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.
IN THIS ARTICLE
Think breast cancer survivors are unlikely to show up in your practice? You should think again.
At last official count, 2.5 million women in the United States had a history of breast cancer.1 Most of them are now free of malignancy, but others are still grappling with the disease in some form or fashion.2 All need continuing health care.
Roughly two thirds of women who have breast cancer have disease that is hormone-receptor–positive.2,3 Recently updated guidelines from the American Society of Clinical Oncology (ASCO) recommend that adjuvant therapy for postmenopausal women who have hormone-positive breast cancer include an aromatase inhibitor (AI) (see a summary of these guidelines on page 36). That makes it likely that a good number of breast cancer survivors who visit your practice are taking one of these medications: anastrozole (Arimidex), letrozole (Femara), or exemestane (Aromasin). These drugs are antiestrogens, given to postmenopausal women to reduce the likelihood of disease recurrence and progression.
The antiestrogenic properties of these drugs are what make them lifesavers. But the same qualities can create a range of health issues, from increased risk of osteoporosis and fracture to vasomotor and joint symptoms. And although ObGyns are not the physicians who prescribe these drugs, you may be the provider one of these women consults about their side effects and related issues.
To find out the latest on the management of women who are taking one of these agents, we inserted ourselves into the busy schedule of Andrew M. Kaunitz, MD, who agreed to address some fundamental—and some not so basic—questions about the drugs. In this extended Q&A, Dr. Kaunitz touches on mechanism of action, benefits versus risks, common side effects, compliance with therapy, and the ill effects of early discontinuation.
Aromatase inhibitors are better than tamoxifen at reducing the risk of breast cancer recurrence in postmenopausal women who have hormone-receptor–positive disease. But, they increase the risk of osteoporosis and fracture and often cause arthralgias and other complaints that ObGyn practitioners may be called upon to manage.
OBG Management: What is the overall aim of adjuvant endocrine therapy in the setting of breast cancer?
Dr. Kaunitz: Endocrine therapy—specifically, use of an AI—prevents the stimulation of breast cancer cells by endogenous estrogen. In other words, aromatase inhibitors suppress the growth of cancer cells that have estrogen receptors. These drugs also inhibit aromatase near any breast tumor and reduce estrogen levels in breast tissue.
OBG Management: What is the mechanism of action of adjuvant endocrine therapy?
Dr. Kaunitz: In postmenopausal women, androgens are converted to estrogens via the aromatase enzyme, which is present in adipose tissue and other sites. By blocking this enzyme, AIs reduce endogenous estrogen levels by as much as 95%.4
OBG Management: How does that differ from the mechanism of action of tamoxifen, another drug used in breast cancer patients?
Dr. Kaunitz: Tamoxifen is a selective estrogen receptor modulator (SERM). It blocks estrogen in breast tissue selectively, by competitively binding to estrogen receptors.5 However, tamoxifen has estrogenic effects in the uterus, bone, and liver, as well as other tissues.
The efficacy of AIs in preventing breast cancer recurrence in the first 2 years after breast cancer surgery is higher than that of tamoxifen. And unlike tamoxifen, the AIs do not increase the risk of venous thromboembolism or cause endometrial disease.
OBG Management: What effects do aromatase inhibitors have in premenopausal women?
Dr. Kaunitz: These agents are not recommended for use in premenopausal women because, in that population, the lion’s share of estrogen production takes place in the ovary rather than in adipose tissue and muscle. If you were to administer an AI to a premenopausal woman, the reduced hypothalamic and pituitary estrogen feedback could lead to ovarian stimulation—which could increase ovarian steroid production.
OBG Management: What about women who become amenorrheic as a result of chemotherapy or other cancer treatment? Do most oncologists assume that they are postmenopausal and prescribe an aromatase inhibitor?
Dr. Kaunitz: Clinicians should not assume that chemotherapy-induced amenorrhea signals permanent cessation of ovarian function. It is common for ovarian function to return in this setting. Accordingly, follicle-stimulating hormone (FSH) and estradiol levels should be assessed before an AI is considered as adjuvant therapy. Some investigators have suggested that the use of an AI in women who have chemotherapy-induced amenorrhea may actually increase the likelihood that ovarian function will return.6
OBG Management: Do all AIs produce the same effects?
Dr. Kaunitz: The AIs used in women with breast cancer are third-generation drugs. These AIs are classified as steroidal (type 1; exemestane) or nonsteroidal (type 2; anastrozole, letrozole). Exemestane, a steroid derived from androstenedione, inhibits the aromatase enzyme irreversibly. The nonsteroidal AIs are reversible.
Although all three AIs have numerous similarities, there are other distinctions between them in pharmacokinetics, mechanism of action, and toxicity—so they are not completely interchangeable.7 However, from our perspective as ObGyns caring for breast cancer survivors, we can assume that all three AIs will have similar effects on skeletal health and produce similar side effects in postmenopausal women.
Key points about AIs in breast Ca
- The American Society of Clinical Oncology recommends that adjuvant therapy for postmenopausal women who have hormone-positive breast cancer include an aromatase inhibitor (AI).
- AIs are not recommended for use in premenopausal women.
- By blocking the aromatase enzyme, AIs reduce endogenous estrogen levels by as much as 95%.4
- AIs are more effective than tamoxifen at preventing recurrence in the first 2 years after breast cancer surgery. Postmenopausal women taking an AI have a longer disease-free survival and time to recurrence than do women taking tamoxifen. They also have a lower incidence of contralateral breast cancer.
- The most prominent side effects of AI therapy include arthralgias and hot flushes, while the most serious health impact appears to be a decrease in bone mineral density (BMD). However, endometrial cancer, vaginal bleeding and discharge, cerebrovascular events, venous thromboembolic events, and hot flushes all are less common among women taking an AI than among those taking tamoxifen.
