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Clinical Cancer Research Vol. 9, 1039-1046, March 2003
© 2003 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Twenty-year Results of the Naples GUN Randomized Trial

Predictive Factors of Adjuvant Tamoxifen Efficacy in Early Breast Cancer1

Sabino De Placido, Michelino De Laurentiis, Chiara Carlomagno, Ciro Gallo, Franco Perrone, Stefano Pepe, Angela Ruggiero, Alfredo Marinelli, Clorindo Pagliarulo, Luigi Panico, Guido Pettinato, Giuseppe Petrella and Angelo Raffaele Bianco2

Cattedra di Oncologia Medica, Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Università ’Federico II,’ 80131 Napoli, Italy [S. D. P., M. D. L., C. C., S. P., A. R., A. M., C. P., A. R. B.]; Cattedra di Metodologia Epidemiologica Clinica, Istituto di Igiene, II Università, Napoli, Italy [C. G.]; Ufficio Sperimentazioni Cliniche Controllate, Istituto Nazionale per lo Studio e la Cura dei Tumori "Pascale," Napoli, Italy [F. P.]; Dipartimento di Anatomia Patologica, Università ’Federico II,’ Napoli, Italy [L. P., G. Pett.]; and Cattedra di Chirurgia Oncologica, Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Università ’Federico II,’ Napoli, Italy [G. Petr.]

Purpose: Tamoxifen (TAM) is increasingly administered to new early breast cancer patients. Because it is not devoid of toxic effects, we studied factors potentially predictive of its efficacy.

Experimental Design: From 1978 to 1983, 433 patients were enrolled in the GUN randomized trial: 206 were assigned to TAM versus 227 controls (no-TAM). Premenopausal patients with axillary lymph node involvement (60 TAM versus 65 no-TAM) also received nine CMF cycles. Eight biological markers were retrospectively assayed for most patients: estrogen; progesterone; prolactin receptors (PrlRs); microvessel count (MVC); S-phase fraction; tumor ploidy; epidermal growth factor receptor (EGFR); and HER2. We performed a multivariate test of the TAM/covariate interactions to establish whether these variables predicted for TAM efficacy. Estimates of the TAM effect were expressed as hazard ratio (HR) of death of TAM over no-TAM patients with 95% confidence intervals (95% CIs).

Results: At a median follow-up of 15 years, PrlRs, MVC, S-phase fraction, ploidy, and EGFR did not influence TAM efficacy. Differently, HER2 had an overall significant predictive effect: HR = 0.59 (95% CI: 0.40–0.87) in HER2-negative subjects versus HR = 1.09 (95% CI: 0.63–1.87) in HER2-positive subjects (interaction test: P = 0.04). The predictive effect of HER2 was also evident in the subgroup of patients with steroid receptor-positive tumors (HER2 positive: HR = 1.33, 95% CI: 0.70–2.51; HER2 negative: HR = 0.73, 95% CI: 0.47–1.14).

Conclusions: With the statistical power of the present randomized trial, S-phase, ploidy, EGFR, PrlR, and MVC do not seem to predict for TAM efficacy. Conversely, our data support the hypothesis that tumors overexpressing HER2 might not benefit from adjuvant TAM.




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