Testing for BRCA Mutations and HRR Status in Prostate Cancer
Insights on when to test for BRCA mutations and HRR (homologous recombination repair) status when treating patients with prostate cancer, and whether to utilize tissue testing or ctDNA assays.
Case: A 65-Year-Old Man With Prostate Cancer
January 2018
Initial Presentation
- A 65-year-old man was diagnosed with localized prostate cancer
- Biopsy revealed adenocarcinoma of the prostate gland, Gleason score 7 [4+3]
- PSA 15.7 ng/mL
- Baseline staging: T3bN1M0 with right seminal vesicle and pelvic lymph node involvement
Initial Treatment
- He undergoes radical prostatectomy with PLND
- PSA nadir of 0.4 ng/mL post-surgery
- Gleason 7 (4 + 3) confirmed
- Positive surgical margins
- Baseline staging confirmed – AJCC Stage IVA
February 2019
Follow-Up Notes
- Serum PSA, 38 ng/mL; ALP, 289 IU/L
- PSMA PET CT:
- Metastatic retroperitoneal LNs outside resection field
- Abdominal nodes
- Bone mets in ribs and thoracic spine
- Genetic testing: BRCA2 mutation-positive
Additional Treatment
- Abiraterone + prednisone initiated
- Improved pain, PSA, and ALP
October 2019
Follow-Up Notes
- Patient reported bone pain
- Laboratory testing revealed rising PSA and ALP (serum PSA, 350 ng/mL; ALP, 2500 IU/L)
- Imaging showed radiologic progression
- ECOG PS 1
- PSMA PET CT: increased uptake in retroperitoneal and abdominal LNs
mCRPC Treatment
- Treated with docetaxel x4 cycles and denosumab
- Serum PSA, 38 ng/mL; ALP, 289 IU/L
- Reporting bone pain increased in back, now reporting pain in hip area
- Bone scan and CT scan:
- Enlargement of retroperitoneal and abdominal LNs
- Additional bone mets noted in pelvic region
Transcript:
Daniel J. George, MD: When I think about genetic testing for tumors in patients, specifically looking for homologous recombinant repair defects or alterations, I think about a couple of times in the disease course. The first is when patients develop recurrent or metastatic disease. This is a critical time because this is where our patients with localized disease now have separated, those who are destined to have a long-term remission and maybe cure from those who have disease recurrence and particularly spread. These are the patients that ultimately have a much higher risk of lethal prostate cancer, and we want to know early on if they’re harboring any genetic alterations that are actionable, things that we would use specific precision medicine approaches towards, and the most common one for that is homologous recombinant repair defects.
The timing to check for those is early in the disease course, as soon as we see evidence of disease recurrence, and we can check for it a couple of different ways. We can use the original tumor tissue, and that’s been the gold standard for looking at these, and my preference. When I have a patient that has a very rapid disease progression from their initial biopsies or surgeries to recurrent or metastatic disease, I like to send that primary tissue because we have a lot of the disease present, and because it hasn’t undergone any stressors or selection processes from systemic therapies. It’s still emblematic of that disease that we’re treating. I like to send that tissue, but I recognize that it’s not perfect. There are circumstances where the tissue doesn’t necessarily reveal the mutations: the sample sent may not be representative of the most aggressive phenotype of disease within that tumor, it can be heterogeneous, and there can be noncancer tissue that is thought to be cancer and then when sent for sampling it isn’t representative of the cancer. There are limitations to those initial prostatectomy or biopsy samples.
Another choice is to biopsy, and in a patient like this, where we see retroperitoneal lymphadenopathy, it’s something that we can biopsy typically through a CT guidance. If the nodes are large enough, it can be done with high yield. It’s another option, particularly if there’s been, say, a treatment selection in between, a hormone radiation approach, to try to knock down this disease following surgery. Then, disease recurs after that. This is now more likely to represent castrate-resistant disease or maybe other biology selection different from the original sample. So biopsy is helpful.
Then a third approach is to use circulating tumor DNA [ctDNA], and I like that because it’s noninvasive. It’s something that’s relatively quick to turn around. It has good concordance, not perfect, but good with the primary tumor, so it can pick up many of the alterations that we’re looking for. If the patient has rapidly progressive disease and new metastases, these are the situations where the yield on the ctDNA is very high. Those are the 3 somatic approaches that’ll undertake in those different circumstances.
Then there’s germline, and I always want to check germline in patients because of 2 things. One, because if we find an alteration, we want to know if that’s inheritable. It has implications both in terms of the truncal nature of that biology, but also in terms of any inherited risk to other family members that could be carriers of that same genetic alteration. Secondly, there are circumstances where our biopsy doesn’t reveal an alteration, but on the germline we find something. These are unusual circumstances, and when I see that, it encourages me to recheck the somatic alterations, usually by a different modality, a new biopsy, or circulating tumor DNA, to see if we can find that alteration because sometimes it can be present and we’ll see it on the germline but not on the initial sample, but on a subsequent sample. Those are the rationales and approaches that I take. The other setting is when patients present with metastatic disease at diagnosis. These are patients I absolutely want to check the genetic alterations for early on, because again, it has prognostic information. But it can also help me and guide in our subsequent treatment approaches to these patients.
Transcript edited for clarity.
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