Purpose: The anti–HER-2/neu monoclonal antibody trastuzumab has been shown to engage both activatory (fragment C receptor [FcγR]IIIa; FcγRIIa) and inhibitory (FcγRIIb) antibody receptors and FcγR polymorphisms have been identified that may affect the antibody-dependent cell-mediated cytotoxicity (ADCC) of natural-killer cells/monocytes. In this study, we tested whether FcγR polymorphisms are associated with clinical outcome of patients with breast cancer who received trastuzumab.Patients and Methods: Fifty-four consecutive patients with HER-2/neu–amplified breast cancer receiving trastuzumab plus taxane for metastatic disease were evaluated for genotype for the FcγRIIIa-158 valine(V)/phenylalanine(F), FcγRIIa-131 histidine(H)/arginine(R), and FcγRIIb-232 isoleucine(I)/threonine(T) polymorphisms. Trastuzumab-mediated ADCC of patients' peripheral blood mononuclear cells (PBMCs) was measured by chromium-51 release using a HER-2/neu–expressing human breast cancer cell line as a target. Controls comprised thirty-four patients treated with taxane alone.Results: Our population was in Hardy-Weinberg equilibrium except for the FcγRIIb polymorphism. The FcγRIIIa-158 V/V genotype was significantly correlated with objective response rate (ORR) and progression-free survival (PFS). Also, there was trend significance in ORR and PFS for the FcγRIIa-131 H/H genotype. The combination of the two favorable genotypes (VV and/or H/H) was independently associated with better ORR and PFS compared with the other combinations. The ADCC analysis showed that V/V and/or H/H PBMCs had a significantly higher trastuzumab-mediated cytotoxicity than PBMCs harboring different genotypes.Conclusion: These data support for the first time the hypothesis that FcγR-mediated ADCC plays an important role in the clinical effect of trastuzumab. Prospective studies are needed to confirm the role of FcγR polymorphisms in predicting clinical outcome of patients with breast cancer treated with trastuzumab-based therapy.

Purpose: This is a noncomparative, randomized, phase II trial of preoperative taxane-anthracycline in combination with trastuzumab, lapatinib, or combined trastuzumab plus lapatinib in patients with human epidermal growth factor receptor 2 (HER2) –positive, stage II to IIIA operable breast cancer. The primary aim was to estimate the percentage of pathologic complete response (pCR; no invasive tumor in breast and axillary nodes). Patients and Methods: In the three arms, chemotherapy consisted of weekly paclitaxel (80 mg/m²) for 12 weeks followed by fluorouracil, epirubicin, and cyclophosphamide for four courses every 3 weeks. The patients randomly assigned to arm A received a 4-mg loading dose of trastuzumab followed by 2 mg weekly; in arm B patients received lapatinib 1,500 mg orally (PO) daily; and in arm C, patients received trastuzumab and lapatinib 1,000 mg PO daily. Results: A total of 121 patients were randomly assigned. Diarrhea and dermatologic and hepatic toxicities were observed more frequently in patients receiving lapatinib. No episodes of congestive heart failure were observed. The rates of breast-conserving surgery were 66.7%, 57.9%, and 68.9% in arms A, B and C, respectively. The pCR rates were 25% (90% CI, 13.1% to 36.9%) in arm A, 26.3% (90% CI, 14.5% to 38.1%) in arm B, and 46.7% (90% CI, 34.4% to 58.9%) in arm C (exploratory P = .019). Conclusion: The primary end point of the study was met, with a relative increase of 80% in the pCR rate achieved with chemotherapy plus trastuzumab and lapatinib compared with chemotherapy plus either trastuzumab or lapatinib. These data add further evidence supporting the superiority of a dual-HER2 inhibition for the treatment of HER2-positive breast cancer.

Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment for HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The Short-HER study was aimed to assess the non-inferiority of 9 weeks vs 1 year of adjuvant trastuzumab combined with chemotherapy. HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT > 2cm, G3, lympho-vascular invasion, Ki-67>20%, age ≤35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9-weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end-point. A DFS Hazard Ratio (HR) <1.29 was chosen as the non-inferiority margin. Analyses according to the frequentist and Bayesian approach were planned. Secondary endpoints included 2-year failure rate and cardiac safety. 1254 patients from 82 centers were randomized (arm A, long: n = 627; arm B, short: n = 626). Five-year DFS is 88% in the long and 85% in the short arm. The HR was 1.13 (90%CI 0.89;1.42), with the upper limit of the CI crossing the non-inferiority margin. According to the Bayesian analysis, the probability that the short arm is non-inferior to the long one is 80%. The 5-yr OS is 95.2% in the long and 95.0% in the short arm (HR 1.07, 90%CI0.74;1.56). Cardiac events are significantly lower in the short arm (risk-ratio 0.33, 95%CI0.22;0.50, p < 0.0001). This study failed to show the non-inferiority of a shorter trastuzumab administration. 1-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse.

BACKGROUND: A series of retrospective studies have reported that patients with human epidermal growth factor receptor 2(HER2)‐positive breast cancer are at a greater risk of central nervous system (CNS) metastases. Trastuzumab, which does not cross the blood‐brain barrier, has been associated with this increased risk.METHODS: The authors evaluated incidence, survival, and risk factors for CNS metastases in the incident breast cancer population systematically collected by the Parma Province Cancer Registry over the 4‐year period between 2004 and 2007.RESULTS: A total of 1458 patients with a diagnosis of stage I to III invasive breast cancer were analyzed for study purposes. At a median follow‐up of 4.1 years, CNS events were observed in 1.3% and 5% of HER2‐negative patients and HER2‐positive patients, respectively (P < .0001). The administration of trastuzumab either as adjuvant therapy or for metastatic disease was associated with a significantly increased risk of CNS involvement at first disease recurrence and after first extracranial recurrence, respectively. According to multivariate analysis, HER2‐positive status and trastuzumab treatment, high Ki‐67 index, and hormone receptor negativity remained independent risk factors for the development of CNS metastasis.CONCLUSIONS: To the authors' knowledge, this is the first population‐based cancer registry study analyzing factors associated with CNS recurrence in a general population of newly diagnosed breast cancer patients with known HER2 status. The data from the current study provide evidence that patients with HER2‐positive breast cancer have a significantly higher incidence of CNS metastasis after treatment with trastuzumab. Improvements in systemic control and overall survival associated with trastuzumab‐based therapy may lead to an “unmasking” of CNS disease recurrence that would otherwise remain clinically silent before a patient's death. Cancer 2011. © 2010 American Cancer Society.

Purpose: The role of immunotherapy in hormone receptor (HR)-positive, HER2-negative breast cancer is underexplored. Patients and Methods: 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 ≥ 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). Results: 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%; P = 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 ≥3 treatment-related adverse events (AE) during nivolumab were γ-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, n = 1). Conclusions: 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.