Differences in Risk Factors for Breast Cancer Molecular Subtypes in a Population-Based Study

Abstract

Analysis of gene expression data suggests that breast cancers are divisible into molecular subtypes which have distinct clinical features. This study evaluates whether pathologic features and etiologic associations differ among molecular subtypes. We evaluated 804 women with invasive breast cancers and 2,502 controls participating in a Polish Breast Cancer Study. Immunohistochemical stains for estrogen receptor A, progesterone receptor, human epidermal growth factor receptors (HER2 and HER1), and cytokeratin 5 were used to classify cases into five molecular subtypes: luminal A, luminal B, HER2-expresing, basal-like, and unclassified. Relative risks were estimated using adjusted odds ratios and 95% confidence intervals. We observed that compared with the predominant luminal A tumors (69%), other subtypes were associated with unfavorable clinical features at diagnosis, especially HER2-expressing (8%) and basal-like (12%) tumors. Increasing body mass index significantly reduced the risk of luminal A tumors among premenopausal women (odds ratios, 0.71; 95% confidence intervals, 0.57-0.88 per fiveunit increase), whereas it did not reduce risk for basal-like tumors (1.18; 0.86-1.64; P heterogeneity = 0.003). On the other hand, reduced risk associated with increasing age at menarche was stronger for basal-like (0.78; 0.68-0.89 per 2-year increase) than luminal A tumors (0.90; 0.95-1.08; P heterogeneity = 0.0009). Although family history increased risk for all subtypes (except for unclassified tumors), the magnitude of the relative risk was highest for basal-like tumors. Results from this study have shown that breast cancer risk factors may vary by molecular subtypes identified in expression studies, suggesting etiologic, in addition to clinical, heterogeneity of breast cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(3):439 -43)

Human epidermal growth factor receptor-2 and estrogen receptor expression, a demonstration project using the residual tissue respository of the Surveillance, Epidemiology, and End Results (SEER) program

“…Accordingly, one would anticipate that HER2+ER+ tumors would be relatively uncommon in the general population [23]. The low prevalence of HER2+ER+ tumor in our Hawaii population (4%) also was similar to that found by Yang et al in a Polish case control study [3] as well as by Carey et al in the Carolina breast cancer study [24].…”

“…Bilous et al reported 12% HER2+ expression in the HER2000 International Study [13]. Yang et al observed 14% HER2+ in a Poland populationbased case control study [3]. Moreover, given the largely favorable prognostic profile for our Hawaii breast cancer population (Table 1), a low prevalence of high-risk HER2+ tumors seems plausible.…”

“…Standard immunohistochemistry with antigen retrieval prior to antibody incubation was performed according to established protocols for estrogen receptor (ER, clone 6F11, dilution 1:200, Novocastra), progesterone receptor (PR, clone PgR636, dilution 1:1,000, Dako), human epidermal growth factor receptor-2 (HER2+, polyclonal, dilution 1:1,000, Dako), epidermal growth factor receptor (EGFR, clone 31G7, dilution 1:500, Zymed), and cytokeratin 5 (CK5, clone XM26, dilution 1:500, Novocastra) [3,4]. A single pathologist (MES) assessed the stains by examining microscopic TMA slides and scanned images of the TMA slides, using the Aperio TMA Lab system (http://www.aperio.com/), as previously described [4].…”

Breast Cancer Molecular Subtypes and Associations with Clinicopathological Characteristics in Iranian Women, 2002-2011

“…Finally, triple-negative breast cancer (ER-negative, PR-negative, and Her-2-negative) is not quite the same as the basal-like subtype. Recent gene expression studies (Carey et al, 2006) have updated the immunohistochemical definition of basal-like subtype as "ER negative, PR negative, HER-2 negative, cytokeratin 5/6 positive, and/or HER-1 positive" and added another molecular subtype as unclassified (negative for all five markers), which is proven to be histologically less aggressive than basal-like tumors and more aggressive than luminal A tumors (Carey et al, 2006;Yang et al, 2007;Huo et al, 2009). However, the majority of triplenegative breast cancers carry the "basal-like" molecular profile on gene expression arrays (Anders & Carey, 2008) …”

Expression of aldehyde dehydrogenase 1 (ALDH1) is associated with basal-like markers and features of aggressive tumours in African breast cancer

“…Five tumour subgroups with different prognosis and response to adjuvant therapy have been identified. Of these, the basal-like and HER2 subtypes are of particular interest as both have a poor prognosis (Sorlie et al, 2001;Yang et al, 2007). The basal-like phenotype (BLP) is characterised by the expression of basal cell markers, and it overlaps with the triple-negative phenotype (TNP; ERÀ/PRÀ/HER2À) (Tischkowitz et al, 2007).…”