Affiliations of authors: U. Veronesi (Scientific Director), P. Maisonneuve, N. Rotmensz, C. Robertson, P. Boyle (Division of Epidemiology and Biostatistics), European Institute of Oncology, Milan, Italy; A. Costa, Division of Senology, European Institute of Oncology, and Fondazione Maugeri, Pavia, Italy; V. Sacchini, Division of Senology, European Institute of Oncology, and Memorial Sloan-Kettering Cancer Center, New York, NY; R. Travaglini, Comitato Prevenzione Tumori al seno, Milan; G. DAiuto, Istituto per lo Studio e la Cura dei Tumori "Fondazione Pascale," Naples, Italy; F. Lovison, Lega Italiana per la lotta contro i tumori, Vincenza, Italy; G. Gucciardo, Ospedale San Camillo-Forlanini, Rome, Italy; M. G. Muraca, Centro per lo Studio e la Prevenzione Oncologica, Florence, Italy; M. A. Pizzichetta, Centro Regionale di Riferimento Oncologico, Aviano, Italy; S. Conforti, Ospedale di Cosenza, Cosenza, Italy; A. Decensi, Division of Pharmacoprevention, European Institute of Oncology.
Correspondence to: Peter Boyle, Ph.D., Division of Epidemiology and Biostatistics, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy (e-mail: director.epi{at}ieo.it).
ABSTRACT
Tamoxifen improves outcome in women with breast cancer and reduces the incidence of estrogen receptor-positive (ER+) breast tumors in prevention trials. Tamoxifen use is associated with an increased risk of potentially serious adverse events, principally endometrial cancer and venous thromboembolic events and, therefore, detailed knowledge of the effects of tamoxifen is important. With more cases of breast cancer being found as the follow-up time increases, it is now possible to perform more detailed analysis of the Italian Randomized Trial of Tamoxifen. Women with hysterectomy (N = 5408) were randomly assigned to receive 20 mg tamoxifen per day (N = 2700) or placebo (N = 2708). After a median of 81.2 months of follow-up, 79 case subjects (34 in the tamoxifen arm and 45 in the placebo arm) were diagnosed with breast cancer. We were able to identify a group of women at increased risk of ER+ breast cancers (high-risk group) on the basis of baseline as well as reproductive and hormonal characteristics (height, age at menarche, parity, age at first birth, and oophorectomy). Tamoxifen administered to women in the high-risk group showed statistically significantly reduced incidence of breast cancer (tamoxifen, 3 and placebo, 15; P = .003), but no such effect was seen in the low-risk group (tamoxifen, 31 and placebo, 30; P = .89). The positive effect of tamoxifen on breast cancer among high-risk women is most marked for ER+ tumors (tamoxifen, 1 and placebo, 11; P = .002). Chemoprevention of breast cancer with tamoxifen appears to be effective in women at high risk of ER+ tumors but not among women at low risk, who may well be protected naturally by late age at menarche or early first pregnancy, or artificially by removal of the ovaries. Tamoxifen could be offered as a preventive agent to women identified at high-risk of breast cancer because of hormone-related risk factors. Such a strategy would greatly reduce the numbers of women who would need to take tamoxifen to obtain the same absolute reduction in breast cancer. These findings are exploratory and need to be confirmed in other randomized trials.
The demonstration of the effectiveness of the Gail Model in predicting risk of breast cancer in the NSABP P1 trial (3) indicates the utility of having some means of identifying women at increased risk of breast cancer. Huang et al. (4) have attempted to indicate lifestyle risk factors for ER+/progesterone-positive (PR+) breast tumors, those most susceptible to prevention by tamoxifen. The strongest predictors of ER+/PR+ in postmenopausal women included age at menarche, nulliparity, age at first birth, and body mass index.
To investigate the effect of tamoxifen on breast cancer incidence and mortality, a double-blinded, placebo-controlled, randomized trial of tamoxifen was undertaken in Italy in women who did not have breast cancer. In view of the potential adverse effect on endometrial cancer, the study was restricted to women who had undergone hysterectomy. This group had an overall risk of breast cancer slightly lower than that of the general population, because in approximately half the women (48%), the procedure had been accompanied by bilateral oophorectomy.
