Poster Spotlight 4: Risk, Genetics, and Outcome

A. Hasenböhler¹, M. Payen de la Garanderie¹, F. Szabo de Edelenyi¹, C. Agaësse¹, A. De Sa¹, I. Huybrechts², S. Hercberg¹, L. Zelek³, M. Deschasaux-Tanguy¹, B. Srour¹, M. Touvier¹; ¹Seine-Saint-Denis, Université Sorbonne Paris Nord and Université Paris Cité, INSERM, INRAE, CNAM, CRESS, EREN, Bobigny, FRANCE, ²Rhône, International Agency for Research on Cancer, World Health Organization, Lyon, FRANCE, ³Seine-Saint-Denis, Université Sorbonne Paris Nord and Université Paris Cité, INSERM, INRAE, CNAM, CRESS, EREN, Paris, FRANCE.

BackgroundExperimental studies suggested negative impacts of some preservative food additives via mechanisms involving advanced glycation end products and mutagenic and potentially carcinogenic activities, but human data are lacking. This study aimed to investigate for the first time the associations between exposures to a wide range of preservative food additives and cancer incidence, in particular breast cancer, in a large population-based cohort.MethodsParticipants (n=105,260; 78.7% women; mean age=42.0y SD=14.5) from the French NutriNet-Santé prospective cohort (2009-2023) completed repeated 24h dietary records (mean=21 SD=18), including industrial food brands. Cumulative time-dependent exposure to food additives was evaluated using multiple composition databases and ad hoc laboratory assays in food matrices. Associations between exposure to preservatives (3 categories: sex-specific tertiles or non-exposed/lower/higher exposed participants separated by the sex-specific median) and cancer incidence were characterised using proportional hazards Cox models adjusted for potential confounders.Results4226 incident cancer cases were diagnosed (mean follow-up=7.57y; SD=4.56) (incl. 1208 breast, 508 prostate, and 352 colorectal cancers). Regarding breast cancer, higher intakes of the following additives were associated with higher incidence: potassium sorbate with (Hazard Ratio (HR)_cat3vs.1= 1.26[1.07-1.49]); potassium metabisulphite (1.20[1.04-1.38]); potassium nitrate (1.22[1.05-1.41]); and sodium erythorbate (1.21[1.04-1.41]). Some associations were also observed for overall, prostate and colorectal cancers.ConclusionsThis large prospective cohort revealed multiple positive associations between exposure to widely used preservatives and higher cancer incidence. If confirmed, these new data could lead to a re-evaluation of the safety of these food additives by European and international public health agencies to improve consumer protection.

C. M. Vachon¹, S. Winham¹, M. Jensen¹, D. Hursh², L. Pacheco-Spann³, A. Norman¹, J. Fischer⁴, S. Schrup⁵, L. Seymour⁴, D. Gehling⁴, S. Nyante⁶, M. Troester⁷, N. Karssemeijer⁸, R. Vierkant¹, D. Radisky⁹, C. Scott¹, S. I. Maimone¹⁰, A. Degnim⁴, M. Sherman³; ¹Quantitative Health Sciences, Mayo Clinic, Rochester, MN, ²Biomedical Imaging Resource, Mayo Clinic, Rochester, MN, ³Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, ⁴Surgery, Mayo Clinic, Rochester, MN, ⁵Mayo Clinic Alix School of Medicine, Mayo Clinic, Rochester, MN, ⁶Department of Radiology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, ⁷Department of Epidemiology, Pathology Laboratory Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, ⁸Screenpoint Medical, Inc., Nijmegen, NETHERLANDS, ⁹Cancer Biology, Mayo Clinic, Jacksonville, MN, ¹⁰Radiology, Mayo Clinic, Jacksonville, FL.

Background: Artificial intelligence (AI) algorithms based on deep learning approaches show promise in improving breast cancer (BC) detection on mammography and may also improve prediction of future BC risk compared with clinical risk prediction models. Historical clinical risk prediction models underperform among women with BBD; however, AI models for BC detection on mammography have not been tested among women at elevated BC risk due to benign breast disease (BBD). We evaluated if an AI cancer detection algorithm can aid BC risk prediction among women with BBD. Methods: We examined women without a prior BC who had an initial BBD biopsy at Mayo Clinic, Rochester, between 2002 and 2013. Incident BC occurring after BBD was identified using the Mayo Tumor Registry and supplemented by follow-up questionnaires. Only women with a full field digital mammogram at least 2 years prior to BC diagnosis were eligible. A breast pathologist evaluated BBD according to increasing severity, as non-proliferative (NP), proliferative disease without atypia (PDWA) or atypical hyperplasia (AH). AI malignancy scores derived from the Transpara detection algorithm (1-10) and volumetric percent density (VPD) from Volpara (per one standard deviation, SD) were assessed from mammograms close to BBD diagnosis. Cox proportional hazards regression models were applied to estimate hazard ratios (HRs) with 95% Confidence Intervals (CIs), adjusted for age and BMI. C-statistics were estimated to assess the contribution of each factor to BC risk prediction. Likelihood ratio tests (LRTs) and bootstrapping methods were used to compare model performance with the addition of AI malignancy score. Results: The BBD cohort with mammography consisted of 3,125 women followed for a median 12.9 years, with 250 incident BC. Of these, 221 BC occurred at least two years after the mammogram and were used in analyses. As expected, increased BC risk was associated with BBD severity [for AH HR=3.18 (95%CI: 2.04, 4.95) and for PDWA HR=1.59 (95%CI: 1.17, 2.14) compared to NP] and with higher VPD [HR=1.24 per SD (95% CI: 1.05, 1.45)] (Table). The AI-malignancy score alone was also associated with BC risk [HR=1.16 per 1 unit score (95%CI: 1.09,1.23)] and showed similar discriminatory accuracy [C-statistic=0.626 (95%CI: 0.586, 0.665)] as the model with BBD severity and VPD combined [C-statistic=0.627, (95%CI: 0.585, 0.669)] (Table). In models with BBD severity and VPD, the AI-malignancy score was an independent risk factor for BC [HR=1.14 (95%CI: 1.07, 1.21); P_LRT<0.001] but only achieved a marginally significant improvement in discriminatory accuracy [C-statistic=0.651 (0.609, 0.693), ΔC-statistic=0.024 (95% CI: 0.000, 0.047)]. Conclusion: In this preliminary study, an AI BC detection algorithm achieved similar performance in predicting future BC risk compared to established risk factors.

