Sauder, Candice A. M.

631 Background: Adolescent and young adult (AYA) women with breast cancer who have not completed their desired childbearing pre-diagnosis may be more likely to decline adjuvant endocrine therapy (ET) and/or to temporarily or permanently stop ET to pursue pregnancy. Fertility counseling and use of fertility preservation strategies (e.g., oocyte/embryo cryopreservation) might impact these decisions. Methods: In the Valuing Opinions and Insights from Cancer Experiences (VOICE) Study, we investigated whether use of fertility preservation strategies were associated with ET initiation and early discontinuation amongst AYAs with fertility concerns. Eligible females were diagnosed with stage 1–3 estrogen-receptor positive breast cancer at age 15-39 during 2013-2022 and responded to a survey in 2023-2024. Those who reported that they had not completed their desired family size or had been unsure about having completed their desired family size at the time of their cancer diagnosis were categorized as having had fertility concerns. ET initiation was defined as 2+ ET prescription fills within 18 months after diagnosis. Among ET initiators, we assessed early discontinuation (defined as lack of ET prescription fill over any 180 day period until 5 years after their first ET fill date). Due to inadequate power, we did not model the relationship between oocyte/embryo cryopreservation and ET initiation. However, we did have power to assess the association between oocyte/embryo cryopreservation and ET discontinuation using multivariable Cox regression to calculate Hazard Ratios (HR) and 95% Confidence Intervals (CI). HRs for discontinuation were adjusted for age at diagnosis, stage, study site, diagnosis year, income, and children before diagnosis (yes/no). Results: Among 518 AYA breast cancer survivors, 56% (N = 290) had fertility concerns at diagnosis. Of these 290, 41% had 1+ child before diagnosis, 90% received fertility counseling, 27% froze eggs or embryos, and 10% had 1+ child after diagnosis. The majority (89%) initiated ET. Among the 32 who did not initiate ET, 7 (22%) reported that fertility concerns impacted that decision. Oocyte/embryo cryopreservation was used by 26% of ET initiators and 34% of ET non-initiators. Among the 258 ET initiators, 89 (35%) discontinued ET early. Compared to those who did not use fertility preservation strategies, patients who froze oocytes/embryos were more likely to discontinue ET (HR 1.89; 95% CI 1.18–3.05). Among those who discontinued ET, 19% had 1+ child after diagnosis (compared to 2% among those who did not discontinue ET). Conclusions: This study confirmed prior studies showing that many AYAs with breast cancer have fertility concerns, and these concerns may impact decisions about ET. In our analysis, those who cryopreserved oocytes/embryos were more likely to discontinue ET early, and a higher proportion who discontinued ET had 1+ live birth after breast cancer.

1564 Background: Adolescent and young adult (AYA) females with early-stage ER-negative and/or HER2-positive breast cancer commonly receive chemotherapy to reduce risk of recurrence. Fertility concerns, counseling, and preservation may influence chemotherapy decisions and time to chemotherapy (TTC) initiation. Methods: We surveyed AYA survivors of stage I–III premenopausal ER-negative and/or HER2-positive breast cancer treated at Kaiser Permanente Northern and Southern California (2013-2022). Fertility concerns were defined as not having completed desired family size or being unsure about having completed desired family size at diagnosis. We summarized receipt of fertility counseling, receipt of chemotherapy, and use of oocyte/embryo cryopreservation for fertility preservation (FP). Among fertility-concerned patients who received chemotherapy, TTC (days from diagnosis) was assessed separately for neoadjuvant chemotherapy (NAC) vs for adjuvant chemotherapy (AdjC). Time to NAC was natural log–transformed and modeled with multivariable log-linear regression to estimate relative differences in TTC, adjusting for stage, study site, ER, HER2, age, and diagnosis year. Results: Of 363 respondents, 197 (54%) had fertility concerns at diagnosis; 183/197 (93%) received chemotherapy, similar to 153/166 (92%) among those without concerns (p=0.7). Of the concerned chemotherapy recipients, 45 (25%) saw a fertility specialist but did not pursue FP while 55 (30%) underwent FP. For the 112 fertility-concerned NAC recipients, FP was associated with longer TTC than no fertility specialist counseling (mean=41 vs. 30 days; adjusted ratio=1.39; 95% CI 1.15–1.69), whereas fertility specialist counseling without FP was not (mean= 31 vs. 30 days, adjusted ratio=1.04; 95% CI 0.86–1.25). For the 71 fertility-concerned AdjC recipients, TTC was similar for patients who did not see a fertility specialist (mean=63 days), those who froze oocytes/embryos (mean=65 days), and those who saw a fertility specialist but did not pursue FP (mean=69 days). Conclusions: In this AYA breast cancer cohort, there was no evidence that fertility concerns led patients to decline chemotherapy. FP was associated with a modest delay in NAC initiation (<2 weeks on average). Time to chemotherapy (TTC) among 183 AYA patients with ER− and/or HER2+ breast cancer and fertility concerns. Fertility-focused care N (n=183) Neoadjuvant chemotherapy (n=112) Mean TTC, days Relative difference in TTC, adjusted ratio (95%CI) Adjuvant chemotherapy (n=71) Mean TTC, days No fertility counseling from a specialist 83 (45%) 55 (49%) 29.6 Reference 28 (39%) 62.6 Received fertility counseling from a specialist No fertility preservation 45 (25%) 28 (25%) 30.7 1.04 (0.86,1.25) 17 (24%) 68.6 Fertility preservation 55 (30%) 29 (26%) 41.2 1.39 (1.15,1.69) 26 (37%) 64.6

