TIL Quantity Greatly Impacts Survival in Metastatic Breast Cancer

Daniel G. Stover, MD

As measured by stromal tumor infiltrating lymphocytes (TILs), immune activation was considerably lower in metastatic breast tumors compared with primary breast tumors, and it appeared to vary according to the metastatic site.¹ These findings come from the post hoc analysis of the phase 3 CALGB (Alliance) 40502 study (NCT00785291).

At the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting, the results presented by Daniel G. Stover, MD showed that in 582 patients with breast cancer, stromal TILs made up a mean of 13.3% primary tumors vs 8.4% metastatic tumors (P =3e-4). Moreover, low vs high immune activation significantly correlated worse progression-free survival (hazard ratio, 1.34; 95% CI 1.1-1.63, P =0.004) and overall survival (hazard ratio, 1.32; 95% CI 1.07-1.63, P =0.009).

In an interview with Targeted Oncology™, Stover, breast medical oncologist at the Ohio State University Comprehensive Cancer Center, highlighted the objective to enhance delivery of endocrine therapy plus CDK4/6 inhibitors to patients with hormone receptor (HR)-positive, HER2-negative breast cancer by utilizing biomarker assessments as a guide to interchange or cease treatment at the most favorable time. He also discusses the post hoc analysis findings from CALGB 40502.

Can you summarize the main points of your presentation?

Stover: First-line therapy for hormone receptor positive HER2-negative metastatic breast cancer remains endocrine therapy plus CDK4/6 inhibitors. But we are seeking to optimize how we deliver those treatments to our patients. And in the three abstracts I discuss. There is an opportunity to refine who starts with CDK4/6 inhibitor, who potentially needs to switch therapy early, and who potentially could extend their first line therapy as we think about finding the right treatment for the right patient.

What has the evolution of CDK4/6 inhibitors and breast cancer looked like over the past few years?

Since the approval palbociclib [Ibrance] in 2015, and subsequent approvals of ribociclib [Kisqali] and abemaciclib [Verzenio], endocrine therapy and 1 of the 3 CDK4/6 inhibitors have really been standard of care. And with the absence of any head-to-head trials, we don't have a lot of guidance as to which CDK4/6 inhibitors should be selected for which patient and if there are ways that we can optimize the delivery of those drugs to our patient.

What might the future hold for research in this area?

I think it is becoming increasingly clear that we need to dive deeper into biomarker assessments for patients receiving first line therapy for HR-positive, HER2-negative metastatic breast cancer. We clearly have 3 effective agents, but which agent is right for which patient remains unclear in the absence of head-to-head studies. And the increasing evidence that biomarkers like rising ESR1 mutant, ctDNA may guide us when to switch therapy. Suggests that there is more to learn from biomarker assessments. And as a field, we really need to take that on as a challenge.

From a community oncology standpoint, what is your main message?

When we think about care delivery in the first line for hormone-receptor-positive HER2-negative metastatic breast cancer, the standard of care remains endocrine therapy, plus CDK4/6 inhibitors, ribociclib or abemaciclib, given overall survival data that we have. However, with the data that we saw here at ASCO, endocrine therapy alone may be appropriate for selected patients and other patients may benefit from early switch to an alternative therapy based on changing biomarkers.

Can you briefly summarize the CALGB 40502study?

Tumor infiltrating lymphocytes (TILs) are part of a complex tumor immune microenvironment ecosystem. We know that stromal TILs are associated with prognosis in early-stage breast cancer response to neoadjuvant chemotherapy. In the metastatic setting associated with response to immune checkpoint inhibitor specifically among triple negative and HER2-positive breast cancers. But no study to date has evaluated the association of Stromal tils with survival outcomes in the metastatic setting in the absence of immune checkpoint inhibitors. The main goal of evaluating Stromal TILs and CALGB 40502 was to evaluate the association of these stromal TILs with survival in patients receiving for sign chemotherapy.

What was the rationale for conducting this post hoc analysis?

We have strong data in the early-stage setting that Stromal TILs are prognostic and predictive of new adjuvant chemotherapy benefit in triple negative and HER2-positive breast cancer. We really do not have any data that has been compiled from a prospective randomized phase three trial, as we have here. Our hope was to evaluate whether Stromal TILs could be an accessible biomarker that can be readily enumerated from a routine HD slide that could potentially guide therapy decisions for our patients in the future.

What findings from this post hoc analysis are were presented at ASCO, and were there any datapoints that were surprising?

In the primary analysis of this study, we found that stromal tils were significantly associated with progression-free and overall survival in this population of patients with metastatic HR-positive HER2-negative breast cancer receiving for assigned chemotherapy when controlling for treatment arm in the study. In the main secondary analysis when also controlling for hormone receptor arm, the trend continued but lost statistical significance. So, the overall take home is that stromal TILs are significantly associated with progression-free and overall survival. But hormone receptor status may impact the association of this biomarker with end point. The other interesting finding from our study and another study presented here at ASCO was that stromal TILs vary significantly when you look at the metastatic setting compared to primary tumors. Stromal TIL are lower in most metastatic sites, but not all. And specific metastatic sites may vary based on the stromal TILs, for example, liver, bone, and in certain sites may have very low stromal TIL values.

What are the next steps or future implications?

Increasingly we have strong data that stromal TILs are prognostic in the early stage setting and now evidence that they may also be prognostic in the metastatic setting. But what we really need to do as a field is to design studies where Stromal tils are an integrated biomarker, and we are guiding therapy based on that to see if they can be more than just a prognostic biomarker. These are incredibly accessible. Anyone with a hematoxylin and eosin can enumerate stromal TILs, so it is not a resource intensive biomarker and can be utilized globally. It really warrants further investigation as an integrated biomarker and future trials.

_REFERENCE:

_{Stover DG, Salgado R, Savekov O, et al. Association of tumor infiltrating lymphocyte quantity with survival in patients (pts) with metastatic breast cancer (MBC) receiving microtubule-targeting agents: Post hoc analysis CALGB 40502 (Alliance). J Clin Oncol. 2023;41(suppl 16): 1010-1010. doi: 10.1200/JCO.2023.41.16_suppl.1010}