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Tumor surroundings may hold key to TNBC treatment optimization

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TNBC and microenvironmental heterogeneity

Of particular interest in the study by Bareche et al. is the different distribution of key immune targets. The observed distinctions between the immunomodulatory and basal-like TNBC subtypes, for example, might enable more rational trial design in which immunotherapy is preferentially evaluated in the more susceptible immunomodulatory tumors rather than basal-like tumors. Their findings also suggest that TNBC tumors other than the immunomodulatory subtype might need additional approaches to make them more susceptible to immune therapy or indeed require completely different treatment approaches. Immunologic differences between TNBC subtype microenvironments are highlighted but there are also higher-level domains identified – such as in the immune response, vascularization, stromal involvement and so on – that could make the research more generally applicable in the study and refinement of novel therapeutic strategies. Their work is just one of many steps forward in looking for predictive markers of a growing number of precision treatments for breast and other cancers.

Lior Z. Braunstein, MD, and Nadeem Riaz, MD, MSc are radiation oncologists at Memorial Sloan Kettering Cancer Center, New York. Dr. Riaz is associate director of genomics operations, Immunogenomics and Precision Oncology Platform. Their comments are summarized from the editorial accompanying the study by Bareche et al.; neither had conflicts of interest.



Tumor microenvironment (TME) profiles could help tailor treatment for triple-negative breast cancer (TNBC), with the TME profile of the immunomodulatory subtype of TNBC making it the most susceptible to the effects of the immune checkpoint inhibitors.

“This study allowed us to gain more insight into the complex interactions between tumor cells and their microenvironment, in particular immune cells,” wrote a team of Belgian and Canadian researchers. Their report is in the Journal of the National Cancer Institute.

At least five molecular subtypes of TNBC have been identified but little was previously known about the heterogeneity of their surroundings, noted Yacine Bareche, MSc, of Institut Jules Bordet, Université Libre de Bruxelles, Brussels, and associates. They looked at a series of 1,512 TNBC samples from four large and publicly available transcriptomic and genomic datasets and their TME, which is made up of many cell types – fibroblasts, adipose, and immune-inflammatory cells – and blood and lymphatic vascular networks.

The researchers explained that each of the four TNBC subtypes identified so far have “distinct mutational profiles, genomic alterations, and biological processes” which were matched by differences in their surrounding environments.

For instance, the immunomodulatory subtype of TNBC was associated with high expression of “adaptive immune-related gene signatures and a fully inflamed spatial pattern appearing to be the optimal candidate for immune check-point inhibitors.” By contrast, Mr. Bareche and coauthors said that “most mesenchymal stem-like and luminal androgen receptor TNBC tumors had an immunosuppressive phenotype with high expression levels of stromal gene signatures.”

The findings include “novel evidence” of how TNBC tumors may become resistant to the effects of immune checkpoint inhibitors.

The results demonstrate that each TNBC subtype is associated with specific TME profiles, “setting the ground for a rationale tailoring of immunotherapy in TNBC patients,” the researchers noted. Mr. Bareche and associates cautioned, however, that “prospective validation of our findings is warranted before their clinical implementation.”

The study was supported by a grant from the Breast Cancer Research Foundation. The researchers had no conflicts of interest.

SOURCE: Bareche Y et al. J Natl Cancer Inst. 2019 Oct 29. doi: 10.1093/jnci/djz208.

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