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.
- 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