TPS619 Background: Adjuvant ET is the standard of care (SOC) for treating ER+/HER2- eBC. Despite advances to optimize adjuvant treatment in high-risk ER+/HER2- eBC, there continues to be a risk of local and metastatic (incurable) recurrence that persists, and new therapies with desirable safety profiles are warranted. Elacestrant is a next-generation oral SERD that provides a novel mechanism of action that has shown both SERD (degradative) and SERM (partial agonist) activity that differs from currently available adjuvant ET (Wardell, ERC 2015). In the EMERALD trial, elacestrant significantly prolonged PFS vs SOC ET in the overall population (HR 0.70; 95% CI 0.55-0.88; P=0.0018) and in patients with ESR1 -mut tumors (HR 0.55; 95% CI 0.39-0.77; P=0.0005) (Bidard, JCO 2022). In patients with ESR1 -mut tumors who received prior ET+CDK4/6i ≥12 mo, mPFS with elacestrant was 8.6 vs 1.9 mo with SOC ET (Bardia, CCR 2024). In a preoperative, window of opportunity ER+/HER2- eBC trial (SOLTI-1905-ELIPSE), elacestrant was associated with complete cell cycle arrest (defined as Ki67<2.7%) rate of 27% and a statistically significant mean change from baseline, shifting tumor biology toward a more endocrine-sensitive and less proliferative tumor phenotype (Vidal, CCR 2025). Given that elacestrant demonstrated efficacy in mBC regardless of ESR1 -mut status relative to SOC ET and has shown biologic activity in eBC, it is hypothesized that elacestrant can prolong invasive breast cancer-free survival (IBCFS) in patients with high-risk eBC who received prior adjuvant ET±CDK4/6i. Methods: ELEGANT (NCT06492616) is a global, multicenter, open-label phase 3 study designed to evaluate elacestrant vs SOC ET (AI or tamoxifen) in patients with eBC and a high risk of recurrence. Patients will be randomized 1:1 to continue SOC ET or to elacestrant for a duration of 5 yrs. Eligible patients are women or men with ER+/HER2− node-positive eBC who have completed 24-60 mo of adjuvant ET±CDK4/6i and have ECOG PS ≤1. Patients who received a prior CDK4/6i or a PARP inhibitor must have already completed or discontinued these treatments. Pre/perimenopausal women and men will be administered a LHRH agonist. Exclusion criteria include inflammatory breast cancer, history of prior invasive breast cancer, and >6 mo continuous interruption of prior SOC adjuvant ET or discontinuation of adjuvant ET >6 mo prior to randomization. The primary endpoint is IBCFS. Key secondary endpoints include distant relapse-free survival, overall survival, invasive disease-free survival, safety, patient-reported outcomes-quality of life, and pharmacokinetics. Status: Planned enrollment is 4,220 patients; recruitment is ongoing. Clinical trial information: NCT06492616 .

Importance:Molecular analyses of biospecimens collected from study participants are essential for identifying biomarkers that can tailor treatments to specific subsets of patients who are most likely to benefit. Sharing of data and biospecimens from clinical trials enables personalized, patient-centric use of cancer therapies and accelerates the development of new treatments. Objective:To describe obstacles to sharing data and biospecimens and to propose strategies to enhance access and collaboration. Evidence Review:This is a Special Communication authored by 53 academic investigators and patient representatives from the breast cancer community with extensive experience in conducting clinical and translational research. The article also evaluates the impact of biomarker research on specifying responsive subpopulations in the 29 registrational clinical trials that have led to approval of a new drug for treatment of breast cancer between 2017 and 2024. Findings:Clinical trial participants are increasingly asked to provide tissue and/or body fluid biospecimens for biomarker research that is typically controlled by the sponsoring pharmaceutical company, but published biomarker studies are rare. Among 29 breast cancer registrational studies reported in the past 8 years, none resulted in biomarker research that restricted a drug's approved indication. Herein, strategies to maximize the value of clinical data and biospecimens contributed by participants are proposed, thereby supporting the shared goals of the pharmaceutical industry and academia to improve patient care. These strategies include (1) establishing coleadership structures involving academia and patients in clinical trial design and conduct, (2) ensuring that informed consent forms state that data and biospecimens will be shared with academia for future research, (3) requiring the sharing of clinical data as a condition for regulatory approval, and (4) enabling access to biospecimens and translational research data for independent studies on biomarkers that may indicate drug efficacy and toxicity. Conclusions and Relevance:Data and biospecimen sharing from registrational trials has been suboptimal. Improving clinical data, biospecimens, and biospecimens' related data sharing requires concrete actions and a multidimensional stakeholder approach to accelerate the impact of clinical cancer research on the quality of patient care.

