Laura Pala

Surrogate End Points for Overall Survival in Neoadjuvant Randomized Clinical Trials for Early Breast Cancer

PURPOSE To assess trial-level surrogacy value for overall survival (OS) of the pathologic complete response (pCR) and invasive disease-free survival (iDFS) in randomized clinical trials (RCTs) for early breast cancer (BC). METHODS Individual patient data of neoadjuvant RCTs with available data on pCR, iDFS, and OS were included in the analysis. We used the coefficient of determination R 2 from weighted linear regression models to quantify the association between treatment effects on OS and on the surrogate end points. RESULTS Eleven RCTs, for a total of 15 treatment comparisons and 12,247 patients, were included in the analysis. There was a weak association between hazard ratios (HRs) for OS and odds ratio of pCR overall ( R 2 , 0.07; 95% CI, 0.00 to 0.48), as well as in all the subgroups explored. Overall, the R 2 for the association between HR OS and HR iDFS was 0.46 (95% CI, 0.08 to 0.71), which is just below the cutoff of 0.5 for moderate surrogacy. In the majority of subgroups explored, the R 2 ranged from 0.5 to <0.7, while in hormone receptor–/human epidermal growth factor receptor 2– subtype, histologic grade 1-2 tumors, and lobular tumors, surrogacy was strong (ie, R 2 ≥0.7). The surrogacy value of iDFS for OS was affected by follow-up (FUP) length: R 2 substantially increased up to 36 months of FUP, with little further improvement after 48 months of FUP. CONCLUSION iDFS with sufficient FUP is an acceptable surrogate end point to confidently anticipate final OS results of neoadjuvant RCTs for early BC. This recommendation holds true across many subgroups, with the notable exception of HR+ disease. There is definite need to reassess whether OS is the optimal end point for treatment efficacy measurement in HR+ early BC.

Fine-Tuning Adjuvant Endocrine Therapy for Early-Stage Breast Cancer: An Expert Consensus on Open Issues for Future Research

Abstract After decades of research, improving the efficacy of adjuvant endocrine therapy (ET) for early-stage breast cancer becomes increasingly difficult. Beyond technological breakthroughs and the availability of new classes of drugs, further improvement of adjuvant ET will require applying a rigorous research approach in poorly investigated areas. We critically discuss some key principles that should inform future research to improve ET efficacy, including identifying specific subgroups of patients who can benefit from escalating or de-escalating approaches, optimizing available and new treatment strategies for different clinical contexts, and dissecting the direct and indirect biological effects of therapeutic interventions. Four main issues regarding adjuvant ET were identified as relevant areas, where a better application of such principles can provide positive results in the near future: (i) tailoring the optimal duration of adjuvant ET, (ii) optimizing ovarian function suppression for premenopausal women, (iii) dissecting the biological effects of estrogen receptor manipulation, and (iv) refining the selection of patients to candidate for treatments escalation.