Abstract Platinum-based chemotherapy remains a cornerstone of treatment for triple-negative breast cancer (TNBC), yet the molecular determinants governing platinum response remain poorly defined. By leveraging the randomized Phase II INFORM trial, which compared neoadjuvant cisplatin to anthracycline-based therapy in BRCA1/2 -mutant breast cancer—we identified miR-362-3p as a specific regulator of cisplatin sensitivity. Higher plasma miR-362-3p expression was exclusively associated with favorable clinical outcome in the cisplatin arm, with no association observed in the AC arm, decoupling platinum-specific vulnerability from general chemotherapy response. We used gain- and loss-of-function TNBC models to establish that miR-362-3p functions as a potent sensitizer to cisplatin in vitro and in vivo . Integrated TCGA analysis and experimental validation identified BCLAF1, a key regulator of DNA damage response, as a direct repression target of miR-362-3p. We uncovered a novel role for the miR-362-3p/ BCLAF1 axis in overcoming platinum resistance in TNBC.

LBA4 Background: ESR1 mutations ( ESR1 m) constitutively activate the estrogen receptor (ER) and are the most common mechanism of acquired resistance to aromatase inhibitor (AI) + CDK4/6i. Molecular monitoring by ctDNA analysis can detect the emergence of ESR1 m during 1L AI + CDK4/6i. Camizestrant, the next-generation selective ER degrader (SERD) and complete ER antagonist, has shown anti-tumor activity in pts with and without detectable ESR1 m. SERENA-6 is the first global registrational Phase 3 trial assessing a ctDNA-guided approach to detect the emergence of ESR1 m during 1L AI + CDK4/6i to inform a switch in therapy ahead of disease progression. Methods: Pts with HR+/HER2– ABC who had received ≥6 months of 1L AI (anastrozole/letrozole) + CDK4/6i (abemaciclib/palbociclib/ribociclib) were enrolled and had ctDNA tested for ESR1 m every 2–3 months, coinciding with routine imaging. At ESR1 m detection, pts without evidence of disease progression were randomized 1:1 to switch to camizestrant (75 mg) with continued CDK4/6i (type and dose maintained) + placebo for AI vs continuing AI + CDK4/6i + placebo for camizestrant. The primary endpoint was investigator-assessed PFS (per RECIST v1.1). Prespecified interim analysis data cutoff was Nov 28, 2024. Results: 3,256 eligible pts were surveilled for ESR1 m using ctDNA until 315 eligible pts were randomized to switch to camizestrant (n=157) or continue with AI (n=158). All pts remained on the same CDK4/6i. ~50% of randomized pts had ESR1 m detected at the first ctDNA test. Baseline characteristics were well balanced between treatments. After 171 PFS events, hazard ratio for PFS was 0.44 (95% CI 0.31–0.60, p<0.00001; median PFS 16.0 vs 9.2 months). PFS benefit was consistent across subgroups. PFS rate at 12 months was 60.7% (95% CI 51.1–69.0) vs 33.4% (95% CI 24.9–42.2) and at 24 months was 29.7% (95% CI 19.0–41.2) vs 5.4% (95% CI 0.7–18.2). PFS2 hazard ratio was 0.52 (95% CI 0.33–0.81; 27% maturity). OS is immature (12%). Camizestrant + CDK4/6i was well tolerated with safety consistent with the known profiles of camizestrant, and of each CDK4/6i. Rates of treatment discontinuation due to adverse events were 1.3% for camizestrant and 1.9% for AI. Conclusions: Camizestrant + CDK4/6i guided by emergence of ESR1 m during 1L AI + CDK4/6i in pts with HR+/HER2– ABC resulted in a statistically significant and clinically meaningful improvement in PFS. SERENA-6 is the first global Phase 3 trial to demonstrate clinical utility of using ctDNA to detect and treat emerging resistance, ahead of disease progression. These findings represent a potential new treatment strategy to optimize and improve 1L patient outcomes. Clinical trial information: NCT04964934 .

