Breast and Ovarian Cancers

201Hereditary Breast and Ovarian Cancers


   Hereditary breast and ovarian cancers (HBOC) is usually attributed to the BRCA mutations 1 and 2. The genetic mutation is found on chromosomes 17q21 and 13q12–13 for BRCA1 and BRCA2, respectively, and 80% of patients have a frame shift mutation. The mutation causes a defect in double stranded (DS) DNA repair and E3 ubiquitination. Inheritance is autosomal dominant and BRCA is known to be a tumor suppressor gene. Up to 30% of ovarian cancers have a genetic mutation. Many are found in the Fanconi anemia pathway. These mutated genes include: Rad50/51/51C/51D, BRIP1, BARD1, CHEK2, MRE11A, MSH2, MLH1, MSH6, PMS2, PPM1Df, POLE, POL-D1, PALB2, 17SNPs, NBN, PALB2, TP53 (1).

   The lifetime risk of HGSTOC for BRCA1 is 25% to 40% and for BRCA2 is 18% to 27%. Penetrance ranges from 41% to 90% for lifetime risk. Penetrance, by definition, is the net risk in the absence of any competing risks. In the Ashkenazi Jewish population the BRCA mutation risk is 1/40 compared to the general population risk: BRCA1: 1/300; BRCA2: 1/800. For patients who are found to harbor BRCA1 or 2 mutations, bilateral salpingo-oophorectomy (BSO) is recommended between the ages of 35 and 40, or when childbearing is completed. Primary fallopian tube cancer (PFTC) is seen in 2% to 17% of patients at the time of risk-reducing salpingo-oophorectomy (RRSO).

   The risk reduction for HGSTOC is with RRBSO over 80%, but there is still an inherent risk of primary peritoneal cancer, possibly due to unrecognized serous tubal intraepithelial carcinoma (STIC), which is 2% to 4.3%. Oral contraceptive pills (OCPs) administered for at least 6 years can provide a 60% risk reduction for HGSTOC for BRCA-positive patients (2).

   The presence of a BRCA mutation has been found to alter disease prognosis: the DFI after chemotherapy was 14 months for mutation carriers versus 7 months in sporadic cancer patients. The complete response (CR) was found to be 3.2 times higher if the patient was BRCA positive. The overall survival (OS) was found to be 101 months in BRCA carriers versus 51 months in sporadic cancer patients. The age of onset for patients who are BRCA1 positive was 52 years.

   Oophorectomy may decrease the incidence of breast cancer for both BRCA1 and 2 carriers. BRCA-positive women are recommended to undergo a BSO by age 40 or after childbearing is completed. BRCA1 breast cancers are often ER negative and commonly are triple negative (ER, PR, Her-2-neu negative). The risk of breast cancer was decreased 56% in BRCA1 patients who underwent a BSO, and was decreased 46% in BRCA2 patients. There was an increase in risk reduction from breast cancer the earlier the BSO was performed (3).


   Patients who have BRCA mutations are categorized as “high risk.” If these patients do not opt for surgical management, chemoprophylaxis with OCPs or bilateral salpingectomy, and delayed oophorectomy can be considered. Screening with every 6- to 12-month pelvic examinations, transvaginal ultrasound, and serum CA-125 levels has not proven beneficial.

   Adnexal neoplasia is found in 5% to 6% of RRSO (high-risk women). Recurrent/metastatic disease has been seen in up to 9% of women with STIC alone. The lag time from a diagnosis of STIC to pelvic recurrence was 4 years (4).

   For those women who undergo RRSO: the Sectioning and Extensively Examining the FIMbriated End (SEE-FIM) of the Fallopian Tube pathological protocol should be applied to their tubes. The tubes should be examined at 5 micrometer sections per 2 mm thick tissue block; as occult STIC may measure 1 mm or less.

   If diagnosed with unilateral breast cancer, the cumulative risk for contralateral breast cancer by age 70 is 83% for BRCA1 and 62% for BRCA2.

   Genetic screening is recommended for:

     Images   Histologically proven HGSTOC.

     Images   Individual from a family with a known BRCA 1/2 deleterious mutation.

     Images   An individual with breast cancer diagnosis meeting any of the following:

          Images   Breast cancer at:

               Images   An early age of ≤45 or

               Images   Age ≤50 years and an additional breast cancer primary, ≥1 close blood relative with breast cancer at any age, ≥1 close relative with pancreatic cancer, ≥1 relative with prostate cancer (Gleason score ≥7), or an unknown or limited family history

               Images   Age ≤60 years with triple negative breast cancer

          Images   Diagnosed at any age and has ≥1 close blood relative with breast cancer ≤50 years, or ≥1 close blood relative with invasive HGSTOC at any age, or ≥2 close blood relatives with breast cancer and/or pancreatic cancer at any age, or and/or prostate cancer (Gleason score ≥7) from a population at increased risk

     Images   Personal history of pancreatic cancer at any age with ≥1 close relative with breast cancer ≤50 and/or invasive HGSTOC at any age, or two relatives with breast, pancreatic cancer, or prostate cancer (Gleason score ≥7) at any age.

     Images   Personal history of pancreatic cancer and Ashkenazi Jewish ancestry.

     Images   An individual with no personal history of cancer but with a family history of any of the following:

          Images   A known mutation in a cancer susceptibility gene within the family, ≥2 breast cancer primaries in a single individual, ≥2 individuals with breast cancer primaries on the same side of the family, ≥1 invasive HGSTOC primary, first or second degree relative with breast cancer ≤46 years old.

          Images   BRCA1/2 mutation detected by tumor profiling in the absence of germline mutation analysis.

