Cowden Syndrome With Germline PTEN Mutations Puts Patients at High Risk of Second Cancers
Cowden syndrome, an autosomal-dominant disorder characterized by the development multiple hamartomas, is associated with increased risk of breast, thyroid, endometrial, and renal cancers in patients with underlying germline PTEN mutations. In a study reported in the Journal of Clinical Oncology, Ngeow et al identified high risks of second malignant neoplasms in these patients.
Study Details
The study was a multicenter prospective study that followed 2,912 adult patients with Cowden syndrome or Cowden syndrome–like disease from 2005 to 2012. All patients underwent PTEN mutational analysis. Second cancers were identified from medical records and confirmed by pathology reports. Standardized incidence ratios (SIRs) for second cancers (excluding nonmelanoma skin cancers) were calculated by comparison with expected number of second cancers based on age-, sex-, and 5-year (calendar year)-specific U.S. incidence rates from the Surveillance, Epidemiology, and End Results (SEER) program from 1973 onward.
40% With Second Cancer
Among all patients, 2,024 had a history of invasive cancer. Germline pathogenic PTEN mutations were found in 114 patients (5.6%). Of these patients, 46 (40%) had a second cancer. Median age at diagnosis of second cancer was 50 years (range, 21–71 years), and the median interval between primary and second cancer was 5 years (range, < 1–35 years).
Risks of Second Cancers
Of the 51 PTEN mutation–positive patients with primary breast cancer, 11 (22%) had a new primary breast cancer, yielding a 10-year second breast cancer cumulative risk of 29% (95% confidence interval = 15.3–43.7). Compared with the general population, PTEN mutation–positive patients had significantly increased risk (all P < .05) of all second cancers (SIR = 7.74), breast cancer (SIR = 8.92), and thyroid cancer (SIR = 5.83); patients had nonsignificantly increased standardized incidence ratios for uterine cancer (14.80), renal cancer (4.09), melanoma (7.41), and colon cancer (6.20).
Excess absolute risk per 10,000 person-years was 364 for all cancers, 430 for breast cancer, 235 for thyroid cancer, 617 for uterine cancer, 310 for renal cancer, 344 for melanoma, and 319 for colon cancer, with the excess risk being significant (all P < .05) for uterine cancer, renal cancer, melanoma, and colon cancer.
The investigators concluded, “Patients with [Cowden syndrome] with germline PTEN mutations are at higher risk for [secondary malignant neoplasms] compared with the general population. Prophylactic mastectomy should be considered on an individual basis given the significant risk of subsequent breast cancer.”
Charis Eng, MD, PhD, of the Genomic Medicine Institute, Cleveland Clinic, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by grants from the National Cancer Institute and a grant from Case Comprehensive Cancer Center. The study authors reported no potential conflicts of interest.
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