PTEN score identifies individuals who need germline testing

Reuters Health Information: PTEN score identifies individuals who need germline testing

PTEN score identifies individuals who need germline testing

Last Updated: 2015-07-17

By Will Boggs MD

NEW YORK (Reuters Health) - The PTEN Cleveland Clinic (CC) score can help identify Cowden syndrome-like patients who need PTEN germline testing, and it does so in a cost-effective manner, new research shows.

"In Cowden syndrome, there are 10-40% who have PTEN mutations arising de novo," Dr. Charis Eng from Cleveland Clinic's Genomic Medicine Institute in Cleveland, Ohio, told Reuters Health by email. "In such a situation, the PTEN CC score is what should be considered."

Cowden syndrome (CS) is a difficult-to-recognize autosomal dominant, highly penetrant genetic disorder associated with germline PTEN mutations that increase the risk of development of several malignant diseases.

Timely identification of these mutations allows for gene-targeted surveillance for affected individuals and predictive testing for their relatives, Dr. Eng and colleagues write in the Journal of Clinical Oncology, online July 13. Previous research has demonstrated that the PTEN CC score provides a well-calibrated estimation of pretest probability of PTEN status.

The researchers examined the diagnostic utility and cost-effectiveness of using the CC score as a clinical predictive tool using data from a prospective cohort of over 3,000 CS and CS-like patients.

Using a CC score at a threshold of 15 (CC15) to prescreen patients for PTEN-gene testing would cost $11,425 to detect one mutation. This strategy carried the lowest cost per mutation detected, irrespective of the patient's age.

Compared with no genetic screening, selective screening with CC15 cost from $58,884 to $107,390 per quality-adjusted life-year (QALY) gained for male probands and from $50,569 to $155,367 per QALY for female probands.

At a cost-effectiveness threshold of $100,000 per QALY, a CC threshold of 10 (CC10) was the most effective strategy for female patients younger than 40 years, whereas CC15 was the most effective strategy for female patients between 40 and 60 years and for male patients of all ages, the researchers found.

"This study lends support to current clinical practice of using a risk models to identify genetically high-risk individuals as being cost-effective," Dr. Eng said. "This has been shown in the past for Hereditary Breast-Ovarian Cancer Syndrome (HBOC, BRCA1/2) and Lynch syndrome (the most common adult-onset heritable colon cancer syndrome) and now CS - all cancer predisposition syndromes with high lifetime risks of developing cancer."

"Unlike the other 2 conditions, CS is far more complicated as patients are at risk of benign as well as malignant growths making screening recommendations more tricky," she explained. "This was why we modeled how age at diagnosis, gender and age of individual cancer screening affected the cost-effectiveness. And indeed, we show that once a PTEN mutation is identified, taking gender and age to begin clinical surveillance is the most cost-effective. This latter has never been done before."

"The cost for gene analysis varies from country to country," Dr. Eng said. "In the U.S., it ranges from health insurance to the patients themselves. In other countries where there is nationalized healthcare, the government pays. In the latter situation, the onus is on their physician-scientists to show the government that testing for the gene mutation and the downstream medical management is value-based and cost-effective."

Robert Pilarski is a genetic counselor at The Ohio State University Comprehensive Cancer Center in Columbus, Ohio. He told Reuters Health by email, "The National Comprehensive Cancer Network (NCCN) has specifically delineated criteria to determine when to offer PTEN testing. Yet it appears that the study inexplicably compares the CC score to the NCCN clinical diagnostic criteria rather than the testing criteria, which is inappropriate and incorrect. The diagnostic criteria are narrower than the testing criteria and are intended to identify those patients who should be managed as if they have PTEN hamartoma tumor syndrome (PHTS)/Cowden, even in absence of an identified PTEN mutation (i.e., either testing was negative or it was not done)."

"Although PTEN mutations are relatively rare, genetic testing is appropriate and appears to be cost-effective for certain patients," Pilarski said. "In my opinion any patient who has two PTEN-related cancers and/or clinical features should be assessed with the NCCN testing criteria or CC score to determine if they are a candidate for testing."

Dr. Gerasimos Tzortzatos from Karolinska University Hospital-Huddinge in Stockholm, Sweden, who has studied Cowden syndrome, said, "Although studies have shown that suspected Cowden syndrome patients should only be tested if the strict NCCN criteria are applied, there are still controversies about what to do and who to test regarding CS-like patients-according to the different definition of CS-like patients also."

"Screening with the CC score should be considered for CS-like individuals and for those that fulfill the strict NCCN criteria," Dr. Tzortzatos told Reuters Health by email. "When CS is suspected the CC score should be used for testing for PTEN mutations in the same individual and all of his/her relatives. Cancer surveillance could also be offered for the patient and his/her relatives."

In response, Dr. Eng wrote in a second email, "In our published article Tan MH et al. Am J Hum Genet 2011, we show that our PTEN CC Score based on prospective collection from the community and nomogram (which is a quantitative way of gauging prior probability of finding a PTEN mutation) are more accurate (actually greater adequacy) than the NCCN criteria."

"And by way of background," she continued, "the NCCN criteria were based on our original operational diagnostic criteria based on retrospective literature review (see Nelen M et al Nature Genet 1996). Thus, the NCCN criteria has become inadequate with time. If we only used the NCCN criteria, which was based on our Nelen paper, then we would be missing a lot of PTEN mutations."

"Please keep in mind," she added, "that our Nelen et al criteria (from whence the NCCN criteria are derived - I wrote these criteria too!) were very strict for research-based gene hunting. Clinical criteria MUST cast a broader net."

In 2015, managing patients as if they have PHTS/Cowden in absence of an identified PTEN mutation is not appropriate, Dr. Eng said, "because the prospective data which derive cancer risk are based on those with PTEN mutations. So we really don't know what the cancer risk is in those that look like Cowden syndrome but without PTEN mutations."

Also, she notes, her team's cancer risk estimates have been validated independently by two other groups, one in Europe and one in the U.S.

"Importantly, since our cost-effectiveness estimates are based on the very same cohort that we calculated cancer risk estimates, we are in fact comparing apples to apples," Dr. Eng concluded.

An online PTEN CC score calculator is available at


J Clin Oncol 2015.

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