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Immune Signatures Outperform TILs for HER2-Positive Breast Cancer Prognoses

NEW YORK – A University of North Carolina at Chapel Hill-led team has identified immune-related expression signatures that appear to outperform tumor-infiltrating lymphocyte (TIL) patterns for predicting pathologic complete response (pCR) to treatment — as well as event-free survival (EFS) — in early-stage ERBB2/HER2-positive breast cancer.

"[A]ccumulating evidence supports the validity of using evidence of immune activation … to stratify patients with early-stage ERBB2/HER2-positive breast cancer into different prognostic groups," senior and corresponding author Lisa Carey, with the University of North Carolina at Chapel Hill's Lineberger Comprehensive Cancer Center, and her colleagues wrote, noting that when both TILs and gene expression are available, the prognostic value of immune-related signatures appears to be superior.

As they reported in JAMA Oncology on Thursday, the researchers analyzed RNA sequences and slide scoring-based TIL patterns in 368 pretreatment tumor biopsy samples from stage I, stage II, or stage III HER2-positive breast cancer patients receiving neoadjuvant treatment combinations through the "Cancer and Leukemia Group B" (CALGB) 40601 and PAMELA trials, comparing the relationships between immune-related gene expression and TILs and HER2-positive breast cancer patient outcomes, particularly pCR and EFS.

"In this retrospective, predictive, and prognostic study, we tested which biomarker, or combination of biomarkers, is the most powerful for response and survival in [two] independent clinical trials," the authors explained, adding that their findings "highlight the essential role of B cells in antitumor immunity and suggest that B-cell immune-related gene expression provides valuable prognostic information for treatment escalation and de-escalation in patients with early-stage ERBB2/HER2-positive breast cancer."

In CALGB 40601 participants, where premenopausal women were overrepresented, the median TIL count was 20 percent, ranging from 13 percent to 45 percent, for example, though the researchers noted that hormone receptor-negative cases had significantly higher TIL levels than their hormone receptor-positive counterparts in both trials. Likewise, they found that nonluminal, basal-like, or HER2-enriched tumor subtypes were linked to enhanced TIL levels relative to tumors from the luminal A or B subtypes.

Across the more than 200 immune signatures considered, the team found that 179 such signatures coincided with the TIL proportions found in the available tumor biopsy samples from the CALGB 40601 trial. In the PAMELA trial, meanwhile, TIL tracked with 174 immune signatures, while 166 TIL-associated immune signatures overlapped in both trials. 

When the investigators considered immune signature and TIL ties to treatment response, they linked pCR rates not only to TILs but also to three dozen immune-related gene expression signatures. They noted that seven immune signatures — including half a dozen B-cell-related signatures — had enhanced pCR predictive potential compared to TIL patterns alone.

When it came to disease-free survival, meanwhile, the researchers identified independent ties between EFS and B-cell signatures, particularly signatures associated with immunoglobulin G (IgG), after adjusting for clinical characteristics and tumor pathology. In contrast, they explained, TILs were not associated with disease progression independent of the other clinicopathologic factors considered.

"Results of this study suggest that multiple B-cell-related signatures were more strongly associated with pCR and EFS than TILs, which largely represent T-cells," the authors wrote, noting that such findings "are especially relevant in early-stage ERBB2/HER2-positive breast cancer, in which multiple trials focus on developing prognostic tools combining tumor and immune cell biomarkers to guide treatment escalation and de-escalation."