Ovarian Cancer – Hereditary/Genetic Factors

Ovarian Cancer – Hereditary/Genetic Factors

1. What every clinician should know

Approximately 10-15% of patients with ovarian cancer are thought to have an inherited genetic predisposition. Although this represents a small percentage of patients with ovarian cancer, great emphasis has been placed on this high risk population, given the associated clinical, social and ethical implications. Although reproductive, demographic and lifestyle factors affect the risk of ovarian cancer, the single largest risk factor for ovarian cancer is a family history of the disease.

An excess of ovarian cancers in some families results from specific mutations in cancer susceptibility genes. Since these genes are on autosomes (not on the X or Y chromosome), a detailed family history from both maternal and paternal lineages must be obtained to determine the genetic susceptibility for woman at risk.

When a parent carries the mutation, each child has a 50:50 chance of inheriting the mutation. Importantly however, not everyone with the genetic predisposition will develop cancer because of incomplete penetrance of the trait and/or gender-restricted expression. This means that although an individal may carry the gene mutation and be at risk for developing cancer, they do not definitely develop the associated cancer. An inherited mutation can be passed on to offspring in subsequent generations. In contrast, an acquired somatic mutation that occurs in cells as a result of DNA damage during life’s various exposures cannot be passed along to offspring.

Ovarian cancer is a component of several autosomal dominant cancer syndromes of which the most frequent is hereditary breast-ovary cancer syndrome. This syndrome accounts for up to 85% of all hereditary ovarian cancer cases and is most frequently associated with mutations in the BRCA1 or BRCA2 genes. Other cancer susceptibility genes known to increase the risk of ovarian cancer include MLH1, MSH2, MHH6 and PMS which are part of the Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Lynch Type II. Lynch type II syndrome accounts for only about 5-10% of hereditary ovarian cancer. Less common genetic syndromes which can also increase the risk of ovarian pathology include Gorlin syndrome and multiple endocrine neoplasia type 1 (MEN1). Germline mutations in these genes are associated with benign ovarian tumors.

See Table I – Hereditary genetic syndromes that include ovarian neoplasms.

Table I.n

Family characteristics that suggest hereditary ovarian cancer syndromes include:

• Multiple cancers within a family.

• Cancers typically occur at an earlier age than the typical age at diagnosis.

• Two or more cancers within one individual. This could include breast and ovarian cancer, endometrial and colon cancer, or bilateral breast cancer.

• Male breast cancer.

When assessing familial cancer risk, remember that small families may not manifest low-penetrance genes, and that families with few female relatives may under-represent female cancers despite the presence of a predisposing family mutation. Similarly, hysterectomy and/or oophorectomy at a young age in multiple family members can mask a hereditary gynecologic cancer predisposition. When evaluating a family history, it is also important to remember that males can transmit gynecologic cancer predisposing genes, and that adoption can limit interpretation of a pedigree. Family history should regularly be updated with the patient to identify any new cancer diagnoses in the family.

Genetic syndromes involving ovarian cancer

BRCA1 and BRCA2

The BRCA1 and BRCA2 genes were identified and linked to hereditary breast and ovarian cancer in the 1990s. BRCA1 is located on chromosome 17q12-21, and BRCA2 is located on chromosome 13q12-13. Although the precise function of the BRCA genes is unknown, they are tumor suppressor genes and they appear to be involved in the recognition and repair of DNA damage. BRCA1 contains 24 exons, and over 1,200 different deleterious mutations have been reported. BRCA2 is a larger gene that contains 27 exons and more than 1,300 different deleterious mutations have been reported. Individuals inherit one defective allele in BRCA1 or BRCA2 from their father or mother, but they still have a second, functional allele. If the second allele becomes non-functional as a result of a somatic mutation or epigenetic silencing, cancer can develop. This is called the “two-hit hypothesis.”

Mutations can occur in numerous locations throughout the entire BRCA1 and BRCA2 genes, with nonsense mutations or frameshift mutations being predominant. Nonsense mutations occur when a single nucleotide substitution results in a stop codon, and frameshift mutation occurs when one or more nucleotides are deleted to produce a downstream stop codon.

