RESUMEN
AIM OF THE STUDY: Results on tumour characteristics and survival of hereditary breast cancer (BC), especially on BRCA2-associated BC, are inconclusive. The prognostic impact of the classical tumour and treatment factors in hereditary BC is insufficiently known. METHODS: We selected 103 BRCA2-, 223 BRCA1- and 311 non-BRCA1/2 BC patients (diagnosis 1980-2004) from the Rotterdam Family Cancer Clinic. To correct for longevity bias, analyses were also performed while excluding index patients undergoing DNA testing 2 years after BC diagnosis. As a comparison group, 759 sporadic BC patients of comparable age at and year of diagnosis were selected. We compared tumour characteristics, the occurrence of ipsilateral recurrence (LRR) and contralateral BC (CBC) as well as distant disease-free (DDFS), BC-specific (BCSS) and overall survival (OS) between these groups. By multivariate modelling, the prognostic impact of tumour and treatment factors was investigated separately in hereditary BC. RESULTS: We confirmed the presence of the particular BRCA1-phenotype. In contrast, tumour characteristics of BRCA2-associated BC were similar to those of non-BRCA1/2 and sporadic BC, with the exception of a high risk of CBC (3.1% per year) and oestrogen-receptor (ER)-positivity (83%). No significant differences between BRCA2-associated BC and other BC subgroups were found with respect to LRR, DDFS, BCSS and OS. Independent prognostic factors for BC-specific survival in hereditary BC (combining the three subgroups) were tumour stage, adjuvant chemotherapy, histologic grade, ER status and a prophylactic (salpingo-)oophorectomy. CONCLUSIONS: Apart from the frequent occurrence of contralateral BC and a positive ER-status, BRCA2-associated BC did not markedly differ from other hereditary or sporadic BC. Our observation that tumour size and nodal status are prognostic factors also in hereditary BC implies that the strategy to use these factors as a proxy for ultimate mortality appears to be valid also in this specific group of patients.
Asunto(s)
Neoplasias de la Mama/genética , Genes BRCA1 , Genes BRCA2 , Adulto , Anciano , Neoplasias de la Mama/mortalidad , Distribución de Chi-Cuadrado , Estudios de Cohortes , ADN de Neoplasias/análisis , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Linaje , PronósticoRESUMEN
The objective of this study was to investigate the occurrence and determinants of non-publication of clinical drug trials in the Netherlands. All clinical drug trials reviewed by the 28 Institutional Review Boards (IRBs) in the Netherlands in 2007 were followed-up from approval to publication. Candidate determinants were the sponsor, phase, applicant, centers, therapeutic effect expected, type of trial, approval status of the drug(s), drug type, participant category, oncology or other disease area, prospective registration, and early termination. The main outcome was publication as peer reviewed article. The percentage of trials that were published, crude and adjusted odds ratio (OR), and 95% confidence interval (CI) were used to quantify the associations between determinants and publication. In 2007, 622 clinical drug trials were reviewed by IRBs in the Netherlands. By the end of follow-up, 19 of these were rejected by the IRB, another 19 never started inclusion, and 10 were still running. Of the 574 trials remaining in the analysis, 334 (58%) were published as peer-reviewed article. The multivariable logistic regression model identified the following determinants with a robust, statistically significant association with publication: phase 2 (60% published; adjusted OR 2.6, 95% CI 1.1-5.9), phase 3 (73% published; adjusted OR 4.1, 95% CI 1.7-10.0), and trials not belonging to phase 1-4 (60% published; adjusted OR 3.2, 95% CI 1.5 to 6.5) compared to phase 1 trials (35% published); trials with a company or investigator as applicant (63% published) compared to trials with a Contract Research Organization (CRO) as applicant (50% published; adjusted OR 1.7; 95% CI 1.1-2.8); and multicenter trials also conducted in other EU countries (68% published; adjusted OR 2.2, 95% CI 1.1-4.4) or also outside the European Union (72% published; adjusted OR 2.0, 95% CI 1.0-4.0) compared to single-center trials (45% published). Trials that were not prospectively registered (48% published) had a lower likelihood of publication compared to prospectively registered trials (75% published; adjusted OR 0.5, 95% CI 0.3-0.8), as well as trials that were terminated early (33% published) compared to trials that were completed as planned (64% published; adjusted OR 0.2, 95% CI 0.1-0.3). The non-publication rate of clinical trials seems to have improved compared to previous inception cohorts, but is still far from optimal, in particular among phase 1, single-center, not prospectively registered, and early terminated trials.
