BRCA for the OB/GYN
/Here’s the RoshReview Question of the Week:
A 37-year-old woman presents to your office for health care maintenance. She reports that her maternal cousin was diagnosed with advanced-stage breast cancer at the age of 35. Genetic testing was performed, and her relative tested positive for breast cancer susceptibility gene 1. Which of the following is associated with this condition?
Check your answer at the links above!
Follow along with ACOG PB 182
What are we talking about, exactly?
Certain germline mutations predispose patients to heritably higher risk of breast and ovarian cancer
In particular, you have probably heard of BRCA1 and BRCA2
Others you may or may not have heard of include:
Lynch syndrome genes (MSH2, MLH1, MSH6, PMS2),
PTEN,
TP53 (Li-Fraumeni syndrome), and
STK11 (Peutz-Jehger Syndrome), just to name a few!
However, we’ll spend today’s podcast focusing on BRCA specifically.
What exactly are the BRCA risks?
Estimates of carrier frequency range from 1/300 to 1/800 for either genes.
BRCA1 is found on Chr 17
BRCA2 is found on Chr 13
Both are tumor suppressor genes that function in DNA repair process.
The inherited mutation is non-functional or defective allele in some way, but patients usually have a second, functional copy.
If the second allele becomes nonfunctional due to somatic mutation, cancer can develop –
Two-hit hypothesis of tumor suppressor genes.
Risk of breast cancer in person without BRCA by age 70: ~12% (1/8)
Risk in patient by age 70 with BRCA1/2: 45-85%
Also more likely to be “triple negative” breast cancer for hormone and HER2 receptor
Risk of ovarian / fallopian tube / primary peritoneal cancer:
BRCA1: 39-46% by age 70
BRCA2: 10-27% by age 70
Both associated with high grade, serous or endometrioid phenotype
BRCA1/2 also associated with prostate, pancreatic, uterine cancers as well as melanoma
Who should I send for genetic counseling?
If your patient has a new cancer, genetics recommended:
New ovarian epithelial cancers (including fallopian tube or primary peritoneal)
Breast cancer at age 45 or less;
Breast cancer, and have a close relative with breast cancer at age 50 or less, or a relative with ovarian cancers at any age; or with limited/unknown family history
Breast cancer with two or more relatives affected by breast cancer at any age
Breast cancer and two or more close relatives with pancreatic cancer or aggressive prostate cancer
Two breast cancer primaries, with the first diagnosed under age 50
Triple negative breast cancer at under age 60
Breast cancer and Ashkenazi Jewish ancestry at any age
Pnacreatic cancer and have 2+ close relatives with breast, ovarian, pancreatic, or aggressive prostate cancer
If your patient does not have a new cancer, genetics recommended based on the history of:
A first-degree or several close relatives that meet the above criteria
A close relative carrying a known BRCA1 or BRCA2 mutation
A close relative with male breast cancer
If you’re not sure but the history seems high risk, a referral to cancer genetics to discuss is always worthwhile – the histories above should definitely prompt your referral though!
And as you’re taking family history - it bears special mention that both maternal and paternal histories are important!
Especially given association with male breast CA, prostate CA, melanoma – be sure to get both sides!
Genetics may recommend performing BRCA mutation testing, which can have a variety of possible outcomes:
True positive: pathogenic BRCA variant identified
True negative: no pathogenic variant identified in someone who has known BRCA variant in family
Uninformative negative: no pathogenic variant identified, but uninformative because of:
a) other family members not tested
b) family carries a variant, but it was not detected because of test limitations
c) family carries a high risk mutation in another gene
d) there is no high risk mutation
Variant of uncertain significance (VUS): abnormality detected in BRCA gene, but unknown whether the variant is associated with increased cancer risk
Patients should be informed about the possible outcomes before undergoing genetic testing so they are aware of potential limitations and importance of family testing.
Unintended consequences of testing can include anxiety/stress and family dynamic issues regarding need for disclosure.
Multigene panel testing also exists to look for mutations beyond BRCA and can be suggested by genetic counselors if indicated.
How do I counsel and care for the patient with BRCA1 or BRCA2 mutation?
Screening
Breast: broken out by age:
Age 25-29: clinical breast exam every 6-12 months and annual screen (preferably by MRI with contrast)
Avoid ionizing radiation at this younger age as this may increase risk of cancer
Age 30+: Annual breast mammography and MRI, generally alternating every 6 months, as well as continuing CBE q6-12 months
Ovarian:
TVUS and CA-125 monitoring routinely is not recommended
However, could be considered for short term surveillance around age 30-35 until patient undergoes risk-reducing BSO.
