Moving Research From Bench to Bedside to Community: There Is Still More to Do

Investment in biomedical research and healthcare in the United States and worldwide has never been greater. The substantial return on these investments is seen in the remarkable scientific breakthroughs of the past few decades and the continually accelerating advances in biomedical knowledge that promise to revolutionize health care and significantly improve health. Women with breast cancer have benefited from these advances, as the death rate from breast cancer has declined 20% over the last ten years. This has been attributed both to earlier-stage diagnoses in association with screening and to the early use of systemic adjuvant treatment aimed at eradicating or postponing micrometastases believed responsible for distant disease spread. The most recent overview of global trials evaluating adjuvant systemic therapy for early breast cancer, formulated by the Early Breast Cancer Trialists’ Collaborative Group, reported that 5 years of treatment with the selective estrogen receptor modulator tamoxifen for women with estrogen receptor (ER) –positive breast cancer translated into a 12% absolute reduction in the likelihood of recurrence at 15 years (33% v 45%), and a 9% reduction in breast cancer–related death (26% v 35%). The magnitude of mortality reduction was almost three times as great at 15 years as it was at 5 years (9% v 3.6%), while the impact on recurrence was mainly seen in the first 5 years. The absolute difference in recurrence rates between those who used and did not use adjuvant tamoxifen for 5 years was 16% for node-positive and 9% for node-negative disease. Multiple studies have addressed optimal duration of tamoxifen adjuvant treatment, including four trials showing significantly better outcomes for postmenopausal women associated with the use of 5 years compared with 2 years of tamoxifen therapy. The maturation of follow-up for the Eastern Cooperative Oncology Group trial and results of the Adjuvant Tamoxifen Longer Against Shorter and Adjuvant Tamoxifen Treatment Offer More trials, as well as other ongoing trials, will provide further basis for informing recommendations about treatment duration. The current standard recommendation of 5 years for adjuvant tamoxifen in women with ER-positive early breast cancer has been stable for several years. Beyond these advances, new studies have shown improved outcomes for postmenopausal women using aromatase inhibitors as initial adjuvant therapy or in a sequential approach beginning with tamoxifen and changing after 2, 3, or 5 years to an aromatase inhibitor. Across multiple studies of postmenopausal women, anastrozole or letrozole alone or in combination with tamoxifen and anastrozole, letrozole, or exemestane used sequentially after 2 years of tamoxifen have been associated with better outcomes than for women treated with tamoxifen alone or who received no adjuvant therapy. Improved outcomes have been documented in terms of disease-free survival, recurrence, and incidence of contralateral breast cancer, although overall survival benefit from aromatase inhibitors has not been clearly demonstrated to date. Continuing analyses have suggested outcomes improve even further with continuation of an aromatase inhibitor for up to 5 years after the completion of an initial adjuvant 5 year regimen of tamoxifen. Recommendations for initial adjunct treatment now include use of tamoxifen, anastrozole, or letrozole for 5 years’ duration or initial treatment with one of these agents followed by an alternate or with exemestane for 5 or more years of therapy. Still, important inquiries regarding the use of adjuvant hormone therapy remain unanswered. Which is the best initial treatment? Is 5 years the optimal duration of adjuvant treatment? Which subsets of patients will benefit from each of the available individual or combinations of adjuvant hormonal regimens? Under what circumstances will sequential treatment be more effective than sustained single-drug treatment? It is gratifying to know that these questions are currently under study. A second important line of inquiry revolves around the prevention and treatment of side effects related to the use of selective estrogen receptor modulators and aromatase inhibitors. With tamoxifen, side effects include early onset of hot flashes and vaginal discharge and later onset of risk for thromboembolic events, endometrial cancer, and uterine sarcomas. With the aromatase inhibitors, prevalent side effects include milder hot flashes, anorexia, myalgias, arthralgias, bone loss, and fractures. The Multicenter Breast International Group Study is currently evaluating the effectiveness and morbidity profile of patients treated with tamoxifen, letrozole, and combinations of these. Further scientific inquiry into the prevention and treatment of morbidities in association with adjuvant treatment should be pursued. For many women receiving tamoxifen, symptoms persist either undetected or unmanaged. The same problem is emerging in relation to problem detection and management for postmenopausal women using aromatase inhibitors. For example, studies are in progress regarding how often diagnoses of osteopenia and osteoporosis should be sought with bone density studies in women using adjunct therapies. Should the threshold for initiating pharmacologic intervention to treat osteopenia or osteoporosis differ for women receiving and not receiving aromatase inhibitors? Despite the need to systematically address these queries, multiple trials have shown that treatment with oral adjuvant hormone agents JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 4 FEBRUARY 1 2008