RESUMEN
BACKGROUND: The germline CHEK2*1100delC variant has been associated with breast cancer in multiple case families where involvement of BRCA1 and BRCA2 has been excluded. METHODS: We have investigated the tumour characteristics and prognosis of carriers of this germline variant by means of a prospective cohort study in an unselected cohort of 1084 consecutive patients with primary breast cancer. Data were collected for 34 patients with a germline CHEK2*1100delC mutation and for 102 patients without this mutation, stratified by age and date of diagnosis of the first primary breast cancer (within 1 year). RESULTS: Carriers developed steroid receptor positive tumours (oestrogen receptor (ER): 91%; progesterone receptor (PR): 81%) more frequently than non-carriers (ER: 69%; PR: 53%; p = 0.04). Mutation carriers more frequently had a female first or second degree relative with breast cancer (p = 0.03), or had any first or second degree relative with breast or ovarian cancer (p = 0.04). Patients with the CHEK2 variant had a more unfavourable prognosis regarding the occurrence of contralateral breast cancer (relative risk (RR) = 5.74; 95% confidence interval (CI) 1.67 to 19.65), distant metastasis-free survival (RR = 2.81; 95% CI 1.20 to 6.58), and disease-free survival (RR = 3.86; 95% CI 1.91 to 7.78). As yet, no difference with respect to overall survival has been found at a median follow up of 3.8 years. CONCLUSION: We conclude that carrying the CHEK2*1100delC mutation is an adverse prognostic indicator for breast cancer. If independently confirmed by others, intensive surveillance, and possibly preventive measures, should be considered for newly diagnosed breast cancer cases carrying the CHEK2*1100delC variant.
Asunto(s)
Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Variación Genética/genética , Mutación de Línea Germinal/genética , Proteínas Serina-Treonina Quinasas/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Quinasa de Punto de Control 2 , Estudios de Cohortes , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Análisis de SupervivenciaRESUMEN
Possible effects of consistently applying published guidelines on healthy women with breast cancer in their family history were analysed. We investigated 1060 unrelated breast cancer patients and calculated the numbers of first-degree relatives that would be referred to a familial cancer clinic if the guidelines were consistently applied. A first-degree relative was considered a candidate for referral if she was female, without breast cancer at the moment of the interview, alive and over the age of 24. The criteria for referral were based on one Dutch and two British guidelines. According to the Dutch guideline, for one affected woman with breast cancer, 0.25 (95% CI 0.22-0.28) healthy first-degree female relatives should be offered a consultation at a familial cancer clinic (FCC). Application of the British guidelines would lead to a similar number of referrals. Of all healthy first-degree female relatives, who should be referred to an FCC, 34-37% had an index case among their family who was already known at a genetic department. If current guidelines are consistently applied, a sharp increase in referrals to FCCs may be expected. These guidelines, however, are arbitrary and only limited data are available on the efficacy of this surveillance for high-risk healthy women.