1016 Background: evERA BC (NCT05306340) is the first Phase III trial to demonstrate a statistically significant and clinically meaningful improvement in investigator-assessed progression-free survival (INV-PFS) with an all-oral, selective ER degrader and full ER antagonist combination (GIRE + E) compared with standard-of-care endocrine therapy combinations (SOC ET + E) in pts with ER+, HER2– aBC post-CDK4/6i + ET (Mayer ESMO 2025). Improvement in INV-PFS was seen in all pts (hazard ratio [HR], 0.56) and in pts whose tumors had a detectable ESR1 mutation ( ESR1 m; HR, 0.38), with no unexpected safety findings. We report exploratory post-progression tx analyses. Methods: Pts with ER+, HER2– aBC who had disease progression (PD) or relapse during/post-CDK4/6i + ET were randomized 1:1 to once-daily oral 30 mg GIRE + 10 mg E or SOC ET (exemestane/ fulvestrant/tamoxifen) + E until PD/unacceptable toxicity. Exploratory analyses included PFS2 (time from randomization to PD on next-line tx, or death), chemotherapy-free survival (CFS; time to first subsequent chemotherapy and/or antibody–drug conjugate [ADC], or death), and types of cancer tx following discontinuation from study tx. Results: Median PFS2 and CFS were longer with GIRE + E vs SOC ET + E in all pts (PFS2 HR, 0.69; CFS HR, 0.61), including in the ESR1 m (PFS2, 0.61; CFS, 0.46) and ESR1 m not detected populations (PFS2, 0.77; CFS, 0.80; Table). Of those receiving follow-up cancer therapy in all pts, and in the ESR1 m and ESR1 m not detected populations, 69.1%, 63.3%, and 73.8%, respectively, received chemotherapy in the GIRE + E arm vs 71.5%, 65.3%, and 79.0% in the SOC ET + E arm; 24.5%, 18.4%, and 29.5% received an ADC in the GIRE + E arm vs 31.4%, 25.3%, and 38.7% in the SOC ET + E arm. Conclusions: Delaying chemotherapy improves clinical and quality of life outcomes in ER+ aBC. These analyses further support the superior INV-PFS of GIRE + E over SOC ET + E observed in all pts and in the ESR1 m population. Improvements in PFS2 and CFS, regardless of ESR1 m status, suggest that the clinical benefit of GIRE + E is sustained beyond initial progression. Clinical trial information: NCT05306340 . All pts ESR1 m ESR1 m not detected GIRE + E (n = 183) SOC ET + E (n = 190) GIRE + E (n = 102) SOC ET + E (n = 105) GIRE + E (n = 81) SOC ET + E (n = 85) PFS2 Event, n (%) 81 (44.3) 108 (56.8) 39 (38.2) 57 (54.3) 42 (51.9) 51 (60.0) Median, mo (95% CI) 19.0(15.5, not evaluable [NE]) 13.2 (11.7, 15.9) 19.0 (15.5, NE) 12.9 (11.8, 17.6) 17.3(13.0, NE) 12.9 (9.8, 20.8) Stratified HR (95% CI) 0.69 (0.51, 0.92) 0.61 (0.40, 0.93) 0.77 (0.51, 1.17) CFS Event, n (%) 111 (60.7) 146 (76.8) 51 (50.0) 78 (74.3) 60 (74.1) 68 (80.0) Median, mo (95% CI) 11.1(9.6, 12.7) 7.9 (6.9, 9.5) 12.6 (10.9, 18.7) 8.5 (7.1, 10.0) 9.5 (7.4, 11.6) 7.2(6.1, 9.5) Stratified HR (95% CI) 0.61 (0.47, 0.78) 0.46 (0.32, 0.66) 0.80 (0.57, 1.14)

BACKGROUND:Tumor-infiltrating lymphocytes (TILs), assessed by visual examination, are prognostic and predictive in early-stage triple-negative breast cancer. Computational assessment may provide a complementary approach. We evaluated the prognostic value of TILs by visual examination and computational assessment. METHODS:Cisplatin vs Paclitaxel for Triple Negative Breast Cancer (TBCRC030; ClinicalTrials.gov identifier NCT01982448) was a randomized phase 2 trial enrolling patients with BRCA1/2-proficient stage I to III triple-negative breast cancer to receive preoperative cisplatin or paclitaxel. The primary endpoint was pathological response at surgery. The TILs were visually scored on digitized pretreatment biopsies per International TILS Working Group recommendations. Computational assessment used the 4D Path QPOR platform to generate TILs, an immune heterogeneity index, and a combined immune/cell cycle biomarker (CmbI). Predictive performance for residual cancer burden 0/1 was assessed using receiver operating characteristic curves and odds ratios (ORs) with 95% CIs; all statistical tests were 2-sided. RESULTS:Of 139 response-evaluable patients, 121 had matched visual examination and computational assessment data (59 on cisplatin, 62 on paclitaxel). Median visual examination TILs were higher in responders (40.0% vs. 10.0%; P = .002) and predicted response (OR = 1.86, 95% CI = 1.24 to 2.87; area under the curve = 0.69, 95% CI = 0.57 to 0.80). Computational assessment CmbI differed by response group and predicted residual cancer burden 0/1 (OR = 3.20, 95% CI = 1.05 to 11.07; area under the curve = 0.62, 95% CI = 0.51 to 0.73). Computational assessment TILs and immune heterogeneity index were not predictive. Visual examination TILs and computational assessment CmbI predicted response to paclitaxel (OR = 2.91, 95% CI = 1.56 to 6.14; OR = 9.17, 95% CI = 2.01 to 66.39, respectively) but not to cisplatin. CONCLUSION:Visual examination TILs and computational assessment CmbI were each associated with response to neoadjuvant chemotherapy in triple-negative breast cancer in the overall cohort and the paclitaxel arm. Computational assessment CmbI did not outperform visual assessment. Further validation is needed before clinical implementation of computational approaches.

