High Levels of Infiltrating Lymphocytes May Identify Better Response to Trastuzumab

Photo Courtesy © SABCS/Todd Buchanan 2013

Sherene Loi, MD, PhD

New evidence suggests that HER2-positive breast cancer may not only be immunogenic, but also that trastuzumab may relieve suppression of antitumor immunity.

Some HER2-positive breast cancers exhibit high levels of tumor infiltrating lymphocytes (TILs), and women with breast tumors and a high number of TILs have better outcomes with trastuzumab, according to Sherene Loi, MD, PhD, at the 2013 San Antonio Breast Cancer Symposium.

Loi, a medical oncologist and head of the Translational Breast Cancer Genomics Lab at the Peter MacCallum Cancer Centre in Melbourne, Australia, and a group of investigators researched cohorts from two clinical trials of adjuvant trastuzumab in the setting of HER2-positive breast cancer to: 1) assess the association between TILs at diagnosis and the response to trastuzumab and 2) understand the composition of immune infiltrates and how trastuzumab may mediate immune effects.

Loi and colleagues had previously shown a significant association between the presence of TILs and trastuzumab benefit, and were first looking to confirm this association.

In an effort to assess the association between TILs and pathologic complete response (pCR), breast tumor samples from 156 patients with operable or locally advanced HER2-positive breast cancer who were enrolled in the GeparQuattro trial were evaluated for lymphocyte infiltration. GeparQuattro was a single-arm prospective study of women with HER2-positive breast cancers treated with neoadjuvant trastuzumab and chemotherapy.

“We confirmed that high levels of lymphocytic infiltration, as a continuous variable, were significantly associated with higher rates of pathologic complete remission,” Loi said. For every 10% increase in the levels of TILs, there was a 16% increase in the number of patients who experienced pCR.

“This confirmed to us that there was a relationship between the immune system and responses to trastuzumab,” said Loi. These investigators then used data from the FinHER study to decipher how trastuzumab modulates the immune tumor microenvironment. The FinHER study involved 13,000 patients randomized to receive trastuzumab or no trastuzumab. Investigators extracted RNA for gene-expression analysis of selected immune genes, selecting 13 immune genes for further evaluation. These 13 genes were then divided into those genes believed to be involved in anti-tumor immunity and those genes thought to be involved in tumor progression, Loi explained.

They found significant correlations between the level of TILs and immune activation, “which supports that pre-existing lymphocytic infiltration at diagnosis represents antitumor immunity,” she said. “However, this immunity is being suppressed, and a number of effectors seem to be doing this.”

Especially high expression of PD-1 was found in tumors, suggesting that it is actually a part of the HER2 microenvironment, according to Loi.

Loi and colleagues also found an association between higher levels of the immunosuppressive genes PD-1 and CTLA-4 and benefit from trastuzumab, which suggests that trastuzumab relieves tumor-mediated immunosuppression.

In a mouse model of HER2-positive breast cancer, the investigators then found that combining trastuzumab with a T-cell checkpoint inhibitor resulted in greater tumor regression compared with trastuzumab alone. These data provide the rationale to evaluate if a T-cell checkpoint inhibitor added to trastuzumab can further improve clinical outcomes in HER2-positive disease.

“Whilst further validation is needed, these data suggest that trastuzumab acts not only directly on the tumor, but may help antitumor immunity,” said Loi, who said that it’s too early for clinicians to be measuring lymphocyte infiltration in HER2-positive breast tumors.

“Why some patients have TILs in their breast tumor at diagnosis and others do not is not currently known,” she said.

Loi S, Michiels S, Salgado R, et al. Tumor infiltrating lymphocytes (TILs) indicate trastuzumab benefit in early-stage HER2-positive breast cancer (HER2+ BC). The 2013 San Antonio Breast Cancer Symposium, December 10—14, 2013. Publication Number: S1-05.

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