Poster Spotlight 1: Addressing Breast Cancer Disparities and Treatment Related Toxicities 

M. T. Halpern¹, K. Y. Eom²; ¹Health Policy and Health Services Administration, University of Texas School of Public Health San Antonio, San Antonio, TX, ²Health Policy and Health Services Administration, University of Texas School of Public Health San Antonioversity, San Antonio, TX.

Introduction: Multiple reports have indicated that rural breast cancer survivors have worse clinical and patient-reported outcomes than do urban/suburban survivors. However, causes of these discrepancies are unclear. While numerous factors contribute to these observed differences, specific causes for diminished outcomes among rural breast cancer survivors must be identified to develop effective interventions and policies to support this underserved population. Methods: We used data from the 2020-2023 National Health Interview Survey (NHIS), a nationally representative household survey of the civilian noninstitutionalized U.S. population. All women aged 18 or older self-reporting a history of breast cancer were included in the study population. Three outcome significantly worse among rural (vs. urban/suburban) survivors were selected: increased emergency department (ED) utilization; decreased self-reported health status; and lower life satisfaction. We conducted causal mediation analysis to identify factors that partially explained the relationship between rural residence and worse outcomes among breast cancer survivors. Potential mediators from the NHIS included access to telemedicine, counseling, and homecare services; health limitations in ability to work; lack of employer-provided sick leave and health insurance; Medicare, Medicaid, or no health insurance; and decreased medication use due to costs. Causal mediation analysis was performed using SAS 9.4, incorporating the statistical design of the NHIS to provide results generalizable to the overall U.S. population. Results: Three NHIS items significantly mediated associations between rural status and poor outcomes among breast cancer survivors: lack of telemedicine use, health limitations in ability to work, and Medicaid insurance. Lack of telemedicine use mediated 20.3% of the association of rural residence and increased ED use (p=0.01), 22.3% of worse health status (p=0.004), and 26.6% of decreased life satisfaction (p=0.04). Health limitation in working significantly mediated 39.1% (p=0.005), 59.4% (p=0.003), and 59.1% (p=0.005) of associations with ED use, health status, and satisfaction, respectively. Medicaid insurance significantly mediated associations of rural residence with worse health status (43.9%, p=0.01) and lower life satisfaction (43.1%, p=0.04). Not receiving homecare marginally (p<0.10) mediated associations of rural residence with ED use and health status. Conclusions: Worse outcomes among rural breast cancer survivors may partially reflect barriers to accessing telemedicine care and homecare services; Medicaid health insurance coverage in rural settings; and health limitations affecting survivors’ ability to work. Causal analyses (including mediation analyses) can provide specific, actionable targets for programs and policies to address diminished outcomes among rural breast cancer survivors, such as increasing telemedicine and homecare services in rural areas, improving benefits or reimbursements associated with Medicaid coverage, and providing focused care to enhance functional status of survivors.

S. Poland¹, J. Freeman², M. Hennessy¹, W. Guo¹, A. Ravichandran³, R. Nanda¹; ¹Hematology/Oncology, The University of Chicago Medicine, Chicago, IL, ²Public Health Sciences, The University of Chicago, Chicago, IL, ³Internal Medicine, The University of Chicago Medicine, Chicago, IL.

