Xiaohong R. Yang

BACKGROUND: Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors. METHODS: We pooled tumor marker and epidemiological risk factor data from 35,568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided. RESULTS: In case-case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR(-) than PR(+) tumors (P = .001). Nulliparity (P = 3 × 10(-6)) and increasing age at first birth (P = 2 × 10(-9)) were less frequent in ER(-) than in ER(+) tumors. Obesity (body mass index [BMI] ≥ 30 kg/m(2)) in younger women (≤50 years) was more frequent in ER(-)/PR(-) than in ER(+)/PR(+) tumors (P = 1 × 10(-7)), whereas obesity in older women (>50 years) was less frequent in PR(-) than in PR(+) tumors (P = 6 × 10(-4)). The triple-negative (ER(-)/PR(-)/HER2(-)) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/or epidermal growth factor receptor [EGFR](+)) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER(+) or PR(+) tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors. CONCLUSIONS: This study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.

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 alpha, 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 five-unit 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.

A study of nasopharyngeal carcinoma (NPC) families with two or more affected members was conducted in Taiwan (265 families with 2,444 individuals, 502 affected and 1,942 unaffected) to determine the association between NPC and potential etiologic factors in NPC high-risk families. Similar to results from a previous case-control study in Taiwan, Guangdong salted fish consumption during childhood, exposure to wood, and betel nut consumption were all associated with elevated NPC risk using conditional logistic regression, although these associations were not as strong as in the case-control study possibly due to shared environment among family members. Risk associated with cumulative wood exposure and salted fish consumption before age 10 was stronger in families with early NPC age-onset [odds ratio (OR(wood)), 5.10; 95% confidence interval (95% CI), 1.50-17.34; OR(fish), 3.94; 95% CI, 1.47-10.55] or three or more affected members (OR(wood), 4.41; 95% CI, 1.58-12.30; OR(fish), 4.27; 95% CI, 1.10-16.47). In contrast, a tendency for elevated risk was noted for betel nut use in late age-onset families (OR, 2.44; 95% CI, 1.16-5.13) and the CYP2E1 c2 allele in families with less than three affected members (OR, 2.06; 95% CI, 1.04-3.35). Risk estimates associated with these exposures were similar when the analyses were restricted to EBV-seropositive subjects. To better adjust for degree of relationship among family members and residual genetic correlations, we also calculated ORs using a variance components model. The results from the two methods were similar indicating that the risk estimates from conditional logistic regression were unbiased.