Factors influencing the decision to share cancer genetic results among family members: An in-depth interview study of women in an Asian setting.

OBJECTIVE: Reluctance to share hereditary cancer syndrome genetic test results with family is reported among Asian patients. This study aims to explore patient factors influencing result sharing with family, to improve overall testing uptake. METHODS: Participants were women with a personal/family history of breast and/or ovarian cancer who received a positive, negative, or variant of uncertain significance test result. In-depth interviews were conducted to theme saturation to explore facilitators and barriers for sharing results with family. Grounded theory with thematic analysis was applied in analysis and interpretation. RESULTS: Twenty-four women participated. Three themes representing facilitators emerged for all results categories: family closeness, involvement of families in the testing process, and perception of low emotional impact of results. In the positive result category, 2 facilitator themes emerged: presence of actionable results and perception of family members' acceptance. In the negative and variant of uncertain significance result categories, 2 themes representing barriers to sharing emerged: perception of no genetic or medical implication for family and result ambiguity. CONCLUSION: Facilitators and barriers for result sharing are similar to those among Western women. A framework to explain Asian patients' decision-making process identifies optimal counselling opportunities to enhance communication with family.

Impact of subsidies on cancer genetic testing uptake in Singapore.

PURPOSE: Previous reports cite high costs of clinical cancer genetic testing as main barriers to patient's willingness to test. We report findings of a pilot study that evaluates how different subsidy schemes impact genetic testing uptake and total cost of cancer management. METHODS: We included all patients who attended the Cancer Genetics Service at the National Cancer Centre Singapore (January 2014-May 2016). Two subsidy schemes, the blanket scheme (100% subsidy to all eligible patients), and the varied scheme (patients received 50%-100% subsidy dependent on financial status) were compared. We estimated total spending on cancer management from government's perspective using a decision model. RESULTS: 445 patients were included. Contrasting against the blanket scheme, the varied scheme observed a higher attendance of patients (34 vs 8 patients per month), of which a higher proportion underwent genetic testing (5% vs 38%), while lowering subsidy spending per person (S$1098 vs S$1161). The varied scheme may potentially save cost by reducing unnecessary cancer surveillance when first-degree relatives uptake rate is above 36%. FINDINGS: Provision of subsidy leads to a considerable increase in genetic testing uptake rate. From the government's perspective, subsidising genetic testing may potentially reduce total costs on cancer management.

Using Quality Improvement Methods and Time-Driven Activity-Based Costing to Improve Value-Based Cancer Care Delivery at a Cancer Genetics Clinic.

PURPOSE: To meet increasing demand for cancer genetic testing and improve value-based cancer care delivery, National Cancer Centre Singapore restructured the Cancer Genetics Service in 2014. Care delivery processes were redesigned. We sought to improve access by increasing the clinic capacity of the Cancer Genetics Service by 100% within 1 year without increasing direct personnel costs. METHODS: Process mapping and plan-do-study-act (PDSA) cycles were used in a quality improvement project for the Cancer Genetics Service clinic. The impact of interventions was evaluated by tracking the weekly number of patient consultations and access times for appointments between April 2014 and May 2015. The cost impact of implemented process changes was calculated using the time-driven activity-based costing method. RESULTS: Our study completed two PDSA cycles. An important outcome was achieved after the first cycle: The inclusion of a genetic counselor increased clinic capacity by 350%. The number of patients seen per week increased from two in April 2014 (range, zero to four patients) to seven in November 2014 (range, four to 10 patients). Our second PDSA cycle showed that manual preappointment reminder calls reduced the variation in the nonattendance rate and contributed to a further increase in patients seen per week to 10 in May 2015 (range, seven to 13 patients). There was a concomitant decrease in costs of the patient care cycle by 18% after both PDSA cycles. CONCLUSION: This study shows how quality improvement methods can be combined with time-driven activity-based costing to increase value. In this paper, we demonstrate how we improved access while reducing costs of care delivery.

Inherited breast cancer predisposition in Asians: multigene panel testing outcomes from Singapore.

