Detecting Germline PTEN Mutations Among At-Risk Patients With Cancer: An Age- and Sex-Specific Cost-Effectiveness Analysis

Abstract

Purpose: Cowden syndrome (CS) is an autosomal dominant disorder characterized by benign and malignant tumors. One-quarter of patients who are diagnosed with CS have pathogenic germline PTEN mutations, which increase the risk of the development of breast, thyroid, uterine, renal, and other cancers. PTEN testing and regular, intensive cancer surveillance allow for early detection and treatment of these cancers for mutation-positive patients and their relatives. Individual CS-related features, however, occur commonly in the general population, making it challenging for clinicians to identify CS-like patients to offer PTEN testing.

Patients and methods: We calculated the cost per mutation detected and analyzed the cost-effectiveness of performing selected PTEN testing among CS-like patients using a semi-quantitative score (the PTEN Cleveland Clinic [CC] score) compared with existing diagnostic criteria. In our model, first-degree relatives of the patients with detected PTEN mutations are offered PTEN testing. All individuals with detected PTEN mutations are offered cancer surveillance.

Results: CC score at a threshold of 15 (CC15) costs from $3,720 to $4,573 to detect one PTEN mutation, which is the most inexpensive among the different strategies. At base-case, CC10 is the most cost-effective strategy for female patients who are younger than 40 years, and CC15 is the most cost-effective strategy for female patients who are between 40 and 60 years of age and male patients of all ages. In sensitivity analyses, CC15 is robustly the most cost-effective strategy for probands who are younger than 60 years.

Conclusion: Use of the CC score as a clinical risk calculator is a cost-effective prescreening method to identify CS-like patients for PTEN germline testing.

Fig 1.

Schematic diagram of genetic screening strategies. A Cowden syndrome (CS) -like patient is prescreened with a clinical calculator (National Comprehensive Cancer Network criteria or Cleveland Clinic score at different thresholds). If the individual meets the threshold, he or she will receive genetic testing for germline PTEN mutations. First-degree relatives of PTEN-mutation-positive individuals will be offered genetic testing for the specific mutations. All individuals who are positive for PTEN mutations will receive cancer surveillance according to recommendations.

Fig 2.

Cost per mutation by patient age, with or without relatives tested. Graph illustrates the cost per mutation detected and patient age in Cowden syndrome (CS) -like patients. Costs per mutation detected decrease as first-degree relatives are included in the testing. CC, PTEN Cleveland Clinic score; CC5, individuals whose CC scores are above the threshold of 5; CC10, individuals whose CC scores are above the threshold of 10; CC15, individuals whose CC scores are above the threshold of 15; NCCN, National Comprehensive Cancer Network guidelines; PTEN all, germline PTEN mutation testing for all enrolled.

Fig 3.

Cost-effectiveness ratio of competing genetic screening strategies by age and sex. Diagram illustrates the cost per quality-adjusted life-year (QALY) gained for each genetic screening strategy in different age and sex groups. The upper panel (A) and lower panel (B) show cost-effectiveness ratios for female and male patients, respectively. The different colors of the bar denote different genetic screening strategies. PTEN Cleveland Clinic score 15 (CC15) has the lowest cost-effectiveness ratios in all age and sex groups. CC5, individuals whose CC scores are above the threshold of 5; CC10, individuals whose CC scores are above the threshold of 10; CC15, individuals whose CC scores are above the threshold of 15; NCCN, National Comprehensive Cancer Network guidelines; PTEN all, germline PTEN mutation testing for all enrolled.

Fig 4.

Cost, effectiveness, and incremental cost-effectiveness ratio (ICER) of competing genetic screening strategies by age and sex. This graph demonstrates the cost, quality-adjusted life-years (QALYs) gained, and ICERs of competing genetic screening strategies. Results for female and male patients are presented in the left (A) and right (B) panels, respectively. Patient ages are indicated by different colors. Each data point represents the cost and QALYs gained of a particular screening strategy. Different strategies are indicated by various shapes. Different filling patterns represent ICERs of different ranges. Not conducting PTEN testing is denoted by a solid circle. CC, PTEN Cleveland Clinic score; CC5, offering germline PTEN mutation testing when CC scores are above the threshold of 5 ; CC10, offering germline PTEN mutation testing when CC scores are above the threshold of 10; CC15, offering germline PTEN mutation testing when CC scores are above the threshold of 15; NCCN, offering germline PTEN mutation testing if National Comprehensive Cancer Network criteria are met; PTEN all, germline PTEN mutation testing for all enrolled.

Fig 5.

One-way sensitivity analysis in the cohort of 40-year-old female Cowden syndrome (CS) -like patients. Tornado diagrams illustrate the range of permutation in incremental incremental cost-effectiveness ratios (ICERs) of PTEN Cleveland Clinic score (CC) 15 compared with no genetic screening (A) and CC10 compared with CC15 (B) as each parameter varies within its plausible ranges. The results are sorted by the range of permutation in ICERs. The vertical dashed lines represent the ICERs derived with use of the base values of these parameters. The results presented in the figure are for 40-year-old female patients; the other groups have a similar pattern. Only parameters that are associated with permutations of > 5,000 $/QALY are shown in this figure. Full results of one-way sensitivity analyses are documented in the Data Supplement. $/QALY, cost per quality-adjusted life-year.

Fig 6.

Probabilistic sensitivity analysis, performed by running the model 10,000 times and within each run, randomly sampling values for all the parameters from their plausible ranges. This diagram illustrates the proportion of iterations in which each strategy is the optimal strategy as a function of willingness to pay. At a cost-effectiveness threshold of $100,000 per quality-adjusted life-year (QALY), offering germline PTEN mutation CC15, CC10, and no genetic screening were the optimal strategies in 48.6%, 30.8 and 18.4% of the iterations, respectively. At a cost-effectiveness threshold of $150,000 per QALY, CC10, CC15, CC5, and no genetic screening were the optimal strategies in 53.2%, 34.1%, 9.5%, and 2.2% of the iterations, respectively. CC5, offering germline PTEN mutation testing when Cleveland Clinic (CC) scores are above the threshold of 5 ; CC10, offering germline PTEN mutation testing when CC scores are above the threshold of 10; CC15, offering germline PTEN mutation testing when CC scores are above the threshold of 15; NCCN, offering germline PTEN mutation testing if National Comprehensive Cancer Network criteria are met; PTEN all, germline PTEN mutation testing for all enrolled.