Abstract Background Invasive lobular carcinoma (ILC) exhibits distinct biological and metastatic behavior compared with invasive breast carcinoma of no special type (BC-NST), yet patterns of central nervous system (CNS) dissemination remain incompletely defined. We examined determinants of CNS metastases and LMD to assess whether histology confers independent CNS risk. Methods Retrospective analysis using data from EMBRACE, a prospectively maintained cohort of patients with metastatic BC (mBC). Patients with BC-NST or ILC were included. CNS mets was defined as parenchymal brain mets and/or leptomeningeal disease (LMD). Associations between histology and CNS mets or LMD were evaluated using logistic regression. Multivariable models were adjusted for age, tumor grade, hormone receptor status, HER2 status, and de novo versus recurrent presentation. Results 3835 patients with mBC (3247 BC-NST; 588 ILC) were included (median follow-up, 16.4 years). Overall, 78.2% had recurrent disease; subtype distribution was HR+/HER2 − (61.2%), HER2 + (19.7%), and TNBC (19.1%). CNS mets occurred in 26.4% of BC-NST and 17.5% of ILC cases. ILC was associated with lower odds of CNS mets in unadjusted analyses (OR 0.59; 95% CI, 0.47–0.74) but not after adjustment (OR 1.08; 0.83–1.41). No histology-based difference was observed in HER2+ disease. Among HER2− tumors, CNS mets were less frequent in ILC than BC-NST (OR 0.63; 0.49–0.81), driven by TNBC (OR 0.25; 0.06–0.74), with no difference in HR+/HER2−. In multivariable models, CNS mets were associated with younger age, higher grade, ER/PR-negative status, HER2+ disease, and recurrent presentation. LMD occurred in 5.7% of BC-NST and 11.1% of ILC cases and was more frequent in ILC in adjusted analyses (OR 3.52; 2.44–5.05). Conclusion Histology differentially influences CNS dissemination in mBC. Although the lower CNS metastasis risk in ILC can be explained by tumor and clinical factors, ILC remains independently associated with a markedly higher risk of LMD.

