“Nailing down” risk and improving outcomes in early-stage breast cancer

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Whether via the strain of academic advancement or hyper-competitive industry-funded drug-development landscape,¹ there has been increasing focus to shift clinical trial design to the highest-risk disease populations. This approach has led to the approval of practice-changing new systemic therapies in patients with metastatic breast cancer (BC), which are then evaluated in large trials for approval in patients with high-risk, early-stage breast cancer (eBC). In countries like the United States, where a high rate of BC screening is coupled with population growth, women are most likely to be diagnosed with “low” or “intermediate” risk eBC. For generations, physicians, patients, and the public have received messaging that eBC is low-risk for premature death. Yet, Marczyck et al. demonstrate how Proust’s law of definite proportions has been pushed out of balance by advances targeting stage III disease, the smallest cohort of patients diagnosed with nonmetastatic disease, resulting in a shift so that eBC accounted for more than 60% of BC-specific death in 2017 (Figure 1).² Yet, despite a 40% reduction in BC mortality in a similar timeframe,³ the risk of BC-specific death has increased only for patients with the earliest-stage disease. Although there are increasing “tools in our toolbox,” our investment in resources is not “drilling down” to align with improving outcomes in the largest population who remain at risk of BC recurrence.