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

USPSTF recommends biennial breast cancer screening beginning at age 50.

The USPSTF today once more made an important update to its 2009 U.S. Preventive Services Task Force (USPSTF) recommendation on screening for breast cancer. The USPSTF recommends biennial screening mammography for women aged 50 to 74 years. (B recommendation).These recommendations were published in the on-line issue of Annals of Internal Medicine on January 12, 2016.

Breast Cancer Screening Recommendations for Average-Risk Women

Agency issuing guidelines	Recommendations
USPSTF 2015
40–49 years	Screening decision should be an informed, individual one, after she weighs the potential benefit against the potential harms.( C recommendations )
50–74 years	Mammography every 2 years (B recommendation)
≥75 years	Data were not sufficient to establish the benefits of mammography screening in women aged 75 years or older.( I statement)
ACOG
40 years ≥	Annual mammograms beginning at age 40.
ACS
45 years	Annual screening beginning at age 45
45-54 years	Annual screening
55 and older	Transition to biennial screening or have the opportunity to continue screening annually depending upon personal preference. Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or longer
NCCN
40 years ≥	Clinical breast exam every 6-12 + annual mammogram beginning at age 40years. Upper age limit for screening not established; screening can continue if the woman is in good health and is expected to live at least 10 more years

  

Breast cancer is the second-leading cause of cancer death among women in the United States.

In 2015, an estimated 232 000 women were diagnosed with the disease and 40,000 women died of it.

There are approximately 125 new cases of breast cancer and about 22 deaths per 100 000 U.S. women each year. The mean age at diagnosis has remained unchanged at 64 years since the late 1970s.

It is most frequently diagnosed among women aged 55 to 64 years, and the median age of death from breast cancer is 68 years.

Across all ages, screening mammography has a sensitivity of approximately 77% to 95% and a specificity of about 94% to 97%

Dr.Christine Laine praises the USPSTF in an accompanying editorial saying that “The USPSTF did a difficult job well, considering updated evidence reviews, fuller panoply of potential harms, and tradeoffs of different screening strategies.”

She also said that “ Although for many years the dogma was that women should have mammograms “once a year for a lifetime” starting at age 40 years, current evidence shows that the balance of risks and benefits of screening, particularly among women in their 40s, warrants more nuanced decision making. Potential harms of over diagnosis and overtreatment of lesions with little progressive potential and harms of false-positive screening results with unnecessary biopsies and multiple repeated examinations must be considered”.

The following recommendation (originally issued in 2009) still stands: Each average-risk woman between the ages of 40 and 49 years should make her own decision about whether to have a mammogram, based on her personal balancing of the benefits and harms of screening (a grade “C” recommendation).

Benefit of Screening

Over a 10-year period, screening 10 000 women aged 60 to 69 years will result in 21 (95% CI, 11 to 32) fewer breast cancer deaths. The benefit is smaller in younger women: Screening 10 000 women aged 50 to 59 years will result in 8 (CI, 2 to 17) fewer breast cancer deaths, and screening 10 000 women aged 40 to 49 years will result in 3 (CI, 0 to 9) fewer breast cancer deaths.

Harms of screening

The harms of screening are over diagnosis and over screening that is diagnosis and treatment of non invasive and invasive cancer that would never have been detected in the absence of screening. Existing technology does not allow us to segregate with precision about how much is over diagnosis and how much was real diagnosis.

The best estimates from randomized, controlled trials (RCTs) evaluating the effect of mammography screening on breast cancer mortality suggest that 1 in 5 women diagnosed with breast cancer over approximately 10 years will be over diagnosed.

Based on data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program: The baseline breast cancer incidence rate was 105 to 111 cases per 100 000 women (depending on whether one considers invasive disease or invasive plus noninvasive disease together). With the widespread diffusion of mammography screening in last 30 years, this rate increased to 165 cases of noninvasive plus invasive disease per 100 000 women in 2011 (an excess of 54 to 60 cases per 100 000 women, or about a 50% increase).

Breast cancer mortality rates have declined at a slower rate, from 31 to 22 cases (or a reduction of 9 deaths) per 100,000 women over the same time period.

The USPSTF concludes that while there are harms of mammography, the benefit of screening mammography outweighs the harms by at least a moderate amount from age 50 to 74 years and is greatest for women in their 60s. For women in their 40s, the number who benefit from starting regular screening mammography is smaller and the number experiencing harm is larger compared with older women.

The current recommendations by USPSTF are based upon modeling studies conducted in support by the Cancer Intervention and Surveillance Modeling Network (CISNET). The investigators at CISNET evaluated data from six models that were grouped according to various screening strategies, various starting age and frequency.  The model with no screening served as reference.

It was seen that strategies involving screening every 2 years were consistently the most efficient for women at average risk for breast cancer.

The models showed that for women in the age group 50 to 74 years, biennial screening would prevent a median of seven breast-cancer deaths, compared with no screening vs. if the screening started at age 40, three additional breast cancer deaths would be prevented, but there would be 1988 more false-positive results and seven more over diagnoses for every 1000 women screened.

Dissatisfaction with the updated guidelines.

Many of the National agencies like National Comprehensive Cancer Network (NCCN) and M.D. Anderson Cancer Center are continue to screen women annually beginning at age 40 till she is within a decade of the predicted end of her life according to Therese Bevers, MD, medical director of the Cancer Prevention Center at the M.D. Anderson Cancer Center in Houston, and chair of NCCN guideline panels on breast cancer screening and diagnosis and breast cancer risk reduction.

National breast cancer screening programs in other countries like the United Kingdom,  Netherlands, Switzerland, Poland, Norway, Luxembourg, Germany, Finland, Denmark, and Belgium offer mammography screening every 2 to 3 years for women aged 50 up to 74 years.

References:

http://annals.org/article.aspx?articleid=2480757

http://annals.org/onlinefirst.aspx

http://www.medscape.com/viewarticle/857027#vp_3

http://jama.jamanetwork.com/article.aspx?articleid=2463262

http://jama.jamanetwork.com/article.aspx?articleid=2463261

http://annals.org/article.aspx?articleid=2480757#r50-2886

http://www.acog.org/Womens-Health/Breast-Cancer-Screening

http://ladiesfirstproviders.vermont.gov/sites/ladiesfirst/files/pdf/NCCN/breast-screening.pdf