Background In human epidermal growth factor receptor 2 (HER2+) breast cancers, neoadjuvant trials of chemotherapy plus anti-HER2 treatment consistently showed lower pathologic complete response (pCR) rates in hormone receptor (HR) positive versus negative tumors. The PerELISA study was aimed to evaluate the efficacy of a de-escalated, chemotherapy-free neoadjuvant regimen in HR+/HER2+ breast cancer patients selected on the basis of Ki67 inhibition after 2-week letrozole. Patients and methods PerELISA is a phase II, multicentric study for postmenopausal patients with HR+/HER2+ operable breast cancer. Patients received 2-week letrozole, and then underwent re-biopsy for Ki67 evaluation. Patients classified as molecular responders (Ki67 relative reduction >20% from baseline) continued letrozole and started trastuzumab-pertuzumab for five cycles. Patients classified as molecular non-responders started weekly paclitaxel for 13 weeks combined with trastuzumab-pertuzumab. Primary aim was breast and axillary pCR. According to a two-stage Simon’s design, to reject the null hypothesis, at least 8/43 pCR had to be documented. Results Sixty-four patients were enrolled, 44 were classified as molecular responders. All these patients completed the assigned treatment with letrozole-trastuzumab-pertuzumab and underwent surgery. A pCR was observed in 9/44 cases (20.5%, 95% confidence interval 11.1% to 34.5%). Among molecular non-responders, 16/17 completed treatment and underwent surgery, with pCR observed in 81.3% of the cases. PAM50 intrinsic subtype was significantly associated with Ki67 response and pCR. Among molecular responders, the pCR rate was significantly higher in HER2-enriched than in other subtypes (45.5% versus 13.8%, P = 0.042). Conclusions The primary end point of the study was met, by reaching the pre-specified pCRs. In patients selected using Ki67 reduction after short-term letrozole exposure, a meaningful pCR rate can be achieved without chemotherapy. PAM50 intrinsic subtyping further refines our ability to identify a subset of patients for whom chemotherapy might be spared. EUDRACT number 2013-002662-40 ClinicalTrials.gov Identifier NCT02411344

The role of immunotherapy in hormone receptor (HR)-positive, HER2-negative breast cancer (BC) is underexplored. Experimental designThe neoadjuvant phase II GIADA trial (NCT04659551, EUDRACT 2016-004665-10) enrolled stage II-IIIA premenopausal patients with Luminal B (LumB)-like BC (HR-positive/HER2negative, Ki67>20% and/or histologic Grade 3). Patients received: three 21-days cycles of epirubicin/cyclophosphamide followed by eight 14-days cycles of nivolumab, triptorelin started concomitantly to chemotherapy, and exemestane started concomitantly to nivolumab. Primary endpoint was pathological complete response (pCR; ypT0/is, ypN0). ResultsA pCR was achieved by 7/43 patients (16.3%; 95%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 BC (4/8, 50%) as compared to other subtypes (LumA 9.1%; LumB 8.3%; p=0.017). Tumor infiltrating lymphocytes (TILs), immune-related gene expression signatures, and specific immune cells 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 >3 treatment-related adverse events (AEs) during nivolumab were: γglutamyltransferase (16.7%), alanine aminotransferase (16.7%), and aspartate aminotransferase (9.5%) increase. Most common immune-related AEs were endocrinopathies (all Grade 1-2; including adrenal insufficiency, n=1). ConclusionsLuminal B-like BCs 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.Research.

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