PTEN loss
PTEN is the brake on the PI3K/AKT growth pathway; when a tumour deletes or mutates it (seen as a lost stain or on sequencing) the pathway runs unopposed. In hormone-treated breast cancer PTEN loss is one of the three changes that qualify a woman for capivasertib, in prostate cancer it marks aggressive disease, and in endometrial cancer it is almost universal in the NSMP group.
Overview
What is measured: loss of the PTEN phosphatase, by deletion, mutation or silencing. How: immunohistochemistry (loss in tumour cells with retained staining in stroma, validated in prostate cancer), next-generation sequencing of tissue or plasma for mutations and homozygous deletion, FISH for 10q23; germline PTEN testing for Cowden syndrome (macrocephaly, hamartomas, breast, thyroid and endometrial cancer risk). Frequencies: 50 to 80 percent of endometrial cancers (NSMP and mismatch repair-deficient classes), about 40 percent of glioblastomas, 20 percent of localised and 40 to 50 percent of castration-resistant prostate cancers (often with TP53 and RB1 loss), 5 to 7 percent of hormone receptor-positive breast cancers (PIK3CA, AKT1 and PTEN together about half), and melanoma and triple-negative breast cancer. What a result changes: in HR-positive, HER2-negative breast cancer after endocrine progression, a PIK3CA, AKT1 or PTEN alteration qualifies for capivasertib with fulvestrant (CAPItello-291, progression-free survival 7.3 against 3.1 months in the altered group); in prostate cancer PTEN loss carries an adverse prognosis, ipatasertib with abiraterone improved radiographic progression-free survival in PTEN-loss tumours in IPATential150 without approval, and capivasertib with abiraterone reported a benefit in CAPItello-281; in endometrial cancer it underpins mTOR and PI3K inhibitor trials and everolimus with letrozole; a germline finding sets lifelong surveillance. Where it matters: HR-positive breast cancer, metastatic prostate cancer, NSMP endometrial cancer and chromophobe RCC.
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