Couch, Fergus J.

11114 Background: Advances in early detection and treatment of breast cancer (BC) have significantly improved survival outcomes. In this growing survivor population, addressing modifiable lifestyle factors such as alcohol intake (AI), a known risk factor for BC and BC recurrence, is critical to improving prognosis and health-related quality of life (HRQoL). This study examines AI patterns and their associations with mental and physical HRQoL in early BC survivorship. Methods: Adult patients newly diagnosed (≤1 year) with stage I–III BC at Mayo Clinic Rochester were invited to enroll in the Mayo Clinic Breast Disease Registry. Of the 3252 patients who consented, 1997 completed surveys approximately one-year post-diagnosis, capturing weekly AI, demographic factors, and PROMIS-10 scores. PROMIS-10 (a 10-item measure of health, well-being, and distress) physical and mental health T-scores (mean = 50, SD = 10) are standardized to the U.S. population. Weekly AI was categorized as minimal/none (<1 drink), mild (1–4 drinks), moderate (5–14 drinks), or high (≥15 drinks). Univariate analyses were performed with Monte Carlo-based Fisher exact tests. Multivariate multinomial logistic regression models using a glogit link function assessed AI as the outcome and PROMIS-10 scores as independent variables, adjusting for financial status, smoking, chemotherapy, and moderate exercise because those were associated with AI at year 1 in prior analyses. Results: Univariate analyses revealed statistically significant associations between AI and PROMIS-10 scores (Table 1). Adjusted multivariate analyses identified that patients with better physical health were more likely to drink 1–4 or 5–14 drinks/week and less likely to abstain (<1 drink/week) than those with poorer physical health (p=0.027). There was no statistically significant association between AI and mental health QoL after adjustment for covariates. Conclusions: Better physical HRQoL during early survivorship was associated with higher AI, suggesting that patients who are feeling physically unwell may be less likely to drink alcohol. Additional public health messaging about the relationship between AI and breast cancer risk and recurrence may be needed, especially for those who are feeling well enough to consume alcohol. Univariate analyses of year 1 PROMIS-10 scores with year 1 alcohol consumption using Monte Carlo-based Fisher exact test. Alcoholic drinks per week at year 1 < 1(N=1204) 1-4(N=600) 5-14(N=175) 15+(N=18) Total(N=1997) P-value PROMIS global mental health T score, Year 1, n (%) 0.008 < 50 466 (63.8%) 200 (27.4%) 54 (7.4%) 10 (1.4%) 730 (37.1%) 50+ 718 (57.9%) 394 (31.8%) 120 (9.7%) 7 (0.6%) 1239 (62.9%) Missing 20 6 1 1 28 PROMIS global physical health T score, Year 1, n (%) <0.001 < 50 440 (66.5%) 165 (24.9%) 50 (7.6%) 7 (1.1%) 662 (33.6%) 50+ 740 (56.7%) 432 (33.1%) 124 (9.5%) 10 (0.8%) 1306 (66.4%) Missing 24 3 1 1 29

12083 Background: Fatigue and sleep disturbance are prevalent during and after cancer treatment; sleep-related symptoms affect 30-50% of patients with cancer, and sleep-wake disruptions persist beyond the immediate post-surgical period in breast cancer (BC) survivors. Identifying demographic- and treatment-related factors associated with sleep-related symptoms during survivorship is critical to inform interventions for those at highest risk of sleep disturbance. Methods: Patients who were seen at least once at Mayo Clinic Rochester following an initial diagnosis of BC at age 18 or older and provided informed consent were prospectively enrolled in the Mayo Clinic Breast Disease Registry. Surveys mailed to this cohort included two 11-point numeric rating scale questions regarding difficulty falling asleep and staying asleep in the past week, with values for each ranging from 0 (no problem) to 10 (as severe as you can imagine). Participants who provided sleep-related information on the Year 1 survey (answered approximately one year after cancer diagnosis) were included. Participants were excluded if they had clinical or pathologic metastatic disease and/or recurrence prior to the Year 1 survey. Associations of sleep-related symptoms with demographic and clinical characteristics were assessed using multivariate linear regression models, fitting the