There are a variety of known risk factors for developing breast cancer, such as obesity, nulliparity, and age at time of menarche and menopause.1 For patients with a particularly high risk of developing breast cancer, including those who have a family history of the disease or have tested positive for deleterious BRCA1 or BRCA2 mutations, there are several options available for risk reduction. Patients may receive closer breast cancer screening, prophylactic mastectomy or oophorectomy, or treatment with a chemoprevention agent. Currently, two hormonal agents, tamoxifen and raloxifene, are FDA approved to reduce the risk of breast cancer in patients at high risk of developing the disease. Exemestane, an aromatase inhibitor (AI), is another agent available for chemoprevention; although it has not been approved by the FDA for this purpose, it has a Category 1 recommendation in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines.2
At a session on December 12 at the San Antonio Breast Cancer Symposium (SABCS) 2013 annual meeting, results were presented from the Phase III IBIS-II trial that evaluated whether another AI, anastrozole, can prevent the development of breast cancer in women at increased risk of the disease.3 This trial randomized 3,684 post-menopausal women aged 40-70 at increased risk of developing breast cancer to receive either placebo or anastrozole (1 mg/day) for a period of five years. Patients could be classified as high risk based on a variety of factors, such as family history, atypia/LCIS, or increased breast density.
After seven years of follow-up time, there was a significantly lower incidence of all breast cancer (2.8% vs. 5.6%, HR=0.47, p<0.0001) and estrogen receptor (ER)-positive invasive breast cancer (1.4% vs. 3.3%, HR=0.42, p<0.001) in the anastrozole arm compared to the placebo arm (see Table 1). A subgroup analysis found that this benefit of anastrozole treatment applied to the development of DCIS (HR=0.47) and invasive ER-positive invasive breast cancer (HR=0.42), but there didn’t appear to be a benefit in preventing the development of invasive ER- breast cancer (HR=0.78, confidence interval crossed “1”).
In the chemoprevention setting where a drug is administered to patients who are currently healthy, safety takes on increased importance. Importantly, anastrozole was well-tolerated by patients. There was an increase in musculosketal adverse events (primarily arthralgia, joint stiffness, and carpal tunnel) in the anastrozole arm (63.9% vs. 57.8%), but since there was such a high rate of musculosketal AEs in the placebo arm, most of these AEs are probably not treatment related. There was also a slight and non-significant increase in the incidence of fractures in patients who received anastrozole (8.5% vs. 7.7%), an important consideration since treatment of breast cancer patients with an AI generally results in decreased bone mineral density. Interestingly, Dr. Cuzick, who presented the data, also mentioned that there was a reduction in other (non-breast) cancers in the anastrozole arm, mainly skin cancers, but because that slide was missing from the presentation, the audience was unable to evaluate those data. As would be expected with five years of drug therapy in healthy people, compliance decreased in both arms across the five years of treatment; at the end of treatment, the compliance rate was slightly but significantly lower in the anastrozole arm (68% vs. 72%, HR=0.84, p<0.005).
How do these data from the IBIS-II trial compare to the data for other chemoprevention agents in breast cancer? In the Phase III NSABP P1 trial, the risk ratio of the development of invasive breast cancer with tamoxifen compared to placebo was 0.51 after 69 months of follow-up time.4 During an 81 month (almost 8 years) follow-up of STAR trial comparing raloxifene to tamoxifen in high risk patients, raloxifen was less effective than tamoxifen in reducing the incidence of invasive breast cancer in high risk patients (risk ratio = 1.24).5 Although tamoxifen appears to be more effective than raloxifene, it comes along with a number of toxicities, including increased incidence of invasive endometrial cancers. In the MAP.3 trial, exemestane reduced the incidence of invasive breast cancer compared to placebo with an impressive hazard ratio of 0.33, with a more benign safety profile than tamoxifen.6 From the IBIS-II results, it appears that anastrozole is more effective and less toxic than tamoxifen; compared to exemestane, it appears to be slightly less effective, with a relatively similar safety profile.
Although longer-term follow-up data for anastrozole will likely be necessary to confirm a reasonable safety profile in this setting, the IBIS-II data suggest that anastrozole could be a new option for breast cancer chemoprevention. However, will it be utilized in practice? Although tamoxifen was approved by the FDA 15 years ago to reduce the development of breast cancer in high risk patients, it is rarely utilized in high-risk patients.7,8 This lack of utilization is likely due to the safety profile of tamoxifen; it could be daunting for a generally healthy high-risk patient to consider the prospect of multiple years of a treatment that can be accompanied by non-trivial adverse events. In this setting, a benign safety profile of a drug will likely be critical for utilization.
In addition, competitive landscape in this segment of the market is complicated by the fact that the different available agents for breast cancer chemoprevention are not only competing against each other, but they are competing against other non-drug treatment options, such as prophylactic mastectomy. While this type of prophylactic surgery can certainly have its own downsides, it does have the advantage of taking a shorter amount of time compared to the long five year commitment for treatment with hormone therapies. It is also probable that patient preferences for the different treatment options available for breast cancer prevention in high risk patients could be influenced by media coverage and popular trends, such as the flood of media coverage of prophylactic mastectomy when actress Angelina Jolie elected to undergo this type of surgery after testing positive for a BRCA mutation. However, for this type of very personal decision, an increasing number of available options can only be a positive development for patients.
By: Stephanie Hawthorne, PhD, Director, Clinical and Scientific Assessment, Kantar Health and Cory Blaiss, PhD, Analyst, Clinical and Scientific Assessment, Kantar Health