Tumor-infiltrating lymphocytes may be good biomarker of response to trastuzumab in breast cancer

Women with HER2-positive breast cancer who had the highest levels of immune cells in their tumors gained the most benefit from presurgery treatment with chemotherapy and trastuzumab, according to results presented here at the 2013 San Antonio Breast Cancer Symposium, held Dec. 10-14.

"We have previously shown that high levels of tumor-infiltrating lymphocytes [immune cells in a tumor] are predictive of response to trastuzumab and chemotherapy administered after surgery for early-stage, HER2-positive breast cancer using samples from patients enrolled on the randomized, adjuvant phase III clinical trial called the FinHER study," said Sherene Loi, M.D., Ph.D., medical oncologist and head of the Translational Breast Cancer Genomics Lab at the Peter MacCallum Cancer Centre in Melbourne, Australia. "Our new data further support the positive relationship between tumor-infiltrating lymphocytes and better outcomes with trastuzumab therapy, this time in a cohort of patients with newly diagnosed HER2-positive breast cancer who received the therapy before surgery.

"It seems, therefore, that levels of tumor-infiltrating lymphocytes may be a good biomarker of response to trastuzumab in primary breast cancer, something that researchers have been looking for with little success for some time," added Loi.

Loi and colleagues evaluated breast tumor samples from 156 patients with operable or locally advanced HER2-positive breast cancer enrolled in the GeparQuattro trial. All these participants received chemotherapy and trastuzumab prior to surgery as part of the trial, which showed that women who received the combination were more likely to have a pathologic complete response; that is, they were more likely to have no residual invasive cancer detectable in the breast tissue and lymph nodes removed during surgery.

Loi and colleagues found that for every 10 percent increase in the levels of tumor-infiltrating lymphocytes there was a 16 percent increase in the number of patients who had a pathologic complete response.

"These data indicate that a patient's immune system influences outcome and trastuzumab response," said Loi. "What we don't know is why some patients have tumor-infiltrating lymphocytes in their breast tumor at diagnosis and others do not. Currently, we are actively investigating this and trying to understand why there is a positive relationship between tumor-infiltrating lymphocytes and better outcomes with trastuzumab therapy."

To address the second point, the researchers analyzed breast tumor samples from patients enrolled in the FinHER study, in which patients with HER2-positive primary breast cancer were randomly assigned to trastuzumab or no trastuzumab with their postsurgery chemotherapy agents. Loi and colleagues found evidence that trastuzumab modulates the immune microenvironment, probably by relieving tumor-mediated immunosuppression through multiple immune-related factors, including one called PD-1.

They also found in a mouse model of HER2-positive breast cancer that combining trastuzumab with either an agent that blocks PD-1 or an agent that blocks a protein to which PD-1 binds, PD-L1, resulted in greater tumor regression compared with trastuzumab alone. "Thus, we suggest that adding an inhibitor that can block factors that suppress patient antitumor immune responses to trastuzumab therapy could potentially improve clinical outcomes," said Loi.