Immune Targeting in Breast Cancer: In Whom and With What?

In this issue of ONCOLOGY, Cimino-Mathews and colleagues present a timely review on immune targeting in breast cancer.[1] Unlike other solid tumor types, such as melanoma, breast cancer has not traditionally been thought of as amenable to immune approaches. However, an increasing volume of correlative biomarker research and preclinical studies, as described in the review, support the concept that the immune microenvironment can be favorably altered in breast cancer in order to improve outcomes. The critical issue facing us now is figuring out which specific immunotherapies and combinations will be the most effective in breast cancer and in whom they will have the biggest effect. Tumor-infiltrating lymphocytes (TILs) have been reported to be positively associated with improved survival, but only in the triple-negative and human epidermal growth factor receptor 2 (HER2)-positive breast cancer subtypes and in early-stage disease.[2-5] This suggests that these breast cancer subtypes may be the groups to target; however, it is not clear why these subtypes present with higher levels of TILs.

High mutational burden, as observed in melanoma and non–small-cell lung cancer, has thus far also been associated with the best responses to T-cell checkpoint inhibitors. This could be due to the likelihood that some mutant peptides can present to major histocompatibility complex (MHC) class I molecules and can activate an antitumor immune response.[6] It is thought that this preexisting immune response is either exhausted or suppressed but can be reactivated by the T-cell checkpoint inhibitors. In general, breast cancer does not have the magnitude of mutational burden seen in other tumor types, although it is usually higher in the triple-negative and HER2-positive groups, as compared with the luminal breast cancers. Therefore, it is likely that only a minority of breast cancer patients will have enough robust preexisting immunity that can be “reactivated.” Indeed, the population that has high levels of TILs (≥ 50%) is small (< 10%), unlike the “programmed cell death ligand 1 (PD-L1)–strong” populations seen in lung and head and neck cancers, which comprised > 20% of the cohorts that had significantly higher objective response rates.[7,8]

As discussed in the review, while early efficacy data on agents targeting the programmed death 1 (PD-1)/PD-L1 axis look promising in advanced triple-negative breast cancer, at this stage the total number of breast cancer patients who have received T-cell checkpoint inhibitors is low compared with other solid tumor types. What is encouraging is that in the small number of patients who did respond, the responses seemed to be durable.[9] There is still much to learn about the immune microenvironment in breast cancer. Why do some patients with breast cancer have TILs while others do not? What is the landscape of T-cell checkpoints in breast cancer patients with TILs? Characterization of the landscape of T-cell–negative regulators in breast cancer may help us design rational future combination studies.

Patients with TILs in their tumor at diagnosis have greater sensitivity to chemotherapy, as evidenced by increased pathologic complete response rates.[10,11] While the exact mechanism is unclear, this suggests that traditional cytotoxic chemotherapy can be immune-enhancing, rather than being immunosuppressive, as was conventionally believed. Preclinical data also support this hypothesis, particularly with regard to agents such as anthracyclines, oxaliplatin, and cisplatin.[12] This implies that cytotoxic chemotherapy can also stimulate immune effects and/or relieve immunosuppression. Hence, it is plausible that future immunotherapeutic strategies in breast cancer are likely to involve combinations, since we already have very effective treatments for breast cancer (eg, trastuzumab, doxorubicin) that are likely to be immune-promoting and have effects that could be enhanced with specific immunotherapy combinations.

The future role of immunotherapy in breast cancer is currently being actively investigated. T-cell checkpoint inhibitors are in phase II/III studies; combinations of T-cell checkpoint inhibitors, adoptive T-cell therapy, and vaccines are also under study by numerous groups. Let us hope that these trials make the effort to collect the necessary correlative biological materials. Performing “immune profiling” of the tumor, including exome-guided neoantigen determination, evaluation of TILs[13] and PD-L1 protein assessment, as well as immune profiling of the peripheral blood, will help us understand the differences between responders and nonresponders. It is likely that these studies will enroll patients rapidly, so we anticipate that we will soon have further clues about the role of immunotherapy in breast cancer patients.

Financial Disclosure:Dr. Loi receives research funding from Roche-Genentech and Merck.

References:

1. Cimino-Mathews A, Foote JB, Emens LA. Immune targeting in breast cancer. Oncology (Williston Park). 2015;29:375-85.

2. Adams S, Gray RJ, Demaria S, et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol. 2014;32:2959-66.

3. Loi S, Michiels S, Salgado R, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol. 2014;25:1544-50.

4. Loi S, Sirtaine N, Piette F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013;31:860-7.

5. Salgado R, Denkert C, Campbell C, et al. Tumor infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early breast cancer treated with lapatinib and trastuzumab (NeoALTTO). JAMA Oncol. 2015; in press.

6. Rooney MS, Shukla SA, Wu CJ, et al. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015;160:48-61.

7. Chow L, Burtness B, Weiss J, et al. A phase Ib study of pembrolizumab (Pembro; MK-3475) in patients (pts) with human papillomavirus (HPV)-positive and negative head and neck cancer (HNC). Presented at the European Society for Medical Oncology (ESMO) 2014 Congress; Sep 26-30, 2014; Madrid, Spain. Abstr LBA31.

8. Garon EB, Gandhi L, Rizvi N, et al. Antitumor activity of pembrolizumab (Pembro; MK-3475) and correlation with programmed death ligand 1 (PD-L1) expression in a pooled analysis of patients (pts) with advanced non-small cell lung carcinoma (NSCLC). Presented at the European Society for Medical Oncology (ESMO) 2014 Congress; Sep 26-30, 2014; Madrid, Spain. LBA43.

9. Nanda R, Chow LQ, Dees EC, et al. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer. San Antonio Breast Cancer Symposium. Dec 9-13, 2014. San Antonio, TX. Abstr S1-09.

10. Denkert C, Loibl S, Noske A, et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010;28:105-13.

11. Denkert C, von Minckwitz G, Brase JC, et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J Clin Oncol. 2015;33:983-91.

12. Apetoh L, Ghiringhelli F, Tesniere A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007;13:1050-9.

13. Salgado R, Denkert C, Demaria S, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26:259-71.