Zirpoli, Gary

Background: Several breast cancer (BC) risk prediction models have been developed to provide personal risk assessments. Though individually validated, their performance has not been systematically evaluated across a wide range of populations or ages. Methods: We harmonized individual-level baseline questionnaire data and incident BC diagnoses from 21 cohorts from North America, Europe, and Australia participating in the Breast Cancer Risk Prediction Project. Five-year absolute risk of invasive BC was estimated for five established risk prediction models using classical risk factors only. Discrimination was evaluated by area under the curve (AUC). Calibration was assessed using average and risk-decile specific expected to observed (E/O) ratios. Performance metrics were meta-analyzed across cohorts and models. Metaregression tested associations between cohort characteristics and performance metrics. Results: This analysis included 1,595,977 women aged 20-75 years, enrolled in studies between 1976-2015, with 19,062 (1.2%) invasive BC cases ascertained within 5 years from exposure assessment. Age-adjusted AUCs were similar across models and cohorts (pooled AUCs by model: 0.57-0.58), while E/O ratios varied substantially (pooled E/O ratios by model: 0.83-1.25). Overestimation was common among predicted high-risk individuals (>3%). No appreciable differences in model performance by cohort age, birth year, race, and variable missingness emerged. Calibration improved after assigning race-specific incidence rates. Conclusion: Existing BC risk prediction models provided similar risk discrimination across multiple cohorts, although there was overestimation of risk for high-risk individuals. Performance variation across cohorts was not driven by specific characteristics, which supports development of a unified risk model for diverse populations that leverages appropriate incidence rates.

Importance Inherited pathogenic variants (PVs) in known predisposition genes can greatly increase breast cancer risk, but the combined impact of PV status, family history, and other factors on breast cancer risk in the general US population has not been well described. Objective To evaluate population-based breast cancer risk estimates for those with established PVs overall and stratified by first-degree family history of breast cancer and other factors. Design, Setting, and Participants This study used pooled data from 13 US-based breast cancer case-control studies participating in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Enrollment for individual studies occurred between 1976 and 2013, and results are based on data released March 2023, with analyses conducted from June 2022 to July 2025. Exposures PVs, breast cancer family history, self-reported race and ethnicity, and established risk factors. Main Outcomes and Measures Breast cancer rate ratios for PVs in 7 genes were estimated from the CARRIERS consortium. PV status and incidence and mortality statistics were combined using the Individualized Coherent Absolute Risk Estimation (iCARE) model to estimate conditional cumulative breast cancer risks and 95% CIs, stratified by family history and standardized to the US population. Models that incorporated population-based data and published estimates for established epidemiologic risk factors were also evaluated. Results A total of 67 692 women were studied, including 33 841 who were diagnosed with breast cancer. PVs in ATM , BRCA1 , BRCA2 , CHEK2 , and PALB2 were strongly associated with breast cancer risk, with BRCA1 and PALB2 PVs showing evidence of heterogeneity by family history. In models considering PVs, family history, and established risk factors, the estimated cumulative risks of breast cancer by age 50 years ranged from 2.4% (95% CI, 2.4-2.4) in women with no PVs and no family history to 35.5% (95% CI, 21.6-55.1) in PALB2 PV carriers with a family history. Among women who have not been diagnosed with breast cancer by age 50 years, the cumulative risk of breast cancer by age 80 years ranged from 11.1% (95% CI, 11.0-11.2) in noncarriers with no family history to 70.5% (95% CI, 52.8-83.5) for PALB2 carriers with a family history. PV-specific cumulative risk estimates varied across subgroups defined by race and ethnicity and potentially modifiable epidemiologic risk factors. Conclusions and Relevance In this study, population-based estimates of cumulative breast cancer risk for established PVs, as informed by the CARRIERS case-control sample, varied by family history and potentially modifiable risk factors. These estimates provide guidance for identifying individuals who will most benefit from enhanced screening and prevention strategies.

