• Nathan Riley, MD

Obgyno Wino Podcast Episode 99 - Hereditary Breast and Ovarian Cancer Syndrome

“I am too intelligent, too demanding, and too resourceful for anyone to be able to take charge of me entirely. No one knows me or loves me completely. I have only myself”

Simone de Beauvoir

2018 Shinola Red Table Wine from Merkin Vineyards

PB #182, Published September 2017 (Reaffirmed 2019)

Five Pearls

1. BRCA mutation carriers have a higher risk for breast and ovarian cancer.

2. BRCA1 has higher risk for both breast and ovarian cancer. Breast cancers tend not to be hormone sensitive. BRCA2 has a lesser risk of both breast and ovarian cancer. Their breast cancers tend to be hormone sensitive.

3. Combination of MRI, mammography, and clinical exam offer the most sensitive model for detecting breast cancer in high-risk patients.

4.Prophylactic BSO should be offered at age 35-40 for BRCA1 and 40-45 for BRCA2 carriers.

5. Prophylactic bilateral mastectomy should be offered at time of diagnosis of BRCA mutation.

BRCA1 and BRCA2 are germline mutations in tumor suppressor genes

- BRCA1 is found on chromosome 17; BRCA2 on chromosome 13

- if these genes are defective, the DNA repair process is impaired

- those with the syndrome inherited one defective allele from a parent, and likely experienced a somatic mutation in the "healthy" allele resulting in the absence of an important functional tumor suppressor gene

- incidence in general population of a defective allele is somewhere between 1/300 and 1/88

- higher incidence among Ashkenazi Jews (1/40), French Canadiens, and Icelanders

- there may also be higher incidence among subsets of Hispanics, African Americans, and Asians

These mutations are associated with cancer

- 10-25% cases of epithelial ovarian cancer are related to a BRCA mutation

- 5% cases of breast cancer

- for a woman with either BRCA mutation, risk of breast cancer is 45-85% by age 70

- a meta-analysis including 10 studies found a cumulative risk of breast cancer of 57% for BRCA1 and 50% for BRCA2

- triple neg cancer (ER- negative, PR-negative, and ERBB2-negative) tends to be associated with BRCA1

- BRCA2 tends to be associated with estrogen-receptor (ER) and progesterone-receptor (PR) positive breast cancers

- BRCA1 carriers have 40-45% chance of developing ovarian cancer (includes fallopian tube cancers); 10-25% chance for BRCA2 carriers

- for BRCA carriers who develop breast cancer, BRCA1 mutation carriers have 13% risk of developing ovarian cancer in 10 years; BRCA2 has 7% risk

- ovarian cancers in BRCA carriers are usually high grade serous or endometrioid (not mucinous or borderline tumors)

- BRCA mutations are also associated with prostate cancer, melanoma, pancreatic cancer, and potentially uterine cancer

Who should be screened? Take a history...

- personal or family history of epithelial ovarian cancer or breast cancer and age at onset

- family history: 1st- and 2nd-degree relatives

- ethnic background

- if a person meets eligibility for genetic evaluation (see Box 1), be mindful that such a diagnosis can be heavy

- refer to a genetics counselor before testing so that your patient knows their management options

- risk assessment models: Gail, BRCAPRO, Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm, International Breast Cancer Intervention Studies (IBIS, also known as Tyrer–Cuzick), or the Claus model

- as with anything, there's a good way to go about counseling related to genetic disorder (See CO#693 for more)

Genetic testing options

- two options: BRCA testing or a multipanel test that includes BRCA and other genetic mutations

- testing should begin with the affected family member first

BRCA testing

- comprises single-site testing, targeted multisite mutation testing, comprehensive gene sequencing, and BRCA rearrangement testing

- if a specific gene mutation is identified in an affected individual, they can undergo single site testing for that specific mutation

Multipanel testing

- looks for combinations of genes involved with a variety of cancers

- especially useful when more than one gene is responsible for an inherited cancer syndrome

- results can be complicated and difficult to interpret

Can anything be done to prevent ovarian cancer in BRCA carriers?

- serial ultrasound or CA-125 have been proposed as screening methods

- neither has panned out as a means of decreasing mortality from ovarian cancer

Prevention through COCs

- one year of COC use may prevent ovarian cancer in BRCA carriers: 30-80% in BRCA1, 60% in BRCA2

- no clear increased risk for breast cancer in BRCA carriers using COCs

Prevention through surgery

- risk-reducing bilateral salpingo-oophorectomy (BSO) remains the best prevention strategy (better than

- ovaries and tubes must be removed entirely

- this goes for BRCA mutations or other mutations like BRIP1, RAD51C, and RAD51D at age 45-50

- for BRCA mutations, BSO reduces risk of ovarian, peritoneal, or fallopian tube cancer by 80% (also decreased mortality

- risks of removing the ovaries include: vasomotor symptoms, decreased sexual functioning. and normal surgical risks of operating in the pelvis (e.g. bladder injury, ureteral injury, injury to nearby organs, VTE, and infection)

- removal of uterus should also be recommended for patients with Lynch syndrome

Note: It is believed epithelial ovarian cancers, which comprise the vast majority of ovarian cancers, arise from the distal ends of the fallopian tubes. More here. For high-risk women, BSO is recommended. In low-risk women, full salpingectomy is a great consideration for the purposes of surgical sterilization due to the additional ovarian cancer risk reduction.

