Annotation Detail

Information
Associated Genes
PTEN
Associated Variants
PTEN DELETION ( ENST00000371953.8 )
PTEN DELETION ( ENST00000371953.8 )
Associated Disease
Her2-receptor positive breast cancer
Source Database
CIViC Evidence
Description
Archival tumor samples from 549 patients from the BOLERO-1 and -3 trials were analyzed for alterations in the PI3K pathway using next-generation sequencing, immunohistochemistry (IHC) and Sanger sequencing. In the BOLERO trials, patients with HER2-overexpressing advanced breast cancer were treated with trastuzumab, chemotherapy and randomized to receive either everolimus or placebo. In the pooled analysis of both trials, patients with PTEN loss (as defined by IHC staining intensity and proportion of positive tumor cells) had a longer progression-free survival with everolimus compared to placebo (HR 0.54 (95%CI 0.31 to 0.96, P=0.04) whereas patients with PTEN normal status had a hazard ration of 1.00 (95%CI 0.8 to 1.26, P=0.97). The same was found when PI3K mutations, PTEN loss and AKT E17K mutations were combined and analyzed as hyperactive PI3K pathway. Patients with PI3K hyperactive pathway had a hazard ratio of 0.67 (95%CI 0.48 to 0.93, P=0.02) compared to HR 1.19 (95%CI 0.87 to 1.62, P=0.28) in patients with PI3K normal pathway. These trends were independently confirmed in both trials but only pooled results showed consistent statistical significance.
Variant Origin
somatic
Variant Origin
Somatic
Evidence URL
https://civic.genome.wustl.edu/links/evidence_items/1297
Gene URL
https://civic.genome.wustl.edu/links/genes/41
Variant URL
https://civic.genome.wustl.edu/links/variants/214
Rating
4
Evidence Type
Predictive
Disease
Her2-receptor Positive Breast Cancer
Evidence Direction
Supports
Drug
Everolimus
Evidence Level
B
Clinical Significance
Sensitivity/Response
Pubmed
27091708
Drugs
Drug NameSensitivitySupported
EverolimusSensitivitytrue