BACKGROUND:Stromal tumour-infiltrating lymphocytes (sTILs) are prognostic in early-stage HER2-positive breast cancer, but their role in the context of dual HER2 blockade remains undefined. We evaluated manual, digital, and artificial intelligence (AI)-based sTIL quantification, together with AI-derived spatial metrics, for prognostic and treatment-benefit stratification using tumour samples from the phase 3 APHINITY trial. METHODS:In the APHINITY trial, 4805 patients were randomly assigned to receive chemotherapy plus trastuzumab with pertuzumab or chemotherapy plus trastuzumab with placebo. Median follow-up was 74·1 months (IQR 68·3-75·4). We analysed 4262 haematoxylin and eosin-stained images using manual assessment, an automated digital approach, AI-based lymphocyte quantification (AI percentage lymphocytes), and two AI-derived spatial features (AI-TIL and immune hotspot). Interobserver reproducibility was assessed in 262 randomly chosen tumour samples scored independently by five pathologists. Multivariable Cox models were used to assess associations between TIL levels and invasive disease-free survival (primary outcome in APHINITY), distant recurrence-free interval, and overall survival. The heterogeneity of pertuzumab benefit was evaluated using subgroup analyses, subpopulation treatment effect pattern plot analyses, and nested Cox models with treatment-by-biomarker interaction terms. FINDINGS:Manual scoring showed high interobserver reproducibility (intraclass correlation coefficient 0·84 [95% CI 0·79-0·88]). Concordance between manual and automated methods was modest. AI-based scoring (AI percentage lymphocytes) reclassified 120 (11·6%) of 1035 node-positive tumours from immune-low (by manual scoring) to immune-high; this subgroup of patients showed greater separation of 5-year invasive disease-free survival curves between pertuzumab and placebo groups compared with patients whose tumours were concordantly classified as immune-low by both manual and AI-based approaches. Higher levels of TILs were associated with improved invasive disease-free survival for all sTIL measurement approaches and spatial measurements (hazard ratios [HRs] 0·41-0·93). Pertuzumab was associated with improved invasive disease-free survival at higher sTIL levels across all measurement approaches (HRs 0·36-0·48), but was not associated with higher values of spatial measures. The largest 6-year absolute improvements with pertuzumab were observed in patients with node-positive disease whose tumours scored in the highest level of immune infiltration of manual sTIL scoring (≥70·0%; mean absolute improvement 12·1 percentage points [SD 2·8]). In nested prognostic and predictive models, AI-based immune hotspot scores provided the most consistent additional information when combined with any sTIL measurement (all p<0·010). INTERPRETATION:Standardised manual sTIL scoring was reproducible, and digital and AI-based methods showed consistent prognostic stratification and potential for treatment-benefit stratification despite only modest correlation between platforms. AI spatial metrics provided complementary information beyond sTIL density and could support more scalable immune assessment. Future studies are needed to validate these approaches in independent cohorts and to clarify their clinical utility for stratifying contemporary HER2-directed therapies. FUNDING:None.

BACKGROUND:Responses to anti-HER2 therapy can vary based on estrogen receptor expression and HER2 gene amplification. This study assessed the magnitude of benefit by adding pertuzumab to trastuzumab and chemotherapy by estrogen receptor and HER2 levels in the APHINITY trial. METHODS:APHINITY (ClinicalTrials.gov identifier NCT01358877; BIG 4-11) was a randomized, double-blind, phase 3 trial comparing pertuzumab with placebo added to adjuvant trastuzumab and chemotherapy in 4804 patients with HER2-positive early breast cancer. The primary endpoint of this exploratory analysis was invasive disease-free survival (IDFS). Subgroup analyses used Cox models across 4 groups defined by HER2 fluorescence in situ hybridization (FISH) ratio and estrogen receptor status, adjusted for treatment arm, chemotherapy regimen, and a combined variable of nodal status and protocol version. Tumors with a FISH ratio below 2 were excluded, leaving 4782 evaluable cases. The HER2 FISH ratio was classified as low (2 to <5) or high (≥5) and estrogen receptor expression by immunohistochemistry as negative or positive using 1% and 10% cutoffs. IDFS, HER2 FISH ratio, and estrogen receptor expression were also analyzed by intrinsic molecular subtype. RESULTS:All subgroups benefited from pertuzumab, with the largest benefit in HER2 FISH-low/estrogen receptor-positive tumors (hazard ratio = 0.70, 95% CI = 0.51 to 0.95). Other subgroups showed smaller benefits, with HER2 FISH-high/estrogen receptor-negative tumors having the least numerical improvement (hazard ratio = 0.85, 95% CI = 0.59 to 1.25). No statistically significant IDFS differences were observed between HER2-enriched and non-HER2-enriched tumors. CONCLUSIONS:Pertuzumab improved IDFS in all subgroups, with the greatest improvement in HER2 FISH-low/estrogen receptor-positive tumors. These exploratory findings are hypothesis generating and support prospective validation of biomarker-guided strategies. TRIAL REGISTRATION:ClinicalTrials.gov identifier NCT01358877.

