Hereditary breast and ovarian cancer (HBOC) syndrome is an inherited disorder in which the risk of breast, ovarian and several other cancers is higher than normal. HBOC is becoming more well-known both in the media and better defined from a scientific standpoint. Most HBOC is due to mutations in breast cancer susceptibility gene 1 (BRCA1) or 2 (BRCA2). All primary care practitioners should have a general understanding of the role of breast cancer genes, along with an in-depth understanding of which patients have a high risk of having the mutations (and therefore a higher risk of developing the cancers themselves). This paper reviews measures that may reduce the risk of developing BRCA-related cancers and addresses the role of progesterone in the carcinogenic process for carriers of BRCA1/2 mutations (mutations in either the BRAC1 or BRAC2 gene).
In the United States, 12% of women will be diagnosed with breast cancer by age 70.1 In women with hereditary breast and ovarian cancer (HBOC) syndrome, breast cancer risk climbs to 40% to 80%.2 Ovarian cancer risk in some women with HBOC may be as high as 40%, compared to a 1% to 2% risk of ovarian cancer in the general population.3 While individuals with HBOC have a high risk for breast and ovarian cancers, HBOC is involved in only 5% to 10% of breast cancers and 10% to 15% of ovarian cancers in the United States.4
Hereditary breast and ovarian cancer syndrome is due to mutations in breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2).2 There are other genes responsible for heritable breast and ovarian cancers—for example, PTEN (Cowden syndrome), TP53 (Li-Fraumeni syndrome), and PALB2—but this review is limited to the role of BRCA1 and BRCA2 specifically.5
Both BRCA1 and BRCA2 are tumor suppressor genes. Located at position 21 of the long arm of chromosome 17 (17q21), BRCA1 was the first genetic aberration to be implicated in HBOC. The BRCA2 gene occupies position 12.3 on the long arm of chromosome 13 (13q12.3). It is also involved in Fanconi anemia and is synonymous with the Fanconi susceptibility gene (FANCD1).
Both BRCA1 and BRCA2 genes are autosomal dominant, meaning even if only 1 parent harbors a deleterious allele, each child has a 50% chance of inheriting it. Autosomal dominance, together with high penetrance in those harboring pathogenic variants, renders BRCA1/2 aberrations the most prevalent heritable causes of breast or ovarian cancer.2
Functional, nonmutant (wild-type) BRCA1 (wild-type BRCA1) and BRCA2 (wild-type BRCA2) encode proteins (BRCA1 or BRCA2 proteins) that are directly or indirectly involved in tumor suppression through DNA repair.6 These genes are essential to the continuous health of all cells of the body, which is why they're known as housekeeping genes. When either the BRCA1 or BRCA2 gene is compromised, its protein product can be incomplete (truncated) or missing altogether.
As with all genes, each parent contributes one allele to its offspring. This means there is one functional allele (wild-type BRCA) from the unaffected parent. The functional allele allows for normal BRCA1 and BRCA2 protein expression and corresponding tumor suppression. It is only when the BRCA1 or BRCA2 gene is no longer functional that DNA repair is compromised and tumor suppression is impaired.
In cancers that involve a BRCA1/2 mutation, often dubbed “BRCA-positive“ cancers, the aberrant BRCA1 or BRCA2 gene turns off the function of the unaffected allele (wild-type BRCA). Silencing of wild-type BRCA leads to loss of tumor suppression through the loss of functional protein (BRCA1 or BRCA2) expression. The majority of the time this event takes place in epithelial cells of the breast, ovaries, or fallopian tubes.7
Reproductive Hormones in BRCA1/2 mutation carriers
Perhaps the strongest evidence that reproductive hormones are causally linked to carcinogenesis in those with HBOC is the reduction in risk of breast cancer in premenopausal women who undergo prophylactic salpingo-oophorectomy. Lesser hormonal influences such as breastfeeding and later menarche appear to have some protective effects as well.8
One study found that circulating levels of both estrogen and progesterone are higher in BRCA1/2 mutation carriers versus noncarriers.9 Carriers of BRCA1/2 mutations also had a thicker endometrial lining during luteal phase and a thinner lining during follicular phase. The authors propose that systemic hormone dysregulation, as well as variations in hormone receptors, contributes to the organ specificity of BRCA1/2 cancers. Further, the authors postulate that higher estrogen and progesterone may contribute to the risk of breast and ovarian cancer and reduce risk of endometrial cancer in BRCA1 mutation carriers. However, this directly contradicts current evidence suggesting less risk of ovarian cancer with use of combined contraceptives (estrogens plus progestins) in all women, including BRCA1/2 mutation carriers.10 The implications on breast cancer, while not consistent, are congruent in implicating the hormonal milieu as a causative factor in women, including BRCA1/2 mutation carriers.
