504 Background: The optimal positioning of implants following skin- (SSM) or nipple-sparing mastectomy (NSM) for breast cancer treatment or prevention is unclear. Pre-pectoral IBBR obviates the need to dissect the major pectoral muscle but provides less soft tissue coverage of the implant. The PREPEC trial hypothesized pre-pectoral IBBR would result in improved long-term quality of life (QoL) compared to sub-pectoral IBBR. Methods: OPBC-02/PREPEC (NCT04293146) was a pragmatic, international, randomized, phase III superiority trial. Women ≥18 years undergoing SSM or NSM for treatment or prevention of breast cancer were randomized (1:1) to pre-pectoral or sub-pectoral IBBR. Surgery otherwise followed standards of care. The primary endpoint was patient-reported physical well-being chest as assessed by BREAST-Q 24 mo after surgery (prespecified MID 4 points; SD 13). 372 pts provided 80% power (two-sided t-test α = 0.05). Multiple imputation was implemented for missing scores across all timepoints (day 10; 1, 6, 12, 18, 24 mo). The IBBR assignment difference at 24 mo was estimated by linear mixed modeling, adjusted for baseline score, stratification factors, pre-selected covariates, and random center effect. Loss or replacement of expander or implant for any reason within 24 mo was the primary safety endpoint. Results: From July 2020 to February 2023, 383 pts were randomized at 26 OPBC centers in 10 countries. The full analysis set comprised 380 pts (191 randomized to pre-pectoral, 189 to sub-pectoral IBBR). Surgery was unilateral in 72.9% of pts and NSM in 58.4%. The setting was therapeutic in 77.9% of pts, therapeutic and preventive in 15.5%, and preventive in 6.6%. BREAST-Q completion was 83-95% across 6 post-baseline timepoints. Pre-pectoral IBBR significantly improved physical well-being at 24 mo compared to sub-pectoral IBBR (least-square means 79.2 [95%CI 75.5-82.8] vs 74.3 [70.7-78.0], respectively). The mean difference of 4.8 (95%CI 1.0-8.7; p = 0.01) surpassed the predefined threshold for a clinically meaningful difference. The effect was robust in sensitivity analyses, and consistent in subgroup analyses. Loss or replacement of expander or implant for any reason within 24 mo occurred in 68 pts, 21.1% vs 14.5% after pre-pectoral and sub-pectoral IBBR, respectively. The covariate-adjusted model estimated 5.7% (95%CI -2.4% - 13.8%) more implant loss with pre-pectoral IBBR. At least one complication occurred in 54.1% vs 55.9% of pts, respectively. Early complications were more frequent after pre-pectoral IBBR (crude estimated increase range 3-5%); late complications were more frequent after sub-pectoral IBBR. Conclusions: Pre-pectoral IBBR significantly and relevantly improved long-term QoL at the cost of a higher risk of loss or replacement of expander or implant compared to sub-pectoral IBBR. Clinical trial information: NCT04293146 .

PURPOSE:To evaluate the clinical benefit of extended endocrine therapy (eET) after 5 years of adjuvant treatment with luteinizing hormone-releasing hormone agonists (LHRHa) in premenopausal women with node-positive, hormone receptor-positive early breast cancer (eBC). METHODS:We conducted a cohort study analysis on two prospectively collected data sets (the Young Women's Breast Cancer Study and IEO Breast Cancer Cohort). Eligible patients were diagnosed with eBC at age ≤40 years (between 2005 and 2016), had node-positive, hormone receptor-positive disease, and remained premenopausal after 5 years of adjuvant LHRHa with no evidence of recurrence. The primary end point was invasive breast cancer-free survival (IBCFS), calculated from the sixth year after the initiation of adjuvant endocrine therapy (ET; study baseline), and adjusted through the propensity score (PS) weighting analysis. RESULTS:A total of 501 patients were included in the analysis: 287 received eET for a median duration of 3.7 years (IQR, 2.3-5.0), including 48% tamoxifen monotherapy and 52% LHRHa plus tamoxifen or aromatase inhibitor. After a median follow-up of 7.3 years from the study baseline, the PS weighted IBCFS rates at 5 years were 85% in the eET group and 78% in the non-eET group (hazard ratio [HR], 0.63 [95% CI, 0.44 to 0.89]; P = .0135). The PS weighted distant recurrence-free survival rates at 5 years were 91% and 83% in the eET and non-eET group, respectively (cause-specific HR, 0.49 [95% CI, 0.31 to 0.79]). In both groups, bone fractures and major cardiovascular events were reported in 1% of patients. CONCLUSION:In this cohort study analysis, extending ET in premenopausal patients with node-positive eBC after 5 years of LHRHa treatment was associated with a clinically meaningful reduction in both invasive and distant breast cancer recurrences.

