The ARTEMIS trial identifies immune activation as a key predictor of neoadjuvant chemotherapy response in...

Selecting treatments for triple-negative breast cancer (TNBC) remains challenging due to its high molecular and phenotypic heterogeneity. To maximize response rates, nearly all patients are treated with an aggressive combination of chemo-immunotherapy. However, since half of patients respond to chemotherapy alone and about a third do not respond at all, the majority of patients would benefit from alternative regimens. Thus, there is a pressing need to better personalize or de-escalate therapy using response-based biomarkers.

To address this need, we conducted the ARTEMIS randomized trial (NCT02276443) to test whether a molecular classifier could predict response to treatment with neoadjuvant chemotherapy alone in early-stage TNBC, and to understand the correlates of response.

This study found that integrating a molecular classifier did not result in a statistically significant improvement in responses to doxorubicin and cyclophosphamide (AC), which increased from 33% pCR to 41% (p = 0.43). To identify more robust correlates of response, we found that the strongest predictors were related to the immune system. Using immune cell markers, tumors could be categorized into three subtypes linked to chemoresponse, "immune hot sensitive," "immune hot resistant," and "immune cold." Notably, 50% of the immune hot tumors exhibited a pathological complete response, compared to only 8% of the immune cold tumors. The immune cold tumors represented a group of TNBC tumors characterized by chemoresistance, a mesenchymal phenotype, and signatures of FGF and TGF-β signaling, suggesting potential therapeutic strategies. Among the immune hot tumors, the sensitive subtype showed a stronger immune response and distinct spatial organization between cancer and immune cells compared to the resistant subtype despite their largely similar gene expression profiles.

These data indicate that the immune contexture is a critical factor in the response to AC chemotherapy and provides a framework for selecting more effective and less toxic therapies for patients with TNBC.

ClinicalTrials.gov ID NCT02276443 2014-10-24.