How hormones affect normal cells or established cancer cells may be different than how they affect cells harboring a BRCA1/2 mutation. For example, progesterone is capable of decreasing estrogen receptor-alpha expression in breast cancer cells11 and inhibits the proliferation of ovarian cancer cells.12 However, progesterone is also highly implicated in carcinogenesis of cells harboring BRCA1/2 mutations via activation of receptor activator of nuclear factor kappaB ligand (RANKL).
While better known for its role in bone remodeling, RANKL is involved in the steroidal development and proliferation of breast tissue. It is also thought to be the linchpin in progestin-driven mammary carcinogenesis.13
Progesterone’s influence on RANKL is mediated through osteoprotegerin (OPG), an endogenous inhibitor of RANKL activity. In women with deleterious BRCA1/2 mutations, there is a lower level of circulating OPG.14 Further, this lower circulating OPG correlates with higher levels of progesterone during the menstrual cycle. High progesterone with low OPG results in less inhibition of RANKL and greater likelihood of RANKL-driven carcinogenesis.
Genetic anticipation is the observation of earlier age of onset or more severe clinical features in ensuing generations with a given genetic disorder or syndrome. This appears to be the case, at least for some pathogenic variants, with BRCA1/2. In one study at the University of Texas MD Andersen Cancer Center, 106 women with a BRCA1/2-related cancer were paired with a family member of the previous generation who also had a diagnosis of breast or ovarian cancer.15 While the average age of diagnosis in the study cohort was 42 years, the prior generation was diagnosed at an average age of 48 years. The newly diagnosed cohort was 7.9 years (P<0.0001) younger at the time of diagnosis, and this held true for both BRCA1 and BRCA2 mutations.
In another study looking at 40 families with BRCA1, 52 families with BRCA2 and 531 families with a familial predisposition without any known BRCA mutation (BRCAx families), anticipation was 6.8, 12.1, and 12.3 years earlier for BRCA1, BRCA2 and BRCAx respectively.16 The authors hypothesized that shorter telomeres may be associated with higher risk. Telomere length was significantly shorter for the BRCA1 and BRCA2 women who were diagnosed with cancer, while the BRCAx cohort did not have significantly shorter telomeres. Shorter telomeres lead to greater destabilization of chromosomal DNA, and this can lead to DNA replication defects. By definition, pathogenic variations in BRCA1/2 genes lead to the inability to repair such defects.17-18
Who is at risk?