sleep difficulty rating scale as the outcome and clinical and demographic factors as exposures. Results: In total, 3,354 participants met inclusion criteria. The average age at BC diagnosis was 59, and most participants were female (99.3%), White (95.4%), non-Hispanic (96.2%), married (78.1%), had at least some college education (80.4%), did not report financial insecurity (76.2%), did not consume alcohol (60.6%) or smoke tobacco (93.2%), and reported at least some weekly exercise (76,6%). Sixty-two percent of participants had clinical stage 0 or I disease; 50.3% underwent lumpectomy (not mastectomy), 59.2% received radiotherapy, 34.1% received chemotherapy, and 67.2% received endocrine therapy. Overall, sleep-related symptoms were relatively low (mean rating for falling asleep = 2.1, mean rating for staying asleep = 3.1). In multivariate analyses, more difficulty falling asleep was associated with higher clinical stage (p < 0.001), more cigarettes smoked per day (p = 0.012), less moderate and/or strenuous exercise (p = 0.001), and more financial hardship (p < 0.001). More difficulty staying asleep was associated with higher clinical stage (0.003), older age (p < 0.001), more education (p = 0.011), and more financial hardship (p < 0.001). Conclusions: In our cohort of BC survivors, factors associated with both increased difficulty with falling and staying asleep at one year after diagnosis are higher clinical stage and more financial hardship. Future research should explore the course of these symptoms over time and across varied treatment trajectories.

12038 Background: CIPN, primarily associated with sensory neuropathy rather than motor or autonomic dysfunction, is a potentially long-term complication of cancer treatment including taxanes and platinums (T/Ps), and can negatively impact quality of life for breast cancer (BC) survivors. This project aims to quantify the severity of neuropathic symptoms at one and three years after diagnosis in BC survivors, comparing recipients of T/P to non-recipients. Methods: In the Mayo Clinic Breast Registry (MCBDR), a longitudinal cohort, surveys and medical record data from patients with stage 1-3 BC were used to understand the burden of neuropathic symptoms at 1- and 3-years post-diagnosis (denoted as Y1 and Y3). Y1 and Y3 raw scores from The Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 (CIPN20) composite (CIPN20-C) and sensory subscale (CIPN-S) were converted to a 0-100 point scale, with lower scores corresponding to worse symptoms. Patients with BC recurrence prior to Y3 or incomplete surveys were excluded. We used two sample t-tests and multivariable linear regression modeling to compare recipients of T/P to non-recipients of T/P (with threshold for statistical significance p <0.05). Results: 786 patients were included, 112 of whom (14.2%) received T/P. T/P recipients were younger (p<0.001), more likely to have Stage II/III disease (p<0.001), and less likely to have received endocrine therapy (p<0.001). Univariate analyses revealed worse CIPN20-C score at Y1 (p=0.02) and worse CIPN20-S scores (p=0.004) at Y1 and Y3 in T/P recipients compared to non-recipients (Table). However, differences between the groups were no longer statistically significant after adjustment for age, stage and endocrine therapy. Conclusions: In this cohort, neuropathic symptom severity at Y1 and Y3 after a breast cancer diagnosis did not differ between recipients of taxane and/or platinum agents and nonrecipients after adjustment for age, stage, and endocrine therapy. These data may reassure patients and clinicians who are concerned about CIPN and considering use of these chemotherapies in this setting. Patient demographics and CIPN20 results. Clinical characteristic T/P recipients Non-recipients of T/P Age at diagnosis, mean (SD) 55.3 (11.6)* 59.8 (11.9) White race, N (%) 108 (96.4%) 660 (97.9%) Clinical stage II/III, N (%) 76 (68.5%)* 250 (37.5%) Endocrine therapy, N (%) 73 (65.2%)* 636 (94.4%) Diabetes mellitus, N (%) 9 (8.9%) 52 (8.6%) Y1 CIPN20-C score, mean (SD) 89.6 (10.9)* 92.0 (9.7) Y3 CIPN-C score, mean (SD) 89.4 (11.4) 91.1 (9.7) Y1 CIPN20- S score, mean (SD) 87.3 (15.1)* 91.3 (13.0) Y3 CIPN20-S score, mean (SD) 88.2 (14.1)* 91.1 (11.7) *Statistically significant (p <0.05) on univariate analysis.

