Case study highlights importance of genomic testing in prostate cancer

A case study recently published in JCO Precision Oncology demonstrates the importance of genomic testing in guiding treatment decisions for patients with prostate cancer and informing at-risk family members.¹

NGS testing revealed a BRCA2 S1982fs mutation at 48.7% variant allele frequency (VAF), as well as an NFE2L2 K389T mutation of unknown clinical significance at 0.9% VAF.

"Our research shows that the identification of these genetic factors, even in geriatric patients, is important for determining targeted treatment and overall patient survival,” said lead author Mahdi Taha, DO, FACOI, FACP, in a news release on the study.² Taha is a hematologist and medical oncologist at Florida Cancer Specialists (FCS) in Palm Beach County, Florida.

The case study reported details of an 85-year-old male patient who presented to FCS with metastatic prostate cancer with a rising prostate-specific antigen (PSA) level.

In the 6 months prior to presentation, the male patient experienced a PSA rise from 4.2 to 80.4, prompting a PET/CT scan. Prostate-specific membrane antigen PET/CT showed avid hypermetabolism along the left half of an enlarged prostate with diffuse retroperineal and left pelvic hypermetabolic adenopathy as well as multiple presacral masses.

The patient was placed on a regimen of 80 mg subcutaneous degarelix (Firmagon) every 28 days as androgen deprivation therapy (ADT) and 60 mg subcutaneous denosumab (Xgeva) every 6 months for the prevention of skeletal-related events from chronic ADT. He has also been prescribed 100 mg fostamatinib (Tavalisse) twice daily, which is a tyrosine kinase inhibitor that has been shown to be effective against steroid-resistant chronic immune thrombocytopenia, of which the patient has a medical history.

In accordance with National Comprehensive Cancer Center (NCCN) guidelines, the patient underwent next-generation sequencing (NGS) testing with circulating tumor DNA (ctDNA) analysis. Findings showed a BRCA2 S1982fs mutation at 48.7% variant allele frequency (VAF), as well as an NFE2L2 K389T mutation of unknown clinical significance at 0.9% VAF.

The authors commented, “Considering the high VAF of the BRCA2 alteration being suspicious for potential germline origin as noted on the ctDNA test results report, this finding was both crucial to determine the treatment plan and inform potential implications to the patient's family members as this mutation was unknown to them prior.”

Further testing with the Invitae BRCA1 and BRCA2 Panel identified a germline BRCA2 exon 11 c.584del (p.Ser1982Argfs*22) heterozygous variant (6174delT). This sequence, according to the authors, creates a premature translational stop in the BRCA2 gene. Upon these findings, the patient and his family were recommended for genetic counseling.

Germline testing discovered that the patient’s daughter, who was in her 50s at the time, also carried a BRCA2 alteration. A subsequent mammogram revealed previously undetected breast cancer. The female patient was then started on treatment.

The authors wrote, “Had genomic testing never been done on our patient with [prostate cancer], the BRCA2 mutation would have been unknown to his daughter. It is unknown at this time whether additional family members received germline testing as well.”

At the time of data report, the patient with prostate cancer was responding positively to therapy, demonstrating a biomarker molecular reduction of PSA from 108.7 ng/mL to 3.4 ng/mL after 14 weeks of treatment. Further, a positive radiographic response was noted, with a 70% reduction of tumor burden on CT of the chest, abdomen, and pelvis and bone scan. If the patient’s cancer is determined to be castration-resistant, he will be prescribed a PARP inhibitor in addition to ADT.

Overall, the authors emphasized the importance of following NCCN guidelines and performing genomic testing, even in older patients.

They concluded, “However, age should not impede the performance of NGS. While the presence of a BRCA2 alteration presents opportunities for targeted therapy, it also holds the potential to offer affected families valuable generational insights, potentially saving numerous lives through an enriched understanding of family medical history.”

References

1. Taha M, Sirmans B, Haines K, Mustafa J, Masannat J. Next-generation sequencing testing can save generations of lives. JCO Precis Oncol. 2024 May:8:e2300695. doi: 10.1200/PO.23.00695

2. Mahdi Taha, DO, FACOI, FACP is lead author of case study demonstrating importance of genomic testing in early identification and treatment of cancer. News release. Florida Cancer Specialists & Research Institute. May 7, 2024. Accessed May 8, 2024. https://www.prnewswire.com/news-releases/mahdi-taha-do-facoi-facp-is-lead-author-of-case-study-demonstrating-importance-of-genomic-testing-in-early-identification-and-treatment-of-cancer-302138665.html