According to the CDC,19 individuals who meet any of the following criteria may have an increased risk for a BRCA1 or BRCA2 gene mutation:
- Several relatives with breast cancer
- Any relatives with ovarian cancer
- Relatives who got breast cancer before age 50
- Relative with cancer in both breasts
- Relative who had both breast and ovarian cancers
- Male relative with breast cancer
- Relative with a known BRCA mutation
- Ashkenazi Jewish ancestry and any relative with breast or ovarian cancer
The US Preventive Services Task Force (USPSTF),20 the American College of Obstetricians and Gynecology (ACOG), and the National Comprehensive Cancer Network (NCCN) have each established guidelines directed to clinicians regarding appropriate referral to discuss genetic testing for HBOC. According to the NCCN, clinicians should refer patients to a genetic counselor when they meet any 1 or more of the following criteria:21
- Individual from a family with a known deleterious BRCA1/2 mutation
- Personal history of breast cancer, AND one or more of the following:
o Diagnosis on or before age 45
o Diagnosis on or before age 50 with:
-An additional breast cancer primary
-1 or more close blood relatives with breast cancer (any age)
-1 or more close relatives with pancreatic cancer
-1 or more relatives with prostate cancer (Gleason 7+)
-An unknown or limited family history
o Diagnosis on or before age 60 with a triple-negative breast cancer
o Diagnosis at any age with:
-1 or more close blood relatives with breast cancer diagnosed before age 50
-2 or more close blood relatives with breast cancer at any age
-1 or more close blood relatives with invasive ovarian cancer
-2 or more close blood relatives with pancreatic cancer and/or prostate cancer (Gleason 7+) at any age
-A close male blood relative with breast cancer
-No family history required for those of Ashkenazi Jewish descent
- Personal history of invasive ovarian cancer (any age)
- Personal history of male breast cancer
- Personal history of prostate cancer (Gleason 7+) at any age, AND 1 or more close blood relatives with breast cancer (<50 years) and/or invasive ovarian and/or pancreatic or prostate cancer (Gleason 7+) at any age
- Personal history of pancreatic cancer at any age with 1 or more close blood relatives with breast (<50 years) and/or invasive ovarian and/or pancreatic cancer at any age
- Personal history of pancreatic cancer and Ashkenazi Jewish descent
Close blood relatives include members of the first, second, and third generations on the same side of the family.
There are ethnic as well as geographic regions whose populations have given rise to specific mutations in BRCA1 or BRCA2. This is a founder effect, where a small group of people that colonizes an area affects the gene pool with distinct genotypes in ensuing generations. The most well-characterized are 3 founder mutations in Ashkenazi Jewish (Eastern European) descendants. Eighty-five percent of the BRCA1 or BRCA2 mutations in Ashkenazi Jewish descendants contain 1 of the 3 founder mutations (BRCA1: 185delAG or 5382insC; BRCA2: 6174delT).22 Other founder mutations are from Italian, Icelandic, Polish, British, Dutch, Norwegian, Swedish, and Russian populations.23
There are ethnic as well as geographic regions whose populations have given rise to specific mutations in BRCA1 nbsp;BRCA2.
Ashkenazi Jewish descendants appear to have the highest prevalence of BRCA1/2 mutations, with an estimated 2.5% affected. This compares to an estimated 1 in 300 to 1 in 500 women in the general population in the United States.24 Thus, the level of suspicion should be high and the threshold for referral to genetic counseling or geneticist low in all patients of Ashkenazi Jewish heritage.
Both the NCCN and USPSTF recommend referral to a geneticist or genetic counselor before testing for HBOC. Consultation with an expert in hereditary cancer ensures fully informed consent before testing. Education regarding the risks and benefits, various options for testing, and availability for follow-up consultations is in the best interest of the patient. Interpretation of genetic tests is not always straightforward and whether the results are positive, negative, or ambiguous (ie, variants of unknown significance), a genetics expert can discuss the ramifications of the results. Lastly, finding out that you have a deleterious mutation can have profound psychological consequences, as you face the decision about how to best proceed for both your own health and that of blood relatives.25
Testing for Hereditary Breast and Ovarian Cancers
Clinicians may recommended testing for those who meet the criteria of high risk as described above. The CDC lists 5 screening tools to help clinicians identify those at high risk of HBOC.26 Essentially, a high level of suspicion should be immediate if a patient presents with a male relative with breast cancer, multiple first and second degree relatives with breast cancer and/or ovarian cancers, or relatives diagnosed with breast or ovarian cancer at a young age (<50 years).
Population-based screening, in which everyone in a given population is tested regardless of their family history of cancer, may be on the horizon. This is the call to action by geneticist Mary-Claire King, PhD, who first discovered and named the gene region associated with inherited breast cancers (BRCA1).27 In a 2014 letter to JAMA, King and colleagues wrote, “because there is 2 decades more experience with BRCA1 and BRCA2 than with most other breast cancer genes, we suggest that population-based screening begin with BRCA1 and BRCA2, with the important understanding that women from severely affected families be tested for all known breast and ovarian cancer genes.”28 King and colleagues go on to advocate for general screening to potentially save hundreds of thousands of women the diagnosis and treatment for cancer. “In the United States as a whole, the number of carriers of actionable mutations in BRCA1 and BRCA2 carriers is estimated to be between 1 in 300 and 1 in 500 women, or between 250,000 and 415,000 adult women for whom breast and ovarian cancer is both highly likely and potentially preventable.”
