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  • Nathan Riley, MD

Obgyno Wino Podcast Episode 69 - Management of Gynecologic Issues in Women With Breast Cancer

“The more clearly we can focus our attention on the wonders and realities of the universe about us, the less taste we shall have for destruction.” ― Rachel Carson


2017 Perlita Malbec-Syrah from Bodega DiamAndes

PB#126 - Published March 2012 (Reaffirmed 2016)


Five Pearls

  1. Rapidly dividing cells - like those in the gonads - are the most susceptible to chemo, so suppressing with GnRH analogues prior to chemo may be protective against ovarian toxicity, but data is mixed.

  2. BRCA mutation carriers are at increased risk for both breast and ovarian cancers, therefore prophylactic BSO is recommended at age 40 or after childbearing is complete

  3. 5 years of tamoxifen use decreases the annual risk of recurrence by 40% and annual mortality risk by 35%

  4. Women treated for breast cancer are at higher risk for bone fracture because chemotherapy, ovarian suppression, and, especially aromatase inhibitors all lead to bone loss and osteoporosis.

  5. HRT has a bad rap historically due to concern that it may predispose women to de novo breast cancer or recurrence, but the findings have been mixed and generally not statistically insignificant.


Chemotherapy can make you menopausal

- patients with breast cancer often receive cyclophosphamide, an alkylating chemotherapy agent that is very toxic to the ovaries

- premature ovarian failure or diminished ovarian reserve may result for women treated early in life

- newer agents (taxanes like paclitaxel and docetaxel) are perhaps slightly less toxic to the ovaries

- amenorrhea results for 50-90% of patients (depends on age and chemo regimen)

- women >40 yrs are more likely to be pushed into menopause iatrogenically

- if a woman does become amenorrhoeic, menses will return within 1 year if it's going to return at all (it's not uncommon for menses to return with irregular patterns)

- a low serum anti-mullerian hormone level may reflect decrease ovarian reserve, but a low value doesn't necessarily preclude the ability to conceive

- rapidly dividing cells - like those in the gonads - are the most susceptible to chemo, so suppressing with GnRH analogues prior to chemo may be protective

- GnRH analogues are also protective for hormonally responsive breast cancer (ER+ or PR+) by suppressing the release of gonadotropins and thus production of ovarian hormones

- GnRH analogues are required, anyways, for aromatase inhibitors to be effective in preventing recurrence of disease post-treatment in pre-menopausal women


Recall: aromatase inhibitors inhibit the production of estrogen from ovarian and adrenal androgens


The Role for Gynecologic Surgery

- bilateral salpingo-oophorectomy (BSO) can be helpful as adjuvant treatment for ER/PR+ by reducing estrogen and progesterone production

- BRCA carriers are at increased risk for both breast and ovarian cancers, therefore prophylactic BSO is recommended at age 40 or after childbearing is complete

- this actually decrease the risk of breast cancer in BRCA carriers and decreases their overall mortality from the disease


The downside of BSO is surgical menopause

- testosterone and estradiol production will drop by 50% and 80% on average, respectively

- hormone replacement therapy is currently not recommended to mitigate menopausal symptoms in these patients (more on this later)

- non-hormonal options are recommended instead:

  • hot flushes --> SSRI, SNRI, gabapentin, clonidine

  • atrophic vaginitis --> vaginal moisturizers, though topical vaginal estrogen or the intravaginal estrogen ring (e.g. NuvaRing) is still an option due to low systemic absorption; testosterone hasn't been found to be helpful


Note: SSRIs and SNRIs are strong inhibitors of the CYD2D6 enzyme within the P450 system. CYP2D6 is required to activate tamoxifen to its active form. Therefore, these medications may actually increase the risk of recurrence for patients on tamoxifen. Fluoxetine, paroxetine, and bupropion are the most egregious violators.


Special notes on libido

- the loss of androgens from BSO can certainly impact libido, but sexual performance is likely more greatly impacted by the disruption of intimate relationships

- patients who undergo breast-conserving surgery (e.g. lumpectomy)

- it is well-documented that mastectomy has far greater long-term consequences for people who identify as women

- serious issues may arise around intimacy, sexual performance (e.g. ability to enjoy sex or achieve orgasm) sense of well-being, and body image...which goes far beyond the loss of ovarian hormone production

- women who also undergo chemo are at even higher risk for sexual dysfunction


What complementary therapies might be helpful with these symptoms?

