ONCAlert | Upfront Therapy for mRCC

Immune Checkpoint Blockade: A New Strategy for the Treatment of Breast Cancer

Antoinette R. Tan, MD, MHSc, FACP, and Sasha E. Stanton, MD, PhD
Published Online: Jul 13,2016


Breast cancer has traditionally not been viewed as immunogenic. There is now a growing body of evidence that immune infiltration has a prognostic role in all breast cancer subtypes, and predicts improved clinical outcome in triple-negative and human epidermal growth factor receptor 2-positive tumors. Immunotherapy is beginning to expand its role as a breast cancer therapeutic. Recent clinical trials of immune checkpoint inhibitors in metastatic breast cancer have shown promising anti-tumor activity. Ongoing studies will help define the role of immune-targeting drugs in the treatment of breast cancer. In this review, we describe the immune environment of breast cancer and summarize the recently reported clinical trial results of immune checkpoint inhibitors in breast cancer.


Breast cancer is a molecularly complex and heterogeneous disease that is comprised of biologically distinct subtypes. Important strides have been made during the last decade with the availability of several targeted agents for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer and for hormone receptor (HR)-positive breast cancer. A portion of patients benefit from such approaches, but resistance frequently develops, and novel treatment options are needed. An increased understanding of the breast tumor immune environment and the nature and role of tumor-infiltrating lymphocytes (TILs) has now led to several clinical investigations of immunotherapeutic approaches in breast cancer.

Infiltration of immune cells, particularly Type I immune cells that are needed to eliminate cancer, has predicted improved prognosis in many different tumor types including colon, ovarian, and lung cancer.1-3 The tumor immune environment was historically not thought to be as important in breast cancer because there was less immune infiltrate than in other tumor types such as melanoma.4 However, multiple lines of evidence have demonstrated that both the magnitude and composition of TILs in breast tumors are important for both response to therapy and improved prognosis.5-7 High TILs prior to therapy has been demonstrated to be a biomarker of good prognosis in multiple large adjuvant and neoadjuvant breast cancer clinical trials, particularly in the more aggressive triple-negative (TN) and HER2-positive subtypes.5,6,8,9 Understanding the baseline immune environment can lead to rational trial designs evaluating checkpoint inhibitor therapy and other combinations to benefit a wider subset of breast cancers.

The tumor immune environment is defined by the presence of cells from both the innate (including dendritic cells, macrophages, and neutrophils) and adaptive (B and T lymphocytes) immune system. The anti-tumor type 1 immunity develops through secretion of cytokines including tumor necrosis factor-alpha (TNF-a) and interferon gamma (IFNγ). The type 1 response is necessary for tumor elimination by triggering the tumor infiltrating antigen-presenting cells (APCs) to increase antigen presentation, releasing Type 1 CD4+ helper T cells (Th1) that improve CD8+ cytotoxic T-cell (CTL) function, and recruiting further type 1 immune response to the tumor.10 However, breast cancer tumors typically develop a type 2 anti-inflammatory response.11 The type 2 immune response promotes maintenance of proliferation signals, maintenance of angiogenesis, and decreased CD8+ T-cell function through release of cytokines including IL-10 and IL-4. Type 2 CD4+ helper T cells (Th2), including CD4+ T cells that express the marker Forkhead box P3 (FOXP3), are important in suppressing the function of CTL and maintaining a type 2 tumor immune environment.12,13 Therefore, in breast cancer, the type of immune response as well as the magnitude of immune response triggered is important in determining clinical outcome.

Lymphocyte Immune Infiltrate and Breast Cancer Prognosis

Increased lymphocytic infiltrate can be seen as early as benign ductal hyperplasia, increases in ductal carcinoma in situ, and is highest in invasive breast cancer.14 In patients with locally advanced breast cancer receiving neoadjuvant chemotherapy, tumors that have >50% lymphocytic infiltrate (lymphocyte predominant breast cancer or LPBC) are more likely to achieve a pathologic complete response (pCR) than patients with tumors with lower immune infiltrate. In a study of 1058 breast cancers, there was ~40% pCR in patients with LPBC tumors (odds ratio 1.38; 95% CI, 1.08-1.78; P=.012) while patients that had tumors with no lymphocytic infiltrate had ~7% pCR.5 Increased CD8+ T cells in the tumor have also been associated with improved survival, as demonstrated in a study of 1334 breast cancer patients (HR 0.55; 95% CI, 0.39-0.78; P = .001).7 However, the presence of FOXP3+ T-cell infiltrate was associated with worse prognosis with patients who had high FOXP3+ infiltrate (above the mean 15 cells/hpf) having decreased relapse-free survival (RFS) (HR 1.58; 95% CI, 1.01-2.47; P = .04) and decreased overall survival (OS) (HR 1.62; 95% CI, 0.96-2.74; P = .07) as compared with patients with tumors containing low FOXP3+.15 The presence of lymphocytic infiltrate and particularly intratumoral type-1 T-cell infiltrate on clinical outcome differs considerably between breast cancer subtypes.

Effect of Tumor Immune Infiltrate Differs by Breast Cancer Subtype

The clinical benefit with even incremental increase in TILs has been most consistently demonstrated in TN breast cancer. In one study of 256 TN tumors, when TILs were evaluated as a continuous variable, each 10% increase in TIL correlated with a 17% increase in disease-free survival (DFS) (HR 0.83; 95% CI, 0.71-0.98; P = .023) and a 27% increase in OS (HR 0.73; 95% CI, 0.54-0.98; P = .035) and this finding has been confirmed in subsequent studies.6,9,16 In the initial large adjuvant breast cancer studies that evaluated the benefit of increased TIL, only HER2-positive breast cancer patients that had had been treated with trastuzumab demonstrated improved prognosis with each 10% increase in TIL and was associated with decreased distant disease recurrence (n=209; HR 0.77; 95% CI, 0.61- 0.98; P = .02).17 However, one study has demonstrated in HER2-positive patients that for each 10% increase in stromal TIL there was 18% increase in OS (n=112; HR 0.82; 95% CI, 0.69-0.96).9 Although TN and HER2 breast cancer subtypes have seen clinical benefit with each 10% increase in TIL, HR-positive breast cancers have not shown this survival benefit even with LPBC. In one study evaluating 1078 HR-positive breast cancer patients, LPBC predicted neither improved DFS (HR 0.89; 95%CI, 0.44-1.8; P = .75) nor improved OS (HR 1.2; 95%CI, 0.53-2.7; P = .68).5,6

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Immune Checkpoint Blockade: A New Strategy for the Treatment of Breast Cancer
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