New study below [1].
A few men here have mentioned Guardant360 testing.
In this study, we get some idea of the probability of particular alterations that have occurred on the road to (metastatic) CRPC. Useful if one has a treatment response to the information.
"Of 514 men with mCRPC, 482 (94%) had ≥1 circulating tumor DNA (ctDNA) alteration. The most common recurrent somatic mutations were in TP53 (36%), androgen receptor (AR) (22%), adenomatous polyposis coli (APC) (10%), neurofibromin 1 (NF1) (9%), epidermal growth factor receptor (EGFR), catenin beta-1 (CTNNB1), and AT-rich interactive domain-containing protein 1A (ARID1A) (6% each); and BRCA1, BRCA2, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%). Clinical outcomes were available for 163 patients, 46 of whom (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations, AR alterations, and amplifications of MYC and BRAF were associated with worse failure-free survival and/or OS. On multivariable analysis, MYC amplification remained significantly associated with OS. Prior therapy and serial profiling demonstrated the evolution of alterations in AR and other genes."
"ctDNA frequently was detected in this large cohort of "real-world" patients with mCRPC, and the alterations appeared to be similar to previously reported tumor tissue alterations. A higher number of alterations, and AR and MYC alterations, appear to compromise clinical outcomes, suggesting a role for immune checkpoint inhibitors and novel AR and BET inhibitors in selected patients."
See also [2].
-Patrick
[1] ncbi.nlm.nih.gov/pubmed/306...
Cancer. 2019 Jan 8. doi: 10.1002/cncr.31959. [Epub ahead of print]
Circulating tumor DNA alterations in patients with metastatic castration-resistant prostate cancer.
Sonpavde G1, Agarwal N2, Pond GR3, Nagy RJ4, Nussenzveig RH2, Hahn AW2, Sartor O5, Gourdin TS6, Nandagopal L7, Ledet EM5, Naik G7, Armstrong AJ8, Wang J9, Bilen MA10, Gupta S11, Grivas P12, Pal SK13, Lanman RB4, Talasaz A4, Lilly MB6.
Author information
1
Dana-Farber Cancer Institute, Boston, Massachusetts.
2
Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
3
Ontario Clinical Oncology Group, Hamilton, Ontario, Canada.
4
Guardant Health Inc, Redwood City, California.
5
Tulane University, New Orleans, Louisiana.
6
Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
7
University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, Alabama.
8
Duke Cancer Center, Durham, North Carolina.
9
University of Arizona Cancer Center at Dignity Health St. Joseph's Hospital and Medical Center, Phoenix, Arizona.
10
Winship Cancer Institute, Emory University, Atlanta, Georgia.
11
University of Minnesota, Minneapolis, Minnesota.
12
University of Washington, Seattle, Washington.
13
City of Hope Comprehensive Cancer Center, Duarte, California.
Abstract
BACKGROUND:
Because cell-free DNA (cfDNA) analysis facilitates the noninvasive genomic profiling of metastatic castration-resistant prostate cancer (mCRPC), the authors evaluated the association between cfDNA alterations and outcomes and evolution with therapy.
METHODS:
Patients with mCRPC underwent cfDNA genomic profiling using Guardant360, which examines major cancer-associated genes. Clinical factors, therapy information, failure-free survival, and overall survival (OS) were obtained for select patients. The association between genomic alterations and outcomes was investigated.
RESULTS:
Of 514 men with mCRPC, 482 (94%) had ≥1 circulating tumor DNA (ctDNA) alteration. The most common recurrent somatic mutations were in TP53 (36%), androgen receptor (AR) (22%), adenomatous polyposis coli (APC) (10%), neurofibromin 1 (NF1) (9%), epidermal growth factor receptor (EGFR), catenin beta-1 (CTNNB1), and AT-rich interactive domain-containing protein 1A (ARID1A) (6% each); and BRCA1, BRCA2, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%). Clinical outcomes were available for 163 patients, 46 of whom (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations, AR alterations, and amplifications of MYC and BRAF were associated with worse failure-free survival and/or OS. On multivariable analysis, MYC amplification remained significantly associated with OS. Prior therapy and serial profiling demonstrated the evolution of alterations in AR and other genes.
CONCLUSIONS:
ctDNA frequently was detected in this large cohort of "real-world" patients with mCRPC, and the alterations appeared to be similar to previously reported tumor tissue alterations. A higher number of alterations, and AR and MYC alterations, appear to compromise clinical outcomes, suggesting a role for immune checkpoint inhibitors and novel AR and BET inhibitors in selected patients.
© 2019 American Cancer Society.
KEYWORDS:
castration resistant; circulating tumor DNA (ctDNA); failure-free survival; genomic profiling; metastatic; prostate cancer; survival
PMID: 30620391 DOI: 10.1002/cncr.31959
***
[2] ncbi.nlm.nih.gov/pubmed/303...
J Clin Oncol. 2018 Oct 19:JCO1800328. doi: 10.1200/JCO.18.00328. [Epub ahead of print]
Identification of Incidental Germline Mutations in Patients With Advanced Solid Tumors Who Underwent Cell-Free Circulating Tumor DNA Sequencing.
Slavin TP1, Banks KC1, Chudova D1, Oxnard GR1, Odegaard JI1, Nagy RJ1, Tsang KWK1, Neuhausen SL1, Gray SW1, Cristofanilli M1, Rodriguez AA1, Bardia A1, Leyland-Jones B1, Janicek MF1, Lilly M1, Sonpavde G1, Lee CE1, Lanman RB1, Meric-Bernstam F1, Kurzrock R1, Weitzel JN1.
Author information
Abstract
PURPOSE:
To determine the potential for detection of incidental germline cancer predisposition mutations through cell-free DNA (cfDNA) analyses in patients who underwent solid tumor somatic mutation evaluation.
PATIENTS AND METHODS:
Data were evaluated from 10,888 unselected patients with advanced (stage III/IV) cancer who underwent Guardant360 testing between November 2015 and December 2016. The main outcome was prevalence of putative germline mutations identified among 16 actionable hereditary cancer predisposition genes.
RESULTS:
More than 50 cancer types were studied, including lung (41%), breast (19%), colorectal (8%), prostate (6%), pancreatic (3%), and ovarian (2%). Average patient age was 63.5 years (range, 18 to 95 years); 43% were male. One hundred and fifty-six individuals (1.4%) had suspected hereditary cancer mutations in 11 genes. Putative germline mutations were more frequent in individuals younger than 50 years versus those 50 years and older (3.0% v 1.2%, respectively; P < .001). Highest yields of putative germline findings were in patients with ovarian (8.13%), prostate (3.46%), pancreatic (3.34%), and breast (2.2%) cancer. Putative germline mutation identification was consistent among 12 individuals with multiple samples. Patients with circulating tumor DNA copy number variation and/or reversion mutations suggestive of functional loss of the wild-type allele in the tumor DNA also are described.
CONCLUSION:
Detection of putative germline mutations from cfDNA is feasible across multiple genes and cancer types without prior mutation knowledge. Many mutations were found in cancers without clear guidelines for hereditary cancer genetic counseling/testing. Given the clinical significance of identifying hereditary cancer predisposition for patients and their families as well as targetable germline alterations such as in BRCA1 or BRCA2, research on the best way to validate and return potential germline results from cfDNA analysis to clinicians and patients is needed.
PMID: 30339520 PMCID: PMC6286162 [Available on 2019-12-10] DOI: 10.1200/JCO.18.00328
Sartor on BAT and genomic profiling (excerpts)