10582 Background: Breast cancer is the most common cancer in young women, with an increasing incidence over the past two decades. This study aims to evaluate the characteristics of young-onset breast cancers among patients aged ≤50 and compare tumor characteristics by germline mutation carrier status. Methods: Patients with breast cancer diagnosis ≤50 years old and evaluated across the Mayo Clinic enterprise between 2000 and 2024 were identified through the prospective Mayo Clinic Breast Cancer Study and the institutional tumor registry. Demographics, tumor characteristics, and clinical outcomes were obtained and described using summary statistics. Germline pathogenic or likely pathogenic variant (PV) carrier status for 5 established breast cancer predisposition genes (BRCA1, BRCA2, ATM, CHEK2 and PALB2) was available in a subset of unselected patients who consented to participation in sequencing studies at Mayo Clinic. Clinical characteristics were compared between PV carriers in each gene and non-carriers utilizing Chi-square test. All tests were two-sided and p-value less than 0.05 was considered statistically significant. Results: Among 8,462 patients (8435 women, 27 men) with breast cancer diagnosis at age ≤50 in the study, the median age of diagnosis of breast cancer was 44 years (range 18 – 49). At diagnosis, 84% had invasive disease, 43% of the tumors were high-grade, 15.8% had triple-negative breast cancer (TNBC), more than two-thirds (67.5%) presented with stage I or II breast cancer, and 3.7% had bilateral breast cancer. Among the 2,527 patients who consented to germline sequencing, 10.1% were found to be carriers of PVs; these included BRCA1 (3.3%), BRCA2 (2.7%), CHEK2 (2.3%), ATM (1.3%), and PALB2 (0.6%). Compared to non-carriers, a significant enrichment (p<0.05) of invasive breast cancer (92.6% vs. 83.3%) and high grade tumors (61.7% vs. 31.4%) were noted in BRCA1 PV carriers, and of bilateral breast cancer (13.4% vs. 3.8%) and high grade tumors (46.4% vs. 31.4%) in BRCA2 PV carriers. After exclusion of in-situ disease, proportion of TNBC was observed to be significantly higher in BRCA1 (61.3%), BRCA2 (15.5%) and PALB2 (30.7%) PV carriers compared to non-carriers (11.2%), whereas >90% of ATM or CHEK2 PV carriers had ER+ breast cancer and none had TNBC. A significant difference in stage at presentation was not observed by germline PV carrier status. Conclusions: The high frequency (>10%) of PVs in young-onset breast cancer underscores the importance for genetic testing in this population. The observed differences in breast cancer phenotypes based on germline PV carrier status among young-women may have significant implications for clinical outcomes and needs to be further explored.

10510 Background: The impact of germline pathogenic or likely pathogenic variants (PVs) in cancer predisposition genes on overall survival (OS) after breast cancer diagnosis is not well defined. In particular, unbiased OS estimates from population-based studies accounting for clinical subtypes of breast cancer (based on ER, PR, and HER2 status) and for genes other than BRCA1/2 are lacking. Methods: The study included 25,168 prospectively followed women with locoregional invasive breast cancer within the population-based CARRIERS study. Germline sequencing using a custom multigene amplicon-based panel was performed to identify PVs. OS was compared between germline PV carriers in ATM, BRCA1, BRCA2, CHEK2 and PALB2 and non-carriers (negative for germline PVs in 13 known breast cancer predisposition genes) for each clinical subtype of breast cancer from the time of breast cancer diagnosis to death or last follow up in a multivariable Cox proportional hazard regression analysis adjusting for age at diagnosis, race/ethnicity, histology, TNM stage, type of surgery, use of adjuvant radiation, chemotherapy and endocrine agents. Results: Among 25,168 women with breast cancer, germline PVs in one of the five breast cancer predisposition genes were detected in 5.8% of the women [ ATM : 0.8%, BRCA1 : 1.3%, BRCA2: 1.6%, CHEK2 : 1.5%, and PALB2 : 0.6%]. Among women with ER+ breast cancer, compared to non-carriers, a significantly worse OS