Unique disease characteristics of younger patients warrants investigation of tumor genomics in young-onset metastatic breast cancer (MBC). Targeted DNA sequencing was completed for tumors of MBC patients diagnosed between 2009-2020. Multivariable logistic regression tested associations between single nucleotide variants (SNVs) and copy number variants and age at MBC diagnosis. Multivariable Cox regression estimated hazard ratios for overall survival (OS) by somatic alterations. Among 2,357 MBC patients, tumors of those ≤40 years at diagnosis (vs. >55) were more likely to harbor amplifications in ERBB2 and MYC (p < 0.01) and mutations in TP53 (odds ratio [OR] = 1.83, p < 0.001), and less likely to harbor mutations in CDH1 and PIK3CA (p < 0.001). OS was shorter among younger recurrent MBC patients [median: 2.8 (≤ 40) vs. 3.6 years ( > 55), p = 0.04], with SNVs in TP53 and PTEN associated with shorter OS. Distinct tumor genomics of young-onset MBC patients suggest differences in tumor biology that should guide investigation of targetable pathways.

BACKGROUND:Whether outcomes of germline BRCA1/2 (gBRCA1/2)-associated breast cancer differ compared with sporadic tumors is controversial. We explored the impact of gBRCA1/2 pathogenic variant (PV) status beyond established prognostic features. METHODS:We conducted 2 retrospective, matched cohort studies comparing gBRCA1/2 PV carriers and noncarriers with HER2-negative, stage I-III breast cancer (Clinical Outcomes Quality Database [COQD] cohort: 185 carriers, 555 noncarriers; Young Women's Breast Cancer Study [YWS] cohort: 113 carriers, 226 noncarriers). Matching factors were age, stage, hormone receptor status, and year of diagnosis. Clinicopathological features, treatments, and survival outcomes were compared between carriers and noncarriers. RESULTS:Most patients in COQD had stage I-II disease (87.2%), and more carriers than noncarriers had genetic testing before diagnosis (33% vs 5.6%, P < .001). In YWS, 22.7% of patients had stage III tumors, and few were tested before diagnosis (14.8% of carriers vs 1.7% of noncarriers; P < .001). Carriers in COQD received chemotherapy more often than noncarriers (81.1 vs 67.0%, P < .001), including platinum (P = .010); the proportion was similar for carriers and noncarriers in YWS. After adjusting for chemotherapy, relapse-free survival was longer in carriers than noncarriers in COQD (adjusted hazard ratio = 0.48 [95% CI = 0.26 to 0.87], P = .016), and a favorable trend was observed for other survival outcomes in both cohorts. Triple-negative tumors appeared to drive the differences. CONCLUSIONS:We observed a trend toward improved outcomes in gBRCA1/2 PV carriers compared with noncarriers. These findings suggest that carriers should not receive more aggressive treatment solely based on their germline mutation status. Prospective clinical trials in this population are warranted.

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.

BACKGROUND:The incidence of early onset breast cancers (BCs) has increased, paralleling rising trends in delayed childbearing. We hypothesize that a distinct postpartum BC (PPBC) subtype, identifiable by time since last birth (TSLB) and biomarker expression, contributes to this trend. METHODS:We applied GeoMx Digital Spatial Profiling (DSP) to measure associations between TSLB and 71 proteins in 640 BCs from women aged ≤40 years included in the Young Women's Breast Cancer Study. We analyzed data using univariable linear regression and multivariable sliced inverse regression to account for higher order interactions among biomarkers. RESULTS:In keratin-rich segments, progesterone receptor (PR) (P = 1.00 × 10-4) and PTEN (P = 1.00 × 10-3) were associated with longer TSLB; multivariable analyses revealed positive associations for GZMB (P = 4.00 × 10-4), SMA (P = 1.00 × 10-4), and NF-1 (P = 1.00 × 10-3). In keratin-poor segments, univariable significant positive associations were found for PR (P = 2.00 × 10-4) and PTEN (P = 1.00 × 10-3), whereas CD20 (P = 3.00 × 10-4) and CTLA4 (P = 4.00 × 10-5) were negatively associated; multivariable significant associations were found for fibronectin (P = 3.00 × 10-5) and pan-Akt (P = 1.00 × 10-3). Associations persisted after adjustment for multiple comparisons and BC molecular subtypes. Associations including for PR, PTEN, and CD20 were strongest among women with the shortest TSLB. OPAL multiplex immunofluorescence assays for PR, PTEN, CD20, SMA, and CTLA4 replicated several DSP findings, particularly when stratified by subtype and with compartment matching. In TCGA, RNA species linked to proteins associated with TSLB correlated strongly with a T-cell exhaustion signature previously linked to poor prognosis among premenopausal women. CONCLUSION:These data support PPBC as a biologically coherent phenotype defined by TSLB and biomarker profile, with potential implications for prevention and therapy.

