Sisyphean Efforts: Establishing the Correct Risk-Benefit Balance for Adjuvant Therapies
Authors: Jonas Bergh, Kathleen I. Pritchard, David Cameron
Journal: Journal of Clinical Oncology (2016)

It is estimated that the annual breast cancer incidence has increased from 600,000 to 1.6 million worldwide, almost three-fold from 1980 through 2010. This imposes a major increased burden on patients, families, and health care systems, and extensive resources will be required for management of different oncologic therapies at primary diagnosis, as well as for the 20% to 30% of patients who experience relapse. However, fine-tuned diagnostics, prognostication, therapy prediction, and adjuvant therapy will reduce the risk of dying as a result of breast cancer. The prognosis for breast cancer has improved markedly in many countries over the last decades, in large part because of prospective randomized adjuvant studies, early diagnosis, improved diagnostic precision, and fine-tuning of surgery and radiotherapy, together with multidisciplinary team management. Research strategies have also revealed altered genoand phenotypic characteristics during tumor progression. We believe systemic therapy cures patients by eradicating micrometastases from primary breast cancers, which are likely, on average, to be less heterogeneous compared with the later occurring macrometastases. Although not proven, this may explain why adjuvant systemic therapies and radiotherapy at time of primary diagnosis may be curative, whereas the same drugs and schedules in the metastatic setting are not. The first meta-analysis of adjuvant therapy was published in 1988 by the Early Breast Cancer Trialists’ Collaborative Group and based on 16,513 women in 28 randomized trials of tamoxifen and 13,442 in 40 trials of chemotherapy. The conclusion was that tamoxifen reduced the risk of breast cancer death by approximately 20% for women age 50 years or older, and chemotherapy reduced the risk of dying as a result of breast cancer by approximately 25%. The datawere immature and lacked power to reveal beneficial effects of tamoxifen in younger women or chemotherapy effects in the elderly. In an updated analysis in 1998, with more data and longer follow-up from 37,000 individuals, there was evidence that tamoxifen had positive effects only in patients with estrogen receptor (ER) –positive disease. Neither age nor stage precluded benefits. More recently, it has been demonstrated that 10 years of adjuvant tamoxifen further improves relative breast cancer survival by approximately 15% compared with 5 years of tamoxifen, corresponding to an additional absolute survival gain of 3% over the 9% improvement in survival achieved with the first 5 years of tamoxifen, albeit at a price of 0.4% mortality resulting from endometrial carcinoma or pulmonary embolism. These two studies also underline the critical importance of sufficiently large patient populations and longer follow-up to provide accurate outcome data. It is worth recalling that previous and smaller studies of more than 5 years of adjuvant tamoxifen indicated the possibility of a worse outcome with extended tamoxifen therapy beyond 5 years, leading the US Food and Drug Administration to issue a warning against prolonged tamoxifen therapy. The credibility of the aTTom (Adjuvant Tamoxifen Treatment: Offer More?)/ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) data on prolonged adjuvant tamoxifen therapy is in line with the concept that patients with ER-positive disease have gained from prolonged therapy blocking the ER-regulated pathway; 5 years of tamoxifen followed by 5 years of letrozole has also been reported to result in a survival gain for the subgroup of patients with initial axillary lymph node–positive disease. The first overview of chemotherapy could not demonstrate a statistically significant benefit for women age 50 years or older. However, with a longer follow-up and approximately 4,000 additional randomly assigned patients, it became obvious that adjuvant chemotherapy was effective irrespective of age. Furthermore, with the inclusion of 100,000 randomly assigned patients and modern regimens, together with additional follow-up, it became obvious that chemotherapy produced the same relative risk reduction for breast cancer recurrence and mortality, independent of age, size, stage, histologic grade, and ER status. It is also obvious from these repeated overview analyses and prolonged follow-up that antracycline-based regimens are more effective overall than cyclophosphamide, methotrexate, and fluorouracil (CMF) –based regimens. Furthermore, taxanes add further value to the average anthracycline-based regimen. In the article that accompanies this editorial, five prospective and randomized studies, which included 4,105 patients who were randomly assigned from 1978 through 1985, are reported, with a median follow-up of 24 years from diagnosis of an operable breast cancer. The International Breast Cancer Study Group (IBCSG) is to be congratulated for this effort, albeit Sisyphean. However, the regimens used in the studies of perioperative CMF, different schedules of CMF, and 1 year of tamoxifen with or without prednisone, are no longer used because they are inferior in efficacy to newer chemotherapy regimens and longer-duration adjuvant tamoxifen or aromatase inhibitors. Ovarian ablation is, however,