Over the years, a number of landmark clinical studies on the management of breast cancer have been published, sharpening how patients are treated today.
Breast cancer is a disease in which there is uncontrolled growth of breast cells. It’s estimated that approximately 1 in 8 U.S. women will develop invasive breast cancer over the course of her lifetime and just under 40,000 women will die from the disease in 2018.
Studies suggest that breast cancer death rates have been decreasing since 1989 with the largest decrease in women under 50 years of age. These decreases are believed to be the result of treatment advances, earlier detection through screening, and increased awareness.1
Over the years, a number of landmark clinical studies on the management of breast cancer have been published, sharpening how patients are treated today. In Part 1, we covered 4 studies that every pharmacist should know about. In this article we will cover 4 additional studies.
1. HERA (2005)2,3
Trastuzumab is a recombinant monoclonal antibody against HER2 that was first approved by the FDA in 1998 to treat patients with metastatic breast cancer who have tumors that overexpress the HER2 protein. HERA was conducted to investigate the role of adjuvant trastuzumab administered after primary treatment consisting of surgery, radiation, and chemotherapy.
The study was an international, open-label, phase 3 randomized trial involving more than 5000 women with HER2-positive early-stage invasive breast cancer who completed locoregional therapy and a minimum of 4 courses of chemotherapy. The trial included 3 groups: women who had observation alone; those treated with trastuzumab given as adjuvant treatment (at a dose of 8 mg/kg intravenously once, then at a dose of 6 mg/kg every 3 weeks) for 2 years; and those treated with trastuzumab at the same dose and on the same schedule for 1 year. The primary end point was disease-free survival, defined as time from randomization to the first occurrence of a number of predefined events.
At the first planned interim analysis (median follow-up of 1 year), results demonstrated a 46% reduction in recurrence at 1 year of trastuzumab treatment compared to observation alone (HR = 0.54; 95% CI: 0.43-0.67; p<0.0001). Overall survival in the 2 groups was not significantly different (29 deaths with trastuzumab vs 37 with observation). Severe cardiotoxicity developed in 0.5% of the women who were treated with trastuzumab. A later publication revealed that 2 years of adjuvant trastuzumab was not more effective than 1 year of treatment in terms of disease-free survival, but did result in more cardiotoxicity.
Trastuzumab after adjuvant chemotherapy significantly improves disease-free survival at 1 year among women with HER2-positive breast cancer. No benefit was seen with 2 years of therapy as compared to 1 year.
2. STAR (2006)4
By 2006, numerous studies had demonstrated a reduction in the risk of breast cancer with both tamoxifen and raloxifene. The STAR trial was conducted to directly compare the two medications in a population of women at increased risk for breast cancer in terms of their relative effects on the risk of developing invasive breast cancer.
The study was designed as a prospective, double-blind, randomized clinical trial conducted in nearly 200 clinical centers throughout North America. The patient population included 19,747 postmenopausal women at least 35 years of age with an increased 5-year breast cancer risk. Participants were randomly assigned to receive either tamoxifen 20 mg/day or raloxifene 60 mg/day for a maximum of 5 years. The primary outcome was incidence of invasive breast cancer with secondary endpoints looking at uterine cancer, noninvasive breast cancer, bone fractures, and thromboembolic events.
After a mean follow-up time of 3.9 years, there was found to be 163 cases of invasive breast cancer in women assigned to tamoxifen and 168 in those assigned to raloxifene (RR = 1.02; 95% CI: 0.82-1.28). There were fewer cases of noninvasive breast cancer in the tamoxifen group than in the raloxifene group although the difference did not reach statistical significance (RR = 1.40; 95% CI: 0.98-2.00). Women in the raloxifene group developed less thromboembolic events (RR = 0.70; 95% CI: 0.54-0.91) and there were fewer cataracts (RR = 0.79; 95% CI: 0.68-0.92). No differences were found for other invasive cancer sites, for ischemic heart disease events, stroke, osteoporotic fractures, or for the total number of deaths.
Tamoxifen and raloxifene are equally effective in reducing the risk of invasive breast cancer although raloxifene resulted in a lower risk of thromboembolic events and cataracts.
3. ATLAS (2013)5
For women with ER-positive early breast cancer 2 or 5 years of adjuvant tamoxifen had been the standard of care to reduce the risk of recurrence and decrease breast cancer mortality. However, it was unclear whether extending the duration of therapy to 10 years would provide improved efficacy with an acceptable side effect profile.
To further answer this question, researchers enrolled nearly 13,000 women with early breast cancer from 36 countries who had completed 5 years of treatment with tamoxifen. Study participants were randomized to continue tamoxifen to 10 years of therapy or stop at 5 years. Just over half of participants were ER-positive and included in the efficacy analysis. Those with ER-negative or unknown disease were only included in the analyses of non-breast cancer outcomes.
Analysis of the data found that continuation of tamoxifen reduced the risk of breast cancer recurrence (RR = 0.84; 95% CI: 0.76—0.94; p=0.002), reduced breast cancer mortality (RR = 0.83; 95% CI: 0.72–0.96; p=0.01), and reduced overall mortality (RR = 0.87, 95% CI: 0.78–0.97; p=0.01). Notably, the main effects on recurrence and on breast cancer mortality became apparent only during the second decade after diagnosis. Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Small, but statistically significant increases were seen with the incidence of pulmonary embolism and endometrial cancer in the extended duration group.
As a result of ATLAS and several related studies, treatment guidelines from the American Society of Clinical Oncology (ASCO) have been updated to recommend that tamoxifen be continued for a total duration of 10 years in select women with ER-positive breast cancer.
In women with ER-positive breast cancer, continuing tamoxifen to 10 years, rather than stopping at 5 years, produces a further reduction in recurrence and mortality. However increases are seen in the rates of pulmonary embolism and endometrial cancer.
4. Canadian National Breast Screening Study (2014)6
The Canadian National Breast Screening Study was conducted to assess the long-term efficacy of annual mammography as compared to regular breast exams. The study first published results in 1992 and subsequently in 2014 with 25 years of follow-up data.
Participants were recruited to the study by a general publicity campaign, reviewing population lists and sending personal invitation letters, group mailings, and through family doctors. Women were eligible if they were aged 40-59, had had no mammography in the previous 12 months, had no history of breast cancer, and were not pregnant. Just under 90,000 women were randomly assigned 1:1 to annual mammography plus breast exam or breast exam alone for a total 5 year period; afterwards patients returned to usual care. The primary outcomes were breast cancer-related mortality and overall mortality.
During the 5 year screening period, 666 invasive breast cancers were diagnosed in the mammography arm and 524 in the control arm. Of those, 180 women in the mammography arm and 171 women in the control arm died of breast cancer during the 25 year follow-up period, a non-significance difference (HR = 1.05; 95% CI: 0.85-1.30). The findings for women aged 40-49 and 50-59 were almost identical. During the entire study period, 3250 women in the mammography arm and 3133 in the control arm had a diagnosis of breast cancer, and 500 and 505, died of breast cancer (HR = 0.99; 95% CI: 0.88-1.12). No significant differences were detected with overall mortality. After 15 years of follow-up, a residual excess of 106 of 484 (22%) screen detected invasive breast cancers were overdiagnosed, representing 1 overdiagnosed breast cancer for every 424 women who received mammography screening in the trial.
Current breast cancer screening guidelines from the U.S. Preventative Task Force recommends biennial screening with mammography in all women aged 50 to 74 years of age and in select women aged 40 to 49.
Annual mammography in women aged 40-59 does not reduce mortality from breast cancer beyond that of physical examination or usual care, with higher rates of overdiagnosis.