Importance:Premenopausal patients with node-positive, hormone receptor-positive, early breast cancer derive benefit from extended endocrine therapy (EET) following 5 years of luteinizing hormone-releasing hormone (LHRH) agonist-based treatment. The benefit of EET may differ according to surrogate breast cancer subtypes in postmenopausal patients. Objective:To evaluate the risk of invasive and distant recurrence across all surrogate breast cancer subtypes among patients with node-positive, hormone receptor-positive early breast cancer who remained premenopausal after completing 5 years of adjuvant therapy with an LHRH agonist who received and did not receive EET. Design, Setting, and Participants:This multicenter cohort study conducted in the United States and Italy used data from 2 prospectively maintained datasets: the Young Women's Breast Cancer Study and the European Institute of Oncology Breast Cancer cohort. Eligible patients were diagnosed with early breast cancer at 40 years of age or younger between January 2005 and December 2016, had node-positive hormone receptor-positive disease, and remained premenopausal after 5 years of adjuvant LHRH agonist therapy with no evidence of recurrence. Median (IQR) follow-up was 7.3 (4.9-10.3) years. Data were analyzed June 2025. Exposure:EET (with tamoxifen monotherapy, LHRH agonist plus tamoxifen, or LHRH agonist plus aromatase inhibitor), irrespective of the duration of EET, measured at study baseline (defined as the first day of the sixth year after the initiation of adjuvant ET). Main Outcomes and Measures:Invasive breast cancer-free survival and distant recurrence-free survival (DRFS) distributions were estimated using the adjusted Kaplan-Meier method among patients with or without the exposure, weighted through propensity score (PS) weighting analysis, with the scientific approach. Results:In total, 487 patients were included (median [IQR] age at diagnosis, 37 [35-39] years in the EET group and 37 [33-39] years in the no EET group), and 276 received EET for a median (IQR) duration of 3.7 (2.2-5.0) years. Overall, 89 patients (18%) had luminal A-like disease, 298 (61%) had luminal B-like disease, and 100 (21%) had ERBB2 (formerly HER2)-positive disease. The PS-weighted hazard ratio (HR) for invasive breast cancer-free survival comparing the EET with the no EET group was 0.68 (95% CI, 0.32-1.45) in luminal A-like, 0.63 (95% CI, 0.40-1.00) in luminal B-like/ERBB2-negative, and 0.62 (95% CI, 0.21-1.87) in ERBB2-positive subgroups. The cause-specific PS-weighted HR for DRFS was 0.25 (95% CI, 0.08-0.75) in luminal A-like, 0.54 (95% CI, 0.32-0.94) in luminal B-like/ERBB2-negative, and 0.54 (95% CI, 0.12-2.53) in ERBB2-positive subgroups. Conclusions and Relevance:In this cohort study, a lower estimated risk with EET use was observed across all surrogate breast cancer subtypes. However, the lower estimated risk was greatest among patients with luminal A-like disease, a finding that warrants confirmation in larger, prospective cohorts.

1064 Background: PIK3CA mutations are a key therapeutic target in ER+ advanced breast cancer (ABC) readily detectable through circulating tumor DNA (ctDNA). The PI3Kα inhibitor alpelisib is approved in ER+ HER2- ABC but it remains unclear when to incorporate it into the current treatment algorithm. To address this, we conducted a phase II study assessing superiority of alpelisib + fulvestrant vs capecitabine in ABC pts with detectable PIK3CA mutant ctDNA following CDK4/6i plus aromatase inhibition (AI). Methods: Eligible pts had ER+ HER2- ABC, prior progression on CDK4/6i+AI and PIK3CA mutations detected via ctDNA ddPCR. Pts were randomized 1:1 to receive alpelisib (300mg daily) + fulvestrant (Arm A), or capecitabine (1000-1250mg/m 2 BD D1-14 q21d) (Arm B); strata were prior chemo for ABC and visceral disease. Primary endpoint was progression free survival (PFS) defined from randomization until progressive disease per RECIST 1.1 or death. Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR) and adverse events (AE). Imaging was q8 weeks. Exploratory objectives included efficacy according to baseline ctDNA levels. Sample size was reduced from 140 to 66 pts randomized for 53 PFS events to detect median PFS of 9 vs 5 mo (HR=0.56;1-sided α=0.1,80% power). Interim inefficacy analysis (60% events) estimated HR>1.0 and IDMC recommended early termination. Follow-up continued until all pts completed alpelisib. Reported are stratified Cox model HR (2-sided 80% CI) and 2-sided log rank test. Results: From July 2020-Oct 2024, 396 pts were screened, 113 (29%) had PIK3CA mutant ctDNA, 58 were randomized and 55 initiated treatment (Arm A: 29/30; Arm B: 26/28). Median age was 56 (32-82 yrs), 75% had visceral disease; 87% had no prior chemo for ABC. At final analysis, 43 PFS events occurred. Median PFS was 7.4 mo for alpelisib + fulvestrant vs 9.4 mo for capecitabine (HR 1.28, 80% CI: 0.84-1.96, p=0.45). For pts with visceral disease, median PFS was 5.4 mo (80% CI:3.7-5.1) for alpelisib + fulvestrant and 12.1 mo (80% CI:5.4-15) for capecitabine. ORR was 24.1% vs 50.0% and CBR 55.2% vs 61.5% for alpelisib + fulvestrant vs capecitabine. Overall, 79.3% pts on alpelisib + fulvestrant had grade 3/4 AEs with 24% grade 3 hyperglycemia vs 46.2% on capecitabine with 12% grade 3 palmar-plantar erythrodysesthesia. Six of 30 pts discontinued alpelisib due to AEs; 5 of the 6 continued fulvestrant. There was no evidence of association between baseline ctDNA levels (PIK3CA mutant copies/ml; median 90; range 2-13678) and PFS (HR 1.03; 90%CI:0.90-1.19). Conclusions: In our trial of pts with PIK3CA mutant ABC after progression on CDK4/6i plus AI, targeted therapy with alpelisib + fulvestrant was not superior to standard chemotherapy with capecitabine. Compared with the targeted therapy, capecitabine was better tolerated and resulted in longer PFS. Clinical trial information: ACTRN12619001117101.