Between October 1992 and December 1997, a total of 5408 women were randomly assigned into the Italian Randomized Trial of Tamoxifen to receive tamoxifen or placebo. The participating women had a median follow-up of 55.3 months for evaluating the side effects of the treatment and 81.2 months for evaluating major endpoints, such as death and cancer diagnosis until February 1, 2001 (Fig. 1). A total of 79 case subjects with breast cancer have been identified. There is no statistically significant difference in breast cancer incidence between the placebo arm (n = 45) and the tamoxifen arm (n = 34) (5).
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Intervention with tamoxifen statistically significantly reduced the incidence of breast cancer in the high-risk group (P = .003) but had no effect in the low-risk group (P = .89) (Fig. 2, A). The effect of tamoxifen in the high-risk group was to reduce the risk of breast cancer by 82% (HR = 0.18, 95% CI = 0.05 to 0.62), whereas the effect in the low-risk group was an increase of 3% (HR = 1.03, 95% CI = 0.62 to 1.70) (Table 1
).
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Ten of the breast cancers (six in the tamoxifen arm and four in the placebo arm) were in situ tumors. All were diagnosed in the low-risk group.
There was no statistically significant difference between tamoxifen and placebo arms among women who never used hormone replacement therapy (HRT) and were in the low-risk group (P = .44) (Fig. 2, B). Among women who never used HRT and were in the high-risk group, there was a statistically nonsignificant difference in favor of tamoxifen (P = .099) (Fig. 2, B
). Among women who had used HRT during the trial and who were in the low-risk group, there was again a statistically nonsignificant difference in favor of tamoxifen (P = .31) (Fig. 2, B
). However, among women who had used HRT and were in the high-risk group, there was a statistically significant difference in favor of tamoxifen (P = .009) (Fig. 2, B
).
In the low-risk group, there was no reduction in the incidence of ER (P = .51) or ER+ tumors (P = .87), whereas, in the high-risk group, there was a strong reduction of ER tumors (P = .002) and a statistically nonsignificant slight reduction of ER tumors (P = .39) (Fig. 2, C), based on a small number of events.
It is important to emphasize several points when considering the findings from this subgroup analysis (7,8). More work should be done on predicting women at increased risk of ER+ breast cancer. The dichotomy used in this analysis was not used as a stratification factor at the time of randomization to receive a given treatment, and it is vital to confirm these findings in the other randomized trials. If these findings are replicated in other studies, it may then prove possible to improve the utility of this dichotomy in the specific setting of identifying women who may be likely to have the greatest benefit from tamoxifen for breast cancer prevention. Family history alone is associated with ER/PR breast cancers (4), and it is possible that a re-analysis of the NSABP P1 restricted to women with a high-risk of ER+/PR+ breast cancer might show a larger protective effect for women in this group.
In conclusion, tamoxifens effect appears to be restricted to women who are predicted to be at high risk of the hormone-dependent form of breast cancer. This is a potentially important finding, which requires confirmation from other trials before the clinical and public health implications are clear. If our findings are true, then the same reduction in the absolute numbers of breast cancers could be obtained by restricting treatment to the group of women at higher risk (which, in this study, was about one eighth of the total cohort). From a public health perspective, this strategy would greatly improve the cost-effectiveness of the intervention and would greatly reduce the overall side effects in a population by avoiding treatment-related symptoms in the majority of women therein.
