Prognostic markers for survival after high-dose chemotherapywith autologous stem-cell transplantation for breast cancer

Abstract

We read with interest the recent article by Schrama et al. [1.Schrama J.G. Faneyte I.F. Schornagel J.H. et al.Randomized trial of high-dose chemotherapy and hematopoietic progenitor-cell support in operable breast cancer with extensive lymph node involvement: final analysis with 7 years of follow-up.Ann Oncol. 2002; 13: 689-698Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar] in the May 2002 issue of the Annals of Oncology presenting the final analysis of a randomized trial of high-dose chemotherapy (HDCT) and autologous stem-cell transplantation (ASCT) in operable breast cancer patients with extensive lymph node involvement. Beside the comparison of the two treatment arms, the authors analyzed the value of clinical and molecular prognostic factors for overall survival (OS) and disease-free survival (DFS). They reported that only T-stage before chemotherapy and the number of tumor-positive axillary lymph nodes (ALN) after induction chemotherapy were significant prognostic factors for OS. The same factors plus estrogen receptor status were factors of borderline significance for DFS. Neither HER-2 nor p53 expression were significantly related to outcome. In our single institutional trial, with 144 patients with high-risk primary breast cancer (HRPBC) who received HDCT with ASCT, we have demonstrated that biological parameters of the tumor could define subgroups of patients that might benefit from HDCT. The clinical parameters (age, tumor stage, menopausal status, number of tumor-involved ALN, nodal ratio, tumor size, grading and hormone receptor status) and biological tumor features [HER-2, p53, Ki67 and bcl-2 protein expression, DNA content of tumor cells (DNA-index) and tumor cell proliferation] were studied, and their relationship to DFS and OS was analyzed. We showed that p53 and HER-2 overexpression, assessed by immunohistochemistry, were the strongest independent negative predictors of OS following HDCT and ASCT. The adverse impact of these biological features in conventionally treated patients was not altered by HDCT. p53 overexpression was the only independent predictor of DFS. Conventional variables (e.g. tumor size, hormone receptor status, number of ALN and age) were not of relevance in this context [2.Hensel M. Schneeweiss A. Sinn H.P. et al.P53 is the strongest predictor of survival in high-risk primary breast cancer patients undergoing high-dose chemotherapy with autologous blood stem cell support.Int J Cancer. 2002; 100: 290-296Crossref PubMed Scopus (28) Google Scholar]. If both HER-2 and p53 expressions were low, patients had a favorable OS rate compared with patients with overexpression of one or both of these factors (Figure 1). These data confirm earlier results published by Somlo et al., who found that p53-overexpression was associated with inferior DFS and OS after HDCT for HRPBC [3.Somlo G. Simpson J. Doroshow J. et al.Prognostic indicators and 7-year outcome following high-dose chemotherapy versus conventional adjuvant chemotherapy in high-risk primary breast cancer.Proc Am Soc Clin Oncol. 2001; 20 (Abstr 1791)Google Scholar]. The predictive value of HER-2 overexpression in a similar patient setting was reported by Nieto et al. [4.Nieto Y. Cagnoni P.J. Nawaz S. et al.Evaluation of the predictive value of Her-2/neu overexpression and p53 mutations in high-risk primary breast cancer patients treated with high-dose chemotherapy and autologous stem-cell transplantation.J Clin Oncol. 2000; 18: 2070-2080Crossref PubMed Scopus (57) Google Scholar]. For HRPBC patients with tumors not overexpressing HER-2 and p53, HDCT may be an appropriate approach to achievelong-term survival and tumor control. For the remainder, novel experimental approaches are probably needed, such as antibody therapies, tumor vaccination or allogeneic transplantation. Thus therapeutic decisions should be based on the molecular biology of the disease, reflecting the heterogeneity in the biology of breast cancer.