H. Harsanyi¹, A. Harper¹, H. Freisling², N. Slot¹, S. Lupichuk³, A. Toriola⁴, L. Yang¹; ¹Cancer Epidemiology & Prevention Research, Alberta Health Services, Calgary, AB, CANADA, ²International Agency for Research on Cancer, World Health Organization, Lyon, FRANCE, ³Medical Oncology, Alberta Health Services, Calgary, AB, CANADA, ⁴Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO.

Introduction: Reproductive factors such as early menarche, late menopause, nulliparity, and exogenous hormone use are well-established risk factors for breast cancer. Physical activity is associated with a lower risk of breast cancer, but whether this protective effect varies across reproductive risk factors is not well characterized. Objective: To investigate whether reproductive risk factors modify the association between physical activity and breast cancer risk. Methods: Females ≥40 years without a history of cancer from UK Biobank provided self-reported data on moderate-to-vigorous intensity physical activity and reproductive factors (2007-2010). Physical activity levels were categorized based on reported metabolic equivalent hours per week (MET-hrs/week), with high levels of physical activity defined as ≥50 MET-hrs/week, moderate levels of physical activity as 10 to <50 MET-hrs/week, and low levels of physical activity as 12 years), parity (number of live births [50 years), use of oral contraceptive and use of menopausal hormone therapy (ever use vs. never use). Additive and multiplicative interactions were assessed using interaction terms within Cox regression and Relative Excess Risk due to Interaction (RERI), respectively. Subgroup analyses were conducted for pre-menopausal and post-menopausal breast cancer risk. Results: The study followed 242 721 participants for a mean of 12.53 years (SD: 2.55). During the study period, 8397 breast cancer cases were identified, including 748 pre-menopausal cases. Participants with high level of physical activity had significantly lower breast cancer risk (HR=0.87, 95%CI=0.82-0.93) compared to those with low level of physical activity. This association was observed for both pre- and post-menopausal breast cancer (HR [95% CI] = 0.78 [0.62-0.97] & 0.88 [0.83-0.94], respectively). The association between increased physical activity and decreased breast cancer risk was consistent across reproductive risk strata defined by age at menarche, parity, age at menopause, and use of oral contraceptive or menopausal hormone therapy (all p-values>0.05 for interaction terms and RERI estimates). Conclusions: Physical activity is a useful breast cancer risk reduction strategy for women, regardless of their reproductive history.

S. Yadav¹, C. Klassen², D. Stan², J. Fraker³, S. Sahni⁴, S. A. Khan⁵, L. Khatri⁶, C. Vachon⁷, D. Schaid⁷, J. P. Sinnwell⁷, E. Carlson⁷, L. Hasadsri⁸, F. J. Couch⁸, S. Pruthi²; ¹Department of Oncology, Mayo Clinic, Rochester, MN, ²Department of Medicine, Mayo Clinic, Rochester, MN, ³Department of General Internal Medicine, Mayo Clinic, Phoenix, AZ, ⁴Department of General Internal Medicine, Mayo Clinic, Jacksonville, FL, ⁵Department of Surgery, Northwestern University, Chicago, IL, ⁶Department of Internal Medicine, Cleveland Clinic, Cleveland, OH, ⁷Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, ⁸Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