Abstract Breast cancer (BC) is the most common cancer among female adolescents and young adults (AYAs; 15-39 years). While advances in treatment have improved survival, cardiovascular disease (CVD) can result from systemic therapies, and CVD is a leading cause of death in AYA cancer survivors. AYAs with BC face nearly a four-fold increased risk of CVD compared to their peers without cancer. However, data on the effects of systemic treatment on CVD in this population remains limited. We estimated risk of CVD in AYAs diagnosed with invasive BC (2006-2020), who survived ≥2 years, and were diagnosed and treated in the Kaiser Permanente (KP) Northern and Southern California. Patients were categorized by receipt of anthracycline-, alkylating-, HER2-, platinum-, and taxane-based therapies within 2 years of diagnosis. We examined the cumulative incidence of CVD starting 2 years post-diagnosis and used Cox proportional hazards regression to determine factors associated with CVD. Among 3,071 AYAs, 35.1% were non-Hispanic (NH) White, 31.6% were Hispanic, 18.3% were NH Asian, and 8.2% were NH Black. Most received systemic therapy (90.6%), including anthracycline- and alkylator without HER2-targeted therapy (41.9%) and HER2-targeted therapy without anthracycline (20.9%). Fewer AYAs received a taxane and alkylator (13.0%) or anthracycline with alkylator and taxane along with a HER2-targeting agent (6.4%). Mean follow-up after cancer diagnosis was 7.2 years (range: 2.0-17.5). The 10-year cumulative incidence of CVD was highest among AYAs who received anthracycline/alkylator/taxane/HER2-targeting therapy (19.6%), intermediate for those with anthracycline/alkylator without HER2-targeting therapy (13.0%) and those who received HER2-targeted therapy without anthracycline (14.6%), and lowest for those who received taxane/alkylator (7.3%). In the multivariable model adjusted for demographic factors and radiation, compared to taxane/alkylator, anthracycline/alkylator/taxane/HER2-targeting therapy (hazard ratio (HR)=2.63, 95% confidence interval (CI) 1.56-4.43); anthracycline/alkylator without HER2-targeting therapy (HR=1.75, CI 1.13-2.71); and HER2-targeting therapy without anthracycline (HR=2.13, CI 1.11-4.09) were associated with an increased risk of CVD. CVD risk was similar for taxane/alkylator and no systemic therapy. Other factors associated with higher risk of CVD included NH Black race/ethnicity (HR=1.90, CI 1.32-2.73 vs. NH White) and public health insurance (HR=1.67, CI 1.00-2.78 vs private). This study identifies AYA BC survivors at higher risk of CVD based on treatment regimens received, with highest risks found for those receiving anthracycline/alkylator/taxane/HER2 treatment combinations. In addition, AYAs of Black race/ethnicity and those with public health insurance experienced more CVD, underscoring the need for targeted interventions to mitigate these disparities. Citation Format: Theresa H. M. Keegan, Candice A. Sauder, Ann M. Brunson, Renata Abrahao, Anne C. Kirchhoff, Eric Haupt, Mallory Casperson, Ted Wun, Chun R. Chao, Andrew B. Smitherman, Hazel B. Nichols, Jessica Chubak, Erin E. Hahn, Lawrence H. Kushi, Kathryn J. Ruddy. Systemic therapy and cardiovascular disease in adolescent and young adult breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5219.

