Pathologic Complete Response after Neoadjuvant Chemotherapy and Impact on Breast Cancer Recurrence and Survival: A Comprehensive Meta-analysis

Abstract

Purpose: While various studies have highlighted the prognostic significance of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAT), the impact of additional adjuvant therapy after pCR is not known.

Experimental design: PubMed was searched for studies with NAT for breast cancer and individual patient-level data was extracted for analysis using plot digitizer software. HRs, with 95% probability intervals (PI), measuring the association between pCR and overall survival (OS) or event-free survival (EFS), were estimated using Bayesian piece-wise exponential proportional hazards hierarchical models including pCR as predictor.

Results: Overall, 52 of 3,209 publications met inclusion criteria, totaling 27,895 patients. Patients with a pCR after NAT had significantly better EFS (HR = 0.31; 95% PI, 0.24-0.39), particularly for triple-negative (HR = 0.18; 95% PI, 0.10-0.31) and HER2⁺ (HR = 0.32; 95% PI, 0.21-0.47) disease. Similarly, pCR after NAT was also associated with improved survival (HR = 0.22; 95% PI, 0.15-0.30). The association of pCR with improved EFS was similar among patients who received subsequent adjuvant chemotherapy (HR = 0.36; 95% PI, 0.19-0.67) and those without adjuvant chemotherapy (HR = 0.36; 95% PI, 0.27-0.54), with no significant difference between the two groups (P = 0.60).

Conclusions: Achieving pCR following NAT is associated with significantly better EFS and OS, particularly for triple-negative and HER2⁺ breast cancer. The similar outcomes with or without adjuvant chemotherapy in patients who attain pCR likely reflects tumor biology and systemic clearance of micrometastatic disease, highlighting the potential of escalation/deescalation strategies in the adjuvant setting based on neoadjuvant response.See related commentary by Esserman, p. 2771.

Figure 1.. Selection of studies for meta-analysis

Based on the search criteria, 3,209 citations with associated abstracts were reviewed. Of these, a total of 166 were selected for full review and ultimately 52 studies met the criteria for inclusion.

Figure 2. A-B. Association of pCR with (A) event free survival and (B) overall survival

Forest plot of the overall hazard ratio (HR) estimate with the 95% probability interval (PI) for the association of pathologic complete response (pCR) with the long term outcomes (A) event free survival (EFS) and (B) overall survival (OS), as compared to residual disease (RD). For comparison, the raw study specific HR estimates are reported. The location of the box indicates the estimated HR for that study; the size of the box represents the relative number of events per study. HR & 95% PI for overall effects are also reported. The dashed line oriented at 1 represents the Null of no difference.

Figure 2. A-B. Association of pCR with (A) event free survival and (B) overall survival

Forest plot of the overall hazard ratio (HR) estimate with the 95% probability interval (PI) for the association of pathologic complete response (pCR) with the long term outcomes (A) event free survival (EFS) and (B) overall survival (OS), as compared to residual disease (RD). For comparison, the raw study specific HR estimates are reported. The location of the box indicates the estimated HR for that study; the size of the box represents the relative number of events per study. HR & 95% PI for overall effects are also reported. The dashed line oriented at 1 represents the Null of no difference.

Figure 3. A-D. Relationship between pCR and EFS overall and among the major breast cancer subtypes

Kaplan-Meier curves depicting the relationship between pathologic complete response (pCR) and event free survival (EFS) overall (A), in triple negative breast cancer (B), HER2-positive breast cancer (C), and hormone receptor-positive breast cancer (D), based on hazard ratio data from the studies. The blue line represents the pCR group and the orange line represents the residual disease group. The shaded regions represent the 95% pointwise probability interval for their respective color.

Figure 4. A-B. Impact of adjuvant chemotherapy on the relationship between pCR and EFS

(A) Kaplan-Meier curves depicting the relationship between pathologic complete response (pCR) and event free survival (EFS) based on receipt of chemotherapy. The color blue represents the patient subpopulation where 10% or less of the patients received adjuvant chemotherapy. The color orange represents the patient subpopulation where 90% or more of the patients received adjuvant chemotherapy. The shaded regions represent the 95% pointwise probability interval for their respective color. (B) The left forest plot is representative of the populations with at least 90% of patients receiving adjuvant chemotherapy while the forest plot on the right is representative of the populations with at most 10% of patients receiving adjuvant chemotherapy, with both comparing pCR to residual disease (RD). The hazard ratio (HR) estimate with the 95% probability interval (PI) are shown overall. For comparison, the raw study specific HR estimates are reported. The location of the box indicates the estimated HR for that study; the size of the box represents the relative number of events per study. The dashed line oriented at 1 represents the Null of no difference.