Role of Anti-HER-2 Therapies in the Neo-Adjuvant Setting: Is Complete Pathological Response a Solid Surrogate?

Breast cancer continues to be a major health problem. Both patients and clinicians demand faster access to drugs that could result in better outcomes. In part motivated by this necessity, there has been a change in the dominant paradigm regarding how drugs become approved. Complete pathological response (pCR), understood as the absence of remanent and viable tumor after a neoadjuvant treatment, is now considered by a large proportion of the medical community as a valid surrogate. The presumption is that patients achieving pCR are less likely to develop tumor recurrence. Consequently, if a drug can improve the number of patients achieving pCR it could then obtain approval by the regulatory agencies. Pertuzumab, an anti-HER- 2 monoclonal antibody, was granted accelerated approval based on this principle. The unprecedented approval of this drug is now an example that can help us to understand the advantages but also the potential risks associated with this new approach. In this review, we will discuss the results of the two clinical trials leading to the FDA-approval of pertuzumab in the neo-adjuvant setting. We will also analyze the outcomes from long term follow up of two important neoadjuvant clinical trials, the NeoALTTO and the NOAH studies. These last ones had provided further insights regarding the magnitude, the quality as well as some limitations of the relationship between pCR and harder endpoints such as event-free or overall survival. It seems evident that the acknowledgement of pCR as a potential surrogate endpoint represents an important step in the right direction. However, it still remains controversial whether this is applicable to all subtypes of breast cancers. Additional investigations may be necessary to safely generalize this concept.