Checkpoint inhibitors in breast cancer: hype or promise?

HM The concept of immunotherapy is not a new one. In fact, back in the 1890s, a surgeon named William Coley noticed that some patients with cancer had spontaneous tumor regressions after a severe infection. After identifying the relationship between infection-related inflammation and tumor regression, Coley undertook experiments whereby he injected patients and their tumors with bacteria—and later, bacterial fragments—in order to induce a systemic immune response as a cancer treatment strategy. For this reason, Coley is considered the forefather of modern immunotherapy. Unfortunately, interest in Coley’s work diminished—in part because of the growing enthusiasm for radiation therapy as a cancer treatment strategy in that era. This history makes it all the more interesting that more than 100 years later, we are actively exploring not only those early principles of induced immune responses as a mechanism for treating cancer, but also strategies that combine immune modulation with localized therapies, such as radiation. Strategies that improve tumorassociated antigen presentation (eg, radiation, cryoablation, or radiofrequency ablation) may be needed because some tumors—including most breast cancers—are not inherently sensitive to immune modulation. In recent years, we have seen tremendous therapeutic innovation in oncology stemming largely from the successful development of checkpoint blockade strategies. Once the immune system is activated, it is normally held in check by interactions between inhibitory receptors and their ligands. Checkpoint blockade antibodies target cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) or the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway, thereby removing inhibitory signals and permitting robust immune responses. If a tumor-specific immune response can be elicited and tumor-specific immune memory can be induced, these strategies may lead to durable antitumor responses—and potentially, cure. The first major success story with checkpoint blockade was in metastatic melanoma. Specifically, the addition of ipilimumab (Yervoy, Bristol-Myers Squibb), a fully human antibody to CTLA-4, to dacarbazine resulted in an unprecedented survival benefit in patients with advanced melanoma.1 Further strides have since been reported with the development of the PD-1–directed antibodies pembrolizumab (Keytruda, Merck) and nivolumab (Opdivo, Bristol-Myers Squibb), as well as combination strategies, such as ipilimumab plus nivolumab. In fact, these drugs have completely transformed the natural history of metastatic melanoma such that 1-year overall survival rates improved from approximately 35% a decade ago to approximately 95% with checkpoint inhibitor strategies.2-8 Given the tremendous successes observed in advanced melanoma, investigators were keen to determine whether responses to checkpoint blockade strategies could also be elicited in other solid tumors. Within the past 5 years, responses have been reported in many tumor types, including kidney cancer, colorectal cancer, and non–small cell lung cancer. Responses in breast cancer have been more recently reported. However, we are still in the early days of learning how to administer these drugs effectively in breast cancer, and it has yet to be determined whether different strategies are required to effectively treat different breast cancer subtypes, whether predictable biomarkers of response can be identified, and whether these strategies need to be tailored to specific clinical scenarios. BREAST CANCER IN FOCUS