Tumor-Infiltrating Lymphocytes Predict Trastuzumab Response

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SAN ANTONIOAmong women newly diagnosed with HER2-positive breast cancer, higher levels of tumor-infiltrating lymphocytes (TILs) are significantly associated with higher clinical benefit to trastuzumab plus chemotherapy, a study concluded at the 2013 San Antonio Breast Cancer Symposium.

“Furthermore, tumor-mediated immunosuppression is evident in the lymphocytic infiltrate,” with the T-cell checkpoint receptor PD-1 and the immunosuppressive marker IDO1 “significantly predictive of trastuzumab benefit,” said Sherene Loi, MD, PhD, of the Translational Breast Cancer Genomics Lab at the Peter MacCallum Cancer Centre in Melbourne, Australia.

Levels of TILs may, therefore, “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,” she added.

Previously, using samples from patients enrolled in the randomized, adjuvant phase 3 FinHER study, high levels of TILs have been shown to be predictive of response to trastuzumab and chemotherapy administered after surgery for early-stage, HER2-positive breast cancer.Dr. Sherene Loi

The objectives of the current study were to confirm the positive association between immune infiltrates and higher responses to trastuzumab and chemotherapy (epirubicin/cyclophosphamide with docetaxel with or without capecitabine) in primary HER2-positive breast cancers using samples from 156 patients enrolled in the GeparQuattro trial and, based on tumor samples from the FinHER trial, to understand the composition of immune infiltrates and how trastuzumab mediates immune effects.

Results from GeparQuattro showed that each 10% increment in TILs was associated with a 16% increase in the number of patients who had a pCR (adjusted odds ratio, 1.14; 95%CI: 1.01-1.29; P = 0.037), supporting the findings from the FinHER study, Dr. Loi said.

“These data indicate that a patient's immune system influences outcome and trastuzumab response,” said Dr. 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.”

In the FinHER study, patients with HER2-positive primary breast cancer were randomly assigned to trastuzumab or no trastuzumab with their postsurgery chemotherapy agents.

“To understand the composition of TILs, correlations between TILs and gene expression levels of 13 predefined immune markers were evaluated from 202 HER2-positive samples,” Dr. Loi said. These represented T- and B-cell infiltration (CD3D, IGKC), Th1 (IFNG, CD8A), chemoattractants (CXCL9, CXCL13), immunosuppression (VEGFA, FOXP3, IDO1) and T-cell checkpoint receptors and ligands (PD-1, PD-L1, CTLA-4, CD80).

Analysis found that trastuzumab modulates the immune microenvironment, most likely by relieving tumor-mediated immunosuppression through multiple immune-related factors, including PD-1. Gene expression analyses using the FinHER samples revealed IDO1 and CXCL13 were most highly correlated with TILs (R = 0.58 and 0.51; P < 0.001, respectively).

In a mouse transplant model of HER2-positive mammary cancer, trastuzumab in combination with several inhibitors of T-cell negative regulation (anti-CTLA4, anti-PD-1, and anti-PD-L1) was shown to result in higher tumor regressions compared with monotherapy, with anti-PD1 (P = 0.02) and anti-PD-L1 (P = 0.008) being the most effective.

In a BALB/c-MMTV-neu transgenic mice mouse model (ie, immune tolerant to HER2 antigen), the combination of trastuzumab and anti-PD1 antibody significantly delayed formation of mammary gland tumors (P < 0.001).

“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,” Dr. Loi concluded, adding that “these combinations warrant evaluation in the clinical setting.”

References

  1. Loi Set al. S1-05. Presented at: San Antonio Breast Cancer Symposium 2013. Dec. 10-14, 2013; San Antonio.

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