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.

Building on the Cairo consensus.

PIP: No major disagreements developed between the North and the South at the 1994 International Conference on Population and Development (ICPD) because the conference preparatory process and the program of action recognized that population as a global problem is not mainly the concern of developing countries, but is instead an integral part of sustainable development and environmental problems. It was accepted early in the preparatory process that overconsumption, extravagant lifestyles, and excessive waste production in the wealthier northern countries contribute to global population and sustainable development problems as much as rapid population growth does in the poorer southern countries. However, political will to address these problems appears to be weak. While there has been no rush to develop population policies, efforts seem to have been stepped up to implement those already existing population policies and to accord population and family planning higher program priority. The author discusses the need to coordinate governmental and nongovernmental agencies in developing comprehensive reproductive health care programs, adolescent sexuality, female genital mutilation, unsafe abortion, maternal mortality, South-South cooperation, and the need for funding.^ieng

The ICPD Programme of Action: pious hope or a workable guide?

PIP: The consensus achieved at the 1994 International Conference on Population and Development (ICPD) signaled a move away from discussing population issues in the context of demographic targets, toward global recognition that the problems associated with rapidly growing human populations are part of a broader human development agenda. Devoid of demographic targets, the ICPD program of action instead challenges countries to change their approach to population programs, family planning, and reproductive health. World Fertility Survey and Demographic and Health Survey data indicate a high level of unwanted fertility in almost all countries covered. The lack of availability or inaccessibility of family planning services is but one reason why there is so much unmet need. There would be greater uptake of family planning if services were planned with community involvement and oriented toward clients, offering them real choices and paying more attention to them as individuals and their overall circumstances. That expansion in concept and of services is at the core of the Cairo agenda. A number of countries around the world have started taking steps to broaden existing family planning and related programs to include other reproductive health information and services. Mexico and India are examples of two developing countries which are making program and structural changes in order to implement the ICPD recommendations, while most African countries have welcomed the approach and are looking for technical and resource help for implementation.^ieng

An overview of unsafe abortion in Africa. Foreword.

PIP: This overview of unsafe abortion in Africa indicates some reforms such as the provision of family planning services close to maternity units or hospitals where women can go for treatment of abortion. Medical students should learn how to perform a safe abortion and to manage incomplete abortions. Modern technology should be available for performing abortions. Abortion law should be examined from the medical and social perspective. The International Planned Parenthood Foundation's Strategic Plan, Vision 2000, in 1978, made the aforementioned recommendations and suggested that action be taken by family planning associations. This article refers to a number of studies that suggest a high rate of maternal mortality related to abortions performed under unsterile and unsafe conditions. Unsafe abortions may be performed by private doctors, traditional healers, or midwives. Unsafe practices include the insertion of IUDs or plastic cannulas or sticks and plants into the cervix. Women may resort to ingestion of unsafe products such as gasoline and other toxic substances in order to induce an abortion. Induced abortion rates among school girls is estimated to be high. There are health risks and health resources are strained from unsafe abortion. Most of the empirical studies of unsafe abortion are conducted in hospitals. Ironically, laws against abortion in Africa are the inheritance from colonial regimes that long ago abolished anti-abortion laws. The medical community is urged to respond with reason, moral sensibility, and social responsibility.^ieng

Reproductive health: towards a brighter future.

In 1972 the World Health Organization initiated the Special Programme of Research, Development and Research Training in Human Reproduction. Now cosponsored by the United Nations Development Programme, the United Nations Population Fund, the World Bank and WHO, the Programme has become the main instrument of research in reproductive health in the United Nations system. The progress that has been made, and the prospects for the future, are reviewed below.

Political and economic factors influencing contraceptive uptake.

International, national and local level politics influence the uptake of contraception through consensuses, laws, financial and moral support or the creation of an enabling atmosphere. Opposition to contraception generally comes from some churches and groups opposed to particular technologies. Socio-economic factors, particularly education, the health care system and the perceived or actual cost of fertility regulation as compared to benefits expected from children also powerfully influence contraceptive use. For many poor women in developing countries their powerlessness in relation to their male partners is an important obstacle.

PIP: Recent estimates put the overall contraceptive prevalence rate (CPR) in less developed countries (LDCs) at over 50%, a 6-fold increase from a 1960 average of 9%. Thailand's rate of 10% in 1971 rose to 50% in 1979 and to 75% in 1992. China, Colombia, Mexico, and Mauritius also have had significant changes in their contraceptive profiles. The contraceptive revolution has been fostered by international agencies through various conferences: the 1965 UN Debate on the population problem, the 1968 Teheran Conference on Human rights, the 1974 and 1984 population conferences, and the 1975 and 1985 conferences on the International Decade of Women. Ardent feminists oppose the distribution of the injectables Depo-Provera and Norplant, while the US Food and Drug Administration requirements take more than 10 years for the development and testing of a contraceptive. The US's so-called Mexico City Policy stated that the US would not fund any organization that promoted abortion, and, thereby, it influenced the availability of contraceptives. The US managed to bring down its total fertility rate from 6.0 to 3.5 between 1842 and 1900. Indonesia achieved the same fertility decline between 1961 and 1984. Colombia, with much stronger programs and higher CPR, achieved it in 15 years, while Thailand, with a very comprehensive program, and China, with an even stronger one and an aggressive political leadership, achieved a similar rate of decline in 7 years. Higher gross national product is correlated to lower total fertility rate except for China, Sri Lanka, and Kerala in India. In communities where children contribute to the family economy, birth control tends to be regarded negatively; while in societies where the family contribution to the child's education is high, contraceptive use is also high. The cost of contraception includes the actual cost of the product, the cost of delivery, and travel costs and waiting time to the consumer.