Background:Annual surveillance mammograms for an unspecified period, after treatment for early breast cancer, are widely practised in the United States of America and Europe. Current UK guidelines recommend annual mammograms for 5 years, then reverts to 3-yearly screening. The aim of this trial was to evaluate whether less than annual mammography was non-inferior in terms of breast cancer-specific survival and cost-effectiveness in women aged 50 years or older at diagnosis and 3 years post curative surgery. Methods:We conducted a multicentre, randomised phase III trial of annual mammography versus less-frequent mammography (2-yearly after conservation surgery or 3-yearly after mastectomy). Women were eligible if aged ≥ 50 years at initial diagnosis of breast cancer (invasive or ductal carcinoma in situ) and recurrence-free 3 years post curative surgery. The trial was conducted at 114 NHS hospitals in the UK. Participants were randomly assigned (1 : 1) to annual or less-frequent mammograms; followed up for 6 years. Coprimary outcomes were breast cancer-specific-survival and cost-effectiveness; secondary outcomes included recurrence-free interval and overall survival. Analyses were by intention to treat, with a pre-planned per-protocol analysis. Planned sample size was 5000. Clinical results are now reported. Results:Five thousand two hundred and thirty-five women were randomised between April 2014 and September 2018. With a median of 5.7-year follow-up, 343 women have died, of whom 116 died of breast cancer (61 on annual arm; 55 on less-frequent arm). Breast cancer-specific-survival at 5 years was 98% on both arms with a hazard ratio of 0.92 (95% confidence interval 0.64 to 1.32), which demonstrated non-inferiority of less-frequent mammograms at the 3% margin (non-inferiority p < 0.0001) and the 1% margin (non-inferiority p = 0.003). Non-inferiority was demonstrated at the 2% level for both recurrence-free interval [hazard ratio 1.00 (95% confidence interval 0.83 to 1.28); non-inferiority p = 0.0024] and overall survival [hazard ratio 1.07 (95% confidence interval 0.87 to 1.33); non-inferiority p = 0.008]. Less-frequent mammograms were associated with a significant cost saving (mean difference £544, 95% confidence interval -£1116 to £26), heavily driven by mammogram costs. Incorporating societal costs resulted in a larger cost-saving (£1543 per person, 95% confidence interval -£2416 to -£669), increasing cost-effectiveness. There was no impact of less-frequent mammograms on patients' quality of life. Conclusion:For patients aged ≥ 50 years and 3 years post diagnosis, less-frequent mammograms were non-inferior and cost-effective compared with annual mammograms, with no detriment to patients' quality of life. Mammo-50 provides evidence to inform guideline development. Limitations:Adherence to the mammographic schedules was 76%, though the per-protocol analysis showed no difference compared to the intention to treat results. The majority of the participants had small lower-grade oestrogen receptor-positive tumours and were from a White ethnic group. Future work:More research is needed for women with ductal carcinoma in situ; women aged under 50 years old at diagnosis and different ethnic groups, especially those women of Black ethnicity who tend to present younger. Funding:This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 11/25/03.

Abstract Introduction: Pathological complete response (pCR) is a strong prognostic marker, but survival outcomes comparing treatment to control do not reliably align with treatment-control differences in pCR rates in breast cancer. A novel Bayesian hierarchical framework models treatments within trials, allowing us to predict treatment effects on distant recurrence-free survival (DRFS) from pCR with greater accuracy. Methods: We analyzed 12 neoadjuvant breast cancer trials (6,000 patients, all HR/HER2 subtypes; including I-SPY2). The framework of Burzykowski, Molenberghs & Buyse (2005) is extended to a novel arm-based hierarchical structure providing a distribution of pCR and DRFS treatment effects controlling for subtype (HR/HER2), N and T stage, grade, and calendar year. Three held-out trials (877 patients; 26 regimens; med follow-up >4 years) validate predictions of DRFS treatment benefit from pCR. All data was used to estimate treatment-effect correlation and the surrogate threshold effect (STE). Analyses were repeated for Residual Cancer Burden Index (binary RCB01, continuous RCB). Results: Predicted probability of DRFS benefit closely matched actual DRFS follow-up (mean absolute error 0.06; Pearson r = 0.9). Across all trials, pCR showed moderate surrogacy (ρ = 0.82, R2 = 0.67). A 60% increase in pCR odds achieves ≥95% probability of DRFS benefit (STE = OR of 1.60). RCB outperforms pCR across all metrics, with 92% sensitivity and 93% specificity for detecting DRFS benefit in 26 validation regimens (Table 1). Conclusion: This novel Bayesian meta-analytic framework reveals that pCR, RCB01 and continuous RCB reliably predict survival benefit across heterogeneous trials, with RCB performing the best in an external validation. This provides a statistical foundation for accelerated approval decisions using robust early biomarkers in modern neoadjuvant trial designs by accurately predicting survival at the treatment arm level. Citation Format: Keli S. Santos-Parker, Jessica R. Santos-Parker, W. Fraser Symmans, Laura J. Esserman, Christina Yau, Angie DeMichele, Laura van't Veer, Doug Yee, Fabien Reyal, Helena Earl, Jean Abraham, David Cameron, Peter Hall, Judy Boughey, Matthew Goetz, Gabe Sonke, Miguel Martín, Sara López-Tarruella, Priyanka Sharma, Rachel Freiberg, Jane Perlmutter, Aditya Bardia, Martin Eklund, Rachel Freiberg, Lajos Pusztai. A novel statistical framework for surrogate endpoint prediction of survival in neoadjuvant breast cancer trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1401.

