Summary Data from a population-based case-control study conducted (Stanford et al., 1986). Complete absence of overlap between risk factors for the two types of breast cancer would provide evidence against a progression from one to the other, while overlap would suggest either that there is a progression or that they are independent outcomes with overlapping aetiologies. The few case-control studies conducted to date (Hildreth et al., 1983;McTiernan et al., 1986;Hislop et al., 1986Hislop et al., , 1988Stanford et al., 1987) suggest that there is some overlap in risk factors for ER+ and ER-breast cancer. This possibility, and the others outlined above, are investigated further in the population-based case-control study reported here, in which risk of ER+ and ER -breast cancer is examined in association with menstrual and reproductive history, dietary intake and other factors. Materials and methods Study subjectsA detailed description of the study methods has been presented elsewhere (Rohan et al., 1988 of breast cancer, who were also resident in the Adelaide metropolitan area and who were registered on the electoral roll. (In South Australia, 97.2% of persons eligible to vote are registered (Australian Electoral Office, 1983).) For each case, one control, matched as closely as possible to the age of the case at diagnosis, was selected at random from the electoral roll. A total of 648 individuals were approached in order to enrol 451 controls. The total study population therefore comprised 451 case-control pairs. Reasons for nonparticipation were recorded during the recruitment of the first 100 controls, which required attempting to recruit 151 persons. Of the 51 who did not participate, 39 refused, 11 were untraceable and one had died.Data collection procedure Subjects were interviewed in their own homes by trained interviewers whose performance was monitored regularly. Interviewers were assigned randomly to case-control pairs. For cases, the average interval between diagnosis and interview was 4.8 months. Each control was interviewed as soon as possible after her case had been enrolled and in a few instances interview of the control preceded that of her case. Approximately 90% of controls were interviewed within two months of the corresponding case. Matching on date of interview was introduced in an attempt to minimise dietary differences between cases and controls due to seasonal influences.Socio-demographic and medical information was collected by use of an interviewer-administered questionnaire which sought basic biographic information, personal medical history, family history of cancer, gynaecological and reproductive history and history of hormone use.Information on usual dietary intake was collected from the study participants by means of a self-administered quantitative food frequency questionnaire. The questionnaire, which was designed to ascertain total daily intake of energy, several nutrients, alcohol and methylxanthines, has been described in detail elsewhere (Baghurst & Baghurst, 1981;Baghurst an...

A possible influence of reproductive and menstrual factors on familial risk of BC has been suggested previously and was also evident in the present study. Three-way interactions between age, family history and parity or age at first childbirth might exist and they merit further investigation.

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Background: Multiparameter gene expression assays (eg, Oncotype DX®) provide prognostic and predictive information in estrogen receptor (ER)+ Her2- negative disease, but are driven largely by proliferation and ER signaling captured by immunohistochemistry (IHC) assays such as IHC4 (Cuzick et al. J Clin Oncol. 2011 10;29:4273-8). However, these assays do not reflect the capacity of individual tumor cells to metastasize, nor interaction with their microenvironment. Using a bench-to-bedside approach, we have identified in animal models and human breast cancer by IHC methods a microanatomic landmark (TMEM) precisely where Mena-overexpressing invasive tumor cells intravasate and hematogenously metastasize by directly interacting with endothelial cells and macrophages (Robinson et al. Clin Cancer Res 2009;15:2433-41). In the present study, we performed a prospective validation study to establish analytic and clinical validity of TMEM in comparison with IHC4 in accordance with recommended guidelines (Simon et al. JNCI 2009;101:1446-52). Methods: A case-control study was performed nested within a cohort of 3760 invasive ductal breast carcinomas, in which cases (subsequent distant recurrence) and controls (no recurrence) were selected using incidence density sampling matched on age at and calendar year of primary diagnosis, resulting in 481 subjects (259 case-control pairs). TMEM and IHC4 were performed as previously reported, and stained slides were read independently by 5 pathologists blinded to outcome. Odds ratios (OR)(95% CI) for the association with TMEM were estimated using logistic regression, with adjustment for clinical variables, including age, tumor size, grade, number of positive lymph nodes, ER, PR, and Her2 expression, lymphovascular invasion (LVI), and use of chemotherapy or hormonal therapy. The ORs for TMEM was compared with those for IHC4. Results: in a multivariate model adjusted for other covariates, TMEM was associated with increased risk of distant metastasis in 62% of subjects with ER+/Her2- tumors (OR [95%CI]high vs. low tertile = 2.70 [1.39-5.26], Ptrend = 0.004), whereas IHC4 had a borderline positive association (OR10 unit increase = 1.06 [1.00-1.13]); the association for TMEM persisted after adjustment for IHC4 (OR [95%CI]high vs. low tertile = 2.68 [1.31-5.49], Ptrend = 0.004). TMEM scores ranged up to a nearly 200-fold from lowest to highest, and did not correlate with tumor size, number of positive lymph nodes, nor IHC4 score (Spearman correlation 0.12 for IHC4). The AUC for a TMEM composite score (0.77), derived from a multivariate logistic regression model with TMEM and clinical variables, was significantly higher than those for TMEM alone (0.65) and for IHC4 (0.62). Neither TMEM nor IHC4 was independently associated with metastatic risk in the triple negative (20%) or HER2+ (18%) tumors. Conclusion: TMEM score, a mechanism-based assay, is positively associated with risk of distant metastasis in ER+/Her2- breast cancer and provides prognostic information that is complementary to IHC4 and other clinicopathologic risk factors. Additional validation studies designed to establish clinical validity are currently being planned. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-11-03.

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