APPENDIX
The Italian Tamoxifen Study Group includes the following physicians and scientists who contributed to this trial (all organizations are in Italy unless otherwise noted): A. Ferrari, Ambulatorio Raphael, Calcinato; E. Chiesa, P. Gallotti, Associazione Life per la prevenzione e la cura dei Tumori, Vigevano; S. Bruno, M. Podda, G. Pardi, Azienda Ospedaliera San Paolo, Milan; G. Bocchiotti, Casa di Cura "Villa Igea," Acqui Terme; M. Valentini, P. Vallivero, Casa di Cura "La Vialarda," Biella; F. Monasterolo, Casa di Cura Citta di Bra, Bra; A. Barros, F. Laginha, Centro de Referencia da Saude da Mulher, Sao Paulo, Brazil; S. Milani, Centro Oncologico, Trieste; M. Rosselli del Turco, Centro per lo Studio e la Prevenzione Oncologica, Florence; A.Veronesi, Centro Regionale di Riferimento Oncologico, Aviano; P. Pagni, Centro Tumori, Rome; P. Carnaghi, E. Giorgetti, Clinica "Mater Domini," Castellanza; G. Peretti, Clinica Ortopedica, Monza; G. Scaltrini, B. Sorrentino, Comitato Prevenzione Tumori al Seno, Milan; R. Guidetti, Consultorio familiare Mirandola, Mirandola; P. M. Mannucci, Ematologia Clinica e del Lavoro, Milan; G. Bernardo, Fondazione Maugeri, Pavia; M. Guazzi, A. Salvioni, Fondazione Monzino, Milan; A. Rancati, Fundacion de la ESO (European School of Oncology), Buenos Aires, Argentina; A. Fini, C. Maltoni, Istituto di Oncologia "F. Addarii," Bologna; B. Bonanni, E. Cassano, G. Farante, A. Guerrieri-Gonzaga, A. Luini, B. Santillo, P. Veronesi, Istituto Europeo di Oncologia, Milan; M. De Liso, F. Schittuli, Istituto Oncologico, Bari; J. Bryce, P. Oliviero, Istituto per lo Studio e la Cura dei Tumori, Naples; R. Rocci, Istituto Provinciale per la Maternita, Milan; L. Bombelli, Lega Italiana per la Lotta contro i Tumori, Como; G. Ravasi, Lega Italiana per la Lotta contro i Tumori, Milan; P. Maggi, Lega Italiana per la Lotta contro i Tumori, Vincenza; G. Dossena, Ospedale "Caduti Bollatesi," Bollate; P. Pellegrino, Ospedale "Mariano Santo," Cosenza; M. Zottar, Ospedale Civile di Gorizia, Gorizia; S. Modena, A. M. Molino, Ospedale Civile Maggiore, Verona; B. Lenzi, Ospedale Civile, Portomaggiore; P. Ghezzi, Ospedale di Arezzo, Arezzo; N. Donadello, Ospedale di Circolo, Varese; G. Baratelli, D. Bettega, Ospedale di Gravedona, Gravedona; F. Lonardi, Ospedale di Legnago, Legnago; M. Luerti, Ospedale di Lodi, Lodi; L. Della Torre, L. Tabacchi, Ospedale di Morbegno, Morbegno; G. Zandonini, Ospedale G. Fornaroli, Magenta; M. Amadori, D. Casadei, Ospedale G. B. Morgani, Forli; A. Ravaioli, M. Scarpellini, Ospedale Infermi, Rimini; G. Brignone, M. Gugliuzza, Ospedale Oncologico "M. Ascoli," Palermo; M. Bonsignori, Ospedale Regionale di Torrette, Ancona; T. Silipo, Ospedale San Camillo-Forlanini, Rome; P. Lorenzi, N. Ragni, M. Valenzano, Ospedale San Martino, Genoa; N. Zizza, Ospedale San Timoteo, Termoli; F. Raia, Ospedale Santa Chiara, Pisa; E. Scolari, Ospedale Val dArda, Cortemaggiore; G. Scambia, Policlinico Gemelli, Rome; L. Carli, A. Rulli, Policlinico Monteluce Clinica Chirurgica, Perugia; L. Canigiula, A. Magro, A. Zocca, Presidio Ospedaliero Macedonio Melloni, Milan; L. DAmore, Università degli studi di Roma "La Sapienza," Rome; C. Di Maggio, A. Pluchinotta, Università degli studi di Padova, Padua.
NOTES
It is a pleasure to acknowledge the participation of the Italian women who took part in this study.
Funded in part by grants from the Italian National Research Council, the Italian Association for Research on Cancer, the American-Italian Cancer Foundation, and the Italian League Against Cancer.
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Manuscript received May 30, 2001; revised October 7, 2002; accepted October 17, 2002.
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