Optimal selection for BRCA1 and BRCA2 mutation testing using a combination of ‘easy to apply’ probability models

Abstract

To establish an efficient, reliable and easy to apply risk assessment tool to select families with breast and/or ovarian cancer patients for BRCA mutation testing, using available probability models. In a retrospective study of 263 families with breast and/or ovarian cancer patients, the utility of the Frank (Myriad), Gilpin (family history assessment tool) and Evans (Manchester) model was analysed, to select 49 BRCA mutation-positive families. For various cutoff levels and combinations, the sensitivity and specificity were calculated and compared. The best combinations were subsequently validated in additional sets of families. Comparable sensitivity and specificity were obtained with the Gilpin and Evans models. They appeared to be complementary to the Frank model. To obtain an optimal sensitivity, five 'additional criteria' were introduced that are specific for the selection of small or uninformative families. The optimal selection is made by the combination 'Frank X16% or Evans2 X12 or one of five additional criteria'. The efficiency of the selection of families for mutation testing of BRCA1 and BRCA2 can be optimised by using a combination of available easy to apply risk assessment models. British Journal of Cancer (2006) Identification of families at high risk of hereditary breast and/or ovarian cancer contributes to the prevention and early detection of breast and ovarian malignancies. Therefore, genetic testing is offered to women with an increased risk of hereditary breast or ovarian cancer based on familial clustering of breast and/or ovarian cancer, particularly in case of early onset or if breast cancer occurs in a male. Selection criteria to test for BRCA mutations vary. Because BRCA testing is laborious and expensive, as well as associated with medical, psychological and social consequences for the patient, careful patient selection is required before testing. To obtain optimal ascertainment, many risk assessment models and prior probability models have been developed and evaluated (de la Hoya et al, 2003;Domchek et al, 2003). Four such models, the Claus, Gilpin, Frank and Evans model (Claus et al, 1998;Gilpin et al, 2000;Frank et al, 2002;Evans et al, 2004) are empirically derived scoring systems, easy to apply in daily practice with the use of a pencil and a paper and easy to understand for both counsellor and patient.With the Claus tables the probability of developing breast cancer can be determined, but not the likelihood of detecting a BRCA mutation (as in prior probability models). These tables are based on series of unselected women with breast cancer. As this model does not account for breast cancer in more than two family members, the presence of ovarian cancer, male breast cancer or bilateral breast cancer, it underestimates the cancer risk in many families and cannot be used solely as a prediction model in the clinic.The Frank model, developed by Myriad Genetics, is an empirical model correlating the prevalence of BRCA mutations with personal and family history of breast and ovarian can...

Germline copy number variation and cancer risk

“…Despite the fact that at least some of the remaining genetic risk will be explained by a combination of multiple low to moderate risk factors, it is plausible to assume that in a considerable number of unexplained families a high cancer risk will largely be determined by a single genetic defect. From all index patients that are counseled for hereditary breast or colorectal cancer in our institute 60% fulfill the criteria for genetic testing of high-penetrance candidate genes (Myriad or FHAT criteria for breast cancer [69] and Amsterdam criteria or Bethesda guidelines for Lynch syndrome [70][71][72]), but disease-causing mutations are detected in only 7-8% of these cases. In addition, in only 46-68% of the families that fulfill the more stringent revised Amsterdam criteria for Lynch syndrome (i.e.…”

Efficiency of BRCAPRO and Myriad II mutation probability thresholds versus cancer history criteria alone for BRCA1/2 mutation detection

“…This suggests that for detection of BRCA1 mutations, BRCAPRO at a threshold of 10% is the method of choice: i.e., it has the same sensitivity as the cancer history criteria and reduces the number of tests by 40%. The fact that these probability models have a better performance for BRCA1 than BRCA2 has been reported previously by James et al [ 23 ] and Bodmer et al [ 24 ], and is related to the lower penetrance of the mutations in BRCA2 . Indeed, as explained in the results section, none of the families of these patients included any of the most characteristic features of the BRCA families, such as OC, bilateral BC or male BC.…”

Risk models for breast cancer

“…женщин из 28 исследовательских центров США. Серия статистических исследований [8,9] позволила получить данные о том, что такие факторы, как применение оральных контрацептивов, курение, использование пищевых добавок для усиления функции щитовидной железы, а также употребление лекарственных средств, не связаны со значительным увеличением риска РМЖ. С умеренным ростом риска развития РМЖ были связаны такие факторы, как употребление алкоголя в умеренных количествах [10], долгосрочная заместительная терапия эстрогенами и высокий рост.…”