Genes Sequenced from Paired Baseline and Four-Year Blood Samples

The influence of young age at diagnosis on prognosis of patients with metastatic breast cancer (MBC) remains unclear. We examined overall survival (OS) within a single-institution prospective study of patients with de novo or recurrent MBC. Kaplan-Meier curves assessed OS by age (≤35 or ≤40 years as the youngest category) and inferred metastatic tumor subtype. Multivariable Cox regression models estimated hazard ratios (HRs) and 95% CIs for OS by age adjusting for clinical factors. Of 4189 women <75 years, 571 were ≤40 years at MBC diagnosis, of whom 260 were ≤35 years. Over half (52%) died during follow-up (median = 5.3 years, IQR = 2.1–9.8 years). Compared to patients 45–55 years, those ≤35 years at diagnosis experienced worse OS (HR = 1.22, 95%CI 1.00–1.48, p = 0.05). This association was driven by HER2-negative/luminal B-like and hormone receptor-positive/HER2-positive tumors. These findings highlight the need to develop more effective therapies for young patients with this metastatic subtype.

All Mutations Identified in One-Year Samples

1075 Background: ET + CDK4/6i is standard-of-care for patients (pts) with hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (MBC). We aimed to identify predictors ET + CDK4/6i tx duration and to compare genomic profiles in pts with intrinsic vs acquired resistance. Methods: Plasma samples were collected from pts with HR+/HER2- MBC enrolled in the EMBRACE cohort study who had plasma collection within 3 months (mo) prior to CDK4/6i initiation to 14 days after initiation. The primary outcome was duration of ET+CDK4/6i tx, defined as time from tx initiation to end of tx. Intrinsic resistance was defined as pts with tx duration < 180 days. Plasma samples were analyzed using the Guardant360 assay, which includes genotyping of > 700 genes and tumor fraction (TF) score. TF was estimated by normalizing cancer-specific differentially methylated regions with matched control regions in each sample. The predictive value of baseline TF (0 vs > 0) was tested using a Cox regression model including age, line of tx, and liver metastases. For comparison of pts with intrinsic vs acquired resistance, analysis was limited to samples with TF >1% to minimize the impact of variation in tumor shed. Gene frequency between intrinsic and acquired resistance samples were compared using q-tests(q < 0.25). Results: A total of 188 pts were included. Median age at MBC diagnosis was 57.5 yrs. ET+CDK4/6i was given in the first-line (1L) in 115 pts, second-line (2L) in 37 pts, and > 2L in 36 pts. Of 167 pts, TF was undetectable (TF = 0) in 19 (11%) and detectable (TF > 0) in 148 (89%). In Cox regression, baseline TF (p = 0.001), line of tx (n = 0.002), and presence of liver metastasis (p = 0.014), but not age, were predictors of duration of tx. Median duration of tx was 44.6 mo in pts with baseline TF = 0 vs. 5.8 mo in pts with baseline TF > 0 (HR 0.28, 95% CI 0.14-0.56). Similar results were found when restricting the analysis to those receiving tx in the 1L or 2L. There were notable differences in the frequency of ESR1 (63% vs 48%), CDH1 (38% vs 18%), PTEN (21% vs 9%), RB1 (32% vs 20%), and CDKN2A (20% vs 5%) alterations in pts with intrinsic vs acquired resistance, though these did not reach statistical significance in the setting of small sample size. ESR1 fusions were seen in 14% (8/56) pts with intrinsic resistance vs 7% (3/44) pts with acquired resistance. Among pts with intrinsic resistance, ERBB2 copy number loss was present in 7(13%) (6 het loss, 1 homozygous deletion), RB1 copy number loss in 10 (18%) (all het loss), and CDKN2A copy number loss in 9(16%) (7 het loss, 2 homozygous deletions). Conclusions: Baseline TF in ctDNA is highly predictive of time on ET+CDK4/6i tx in pts with HR+/HER2- MBC. Baseline genomic profiles differ qualitatively between pts with intrinsic vs acquired resistance. If validated, baseline plasma may provide a valuable tool in tx selection.