636 Background: Invasive lobular carcinoma (ILC) differs biologically from invasive ductal carcinoma (IDC) and has been associated with delayed recurrence. However, long-term patterns of breast cancer-specific mortality (BCSM) following ILC remain incompletely described. We aimed to characterize temporal patterns of BCSM associated with ILC vs IDC over extended follow-up. Methods: We conducted a population-based study using the SEER program. Women diagnosed with stage I–III IDC or ILC from 1990 to 2012 were included. BCSM was the primary endpoint, with death from other causes treated as a competing event. Unadjusted cumulative incidence functions estimated BCSM by histology. Fine-Gray competing risks models were used to compare histologies overall and within hormone receptor (HR)-defined subgroups, with all models adjusted for age at diagnosis, year (y) of diagnosis, HR status (where applicable), tumor size, nodal status, tumor grade, surgery, radiation, and chemotherapy. Non-proportional effects were identified visually and modeled using time-varying coefficients. Landmark competing risks analyses assessed late BCSM among long-term survivors. Results: Among 423,479 women included, 41,027 (9.7%) had ILC and 382,452 (90.3%) had IDC; median follow-up was 16.7 y (range 0.1–33 y). During follow-up, 77,926 breast cancer deaths and 111,814 deaths from other causes occurred. In unadjusted analyses of the overall population, BCSM was lower for ILC than IDC at 5 and 10 years and higher for ILC at 20 and 30 years (Table). In adjusted Fine-Gray models, lobular histology demonstrated a significant time-varying association with BCSM (p<0.001). Associations between histology and BCSM differed by HR status (p for interaction=0.0029). In time-varying models restricted to HR+ disease, the adjusted subdistribution hazard ratio (sHR) for ILC versus IDC increased over time, reaching 1.19 (95% CI 1.15–1.23) at 10 y, 1.34 (1.28–1.41) at 20 y, and 1.44 (1.36–1.54) at 30 y. In landmark analyses among HR+ survivors, ILC remained associated with higher late BCSM beyond 10 y (sHR 1.36, 95% CI 1.29–1.43) and beyond 15 y (sHR 1.32, 95% CI 1.20–1.45). Conclusions: ILC is associated with a distinct temporal pattern of BCSM compared with IDC. Although unadjusted early BCSM is lower for ILC, adjusted risk increases over time and exceeds that of IDC in the late post-diagnosis period, particularly among HR+ disease. These findings highlight the importance of long-term risk assessment and survivorship strategies tailored to lobular histology. Unadjusted cumulative incidence of BCSM by histology (%; 95% CI). Overall population HR+ Y since diagnosis IDC ILC IDC ILC 5 9.8 (9.7–9.9) 7.3 (7.0–7.5) 6.5 (6.4–6.6) 6.4 (6.1–6.6) 10 15.0 (14.9–15.2) 14.3 (13.9–14.6) 11.9 (11.8–12.0) 13.4 (13.1–13.8) 20 19.6 (19.5–19.8) 21.6 (21.2–22.1) 17.2 (17.0–17.4) 21.0 (20.5–21.4) 30 22.0 (21.8–22.2) 24.5 (23.9–25.2) 19.8 (19.5–20.0) 23.9 (23.1–24.6)

BACKGROUND:Immune checkpoint inhibitor (ICI)-based regimens can be associated with prolonged survival and disease control after treatment discontinuation without further anticancer therapy. An integrated, comprehensive partitioned survival analysis describes how patients spend overall survival (OS) time both on/off treatment and with/without toxicity. Previous analysis of first-line (1L) nivolumab+ipilimumab for advanced renal cell carcinoma (aRCC) in CheckMate 214 showed treatment-free survival (TFS; time between 1L and second-line (2L) therapies) was twice as long versus sunitinib. TFS and survival states for ICI plus vascular endothelial growth factor receptor-tyrosine kinase inhibitor are of interest. METHODS:In CheckMate 9ER, 651 randomized patients with aRCC received 1L nivolumab+cabozantinib or sunitinib. Minimum follow-up was 4 years. We partitioned area under the Kaplan-Meier OS curve into three survival states defined from randomization: time on 1L protocol therapy, TFS, and survival after 2L subsequent systemic therapy initiation. TFS and protocol therapy were subdivided into mean times with/without grade 2+ treatment-related adverse events. Areas under and between Kaplan-Meier curves were estimated by 48-month restricted mean times to event. Bootstrapped 95% CIs for between-group differences are reported. RESULTS:At 4 years post-randomization, Kaplan-Meier OS estimates were 49.2% versus 40.2% with nivolumab+cabozantinib and sunitinib, respectively; 17.6% versus 4.7% of patients were in TFS; 15.8% versus 8.2% remained on 1L protocol therapy. The 48-month mean time on protocol therapy for nivolumab+cabozantinib versus sunitinib was 22.6 and 14.1 months; 48-month mean TFS was 7.0 and 4.6 months (difference, 2.4 (95% CI 0.8 to 3.9)); 48-month mean survival after 2L therapy initiation was 5.5 and 12.0 months, respectively. The nivolumab+cabozantinib group spent 8.5 (95% CI 6.2 to 10.8) months more mean survival time on 1L protocol therapy, whereas the sunitinib group had 6.5 (95% CI 4.4 to 8.6) months more mean survival time after 2L therapy initiation. Both treatment groups spent at least half of TFS with grade 2+toxicity, resulting in a difference in mean TFS without toxicity of 0.7 (95% CI -0.4 to 1.8) months. CONCLUSIONS:Partitioned survival analysis over 4 years after initiation of 1L therapy for aRCC indicated that longer OS with nivolumab+cabozantinib versus sunitinib involved more time on 1L therapy and in TFS, and less survival time after 2L therapy initiation. TRIAL REGISTRATION NUMBER:NCT03141177.