Asunto(s)
Neoplasias de la Mama/genética , Adhesión a Directriz/tendencias , Derivación y Consulta , Anciano , Neoplasias de la Mama/diagnóstico , Estudios de Cohortes , Inglaterra , Femenino , Humanos , Tamizaje Masivo/tendencias , Persona de Mediana Edad , Países BajosRESUMEN
The overall rate of an ipsilateral breast tumour recurrence (IBTR) after breast-conserving therapy (BCT) ranges from 1% to 2% per year. Risk factors include young age but data on the impact of BRCA1/2 mutations or a definite positive family history for breast cancer are scarce. We investigated IBTR after BCT in patients with hereditary breast cancer (HBC). Through our family cancer clinic we identified 87 HBC patients, including 26 BRCA1/2 carriers, who underwent BCT between 1980 and 1995 (cases). They were compared to 174 patients with sporadic breast cancer (controls) also treated with BCT, matched for age and year of diagnosis. Median follow up was 6.1 years for the cases and 6.0 years for controls. Patient and tumour characteristics were similar in both groups. An IBTR was observed in 19 (21.8%) hereditary and 21 (12.1%) sporadic patients. In the hereditary patients more recurrences occurred elsewhere in the breast (21% versus 9.5%), suggestive of new primaries. Overall, the actuarial IBTR rate was similar at 2 years, but higher in hereditary as compared to sporadic patients at 5 years (14% versus 7%) and at 10 years (30% versus 16%) (P=0.05). Post-relapse and overall survival was not different between hereditary and sporadic cases. Hereditary breast cancer was therefore associated with a higher frequency of early (2-5 years) and late (>5 years) local recurrences following BCT. These data suggest an indication for long-term follow up in HBC and should be taken into account when additional 'risk-reducing' surgery after primary BCT is eventually considered.
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Neoplasias de la Mama/cirugía , Mastectomía Segmentaria/métodos , Mutación/genética , Neoplasias Primarias Secundarias , Adulto , Anciano , Neoplasias de la Mama/genética , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Genes BRCA1 , Genes BRCA2 , Predisposición Genética a la Enfermedad , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Pronóstico , Modelos de Riesgos Proporcionales , Factores de RiesgoRESUMEN
In the MRISC study, women with an inherited risk for breast cancer were screened by a 6-month clinical breast examination (CBE) and yearly MRI and mammography. We found that the MRISC screening scheme could facilitate early breast cancer diagnosis and that MRI was a more sensitive screening method than mammography, but less specific. In the current study we investigated the contribution of MRI in the early detection of breast cancer in relation to tumor characteristics. From November 1999 to October 2003, 1909 women were included and 50 breast cancers were detected, of which 45 were evaluable and included in the current study. We compared the characteristics of tumors detected by MRI-only with those of all other (non-palpable) screen-detected tumors. Further, we compared the sensitivity of mammography and MRI within subgroups according to different tumor characteristics. Twenty-two (49%) of the 45 breast cancers were detected by MRI and not visible at mammography, of which 20 (44%) were also not palpable (MRI-only detected tumors). MRI-only detected tumors were more often node-negative than other screen-detected cancers (94 vs. 59%; P=0.02) and tended to be more often Asunto(s)
Neoplasias de la Mama/diagnóstico por imagen
, Tamizaje Masivo/métodos
, Neoplasias de la Mama/genética
, Neoplasias de la Mama/patología
, Diagnóstico Precoz
, Femenino
, Predisposición Genética a la Enfermedad
, Humanos
, Imagen por Resonancia Magnética
, Mamografía
, Sensibilidad y Especificidad
RESUMEN
BACKGROUND: A higher incidence of contralateral breast cancer and ipsilateral recurrence has been reported in familial breast cancer than in sporadic cancer. This study investigated the influence of contralateral cancer and tumour stage on survival in patients with familial non-BRCA1/BRCA2-associated breast cancer. METHODS: The incidences of contralateral breast cancer, ipsilateral recurrence, distant disease-free and overall survival were assessed in 327 patients from families with three or more breast and/or ovarian cancers, but no BRCA1 or BRCA2 gene mutation (familial non-BRCA1/2), and in 327 control subjects with sporadic breast cancer, matched for year and age at detection. RESULTS: Mean follow-up was 7.3 years for patients with familial-non-BRCA1/2 cancers and 6.5 years for patients with sporadic breast cancer. Tumours were stage T1 or lower in 62.1 per cent of familial non-BRCA1/2 cancers versus 49.9 per cent in sporadic breast cancers (P = 0.003), and node negative in 55.8 versus 52.1 per cent, respectively (P = 0.477). After 10 years the incidence of metachronous