Decoding the Impact of CHIP on Prostate Cancer Treatment: Implications for PARP Inhibitor Eligibility - Kendal Jensen
October 11, 2021
Thomas Keane hosts Kendal Jensen who presents his team’s groundbreaking research on the interference of Clonal Hematopoiesis in DNA Repair Genes with Prostate Cancer Plasma Cell-free DNA Testing. Dr. Jensen's study, conducted in collaboration with Dr. Colin Pritchard of the University of Washington, reveals that Clonal Hematopoiesis of Indeterminate Potential (CHIP) can significantly interfere with cell-free DNA testing, leading to potential misdiagnosis and over-treatment with PARP inhibitors. The study emphasizes the high prevalence of CHIP, particularly among older patients, and its impact on treatment recommendations. Dr. Jensen strongly advocates for the inclusion of whole blood control in cfDNA testing to ensure accurate results. Both Drs. Keane and Jensen agree that the findings represent a major advancement in the treatment of prostate cancer patients.
Biographies:
Kendal Jensen, MD, PhD, Fellow, Molecular Genetic Pathology, Clinical Pathologist, University of Washington Medical Center
Thomas E. Keane, MBBCh, FRCSI, FACS, Department of Urology, The Medical University of South Carolina, Charleston, South Carolina
Biographies:
Kendal Jensen, MD, PhD, Fellow, Molecular Genetic Pathology, Clinical Pathologist, University of Washington Medical Center
Thomas E. Keane, MBBCh, FRCSI, FACS, Department of Urology, The Medical University of South Carolina, Charleston, South Carolina
Read the Full Video Transcript
Thomas Keane: Good afternoon, everybody. This is Tom Keane coming to you from UroToday. Today we have a very interesting topic. There was a fascinating paper that was published in JAMA Oncology recently, and the lead author was Kendal Jensen, who is an MD, Ph.D. He's a Molecular Genetic Pathologist and a Clinical Pathologist, and he is working at Sharp HealthCare as The Director of Molecular Genetic Pathology, which is the administration of molecular genetics and supervising the formation of LDTs and genetic reporting for Sharp Health System and the Pacific Rim Pathology Group.
He's been in this position since 2020, and he recently published a paper called the Association of Clonal Hematopoiesis in DNA Repair Genes with Prostate Cancer Plasma Cell-free DNA Testing Interference. The reason this caught my eye is it is relevant to some of the more recent treatments which we have been using for prostate cancer, particularly some of the novel compounds.
I don't want to steal his thunder, so I will let him go ahead. He's going to do a presentation for us today, and then hopefully will answer some questions at the end of it. So Kendal, thank you very much for coming on, and we look forward to hearing what you have to say.
Kendal Jensen: Thank you, Dr. Keane, for having me. I would also like to thank Dr. Colin Pritchard of the University of Washington. The University of Washington performs whole blood control alongside plasma so that they can make better recommendations for PARP inhibitors. PARP inhibitors are considered a breakthrough therapy for metastatic prostate cancer. The eligibility for PARP inhibitor therapy is based on gene mutations within metastatic castration-resistant prostate cancer.
I became part of this project at the University of Washington while I was doing tumor boards as a fellow, and we happened to have a patient that was referred out for cell-free DNA testing at a reference laboratory and received a result that said that there was a BRCA2 mutation, and there was a recommendation for PARP inhibitors on that report. And since we also performed testing of the same patient's cell-free DNA, we found the same mutation. However, we saw that that mutation was associated with a white blood cell clone and not the patient's prostate cancer.
So, Colin and I planned this project to retrospectively review several years' worth of cell-free DNA testing and determine which patients had clonal hematopoiesis of indeterminate potential (CHIP) clones. We did not realize at the time the impact of our study. We expected that there would be a prevalence rate for CHIP, but we just did not anticipate that the prevalence would be so high. And in the higher age group especially, the decade of life 80 to 90-year-olds, CHIPs were the majority of patients rather than the minority, and the prevalence was still at 20% for the 70 to 80-year-old decade.
So in addition to CHIP, we also were able to determine germline variation by using a whole blood control where we are able to see both CHIP and germline mutations. This plot shows all patients that we analyzed, and these came between the ages of 40 and 87. And we plotted the CHIP interference and the somatic, the real prostate cancer mutations, and the germline mutations.
We found that most of the mutations seen within the PARP inhibitor eligibility were within the ATM gene. And we also saw one in BRCA2, which I mentioned, and one in CHEK2. We also saw other genes that were important: ASXL 1, DMT 3A, TET2, and TP53. We had a total of seven CHIP clones, five of these were in the ATM gene, one was in the BRCA2 gene, and one was in CHEK2.
We felt it was important to mention that the mutation that we observed in ATM ... or that we observed one in ATM and one in BRCA2 that were both reported by outside laboratories, and there was a recommendation for PARP inhibitor treatment in the BRCA2.
So of all positives reported, 65% of these were correct before the CHIP correction that we performed. However, after correction, it was 100%, meaning that these patients would go on to be referred for PARP inhibitor therapy regardless of the true positivity.
