JNCI J Natl Cancer Inst (2016) 108(5): djv424 doi:10.1093/jnci/djv424 First published online February 8, 2016 Editorial
editorial Genomic Testing for Gemcitabine-Based Treatment of Pancreatic Cancer Affiliation of authors: Department of Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY (JZ, SNH). Correspondence to: Steven N. Hochwald, MD, Department of Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263 (e-mail: [email protected]).
Pancreatic cancer is a deadly condition with a single-digit overall five-year survival rate. Most tumors are metastatic upon diagnosis, and patients are left with palliative treatment options. Nucleoside analogue-based chemotherapy and, more recently, oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) are the options most frequently recommended for most patients with advanced disease. Gemcitabine as a single agent remains a standard first line of defense for metastatic disease, especially in patients with poor performance status. However, only a subset of patients benefit from gemcitabine monotherapy, with objective response rates of only 9.4% (1). It is essential and urgent to develop a genomic screening method for the identification of patients who are most likely to respond to gemcitabine treatment. This can not only prolong the lives of gemcitabine-sensitive patients but also avoid nonbeneficiary treatments among the individuals who could benefit from other therapies such as 5-fluorouracil-based therapy or other more novel treatments. Based on a genome-wide association study (2), Schirmer et al. (3) have linked the single-nucleotide polymorphism (SNP) of WWOX rs11644322 to worse prognosis among gemcitabinetreated patients harboring advanced pancreatic cancer. The genetic polymorphism WWOX rs11644322 involves a “G” to “A” mutation. The patients who possess the AA or GA alleles live significantly shorter lives than the ones with the GG (wild-type) genotype. Furthermore, after adjustment for age, ECOG status, TNM, grading, and resection status, SNP rs11644322 is comparable with the most predictive prognostic factors among 381 patients with pancreatic ductal adenocarcinoma and treated with gemcitabine-based therapy. It has been reported that WWOX protein can act as a tumor suppressor through interaction with p53 and modulation of apoptosis in mouse and human cell cultures (4–6). From their laboratory-based studies, the researchers demonstrate that lymphoblastoids harboring the AA genotype and pancreatic cancer cells with RNAi-suppressed WWOX expression are less sensitive to gemcitabine treatment as compared with their controls. In addition, the experimental
results of electrophoretic mobility shift assay indicate that the G-to-A mutation reduces Sp1/3 binding to the promoter of the WWOX gene, leading to low levels of WWOX expression in pancreatic cancer cells. The association of WWOX rs11644322 and low overall survival among patients with metastatic pancreatic cancer treated with gemcitabine-based therapy should be explored to assess if such genomic testing can screen appropriate patients for gemcitabine therapy. After additional clinical trials on large populations of pancreatic cancer patients are performed to confirm this finding, SNP rs11644322 tests could help physicians select patients who would likely respond to and benefit from gemcitabine treatment. However, there are factors that may affect the clinical application of SNP rs11644322 as a major prognostic factor. The WWOX gene is located within one of the fragile regions of the human genome. DNA breakage and deletion of the WWOX gene have been detected in multiple myeloma, breast, and prostate cancer (7–9). Assessment of the association between deletion/breakage of the WWOX gene with gemcitabine-resistant pancreatic cancer and detection of the gene deletion can help screen patients harboring the deleted WWOX gene. However, deletion of the SNP rs11644322–containing region may interfere with the detection of SNP rs11644322. It is possible that the combination of both SNP rs11644322 and gene deletion assessments may be a comprehensive approach for screening gemcitabine-responsive individuals with advanced pancreatic cancer. Apart from rs11644322, other SNPs such as rs763780 and rs505922 have been associated with either gemcitabine responsiveness or the risk of pancreatic cancer (3,10). It is unclear how these SNPs or genes interact amongst each other and whether they can contribute to gemcitabine resistance and/or tumorigenesis of pancreatic cancer. This warrants further investigation. Nevertheless, the development of a multi-SNP panel to predict the responsiveness of pancreatic cancer patients to gemcitabine therapy is expected to be more inclusive and accurate.
Received: December 7, 2015; Accepted: December 14, 2015 © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].