Background: Hormone receptor-positive (HR+) breast cancer is the most common form of metastatic breast cancer in the US, and first-line treatment with endocrine therapy (ET) plus a CDK4/6 inhibitor (CDK 4/6i) has substantially improved overall survival. Despite advances, Black and Hispanic patients (pts) continue to fare worse than other racial and ethnic groups. However, limited data exist on how patterns of metastatic presentation and timing of treatment initiation vary by race and socioeconomic status, specifically among pts with de novo metastatic HR+/HER2- breast cancer. Methods: Pts diagnosed with de novo metastatic HR+/HER2− breast cancer between 2010–2022 were identified using the National Cancer Database (NCDB). Sociodemographic and clinical characteristics were compared across racial/ethnic groups. Pattern of metastatic spread at diagnosis and time from diagnosis to initiation of ET, chemotherapy, and radiation therapy were assessed. Of note, CDK4/6i are not coded specifically in NCBD and are categorized as chemotherapy. Multivariable linear regression was used to examine differences in time (in days) to treatment by race/ethnicity, insurance status, area-level income and education, and facility type, adjusting for relevant clinical covariates. We calculated regression coefficients (β) and 95% CIs to determine differences in treatment timing. Results: A total of 72,874 pts were identified with de novo metastatic HR+/HER2− breast cancer. Mean age was 63.4 years (SD, 13.8); 74.2% were White, 15.1% Black, 6.2% Hispanic, and 3.5% Asian/Pacific Islander. At diagnosis, 5.7% presented with brain metastases, 44.2% with bone-only disease, and 36.9% with visceral disease. Of pts with bone only metastatic disease, a higher proportion were White (66.3%) compared to 60.8% Hispanic, 58.4% Asian/Pacific Islander, and 57.9% Black (p<.001). A higher proportion of Black (43.4%) and Asian/Pacific Islanders (42.5%) had visceral metastases as compared to White pts (36.9%) (p<.001). Brain metastases were less common overall, but Hispanic (7.5%) and Black (6.4%) pts had higher rates than White pts (5.7%) (p<.001). ET was the first line of treatment in 78.8% of pts, with lower rates in Black (73.3%) and Hispanic (76.8%) pts compared to White pts (80.1%) (p<.001). Chemotherapy was administered to 58.9% of pts, and radiation therapy to 32.5%, with significant variations by race/ethnicity. In adjusted models, Black (vs. White) race was associated with delayed initiation of ET (β = 6.6 days; 95% CI, 4.5–8.8), chemotherapy (β = 3.6; 95% CI, 1.4–5.8), and radiation (β = 11.3; 95% CI, 5.9–16.7). Compared with White pts, delays were also observed for Hispanic pts across all modalities: ET (β = 8.3; 95% CI, 5.2–11.5), chemotherapy (β = 12.3; 95% CI, 9.2–15.5), and radiation therapy (β = 18.6; 95% CI, 11.0–26.2). Community or integrated network facilities and those residing in lower income and education areas were associated with ET delays; Medicaid/Medicare insurance was associated with delays in chemotherapy initiation (β = 11.9; 95% CI, 5.0–18.7, β = 11.6; 95% CI, 3.7–19.6, respectively). Presence of brain metastases was associated with shorter time to initiation for all treatments. Conclusions: Among pts with de novo metastatic HR+/HER2− breast cancer, racial and socioeconomic disparities were observed in patterns of metastatic disease at presentation as well as time to treatment initiation. Black and Hispanic pts were more likely to present with visceral or brain metastases and experienced longer time to treatment initiation, independent of clinical and system-level factors. These findings highlight persistent inequities in access to timely cancer care in the metastatic setting in the US.

M. N. Birhiray¹, S. Ranger², R. E. Birhiray³; ¹N/A, Indy Hematology Education, Indianapolis, IN, ²N/A, Indy Hematology Education, Carmel, IN, ³Oncology and Hematology, Hematology Oncology of Indiana, PC, Indianapolis, IN.

