SAN ANTONIO – Tumor-infiltrating lymphocyte levels at breast cancer diagnosis predict response to therapies for both HER2-positive and triple-negative breast cancers, according to studies presented at the San Antonio Breast Cancer Symposium.

Tumor-infiltrating lymphocytes (TILs) appeared to be a useful biomarker of response to trastuzumab (Herceptin) as well as to chemotherapy. By extension, breast cancers appear to be immunogenic, contrary to traditional thinking. Trastuzumab and chemotherapy appear to act not only on the tumor, but to enhance antitumor immunity as well.

The findings could result in a paradigm shift in treatment approaches. Clinical outcomes could potentially be improved in women with HER2-positive or triple-negative breast cancers by targeting the immune system with immunomodulatory agents in addition to providing standard therapies, according to Dr. Sherene Loi, a medical oncologist and head of the translational breast cancer genomics laboratory at the Peter MacCallum Cancer Center in Melbourne.

Dr. Loi presented an analysis of breast cancer samples from 156 women with operable or locally advanced HER2-positive breast cancer who participated in the previously reported GeparQuattro trial. All of the women received neoadjuvant trastuzumab and cytotoxic chemotherapy. In a multivariate analysis, for every 10% increase in the level of stromal TILs there was a 16% increase in the pathologic complete response rate, meaning no residual invasive cancer in the breast or lymph nodes at surgery.

"These data reinforced for us that there is a relationship between the immune system and responses to trastuzumab and chemotherapy," she said.

In another study presented at the meeting, Dr. Sylvia Adams demonstrated the prognostic value of TILs in patients with triple-negative breast cancer. Tumors were analyzed from 481 participants in Eastern Cooperative Oncology Group 2197 and 1199, two previously reported phase III randomized, prospective trials of adjuvant chemotherapy in triple-negative breast cancer.

At least 10% lymphocytic infiltration in the tumor stroma was seen in 80% of tumors, meaning that 10% or more of all cells in the stroma were TILs. For each 10% increment in stromal TILs at the time of breast cancer diagnosis, there was an 18% reduction in the risk of distant recurrence and a "very impressive" 19% reduction in the risk of mortality at a median followup of 10.6 years, reported Dr. Adams of New York University.

She noted that this new analysis confirms an earlier study led by Dr. Loi, the prospective, randomized BIG 02-98 trial. In that study, TILs were associated with improved prognosis in patients with operable triple-negative breast cancer. The new validation study, Dr. Adams noted, raises to Level I the evidence that supports measuring stromal TILs as a biomarker in triple-negative breast cancer.

"The data provide strong evidence for the incorporation of this feature into the AJCC (American Joint Committee on Cancer) staging for triple-negative breast cancer and for utilization of stromal TILs as a stratifier in clinical trials," Dr. Adams said. "And most important, I would like to say – because some may ask ‘Is this just another prognostic factor for breast cancer?’ – is that these data really help provide additional evidence that some breast cancers can be immunogenic and that the endogenous immune response to cancer is predictive of survival in triple-negative breast cancer. So this actually opens up the area for introducing immunotherapies in triple-negative breast cancer. There is a hope that by targeting and harnessing the immune system we can improve cure rates."

Dr. Loi provided a glimpse into the possible way forward. In an effort to learn how trastuzumab affects antitumor immunity, she and her colleagues performed gene expression analyses on HER2-positive breast tumor specimens from 202 participants in the phase III randomized FinHER clinical trial of adjuvant trastuzumab or no trastuzumab along with postoperative chemotherapy. The greatest clinical response to trastuzumab was seen in patients whose tumors highly expressed the immunosuppressive gene known as programmed cell death 1 (PD-1).

This led to studies conducted in a mouse model of HER2-positive breast cancer. Dr. Loi and her colleagues showed that combining trastuzumab with a T-cell checkpoint inhibitor – an anti-PD-1 agent resulted in greater reductions in tumor size than with trastuzumab alone.

More than half a dozen T-cell checkpoint inhibitors are in the developmental pipeline for treatment of a range of malignancies, including the anti-PD-1 agents nivolumab, lambrolizumab, and pidilizumab. Clinical trials testing the combination of trastuzumab and a PD-1 inhibitor in HER2-positive breast cancer patients are being planned.

Dr. Loi’s work was funded by the European Union RESPONSIFY project, the Breast Cancer Research Foundation, and the Fonds J.C. Heuson. She and Dr. Adams reported having no relevant financial conflicts of interest.

bjancin@frontlinemedcom.com

Findings set stage for immunomodulatory approaches in breast cancer