BRCA mutation testing for first-degree relatives of women with high-grade serous ovarian cancer.

BACKGROUND: Women with high-grade serous ovarian cancer (HGSC) have a 20% chance of carrying a BRCA1 or 2 mutation. Not all undergo genetic testing, and there is a large legacy group of untested patients. Their female first-degree relatives (FDR) may not qualify for testing unless they have specific ethnicity, or personal/family cancer history. We conducted a cost-effectiveness analysis to evaluate risk-reducing strategies for these FDR who are ineligible for testing. METHODS: A Markov Monte Carlo simulation model estimated the costs and benefits of 3 strategies for female FDR of HGSC patients whose BRCA status is unknown: (1) no BRCA testing; (2) universal BRCA testing, followed by risk-reducing bilateral salpingo-oophorectomy (RRBSO) for mutation carriers; (3) universal RRBSO, without BRCA testing. Effectiveness was estimated in quality-adjusted life year (QALY) gains over a 50-year time horizon. Sensitivity analyses accounted for uncertainty around various parameters. RESULTS: Universal BRCA testing for female FDR of women with HGSC yielded a higher average QALY gain at acceptable cost compared to no BRCA testing, with an incremental cost-effectiveness ratio of $7888 per QALY. Universal BRCA testing was more effective and less costly than universal RRBSO (19.20 QALYs vs. 18.52 QALYs, and $10,135 vs. $14,231, respectively). Results were stable over wide ranges of plausible costs and estimates. Compliance with hormone replacement therapy had to exceed 79.3% for universal RRBSO to be the most effective strategy. CONCLUSION: BRCA mutation testing should be offered to all female first-degree relatives of women with high-grade serous ovarian cancer when BRCA mutation status is unknown.

Costs and Benefits of Extended Endocrine Strategies for Premenopausal Breast Cancer.

Background: After completing 5 years of adjuvant tamoxifen, women with estrogen receptor (ER)-positive breast cancer benefit from 5 more years of endocrine therapy, either with tamoxifen or an aromatase inhibitor (AI). For premenopausal women, ovarian ablation (OA) would be required before starting an AI (OA/AI). According to the SOFT/TEXT studies, OA/AI improves 5-year disease-free survival compared with tamoxifen alone, suggesting that OA/AI could be superior to tamoxifen as extended endocrine therapy. The long-term costs and consequences of premature menopause from OA are unknown, but could be estimated through a cost-effectiveness analysis. Methods: A Markov chain Monte Carlo simulation model estimated the costs and benefits of 3 extended endocrine strategies in a hypothetical cohort of premenopausal women with ER-positive early breast cancer: (1) no further treatment; (2) tamoxifen for 5 years (extended tamoxifen); or (3) OA/AI for 5 years. Effectiveness was measured in years of life expectancy gain. Sensitivity analyses accounted for uncertainty surrounding various parameters. Monte Carlo simulation estimated the number of adverse events and deaths from each strategy in the US population over a 40-year period. Results: Extended tamoxifen yielded a higher average life expectancy gain than OA/AI (17.31 vs 17.06 years) at lower average cost ($3,550 vs $14,312). For 18,000 premenopausal ER-positive women, the simulation estimated 13,236, 12,557, and 11,338 deaths with no further treatment, extended tamoxifen, and OA/AI, respectively, but an additional 1,897 deaths from OA, for a total of 13,235 deaths associated with OA/AI. After 24.6 years of follow-up, more women are expected to die from OA/AI than extended tamoxifen. Conclusions: For premenopausal women with ER-positive cancer who have completed adjuvant tamoxifen, another 5 years of tamoxifen is the preferable extended endocrine strategy. The potential long-term health consequences of OA could affect overall survival when it precedes the use of an AI.

Long-term consequences of ovarian ablation for premenopausal breast cancer.

