CAM-H2 effectively targets and treats HER2 positive brain lesions: A comparative preclinical study with trastuzumab

Abstract

Background: Neratinib is an oral small-molecule irreversible pan-HER tyrosine kinase inhibitor in late stage clinical development for advanced HER-2 positive breast cancer. Prophylactic loperamide (4mg qds Day 1, tds days 2-14, bd days 15-28 then prn) and budesonide (9mg od for 28 days) are required to reduce the incidence and severity of diarrhoea. Methods: Patients enrolled within the Puma Biotechnology Neratinib Managed Access Program between 01/01/2016 and 01/06/2018 with advanced HER2 positive breast cancer were identified for this retrospective analysis. Data were collected from electronic patient records. The primary endpoint was progression free survival (PFS). Secondary objectives were overall survival (OS), response rate (RR, RECIST v1.1), clinical benefit rate (CBR) and toxicity graded by CTCAE v4.0. Results: We identified 29 patients, median age 54 years (IQR: 50-61) who received a median of 4 (range 1-6) prior lines of therapy for advanced breast cancer. 15 patients (51.7%) received neratinib 240mg/day as monotherapy (one with sc trastuzumab), 14 (48.2%) in combination with capecitabine 1500mg/m 2 /day for 2 weeks of a 3 week cycle. Median follow-up was 8.5 months (IQR: 5.1-11.6). Median PFS was 7.4 months (95%CI 3.5-17.9) and was significantly longer with combination therapy than mono-therapy (17.9 (3.5-NR) vs 5.8 months (2.0-10.2), P ¼ 0.043). Median OS was not reached but was not significantly different in the two treatment cohorts. The RR in monotherapy patients was 33% compared to 57% in combination patients. Two combination patients had complete responses which remain ongoing at 17 and 25 months. The CBR was 47% and 79% respectively. Grade 3-4 toxicities were reported in 4 patients (13.8%). Dose delays were required in 19 patients (65.5%), dose reductions in 4 (13.8%) and discontinuation in 4 due to pneumonitis (n ¼ 1); nausea and vomiting (n ¼ 2) and diarrhoea (n ¼ 1). Any grade diarrhoea was reported by 15 patients (51.7%) despite prophylaxis, as above. There was no grade 3-4 diarrhoea. Conclusions: In this cohort of heavily pre-treated HER2 positive advanced breast cancer patients, neratinib demonstrated durable anti-cancer activity with a manageable toxicity profile both as monotherapy and in combination with capecitabine. Background: CD146 or Mel-CAM, a member of the immunoglobulin-like CAM family , is activated through a dimerization of its ligand, leading to a cascade of signal trans-duction events. While CD146 is a promoter of melanoma and prostate cancer, its role in BC remains nascent and controversial. However, we have recently reported that CD146, a negative transcriptional target of CD44-HA downstream signaling, suppresses breast tumor cell invasion; this has prompted us to generate the hypothesis that CD146 acts as a tumor suppressor in BC via its downstream transcriptional targets. Methods: To test this hypothesis, we developed both in vitro and in vivo tetracycline (tet On)-inducible system of CD146 using MDA-MB-231 founder BC cell line. Our results demonstrated that induction of CD146 suppressed BC cell migration and invasion in vitro as well as tumor growth and progression in mouse breast xenograft model. Microarray gene expression profiling revealed latexin (LXN: a variant of Tissue Inhibitor of Metalloproteinases) as a novel potential CD146-downstream signaling transcriptional target, which was validated using various in vitro approaches. Results: To further validate our finding in vivo, immunohistochemical analysis of breast tumor tissues from both human and mouse (tet-inducible system) breast tissues showed that, while the expression of both CD146 and LXN were highly expressed in the early stages of BC (normal and benign tissues), it was lost in advanced stages (malignant and metastatic tissues). Pharmacological approach combined with luciferase assay revealed that NFjB activation via Akt pathway couples CD146 to the transcription of LXN in BC CD146inducible cells. Conclusions: The present study discovers the main molecular players of a novel signal-ing pathway, CD146/LXN/Akt/N-jB, by which CD146 acts as a suppressor of BC progression. Legal entity responsible for the study: Allal Ouhtit.