MET Amplification and Exon 14 Splice Site Mutation Define Unique Molecular Subgroups of Non-Small Cell Lung Carcinoma with Poor Prognosis.

PURPOSE: Activation of MET oncogene as the result of amplification or activation mutation represents an emerging molecular target for cancer treatment. We comprehensively studied MET alterations and the clinicopathologic correlations in a large cohort of treatment-naïve non-small cell lung carcinoma (NSCLC). EXPERIMENTAL DESIGN: Six hundred eighty-seven NSCLCs were tested for MET exon 14 splicing site mutation (METΔ14), DNA copy number alterations, and protein expression by Sanger sequencing, FISH, and IHC, respectively. RESULTS: METΔ14 mutation was detected in 2.62% (18/687) of NSCLC. The mutation rates were 2.6% in adenocarcinoma, 4.8% in adenosquamous carcinoma, and 31.8% in sarcomatoid carcinoma. METΔ14 mutation was not detected in squamous cell carcinoma, large cell carcinoma, and lymphoepithelioma-like carcinoma but significantly enriched in sarcomatoid carcinoma (P < 0.001). METΔ14 occurred mutually exclusively with known driver mutations but tended to coexist with MET amplification or copy number gain (P < 0.001). Low-level MET amplification and polysomy might occur in the background of EGFR or KRAS mutation whereas high-level amplification (MET/CEP7 ratio ≥5) was mutually exclusive to the major driver genes except METΔ14. Oncogenic METΔ14 mutation and/or high-level amplification occurred in a total of 3.3% (23/687) of NSCLC and associated with higher MET protein expression. METΔ14 occurred more frequently in older patients whereas amplification was more common in ever-smokers. Both METΔ14 and high-level amplification were independent prognostic factors that predicted poorer survival by multivariable analysis. CONCLUSIONS: The high incidence of METΔ14 mutation in sarcomatoid carcinoma suggested that MET inhibition might benefit this specific subgroup of patients. Clin Cancer Res; 22(12); 3048-56. ©2016 AACRSee related commentary by Drilon, p. 2832.

Profiling of Oncogenic Driver Events in Lung Adenocarcinoma Revealed MET Mutation as Independent Prognostic Factor.

INTRODUCTION: Oncogenic driver mutations activating receptor tyrosine kinase pathways are promising predictive markers for targeted treatment. We investigated the mutation profile of an updated driver events list on receptor tyrosine kinase/RAS/PI3K axis and the clinicopathologic implications in a cohort of never-smoker predominated Chinese lung adenocarcinoma. METHODS: We tested 154 lung adenocarcinomas and adenosquamous carcinomas for EGFR, KRAS, HER2, BRAF, PIK3CA, MET, NRAS, MAP2K1, and RIT1 mutations by polymerase chain reaction-direct sequencing. MET amplification and ALK and ROS1 translocations were assessed by fluorescent in situ hybridizations. MET and thyroid transcription factor-1 protein expressions were investigated by immunohistochemistry. RESULTS: Seventy percent of lung adenocarcinomas carried actionable driver events. Alterations on EGFR (43%), KRAS (11.4%), ALK (6%), and MET (5.4%) were frequently found. ROS1 translocation and mutations involving BRAF, HER2, NRAS, and PIK3CA were also detected. No mutation was observed in RIT1 and MAP2K1. Patients with EGFR mutations had a favorable prognosis, whereas those with MET mutations had poorer overall survival. Multivariate analysis further demonstrated that MET mutation was an independent prognostic factor. Although MET protein expression was detected in 65% of lung adenocarcinoma, only 10% of the MET-immunohistochemistry positive tumors harbor MET DNA alterations that drove protein overexpression. Appropriate predictive biomarker is essential for selecting patients who might benefit from specific targeted therapy. CONCLUSION: Actionable driver events can be detected in two thirds of lung adenocarcinoma. MET DNA alterations define a subset of patients with aggressive diseases that might potentially benefit from anti-MET targeted therapy. High negative predictive values of thyroid transcription factor-1 and MET expression suggest potential roles as surrogate markers for EGFR and/or MET mutations.

Statement on steroidal oral contraception.

PIP: This report summarizes a meeting of the IPPF International Medical Advisory Panel (IMAP) held in November, 1986, at which information on steroidal oral contraception (OC), Acquired Immunodeficiency Syndrome (AIDS), and female sterility were discussed. Regarding the multiphasic OC now in use, the benefits to health and well-being outweigh the possible side-effects and infrequent complications. Use is associated with a lower incidence of pelvic inflammatory disease, 96-98% effective prevention of pregnancy, a protective effect against ovarian and endometrial cancer, and regulation of erratic menstrual cycles. Minor side effects include nausea, vomiting, dizziness, headache, fluid retention, and inter-menstrual spotting. Adverse effects are circulatory system disease, myocardial infarction, venous thromboembolism, elevated blood pressure, and liver disease. Data on possible carcinogenicity have been conflicting. For women over age 40 OCs should be prescribed with caution. IMAP also drew up recommendations to assist FPAs to play a more active role in controlling the spread of AIDS. An effective program of Information and Education is of primary importance, targeting family planning workers and clients, teachers, parents, and employers. Wide promotion of condom use is a priority. Studies in Africa have revealed a major epidemic of AIDS, with the major mode of transmission heterosexual. The only immediate practical step in prevention of spread is by changes in sexual behavior. The last topic discussed is that of sterility in African women. The naturally occurring level of infertility expected in all populations of women is 3%; high levels in Africa vary by region from 3-32%. These levels of sterility are acquired through infection with Neisseria gonorrheae and Chlamydia trachomatis. Silent infection of women with Chlamydia make treatment especially difficult.^ieng

Australia antigen and hepatitis in Accra, Ghana.

Viral hepatitis in young adults in Accra, Ghana, is associated with Australia antigen (H.A.A.). Sera from 85 patients in hospital with viral hepatitis were available for determinations of H.A.A. Of the 16 patients whose serum was obtained within the first week of symptoms, 15 were positive. The only factor related to finding H.A.A. was the time between onset of symptoms and the collection of the serum sample. Persistence of H.A.A. was associated with persistence of jaundice in men but not in women. Previous epidemiological studies in Accra found no evidence for parenteral transmission of viral hepatitis and showed a shanty-town predilection pointing to faecal-oral transmission. It thus seems that H.A.A.-associated hepatitis is transmitted in West Africa either faecal-orally or by shanty-town associated arthropods. The finding that H.A.A. hepatitis is the usual hepatitis in young adults in Accra is in accord with the high prevalence of H.A.A. elsewhere in the general population in Africa and may be related to the high rate of cirrhosis and hepatoma in Africa.