Missing content? – Request curation!
Request curation for specific Genes, Variants, or PubMed publications.
Have questions, comments, or suggestions? - Let us know!
Email us at : ckbsupport@genomenon.com
| Ref Type | Journal Article | ||||||||||||
| PMID | (31176623) | ||||||||||||
| Authors | Isaacsson Velho P, Fu W, Wang H, Mirkheshti N, Qazi F, Lima FAS, Shaukat F, Carducci MA, Denmeade SR, Paller CJ, Markowski MC, Marshall CH, Eisenberger MA, Antonarakis ES | ||||||||||||
| Title | Wnt-pathway Activating Mutations Are Associated with Resistance to First-line Abiraterone and Enzalutamide in Castration-resistant Prostate Cancer. | ||||||||||||
|
|||||||||||||
| URL | |||||||||||||
| Abstract Text | Wnt signaling is a cellular pathway involved in embryogenesis, development, and neoplasia. Wnt-pathway activation may accelerate prostate cancer androgen-independent growth and mediate antiandrogen resistance. Since 10-20% of advanced prostate cancers harbor Wnt-activating mutations, we aimed to characterize the clinical features and response to novel antiandrogens in such patients.To determine whether men with metastatic castration-resistant prostate cancer (mCRPC) who harbor Wnt-pathway mutations have poorer responses to first-line novel hormonal therapies: abiraterone/enzalutamide.Patients with mCRPC who received first-line abiraterone or enzalutamide were retrospectively evaluated. Using tumor DNA analyses, we queried for activating mutations in CTNNB1 or inactivating mutations in APC or RNF43, all of which are predicted to stimulate Wnt signaling. Presence or absence of at least one Wnt-activating alteration was correlated with clinical-pathologic characteristics and treatment outcomes.Time to prostate-specific antigen (PSA) progression, overall survival (OS), and PSA response were measured. Cox regression models were used to test associations between Wnt status and clinical-pathologic outcomes; Kaplan-Meier and log-rank analyses were used to compare time-to-event endpoints.Of 137 patients evaluated, 11% (n=15) had tumor DNA analysis showing at least one Wnt-stimulating alteration. Patients with Wnt-activating mutations had numerically fewer T3/T4 tumors than Wnt wild-type patients (31% vs 51%), but were otherwise generally balanced. Median time to PSA progression on first-line abiraterone/enzalutamide was shorter in Wnt-activated patients (6.5 vs 9.6mo, hazard ratio [HR] 2.34, p=0.003), as was OS (23.6 vs 27.7mo, HR 2.28, p=0.01). PSA responses were numerically worse in Wnt-activated patients (53% vs 75%, p=0.12). Presence of Wnt-activating alterations (adjusted HR [aHR] 2.33, p=0.007) and use of previous chemotherapy (aHR 1.83, p=0.004) were both independently associated with increased hazard of progression.Patients with somatic Wnt-pathway activating mutations have worse outcomes to first-line abiraterone/enzalutamide than Wnt wild-type patients. Our data suggest that additional genomically informed therapies are needed for this relevant subset of mCRPC patients.In this report, we retrospectively examined outcomes of metastatic prostate cancer patients with or without Wnt-pathway mutations who received abiraterone or enzalutamide for the first time, in order to examine whether these mutations affect the prognosis. Our study suggested that patients who have Wnt-pathway activating mutations derived less benefit from abiraterone and enzalutamide when compared to patients without these mutations. We conclude that Wnt-pathway mutations might decrease the effectiveness of abiraterone and enzalutamide, and we propose that the Wnt pathway might be a good therapeutic target for these patients, in order to potentially reverse or prolong resistance to abiraterone and enzalutamide in men with Wnt mutations. | ||||||||||||
| Molecular Profile | Treatment Approach |
|---|
| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
|---|
| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
|---|
| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
|---|
| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
|---|---|---|---|---|---|
| TSC2 | A678T | missense | unknown | TSC2 A678T does not lie within any known functional domains of the Tsc2 protein (UniProt.org). A678T has been identified in sequencing studies (PMID: 29642553, PMID: 31176623, PMID: 35358259), but has not been biochemically characterized and therefore, its effect on Tsc2 protein function is unknown (PubMed, Oct 2024). |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| APC inact mut | prostate cancer | decreased response | Abiraterone | Clinical Study | Actionable | In a clinical study, metastatic castrate-resistant prostate cancer patients harboring a Wnt pathway activating alteration demonstrated shorter median overall survival (23.6 mo vs 27.7 mo) and median time to PSA progression (6.5 mo vs 9.6 mo) following Zytiga (abiraterone) or Xtandi (enzalutamide) treatment compared to patients without Wnt pathway alterations, and APC or RNF43 inactivating mutations were independently associated with increased hazard of PSA progression (aHR 1.83; p=0.004) (PMID: 31176623). | 31176623 |
| APC inact mut | prostate cancer | decreased response | Enzalutamide | Clinical Study | Actionable | In a clinical study, metastatic castrate-resistant prostate cancer patients harboring a Wnt pathway activating alteration demonstrated shorter median overall survival (23.6 mo vs 27.7 mo) and median time to PSA progression (6.5 mo vs 9.6 mo) following Zytiga (abiraterone) or Xtandi (enzalutamide) treatment compared to patients without Wnt pathway alterations, and APC or RNF43 inactivating mutations were independently associated with increased hazard of PSA progression (aHR 1.83; p=0.004) (PMID: 31176623). | 31176623 |