Zheng, Yue

Abstract 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.

Abstract Background Breast cancer (BC) diagnosed during pregnancy or postpartum often presents with aggressive features, potentially influenced by hormonal, immunological, 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).

Abstract Purpose: The role of tumor-infiltrating lymphocytes (TIL) remains unclear in hormone receptor (HR)–positive/HER2-negative breast cancer, particularly in young patients, whose immune microenvironment could be altered by age-related host and tumor differences. Experimental Design: Patients with stage I to III HR-positive/HER2-negative tumors were identified from a prospective cohort study of patients with breast cancer diagnosed at age ≤40 years. Multiplexed immunofluorescence and semiautomated quantitative software measured cytotoxic T, non–CD8 T, T regulatory, exhausted T, and PDL1+ cells in stroma and tumor. Univariate analyses assessed differences in clinicopathologic characteristics by high versus low immune infiltration, divided based on median. TIL subtypes were evaluated as a continuous variable per 10% increase in Cox regression analyses for invasive breast cancer–free survival, distant disease–free survival (DDFS), and overall survival, adjusted for clinicopathologic parameters. Results: Among 390 patients, high immune infiltration was associated with increasing age, Black race, grade 3 tumors, and metaplastic or micropapillary histologic subtypes. Over a median follow-up of 8 years, higher stromal and intratumoral non–CD8 T-cell infiltration, T regulatory–cell infiltration, and PDL1 expression were associated with improved invasive breast cancer–free survival. Higher intratumoral non–CD8 T-cell infiltration, T regulatory–cell infiltration, and PDL1 expression were associated with improved DDFS; higher stromal PDL1 expression was also associated with improved DDFS. Higher intratumoral cytotoxic T-cell infiltration and PDL1 expression were associated with improved overall survival. Conclusions: Characterization of immune subpopulations could help refine the prognostic value of TILs in young patients with HR-positive breast cancer, who may benefit from risk stratification for treatment individualization. See related commentary by Salgado and Kok, p. 2133

PURPOSE Given the extended survivorship of young adults with breast cancer, characterizing health care utilization and adherence to surveillance guidelines can inform gaps in care. PATIENTS AND METHODS Patients age 40 years and younger at diagnosis of stage 0-III breast cancer enrolled in a prospective cohort study completed a survey 7 years after diagnosis assessing receipt of care and surveillance. We evaluated factors associated with transition to a primary care provider (PCP) for cancer-related follow-up and adherence to mammography and bone density scans. RESULTS Among 660 women, 92% reported having a PCP, although for cancer-related follow-up, 57% saw only an oncology provider, 29% saw both a PCP and oncology provider. In the past 2 years, 68% reported getting a flu shot, 76% a pap test/pelvic examination, 56% cholesterol screening, and 42% (n = 232 endocrine therapy [ET] users) a bone density scan. Among women who had a unilateral mastectomy or lumpectomy (n = 356), 82% reported a mammogram in the past year. In multivariate analyses, those with stage 0 ( v I disease) were more likely to see a PCP for follow-up ( v PCP + oncology provider); ET users and those more concerned about recurrence were less likely. Patients with human epidermal growth factor receptor 2-positive (HER2) disease were more likely to adhere to mammography; those with a BRCA mutation and those with a unilateral mastectomy were less likely. Patients with a BRCA mutation and who had chemotherapy were more likely to report a bone density scan. CONCLUSION Although most have a PCP, over half of young survivors continue to see an oncology provider for follow-up in long-term survivorship. Mammography uptake was high; uptake of other health maintenance practices was lower. Identification of barriers/facilitators to receipt of guideline-concordant care may inform strategies to optimize survivorship.