While the economics of testing all women regardless of risk will continue to be debated, there is agreement that all women at high risk should be identified and tested for HBOC-relevant genetic mutations.
Recommendations against such screening are, at least partly, rooted in economics. The American College of Obstetrics and Gynecology has taken a stance against genetic screening for BRCA1/2 mutations in the general population, citing concerns about the “harms and benefits as well as cost-effectiveness.”29 Separately, a February 2016 systematic review of studies on the economical evaluations of BRCA1/2 genetic testing concluded that “BRCA1/2 population-based screening represents good value for the money among Ashkenazi Jews only. Family history (FH)–based screening is potentially very cost-effective, although further studies that include costs of identifying high-risk women are needed.” They implied that once the cost is reduced it will become worth doing: “Cost-effectiveness is highly sensitive to the cost of BRCA1/2 testing.”30 Like so many screening tests in medicine, they become broadly available once the cost comes down to a certain price point.
While the economics of testing all women regardless of risk will continue to be debated,31 there is agreement that all women at high risk should be identified and tested for HBOC-relevant genetic mutations.32 However, the physician track record of identifying who these high-risk women are and referring to genetic counseling for testing consideration is so poor that the current lack of proper referrals is used as a rational argument for testing of the general public.25,33-34
Removal of susceptible organs is by far the most reliable means of reducing risk of breast and ovarian cancers. According to the National Cancer Institute, bilateral mastectomy results in a 95% reduction of breast cancer diagnoses in BRCA1/2 mutation carriers.35 Prophylactic bilateral salpingo-oophorectomy has been shown to reduce diagnosis of both ovarian (90%) and breast cancer (50%) in BRCA1/2 carriers.36-37 The reduction in breast cancer with removal of the ovaries again implies a role of hormones involved in ovulation.
Clinicians should note that bilateral salpingo-oophorectomy (BSO) does not completely remove the risk of peritoneal cancer. In a study of 195 consecutive BRCA1 carriers in Poland who underwent BSO, there were 2 cases of peritoneal cancers and 14 cases of breast cancer (with a median follow-up of 80 months).38 A diagnosis of breast cancer prior to the BSO tripled the risk of peritoneal cancer. In addition, delaying BSO more than 5 years after breast cancer diagnosis conferred a much higher risk of peritoneal cancer than having BSO within 5 years of diagnosis (HR: 5.0; P=0.03). This implies that women who have had breast cancer and harbor a deleterious mutation in BRCA1/2 should consider BSO as soon as possible.
Given that penetrance is high but not 100% for carriers of pathogenic BRCA1/2 mutations, there is urgent need to understand what, if any, lifestyle measures may affect risk. Along with general recommendations that apply to everyone, such as healthy weight, sound diet, and exercise, are there specific recommendations we can make for BRCA1/2 mutation carriers?
In general, a diet that consists of at least two-thirds plant-based foods is associated with a lower cancer risk. There is limited research in BRCA1 or BRCA2 mutation carriers specifically. However, a Canadian epidemiological study suggested it is not just quantity of fruits and vegetables, but a wider variety that is associated with a lower risk of cancers in BRCA1/2 mutation carriers.39
In a small case-control study of BRCA1 mutation carriers in Poland, 14 circulating micronutrients were queried. The only nutrient found to correlate with breast cancer incidence was iron. Those within the highest tertile of plasma iron levels had a 57% lower risk of breast cancer than the lowest tertile.40
No interventional or epidemiological studies have assessed folate intake or status in women with BRCA1/2 mutations. It is plausible that pathogenic variants of BRCA1/2 leave cells more vulnerable to folate deficiency–induced carcinogenesis. Folate is necessary for proper methylation of DNA, and low folate due to alcohol consumption is associated with higher risk of sporadic breast cancer.41 Folate deficiency leads to DNA strand breaks, chromosomal instability, and impaired DNA repair and results in increased mutations.42 Products of BRCA1/2 genes are integral to double-strand DNA repair.43 Given that the risk in HBOC is due to faulty DNA repair and DNA is damaged when folate is deficient, folate deficiency is a plausible contributor to carcinogenesis in cells harboring BRCA1/2 pathogenic variants.44
We should advise patients to avoid nutritional supplements with high doses of folic acid and encourage them to eat foods high in folate as the preferred method for increasing folate consumption.
