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  • 1
    Keywords: APOPTOSIS ; CANCER ; POPULATION ; RISK ; GENE ; MECHANISM ; CELL-CYCLE ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; breast cancer ; BREAST-CANCER ; HEALTH ; DECREASE ; REDUCED RISK ; CARCINOMAS ; PREDISPOSITION ; COMMON VARIANTS ; BRCA2 MUTATION CARRIERS ; CASPASE-8 GENE ; INACTIVATING MUTATIONS
    Abstract: Background: The genes caspase-8 (CASP8) and caspase-10 (CASP10) functionally cooperate and play a key role in the initiation of apoptosis. Suppression of apoptosis is one of the major mechanisms underlying the origin and progression of cancer. Previous case-control studies have indicated that the polymorphisms CASP8 D302H and CASP10 V410I are associated with a reduced risk of breast cancer in the general population. Methods: To evaluate whether the CASP8 D302H (CASP10 V410I) polymorphisms modify breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers, we analyzed 7,353 (7,227) subjects of white European origin provided by 19 (18) study groups that participate in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A weighted cohort approach was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). Results: The minor allele of CASP8 D302H was significantly associated with a reduced risk of breast cancer (per-allele HR, 0.85; 95% CI, 0.76-0.97; P-trend = 0.011) and ovarian cancer (per-allele HR, 0.69; 95% CI, 0.53-0.89; P-trend = 0.004) for BRCA1 but not for BRCA2 mutation carriers. The CASP10 V410I polymorphism was not associated with breast or ovarian cancer risk for BRCA1 or BRCA2 mutation carriers. Conclusions: CASP8 D302H decreases breast and ovarian cancer risk for BRCA1 mutation carriers but not for BRCA2 mutation carriers. Impact: The combined application of these and other recently identified genetic risk modifiers could in the future allow better individual risk calculation and could aid in the individualized counseling and decision making with respect to preventive options in BRCA1 mutation carriers.
    Type of Publication: Journal article published
    PubMed ID: 20978178
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  • 2
    ISSN: 1569-8041
    Keywords: breast cancer ; conservative treatment ; local recurrence ; risk factors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Risk factors for local recurrence after breast-conservingtreatment of early breast cancer have not previously been evaluated insettings where mammography has been a major pathway to diagnosis of bothprimary tumour and recurrences, or in patients treated surgically by a formalsector resection. Patients and methods: Three hundred eighty-one women with stage Iprimary breast cancer were randomised after a standardised sector resectionto either a course of postoperative radiotherapy to 54 Gy to the breast (XRTgroup) or to surgery alone (non XRT group). At five years, 43 localrecurrences, six of them in the XRT group, appeared. Patient characteristicscollected from the medical records, histopathological characteristicsdetermined by re-examination of slides, and mammographic characteristcs fromthe pre-operative mammograms were evaluated as risk factors for recurrence byunivariate and multivariate Cox proportional hazards models. Results arereported as relative hazards (RH) with 95% confidence intervals(95% CI). Results: In the univariate analysis comedo cancer, RH 3.5 (95%CI 1.8–6.7), lobular cancers RH 2.8 (95% CI 1.1–7.1),mammographic appearance as circular/oval shaped density, RH 2.3 (95%CI 1.1–4.5), and mammographic appearance as a stellate lesion withmicrocalcifications inside the lesion, RH 3.8 (95% CI 1.1–13.0)were identified as risk factors for local recurrence. Age, with a RH of 0.97(95% CI 0.94–0.99) for each increasing year was inverselyassociated with risk. A multivariate analysis, which also took postoperativeradiotherapy into account, only showed comedo cancers with a RH 2.6(95% CI 1.3–5.0) and mammographic appearance of a stellate lesionwith microcalcification inside the lesion RH 4.5 (95% CI1.1–17.6) to be statistically significant. The estimates for age RH 0.98(95% CI 0.95–1.0) and lobular cancers RH 2.5 (95% CI0.98–6.6) were marginally changed, with widened CIs. Patients 〉 60years of age, without comedo or lobular carcinomas were found to be at lowrisk (5.9% at five years in Kaplan–Meyer estimate) of localrecurrence, even without postoperative radiotherapy. Conclusion: Low age, comedo and lobular cancers and mammographicappearance of the tumour as a stellate lesion with microcalcifications insidethe lesion indicate an increased risk for local recurrence after sectorresection in stage I tumours at five years. Patients 〉60 years of agewithout comedo or lobular cancers are at low risk for local recurrence at fiveyears even without postoperative radiotherapy.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1569-8041
    Keywords: breast cancer ; conservative treatment ; cost-effectiveness ; randomized trial
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Cost-effectiveness of routine postoperative radiotherapyafter breast-conserving surgery has not been prospectively evaluatedearlier. In times of rationing of medical resources, valid assessments ofcost-effectiveness are important for rational allocation of resources. Purpose: Cost and cost-effectiveness of routine postoperativeradiotherapy was calculated in a prospective randomized trial comparingsector resection plus axillary dissection with (XRT group) or without(non-XRT group) postoperative radiotherapy in breast cancer stage I. Threehundred eighty-one patients were included. After a median follow-up of fiveyears 43 local recurrences, six of them in the XRT-group occurred (P 〈0.0001). No difference in regional and distant recurrence (P = 0.23) orsurvival (P = 0.44) was observed. Patients and methods: Direct medical costs as well as indirect costs interms of production lost during the treatment period and travel expenseswere estimated from data in the medical records and the national insuranceregistry of each patient. Average costs of different treatment activitiesand measures were estimated for the XRT-group and the non-XRT grouprespectively. From these estimates differences in costs and effectivenessbetween the groups were calculated and marginal cost-effectiveness ratioswere estimated. For the construction of QALYs each life-year wasquality-adjusted by a utility value depending on which health state thepatient was considered to perceive. Results: Taking into account the cost of primary treatment, the cost offollow-up, the cost of treatment of a local recurrence, travel expenses andindirect costs (production lost) excluding costs for treatment of regionaland distant recurrence the cost per avoided local recurrence at five yearswas SEK 337,727 ($44,438, £27,018). Adjustment for quality of life showed a cost for every gained QALY to beSEK ∼1.6 million, ($210,526, £128,000), range SEK0.2–3.9 million ($26,315–513,158;£16,000–312,000). Conclusion: The cost of routine postoperative radiotherapy after sectorresection and axillary dissection in breast cancer stage I per avoided localrecurrence and gained QALY is high. The cost per gained QALY show greatvariation depending on utility value, which in this study was derived fromexternal observers and not from the patients themselves. These results stressthe importance of identifying risk factors for local recurrence, betterunderstanding of impact on quality of life of a local recurrence and addingcost evaluations to clinical trials in early breast cancer.
    Type of Medium: Electronic Resource
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