In general, these mutations result in missing or non-functional proteins. It is estimated that approximately 1 in 400-800 individuals in the general population carry a mutation in BRCA1 or BRCA2. In certain populations founded by a small ancestral group with high rates of intermarriage, a specific mutation in BRCA1 or BRCA2 may occur more frequently. Such “founder mutations” are notable in Ashkenazi (Eastern European) Jewish, French Canadians and Icelandic, Swedish and Netherlander populations.

In the United States, it is estimated that 1 in 40 Ashkenazi Jews carries one of the three specific Ashkenazi Jewish founder mutations: 185del AG and 5382insC on BRCA1 and 6174delT on BRCA2. Studies have found that 40-60% of Jewish patients with non-mucinous epithelial ovarian or tubal cancer have a mutation in BRCA1 or BRCA2, in contrast to 5% of non-Jewish women with ovarian or tubal cancer.

Fallopian tube cancer is also part of the BRCA-associated phenotype and current data suggests that the fallopian tube epithelium may be the site of origin for the majority of serous pelvic cancers in BRCA mutation carriers that have previously been classified as ovarian cancer. The majority of occult cancers noted in the adnexa of BRCA mutation carriers at the time of prophylactic bilateral salpingo-oophorectomy are tubal cancers, most commonly arising in the tubal fimbria. While fallopian tube cancer is very rare among the general population, BRCA1 mutation carriers have a 120-fold increased risk of developing tubal cancer compared to non-mutation carriers. Recent data shows 30% percent of all women with fallopian tube cancer will have germline BRCA mutations.

The lifetime risk of ovarian/tubal cancer for patients with BRCA1 mutations is 39-46%, and the lifetime risk of ovarian/tubal cancer for BRCA2 mutation carriers is 10-22%. The estimated lifetime risk for breast cancer for a woman with a BRCA1 or BRCA2 mutation is 65-74%. For women with breast cancer, the 10-year actuarial risk of developing a subsequent ovarian cancer is 12.7% for BRCA1 mutation carriers and 6.8% for BRCA2 mutation carriers.

See Table II – Lifetime risks of developing ovarian cancer by BRCA1/BRCA2 mutation.

Table II.n

BRCA-associated ovarian and tubal cancers have features distinct from sporadic ovarian or tubal cancers. BRCA-associated ovarian and tubal cancers are predominantly high grade serous histology which tend to present at advanced stage. Mucinous and borderline ovarian cancers do not appear to be part of the BRCA spectrum of disease. Patients with BRCA1-associated ovarian cancer appear to be diagnosed at a younger age than patients with sporadic ovarian cancer or BRCA2-associated ovarian cancer.

Recent data shows that the BRCA mutations confer a survival advantage for women with ovarian and tubal cancer compared to sporadic cancers. These cancers appear to have an enhanced sensitivity to the cytotoxic effects of platinum-based chemotherapy, which is used as first-line treatment for ovarian cancer. Specifically, BRCA2 mutation carriers with ovarian cancer have better survival than BRCA1-associated or sporadic ovarian cancer.

More recently a novel targeted therapy called PARP (polyadenosine ribose polymerase) inhibition has proven to be a very effective treatment for women with BRCA-associated ovarian cancer. PARP is involved in the repair of single-stranded DNA breaks through base-excision repair, while BRCA genes are thought to be active in the repair of double stranded DNA breaks through homologous recombination. The synergistic effects of a PARP inhibitor in a BRCA deficient tumor is thought to lead to enhanced cell death and better response rates for BRCA mutation carriers treated with DNA damaging cytotoxic agents compared to non-BRCA mutation carriers.

Lynch syndrome/HNPCC

The HNPCC syndrome accounts for approximately 5-10% of all hereditary ovarian cancer cases. It is an autosomal-dominant genetic syndrome characterized by three or more first-degree relatives with colon cancer (over 70% in the proximal colon), endometrial cancer, or other rare syndrome related cancers where one is a first degree relative of the other two, and two of them must be diagnosed with cancer before age 50 years.