How family planning can save lives in Africa.

PIP: A pregnant woman in subSaharan Africa is 75 times more likely to die as a result of her pregnancy than a woman in western Europe. Most African doctors probably concentrate upon preventing and treating the medical causes of maternal mortality such as hemorrhage, toxemia, difficult and prolonged labor, incomplete abortion, and puerperal infection, but give less attention to non-medical factors such as multiparity, nutritional deficiencies, socioeconomic conditions, or whether women want children or not. Evidence from around the world shows that the risk of maternal or infant illness and death is highest in pregnancies before age 18 and after age 35 years, pregnancies after four births, and pregnancies spaced less than two years apart. Approximately 5.6 million infant deaths and 200,000 maternal deaths could thus be avoided annually if women chose to have their children within the safest years, with adequate spacing between births, and had completed families of moderate size. Good availability and use of effective and safe contraception could help reduce the number of women dying in childbirth from high-risk pregnancies and botched abortions. The author, president of the International Planned Parenthood Federation, urges doctors to promote family planning and recommends re-educating all health workers in family skills and the vital importance of contraceptive services for family health. The importance of reaching rural women and applying community-based distribution and social marketing approaches is stressed.^ieng

Safe Motherhood Initiative: getting our priorities straight.

PIP: Developing countries, nongovernmental organizations, and the international development community support the Safe Motherhood Initiative. These partners know why they need to take action to assure safe motherhood, but do not agree on how to make motherhood safe. The dominant view is that the 1st priority is to provide and/or improve needed obstetric care at the 1st referral level and manage complications once they occur. It is based on the fact that the medical community cannot yet identify most women with pregnancy complications in time to prevent their occurrence. 2 safe motherhood advocates challenge this view. They point out that it only centers on reducing maternal mortality. 2nd they believe that prenatal care and health education do play a strategic role in making motherhood safe because they can inform, motivate, and empower women to use formal emergency care services. 3rd health workers should not dismiss prenatal care since some interventions are indeed effective, e.g., prevention, detection, and investigation of anemia and hypertensive disease of pregnancy and prevention and treatment of sexually transmitted diseases. Finally some areas in developing countries do not have the resources to establish or upgrade referral level health facilities so they must maximize existing resources to intervene and treat complications such as training midwives, nurses, and traditional birth attendants. The advocates propose 3 tired strategies to bring about safe motherhood. The provision of prenatal care, trained attendance at delivery, accessible emergency services, and family planning and abortion services comprise the 1st tier. The 2nd tier of activities targets youth. These activities include sexual and reproductive health programs, education, female employment opportunities, and legislation on age of marriage. The 3rd tier embraces all factors that influence women's health and status: sexual and reproductive health, education, income, social and cultural practices, and laws that govern women and their social position.^ieng

Open letter to Pope John Paul II.

PIP: In an Open Letter to Pope John Paul II, written on World Population Day (July 11) 1991, Dr. Fred Sai, President of International Planned Parenthood Federation (IPPF), called for a dialogue on voluntary family planning as a means of avoiding unwanted pregnancy. A half million women die each year from pregnancy-related causes--a death toll that could be dramatically reduced by universal access to low cost, effective contraception. Family planning further represents the best protection against abortion. The Catholic Church's vehement opposition to abortion and family planning methods other than periodic abstinence is in marked contrast to its support to human rights in other settings. The Church has supported struggles for economic ju stice in and among nations, sided with the poor, and advocated for transitions to democracy. At the same time, the family planning movement--which has as its overall objective the protection of the health and welfare of women, children, and families--is viewed by the Vatican as a vehicle for the enslavement rather than liberation of women. The opening of a sensitive dialogue between the Catholic Church and supporters of voluntary family planning could help couples make sound moral decisions about their families and contribute to saving the lives of millions of women, most of them poor.^ieng

The need for a reproductive health approach.

A reproductive health approach recognizes that the foundations of women's health are laid in childhood and adolescence, and are influenced by factors such as nutrition, education, sexual roles and social status, cultural practices, and the socioeconomic environment. Reproductive health care strategies to meet women's multiple needs include education for responsible and healthy sexuality, safe and appropriate contraception, and services for sexually transmitted diseases, pregnancy, delivery, and abortion.

Child spacing: impact on health.

PIP: The incidence and pattern of infant death and child illness and death are closely linked to fertility levels and birth intervals. Estimates from the World Fertility Survey data for all countries combined show that infant mortality is 60-70% higher for children born within 2 years or less of birth of an older sibling. Risk for the older child is 77% higher if a new baby is born within 1 year. About 1 in 7 of the 14 million deaths among children under 5 are associated with poor birth spacing. The detailed risk factors explaining these deaths include stopping breast feeding too soon, which increases likelihood of succumbing to diarrhea and respiratory infections. Breast feeding into the 2nd and 3rd years supplements nutrition where malnutrition is common. Since breast feeding has a natural contraceptive effect, early weaning may be a cause of rapid pregnancy as well as a result. A major advantage of longer birth intervals is reduced chance of low birth weight, a major contributing factor in infant deaths. Family health is another effect of longer child spacing because the mother has time to recover physically, to care for other young children, and give them time and attention. With fewer youngsters, change of infection passing between them is much lower. Women need access to family planning and education about the importance of breast feeding.^ieng