- black cohosh

- breathwork and relaxation techniques

- acupuncture

- yoga

- hypnosis

- homeopathy


Note: soy products haven't been found to work well, and they have estrogenic effects, which is why oncologists recommend against them in patients with history of hormone-sensitive breast cancer


Estrogen agonists/antagonists

- tamoxifen, raloxifene, and toremifene are available in the U.S.

- they selectively antagonize estrogen receptors in the breast and agonize receptors in the uterus


Tamoxifen

- approved by FDA as adjuvant treatment of hormone-sensitive breast cancer

- 5 years of tamoxifen use decreases the annual risk of recurrence by 40% and annual mortality risk by 35% independent of age, chemotherapy status, menopausal status, or lymph node status (little data to support treatment beyond 5 years)


Raloxifene

- approved by FDA for prevention of breast cancer in postmenopausal women who have risk factors

- 40% reduced risk of invasive or non-invasive breast cancer (comparable to tamoxifen)

- also approved for the prevention and treatment of osteoporosis in postmenopausal women


Toremifene

- approved for treatment of metastatic cancer

- comparable efficacy to tamoxifen


Downsides to estrogen agonist/antagonists vary by drug

- increased VTE risk: raloxifene < tamoxifen

- menstrual irregularities, ovarian cysts, endometrial hyperplasia/cancer, endometrial polyps, fibroid growth, and postmenopausal bleeding: tamoxifen has been best studied (2 of 1000 women on tamoxifen will develop endometrial cancer); raloxifene has not been shown to increase risk compared to placebo

- vasomotor symptoms: 50% of women on tamoxifen will develop hot flushes (symptoms decrease with time); comparable risk for raloxifene and toremifene


Should I routinely screen my patients for endometrial malignancy while on tamoxifen?

- No. Just screen if they develop vaginal bleeding

- ultrasound alone has high false positive rate

- hysteroscopy or sonohysterography are better, especially due to increased risk for polyps


Aromatase inhibitors

- clinically very effective: outperform tamoxifen as an adjuvant therapy in early stage, hormone-sensitive breast cancer

- three approved for use in the U.S.: anastrozole, exemestane, and letrozole

- anastrozole and letrozole are approved by FDA as first-line treatment for early stage breast cancer

- exemestane is approved as adjuvant therapy in postmenopausal women and for prevention of recurrence

- optimal duration of treatment is unknown

- not helpful if ovaries are in place; aromatase inhibitors inhibit the production of estrogen by the ovaries, but the pituitary will merely pump out more FSH/LH and overwhelm the inhibition

- if ovaries are still in place, GnRH analogues must be used to suppress the hypothalamic-pituitary-ovarian axis altogether



Downsides to aromatase inhibitors

- Musculoskeletal effects: increased risk of bone fracture; anastrozole found to have higher risk when used alone compared to tamoxifen alone or in combination during treatment but risks comparable post-treatment; aromatase inhibitors also associated with joint pain (45%; major cause of discontinuation)

- Gyn issues: less bleeding or discharge with anastrozole than tamoxifen, OR 0.25 of endometrial cancer w/ anastrozole; vaginal dryness and dyspareunia more common w/ aromatase inhibitors

- Cardiovascular disease: possible increased risk w/ aromatase inhibitors, but data is mixed (possibly related to the tendency for lipid levels to climb in hypoestrogenic state)


Risk assessment and management of osteoporosis in patients with history of breast cancer

- these patients are at higher risk for bone fracture because chemotherapy, ovarian suppression, and, especially aromatase inhibitors all lead to bone loss and osteoporosis

- BMD testing and monitoring is recommended

- first-line agents for prevention and treatment: bisphosphonates and raloxifene

- lifestyle factors: diet, exercise, sleep, reducing alcohol consumption, and smoking cessation

- BMD testing by DEXA

- consider the whole clinical picture! fractures are more likely in: older women, women w/ personal or family history of osteoporosis or fracture, chronic steroid use, low levels of physical activity, smoking, low BMI, and excessive alcohol consumption

