Photo Courtesy © SABCS/Todd Buchanan 2013Jack Cuzick, PhD
Findings from the International Breast Cancer Intervention Study II (IBIS II) examining the efficacy of the aromatase inhibitor anastrozole as a breast cancer preventive show that the oral agent provided significant benefit to postmenopausal women deemed at high risk, reducing their risk of getting the disease by more than half with very few side effects.
The results were announced at the 36th annual San Antonio Breast Cancer Symposium (SABCS) and published online ahead of print simultaneously in the Lancet.1 The researchers noted that their findings are similar to results previously reported for exemestane in breast cancer prevention for postmenopausal women in the MAP.3 trial. In that trial, exemestane reduced the incidence of all breast cancer in that population by 53% and invasive breast cancer by 65% after 3 years of follow-up.2
In the IBIS II study, conducted between 2003 and 2012, 3864 postmenopausal women at high risk for breast cancer from 18 countries were randomly assigned to receive 1 mg oral anastrozole daily (n = 1920) or placebo (n = 1944). The median age of the participants was 59.3 years, and 47% of the women had used HR therapy in the past.
Criteria used to determine high breast cancer risk included having ≥2 blood relatives with breast cancer, having a mother or sister who developed breast cancer before age 50, and having a mother or sister with bilateral breast cancer.
Histologically confirmed breast cancer was the study’s primary endpoint. Forty women in the anastrozole- treated group (2%) and 85 in the placebo group (4%) developed breast cancer after 5 years of follow-up (HR = 0.47; CI, 0.32-0.68; P <.0001)—a finding investigators said would represent a 7-year 5.6% cumulative incidence of breast cancer in the placebo arm versus 2.8% in patients receiving the aromatase inhibitor, a reduction of 53%. Anastrozole also cut the incidence of ER-positive breast cancer by 58%—from 3.3% in placebo-treated patients to 1.4% in those taking anastrozole (P =. 001)—but the agent demonstrated little effect in ER-negative cancers
Adherence to treatment was similar in both arms: 68% in the anastrozole cohort and 72% in the placebo group; the main reason for treatment discontinuation in both groups was adverse events, which occurred in 20% and 15% of each population, respectively.
Overall, the researchers noted, most side effects were not attributable to treatment, and most also increased in the placebo group. Whereas the total number of fractures was similar between the two groups, musculoskeletal adverse events occurred in more women receiving anastrozole versus women receiving placebo (64% and 58%, respectively), a significant difference (P = .0001).
Whereas significant differences were not observed in the incidence of mild or severe arthralgia between the two groups, the researchers reported that the incidence of moderate arthralgia was significantly higher in the treatment arm, as was the incidence of dry eyes among those in the anastrozole group.
Among the unexpected findings reported by investigators was a reduction in other cancers in the treatment group, notably a higher incidence of skin and gastrointestinal (GI) cancers in the placebo arm. Fourteen women in the anastrozole group developed skin cancer versus 27 receiving placebo. For GI cancers, the numbers were 4 and 12, respectively.
The study’s lead author, Jack Cuzick, PhD, head of the Cancer Research UK Centre for Cancer Prevention and director of the Wolfson Institute of Preventive Medicine at Queen Mary University in London, presented the findings at SABCS.
Planned follow-up is at least 10 years and hopefully much longer, he noted.
“We want to determine if anastrozole has a continued impact on cancer incidence even after stopping treatment, if it reduces deaths from breast cancer, and to ensure that there are no long-term adverse side effects.”
1. Cuzick J, Sestak I, Forbes JF, et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomized placebo-controlled trial [published online December 12, 2013]. Lancet. doi:10.1016/S0140-6736(13)62292-62298.
2. Goss PE, Ingle JN, Ales-Martinez JE, et al. Exemestane for breast cancer prevention in postmenopausal women. N Engl J Med. 2011;364(25):2381-2391.
The results from the International Breast Cancer Intervention Study II that anastrozole can provide benefit in breast cancer reduction in postmenopausal high-risk women are exciting. A 53% reduction in the risk of breast cancer was found by proving that only 2% of the anastrozole-treated group developed breast cancer after 5 years of follow up compared with 4% in the placebo group.
Breast cancer risk assessment is more prevalent now than ever. We now have risk models such as the Tyrer-Cuzick Model, Claus Model, BOADICEA, and BRCAPRO to help calculate a woman’s personal risk of breast cancer. The NCCN has published guidelines for the management of women who are at greater than average risk for breast cancer, usually defined by a score of 20% or more on widely accepted models.
The use of current chemopreventive agents, tamoxifen and raloxifene, are reported to be vastly underutilized. In my clinical opinion, underutilization of these agents is multifactorial. For some women, these drugs are contraindicated due to existing comorbidities. Fear of side effects such as hot flashes, risk of endometrial cancer, venous thromboembolism, and cataracts keep some women from using these agents. Many women have not been educated regarding their personal risk of breast cancer and their options with regard to high-risk management and candidacy for use of a risk-reducing medication.
It is exciting to know that there is another drug to offer women. The potential side effect profile of anastrozole includes musculoskeletal pain and declining bone density. Routine DEXA screening is advised with anastrozole use to detect osteopenia or osteoporosis. As clinicians, we must look at high-risk patients individually and guide them on what risk-reducing medication may be the best option based on their menopausal status and personal and family history.
Interestingly, reduction of skin and gastrointestinal cancers was noted in this study. This is very thought provoking and certainly suggests opportunities for additional research. Furthermore, research could be entertained regarding comparing the available chemopreventive agents head-to-head to determine efficacy. Lastly, it is important as clinicians for us to promote preventive medicine, and we have a unique opportunity to educate highrisk women about their options for breast cancer prevention.