How Long Do You Continue Chemoprevention

Breast Cancer Chemoprevention Effect Maintained Long After Stopping Anastrozole Therapy

For postmenopausal women at high risk for developing breast cancer—largely based on family history—anastrozole taken for 5 years maintained a preventive effect for at least an additional 7 years after stopping the drug in the IBIS-II trial, which included nearly 4,000 subjects. Women randomly assigned to receive anastrozole were 49% less likely to develop breast cancer than women in the placebo arm, according to Jack Cuzick, PhD, Director of the Wolfson Institute of Preventive Medicine, Head of the Centre for Cancer Prevention, and the John Snow Professor of Epidemiology at Queen Mary University, London.¹

Jack Cuzick, PhD

"These data provide further support for the use of anastrozole for breast cancer prevention in high-risk postmenopausal women. Treatment stops at 5 years, but anastrozole carries on and keeps producing benefits right on to 12 years," Dr. Cuzick said during a press briefing at the 2019 San Antonio Breast Cancer Symposium.

Analysis done at the end of 5 years of treatment showed a 61% reduction in breast cancer incidence with anastrozole. For years 5 to 12—the primary subject of the current analysis—the reduction was slightly less, at 36%, but was still statistically significant and better than the 30% or so reduction achieved with tamoxifen in other studies, he said.

Analyzing the preventive effect across the whole time period, Dr. Cuzick noted, "You end up with a substantial benefit over 12 years. Almost half the breast cancers (49%) were prevented, and the number needed to treat dropped to 29." This is far less than the number needed to treat with tamoxifen—49—to prevent one cancer for the same time period.

IBIS-II Details

The double-blind trial enrolled 3,864 postmenopausal women at increased risk of developing breast cancer based on a strong family history or diagnosis of atypical hyperplasia or lobular carcinoma in situ. Patients were randomly assigned to 5 years of treatment with anastrozole at 1 mg/d or placebo. Median follow-up for the current analysis was 10.9 years.

"These data provide further support for the use of anastrozole for breast cancer prevention in high-risk postmenopausal women."

— Jack Cuzick, PhD

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A total of 241 breast cancers have been reported in the study. Breast cancer incidence for the years 5 to 12 (off treatment) was 4.4% in the placebo arm vs 3.5% in the anastrozole arm (hazard ratio [HR] = 0.64; P < .014). At year 5, the incidence was 4.6% vs 1.8%, respectively (HR = 0.64; P = < .0001). Across the whole 12-year period, breast cancer incidence was 8.8% in the placebo arm and 5.3% in the anastrozole arm (HR = 0.51; P < .0001); therefore, the reduction in long-term risk was 49%.

The main effect was for estrogen-positive cancers (HR = 0.46), but there also was a somewhat surprising effect on estrogen-negative cancers (HR = 0.77), although this was not significant.

The effect on ductal carcinoma in situ (DCIS) was also considerable (HR = 0.41). "This was especially apparent in the first 5 years (HR = 0.29), but it continued in the long term (HR = 0.56)," he said. In patients in whom assays for estrogen receptor status were available, "we saw a dramatic 78% reduction in DCIS."

Asked whether the magnitude of effect might have been even greater had women continued on anastrozole, Dr. Cuzick acknowledged, "The effect in the posttreatment period is not as big as during active treatment, so it does raise the question as to whether we should consider longer treatment. I think it would be nice if we had some kind of biomarker assay to determine who most needs this."

A total of 129 deaths have been reported in the study population, with no significant difference in all-cause mortality between the two treatment arms, and only 5 deaths from breast cancer. "We will need another 10 years of follow-up to sort out whether this dramatic reduction in incidence will result in a mortality benefit or not," he said.

Good Tolerability

"The adverse -event profile was reassuring," Dr. Cuzick continued. "We saw nothing serious. There were no differences in fractures and cardiovascular events." Interestingly, there was a reduction in cancer in the anastrozole arm (odds ratio [OR] = 0.72), largely driven by a "dramatic" reduction in (mostly nonmelanoma) skin cancer (OR = 0.61), "for which we don't have understanding, but which is highly significant," he noted.

Dual energy x-ray absorptiometry (DEXA) scans were performed at baseline. Bisphosphonates were required for patients with osteoporosis and were recommended for those with osteopenia. The assessment for bone fracture risk and the use of bisphosphonates may be responsible for the comparable rate of fractures: 380 with anastrozole and 373 with placebo, with no cases of osteonecrosis of the jaw.

"In the first 5 years on treatment, lots of women reported musculoskeletal events…. Many of these reported effects are actually not treatment-related, but more likely due to aging."

— Jack Cuzick, PhD

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Treatment adherence was high: 77% in the placebo arm and 75% in the anastrozole arm. "In the first 5 years on treatment, lots of women reported musculoskeletal events, including 64% in the treatment arm but also 58% on placebo. Given the high rate in the placebo arm, many of these are actually not treatment-related, but more likely due to aging. We have to be careful in interpreting them. Only an added 2.5% of patients did not continue treatment with anastrozole beyond the dropout seen in the placebo arm," he added.

Reaffirming his conclusion that the study provides additional support for the use of anastrozole to prevent breast cancer in women at high risk, Dr. Cuzick noted that this measure is recommended by the U.S. Preventive Services Task Force. "It is being used, though not as much as we would hope."

He said the analysis of the data is continuing, including molecular analyses to better elucidate the risk factors within the study population.

DISCLOSURE: Dr. Cuzick receives royalties from Myriad Genetics for development of the Prolaris cell-cycle progression score, has been a consultant for Myriad Genetics, and has received research funding from AstraZeneca.

REFERENCE

1. Cuzick J, Sestak I, Forbes J, et al: Ten-year results of the International Breast Cancer Intervention Study II. 2019 San Antonio Breast Cancer Symposium. Abstract GS4-04. Presented December 12, 2019.

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Source: https://ascopost.com/issues/january-25-2020/breast-cancer-chemoprevention-effect-maintained-long-after-stopping-anastrozole-therapy/

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