OP-JNCI200154 349..350

By now, most are familiar with the graph of the distinctive arching breast cancer mortality curve from about 1975 (the advent of Surveillance, Epidemiology, and End Results reporting) and currently tracking 4 decades forward. The curve, peaking around 1990 and then beginning an impressive decline, marks the turning point in progress attributable to more comprehensive screening and genuinely effective treatment (1). When plotted separately for White and Black women (Figure 1), a strikingly different pattern emerges, with the peak for Black women being higher and occurring later (about 1995, despite lower breast cancer incidence than White women throughout this period), followed by a less pronounced descent resulting in a consistent mortality gap exceeding 9 deaths per 100 000 in 2010, much wider than the pre-1990 disparity. The gap persists to present, at best no longer widening and possibly converging slightly in more recent years, with an average mortality rate difference of 7.8 over 2013-2017 (1,2). The convergence is encouraging but slow and not guaranteed to continue. A multitude of investigations across diverse settings have explored potential causal factors from multiple domains, with disparities in clinical, biologic, care access and delivery, and health status all emerging as contributory. A consistent focus has been on greater frequency of unfavorable disease features, including more clinically advanced disease and absence of hormone receptors (later combined with HER2 negative status) among Black patients. In contrast, the study in this issue of the Journal by Albain et al. (3) among participants in the landmark TAILORx trial focuses on the historically better-prognosis patients, who have estrogen receptor (ER)þ, HER2 tumors and negative lymph nodes. It is worth noting that despite proportional overrepresentation in higher risk groups by Black women, the ERþ, HER tumor type represents the majority diagnosis in all race groups (1,2), and here we perhaps expect more similar outcomes given the clear treatment rubric. Earlier (clinical trial– based) studies predating widespread HER2 testing found variable results among ERþ patients, with one study showing mostly similar breast cancer outcomes for Black women and White women (mostly lymph node–negative) and another finding a moderate disparity in trials of node-positive patients (4,5). The studies were statistically congruent for overall survival (OS) disparities (6). A subsequent study incorporating HER2 status showed less favorable outcomes for Black women specifically for ERþ, HER2 disease (7). The current investigation, like other contemporary studies among ERþ, HER2 trial participants cited therein, does show a deficit in outcome for Black women compared with Whites (3). For the primary trial endpoint (invasive disease-free survival) and OS, at least a small degree of deficit is perhaps unsurprising, because invasive disease-free survival includes second primary cancers, for which incidence and survival disparities are present in Black women for several types, and both endpoints include noncancer deaths. There remains a substantial life expectancy gap that persists throughout life between Black and White women, equaling about 2.1 years among those reaching 50 years of age (8). Although the trial excluded those with profound comorbidities, some important health conditions did differ, including body mass index (likely a greater contributor to OS than breast cancer endpoints). Thus, the trial cohort appropriately reflects health disparities in the population at large, and, consequently, a degree of influence on endpoints such as OS may thus manifest within the trial, particularly over longer follow-up. The differences in breast cancer–specific outcomes (relapsefree interval and distant disease-free interval) raise concern regarding both unmeasured tumor heterogeneity that influences treatment response potential among ERþ, HER2 patients as well as the myriad of other factors, including treatment nonadherence, that could exert sufficient influence to diminish treatment efficacy even in a clinical trial setting. There were moderate differences in potential disease explanatory factors, but interestingly the 21-gene recurrence score was not among these, suggesting that to the extent that the score captures predicted risk based on tumor biology, both broadly (ie, the discrete risk partitions commonly employed) and on a continuous scale, it does so similarly across race and ethnic groups. The difference emerges relatively early for relapse-free interval, and it may be of interest to parse the distribution of anatomic failure sites to explore any difference in local disease control, a prior focus of interest in relation to race (9). As in the case of diseasefree survival and OS, it is useful to examine events comprising the composite recurrence endpoint to glean all available information about sources of differential outcomes. ED IT O R IA L