Four genes that are part of the DNA mismatch repair (MMR) pathway have been identified as being responsible for the HNPCC phenotype: hMSH2 or MSH6 (chromosome 2p), hMLH1 (chromosome 3p), hPMS1 (chromosome 2q) or hPMS2 (chromosome 7p). An inherited defect in any one of these genes increases an individual’s risk of developing cancer because of an impaired ability of DNA mismatch repair.

HNPCC syndrome family members are at risk for cancer of other gastrointestinal sites, the urinary tract and the ovary. The risk of endometrial cancer among women in the HNPCC syndrome is estimated to be 40-60% by the age of 70 compared to 1.5% in the general population. Limited studies have reported a 3.5-fold increase in the risk of ovarian cancer in members of these families of up to 12% lifetime risk.

Genetic evaluation for ovarian cancer hereditary syndromes

ASCO (American Society of Clinical Oncology) guidelines currently recommend offering testing to anyone with personal or family history features suggestive of a genetic cancer susceptibility condition if the test result can be interpreted and will influence medical management.

See Table III – Population estimates of the likelihood of having a BRCA1 or BRCA2 mutation, and Table IV – Society Gynecologic Oncology and ACOG criteria for genetic risk assessment.

Table III.n

Table IV.n

First and second-degree relatives of an affected individual from a breast-ovarian cancer syndrome family carrying a mutation of the BRCA1 or BRCA2 gene should be offered genetic testing. Genetic testing for the mismatch repair genes should be considered when there is a first-degree relative with a known mutation, and when the patient meets the Amsterdam or the Bethesda Criteria for hereditary non polyposis colorectal cancer syndrome.

See Table V – Clinical criteria for HNPCC/Lynch II.

Table V.n

What is genetic counseling?

Hereditary cancer risk assessment is a process that combines education and counseling and is conducted by a physician, genetic counselor or provider with expertise in cancer genetics. Genetic testing may be performed, if the patient desires, after appropriate counseling. Patients must be counseled regarding the potential advantages, disadvantages and potential uncertainty of genetic testing, as well as the utility of screening and prophylactic measures that are available.

The first concern in genetic testing is the scientific and technical utility of the test: their reliability, their interpretation, and ultimately their ability to prevent cancer in patients who test positive. The second major concern relates to the ethical, legal, and social implications of genetic testing. The proper selection of patients for testing is very important. A comprehensive family history can provide an estimate of an individual’s risk of carrying a genetic mutation; however, genetic testing provides more accurate information regarding the chance that an individual patient will develop cancer.

Genetic testing should begin with an affected member of the family who has had cancer if they are available for testing. The index family member will often need comprehensive gene sequencing, and subsequent individuals can then be tested for the identified mutation, which may be unique to this particular family. Certain ethnic and geographic groups are at risk for specific gene alterations called founder mutations. For members of these special patient populations, common mutations can be tested with less expense than full sequence testing. In the Ashkenazi Jewish population, genetic testing for all 3 founder mutations is required because of the high carrier frequency in this population, and occasional reports of individuals with both BRCA1 and BRCA2 mutations.

Test results may come back positive or negative for an identifiable mutation, or may report a mutation of indeterminate clinical significance. When a test returns negative, interpretation will depend on the patient’s family history. If an affected family member has tested positive for a mutation, then the patient has likely not inherited the deleterious mutation, and her cancer risk approximates that of the general population. If there is no documented positive mutation in the family, it is still possible that the patient has a cancer-associated mutation that is not detectable with current testing. Approximately 12% of current testing results are genetic variants or polymorphisms, reported as indeterminate clinical significance.

The rate of variants of unknown significance (VUS) varies among different ethnic groups. African Americans have the highest rate (17%) of VUS. Further study of these genetic variants and associated cancer risks in large populations will help reduce the number of indeterminate reports. Periodically, a VUS may be reclassified as either deleterious or as a polymorphism if sufficient follow-up information has been collected and analyzed.

Even in families with a documented hereditary cancer syndrome, the risk of developing ovarian, endometrial or colon cancer in a woman under the age of 21 is exceedingly low. The discovery of a mutation associated with one of these hereditary cancer syndromes would not be expected to change the management of a young woman in this age group and may have significant negative consequences. Consequently, genetic testing of individuals under age 21 for hereditary ovarian cancer syndromes is not advised.

