Evaluating the performance of the breast cancer genetic risk models BOADICEA, IBIS, BRCAPRO and Claus for predicting BRCA1/2 mutation carrier probabilities: a study based on 7352 families from the German Hereditary Breast and Ovarian Cancer Consortium.
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND: Risk prediction models are widely used in clinical genetic counselling. Despite their frequent use, the genetic risk models BOADICEA, BRCAPRO, IBIS and extended Claus model (eCLAUS), used … to estimate BRCA1/2 mutation carrier probabilities, have never been comparatively evaluated in a large sample from central Europe. Additionally, a novel version of BOADICEA that incorporates tumour pathology information has not yet been validated. PATIENTS AND METHODS: Using data from 7352 German families we estimated BRCA1/2 carrier probabilities under each model and compared their discrimination and calibration. The incremental value of using pathology information in BOADICEA was assessed in a subsample of 4928 pedigrees with available data on breast tumour molecular markers oestrogen receptor, progesterone receptor and human epidermal growth factor 2. RESULTS: BRCAPRO (area under receiver operating characteristic curve (AUC)=0.80 (95% CI 0.78 to 0.81)) and BOADICEA (AUC=0.79 (0.78-0.80)), had significantly higher diagnostic accuracy than IBIS and eCLAUS (p<0.001). The AUC increased when pathology information was used in BOADICEA: AUC=0.81 (95% CI 0.80 to 0.83, p<0.001). At carrier thresholds of 10% and 15%, the net reclassification index was +3.9% and +5.4%, respectively, when pathology was included in the model. Overall, calibration was best for BOADICEA and worst for eCLAUS. With eCLAUS, twice as many mutation carriers were predicted than observed. CONCLUSIONS: Our results support the use of BRCAPRO and BOADICEA for decision making regarding genetic testing for BRCA1/2 mutations. However, model calibration has to be improved for this population. eCLAUS should not be used for estimating mutation carrier probabilities in clinical settings. Whenever possible, breast tumour molecular marker information should be taken into account.

Authors: C. Fischer, K. Kuchenbacker, C. Engel, S. Zachariae, K. Rhiem, A. Meindl, N. Rahner, N. Dikow, H. Plendl, I. Debatin, T. Grimm, D. Gadzicki, R. Flottmann, J. Horvath, E. Schrock, F. Stock, D. Schafer, I. Schwaab, C. Kartsonaki, N. Mavaddat, B. Schlegelberger, A. C. Antoniou, R. Schmutzler

Date Published: 9th Apr 2013

Publication Type: Not specified

Human Diseases: hereditary breast ovarian cancer syndrome

Validation of the Manchester scoring system for predicting BRCA1/2 mutations in 9,390 families suspected of having hereditary breast and ovarian cancer.
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

The Manchester scoring system (MSS) allows the calculation of the probability for the presence of mutations in BRCA1 or BRCA2 genes in families suspected of having hereditary breast and ovarian cancer. … In 9,390 families, we determined the predictive performance of the MSS without (MSS-2004) and with (MSS-2009) consideration of pathology parameters. Moreover, we validated a recalibrated version of the MSS-2009 (MSS-recal). Families were included in the registry of the German Consortium for Hereditary Breast and Ovarian Cancer, using defined clinical criteria. Receiver operating characteristics (ROC) analysis was used to determine the predictive performance. The recalibrated model was developed using logistic regression analysis and tested using an independent random validation sample. The area under the ROC curves regarding a mutation in any of the two BRCA genes was 0.77 (95%CI 0.75-0.79) for MSS-2004, 0.80 (95%CI 0.78-0.82) for MSS-2009, and 0.82 (95%CI 0.80-0.83) for MSS-recal. Sensitivity at the 10% mutation probability cutoff was similar for all three models (MSS-2004 92.2%, MSS-2009 92.2%, and MSS-recal 90.3%), but specificity of MSS-recal (46.0%) was considerably higher than that of MSS-2004 (25.4%) and MSS-2009 (32.3%). In the MSS-recal model, almost all predictors of the original MSS were significantly predictive. However, the score values of some predictors, for example, high grade triple negative breast cancers, differed considerably from the originally proposed score values. The original MSS performed well in our sample of high risk families. The use of pathological parameters increased the predictive performance significantly. Recalibration improved the specificity considerably without losing much sensitivity.

Authors: K. Kast, R. K. Schmutzler, K. Rhiem, M. Kiechle, C. Fischer, D. Niederacher, N. Arnold, T. Grimm, D. Speiser, B. Schlegelberger, D. Varga, J. Horvath, M. Beer, S. Briest, A. Meindl, C. Engel

Date Published: 15th Nov 2014

Publication Type: Not specified

Human Diseases: breast cancer, ovarian cancer

Claus
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Motivation: The eClaus model can be used to calculate mutation risks for BRCA1/2 as well as life-time risks for breast cancer in women from families with multiple and/or early onset cases of breast and ovarian cancer. The model can be used to assist genetic counselors in clinical decision making regarding genetic testing, intensified surveillance, and prophylatic surgery.

Description: The Claus model is a genetic breast cancer risk calculation model assuming a single rare, highly penetrant gene. ...

Creators: Christoph Engel, Silke Zachariae, Claus, E.B. et al. (1991 and 1994)

Submitter: Silke Zachariae

Manchester Scoring System
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Motivation: The "Manchester Scoring System" can be used to assist clinicians and genetic counselors in the clinical management of families suspected of having hereditary breast and ovarian cancer and to decide whether genetic testing should be performed.

Description: The "Manchester Scoring System" is an empirical mutation risk prediction model. In its current form, a risk score for the identification of a pathogenic BRCA1/2 mutation is being calculated based on the number of breast and ovarian ...

Creators: Christoph Engel, Silke Zachariae, Evans, D.G. et al. (2009)

Submitter: Silke Zachariae

GC-HBOC Mutation Frequency Explorer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Motivation: The "GC-HBOC Mutation Frequency Explorer" can be used to assist clinicians and genetic counselors in the clinical management of families suspected of having hereditary breast and ovarian cancer and to decide whether genetic testing should be performed.

Description: The "GC-HBOC Mutation Frequency Explorer" is a tool to determine the observed frequencies of pathogenic BRCA1 and BRCA2 mutations based on familial cancer history data collected since 1996 by the German Consortium for ...

Creators: Christoph Engel, Silke Zachariae

Submitter: Silke Zachariae

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