The NCCN add new inherited genetic mutations that are linked to ovarian and breast cancer.

The National Comprehensive Cancer Network (NCCN) has implicated several additional mutations when planning risk management strategies in patients with hereditary breast and ovarian cancer. These mutations confer a risk of either or both cancers with relatively high penetrance.

Dr. Tuya Pal  MD, from the Moffitt Cancer Center, Tampa, Florida said “ the recent discovery that the genetic mutation PALB2 is associated with an aggressive form of breast cancer, as well as the realization that the newer ovarian cancer genes RAD51C, RAD51D, and BRIP1 pose an added lifetime risk for ovarian cancer, should prompt physicians to discuss possible prophylactic procedures with patients who are found to carry these mutations” at 21^st Annual National Comprehensive Cancer Network (NCCN) conference in Hollywood, FL.

It is known that women who have BRCA1 carriers have a 55 to 65 percent chance of developing breast cancer and 35 to 70 % chance of developing ovarian by age 70 and the corresponding numbers for BRCA2 carriers are 45% and 10-30% respectively. Women with Lynch syndrome have around 10% chance of developing ovarian cancer. The researchers at the conferences implicated additional mutation BARD1, BRIP1, RAD51C, RAD51D and PALB2 with similar level of evidence as BRCA1/2 for ovarian cancer.

Together with established Ovarian Cancer (OC) genes, this addition bring the total number of genes suspected to cause hereditary OC to 11.

Till now, the NCCN was advising or recommending risk reduction surgery of salpingo-oophorectomy as a part of preventive strategy in BRCA1/2 mutation carrier. According to National Cancer Institute( NCI) the lifetime risks of ovarian cancer are 5.2% in RAD51C mutation carriers, 5.8% in BRIP1 mutation carriers, and 12% in RAD51D mutation carriers; risk-reducing salpingo-oophorectomy (RRSO) may be considered for these patients upon completion of childbearing. 

Genes such as CHEK2 and ATM are associated with a 20% or higher lifetime risk of breast cancer; similarly, genes such as RAD51C, RAD51D, and BRIP1 are associated with a 5% to 10% risk of ovarian cancer; many of these genes are now included on multi-gene panels, although the clinical actionability of these findings remains uncertain and under investigation.

Screening for these genes is specifically important in regards to Ovarian cancer as there are no screening test and diagnostic modalities at present to catch the disease at an early stage.

A family history should always be taken into account and with strong family history; prophylactic risk management in the form of oophorectomy should be considered.

PALB2 is also an important genetic mutation added to the list along with PTEN, and PT53 that causes the Breast cancer. Women with an abnormal PALB2 gene have a 14% risk of developing breast cancer by age 50 and a 35% risk of developing breast cancer by age 70. It is also seen that cancers developing in patients with the genetic mutation PALB2   are very aggressive and in a polish study  survival for women with breast cancer and a PALB2 mutation was 48·0% compared with 74·7% for patients without a mutation.

So, genetic testing at this point of time has become an important part of cancer management, because if we are proactive we can diagnose the cancer at very early stage or prevent it altogether if we know our risk for them.

Much progress has been made in the field of genetic testing with increased use of multi-gene testing. Genetic testing allow the patients to make an informed decision, about there course of treatment, prognosis and any other cancer risks due to genetic mutation.

The updated NCCN Guidelines for Women with Mutations in PALB2, ATM, CHEK2, BRIP1, RAD51C, and RAD51D

1) Breast Cancer Screening:

Annual MRI beginning at age 30 or earlier, based on family breast cancer history for women with mutations in following genes: ATM, CHEK2 and PALB2

2) Breast Cancer Risk Management
Discussing the option of risk-reducing mastectomy for women with mutations in: PALB2

3) Ovarian Cancer Risk Management

Women with mutations in following genes should consider risk-reducing removal of ovaries and fallopian tubes: BRIP1, RAD51C and RAD51D.

References:

http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2815%2970142-7/fulltext?rss=yes

http://www.cancer.gov/types/breast/hp/breast-ovarian-genetics-pdq

http://ww5.komen.org/BreastCancer/InheritedGeneticMutations.html

http://www.facingourrisk.org/understanding-brca-and-hboc/information/risk-management/introduction/basics/nccn_guidelines_for_women_with_brca.php#text

https://www.sciencedaily.com/releases/2016/02/160210135406.htm

http://www.cancer.gov/types/breast/hp/breast-ovarian-genetics-pdq#section/_589

Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population JCO (2015) 33 (26): 2901-2907

Endocrine Disruptors linked to Endometriosis, Fibroids and rising healthcare costs!

