Historically, interest in the study of immunotherapy in breast cancer has remained somewhat limited on the basis knowledge that this type of tumor was not markedly immunogenic. Nevertheless, more recent studies have shown that some subtypes of breast cancer, particularly HER2-positive and triple-negative, are in fact immunogenic. Evidence from literature shows that breast carcinomas with a more pronounced expression of hormone receptors show minimal intratumoral lymphocyte infiltrate and significantly lower mutational load compared to other subtypes, thus resulting less immunogenic and less sensitive to PD1 / PD-L1 inhibitors.Tumors in carriers of germline mutations in BRCA1/2 lack effective DNA repair and are genomically unstable, with a high mutational load and the expression of neoantigens. Breast cancers arising in carriers of germline mutations in BRCA1 and BRCA2 may rely on the PD-1/PDL-1 pathway to avoid immune destruction. Evidence from preliminary findings suggests a high rate of PDL-1 expression in BRCA1/2 mutated breast cancers, regardless of intrinsic subtype, although the highest rate of expression has been seen in basal breast cancers. While it appears that immunogenic tumors are more sensitive to checkpoint inhibitors, the correlation between mutational load and PD-L1 density is still under active investigation and further studies are needed to determine the actual relationship between mutational burden and PD-L1 expression. single cell analysis is crucial for elucidating cellular diversity in liquid biopsy specimens, such as circulating tumor cells (CTCs), to clarify prominent molecular alterations to distinguish luminal from BRCA1/2 mutated breast cancers in order to identify preferential mediators of sensitivity and resistance to immunotherapies.
Immunotherapies are moving to the forefront of cancer treatment. Nevertheless, only subgroups of patients achieve durable benefit and long-term survival with immunotherapy. The use of PD-L1 immunohistochemistry in tumor tissue as a predictive biomarker is confounded by multiple unresolved technical issues and the expression of PD-L1 alone might not be sufficient to identify patients responding to immunotherapy. The observation that PD-L1 status is a dynamic parameter together with the lack of standardization in available assays hamper its use as ideal predictive biomarker in tumor biopsy. Liquid biopsy, through the accessible and repeatable isolation of tumor cells into the bloodstream, might by contrast allow for a dynamic characterization of PD-L1 expression which can be monitored through the course of the disease. Since circulating tumor cells (CTCs) arise from tumor cells, it is conceivable that, under evolutionary pressure, they might share some of the immune escape mechanisms inherent to tumor cells and reveal the mediators of sensitivity and resistance to immunotherapy in different breast cancer subtypes.
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