CYP2D6 Genotype and Tamoxifen Response in Postmenopausal Women with Endocrine-Responsive Breast Cancer: The Breast International Group 1-98 Trial

Background Adjuvant tamoxifen therapy is effective for postmenopausal women with endocrine-responsive breast cancer. Cytochrome P450 2D6 (CYP2D6) enzyme metabolizes tamoxifen to clinically active metabolites, and CYP2D6 polymorphisms may adversely affect tamoxifen efficacy. In this study, we investigated the clinical relevance of CYP2D6 polymorphisms. Methods We obtained tumor tissues and isolated DNA from 4861 of 8010 postmenopausal women with hormone receptor-positive breast cancer who enrolled in the randomized, phase III double-blind Breast International Group (BIG) 1-98 trial between March 1998 and May 2003 and received tamoxifen and/or letrozole treatment. Extracted DNA was used for genotyping nine CYP2D6 single-nucleotide polymorphisms using polymerase chain reaction-based methods. Genotype combinations were used to categorize CYP2D6 metabolism phenotypes as poor, intermediate, and extensive metabolizers (PM, IM, and EM, respectively; n = 4393 patients). Associations of CYP2D6 metabolism phenotypes with breast cancer-free interval (referred to as recurrence) and treatment-induced hot flushes according to randomized endocrine treatment and previous chemotherapy were assessed. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. Results No association between CYP2D6 metabolism phenotypes and breast cancer-free interval was observed among patients who received tamoxifen monotherapy without previous chemotherapy (P = .35). PM or IM phenotype had a non-statistically significantly reduced risk of breast cancer recurrence compared with EM phenotype (PM or IM vs EM, HR of recurrence = 0.86, 95% CI = 0.60 to 1.24). CYP2D6 metabolism phenotype was associated with tamoxifen-induced hot flushes (P = .020). Both PM and IM phenotypes had an increased risk of tamoxifen-induced hot flushes compared with EM phenotype (PM vs EM, HR of hot flushes = 1.24, 95% CI = 0.96 to 1.59; IM vs EM, HR of hot flushes = 1.23, 95% CI = 1.05 to 1.43). Conclusions CYP2D6 phenotypes of reduced enzyme activity were not associated with worse disease control but were associated with increased hot flushes, contrary to the hypothesis. The results of this study do not support using the presence or absence of hot flushes or the pharmacogenetic testing of CYP2D6 to determine whether to treat postmenopausal breast cancer patients with tamoxife

Separate and combined analysis of successive dependent outcomes after breast-conservation surgery: recurrence, metastases, second cancer and death

<p>Abstract</p> <p>Background</p> <p>In the setting of recurrent events, research studies commonly count only the first occurrence of an outcome in a subject. However this approach does not correctly reflect the natural history of the disease. The objective is to jointly identify prognostic factors associated with locoregional recurrences (LRR), contralateral breast cancer, distant metastases (DM), other primary cancer than breast and breast cancer death and to evaluate the correlation between these events.</p> <p>Methods</p> <p>Patients (n = 919) with a primary invasive breast cancer and treated in a cancer center in South-Western France with breast-conserving surgery from 1990 to 1994 and followed up to January 2006 were included. Several types of non-independent events could be observed for the same patient: a LRR, a contralateral breast cancer, DM, other primary cancer than breast and breast cancer death. Data were analyzed separately and together using a random-effects survival model.</p> <p>Results</p> <p>LRR represent the most frequent type of first failure (14.6%). The risk of any event is higher for young women (less than 40 years old) and in the first 10 years of follow-up after the surgery. In the combined analysis histological tumor size, grade, number of positive nodes, progesterone receptor status and treatment combination are prognostic factors of any event. The results show a significant dependence between these events with a successively increasing risk of a new event after the first and second event. The risk of developing a new failure is greatly increased (RR = 4.25; 95%CI: 2.51-7.21) after developing a LRR, but also after developing DM (RR = 3.94; 95%CI: 2.23-6.96) as compared to patients who did not develop a first event.</p> <p>Conclusion</p> <p>We illustrated that the random effects survival model is a more satisfactory method to evaluate the natural history of a disease with multiple type of events.</p

Variables with time-varying effects and the Cox model: Some statistical concepts illustrated with a prognostic factor study in breast cancer

International audienceBACKGROUND: The Cox model relies on the proportional hazards (PH) assumption, implying that the factors investigated have a constant impact on the hazard - or risk - over time. We emphasize the importance of this assumption and the misleading conclusions that can be inferred if it is violated; this is particularly essential in the presence of long follow-ups. METHODS: We illustrate our discussion by analyzing prognostic factors of metastases in 979 women treated for breast cancer with surgery. Age, tumour size and grade, lymph node involvement, peritumoral vascular invasion (PVI), status of hormone receptors (HRec), Her2, and Mib1 were considered. RESULTS: Median follow-up was 14 years; 264 women developed metastases. The conventional Cox model suggested that all factors but HRec, Her2, and Mib1 status were strong prognostic factors of metastases. Additional tests indicated that the PH assumption was not satisfied for some variables of the model. Tumour grade had a significant time-varying effect, but although its effect diminished over time, it remained strong. Interestingly, while the conventional Cox model did not show any significant effect of the HRec status, tests provided strong evidence that this variable had a non-constant effect over time. Negative HRec status increased the risk of metastases early but became protective thereafter. This reversal of effect may explain non-significant hazard ratios provided by previous conventional Cox analyses in studies with long follow-ups. CONCLUSIONS: Investigating time-varying effects should be an integral part of Cox survival analyses. Detecting and accounting for time-varying effects provide insights on some specific time patterns, and on valuable biological information that could be missed otherwise