- The FDA strongly discourages the use of estrogen therapy—systemic or local—in women who are taking an AI. Accordingly, bisphospho-nate therapy is recommended as first-line treatment of low bone mineral density. Vaginal lubricants and moisturizers are the mainstay strategy for symptomatic genital atrophy. And gabapentin, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors are the mainstay of therapy for vasomotor flushes.
- Roughly 50% of women who are prescribed adjuvant endocrine therapy with tamoxifen or an AI discontinue the drug early.32 Early discontinuation is associated with an increase in mortality.33
How much do we know about these drugs?
OBG Management: How long does a woman typically take an AI?
Dr. Kaunitz: At present, in women treated for early-stage, hormone-positive breast cancer, the optimal duration of treatment is unknown. Most oncologists prescribe an AI for 5 years, the length of treatment in a prominent trial of the drugs.8
OBG Management: Is that duration likely to increase as more data come in?
Dr. Kaunitz: The optimal duration of adjuvant AI therapy will be determined by the findings of long-term clinical trials. The National Surgical Adjuvant Breast and Bowel Project B-42 trial may provide new insights into optimal duration of AI treatment after initial tamoxifen therapy.9
OBG Management: How thoroughly have AIs been studied in regard to their use in breast cancer survivors and women who have early-stage disease? How would you characterize the quantity and quality of data that we have so far?
Dr. Kaunitz: AIs have been extensively studied. The most important clinical trials of AIs in this setting, including the Anastrozole, Tamoxifen Alone or in Combination (ATAC) trial (over 6,000 participants, median follow-up of 100 months) and the Breast International Group (BIG) trial (almost 5,000 participants, median follow-up of 76 months) have been detailed in the recent ASCO report.10 These two large landmark trials, in particular, formed the basis for ASCO’s recommendations to routinely incorporate AIs into the therapy of postmenopausal women who have hormone-receptor–positive breast cancer.
OBG Management: In treating breast cancer, what other applications are AIs used for?
Dr. Kaunitz: AIs appear to be slightly more effective than tamoxifen in treating postmenopausal women who have metastatic breast cancer.11
They are approved as first-line therapy for breast cancer in:
- postmenopausal women who have hormone-receptor–positive disease
- postmenopausal women who have locally advanced disease when the hormone receptor is unknown
- postmenopausal women who have metastatic disease.
In addition, they are approved as second-line treatment of advanced breast cancer in postmenopausal women who have disease progression following tamoxifen therapy.12
How effective is AI therapy?
OBG Management: What do we know about the efficacy of these drugs?
Dr. Kaunitz: Most of the studies that have explored efficacy compare an AI with tamoxifen rather than with placebo. In the ATAC trial, after a median follow-up of 33 months, women who were taking anastrozole for early-stage breast cancer had longer disease-free survival and time to recurrence and a lower incidence of contralateral breast cancer than did women taking tamoxifen.8
After 4 years of follow-up in the ATAC trial, women taking anastrozole continued to have more favorable disease-free survival (86.9% vs 84.5% for anastrozole and tamoxifen, respectively; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.76–0.99; P =.03).13 They also had a more favorable time to recurrence than did women taking tamoxifen (HR, 0.83; 95% CI, 0.71–0.96; P =.015). And women taking anastrozole had a lower incidence of contralateral breast cancer, as well, although this different did not achieve statistical significance (HR, 0.62; 95% CI, 0.38–1.02; P =.062).13
In the BIG study, women taking letrozole had a 5-year disease-free survival estimate of 84.0%, compared with 81.4% for women taking tamoxifen.14 In addition, women taking letrozole were significantly less likely than those taking tamoxifen to experience an event that ended a period of disease-free survival (HR, 0.81; 95% CI, 0.70–0.93; P =.003), especially the event of distant recurrence (HR, 0.73; 95% CI, 0.60–0.88; P =.001).14
And a phase-3 study of exemestane versus tamoxifen in women who had metastatic breast cancer found that the AI produced a superior response rate (46% vs 31% for exemestane and tamoxifen, respectively; odds ratio [OR], 1.85; 95% CI, 1.21–2.82; P =.005). In addition, median progression-free survival was greater with exemestane (9.9 months; 95% CI, 8.7–11.8 months) than with tamoxifen (5.8 months; 95% CI, 5.3–8.1 months). However, there was no difference between arms in progression-free survival or overall survival.
ASCO guidelines emphasize the importance of aromatase inhibitors
Postmenopausal women who have hormone-receptor–positive breast cancer should consider taking an aromatase inhibitor (AI) to lengthen disease-free survival and lower the risk of recurrence. That’s one of the recommendations in updated guidelines issued earlier this year by the American Society of Clinical Oncology (ASCO). The guidelines suggest a duration of AI therapy of 5 years. In the event that a woman discontinues AI therapy before 5 years are up, she should consider using tamoxifen to bring the total duration of treatment to 5 years.
Other recommendations in the guidelines include:
- Women who have taken tamoxifen for 5 years stand to benefit from switching to an AI for as long as 5 additional years.
- When advising a woman about adjuvant therapy with an AI, clinicians should consider the potential adverse effects, which include osteoporosis, fracture, and arthralgias.
- The third-generation AIs on the market today have not been found to have clinically important differences between them. A woman who cannot tolerate a particular AI should consider switching to a different AI.
- Switching from an AI to tamoxifen (or vice versa) may be an appropriate option for patients who cannot tolerate a drug’s adverse effects. In the event of a switch to tamoxifen, the clinician should counsel the patient about its adverse effects, which include venous thromboembolism and endometrial polyps, hyperplasia, and cancer.