Cohort Characteristics Broken Down by CH (Any VAF)

Though there has been substantial progress in the development of anti-human epidermal growth factor receptor 2 (HER2) therapies to treat HER2-positive metastatic breast cancer (MBC) within the past two decades, most patients still experience disease progression and cancer-related death. HER2-directed tyrosine kinase inhibitors can be highly effective therapies for patients with HER2-positive MBC; however, an understanding of resistance mechanisms is needed to better inform treatment approaches. We performed whole-exome sequencing on 111 patients with 73 tumor biopsies and 120 cell-free DNA samples to assess mechanisms of resistance. In 11 of 26 patients with acquired resistance, we identified alterations in previously characterized genes, such as PIK3CA and ERBB2, that could explain treatment resistance. Mutations in growing subclones identified potential mechanisms of resistance in 5 of 26 patients and included alterations in ESR1, FGFR2, and FGFR4. Additional studies are needed to assess the functional role and clinical utility of these alterations in driving resistance.

CHIP Mutations Identified in One-Year Samples

BACKGROUND:Compared to older adults with breast cancer (BC), adolescents and young adults (AYAs) develop more aggressive disease necessitating more intensive therapy with curative intent, which is disruptive to planned life trajectories. The burden of unmet needs among AYA BC survivors exists in two domains: (1) symptoms (e.g., sexual problems, anxiety, fatigue, stress, hot flashes) and (2) AYA concerns (e.g., fertility, genetics, relationships, economic attainment). Improved attention to concerns and symptoms may improve symptom management and quality of life. The Young, Empowered and Strong (YES) trial tests the efficacy of a 9-month, multicomponent digital health intervention that includes monthly assessments of prevalent symptoms, a chat room, and journal to engage and support AYAs with BC by providing tailored information, resources, and support outside of the clinical setting. METHODS:YES is a multicenter, randomized controlled trial across three academic institutions in the United States with 400 participants randomized to either the YES intervention or usual care arm. Inclusion criteria include biologically female; 15-39 years of age at diagnosis of stage 0-III BC; within 3 years of diagnosis; no known evidence of recurrence; no prior history of new malignancy since initial BC diagnosis; and ability to access medical records from treatment site. All participants complete REDCap surveys at baseline, and at 3, 6, and 9 months post-enrollment. The primary outcome is quality of life as measured by the Quality of Life in Adult Cancer Survivors Scale (QLACS), with changes from baseline to 6-months in QLACS scores, compared by arm. Secondary outcomes include patient reported AYA concerns/needs, emotional symptoms, general health, physical symptoms, and health behaviors, DISCUSSION: Study findings will provide valuable insight into the ability of the YES digital health intervention to address symptoms and concerns of AYA BC survivors and assist them to track and self-manage their own symptoms, concerns, and needs related to their cancer outside of the clinic. TRIAL REGISTRATION:Clinicaltrials.gov, NCT04906200, registered May 13, 2021.

Longitudinal Mutation Analysis in the YWS

P53 or PPM1D Mutations And Prior Cytotoxic Exposure

Possible germline mutations (VAF > 0.35) predicted to impair protein function via premature stop (nonsense), splicing alterations, or a frameshift