1024 Background: Invasive lobular carcinoma (ILC) is a distinct breast cancer (BC) subtype with dissemination patterns differing from invasive breast carcinoma of no special type (IBC-NST). While genomic differences between ILC and IBC-NST have been described, the extent to which molecular and immune profiles vary by metastatic organ and histology is poorly characterized. Methods: We conducted a retrospective analysis to evaluate organ- and histology-specific molecular features of metastatic BC (mBC). Patients with metastatic IBC-NST or pure ILC underwent NGS (592, NextSeq; WES/WTS, NovaSeq; Caris Life Sciences). Tumor mutational burden (high ≥10 mut/Mb), PD-L1 expression (22C3), and immune cell fractions (RNAseq deconvolution, quanTIseq) were assessed. Analyses were restricted to sites with ≥10 biopsies per histology. Comparisons used chi-square or Mann–Whitney U tests with multiple testing correction (q < 0.05). Results: A total of 2645 mBC biopsies (605 ILC; 2040 IBC-NST) were analyzed (Table). In ILC, ERBB2 mut frequency differed by metastatic site (q<0.01), with higher prevalence in liver (32.7%) and lower in gastrointestinal (GI) lesions (3.7%). In IBC-NST, ESR1 and GATA3 mut and FGFR1 amplification were enriched in liver metastases, whereas PD-L1 expression was highest in skin (20.7%) and lowest in liver (5.0%). No organ-specific differences were observed for PIK3CA, AKT, PTEN, BRCA1/2 or RB1 . Across metastatic sites, both ILC and IBC-NST showed differences in B cells, macrophages (M1/M2), neutrophils, NK cells, dendritic cells, CD8+ T cells, and Tregs (all q < 0.05); CD4+ T-cell differences were observed only in IBC-NST (q = 0.002). In organ-specific ILC vs IBC-NST comparisons, CDH1 mut were more frequent in ILC across sites, along with higher PIK3CA mut in skin (ILC 51.3% vs IBC-NST 34.4%) and higher ERBB2 mut in liver (32.7% vs 3.3%), whereas a higher TP53 mut frequency was observed in IBC-NST in skin (28.5% vs 52.3%) and lymph nodes (LND) (23.5% vs 55.5%) (all q < 0.01). Conclusions: mBC exhibits marked organ-specific molecular and immune heterogeneity that differs by histology. These findings support histology- and site-aware interpretation of metastatic biopsies and may inform biomarker assessment and treatment decisions in advanced disease. BC-NST ILC Skin LND Bone Breast Liver Perit. CNS q-value Skin LND Bone Breast GI Liver GYN Perit. CNS q-value N (specimens) 785 401 109 361 220 15 44 - 172 84 62 56 56 54 43 37 11 - ERBB2 mut (%) 3.2 3.1 3.2 2.3 3.3 7.1 2.5 1.0 7.1 7.4 16.4 15.4 3.7 32.7 2.4 5.7 11.1 <0.01 ESR1 mut (%) 9.4 5.2 8.3 16.0 28.2 7.1 2.4 0.0 7.8 7.2 8.9 9.8 16.7 26.0 4.9 20.0 0.0 0.9 FGFR1 amp (%) 10.1 6.6 5.6 12.8 16.5 0.0 9.7 0.02 4.4 3.4 6.7 6.1 2.4 5.6 7.7 18.5 0.0 1.0 IHC-PD-L1 (%) 20.7 - 5.3 16.0 5.0 11.1 10.3 0.02 8.9 - 5.0 5.7 6.1 0.0 0.0 0.0 14.3 1.0 TMB-High (%) 10.7 10.1 8.8 8.8 8.5 14.3 21.4 0.8 27.6 11.0 19.6 28.0 11.3 19.6 9.8 32.4 22.2 0.8 Perit: peritoneum; CNS: central nervous system; GYN: genital tract.

LBA1007 Background: CAMI is a next-generation SERD and complete ER antagonist. SERENA-6 enrolled patients (pts) with HR+/HER2− ABC receiving 1L aromatase inhibitor (AI) + CDK4/6i and without disease progression. Switching to CAMI, with continued CDK4/6i, at ESR1 m emergence during 1L AI + CDK4/6i significantly improved PFS (HR: 0.44 [95% CI: 0.31–0.60]; p<0.0001; median follow-up: 12.6 mo). Here, we report the final PFS2 results. Methods: SERENA-6 was powered for PFS (primary endpoint) and the key secondary endpoint of investigator-assessed PFS2 (time from randomization to the earliest of disease progression after first subsequent therapy or death). Pts had scans to assess PFS2 every 8–12 weeks after first progression. PFS2 analysis was planned after ~158 PFS2 events (77% power to detect HR of 0.65) and analyzed using an adjusted log-rank test and a 2-sided significance level of ~5%. Chemotherapy/ADC-free survival was a secondary endpoint. Results: 157 pts were randomized to CAMI + CDK4/6i and 158 pts to AI + CDK4/6i. After 23.5 mo median follow-up (data cutoff: Jan 3, 2026), median PFS2 was 25.7 mo with CAMI + CDK4/6i vs 19.1 mo with AI + CDK4/6i; statistically significant improvement, HR: 0.63 (95% CI: 0.46–0.86); p=0.00373 (Table). Endocrine-based therapy was the most common first subsequent treatment (CAMI + CDK4/6i arm, 55.2%; AI + CDK4/6i arm, 66.7%). CAMI + CDK4/6i prolonged chemotherapy/ADC-free survival (HR: 0.64 [95% CI: 0.47–0.87]; nominal p=0.00375; Table) and TTD in GHS/QoL (0.48 [0.31–0.76]); nominal p<0.001). PFS benefit with CAMI + CDK4/6i was maintained with longer follow-up (Table); 30-mo PFS rate was 30.4% vs 2.7% with continued AI + CDK4/6i. PFS benefit was not impacted by common co-mutations ( PIK3CA in 41.3% of pts, HR: 0.44 [95% CI: 0.28–0.68]; TP53 in 25.4% of pts, 0.49 [0.30–0.82]). At 30% maturity, OS HR was 0.87 (0.57–1.30). Safety was consistent with previous results. Conclusions: Switching to CAMI + CDK4/6i at ESR1 m emergence continued to result in PFS benefit, with approximately a third of pts still progression-free at 30 mo. PFS benefit was maintained beyond first progression; PFS2 was significantly improved and the clinically meaningful endpoint of chemotherapy/ADC-free survival was prolonged vs continuing AI + CDK4/6i. These results continue to support a switch to CAMI + CDK4/6i for pts with ESR1 m during 1L therapy to delay disease progression and deteriorations in QoL. Clinical trial information: NCT04964934 . DCO3 CAMI + CDK4/6i (n=157) AI + CDK4/6i (n=158) HR (95% CI) PFS Events, n (%)Median, mo24-mo rate, %30-mo rate, % 99 (63.1)16.834.930.4 124 (78.5)9.214.22.7 0.45 (0.34–0.59); p<0.00001 PFS2 Events, n (%)Median, mo24-mo rate, %30-mo rate, % 80 (51.0)25.750.841.5 90 (57.0)19.136.329.7 0.63 (0.46–0.86); p=0.00373 Chemotherapy/ADC-free survival Events, n (%)Median, mo 85 (54.1)22.6 98 (62.0)18.7 0.64 (0.47–0.87); nominal p=0.00375

