Influence of TP53 gene alterations and c-erbB-2 expression on the response to treatment with doxorubicin in locally advanced breast cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2001-03, Vol.61 (6), p.2505-2512
• Main Authors: GEISLER, Stephanie, LØNNING, Per Eystein, AAS, Turid, JOHNSEN, Hilde, FLUGE, Øystein, HAUGEN, Dagny Faksvag, LILLEHAUG, Johan Richard, AKSLEN, Lars Andreas, BØRRESEN-DALE, Anne-Lise
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic - therapeutic use; Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; c-erbB-2 gene; Chemotherapy; Disease-Free Survival; doxorubicin; Doxorubicin - therapeutic use; Drug Resistance, Neoplasm - genetics; Female; Follow-Up Studies; Gene Expression; Genes, p53 - genetics; Humans; Immunohistochemistry; Loss of Heterozygosity; Medical sciences; Middle Aged; Mutation; Pharmacology. Drug treatments; Predictive Value of Tests; Prospective Studies; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Receptor, ErbB-2 - biosynthesis; Receptor, ErbB-2 - genetics; Survival Rate
• ISSN: 0008-5472; 1538-7445

TP53 status [mutations, immunostaining, and loss of heterozygosity (LOH)], expression of c-erbB-2, bcl-2, and histological grading were correlated to the response to doxorubicin monotherapy (14 mg/m2) administered weekly to 90 patients with locally advanced breast cancer. Mutations in the TP53 gene, in particular those affecting or disrupting the loop domains L2 or L3 of the p53 protein, were associated with lack of response to chemotherapy (P = 0.063 for all mutations and P = 0.008 for mutations affecting L2/L3, respectively). Similarly, expression of c-erbB-2 (P = 0.041), a high histological grade (P = 0.023), and lack of expression of bcl-2 (P = 0.018) all predicted chemoresistance. No statistically significant association between either p53 immunostaining or TP53 LOH and response to therapy was recorded, despite the finding that both were associated with TP53 mutation status (p53 immunostaining, P < 0.001; LOH, P = 0.021). Lack of immunostaining for p53 despite mutation of the TP53 gene was particularly seen in tumors harboring nonsense mutations or deletions/splices (7 of 10 negative for staining compared with 4 of 16 with missense mutations). TP53 mutations (total/affecting L2/L3 domains) were associated with expression of c-erbB-2 (P < 0.001 for both), high histological grade (P = 0.001 and P = 0.025), and bcl-2 negativity (P = 0.003 and P = 0.002). TP53 mutations, histological grade, and expression of bcl-2 (but not LOH or c-erbB-2 expression) all predicted for relapse-free as well as breast cancer-specific survival in univariate analysis (Ps between