INTRODUCTION: Historical migration patterns, systemic inequities, and biological factors such as genetic polymorphisms and microbiome diversity all contribute to varied treatment responses among different racial and ethnic groups. Dr. Yedjou’s “Health and Racial Disparity in Breast Cancer” reported that while there is only a 2.6% difference in the incidence rate of breast cancer between White and Black women, Black women are 42% more likely to die from breast cancer than White women. While there may be other factors that play a role in these statistics, current trial designs often fail to account for the differences present amongst race and ethnic groups, leading to regulatory approvals based on non-generalizable data. Generalizability refers to the ability to infer the average treatment effect from a sample to the entire target population. In order to further evaluate the generalizability of breast cancer drugs from the past decade (2015 to 2025), we reviewed the FDA’s “Oncology (Cancer) /Hematologic Malignancies Approval Notifications” webpage. METHODS: Between February 3, 2015 and January 27, 2025, we identified 33 breast cancer drug approvals and used the DRIVE calculator to evaluate the generalizability of drug approval for target populations for which they will be used. Each study was examined for the inclusion of demographic data and reporting of the racial/ethnic composition of its participants. Following this review, a DRIVE score, ranging from 0 to 5, was assigned to each study, with a designation of “0x” or “0*” given if the racial/ethnic data was not reported or was reported separately, respectively. We have previously defined a minimum DRIVE score of 3 as the benchmark for clinical excellence and relevance based on racial representation. Demographic information was recorded as it was available at the time of abstract submission, based on the NCI clinical trial results section. RESULTS: A total of 9 breast cancer clinical trials met the criteria for clinical trial excellence, revealing an overwhelming lack of generalizability within these FDA drug approvals. Over this ten year period, 24 clinical trials failed to meet the minimum requirements for clinical trial excellence. The full score breakdown is as follows: 3 received a score of 0x, 2 received a score of 0, 5 received a score of 0*, 13 received a score of 1, 1 received a score of 2, 8 received a score of 3, 1 received a score of 4, and 0 received a score of 5. CONCLUSION: Our findings reveal that 9 out of 33 of the clinical trials associated with FDA approvals met the minimum criteria for clinical trial excellence. Although all the breast cancer drugs evaluated have received FDA approval, 72.5% do not accurately represent the intended patient populations. This lack of representation exacerbates disparities, particularly among minoritized populations, and leaves critical gaps in understanding potential adverse reactions or side effects. The aim of this analysis is to emphasize the need to minimize therapeutic misconceptions, the assumption that approved drugs with promising clinical trial data have demonstrated effectiveness across all patient populations. A clear understanding of the DRIVE Score Ranking and its purpose can assist clinicians and patients identify which drugs are supported by generalizable and transportable data, ultimately guiding more inclusive and equitable clinical research practices. For these reasons, we advocate for the exclusive use of trials meeting the minimum standards for “clinical trial excellence” as the basis of FDA approvals ensuring equitable benefits for all patients.

M. Taylor¹, M. Stefanou², G. Gong², M. Lustberg², A. Silber²; ¹Medical Oncology, UCSF, San Francisco, CA, ²Medical Oncology, Yale Cancer Center, New Haven, CT.

Background: Despite advances in cancer screening and therapeutics, persistent barriers to equitable cancer care and clinical trial access remain for underrepresented populations, including racial and ethnic minorities, non-English speaking patients, Medicaid recipients, elderly patients, and younger patients. Clinical trial enrollment remains disproportionately low among these groups, and trial participants often do not reflect the current demographics of the United States. While artificial intelligence (AI) tools have improved clinical trial patient matching, multiple barriers continue to limit trial participation. Addressing these barriers is essential to improve clinical trial representation.Methods: We developed a three-phase prospective pilot project at a large academic cancer center titled IMPACCT (Improving Participation in Cancer Clinical Trials) to improve clinical trial representation among breast and GI cancer patients. The project integrates community engagement, provider education, and evaluation of outcomes. Phase I – To build community trust, we established a multidisciplinary team of investigators, two community research fellows, and breast cancer survivors with prior trial experience. Outreach included collaborations with local businesses, event sponsorships, and support from the Yale Center for Community Engagement and Health Equity (CEHE) and the Community Research Fellow (CRF) program to sustain advisory boards and partnerships.Phase II – Providers on the breast and GI oncology teams completed “Just Ask,” an implicit bias training developed by ASCO and ACCC. This curriculum included six e-learning modules on diversity, equity, and strategies to improve inclusive trial recruitment. The training served as the primary intervention.Phase III – Post-training evaluation included provider and patient surveys. Providers completed surveys assessing perceived barriers to offering trials, while eligible patients completed surveys evaluating motivations and perceived barriers to trial participation. Additional metrics include trial offer rates, eligibility screening, and enrollment rates among underrepresented populations, categorized by care coordination, patient experience, and provider experience. We will also evaluate pre/post screening rates.Results: The “Just Ask” training intervention was implemented in January 2025. In the six months prior to the intervention, the breast cancer program enrolled 41 patients in clinical trials. In the six months following the intervention, enrollment increased to 75 patients as of June 2025. A total of 31 providers participated in the training, including 20 from the breast medical oncology group (14 medical oncologists, 2 surgical oncologists, 1 radiation oncologist, and 3 radiologists) and 11 from the gastrointestinal oncology group (9 medical oncologists, 1 colorectal surgeon, and 1 radiologist). To date, 14 of the 31 participating providers have completed consent for Phase III of the study, and 7 have completed post-intervention surveys.Conclusion: The IMPACCT project demonstrates early feasibility and promising signals of impact using the “Just Ask” intervention to improve clinical trial enrollment. The integration of community-based participatory research has proven both practical and effective, strengthening engagement between the cancer center and the community. These early findings suggest the intervention may be scalable across cancer types and clinical settings, with potential to inform broader equity-focused recruitment strategies in oncology trials.

