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Immunotherapy in Breast Cancer

par Agostinetto, Elisa
Président du jury Lybaert, Pascale
Promoteur Buisseret, Laurence
Publication Non publié, 2026-04-22

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Résumé :

The combination of chemotherapy and anti–PD-(L)1 immune checkpoint inhibitors is the standard of care for patients with PD-L1–positive advanced or metastatic triplenegative breast cancer (TNBC). Despite meaningful improvements in outcomes, unmet clinical needs remain, as not all patients derive benefit from this treatment. To address this, the phase I/II SYNERGY trial (NCT03616886) investigated whether enhancing immune activation by targeting the immunosuppressive adenosine pathway with the anti-CD73 antibody oleclumab, added to durvalumab plus carboplatin–paclitaxel, could improve responses in untreated advanced TNBC. Among 133 enrolled patients, carboplatin–paclitaxel plus durvalumab was administered with (arm A) or without (arm B) oleclumab, followed by maintenance therapy until progression. With a median follow-up of 21.7 months, we showed that the addition of oleclumab to chemo-immunotherapy did not improve PFS or OS. A subgroup of 12 patients across both arms experienced long-lasting response, indicating sustained and prolonged benefit in selected cases. Circulating tumor DNA (ctDNA) detection, assessed via low-coverage genome-wide sequencing of 343 plasma samples collected at baseline, week 3, and week 13, declined markedly during treatment and consistently correlated with poorer outcomes. Notably, all exceptional responders evaluable for ctDNA analysis experienced ctDNA clearance, underscoring the potential of ctDNA as a biomarker in this disease/setting. Complementing these clinical findings, we performed a temporal multi-omics analysis of advanced TNBC from 122 patients treated with ICIs in SYNERGY and the EORTC-1553-SPECTA profiling initiative (NCT02834884), integrating multiple sequencing and imaging technologies. Baseline multi-omic signatures revealed distinct immune and molecular profiles associated with survival, while ontreatment analyses showed that early progressors developed a more immunosuppressive tumor microenvironment characterized by reduced tumor-cell PD-L1 expression, expansion of fibrotic stroma, and increased macrophage infiltration driven by TGFB1 and IL10. These data suggest that resistance to chemoimmunotherapy involves a fibro-vascular reprogramming of the tumor microenvironment, with macrophage-mediated immunosuppression emerging as a key barrier to durable response. Together, the clinical and multi-omics results highlight that TNBC is a highly heterogeneus disease. While adding oleclumab did not improve outcomes overall, chemo-ICI induced substantial and durable response in at least a subgroup of patients, 12 of whom are still under maintenance treatment and progression-free as of today. Among patients experiencing early progression, we identified potential therapeutic targets related to fibrosis, angiogenesis, macrophages, and PI3K signaling, to be tested in future ICI-based trials in TNBC.