Cancer du sein opéré d'emblée, N+ (valeur pronostique des emboles néoplasiques)

BORDEAUX2-BU Santé (330632101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Cancer du sein opéré d'emblée chez la femme de moins de 40 ans (facteurs pronostiqués de la rechute métastatique)

BORDEAUX2-BU Santé (330632101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Tumeur stromale gastrointestinale (GIST) (analyse bibliographique et revue de quatre observations de patients traités au pôle CHU-Centre H. Becquerel de Rouen)

ROUEN-BU Médecine-Pharmacie (765402102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Modalités diagnostiques du cancer du sein chez la femme, à partir de 75 ans, en Gironde (rôle du médecin généraliste)

Le cancer du sein de la femme âgée est un problème majeur de santé publique, qui va s amplifier dans les années à venir. L objectif de notre étude est de faire l état des lieux des modalités diagnostiques du cancer du sein chez les femmes à partir de 75 ans, en Gironde, après la fin du dépistage organisé (DO). Les données collectées à l Institut Bergonié, dans le Registre du Cancer de Gironde et de Côte d Or montrent que les diagnostics sont portés à des stades de plus en plus tardifs avec l âge. Deux catégories de femmes se distinguent : une première continue une démarche de dépistage mammographique, malgré l absence de bénéfice démontré ; une autre catégorie, à l inverse, n a pas d examen clinique mammaire régulier. Ceci n est pas sans conséquences en termes de pronostic, de complexité de la prise en charge, de qualité de vie et d impact psychologique. Si l absence d examen clinique mammaire est remarquée, le manque de sensibilisation des femmes doit également être souligné. Lors de notre enquête auprès des structures départementales de gestion du dépistage organisé des cancers, l hétérogénéité de l information donnée aux femmes à la sortie du DO en est une illustration. Afin de promouvoir un diagnostic plus précoce du cancer du sein dans cette population, une approche a été élaborée en Gironde autour de la promotion de l examen clinique mammaire et de la sensibilisation des femmes. Une lettre d information est désormais envoyée à toutes les femmes girondines à 75 ans. Des actions de sensibilisation des médecins généralistes et spécialistes concernés seront également réalisées. L impact pourra être évalué en comparant l évolution des stades au diagnostic dans les Registres du Cancer de Gironde et de Côte d Or, ainsi que par des méthodes intermédiaires appréciant la sensibilisation des femmes et des médecins.Breast cancer among older women is a major and increasing public health issue. This study assesses the current situation of the diagnostic conditions of breast cancer among women aged 75 and over, in Gironde, after they reach the limit-age of state-organized screening. Data collected from Insitut Bergonié and from cancer registries of Gironde and Côte d Or show that breast cancer are diagnosed at later stages with age. Two categories of women can be dissociated: on one hand, women who continue systematic mammographic screening, even if there is little direct evidence of its benefits; on the other hand, a large category of women do not receive breast clinical examination. Consequences in terms of prognostic, complexity of treatment, quality of life and psychological impact are real. With the lack of clinical examination, the poor awareness of women must also be highlighted. This is reflected in the heterogeneity of the information given by breast cancer organized-screening agencies. An approach to promote earlier diagnosis in this population is elaborated in Gironde, by increasing awareness of women and promoting clinical breast examination. An information letter is now sent to all women aged 75 in Gironde. Information of general practioners and other involved specialists will also be realised. The impact of these actions will be evaluated in the cancer registry of Gironde, and compared in Côte d Or. Intermediate assessment of women and practioners awareness is also to be evaluated.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

[Diagnosis and treatment of soft-tissue tumors]

International audienceThe diagnostic and therapeutic management of patients with soft-tissue tumors would be similar to the approach used for bone tumors if it were not for one crucial factor: the absolute necessity to recognize a sarcoma. The predominant features are the size of the tumor and its superficial or deep localization. If the tumor is small and superficial, biopsy can be associated with immediate resection without risk of dissemination to the deep tissues: this is the biopsy-resection approach. If the tumor is deep or superficial but large sized, search for locoregional spread with MRI is necessary before undertaking any surgical procedure. MRI can help guide the biopsy and plan resection if the tumor is a sarcoma. A first biopsy is necessary to establish the histological diagnosis and elaborate the therapeutic strategy. Samples should be sent immediately to the pathology lab which should examine sterile fresh tissue. Experience has demonstrated that proper rules for diagnosis and treatment are not necessarily applied initially in approximately one-fourth of all subjects with a malignant soft-tissue tumor. Besides the medical problems caused by this situation, the patient loses a chance for cure. When the tumor is a sarcoma, surgery is the basis of treatment. Complementary radiation therapy may be necessary, particularly for high-grade tumors or if the surgical margin was insufficient. Systemic or locoregional chemotherapy can also be used for high-grade or non-resectable tumors