What issues should be addressed during genetic counseling?

Genetic counseling should include a discussion of possible outcomes of testing – specifically addressing the issues of positive, negative, uninformative test results or VUS. Options for surveillance, chemoprevention and risk-reducing surgery should be discussed before testing. Possible psychological and familial implications of test results also should be considered. The genetic counseling session also should discuss the cost of genetic testing. Many insurance companies, including Medicare, will cover a significant portion of the expense for certain individuals. Medicare and other insurance companies have written guidelines for coverage of the cost of genetic testing. (Medicare guidelines accessible at https://www.noridianmedicare.com/macj3/lcd_policies/active/PartB/Genetic_Testing.html)

An important aspect of genetic counseling is discussion of current legislation regarding genetic discrimination and the privacy of genetic information. The federal Health Insurance Portability and Accountability Act (HIPAA) prohibits group (but not individual) health plans from denying eligibility for benefits based on an individual’s genetic information. The federal Genetic Information Nondiscrimination Act of 2008 (P.L. 110-233, 122 Stat. 881) also referred to as GINA, prohibits discrimination in health coverage and employment based on genetic information. Many states also have state laws that provide broader protection than the federal law and provide protection against employment discrimination. To date, there have been no documented cases of discrimination in healthcare or employment based on an individual’s BRCA testing. These laws do not apply to other forms of insurance which may include life or disability.

Risk reduction strategies

BRCA1, BRCA2

How women with mutations in BRCA1 or BRCA2 should be counseled to reduce the risk of ovarian and fallopian tube cancer?

Current strategies to reduce the risk of developing ovarian or fallopian tube carcinoma in women at high-risk with known deleterious BRCA mutations include surveillance, chemoprevention and surgery. Available screening modalities have not significantly improved the detection of early stage invasive, epithelial ovarian cancer, with minimal impact on the survival among screened patients. The National Institute of Health Consensus Statement on Ovarian Cancer and the Cancer Genetic Studies Consortium (CGSC) recommend screening starting at ages 25-35 or at age 5-10 years earlier than the earliest age of first ovarian cancer diagnosis in the family. However, the benefit is not established and evidence is based on expert opinion.

See Table VI – Risk-reducing strategies for women with HNPCC and BRCA mutations.

Table VI.n

As better serum markers and improved screening algorithms are developed to enhance detection of earlier stage disease, especially among premenopausal women, future ovarian cancer trials may improve survival through a shift the stage distribution of the screened patients. Novel, combined biomarker panels in conjunction with enhanced imaging hold the most promise based on large ovarian cancer screening studies in low risk populations.

Chemoprophylaxis with oral contraceptive pills (OCP) for 5 years decreases ovarian cancer risk by 50% in the general population. The benefits and magnitude of reduced risk with oral contraceptives for women with a BRCA mutation has not been as consistently reported. Most studies report a reduced risk of ovarian cancer for ever-use of OCP, meaning that there is a benefit seen with use of OCP for any length of time, but in particular, for longer duration use (more than 6 years). However, some studies have suggested that oral contraceptives formulated before 1975 may be associated with an increased risk of breast cancer in women with BRCA mutations. The relative risks and benefits for both chemoprevention and reproductive control should be carefully weighed by the patient and her physician. Other protective factors, including parity, breast-feeding, tubal ligation and hysterectomy, also have been associated with a reduction in the risk of ovarian cancer among BRCA mutation carriers.

Given the limitations of current ovarian cancer screening approaches, prophylactic risk-reducing surgery, include removal of the ovaries and as much of the fallopian tube as possible, should be strongly considered after the conclusion of childbearing. This procedure has been shown to reduce the risk of ovarian and fallopian tube and peritoneal carcinoma by approximately 80-90% in women with known BRCA mutations. In addition, bilateral salpingo-oophorectomy has been shown to decrease overall mortality in women with a BRCA1 or BRCA2 mutation and reduce the risk of breast cancer in pre-menopausal BRCA mutation carriers by 50%. Removal of just the fallopian tubes, an interval salpingectomy, has recently been described as an alternative risk-reducing surgery strategy to allow women to retain ovarian function for an additional period of time but remove the fallopian tubes which are believed to be at the highest risk of developing early cancers. Some unresolved issues regarding the interval salpingectomy include how long it is safe to retain the ovaries and the risks of an additional surgery at a later time to remove the ovaries.

