PURPOSE: Patients with PTEN Hamartoma Tumor Syndrome (PHTS) have high hereditary cancer risks for breast, endometrial, and thyroid cancer. Patients develop multiple primary cancers, but these risks remain uncertain. We aimed to provide the second primary cancer risk.

METHODS: This European cohort study assessed second primary cancer risks with Kaplan-Meier analyses using data from medical files and/or registries.

RESULTS: Overall, 279 adult patients with PHTS with cancer were included (80% female). Among females, 112 (54%) developed a PHTS-related second primary cancer after PHTS-related first primary cancer, whereas 11 (30%) males developed a PHTS-related second primary cancer after PHTS-related first primary cancer. Five- and ten-year PHTS-related second primary cancer risks were 23% (95%CI=16-31) and 46% (95%CI=37-56) for females, and 18% (95%CI=8-38) and 23% (95%CI=11-45) for males, respectively. Furthermore, five- and ten-year risks for second primary breast cancer after first primary breast cancer were 23% (95%CI=15-35) and 46% (95%CI=33-60), respectively.

CONCLUSION: This study demonstrated that patients with PHTS have high second primary cancer risks, which is driven by breast cancer in females. Hence, identifying patients with PHTS before or at first primary cancer diagnosis is essential to enable potential early detection or prevention of second primary cancer through surveillance or risk-reducing surgery.