CG Consult of the week 08.11.2023

Case History

An 80-year-old male was diagnosed with metastatic prostate cancer when he presented with back pain. PSMA-based PET imaging showed oligometastatic disease with nodal and bone lesions. The patient received radiotherapy and started on androgen deprivation therapy plus upfront docetaxel and completed 8 cycles, then therapy was switched to enzalutamide. PSA initially improved and then started rising. The patient started on Lutetium-177 PSMA therapy in addition to enzalutamide. The patient received four cycles with significant improvement in PSA. PSMA-based imaging before the next cycle showed mixed response. A new biopsy was taken and sent for genomic profiling to aid clinical decision making going forward.

Genomic Profiling Results:

  • FBXW7 R505C
  • MTOR G5R
  • NOTCH1 P1641S
  • AR amplification
  • RAD21 amplification
  • LYN amplification
  • TP53 V272M

Questions from the oncologist:

  • Are there any targetable mutations here to inform further treatment?
  • Might this patient benefit from PARP inhibitors?
  • Are there any novel therapeutic combinations we should be aware of?


This tumor multiple aberrations in the PI3K-AKT-mTOR pathway, which suggest pathogenesis through PI3K pathway signalling (detected 40% of prostate cancers) activated through FBXW7 and MTOR mutations (1). The AR amplification may have been selected by prior therapy, as it confers resistance to hormonal therapies like enzalutamide (2).
Part of the ubiquitin ligase complex, FBXW7 recognizes and binds target proteins for ubiquitination and degradation. Loss of FBXW7 function is associated with increased mTOR pathway signalling activity, as mTOR is one of its substrates (3). The mTORC1 inhibitor everolimus has shown limited clinical efficacy, albeit with high rates of adverse events in prostate cancer patients (4-6). AKT inhibition has shown promise in patients with metastatic prostate cancers with PTEN loss, as shown in the phase III IPATential 150 trial, but the trial excluded patients who had prior treatment for castration-resistant disease, so it is unclear whether these data apply here (7). One might consider a clinical trial of an AKT inhibitor like capivasertib in a case like this (8).
The question raised about PARP inhibitors may refer to the RAD21 amplification, a gene involved in the DNA repair pathway. A recent study suggested that patients with ovarian cancer harboring RAD21 amplification had inferior outcomes (9-10).
There is interest in dasatinib for prostate cancer patients with LYN-activated tumors. LYN is a Src-family kinase and preclinical data in prostate cancers suggest that LYN overexpression enhances AR transcriptional activity and accelerates growth of CRPC cells (11). Although dasatinib showed limited activity in advanced mCRPC in a phase III study (12), the response was definitive, but with significant toxicity in earlier trials (13). Treatment with a regimen of dasatinib and docetaxel demonstrated improvements in bone scans and high rates of soft tissue responses (13). Notably, two subjects survived after 2.5 years on dasatinib single agent therapy after discontinuing docetaxel treatment(14).

Learnings From This Case: 

  • Comprehensive genomic profiling can offer insights into difficult-to-treat cancer such as mCRPC
  • Recent clinical trial data from studies exploring AKT inhibitors in prostate cancer is promising
  • Not all genes in DNA damage repair pathway behave equally
  • The addition of dasatinib to docetaxel may provide meaningful benefit to some patients with metastatic CRPC



Disclaimer: all CGCotW cases are based on a true story. No resemblance to persons alive or deceased is intended or should be inferred. ©️ CGC Genomics Consults AG

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