563 Background: Adjuvant abemaciclib reduces recurrence risk and improves overall survival in patients with high-risk node-positive early HR+/HER2- breast cancer. However, treatment-emergent diarrhea may lead to dose modifications, treatment discontinuation, and impaired quality of life. The gut microbiome influences treatment response and toxicity across multiple cancer therapies; its role in abemaciclib-associated diarrhea remains undefined. We evaluated features of the gut microbiome during the initiation of adjuvant abemaciclib and any association with diarrhea. Methods: 90 patients with HR+/HER2− early breast cancer enrolled in the TRADE trial (NCT06001762) and were treated with dose-escalated adjuvant abemaciclib (50 mg BID x 14 days, then 100 mg BID x 14 days, then 150 mg BID onwards) plus endocrine therapy. Stool samples were collected at baseline, cycle 2 day 1 (C2D1), and end of treatment (EOT). Whole-genome shotgun metagenomic sequencing was performed, and species-level profiles were generated using MetaPhlAn4. Diarrhea was analyzed as a binary outcome (ever vs none). Associations between microbiome features and clinical variables were evaluated using linear mixed modeling with a random effect for repeated samples from the same individual (alpha diversity) or per-timepoint using PERMANOVA (beta diversity) and MaAsLin3 (species and genes, with false discovery rate correction). Models were adjusted for age, cancer stage, and type of endocrine therapy. Results: A total of 142 samples were analyzed (77 baseline, 58 C2D1, and 7 EOT; 77 total subjects, 28 with diarrhea, 49 without). Treatment was associated with a consistent microbiome shift from baseline to C2D1, characterized by a decline in alpha diversity (-0.26, 95% CI -0.39 to -0.14, p < 0.001) and a phylum-level shift with increased Bacteroidota and decreased Firmicutes abundance (p < 0.002 and p = 0.001, respectively, paired T-test). When assessing by timepoint, having any-grade diarrhea was not associated with differences in beta diversity or alpha diversity, nor with individual microbial species; pathway-level enrichment suggested diarrhea-associated functional trends that did not meet FDR significance. Limited EOT samples suggested partial recovery following treatment. Conclusions: Adjuvant abemaciclib induced consistent, treatment-related shifts in gut microbiome composition, characterized by reduced diversity and a phylum-level shift from Firmicutes to Bacteroidota, suggesting an early broad ecological treatment effect from exposure to a CDK4/6 inhibitor. This pattern has been reported in patients with inflammatory bowel disease. A species-specific diarrhea signature or predictive relationship between microbiome signature and the development of diarrhea was not observed. Further evaluation of the microbiome's evolution at EOT is ongoing. Clinical trial information: NCT06001762 .

