Is pathologic complete response a valid surrogate parameter of treatment efficacy in HER2 positive breast cancer patients undergoing primary chemotherapy plus trastuzamab? [13]

TO THE EDITOR: Data from multiple clinical trials have indicated that pathologic complete response (pCR) after primary chemotherapy in patients with breast cancer (BC) (ie, no residual cancer in the breast or lymph nodes) is associated with an excellent long-term prognosis.1 These results have suggested that pCR can be used as a surrogate marker of efficacy. Many primary chemotherapy trials have been designed with this as the primary end point. It should be noted however, that while this data has demonstrated pCR as a strong prognostic parameter, this does not necessarily imply that it is also a valid surrogate end point of efficacy. pCR, in fact, may have selected a subgroup of patients already destined to a better outcome even without treatment. Prentice provided a definition and a set of criteria to be used to identify a surrogate end point of treatment efficacy.2 Accordingly, to prove that pCR is a surrogate parameter of efficacy of primary chemotherapy, it is not sufficient to demonstrate that it occurs with treatment and correlates with overall outcome. We should also demonstrate that any difference in survival disappears once we adjust for pCR. In other words, prognosis, once the surrogate is known, should be independent of treatment, and responders to more and less active treatment should have the same survival.