ImportanceThe American Institute for Cancer Research and American Cancer Society regularly publish modifiable lifestyle recommendations for cancer prevention. Whether these recommendations have an impact on high-risk breast cancer survival remains unknown.ObjectiveTo investigate whether adherence to cancer prevention recommendations before, during, and 1 and 2 years after breast cancer treatment was associated with disease recurrence or mortality.Design, Setting, and ParticipantsThe Diet, Exercise, Lifestyles, and Cancer Prognosis Study (DELCaP) was a prospective, observational cohort study designed to assess lifestyles before diagnosis, during treatment, and at 1 and 2 years after treatment completion, implemented ancillary to the Southwest Oncology Group (SWOG) S0221 trial, a multicenter trial that compared chemotherapy regimens in breast cancer. Participants were chemotherapy-naive patients with pathologic stage I to III high-risk breast cancer, defined as node-positive disease with hormone receptor–negative tumors larger than 1 cm or any tumor larger than 2 cm. Patients with poor performance status and comorbidities were excluded from S0221. The study was conducted from January 1, 2005, to December 31, 2010; mean (SD) follow-up time for those not experiencing an event was 7.7 (2.1) years through December 31, 2018. The analyses reported herein were performed from March 2022 to January 2023.ExposureAn aggregated lifestyle index score comprising data from 4 time points and 7 lifestyles, including (1) physical activity, (2) body mass index, (3) fruit and vegetable consumption, (4) red and processed meat intake, (5) sugar-sweetened beverage consumption, (6) alcohol consumption, and (7) smoking. Higher scores indicated healthier lifestyle.Main Outcomes and MeasuresDisease recurrence and all-cause mortality.ResultsA total of 1340 women (mean [SD] age, 51.3 [9.9] years) completed the baseline questionnaire. Most patients were diagnosed with hormone-receptor positive breast cancer (873 [65.3%]) and completed some education beyond high school (954 [71.2%]). In time-dependent multivariable analyses, patients with highest vs lowest lifestyle index scores experienced a 37.0% reduction in disease recurrence (hazard ratio, 0.63; 95% CI, 0.48-0.82) and a 58.0% reduction in mortality (hazard ratio, 0.42; 95% CI, 0.30-0.59).Conclusions and RelevanceIn this observational study of patients with high-risk breast cancer, strongest collective adherence to cancer prevention lifestyle recommendations was associated with significant reductions in disease recurrence and mortality. Education and implementation strategies to help patients adhere to cancer prevention recommendations throughout the cancer care continuum may be warranted in breast cancer.

Abstract Purpose To estimate the risk of contralateral breast cancer (CBC) among women in the general population with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. Methods Among 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer, a subset of 14,237 women were identified from population-based studies. The risk of CBC was estimated for PV carriers in each gene compared to women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor status. Results Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (Hazard ratio ≥ 1.9, p< 0.05) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks. In contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 15-year cumulative incidence of CBC was >20% for BRCA1, BRCA2 and CHEK2 PV carriers with breast cancer, and for PALB2 PV carriers with ER-negative breast cancer. The 15-year cumulative incidence of CBC among postmenopausal PV carriers was < 20% for PV carriers in any of the 5 genes. Conclusions Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk-reduction strategies. Citation Format: Siddhartha Yadav, Nicholas J. Boddicker, Jie Na, Eric C. Polley, Chunling Hu, Steven N. Hart, Rohan D. Gnanaolivu, Nicole Larson, Carolyn Dunn, Susan Holtegaard, Huaizhi Huang, Lauren R. Teras, Alpa V. Patel, James V. Lacey Jr., Susan Neuhausen, Leslie Bernstein, Elena Martinez, Christopher Haiman, Fei Chen, Kathryn Ruddy, Janet Olson, Esther John, Allison W. Kurian, Dale P. Sandler, Katie M. O’Brien, Jack A. Taylor, Clarice R. Weinberg, Hoda Anton-Culver, Argyrios Ziogas, Gary R. Zirpoli, David E. Goldgar, Katherine L. Nathanson, Susan Domchek, Julie R. Palmer, Jeffrey Weitzel, Peter Kraft, Fergus J. Couch. Population-based Estimates of contralateral Breast Cancer Risk among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-04.

PURPOSE To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. METHODS The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status. RESULTS Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2. CONCLUSION Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.

Abstract Background Although physical activity has been consistently associated with reduced breast cancer mortality, evidence is largely based on data collected at one occasion. We examined how pre- and postdiagnosis physical activity was associated with survival outcomes in high-risk breast cancer patients. Methods Included were 1340 patients enrolled in the Diet, Exercise, Lifestyle and Cancer Prognosis (DELCaP) Study, a prospective study of lifestyle and prognosis ancillary to a SWOG clinical trial (S0221). Activity before diagnosis, during treatment, and at 1- and 2-year intervals after enrollment was collected. Patients were categorized according to the Physical Activity Guidelines for Americans as meeting the minimum guidelines (yes/no) and incrementally as inactive, low active, moderately active (meeting the guidelines), or high active. Results In joint-exposure analyses, patients meeting the guidelines before and 1 year after diagnosis experienced statistically significant reductions in hazards of recurrence (hazard ratio [HR] = 0.59, 95% confidence interval [CI] = 0.42 to 0.82) and mortality (HR = 0.51, 95% CI = 0.34–0.77); associations were stronger at 2-year follow-up for recurrence (HR = 0.45, 95% CI = 0.31 to 0.65) and mortality (HR = 0.32, 95% CI = 0.19 to 0.52). In time-dependent analyses, factoring in activity from all time points, we observed striking associations with mortality for low- (HR = 0.41, 95% CI = 0.24 to 0.68), moderate- (HR = 0.42, 95% CI = 0.23 to 0.76), and high-active patients (HR = 0.31, 95% CI = 0.18 to 0.53). Conclusions Meeting the minimum guidelines for physical activity both before diagnosis and after treatment appears to be associated with statistically significantly reduced hazards of recurrence and mortality among breast cancer patients. When considering activity from all time points, including during treatment, lower volumes of regular activity were associated with similar overall survival advantages as meeting and exceeding the guidelines.

