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Concordance of genomic alterations between primary and recurrent breast cancer.
Mol Cancer Ther 2014; 13(5):1382-9MC

Abstract

There is growing interest in delivering genomically informed cancer therapy. Our aim was to determine the concordance of genomic alterations between primary and recurrent breast cancer. Targeted next-generation sequencing was performed on formalin-fixed paraffin-embedded (FFPE) samples, profiling 3,320 exons of 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer. Point mutations, indels, copy-number alterations (CNA), and select rearrangements were assessed in 74 tumors from 43 patients (36 primary and 38 recurrence/metastases). Alterations potentially targetable with established or investigational therapeutics were considered "actionable." Alterations were detected in 55 genes (mean 3.95 alterations/sample, range 1-12), including mutations in PIK3CA, TP53, ARID1A, PTEN, AKT1, NF1, FBXW7, and FGFR3 and amplifications in MCL1, CCND1, FGFR1, MYC, IGF1R, MDM2, MDM4, AKT3, CDK4, and AKT2. In 33 matched primary and recurrent tumors, 97 of 112 (86.6%) somatic mutations were concordant. Of identified CNAs, 136 of 159 (85.5%) were concordant: 37 (23.3%) were concordant, but below the reporting threshold in one of the matched samples, and 23 (14.5%) discordant. There was an increased frequency of CDK4/MDM2 amplifications in recurrences, as well as gains and losses of other actionable alterations. Forty of 43 (93%) patients had actionable alterations that could inform targeted treatment options. In conclusion, deep genomic profiling of cancer-related genes reveals potentially actionable alterations in most patients with breast cancer. Overall there was high concordance between primary and recurrent tumors. Analysis of recurrent tumors before treatment may provide additional insights, as both gains and losses of targets are observed.

Authors+Show Affiliations

Authors' Affiliations: Departments of Investigational Cancer Therapeutics, Surgical Oncology, Bioinformatics and Computational Biology, Pathology, Systems Biology, and Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Foundation Medicine, Cambridge, Massachusetts; Albany Medical College, Albany, New York; Fundacion para la Investigacion; Departments of Hematology-Oncology and Pathology, Hospital Clinico Universitario de Valencia; and INCLIVA Biomedical Research Institute, Valencia, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24608573

Citation

Meric-Bernstam, Funda, et al. "Concordance of Genomic Alterations Between Primary and Recurrent Breast Cancer." Molecular Cancer Therapeutics, vol. 13, no. 5, 2014, pp. 1382-9.
Meric-Bernstam F, Frampton GM, Ferrer-Lozano J, et al. Concordance of genomic alterations between primary and recurrent breast cancer. Mol Cancer Ther. 2014;13(5):1382-9.
Meric-Bernstam, F., Frampton, G. M., Ferrer-Lozano, J., Yelensky, R., Pérez-Fidalgo, J. A., Wang, Y., ... Gonzalez-Angulo, A. M. (2014). Concordance of genomic alterations between primary and recurrent breast cancer. Molecular Cancer Therapeutics, 13(5), pp. 1382-9. doi:10.1158/1535-7163.MCT-13-0482.
Meric-Bernstam F, et al. Concordance of Genomic Alterations Between Primary and Recurrent Breast Cancer. Mol Cancer Ther. 2014;13(5):1382-9. PubMed PMID: 24608573.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Concordance of genomic alterations between primary and recurrent breast cancer. AU - Meric-Bernstam,Funda, AU - Frampton,Garrett M, AU - Ferrer-Lozano,Jaime, AU - Yelensky,Roman, AU - Pérez-Fidalgo,Jose A, AU - Wang,Ying, AU - Palmer,Gary A, AU - Ross,Jeffrey S, AU - Miller,Vincent A, AU - Su,Xiaoping, AU - Eroles,Pilar, AU - Barrera,Juan Antonio, AU - Burgues,Octavio, AU - Lluch,Ana M, AU - Zheng,Xiaofeng, AU - Sahin,Aysegul, AU - Stephens,Philip J, AU - Mills,Gordon B, AU - Cronin,Maureen T, AU - Gonzalez-Angulo,Ana M, Y1 - 2014/03/07/ PY - 2014/3/11/entrez PY - 2014/3/13/pubmed PY - 2015/1/3/medline SP - 1382 EP - 9 JF - Molecular cancer therapeutics JO - Mol. Cancer Ther. VL - 13 IS - 5 N2 - There is growing interest in delivering genomically informed cancer therapy. Our aim was to determine the concordance of genomic alterations between primary and recurrent breast cancer. Targeted next-generation sequencing was performed on formalin-fixed paraffin-embedded (FFPE) samples, profiling 3,320 exons of 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer. Point mutations, indels, copy-number alterations (CNA), and select rearrangements were assessed in 74 tumors from 43 patients (36 primary and 38 recurrence/metastases). Alterations potentially targetable with established or investigational therapeutics were considered "actionable." Alterations were detected in 55 genes (mean 3.95 alterations/sample, range 1-12), including mutations in PIK3CA, TP53, ARID1A, PTEN, AKT1, NF1, FBXW7, and FGFR3 and amplifications in MCL1, CCND1, FGFR1, MYC, IGF1R, MDM2, MDM4, AKT3, CDK4, and AKT2. In 33 matched primary and recurrent tumors, 97 of 112 (86.6%) somatic mutations were concordant. Of identified CNAs, 136 of 159 (85.5%) were concordant: 37 (23.3%) were concordant, but below the reporting threshold in one of the matched samples, and 23 (14.5%) discordant. There was an increased frequency of CDK4/MDM2 amplifications in recurrences, as well as gains and losses of other actionable alterations. Forty of 43 (93%) patients had actionable alterations that could inform targeted treatment options. In conclusion, deep genomic profiling of cancer-related genes reveals potentially actionable alterations in most patients with breast cancer. Overall there was high concordance between primary and recurrent tumors. Analysis of recurrent tumors before treatment may provide additional insights, as both gains and losses of targets are observed. SN - 1538-8514 UR - https://www.unboundmedicine.com/medline/citation/24608573/Concordance_of_genomic_alterations_between_primary_and_recurrent_breast_cancer_ L2 - http://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=24608573 DB - PRIME DP - Unbound Medicine ER -