Background: Incorporation of Polygenic Risk Scores (PRS) can refine traditional breast cancer (BC) risk assessment models to provide precise estimates of BC risk. However, the impact of such an integrated model on BC risk estimates and clinical decision-making related to BC screening and preventive strategies in germline pathogenic variant (PV) carriers is not fully understood. Methods: The GENRE-2 is a prospective single-arm multisite clinical trial (NCT04474834) incorporating 313-PRS into standard BC risk assessment models to determine the impact of PRS on risk estimates and clinical decisions on prevention and screening. All women received pre- and post-PRS BC risk estimates and completed surveys on their screening and cancer prevention decisions before and after integrating PRS estimates. Herein, we report on the impact of integrating PRS into CanRisk-based BC risk estimates among women enrolled in GENRE-2 due to PVs in ATM, BRCA1, BRCA2, CHEK2, or PALB2. Women were categorized into average risk (40%) for BC based on clinically relevant lifetime risk thresholds for supplemental MRI screening and risk-reducing bilateral mastectomies. Changes in categories of lifetime BC risk estimates were then evaluated before and after integration of PRS. Impact of PRS on patient decisions to undertake screening or preventive action (medication or prophylactic mastectomy) was evaluated based on pre- and post-PRS surveys. Results: Between 2020 and 2025, 933 women were enrolled, 633 received PRS results and completed a survey to date. Of those who received PRS results, 214 (33.8%) were PV carriers (ATM: 24, BRCA1: 54, BRCA2: 73, CHEK2: 54 and PALB2: 9). Among PV carriers, the CanRisk-based median 10-year and lifetime pre-PRS risk estimates were 6.0% and 23.9% for ATM, 22.5% and 77.5% for BRCA1, 17.9% and 77.6% for BRCA2, 7.1% and 26.6% for CHEK2, and 16.6% and 42.4% for PALB2, respectively. A total of 7 (29.2%) ATM PV carriers had a shift in lifetime BC risk categories after integration of PRS, with 1 (4.2%) shifting from average to moderate-risk, 3 (12.5%) shifting from moderate to average-risk category, and 3 (12.5%) shifting from moderate to high-risk category. Among CHEK2 PV carriers, 9 (16.7%) had a shift in lifetime risk categories, with 4 (7.4%) shifting from moderate to average-risk, 2 (3.7%) shifting from moderate to high-risk, and 3 (5.6%) shifting from high to moderate-risk. None of the BRCA1 and 4.1% of BRCA2 PV carriers had a shift in lifetime risk categories after PRS integration. Only 1 (11.1%) PALB2 PV carrier had a change in lifetime risk category after integration of PRS, although this was limited by a small sample. A significantly higher proportion of PV carriers with a high lifetime risk intended to take preventative action compared to the PV carriers with average lifetime risk (41.4% vs. 20.0%, p=0.007). Conclusions: Integration of PRS into BC lifetime risk estimates led to a clinically meaningful change in risk categories in 29.2% of ATM PV carriers and 16.7% of CHEK2 PV carriers, but in <5% of BRCA1 or BRCA2 PV carriers. These findings suggest that PRS may be helpful for BC risk stratification in moderate-risk genes such as ATM and CHEK2 but may have limited clinical utility in high-risk genes such as BRCA1 or BRCA2.

H. Huang¹, C. Hu¹, J. Na², M. Kucera³, T. Simmons³, E. Mundt⁴, C. C. Young⁵, Z. Heidari⁵, P. C. Lyra⁶, Y. Y. Tan⁷, K. L. Nathanson⁸, T. Pal⁹, R. Karam¹⁰, T. Pesaran¹¹, S. Yadav¹², S. M. Domchek⁸, A. N. Monteiro⁶, E. Hughes³, N. Boddicker², W. Chen², M. E. Richardson⁵, F. J. Couch¹; ¹Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, ²Quantitative Health Sciences, Mayo Clinic, Rochester, MN, ³Biostatistics, Myriad Genetics, Salt Lake City, UT, ⁴Clinical Genomics, Myriad Genetics, Salt Lake City, UT, ⁵Clinical Research, Ambry Genetics, Aliso Viejo, CA, ⁶Cancer Epidemiology, H. Lee Moffitt Cancer Center, Tampa, FL, ⁷Obstetrics and Gynecology, Medical University of Vienna, Vienna, AUSTRIA, ⁸Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, ⁹Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN, ¹⁰Research & Development, Ambry Genetics, Aliso Viejo, CA, ¹¹Genomic Sciences, Ambry Genetics, Aliso Viejo, CA, ¹²Oncology, Mayo Clinic, Rochester, MN.

Background: BRCA2 variants with partially aberrant RNA splicing have been associated with a relatively lower breast cancer risk (reduced penetrance) relative to canonical pathogenic variants. However, the existence of partial loss of function (hypomorphic) missense variants, conferring reduced penetrance, is less certain. Identification and assessment of the clinical relevance of such reduced penetrance pathogenic variants (RPPVs) is needed to provide accurate risk estimates. Methods: Comprehensive functional characterization of hypomorphic missense variants (n=70) in the BRCA2 DNA-binding domain, initially identified through homology-directed DNA repair (HDR) assays, was conducted through multiple independent functional assays, including HDR, CRISPR/Cas9-based endogenous targeting, RAD51 foci formation assay, and Poly(ADP-ribose) polymerase (PARP) inhibitor response assay. Risk estimates were obtained using two large datasets from patients referred for hereditary cancer testing. A ClinGen/ACMG/AMP model was used for clinical classification. Results: The variants consistently demonstrated hypomorphic HDR activity and endogenous survival in HAP1 targeted cells, decreased RAD51 foci formation, and increased sensitivity to PARP inhibitors. These variants were associated with a moderate increase in breast cancer risk, as shown in two independent studies: one using multivariable logistic analysis adjusted for age, ancestry and family history (OR=2.41, 95%CI=1.51-3.85) and another comparing frequencies of variants in breast cancer cases to public reference controls adjusted for ancestry (OR=2.09, 95% CI=1.16-4.08). The mean age of breast cancer diagnosis for carriers of hypomorphic variants was 57 years, which was significantly older than the mean age of diagnosis of 51 years for carriers of protein truncating variants. Functional data were combined with other evidence sources in a ClinGen/ACMG/AMP model to classify 14 variants as “likely pathogenic”. Conclusions: We identified partially functional, hypomorphic missense variants associated with reduced penetrance for breast cancer. Cancer risk management guidelines for this new category of variants should be revisited given that the associated breast cancer risks warrant high risk screening but do not meet the threshold at which risk reducing mastectomy is offered. This study supports a shift in paradigm to considering variant-based risks on a continuum, with implications for risk-appropriate cancer risk management.

