This study indicates not enough metastatic PCa patients are having Next Generation Sequence testing (NGS)

[Graham49]

This cohort study indicates that more and earlier NGS testing may prolong the radiographic survival of patients with BRCA or other homologous recombination repair (HRR) alterations.

Trends and Disparities in Next-Generation Sequencing in Metastatic Prostate and Urothelial Cancers

JAMA Netw Open. 2024;7(7):e2423186. doi:10.1001/jamanetworkopen.2024.23186

“Question What is the association between social determinants of health and rates of next-generation sequencing (NGS) in patients with metastatic prostate or urothelial cancer?”

“Findings In this cohort study of 11 927 patients with metastatic prostate cancer and 6490 patients with advanced urothelial carcinoma, NGS rates increased over time. Black race, low socioeconomic status, and Medicaid and Medicare insurance coverage were associated with lower NGS rates in both cohorts.”

“Meaning These findings suggest that despite the presence of actionable susceptible alterations in prostate and urothelial cancers, the majority of patients still do not undergo NGS, stressing the need to improve access to quality health care.”

“For instance, the presence of BRCA or other homologous recombination repair (HRR) alterations, found in approximately 30% of patients with advanced prostate cancer,6 makes patients eligible for poly (ADP-ribose) polymerase inhibitor (PARPi) monotherapy with olaparib or rucaparib or PARPi-based combinations, such as olaparib with abiraterone, niraparib with abiraterone, and talazoparib with enzalutamide, in the metastatic castration-resistant prostate cancer (mCRPC) setting.7-9 Furthermore, in patients with metastatic hormone-sensitive prostate cancer (mHSPC), the presence of SPOP-susceptible alterations was associated with improved outcomes in patients receiving androgen deprivation therapy intensification with an androgen receptor pathway inhibitor.”

“Importance Targeted therapies based on underlying tumor genomic susceptible alterations have been approved for patients with metastatic prostate cancer (mPC) and advanced urothelial carcinoma (aUC).”

“In patients with mPC, the rate of NGS increased from 19.0% in 2015 to 27.1% in 2022. This low rate in 2022 aligns with previous data suggesting a low testing rate in patients with prostate cancer, who were 10 times less likely to undergo NGS testing than patients with lung cancer and 4 times less likely than those with colorectal cancer.31 In another study, only 10.4% of patients with mPC underwent testing within 30 days of the metastatic disease diagnosis.”

“The PARPis have substantially improved survival outcomes in patients with mCRPC. For instance, in the PROfound (Olaparib [Lynparza] Versus Enzalutamide or Abiraterone Acetate in Men With mCRPC) trial, patients harboring HRR alterations who received olaparib had a 51% reduction in the risk of radiographic progression or death compared with those treated with the physician’s choice of enzalutamide or abiraterone. Similarly, in the TALAPRO-2 (Talazoparib Plus Enzalutamide Versus Enzalutamide Monotherapy in mCRPC) trial, patients with HRR alterations treated with talazoparib and enzalutamide had a 54% reduction in the risk of radiographic progression or death compared with those treated with enzalutamide alone. It is important to highlight that delays in NGS testing of tumors may lead to difficulties with NGS assessment due to loss of tumor tissue quantity and quality over time. For example, in the PROfound trial, one-third of patients could not enroll due to unsuccessful sequencing.“

[cesanon]

Hmmm

For instance, the presence of BRCA or other homologous recombination repair (HRR) alterations, found in approximately 30% of patients with advanced prostate cancer

I didn't realize that genetic aberrations are so common that they can inform treatments so often.

[Graham49 in reply to cesanon]

This statement is from Reference 6 of the paper: "Metastatic castration-resistant prostate cancer is a heterogeneous disease with poor outcomes.1-6 Tumors in up to 30% of patients harbor deleterious aberrations in genes involved in repairing DNA damage.1-3 Among the most common of these alterations, BRCA1 and BRCA2 are well-characterized genes involved in homologous recombination repair, and ATM functions as a DNA-damage checkpoint and indirectly activates homologous recombination repair.7,8"

I have not checked Refrerences 1 and 3 of that paper. I leave that to you or another member!

