Ovarian suppression resulted in significant additional AEs, including depression and menopausal symptoms. The authors of the study also pointed out the additional risk of hypertension, musculoskeletal AEs, and decreased bone density. Furthermore, the OS data from these studies are premature, because the patients had fewer AEs than initially anticipated; this resulted in an only 5% mortality at publication.
The study design also raised several interesting questions. The primary endpoint was disease-free survival. The authors defined this as the time from randomization to the first appearance of invasive recurrence of breast cancer (local, regional, or distant), invasive contralateral breast cancer, second (non-breast) invasive cancer, or death without breast cancer recurrence or second invasive cancer. When studying adjuvant therapy for diseases, such as breast cancer, which carry long-term survival, studies often use PFS with various modified definitions as a surrogate marker for OS. Clinicians are then left to decide whether this surrogate marker is an accurate predictor of OS or other important clinical outcomes.
In the combined analysis of the TEXT and SOFT trials, only 60% of the first recurrences, second invasive cancers, or deaths involved recurrence of breast cancer
at a distant site. 9 Because locally recurrent breast cancer is highly treatable and often curable, clinicians must ask whether the increased toxicities of ovarian suppression are worth the large number of women who experienced local recurrence given the still relatively small absolute reduction in recurrence risk.
Last, the study authors retrospectively reviewed data from the International Breast Cancer Study Group and U.S. Intergroup trials and concluded that women aged < 35 years were most likely to be at high-risk for AEs. 10,11 A subgroup analysis of women aged < 35 years in the SOFT trial noted that breast cancer recurred within 5 years in one-third of women receiving tamoxifen alone, whereas only in one-sixth of women receiving exemestane plus ovarian suppression. 8 This is the basis for the conclusion that premenopausal women, particularly those aged < 35 years, with high-risk disease who receive chemotherapy and remain premenopausal after chemotherapy, benefit from ovarian suppression in combination with tamoxifen, and even more impressively from ovarian suppression combined with exemestane.
The problem is that the study did not risk-stratify patients based on those aged < 35 years, and the conclusion is based on a subgroup analysis using a primary endpoint that may not accurately predict OS. Nonetheless, although not definitive, the data from the TEXT and SOFT trials raise interesting therapeutic questions that require further study and certainly provide tempting therapeutic options in patients who are clinically at high risk for recurrence.
HER2-Positive Breast Cancer
Up to 20% of invasive breast cancers are a result of HER2 gene amplification or overexpression of the HER2 protein, a tyrosine kinase transmembrane receptor, resulting in a more aggressive phenotype and a poor prognosis. Anti-HER2 drugs have changed the landscape of the disease previously known as aggressive breast cancer with a poor survival rate.
Treatment with the anti-HER2 humanized monoclonal antibody trastuzumab in addition to chemotherapy, compared with chemotherapy alone, significantly improves PFS and OS among patients with HER2-positive metastatic as well as early breast cancer. However, in most patients with HER2-positive metastatic breast cancer, the disease progresses, highlighting the need for new, targeted therapies for advanced disease.