The optimal timing of prophylactic bilateral salpingo-oophorectomy (PBSO) for a high-risk BRCA mutation carrier will be determined by their life factors, desire for fertility and natural hormones, family history and BRCA mutation. The cancer risks must be carefully balanced against the effects of surgical menopause and the emerging literature of the effects of a premature estrogen deprivation on the risks of cardiac disease, dementia and osteoporosis.

For women with BRCA1 mutations the risk of ovarian cancer markedly increases during the 40s, with 10-21% of BRCA1 mutation carriers developing ovarian cancer by age 50. The risk of premenopausal ovarian cancer is much lower in BRCA2 mutation carriers, with no more than 3% developing ovarian cancer by age 50. Given the different timing of ovarian cancer risk, consideration can be made for counseling patients with BRCA1 mutations differently than BRCA2 mutation carriers. However, women with BRCA2 mutations have a 26-34% chance of developing breast cancer by age 50, and the maximum benefit of removing the ovaries on breast cancer risk reduction is achieved the earlier the ovaries are removed.

How should PBSO be technically performed? How should surgical specimens be examined?

Prophylactic bilateral salpingo-oophorectomy is most commonly performed laparoscopically. Laparoscopy allows for minimally invasive surgery with a thorough inspection of peritoneal surfaces. Peritoneal washings should be taken. The diaphragm, liver, omentum, bowel, paracolic gutters and appendix are inspected in the upper abdomen. The ovaries, tubes, uterus, bladder serosa and cul-de-sac are inspected in the pelvis.

Any abnormal appearing areas should be biopsied. Pelvic washings should be obtained at the time of risk-reducing surgery and sent to pathology as a cytology specimen. There is no proven benefit in taking routine peritoneal or omental biopsies. The ovarian vessels should be isolated and ligated proximal to the end of identifiable ovarian tissue to ensure that all ovarian tissue is complete removed. If a hysterectomy is not being performed, the fallopian tube should be divided at its insertion into the uterine cornua.

To optimize preservation of the ovarian surface epithelium, the specimens can be placed in an endoscopic bag prior to removal from the abdomen. Intra-operative pathology review should include a close examination for possible occult disease. If cancer is identified, surgical staging with lymphadenectomy and omentectomy may be performed at the time of risk-reducing surgery, providing appropriate preoperative consent has been obtained. It is also reasonable, however, to await final pathology and proceed with definitive surgery in an expeditious manner if invasive cancer is identified. The optimal approach will depend on patient and physician preference as well as availability of expertise to perform adequate staging.

Uterine cancer does not appear to be part of the BRCA-associated spectrum of disease. Despite a theoretical risk of residual fallopian tube in the cornua of the uterus if a concomitant hysterectomy is not performed, there have been no cases of isolated cornual uterine carcinomas. For women with BRCA1 and BRCA2 mutations, salpingo-oophorectomy alone confers a significant cancer risk reduction with less surgical risk and postoperative recovery. Hysterectomy may be considered when there are other medical indications for removal of the uterus and cervix. For women taking tamoxifen, hysterectomy may be considered to reduce their endometrial cancer risk. For the premenopausal unaffected woman interested in hormone replacement therapy, hysterectomy can simplify their future hormone replacement regimen by eliminating the need for progestins. The decision to perform a concurrent hysterectomy should be individualized.

The surgical pathologist must be alerted to perform a careful examination of the patient’s ovaries and fallopian tubes, given the frequent reports of occult ovarian and tubal carcinoma from series of prophylactic BSO specimens (4-15%). Rather than taking only one or two representative sections from each ovary, the complete ovaries and tubes should be serially sectioned and evaluated, as this procedure has been demonstrated to improve detection of occult disease. The majority of occult carcinomas have been found in the tubal fimbriae. Possible explanations for this observation include the relatively larger amount of epithelium within the fimbriae compared to the other sections of the tube and the proximity of this epithelium to the ovary and peritoneal cavity.