- use the WHO's FRAX tool to calculate 10-year risk of fracture

- bisphosphonates can be administered with aromatase inhibitors to counteract their action at the bone


Recall: bisphosphonates work to strengthen bone by inhibiting bone resorption


Start medication if your DEXA score is low

- if DEXA T-score is > -1, you can forgo pharmaceuticals

- if < -2.0: start a bisphosphonate or raloxifene

- alternatively, a FRAX calculation of major fracture risk over 10 years is > 20% or hip fracture risk is > 3%, pharmaceuticals should be recommended



WHO's guidelines

- annual monitoring is recommended if your patient is on treatment, otherwise 2-year monitoring is sufficient

- downsides of bisphosphonates is the suggestion that they may be associated with atypical femur fractures and osteonecrosis of the jaw


Fun fact: bisphosphonates seems to have some anti-tumor activity but the proposed mechanism is still unclear (maybe angiogenesis?)


Can I use hormone replacement therapy if my patient had breast cancer?


Short answer:

- benefits may outweigh the risks for many women


Long answer:

- throughout the 80s and 90s, multiple prospective and retrospective studies have been done to evaluate the influence of HRT on breast cancer risk (with and without a history) --> results mixed

- in 1991, the Women's Health Initiative (WHI) was kicked off: a collaborative, 15-year study across 40 medical centers in the U.S. to evaluate the long-term health outcomes of postmenopausal women aged 50-79, including the long-term consequences of hormone replacement therapy (HRT)

- in JAMA 2002, the WHI terminates the estrogen-progestin arm of their study due to what appeared to be a strong link between HRT and breast cancer, though the results were not statistically significant

- in 2003, the WHI reports again an increase in breast cancer risk of about 1%

- in 2003, the Lancet publishes "The Million Women Study", which supports the notion that there is an increased risk of breast cancer with HRT with a few caveats

- in 2004, the WHI reports no increased breast cancer risk with estrogen therapy alone

- in 2004, the WHI flips the script, reaffirming the 2004 statements but also suggesting that patients with past use of HRT actually have lower risk of breast cancer

- a flood of additional studies from around the world then suggest that HRT does not increase breast cancer risk, including patients with multiple risk factors

- many studies, like this one, have also looked at breast cancer recurrence risk and have found no increased risk; it also suggests that HRT is a reasonable means of managing menopausal symptoms in this patient population

- on the other hand, the Lancet also published the HABITS trial in 2004, which recruited 434 women with history of breast cancer were randomized to HRT therapy or non-hormone therapy for vasomotor symptoms was actually terminated early due to "unacceptable risk for women exposed to HRT"

- for more on the history and risks/benefits of HRT, look no further

- as always, risks versus benefits should guide your counseling



Notes on fertility after breast cancer

- tamoxifen can actually induce ovulation if ovarian function remains intact (but inducing ovulation may also more rapidly deplete her already tenuous ovarian reserve)

- pregnancy is not associated with higher recurrence risk

- prior to treatment, consultation with a fertility specialist may be a good idea for egg harvestation and preservation

- use of GnRH analogues has been proposed as a means of ovarian function making the patient's ovarian reserve less susceptible to the toxic effects of chemo: data is mixed

- IVF usually includes periods of high dose HRT to stimulate follicle development, but it's unclear if this may be deleterious in the presence of breast cancer; natural cycle IVF is also an option


What forms of contraception are safe for patients with breast cancer?

- nearly 2/3 of breast cancer are hormone-sensitive so the U.S. Medical Eligibility Criteria for Contraception Use classifies hormonal contraception as category 4 (relatively contraindicated) for women with active breast cancer including patients on tamoxifen

- for women with 5+ year history of breast cancer, hormonal contraceptives are category 3 (risks usually outweigh advantages)

- for patients with breast cancer that's not thought to be hormone-sensitive, data is limited, so it's considered category 4

- copper IUD and barrier methods are the recommended

- levonorgestrel intrauterine systems haven't been well-studied in this patient population, but we will likely find them to be safe in the long-run due to poor systemic absorption


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