Assessment of Breast Cancer Risk Factors Reveals Subtype Heterogeneity

Abstract

Subtype heterogeneity for breast cancer risk factors has been suspected, potentially reflecting etiologic differences and implicating risk prediction. However, reports are conflicting regarding the presence of heterogeneity for many exposures. To examine subtype heterogeneity across known breast cancer risk factors, we conducted a case-control analysis of 2,632 breast cancers and 15,945 controls in Sweden. Molecular subtype was predicted from pathology record-derived IHC markers by a classifier trained on PAM50 subtyping. Multinomial logistic regression estimated separate ORs for each subtype by the exposures parity, age at first birth, breastfeeding, menarche, hormone replacement therapy use, somatotype at age 18, benign breast disease, mammographic density, polygenic risk score, family history of breast cancer, and BRCA mutations. We found clear subtype heterogeneity for genetic factors and breastfeeding. Polygenic risk score was associated with all subtypes except for the basal-like ( < 0.0001). "Never breastfeeding" was associated with increased risk of basal-like subtype [OR 4.17; 95% confidence interval (CI) 1.89-9.21] compared with both nulliparity (reference) and breastfeeding. Breastfeeding was not associated with risk of HER2-overexpressing type, but protective for all other subtypes. The observed heterogeneity in risk of distinct breast cancer subtypes for germline variants supports heterogeneity in etiology and has implications for their use in risk prediction. The association between basal-like subtype and breastfeeding merits more research into potential causal mechanisms and confounders. .

Prevalence of BRCA1 and BRCA2 pathogenic variants in a large, unselected breast cancer cohort

“…HER2 status was dichotomized (positive/negative) in accordance with the Swedish Society of Pathology's guidelines: negative if protein expression showed 0 or 1+, or was higher with no confirmed gene amplification by FISH, and positive if FISH showed gene amplification . Proliferation marker Ki67 was measured according to contemporary guidelines and reported as percent staining (low if <20% and high otherwise) . HER2 and Ki67 markers were not assessed, and thus not available in medical records, prior to 2005.…”

“…HER2 and Ki67 markers were not assessed, and thus not available in medical records, prior to 2005. Breast cancer subtype was assigned using a random forest algorithm (caret R package, v. 6.0.58) described in Ref. 20.…”

“…19 Data on molecular markers were retrieved in 2015-2016 from medical and pathology records at treating hospitals (previously described in Ref. 20 ). HER2 status was dichotomized (positive/negative) in accordance with the Swedish Society of Pathology's guidelines: negative if protein expression showed 0 or 1+, or was higher with no confirmed gene amplification by FISH, and positive if FISH showed gene amplification.…”

“…Breast cancer subtype was assigned using a random forest algorithm (caret R package, v. 6.0.58) described in Ref. 20. The algorithm was trained to predict subtype based on a subset of individuals with PAM50 subtype derived from gene expression data (n = 237).…”

The Relationship of Reproductive Risk Factors and Histologic Patterns with Molecular Subtypes of Breast Cancer

“…The close link between these subtypes and different clinical behaviors of breast cancers as well as its different response to therapeutic chemotherapy regimens has also been identified (1,2). It is, thus, suggested a significant association between these molecular subtypes and known risk factors for breast cancer through different etiological pathways (3,4). For instance, in large nested case-control studies, mammographic density was introduced as a strong risk factor for breast cancer that was closely linked to some specific molecular subtypes of breast cancer (5,6).…”