Immune Cell Levels in Tumor May Predict Trastuzumab Response

The number of tumor-infiltrating lymphocytes (TILs) detected in early-stage HER2-positive tumors may predict a better response to treatment with trastuzumab and chemotherapy, according to a confirmation study presented at the 2013 San Antonio Breast Cancer Symposium (SABCS).

Every 10% increase in the number of TILs was associated with a 16% increase in the pathologic complete response (pCR) rate (adjusted odds ratio [OR] = 1.14; P = .037) following trastuzumab plus neoadjuvant chemotherapy treatment. Combining trastuzumab with one of several T-cell checkpoint inhibitor antibodies in mouse models resulted in enhanced tumor responses.

“This was independent and statistically significant data and confirmed our previous observation, reinforcing that there is a relationship between the immune system and responses to trastuzumab,” said Sherene Loi, MD, of the Peter MacCallum Cancer Centre in Melbourne, during a press briefing.

Previous results from the adjuvant phase III FinHer clinical trial showed that the number of TILs within the patient’s tumor was predictive of benefit. The trial randomized women post-surgery to either chemotherapy alone or chemotherapy combined with trastuzumab for 9 weeks. Results from this trial were presented at the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting.

The new results presented at SABCS from a neoadjuvant trial confirm these initial findings. Loi and colleagues used data from 156 early-stage HER2-positive breast cancer patients who took part in the GeparQuattro neoadjuvant trial.

The GeparQuattro trial showed that women who received the combination therapy were more likely to have a pCR (no residual invasive cancer detected in the breast and lymph nodes).

Analysis of the TIL composition of patients from the FinHer trial suggests that trastuzumab may be modulating the immune microenvironment of the tumor, including relieving the tumor’s immunosuppression activity.

“The data suggest that trastuzumab is somehow managing to change the balance of this tumor environment and make it more favorable for the immune system,” said Loi.

TILs from 202 patients in the FinHer trial were analyzed for 13 prespecified immune biomarkers. The markers included T-cell checkpoint receptors and ligands (PD-L1, PD-1, CTLA-4, CD80), immunosuppression markers (VEGF, FOXP3, IDO1), and T- and B-cell infiltration markers (CD3D, IGKC), among others. The authors found that expression of PD-1 and IDO1 were significantly associated with better distant-disease–free survival from trastuzumab therapy (PD-1, P = .029; IDO1, P = .039).

Breast cancer has not been considered an immunogenic cancer, especially when compared with other solid tumor types, such as melanoma and kidney cancer.

To further study whether boosting T-cell responses is synergistic with trastuzumab therapy, the authors combined trastuzumab with several checkpoint-modulating antibodies in transplant mouse models with HER2-positive mammary cancer. Trastuzumab, when combined with anti–PD-1 (P = .02) or with anti–PD-L1 (P = .008), resulted in higher tumor regression compared with treatment with trastuzumab alone. Experiments with a mouse transgenic model showed the combination of trastuzumab with an anti–PD-1 antibody significantly delayed the formation of mammary gland tumors (P < .001).

“This provides a proof of principle in the preclinical setting to warrant evaluation in the clinic,” said Loi during the press briefing. “These data suggest that trastuzumab not only acts on the tumor directly but also helps antitumor immunity.”

Further validation of these results is still needed before any application in the clinic. Researchers don’t yet understand why some breast cancer patients have higher baseline TILs within their breast tumor compared with others. This is an active area of research-to understand the differences among patients and to find ways to boost patients’ immune responses to their tumors.

The study was funded by the European Union Seventh Framework Programme RESPONSIFY project and the Breast Cancer Research Foundation.