E. Blondeaux¹, A. Meacci², M. Fragío Gil², E. Klocker³, F. Coussy⁴, H. Kim⁵, R. Bernstein Molho⁶, F. Hilbers⁷, A. Di Meglio⁸, A. Kwong⁹, K. Pogoda¹⁰, J. Bajpai¹¹, H. Wildiers¹², E. Agostinetto¹³, J. Balmana¹⁴, H. C. Moore¹⁵, K. Phillips¹⁶, A. H. Partridge¹⁷, C. Rousset-Jablonski¹⁸, F. A. Peccatori¹⁹, A. Toss²⁰, T. Renaud²¹, C. Anghelone²², A. Benitez Cruz²³, S. Paluch-Shimon²⁴, J. Lee²⁵, R. Fruscio²⁶, W. Cui¹⁶, S. M. Wong²⁷, M. Lee²⁸, M. Rozenblit²⁹, C. Vernieri³⁰, C. Villarreal-Garza³¹, A. Matikas³², M. Dieci³³, L. De Marchis³⁴, J. K. Plichta³⁵, K. J. Ruddy³⁶, D. Can Guven³⁷, F. Puglisi³⁸, Z. Kemp³⁹, P. A. Meireles⁴⁰, L. Del Mastro⁴¹, V. Delucchi⁴², M. Lambertini⁴³; ¹U.O. Epidemiologia Clinica, IRCCS Ospedal Policlinico San Martino, Genova, ITALY, ²Department of Medical Oncology, IRCCS Ospedale Policlinico San Martino, Genova, ITALY, ³Department of Medical Oncology, IRCCS Ospedal Policlinico San Martino, Genova, ITALY, ⁴Department of Medical Oncology, Institut Curie-Institut of Women’s Cancers, Paris, FRANCE, ⁵Division of Breast Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, KOREA, REPUBLIC OF, ⁶Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheb, Tel Aviv University, Tel Aviv, ISRAEL, ⁷Department of Molecular Pathology, Netherlands Cancer Institute (NKI), Amsterdam, NETHERLANDS, ⁸Département Médecine Oncologique, Gustave Roussy, Paris, FRANCE, ⁹-, Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong, HONG KONG, ¹⁰Department of Breast Cancer and Reconstructive Surgery, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, POLAND, ¹¹Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, INDIA, ¹²Department of General Medical Oncology, University Hospitals Leuven, Leuven, BELGIUM, ¹³Université libre de Bruxelles (ULB), Institut Jules Bordet, Bruxelles, BELGIUM, ¹⁴Hereditary Cancer Genetics Unit, Medical oncology Department, Vall d´Hebron University Hospital, Barcelona, SPAIN, ¹⁵Department of Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, ¹⁶Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, AUSTRALIA, ¹⁷Department of Medical Oncology, Dana-Farber Cancer Institute,, Boston, MA, ¹⁸Department of Surgery, Leon Berard Cancer Center, Lyon, FRANCE, ¹⁹Gynecologic Oncology Department, European Institute of Oncology (IRCCS), Milano, ITALY, ²⁰Department of Oncology and Haematology, Azienda Ospedaliero-Universitaria Policlinico di Modena, Modena, ITALY, ²¹Cancer Genetics Unit, Bergonie Institute, Bordeaux, FRANCE, ²²Hereditary Breast and Ovarian Cancer (HBOC) Unit and General Surgery 3 – Senology, Breast Cancer, Fondazione IRCCS Policlinico San Matteo, Pavia, ITALY, ²³-, SUMA (Grupo Cooperativo Argentino para el Estudio y la Investigación del Cáncer de Mama), -, ARGENTINA, ²⁴Hadassah University Hospital, Sharett institute of oncology, Hadassah University Hospital, Jerusalem, ISRAEL, ²⁵Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, KOREA, REPUBLIC OF, ²⁶Department of Medicine and Surgery, IRCCS San Gerardo dei Tintori, Monza, ITALY, ²⁷Stroll Cancer Prevention Centre, Jewish General Hospital, Montreal, QC, CANADA, ²⁸-, Memorial Sloan Kettering Cancer Center MSKCC, New York, NY, ²⁹Medical Oncology, Yale University, New Haven, CT, ³⁰Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ITALY, ³¹Breast Cancer Center, Hospital Zambrano Hellion – TecSalud, Tecnologico de Monterrey, Monterrey, MEXICO, ³²Department of Oncology/Pathology, Karolinska Institute and Breast Center, Karolinska University Hospital, Stockholm, SWEDEN, ³³Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Università di Padova, Padova, ITALY, ³⁴Division of Medical Oncology, Department of Radiological, Oncological and Pathological Sciences, “Sapienza” University of Rome, Roma, ITALY, ³⁵Department of Surgery, Duke University, Durham, NC, ³⁶Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, ³⁷-, Hacettepe University Cancer Institute, Ankara, TURKEY, ³⁸Department of Medicine, University of Udine, Udine, ITALY, ³⁹Breast Medical Oncology and Cancer Genetics Units, Royal Marsden Hospital, London, UNITED KINGDOM, ⁴⁰Medical Oncology Department, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lison, PORTUGAL, ⁴¹Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genova, Genova, ITALY, ⁴²U.O. Epidemiologia Clinica, IRCCS Ospedale Policlinico San Martino, Genova, ITALY, ⁴³Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genova, Genoa, ITALY.

