Do All Patients with Breast Cancer Require Systemic Adjuvant Therapy

Over the last three decades, we have witnessed a remarkable reduction in breast cancer mortality in part because of the contribution of systemic adjuvant therapy, including endocrine treatment, chemotherapy, and more recently, anti-HER2 agents (1–3). It is clear, however, that the vast majority of patients with stages I and II breast cancer are cured by local treatment alone, and furthermore, that adjuvant therapy reduces the risk of recurrence by only one-third to one-half in those who are destined to have a recurrence in the absence of treatment. Given the nearly universal side effects that can adversely affect quality of life and the occasionally life-threatening toxicities, as well as the enormous costs associated with adjuvant therapy, investigators have searched for prognostic and predictive factors that might permit more rational and efficient application of this life-saving but taxing strategy. At the tumor boards of the University of Michigan Comprehensive Cancer Center and among ourselves, we often ask “Whom should we treat?” Patients appear to prefer treatment for very small potential absolute benefits (4,5). Prognostic and predictive factors are used to select patients in whom we can omit adjuvant therapy when we otherwise would have given it. Because omitting adjuvant therapy might allow an otherwise preventable recurrence and therefore loss of curative potential, the stakes in these clinical decisions are high. It is thus essential that prognostic and predictive factors be highly accurate and well validated. Unfortunately, very few such factors have clinical usefulness, and it has been nearly impossible to identify a group of patients based on these factors who will do so well that they should not receive any adjuvant systemic therapy (6,7). In this issue of the Journal, Christiansen et al. (8) describe standardized mortality rates among a large population-based sample of women in Denmark with node-negative hormone receptor–positive breast cancer diagnosed between November 1, 1989, and April 30, 2001 and treated with only locoregional therapy. The objective of the study was to determine whether there is a group of women whose overall survival is the same as age-matched unaffected women, and therefore, who would presumably not have benefited from any adjuvant therapy, including endocrine therapy. As expected, they observed that younger age ( 3000 patients) and has a long and careful follow-up (median of 14.8 years). In addition, they validated their findings in a more recent cohort of patients diagnosed between July 1, 1998, and June 1, 2005, who, likewise, did not receive any adjuvant therapy. The persistent risk of breast cancer recurrence even many years after diagnosis weakens the contributions of the latter group in whom the follow-up period was only 5 years. This study (8) is limited by lack of information on patient comorbidity and on other key tumor biological features, such as HER2 status and the biological features identified through genomic assays, none of which were routinely assessed during the years of diagnosis in this cohort (1989 through 2001). In addition, methods for determining hormone receptor status likely changed from ligand-based assays early on in the study period to immunohistochemistry in the later years; it is possible that the tumors of the included patients differ from hormone receptor–positive tumors in the present era and perhaps in the tumors from patients in the validation cohort. What does this study (8) tell us? First, in the absence of modern biomarker analysis, there are few patients with invasive breast cancer from whom we can safely withhold adjuvant therapy. The findings of this study are consistent with those of other studies that have demonstrated that, although effective in reducing the risk of ipsilateral and contralateral breast events, adjuvant endocrine therapy does not reduce the risk of mortality in patients with very small, node-negative hormone receptor–positive breast cancer because the risk of mortality is already extremely low (9,10). For example, the National Surgical Adjuvant Breast and Bowel Project conducted a study designed to identify the role of tamoxifen and breast radiation on risk of recurrence (NSABP B-21) in women with breast cancers measuring 1 cm or more in greatest dimension (9). Radiation therapy and tamoxifen were effective in reducing the risk of ipsilateral recurrence, and tamoxifen was effective in reducing the risk of contralateral breast events. Tamoxifen was not associated, however, with a reduction in the risk of distant metastases (9). Recently, investigators have examined the prognostic role of single-gene proliferative markers (such as Ki67) and perhaps more accurate multiparameter assays, such as the 21-gene recurrence score, which can quantify the risk of distant recurrence in patients who take adjuvant tamoxifen. Such tumor attributes have the potential to identify node-negative hormone receptor–positive patients with such a favorable prognosis that they should be treated with endocrine treatment only and simply do not require chemotherapy (11–13). These studies, of course, presume acceptance of endocrine therapy. One wonders if pathological grading can suffice without the more expensive and technically demanding assays required for these markers, but in head-to-head comparisons, the poor interobserver variability of grading renders grade less valuable in decision making (12–15). Although many patients might not benefit from chemotherapy, can we also avoid less toxic, but still bothersome, endocrine therapy? As described above, endocrine therapy has consistently been shown to reduce the risk of ipsilateral and contralateral breast cancers (16,17) and to reduce the risk of a first cancer in women at high risk of developing the disease (18,19). It is exceedingly unlikely that women with these very low-risk invasive cancers, such as those identified in the study by Christiansen et al. (8), and previously unaffected women at modestly high risk of developing a first breast cancer will reap a survival benefit from such treatment. Many women will wish, however, to take endocrine therapy for ipsilateral and contralateral risk reduction. Clearly, patient preferences regarding risks and benefits of endocrine therapy play a critical role in decision making, and high-quality information support is essential in these settings. In summary, the study by Christiansen et al. (8) further documents the high likelihood of cure of invasive breast cancer by local therapy alone in a small highly defined group of older women with small, node-negative, hormone receptor–positive low-grade breast cancers. This subset of patients, however, represents only a small fraction of the vast majority of women diagnosed with this disease. We continue to need better prognostic, and in particular, predictive factors to truly personalize our care for our patients.