Early-career investigators face growing challenges: dwindling public funding, limited trial leadership opportunities, systemic mentorship barriers, and widening global disparities. At the 20th Breast International Group (BIG) – NCI National Clinical Trials Network (NCTN) annual meeting, four key themes emerged: funding, mentorship, clinical trials, and translational research. This report outlines recommendations for funding and mentorship. Investment in this area is strategic to ensure continued advances for patients globally.

PURPOSE:Gene fusions are molecular rearrangements with oncogenic potential. However, their role in disease progression and therapy resistance remains largely unexplored, particularly in breast cancer. EXPERIMENTAL DESIGN:In this study, we utilized multiomics data from the AURORA program to characterize gene fusions in metastatic breast cancer. We analyzed RNA sequencing data from 325 primary tumors and 350 metastatic lesions across 476 patients to develop a high-confidence catalog of gene fusions. RESULTS:In a subset of 398 matched samples from 199 patients, we observed a higher burden of gene fusions in metastatic tumors compared with their corresponding primary tumors. Metastatic-specific (acquired) gene fusions were characterized by few recurrent rearrangements and were generally absent in patients with de novo metastatic disease. We observed a colocalization of gene fusions with subtype-specific copy-number gains. Various scores indicative of genomic instability were found to be associated with the gene fusion burden. Fusions involving genes located within the same topologically associating domain (TAD) were common in HER2-positive tumors and frequently acquired in metastatic triple-negative breast cancer. The presence of gene fusions, particularly those that were acquired or involved in genes within the same TAD, was associated with poor prognosis in estrogen receptor-positive/HER2-negative tumors. Patients with acquired ESR1 fusions exhibited a more aggressive disease course, characterized by shorter treatment response and poorer clinical outcomes. CONCLUSIONS:The AURORA gene fusion catalog may serve as a valuable resource for identifying targetable genetic alterations, thereby supporting the development of more effective therapeutic strategies for breast cancer.

Involving those with a lived experience of the relevant condition in the design of clinical research ensures that studies address real-world needs and priorities, enabling more relevant, ethical, and impactful outcomes. In 2019, the Breast International Group (BIG) established the BIG Patient Partnership to facilitate the meaningful involvement of people affected by breast cancer in the design and conduct of its studies. The members provide a strong international patient voice in academic breast cancer research. The partnership is based on 4 pillars: foundational and ongoing training, meaningful and systematic involvement, patients as a strategic driving force in BIG’s research, and promoting the value of the patients’ voice in research. In this paper, we describe a model to enable performing transnational clinical research for and with patient partners. We hope to inspire organizations and people who are burdened by cancer from different cultural backgrounds to develop an interactive, engaging, and empowering process for researchers and patient partners to work together.

