Second malignant neoplasms (SMN) in Cowden syndrome patients with underlying germline PTEN mutations.

Abstract

1527 Background: Cowden syndrome (CS) patients with underlying germline PTEN mutations are at significantly increased risks of breast, thyroid, endometrial and renal cancers. Current estimates of lifetime cancer risks do not provide the majority of patients who present after their first cancer a meaningful gauge of their risk of a SMN. Quantification of the risk of a SMN will allow patients to be better informed and provide clinicians a much needed guide to finally address patients’ question of “how likely am I to have a second cancer and will it likely be the same primary?” Methods: We conducted a 5-year, multi-center prospective study of CS and CS-like patients, all of whom had comprehensive PTEN analysis done. Patients’ records were reviewed for prior history of invasive cancers. Invasive SMNs were confirmed by pathology reports or physician reports where possible. All metastatic disease, synchronous primary cancer at the same site and non-melanoma skin cancers were excluded. Incidences of SMNs were compared between patients with pathogenic PTEN mutations (PTENmut+) and wildtype PTEN (PTENwt). Standardized incidence ratios (SIR), cumulative incidences and excess absolute risks for SMNs were calculated comparing against SEER-derived data. Results: Of 2,792 CS/CS-like patients who present with 1 or more cancers, there were 100 (4%) PTENmut+patients. Compared with PTENwt CS/CS-like patients with SMNs (223/2039; 11%), PTENmut+cases (42/100; 42%) were more likely to develop SMNs (p<0.0001). PTENmut+ cases were also younger at median age of SMN diagnosis (48yrs vs 54 yrs; p=0.30). PTENmut+ patients were 56-fold more likely to develop any SMN compared with the general population (95%CI 41-55); corresponding to an excess absolute risk of 731/10000 person years. Breast cancer was the most common SMN encountered in PTENmut+CS/CS-like patients (SIR 73; 95%CI 45-122) followed by endometrial (SIR 44; 95% CI 18-92), renal (SIR 47; 95% CI 15-113) and thyroid cancers (SIR 222; 95% CI 37-734). Conclusions: Our study shows that PTENmut+CS/CS-like patients are significantly more likely to present with a SMN compared to PTENwt CS/CS-like patients and the general population, and should be advised and surveillanced accordingly.