3055 Background: Risk of recurrence for patients (pts) with HR+/HER2- breast cancer persists for decades. Most distant recurrences occur in the ‘late’ adjuvant setting, > 5 years (yrs) from diagnosis. In CHiRP (ASCO 2022), we showed that minimal residual disease (MRD) was detectable in the late adjuvant setting: ctDNA was detected in 8/83 (9.6%) pts in the cohort and 6/8 (75%) pts with positive ctDNA (+ctDNA) had developed distant recurrence when initially reported (median follow-up 2 years from first plasma sample collected on study). Here, we report updated clinical outcomes and investigate the meaning of a ctDNA test result during surveillance with longer follow-up. Methods: In CHiRP, pts with stage II-III HR+/HER2- breast cancer at high risk of recurrence diagnosed > 5 yrs prior with no evidence of recurrence were prospectively identified. All pts provided informed consent for prospective plasma collection every 6-12 months at routine follow-up visits for batched, retrospective ctDNA testing using RaDaR, a tumor-informed whole exome sequencing-based assay. Pts were followed at the discretion of the clinical provider without any routine surveillance imaging, as per guideline-concordant care. See CHiRP ASCO 2022 presentation for additional methods. Results: Of 83 pts in the analytic cohort, 57 (68.7%) pts had stage III disease, and most (n = 75, 90.4%) underwent (neo)adjuvant chemotherapy. All pts received endocrine therapy. In this update, median follow-up from first sample collection was 4.4 yrs (interquartile range 4.0, 4.9). 214 plasma samples were collected prior to any known recurrences and included in this analysis. 8/83 (9.6%) pts had +ctDNA at any timepoint including 4/83 (4.8%) with +ctDNA on first study plasma sample. In pts initially ctDNA-negative (-ctDNA; n = 4), median time from first sample collection to MRD detection was 1.29 yrs (range, 0.72 – 3.05). During follow-up, 8 (9.6%) pts developed distant recurrence and 1 (1.2%) pt had a local recurrence. With additional follow-up included in this update, all 8/8(100%) pts with +ctDNA developed distant recurrence with a median lead time of 1.39 years (range 0.01 – 4.24). Among -ctDNA plasma samples with > 2 yrs of follow-up (n = 185), the negative predictive value (NPV) of a -ctDNA test for lack of clinical recurrence for > 2 yrs post-test was 98.4% (3/185). The NPV indicating freedom from recurrence > 1 and > 3 yrs was 100% (0/196) and 96.6% (5/147), respectively. Conclusions: In pts with high-risk HR+/HER2- breast cancer in the late adjuvant setting, all pts with +ctDNA developed distant metastasis. A -ctDNA test was strongly associated with lack of recurrence over a 3 yr follow-up period. Future studies are needed to determine if ctDNA-guided intervention can impact clinical outcomes for early-stage breast cancer and to determine the optimal role of MRD surveillance during follow-up.

Background: Among patients with ER+/HER2- breast cancer (BC), IHC-defined HER2-low and HER2-0 tumors do not appear to significantly differ molecularly (Tarantino P. et al. Nat Comm 2023). However, this may be due to lack of sensitivity of IHC, which is currently used to select patients for T-DXd treatment, despite major diagnostic challenges. To better characterize the biologic correlates of HER2-low expression, we analyzed molecular profiles by quantitative ERBB2 mRNA expression and characterized the features of tumors harboring ERBB2del, for which resistance to T-DXd has been suggested. Methods: Genomic, transcriptomic and proteomic data from ER+/HER2- BCs were analyzed from the METABRIC, TCGA (early BC) and MSK MetTrospism (metastatic BC, MBC) databases. Genomic landscapes, gene expression and HER2 protein expression were compared between subgroups based on HER2 mRNA tertiles (ERBB2-low, -intermediate, -high), by HER2 IHC score (IHC 0, 1+, 2+/not amplified) and by ERBB2del. Further validation was conducted in two DFCI cohorts, including patients with HER2- early BC with tumors tested for OncotypeDX between 1/2018 - 12/2022 and patients with MBC with tumors that had undergone next-generation sequencing (NGS) between 7/2013 - 12/2020. Results: All ER+/HER2- BCs from the METABRIC (n=1298), TCGA (n=524) and early DFCI (n=971) cohorts exhibited some degree of ERBB2 mRNA expression. In both METABRIC and TCGA, the ERBB2 mRNA high group was enriched in pathways related to ER signaling (Hallmark estrogen response early), while the ERBB2 mRNA low group was enriched in genes involved in cell proliferation (Hallmark E2F targets, MYC targets) and immune response (Hallmark allograft rejection, TNF signaling via NF-kB, IFN-α response, IFN-γ response). At the genomic level, PIK3CA mutations were enriched in the ERBB2 mRNA-intermediate and -high groups (both p<0.01), whereas TP53 mutations were enriched in the ERBB2 mRNA-low subgroup (p<0.001). Notably, ERBB2del were common in the ERBB2 mRNA-low group of both METABRIC and TCGA (35% and 54%), but less frequent in the ERBB2 mRNA-intermediate and -high cohorts (METABRIC: 9% and 4%; TCGA: 14% and 5%). No significant difference in the distribution of PIK3CA, TP53 and ERBB2del was noted between HER2 IHC subgroups. Among tumors with ERBB2-low mRNA, >90% of ERBB2del tumors had a concurrent TP53 heterozygous deletion (TP53del), compared with only 25-36% of non-ERBB2del tumors (both on chromosome 17). ERBB2del tumors were found enriched in the expression of genes related to cell proliferation and immune response, while non-ERBB2del BCs were enriched in genes related to ER signaling. ERBB2del tumors were found scattered across HER2 IHC subgroups (30.7% of IHC 0, 23.9% of IHC 1+, 15.8% of IHC 2+), had lower ERBB2 mRNA and HER2 protein levels, lower ER signaling and higher expression of proliferation genes within each HER2 IHC category. In the DFCI cohort of ER+/HER2- MBC with clinical NGS (n=749), the prevalence of ERBB2del was 14.3%, with 87.9% of ERBB2del tumors having concurrent TP53del. A significant difference in overall survival (OS) was observed between ERBB2del vs. non-ERBB2del tumors (33.8 vs 47.8 months, p=0.037), irrespective of the presence of TP53del, whereas no difference in OS was observed by HER2 IHC score (p=0.26). Similarly, in the MSK MetTrospism cohort (n=883), patients with ER+/HER2- MBC and an ERBB2del had worse OS (16.4 vs 30.8 months, p<0.0001), while the presence of TP53del was not associated with OS (32.1 vs 34.2 months; p=0.62). Conclusions: ERBB2del are frequent events in ER+/HER2- BC that are characterized by low ERBB2 mRNA levels, and are associated with TP53del, higher proliferation and immunogenicity, lower ER signaling and HER2 protein expression, and decreased OS in the metastatic setting. Citation Format: Paolo Tarantino, Xintao Qiu, Rong Li, Albert Grinshpun, Hersh Gupta, Melissa E. Hughes, Gregory Kirkner, Lynette Sholl, Bruce E. Johnson, Matthew L. Meyerson, Andrew D. Cherniack, Yijia Jiang, Ningxuan Zhou, Nancy U. Lin, Henry W. Long, Sara M. Tolaney, Rinath M. Jeselsohn. Molecular characterization of estrogen receptor (ER)+/HER2- breast cancer unveils a biologically and clinically distinct entity with ERBB2 hemizygous deletion (ERBB2del) [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 P4-03-20.

