Canadian cost-effectiveness model of BRCA-driven surgical prevention of breast/ovarian cancers compared to treatment if cancer develops.

OBJECTIVES: To assess the cost effectiveness from a Canadian perspective of index patient germline BRCA testing and then, if positive, family members with subsequent risk-reducing surgery (RRS) in as yet unaffected mutation carriers compared with no testing and treatment of cancer when it develops. METHODS: A patient level simulation was developed comparing outcomes between two groups using Canadian data. Group 1: no mutation testing with treatment if cancer developed. Group 2: cascade testing (index patient BRCA tested and first-/second-degree relatives tested if index patient/first-degree relative is positive) with RRS in carriers. End points were the incremental cost-effectiveness ratio (ICER) and budget impact. RESULTS: There were 29,102 index patients: 2,786 ovarian cancer and 26,316 breast cancer (BC). Using the base-case assumption of 44 percent and 21 percent of women with a BRCA mutation receiving risk-reducing bilateral salpingo-oophorectomy and risk-reducing mastectomy, respectively, testing was cost effective versus no testing and treatment on cancer development, with an ICER of CAD 14,942 (USD 10,555) per quality-adjusted life-year (QALY), 127 and 104 fewer cases of ovarian and BC, respectively, and twenty-one fewer all-cause deaths. Testing remained cost effective versus no testing at the commonly accepted North American threshold of approximately CAD 100,000 (or USD 100,000) per QALY gained in all scenario analyses, and cost effectiveness improved as RRS uptake rates increased. CONCLUSIONS: Prevention via testing and RRS is cost effective at current RRS uptake rates; however, optimization of uptake rates and RRS will increase cost effectiveness and can provide cost savings.

Targeted surgical prevention of epithelial ovarian cancer is cost effective and saves money in BRCA mutation carrying family members of women with epithelial ovarian cancer. A Canadian model.

OBJECTIVE: Survival but not cure rates have improved for epithelial ovarian cancer (EOC), demonstrating the need for effective prevention. Targeted prevention in BRCA carriers by risk reducing surgery (RRS) prevents 80% of cases but incurs additional up-front costs, compensated for by the potential for long term savings from treatment avoidance. Does prevention represent value for money? In the absence of long-term data from prospective trials, determining the cost effectiveness of a prevention strategy requires economic modelling. METHODS: A patient level simulation was developed comparing outcomes between two groups, using Canadian data. Group 1: no mutation testing with treatment if EOC developed. Group 2: cascade testing (index patient BRCA tested and the first and second-degree relatives tested if index patient or first-degree relative respectively were positive) with RRS in carriers. End points were Incremental Cost-Effectiveness Ratio (ICER) and budget impact. RESULTS: 2786 women with EOC (1 year incidence) had 766 first and 207 second-degree female relatives. BRCA mutations were present in 390 index cases, 366 first and 49 second-degree relatives. With 100% RRS uptake, 59 EOC were prevented and testing dominated no testing (more effective and less costly; ICER -$8919). The total cost saving over 50 years was $2,904,486 (cost saving of $9,660,381 in treatment costs versus increased cost from cascade testing/RRS of $6,755,895). At a threshold of $100,000 per QALY, prevention was cost effective in all modelled scenarios. CONCLUSIONS: Targeted prevention in BRCA mutation carriers not only prevents EOC but is cost-effective compared to treating EOC if it develops.

Evolution of genetic assessment for BRCA-associated gynaecologic malignancies: a Canadian multisociety roadmap.

The landscape of genetic testing in ovarian cancer patients has changed dramatically in recent years. The therapeutic benefits of poly ADP-ribose polymerase (PARP) inhibitors in treatment of BRCA1/2-related ovarian cancers has resulted in an increased demand and urgency for genetic testing results, while technological developments have led to widespread use of multi-gene cancer panels and development of tumour testing protocols. Traditional genetic counselling models are no longer sustainable and must evolve to match the rapid evolution of genetic testing technologies and developments in personalized medicine. Recently, representatives from oncology, clinical genetics, molecular genetics, pathology, and patient advocacy came together to create a national multi-disciplinary Canadian consortium. By aligning stakeholder interests, the BRCA Testing to Treatment (BRCA TtoT) Community of Practice aims to develop a national strategy for tumour and germline BRCA1/2 testing and genetic counselling in women with ovarian cancer. This article serves to provide an overview of the recent evolution of genetic assessment for BRCA1/2-associated gynecologic malignancies and outline a Canadian roadmap to facilitate change, improve genetic testing rates, and ultimately improve outcomes for hereditary ovarian cancer patients and their families.

Assessment of Her-1, Her-2, And Her-3 expression and Her-2 amplification in advanced stage ovarian carcinoma.

The human epidermal growth factor receptor (Her) family of receptor tyrosine kinases includes Her-1, Her-2, and Her-3. The overexpression of Her-1 and Her-2 have been reported previously in surface epithelial ovarian cancer. Although up to one-third of ovarian carcinomas have been found to have amplification or overexpression of Her-2, responses to trastuzumab therapy in these patients have been disappointing. In this study, we examined Her-1, Her-2, and Her- 3 protein expression as well as the frequency of Her-2 amplification in a series of 103 high-grade, advanced-stage (FIGO stage III or IV) ovarian surface epithelial carcinomas. Immunohistochemical staining using commercially available antibodies against Her-1-3 and fluorescence in situ hybridization (FISH) using probes against Her-2 and chromosome 17 centromere (CEP) were performed on a tissue microarray containing cores of tumor from 103 surface epithelial carcinomas (85 serous, 6 mixed surface epithelial, 5 clear cell, 3 endometrioid, 3 undifferentiated, 1 mucinous). Nine of 99 (9.1%) tumors were positive for Her-1 expression and 5 of 102 (4.9%) tumors were positive for Her-2 expression, with 1 showing strong immunoreactivity. None of the Her-1 positive tumors exhibited Her-2 immunoreactivity. There was no correlation between Her-1 or Her-2 expression and survival. Using Her-2:centromere fluorescence ratios of 2.0 or 1.5 as cutoffs in assessment of Her-2 amplification, 8 of 75 (10.7%) and 25 of 75 (33.3%) tumors, respectively, showed Her-2 amplification. Two of eight tumors that showed higher level (>2) Her-2 amplification by FISH also were positive for Her-2 by immunohistochemistry. Only 3 of 103 tumors expressed Her-3. Immunoreactivity for Her-1 and Her-2 was less frequently observed in this series than has been previously reported. The strong correlation between Her-2 immunostaining and amplification characteristic of breast carcinoma is not seen in ovarian carcinoma. These results indicated that few patients with ovarian carcinoma have tumors that would benefit from therapy targeted specifically against Her-1, Her-2, or Her-3.