30 OBG Management complaints thatObGynpractitioners maybecalledupontomanage. andoftencausearthralgias andother andfracture osteoporosis theriskof disease.But,theyincrease hormone-receptor–positive inpostmenopausalwomenwhohave cancerrecurrence of breast a | romatase inhibitors are better than tamoxifen at reducing therisk betterthantamoxifenat reducing inhibitorsare romatase October 2010 | Vol. 22 No. 10 obgmanagement.com SteVe OH fOr obg MaNaGeMeNt Q&A WIth AnDreW M. KAunItz, MD An ObGyn’s guide to aromatase inhibitors as adjuvant therapy for breast CA You may not prescribe anastrozole, letrozole, or exemestane, but there’s a strong possibility that some of your patients are taking one of these medications. Here’s what you need to know to encourage compliance and ease their ill effects. Janelle Yates Senior Editor, OBG ManaGeMent hink breast cancer survivors are un- anastrozole (Arimidex), letrozole (Femara), likely to show up in your practice? or exemestane (Aromasin). These drugs are T You should think again. antiestrogens, given to postmenopausal At last official count, 2.5 million women In thIs women to reduce the likelihood of disease Article in the United States had a history of breast recurrence and progression. cancer.1 Most of them are now free of malig- The antiestrogenic properties of these Key points for nancy, but others are still grappling with the drugs are what make them lifesavers. But the ObGyns 2 disease in some form or fashion. All need same qualities can create a range of health is- page 32 continuing health care. sues, from increased risk of osteoporosis and Roughly two thirds of women who have fracture to vasomotor and joint symptoms. What can be done breast cancer have disease that is hormone- And although ObGyns are not the physicians about the most receptor–positive.2,3 Recently updated guide- who prescribe these drugs, you may be the prominent risks? lines from the American Society of Clinical provider one of these women consults about Oncology (ASCO) recommend that adju- their side effects and related issues. page 36 vant therapy for postmenopausal women To find out the latest on the management who have hormone-positive breast cancer of women who are taking one of these agents, ASCO guidelines include an aromatase inhibitor (AI) (see a we inserted ourselves into the busy schedule on adjuvant summary of these guidelines on page 36). of Andrew M. Kaunitz, MD, who agreed to ad- endocrine therapy That makes it likely that a good number of dress some fundamental—and some not so page 38 breast cancer survivors who visit your prac- basic—questions about the drugs. In this ex- tice are taking one of these medications: tended Q&A, Dr. Kaunitz touches on mecha- Dr. Kaunitz details nism of action, benefits versus risks, common bone-protective Dr. Kaunitz is Professor and associate Chairman side effects, compliance with therapy, and strategies for women of the Department of Obstetrics and Gynecology the ill effects of early discontinuation. at the University of florida College of Medicine– taking an AI, Jacksonville in Jacksonville, fla. He serves on at obgmanagement.com the OBG ManaGeMent Board of editors. OBG Management: What is the overall aim of adjuvant endocrine therapy in the setting Dr. Kaunitz reports no financial relationships relevant to this article. of breast cancer? Dr. Kaunitz: Endocrine therapy—specifically, obgmanagement.com Vol. 22 No. 10 | October 2010 | OBG Management 31 Aromatase inhibitors another drug used in breast cancer patients? Key points about AIs in breast Ca Dr. Kaunitz: Tamoxifen is a selective estrogen receptor modulator (SERM). It blocks es- • The american Society of Clinical Oncology recommends that trogen in breast tissue selectively, by com- adjuvant therapy for postmenopausal women who have hormone- petitively binding to estrogen receptors.5 positive breast cancer include an aromatase inhibitor (aI). However, tamoxifen has estrogenic effects in the uterus, bone, and liver, as well as other • aIs are not recommended for use in premenopausal women. tissues. • By blocking the aromatase enzyme, aIs reduce endogenous The efficacy of AIs in preventing breast 4 estrogen levels by as much as 95%. cancer recurrence in the first 2 years after • AIs are more effective than tamoxifen at preventing recurrence breast cancer surgery is higher than that of in the first 2 years after breast cancer surgery. Postmenopausal tamoxifen. And unlike tamoxifen, the AIs do women taking an aI have a longer disease-free survival and time not increase the risk of venous thromboem- to recurrence than do women taking tamoxifen. they also have a bolism or cause endometrial disease. lower incidence of contralateral breast cancer. OBG Management: What effects do aroma- • The most prominent