The GIADA trial gave premenopausal women with a type of breast cancer three drugs: standard chemo, an immune‑checkpoint blocker (nivolumab), and a hormone‑blocking peptide (triptorelin). Only about 16% of all patients saw their tumor disappear completely, but those whose tumors looked more like the basal subtype had a 50% complete‑response rate. The benefit seemed tied to immune‑related factors, not the peptide itself, and side effects were mainly liver‑enzyme rises and mild hormone issues.

The role of immunotherapy in hormone receptor (HR)-positive, HER2-negative breast cancer is underexplored. The neoadjuvant phase II GIADA trial (NCT04659551, EUDRACT 2016-004665-10) enrolled stage II-IIIA premenopausal patients with Luminal B (LumB)-like breast cancer (HR-positive/HER2-negative, Ki67 &#x2265; 20%, and/or histologic grade 3). Patients received: three 21-day cycles of epirubicin/cyclophosphamide followed by eight 14-day cycles of nivolumab, triptorelin started concomitantly to chemotherapy, and exemestane started concomitantly to nivolumab. Primary endpoint was pathologic complete response (pCR; ypT0/is, ypN0). A pCR was achieved by 7/43 patients [16.3%; 95% confidence interval (CI), 7.4-34.9]; the rate of residual cancer burden class 0-I was 25.6%. pCR rate was significantly higher for patients with PAM50 Basal breast cancer (4/8, 50%) as compared with other subtypes (LumA 9.1%; LumB 8.3%; <i>P</i> = 0.017). Tumor-infiltrating lymphocytes (TIL), immune-related gene-expression signatures, and specific immune cell subpopulations by multiplex immunofluorescence were significantly associated with pCR. A combined score of Basal subtype and TILs had an AUC of 0.95 (95% CI, 0.89-1.00) for pCR prediction. According to multiplex immunofluorescence, a switch to a more immune-activated tumor microenvironment occurred following exposure to anthracyclines. Most common grade &#x2265;3 treatment-related adverse events (AE) during nivolumab were &#x3b3;-glutamyltransferase (16.7%), alanine aminotransferase (16.7%), and aspartate aminotransferase (9.5%) increase. Most common immune-related AEs were endocrinopathies (all grades 1-2; including adrenal insufficiency, <i>n</i> = 1). Luminal B-like breast cancers with a Basal molecular subtype and/or a state of immune activation may respond to sequential anthracyclines and anti-PD-1. Our data generate hypotheses that, if validated, could guide immunotherapy development in this context.