Published in UAB Insight, Summer 2006
ABSTRACT: Estrogen-receptor blockers and aromatase inhibitors are improving adjuvant therapy as well as breast cancer prevention for women at high risk for the disease.CME
OBJECTIVE: The reader will understand the research behind current recommendations for adjuvant therapy in pre- and postmenopausal women with breast cancer and prevention options for high-risk women.
John T. Carpenter, MD, grants AstraZeneca, Lilly, Pfizer; consultant Abbott Labs, Millennium; honorarium AstraZeneca, Genentech, Amgen
Emerging data continue to support superiority of aromatase inhibitors over tamoxifen for adjuvant therapy of hormone-receptor-positive breast cancer in postmenopausal women. Large clinical trials have now reported more favorable outcomes with aromatase inhibitors, and standard postoperative treatment for breast cancer in postmenopausal women is shifting from 5 years of tamoxifen therapy to sequential or initial treatment with an aromatase inhibitor, says UAB oncologist John T. Carpenter, MD.
“Unlike tamoxifen, which modulates estrogen’s effects by competitively binding to estrogen receptors, aromatase inhibitors block estrogen synthesis, lowering estrogen levels in postmenopausal women by up to 97%,” he says. “Aromatase inhibitors’ simpler action has little interaction with other organ systems, resulting in less toxicity.”
The most recent published data comparing an aromatase inhibitor with tamoxifen, reported by the Breast International Group (BIG) 1-98 Collaborative Group, found letrozole, a nonsteroidal aromatase inhibitor, improved disease-free survival. Investigators randomized more than 8000 postmenopausal women with hormonally sensitive breast cancer to 5 years of treatment with 1 of 4 regimens: letrozole, letrozole followed by tamoxifen, tamoxifen, and tamoxifen followed by letrozole. The analysis compared the two groups receiving letrozole initially with the groups who received tamoxifen first. At 5 years, 84% of women in the letrozole group were disease free compared with 81.4% in the tamoxifen group. Letrozole also significantly reduced the rate of distant metastases compared with tamoxifen, 4.4% vs 5.8% (N Engl J Med. 2005;353:2747-2757).
BIG 1-98 had a short 26-month follow up. However, the trial’s results are similar to the Arimidex and Tamoxifen, Alone or in Combination (ATAC) trial, which followed participants for 5 years and compared another nonsteroidal aromatase inhibitor, anastrozole (Arimidex), with tamoxifen. ATAC randomized 9366 participants to three arms: anastrozole, tamoxifen, or combined anastrozole and tamoxifen. At 5-year follow up, investigators found no difference in disease-free survival in the tamoxifen and combination groups. The anastrozole group, however, had statistically better disease-free survival, time to recurrence, and incidence of contralateral breast cancer (Lancet. 2005;365:60-62).
The Italian Tamoxifen Arimidex (ITA) trial and the Intergroup Exemestane Study (IES) randomly assigned women who had received 2 or 3 years of tamoxifen to completing 5 years of adjuvant therapy with tamoxifen or an aromatase inhibitor — anastrozole in the ITA trial and exemestane, a steroidal aromatase inhibitor, in the IES study. Both trials found sequential treatment reduced breast cancer recurrence (J Clin Oncol. 2005;23:5138-5147 and N Engl J Med. 2004;350:1081-1092).
MA-17, a trial investigating benefits of continuing adjuvant therapy beyond the standard time period, randomized women who completed 5 years of tamoxifen to an additional 5 years of letrozole or placebo. Trial monitors halted the trial after 4 years when preliminary data showed letrozole significantly reduced disease recurrence. The risk of recurrence was 5% lower in the letrozole arm, which also had a 39% reduction in distant metastases (J Natl Cancer Inst. 2005;97:1254-1261).
Adjuvant Endocrine Therapy
Breast cancer is an extremely heterogenous condition, and physicians must tailor treatment to characteristics of the patient’s disease, Carpenter says. Tamoxifen is not effective for patients with hormone-receptor-negative tumors — about 25% of women with breast cancer — and no study has evaluated aromatase inhibitors in this group.