- risk-reducing BSO should be recommended at age 35-40 for BRCA1 and age 40-45 for BRCA2

- <2-3% of ovarian cancers in BRCA1 or BRCA2 carriers are diagnosed at <40 years

- 10-20% of BRCA1 carriers develop ovarian cancer by age 50

- ≤3 of BRCA2 carriers develop ovarian cancer by age 50

- all of this being said, BRCA2 carriers have 25-35% risk of developing breast cancer by age 50, and recall that BRCA2 carriers tend to develop hormone-sensitive breast cancers

- risks must be weighed against reality of surgical menopause and desire for fertility preservation

Who should do the prophylactic BSO surgery? How is it done?

- first off, consent your patient for everything including the possible need for surgical staging

- intraoperatively, pelvic washings should be collected, and you should evaluate the pelvis and peritoneal cavity carefully for any evidence of malignancy

- ovarian vessels should be ligated 2 cm proximal to identifiable ovarian tissue

- if uterus is being left, the fallopian tube and utero-ovarian ligaments should be transected as close to the uterine cornua and corpus, respectively, as possible

- a generalist can handle this surgery if comfortable with biopsies, though it's best to have gyn/onc on call if you visualize cancer during the prophylactic surgery OR if gross pathologic examination of any specimens on frozen section intraoperatively reveal cancer

- if either of these scenarios plays out, surgical staging with lymphadenectomy and omentectomy

- removal of the uterus provides more definitive prevention of uterine cancer in the future and can also help simplify hormone therapy strategies going forward (e.g. estrogen only HRT is OK without a uterus or reassurance despite tamoxifen use)

Prevention of breast cancer in BRCA carriers

- q6-12 month clinical exam is recommended starting at age 25-29

- also annual mammography

- breast MRI with contrast can be considered alternatively in this age group in order to reduce total radiation exposure given the recommended high frequency

- MRI is more sensitive than mammography for detecting breast cancer

- combination of MRI, mammography, and clinical exam offer the most sensitive model for detecting breast cancer in high-risk patients

- starting at age 30, these patients should undergo annual MRI and breast mammography alternating every 6 months

- screening does still carry the risks of patient anxiety, false positives, and unnecessary treatments (risks versus benefits)

Prevention through SERMs

- selective estrogen receptor modulators (SERMS) can be useful in this population: tamofixen and raloxifene

- tamoxifen: may reduce risk of breast cancer by 60% in BRCA2 (similar to prevention of hormone-sensitive breast cancer in general population)

- not as useful in BRCA1 carriers as they are not predisposed to hormone-sensitive breast cancer

- raloxifene: useful in preventing breast invasive cancer in any woman at risk (including merely having a family hx)

- hasnt been studied in women w BRCA mutations

- like tamoxifen, only found to reduce risk of hormone-sensitive breast cancer

- RR 1.24 favoring tamoxifen when compared head-to-head

- downsides to tamoxifen: vasomotor symptoms and vaginal symptoms like dryness; also RR ~2 of VTE or endometrial cancer

- downsides to raloxifene: vasomotor symptoms, leg cramps, dyspareunia, and weight gain

- aromatase inhibitors may be a reasonable alternative for women who can't take tamoxifen

Preventative surgery

- BRCA mutation carriers (or similar deleterious mutations) should be offered prophylactic bilateral mastectomy

- reduces risk of breast cancer by 85-100% depending on the specific type of surgery

- total mastectomy: entire breast, nipple, and areola removed

- nipple-sparing mastectomy: entire breast removed (nipple and areola preserved)

- no studies have compared outcomes between these two methods

- contralateral mastectomy is recommend for BRCA mutation carriers who develop breast cancer (30% risk of contralateral recurrence over 10 years following initial diagnosis)

- risks of mastectomy include: 3-60% risk of surgical complications (infection, hematoma, flap necrosis, and failed reconstruction), 65-85% risk of postsurgical symptoms (including pain , numbness, tingling, swelling, and breast hardness)

- after prophylactic surgery, 75% reported decreased anxiety about breast cancer and 70% were satisfied with their surgery

- prophylactic BSO may reduce risk cancer by 37-100% further in BRCA2 mutation carriers, but this effect only applies to premenopausal women (data is mixed)


- premenopausal patients who undergo prophylactic BSO without evidence of breast cancer should be offered hormone therapy to mitigate the effects of surgical menopause

- however, long term effects of HRT in these patients is unknown (short-term effects are great, though!)

- no surveillance methods are great apart from counseling your patients on body awareness to identify and act on symptoms that might reflect cancer (along with routine well-woman visits)

BRCA carriers and fertility

- given prophylactic BSO is recommended at age 35-45, extensive counseling with oocyte preservation if fertility is desired should happen before surgery

What if my patient has a strong family history but tests negative for a BRCA mutation?

- family history should still be taken into consideration

- still significant risk for breast cancer, but not ovarian cancer

- consider referral to a genetics counselor to dive deep into any residual risks in these patients

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