Neoadjuvant treatment of HER2-positive breast cancer – pathological complete response (pCR) as a surrogate of long term outcomes in the context of regulatory guidelines and reimbursement recommendations.

Abstract

Background: The vast heterogeneity of breast cancer (BC) patients, together with relatively long survival in the early stages of the disease, leads to methodological issues in designing clinical trials, particularly in case of therapies targeted for narrow patients subsets. That situation led to the need and search for early, reliable predictors of long-term outcomes.However, in countries adopting HTA methodology to reimbursement decisions non-final (“surrogate”) endpoints may not be accepted as a measure of clinical benefit. Methods: We searched PubMed and EMBASE for meta-analyses investigating association of pathologic complete response to BC neoadjuvant therapy with longer-term clinical outcomes. To be eligible analyses had to pool primary studies identified in a systematic manner. The results of the included studies were discussed in the context of current regulatory and reimbursement recommendations. Results: The 4 included meta-analyses varied in methodological approaches, eligibility criteria and number of included patients. Three of them assessed predictive value of pCR in overall non-metastatic BC population and two – in HER2-positive subgroup. The existing differences in conclusions are consistent with the variability in methodological assumptions. Conclusion: Significant heterogeneity of BC population and low number of studies showing substantial treatment effect on pCR could bias the results of “trial-level” analyses. In contrast, studies consistently show significant patient-level association of pCR with clinical outcomes, particularly strong for aggressive tumour subtypes. The existing EMA and FDA guidelines show how to make use of the existing evidence, in spite of its limitations, in a pursuit of satisfying the unmet medical needs.