Genetic testing for germline mutations in breast cancer predisposition genes can potentially identify individuals at a high risk of developing breast and/or ovarian cancer. There is a paucity of such mutational information for Asians. Panel testing of 25 cancer susceptibility genes and BRCA1/2 deletion/duplication analysis was performed for 220 Asian breast cancer patients or their family members referred for genetics risk assessment. All 220 participants had at least one high-risk feature: having a family history of breast and/or ovarian cancer in first- and/or second-degree relatives; having breast and ovarian cancer in the same individual or bilateral breast cancer; having early-onset breast cancer or ovarian cancer (⩽40 years of age). We identified 67 pathogenic variants in 66 (30.0%) patients. Of these, 19 (28.3%) occurred in BRCA1, 16 (23.9%) in BRCA2, 7 (10.4%) in PALB2, 6 (9.0%) in TP53, 2 (3.0%) in PTEN, 2 (3.0%) in CDH1 and 15 (22.4%) in other predisposition genes. Notably, 47.8% of pathogenic variants were in non-BRCA1/2 genes. Of the 66 patients with pathogenic mutations, 63.6% (42/66) were under the age of 40 years. Family history of breast and/or ovarian cancer is enriched in patients with BRCA1/2 pathogenic variants but less predictive for non-BRCA1/2 related pathogenic variations. We detected a median of three variants of unknown significance (VUS) per gene (range 0-21). Custom gene panel testing is feasible and useful for the detection of pathogenic mutations and should be done in the setting of a formal clinical cancer genetics service given the rate of VUS.

Germline hemizygous deletion of CDKN2A-CDKN2B locus in a patient presenting with Li-Fraumeni syndrome.

Li-Fraumeni syndrome (LFS) is a rare cancer predisposition syndrome usually associated with TP53 germline alterations. Its genetic basis in TP53 wild-type pedigrees is less understood. Using whole-genome sequencing, we identified a germline hemizygous deletion ablating CDKN2A-CDKN2B in a TP53 wild-type patient presenting with high-grade sarcoma, laryngeal squamous cell carcinoma and a family history suggestive of LFS. Patient-derived cells demonstrated reduced basal gene and protein expression of the CDKN2A-encoded tumour suppressors p14ARF and p16INK4A with concomitant decrease in p21 and faster cell proliferation, implying potential deregulation of p53-mediated cell cycle control. Review of 13 additional patients with pathogenic CDKN2A variants suggested associations of germline CDKN2A mutations with an expanded spectrum of non-melanoma familial cancers. To our knowledge, this is the first report of a germline gross deletion of the CDKN2A-CDKN2B locus in an LFS family. These findings highlight the potential contribution of germline CDKN2A deletions to cancer predisposition and the importance of interrogating the full extent of CDKN2A locus in clinical testing gene panels.

[Gliomas and BRCA genes mutations: fortuitous association or imputability?]. / Gliomes et mutations des gènes BRCA : association fortuite ou imputabilité ?

BRCA is a tumor suppressor gene implicated in the major mechanisms of cellular stability in every type of cell. Its mutations are described in numerous cancers, mainly breast and ovarian in women. It was also found an increase of lifetime risk of pancreas, colon, prostate cancer or lymphoma in men carriers. We report the cases of two female patients aged 40 and 58-years-old female patients and one 35-years-old male patient, with brain or medullar gliomas, carriers of a germline mutation of BRCA gene. Those gliomas were particularly aggressive and were not responding to the standard treatment, with chemo and radiotherapy. The very unusual characteristics in location and evolutive profile of these central nervous system tumors raise the question of a genetical underlying mechanism, maybe linked to the BRCA gene mutation that carry these patients. In addition, a non-fortuitous association between germline mutation of BRCA and occurrence of a glioma can be evoked according to the embryological, epidemiological and biomolecular findings noted in the literature. Other clinical and experimental studies are necessary to precise the physiopathological link existing between BRCA mutations and the occurrence of a glioma; this could have therapeutical and clinical implications in the future.