Dietary folate occurs as one of several polyglutamates that must be converted into “active” methylfolate by the enzyme methylene tetrahydrofolate reductase (MTHFR). Studies suggest that whether BRCA1/2 carriers harboring single nucleotide polymorphisms (SNPs) in MTHFR have a higher risk of breast cancer may depend on ethnicity as well as the precise genetic variations of both the BRCA1/2 aberration as well as the SNP.45 Ensuring repletion of active folate without pharmacological dosing seems a rational approach to such patients.
Repletion of folate should not be confused with folic acid supplementation. In mice, folic acid as a supplement has led to proliferation of mammary tumors.46 We should advise patients to avoid nutritional supplements with high doses of folic acid and encourage them to eat foods high in folate as the preferred method for increasing folate consumption.
Selenium status appears to affect risk in BRCA1/2 carriers as well. Selenium repletion may preserve chromosomal integrity in BRCA1 mutation carriers. Using lymphocytes from BRCA1 mutation carriers and noncarriers, chromosomal damage was greater in carriers after in vitro exposure to bleomycin. After 1 to 3 months of selenium supplementation, the number of chromosomal breaks measured upon retesting were reduced significantly, approaching levels found in the non-mutational BRCA control patients.47 Another study measured toenail selenium levels and DNA repair mechanisms after irradiation in women with and without mutations in BRCA1. There was an inverse association between selenium and chromosomal damage only in BRCA1 mutation carriers.48
Exercise is well-documented to lessen incident breast cancer in women, as well as lessen breast cancer and overall mortality risk after a diagnosis of breast cancer.49 There is an ongoing study to see if “more is better” in women with deleterious mutations in BRCA1 or BRCA2. The study is designed with 3 arms: control, low-dose (150 min/week), or high-dose (300 min/week) exercise.50 Results of this BRCA mutational carrier-specific trial will not be known for several years. Meanwhile, it is safe to assume that exercise is essential, with 150 minutes per week of moderate exercise at a minimum.
Weight gain in adulthood has also been associated with significantly increased risk in BRCA1/2 mutation carriers. One study suggested a greater than 4-fold increased risk in those with weight gain since age 18, and in those gaining weight after age 30.51 The same study found that there was a greater than 2.5-fold increased risk in those with excess energy intake (eating more calories than one burns).
Isoflavones from soy influence multiple pathways of cancer growth and invasion, including many epigenetic events crucial to cancer development.52 There is evidence suggesting some protective effect from recurrence in subpopulations of women with a history of breast cancer.53 It has long been assumed that soy consumption contributes to the lower prevalence of breast cancer in Asian countries. The benefits of soy appear not to be isolated only to Asians. A recent prospective observational study of Seventh Day Adventists found that women in the highest quintile of total isoflavone intake (median of 44.4 mg/d) had a 22% reduced risk of breast cancer compared to those with a median intake of 1.15 mg per day [relative risk (RR): 0.78; 95% confidence interval (CI): 0.63-0.97; P for trend =0.01].54 Which begs the question: Does this benefit extend to those with HBOC?
The ongoing Korean Hereditary Breast Cancer Study (KHBCS) set out to answer this question. They reported in a 2013 publication that higher soy intake was associated with a significantly reduced risk of breast cancer in BRCA1/2 mutation carriers versus noncarriers [hazard ratio (HR): 0.39; 95% CI: 0.19-0.79 for the highest quartile)].55 They also found that BRCA mutation carriers who consumed the highest amount of meat were nearly twice as likely to develop cancer (HR: 1.97; 95% CI: 1.13-3.44 ) as low meat consumers. The associations for both soy and meat were “more prominent” in BRCA2 carriers.