[MarylandGuy in reply to cesanon]

I am one of those patients. I am on a parp inhibitor now after nebeqa stopped working.

[dentaltwin]

I assumed that this referred to NGS of somatic mutations, but this in fact is not clear; from the limitations:

"Furthermore, this study does not differentiate between patients who underwent somatic vs germline NGS testing."

Maybe both, but to me this is a pretty glaring omission.

[Graham49 in reply to dentaltwin]

The source data includes somatic and germline data.

1.

Abida W, Armenia J, Gopalan A, et al.

Prospective genomic profiling of prostate cancer across disease states reveals germline and somatic alterations that may affect clinical decision making. JCO Precis Oncol 2017 May 31 (Epub ahead of print).

doi.org/10.1200/PO.17. 00029

“We successfully sequenced 504 tumors from 451 patients with prostate cancer. Potentially actionable alterations were identified in DNA damage repair, phosphatidylinositol 3-kinase, and mitogen-activated protein kinase pathways. Twenty-seven percent of patients harbored a germline or a somatic alteration in a DNA damage repair gene that may predict for response to poly (ADP-ribose) polymerase inhibition. Profiling of matched tumors from individual patients revealed that somatic TP53 and BRCA2 alterations arose early in tumors from patients who eventually developed metastatic disease. In contrast, comparative analysis across disease states revealed that APC alterations were enriched in metastatic tumors, whereas ATM alterations were specifically enriched in castration-resistant prostate cancer.

“In total, 24% of patients carried somatic alterations in the PI3K/AKT pathway, including in PTEN, PIK3CA, PIK3CB, PIK3R1, AKT1, and AKT3 (Appendix Fig A4). The majority of point mutations in PIK3CA, AKT1, and AKT3 were known activating hotspot mutations in those genes.11 In addition, 5% of patients harbored somatic alterations in mitogen-activated protein kinase pathway genes (Appendix Fig A5), including hotspot mutations in BRAF, HRAS, KRAS, and MAP2K1.”

“Fifteen percent of patients carried somatic alterations in the Wnt-β catenin pathway, including in APC, CTNNB1, and RNF43 (Appendix Fig A6). Consistent with the results of the SU2C-PCF study, 22% of patients harbored a somatic alteration in a gene that is involved in DDR by homologous recombination, including BRCA2, BRCA1, ATM, FANCA, RAD50, PALB2, and CDK1217-21 (Fig 3A and Appendix Fig A7).”

2.

Robinson D, Van Allen EM, Wu YM, et al.

Integrative clinical genomics of advanced prostate cancer. Cell 2015;161:1215-

doi: 10.1016/j.cell.2015.05.001

“Abstract

Toward development of a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53, and PTEN were frequent (40%-60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF. Moreover, aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared to those in primary prostate cancers. 89% of affected individuals harbored a clinically actionable aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides clinically actionable information that could impact treatment decisions for these affected individuals.”

3.

Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med 2016;375:443-453.

DOI: 10.1056/NEJMoa1603144

“We recruited 692 men with documented metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis. We isolated germline DNA and used multiplex sequencing assays to assess mutations in 20 DNA-repair genes associated with autosomal dominant cancer-predisposition syndromes.

RESULTS

A total of 84 germline DNA-repair gene mutations that were presumed to be deleterious were identified in 82 men (11.8%); mutations were found in 16 genes, including BRCA2 (37 men [5.3%]), ATM (11 [1.6%]), CHEK2 (10 [1.9% of 534 men with data]), BRCA1 (6 [0.9%]), RAD51D (3 [0.4%]), and PALB2 (3 [0.4%]). Mutation frequencies did not differ according to whether a family history of prostate cancer was present or according to age at diagnosis. Overall, the frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of 4.6% among 499 men with localized prostate cancer (P<0.001), including men with high-risk disease, and the prevalence of 2.7% in the Exome Aggregation Consortium, which includes 53,105 persons without a known cancer diagnosis (P<0.001).”

[dentaltwin]

Yeah, I see that. Of course, had he recognized this as a limitation, his inclusion criteria could easily have specified.