Efficacia di immunoterapia e chemioterapia come trattamento neoadiuvante nel carcinoma mammario Luminal B-like: risultati dello studio di fase II GIADA.

Background. Among hormone receptor (HR)-positive tumors, Luminal B-like breast cancer (BC) harbors immunogenic features as high proliferation rate and high mutational load that can promote sensitivity to immune checkpoint inhibitors. Furthermore, cytotoxic drugs and hormonal treatments have been shown to modulate the immune system. The role of immunotherapy in HR-positive, HER2-negative early BC is underexplored. Methods. The prospective multicentric phase 2 GIADA trial enrolled premenopausal patients with Luminal B-like BC (HR-positive, HER2-negative, with Ki67>20% and/or histologic Grade 3) candidate to neoadjuvant chemotherapy from four Italian Institutions. Patients received: three 21-days cycles of intravenous epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) followed by eight 14-days cycles of intravenous nivolumab (240 mg), intramuscular triptorelin (3.75 mg every 28 days) started concomitantly to chemotherapy, and oral exemestane (25 mg daily) started concomitantly to nivolumab. Tumor tissue samples were collected at baseline (t0), after chemotherapy before nivolumab (t1), and at surgery (t2). BC intrinsic subtypes were determined using PAM50 assay. Tumor infiltrating lymphocytes (TILs) were centrally assessed following TILs Working Group Recommendations. Primary endpoint was pathological complete response (pCR; ypT0/is, ypN0). At least 8 pCR were required to satisfy the statistical hypothesis. Results. A pCR was achieved by seven out of 43 patients (16.3%; 95%CI 7.4-34.9). The rate of Residual Cancer Burden class 0-1 was 25.6% (n=11), and 70.6% patients (n=24 of 34 evaluable) obtained an objective response in the breast. pCR rate was significantly higher for patients with PAM50 Basal BC (50%, 4/8) as compared to other subtypes (Luminal A 9%, 1/11; Luminal B 8%, 2/24; p=0.017). Immune-related biomarkers including TILs and gene expression signatures tracking immune processes 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. A significant enrichment in TILs occurred from t0 to t1. Most common Grade >3 treatment-related adverse events (AEs) during nivolumab were alanine aminotransferase (16.7%, n=7) and aspartate aminotransferase (9.5%, n=4) increase. Most common immune-related AEs were endocrinopathies, mostly hypothyroidism (14.3%, n=6), all of Grade 1-2. Conclusion. Although the trial did not meet its primary endpoint, the results show that a subset of Luminal B-like BC patients may respond to sequential anthracyclines and anti-PD-1, especially in presence of a state of tumor inflammation and/or Basal subtype. Our data provide novel hints to trace the path of immunotherapy development in this context.