In May 2013, I was invited to give a talk with my colleague Dr. Carol Connor at the annual meeting of the American Society of Breast Surgeons.  Our topic was “Endocrine Therapy for Breast Cancer”, and we discussed the literature supporting the use of tamoxifen and aromatase inhibitors for breast cancer, as well as adverse effects and treatment of adverse effects. We were then invited to submit a manuscript which was published in the Annals of Surgical Oncology. The following is a summary of our talk and manuscript. I would like to express my appreciation to the #BCSM Community, who responded to my request for information about adverse effects  – it allowed me to discuss not only the literature, but also real patient experiences.

Dr. Connor reviewed the indications for therapy and discussed the key clinical trials. The primary conclusions:

– 70% of patients with breast cancer are hormone receptor positive (ER or PR positive) and will be advised regarding the potential risks and benefits of endocrine therapy.

–  Estrogen promotes the growth of breast cancer by binding and activating the estrogen receptor (ER). This process can be interrupted in 3 ways: 1.) drugs may bind to and block the estrogen receptor (tamoxifen [TAM] or raloxifene [not used for breast cancer treatment]); 2.) medications such as fulvestrant can “down regulate” the estrogen receptor, making it less available for estrogen binding; 3.) and aromatase inhibitors (AIs) can reduce the circulating levels of estrogen or the ovaries may be suppressed or ablated – either by medications or by surgical removal.

– In premenopausal women, the ovary is the main source of estrogen, and options include tamoxifen alone, or tamoxifen with ovarian suppression / ablation. Aromatase inhibitors are not indicated in premenopausal women. Placebo-controlled studies have demonstrated improved disease-free and overall survival in patients taking tamoxifen. Recent studies have shown that 10 years of therapy results in improved survival rates compared to 5 years of therapy.

–  In postmenopausal women, aromatase inhibitors result in improved disease-free and overall survival compared to tamoxifen therapy. Patients who become menopausal while on tamoxifen will benefit from switching to an aromatase inhibitor after 2-3 years. It remains to be seen if extended aromatase inhibitor therapy (10 years) results in improved survival as seen in extended tamoxifen therapy. There are 3 aromatase inhibitors (anastrozole, letrozole, and exemestane) and it appears that they have equivalent efficacy and similar adverse effects.

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My portion of the talk covered adverse effects and their treatment. Review of the literature from the early studies consistently found that in general adverse effects were considered to be “mild, tolerable, and self-limited”.  Here are some of the main points, summarized by adverse effect classification:

Cardiovascular:

• TAM increased the risk of blood clots 1-2% compared to AIs
• AIs increased cardiovascular disease but <1% difference between AI and TAM for “serious” cardiac disease
• TAM has a favorable effect on lipid profiles (cholesterol, etc)

Management of pre-existing cardiovascular disease and elevated cholesterol is recommended, as well as counseling regarding proper diet and exercise, tobacco avoidance, and limitation of alcohol intake.

Musculoskeletal:

• AIs were associated with a 2-4% increased bone fracture, as well as greater loss of bone mineral density
• Arthralgia/Myalgias (joint/muscle pain) with AIs occur in up to 50% of patients; also occurs with TAM – most report symptoms as mild to moderate

Bisphosphonate medications are recommended in patients on AIs if decreased bone mineral density is demonstrated. Patients who experience a continued decrease in bone mineral density may be changed to tamoxifen. In addition, counseling regarding weight-bearing exercise, smoking cessation, limitation in alcohol intake, and vitamin D / calcium supplementation in moderation is recommended.

Arthralgias and myalgias may improve after switching to a different AI, or switching from an AI to tamoxifen. Over the counter medications such as aspirin or ibuprofen may be of benefit. In addition, exercise, weight loss, physical therapy, acupuncture, and glucosamine/chondroitin have all been shown to improve symptoms.

Gynecologic:

• Uterine cancer occurs in <1% of patients on TAM; the ATLAS trial (10 years of  TAM) reported a 3.1% rate of uterine cancer and a 0.4% mortality from uterine cancer
• Approximately 5% of TAM patients required hysterectomy for benign disease

Patients on tamoxifen should undergo annual gynecologic exams. Any abnormal vaginal bleeding requires an appropriate workup. AI use in postmenopausal women should be considered as AIs do not increase the risk of endometrial cancer.

Menopausal including hot flashes, libido, cognitive, emotional:

• Hot flashes in 30-50% of patients – TAM or AI
• TAM results in vaginal discharge;  AIs result in vaginal dryness and irritation
• Decreased libido TAM or AI as high as 50%. In one study, 30% of patients continued to report considerable loss of libido even after treatment

Antidepressants can result in significant improvement in the frequency and severity of hot flashes. However, many antidepressants are metabolized using the same enzymes as tamoxifen, and may interfere with the effectiveness of tamoxifen. Therefore in patients on tamoxifen, venlafaxine (Effexor) is the recommended antidepressant. Patients on AIs may be tried on any of the available antidepressant medications. Acupuncture has also been shown to be effective in patients with signifiant hot flashes, and there are no adverse effects reported. It is not recommended that patients with breast cancer use hormone replacement therapy to treat hot flashes.

Various lubricants and moisturizers as well as olive oil have been used in patients who experience severe vaginal dryness and pain. Vaginal estrogen preparations may be considered if relief is not obtained with non-hormonal medications, however it is important to realize that there is some absorption into the circulation even when using small amounts of vaginal estrogen. This does not seem to result in increased rates of breast cancer recurrence, although more study is needed.

Cognitive dysfunction (“chemobrain”) related to endocrine therapy has received limited attention compared to chemotherapy, however this is increasingly reported, and this is the subject of active study regarding which patients may be at increased risk as well as options for treatment.

Other:  both TAM and AIs may result in eye symptoms, headache, fatigue, GI symptoms, psychiatric conditions, and cognitive dysfunction – there was no significant difference in the incidence of these adverse effects reported.

It has been reported that up to 20-50% of patients discontinue therapy early, whether they are on TAM or an AI, and many patients discontinue without first consulting their physician. Not surprisingly, patients are more likely to discontinue therapy if they experience adverse effects or if they are not prepared for the adverse effects.  Women who expressed worry regarding recurrence were more likely to complete therapy, and women who reported receiving less information about therapy were less likely to begin therapy.

In listening to the responses from the members of the #BCSM Community, several points were striking:

– Many patients experienced adverse effects that had significant impact on quality of life, but were reluctant to discuss with their physician

– Many physicians did not specifically ask their patients about treatment-related side effects, especially sexual side effects

– Many patients feel they cannot continue their medications, but then experience significant anxiety (related to the fear of breast cancer recurrence) if they stop their medications, even if approved by their oncologist. Guilt over not being able to complete therapy was also expressed.

Conclusions:

There is no question that TAM and AIs will improve survival and recurrence rates in patients with ER receptor positive breast cancer. However, it is also clear that more research is needed both for ways to reduce recurrence risk as well as improved treatments for adverse effects.

We don’t have all the answers – ideally we’d be able to more accurately predict based on the genetic makeup of the tumor the likelihood of recurrence and have a safe nontoxic therapy, but we’re not there yet. In the meantime, I would encourage any patient experiencing adverse effects to please speak up!