side effects of aI therapy include arthralgias and tase inhibitors have in premenopausal women? hot flushes, while the most serious health impact appears to be a Dr. Kaunitz: These agents are not recom- decrease in bone mineral density (BMD). However, endometrial mended for use in premenopausal women cancer, vaginal bleeding and discharge, cerebrovascular events, because, in that population, the lion’s share venous thromboembolic events, and hot flushes all are less common of estrogen production takes place in the ova- among women taking an aI than among those taking tamoxifen. ry rather than in adipose tissue and muscle. If • The fDa strongly discourages the use of estrogen therapy—systemic you were to administer an AI to a premeno- or local—in women who are taking an aI. accordingly, bisphospho- pausal woman, the reduced hypothalamic nate therapy is recommended as first-line treatment of low bone and pituitary estrogen feedback could lead mineral density. Vaginal lubricants and moisturizers are the mainstay to ovarian stimulation—which could increase strategy for symptomatic genital atrophy. and gabapentin, selective ovarian steroid production. serotonin reuptake inhibitors, and serotonin norepinephrine reuptake OBG Management: What about women inhibitors are the mainstay of therapy for vasomotor flushes. who become amenorrheic as a result of che- motherapy or other cancer treatment? Do • Roughly 50% of women who are prescribed adjuvant endocrine therapy with tamoxifen or an aI discontinue the drug early.32 early most oncologists assume that they are post- discontinuation is associated with an increase in mortality.33 menopausal and prescribe an aromatase inhibitor? Dr. Kaunitz: Clinicians should not assume use of an AI—prevents the stimulation of that chemotherapy-induced amenorrhea breast cancer cells by endogenous estrogen. signals permanent cessation of ovarian func- In other words, aromatase inhibitors sup- tion. It is common for ovarian function to press the growth of cancer cells that have return in this setting. Accordingly, follicle- estrogen receptors. These drugs also inhibit stimulating hormone (FSH) and estradiol aromatase near any breast tumor and reduce levels should be assessed before an AI is con- estrogen levels in breast tissue. sidered as adjuvant therapy. Some investiga- OBG Management: What is the mechanism tors have suggested that the use of an AI in of action of adjuvant endocrine therapy? women who have chemotherapy-induced Dr. Kaunitz: In postmenopausal women, amenorrhea may actually increase the likeli- androgens are converted to estrogens via the hood that ovarian function will return.6 aromatase enzyme, which is present in adi- OBG Management: Do all AIs produce the pose tissue and other sites. By blocking this same effects? enzyme, AIs reduce endogenous estrogen Dr. Kaunitz: The AIs used in women with levels by as much as 95%.4 breast cancer are third-generation drugs. OBG Management: How does that differ These AIs are classified as steroidal (type from the mechanism of action of tamoxifen, 1; exemestane) or nonsteroidal (type 2; conTinuEd on pAgE 35 32 OBG Management | October 2010 | Vol. 22 No. 10 obgmanagement.com Aromatase inhibitors anastrozole, letrozole). Exemestane, a steroid ASCO report.10 These two large landmark tri- derived from androstenedione, inhibits the als, in particular, formed the basis for ASCO’s aromatase enzyme irreversibly. The nonste- recommendations to routinely incorpo- roidal AIs are reversible. rate AIs into the therapy of postmenopausal Although all three AIs have numerous women who have hormone-receptor–posi- similarities, there are other distinctions be- tive breast cancer. tween them in pharmacokinetics, mecha- OBG Management: In treating breast can- nism of action, and toxicity—so they are not cer, what other applications are AIs used for? completely interchangeable.7 However, from Dr. Kaunitz: AIs appear to be slightly more our perspective as ObGyns caring for breast effective than tamoxifen in treating post- cancer survivors, we can assume that all menopausal women who have metastatic three AIs will have similar effects on skeletal breast cancer.11 health and produce similar side effects in They are approved as first-line therapy postmenopausal women. for breast cancer in: • postmenopausal women who have hor- mone-receptor–positive disease how much do we know • postmenopausal women who have lo- about these drugs? cally advanced disease when the hor- OBG Management: How long does a woman mone receptor is unknown typically take an AI? • postmenopausal women who have met- Dr. Kaunitz: At present, in women treated astatic disease. for early-stage, hormone-positive breast can- In addition, they are approved as second-line cer, the optimal duration of