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Breast Cancer and Side Effects
Ernest H. Rosenbaum, MD

Early menopause due to chemotherapy-induced ovarian failure or surgical or chemical ablation - women with hormone positive cancers often have an early menopause. This includes treatments with SERMs (selective estrogen-receptor modulators, such as Tamoxifen or aromatase inhibitors {Letrozole, Anastrozole, or Exemestane}). For premenopausal women, who are still menstruating, the ovaries are still producing estrogen, which is increased through enhancing the negative hypothalamic feedback loop.

The SERMs or the aromatase inhibitors that inhibit estrogen-induced cancer growth have different functions. The SERMs have both estrogenic and anti-estrogenic activities that are tissue-specific, and the aromatase inhibitors block estrogen production and are therefore completely anti-estrogenic.

Some of the side effects include hot flashes associated with the therapy, and symptoms can be relieved with estrogen, but this is, in general, contraindicated for breast cancer survivors, especially if they have estrogen-receptor positive tumors. Certain serotonin-reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine-reuptake inhibitors (SSNRIs), venlafaxine (Effexor), as well as gabapentin, can help reduce hot flashes in about 50% of women. The SSRI, paroxetine, may help prevent the metabolic activation of Tamoxifen, and therefore should not be used with Tamoxifen therapy.

Sexual dysfunction is often a major problem, where there may be psychological problems from a loss of body-image, depending on the treatments used. This includes anti-estrogen therapy, which can cause painful intercourse (dyspareunia), which is vaginal dryness. This can, in part, be relieved by estrogenic local preparations, such as the Estradiol vaginal ring or lotions. Increased urinary frequency and infections are not uncommon.

Caution is recommended for women with estrogen-receptor positive breast cancer patients taking aromatase inhibitors with use of intra-vaginal estrogen preparations. Non-hormonal moisturizers and lubricants can also be of help for vaginal dryness to improve sexual relations.

Other complaints can include myalgias, arthralgias, fatigue, depression and weight gain.

Osteoporosis, which is often related to an earlier menopause secondary to anti-breast cancer therapy, such as adjuvant chemotherapy or aromatase inhibitors. The risk for fractures is increased. Tamoxifen has been reported to reduce the risk of osteoporosis. Treatments for bone loss can include calcium, vitamin D, and bisphosphonates, such as Pamidronate or Zoledronic acid, given every six months can be effective. Raloxifene (Evista), which is a SERM somewhat like Tamoxifen, is used as a treatment for osteoporosis. Use of Tamoxifen over five years has been associated with breast cancer recurrence. The use of combined Tamoxifen with an aromatase inhibitor was shown to be less effective than the aromatase inhibitor alone. For patients with osteopenia, taking aromatase inhibitor bisphosphonate therapy is recommended. Bone density tests should be done annually or biannually as indicated.

An adverse side effect of bisphosphonates is osteonecrosis of the jaw, and a dental evaluation pretreatment is merited, and any dental injuries, such as pulling a tooth or gum problems, merit treatment to avoid osteonecrosis.

Patients who have received left chest wall radiation therapy have approximately a 20-30% increase of long-term risks of cardiovascular events. The value of radiation therapy to reduce recurrence and decrease earlier mortality outweighs the risk of cardiovascular disease.

There is also a risk with adjuvant systemic therapy, especially with use of anti-estrogenic therapeutic strategies, and Tamoxifen, when compared to a placebo (under study). This has shown a possible reduction in the risk of cardiovascular disease. There is a profound decrease in estrogen level with the use of aromatase inhibitors. Low-dose estrogen has been shown to be of value for women in their late 40s in preventing earlier heart disease.

Following cardiovascular risk factors, which include not smoking, controlling hypertension and lipid levels, as well as moderate exercise, can be of value in prevention of heart disease.

Anthracyclines and trastuzumab have been known to cause congestive heart failure, and it is believed there is a direct relation to the cumulative dose. Even lower doses of anthracyclines, such as 240-360 mg/m2 have a risk for 0.5-1.0% of patients in the first five years post treatment. There is a 5% incidence of diminished cardiac function with the use of trastuzumab (Herceptin), this is often reversible. Long-term follow-up studies are in progress. Venous thromboses are not uncommon, especially with use of Tamoxifen, which increases the risk of deep venous thrombosis and cerebrovascular disease approximately three times. For patients who've had these problems, Tamoxifen is contraindicated. The risk is small and does not merit screening.

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