The TEXT and SOFT trials concluded that an aromatase inhibitor (AI) with ovarian ablation (OA) yields a higher 5-year disease-free survival than tamoxifen alone in premenopausal ER+ high-risk early breast cancer. However, the long-term health consequences and costs of OA, either by GnRH agonist or oophorectomy, have not been evaluated. The objective was to conduct a cost-effectiveness analysis comparing tamoxifen to OA with AI. Markov Monte Carlo simulation model estimated the costs and benefits of 3 endocrine strategies: (1) tamoxifen; (2) GnRH agonist with AI (GnRHa-AI); (3) bilateral salpingo-oophorectomy with AI (BSO-AI). Effectiveness was measured in life expectancy gain (years), and costs were averaged over a lifetime (USD 2015). Adverse events and deaths from each strategy were modeled in the United States population over a time horizon of 40 years. For women without prior chemotherapy (low-risk), tamoxifen alone was more effective (18.03 years) and less costly ($1566) than GnRHa-AI (17.66 years, $93,692) or BSO-AI (17.63 years, $25,892). For those with prior chemotherapy (high-risk), BSO-AI was more costly but more effective (16.78 years, $25,368) than tamoxifen alone (16.55 years, $1523) with an ICER of $102,290, while GnRHa-AI yielded an ICER of $443,376. The simulation estimated 787 and 577 deaths attributable to OA among 9320 high-risk women after BSO-AI and GnRHa-AI, respectively. There may be a role for ovarian ablation in premenopausal women with ER+ high-risk early breast cancer; however, this analysis raises concerns about the long-term health consequences of ovarian ablation and the potential effects on overall survival.

A Technical Assessment of the Utility of Reverse Phase Protein Arrays for the Study of the Functional Proteome in Non-microdissected Human Breast Cancers.

INTRODUCTION: The lack of large panels of validated antibodies, tissue handling variability, and intratumoral heterogeneity potentially hamper comprehensive study of the functional proteome in non-microdissected solid tumors. The purpose of this study was to address these concerns and to demonstrate clinical utility for the functional analysis of proteins in non-microdissected breast tumors using reverse phase protein arrays (RPPA). METHODS: Herein, 82 antibodies that recognize kinase and steroid signaling proteins and effectors were validated for RPPA. Intraslide and interslide coefficients of variability were <15%. Multiple sites in non-microdissected breast tumors were analyzed using RPPA after intervals of up to 24 h on the benchtop at room temperature following surgical resection. RESULTS: Twenty-one of 82 total and phosphoproteins demonstrated time-dependent instability at room temperature with most variability occurring at later time points between 6 and 24 h. However, the 82-protein functional proteomic "fingerprint" was robust in most tumors even when maintained at room temperature for 24 h before freezing. In repeat samples from each tumor, intratumoral protein levels were markedly less variable than intertumoral levels. Indeed, an independent analysis of prognostic biomarkers in tissue from multiple tumor sites accurately and reproducibly predicted patient outcomes. Significant correlations were observed between RPPA and immunohistochemistry. However, RPPA demonstrated a superior dynamic range. Classification of 128 breast cancers using RPPA identified six subgroups with markedly different patient outcomes that demonstrated a significant correlation with breast cancer subtypes identified by transcriptional profiling. CONCLUSION: Thus, the robustness of RPPA and stability of the functional proteomic "fingerprint" facilitate the study of the functional proteome in non-microdissected breast tumors.

Are there regional differences in gynecologic cancer outcomes in the context of a single-payer, publicly-funded health care system? A population-based study.

BACKGROUND: Canada has a single-payer, publicly-funded health care system that provides comprehensive health care, and therefore significant disparities in health outcomes are not expected in our population. The objective of this study was to determine if differences exist in endometrial cancer outcomes across regions in Ontario. METHODS: This was a population-based study of all endometrial (uterine) cancer cases diagnosed from 1996 to 2000 in Ontario and linked to various administrative databases. Univariate analyses examined trends in demographics (age, income, co-morbidities), treatment (surgical staging and adjuvant pelvic radiotherapy), and pathology (grade, histology, stage) across 14 geographic regions defined by local health integration networks (LHINs) in Ontario. Primary outcome was 5-year overall survival among LHINs, which were compared in a multilevel Cox regression model to account for clustering of patient data at the hospital level. RESULTS: There were 3,875 evaluable cases with complete information on demographics, treatment, pathology, and outcomes. There was significant variation in patient demographics, treatment, and pathology across the 14 LHINs. Low income level and surgery at a low-volume, community hospital without gynecologic oncologists were not associated with a higher risk of death. There was a trend towards clustering of patients within hospitals. After adjustment for covariates, there was no significant difference in survival across LHINs. CONCLUSIONS: In the context of a single-payer, publicly-funded health care system, we did not find significant regional differences in endometrial cancer outcomes.