Medical
Breast:
Tamoxifen and raloxifene can be considered (SERMs)
Can be considered in patients age 35 or older and not planning on pregnancy, or on prophylactic mastectomy
Tamoxifen is used in pre-menopausal and post-menopausal women, and may reduce breast cancer risk by 62% in BRCA2 carriers, but has not been found to reduce risk of cancer in BRCA1 carriers (likely due to higher triple-negative rates in this pop)
Raloxifene has been found to be effective in reducing invasive breast cancer in postmenopausal women at increased risk, though not evaluated specifically in BRCA mutation carriers
Tamoxifen may have a more significant risk reduction based on one head-to-head trial
Recall side effects of SERMs: vasomotor symptoms, vaginal symptoms (dryness, itching, dyspareunia), and increased risk of VTE!
Tamoxifen: also associated with concern for endometrial hyperplasia. While generally preferred in pre-menopausal patients, consider this in patietns with risk factors for endometrial hyperplasia!
Raloxifene: other significant side effect is leg cramps! Does not act on endometrium so may be considered in patients with significant risk factors.
Aromatase inhibitors
Two trials have shown reduction in breast cancer risk in at-risk postmenopausal individuals; could be considered as alternative if contraindication to SERM
Not used in premenopausal women because it would end up actually stimulating ovarian function (i.e., ovulation induction)
Ovarian:
OCPs are reasonable to use for cancer prophylaxis until BSO:
Reduction of ovarian cancer risk estimated at 33-80% for BRCA1, 58-63% for BRCA2
No increased risk of breast cancer in those with BRCA mutations using OCPs
Surgical
Breast: bilateral mastectomy
Can be offered to any patient with BRCA mutation; reduces risk by 85-100%, depending on procedure type
However, this is big surgery - should be referred to breast surgeon to discuss risks of surgery in short term (surgical issues like hematomas, flap issues, infection) and long-term (pain, numbness, swelling, breast hardnes)
70+% of patients report satisfaction with choice to undergo mastectomy at a follow up of 14.5 years
Ovarian: bilateral salpingoophorectomy
Most effective option for risk reduction; should be considered by age 35-40 for BRCA1 patients, 40-45 for BRCA2 patients
This can be individualized based on patient’s family history and plans for childbearing
Also worth discussion of fertility-preservation with oocyte or embryo cryoperservation
Salpingectomy alone is not recommended at this time; however, the PB notes that salpingectomy followed by future oophorectomy could be reasonable to consider for some patients desiring this.
How to perform a risk-reducing BSO:
Perform a survey on entry - visualize peritoneal surfaces for any obvious disease and perform pelvic washings
Inspect diaphragm, liver, omentum, bowel, paracolic gutters, appendix, ovaries, falliopian tubes, uterus, bladder serosa, and cul-de-sac; biopsy any abnormal areas
All tissue from ovaries and fallopian tubes need to be removed!
Ligate IP 2cm proximal to the end of identifiable ovarian tissue
Beware of your ureter!
If hysterectomy not performed, tubes should be divided at insertion to cornua, and ovary removed from utero-ovarian ligament as close to uterus as possible.
Frozen pathology not necessary, as most malignancies identified from this procedure are occult
Your pathologist needs to know that the patient is BRCA-carrier though! This will prompt them to perform complete, serial sectioning of the tissue with microscopic screening (rather than representative sections typically performed with other benign BSO)
Hysterectomy can be considered simultaneously:
Advantages: simplifies hormone therapy (estrogen alone, vs E-P if retained); removal of cornual aspect of fallopian tube; reduce endometrial cancer risk if genetically-predisposed or taking tamoxifen
Disadvantages: bigger surgery, longer recovery, higher risk of complications from surgery
After BSO:
Patients who are premenopausal will need HRT to mitigate effects of early menopause and help with cardiovascular health and bone protection
Recall that HRT in the WHI increased risk of breast cancer in the estrogen-progesterone arm, but not in the estrogen-alone arm.
Given the higher rates of triple-negative breast cancer in BRCA population – HRT would not alter that course. Data suggests that HRT does not seem to reduce the protective effects of risk-reducing surgery overall.
In post-menopausal patients, this is controversial – other options are generally preferred to HRT for VMS management.
Local estrogen therapy for vaginal symptoms (genitourinary syndrome of menopause) is safe and effective in BRCA population – please use it!
Ongoing surveillance after BSO is not necessary - so no need to collect CA125 or perform surveillance imaging. Patients should report any concerning symptoms.