Importance Women diagnosed with breast cancer at a young age are felt to have a higher risk for locoregional recurrence (LRR) regardless of type of local therapy. Objective To assess the long-term incidence of isolated LRR by molecular subtype in a modern multicenter cohort of young women. Design, Setting, and Participants This cohort study, a multicenter prospective study named the Young Women’s Breast Cancer Study, enrolled 1302 women diagnosed with breast cancer at 40 years or younger from 2006 to 2016. Treatment information and incident LRR (ipsilateral breast/chest or lymph node recurrence) were self-reported on study surveys and confirmed with medical record review; molecular subtype was determined by record review. Analysis was reported from February 2023 to May 2025. Main Outcomes and Measures Cumulative incidence of isolated LRR was calculated using the Kaplan-Meier method; hazard ratios were estimated by Cox proportional hazards regression. Results The cohort included 1135 women with stage I through III breast cancer who had a median follow-up of 10.1 years (range, 0.4-16.3 years). The age at diagnosis was younger than 30 years for 145 patients (12.8%), 31 to 35 years for 318 patients (28.0%), and 36 to 40 years for 672 patients (59.2%). There were 59 isolated local recurrences (5.2%) and 4 isolated regional recurrences (0.4%). Among patients with local therapy and subtype data available (n = 1128), 366 (32%) had luminal A–like tumors; 240 (21%), luminal B–like tumors; 231 (20%) luminal ERBB2 positive (+)–like (formerly HER2 positive); 90 (8%) ERBB2 +-like; and 201 (18%) triple negative. A total of 346 women (30%) had breast-conserving therapy (BCT) (98% of whom had radiation), 296 (26%) unilateral mastectomy, and 487 (43%) bilateral mastectomy. Of women who had mastectomy, 425 (54%) had radiation. The cumulative incidence of LRR at 10.1 years by subtype was as follows: luminal A, 4.4% (range, 1.0%-6.9%); luminal B, 4.7% (range 1.8%-7.7%); luminal ERBB2 +, 6.1% (range, 3.1%-8.3%); ERBB2 +, 2.2% (range, 0%-6.3%); and triple negative, 6.5% (range, 4.2%-10.1%). The cumulative incidence of LRR by locoregional treatment type at 10.1 years was 6.7% after BCT (range, 4.3%-10.1%), 6.5% after mastectomy without radiation (range, 0%-7.7%), and 2.4% after mastectomy with radiation (range, 1%-4.2%). Although mastectomy with radiation was associated with the lowest risk of LRR on multivariable analysis, when examined within molecular subtype, there were no differences seen. Conclusions and Relevance In this contemporary cohort of women diagnosed with breast cancer at age 40 years or younger, risk of isolated LRR was relatively low (5.6%) at a median follow-up of 10.1 years, and significant differences were not seen by tumor subtype. Concerns for long-term risk of LRR should not influence surgical decision-making with young women, irrespective of molecular subtype.

IMPORTANCEYoung adults aged 18 to 39 years represent the minority of breast cancer diagnoses but are particularly vulnerable to financial hardship. Factors contributing to sustained financial hardship are unknown.OBJECTIVESTo identify financial hardship patterns over time and characterize factors associated with discrete trajectories; it was hypothesized that treatment-related arm morbidity, a key source of expense, would be associated with long-term financial difficulty.DESIGN, SETTING, AND PARTICIPANTSThis cohort study included US young adults aged 40 years or younger treated between 2006 and 2016. Eligible patients were treated for stage 0 to stage III breast cancer at institutions participating in the Young Women’s Breast Cancer Study, which included a specialized cancer institute and 12 other academic and community hospitals. Patients who responded at baseline and returned a 1-year survey were included in analysis. Data were analyzed in March 2024.MAIN OUTCOMES AND MEASURESTrajectory modeling classified patterns of financial difficulty from baseline through 10 years postdiagnosis using the Cancer Rehabilitation Evaluation System (CARES) scale. Multinomial regression examined characteristics, including treatment-related arm morbidity, associated with each trajectory.RESULTSA total 1008 patients were included (median [IQR] age at diagnosis, 36 [33-39] years; 60 Asian [6.0%], 35 Black [3.5%], 47 Hispanic [4.7%], 884 White [87.7%]); 840 patients were college graduates (83.3%), 764 were partnered at baseline (75.8%), 649 were nulliparous (64.4%), and 908 were without comorbidities at enrollment (90.1%). Patients’ tumors were primarily stage I-II (778 [77.2%]), estrogen receptor/progesterone receptor–positive (754 [74.8%]), and ERBB2-negative (formerly HER2) (686 [68.1%]). Patients were more frequently treated with mastectomy than breast conservation (771 [76.5%] vs 297 [29.5%]; P < .001). A majority of patients received radiation therapy (627 [62.2%]), chemotherapy (760 [75.4%]), and endocrine therapy (610 [60.6%]). A total of 727 patients (72.1%) reported arm symptoms within 2 years of surgery. Three distinct trajectories of experiences with finances emerged: 551 patients (54.7%) had low financial difficulty (trajectory 1), 293 (29.1%) had mild difficulty that improved (trajectory 2), and 164 (16.3%) had moderate to severe difficulty peaking several years after diagnosis before improving (trajectory 3). Hispanic ethnicity (OR, 3.71; 95% CI, 1.47-9.36), unemployment at baseline and 1 year (OR, 2.66; 95% CI, 1.63-4.33), and arm symptoms (OR, 1.77; 95% CI, 1.06-2.96) were associated with increased odds of experiencing trajectory 3. Having a college degree (OR, 0.20; 95% CI, 0.12-0.34) or being partnered (OR, 0.24; 95% CI, 0.15-0.38) were associated with increased odds of experiencing trajectory 1.CONCLUSIONIn this cohort study of young adults with breast cancer, we identified a subset of patients who experienced a high degree of financial difficulty persisting into early survivorship. Targeted interventions to mitigate financial toxicity—modifiable factors that include support for the employability or return to work support for those experiencing arm symptoms after treatment—are needed.