Cost-effectiveness analysis of treatment strategies for Stage I and II endometrial cancer.

OBJECTIVE: Practice patterns vary across Canada with respect to indications for surgical staging and adjuvant radiotherapy in early endometrial cancer. We evaluated the cost-effectiveness of two common strategies for managing early endometrial cancer as part of an Ontario population-based study. METHODS: A decision-analytic model (DATA 4.5) was developed for Stage I and II endometrioid-type cancer using empiric data from Ontario. On the basis of preoperative biopsy grade, one of two surgical procedures was selected: (1) hysterectomy and bilateral salpingo-oophorectomy (HBSO) or (2) surgical staging (HBSO and pelvic +/- para-aortic lymphadenectomy). Adjuvant radiotherapy (RT) was administered according to final grade and stage. After HBSO, pelvic RT was indicated for Grades 1 and 2 if Stage IC, IIA with > 50% myometrial invasion (MI), or IIB, and for Grade 3 if Stage IB, IC, IIA, or IIB. After staging, pelvic RT was indicated for Grades 1 and 2 if Stage IIB, and for Grade 3 if Stage IC, IIA with > 50% MI, or IIB. Main outcome measures were quality-adjusted life-years (QALY) and incremental cost-effectiveness ratios (ICER). Sensitivity analyses were used to evaluate uncertainty around various parameters. RESULTS: The most cost-effective (dominant) strategies were determined for each preoperative grade. For Grade 1, HBSO strongly dominated surgical staging. For Grade 2, neither strategy was dominant; surgical staging had an ICER of $5216 per QALY. For Grade 3, surgical staging strongly dominated HBSO. These results were stable over a wide range of estimates for costs and utilities (i.e., patient preferences for a particular health state). CONCLUSION: The most cost-effective treatment strategies for early endometrial cancer in Ontario differ according to preoperative grade.

Factors that influence length of stay for in-patient gynaecology surgery: is the Case Mix Group (CMG) or type of procedure more important?

OBJECTIVES: To compare the association between the Case Mix Group (CMG) code and length of stay (LOS) with the association between the type of procedure and LOS in patients admitted for gynaecology surgery. METHODS: We examined the records of women admitted for surgery in CMG 579 (major uterine/adnexal procedure, no malignancy) or 577 (major surgery ovary/adnexa with malignancy) between April 1997 and March 1999. Factors thought to influence LOS included age, weight, American Society of Anesthesiologists (ASA) score, physician, day of the week on which surgery was performed, and procedure type. Procedures were divided into six categories, four for CMG 579 and two for CMG 577. Data were abstracted from the hospital information costing system (T2 system) and by retrospective chart review. Multivariable analysis was performed using linear regression with backwards elimination. RESULTS: There were 606 patients in CMG 579 and 101 patients in CMG 577, and the corresponding median LOS was four days (range 1-19) for CMG 579 and nine days (range 3-30) for CMG 577. Combined analysis of both CMGs 577 and 579 revealed the following factors as highly significant determinants of LOS: procedure, age, physician, and ASA score. Although confounded by procedure type, the CMG did not significantly account for differences in LOS in the model if procedure was considered. Pairwise comparisons of procedure categories were all found to be statistically significant, even when controlled for other important variables. CONCLUSION: The type of procedure better accounts for differences in LOS by describing six statistically distinct procedure groups rather than the traditional two CMGs. It is reasonable therefore to consider changing the current CMG codes for gynaecology to a classification based on the type of procedure.