Background Young age is a known risk factor for breast cancer recurrence and mortality, particularly in hormone receptor-positive disease. However, no specific evidence exists on whether age at diagnosis influences clinical behavior and outcomes among carriers of germline BRCA pathogenic or likely pathogenic variants (PVs). Methods The BRCA BCY Collaboration (NCT03673306) is an international, multicenter, hospital-based, retrospective cohort study including women with germline BRCA1 and/or BRCA2 PVs and diagnosed with stage I-III breast cancer at the age of 40 years or younger between January 2000 and December 2020. The present analysis aimed to evaluate clinical features and outcomes of breast cancer in young BRCA carriers according to age at diagnosis, by comparing patients aged ≤30 years with those aged 31-35 and 36-40 years at breast cancer diagnosis. The primary endpoint was disease-free survival (DFS). Overall survival (OS) was a secondary endpoint. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs), adjusting for risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) (time-dependent), and stratifying by country, year of diagnosis, tumor size, nodal involvement, tumor grade and hormone receptor status. Results From 109 centers in 5 continents, 5350 young BRCA carriers were included, of whom 1106 (20.7%) were ≤30 years of age, 1945 (36.4%) were 31-35 years and 2299 (43.0%) were 36-40 years at the time of breast cancer diagnosis. Compared to patients aged 31-35 and 36-40 years, those aged ≤30 years were more likely to harbor BRCA1 PVs (71.3%, 62.4%, 61.1%, respectively), to present with high-grade (G3 in 71.3%, 66.6%, 65.0%, respectively), triple-negative breast cancer (56.3%, 48.1%, 46.6%, respectively), and less frequently smaller tumor size (T1: 31.7%, 36.6% and 39.5%, respectively). Consequently, chemotherapy was administered more frequently among patients aged ≤30 years (94.4%, 92.6%, 89.7%, respectively). At a median follow-up of 8.2 years (IQR, 4.7-12.8), 8-year DFS rate was 65.0% among patients aged ≤30 years, 64.7% in the 31-35 years group, and 65.8% in the 36-40 years group. No significant association between age at diagnosis and DFS outcome was observed (31-35 vs. ≤30 years: aHR 1.03, 95% CI 0.89-1.19; 36-40 vs. ≤30 years aHR 1.00, 95% CI 0.87-1.16). Similarly, no significant association between age at diagnosis and OS was observed (31-35 vs. ≤30 years: aHR 1.10, 95% CI 0.86-1.41; 36-40 vs. ≤30 years: aHR 1.11, 95% CI 0.87-1.43). Subgroup analyses by specific BRCA gene, tumor subtype, tumor size, nodal status, and chemotherapy use revealed no statistically significant interaction with age at diagnosis in terms of DFS or OS (all p for interaction > 0.05). Specifically, no significant differences between age groups were observed among patients with luminal-like tumors for both DFS and OS. Conclusions In this unique international cohort of BRCA carriers diagnosed with breast cancer at a young age (≤40 years), we found no significant differences in DFS nor OS across different age groups. Notably, very young age (≤30 years) at diagnosis was not associated with worse outcomes compared to 31-35 years or 36-40 years. Age per se should not be considered a negative prognostic factor in BRCA carriers when appropriate treatment is provided.

S. Yadav¹, Q. Li², Z. Tan³, K. E. Mishkin⁴, J. F. Hayes⁵, X. Xu², F. J. Couch¹; ¹Department of Oncology, Mayo Clinic, Rochester, MN, ²Oncology Outcomes Research, AstraZeneca, Gaithersburg, MD, ³Oncology Outcomes Research, AstraZeneca, Mississauga, ON, CANADA, ⁴Department of Oncology, Merck & Co., Inc., Rahway, NJ, ⁵US Medical Affairs Oncology, AstraZeneca, Gaithersburg, MD.

