Vemurafenib in non-small-cell lung cancer patients with BRAFV600 and BRAFnonV600 mutations.

BACKGROUND: BRAF mutations occurring in 1%-5% of patients with non-small-cell lung cancer (NSCLC) are therapeutic targets for these cancers but the impact of the exact mutation on clinical activity is unclear. The French National Cancer Institute (INCA) launched the AcSé vemurafenib trial to assess the efficacy and safety of vemurafenib in cancers with various BRAF mutations. We herein report the results of the NSCLC cohort. PATIENTS AND METHODS: Tumour samples were screened for BRAF mutations in INCA-certified molecular genetic centres. Patients with BRAF-mutated tumours progressing after ≥1 line of treatment were proposed vemurafenib 960 mg twice daily. Between October 2014 and July 2018, 118 patients were enrolled in the NSCLC cohort. The primary outcome was the objective response rate (ORR) assessed every 8 weeks (RECIST v1.1). A sequential Bayesian approach was planned with an inefficacy bound of 10% for ORR. If no early stopping occurred, the treatment was of interest if the estimated ORR was ≥30% with a 90% probability. Secondary outcomes were tolerance, response duration, progression-free survival (PFS), and overall survival (OS). RESULTS: Of the 118 patients enrolled, 101 presented with a BRAFV600 mutation and 17 with BRAFnonV600 mutations; the median follow-up was 23.9 months. In the BRAFnonV600 cohort, no objective response was observed and this cohort was stopped. In the BRAFV600 cohort, 43/96 patients had objective responses. The mean Bayesian estimated success rate was 44.9% [95% confidence intervals (CI) 35.2%-54.8%]. The ORR had a 99.9% probability of being ≥30%. Median response duration was 6.4 months, median PFS was 5.2 months (95% CI 3.8-6.8), and OS was 10 months (95% CI 6.8-15.7). The vemurafenib safety profile was consistent with previous publications. CONCLUSION: Routine biomarker screening of NSCLC should include BRAFV600 mutations. Vemurafenib monotherapy is effective for treating patients with BRAFV600-mutated NSCLC but not those with BRAFnonV600 mutations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02304809.

Perinatal xenohormone exposure impacts sweet preference and submandibular development in male rats.

OBJECTIVE: To determine the effect of perinatal exposure to low doses of genistein and/or vinclozolin on submandibular salivary gland (SSG) development in juvenile and adult male rats and to establish a link with sweet preference. MATERIAL AND METHODS: Female rats received orally (1 mg kg(-1) body weight/day) genistein and vinclozolin, alone or in combination, from the first gestational day up to weaning. Sweet preference was assessed at weaning and in adulthood in male offspring; submandibular glands were then collected to study the morphogenesis and mRNA expression of steroid receptors, growth factors and taste related proteins. RESULTS: Exposure to genistein and/or vinclozolin resulted in a higher saccharin intake on postnatal day 25 (P < 0.05) linked to a higher number of pro-acinar cells (P < 0.01) and mRNA expression of progesterone receptor, growth factors and gustine (P < 0.01). These increases disappeared in adulthood, but mRNA expressions of sex hormone receptors and growth factors were strongly repressed in all treated groups (P < 0.01). CONCLUSION: Our findings confirm that the SSG are target for xenohormones and provide evidence that perinatal exposure to low doses of genistein and/or vinclozolin could simultaneously disrupt not only the salivary gland prepubertal development and sweet intake but also endocrine gene mRNA expression later in life.

Cellular differentiation determines the expression of the hypoxia-inducible protein NDRG1 in pancreatic cancer.

N-myc downstream-regulated gene-1 (NDRG1) is a recently described hypoxia-inducible protein that is upregulated in various human cancers. Pancreatic ductal adenocarcinoma, called pancreatic cancer, is a highly aggressive cancer that is characterised by its avascular structure, which results in a severe hypoxic environment. In this study, we investigated whether NDRG1 is upregulated in these tumours, thus providing a novel marker for malignant cells in the pancreas. By immunohistochemistry, we observed that NDRG1 was highly expressed in well-differentiated cells of pancreatic cancer, whereas the poorly differentiated tumour cells were negative. In addition, hyperplastic islets and ducts of nonquiescent pancreatic tissue were positive. To further explore its selective expression in tumours, two well-established pancreatic cancer cell lines of unequal differentiation status were exposed to 2% oxygen. NDRG1 mRNA and protein were upregulated by hypoxia in the moderately differentiated Capan-1 cells; however, its levels remained unchanged in the poorly differentiated Panc-1 cell line. Taken together, our data suggest that NDRG1 will not serve as a reliable marker of tumour cells in the pancreas, but may serve as a marker of differentiation. Furthermore, we present the novel finding that cellular differentiation may be an important factor that determines the hypoxia-induced regulation of NDRG1.

Molecular mechanisms underlying the interaction between ZD1839 ('Iressa') and cisplatin/5-fluorouracil.

ZD1839 ('Iressa'), an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is currently being investigated in clinical trials as a treatment for cancer. 'Iressa' is a trademark of the AstraZeneca group of companies. We have previously demonstrated a synergistic interaction between ZD1839 and cisplatin/5-fluorouracil (5FU) in CAL33, a human head and neck cancer cell line that markedly expresses EGFR. This study examined the effects of this drug combination on the cell cycle, cell cycle regulators, apoptosis-related factors, EGFR-related signalling and DNA repair in CAL33 cells. The cells were incubated with ZD1839 alone for 48 h, then cisplatin and 5FU were added. Exposure to the drug combination continued for a further 48 h. ZD1839 alone induced accumulation of cells in the G0/G1 phase of the cell cycle at 24 h accompanied by a concomitant increase in p21, p27 and Bax, a significant decrease in Bcl2 and a decrease in Akt phosphorylation. A decrease in DNA-PK was observed at 48 h. ZD1839 alone had no effect on caspase-3 activity, but addition of ZD1839 to cisplatin-5FU led to a significant increase in caspase-3 activity at 96 h. Thus, ZD1839 affects key cellular pathways controlling cell proliferation, apoptosis and DNA repair. These data provide a rationale to support clinical trials combining ZD1839 and cisplatin-5FU and other protocols that combine EGFR-targeting agents with chemotherapy or radiotherapy.