Importance:Trends in the incidence of de novo stage IV breast cancer in the general population and in the percentage with stage IV disease remain underreported. Objectives:To evaluate the incidence, percentage, and survival of people with de novo stage IV breast cancer diagnosed from 2010 through 2021. Design, Setting, and Participants:This population-based cohort study used data from the Surveillance, Epidemiology, and End Results program to identify all individuals diagnosed with de novo invasive breast cancer between January 1, 2010, and December 31, 2021. No exclusion criteria were applied. Data analyses were conducted from January 2024 to June 2025. Main Outcomes and Measures:Age-adjusted incidence rates of breast cancer and annual percentage changes (APC) from 2010 through 2021 were calculated. Among the diagnosed breast cancers, the yearly percentage of stage IV disease was also calculated. Changes in overall survival (OS) were evaluated for patients with stage IV breast cancer using multivariable Cox proportional hazards regression models stratified by tumor subtype. Results:Of 761 471 breast cancer diagnoses (median [IQR] age at diagnosis, 60 [50-70] years; 99.2% female), 43 934 (5.8%) were stage IV. Stage IV incidence increased from 9.5 (95% CI, 9.2-9.9) cases per 100 000 females in 2010 to 11.2 (95% CI, 10.9-11.6) cases per 100 000 females in 2021, an APC of 1.2% (95% CI, 0.8%-1.6%). The incidence of stages I to III disease also increased, from 163.0 (95% CI, 161.6-164.4) cases per 100 000 females in 2010 to 177.4 (95% CI, 176.1-178.8) cases per 100 000 females in 2021. Stage IV incidence increased across all tumor subtypes, with an APC of 2.0% (95% CI, 1.5%-2.6%) for hormone receptor (HR)-positive/ERBB2-negative, 1.6% (95% CI, 0.2%-2.9%) for HR-positive/ERBB2-positive, 1.3% (95% CI, -0.1%-2.7%) for HR-negative/ERBB2-positive, and 2.7% (95% CI, 1.4%-4%) for triple-negative disease. Stage IV incidence increased statistically significantly across all age groups and numerically across all racial groups. Among males, there was a statistically significant increase in stage IV incidence, with an APC of 3.7% (95% CI, 1.0%-6.5%). The percentage of stage IV diagnoses increased statistically significantly from 2010 through 2021 in each tumor subtype: 4.4% to 95.4% for HR-positive/ERBB2-negative, 8.1% to 91.6% for HR-positive/ERBB2-positive, 10.4% to 89.4% for HR-negative/ERBB2-positive disease, and 6.7% to 92.9% for triple-negative breast cancer. For each successive year, OS among patients diagnosed with stage IV improved, with adjusted hazard ratios of 0.99 (95% CI, 0.98-0.99) for HR-positive/ERBB2-negative, 0.97 (95% CI, 0.95-0.99) for HR-positive/ERBB2-positive, and 0.97 (95% CI, 0.94-0.99) for HR-negative/ERBB2-positive; changes for triple-negative breast cancer were not statistically significant (AHR, 0.99 [95% CI, 0.97-1.01]; P = .33). Conclusions and Relevance:In this cohort study of individuals with stage IV breast cancer, incidence increased significantly overall, across ages, and for both sexes from 2010 through 2021. The percentage of individuals with stage IV vs stages I to III diagnoses also increased. Although OS improved, research is warranted to determine factors contributing to increased incidence, including potential changes in natural history of breast cancer, disease screening, and incidence and mortality of other conditions.

BACKGROUND:An adjusted Breast Cancer Index (BCI) model with an additional cutpoint identified postmenopausal women with hormone-receptor-positive node-negative disease at minimal (<5%) risk of distant recurrence (DR) within 10 years. METHODS:2025 premenopausal patients with hormone-receptor-positive node-negative breast cancer, randomized to adjuvant endocrine therapy in SOFT and TEXT (35.6% and 40.4% received adjuvant chemotherapy, respectively), previously had BCI assessed. The additional BCI cutpoint re-classified a subset of the low-risk group into minimal-risk; those in intermediate- or high-risk groups were unchanged. The 10-year DR was estimated by Kaplan-Meier method. RESULTS:The adjusted BCI model re-classified 17.8 % and 19.6 % of node-negative disease in SOFT and TEXT into BCI minimal-risk groups; 43.2 % and 38.3 % remained classified in low-risk groups, respectively. In SOFT, the estimated 10-year DR was 2.3 % (95 %CI 0.9-6.0 %) and 4.1 % (95 %CI 2.6-6.5 %) in the minimal-risk and revised low-risk groups, respectively. In TEXT, the estimated 10-year DR was 2.0 % (95 %CI 0.7-6.2 %) and 4.6 % (95 %CI 2.8-7.7 %) in the minimal- and low-risk groups, respectively. CONCLUSIONS:This study confirmed prognostic ability of the minimal-risk BCI cutpoint to classify patients estimated to have minimal-risk of distant recurrence within 10 years among premenopausal patients treated for hormone-receptor-positive node-negative breast cancer, providing relevant information for personalizing adjuvant endocrine therapy. SOFT: (clinicaltrials.gov NCT00066690) TEXT: (clinicaltrials.gov NCT00066703).

