using inverse probability of treatment weighting (IPTW). Relative risks (RRs) for rwpCR and hazard ratios (HRs) for rwEFS were calculated, before and after MAIC-weighting.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: A total of 311 patients in the RW cohort met eligibility criteria aligned with the KEYNOTE-522 clinical trial. The adjusted HR for rwEFS and RR for rwpCR were 1.00 (95% CI: 0.72, 1.38; p=0.980) and 0.96 (95% CI 0.80, 1.14; p=0.627), respectively. A sensitivity analysis for rwEFS that censored RW patients at the time of immunotherapy treatment gave consistent results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: EFS and pCR were concordant between the RW cohort and the KEYNOTE-522 control arm. RW results can reflect clinical trial outcomes in a matched real-world population. These findings increase confidence in the replicability of early-stage trial estimates in RW settings.\u003c/p\u003e","manuscriptTitle":"Real-World Event-Free Survival and Real-World Pathological Complete Response in Early-Stage Triple-Negative Breast Cancer: Concordance with Estimates from the control arm of the KEYNOTE-522 Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-01 08:29:56","doi":"10.21203/rs.3.rs-8098549/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":"f23151ca-ca30-498f-bf8c-ffbf5620f2dd","owner":[],"postedDate":"December 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":58773602,"name":"Biological sciences/Cancer"},{"id":58773603,"name":"Health sciences/Medical research"},{"id":58773604,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2025-12-26T14:23:58+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-01 08:29:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8098549","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8098549","identity":"rs-8098549","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}