Many pathologists have endorsed a specific accessioning protocol in which the fimbriae are bisected near the fimbriated end and then sectioned longitudinally to allow maximal examination of the plicae. Adherence to a comprehensive pathologic evaluation of the entire adnexa has been shown to significantly increase the detection of occult carcinomas. Despite the microscopic tumors identified, they are often high grade, and information from the peritoneal washings may reflect the aggressiveness of the disease. Since occult cancers may be found only through serial sectioning and thorough evaluation of the ovaries and tubes, it is possible that subsequent primary peritoneal carcinomas actually represent the recurrence of a previously unrecognized occult cancer.

What surveillance for primary peritoneal cancer should be performed for women after PBSO?

Since the risk of cancer is greatly reduced after prophylactic bilateral salpingo-oophorectomy and peritoneal cancer is relatively uncommon (1-6% cumulative risk for all BRCA mutation carriers), the benefit of surveillance after risk-reducing surgery is unclear. Moreover, there is no consensus regarding the optimal screening strategy; CA 125, transvaginal ultrasound, physical exam or all of the above.

However, patients should be counseled regarding the possibility of a subsequent primary peritoneal cancer despite removal of the tubes and ovaries. Recent prospective studies have reported a 1-4% risk of developing primary peritoneal cancer with extended follow up. It is believed that all coelomic epithelium including the peritoneal covering of the entire abdominal/pelvic cavity is prone to malignant transformation in BRCA mutation carriers, although the risk is significantly reduced by PBSO. An ongoing trial (GOG199) is examining whether serial CA125 is helpful in diagnosing early peritoneal cancer in women at inherited risk. Until results of this trial are available, women should be informed that screening for primary peritoneal cancer is investigational, and that limited information is available regarding the relative risks and benefits.

What is the safety of hormone replacement therapy following risk-reducing surgery in BRCA mutation carriers?

Limited data is available on the long-term safety of hormone replacement following risk-reducing PBSO. Two small studies suggest that short-term use of HRT in BRCA mutation carriers following PBSO does not increase the risk of breast cancer and does not negate the protective effect of oophorectomy on breast cancer risk seen in pre-menopausal women.

HNPCC

Hereditary non-polyposis colorectal cancer (HNPCC) Lynch Type II

Prophylactic surgery for women with HNPCC, Lynch Type II syndrome has been shown to prevent endometrial carcinoma. Current guidelines advocate CA 125, transvaginal ultrasound and endometrial sampling between the ages of 25 and 35 and consideration of risk-reducing hysterectomy and bilateral salpingo-oophorectomy after childbearing is complete. However, because most HNPCC-associated endometrial cancers are diagnosed at an early stage and cured with surgery, it is feasible that risk-reducing surgery will not have any impact on patient mortality. [See Table VI Risk-reducing strategies in HNPCC mutation carriers].

2. What is the evidence for specific management and treatment recommendations?

BRCA

Struewing, JP, Hartge, P, Wacholder, S. “The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews”. N Engl J Med. vol. 336. 1997. pp. 1401-8.

Zhang , S , Royer, R, Li, S, McLaughlin, JR, Rosen, B, Risch, HA, Fan, I, Bradley, L, Shaw, PA, Narod, SA. “Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer”. Gynecol Oncol. vol. 121. 2011. pp. 353-57.

King, MC, Marks, JH, Mandell, JB. “Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2”. Science. vol. 302. 2003. pp. 643-6.

Boyd, J, Sonoda, Y, Federici, MG. “Clinicopathologic features of BRCA-linked and sporadic ovarian cancer”. JAMA. vol. 283. 2000. pp. 2260-5.

Pal, T, Permuth-Wey, Bets. “BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases”. Cancer. vol. 104. 2005. pp. 2807-16.

McGuire, V, Felberg, A, Mills, M. “Relation of contraceptive and reproductive history to ovarian cancer risk in carriers and noncarriers of BRCA1 gene mutations”. Am J Epidemiol. vol. 160. 2004. pp. 613-8.

Narod, SA, Risch, H, Moslehi, R. “Oral contraceptives and the risk of hereditary ovarian cancer”. N Engl J Med. vol. 339. 1998. pp. 424-8.