Background: International guidelines recommend that all patients (pts) with metastatic breast cancer (mBC) are offered testing for germline BRCA1/BRCA2 mutations (gBRCAm) and other biomarkers to aid treatment decisions. This retrospective study describes real-world testing patterns for germline/tumor (g/t)BRCAm and other biomarkers among US pts with HER2-negative [HER2−] mBC. Methods: Data were captured from US pts aged ≥18 years with HER2− mBC from January 12, 2018, to March 31, 2024, in the deidentified, electronic health record-derived Flatiron Health Research Database. Demographics, clinical characteristics, and testing patterns for g/tBRCAm and other actionable biomarkers were examined. Testing rates, test timing, and biomarker status were described across subgroups defined by demographics (including age, race, and ethnicity), tumor subtype (hormone receptor-positive [HR+]/HER2− mBC or triple-negative mBC [mTNBC]), and disease stage at mBC diagnosis (recurrent/de novo). Results: The BRCA testing rate among pts with mBC increased from 2018 (48%) to 2023 (62%); the overall testing rate was 19,820/34,379 (58%): 5880 pts (17%) received a gBRCA test only, 7285 (21%) received a tBRCA test only, and 6655 (19%) received both gBRCA and tBRCA tests. BRCA testing rates were numerically lower in pts with HR+/HER2− mBC (56%) versus mTNBC (68%), and in pts aged >65 years (HR+/HER2− mBC, 48%; mTNBC, 62%) versus ≤65 years (HR+/HER2− mBC, 64%; mTNBC, 74%; Table). The proportion of pts who received a test before initiation of first-line (1L) therapy was lower among pts with HR+/HER2− mBC than with mTNBC (recurrent, 60% vs 81%; de novo, 37% vs 57%). Among tested pts, 1067/15,168 (7%) with HR+/HER2− mBC and 494/4539 (11%) with mTNBC had a positive result for g/tBRCAm; 365/1067 (34%) pts with g/tBRCAm HR+/HER2− mBC and 138/494 (28%) pts with g/tBRCAm mTNBC were aged >65 years. Among 528 pts with gBRCAm HR+/HER2− mBC, co-mutations in PIK3CA, ESR1, PTEN, and AKT1 were identified in 48 (9%), 38 (7%), 20 (4%), and 3 (<1%) pts, respectively. Among pts diagnosed with gBRCAm HR+/HER2− mBC in 2020-2023 (median follow-up: 15 months), 175/371 (47%) did not receive a test for PIK3CA mutations at any time, and 48/97 (49%) pts diagnosed in 2023 (median follow-up: 6 months) did not receive a test for ESR1 mutations. In 2021-2023, 72/256 (28%) pts with g/tBRCAm mTNBC had tumors with programmed cell death-ligand 1 (PD-L1) combined positive score ≥10; 88 (34%) pts did not receive a PD-L1 test. Conclusions: Although BRCA testing rates increased from 2018 to 2023, 38% of US pts diagnosed with HER2− mBC in 2023 did not receive any BRCA test. BRCA testing rates were low among pts with HR+/HER2− mBC and/or aged >65 years, suggesting that many g/tBRCAm remained undetected. Wider and timelier testing for germline and tumor biomarkers is warranted to identify pts who are eligible for targeted therapies. Table. BRCA testing rates and BRCA status

P. Zagami¹, A. Marra¹, S. Perazzo², C. Grazia¹, A. Carnevale Schianca¹, B. Malagutti¹, E. Giordano¹, M. Calvello³, M. Marabelli³, D. Trapani¹, N. Fusco⁴, E. Guerini Rocco⁴, S. Gandini⁵, E. Munzone⁶, A. Guerrieri-Gonzaga³, B. Bonanni³, G. Curigliano¹; ¹New Drugs and Early Drug Development for Innovative Therapies Division, European Institute of Oncology (IEO), university of Milan, Milan, ITALY, ²New Drugs and Early Drug Development for Innovative Therapies Division, european institute of oncology (IEO), Milan, ITALY, ³Division of Cancer Prevention and Genetics, European Institute of Oncology (IEO), Milan, ITALY, ⁴Division of Pathology, European Institute of Oncology (IEO), university of Milan, Milan, ITALY, ⁵Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, ITALY, ⁶Division of Medical Senology, European Institute of Oncology (IEO), Milan, ITALY.

BackgroundThere is limited evidence on the effect of extended adjuvant endocrine therapy (ET) in patients with hormone receptor-positive/HER2-negative (HR+/HER2-) early breast cancer (EBC) carrying germline BRCA1 and/or BRCA2 (gBRCA) pathogenic/likely pathogenic variants (PVs)compared to non-carriers. We investigated the association between extended ET (eET) versus standard-duration ET and clinical outcomes in gBRCA PV carriers with HR+/HER2- EBC.Methods This cohort study derived from an institutional database, including all consecutive patients with BC who underwent genetic counselling at the European Institute of Oncology (May 2002-Jan 2024). Eligible patients had stage I-III HR+/HER2- EBC diagnosed between Jan 2000 and Dec 2022, received adjuvant ET and had complete treatment and follow-up data available. eET was defined as therapy administered for more than 5 years. Primary endpoints were distant relapse-free interval (DRFI) and invasive disease-free survival (iDFS), as defined by STEEP 2.0 criteria. Survival analyses were conducted using univariate and multivariate Cox proportional-hazard models, stratified by year of diagnosis, use of (neo)adjuvant chemotherapy, nodal status, tumor size and grade, stage, ET duration and type BC surgery and BRCA PVs. Left-truncated models were used to account for the interval between BC diagnosis and genetic testing. Landmark analysis was performed to calculate the cumulative incidence of events over time. Results Among 1,225 eligible patients, the median duration of adjuvant ET was 60 months (IQR 49-74), with a median age of 41 years (IQR 36-47). The majority were premenopausal (79%, n=973), and 42% had stage I disease. Sixty percent received eET and 80% received LHRH agonists. Over half received tamoxifen, while 33% received aromatase inhibitors (AI), and 14% switched from tamoxifen to AI. Overall, 164 patients (13%) were gBRCA1/2 PV carriers, mostly gBRCA2 (76%). Carriers were younger than non-carriers (39 years, IQR 35-44 vs. 42 years, IQR 36-48), and more likely to have higher tumor stage (68% vs. 56% stage II/III) and grade (53% vs. 25% grade 3), to receive adjuvant chemotherapy and mastectomy, and to undergo BRCA testing earlier. The median duration of ET was similar in both groups, although a smaller proportion of BRCA PV carriers received eET compared to non-carriers (54% vs. 61%). At a median follow-up of 11.1 years (IQR [8.2-15.2]), extended ET was associated with significantly improved iDFS (adjusted HR [aHR] 0.31, 95% CI 0.26-0.39, p<0.001) and DRFI (aHR 0.29, 95% CI 0.22-0.38, p<0.001), compared to standard-duration ET. BRCA PVs status was associated to reduced iDFS (aHR 1.5, 95% CI 1.14-1.96, p=0.003), but not with DRFI. In the subgroup of BRCA PV carriers, with a median follow up of 12.3 years (IQR 9.3 vs 15.4), eET remained significantly associated with improved iDFS (aHR 0.30, 95% CI 0.18-0.49) and DRFI (aHR 0.34, 95% CI 0.17-0.65) compared to ET of 5 years or less. Landmark analysis showed that eET was consistently associated with improved DRFI at 60 months (aHR 0.21, 95% CI 0.13-0.33, p<0.001), 84 months (aHR 0.27, 95% CI 0.18-0.43, p<0.001), and 120 months (aHR 0.57, 95% CI 0.37-0.89, p=0.013). Conclusions In this cohort of BRCA PV carriers with HR+/HER2- EBC, extended adjuvant ET (>5 years) was significantly associated with improved invasive disease-free survival and distant relapse-free interval compared to 5 years of ET. These findings support the potential benefit of prolonged endocrine therapy in this high-risk population.