     Images   Personal and/or family history of three or more of the following: pancreatic cancer, prostate cancer (Gleason score ≥7); sarcoma; adrenocortical carcinoma; brain tumors; endometrial cancer; thyroid cancer; kidney cancer; dermatologic manifestations and/or macrocephaly; hamartomatous polyps of the gastrointestinal (GI) tract; diffuse gastric cancer; invasive HGSTOC male breast cancer are indications for further genetic risk evaluation.


   If HBOC testing criteria are met: order genetic testing with informed consent:

     Images   If the deleterious familial mutations is/are known, then test for that specific mutation.

     Images   If a mutation is not known, then comprehensive BRCA gene testing of the patient or proband is recommended, or multigene testing.

   Screening and risk reduction:

     Images   Breast awareness counseling to start at age 18.

     Images   Clinical breast exam every 8 to 12 months starting at age 25; annual breast MRI or mammogram if MRI not available ages 25 to 30; annual mammogram and breast MRI screening QO6-12m ages 30 to 75; after age 75, individualize testing/management.

     Images   If treated for breast cancer, screening of remaining breast tissue with annual mammography and breast MRI should continue.

     Images   Consider risk-reducing mastectomy to include reconstruction options after completion of breast feeding. If declines: tamoxifen prophylaxis should be initiated.

     Images   Consider RRSO between ages 35 and 40 or after completion of childbearing. If declines: OCP prophylaxis should be initiated. Salpingectomy alone is not the standard of care. The concern is that women are still at risk for developing ovarian cancer. In premenopausal women, oophorectomy reduces the risk of developing breast cancer by 60%. Interval salpingectomy followed by oophorectomy (a staged procedure) can be considered if patients are highly concerned of early surgical menopause.

     Images   Management of menopausal symptoms (try to not use hormonal therapies): selective serotonin reuptake inhibitors (SSRIs), clonidine, belladonna, and other therapies.

   There was a 25% incidence of germline BRCA1 and 2 mutations identified when a histology-based referral specific to high-grade serous ovarian subtypes was employed. This suggests the genetic assessment of all women diagnosed with high-grade serous carcinoma will improve detection rates and capture mutation carriers otherwise missed by referral based on family history alone (5).

   A 2% rate of BRCA1 mutations was identified in uterine serous cancer patients. This is compared to the 0.06% rate of BRCA1 mutations in the general population. Nine percent of women with a history of breast cancer, and then uterine serous cancer (USC), had a BRCA1/2 mutation. Hysterectomy can be discussed in patients with BRCA1 mutations although this is less than the accepted positive predictive value (6).

   Pregenetic screening, counseling, and testing can be offered to those considering children.


   Characteristics: hereditary nonpolyposis colon cancer (HNPCC) can contribute to about 10% of hereditary ovarian cancers. HNPCC is also called Lynch II syndrome. There is an increase in colon, endometrial, ovarian, pancreatic, central nervous system (CNS) and urothelial cancers. The mutations responsible for these cancers are MLH1, MSH2, MSH6, PMS1, PMS2, and EPCAm gene deletion. These mutations cause defects in DNA mismatch repair mechanisms. 60% of the cancers present as colon cancer, and 60% present as endometrial cancer. 20–30% of uterine cancers have MLH1 silenced by noninherited methylation of the MLH1 promoter.


   The 2004 HNPCC Bethesda Guidelines were modified to include endometrial cancer as a sentinel cancer. Bethesda Guidelines for Lynch Syndrome (LS): this guides tumor testing for microsatellite instability (MSI) in individuals with the following:

     Images   Diagnosed in a patient who is younger than 50 years of age.

     Images   Presence of synchronous, or metachronous, colorectal cancer (CRC) or other LS-related tumors, regardless of age.

     Images   CRC with IHC deficient MSI histology diagnosed in a patient who is younger than 60 years of age.

     Images   CRC diagnosed in a patient with one or more first-degree relatives with an LS-related cancer with one of the cancers being diagnosed before age 50 years.

     Images   CRC diagnosed in a patient with two or more first- or second-degree relatives with LS-related cancers regardless of age.

   Amsterdam Criteria I: at least three relatives with CRC; all of the following criteria should be present:

     Images   One should be a first-degree relative of the other two.

     Images   At least two successive generations must be affected.

     Images   At least one of the relatives with CRC must have received the diagnosis before the age of 50 years.

     Images   Familial adenomatous polyposis (FAP) should be excluded.

     Images   Tumors should be verified by pathologic examination.

   Amsterdam Criteria II: at least three relatives must have a cancer associated with LS (colorectal, cancer of endometrium, small bowel, ureter, or renal-pelvis); all of the following criteria should be present:

     Images   One must be a first-degree relative of the other two.

     Images   At least two successive generations must be affected.

     Images   At least one relative with cancer associated with LS should be diagnosed before age 50 years.

     Images   FAP should be excluded in the CRC case(s) (if any).

     Images   Tumors should be pathologically verified whenever possible.

   Patients should be screened for Lynch/HNPCC syndrome if:

     Images   They have an endometrial or ovarian cancer and have a synchronous or metachronous colon or other Lynch/HNPCC-associated tumors at any age to include: stomach, ovarian, pancreas, ureter, renal pelvis, biliary tract, brain glioblastoma as seen in Turcot syndrome, sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome, carcinoma of the small bowel.

     Images   Patients with colorectal cancer with tumor infiltrating lymphocytes, peritumoral lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern diagnosed before the age of 60.

     Images   Patients with endometrial or colorectal cancer and a first-degree relative with a Lynch/HNPCC-associated tumor diagnosed before the age of 50.

     Images   Patients with colorectal or endometrial cancer diagnosed at any age with two or more first degree or second degree relatives with Lynch/HNPCC-associated tumors regardless of age.


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Jul 3, 2018 | Posted by in GYNECOLOGY | Comments Off on Breast and Ovarian Cancers
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