Importance Despite treatment advances, metastatic recurrence continues to be a leading cause of morbidity and mortality. Empirical data on the incidence and survival after metastatic recurrence remain limited, as cancer registries historically do not collect data on recurrence. Objective To estimate the cumulative incidence (CMI) of metastatic recurrence among adolescents and young adults diagnosed with earlier-stage disease and compare survival to those with metastatic disease at diagnosis. Design, Setting, Participants This was a retrospective cohort study of adolescents and young adults aged 15 to 39 years who were diagnosed with nonmetastatic cancers from 2006 to 2018. Adolescents and young adults were identified from the California Cancer Registry linked with statewide hospitalization, emergency department, and ambulatory surgery encounters from the California Department of Health Care Access and Information. Data were analyzed from December 2023 to June 2025. Exposures Cancer types, including melanoma, sarcoma, and breast, cervical, colorectal, testicular, and thyroid cancers. Main Outcomes and Measures Metastatic recurrence was identified using International Classification of Diseases, Ninth Revision, Clinical Modification, and Tenth Revision, Clinical Modification, metastatic disease codes at least 6 months after cancer diagnosis or from an underlying cancer cause of death. Follow-up was through December 31, 2020. Results Of a total of 48 406 adolescents and young adults (median [IQR] age at diagnosis, 33.0 [28.0-37.0] years; 67.4% female), 9.2% had metastatic disease at diagnosis, and 9.5% had metastatic recurrence. Among 43 935 adolescents and young adults who presented with nonmetastatic disease, the 5-year CMI of metastatic recurrences was highest among patients with sarcoma (24.5%; 95% CI, 22.6%-26.6%) and colorectal cancer (21.8%; 95% CI, 20.3%-23.4%) and intermediate for cervical (16.3%; 95% CI, 15.0%-17.6%) and breast (14.7%; 95% CI, 14.0%-15.4%) cancers. The CMI for metastatic recurrence increased with increasing stage at diagnosis, with 5-year CMIs higher than 30% for all stage III cancers (except thyroid). The 5-year CMI of metastatic recurrence also increased over time for cervical cancer (2006-2009: 12.7% [95% CI, 10.8%-14.8%]; 2015-2018: 20.4% [95% CI, 17.5%-23.6%]) and decreased for colorectal cancer (2006-2009: 24.4% [95% CI, 21.3%-27.6%]; 2015-2018: 19.2% [95% CI, 16.4%-22.2%]). Survival after metastatic recurrence was worse than metastatic disease at diagnosis for all cancer types, except for testicular and thyroid cancers. Conclusions and Relevance The findings from this cohort study highlight the overall burden of metastatic disease in adolescents and young adults, expanding the knowledge of metastatic recurrences that help improve care for adolescent and young adult survivors throughout the cancer survivorship spectrum.

Abstract Background Few studies have assessed the burden of chronic medical conditions in adolescent and young adult (AYA) cancer survivors. This study estimated the risk of these conditions among AYA survivors compared to a matched cohort without cancer. Methods This retrospective cohort study included 2‐year survivors ( n = 14,917) of 11 common AYA (15–39 years) cancers diagnosed at the integrated health care organizations of Kaiser Permanente (KP) Southern and Northern California during 2006–2020. A comparison cohort ( n = 149,164) without cancer (matched 10:1 by age, sex, calendar year, and KP site) was included. Cumulative incidence (CMI) accounting for death as a competing risk was calculated. Poisson regression estimated the incidence rate ratio (IRR) of each condition in cancer survivors versus the matched cohort, adjusting for age, sex, and race/ethnicity. Results The 5‐year CMI was highest for thyroid (17.4%), respiratory (6.6%), cardiovascular (5.0%), and liver (4.8%) diseases. At 10 years, the CMI of any condition was 39% in survivors versus 26% in the matched cohort. Survivors had a 2‐fold increased risk of being diagnosed with any medical condition (IRR, 2.0; 95% confidence interval [CI], 1.9–2.0) as well as two or more conditions (IRR, 2.3; 95% CI, 2.2–2.5). Risk was highest among survivors of hematologic cancers and those diagnosed with distant stage disease. Elevated risks were observed within all sociodemographic groups of this insured population. Conclusion AYAs with cancer had a higher risk of chronic medical conditions compared to those without cancer. Long‐term surveillance, risk mitigation through lifestyle modifications and effective disease management are crucial to reduce premature mortality.

