Translational Research Aims to Guide Targeted Approaches for High-Risk TNBC Subgroups

At the San Antonio Breast Cancer Symposium in San Antonio, Justin Balko, PharmD, PhD, discussed ongoing translational research efforts aimed at identifying and validating biomarkers that could better guide immunotherapy use in early-stage triple-negative breast cancer (TNBC). He explained that while current retrospective findings are encouraging, these biomarkers must ultimately be evaluated within large, prospective, phase 3 randomized controlled trials using predefined protocols to ensure accurate assessment and clinical relevance.

Pharmacy Times: 1. Your data show that combining tsMHC-I/II expression with tumor immune spatial organization more accurately differentiates response than individual biomarkers. How close do you think we are to integrating this type of composite biomarker into clinical decision-making for breast cancer?

Justin Balko, PharmD, PhD: So this is one of our goals as a translational research program: to try to not just identify these biomarkers but bring them into clinical practice. There's a very high bar for doing that, as you might expect. So the results that we're presenting today are something that is very validating in past cohorts of patients that we've looked at retrospectively, but ultimately what we would need to be able to do is to perform these very similar analyses on a large phase 3, prospectively performed, randomized controlled trial. Even if that assessment of those biomarkers is done in a retrospective manner, they would need to follow a very specific protocol for assessment and for quantification of the markers and would need to have predefined endpoints that were specified before looking into the data.

So we're actively working on this. We want to integrate these into clinical care eventually for them to be useful for patients, and that's a big deal right now because currently all early-stage triple-negative breast cancer patients that are stage 2 and 3 would be candidates for immunotherapy. However, these drugs only really provide benefit, tangible benefit, to about five to ten percent of triple-negative breast cancer patients treated. They also, while they have very different toxicity profiles than chemotherapy, have very significant toxicities and adverse drug events that are often autoimmune conditions. Some of these can last for a patient's entire life after being treated. And so, while we want patients to get the benefit of these drugs, we really want to identify that small percentage that actually need these drugs to achieve a cure.

Pharmacy Times: Immune desert tumors demonstrated exceptionally poor response rates in your analysis. What alternative therapeutic strategies or trial approaches do you believe hold the most promise for this subgroup moving forward?

Balko: So the short answer is we don't know yet. We haven't—I don't think that there's enough data in the field yet to know what kind of therapies to propose for this subgroup. However, what we do know is that they have a very poor outcome compared to other patients in this setting, where we're actually giving these patients four different cytotoxic chemotherapy agents, as well as immunotherapy. To me, this suggests that there is something else entirely going wrong with these patients' tumors, and part of our goal as translational researchers is to figure out what that is.

Now that we've defined that this subgroup of patients have very, very poor outcomes on our standard Keynote-522 regimen, our goal as a research lab is to use molecular analyses to try to figure out: are there specific pathways or other features that might be targetable within these tumors. Once we have that, we can go forward and select those patients in a prospective clinical trial, probably starting with something like a phase 1 or phase 2 trial, and evaluate whether specifically that subgroup of patients can now get to a pathological complete response and good outcomes with a very targeted therapy that's specific for that subtype.