Parsing Progress in Breast Cancer

When the National Cancer Act was signed into law in 1971, mastectomy was the only accepted surgical option for breast cancer treatment, and there were a limited number of systemic therapies, none formally approved as adjuvant therapy. Tamoxifen was still 6 years away from approval as a breast cancer therapy in the United States. One randomized trial of screening mammography was underway, and none had reported results. BRCA mutations and their relationship with breast cancer risk would not be discovered for another two decades. The annual age-adjusted breast cancer mortality rate was about 31 per 100,000, and at least 25% of all patients with breast cancer died as a result of their disease within 5 years of diagnosis. The past 40 years have seen remarkable advances in breast cancer treatment, early detection, and outcomes. Breast conservation was established as equivalent to mastectomy. Adjuvant therapy was shown to reduce risks of recurrence and death leading to global adoption of evidence-based postoperative systemic treatments. Early detection has been accepted as a key component of breast cancer care, and now more than two thirds of women age 40 years or older receive screening mammography. With gene sequencing technologies, we can identify BRCA mutation carriers and offer them more intensive screening and options to reduce their breast cancer risk. Now, despite an aging and more obese population, annual age-adjusted breast cancer mortality is about 21 per 100,000, and 5-year relative survival exceeds 90%. Clearly we have made progress, but planning for additional gains means, in part, determining where we have done well and which interventions, if any, might be less useful than we thought. In the accompanying article, Park et al examine trends in breast cancer characteristics and outcomes from 1973 through 2010, attempting to explain the proportions of observed improvement in breast cancer mortality and survival that are associated with changes in the distribution of tumor characteristics, specifically size and estrogen receptor (ER) status. Their motivating logic is that changes in tumor characteristics likely reflect interventions such as screening that occur before diagnosis. The proportion of improvement that remains unexplained by trends in tumor characteristics must be explained by interventions that happen after diagnosis, chiefly treatment. Using population-based data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry program, Park et al compare breast cancer–specific mortality and survival in cohorts diagnosed from 2005 to 2010 with those diagnosed from 1973 to 1979, stratified by stage and age at diagnosis. They find that, in the first 5 years after diagnosis in women age 50 to 69 years with localized disease, change in the distribution of tumor size explained less than 20% of the observed improvement in breast cancer–specific mortality. It also explained less than 10% of the mortality improvement in those with regional or distant disease. Among women age 70 years or older, changes in tumor size explained a much larger proportion of the observed improvement in cancer-specific mortality: 49%, 38%, and 20%, respectively, in those with local, regional, and distant disease. Changes in the distribution of ER status did not seem to explain a substantial fraction of improvement in breast cancer outcomes, beyond the proportion explained by changes in tumor size. Comparing cohorts diagnosed from 2005 to 2010 with those diagnosed from 1990 to 1995 (when information on ER status was first available in SEER), changes in ER status seemed to have the greatest explanatory power among women with metastatic disease in all age groups, both less than 5 years after diagnosis and 5 or more years after diagnosis. Although the incidence of ER-positive breast cancer has increased over time, particularly among screen-detected cancers, its greater role in explaining mortality trends for advanced disease rather than localized disease suggests that the impact of ER status on population outcomes may reflect the expansion and dissemination of hormonal therapy options more than the uptake of screening. Overall, the findings from Park et al suggest that aspects of breast cancer treatment underlie much of the observed improvement in breast cancer mortality and survival between the 1970s and 2000s. Those decades saw remarkable scientific advances, including identification of the human epidermal growth factor receptor 2-neu (HER2neu) oncogene and development of the targeted agent trastuzumab, which extends survival in both the adjuvant and metastatic settings for the 15% to 25% of patients with HER2-positive tumors. Information regarding HER2 status was not routinely collected in SEER before 2010, and therefore its contribution to improvements in breast cancer mortality and survival could not be studied here. However, this advance, in addition to the switch from tamoxifen to aromatase inhibitors for postmenopausal women and the use of taxanes and dose-dense chemotherapy regimens for higher-risk early-stage presentations, should mean that the total impact of therapy has indeed increased. During that time, consensus conferences and expert guidelines promoted the more consistent use of these treatments, likely increasing the proportion of women appropriately receiving beneficial systemic therapy. Prior studies have drawn similar conclusions but found a greater contribution of screening to observed changes in outcomes. Using methods similar to those of Park et al but comparing women diagnosed from 1995 to 1999 with women diagnosed from 1975 to 1979, we found that changes in the tumor size distribution explained 61% of JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 26 SEPTEMBER 1