19-05-2025
New High-Risk TNBC Subgroup Identified
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.
