[Concurrent radiation therapy and dual HER2 blockade in breast cancer: Assessment of toxicity]. / Association du double blocage de HER2 et radiothérapie dans la prise en charge du cancer du sein exprimant HER2.

PURPOSE: The tolerance of the concurrent use of radiotherapy, pertuzumab and trastuzumab is unknown. The purpose of this study was to evaluate the toxicity of this association in patients treated for HER2 positive metastatic and/or locally recurrent unrespectable breast cancer. MATERIAL AND METHODS: A retrospective study was performed in our institution for all consecutive patients treated with concurrent irradiation, pertuzumab and trastuzumab. The radiotherapy was performed while pertuzumab and trastuzumab were administrated as a maintenance treatment at the dose of 420mg (total dose) and 6mg/kg respectively every 3 weeks without chemotherapy. Toxicity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Left ventricular ejection fraction (LVEF) was measured at baseline and then every 3-4 months. RESULTS: We studied 77 patients. treated in between 2013 and 2019 with median follow-up of 38 months (range 0-264 months). Median age was 53 years (33-86). There were 50 patients (64.9%) with metastatic and 27 patients (35.1%) with recurrent disease. All patients received docetaxel followed by P-T as first line treatment and they received 34 cycles (10-85) of pertuzumab and trastuzumab. All patients experienced partial or complete response according to RECIST criteria. Irradiation volumes were whole breast (41 patients, 53.2%) and chest wall (29 patients, 37.7%) at a dose of 50Gy with a median duration of 39 days. Radiotherapy of lymph nodes was performed in 53 patients (68.8%) as following: supraclavicular-infraclavicular and axillary lymph nodes in 52 patients (67.5%), and internal mammary nodes in 31 patients (40.3%). For 20 patients. (26.0%) radiotherapy was palliative: bone irradiation (12 patients, 15.6%), whole-brain radiotherapy (2 patients, 2.6%), cerebral metastasis irradiation (6 patients). As early toxicity we observed: radio dermatitis as following: 36 patients (46.8%) presented grade I, 17 patients (22.1%) presented grade II, and 3 patients (3.9%) presented grade III. One patient (1.3%) presented grade II esophagitis. One patient (1.3%) presented asymptomatic decrease of LVEF during treatment and 6 patients (7.7%) presented a decrease of LVEF. There was no radiation-induced pneumonitis. As late toxicity, we observed 1 (1.3%) case of grade I and 1 (1.3%) with grade II telangiectasia. There was 1 case (1.3%) of grade III cardiac toxicity, 8 months after the concurrent treatment. CONCLUSION: The concurrent use of radiotherapy, pertuzumab and trastuzumab is feasible with good tolerance. Larger prospective data with longer follow-up is needed to confirm these results.

Response to dual HER2 blockade in a patient with HER3-mutant metastatic breast cancer.

BACKGROUND: HER3 activating mutations have been shown in preclinical models to be oncogenic and ligand-independent, but to depend on kinase-active HER2. PATIENTS AND METHODS: Whole-exome sequencing of the primary HER2-negative breast cancer and its HER2-negative synchronous liver metastasis from a 46-year-old female revealed the presence of an activating and clonal HER3 G284R mutation. RESULTS: HER2 dual blockade with trastuzumab and lapatinib as third-line therapy led to complete metabolic response in 2 weeks and confirmed radiological partial response after 8 weeks. Following the resection of the liver metastasis, the patient remains disease-free 40 weeks after initiation of the HER2 dual blockade therapy. Immunohistochemical analysis demonstrated a substantial reduction of phospho-rpS6 and phospho-AKT in the post-therapy biopsy of the liver metastasis. DISCUSSION: This is the first-in-man evidence that anti-HER2 therapies are likely effective in breast cancers harboring HER3 activating mutations.

Randomised proof-of-concept phase II trial comparing targeted therapy based on tumour molecular profiling vs conventional therapy in patients with refractory cancer: results of the feasibility part of the SHIVA trial.

BACKGROUND: The SHIVA trial is a multicentric randomised proof-of-concept phase II trial comparing molecularly targeted therapy based on tumour molecular profiling vs conventional therapy in patients with any type of refractory cancer. RESULTS of the feasibility study on the first 100 enrolled patients are presented. METHODS: Adult patients with any type of metastatic cancer who failed standard therapy were eligible for the study. The molecular profile was performed on a mandatory biopsy, and included mutations and gene copy number alteration analyses using high-throughput technologies, as well as the determination of oestrogen, progesterone, and androgen receptors by immunohistochemistry (IHC). RESULTS: Biopsy was safely performed in 95 of the first 100 included patients. Median time between the biopsy and the therapeutic decision taken during a weekly molecular biology board was 26 days. Mutations, gene copy number alterations, and IHC analyses were successful in 63 (66%), 65 (68%), and 87 (92%) patients, respectively. A druggable molecular abnormality was present in 38 patients (40%). CONCLUSIONS: The establishment of a comprehensive tumour molecular profile was safe, feasible, and compatible with clinical practice in refractory cancer patients.

Platinum-based chemotherapy in metastatic triple-negative breast cancer: the Institut Curie experience.

BACKGROUND: Although recent experimental data strongly suggest that platinum-based chemotherapy (PBCT) could improve the outcome of triple-negative breast cancer (TNBC), clinical data are lacking. Here, the authors reviewed clinical outcome in patients with metastatic TNBC treated with PBCT. PATIENTS AND METHODS: We conducted a retrospective analysis of all patients (N=143) treated for metastatic breast cancer with PBCT between 2000 and 2008, at Institut Curie, Paris, France. Ninety-three of them (63.7%) had TNBC. One-hundred twenty patients received cisplatin (CDDP). The main combination used was CDDP-ifosfamide, in 101 patients (70.2%). RESULTS: Median follow-up was 44 months. For the overall population (N=143), median overall survival (OS) and median progression-free survival (PFS) were 11 and 5 months, respectively. Objective response rate was 33.3% in the TNBC group versus 22% in non-TNBC, P=0.1. We observed no difference of OS, PFS and response duration. Other prognostic factors for poor OS were visceral metastasis sites (P<0.001). One patient died from sepsis during aplasia, 15 had to switch from CDDP to carboplatin because of CDDP-related toxicity. CONCLUSIONS: Metastatic TNBC patients treated with PBCT tended to have a higher response rate, without a significant improvement of PFS or OS, compared with other subtypes. Toxicity was acceptable. Longer observation and further analysis are warranted.