Neoadjuvant trials in early breast cancer: pathological response at surgery and correlation to longer term outcomes - what does it all mean?

Abstract

Background: Neoadjuvant breast cancer trials are important for speeding up the introduction of new treatments for patients with early breast cancer and for the highly productive translational research which they facilitate. Meta-analysis of trial data shows clear correlation between pathological response at surgery after neoadjuvant chemotherapy and longer-term outcomes at an individual patient level. However, this does not appear to be present on individual trial level analysis, when correlating improved outcome for the investigational arm for the primary endpoint (pathological response) with longer-term outcomes.

Discussion: The correlation between pathological response and longer-term outcomes in trials is dependent on many factors. These include definitions of pathological response, both complete and partial; assessment methods for pathological response at surgery; subtype and prognosis of breast cancer at diagnosis; number of patients recruited; adjuvant treatments; the mechanism of action of the investigational drug; the length of follow-up at the time of reporting; the definitions used in longer-term outcomes analysis; clonal heterogeneity; and new adaptive trial designs with additional neo/adjuvant treatments. Future developments of neoadjuvant breast cancer trials are discussed. With so many factors influencing the correlation of longer-term outcomes for trial-level data, we conclude that the main focus of neoadjuvant trials should remain the primary endpoint of pathological response. Neoadjuvant breast cancer trials are very important investigational studies that will continue to increase our understanding of the disease and offer the potential of more rapid introduction of new treatments for women with high-risk early breast cancer. In the future, we are likely to see both novel trial designs adopted in the neoadjuvant context and modifications of neo/adjuvant treatments for pathological non-responders within clinical trials. Both of these have the intention of improving longer-term outcomes for patients who do not have a good pathological response to first-line neoadjuvant treatment. If successful, these developments are likely to reduce further any positive correlation between pathological response and longer-term outcomes.

Fig. 1

Associations between pathological complete response and event-free survival and overall survival. The ypT0/is ypN0 definition of pathological complete response was used (i.e. absence of invasive cancer in the breast and axillary nodes, irrespective of ductal carcinoma in situ). CI confidence interval, HR hazard ratio. (Reproduced with permission from The Lancet, Cortazar et al. [5]: License Number 3666940645625)

Fig. 2

Associations between three definitions of pathological complete response and event-free survival and overall survival. We compared event-free survival and overall survival between patients who did and did not achieve a pathological complete response according to one of three definitions. Patients who did not achieve pathological complete response are not shown. The number of patients who achieved a pathological complete response is listed for each pathological complete response definition. Patients could achieve pathological complete response according to more than one definition. ypT0ypN0 = absence of invasive cancer and in situ cancer in breast and axillary nodes. ypT0/is ypN0 = absence of invasive cancer in breast and axillary nodes, irrespective of ductal carcinoma in-situ. ypT0/is = absence of invasive cancer in breast, irrespective of ductal carcinoma in-situ or nodal involvement. CI confidence interval, HER2 human epidermal growth factor receptor 2, HR hazard ratio. (Reproduced with permission from The Lancet, Cortazar et al. [5]: License Number 3666940645625)

Fig. 3

Percentage of patients achieving pathological complete response (a) and HRs for overall survival (b), by subgroup.Information about clinical tumour stage available for 11 869 patients, about clinical nodal status for 11 807 patients, about histological type for 10,263 patients, about tumour grade for 8035 patients, and about clinical subtype for 5694 patients. ypT0/isypN0 definition of pathological complete response used. No multiplicity adjustment was made. HR hazard ratio, CI confidence interval, HER2 human epidermal growth factor receptor 2. (Reproduced with permission from The Lancet, Cortazar et al. [5]: License Number 3666940645625)

Fig. 4

Expected event-free survival curves for trastuzumab as well as for the combination of trastuzumab and lapatinib are shown based on the NeoALTTO results. (Reproduced with permission from Clinical Cancer Research, DeMichele et al. [41]: License Number 3666990663029)