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Can Immunotherapy Conquer Triple-Negative Breast Cancer?

Triple-negative breast cancer (TNBC) is a subtype of breast cancer, the most common cancer in women. TNBC is clinically negative for expression of the estrogen receptor (ER) and progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2). This disease is highly aggressive and lacks effective targeted therapies. Currently, chemotherapy is the only therapeutic option in the adjuvant or metastatic setting for TNBC.

Although numerous targeted therapies for TNBC have been investigated, the clinical trial efficacies of these therapies are unsatisfactory or remain unclear. Recently, cancer immunotherapy has achieved successes in treating a variety of cancers including refractory malignancies such as metastatic melanoma, advanced lung cancer, and Hodgkin’s lymphoma. Thus, immunotherapy for TNBC is being considered as a viable clinical objective, especially considering the very limited therapeutic options currently available for TNBC.

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One of the most exciting advances in cancer immunotherapy is the blockade of immune checkpoint molecules such as cytotoxic T-lymphocyte-associated protein 4 (CTLA4), programmed cell death protein 1 (PD1), and programmed cell death 1 ligand (PD-L1). Another notable advance in cancer immunotherapy is the chimeric antigen receptor (CAR) T cell therapy. This method has been successfully used to treat refractory leukemia and lymphoma. However, currently, these immunotherapeutic strategies only show beneficial effects in less than 20% of cancer patients. Hence, it is important to find molecular biomarkers that are useful for predicting responders to cancer immunotherapy. Researchers have discovered some such biomarkers, such as tumor mutation burden, neoantigen load, PD-L1 expression, and deficient DNA mismatch repair.

It should be noted that with the rapid advancement of the next-generation sequencing (NGS) technology, it is possible to discover the genomic features that are associated with the cancer immunotherapeutic responsiveness. For example, researchers have found that the tumor mutation load has a positive correlation with clinical response of cancer patients to CTLA4 or PD1 blockade. The high DNA mismatch repair deficiency correlates with active clinical response to cancer immunotherapy.

Immunotherapy has not been clinically used for breast cancer because compared to melanoma, lung cancer, renal cancer, lymphoma, bladder cancer, or head and neck cancer, breast cancer, in general, has weaker immunogenicity. However, researchers showed the existence of distinct immunogenic activity in breast cancer subtypes. Based on a couple of large-scale breast cancer genomics data, researchers performed a comprehensive and exhaustive analysis of various immunogenic signatures in breast cancer.

Strikingly, they found that all the immunogenic signatures showed a significantly stronger signal in TNBC compared to non-TNBC, demonstrating that TNBC has the strongest tumor immunity of all breast cancer subtypes. Particularly, the gene or genomic features such as PD-L1 expression, tumor mutation burden, and neoantigen load that are active signatures for cancer immunotherapeutic response, show significantly higher levels in TNBC than in non-TNBC, indicating that TNBC is the breast cancer subtype most propitious to immunotherapy.

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Another interesting finding is that most of the immunogenic signatures have a positive correlation with survival prognosis in TNBC. Finally, researchers showed that TNBC had significantly higher expression levels of most of the genes targeted by immunotherapy agents in clinical use or trials or in preclinical development than non-TNBC, indicating that these agents may be good candidates for clinical trials for TNBC immunotherapy.

In conclusion, these findings suggest that of the various breast cancer subtypes, TNBC likely exhibits the strongest immunogenicity, and warrant immunotherapeutic options for TNBC.

These findings are described in the article entitled A Comprehensive Immunologic Portrait of Triple-Negative Breast Cancer, recently published in the journal Translational Oncology. This work was conducted by Zhixian Liu, Mengyuan Li, Zehang Jiang and Xiaosheng Wang from China Pharmaceutical University.

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