R. Sandoval¹, L. Tianyu², M. Bottosso³, R. Delgado⁴, C. Orr⁴, S. Cahil⁵, A. Rodriguez Hernandez⁵, N. Polidorio⁶, B. Bychkovsky⁷, B. Verret⁸, O. Caron⁸, M. Imbert-Bouteille⁹, C. Noguès¹⁰, P. Rochefort¹¹, E. Barbieri¹², A. Gennari¹³, N. Tayob², M. Achatz¹⁴, K. Mawell⁴, F. André⁸, J. Garber⁵; ¹Oncology, Hospital Sírio Libanes, Sao Paulo, BRAZIL, ²Data Science, Dana Farber Cancer Institute, Boston, MA, ³Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padova, ITALY, ⁴Perelman School of Medicine at the University of Pennsylvania, Penn University, Philadelphia, PA, ⁵Cancer Genetics and Prevention, Dana Farber Cancer Institute, Boston, MA, ⁶Mastologia, DASA, Brasília, BRAZIL, ⁷Cancer genetics and prevention, Dana Farber Cancer Institute, Boston, MA, ⁸Medical Oncology, Institut Gustave Roussy, Villejuif, FRANCE, ⁹Medical Oncology, Institut du Cancer de Montpellier, Montpellier, FRANCE, ¹⁰Cancer Risk Management, Institut Paoli-Calmettes, Marseille, FRANCE, ¹¹Département de Cancérologie Médicale, Centre Léon-Bérard, Lyon, FRANCE, ¹²Oncology and Haematology, Azienda Ospedaliero-Universitaria di Modena, Modena, ITALY, ¹³Translational Medicine, University of Piemonte Orientale, Novara, ITALY, ¹⁴Oncology, Hospital Sírio Libanes, São Paulo, BRAZIL.

INTRODUCTION:Hormone receptor (HR) positive HER2 negative breast cancer (BC) is the most common cancer affecting women in general as well as women with a pathogenic/likely pathogenic (P/LP) germline variant in TP53 (TP53-associated BC). However, while most HR+/HER2- BC in the general population has a good prognosis, early HR+/HER2- invasive BC in TP53 carriers seems to have a worse prognosis in comparison to other BC subtypes.² To investigate the prognostic value of HR expression in TP53-associated BC, we analyzed real-world data from a large international cohort of TP53 germline P/LP women with BC and comprehensive treatment data and follow-up.METHODOLOGY:Women (age ≥18 years) with a first invasive nonmetastatic TP53-associated BC, diagnosed between 2000 and 2020, were identified from an international multicenter database created in 2022. This ongoing international collaboration involves 10 institutions from USA, Brazil, France, and Italy. Restrospective and prospective data are collected. For this analysis, patients with a P/LP germline variant in other BC genes, TP53 variants confirmed as clonal hematopoiesis of indeterminate potential, and tumors with unknown HR status were excluded. Tumor size, nodal involvement and tumor features were based on pathological staging and final surgical specimens. For patients who received neoadjuvant therapy, we used clinical staging and pathology reports from the initial biopsy. Recurrence free survival in 5 years (5y-RFS) was estimated by Kaplan-Meier method according to HR status and BC subtype (combined HR and HER2 status). Log-rank test was reported. RFS was defined as time from primary diagnosis of the first BC to first recurrence (local, regional, distant) or death. Patients without events were censored at last follow-up date. Univariate analyses included age, year of diagnosis, tumor size, grade, nodal involvement, HER2 status, type of breast surgery, radiation therapy and neo/adjuvant chemotherapy. Chi-square test was used for comparison of type of recurrence events by HR status and BC subtype.RESULTS:Among 463 patients from the database, 250 met criteria for this analysis. Median age of first BC diagnosis was 34.5 years (range 19.0-81.0), 74.0% were HR+, and 72% of the cohort received BC treatment between 2011-2020. Most tumors were HR+/HER2- (41.6%), followed by HR+/HER2+ (30.0%) and HR-/HER2+ (18.4%). T1 and T2 represented 44.8% and 40.0% of tumors, respectively. Approximately half of the cohort had nodal involvement at diagnosis (N1 32.4%, N2 11.2%, N3 4.8%). Regarding tumor grade, 51.6% were G3 and 34.0% G2. Regarding BC treatment, 75.6% of patients received mastectomies, 81.2% chemotherapy, 37.2% radiation therapy, and 66.4% endocrine therapy. Fifty-six patients had recurrences, 26 isolated locoregional and 30 distant events. With a median follow-up of 7.2 years (IQR 4.7-13.4), the 5-yr RFS was 79% (95%CI: 74%-85%). In the univariate analysis, age, year of diagnosis, tumor size, grade, nodal involvement, surgery type, chemotherapy and radiation therapy were not associated with RFS in this cohort. RFS was not statistically different between HR+ vs HR- tumors. HER2- tumors were associated with a worse outcome in comparison to HER2+ tumors (5y-RFS rate 72% vs 85%, p<.01). By BC subtype, HR+HER2- tumors also had a worse outcome in comparison to other subtypes (5y-RFS rate 70% vs 86%, p<.001), and relapsed more frequently as distant metastasis (66.7% vs 36.4%, p=0.027).CONCLUSION:In this large cohort of TP53-associated BC, we confirmed a worse outcome for HR+/HER2- tumors. The higher rate of distant relapse after appropriate treatment in this group suggest more aggressive biology. Immune mechanisms are also considered.REFERENCE:1.Sandoval RL, et al. J Natl Cancer Inst. 2024 Aug 1;116(8):1246-1254.

