Ancestry Determines Effective and Harmful Dose in Breast Cancer

Racial disparity in treatment efficacy in breast cancer is well known, with African American women known to present with inferior outcomes, likely due to a combination of higher stage, grade, and poor response to treatment. Authors have now found an association between genetic inheritance and patients’ response to efficacy and toxicity in the phase 3 ECOG-ACRIN-5103 trial.

The trial assigned nearly 5000 patients with node-positive or high-risk node-negative breast cancer, who were epidermal growth factor receptor 2—negative, to receive:

• Intravenous doxorubicin and cyclophosphamide every 2 or 3 weeks for 4 cycles, followed by 12 weeks of paclitaxel alone (arm A)
• Intravenous doxorubicin and cyclophosphamide every 2 or 3 weeks for 4 cycles with concurrent bevacizumab (arm B)
• Intravenous doxorubicin and cyclophosphamide every 2 or 3 weeks for 4 cycles with concurrent and sequential bevacizumab (arm C)

Genome-wide single-nucleotide polymorphism (SNP) assays were conducted in 2 subsets. The final outcomes were compared between 386 African American patients and 2473 patients who presented with a European ancestry. The primary efficacy endpoint of the study was invasive disease-free survival (DFS); the study also followed toxicities experienced by patients following their treatment regimens, and clinically significant toxicities were compared, including anthracycline-induced congestive heart failure (CHF), taxane-induced peripheral neuropathy (TIPN), and bevacizumab-induced hypertension.

Efficacy analysis showed that, overall, patients with African American ancestry had a significantly lower DFS (P = .002; hazard ratio, 1.5) compared with their counterparts with European heritage, particularly if they were estrogen receptor—positive (P = .03). Patients diagnosed with triple negative breast cancer had a similar trend that was, however, not significant between the 2 cohorts (P = .12).

With respect to toxicity, the African American patients experienced significantly more grades 3 to 4 TIPN (odds ratio [OR], 2.9; P = 2.4 × 10⁻¹¹) and grades 3 to 4 bevacizumab-induced hypertension (OR, 1.6; P = .02), with a trend for more CHF (OR, 1.8; P = .08). This subgroup also required more dose reductions in paclitaxel (P = 6.6 × 10⁻⁶), which in turn had a negative influence on their DFS (P = .03), unlike women with a European ancestry (P = .35).

An important point to note is that in addition to the genetic differences based on ancestral influence, the study identified specific genetic markers, beyond an individual’s race, to elucidate biological differences in efficacy and toxicity response to treatment.

Based on their analysis, the authors recommend paying increased attention to recognizing the biological differences between a normal and tumor breast tissue as well as inherited genetic differences based on a person’s ancestry. Personalized counseling, they write, would play an important role in understanding the risk-to-benefit ratio in African American women who, according to this study, have a lower DFS and are more susceptible to toxic effects of these treatments.

Reference

Impact of genetic ancestry on outcomes in ECOG-ACRIN-5103 [published online August 21, 2017]. JCO Precis Oncol. doi: 10.1200/PO.17.00059.