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Many women with hormone receptor–positive breast cancer will receive tamoxifen at some point in their treatment course. Tamoxifen is biotransformed to the potent antiestrogen endoxifen almost exclusively through the cytochrome P450 (CYP) 2D6 isoform. Although prospective data are lacking, the balance of evidence available currently suggests that a single nucleotide polymorphism in the CYP2D6 gene, particularly the presence of 2 null alleles, predicts for reduced tamoxifen metabolism and possibly poorer outcome than expected in patients with a wild-type genotype. Studies evaluating the impact of genetic polymorphisms that result in CYP2D6 with reduced or no activity on long-term outcome have been mostly retrospective and conducted on archival tissues or those obtained previously in prospective studies of tamoxifen. Until data are available from retrospective examinations of the large prospective trials already conducted, or adequately powered prospective analyses, transforming this information into guidelines for individual patients remains challenging. The authors do not currently recommend routine testing for CYP2D6 genotype for making clinical decisions regarding tamoxifen. Use of concomitant strong or intermediate inhibitors of CYP2D6 should be avoided when alternate medications are available. Ongoing research is directed toward identifying other polymorphisms that may influence the efficacy and safety of tamoxifen, other hormonal agents, and chemotherapies used to treat breast cancer. The hope is that in the future, not only tumor-associated factors but also germ-line host genetics can be used to determine whether a woman should receive treatment, and with which specific agents, to prevent breast cancer recurrence or death or avoid drug-related toxicities.

The KEYNOTE-522 study is a practice-changing phase III randomized study that demonstrated that the addition of pembrolizumab to polychemotherapy improves outcomes in patients with high-risk early-stage triple-negative breast cancer (TNBC). This regimen is highly efficacious with unprecedented pathologic complete response (pCR) rates, and clinically meaningful improvements in event-free survival (EFS). However, the combination is also associated with significant high-grade treatment-related toxicity. The backbone regimen deviated from common practice, including the addition of carboplatin, lack of dose dense anthracyclines, and adjuvant capecitabine for residual disease, thus brining important questions regarding real-world translation of these results. This brief report practically addresses some of the most relevant questions physicians and patients face in optimizing care using the best available evidence.