I. Jackson¹, X. Lei², M. Sullivan¹, S. H. Giordano³, M. Chavez-MacGregor³; ¹Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, ²Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX, ³Department of Health Services Research and Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Background: NACT-IO has transformed the treatment landscape for early-stage, high-risk TNBC, a clinically aggressive subtype of breast cancer (BC) associated with less favorable survival outcomes. However, the real-world adoption and impact of NACT-IO on BC outcomes are not clearly understood. Using data from a large national hospital-based cancer registry, we examined trends and factors associated with NACT-IO use and pathologic complete response (pCR), and the impact on breast-conserving surgery (BCS) and overall survival (OS).Methods: Patients aged 18 years or older with clinical stage II-III TNBC diagnosed between 2017-2022 who received neoadjuvant chemotherapy (NACT) and underwent surgery were identified in the National Cancer Database. Trends in NACT-IO use and pCR over time were evaluated using the Cochran-Armitage test for time trend. Multivariable logistic regression was used to assess factors associated with receipt of NACT-IO and likelihood of pCR. The association between NACT-IO use and receipt of BCS was also examined using multivariable logistic regression. The impact of pCR on OS was evaluated using a multivariable Cox proportional hazards model with propensity score (PS) weighting and 1:1 matching by year of diagnosis and clinical stage.Results: Among 41,339 patients with early-stage TNBC who received NACT, 28.8% received NACT-IO. NACT-IO use increased significantly over time from 2.9% in 2017 to 81.9% in 2022 (p<0.001). Compared to non-Hispanic White (NHW) patients, Black (aOR=0.81; 95%CI 0.76-0.88) and Hispanic (aOR=0.88; 95%CI 0.80-0.97) patients had lower odds of receiving NACT-IO. Patients with Medicaid (aOR=0.89; 95%CI 0.82-0.98), Medicare (aOR=0.82; 95%CI 0.75-0.90), or no insurance (aOR=0.79; 95%CI 0.65-0.95) were also less likely to receive NACT-IO compared to those with private insurance. Higher nodal stage, higher income, and treatment at academic centers were associated with greater odds of NACT-IO use, while older age, higher comorbidity burden and urban residence were associated with lower odds. Patients treated with NACT-IO were more likely to undergo BCS compared to those who received NACT alone (aOR=1.05; 95%CI 1.01-1.11). Among NACT-IO recipients, pCR rates increased from 38.8% in 2017 to 51.6% in 2022 (p<0.001). Black patients (aOR=0.88; 95%CI 0.80-0.97), larger tumor size and higher nodal stage were associated with lower pCR rates. Notably, achieving a pCR was associated with significantly lower risk of death (aHR=0.21; 95%CI 0.16-0.27). Conclusions: Since the approval of NACT-IO for early-stage, high-risk TNBC, its use has increased substantially, accompanied by rising pCR rates and greater likelihood of BCS. However, significant disparities persist, with Black and Hispanic patients and those with public or no insurance less likely to receive NACT-IO. Achieving a pCR was strongly associated with improved OS, emphasizing the importance of optimizing treatment delivery and outcomes. These findings highlight the need for equitable access to innovative therapies and ongoing real-world evaluation of their impact to maximize benefit for all eligible patients.