So in conclusion, CHIP interferes with cfDNA testing for somatic variants in metastatic prostate cancer, and there is a real risk for misdiagnosis and over-treatment of men by PARP inhibitor therapy, and whole blood control is able to control for this. And so, we highly recommend to labs performing testing that they perform a whole blood control alongside the plasma or whichever method they prefer, that they still should be performing a whole blood control on cfDNA testing. Thank you.
Thomas Keane: That was great. I really do believe it is a very important thing that people be aware of, but also for the companies who do this work, that they are aware of it, and I think it's a huge step forward, if you like, in identifying who should or shouldn't get these compounds. They are great, but only with the right people.
Kendal Jensen: That's right. And yeah, it's tragic to know that people are administered treatments that are not going to benefit from them.
Thomas Keane: Yeah, absolutely. Well listen, thank you very much for doing this. We will be in touch, and congratulations because it really is, in my opinion, a major change and a major addition to how we treat our patients. So, thank you very much.
Thomas Keane: Good afternoon, everybody. This is Tom Keane coming to you from UroToday. Today we have a very interesting topic. There was a fascinating paper that was published in JAMA Oncology recently, and the lead author was Kendal Jensen, who is an MD, Ph.D. He's a Molecular Genetic Pathologist and a Clinical Pathologist, and he is working at Sharp HealthCare as The Director of Molecular Genetic Pathology, which is the administration of molecular genetics and supervising the formation of LDTs and genetic reporting for Sharp Health System and the Pacific Rim Pathology Group.
He's been in this position since 2020, and he recently published a paper called the Association of Clonal Hematopoiesis in DNA Repair Genes with Prostate Cancer Plasma Cell-free DNA Testing Interference. The reason this caught my eye is it is relevant to some of the more recent treatments which we have been using for prostate cancer, particularly some of the novel compounds.
I don't want to steal his thunder, so I will let him go ahead. He's going to do a presentation for us today, and then hopefully will answer some questions at the end of it. So Kendal, thank you very much for coming on, and we look forward to hearing what you have to say.
Kendal Jensen: Thank you, Dr. Keane, for having me. I would also like to thank Dr. Colin Pritchard of the University of Washington. The University of Washington performs whole blood control alongside plasma so that they can make better recommendations for PARP inhibitors. PARP inhibitors are considered a breakthrough therapy for metastatic prostate cancer. The eligibility for PARP inhibitor therapy is based on gene mutations within metastatic castration-resistant prostate cancer.
I became part of this project at the University of Washington while I was doing tumor boards as a fellow, and we happened to have a patient that was referred out for cell-free DNA testing at a reference laboratory and received a result that said that there was a BRCA2 mutation, and there was a recommendation for PARP inhibitors on that report. And since we also performed testing of the same patient's cell-free DNA, we found the same mutation. However, we saw that that mutation was associated with a white blood cell clone and not the patient's prostate cancer.
So, Colin and I planned this project to retrospectively review several years' worth of cell-free DNA testing and determine which patients had clonal hematopoiesis of indeterminate potential (CHIP) clones. We did not realize at the time the impact of our study. We expected that there would be a prevalence rate for CHIP, but we just did not anticipate that the prevalence would be so high. And in the higher age group especially, the decade of life 80 to 90-year-olds, CHIPs were the majority of patients rather than the minority, and the prevalence was still at 20% for the 70 to 80-year-old decade.
So in addition to CHIP, we also were able to determine germline variation by using a whole blood control where we are able to see both CHIP and germline mutations. This plot shows all patients that we analyzed, and these came between the ages of 40 and 87. And we plotted the CHIP interference and the somatic, the real prostate cancer mutations, and the germline mutations.
We found that most of the mutations seen within the PARP inhibitor eligibility were within the ATM gene. And we also saw one in BRCA2, which I mentioned, and one in CHEK2. We also saw other genes that were important: ASXL 1, DMT 3A, TET2, and TP53. We had a total of seven CHIP clones, five of these were in the ATM gene, one was in the BRCA2 gene, and one was in CHEK2.
We felt it was important to mention that the mutation that we observed in ATM ... or that we observed one in ATM and one in BRCA2 that were both reported by outside laboratories, and there was a recommendation for PARP inhibitor treatment in the BRCA2.
So of all positives reported, 65% of these were correct before the CHIP correction that we performed. However, after correction, it was 100%, meaning that these patients would go on to be referred for PARP inhibitor therapy regardless of the true positivity.
So in conclusion, CHIP interferes with cfDNA testing for somatic variants in metastatic prostate cancer, and there is a real risk for misdiagnosis and over-treatment of men by PARP inhibitor therapy, and whole blood control is able to control for this. And so, we highly recommend to labs performing testing that they perform a whole blood control alongside the plasma or whichever method they prefer, that they still should be performing a whole blood control on cfDNA testing. Thank you.
Thomas Keane: That was great. I really do believe it is a very important thing that people be aware of, but also for the companies who do this work, that they are aware of it, and I think it's a huge step forward, if you like, in identifying who should or shouldn't get these compounds. They are great, but only with the right people.
Kendal Jensen: That's right. And yeah, it's tragic to know that people are administered treatments that are not going to benefit from them.
Thomas Keane: Yeah, absolutely. Well listen, thank you very much for doing this. We will be in touch, and congratulations because it really is, in my opinion, a major change and a major addition to how we treat our patients. So, thank you very much.