Tracking and evaluating molecular tumor markers with cancer registry data: HER2 and breast cancer.

First noted in 1948 by Johannes Clemmesen from the Danish Cancer Registry (1), patterns of female breast cancers in developed countries are consistent with a “mixture model” with at least two main parts (2–5). The first is largely premenopausal with peak incidence near age 50 years; the second is largely postmenopausal with a peak around age 70 years (6–8). Using the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) 17 Registries Database (covering approximately 28% of the US population), Howlader et al. (9), in this issue of the Journal, provide additional molecular insight into breast cancer heterogeneity by studying newly available data—specifically, the recent addition of human epidermal receptor 2 (HER2) to the list of breast tumor characteristics captured by the SEER program. Prior laboratory work had strongly suggested that breast cancers are molecularly heterogeneous. Indeed, unsupervised hierarchal clustering of gene expression profiles of various tumor collections has demonstrated four to 10 molecular subtypes of breast cancer (10,11). Of these various classifications, the four so-called “intrinsic” subtypes are the best-known and most well-characterized molecular signatures (10,12,13). The four intrinsic types consist of two main classes by hormone receptor (HR) status (estrogen receptor [ER] and/or progesterone receptor [PR]) and epithelial cell of origin (luminal and basal-like). There are two HR-positive subtypes (luminal A and luminal B) and two HR-negative subtypes (HER2-enriched [HER2E] and basal-like). Fortunately for cancer surveillance researchers, the intrinsic molecular subtypes can be approximated by the joint protein expression of HR± and HER2± (14,15). Howlader et al. (9) describe for the first time the demographic characteristics, tumor features, and area-level poverty data for the four recapitulated subtypes in the entirety of SEER 17, summarized by us in Figure 1. Seventy-three percent of the breast cancers were luminal A (HR+/ HER2−), 10% were luminal B (HR+/HER2+), 5% were HER2E (HR−/HER2+), and 12% were triple-negative (HR−/HER2−). SEER began in 1973 and has recorded HR expression since 1990 but did not collect HER2 data until 2010 (the most recent year for which complete SEER data are available). For the past two decades, the HR (especially ER) status has been an epidemiologically useful correlate for population-based breast cancer heterogeneity. So, it might be asked if the new HER2 data add much to HR status. The answer is a definite yes. Overall, approximately 15% of cases were HER2-positive (Figure 1). Importantly, what Howlader and colleagues (9) have been able to do is split the HR-positive group into two pieces and the HR-negative group into two pieces. We now know that almost one in three HR-negative tumors coexpress HER2 (5 / [5 + 12] or 29% of HR− tumors) (Figure 1). Conversely, approximately one in eight HR-positive tumors also expresses HER2 (10/ [10+73] or 12% of HR+ tumors, Figure 1). Earlier clinical trial data had suggested that 15%–30% of all invasive breast cancers were HER2positive (16,17). Furthermore, the trial data also suggested that half of the HER2-positive tumors were HR-positive (16), when in fact the true figure in the population is actually two-thirds (10% / [10%+5%]) (Figure 1). The initial estimates were largely obtained from high-risk breast cancer cohorts in randomized clinical trials (18,19), which we now know are substantially different from those in the general population.