O. M. Mbah, G. G. Ho, C. Keane, A. Dolor, C. Ryals; N/A, Flatiron Health, New York, NY.

Background: Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with Black women facing the highest incidence and poorest survival. While novel therapies, including immunotherapy (IO), antibody-drug conjugates (ADCs), and poly ADP-ribose polymerase (PARP) inhibitors, have improved outcomes, there is limited evidence on whether there are inequities in access and treatment related outcomes. This study examined racial/ethnic inequities in biomarker testing, access to IOs, PARP inhibitors, and ADCs and overall survival (OS), among patients with metastatic TNBC (mTNBC). Methods: We used the US-based Flatiron Health Research Database focusing on women aged ≥18 years, diagnosed with mTNBC between January 2018 and December 2024 (follow up through March 2025). Outcomes included biomarker testing (PD-L1 or BRCA1/BRCA2), use of IO, PARP or ADC, and OS among patients on IO, PARP, or ADC. We estimated a series of multivariable Cox proportional hazard models assessing racial/ethnic inequities in outcomes and potential mediation by area-level social determinants of health (SDOH). Models sequentially adjusted for clinical factors (e.g., age, year of diagnosis, stage) followed by area-level SDOH (neighborhood residential segregation, urbanicity [rural/urban], residence in medically underserved areas, vehicle ownership, and English proficiency). Results: The cohort included 5872 patients (52.5% White, 17.9% Black, 7.0% Latinx, and 20.6% Other/Unknown). Overall, testing rates were about 39% for PD-L1 and 25% for BRCA1/BRCA2. There were no significant racial/ethnic differences in PD-L1 or BRCA1/BRCA2 testing and biomarker positivity rates were similar across groups. However, Black patients were less likely than White patients to receive PARP inhibitors (adjusted HR: 0.64; 95% CI: 0.43-0.96), an inequity partially mediated by SDOH factors (mediated HR: 0.72; 95% CI: 0.30-1.73). Beyond PARP inhibitors, there were no other racial/ethnic differences in treatment receipt. In survival analyses, Latinx patients had better survival than White patients (HR: 0.73; 95% CI: 0.57-0.95), whereas Black patients had worse survival (HR: 1.17; 95% CI: 1.00-1.37). Conclusions: Despite equitable rates of biomarker testing, racial/ethnic inequities exist in access to PARP inhibitors and survival among patients with TNBC. Black patients were less likely to receive PARP inhibitors and had worse OS, with SDOH partially mediating some of these inequities.These findings underscore the need for targeted efforts to address structural barriers to care and promote equitable access to emerging therapies and outcomes in TNBC care.

I. Schlam¹, D. Trapani², S. Kim³, M. Faggen⁴, N. Sinclair¹, P. Sanz-Altamira¹, C. Battelli⁵, S. Berwick⁶, S. Lo⁷, J. Acevedo⁸, S. Sinclair⁹, A. Malcom¹, L. Varella¹, S. L. Sammons¹, S. T. Schumer¹, P. D. Poorvu¹, E. P. Wallace¹, E. Pasternak¹, N. Tayob³, S. M. Tolaney¹, E. L. Mayer¹; ¹Medical oncology, Dana Farber Cancer Institute, Boston, MA, ²Medical oncology, European Institute of Oncology, IRCCS, Milan, ITALY, ³Statistics, Dana Farber Cancer Institute, Boston, MA, ⁴Medical Oncology, Dana Farber Cancer Institute, Boston, MA, ⁵Medical oncology, New England Cancer Specialists, Portsmouth, NH, ⁶Medical oncology, Beth Israel Deaconess Medical Center, Boston, MA, ⁷Medical oncology, Stamford Health, Stamford, CT, ⁸Medical oncology, Boston Medical Center, Boston, MA, ⁹Medical oncology, Northern Light Health, Brewer, NH.