Finch, A, Beiner, M, Lubinski, J. “Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 Mutation”. JAMA. vol. 296. 2006. pp. 185-92.

Iodice, S, Barile, M, Rotmensz, N. “Oral contraceptive use and breast or ovarian cancer risk in BRCA1/2 carriers: a meta-analysis”. Eur J Cancer. vol. 46. 2010. pp. 2275-84.

Powell, CB, Kenley, E, Chen, LM. “Risk-reducing salpingo-oophorectomy in BRCA mutation carriers: role of serial sectioning in the detection of occult malignancy”. J Clin Oncol. vol. 23. 2005. pp. 127-32.

Rebbeck, TR, Kauff, ND, Domcheck, SM. “Meta-analysis of risk-reducing estimates associated with risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer”. J Natl Cancer Inst . vol. 101. 2009. pp. 80-7.

Van der Velde, NM, Moutits, MJ, Arts, HJ. “Time to stop ovarian cancer screening in BRCA1/2 mutation carriers?”. Int J Cancer. vol. 124. 2009. pp. 919-23.

Audeh, MW, Carmichael, J, Penson, RT. “Oral poly (ADP-ribose) poymerase inhibitor in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: proof of concept trial”. Lancet. vol. 376. 2010. pp. 245-51.

Vicus, D, Finch, A, Cass, I, Rosen, B. “Prevalence of BRCA1 and BRCA2 germ line mutations among women with carcinoma of the fallopian tube”. Gynecol. Oncol. vol. 118. 2010. pp. 299-302.

Yang, D, Khan, S, Hess, K, Shmulevich, I, Sood, A, Zhang, W. “Associations of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity and gene mutator phenotype in patients with ovarian cancer”. JAMA. vol. 306. 2011. pp. 1557-65.

Bolton, K, Chenevix-Trench, G, Goh, C. “Association between BRCA1 and BRCA2 Mutations and Survival in Women with Invasive Epithelial Ovarian Cancer”. JAMA. 2011.

Antoniou, A, Pharoah, P, Narod, SA. “Average risks of breast and ovarian cancer associated with BRCA1 and BRCA2 mutations detected in a case series unselected for family history: a combined analysis of 22 studies”. Am J Human Genet. vol. 72. 2003. pp. 1117-30.

Chen, S, Parmigiani, G. “a meta-analysis of BRCA1 and BRCA2 penetrance”. JCO. vol. 25. 2007. pp. 1329-33.

HNPCC

Schmeler, KM, Lynch, HT, Chen, L, Munsell, MF. Prophylactic surgery to reduce the risk of gynecologic cancers in the lynch Syndrome NEJM. vol. 354. 2006. pp. 261-9.

Lindor, NM, Petersen, GM, Hadley, DW, Kinney, AY, Miesfelt, S. “Recommendations for the care of individuals with an inherited predisposition to Lynch Syndrome”. JAMA. vol. 296. 2006. pp. 1507-17.

Other resources

Robson, ME, Storm, C, Weitzel, J, Wollins, DS, Offit, K. “American Society of Clinical Oncology Policy Statement Update”. Genetic and Genomic Testing for Cancer Susceptibility JCO. vol. 121. 2010. pp. 893-901.

“NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian”. 2011.

Lancaster, JM, Powell, CB, Kauff, ND. “Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer predispositions”. Gynecol Oncol. vol. 107. 2007. pp. 159-62.

“Hereditary Breast and Ovarian Cancer Syndrome ACOG Technical Bulletin Obstetrics and Gynecol”. 2009. pp. 957-66.

“U.S. Preventative Services Task Force: Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement”. Ann Intern Med . vol. 143. 2005. pp. 355-61.

Burke, W, Daly, M, Garber, J. “Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium”. JAMA. vol. 277. 1997. pp. 997-1003.

Burke, W, Petersen, G, Lynch, P. “Cancer genetics studies consortium. Recommendations for follow-up care of individuals with inherited predispotion to cancer I”. JAMA. vol. 277. 1997. pp. 915-19.

“Genetics of Breast and Ovarian Cancer PDQ NCI”.

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