Sherene Loi, MD PhD, Head of the Translational Breast Cancer Genomics Lab at the Peter McCallum Cancer Centre, Victoria, Australia, commented on the N9831 study presentation and referred to her group’s own work on tumor-infiltrating lymphocytes. These investigators have shown a positive association between the presence of tumor-infiltrating lymphocytes in the tumor at baseline and response to adjuvant trastuzumab (Herceptin) in the FinHER trial.¹ They also found tumor-infiltrating lymphocytes to be related to pathologic complete response to trastuzu­mab in the GeparQuattro study.²

“There is increasing evidence that immunity is important in certain subtypes of breast cancer, particularly HER2-positive and triple-negative disease,” she said in her discussion.

“Dr. Perez’s group used a large randomized landmark trial showing the benefit of adjuvant trastuzumab, sequentially or concurrently with chemotherapy. Randomization allows us to discern predictive effects,” she said. “The study needs further validation, but now we have two biomarker studies from randomized clinical trials [FinHER and N9831] supporting the concept that immunity is important for trastuzumab efficacy.”

Unanswered Questions

Questions include how to bring this approach into the clinical setting, and what are the implications for biomarkers and therapeutic drug development? Importantly, which immune biomarker will be most important in breast cancer?

“Can we just use [tumor-infiltrating lymphocytes] or do we need the immune gene signature? I think we don’t know yet. Ultimately, clinical utility will define the biomarker,” she predicted.

A biomarker will likely not be used to select patients for trastuzumab, she pointed out, as all HER2-positive patients warrant treatment. But it may be useful in determining which patients can limit treatment to trastuzumab alone, and who requires dual anti-HER2 treatment. If HER2 signaling is found to promote immunosuppression, perhaps dual blockade will most help patients without lymphocytic infiltration, she said.

“The most tantalizing possibility is that we could select patients more suitable for immune modulation,” she said, referring to the anti–PD-1/PD-L1/CTLA-4 inhibitors. The global phase Ib/II PANACEA trial of the anti–PD-1 monoclonal antibody pembrolizumab (MK-3475) in advanced trastuzumab-resistant HER2-positive patients with confirmed PD-L1 expression will try to answer this question. The trial, which Dr. Loi heads up, starts this summer. ■

Disclosure: Dr. Loi reported no potential conflicts of interest.

References

1. Loi S, et al: Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer. Ann Oncol. April 29, 2014 (early release online).

2. Loi S, et al: Tumor infiltrating lymphocytes indicate trastuzumab benefit in early-stage HER2-positive breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S1-05. Presented December 11, 2013.