While tamoxifen benefits both pre- and postmenopausal women, aromatase inhibitors are ineffective in women with functioning ovaries. “These women produce too much aromatase for effective inhibition,” Carpenter says. Women who are premenopausal at diagnosis may experience chemotherapy–related amenorrhea. But some retain a measure of ovarian function, or regain it, usually within 2 years of completing chemotherapy. “These women should receive initial tamoxifen and have periodic ovarian function assessments,” he says. “If they remain postmenopausal after 2 years, it is reasonable to switch to an aromatase inhibitor for duration of therapy.”
According to the most recent technology assessment from the American Society of Clinical Oncology, optimal adjuvant therapy for postmenopausal women with receptor-positive breast cancer should include an aromatase inhibitor, either as initial treatment or after tamoxifen (J Clin Oncol. 2005;23:619-629).
Carpenter agrees with this recommendation and has included aromatase inhibitors in clinical practice for several years, but notes important questions about timing, duration, and selection of aromatase inhibitors are still unanswered. “When women are postmenopausal, I begin therapy with an aromatase inhibitor. Patients treated for 1 to 2 years with tamoxifen may be switched to an aromatase inhibitor to complete 5 years of adjuvant therapy,” he says. “Postmenopausal women with appreciable risk for disease recurrence who finish 5 years of tamoxifen should be offered continuing therapy with an aromatase inhibitor.”
The benefits of continuing aromatase inhibitor therapy beyond 5 years are not clear for women with noninvasive cancer. “The risk of developing a new cancer in either breast is about 1% a year, and at that point, the drug’s cost and side effects may begin to outweigh whatever small benefit might accrue with treatment,” Carpenter says. “While aromatase inhibitors are better tolerated than tamoxifen, they are not free from side effects, and physicians and patients must weigh individual risks and benefits.”
Aromatase inhibitors are less toxic than tamoxifen in two important aspects, Carpenter says. “Unlike tamoxifen, which increases risk for blood clots, including stroke, aromatase inhibitors do not promote clotting. And they do not raise risk for endometrial cancer, tamoxifen’s other major adverse effect.”
However, the estrogen suppression of aromatase inhibitors increases osteoporosis and fracture risk, which is not a problem with tamoxifen. “Women taking aromatase inhibitors need periodic bone density assessments,” he says. Aromatase inhibitors also can cause flushing, musculoskeletal pain, and vaginal dryness. “Sexual side effects are often of special concern to women, and physicians should not underestimate the importance of addressing these issues,” he says.
Prevention
Early studies of tamoxifen showed women receiving adjuvant treatment with the drug had a significantly lower incidence of contralateral breast cancer, a finding that led to use of the agent for disease prevention. Final results from the Breast Cancer Prevention Trial showed incidence of new breast cancers remained stable for 2 years after participants stopped taking the drug, indicating a continuing benefit (J Natl Cancer Inst. 2005;97:1652-1662).
“In pre- and postmenopausal women at high risk for breast cancer, preventive treatment with tamoxifen reduces incidence of receptor-positive breast cancer by 50%,” he says. “But, the drug’s side effects, which are often acceptable to cancer patients, limit use in healthy women.”
Clinical trials show aromatase inhibitors decrease incidence of contralateral breast cancer by 75%. “We are now testing aromatase inhibitors for breast cancer prevention to see if these agents will have equivalent or superior benefits to tamoxifen with less toxicity,” he says.
Carpenter is principal investigator for the UAB arm of ExCel, an international breast cancer prevention trial recruiting 4500 patients. Investigators are testing exemestane in postmenopausal women 35 years and older at increased risk for the disease. Participants will receive 5 years of treatment with placebo or exemestane.
Other drug classes also show promise. Initial results from the Study of Tamoxifen and Raloxifene trial report that raloxifene, a selective estrogen response modulator used by 500,000 US women to treat osteoporosis, is as effective as tamoxifen for reducing risk of invasive breast cancer and has fewer side effects.
“In the United States, death rates for breast cancer have decreased every year since 1989,” Carpenter says. “Use of aromatase inhibitors and other more effective, less toxic agents for prevention and treatment will continue to improve outcomes.”
For more information:
Dr. John Carpenter
1.800.UAB.MIST
mist@uabmc.edu