PURPOSE:Biochemical recurrence (BCR) of prostate cancer (PCa) after definitive surgery and/or radiation (including salvage strategies) is a burgeoning area of clinical research inspired by ultrasensitive next-generation imaging. Most phase III trials in PCa have focused on metastatic disease, defined by conventional imaging. Despite the emergence of new imaging, clinical trial principles from metastatic studies will not optimize future BCR trials. METHODS:A Working Group convened at the National Cancer Institute on November 13, 2024 (NCI BCR WG). Key areas of discussion included nomenclature, baseline criteria for data capture, imaging considerations, delineation of high-risk populations to be targeted for trial development, requirements of metastasis-directed therapy (MDT) or hormonal therapy, quality-of-life considerations, and potential study end points. RESULTS:The NCI BCR WG defined the novel term "prostate-specific membrane antigen (PSMA)+BCR" to identify the emerging concept of recurrent PCa identifiable only on PSMA positron emission tomography (PET), overlapping with BCR and distinct from metastatic hormone-sensitive PCa as traditionally defined by conventional imaging. The WG suggested defining high-risk BCR with a prostate-specific antigen doubling time of ≤6 months, regardless of PET findings. The WG provided recommendations for baseline data capture and imaging requirements. Neither systemic therapy nor MDT were considered mandatory for control arms. The WG also discussed novel end points and quality-of-life metrics in this disease space. CONCLUSION:These discussions should inform future clinical BCR trials in this distinct disease space relative to metastatic disease defined by conventional imaging. The NCI BCR WG strongly advocates that future trials explore deintensification of treatment to minimize toxicity in this relatively indolent disease state.

505 Background: Long-term follow-up of the SOFT and TEXT randomized trials has shown persistent reduction of recurrence from inclusion of OFS in adjuvant endocrine therapy, and clinically meaningful improvement in overall survival (OS) among patients at higher baseline risk of recurrence. We report a final update after a median follow-up of 15y in SOFT and 16.6y in TEXT. Methods: SOFT and TEXT enrolled premenopausal women with HR+ early BC from November 2003 to April 2011 (2660 in TEXT, 3047 in SOFT intention-to-treat populations). TEXT randomized women within 12 weeks of surgery to 5y E+OFS vs T+OFS; chemotherapy (CT) was optional and concurrent with OFS. SOFT randomized women to 5y E+OFS vs T+OFS vs T alone, within 12 weeks of surgery if no CT planned, or within 8 months of completing (neo)adjuvant CT. Both trials were stratified by CT use. The primary endpoint was disease free survival (DFS) which included invasive local, regional, distant and contralateral breast events, second non-breast malignancies and deaths. Secondary endpoints included invasive breast cancer-free interval (BCFI), distant recurrence free interval (DRFI) and OS. 20y data collection was completed in Q4’2024: 80% of surviving patients had final follow-up during or subsequent to 2020, for 70% it was during 2023-2024. 15y Kaplan-Meier estimates and hazard ratios (HR) with 95% CIs are reported. Results: There were 815 DFS events and 388 deaths reported in SOFT; and 669 DFS events and 325 deaths in TEXT. In SOFT, a moderate DFS benefit of T+OFS vs T (HR 0.85; 0.72-1.00) persisted, however 1/6 DFS events were not BC related; BCFI benefit was HR 0.82 (0.69-0.98). E+OFS vs T further reduced DFS events (HR 0.73; 0.61-0.86). The 15y DFS in SOFT was 67.0% for T, 70.5% for T+OFS and 73.5% for E+OFS. There were consistent but non-significant decreased hazards of death for T+OFS vs T (HR 0.87; 0.68-1.10) and E+OFS vs T (HR 0.85; 0.67-1.08). 15y OS was 85.3%, 86.7%, 86.9% respectively. For the TEXT+SOFT combined analysis of E+OFS vs T+OFS (n=2346 vs 2344) DFS, BCFI and DRFI continued as significantly improved for E+OFS over T+OFS. 15y DFS was 74.9% vs 71.3% (HR 0.82; 0.73-0.92). 15y OS was 87.8% vs 87.0% (HR 0.94; 0.80-1.11) respectively. 15y estimates by CT use are tabulated. Conclusions: The high level 15y final results of the SOFT and TEXT confirm a role for OFS- and aromatase inhibitor-containing adjuvant endocrine therapy for premenopausal women. Analysis is ongoing. Clinical trial information: NCT00066690 (SOFT) and NCT00066703 (TEXT) . 15y (%) Events SOFT Prior CT (n=1628) SOFT no CT (n=1419) CT+noCT T / T+OFS / E+OFS T / T+OFS / E+OFS DFS 536+279 60.9 / 63.0 / 66.3 73.9 / 79.1 / 82.1 DRFI 367+56 73.5 / 73.8 / 77.6 94.7 / 94.7 / 96.8 OS 318+70 77.4 / 79.4 / 79.8 94.4 / 95.1 / 95.2 TEXT CT (n=1607) TEXT no CT (n=1053) T+OFS / E+OFS T+OFS / E+OFS DFS 456+213 68.5 / 72.1 76.8 / 81.8 DRFI 286+69 79.0 / 81.3 91.6 / 94.6 OS 266+59 82.7 / 84.3 94.1 / 94.8

