Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype

Abstract

To determine the long-term prognosis in each phenotypic subset of breast cancer related to residual cancer burden (RCB) after neoadjuvant chemotherapy alone, or with concurrent human epidermal growth factor receptor 2 (HER2)-targeted treatment. MethodsWe conducted a pathologic review to measure the continuous RCB index (wherein pathologic complete response has RCB = 0; residual disease is categorized into three predefined classes of RCB index [RCB-I, RCB-II, and RCB-III]), and yp-stage of residual disease. Patients were prospectively observed for survival. Three patient cohorts received paclitaxel (T) followed by fluorouracil, doxorubicin, and cyclophosphamide (T/FAC): original development cohort (T/FAC-1), validation cohort (T/FAC-2), and independent validation cohort (T/FAC-3). Another validation cohort received FAC chemotherapy only, and a fifth cohort received concurrent trastuzumab (H) with sequential paclitaxel and fluorouracil, epirubicin, and cyclophosphamide (FEC; H+T/FEC). Phenotypic subsets were defined by hormone receptor (HR) and HER2 status at diagnosis, classified as HR-positive/HER2-negative, HER2-positive (HR-negative/HER2-positive or HR-positive/HER2-positive), or triple receptor-negative. Relapse-free survival estimates were determined from Kaplan-Meier analysis and compared using the log-rank test. Results Five cohorts (T/FAC-1 [n = 219], T/FAC-2 [n = 262], T/FAC-3 [n = 342], FAC [n = 132], and H+T/FEC[n = 203]) had median event-free follow-up of 13.5, 9.1, 6.8, 16.4, and 7.1 years, respectively. Continuous RCB index was prognostic within each phenotypic subset, independent of other clinicalpathologic variables. RCB classes stratified prognostic risk overall, within each phenotypic subset, and within yp-stage categories. Estimates of 10-year relapse-free survival rates in the four RCB classes (pathologic complete response, RCB-I, RCB-II, and RCB-III) were 86%, 81%, 55%, and 23% for triple receptor-negative; 83%, 97%, 74%, and 52% for HR-positive/HER2-negative in the combined T/FAC cohorts; and 95%, 77%, 47%, and 21% in the H+T/FEC cohort. ConclusionRCB was prognostic for long-term survival after neoadjuvant chemotherapy in all three phenotypic subsets of breast cancer. Our institutional findings should be externally validated.

Tumor Biology and Response to Chemotherapy Impact Breast Cancer-specific Survival in Node-positive Breast Cancer Patients Treated With Neoadjuvant Chemotherapy

“…Estimation of extent of disease by Residual Cancer Burden has been proposed as an informative method for assessment of extent of residual disease after neoadjuvant chemotherapy, since RCB class has been shown to correlate with survival. [15, 21–23] As demonstrated in our data, and in keeping with previous reports, the RCB class provides additional discrimination, in particular to identify those patients with the poorest outcome, as identified by RCB class III. RCB-III is a group of patients at significantly higher risk of relapse and identifies a patient group which may benefit from further systemic therapy and an area to focus additional research.…”

Comparison of residual cancer burden, American Joint Committee on Cancer staging and pathologic complete response in breast cancer after neoadjuvant chemotherapy: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657)

“…Our analysis revealed three key findings: 1) RCB and yAJCC identify patients at high risk of early relapse, 2) predictive ability of these staging systems increases when HR/HER2 subtype is taken into account, and 3) RCB and yAJCC often produce discrepant results, largely driven by differential treatment of lymph nodes and the inclusion of cellularity in calculation of RCB. These findings complement a recent, multi-cohort analysis of RCB [17]. …”

Stress-inducible gene Atf3 in the noncancer host cells contributes to chemotherapy-exacerbated breast cancer metastasis

“…Significantly, a recent study showed that residual cancer burden after neoadjuvant chemotherapy is associated with worse clinical outcome (66). Thus, elucidating the mechanisms by which chemotherapy exacerbates cancer progression has clinical relevance.…”