contralateral breast cancer was 6.4 per cent for familial non-BRCA1/2 tumours versus 5.4 per cent for sporadic cancers. The rate of ipsilateral recurrence was not significantly increased (17.0 versus 14.2 per cent, respectively, at 10 years; P = 0.132). Tumour size (hazard ratio (HR) 1.02 per mm increase, P = 0.016) and node status (HR 2.6 for three or more involved nodes versus node negative, P = 0.017) were independent predictors of overall survival in the familial non-BRCA1/2 group, and in the whole group, whereas contralateral breast cancer (HR 0.7, P = 0.503) and risk-reducing contralateral mastectomy (HR 0.4, P = 0.163) were not. CONCLUSION: Stage at detection was a key determinant of prognosis in familial non-BRCA1/2 breast cancer, whereas contralateral cancer was not. Risk-reducing contralateral mastectomy did not significantly improve survival, but early detection can. Decisions on breast-conserving treatment can be made on the same grounds in patients with familial and sporadic breast cancer.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias Primarias Secundarias/genética , Adulto , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/cirugía , Supervivencia sin Enfermedad , Femenino , Humanos , Mastectomía Segmentaria/métodos , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/cirugía , Linaje , Pronóstico , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
Already published data were further analyzed regarding the association between the CHEK2*1100delC germ line mutation and estrogen receptor (ER) status in patients with breast cancer. The CHEK2*1100delC mutation was more prevalent among the patients with a positive ER status (4.2% versus 1.0%). An ER-negative status was beside CHEK2*1100delC mutation and independently associated with an earlier of age onset of breast cancer. There was a trend that an ER-negative status, beside the presence of a CHEK2*1100delC mutation, was associated with a worse disease-free survival. There might be an association between ER status and a CHEK2*1100delC mutation. More studies with larger number of patients are needed to further investigate the relation between CHEK2*1100delC and ER status.
Asunto(s)
Neoplasias de la Mama/genética , Mutación de Línea Germinal/genética , Proteínas Serina-Treonina Quinasas/genética , Receptores de Estrógenos/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Quinasa de Punto de Control 2 , Femenino , Genes BRCA1 , Genes BRCA2 , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Studies comparing survival in BRCA1-associated and sporadic breast cancer (BC) report inconsistent results and frequently concern small sample sizes. Further, the prognostic impact of the classical tumour and treatment factors is unclear in BRCA1-associated BC. PATIENTS AND METHODS: We selected 223 BC patients diagnosed between 1980 and 2001 within families with a deleterious germline BRCA1-mutation ascertained at the Rotterdam Family Cancer Clinic. To correct for ascertainment bias, the group of index patients undergoing DNA testing more than 2 years after BC diagnosis (n = 53) was separated from the other BRCA1-patients (n = 170). All BRCA1-associated patients were matched in a 1:2 ratio for age and year of diagnosis to sporadic BC patients. We compared the occurrence of ipsi- and contralateral BC (CBC) as well as distant disease-free (DDFS), BC-specific (BCSS) and overall survival (OS). By multivariate modelling, the prognostic impact of tumour and treatment factors was investigated separately in BRCA1-associated and sporadic breast cancers. RESULTS: For the total group of 669 cases, the median follow-up was 5.1 years, the median age at diagnosis 39 years. We confirmed the existence of the typical BRCA1-associated tumour type and the high CBC incidence. No significant differences between BRCA1-associated and sporadic tumours were found with respect to ipsilateral BC recurrence (HR(mult) 0.7; P = 0.24), DDFS (HR(mult) 1.2; P = 0.37) or BC-specific survival (HR(mult) 1.3; P = 0.23). A trend towards a worse survival was found for BRCA1-associated ductal BC (HR(mult) 1.5, P = 0.07). Prognostic factors for BRCA1-associated BC were age at diagnosis, tumour size and morphology, and nodal status. Further, survival was non-significantly improved by systemic treatment and a bilateral salpingo-oophorectomy. No effect on survival of a contralateral prophylactic mastectomy was seen. CONCLUSIONS: BRCA1-associated BC is characterised by specific tumour characteristics, a high incidence of CBC and a trend towards a worse survival for the ductal tumour type. Our observation that tumour size and nodal status are also prognostic factors for BRCA1-associated BC implies that the strategy to use these factors as a proxy for ultimate mortality, for instance in BC screening programmes or the consideration of (contralateral) preventive mastectomy, appears to be valid in this specific group of patients.