The Biomarker Gap in Triple-Negative Breast Cancer: Justin Balko, PharmD, PhD

Patients with stage 2 and stage 3 triple-negative breast cancer (TNBC) now receive 4 chemotherapy drugs plus immunotherapy up front, yet the field still cannot identify in advance which of them will fail to respond — a gap that Justin M. Balko, PharmD, PhD, of Vanderbilt-Ingram Cancer Center, argues is the central unmet need in personalizing care for this population.

Why Residual Disease Reflects a Biology Gap

Balko describes the current neoadjuvant regimen as difficult for patients to tolerate, with marginal added benefit from each successive drug. Once residual disease is present after that regimen, he says it is hard to argue that these patients simply need more therapy; they need something different.

Speaking as a translational researcher, Balko says the field is perhaps not overtreating these patients so much as mistreating them. There is a subset whose tumor biology remains poorly understood, evidenced by the fact that they are receiving multiple agents and still not responding. The goal of his work is to find biomarkers that flag those patients before they cycle through 5 drugs unsuccessfully.

What Is Being Tested in the Residual Disease Setting

Patients who achieve a pathological complete response (pCR) have excellent outcomes, Balko notes, whereas a significant portion of those with residual disease will eventually recur. Several large cooperative group trials are now testing whether newer antibody-drug conjugates (ADCs) are effective in that setting. He acknowledges the difficulty of watching patients who have already been through multiple regimens face another effective but toxic therapy while the field determines whether it helps. Cell-free DNA monitoring, he expects, will become a significant tool in the next several years, in part because even within the residual disease population some patients are already cured.

Why Biomarkers Struggle to Reach Clinical Practice

Balko also outlines why the bar to clinical utility is so high. Unless a pharmaceutical company incorporates a biomarker into the primary analysis of a phase 3 registration trial, validation ultimately requires repeating the work in a large population through a cooperative group or the National Cancer Institute. The statistics compound the problem: if pCR rates move from roughly 50% to 55% up to 60% or 65%, with an overall recurrence difference near 8%, isolating what distinguishes that 5% to 10% of patients is exceptionally difficult. Regulatory hurdles add another layer. Still, Balko points to ongoing phase 3 trials wrapping up over the next few years that are beginning to surface potentially useful biomarkers.