BACKGROUND:The optimal scheduling of PD-1 inhibitors with neoadjuvant chemotherapy in patients with early triple-negative breast cancer is unknown. We aimed to investigate the activity of two differing schedules of neoadjuvant nivolumab initiation with 12 weeks of carboplatin and paclitaxel for this patient population. METHODS:Neo-N is an investigator-initiated, non-comparative, open-label, randomised, phase 2 trial conducted at 12 hospitals in Australia, one in New Zealand, and one in Italy. Participants had to be aged 18 years or older; have an Eastern Cooperative Oncology Group performance status of 0-1, clinical stage I (cT1cN0) or II (cT1cN1, cT2cN0-1, or cT3cN0), oestrogen receptor expression of less than 1%, and progesterone receptor expression of less than 10%; had to be HER2 negative; and have previously untreated operable breast cancer with adequate organ function. Participants were stratified according to age and randomly assigned (1:1) centrally using a computer-generated sequence with a minimisation algorithm to either nivolumab 240 mg then 2 weeks later nivolumab 360 mg and carboplatin AUC5 every 3 weeks with concurrent paclitaxel 80 mg/m2 once per week for 12 weeks (lead-in group) or concurrent nivolumab 360 mg and carboplatin AUC5 every 3 weeks with once per week paclitaxel 80 mg/m2 for 12 weeks then 240 mg nivolumab 2 weeks later (concurrent group). Data were collected from registration until the 100-day safety follow-up visit, and survival follow-up continues. The primary endpoint was pathological complete response (ypT0/Tis ypN0) at the time of surgery, analysed in each group separately and in all patients who received at least one dose of all three study treatment (modified intention-to-treat population). The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12619001308189, and EudraCT, 2019-003465-18, and is ongoing. FINDINGS:Between July 6, 2020, and April 1, 2022, 124 participants were enrolled and 14 were ineligible. 110 participants were randomly assigned and 108 were included in the modified intention-to treat analysis (53 in the lead-in group and 55 in the concurrent group). Median follow-up was 12 months (IQR 7-18). All patients were female with a median age of 49 years (IQR 43-60). 18 (17%) patients had clinically node-positive disease; 37 (34%) had clinical stage I, 70 (65%) had stage II, and one (1%) had stage III disease. The pathological complete response rate was observed in 27 (51% [39-63]) of 53 patients in the nivolumab lead-in group and in 30 (55% [43-66]) of 55 in the concurrent group. Treatment-related grade 3-4 adverse events occurred in 70 (65%; 32 [60%] of 53 in the lead-in group and 38 [69%] of 55 in the concurrent group) of 108 patients, with the most common being decreased neutrophil count (25 [47%] of 53 in the lead-in group vs 28 [53%] of 55 in the concurrent group), anaemia (six [11%] vs ten [19%]), and increased alanine aminotransferase (three [6%] vs three [6%]). Serious adverse events were reported in 16 (30%) patients in the lead-in group and 26 (47%) in the concurrent group. Treatment-related serious adverse events occurred in seven (13%) patients in the lead-in group and 20 (36%) in the concurrent group. No treatment-related deaths occurred during the study. INTERPRETATION:While this study did not support the hypothesis that lead-in nivolumab before chemotherapy was associated with a pathological complete response advantage, high pathological complete response rates were reached supporting shorter duration, non-anthracycline regimens in patients with newly diagnosed triple-negative breast cancer. Future trials are warranted to compare this regimen with the current standards of care. FUNDING:Breast Cancer Trials and Bristol Myers Squibb.

Importance:The Breast Cancer Index (BCI) previously identified premenopausal patients with tumors in which the ratio of expression of HOXB13 relative to IL17BR (hereafter, BCI [H/I]-low tumors) as likely to derive greatest benefit from ovarian function suppression (OFS)-containing adjuvant therapy in the Suppression of Ovarian Function Trial (SOFT) trial. Objectives:To assess BCI as a predictive biomarker of benefit from exemestane plus OFS vs tamoxifen plus OFS and to validate BCI as a prognostic biomarker for premenopausal patients. Design, Setting, and Participants:This prognostic study used a prospective-retrospective translational design within the Tamoxifen and Exemestane (TEXT) and SOFT trials (enrolled November 2003 to April 2011). Blinded BCI testing in all available tumor samples was completed in March 2024. Premenopausal women with hormone receptor-positive breast cancer randomized to tamoxifen plus OFS or exemestane plus OFS who had BCI assessed were included. Analysis occurred from March to August 2024. Exposure:5 years of adjuvant tamoxifen plus OFS or exemestane plus OFS. Main Outcomes and Measures:The primary outcomes were breast cancer-free interval (BCFI) for predictive analyses and distant recurrence-free interval (DRFI) for prognostic analyses after a median follow-up of 13 years in the TEXT cohort. Secondary objectives examined the predictive performance of BCI (H/I) in the combined TEXT and SOFT cohort overall and in prespecified clinical subgroups. Results:Of 1782 patients in the TEXT study, 1034 (58.0%) had BCI (H/I)-low tumors; 915 (51.3%) of patients had N0 disease and 1077 (60.4%) were younger than 45 years. Patients with BCI (H/I)-low tumors had a 6.6% absolute benefit in 12-year BCFI (HR, 0.61; 95% CI, 0.44-0.85) for exemestane plus OFS vs tamoxifen plus OFS, while those with BCI (H/I)-high tumors had a 6.3% absolute benefit (HR, 0.78; 95% CI, 0.57-1.07; P for interaction = .29). Results were consistent in the combined TEXT plus SOFT cohort (2896 patients) and adjusting for clinicopathological variables. Clinical subgroup analyses consistently showed benefit of exemestane plus OFS vs tamoxifen plus OFS for BCI (H/I)-low tumors, and more variable relative treatment effects among BCI (H/I)-high tumors, including by age. Post hoc exploratory time-varying estimates suggested the treatment × BCI associations may differ in years 0 to 5 vs greater than 5 years. BCI and BCI N+ as continuous indices were prognostic for distant recurrence in N0 (HR, 1.27; 95% CI, 1.11-1.44; P < .001) and N1 (HR, 1.58; 95% CI, 1.21-2.05; P < .001) cancers. The 12-year DRFI was 96.3%, 90.3%, and 84.9% for BCI low-, intermediate-, and high-risk N0 cancers, respectively. Conclusions and Relevance:In this study of premenopausal women with hormone receptor-positive breast cancer, BCI (H/I) status did not clearly predict greater benefit of adjuvant exemestane plus OFS vs tamoxifen plus OFS for women with BCI (H/I)-low tumors than for those with BCI (H/I)-high tumors; BCI continuous indices were reconfirmed as prognostic for premenopausal women. These findings support prior results of SOFT, which compared tamoxifen-alone vs OFS with either exemestane or tamoxifen, indicating premenopausal patients with BCI (H/I)-low tumors may benefit from more intensive endocrine therapy.