 European Union data revealed that Women are facing a potential risk of several reproductive disorders being exposed common chemicals in the household and incurring huge public health cost.

Endocrine-disrupting compounds (EDCs) act as covert bombers of environmental toxins on human body. They are ubiquitous in our environment, entering our bodies without our knowledge-plastic linings in cans, water bottles, toys and most recently in the thermal paper used in cash register and gas pump receipts.

The recent study led by Patricia Hunt, PhD, at Washington State University was published online March 22, 2016 in the Journal of Clinical Endocrinology & Metabolism. The researchers found that exposure to controversial chemicals, like phthalates and diphenyldichlorethene (DDE), increase a woman’s likelihood of developing endometriosis and fibroids, causing reproductive health problems and incurring a whopping sum of  estimated €1.4 billion ($1.5 billion) a year in health care expenditures and lost earning potential to European Union.

Senior author Leonardo Trasande, MD, MPP, associate professor of pediatrics, environmental medicine & population health at NYU Langone Medical Center, New York, opines that this is just the tip of the iceberg of the entire female reproductive disease burden due to EDC.

Hunt and her colleagues identified other chemicals namely dioxins and polychlorinated biphenyls (PCBs), among others -- but decided to focus on phthalates and diphenyldichlorethene (DDE) as most robust set of data existed for these chemicals. 

DDE is a breakdown product of the insecticide DDT that, although banned in the United States in 1972 and in Europe starting in the 1970s still lingers in the environment and enters our body through food. The main exposure to phthalates is through eating food and drink stored in plastic containers that have phthalates.

In both cases, the epidemiological evidence was low and toxicological evidence was moderate but of all the total cases 20%–39% cases were attributed to these chemicals.

The researchers determined that 145,000 cases of endometriosis among women aged 20 to 44 years and 56,700 cases of uterine fibroids in Europe could be attributed to exposure to endocrine-disrupting chemicals.

In women 15-54 of age, the exposure to DDE was measured in 12 studies by taking a sample of cord blood. They then adapted an Intergovernmental Panel on Climate Change (IPCC) model for determining the probability of causation. The women were separated into groups according to degree of exposure, with the lowest level used as the base and than the odds ratio for developing fibroid was calculated.

The process for phthalate attributable endometriosis was similar, but the investigators relied on data from a large biomonitoring study called as DEMOnstration of a study to COordinate and Perform Human biomonitoring on a European Scale (DEMOCOPHES). Human biomonitoring (HBM) involves collecting samples from human volunteers – blood, hair, saliva or urine – and measuring the levels of indicators of chemicals uptake (known as biomarkers) that are of interest.

The authors further added that "Although it is highly appropriate to focus on these extremely important uterine tract health deficits, [polycystic ovary syndrome], infertility, and pregnancy complications also affect a considerable number of women, have major cost implications, and are increasingly linked to EDC exposures." For instance, phthalate exposure has a 40% to 69% likelihood of causing 618,000 additional assisted reproductive technology procedures each year, and a 20% to 69% likelihood of causing 42,400 new cases of childhood obesity each year.

The director of the National Institute of Environmental Health Sciences and the National Toxicology Program Linda S. Birnbaum said “Some of these chemicals, including PCBs and dioxins, have already been restricted through a treaty called the Stockholm Convention on Persistent Organic Pollutants, which went into effect in 2004.”

The current study is important because it focused on chemicals that have not been restricted, and in the case of DDE -- which persists in the environment -- are not able to be restricted.

"This study is kind of a wake-up to say endocrine disruptors impact the female reproductive system, and we have some evidence they are associated with an increase in endometriosis and fibroids and it costs a lot of money," Birnbaum said.

Not all researchers are convinced by the methodology. They say that to imply causation based on current data is highly speculative because most of the data is based on observational study and trials is human are hard to do.

Even with all the questions that remain, and few regulations in place, "there are safe and simple steps that families and women can take to reduce exposure to endocrine-disrupting chemicals," Trasande said.

