Predictive value of tumour cell proliferation in locally advanced breast cancer treated with neoadjuvant chemotherapy

• Published in: European journal of cancer (1990) 2003-03, Vol.39 (4), p.438-446
• Main Authors: Aas, T., Geisler, S., Eide, G.E., Haugen, D.F., Varhaug, J.E., Bassøe, A.M., Thorsen, T., Berntsen, H., Børresen-Dale, A.-L., Akslen, L.A., Lønning, P.E.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Analysis of Variance; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Apoptotic factors; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Division; Cell proliferation; Chemotherapy resistance; Chemotherapy, Adjuvant; Disease-Free Survival; Doxorubicin - therapeutic use; Drug Resistance, Neoplasm; Female; Genes, erbB-2 - genetics; Gynecology. Andrology. Obstetrics; Humans; Immunohistochemistry; Immunotherapy; Ki-67 Antigen - metabolism; Locally advanced breast cancer; Mammary gland diseases; Medical sciences; Middle Aged; Mitosis; Mutation - genetics; Pharmacology. Drug treatments; Predictive Value of Tests; Receptors, Estrogen - metabolism; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/S0959-8049(02)00732-3

We previously reported that defects in apoptotic pathways (mutations in the TP53 gene) predicted resistance to doxorubicin monotherapy. The aim of this study was to evaluate whether cell proliferation, as assessed by mitotic frequency and Ki-67 levels, may provide additional predictive information in the same tumours and to assess any potential correlations between these markers and mutations in the TP53 gene and erbB-2 overexpression. Surgical specimens were obtained from ninety locally advanced breast cancers before commencing primary chemotherapy consisting of weekly doxorubicin (14 mg/m 2) for 16 weeks. 38% of the patients had a partial response (PR) to therapy, 52% had stable disease (SD) while 10% had progressive disease (PD). Univariate analysis showed a significant association between a high cell proliferation rate (expressed as a high mitotic frequency) and resistance to doxorubicin ( P=0.001). Further analyses revealed this association to be limited to the subgroup of tumour expressing wild-type TP53 ( P=0.016), and TP53 mutation status was the only factor predicting drug resistance in the multivariate analyses. The finding that a high mitotic frequency, as well as a high Ki-67 staining, correlated to TP53 mutations ( P=0.001 for both), suggests TP53 mutations are the key predictor of drug resistance, although cell proliferation may play an additional role in tumours harbouring wild-type TP53. Regarding overall (OS) and relapse-free survival (RFS), multivariate analyses (Cox' proportional hazards regression) revealed a high histological grade and negative oestrogen receptor (ER) status to be the variables that were most strongly related to breast cancer death ( P=0.001 and P=0.001, respectively). A key reason for this difference with respect to the factors predicting chemotherapy resistance could be due to the adjuvant use of tamoxifen in all patients harbouring ER-positive tumours.