PURPOSE Despite reported widespread use of dietary supplements during cancer treatment, few empirical data with regard to their safety or efficacy exist. Because of concerns that some supplements, particularly antioxidants, could reduce the cytotoxicity of chemotherapy, we conducted a prospective study ancillary to a therapeutic trial to evaluate associations between supplement use and breast cancer outcomes. METHODS Patients with breast cancer randomly assigned to an intergroup metronomic trial of cyclophosphamide, doxorubicin, and paclitaxel were queried on their use of supplements at registration and during treatment (n =1,134). Cox proportional hazards regression adjusting for clinical and lifestyle variables was used. Recurrence and survival were indexed at 6 months after enrollment using a landmark approach. RESULTS There were indications that use of any antioxidant supplement (vitamins A, C, and E; carotenoids; coenzyme Q10) both before and during treatment was associated with an increased hazard of recurrence (adjusted hazard ratio [adjHR], 1.41; 95% CI, 0.98 to 2.04; P = .06) and, to a lesser extent, death (adjHR, 1.40; 95% CI, 0.90 to 2.18; P = .14). Relationships with individual antioxidants were weaker perhaps because of small numbers. For nonantioxidants, vitamin B12 use both before and during chemotherapy was significantly associated with poorer disease-free survival (adjHR, 1.83; 95% CI, 1.15 to 2.92; P < .01) and overall survival (adjHR, 2.04; 95% CI, 1.22 to 3.40; P < .01). Use of iron during chemotherapy was significantly associated with recurrence (adjHR, 1.79; 95% CI, 1.20 to 2.67; P < .01) as was use both before and during treatment (adjHR, 1.91; 95% CI, 0.98 to 3.70; P = .06). Results were similar for overall survival. Multivitamin use was not associated with survival outcomes. CONCLUSION Associations between survival outcomes and use of antioxidant and other dietary supplements both before and during chemotherapy are consistent with recommendations for caution among patients when considering the use of supplements, other than a multivitamin, during chemotherapy.

Abstract Introduction. Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel treatment. There is conflicting data on the benefits and harms of supplement use for the treatment and prevention of CIPN. We examined dietary supplement use before diagnosis and during treatment in relation to CIPN among breast cancer patients registered to a clinical trial (SWOG 0221; ClinicalTrials.gov Identifier: NCT00070564) before diagnosis and during treatment in relation to CIPN. Methods. At trial registration (baseline), breast cancer patients (n = 1,225) completed questionnaires to capture use before and at diagnosis of multivitamins and other dietary supplements. Of these patients, 1,068 completed a 6-month follow-up questionnaire to capture use during treatment. We examined the use of multivitamins, vitamins C, D, E, B6, and B12, folic acid, iron, calcium, glucosamine, and combined fish oil, eicosapentaenoic acid (EPA), omega-3, flaxseed and cod liver oil at these timepoints in relation to CIPN. CIPN was assessed via the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity (FACT/GOG-Ntx) subscale. Odds ratios and 95% confidence intervals were computed using unconditional logistic regression. Results. Multivitamin use before diagnosis was associated with reduced symptoms of CIPN (CTCAE adjusted OR = 0.60, 95% CI = 0.42-0.87; FACT/GOG-Ntx adjusted OR = 0.78, 95% CI = 0.61-1.00). Although in a similar direction as use prior to diagnosis, multivitamin use during treatment was less strongly associated with CIPN (CTCAE adjusted OR = 0.73, 95% CI = 0.49-1.08; FACT/GOG-Ntx 0.77, 95% CI = 0.60-0.99). Other supplement use, either before diagnosis or during treatment, was not associated with CIPN. Conclusions. Our results indicate that supplement use during treatment may not appreciably affect experience of CIPN symptoms. Future analyses of the relationships between supplement use and survival outcomes will better inform patient decision making. Acknowledgments: supported by R01 CA116395 (CBA); S0221 supported, in part, by National Cancer Institute/Division of Cancer Prevention SWOG NCORP Research Base grant 5UG1CA189974-02; National Cancer Institute (NCI), National Clinical Trials Network (NCTN): CA180888, CA180819; and in part by Amgen, Inc. Citation Format: Gary R. Zirpoli, Susan E. McCann, Lara E. Sucheston-Campbell, Dawn L. Hershman, Gregory Ciupak, Warren Davis, Joseph M. Unger, Halle C.F. Moore, James A. Stewart, Claudine Isaacs, Timothy J. Hobday, Muhammad Salim, Robert B. Livingston, Gabriel N. Hortobagyi, Julie R. Gralow, Daniel F. Hayes, G. Thomas Budd, Kathy S. Albain, Christine B. Ambrosone. Supplement use and chemotherapy-induced peripheral neuropathy in breast cancer patients treated on SWOG study S0221. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3413.