NeoALTTO TIL Analysis Shows EFS, OS Association in HER2+ Breast Cancer

The level of tumor infiltrating lymphocytes (TILs) identified at the time of diagnosis were found to be an independent prognostic marker for pathologic complete response (pCR) and event-free survival (EFS) in patients treated with neoadjuvant HER2-target therapy plus chemotherapy for HER2-positive early breast cancer, according to a study published in theJournal of the American Medical Association.

"In this prospectively planned analysis of a neoadjuvant clinical trial of HER2-positive early-stage breast cancer, we have shown for the first time, to our knowledge, that higher levels of stromal TILs were associated with good outcomes, independent of the anti-HER2 agent given (trastuzumab or lapatinib or the combination) with standard anthracycline and taxane-based chemotherapy," the authors of the study wrote.

NeoALTTO Study Shows Similar Outcomes Across Arms

Findings were uncovered in an analysis of the phase III NeoALTTO study that explored neoadjuvant trastuzumab, lapatinib, or the combination of the two agents as neoadjuvant treatment of early breast cancer.

In the 3-year analysis of the study, outcomes for EFS and OS were similar across all treatment arms. Outcomes were improved in those who achieved a pCR.

Patients who achieved a pCR experienced an EFS rate of 86% compared with 72% for patients who did not have a pCR (HR = 0.38;P= .0003). Additionally, overall survival was significantly higher with pCR (94% vs 87%; HR = 0.35;P= .005).

TIL Analysis Reveals Association

In the 455-patient trial, 387 tumor samples were available for analysis (85.1%). The median level of TILs was 12.5%, this was lower in those who were both HER2-positive and HR-positive (10%). Overall, TILs greater than 5% were associated with a higher rate of pCR, independent of treatment (odds ratio = 2.60; 95% CI, 1.26-5.39;P= .01).

At a median follow-up of 3.77 years, it was found that for every 1% increase in TILs there was a 3% decrease in events (adjusted HR = 0.97; 95% CI, 0.95-0.99;P= .002). The EFS rate was 88% with at least 12.5% TILs; however, in those with less than 12.5%, the EFS rate was 71%. Even more strikingly, in those with >40% TILs, the EFS was 97%.

"Of interest, patients who had higher TIL levels (greater than the median) and did not achieve pCR had EFS similar to those who did achieve pCR," the authors wrote. "Patients who did not achieve pCR and had low levels of TILs had the poorest survival."

Clinical Utility

The challenge facing implementation involves the proper identification of a TIL level cutoff. Additionally, as with most neoadjuvant findings, the results would need to be validated in the adjuvant setting.

"Patients with high TIL levels can have an excellent outcome with the current standard of trastuzumab therapy alone with chemotherapy, although we acknowledge the difficulty of proposing such cutoffs for clinical implementation," the authors wrote.

Investigation into exome and RNA sequencing samples from the NeoALTTO trial could reveal more information and remains ongoing. These analyses could find mutant peptides, which have been hypothesized to initiate a T-cell response.

Salgado R, Denkert C, Campbell C, et al. Tumor-Infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: A secondary analysis of the NeoALTTO trial.JAMA Oncol. Published online April 30, 2015. doi:10.1001/jamaoncol.2015.0830