Since Kuerer’s original publication, pCR has repeatedly predicted individual long-term survival in a large number of studies. 12 While only 16% of patients in the study achieved a pCR, those who did had significantly improved 5-year OS and disease-free survival (DFS) (89% and 87%, respectively) as compared with those without pCR (64% and 58%, respectively). first described tumour characteristics of 372 patients with locally advanced breast cancer who underwent neoadjuvant chemotherapy with fluorouracil, doxorubicin and cyclophosphamide. In individual studies looking at all patients who achieved pCR after chemotherapy compared with those who did not, pCR seemed to consistently predict long-term survival. Pathologic complete response and risk of breast cancer recurrence 11 This paper will discuss the basis for using pCR as a surrogate endpoint in breast cancer, compare the validity of pCR amongst different immunohistochemistry-based receptor subtypes (or simply, receptor subtypes) of breast cancer, examine the relationship between pCR and survival, and evaluate whether or not pCR meets the criteria of a valid and useful surrogate endpoint. 6 This decision was somewhat controversial because the relationship between pCR and hard survival endpoints is not straightforward, 10 and the definition of pCR can vary between studies. 9 However, FDA approval for the use of pertuzumab in the neoadjuvant setting was based on a primary endpoint of pCR in the NeoSphere study. 1,6–8 Pertuzumab, for example, a monoclonal antibody used to treat human epidermal growth factor receptor 2 (HER2) positive (HER2+) breast cancer, was originally approved by the US Food and Drug Administration (FDA) in the metastatic setting based on the primary endpoint of overall survival (OS) in the CLEOPATRA study. In breast cancer, neoadjuvant trials have become an increasingly common setting in which to develop and gain approval for new drugs. Neoadjuvant trials, in contrast, which study therapies administered prior to surgical intervention and commonly utilize the post-operative surrogate endpoint of pathologic complete response (pCR), offer a more efficient and potentially beneficial framework for drug development. Adjuvant trials, which study therapies administered following surgical intervention, may offer patients an increased chance of cure, but they also generally depend on survival endpoints for analysis, which, in the case of estrogen receptor positive (ER+) breast cancer, can take years (or even decades) to complete. 1–4 Furthermore, these trials are often lengthy and expensive because they typically depend on survival endpoints in order to gain regulatory approval or to be considered for use in earlier disease stages. These trials, however, often involve sicker patients who can confound the results, and do not directly offer patients the chance of cure. This seems like a natural population in which to start because patients have often exhausted the armamentarium of approved agents and, therefore, clinical equipoise is easier to achieve. The metastatic setting has traditionally been the initial venue for the development of new drugs in breast cancer. Keywordsīreast cancer, chemotherapy, neoadjuvant, pathologic complete response Article: This review discusses the basis for using pCR as a surrogate endpoint in breast cancer, compares the validity of pCR amongst different receptor subtypes of breast cancer, examines the relationship between pCR and event-free survival, and evaluates whether or not pCR meets the criteria of a valid and useful surrogate endpoint. Neoadjuvant trials, however, which commonly utilize the post-operative surrogate endpoint of pathologic complete response (pCR), offer a more efficient and potentially beneficial framework for drug development.
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