Abstract: Breast cancer is the most common type of cancer affecting women in the United States. Triple-negative breast cancer remains the most aggressive molecular subtype secondary to a lack of therapeutic targets. The search for a target has led us to investigate immunotherapeutic agents. Immunotherapy has recently demonstrated significant breakthroughs in various types of cancers that are refractory to traditional therapies including melanoma and Non-Small Cell Lung Cancer (NSCLC). Breast cancer however remains one of the tumors that was initially least investigated because of being considered to have a low immunogenic potential and a low mutational load. Over the past few years, antiPD1/PDL1 drugs have started to make progress in the triple-negative subtype with more promising outcomes. In this report, we review the treatment of triple-negative breast cancer and specifically shed light on advances in immunotherapy and newly approved drugs in this challenging disease.


Keywords: breast cancer, immunotherapy, PD1, PDL1, atezolizumab


Background


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Breast cancer is the most common cancer diagnosed in women, representing 15.3% of all new cancer cases in the United States.1 The rate of new breast cancer diagnoses has remained relatively stable over the last 10 years, and mortality rates have decreased since 2006.1 Prognosis for those with a breast cancer diagnosis is encouraging, with a 5-year survival rate of 89.7%.1 However, not all subtypes of breast cancer have made significant therapeutic advances. Triple-negative breast cancer (TNBC) applies to breast cancers that are low in expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).2–4 TNBC accounts for approximately 10–15% of all breast cancers diagnosed and is associated with a worse prognosis than ER-positive, PR-positive, or HER2-positive breast cancers.5–9 In a study of over 50,000 women with breast cancer, 5-year survival was found to be 77% in TNBC compared to 93% for other breast cancer subtypes.5,10 Additionally, in a 2012 study of over 12,000 women, patients with TNBC experienced worse breast cancer-specific survival (hazard ratio 2.88, 95% CI 2.59–3.45) and worse overall survival (hazard ratio 2.72, 95% CI 2.39–3.10).9 The poorer prognosis in TNBC is explained by early recurrence rates of 10–15% per year for the first several years after initial surgery, compared to 3–5% per year in ER-positive and PR-positive breast cancer, which can recur decades after diagnosis.5,6 Despite remarkable progress with multiple novel agents targeting HER2 or ER, treatment options in TNBC have been limited to cytotoxic chemotherapy as the mainstay of systemic therapy, and few options have been available over the past 20 years (Figure 1).5,11,12

The search for therapeutic targets in this challenging disease has led us first to PARP inhibitors. The advent of PARP inhibition in the BRCA1/2 mutation carriers has recently brought some progress into treating this small subpopulation of triple-negative breast cancer. The EMBRACA study which randomized to talazoparib (a parp inhibitor) vs physician choice of standard therapy (capecitabine, eribulin, gemcitabine, or vinorelbine) in patients with locally advanced or metastatic breast cancer with a germline BRCA1/2 mutation revealed significantly longer progression-free survival (PFS) of 8.6 months with talazoparib versus 5.6 months with physician’s choice (HR 0.54, 95% CI 0.41–0.71, p<0.001).13 Median overall survival at the interim analysis was also statistically significant, 22.3 months in the talazoparib group versus 19.5 months in the standard therapy group (HR 0.76, CI 0.55–1.06), p=0.11). Remarkably, there was also a total of 5.5% of patients in the talazoparib group that had a complete response (CR) compared with no patients in the standard therapy group. More importantly, the safety profile of talazoparib was better tolerated compared to standard chemotherapy, which was supported by the patient-reported quality-of-life outcomes. The OLYMPIAD study which randomized olaparib (another parp inhibitor) to physician’s choice of standard therapy (capecitabine, eribulin, or vinorelbine) also revealed significantly improved efficacy and safety profiles of the PARP inhibitor compared to standard chemotherapy in patients with metastatic breast cancer and a germline BRCA mutation.14 The PFS was significantly longer in the olaparib group compared to the standard therapy group (7.0 months vs 4.2 months; HR 0.58; 95% CI 0.43–0.80; p<0.001). Additionally, olaparib was better tolerated compared to standard chemotherapy. Rates of grade 3 adverse events were lower in the olaparib group compared to the standard therapy group (36.6% vs 50.5%, respectively). Although PARP inhibitors appear to be a promising therapeutic target, only approximately 5% of patients with breast cancer carry a germline BRCA mutation, and even fewer patients with triple-negative breast cancer carry the mutation. Therefore, this does not address most triple-negative breast cancer patients who are actually non-BRCA carriers.

The first proposition that the immune system and cancer are associated was in the 19th century, based on the frequent appearance of tumors at sites of chronic inflammation and the presence of immune cells in tumor tissues.15,16 The use of immune therapy and specifically checkpoint inhibition made a first impression initially in lung cancer and melanoma. Several immunotherapy treatments have been heavily utilized in melanoma with promising outcomes such as interferon (INF) a-2b, peginterferon a-2b, interleukin-2 (IL-2), as well as checkpoint inhibition.15 In 2010, a trial with ipilimumab, a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor was conducted and was the first treatment to show improvement in overall survival in patients with metastatic melanoma.17 Following, this landmark and groundbreaking trial, several trials in melanoma with combination immunotherapies, nivolumab and ipilimumab were conducted as well as single-agent nivolumab, and single-agent pembrolizumab.18–25 In lung cancer, several checkpoint inhibitors have been approved in those with PD-L1 expression, which is defined as PD-L1 levels of at least 50%.26 The PD-1 inhibitors used to treat metastatic non-small cell lung cancer (NSCLC) are nivolumab and pembrolizumab, and the PD-L1 inhibitors are atezolizumab and durvalumab. Additionally, in NSCLC, combination chemotherapy, immunotherapy, and targeted therapy have been studied and obtained FDA approval.26–35

Although immunotherapy has been successfully studied in melanoma and lung cancers, when checkpoint inhibitors were tested as monotherapy in breast cancer patients, those studies were not very promising. Early studies with Phase 1, 2 clinical trials evaluating PD1 protein blockade in advanced triple-negative were very disappointing. Response rates were less than 10%.36–41 Those studies proved that breast cancer is not a highly immunogenic disease and patients with breast cancer need to be selected for a preexisting predisposition to mount an immune response. This highlighted the importance of the host as well as the tumor in selecting the best treatment approach. In October 2018, the IMPASSION 130 study led to the approval of Atezolizumab in a preselected population with advanced triple-negative breast cancer.42 This approval was the first meaningful step in moving immunotherapy into the breast cancer arena. Since then, multiple efforts have been generated to advance immunotherapeutic agents in triple-negative breast cancer. In this report, we will review the main advances and shed light on the emerging data in this exciting field.

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