Introduction: Abemaciclib, a CDK4/6 inhibitor, reduces the risk of recurrence in patients (pts) with high-risk HR+/HER2- early breast cancer; use is associated with toxicities, particularly diarrhea, which can impact pts’ ability to maintain dose and/or remain on therapy. TRADE (NCT06001762) is a phase 2, investigator-initiated single-arm trial designed to evaluate whether an initial dose-escalation strategy improves adjuvant abemaciclib tolerability. The study met its primary endpoint, showing the dose escalation strategy reduced treatment discontinuation and improved ability to reach/maintain the target dose of 150 mg BID at 12 weeks (wks), compared to historical controls. Here, we present 6-month follow-up results from TRADE. Methods: Pts with HR+/HER2- early breast cancer eligible for abemaciclib with adjuvant endocrine therapy were enrolled. All pts initiated abemaciclib at 50 mg BID for 2 wks, escalated to 100 mg BID for 2 wks, and then to 150 mg BID onward for a planned 2-year course. Dose escalation required the absence of ongoing grade 3/4 or persistent grade 2 adverse events (AEs). Management of AEs and dose reductions beyond 12 wks was per standard of care. Data on adherence to oral therapy and ctDNA dynamics were collected. Results: Ninety pts were enrolled; median age was 58 years (range 24-78), and the majority were White (80.0%). 51.1% had stage II disease and 48.9% stage III disease. 73.3% had received chemotherapy in the neo/adjuvant setting. All pts received an adjuvant aromatase inhibitor (AI), 17.8% with ovarian function suppression. One pt had progression within 24 wks of treatment, hence was excluded from dose-related analyses. Out of 89 evaluable pts, 72 (80.9%) remained on treatment at 24 wks; 46 (63.9%) were receiving abemaciclib at 150 mg BID, 18 (25.0%) at 100 mg BID and 8 (11.1%) at 50 mg BID. Abemaciclib discontinuation occurred in 6 pts (6.7%) during the first 12 wks and in an additional 11 pts (12.4%) between wks 12 and 24, resulting in a cumulative discontinuation rate of 19.1% (n=17) over the initial 24 wks of exposure. The most common reasons for discontinuation were AEs (7, 7.9%) and withdrawal of consent/patient preference (6, 6.7%). Specific AEs contributing to discontinuation included diarrhea (2, 2.2%), pneumonitis (2, 2.2%), transaminitis (1, 1.1%), allergic reaction (1, 1.1%), and other (1, 1.1%). Of those who discontinued for patient preference, 5 of the 6 had reached target dose, of whom 3 did not have a dose reduction. A total of 12 pts (13.5%) did not reach target dose, and 29 (32.6%) required dose reductions within 24 wks, primarily due to gastrointestinal or hematologic toxicities, 22 (24.7%) with reductions from 150 mg dosing. The most frequently reported AEs overall were diarrhea (grade ≥2 32.2%, grade 3 5.6%), neutropenia (31.1%, grade ≥3 4.4%), and fatigue (25.6%, no grade ≥3). When analyzed by 4-wk intervals, rates of grade >2 diarrhea were 8.9% (wks 1-4), 19.1% (wks 5-8), 16.5% (wks 9-12), 12.0% (wks 13-16), 8.9% (wks 17-20), and 9.5% (wks 21-24), showing an early peak and gradual decline over time. Patient-reported outcomes, measured by FACT-B assessments, indicated that quality of life remained stable throughout the study period. Additional analyses, including evaluation of adherence and ctDNA, are ongoing. Conclusions: In the TRADE study, after initial dose escalation, abemaciclib was generally well tolerated, with a cumulative discontinuation rate of 19.1% at 24 wks, 7.9% for AE. The incidence of grade >2 diarrhea peaked at month 2 and declined over time. The majority of pts maintained quality of life and were able to remain on therapy with manageable and expected toxicities. These updated findings continue to support the feasibility of an initial abemaciclib dose-escalation approach to optimize drug exposure and reduce early discontinuation, while preserving therapeutic intensity.

K. Spath¹, C. Fung¹, J. Guido¹, G. Morrow¹, M. Janelsins¹, C. Kamen¹, J. McGuire¹, L. Mattick¹, P. Kumar², J. Fukui³, D. Doster⁴, L. J. Peppone¹; ¹Surgery; Supportive Care in Cancer, University of Rochester, Rochester, NY, ²Medicine, Metro Minnesota Community Oncology Research Consortium, Minneapolis, MN, ³Hawaii Minority Underserved NCORP, University of Hawaii Cancer Center, Honolulu, HI, ⁴Upstate Carolina Consortium Community Oncology Research Program, Anderson Area Cancer Center, Anderson, SC.