K. Metcalfe¹, A. Stachowski², F. Couch³, M. Marabelli⁴, S. Wong⁵, S. Domchek⁶, A. Aeilts⁷, A. Eisen⁸, R. Kim⁹, T. Ramon y Cajal¹⁰, R. Fruscio¹¹, S. Yadav¹², C. Hoey¹, S. Karamali¹, P. Sun¹, J. Lubinski², S. Narod¹, T. Pal¹³; ¹Breast Cancer Research, Women’s College Research Institute, Toronto, ON, CANADA, ²Oncology, Pomeranian Medical University, Szczecin, POLAND, ³Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, ⁴Breast Cancer Research, Istituto Europeo di Oncologia, Milano, ITALY, ⁵Surgery, Jewish General Hospital, Montreal, QC, CANADA, ⁶Abrahamson Cancer Center, University of Pennsylvania, Philadelphia, PA, ⁷Genetics, Ohio State University, Columbus, OH, ⁸Medical Oncology, Sunnybrook Health Sciences Centre, Toronto, ON, CANADA, ⁹Genetics, University Health Network, Toronto, ON, CANADA, ¹⁰Oncology, Hospital de la Santa Creu I Sant Pau, Barcelona, SPAIN, ¹¹Medicine and Surgery, University of Milan-Bicocca, Monza, ITALY, ¹²Oncology, Mayo Clinic, Rochester, MN, ¹³Oncology, Vanderbilt University, Nashville, TN.

Introduction: Women with a germline pathogenic variant (PV) in PALB2 face a lifetime risk of breast cancer, generally exceeding 40%. We have initiated an international clinical follow up study of women with stage 0 to stage 4 breast cancer and a PALB2 PV to evaluate clinical characteristics and to determine optimal treatments. The objective of the current study was to estimate and to identify factors predictive of contralateral breast cancer (CBC) risk.Methods: Clinical data, including diagnostic, treatment, and follow-up data, were collected by medical record review for eligible women with breast cancer and a germline PV in PALB2. PV carriers were followed every two years to collect information about recurrences, new cancers, and vital status. Data was summarized using descriptive statistics. The risk of CBC was estimated by following women from the date of breast cancer diagnosis until the date of: 1) contralateral breast cancer, 2) contralateral mastectomy, 3) death from any cause, or 4) last follow-up. The cumulative incidence of CBC was calculated with the Kaplan-Meier method. Cox proportional hazards regression was used to identify factors associated with contralateral breast cancer risk. Covariates included age at diagnosis, ER status, grade, nodal status, chemotherapy, radiation therapy, tamoxifen, and bilateral salpingo-oophorectomy (time-dependent).Results: Among 888 PALB2 carriers, the mean age at diagnosis of breast cancer was 49.3 years (range 22 to 83 years). Overall, 36 women (4.1%) were diagnosed with synchronous bilateral breast cancer. 73.6% of the breast cancers were ER-positive, and 29% were lymph node-positive. Patients were followed for a mean of 5.6 years (range 0.3 to 22 years) from date of diagnosis. During the follow-up period, 53 patients were diagnosed with a metachronous CBC. The 15-year risk of metachronous CBC was 26.4% overall; 19.5% for those diagnosed younger than 50 years, and 34.8% for those diagnosed at 50 years or older. In a multivariate analysis, ER status was not significantly associated with CBC risk (RR 1.15, 95%CI 0.45-2.93, p=0.77). Bilateral salpingo-oophorectomy (BSO) was associated with a significant reduction in the risk of CBC (RR 0.17, 95%CI 0.04-0.70, p=0.02). In the follow-up period, 47 women were diagnosed with another incident cancer, including seven with pancreatic cancer and three with ovarian cancerConclusion: The high 15-year risk of contralateral breast cancer suggests that bilateral mastectomy should be considered for primary surgical intervention. Moreover, bilateral salpingo-oophorectomy (BSO) significantly reduces the risk of CBC and should be considered post-treatment.