504 Background: Axillary surgery in breast cancer is used for staging and therapeutic purposes, but axillary lymph node dissection (ALND) confers high risk of complications including lymphedema. Accordingly, trials have focused on right-sizing axillary surgery, with options ranging from complete omission of surgery, sentinel lymph node (SLN) surgery, targeted axillary dissection (TAD), or ALND. Identifying a biomarker to reliably predict nodal burden would facilitate accurate selection of surgical management. We evaluated whether the presence or absence of ctDNA in the blood pre and post NAC is associated with residual nodal burden. Methods: I-SPY2 is a prospective, multicenter NAC trial for patients with clinical stage II-III high-risk breast cancer. Patients are randomized to novel NAC agents, with pathologic complete response being the primary endpoint. As part of the trial, serial ctDNA is assessed with a highly sensitive tumor-informed assay using up to 16 patient-specific tumor mutations (Signatera) at baseline, 3 weeks, 12 weeks, and post-NAC. We determined whether ctDNA positivity or negativity post-NAC, and the change in ctDNA status baseline/post-NAC (-/-, -/+, +/+, +/-) are associated with ypN category (N0, N1, N2). Results: ctDNA status was available post-NAC in 495 patients and change in ctDNA status from baseline was available in 493. At baseline, ctDNA was detected in 160/220 (72.3%) cN0 patients and 227/273 (83.2%) cN+ patients (p=0.006). Post-NAC, ctDNA was detected in 11/220 (5%) cN0 patients and 34/273 (12.5%) cN+ patients (p=0.004). While baseline ctDNA status was not associated with ypN category, there was a significant association between post-NAC ctDNA status and ypN category. For ctDNA + patients post-NAC, 33.3% were ypN0, 31.1% were ypN1, and 35.6% were ypN2 at surgery; in contrast, for ctDNA - patients post-NAC, 67.1% were ypN0, 23.1% were ypN1, and 9.8% were ypN2 (p<0.0001). Dynamic ctDNA changes were also associated with ypN category, with significantly more ypN0 patients among ctDNA -/- or ctDNA +/- cases, and more ypN2 patients in those who did not clear ctDNA (+/+) (p=0.0001, Table). Conclusions: To our knowledge this is the first study to demonstrate a significant relationship between ctDNA and ypN category, which has important surgical implications. CtDNA negativity was associated with low likelihood of ypN2 disease, making these patients excellent candidates for SLN surgery or TAD. Ongoing analyses will incorporate receptor subtype and timing of clearance of ctDNA. CtDNA in breast cancer may help tailor surgical management of the axilla, potentially reducing patient morbidity without compromising prognostic information. ctDNA baseline/post-NAC ypN0 (n=317) ypN1 (n=116) ypN2 (n=60) ctDNA -/- (n=105) 72.4% 19.1% 8.6% ctDNA -/+ (n=1) 0.0% 100.0% 0.0% ctDNA +/+ (n=44) 34.1% 29.6% 36.4% ctDNA +/- (n=343) 65.9% 23.9% 10.2%

Neoadjuvant chemotherapy (NAC) increases rates of successful breast-conserving surgery (BCS) in patients with breast cancer. However, some studies suggest that BCS after NAC may confer an increased risk of locoregional recurrence (LRR). We assessed LRR rates and locoregional recurrence-free survival (LRFS) in patients enrolled on I-SPY2 (NCT01042379), a prospective NAC trial for patients with clinical stage II to III, molecularly high-risk breast cancer. Cox proportional hazards models were used to evaluate associations between surgical procedure (BCS vs mastectomy) and LRFS adjusted for age, tumor receptor subtype, clinical T category, clinical nodal status, and residual cancer burden (RCB). In 1462 patients, surgical procedure was not associated with LRR or LRFS on either univariate or multivariate analysis. The unadjusted incidence of LRR was 5.4% after BCS and 7.0% after mastectomy, at a median follow-up time of 3.5 years. The strongest predictor of LRR was RCB class, with each increasing RCB class having a significantly higher hazard ratio for LRR compared with RCB 0 on multivariate analysis. Triple-negative receptor subtype was also associated with an increased risk of LRR (hazard ratio: 2.91, 95% CI: 1.8–4.6, P < 0.0001), regardless of the type of operation. In this large multi-institutional prospective trial of patients completing NAC, we found no increased risk of LRR or differences in LRFS after BCS compared with mastectomy. Tumor receptor subtype and extent of residual disease after NAC were significantly associated with recurrence. These data demonstrate that BCS can be an excellent surgical option after NAC for appropriately selected patients.