Stromal TILs relevant to chemotherapy benefit in early-stage, HER-2–positive breast cancer

Issue: December 25, 2014

SAN ANTONIO — Higher levels of stromal tumor-infiltrating lymphocytes were associated with longer RFS among patients with early-stage, HER-2–positive breast cancer treated with chemotherapy alone, according to phase 3 study results presented at the San Antonio Breast Cancer Symposium.

However, the level of stromal tumor-infiltrating lymphocytes (TILs) had no impact on RFS among patients treated with chemotherapy plus the HER-2–targeted therapy trastuzumab (Herceptin, Genentech).

Edith A. Perez

“For the 10% of patients whose tumors are very highly infiltrated with lymphocytes, we cannot really prove that there is a benefit to using chemotherapy plus trastuzumab, at least based on the trend we observed in this study,” Edith A. Perez, MD, deputy director at large for Mayo Clinic Cancer Center, professor at Mayo Clinical College of Medicine in Jacksonville, Fla., and a HemOnc Today Editorial Board member, said during a presentation.

Prior studies showed stromal tumor-infiltrating lymphocytes (TILs) are prognostic in patients with triple-negative breast cancer. Also, a study by Loi and colleagues — which included 209 patients with HER-2–positive breast cancer — concluded higher levels of stromal TILs were associated with greater benefit from trastuzumab.

In the Alliance N9831 trial, Perez and colleagues strived to evaluate the prognostic and predictive association between stromal tumor-infiltrating lymphocytes (TILs) in patients with HER-2–positive breast cancer treated with chemotherapy alone or chemotherapy plus trastuzumab.

Researchers enrolled 945 patients. They randomly assigned 489 to chemotherapy alone. The other 456 patients received chemotherapy plus trastuzumab, a regimen that has become the standard of care for patients with HER-2–positive breast cancer. Fifty-four percent of patients in each arm were HR-positive, and 14% of patients were node-negative.

The percentages of patients with lymphocyte-predominant breast cancer (LPBC) — defined as those with ≥60% stromal TILs — and those with non-LPBC — defined as <60% stromal TILs — were comparable between the chemotherapy-alone arm and the chemotherapy-plus-trastuzumab arm (9.8% vs. 10.1% for LPBC; 90.2% vs. 89.9% for non-LPBC).

Median follow-up was 6.9 years.

Univariable results showed patients with LPBC derived a statistically significant 10-year RFS benefit from chemotherapy alone (90.9% vs. 64.3%; HR=0.22; 95% CI, 0.07-0.68) compared with those who had non-LPBC. Researchers did not observe an association between 10-year RFS and LPBC status in the chemotherapy-plus-trastuzumab arm (80% for LPBC vs. 79.6% for non-LPBC; HR=1.13; 95% CI, 0.45-2.84).

Among patients with LPBC, those who received chemotherapy alone demonstrated a trend toward improved 10-year RFS compared with those who received chemotherapy plus trastuzumab (90.9% vs. 80%; HR=2.43; 95% CI, 0.58-10.22). The difference was not statistically significant. Among patients with non-LPBC, those who received chemotherapy alone demonstrated a significantly lower rate of 10-year RFS than those who received chemotherapy plus trastuzumab (64.3% vs. 79.6%; HR=0.49; 95% CI, 0.35-0.6).

Multivariable analysis adjusted for nodal status, HR status, tumor size, tumor grade and age showed LPBC was associated with RFS in the chemotherapy-alone arm (HR=0.19; 95% CI, 0.06-0.61) but was not associated with RFS in the chemotherapy-plus-trastuzumab arm (HR=1.01; 95% CI, 0.39-2.6). Researchers determined the interaction of treatment arm and LPBC status was significant (P=.042).

“These results suggest that levels of tumor-infiltrating immune cells may provide a biomarker to identify patients who might do well without trastuzumab,” Perez said. “But we must conduct additional large clinical trials before we can consider changing clinical practice and omitting HER-2–targeted therapy from the treatment regimens for patients who have high levels of tumor-infiltrating immune cells.”

Researchers intend to corroborate their findings in a separate cohort, identify subtypes of stromal TILs, correlate the presence of stromal TILs with immune gene profiles and determine whether changing the type and amount of stromal TILs will improve patient outcome, Perez said.

For more information:

Perez EA. Abstract #S1-06. Presented at: San Antonio Breast Cancer Symposium; Dec. 9-13, 2014; San Antonio.
Loi S. Ann Oncol. 2014;25:1544-1550.

Disclosure: The researchers report no relevant financial disclosures.