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New data support integrating tumor-infiltrating lymphocyte levels with nodal status to improve risk stratification in women with triple-negative breast cancer (TNBC) and pathological complete response (pCR) following neoadjuvant treatment.

Specifically, patients with lower levels of tumor-infiltrating lymphocytes had a higher risk for relapse and worse overall survival than those with higher levels, said Davide Massa, MD, medical oncologist, University of Padua, Padua, Italy.

“For every 5% increase in [tumor-infiltrating lymphocytes], we saw a 10% reduction in the risk of distant relapse-free survival and an 11% reduction in the risk of death,” he reported in an oral presentation at the ESMO Breast Cancer 2025 meeting.

And when combining tumor-infiltrating lymphocytes and nodal status, “we could identify a previously unrecognized high-risk subgroup — patients with low tumor-infiltrating lymphocytes and positive nodal involvement,” Massa noted.

These data may help guide post-neoadjuvant strategies for patients otherwise considered to have favorable long-term outcomes, he added.

Refining Risk Stratification

In TNBC, pCR after neoadjuvant treatment is associated with favorable outcomes, but a subset of patients remains at risk for relapse. Massa and his colleagues wanted to find out if they could identify these patients.

Stromal tumor-infiltrating lymphocytes in TNBC are a strong independent prognostic biomarker associated with improved outcomes, yet their role in risk stratification within the pCR subgroup has been underexplored.

The retrospective study included 1532 patients with stage I-III TNBC who received neoadjuvant therapy between 2000 and 2023 at 12 European centers. Of these patients, 733 (48%) had a pCR. Tumor-infiltrating lymphocyte levels, assessed in treatment-naive biopsies, were available for 613 patients with a pCR (84%), which comprised the study cohort. The median follow-up was 4.2 years.

In multivariate analyses, both tumor-infiltrating lymphocytes and nodal status were independent prognostic factors for distant relapse-free survival and overall survival in patients with a pCR.

Patients with positive nodal status had significantly worse distant relapse-free survival (adjusted hazard ratio [aHR], 2.38) and overall survival (aHR, 3.45) compared with those with negative nodal status.

When evaluating tumor-infiltrating lymphocytes at a predefined cutoff of 30%, patients with higher tumor-infiltrating lymphocyte levels demonstrated better survival outcomes.

Patients with tumor-infiltrating lymphocyte levels ≥ 30% had a 5-year distant relapse-free survival elapsed survival rate of 96.3% compared with 89.5% in patients with levels < 30% (aHR, 0.42). Similarly, in patients with higher tumor-infiltrating lymphocyte levels, 5-year overall survival was 98.1% compared with 91.5% in those with lower levels (aHR, 0.33). 

When combining tumor-infiltrating lymphocyte and nodal status information, patients with low tumor-infiltrating lymphocyte levels and positive nodal involvement had significantly worse 5-year distant relapse-free survival compared with all other subgroups (82.6% vs at least 94.7%; aHR, 3.17). This finding held for 5-year overall survival (84.3% vs at least 97%; aHR, 5.09).

Sensitivity analyses confirmed the study findings for both distant relapse-free survival and overall survival.

“This is a simple, cost-effective, and universally applicable stratification tool that relies only on hematoxylin and eosin-stained slides and no proprietary technology, which can be implemented in treatment-tailoring trials,” Massa said.

Massa noted that a prospective study to validate these findings is ongoing.

Kevin Kalinsky, MD, with Winship Cancer Institute, Emory University, Atlanta, who served as study discussant, called the results “intriguing” and “hypothesis-generating.”

Kalinsky said it will be important to validate whether low tumor-infiltrating lymphocytes are associated with worse outcomes regardless of pCR. And, if so, what is the role of antibody-drug conjugates with or without immunotherapy — a question that may be answered in the ongoing OptimICE-pCR trial, he added.

Another question is whether patients with stage I TNBC and high tumor-infiltrating lymphocytes can opt out of systemic therapy, as is being explored in the OPTImaL and ETNA trials.

Finally, Kalinsky said it will be worth exploring the use of tumor-infiltrating lymphocytes and other markers to tailor the selection of chemotherapy in TNBC, something the NeoTRACT trial is investigating.

The study had no commercial funding. Massa had disclosed relationships with Eli Lilly and Company and Pfizer. Kalinsky had disclosed relationships with Genentech/Roche, Gilead Sciences, Seattle Genetics, Inc., AstraZeneca, Daiichi Sankyo, Puma Biotechnology, Inc., Mersana Therapeutics, Menarini Silicon Biosystems, Myovant Sciences Ltd., Merck, Eli Lilly and Company, Pfizer, Novartis, ProteinQure, BioTherapeutics, Inc., Regor Therapeutics, and Relay Therapeutics.