"They can eat organic, reduce canned food consumption, which reduces exposure to BPA, and avoid packaged or highly processed food, which is a major route for phthalates to enter food. They can also open windows to allow chemical dust, which accumulates on the carpet and electronics, to circulate out of homes."

Although the study had several limitations: it focused on adult EDC exposure only; it relies on assumption of causation; and it focuses only on two reproductive disorders and two EDCs, it does draws attention on urgent need of  further research , government regulations and public awareness on the issue of toxic chemicals in the environment.

References:

http://press.endocrine.org/doi/10.1210/jc.2015-2873

http://saferchemicals.org/health-report/chemicals-and-our-health/reproduction/

http://www.aboutlawsuits.com/endocrine-disruptor-women-study-97423/

http://www.medpagetoday.com/OBGYN/GeneralOBGYN/56864

http://www.eu-hbm.info/democophes

http://www.thedoctorwillseeyounow.com/content/womens_health/art4602.html

https://www.endocrine.org/news-room/current-press-releases/womens-health-endocrine-disruptors-diabetes-research-will-be-in-spotlight-at-endo-2016

Incidence of still births halved after Seasonal Trivalent Influenza Vaccination During Pregnancy: First Population-Based Retrospective Cohort Study.

The Obstetric Practice and Immunization Expert Work Group of the American College of Obstetricians and Gynecologists (ACOG) updated the committee opinion that all pregnant women should receive influenza vaccination back in 2014. World Health Organizations and CDC guidelines recommend seasonal influenza vaccinations(inactivated influenza vaccine ) for pregnant women in any trimester. However, the live attenuated vaccine is not recommended for pregnant women but can be used safely during the postnatal period.

Pregnancy puts women at increased risk pneumonia and acute respiratory illnesses because of lowered immunity. Antenatal Infections are also linked to fetal mortality and preterm labor. But, in spite of it only 50% of women get themselves immunized due to safety concerns for the fetus.

Recent research shows that there are other maternal and fetal benefits of seasonal influenza vaccination, other than just preventing the flu. A Canadian study by published in Canadian Medical Association Journal has shown that Influenza Vaccination in pregnancy reduces the odds of having a preterm delivery or delivery of a low-birth-weight baby compared with pregnant women who did not get the vaccine.

A recent Population based retrospective study by published online on March 30, 2016 in the journal of Clinical Infectious Diseases  have shown that women in western Australia who received the vaccine have half the risk of stillbirths as compared to women who do not receive the shot.

The lead author Annette K. Regan, MPH, from the School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, and Western Australia Department of Health, Shenton Park said in a news release “During the 2009 H1N1 pandemic, we saw a similar reduction in stillbirths following vaccination,” she added that “Our results are particularly exciting since they show we can get the same protection during seasonal epidemics, which occur every winter. Unfortunately, we know that about 40 percent of pregnant women go unvaccinated, missing out on these benefits.”

The researchers in Australia analyzed midwives’ data retrospectively. A total of 58,008 women delivered during the winter flu season in the year 2012 and 2013 in Western Australia. Out of which 5076 women received the influenza vaccine, and 377 stillbirths occurred. After adjusting for confounders (maternal smoking, indigenous status, and propensity for vaccination) the risk of stillbirth among vaccinated mothers was 51 percent lower than the risk among women who had not been vaccinated.

The observed rate of stillbirths also increased around the time of Influenza virus circulation, suggesting a link between the virus and stillbirths.

The authors call for further research to look into causes of decrease in still birth rates following Influenza vaccination.

"Given the growing body of evidence supporting the health benefits to mother and infant, concerted efforts are needed to improve seasonal influenza vaccine coverage among pregnant women," the researchers conclude.

The study limitations were being retrospective, depending upon data reporting by healthcare workers and generalizability of findings to women in developing countries.

The study also has wider implications on global public health level as vaccination against Influenza is an attainable step to avert stillbirths. In 2015, an estimated 2·6 million (uncertainty range 2·4–3·0 million) babies were stillborn, with 70% of infant death around the time of birth.

References:

http://www.thelancet.com/pdfs/journals/langlo/PIIS2214-109X%2815%2900275-2.pdf

http://www.eurekalert.org/pub_releases/2016-03/idso-siv032916.php

http://cid.oxfordjournals.org/content/early/2016/03/10/cid.ciw082.abstract