TPS1162 Background: Triple-negative breast cancer (TNBC) refers to a heterogenous group of breast cancers that lack expression of ER, PR, and HER2. Despite recent advances with immunotherapy (IO) and antibody-drug conjugates (ADCs), TNBC remains the most aggressive subtype, with short overall survival in the metastatic setting. Breast tumors with low levels of ER and PR expression (1-10%) clinically behave like TNBC, and clinical management follows the TNBC treatment (tx) paradigm. We and others have identified a subset of ER/PR/HER2-negative breast cancers (BCs) that express the androgen receptor (AR). Enzalutamide (enza), an AR-antagonist, has demonstrated activity in AR-positive metastatic TNBC (Traina et al, JCO 2018). Activation of the glucocorticoid receptor (GR) has been implicated as a mechanism of resistance to AR inhibition in prostate and BCs (Kach et al, Sci Transl Med 2015). Effective therapies for advanced TNBC remain an unmet need, particularly in patients who are ineligible for or progress following a checkpoint inhibitor. This randomized study evaluates the efficacy of enzalutamide or enzalutamide plus the GR antagonist mifepristone (mif) as compared to physician’s choice chemotherapy (TPC). Methods: This is a randomized phase II trial; 201 patients (pts) will be randomized in a 1:1:1 fashion to enza, enza with mif, or TPC (carboplatin, paclitaxel, eribulin, or capecitabine). The primary endpoint (endpt) is progression-free survival (PFS), and the trial is designed to test the hypothesis that PFS in the pooled enza arms is superior to TPC; there is 80% power to detect a hazard ratio (HR) of 0.70, corresponding to an increase in median PFS from 3.5 months (mos) with TPC to 5.0 mos with enza-based tx. Secondary endpts include comparisons of PFS among the 3 arms and evaluation of response rate, clinical benefit rate, duration of response, overall survival, safety, and patient-reported outcomes by arm. Exploratory endpts include correlation of tumor and circulating markers (constitutively active AR variants in circulating tumor cells and cfDNA) with tx response. Eligible pts must have: ECOG 0-2, metastatic measurable or evaluable disease (dz), normal organ function, no history of brain mets, < prior lines of chemotx, any # of prior endocrine txs, no prior anti-AR tx, no prior mif, no concurrent CYP17 inhibitor use. Tumors must test ER/PR low or negative, HER2 negative, AR >10%. Pts with PD-L1+ BC must have received prior IO if not contraindicated. As of December 28, 2025, 32 of 201 pts have been enrolled on study. Clinical trial information: NCT06099769 .

Triple-negative breast cancer (TNBC) patients with brain metastases have a poor prognosis and limited treatment options. Preclinical and clinical evidence suggests that radiotherapy may act synergistically with immune checkpoint inhibitors. We conducted an open-label, single-arm, phase II study of atezolizumab plus stereotactic radiosurgery (SRS) in metastatic TNBC patients with brain metastases. The primary endpoint was progression-free survival (PFS) according to the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) bi-compartmental model. Secondary endpoints included extracranial objective response rate, overall survival (OS), and safety and tolerability. A safety run-in analysis for dose-limiting toxicity (DLT) was performed after the first 6 patients were enrolled and completed the assessment period. Six patients were enrolled into the safety run-in phase between May 11, 2018 and October 24, 2019. No DLTs were observed, but the study was closed early due to slow accrual. Patients received a median of 2 atezolizumab cycles (range: 2—16), and SRS was administered to all 6 patients. Treatment-related adverse events (TRAEs) occurred in 4 participants (66.7 https://www.clinicaltrials.gov NCT03483012. Trial Open to Accrual: 05/01/2018.

BACKGROUND:Breast cancer (bc) diagnosed during pregnancy or postpartum often presents with aggressive features, potentially influenced by hormonal, immunologic, and tissue remodeling changes. Studies have suggested that postpartum bc may be associated with worse outcomes, though most evidence is retrospective and constrained by methodological limitations. This study evaluated associations between pregnancy history, recency of childbirth, and long-term outcomes in a prospective cohort of young patients with early-stage bc. PATIENTS AND METHODS:Patients aged ≤40 years with stage I-III bc enrolled in the Young Women's Breast Cancer Study were categorized at diagnosis as nulligravid, nulliparous, pregnant, or parous (≤5 vs 5 to 10 years postpartum). Analyses were stratified by bc subtype [estrogen receptor-positive [ER+]/HER2-, HER2+, and triple-negative (TNBC)], with distant recurrence-free survival (DRFS) as the primary endpoint. RESULTS:Among 859 patients, 257 (29.9%) were nulligravid, 50 (5.8%) nulliparous, 37 (4.3%) pregnant, and 515 (60.0%) parous. Pregnant patients had proportionally more TNBC, nodal involvement, T3/T4, and grade 3 tumors. After 11.1 years median follow-up, pregnancy or postpartum status was not independently associated with DRFS in multivariable models adjusted for age, tumor characteristics, and treatment, with consistent findings across ER+/HER2-, HER2+, and TNBC subtypes. Sensitivity analyses, including further categorization of postpartum diagnoses (<2 vs 2 to 5 years), yielded consistent results. CONCLUSIONS:Pregnancy history and recency of childbirth were not independently associated with long-term DRFS. Despite more aggressive features at diagnosis, patients diagnosed during or after pregnancy had comparable outcomes after adjustment, suggesting no adverse prognostic impact. CLINICAL TRIAL REGISTRATION:NCT01468246 (https://clinicaltrials.gov/study/NCT01468246?term=NCT01468246&rank=1).

Hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2–) breast cancer comprises approximately 70

PURPOSE:In TBCRC 022 (NCT01494662), neratinib and ado-trastuzumab emtansine (T-DM1) demonstrated intracranial activity among patients with HER2-positive breast cancer brain metastases. However, gastrointestinal (GI) toxicities-particularly diarrhea-were common, potentially impacting quality of life. Clinician-reported adverse event (CTCAE) grading may underestimate the patient experience. We report GI toxicities using patient-reported outcomes (PROs) in TBCRC's neratinib-T-DM1 cohort. METHODS:Patients received neratinib (160 mg daily) and T-DM1 (3.6 mg/kg IV every 21 days). A pre-planned analysis assessed patient-reported GI toxicities during Cycles 1-4 using the Patient-reported Outcomes Measurement Information System (PROMIS) GI Diarrhea scale, Systemic Therapy-Induced Diarrhea Assessment Tool (STIDAT), and PRO-CTCAE. Descriptive statistics and linear mixed effects models evaluated symptom trajectories over time. We evaluated agreement for PRO and clinician-reported data. RESULTS:Forty-four patients enrolled; all completed ≥1 PRO. GI symptom burden increased over Cycles 1-3. PROMIS scores worsened significantly by Cycle 2, with a peak mean increase of 6.62 (95% confidence interval (CI): 2.67-10.59; p = 0.002) at Cycle 3. STIDAT scores also worsened by Cycle 3 (mean change 0.50; 95%CI: 0.11-0.90; p = 0.015). Based on maximum PRO-CTCAE scores, moderate-to-severe symptoms were reported by 20.5% (diarrhea), 24.4% (appetite loss), and 41.0% (constipation). Agreement between PRO-CTCAE and clinician-reported CTCAE was low (kappa <0.2) with clinicians reporting less toxicity. PROMIS and STIDAT scores were significantly correlated. CONCLUSION:This GI-focused PRO analysis highlights the value of PROs in capturing patient-experienced toxicities that impact quality of life yet are underestimated by clinicians. Incorporating PROs into clinical trials can inform supportive care and prophylactic strategies.

TPS1156 Background: Endocrine therapy (ET) in combination with targeted treatments can effectively treat metastatic ER-positive (ER+) breast cancer (BC); however, nearly all patients ultimately progress on these therapies, eventually requiring treatment with chemotherapy. Current standard of care, based on older data, is to discontinue ET when starting chemotherapy. Many of these studies used tamoxifen, which has partial agonist activity, in combination with chemotherapy. Newer estrogen-targeting agents, e.g. oral selective ER degraders (SERDs), function as ER antagonists. Preclinical work investigating the combination of SERD and chemotherapy has demonstrated an additive effect of the agents in ER wildtype tumors and a synergistic effect in tumors with ESR1 mutation ( ESR1m ); this synergy was attenuated with P53 silencing. Methods: CAPELA, an investigator-initiated, multicenter, open-label randomized phase II study, is designed to assess the safety and efficacy of capecitabine monotherapy vs. capecitabine + elacestrant in patients with advanced/unresectable ER+ HER2- BC. Eligible patients will have progressed on a CDK4/6 inhibitor and had no prior treatment with chemotherapy for metastatic disease. At least 50% of enrolled patients are required to have ESR1m tumors. Patients will be randomized 1:1 to receive capecitabine 1000mg/m 2 PO BID days 1-14 of a 21-day cycle +/- the oral SERD elacestrant 345 mg PO daily. Randomization will be stratified by prior lines of ET in the metastatic setting (1 vs. >1), visceral disease (yes/no), TP53 mutation status, and ESR1m status. Patients with tumors with an ESR1m who are randomized to the monotherapy arm will have the option to crossover to elacestrant monotherapy at the time of progression to evaluate benefit of concurrent vs. sequential use of these agents. The primary endpoint is hierarchical assessment of median progression free survival (mPFS) in 1) the ESR1m population and if positive 2) the intention to treat (ITT) population. Secondary endpoints include safety/tolerability, median overall survival (OS), objective response rate, median time to second progression, clinical benefit rate, and patient reported outcomes in the ESR1m and ITT populations. PFS and OS in the ESR1m not detected population will also be evaluated. Exploratory correlative studies on collected plasma, serum, and archival tissue will also be conducted. The study will enroll 297 patients over an estimated 3 years. The trial will open at 10 sites through the Translational Breast Cancer Research Consortium (TBCRC). Clinical trial information: NCT07222215 .