was noted for BRCA1 (Hazard Ratio (HR): 1.8, 95% Confidence Interval (CI): 1.1 – 3.0, p=0.02) and BRCA2 (HR: 1.8, 95%CI: 1.4 – 2.4, p<0.001), but not for ATM (HR: 1.2, 95%CI: 0.8 – 1.7, p=0.40) or CHEK2 (HR:1.0, 95%CI: 0.8 – 1.3, p=1.0) PV carriers. Worse OS was noted in PALB2 PV carriers with ER+ breast cancer (HR:1.5, 95%CI: 0.9 – 2.2, p=0.09), although it did not reach statistical significance. Similar HR estimates for OS as with ER+ breast cancer were observed in women with ER+/HER2- breast cancer for BRCA1 , BRCA2 and PALB2 PV carriers, but only BRCA2 results were statistically significant. Among women with ER-negative breast cancer, compared to non-carriers, a significant difference in OS was not observed for PV carriers in ATM (HR:0.8, 95%CI: 0.4 – 1.8, p=0.63), BRCA1 (HR:1.2, 95%CI: 0.8 – 1.7, p=0.35), BRCA2 (HR: 0.8, 95%CI: 0.5 – 1.2, p=0.29), CHEK2 (HR: 0.7, 95%CI: 0.3 – 1.4), or PALB2 (HR: 0.9, 95%CI: 0.5 -1.7, p=0.78). Conclusions: The suggestive differences in OS by ER status of the tumor in BRCA1 and BRCA2 PV carriers warrant further investigation of underlying tumor biology and assessment of endocrine sensitivity of breast cancer in germline PV carriers.

10544 Background: Incorporation of Polygenic Risk Scores (PRS) can refine traditional breast cancer risk assessment models to provide precise estimates of breast cancer risk. However, the impact of such an integrated model on clinical decision-making related to breast cancer surveillance and preventive strategies is not fully understood. Methods: The GENRE-2 is a prospective single-arm multisite clinical trial (NCT04474834) incorporating PRS into standard breast cancer risk assessment models to determine the impact of PRS on clinical decisions on breast cancer prevention and surveillance. Women at high risk of breast cancer due to NCI-BCRAT 5-year risk of ≥ 3%, or IBIS (Tyrer-Cuzik) 10-year breast cancer risk of ≥5%, biopsy-proven high-risk breast lesion, or a pathogenic variant (PV) in ATM , BRCA1, BRCA2, CHEK2 or PALB2 , were enrolled from five sites in the United States. All women were invited to complete surveys on their breast surveillance and cancer prevention decisions based on pre-PRS standard risk models and post-PRS risk estimation, and further annual surveys are planned for 10 years. Results: Among 902 women enrolled in the study, 605 (median age: 52 years) received PRS results and completed a survey to date. Of those who received PRS results,195 (32.2%) were PV carriers. Among non-carriers, the median 10-year and lifetime pre-PRS IBIS-based risk was 10.0% and 28.7%, respectively. Among PV carriers, the CanRisk-based 10-year and lifetime pre-PRS risk estimates were 6.3% and 25.2% for ATM , 22.3% and 77.6% for BRCA1 , 18.5% and 77.7% for BRCA2 , 7.1% and 25.7% for CHEK2 , and 16.8% and 38.0% for PALB2 PV carriers, respectively. After the incorporation of PRS, the lifetime risk of breast cancer increased by at least 10% in 31% of non-carriers and 7.7% of PV carriers and decreased by at least 10% in 10.7% of non-carriers and 7.7% of PV carriers. The proportion of non-carriers with lifetime risk < 20% or > 40% changed from 17.3% and 22.0%, respectively, in the pre-PRS evaluation to 24.4% and 32.9%, in the post-PRS evaluation. A higher lifetime post-PRS score was associated with intent to take preventive action (surgery or endocrine agents). In non-carriers, the proportion of women with a lifetime risk < 20% with intent to take preventive action was 11%, compared to 36.8% of those with a lifetime risk > 40% (p < 0.001). Similarly, in PV carriers, the proportion of women with lifetime risk < 20% with intent to take preventive action was 20.8% compared to 41.1% of those with lifetime risk > 40% (p = 0.015). Conclusions: The GENRE-2 trial demonstrates that the incorporation of PRS into breast cancer risk assessment models in high-risk women is feasible and leads to clinically meaningful changes in breast cancer risk estimates and decision-making regarding preventive strategies. Evaluation of the implementation of breast cancer risk management strategies in study participants is ongoing and will be reported. Clinical trial information: NCT04474834 .