Background and objective: Patients receiving immune checkpoint blockade (ICB) therapy may experience periods of prolonged disease control without a need for systemic therapy. Treatment-free survival (TFS) is an important measure for this period, but no data are available for patients with metastatic renal cell carcinoma (mRCC) starting first-line agents. Our aim was to analyze TFS outcomes for patients with mRCC starting first-line therapy. Methods: We analyzed data for patients with mRCC starting first-line systemic therapy with VEGFR-targeted monotherapy, an ICB + VEGFR combination, or an ICB doublet from February 1, 2014 to February 1, 2023 from the multicenter International Metastatic RCC Database Consortium (IMDC) database. We estimated 36-mo TFS as the difference in restricted mean survival time between (1) the time to first-line therapy discontinuation and (2) the time to subsequent systemic therapy initiation. Key findings and limitations: The study population included 3758 patients receiving either first-line VEGFR monotherapy (n = 2635), an ICB + VEGFR combination (n = 354), or doublet ICB (n = 769) were included. For the IMDC favorable-risk cohort, the 36-mo TFS estimate was 3.1 mo (95% confidence interval [CI] 1.5-4.6) for the VEGFR monotherapy group and 3.7 mo (95% CI 0.2-7.2) for the ICB + VEGFR group. For the IMDC intermediate-/poor-risk cohort, TFS was 2.1 mo (95% CI 1.4-2.8) for the VEGFR monotherapy group, 3.7 mo (95% CI 1.0-6.4) for the ICB + VEGFR group, and 5.3 mo (95% CI 3.8-6.8) for ICB doublet group. Limitations include the retrospective design and an inability to quantify time spent with adverse events. Conclusions and clinical implications: Our study demonstrates that patients with IMDC intermediate or poor risk treated with ICB doublet therapy experienced longer TFS than those treated with VEGFR monotherapy in the first-line setting. These results emphasize the utility of TFS as an informative endpoint and provide survival estimates to inform decision-making in mRCC. Patient summary: For patients with metastatic kidney cancer, we compared the survival time free from a second treatment line for different first-line treatment options. The results show that the time free from second-line treatment was longer when first- line treatment was with a combination of two immunotherapy drugs (ipilimumab and nivolumab) in comparison to other treatment options. Association of Urology. Published by Elsevier B.V. All rights are e for text and data mining, AI training, and similar technologies.

PURPOSE:The aim of PREDICT was to confirm clinical validity and the potential for clinical utility of serial circulating tumor cell (CTC) enumeration in patients with metastatic breast cancer, focusing on its prognostic value in different breast cancer subtypes and clinical settings. EXPERIMENTAL DESIGN:In total, 4,436 individual patient-level data with CTC results from both baseline and one follow-up (CellSearch; Menarini Silicon Biosystems) were analyzed to evaluate the association between CTC detection and overall survival (OS) in the full patient cohort and separately for tumor and treatment types. RESULTS:Using the cutoff ≥1 CTC for CTC positivity, 913 (20.6%) patients had 0 CTCs at both time points (neg/neg) and 325 (7.3%) and 1,189 (26.8%) patients converted from CTC negative to CTC positive (neg/pos) or vice versa (pos/neg), whereas 2,009 (45.3%) patients had at least one CTC at both time points (pos/pos). The median OS for the neg/neg, neg/pos, pos/neg, and pos/pos group was 45.6, 26.1, 32.3, and 17.3 months, respectively (P < 0.0001, global log-rank test). CTC responders (pos/neg) showed a lower risk of death compared with CTC nonresponders (pos/pos; HR, 0.48; 95% confidence interval, 0.44-0.53). Similar results were obtained in subgroup analyses according to hormone receptor and HER2 subtype, treatment type, and with a ≥5 CTC cutoff for CTC positivity. CONCLUSIONS:Follow-up CTC assessments strongly predict OS independently from tumor subtype and treatment. New randomized trials to define the clinical utility of CTC monitoring for risk stratification and as an early response marker in metastatic breast cancer are urgently needed.

Phosphorylation of the JNK (pJNK) protein promotes an immunosuppressive tumor microenvironment (TME), enhancing aggressiveness in inflammatory triple-negative breast cancer (TNBC). This study evaluated the role of JNK signaling using a gene signature. RNA sequencing was performed on 347 TNBC tumors from the phase 3 International Breast Cancer Study Group (IBCSG) 22-00 trial, which evaluated adjuvant low-dose cyclophosphamide and methotrexate (CM). Immune-related tumors were identified by TNBC subtype or tumor-infiltrating lymphocytes (TILs). Associations between JNK and outcomes were analyzed using Cox models. Low pJNK levels were associated with better disease-free survival (DFS) in immune-related tumors. These tumors also had lower Treg levels and higher CD8+/Treg ratios. Notably, immunomodulatory (IM) tumors with high pJNK showed improved DFS when treated with CM. High pJNK expression identifies immunosuppressive TMEs with poor prognosis in inflamed TNBC. However, these tumors may benefit from CM, supporting pJNK as a potential biomarker for immunotherapy strategies.