The apparent breast cancer risk reduction from soy intake may be due to the isoflavone genestein.56 It may also be partly attributed to equol. Equol is a product of gut microflora metabolism of the isoflavones diadzein and diadzin, and it is dependent on the presence of select species of microbes. In a study of several breast cancer cell lines, equol led to demethylation of BRCA1 and BRCA2 promoter regions. This preserves expression of BRCA1/2, resulting in greater levels of tumor-suppressive BRCA1/2 protein products in the cytoplasm and nuclei.57
Epidemiological evidence from the Nurses’ Health Study (N=85,987) found coffee consumption had an inverse association with breast cancer incidence in a postmenopausal population with unknown BRCA mutation status.58 An inverse association may be true for BRCA1/2 mutational carriers as well. An epidemiological case-control study that spanned 40 centers and involved 1,690 women who carried BRCA1/2 mutations found an inverse association between coffee intake and breast cancer incidence.59 The association was stronger with greater coffee consumption and only included caffeinated coffee. They found the odds ratios (ORs) for breast cancer in BRCA carriers who habitually drank 0, 1 to 3, 4 to 5, and 6 or more cups of coffee were 1.00, 0.90 (95% CI: 0.72-1.12), 0.75 (95% CI: 0.47-1.19) and 0.31 (95% CI: 0.13-0.71; P for trend=0.02). The dose-response relationship implies this observational finding may be causally linked.
In follow-up analysis of this same data, only women who were less efficient metabolizers of caffeine derived significant benefit from coffee consumption.60 Cytochrome P450 1A2 (CYP1A2) metabolizes caffeine, and there is a common single nucleotide polymorphism (SNP) that impairs metabolism, leading to higher levels of caffeine in circulation. For the analysis, sufficient data on both coffee intake and CYP1A2 genotype was available for 411 BRCA1 mutation carriers (170 cases, 241 controls). Notably, the CYP1A2 genotype alone did not affect breast cancer risk. Habitual coffee consumption (any quantity) before the age of 35 in those who harbored a SNP in CYP1A2 was associated with a 64% reduction in breast cancer risk compared with women who never consumed coffee (OR: 0.36; 95% CI: 0.18-0.73).
It is also possible that other constituents in the coffee are having an effect. A separate study on women with unknown BRCA mutation status showed fewer estrogen receptor-positive and postmenopausal breast cancers in those with the highest coffee consumption (>5 cups/day).61
Current guidelines for genetic testing of HBOC require some vigilance on the part of primary care physicians to recognize appropriate patients for testing. Referrals to genetic experts are essential, as the landscape of testing technology and our understanding of new genetic aberrations continually grows. Testing is always preferred in the family member that has been affected by cancer, rather than relatives. If the affected family member carries a deleterious mutation in BRCA1 or BRCA2, then further testing of family members should be discussed with a genetic expert.
Men also can harbor mutations in BRCA1/2 that increase risk for several cancers. Prostate cancer is diagnosed in up to 39% and breast cancer in up to 10% of men with deleterious BRCA1/2 mutations.62 From a clinical standpoint, any male patients with a strong family history of breast, ovarian, or prostate cancer should engender a higher level of suspicion. If he is also of Ashkenazi Jewish decent or has any family members that have HBOC at any age or a family history of cancer in younger (<50 years) relatives, he should be referred to a genetics counselor for testing and guidance in decision-making.
In addition, regardless of gender, those harboring mutations in BRCA1/2 have higher rates of several other cancers, including pancreatic cancer (1%-7%),3 melanoma (0.1%-2.4%), and nonmelanoma skin cancers.63 This is important for clinicians to keep in mind for care of their patients with known pathogenic mutations in BRCA1/2.
The evidence to date suggests that progesterone/progestins should not be given to BRCA1/2 mutation carriers. As described above, endogenous progesterone is implicated in the organ specificity of the cancers in BRCA1/2 mutation carriers through its interaction with RANKL. Higher circulating progesterone and estrogen in BRCA1/2 mutation carriers is thought to contribute to risk. Correspondingly, oophorectomy lowers not only the risk of ovarian cancer but the risk of breast cancer as well, implying a causative role of estrogen and/or progesterone. Lastly, both the Women’s Health Initiative and the Million Women Study64-65 trials showed an increase in breast cancer with the use of hormone replacement therapies containing progestin compounds such as medroxyprogesterone acetate (MPA) in combination with estrogens.