Abstract There are limited prospective data on whether established risk factors modify breast cancer risk in women with pathogenic variants (PV) in BRCA1/2 and virtually no risk modification data for ATM, CHEK2, or PALB2. We conducted a nested case–control study in the Women’s Health Initiative (WHI), randomly selecting women with and without breast cancer for DNA sequencing. We evaluated breast cancer odds associated with obesity, family cancer history, smoking, alcohol, parity, breastfeeding, oophorectomy, tubal ligation, neighborhood socioeconomic status, and menopausal hormone therapy (MHT) with estrogen and progestin or estrogen only in PV carriers and noncarriers. In exploratory analyses, we grouped genes by established predisposition for estrogen receptor (ER)-positive (ATM and CHEK2) or ER-negative (BRCA1 and PALB2) disease. Multivariable models with interaction terms were used to assess differential risk modification by PVs. Among 12,957 WHI participants, 287 carried PVs. Breastfeeding was modestly associated with reduced risk for PALB2 [OR = 0.08; 95% confidence interval (CI), 0.00–0.92; P value = 0.042]. With one-sided 95% CI, power was sufficient to exclude OR ≥2.0 with obesity for ATM and BRCA2; smoking and alcohol for CHEK2; no breastfeeding for ATM; no oophorectomy for BRCA2 and CHEK2; no tubal ligation for CHEK2; and neighborhood socioeconomic status for all genes. Estrogen + progestin MHT was modestly associated with increased risk for ER-positive PVs (OR = 7.31; 95% CI, 1.14–64.20; P = 0.036). PVs did not modify risk (interaction P ≥ 0.05). BRCA1/2, ATM, CHEK2, and PALB2 PV carriers do not have breast cancer OR ≥2.0 with many established risk factors. However, MHT warrants additional study in PV carriers. Significance: There is limited information on whether established risk factors increase breast cancer risk from PVs. In the WHI, PV carriers had no substantial (≥2-fold) increase with most risk factors, except potentially MHT in ATM or CHEK2 carriers. The results may inform counseling and research on MHT.

Abstract Purpose: While an addition of immune checkpoint inhibitor (ICI), pembrolizumab, has improved outcomes of patients with TNBC, early-stage TNBC patients with residual cancer burden (RCB) II/III after neoadjuvant chemotherapy in combination with pembrolizumab (NAP) still have poor outcomes. Previously, we demonstrated that intratumoral HLA-DRA expression and interferon-alpha (IFNα) responses were associated with immune-inflamed phenotype and better outcomes in TNBC patients receiving chemotherapy. This study utilized the CosMx™ SMI to investigate in early-stage TNBC treated with NAP. Methods: Of 151 samples from TNBC patients treated with NAP at Mayo Clinic, 8 pre-treatment biopsy samples (5 pCR and 3 RCB II/III were analyzed using the CosMx™ SMI platform. Linear mixed models to assess differential expression (DE), adjusting for hierarchical data structures. DE analyses were expressed as log2-fold changes (logFC), with the Benjamini-Yekutieli method. GSEA and IPA for signaling pathway exploration. Results: 1.7 million cells were identified across 8 samples after stringent quality control. Immune cell profiling revealed higher B cells, plasma cells, plasmablasts, and T cells (CD4 and CD8) in responders, whereas fibroblasts and myeloid cells were enriched in non-responders. DE analysis showed significantly elevated expression of HLA-DRA (logFC 1.955, p&lt;0.001), other MHC class I and II components, and IFNα in responders. Tumor cells in responders exhibited the highest IFNα expression across cell types. GSEA and IPA analysis revealed enrichment in interferon signaling, antigen presentation, and the cGAS-STING pathway, which drives IFNα production. Spatial analysis categorized cells by their proximity to tumor cells: within 50 µm, 50-100 µm, and over 100 µm. T cells, particularly CD8 T cells, showed a distance-dependent distribution, with a higher abundance near tumor cells in responders. CD8 T cell activation scores declined with increasing distance from IFNα-positive tumor cells but remained consistently low near IFNα-negative tumor cells. IFNγ-positive CD8 T cells exhibited higher activation compared to IFNγ-negative cells, with activation levels influenced by proximity to tumor cells. Lastly, MHC expression in tumor cells was examined relative