BACKGROUND:The role of postmastectomy chest-wall irradiation in patients with breast cancer classified as pN1 (with involvement of one to three axillary nodes) or pN0 (pathologically node negative) with additional risk factors is uncertain. METHODS:In this international, phase 3, randomized trial, we evaluated the omission of chest-wall irradiation in women with "intermediate-risk" breast cancer - defined as cancer that was stage pT1N1, pT2N1, or pT3N0 or stage pT2N0 with a histologic grade of 3, lymphovascular invasion, or both (tumor size: T1, ≤2 cm; T2, >2 cm to 5 cm; or T3, >5 cm) - that was treated with mastectomy, an axillary procedure, and systemic therapy. Patients were assigned to undergo chest-wall irradiation (40 to 50 Gy; the irradiation group) or not to undergo chest-wall irradiation (the no-irradiation group). The primary end point was overall survival, with 10 years of follow-up. Chest-wall recurrence, regional recurrence, disease-free survival, distant metastasis-free survival, causes of death, and radiation-related adverse events were also assessed. RESULTS:The intention-to-treat population included 808 patients in the irradiation group and 799 in the no-irradiation group. The median follow up was 9.6 years. Overall survival was 81.4% with chest-wall irradiation and 81.9% with no chest-wall irradiation according to 10-year Kaplan-Meier estimates (hazard ratio for death, 1.04; 95% confidence interval [CI], 0.82 to 1.30; P = 0.80). A total of 29 patients had a chest-wall recurrence - 9 (1.1%) in the irradiation group and 20 (2.5%) in the no-irradiation group (between-group difference, <2 percentage points; hazard ratio, 0.45; 95% CI, 0.20 to 0.99). Disease-free survival was 76.2% in the irradiation group and 75.5% in the no-irradiation group (hazard ratio for recurrence or death, 0.97; 95% CI, 0.79 to 1.18), and distant metastasis-free survival was 78.2% and 79.2%, respectively (hazard ratio for distant metastasis or death, 1.06; 95% CI, 0.86 to 1.31). CONCLUSIONS:In this trial, chest-wall irradiation did not result in higher overall survival than no chest-wall irradiation among patients with intermediate-risk, early breast cancer treated with mastectomy and contemporary adjuvant systemic therapy. (Funded by the Medical Research Council and others; SUPREMO ISRCTN Clinical Study Registry number, 61145589.).

Low-dose radiotherapy had historically been used to treat both bacterial and viral pneumonias. In the present day, this is not in use due to the development of antibiotics and other supportive measures as well as a concern regarding late radiation toxicities. COVID-19 presented us with a novel respiratory illness without a strong evidence-based best practice; it was thought, therefore, that there may be a role for low-dose radiotherapy in the absence or failure of a standard treatment. The rationale for this was based around the ability of low-dose radiation to reduce an inflammatory state. We treated two individuals suffering from severe COVID-19 with low-dose whole lung radiotherapy, in the setting of a phase I trial. Both patients improved clinically, biochemically, and radiologically within a matter of days. We discuss why the meta-analyses may not have shown this advantage.

Background The frequency of mammographic surveillance for women after diagnosis of breast cancer varies globally. The aim of this study was to evaluate whether less than annual mammography was non-inferior in terms of breast cancer-specific survival in women aged 50 years or older. Methods Mammo-50 was a multicentre, randomised, phase 3 trial of annual versus less frequent mammography (2-yearly after conservation surgery; 3-yearly after a mastectomy) for women aged 50 years or older at initial diagnosis of invasive or non-invasive breast cancer and who were recurrence free 3 years post curative surgery. The trial was conducted at 114 National Health Service hospitals in the UK. Participants were randomly assigned (1:1) to annual or less frequent mammograms at 3 years post curative surgery and were followed up for 6 years. The co-primary outcomes were breast cancer-specific survival and cost-effectiveness. The cost-effectiveness analysis will be reported elsewhere. Breast cancer-specific survival was assessed in the intention-to-treat population. Secondary outcomes were recurrence-free interval, overall survival, and referrals back to the hospital system. 5000 women provided 90% power to detect a 3% absolute non-inferiority margin for breast cancer-specific survival with 25% one-sided significance. The trial was registered with the ISRCTN registry, ISRCTN48534559; recruitment is complete but longer-term followup is ongoing. Findings Between April 22, 2014, and Sept 28, 2018, 5235 women were randomly assigned to annual mammography (n=2618) or less frequent mammography (n=2617). 3858 (736%) women were aged 60 years or older, 4202 (803%) had undergone conservation surgery, 4576 (874%) had invasive disease, 1159 (221%) had node positive disease, and 4330 (827%) had oestrogen receptor-positive tumours. With a median of 57 years follow-up (IQR 50-60; 87 years post curative surgery), 343 women died, including 116 who died of breast cancer (61 in the annual mammography group and 55 in the less frequent mammography group). 5-year breast cancer-specific survival was 981% (95% CI 975-986) in the annual mammography group and 983% (978-988) in the less frequent mammography group (hazard ratio 092, 95% CI 064-132), demonstrating non-inferiority of less frequent mammography at the pre- specified 3% margin (non-inferiority p<00001). 5-year recurrence-free interval was 941% (95% CI 931-949) in the annual mammography group and 945% (935-953) in the less frequent mammography group. Overall survival at 5 years was 947% (95% CI 938-955%) and 945% (935-953), respectively. 224 (649%) of 345 breast cancer events were detected from emergency admissions or symptomatic referrals back to the hospital system, including 108 (617%) of 175 in the annual mammography group and 116 (682%) of 170 in the less frequent mammography group. Interpretation For patients aged 50 years or older and at 3 years post diagnosis, less frequent mammograms were non-inferior compared with annual mammograms for breast cancer-specific survival, recurrence-free interval, and overall survival, and should be considered for this population.