Background: Despite guideline-based antiemetics, refractory nausea remains common and significantly impairs quality of life (QOL) in patients receiving emetogenic chemotherapy. In this secondary analysis of a Phase III NCORP trial, we assessed whether olanzapine’s (OLZ) effects on QOL were mediated by reductions in nausea, using a moderated mediation model. We also evaluated subgroup differences by chemotherapy emetogenicity (HEC vs. MEC). Methods: In the parent RCT (NCT03367572), 1,363 chemotherapy-naïve breast cancer patients were screened across 21 NCORP sites while initiating highly (HEC) or moderately emetogenic chemotherapy (MEC). All received ASCO-recommended antiemetics. Three timepoints were defined: baseline prior to chemotherapy initiation (T1); immediately following Cycle 1 and prior to randomization (T2); and immediately prior to Cycle 2, post-randomization (T3). After Cycle 1 (T2), 310 patients with moderate nausea (≥3 on a 1-7 scale) were randomized 1:1:1 to receive olanzapine (OLZ), prochlorperazine (PC), or placebo, in addition to the standard regimen. This secondary analysis focused on the OLZ arm due to its superior QOL effects in the parent trial. Nausea was assessed using a 4-day home diary, with the maximum reported score across all diary entries used for analysis. QOL was measured via the FACT-G. We applied structural equation modeling (SEM) to evaluate whether OLZ’s effect on QOL at T3 was mediated by reductions in nausea, with moderation by time and treatment. Subscale analyses emphasized physical well-being (PWB). Clinically meaningful changes were defined as ≥5 points for FACT-G and ≥2 for subscales. Bonferroni correction (α = 0.00625) adjusted for multiple comparisons. Results: OLZ significantly improved QOL at T3, with 50.5% of the total FACT-G effect (Mean Difference [MD] = 4.67; p=0.002) mediated by reduced nausea (MD=2.36; p=0.001). In the HEC subgroup, the total FACT-G improvement was clinically meaningful (MD=6.50; p=0.001), with 3.82 points (58.8%) mediated (p<0.001). For PWB, OLZ led to a 2.53-point increase (p=0.001), with 59.4% (1.50 points) mediated by nausea reduction (p<0.001); in HEC patients, PWB increased by 3.20 points, with 72.2% (2.30 points) mediated (p<0.001). No significant effects were observed in the MEC group. A significant time-by-arm interaction (p<0.001) indicated greater improvement in nausea for OLZ compared to other arms between T2 and T3, the period during which OLZ was administered. Conclusions: In this secondary analysis, over half of OLZ’s benefit on overall QOL, and up to 72% of its benefit on physical well-being, was mediated by reductions in nausea. While effects were most pronounced in patients receiving HEC, clinically meaningful improvements were also observed in the MEC group, underscoring olanzapine’s broad utility across emetogenic risk levels. These findings highlight the critical role of nausea control in enhancing QOL and patient-reported outcomes, while supporting the integration of OLZ into standard antiemetic regimens for patients undergoing emetogenic chemotherapy.

A. Alpert¹, M. Makarov¹, S. Mor¹, D. Aran², A. Shai¹; ¹Oncology, Rambam Health Care Campus, Haifa, ISRAEL, ²Biology, Technion – Israel Institute of Technology, Haifa, ISRAEL.

Background: Immunotherapy is a cornerstone in the treatment of early stage, high-risk triple-negative breast cancer (TNBC), leading to improved pathological complete response rates and overall survival. However, a substantial proportion of patients experience immune-related adverse events (irAEs), which can be severe or even life-threatening. At present, there are no validated biomarkers capable of predicting the risk of high-grade irAEs among breast cancer patients undergoing immunotherapy. While therapeutic efficacy is largely dictated by tumor-intrinsic characteristics, evidence from studies in non-small cell lung cancer (NSCLC) suggests that irAE susceptibility is significantly influenced by the host’s baseline immune status. Advances in immunological profiling have enabled the quantification of immune system function by leveraging the physiological decline in immune competence that accompanies aging. These metrics—collectively referred to as immune age—offer a clinically meaningful assessment of immune system integrity that surpass chronological age in their clinical predictive value. Methods: Peripheral serum samples were collected from 145 treatment-naıve patients with stage I-III breast cancer (age range: 28-75 years). Baseline serum concentrations of 96 inflammatory proteins were quantified using the Olink inflammation panel. To derive immune age, we trained an elastic net linear regression model with cross-validation to predict chronological age from inflammatory protein profiles in post-surgical, treatment-naıve samples (n = 57), minimizing tumor-induced immune perturbation. The trained model was then applied to the full cohort to compute immune age. Immune age acceleration was defined as the difference between immune age and chronological age. Among 33 TNBC patients treated with perioperative pembrolizumab and chemotherapy, we compared immune age acceleration at baseline between those who did and did not develop high-grade (grades 3-4) irAEs. Results: The immune-age model accurately predicted chronological age in both training (post-surgery) and test (pre-surgery) cohorts, with Pearson correlation coefficients of 0.783 and 0.628, respectively. Immune age was positively associated with increased levels of inflammatory markers including CXCL9 and CCL11 (BH-adjusted P = 0.014 and P = 0.008, respectively), consistent with known hallmarks of immune aging. Across all measured inflammatory proteins, correlations with immune age were significantly stronger than with chronological age (paired t-test, P = 2.5 × 10⁻¹⁰), highlighting the superior capacity of immune age to capture individual baseline inflammatory status. Immune age acceleration followed a normal distribution centered around zero with a standard deviation of 4.7 years, reflecting the high inter-individual variability in the rates of immune aging. Among TNBC patients treated with perioperative pembrolizumab (n = 33), 13 (39.4%) developed grade 3-4 irAEs. Patients who developed high-grade irAEs exhibited significantly higher immune age acceleration at baseline (prior to treatment) compared to those who did not develop irAEs (t-test, P = 0.025), while chronological age showed no significant association with irAE development (median age: 44.0 vs. 46.9 years; P = 0.26). Conclusion: Immune age acceleration is associated with increased risk of severe irAEs in early-stage TNBC and may serve as a novel predictive biomarker. This immune-aging framework offers a host-centric approach to stratify risk prior to immunotherapy initiation, with potential implications for personalized surveillance and toxicity mitigation strategies.

