NOTE: THIS STUDY IS NOW CLOSED. Funded testing is available for British Columbia patients with metastatic prostate cancer. Please see our Prostate Cancer page for details.
OVERVIEW
Metastatic castration-resistant prostate cancer is a heterogeneous disease that is often associated with a poor outcome. Loss of function mutations in genes involved in homologous recombination repair or DNA damage checkpoints, including BRCA1, BRCA2 and ATM, are identified in ~16% of patients. Prostate and other cancers with a mutation in one of these genes have been shown to be sensitive to treatment with poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors.
This next generation sequencing panel is offered to patients with metastatic castration-resistant prostate cancer who meet the pre-determined inclusion criteria (see below) and is currently funded by AstraZeneca and Merck Sharp. Sequencing of BRCA1, BRCA2 and ATM is performed on both the circulating tumour DNA (ctDNA) and genomic DNA isolated from peripheral blood leukocytes. Patients with a pathogenic or likely pathogenic mutation identified in one of these genes may be eligible to receive PARP inhibitor therapy.
The genes in this sequencing panel are strongly associated with inherited cancer predisposition syndromes and so patients with a mutation in their genomic DNA have an increased risk to develop other cancers. These patients would benefit from genetic counselling and a referral to the Hereditary Cancer Program at BC Cancer (or to the appropriate Medical Genetics program in the patient’s jurisdiction) is recommended.
The results of this test are not a substitute for germline screening. If a patient has clinical features or a personal or family history suggestive of an inherited syndrome then a Hereditary Cancer referral should be made, regardless of the results of this testing.
If sequencing of the cfDNA fraction fails to yield interpretable results, this patient may qualify for tumour based sequencing, please contact Hanxin Lin 
at London Health Sciences Centre for more information.
This video (https://drive.google.com/file/d/18BTEikOEow4uVFR9JHbW7PYp3NnT2N-x/view) provides more information on the biology of ctDNA and possible results of this testing.
INCLUSION CRITERIA FOR TESTING:
- Symptomatic or radiographic progression while on or immediately following current therapy (ARAT or taxane in combination with ongoing androgen deprivation therapy or prior surgical castration)
- ECOG performance status <= 2
- Lymph node only disease + high LDH higher than the upper limit of normal
PRIORITIZATION:
- Rising PSA
- Visceral or > 10 bone lesions (or lower number of metastatic lesions but with higher ALP)
- LDH > upper limit of normal
- ALP > upper limit of normal
EXCLUSION CRITERIA FOR TESTING:
- All: responding to current treatment
- Lymph node only (with LDH lower than the upper limit of normal)
- Prior Foundation Medicine / similar genomic testing
- Neuroendocrine prostate cancer
- ECOG performance status >= 3
METHOD
Peripheral blood is collected in Streck cfDNA tubes. The buffy coat is removed and genomic DNA is treated with proteinase K and extracted using a modified protocol. The circulating tumour DNA in the plasma is isolated following manufacturer’s recommendations (Promega Maxwell).
Sequencing and informatics services for this assay are provided by PHSA’s Centre for Clinical Genomics and results are interpreted by CGL. Single base and small insertion/deletion variants are screened in the targeted gene regions and variant classification is adapted from AMP/ASCP/CAP guidelines (Li et al. (2017) PMID:27993330) for ctDNA variants and ACMG guidelines (Richards et al. (2015) PMID: 25741868) for genomic DNA variants. Currently, homozygous copy number variants are identified and reported for the ctDNA portion of the analysis.
The limit of detection for single base and small insertion/deletion variants is 1% in the ctDNA and 10% for single base and small insertion/deletion variants in the germline. Large copy number alterations (duplication or deletion) > 30 bp, heterozygous copy number changes, other structural rearrangements including gene fusions, and variants in the promoter and other non-coding regions may are not detected by this test.