363 Background: The incidence of BC in young adults is increasing; given their extended survivorship, characterizing healthcare utilization and adherence to surveillance guidelines can inform unmet health needs and gaps in care. Methods: The multi-center Young Women’s BC Cohort Study enrolled 1302 women ≤40 yrs with newly diagnosed (dx) BC from 2006-2016. Participants completed surveys every 6 mos for 3 yrs post-dx, then annually. The current analysis includes patients with Stage 0-III BC without recurrence who completed the 7-yr survey assessing survivorship care, including types of providers visited, BC surveillance, and other health maintenance practices. Multivariate logistic regression evaluated factors (clinical, demographics, concern about recurrence) associated with 1) full transition to a primary care provider (PCP) for follow-up; adherence to 2) mammography (among women who had a unilateral mastectomy or lumpectomy) and 3) bone density scans (among current hormonal therapy [HT] users), per ASCO/ACS guidelines. Results: Of 660 women with Stage 0-III BC, median age at dx was 37 (range: 17-40); 89% identified as White, 5%, Asian, 3%, Black, 3% as other/multiracial, and 4%, Hispanic. Most had received chemotherapy (75%) and radiation (61%) and 35% reported current HT; 12% had a BRCA1/2 mutation. For cancer-related follow-up, 57% reported seeing an oncology provider only, 12%, PCP only, and 29% saw a PCP + oncology provider. Among women with remaining breast(s) (n=348), 90% reported a mammogram in the last year. Adherence to other health maintenance practices varied: 68% reported having had a flu shot, 76% a pap test/pelvic exam, and 56% cholesterol screening within the last 2 yrs. Among current HT users (n=210), 46% reported a bone density scan within the last 2 yrs. In multivariate analyses assessing the odds of seeing a PCP only (vs. oncology + PCP), having stage 0 vs I disease (OR 2.74 95% CI 1.01-6.80) was associated with higher odds while any HT use (OR .31 95% CI .16-.58) and concern about recurrence (OR .23 95% CI .12-.47) were associated with lower odds. The table includes factors significantly associated with non-adherence to mammography and bone density scans. Conclusions: At 7-years post-dx, most young survivors participating in a cohort study receive cancer follow-up care from an oncology provider and have not fully transitioned their care to a PCP. Adherence to recommendations related to bone health among HT users was suboptimal. Additional research to identify barriers/facilitators to receipt of guideline-concordant follow-up care at the patient, provider, and systems levels may inform strategies to optimize survivorship in young BC survivors. Multivariable analysis: factors associated with non-adherence. MammogramOR 95% CI Bone density scanOR 95% CI Her2+ .38, .15 -.98 NS BRCA1/2 + 8.36, 1.38-50.47 .17, .05 -.62 Chemotherapy NS .22, .06 -.78 Unilateral mastectomy vs lumpectomy 6.64, 2.69-16.34 NS