N. L. Henry¹, A. Stickland¹, A. W. Schmidt¹, K. M. Kidwell², E. V. Joyce¹, S. Kozar¹, A. F. Schott¹, C. Van Poznak¹, K. Kemmer¹, T. M. Schmidt¹; ¹Internal Medicine, University of Michigan, Ann Arbor, MI, ²Biostatistics, University of Michigan, Ann Arbor, MI.

Background: AIMSS commonly affect AI- treated patients, and can lead to treatment discontinuation. The etiology of AIMSS is poorly understood. Alterations in the bacterial composition of the gut microbiome have been associated with inflammation. In particular, the presence of Bifidobacteria, members of the phylum Actinomycetota, in the stool has been associated with decreased systemic inflammation. Studies have shown that the gut microbiome is both influenced by estrogen and influences estrogen levels. We examined whether estrogen deprivation with AI therapy alters the composition of the gut microbiome and whether there are associations between the microbial composition and development of AIMSS. Methods: We enrolled females who were starting AI therapy (Clinicaltrials.gov NCT05700006). 53 patients with breast cancer starting AI therapy collected a total of 151 stool samples, before initiation of treatment (n=53) and after 4 and/or 12 weeks (n=98). Stool samples were also collected and analyzed from 10 patients with breast cancer who were not initiating endocrine therapy. DNA was extracted from stool samples, and 16S rRNA gene sequences were used to characterize and compare microbial communities. Participants were followed prospectively to assess persistence with AI therapy and reasons for discontinuation. Wilcoxon signed rank tests were used to compare microbial communities from patients who did and did not develop AIMSS. Results: Of the 53 enrolled participants who were starting AI therapy, mean age was 63.4 years (SD 9.0), mean body mass index was 29.2 kg/m² (SD 6.1), and 12 (22.6%) had received chemotherapy. Fifty-two (98%) initiated anastrozole, and 1 received exemestane. During the follow-up period, 12 (22.6%) discontinued the initially-prescribed AI therapy because of AIMSS. Stool samples from baseline compared to 4 and/or 12 weeks after initiation of AI therapy revealed no change over time in bacterial composition of the stool, as assessed using measures of both alpha and beta diversity. Comparing baseline samples from AI-treated patients who did and did not discontinue AI therapy because of AIMSS, there was a trend toward increased relative abundance of Actinomycetota in individuals that did not discontinue due to AIMSS (p=0.057). Differences were not identified for 6 other phyla examined. When species within Actinomycetota were examined, patients who did not discontinue AI therapy because of AIMSS had a trend toward higher relative levels of Bifidobacteria (p=0.058). Conclusions: This study demonstrated a potential association between increased relative levels of Bifidobacteria before AI therapy initiation and decreased likelihood of developing AIMSS. Future studies can investigate whether dietary manipulations that have been shown to increase levels of Bifidobacteria in the gut could decrease the incidence of AIMSS, thereby enabling increased persistence with AI therapy and improved quality of life.