New procedures for genetic testing and counselling of patients with breast or ovarian cancer

Abstract

The aim of this PhD project was to evaluate alternative procedures for genetic testing and counselling of patients newly diagnosed with breast or ovarian cancer, in order to meet the expected increasing need of this health service. We performed a prospective study, the DNA-BONus study, in which we consecutively offered BRCA testing and familial risk assessment to unselected patients with newly diagnosed breast (N=893) or ovarian (N=122) cancer between September 2012 and February 2015, without formal pre-test genetic counselling. Out of the 488 patients who underwent genetic testing 7 of 405 patients (2%) with breast cancer and 19 of 83 patients (22%) with ovarian cancer carried a germline pathogenic BRCA variant (Paper I). All carriers fulfilled at least one of the Norwegian BRCA test criteria (Paper I). There was a significant decline in the mean levels of anxiety symptoms (Paper I) and cancer related psychological distress (Paper II) from inclusion to six months after dissemination of the BRCA test result. Predictors of increased distress were young age, short time since diagnosis, low level of perceived social support, high level of decisional conflict, diagnosis of ovarian cancer, and living with a partner (Paper II). By investigating RNA splicing, we showed that the intronic BRCA1 c.5407-25T>A variant leads to partial skipping of exon 22, resulting in the truncated protein p.Gly1803GlnfsTer11. Combined with allele frequency data and clinical information from 20 families, this indicated that BRCA1 c.5407-25T>A is a likely pathogenic variant with reduced penetrance (Paper III). In conclusion, the current thesis showed that a simplified procedure for BRCA testing was accepted and overall well tolerated by women newly diagnosed with breast or ovarian cancer. However, we also identified more vulnerable subgroups that may need more counselling and support to benefit from diagnostic BRCA testing. Testing of large groups of individuals with low a priori risk of carrying a germline BRCA pathogenic variant, like unselected patients with breast cancer in our study, may lead to detection of more DNA variants with reduced penetrance.