Using patient-reported outcomes (PROs) and more objective measures, we evaluated adherence to adjuvant palbociclib and ET in the PALLAS trial, and the impact of palbociclib on ET adherence. The open-label, global, phase 3 PALLAS trial randomized patients with hormone receptor-positive (HR+), HER2-negative stage II–III breast cancer (1:1) to either 26 cycles of palbociclib (125 mg/day for 21 days and then 7 days off) plus adjuvant ET, versus ET alone. After 23.7 months median follow-up, palbociclib was stopped due to futility of the intervention and patients were moved to follow-up. For each cycle, daily adherence to ET was measured with study diaries; for palbociclib, study diaries and pill counts. At cycles 2, 3, 6, 12, 18 and 24, patients completed the Morisky Medication Adherence Scale-4 plus an additional item and the McHorney Adherence Questionnaire. Mean persistence was defined in months from treatment initiation to cessation. Four thousand six hundred eighty-eight of 5796 total PALLAS participants were included. Across all cycles, mean daily ET adherence values measured by study diary were > 98.0

BACKGROUND:We report ophthalmological assessments, patient-reported visual symptoms/functioning, and characterization of visual effect AEs from the SERENA-6 study. MATERIALS AND METHODS:This double-blind, placebo-controlled phase III study included 315 patients with ER-positive advanced breast cancer receiving first-line aromatase inhibitor (AI)+CDK4/6 inhibitor (CDK4/6i). Patients with emerging ESR1 mutations in ctDNA and no radiological progression were randomized 1:1 to switch to camizestrant+CDK4/6i or continue AI+CDK4/6i. Predefined group term visual effect AEs were graded (NCI-CTCAE v5.0). Ophthalmological assessments were conducted at baseline, as indicated, and at the end of treatment. Analyses of patient-reported visual effects/functioning were exploratory. RESULTS:Visual effect AEs were reported in 49 (31.6%) patients receiving camizestrant+CDK4/6i and 25 (16.1%) patients receiving AI+CDK4/6i; 90% were grade 1; none led to discontinuation. No changes in visual acuity or ocular structure were observed. Patient-reported visual effects occurred early (by week 2) and were reversible post-treatment. The proportion of patients in the camizestrant+CDK4/6i and AI+CDK4/6i arm reporting short-lived visual effects (<1 minute) ranged from 60% to 67% vs 50% to 69%, respectively; visual effects causing no/a low degree of bother: 78%-88% vs 50%-75%, respectively. During treatment, visual functioning was comparable to baseline and between arms. CONCLUSION:If experienced, patient-reported visual effects (including photopsia) with camizestrant+CDK4/6i were short-lived and reversible post-treatment. Visual effect AEs with camizestrant+CDK4/6i were mostly mild and did not require treatment discontinuation or ophthalmological management. There was no impact on ocular structure, function, or visual acuity; visual effects had little/no impact on daily functioning. These findings support clinical decision-making by further characterizing the visual safety profile of camizestrant in this setting. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov, NCT04964934.

To investigate real-world demographics, clinical characteristics, treatment patterns, and outcomes in US patients with ≥ 1 line of therapy (LOT) for hormone receptor–positive (HR+) HER2-low metastatic breast cancer (mBC). This retrospective cohort study used a US-based electronic health record-derived de-identified database of patients with mBC diagnosed in 2018–2023. Patient demographics, clinical characteristics at date of mBC diagnosis, treatment patterns, and real-world overall survival (rwOS) and progression-free survival (rwPFS) were analyzed. Of 2662 patients, 49.4