Elsevier

Pharmacology & Therapeutics

Volume 156, December 2015, Pages 90-101
Pharmacology & Therapeutics

Associate Editor: B. Teicher
Immunotherapeutic options on the horizon in breast cancer treatment

https://doi.org/10.1016/j.pharmthera.2015.09.003Get rights and content

Abstract

It is increasingly acknowledged that breast cancer can be an immunogenic disease. Immunogenicity appears to differ between subtypes. For instance, in triple negative breast cancer (TNBC) and HER2-positive breast cancer tumor infiltrating lymphocytes (TILs) are prognostic and predictive for response to chemotherapy containing anthracyclines, but in other subtypes they are not. Preclinical evidence suggests important immune based mechanisms of conventional chemotherapeutics, in particular anthracyclines. Early clinical studies with monoclonal antibodies targeting programmed death protein 1, programmed death-ligand 1 and cytotoxic T-lymphocyte-associated antigen 4 have shown anti-tumor efficacy. Tumor vaccines designed to increase the body's own anti-tumor immunity have shown an increased anti-tumor immunity, however clinical efficacy has not yet been demonstrated. Novel strategies will likely follow. In light of the increased interest in immune modulation, this review focuses on predictive immune-based biomarkers, immune-mediated effects from conventional therapies, as well as recent results and ongoing studies concerning immunotherapies in breast cancer.

Introduction

Breast cancer is the most common cancer in women and represents a major public health issue with 1.38 million cases and 458,000 deaths yearly worldwide (Bray et al., 2012). Although there have been clear advances in the treatment of metastatic breast cancer patients, most patients still die of their disease (Jemal et al., 2010). Drug choices are based on tumor characteristics. Breast cancer biology is essentially dictated by the estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), and proliferation. Therefore ER and HER2 targeting compounds, and chemotherapy are the cornerstones of today's treatment (Paik, 2011). For all these systemic treatment strategies eventually resistance will develop requiring new treatment consideration (Osborne & Schiff, 2011). Furthermore, targeted agents for triple negative breast cancer (TNBC), defined by the absence of ER, progesterone receptor (PR) and HER2 expression, are lacking in standard practice. This subtype is still notoriously difficult to treat, and maintains a poor prognostic outcome. Therefore, despite advances in this field, additional strategies are needed. A focus on potential tumor targets outside the breast cancer cell, are clearly of interest. In this respect, the potential exploitation of the immune system for anti-cancer effect, is rapidly gaining interest.

Cancer immunotherapies, including treatments aiming to stimulate immune cells to attack tumors, have undergone enormous developments recently. They were announced “Breakthrough of the Year 2013” by the editors of Science (Couzin-Frankel, 2013). In this era, certain cancer types, such as metastatic melanoma, may even become curable in selected patients. The initial enthusiasm for immune checkpoint inhibitors is mainly based on results obtained in melanoma, lung cancer, bladder cancer and renal cell carcinoma (Ascierto, 2013). But also in breast cancer, preliminary data from the first clinical studies is encouraging. Interestingly, conventional breast cancer treatments, including some chemotherapy regimens and the anti-HER2 targeting antibody trastuzumab, derive part of their effect from interacting with the immune system. The role of tumor infiltrating lymphocytes (TILs) in treatment response is increasingly recognized. Improved insight in the connection between the immune system and breast cancer may support optimal treatment and outcome.

The present review focuses on predictive immune-based biomarkers, immune-mediated effects from conventional therapies, as well as recent results and ongoing studies concerning immunotherapies in breast cancer.

Section snippets

Search strategy

An English language literature search was conducted during the period of September 2014 until June 2015, which included PubMed and the ClinicalTrials.gov database. Abstracts of the American Society of Clinical Oncology (ASCO) annual meetings, San Antonio Breast Cancer symposium, American Association of Cancer Research (AACR) annual meeting and the annual congresses of the European Society of Medical Oncology (ESMO) were checked. The search strategy focused on all immunotherapies in a breast

Tumor immunity and breast cancer subtypes

The interaction of the immune system with tumor cells in breast cancer appears to be breast cancer subtype specific (Fig. 1). TNBC and HER2-positive breast cancer harbor higher genomic instability compared to the St. Gallen defined luminal A and B subtypes, leading to increased DNA damage or mutational load (Hu et al., 2009, Goldhirsch et al., 2013, Marcus et al., 2014). Emerging evidence indicates that a higher mutational load causes production of higher tumor-specific antigen levels and can

Biomarkers

Infiltration of lymphocytes has prognostic and predictive value in the TNBC and HER2-positive subtypes, contrary to the luminal subtypes. In the BIG 02-98 trial 2009 lymph node positive breast cancer patients were treated with anthracycline containing adjuvant chemotherapy. Stromal TILs (sTILs), defined as the percentage of tumor stroma containing lymphocytic infiltrate, were only related to outcome in the 256 TNBC patients (Loi et al., 2013). For every 10% increment in the number of sTILs in

Immunologic aspects of chemotherapy

It is increasingly recognized that chemotherapeutic agents can elicit immune responses and that a functional immune system can even be crucial for their efficacy (Table 1), for an extensive review see (Galluzzi et al., 2012, Bracci et al., 2014). Preclinical data suggests that anthracyclines have important immune mediated antitumor mechanisms (Loi, 2013). For example in mice inoculated with syngeneic tumor cell lines efficacy of doxorubicin was partly dependent on increased proliferation of

Immune checkpoint blockade

Ipilimumab, a monoclonal antibody blocking CTLA-4 is already part of standard of care in the treatment of metastatic melanoma (Robert et al., 2011). CTLA-4 inhibits the cytotoxic effects of CTLs. Increased expression of CTLA-4 on T cells in breast cancer patients might explain the evasion of anti-tumor immune responses (Mao et al., 2010). In mice mammary cancer models CTLA-4 inhibition stimulates T cell proliferation (Fig. 2) (Walunas et al., 1994, Walunas et al., 1996; Sansom, 2000, Allard et

Future perspectives

At present, knowledge about the interaction between immunity, carcinogenesis and tumor biology is rapidly increasing. The predictive and prognostic value of TILs and immune-mediated effects of conventional chemotherapy underline the importance of the immune system for the current treatment of breast cancer. The first clinical data from new immune-mediated therapies in breast cancer are available and especially promising for TNBC and HER2-positive breast cancer, possibly due to higher

Conflict of interest statement

EGE de Vries has research grants from Roche/Genentech, Amgen, Novartis, Pieris and Servier to the institute, is member data monitoring committee Biomarin, and participated in advisory board Synthon. The other authors declare that there are no conflicts of interest.

Role of the funding source

The funding agency had no role in design, analyses, decision to publish, or preparation of the manuscript.

Acknowledgments

This work was supported by the European Research Council (ERC) Advanced Investigator Grant 2011: OnQview and the Dutch Cancer Society Grant RUG 2010–4739: Molecular imaging to guide targeting the breast cancer microenvironment.

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