Targeting Adjuvant Chemotherapy: A Good Idea That Needs to Be Proven!

The success of adjuvant therapy in reducing recurrence and mortality has been established for endocrine therapy, chemotherapy, and more recently, trastuzumab Indeed, Berry et al have suggested that at least one half of the remarkable reduction in breast cancer mortality observed over the last 30 years can be attributed to widespread application of adjuvant systemic therapy. The Oxford Worldwide Overview of early breast cancer trials, conducted by the Early Breast Cancer Trialists Collaborative Group (EBCTG) demonstrated definitively that, without respect to subgrouping, chemotherapy appears to reduce breast cancer recurrence and mortality by approximately 30% and 20%, respectively. However, this success does not come without a price. All oncologists and their patients recognize that chemotherapy is almost universally associated with bothersome adverse effects and occasionally with life-threatening toxicities (approximately 1% in most cooperative group trials), as well as enormous direct and indirect financial costs. In this regard, breast cancer is arguably the paradigm for personalized cancer care. Clinicians can confidently use the highly validated biomarkers estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) to withhold endocrine and antiHER2 therapies from patients who are so unlikely to benefit that the risks and costs of treatment cannot be justified. Are there prognostic or predictive factors for chemotherapy? Until recently, no test has reliably distinguished a group of patients who either do not need (prognosis), or will not respond (prediction) to chemotherapy. These semantic distinctions are important, since one might withhold potentially effective therapy for one of two reasons: (1) if a patient has such a favorable prognosis that even if the therapy works, it is not worth the toxicities; or (2) even if the patient’s prognosis is poor, ineffective therapy cannot be justified. Early adjuvant chemotherapy trials were conducted in relatively poor prognostic subgroups, based principally on anatomic/pathologic findings, such as tumor size and the presence or absence of axillary nodal metastases. By consensus, prognosis for patients with small, node-negative, welldifferentiated invasive primary cancers is so favorable that chemotherapy has not been recommended. However, these are relatively crude measures of prognosis, and the identified subgroups are small. Since patient-choice studies have suggested that patients are willing to take chemotherapy for small absolute benefits, adjuvant chemotherapy has been delivered since the early 1990s to almost all patients, except this small, highly favorable subset. Are there biologic factors that might refine prognostic estimates? Many years ago, McGuire and others proposed that patients with ER-positive breast cancers had better prognosis than those with ER negative tumors, but subsequent studies demonstrated that ER positivity alone was not a sufficiently favorable prognostic factor to justify withholding chemotherapy. More recently, multigene expression assays have been developed that are strongly prognostic. Of these, the 21-gene recurrence score (RS) has been the most highly validated for clinical utility as a prognostic factor in patients with node-negative, ER-positive breast cancer. Women in this subgroup who have low 21-gene RSs have such a favorable prognosis that even if chemotherapy reduces the risk of recurrence by 30% (as predicted by the EBCTCG data), the absolute number of patients who would benefit is still less than two to three women out of 100 treated, which barely exceeds the approximately 1% risk of life-threatening toxicities of chemotherapy. This test is now part of routine evaluation of patients with newly diagnosed, node-negative, ER-positive breast cancer, resulting in less administration of adjuvant chemotherapy in these women. More relevant to this debate is whether there are tests that predict that chemotherapy will not work, even if prognosis is poor? Again, we turn to ER as a potentially useful biomarker. In 1978, Lippman et al reported an exploratory study suggesting that patients with ER negative, compared with ER-positive, metastatic breast cancer were more likely to respond to chemotherapy. Although this hypothesis was extensively studied with widely disparate results, in the last decade, data from both classic and neoadjuvant chemotherapy studies have suggested, on the whole, that ER is indeed a negative predictive factor for chemotherapy response. However, ER is not the entire story. Investigators from Cancer and Leukemia Group B demonstrated that although patients with ER-negative tumors always benefited from investigational chemotherapy advances more than those with ERpositive cancers, the latter still gained some advantage compared with the control treated groups. These studies are complemented by additional correlative science studies that have reported that both HER2 and Ki67 are associated with chemotherapy response and benefit. Taken together, they suggest that perhaps a multifactoral predictor might be useful in identifying a group of patients who, regardless of prognosis, simply do not benefit from adjuvant chemotherapy. In this regard, Paik et al performed an exploratory study of the predictive role for chemotherapy effect in National Surgical Adjuvant Breast and Bowel Project (NSABP) B20, the same clinical trial in which the 21-gene RS algorithm was developed, and observed that the proportional reduction in JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 30 NUMBER 12 APRIL 2