Admittedly, the data causally linking estrogen/progesterone in BRCA1/2 cancers is inconsistent. While prescription birth control may lessen ovarian cancer risk, evidence regarding breast cancer is mixed. However, our mandate to “first, do no harm” implores that we use a level of caution that protects our patients from any risk, theoretical or proven. Without proof of benefit, practitioners should adhere to the cautionary principle.
Even though the US government ensures that health insurance cannot be denied to someone due to genetic predisposition, life insurance, long-term care insurance, and disability insurance rights are not protected.
Further supporting the need for an abundance of caution in the use of any form of progesterone is the pursuit of drugs designed to block progesterone as therapeutic agents in BRCA1/2-associated cancers.66 As an extension of this, direct RANKL inhibition with denosumab (Xgeva/Prolia) is currently being studied as a chemopreventive agent in BRCA1/2 mutational carriers specifically.
There is a burgeoning niche in direct-to-consumer genetic testing, some of which include tests for BRCA1/2 mutations. The ramifications of self-testing need to be considered.67 As mentioned, the patient may or may not have contemplated the psychological consequences associated with testing. There are technical aspects regarding the depth and breadth of genomic testing that involve the molecular technique used. The nuances of how different genotype mapping techniques can lead to false negatives, miss entire genomic shifts, or simply not test for relevant genomic information would be nearly impossible for consumers to discern. Add to this that there are no regulations on the techniques used, the accuracy (sensitivity/specificity) of testing, or the number of genomic variations being tested, and the reliability of such testing is called into serious question. On a more practical note, even though the US government ensures that health insurance cannot be denied to someone due to genetic predisposition, life insurance, long-term care insurance, and disability insurance rights are not protected, and denials due to BRCA mutational status have been reported.68
Clinicians who are able to identify patients at risk for hereditary breast and ovarian cancer due to BRCA1 or BRCA2 mutations can promptly and appropriately refer their clients to genetic experts, possibly sparing those with confirmed HBOC syndrome a cancer diagnosis. Primary care practitioners do not need to understand the details of molecular genetics to serve their patients well by recognizing appropriate times to refer to genetic experts. While research continues on lifestyle modifiers of risk, it is clear that prescribing progesterone/progestin in any form places BRCA1/2 mutation carriers at risk. Providers should caution patients about its use as well, since progesterone can be purchased over the counter.
- National Cancer Institute: Surveillance, Epidemiology, and End Results Program (SEER). SEER Stat Fact Sheets: Female Breast Cancer. http://seer.cancer.gov/statfacts/html/breast.html. Accessed June 1, 2016.
- Petrucelli N, Daly MB, Feldman GL. BRCA1 and BRCA2 Hereditary Breast and Ovarian Cancer. In: Pagon RA, Adam MP, Ardinger HH, eds. GeneReviews. Seattle, WA: University of Washington, Seattle;1993-2016. http://www.ncbi.nlm.nih.gov/books/NBK1247/. Accessed May 20, 2016.
- Carroll JC, Cremin C, Allanson J, et al. Hereditary breast and ovarian cancers. Can Fam Physician. 2008;54(12):1691-1692.
- Division of Cancer Prevention and Control, Centers for Disease Control and Prevention. Inside Knowledge: Get the Facts About Gynecologic Cancer. Hereditary Breast and Ovarian Cancer Syndrome. http://www.cdc.gov/cancer/knowledge/provider-education/genetics/hboc-syndrome.htm. Updated September 14, 2015. Accessed May 31, 2016.
- Hereditary breast and ovarian cancer. Cancer.net website. http://www.cancer.net/cancer-types/hereditary-breast-and-ovarian-cancer. Approved November 2015. Accessed June 29, 2016.