Importance Triple-negative breast cancer is an aggressive subtype with a high incidence in young patients, a high incidence in non-Hispanic Black women, and a high risk of progression to metastatic cancer, a devastating sequela with a 12- to 18-month life expectancy. Until recently, one strategy for treating early-stage triple-negative breast cancer was chemotherapy after surgery. However, it was not known whether the addition of immune therapy to postsurgery chemotherapy would be beneficial. Objective To evaluate the addition of immune therapy in the form of atezolizumab to postoperative chemotherapy in patients with the high-risk triple-negative breast cancer subtype. Design, Setting, and Participants In this open-label international randomized phase 3 trial conducted in more than 330 centers in 31 countries, patients undergoing surgery as initial treatment for stage II or III triple-negative breast cancer were enrolled between August 2, 2018, and November 11, 2022. The last patient follow-up was on August 18, 2023. Interventions Patients were randomized (1:1) to receive standard chemotherapy for 20 weeks with (n = 1101) or without (n = 1098) the immune therapy drug atezolizumab for up to 1 year. Main Outcomes and Measures The primary end point was invasive disease-free survival (time between randomization and invasive breast cancer in the same or opposite breast, recurrence elsewhere in the body, or death from any cause). Results The median age of enrolled patients was 53 years and most self-reported as being of Asian or White race and neither Latino nor Hispanic ethnicity. The study independent data monitoring committee halted enrollment at 2199 of 2300 planned patients. All patients stopped atezolizumab following a planned early interim and futility analysis. The trial continued to a premature final analysis. With invasive disease-free survival events in 141 patients (12.8%) treated with atezolizumab-chemotherapy and 125 (11.4%) with chemotherapy alone (median follow-up, 32 months), the final stratified invasive disease-free survival hazard ratio was 1.11 (95% CI, 0.87-1.42; P = .38). Compared with chemotherapy alone, the regimen of atezolizumab plus chemotherapy was associated with more treatment-related grade 3 or 4 adverse events (54% vs 44%) but similar incidences of fatal adverse events (0.8% vs 0.6%) and adverse events leading to chemotherapy discontinuation. Chemotherapy exposure was similar in the 2 treatment groups. Conclusions and Relevance The addition of the immune therapy drug atezolizumab to chemotherapy after surgery did not provide benefit among patients with triple-negative breast cancer who are at high risk of recurrent disease. Trial Registration ClinicalTrials.gov Identifier: NCT03498716

Background: Approximately 1% of all new cases of breast cancer (BC) cases occur in men. Treatment and symptom management for male BC patients are largely based on strategies developed for women. While the impact of BC diagnosis and treatment on the quality of life (QoL) in women with BC is well documented, there is a paucity of comprehensive, prospective data on QoL in men treated for BC. Due to absence of a validated QoL questionnaire, QoL in male BC patients has recently been assessed using the EORTC QLQ-C30 and the breast module QLQ-BR23 with female-specific items replaced by male-specific items from the EORTC QoL prostate module (EORTC QLQ-PR25). The development of the first validated worldwide questionnaire for male BC is sponsored by the EORTC QoL Group and is conducted in collaboration with the EORTC BCG and the International Male BC Program (a collaboration of EORTC-BCG, TBCRC, within the BIG and NABCG networks). The trial design was presented at SABCS 2000 (abstract OT-14-01). This report presents the results from phase 1 and 2 of the EORTC module development study to assess QoL in male BC patients. Methods: Phase I and II of the EORTC module development study focused on identifying QoL issues relevant to male BC and translating these issues into a questionnaire for a comprehensive QoL assessment. The development process included a systematic literature review, interviews with patients and healthcare professionals (HCPs) and consultations with experts in oncology and QoL. According to the recommendations of the EORTC module development manual, an issue was included to the issue list if it had a patient and/or HCP relevance rating ≥ 2 (on a scale of 1 to 4) and there was a patient and/or HCP priority rating ≥ 30 %. The relevant issues were translated into items with the help of the EORTC item library and the experts, resulting in a preliminary questionnaire. This questionnaire has been reviewed by the EORTC Quality of Life Department translation unit and will be tested in the phase III. Results: The mixed methods approach (systematic literature search, questionnaires review, investigator brochures, focus group, research group meetings) identified 86 issues that appear to be related to QoL in male BC patients. An issue list was created and used for interviews with patients and HCPs, who rated each issue according to relevance for male BC patients (using a four-point EORTC response format: not at all, a little, quite a bit, very much) and priority (yes/no response format). Interviews were conducted with male patients (N=64) with histologically confirmed diagnosis of BC from a total of eleven centres. A total of 29 HCPs from seven centres representing different specialities participated in this study. Centres were located in northern, southern and eastern Europe, USA, Egypt, and Asia. Of the initial 86 issues, 27 (rated by patients) and 46 (rated by HCPs) fulfilled both inclusion criteria. Additionally, 24 issues are covered by the BR-45 (updated BR-23 module Phase III) and/or the PR-25, and 25 are new issues not covered by these modules. In phase II, these issues were translated into items and a preliminary Phase II module/questionnaire with 68 items to assess QoL in male BC patients was created and will be presented at SABCS 2024. Conclusion: The results of the phases I-II highlight that the current practice of using combining parts of the EORTC QLG breast module and prostate module does not sufficiently cover all the relevant QoL issues for male BC patients. Ten items commonly used in the assessment may not add value, and 25 potentially valuable new items are not included in existing modules. Therefore, a new, male BC dedicated QoL questionnaire should be developed. A preliminary phase II questionnaire will be tested in phase III of the EORTC module development. Note. This document represents preliminary findings of the module development and is subject to revision; subsequent modifications of the module in the next stages may reflect significant changes. Citation Format: Vesna Bjelic-Radisic, Fatima Cardoso, Joachim Weis, Evelien Bleiker, David Cameron, Galina Velikova, Katarzyna Pogoda, Samantha Serpentini, Kevin Punie, Rinat Yerushalmi, Erika Matos, Birgit Carly, Luisa Zoe Probst, Sina Schafer, Nora Nevries, Ivana Bozovic-Spasojevic, Nicola Russell, Adelheid Roelstraete, Sofie Tombeur, Joanna Vermeij, Ruddy Kathryn, Juan Ignatio Arraras, Carolina De la Pinta, Omar Shamieh, Yuichiro Kikawa, Edward Chow, Tom Bootsma, Ibrahim Sallam, Fatjona Kraja, Andrew Bottomley. Adaptation of the EORTC Quality of Life Breast Cancer Module for male Breast Cancer – Results of the Phase I-II module [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-01-04.

