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The World Cancer Research Fund (WCRF) International and the University of Bristol have developed a novel framework for providing an overview of mechanistic pathways and conducting a systematic literature review of the biologically plausible mechanisms underlying exposure–cancer associations. Two teams independently applied the two-stage framework on mechanisms underpinning the association between body fatness and breast cancer to test the framework feasibility and reproducibility as part of a WCRF-commissioned validation study. In stage I, a “hypothesis-free” approach was used to provide an overview of potential intermediate mechanisms between body fatness and breast cancer. Dissimilar rankings of potential mechanisms were observed between the two teams due to different applications of the framework. In stage II, a systematic review was conducted on the insulin-like growth factor 1 receptor (IGF1R) chosen as an intermediate mechanism. Although the studies included differed, both teams found inconclusive evidence for the body fatness–IGF1R association and modest evidence linking IGF1R to breast cancer, and therefore concluded that there is currently weak evidence for IGF1R as mechanism linking body fatness to breast cancer. The framework is a good starting point for conducting systematic reviews by integrating evidence from mechanistic studies on exposure–cancer associations. On the basis of our experience, we provide recommendations for future users. Cancer Epidemiol Biomarkers Prev; 26(11); 1583–94. ©2017 AACR.

Evidence linking coding germline variants in breast cancer (BC)-susceptibility genes other than BRCA1, BRCA2, and CHEK2 with contralateral breast cancer (CBC) risk and breast cancer-specific survival (BCSS) is scarce. The aim of this study was to assess the association of protein-truncating variants (PTVs) and rare missense variants (MSVs) in nine known (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53) and 25 suspected BC-susceptibility genes with CBC risk and BCSS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox regression models. Analyses included 34,401 women of European ancestry diagnosed with BC, including 676 CBCs and 3,449 BC deaths; the median follow-up was 10.9 years. Subtype analyses were based on estrogen receptor (ER) status of the first BC. Combined PTVs and pathogenic/likely pathogenic MSVs in BRCA1, BRCA2, and TP53 and PTVs in CHEK2 and PALB2 were associated with increased CBC risk [HRs (95% CIs): 2.88 (1.70-4.87), 2.31 (1.39-3.85), 8.29 (2.53-27.21), 2.25 (1.55-3.27), and 2.67 (1.33-5.35), respectively]. The strongest evidence of association with BCSS was for PTVs and pathogenic/likely pathogenic MSVs in BRCA2 (ER-positive BC) and TP53 and PTVs in CHEK2 [HRs (95% CIs): 1.53 (1.13-2.07), 2.08 (0.95-4.57), and 1.39 (1.13-1.72), respectively, after adjusting for tumor characteristics and treatment]. HRs were essentially unchanged when censoring for CBC, suggesting that these associations are not completely explained by increased CBC risk, tumor characteristics, or treatment. There was limited evidence of associations of PTVs and/or rare MSVs with CBC risk or BCSS for the 25 suspected BC genes. The CBC findings are relevant to treatment decisions, follow-up, and screening after BC diagnosis.

Background: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. Methods: We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values-8 as genome-wide significant, and p-values-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants.Results: None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values5. The strongest evidence was found for rs4674019 (p-value=2.27x10-7), which showed genome-wide significant interaction (p-value=3.8x10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. Conclusions: In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT–breast cancer risk association.

Background: Studies have reported differences in associations between breast cancer risk factors and subtypes defined by hormone receptor status, particularly estrogen receptor (ER) positive versus ER negative tumors. Most studies have been conducted in women of European descent, and an expanding body of literature in other populations suggests differences by race/ethnicity. Clarifying whether associations between risk factors and disease subtypes are consistent across racial/ethnic populations has important implications for understanding disease etiology and for improving risk prediction models. To address this question, we conducted a qualitative literature review to investigate the consistency in associations between multiple breast cancer risk factors and risk of tumor subtypes in women of African, Asian, Hispanic, and European descent. Methods: We searched PubMed for publications between January 1, 1990 and June 8, 2021 that reported associations between breast cancer risk factors and risk of subtypes of the disease. We evaluated 19 risk factors, including reproductive, anthropometric, lifestyle, and diet factors, as well as medical history and use of menopausal hormone therapy (MHT). Subtypes were defined as ER positive or negative (specifically triple negative when available). We prioritized review studies (i.e., meta-analyses, systematic reviews, and pooled analyses) and included individual studies with populations not included in the reviews. The number of publications per risk factor ranged from 3 for calcium intake to 28 for parity, with up to 7 reviews per risk factor. Most publications reported estimates for women of European descent, followed by Asian, African, and Hispanic. Evidence of subtype heterogeneity was determined by expert review. Results: There was strong evidence of association between reproductive factors and MHT with risk of ER positive but not ER negative disease. Parity, younger age at first birth and older age at menarche were associated with lower risk of ER positive disease, while MHT use was associated with higher risk of ER positive disease. For these risk factors, we did not find evidence that risk associations or etiologic heterogeneity varied by race/ethnicity. For the other risk factors, there was limited or no evidence of heterogeneity in risk associations by subtype, which was consistent across racial/ethnic groups. Few publications, however, specifically studied women of non-European ancestry. Conclusion: For most breast cancer risk factors, evidence is insufficient to evaluate differences in ER-specific risk associations by race/ethnicity. More studies are needed to evaluate subtype-specific breast cancer risk factors in diverse populations, which will be important for informing the development of multi-ethnic/racial BC risk prediction models that account for subtype heterogeneity. Citation Format: Amber N. Hurson, Thomas U. Ahearn, Renske Keeman, Mustapha Abubakar, Audrey Y. Jung, Pooja Middha Kapoor, Hela Koka, Xiaohong R. Yang, Jenny Chang-Claude, Elena Martínez, Rulla M. Tamimi, Melissa A. Troester, Elisa V. Bandera, Marjanka K. Schmidt, Montserrat Garcia-Closas. Systematic literature review of risk factor associations with breast cancer subtypes in women of African, Asian, Hispanic, and European descents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3670.