- BRCA1. National Library of Medicine. Genetics Home Reference. Bethesda, MD: The Library; 2016. https://ghr.nlm.nih.gov/gene/BRCA1#location. Published June 14, 2016. Accessed May 22, 2016.
- Patient education fact sheet: BRCA1 and BRCA2 mutations. The American Congress of Obstetricians and Gynecologists website. http://www.acog.org/Patients/FAQs/BRCA1-and-BRCA2-Mutations. Updated March 2015. Accessed June 29, 2016.
- Friebel TM, Domchek SM, Rebbeck TR. Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: systematic review and meta-analysis. J Natl Cancer Inst. 2014;106(6):dju091.
- Widschwendter M, Rosenthal AN, Philpott S, et al. The sex hormone system in carriers of BRCA1/2 mutations: a case-control study. Lancet Oncol. 2013;14(12):1226-123.
- Moorman PG, Havrilesky LJ, Gierisch JM, et al. Oral contraceptives and risk of ovarian cancer and breast cancer among high-risk women: a systematic review and meta-analysis. J Clin Oncol. 2013;31(33):4188-4198.
- Mohammed H, Russell IA, Stark R, et al. Progesterone receptor modulates ERα action in breast cancer. Nature. 2015;523(7560):313-317.
- Jeon SY, Hwang KA, Choi KC. Effect of steroid hormones, estrogen and progesterone, on epithelial mesenchymal transition in ovarian cancer development. J Steroid Biochem Mol Biol. 2016;158:1-8.
- Schramek D, Leibbrandt A, Sigl V, et al. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature. 2010;468(7320):98-102.
- Widschwendter M, Burnell M, Fraser L, et al. Osteoprotegerin (OPG), the endogenous inhibitor of receptor activator of NF-?B ligand (RANKL), is dysregulated in BRCA mutation carriers. EBioMedicine. 2015;2(10):1331-1339.
- Litton JK, Ready K, Chen H, et al. Earlier age of onset of BRCA mutation-related cancers in subsequent generations. Cancer. 2012;118(2):321-325.
- Martinez-Delgado B, Yanowsky K, Inglada-Perez L, et al. Genetic anticipation is associated with telomere shortening in hereditary breast cancer. PLoS Genet. 2011;7(7):e1002182.
- Badie S, Escandell JM, Bouwman P, et al. BRCA2 acts as a RAD51 loader to facilitate telomere replication and capping. Nat Struct Mol Biol. 2010;17(12):1461-1469.
- McPherson JP, Hande MP, Poonepalli A, et al. A role for Brca1 in chromosome end maintenance. Hum Mol Genet. 2006;15(6):831-838.
- Division of Cancer Prevention and Control, Centers for Disease Control and Prevention. Bring Your Brave Campaign. Groups at Higher Risk for BRCA Gene Mutations. http://www.cdc.gov/cancer/breast/young_women/bringyourbrave/hereditary_breast_cancer/higher_risk_brca.htm. Updated April 8, 2015. Accessed May 25, 2016.
- US Preventive Services Task Force. Final Update Summary: BRCA-Related Cancer: Risk Assessment, Genetic Counseling, and Genetic Testing. July, 2015. http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/brca-related-cancer-risk-assessment-genetic-counseling-and-genetic-testing. Accessed May 30, 2016.
- NCCN Guidelines. National Comprehensive Cancer Network website. https://www.nccn.org/professionals/physician_gls/f_guidelines.asp#detection. Accessed June 29, 2016.
- McClain MR, Nathanson KL, Palomaki GE, Haddow JE. An evaluation of BRCA1 and BRCA2 founder mutations penetrance estimates for breast cancer among Ashkenazi Jewish women. Genet Med. 2005;7(1):34-39.
- Górski B, Byrski T, Huzarski T, et al. Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer. Am J Hum Genet. 2000;66(6):1963-1968.
- Gabai-Kapara E, Lahad A, Kaufman B, et al. Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2. Proc Natl Acad Sci U S A. 2014;111(39):14205-14210.
- Lerman C, Lustbader E, Rimer B, et al. Effects of individualized breast cancer risk counseling: a randomized trial. J Natl Cancer Inst. 1995;87(4):286-292.
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