PURPOSE Long-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)–positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need. METHODS In the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia. RESULTS After a median follow-up of 5.8 years, 11 iDFS events were observed in the T-DM1 arm, consistent with a 5-year iDFS of 97.0% (95% CI, 95.2 to 98.7). At 5 years, the recurrence-free interval (RFI) was 98.3% (95% CI, 97.0 to 99.7), the overall survival was 97.8% (95% CI, 96.3 to 99.3), and the breast cancer-specific survival was 99.4% (95% CI, 98.6 to 100). Comparable iDFS was observed with T-DM1 irrespective of tumor size, hormone receptor status, centrally determined HER2 immunohistochemical score, and receipt of T-DM1 for more or less than 6 months. Although ATEMPT was not powered for this end point, the 5-year iDFS in the TH arm was 91.1%. Among patients with sufficient tissue for HER2DX testing (n = 187), 5-year outcomes significantly differed according to HER2DX risk score, with better RFI (98.1% v 81.8%, hazard ratio [HR], 0.10, P = .01) and iDFS (96.3% v 81.8%, HR, 0.20, P = .047) among patients with HER2DX low-risk versus high-risk tumors, respectively. CONCLUSION Adjuvant T-DM1 for 1 year leads to outstanding long-term outcomes for patients with stage I HER2-positive breast cancer. A high HER2DX risk score predicted a higher risk of recurrence in ATEMPT.

1518 Background: Despite high interest among young women diagnosed with breast cancer (BC) in future fertility, prior research has been hampered by short follow-up and lack of prospective assessment of pregnancy attempts. We sought to describe fertility outcomes among young women participating in a prospective cohort who reported pregnancy attempt post-BC diagnosis. Methods: Women with stage 0-III BC in the Young Women's Breast Cancer Study (YWS, NCT01468246), a multicenter, prospective cohort of women diagnosed at age ≤40 from 2006-2016 who reported attempting pregnancy post-diagnosis were included. Those with prior hysterectomy, bilateral oophorectomy, or metastatic disease at diagnosis were excluded. Data on attempting pregnancy and fertility outcomes were obtained from serial surveys. Multivariable logistic regression with stepwise model selection was used to identify factors associated with pregnancy and live birth. Results: Among 1213 eligible participants, 197 reported any attempt of pregnancy (16%) over a median follow-up of 11 years (range: 3-17). Among attempters, median age at diagnosis was 32 years (range: 17-40); 74% were non-Hispanic White; 41% had stage I, 35% stage II, 10% stage III, and 14% stage 0 BC; 76% had HR+ disease; 68% received chemotherapy; 57% received endocrine therapy within one year post-diagnosis; 13% were BRCA1/2 pathogenic variant (PV) carriers; 51% reported financial comfort at baseline; 51% were nulligravida and 72% nulliparous at diagnosis; 28% had undergone fertility preservation consisting of egg/embryo freezing at diagnosis; 15% reported a history of infertility before BC diagnosis. Most (73%) reported ≥1 pregnancy after diagnosis and 65% reported ≥1 live birth. Median time from diagnosis to first pregnancy was 48 months (range: 6-125). In the multivariable model, greater age at diagnosis (odds ratio [OR] 0.82 per year increase, 95% CI 0.74-0.90, P<0.0001) was negatively associated with pregnancy, while financial comfort at baseline (OR 2.04, 95% CI 1.01-4.12, P=0.047) was predictive of pregnancy. For live births, greater age at diagnosis was negatively associated (OR 0.82 per year increase, CI 95% 0.76-0.90, P<0.0001) while having undergone fertility preservation at diagnosis was predictive (OR 2.78, 95% CI 1.29-6.00, P=0.009). History of infertility, nulliparity at diagnosis, tumor characteristics, cancer treatment, race, ethnicity, and BRCA1/2 PV status were not associated with either outcome. Conclusions: This is the first prospective study with greater than 10 years of follow-up to report fertility outcomes in young BC survivors accounting for attempting pregnancy. The majority achieved a pregnancy and most reported a live birth. Our findings can be incorporated into the counseling of young BC patients and survivors, and highlight the need for accessibility of fertility preservation services for this population. Clinical trial information: NCT01468246 .

