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Background <p>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.</p> Methods <p>To address this need, we conducted the ARTEMIS randomized trial (NCT 02276443) 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.</p> Results <p>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% (<i>p</i> = 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.</p> Conclusions <p>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.</p> Trial registration <p>ClinicalTrials.gov ID NCT02276443 2014-10-24.</p>

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The ARTEMIS trial identifies immune activation as a key predictor of neoadjuvant chemotherapy response in triple-negative breast cancer

  • 期刊论文

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  • 发表日期：

    2026年5月6日

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  • Sahil Seth,
  • Clinton Yam,
  • Lei Huo,
  • Bora Lim,
  • Amanda L. Rinkenbaugh,
  • Jason B. White,
  • Elizabeth E. Ravenberg,
  • Xingzhi Song,
  • Jennifer K. Litton,
  • Debu Tripathy,
  • Vicente Valero,
  • Senthil Damodaran,
  • Banu Arun,
  • Naoto T. Ueno,
  • Anthony Lucci,
  • Alastair M. Thompson,
  • Elizabeth A. Mittendorf,
  • Gaiane M. Rauch,
  • Beatriz Adrada,
  • Rosalind P. Candelaria,
  • Qingqing Ding,
  • Reid T. Powell,
  • Nour K. Abuhadra,
  • Jianhua Zhang,
  • Andrew Futreal,
  • Giulio F. Draetta,
  • Helen Piwnica-Worms,
  • William F. Symmans,
  • Jeffrey T. Chang,
  • Stacy L. Moulder

摘要

Background

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.

Methods

To address this need, we conducted the ARTEMIS randomized trial (NCT 02276443) 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.

Results

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.

Conclusions

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.

Trial registration

ClinicalTrials.gov ID NCT02276443 2014-10-24.