Background: Adjuvant endocrine therapy (ET) is the standard of care (SOC) for the treatment of estrogen receptor-positive (ER+) human epidermal growth factor receptor-2 negative (HER2-) early-stage breast cancer. Despite optimized adjuvant treatments for patients with high risk of recurrence, patients continue to experience local and distant relapses, and new therapies are warranted. In the phase 3 EMERALD trial, single-agent elacestrant was evaluated vs SOC ET in ER+/HER2− metastatic breast cancer. Elacestrant significantly prolonged progression-free survival (PFS) vs SOC ET in the overall population (HR = 0.70; 95% CI, 0.55-0.88; P = 0.0018) and in patients with ESR1-mut tumors (HR = 0.55; 95% CI, 0.39-0.77; P = 0.0005) (Bidard, JCO 2022). In those pts with ≥12 months of prior ET+ CDK4/6 inhibitor (CDK4/6i) and ESR1-mut tumors, median PFS with elacestrant was 8.6 vs 1.9 months with SOC ET (Bardia, SABCS 2022). In patients with tumors without detectable ESR1-mut, a numerical difference was observed (HR = 0.86; 95% CI: 0.63-1.19). As elacestrant significantly prolonged PFS in the metastatic setting relative to endocrine monotherapy, with more pronounced activity in patients with endocrine-sensitive tumors, it is hypothesized that elacestrant should prolong invasive breast cancer-free survival (IBCFS) in the earlier adjuvant setting among patients who received prior adjuvant ET with or without a CDK4/6i. In addition, elacestrant can antagonize the estrogen receptor in tumor cells with a non-degradative antagonist function. Unlike other oral SERDs in development, elacestrant exhibits both degradative and partial agonist properties (Wardell, ERC 2015). Elacestrant could offer a new class of medication in the adjuvant setting and merits further therapeutic evaluation for patients with ER+/HER2- breast cancer with a high risk of recurrence. Methods: ELEGANT (NCT06492616) is a global, multicenter, randomized, open-label phase 3 study designed to evaluate elacestrant compared with SOC ET (aromatase inhibitor or tamoxifen) in patients with early breast cancer and a high risk of recurrence. A total of 4,220 patients will be randomized 1:1 to continue SOC ET or switch to elacestrant therapy for a duration of 5 years. Eligible patients are women or men with ER+/HER2− node-positive breast cancer who have completed 24 months (but not more than 60 months) of adjuvant ET and have ECOG PS ≤1. Patients who received a prior CDK4/6i or a poly ADP-ribose polymerase (PARP) inhibitor must have already completed or discontinued these treatments. Exclusion criteria include inflammatory breast cancer, any history of prior invasive breast cancer, and >6 months continuous interruption of prior SOC adjuvant ET or discontinuation of adjuvant ET >6 months prior to randomization. The primary endpoint is IBCFS. Key secondary endpoints include distant relapse-free survival (DRFS) and overall survival (OS). Additional secondary endpoints include invasive disease-free survival (IDFS), safety, and patient-reported outcomes. Exploratory endpoints include PK and biomarker analyses. Time-to-event endpoints will be reported using Kaplan-Meier estimates. Baseline demographics and other characteristics will be descriptively summarized. Citation Format: Aditya Bardia, Virginia Kaklamani, Joyce O’Shaughnessy, Peter Schmid, J. Thaddeus Beck, Michelino De Laurentiis, Giuseppe Curigliano, Hope S. Rugo, Debu Tripathy, William J. Gradishar, Michail Ignatiadis, David A. Cameron, Giulia Tonini, Simona Scartoni, Jennifer Crozier, Leo Viana Nicacio, Tomer Wasserman, Sara M. Tolaney. ELEGANT: Elacestrant versus standard endocrine therapy in women & men with node-positive, estrogen receptor-positive, HER2-negative, early breast cancer with high risk of recurrence in a global, multicenter, randomized, open-label phase 3 study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-08-21.

