Could Cytotoxic TILs Guide Treatment in Metastatic HER2+ Breast Cancer?

Low levels of cytotoxic stromal tumor-infiltrating lymphocytes (sTILs) are predictive of benefit derived from antibody- vs small molecule–based drug approaches to HER2-positive metastatic breast cancer, according to a new study.

“The TIL count predicts a pathologic complete response to neoadjuvant chemotherapy, trastuzumab, and lapatinib,” wrote study authors led by Shuzhen Liu, MD, of the University of British Columbia in Vancouver. Research is lacking, however, in the metastatic setting, and overall TIL counts obscure the fact that different types of TIL imply different types of immune reactions.

The Canadian Cancer Trials Group MA.31 phase III trial included 652 patients (647 treated) from 21 countries with HER2-positive metastatic breast cancer; they were randomized to receive either trastuzumab or lapatinib, in combination with a taxane. Tumor tissue collected for primary diagnosis was used to asses TIL expression. The results were published online ahead of print in JAMA Oncology.

Of 614 assessable patients, 215 (35%) had sTIL counts above 5%, which was considered “high,” though this did not prove to have prognostic value.

A univariate analysis found that patients with low numbers of CD8⁺ cytotoxic sTILs who were treated with lapatinib had a higher risk of disease progression as compared with those treated with trastuzumab, with a hazard ratio of 2.94 (95% CI, 1.40–6.17; P = .003). Those with high numbers of CD8⁺ sTILs saw less of this effect, with an HR of 1.36 (95% CI, 1.05–1.75; P = .02). A multivariate analysis confirmed “that having low levels of CD8⁺ sTILs in the original biopsy specimen predicts inferior response to lapatinib relative to trastuzumab in the metastatic setting,” the authors wrote. In other words, though trastuzumab offered superior outcomes in all groups, the degree to which lapatinib was inferior was greatest in those women who had low levels of CD8⁺ cells.

A similar trend was seen for overall survival, but this did not maintain significance on a multivariate analysis. No other assessed biomarkers showed an association with outcome.

Lapatinib’s indications in breast cancer are now limited due to trials showing inferior survival outcomes and higher rates of toxic effects than the newer anti-HER2 agents, but the authors noted that small molecule-based drugs have some advantages including oral delivery and lower production costs. “Our findings suggest that investigating whether low pre-existing immune infiltrate levels identify a group of patients better treated with antibody-based therapies may be worthwhile, not only for breast cancer but also for other types of cancer,” the investigators concluded.