INTRODUCTION:Older adults with breast cancer experience worse survival than their younger counterparts. However, data are limited on the patterns of presentation, treatment, and outcomes for older patients with metastatic breast cancer (MBC) outside of registry studies and selected clinical trial populations. MATERIALS AND METHODS:We identified patients aged ≥60 years from a single, NCI-designated cancer center with MBC diagnosed between 1999 and 2022. Using Chi-square testing, we compared clinicopathologic characteristics by age. We also examined treatment patterns and reasons for treatment discontinuation; overall survival (OS) was examined by subtype and age using Kaplan-Meier methods. RESULTS:The final analytic cohort included 1115 patients with a median follow-up of 2.9 years (1.0-18.5); median age at metastatic diagnosis was 66.3 (60.0-95.4). Disease subtypes included: 70.7 % hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-), 11.9 % any HR/HER2+, 17.4 % triple negative (TN). In those with HR+/HER2- disease receiving first-line (1 L) therapy (n = 783), 1 L endocrine-based therapy was frequent (79.3 % for ages 60-65, 94.7 % for >80), and administration of 1 L chemotherapy varied by age (21.0 % in ages 60-65, 5.3 % in >80). Among those with TN and HER2+ disease, ≥84 % received a 1 L chemotherapy or trastuzumab-containing regimen. Across subtypes, most patients (80.5 %) discontinued 1 L therapy for progression, not toxicity. Among patients ages 60-65, 16.5 % stopped treatment after 1 L therapy; 42.2 % of those >age 80 received treatment after 1 L. Clinical trial enrollment declined with age (40 % in 60-65 vs. 13 % for >80; p = 0.0004), as did median OS (4.4 years in ages 60-65 vs. 2.7 years for >80; p < 0.005). For ages 60-65, 37.8 %, 17.1 %, and 40.3 % with HR + HER2-, TN, and HER2+ disease, respectively, were alive at two years. For ages >80, 23.7 %, 0 %, and 33.3 % with HR + HER2-, TN, and HER2+ disease, respectively, were alive at two years. DISCUSSION:In a unique, large prospective cohort of older adults with MBC, the number of treatment lines decreased with increasing age, and OS outcomes were poor, particularly for those >80 years where most patients were not alive at two years after MBC diagnosis. Therapeutic approaches, with improved supportive care, are urgently needed to optimize outcomes in the oldest patients with MBC.