Abstract Background. Approximately 12,000 women aged 40 years or younger are diagnosed with breast cancer every year in the United States alone. Limited data exist regarding survival in young women with metastatic breast cancer (MBC), particularly when considering modern tumor subtyping and treatment, though previous studies have suggested that patients presenting with MBC at diagnosis (de novo stage IV) have better prognosis than those who develop recurrent MBC after initial diagnosis of stage 0-III disease. We sought to determine survival rates in young patients with MBC stratified by disease presentation (de novo versus recurrent) and subtype. Methods. The Young Women’s Breast Cancer Study (YWS) is a multicenter, prospective cohort which enrolled 1,302 women diagnosed with stage 0-IV breast cancer at age ≤40 from 13 North American academic and community-based sites from 2006-2016. The current median follow-up is 10.1 (range 0.4-16.3) years. Histopathology slides were centrally reviewed for 97% of the participants, and clinical tumor molecular subtypes have been detailed. In the recurrent group, receptors were obtained from the initial breast surgery. Descriptive analyses were used to characterize patients with de novo or recurrent MBC, including demographic and disease characteristics, and survival rates. Overall survival was estimated using the Kaplan-Meier method and compared by log-rank test between those who presented with de novo and relapsed disease overall and within tumor subtypes. Results. Among 246 patients included in this analysis, 74.0% (n=182) had recurrent MBC and 26.0% (n=64) had de novo MBC. Most patients were white (n=208, 84.6%), while 6.9% were Asian (n=17), 4.5% Black (n=11), 0.8% Native American (n=2), 0.8% multiracial (n=2) and 2.4% other/unknown (n=6). A total of 4.5% of patients were Hispanic (n=11). Median age at diagnosis of de novo MBC was 37 years and 40 years for diagnosis of metastasis in the recurrent group. Median disease-free interval was 3.23 (range 0.32 – 13.84) years for the recurrent MBC group. Among all patients with MBC, most (55.7%, n=137) had estrogen receptor (ER) and/or progesterone receptor (PR)-positive, human epidermal growth factor receptor 2 (HER2)-negative disease, whereas 17.9% (n=44) had ER and/or PR-positive HER2-positive, 7.3% (n=18) had ER/PR-negative HER2-positive, and 18.7% (n=46) had triple-negative tumors. A greater proportion of participants (43.8%, n=28) had HER2-positive disease in the de novo group than in the recurrent group (18.7%, n=34), P=&lt; 0.0001. A total of 10.9% (n=7) of de novo patients had a germline BRCA mutation, compared to 13.7% (n=25) in the recurrent group. Median survival was 5.09 (95% CI: 3.74 – 6.38) years in the de novo group and 2.63 (95% CI: 1.98 – 3.21) years in the recurrent MBC group (P=0.0004). When stratifying by subtype, survival among patients with de novo ER and/or PR-positive HER2-positive disease was longer than among patients with recurrent disease (P=0.0149), whereas there were no statistically significant differences in survival between the de novo and recurrent disease groups in other disease subtypes (Table 1). Conclusion. Survival in young women with MBC is highly heterogeneous and varies substantially by tumor subtype and disease presentation. Those with de novo ER and/or PR-positive HER2-positive subtype appear to have better outcomes than those with recurrent MBC with the same subtype. These findings can inform patient care and potential future research to improve outcomes for young patients with MBC. Table 1: Median survival by disease presentation and subtype * 1 patient with recurrent MBC was not included because the initial diagnosis was DCIS MBC: metastatic breast cancer; OS: overall survival; CI: confidence interval; ER: estrogen receptor; PR: progesterone receptor; HER2: human epidermal growth factor receptor 2 Citation Format: Leticia Varella, Yue Zheng, Shoshana Rosenberg, Gregory Kirkner, Craig Snow, Kathryn Ruddy, Rulla Tamimi, Jeffrey Peppercorn, Lidia Schapira, Virginia Borges, Steven Come, Laura Collins, Ellen Warner, Kate Dibble, Eric Winer, Ann Partridge. Survival in Young Women with De Novo or Recurrent Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-05-14.