to CD8 T cell proximity. HLA-DRA and CIITA expression decreased as tumor cells were farther from CD8 T cells. Conclusions: This spatially resolved single-cell analysis highlights the pivotal role of tumor-immune interactions in response to pembrolizumab in TNBC. Our data suggest that tumor cells secrete IFNα through the activation of the cGAS-STING pathway, which activates T cells within close proximity, highlighting the potential role of cGAS-STING agonist as well as IFNα signaling and antigen presentation in augmenting TNBC responses to ICIs. Citation Format: Yi Liu, Saranya Chumsri, Yaohua Ma, Jodi M. Carter, Aziza Nassar, Edith Perez, Roberto A. Leon-Ferre, David Zahrieh, David W. Hillman, Judy C. Boughey, James Ingle, Krishna R. Kalari, Fergus J. Couch, Matthew P. Goetz, Keith L. Knutson, E. Aubrey Thompson. Spatially resolved single-cell analysis reveals cGAS-STING-mediated tumor-immune interactions via IFNα as determinants of pembrolizumab sensitivity in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7130.

Background: Breast cancer survivors face a risk of significant psychological distress, which can persist for years after their initial diagnosis. Although numerous guidelines and tools exist to help screen for and measure distress in patients with cancer, additional longitudinal studies are needed to better characterize the trajectory of distress over time. Patients and Methods: We conducted a longitudinal study to evaluate distress and health-related quality of life in patients with breast cancer. Annual assessments included global mental and physical health scores using the Patient-Reported Outcomes Measurement Information System Global-10 (PROMIS-10), posttraumatic stress symptoms using the Impact of Event Scale-Revised (IES-R), and depressive symptoms using the Patient Health Questionnaire-2 (PHQ-2). Eligible participants had stage 0–III breast cancer, with baseline surveys administered within 1 year of diagnosis. Annual follow-up surveys were conducted through year 4 after the baseline survey. Only patients who completed the baseline survey and at least one follow-up survey were included in this analysis. Individuals with stage IV or recurrent breast cancer were excluded. Results: A total of 2,140 individuals were included. Over time, global mental health scores declined slightly, with differences in T-scores from baseline ranging from 0.4 to 0.9. In contrast, global physical health scores improved, with differences in T-scores ranging from 0.3 to 0.6. Mean scores remained in the normative range. Depressive symptoms remained stable throughout the study period, while posttraumatic stress symptoms showed improvement over time. Conclusions: This study provides important longitudinal data on distress subtypes in breast cancer survivors with nonmetastatic disease. Although global mental health declined slightly, depression symptoms remained stable, and posttraumatic stress symptoms improved. Investigation of distress subtypes over time merits further study to advance detection of significant distress across the cancer continuum.

Abstract Background: Prior research on the associations of p16, COX-2, and Ki67 immunopositivity in ductal carcinoma in situ (DCIS) tissue with the risk of subsequent ipsilateral invasive breast cancer (IBC) is limited. Methods: In a case–control study nested in a cohort of women diagnosed with DCIS, immunostaining for p16, COX-2, and Ki67 was performed on DCIS tissue from those who developed subsequent ipsilateral IBC (cases; n = 146) and on matched subjects who did not develop IBC (controls; n = 273). Conditional logistic regression was used to estimate ORs and 95% confidence intervals for the associations between immunopositivity for p16, COX-2, and Ki67 and the risk of subsequent ipsilateral IBC. Results: There was no association between p16, COX-2, and Ki67 immunopositivity, examined either individually or in combination, and a risk of ipsilateral IBC. Compared with all other groups, the multivariable OR (95% confidence interval) for women who were triple positive for the three markers was 1.16 (0.38–3.54). Conclusions: p16, COX-2, and Ki67 immunopositivity was not associated with altered risk of ipsilateral IBC in women with DCIS. Impact: p16, COX-2, and Ki67 may not be prognostic for ipsilateral IBC in women with DCIS.