Potential New Immunotherapy Targets for Treatment of Breast Cancer

By Cameron Kelsall, MD /alert Contributor
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An article in Cancer Discovery highlighted the complicated relationship between tumor cells and immune cells in breast cancer, shedding light on the difficulties of developing immunotherapies for this common cancer subtype.

Breast cancer affects 1 in 8 women in the US and remains the second-leading cause of cancer death in women. The classification of breast cancers involves the recognition of molecular and histologic subtypes, the combinations of which make the condition highly heterogeneous.

“Although breast cancer can perhaps be distinguished as one of the first malignancies to be approached with precision medicine strategies through the use of estrogen receptor- and HER2-targeted therapies, additional strategies are required to improve long-term outcomes of patients with this disease,” wrote Dario A.A. Vignali, PhD, professor and interim chair of the department of immunology at the University of Pittsburgh, and colleagues. “Our current classification of breast cancers is largely naïve to the immune state of each tumor type.”

Although some targeted immune therapies, such as pembrolizumab and atezolizumab, showed promise as potential therapeutic candidates for patients with breast cancer, their overall efficacy has not equaled those seen in other cancer subtypes, such as lung cancer or melanoma. In their review, Vignali and colleagues offered insight on the potential for effective immunotherapies by breast cancer subtype by discussing the molecular and histologic targets of the disease.

The authors noted that clinicians and researchers have worked to expand the understanding of tumor classification beyond receptor status, with new classifications added to better refine traditional subtypes. For example, RNA sequencing has led to the identification of four new classifications within the triple-negative breast cancer subtype—basal-like immune suppressed, immunomodulatory, mesenchymal subtype, and luminal androgen receptor—each of which correlates with a preferred course of treatment.

Tumor mutational burden has also been linked to the tumor immune microenvironment, which can be used as a tool for targeted treatment. The authors cited a study that found a higher tumor mutational burden in patients with triple-negative breast cancer, in comparison to HER2-positive and HR-positive cancers. “Tumor mutational burden should be considered as a continuous variable with immune responses varying accordingly across the tumor mutational burden spectrum,” they wrote. “[I]t becomes apparent that compared with other cancers, breast cancers as a whole harbor a much lower level of hypermutation.”

Other factors that might contribute to cancer cell-intrinsic immune differences identified by the authors included: HLA class I expression, which can affect antigen presentation and T-cell interactions; PD-L1 expression within the cancer cells, with certain subtypes harboring higher or lower levels of expression; and the metabolic programming of the tumor immune microenvironment. The authors also reviewed the growing understanding of the tumor immune microenvironment based on breast cancer subtype, refuting the previously prevalent belief that breast cancer is “immunologically silent.” Triple-negative breast cancer, for example, is associated with high levels of stromal tumor-infiltrating lymphocytes that respond to neoadjuvant chemotherapy. This subtype is also associated with high levels of cellular stromal and intramural CD8-positive and CD4-positive T-cell infiltration.

“In the HER2-positive tumor immune microenvironment, the HER2 protein itself serves as a unique target that has been shown to be recognized by T cells and B cells and is amenable to immunotherapeutic intervention,” the authors wrote. “Increased CD8-positive T cells, including CD8-positive tissue resistant memory cells, and higher immune cell expression of IFNγ have been correlated with better prognosis, improved pathologic complete responses with therapy, and significantly increased OS in HER2-positive disease after analysis of stromal tumor-infiltrating lymphocytes in the GeparQuattro and GeparQuinto trials.”

The tumor immune microenvironment of HR-positive breast cancers varies highly based on the two recognized molecular subtypes within this cancer: Luminal A and Luminal B. “Although limited, the existing data suggest that the immune infiltrate in the primary HR-positive tumor microenvironment is dominated by CD8-positive and CD4-positive T cells and tumor-associated macrophages,” the authors wrote. Metastatic disease and histology, such as invasive lobular carcinoma or invasive ductal cancer, can also influence the tumor immune microenvironment and be useful in determining an appropriate course of treatment.

The authors highlighted some promising therapeutic options for the targeted treatment of patients with breast cancer. Although single-agent immunotherapy has heretofore shown limited efficacy, the combination of immune checkpoint inhibition and standard therapies such as radiation or cytotoxic chemotherapy may lead to positive outcomes. Adoptive cellular therapies, such as neoantigen-specific T-cell therapy, may also be beneficial.

Efforts to overcome immune resistance might lie in dampening the tumor immune microenvironment as a means of preventing immune evasion, or in targeting cancer-associated fibroblasts through the use of anti-IL6R antibodies.

“For the success of immunotherapeutic modulation, it is imperative that future studies are designed with an eye on the unique features for each of the subtype tumor immune microenvironments,” the authors concluded. “It is becoming increasingly clear that immunotherapy as monotherapy might not be optimal to treat any subtype of breast cancer. Multipronged, innovative approaches for targeting tumor and immune cells together might be the path forward for breast cancer.”

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Disclosures: Some authors declared financial ties to drugmakers. See full study for details.

Photo Credit: Getty Images.


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