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Comprehensive genomic sequencing of paired ovarian cancers reveals discordance in genes that determine clinical trial eligibility.

Abstract

OBJECTIVE

We analyzed comprehensive genomic sequencing results from paired ovarian cancer samples to identify changes in mutational events over time.

METHODS

DNA from paired FFPE tumor samples from 50 ovarian cancer patients in the Clearity Foundation Data Repository was analyzed for genomic mutations (GM), copy number alterations (CNA), microsatellite status (MS), tumor mutation burden (TMB), and loss of heterozygosity (LOH) by hybrid-capture, next-generation sequencing of up to 315 genes. Genomic profiles were compared between samples from the same patient. Poor quality results excluded 6 pairs from all analyses and 9 from CNA or LOH.

RESULTS

Forty-four patients with predominantly advanced stage disease (34, 77%) and serous histology (31, 70%) received a median of 3 intervening treatment regimens (range 1-13). Analysis of 22 primary and recurrent sample pairs and 22 recurrent tumor pairs detected a median of 2 GM (range 0-5) and 1 CNA (range 0-6)/sample. TMB, MS, and LOH results were mostly concordant across paired samples. GM were consistent across most pairs [32/44 (73%) concordant], while CNA concordance was less [18/35 (51%)]. No changes were detected in therapeutically relevant GM, but 23% of patients had GM or CNA in the second sample that affect clinical trial eligibility.

CONCLUSIONS

Paired ovarian cancer samples demonstrate stable genomic alterations across time. However, discordance was observed for some genes used as eligibility criteria for molecularly targeted clinical trials. Repeat tumor testing may be useful in cases where eligibility for such trials is deemed important after consideration of testing costs and potential clinical benefit.

Authors+Show Affiliations

Gynecologic Oncology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.Gynecologic Oncology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.Foundation Medicine, Inc, Cambridge, MA, USA.Foundation Medicine, Inc, Cambridge, MA, USA.Gynecologic Oncology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.The Clearity Foundation, San Diego, CA, USA. Electronic address: dzajchowski@clearityfoundation.org.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31703812

Citation

Fehniger, Julia E., et al. "Comprehensive Genomic Sequencing of Paired Ovarian Cancers Reveals Discordance in Genes That Determine Clinical Trial Eligibility." Gynecologic Oncology, 2019.
Fehniger JE, Berger AA, Juckett L, et al. Comprehensive genomic sequencing of paired ovarian cancers reveals discordance in genes that determine clinical trial eligibility. Gynecol Oncol. 2019.
Fehniger, J. E., Berger, A. A., Juckett, L., Elvin, J., Levine, D. A., & Zajchowski, D. A. (2019). Comprehensive genomic sequencing of paired ovarian cancers reveals discordance in genes that determine clinical trial eligibility. Gynecologic Oncology, doi:10.1016/j.ygyno.2019.10.004.
Fehniger JE, et al. Comprehensive Genomic Sequencing of Paired Ovarian Cancers Reveals Discordance in Genes That Determine Clinical Trial Eligibility. Gynecol Oncol. 2019 Nov 5; PubMed PMID: 31703812.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comprehensive genomic sequencing of paired ovarian cancers reveals discordance in genes that determine clinical trial eligibility. AU - Fehniger,Julia E, AU - Berger,Amnon A, AU - Juckett,Luke, AU - Elvin,Julia, AU - Levine,Douglas A, AU - Zajchowski,Deborah A, Y1 - 2019/11/05/ PY - 2019/06/28/received PY - 2019/09/27/revised PY - 2019/10/05/accepted PY - 2019/11/10/entrez KW - Copy number alterations KW - Mutation KW - Next generation sequencing KW - Ovarian cancer KW - Precision medicine KW - Recurrence JF - Gynecologic oncology JO - Gynecol. Oncol. N2 - OBJECTIVE: We analyzed comprehensive genomic sequencing results from paired ovarian cancer samples to identify changes in mutational events over time. METHODS: DNA from paired FFPE tumor samples from 50 ovarian cancer patients in the Clearity Foundation Data Repository was analyzed for genomic mutations (GM), copy number alterations (CNA), microsatellite status (MS), tumor mutation burden (TMB), and loss of heterozygosity (LOH) by hybrid-capture, next-generation sequencing of up to 315 genes. Genomic profiles were compared between samples from the same patient. Poor quality results excluded 6 pairs from all analyses and 9 from CNA or LOH. RESULTS: Forty-four patients with predominantly advanced stage disease (34, 77%) and serous histology (31, 70%) received a median of 3 intervening treatment regimens (range 1-13). Analysis of 22 primary and recurrent sample pairs and 22 recurrent tumor pairs detected a median of 2 GM (range 0-5) and 1 CNA (range 0-6)/sample. TMB, MS, and LOH results were mostly concordant across paired samples. GM were consistent across most pairs [32/44 (73%) concordant], while CNA concordance was less [18/35 (51%)]. No changes were detected in therapeutically relevant GM, but 23% of patients had GM or CNA in the second sample that affect clinical trial eligibility. CONCLUSIONS: Paired ovarian cancer samples demonstrate stable genomic alterations across time. However, discordance was observed for some genes used as eligibility criteria for molecularly targeted clinical trials. Repeat tumor testing may be useful in cases where eligibility for such trials is deemed important after consideration of testing costs and potential clinical benefit. SN - 1095-6859 UR - https://www.unboundmedicine.com/medline/citation/31703812/Comprehensive_genomic_sequencing_of_paired_ovarian_cancers_reveals_discordance_in_genes_that_determine_clinical_trial_eligibility L2 - https://linkinghub.elsevier.com/retrieve/pii/S0090-8258(19)31561-6 DB - PRIME DP - Unbound Medicine ER -