541 Background: Systemic treatment decisions for young BRCA carriers with small node-negative breast cancers present unique challenges due to limited evidence on the benefits of chemotherapy in this setting. This study evaluated chemotherapy use and survival outcomes among these patients. Methods: The BRCA BCY collaboration (NCT03673306) is an international, multicenter, hospital-based, retrospective cohort study that included carriers of germline pathogenic variants in BRCA1/2 diagnosed with invasive breast cancer at the age of ≤40 years between January 2000 and December 2020. Among patients diagnosed with T1N0 disease, survival outcomes - disease-free survival (DFS) and overall survival (OS) defined from breast cancer diagnosis - were compared between patients who received chemotherapy and those who did not, using multivariate Cox models adjusted for propensity score (including age at diagnosis, histology, grade, country and year of diagnosis) and risk-reducing surgeries (bilateral risk-reducing mastectomy (RRM) and/or risk-reducing salpingo-oophorectomy (RRSO)), and accounting for the delayed entry at the time of BRCA testing (i.e. left truncation). Subgroup analyses were performed according to tumor subtype (HR+/HER2- vs triple negative breast cancer (TNBC)). Results: Out of 5660 from 109 centers, 1280 patients had T1N0 breast cancer: T1mic (n = 14, 1.1%), T1a (n = 92, 7.2%), T1b (n = 303, 23.7%), T1c (n = 778, 60.8%), and T1 size unknown (n = 93, 7.3%). Most patients received chemotherapy (80%), although use was less frequent over time. Among patients who received chemotherapy, the majority were treated with an anthracycline-containing regimen (83.6%) and in the adjuvant setting (85.7%). Patients who received chemotherapy were younger and more likely to have high grade, TNBC or larger tumors compared to those who did not. The median follow-up was 8.7 years (IQR 5.0-13.4 years), during which 428 had DFS events including second primary breast cancer (n = 174), locoregional (n = 130), distant relapse (n = 65), second primary non breast cancer (n = 53), and 88 had died. Overall, 8-year DFS was 69.4%. In multivariate analysis, no significant differences in DFS or OS were observed between patients who received chemotherapy and those who did not (DFS HR = 0.92, 95% CI 0.65-1.31; OS HR = 0.68, 95% CI 0.37-1.24). No significant difference in 8-year DFS was observed between patients with HR+/HER2- breast cancer (n = 474) treated with or without chemotherapy (HR 0.91: 95% CI 0.59-1.43), or between patients with TNBC (n = 637) treated with or without chemotherapy (HR 0.84: 95% CI 0.46-1.53). Conclusions: In this global study of young BRCA carriers with T1N0 breast cancer, chemotherapy was not associated with better DFS or OS overall. However, these patients remain at high risk of events and warrant investigation of additional risk-reduction strategies.

BACKGROUND:Treatment-free survival (TFS; time spent free of systemic anticancer therapy) is increasingly used to support traditional endpoints. TFS was previously evaluated in patients with advanced melanoma treated with nivolumab plus ipilimumab. This analysis compared TFS for nivolumab plus relatlimab and nivolumab monotherapy in patients with advanced melanoma. METHODS:Data were from 714 patients in the phase 2/3 RELATIVITY-047 trial (ClinicalTrials.gov identifier: NCT03470922). TFS was defined as the difference in restricted mean event times between the Kaplan-Meier curves for time to protocol therapy cessation and time to subsequent systemic anticancer therapy initiation or death. TFS was further partitioned into time with and time without grade ≥3 treatment-related adverse events (TRAEs). Subgroup analysis based on tumor BRAF mutational status and tumor programmed death ligand 1 (PD-L1) expression level was conducted. Between-treatment group differences were calculated with bootstrapped 95% CIs. RESULTS:At 48 months from randomization, Kaplan-Meier estimates of overall survival were 52% and 43% for patients in the nivolumab plus relatlimab and nivolumab groups, respectively; 38% and 33% of patients in these respective groups were free of subsequent systemic therapy. The 48-month mean TFS was 2.9 months (95% CI 1.0 to 4.9) longer with nivolumab plus relatlimab than with nivolumab (9.7 vs 6.8 months, respectively). Mean TFS represented 20% and 14% of the 48-month period after initiating nivolumab plus relatlimab and nivolumab, respectively. Considering only time without grade ≥3 TRAEs, the 48-month mean TFS was 2.6 months (95% CI 0.8 to 4.5) longer with nivolumab plus relatlimab than with nivolumab (9.1 vs 6.5 months, respectively). The 48-month mean total TFS was consistently longer with nivolumab plus relatlimab than with nivolumab in the BRAF mutant (9.4 vs 6.5 months), BRAF wild-type (9.9 vs 6.9 months), PD-L1 ≥1% (12.3 vs 7.7 months), and PD-L1<1% (7.9 vs 6.2 months) subgroups. CONCLUSIONS:This analysis demonstrated TFS benefit during the 48 months since initiating nivolumab plus relatlimab compared with nivolumab alone in patients with advanced melanoma. A direct comparison between nivolumab plus relatlimab and nivolumab plus ipilimumab is needed to determine the differences between the regimens in TFS and those in traditional endpoints.