BACKGROUND:Integration of sustainability measures into clinical research would translate into less healthcare related climate impacts. METHODS:We assessed climate change impacts, existing sustainability engagement, and challenges and facilitators to climate change mitigation strategies among Breast International Group (BIG) members. A 30 item web based survey assessing climate impacts, sustainability engagement, challenges to and facilitators of engagement, and sustainability integration in funding applications was developed, and circulated electronically between November 2023 and March 2024. RESULTS:Thirty four members (research groups and data centres) and participating sites across 5 continents, and BIG headquarters responded. Twenty six responses were received from 21 organisations, 20 from 17 participating sites. No responses were obtained from 28 groups. Trial conduct at a third of member groups had been impacted by climate change impacts such as destroyed infrastructure. 78 % of groups agreed that sustainability should feature in future funding applications. Most respondents engaged in sustainability initiatives at a host institute and organisational level. However, 39 % of coordinating centres and 65 % of representative sites had none within clinical trials conducted by their organisation. The majority of respondents foresaw challenges to sustainability engagement including competing time pressure, staff attitudes and resource constraints. Of nine potential facilitators to engagement, funding, an evidence base for sustainable research practice and training were the leading themes. CONCLUSION:In the first global survey of its kind, a third of respondents reported that climate change had impacted trial conduct. Integration of sustainability measures was absent in a significant minority. Funding and dedicated resourcing would facilitate increased engagement in cancer clinical trials.

Percentage change in Ki67 between pretreatment (baseline) and surgery for part 1 (A) and part 2 (B); Kaplan–Meier estimates by treatment group for relapse free survival (C) and overall survival (D). A, Waterfall plots for part 1 and part 2: for each patient, bar height represents percentage change at surgery from baseline. Percentage change was calculated as [(surgery score + 0.1) − (pretreatment score + 0.1)]/[(pretreatment score + 0.1)]*100. The constant of 0.1 was added to accommodate cases with a value of 0%. Negative values represent decrease from baseline, positive values represent increase from baseline. pCR in breast: patients with pCR (no disease in ether breast or nodes) plus two additional patients with 0% breast cellularity but nodal involvement are represented as bars of height −120% at the left of the figures and noted “pCR in breast;” any existing Ki67 values for these patients have been excluded of the main analysis; in a sensitivity analysis, we imputed a value of −100% change for these patients (Appendix 2). Small triangles indicate patients with RCB1. Disease recurrences are also indicated at the top of each figure with circles and crosses. B, RFS is represented in the time interval of up to 6 years after randomization, as no RFS event occurred later. Overall survival is represented in the fully observed range of values. Log-rank test comparing concurrently randomized treatment groups are reported in the figures. In the figure, trastuzumab and control part 1 and part 2 groups are combined to improve readability. C, control; L, lapatinib; T, trastuzumab; T+L, combination; P1, part 1; P2, part 2; all, P1&P2; P, P value.

Association of perioperative changes in biological markers with RFS (A) by categories of Ki67 relative change, (B) by categories of Ki67 absolute change, (C) by baseline TILs, (D) by surgery TILs. RFS is represented in the time interval 0 to 6 years, as no RFS events occurred beyond 6 years from randomization. All treatment groups are combined; log-rank tests are stratified by treatment group (P = P value). For A and B, a value of −100% Ki67 change (ΔKi67) has been imputed for patients with a pCR in breast. For B, we have categorized both baseline and surgery Ki67 into high if ≥10% or low if <10%. No patient increased Ki67 from low to high after 11 days of perioperative treatment. Because of small number of patients in the “low–low” group, we have compared patients with “high” value at surgery with patients with “low” value at surgery.