1 of 2
Downloaded from http://jnci.oxfordjournals.org/ at University of California, San Diego on February 11, 2016
Jianliang Zhang, Steven N. Hochwald
2 of 2 | JNCI J Natl Cancer Inst, 2016, Vol. 108, No. 5
The establishment of the association between WWOX rs11644322 and worse overall survival among gemcitabinetreated patients with metastatic pancreatic cancer provides a molecular basis for the development of a simple genomic screening test for tailoring future gemcitabine therapy. Furthermore, the potent tumor suppressor gene WWOX may contribute to gemcitabine-induced apoptosis, which can help better understand drug-specific sensitivity or resistance in pancreatic cancer treatment.
References
Downloaded from http://jnci.oxfordjournals.org/ at University of California, San Diego on February 11, 2016
1. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–1825. 2. Innocenti F, Owzar K, Cox NL, et al. A genome-wide association study of overall survival in pancreatic cancer patients treated with gemcitabine in CALGB 80303. Clin Cancer Res. 2012;18(2):577–584.
3. Schirmer MA, Luske CM, Roppel S, et al. Relevance of Sp binding site polymorphism in WWOX for treatment outcome in pancreatic cancer. J Natl Cancer Inst. 2015;108(5):XXX-XXX. 4. Chang NS, Pratt N, Heath J, et al. Hyaluronidase induction of a WW domaincontaining oxidoreductase that enhances tumor necrosis factor cytotoxicity. J Biol Chem. 2001;276(5):3361–3370. 5. Bednarek AK, Keck-Waggoner CL, Daniel RL, et al. WWOX, the FRA16D gene, behaves as a suppressor of tumor growth. Cancer Res. 2001;61(22):8068–8073. 6. Chang NS, Doherty J, Ensign A. JNK1 physically interacts with WW domaincontaining oxidoreductase (WOX1) and inhibits WOX1-mediated apoptosis. J Biol Chem. 2003;278(11):9195–9202. 7. Mignot C, Lambert L, Pasquier L, et al. WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation. J Med Genet. 2015;52(1):61–70. 8. Finnis M, Dayan S, Hobson L, et al. Common chromosomal fragile site FRA16D mutation in cancer cells. Hum Mol Genet. 2005;14(10):1341–1349. 9. Jiang Y, Lucas I, Young DJ, et al. Common fragile sites are characterized by histone hypoacetylation. Hum Mol Genet. 2009;18(23):4501–4512. 10. Amundadottir L, Kraft P, Stolzenberg-Solomon RZ, et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet. 2009;41(9):986–990.
editorial Genomic Testing for Gemcitabine-Based Treatment of Pancreatic Cancer Affiliation of authors: Department of Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY (JZ, SNH). Correspondence to: Steven N. Hochwald, MD, Department of Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263 (e-mail: [email protected]).
Pancreatic cancer is a deadly condition with a single-digit overall five-year survival rate. Most tumors are metastatic upon diagnosis, and patients are left with palliative treatment options. Nucleoside analogue-based chemotherapy and, more recently, oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) are the options most frequently recommended for most patients with advanced disease. Gemcitabine as a single agent remains a standard first line of defense for metastatic disease, especially in patients with poor performance status. However, only a subset of patients benefit from gemcitabine monotherapy, with objective response rates of only 9.4% (1). It is essential and urgent to develop a genomic screening method for the identification of patients who are most likely to respond to gemcitabine treatment. This can not only prolong the lives of gemcitabine-sensitive patients but also avoid nonbeneficiary treatments among the individuals who could benefit from other therapies such as 5-fluorouracil-based therapy or other more novel treatments. Based on a genome-wide association study (2), Schirmer et al. (3) have linked the single-nucleotide polymorphism (SNP) of WWOX rs11644322 to worse prognosis among gemcitabinetreated patients harboring advanced pancreatic cancer. The genetic polymorphism WWOX rs11644322 involves a “G” to “A” mutation. The patients who possess the AA or GA alleles live significantly shorter lives than the ones with the GG (wild-type) genotype. Furthermore, after adjustment for age, ECOG status, TNM, grading, and resection status, SNP rs11644322 is comparable with the most predictive prognostic factors among 381 patients with pancreatic ductal adenocarcinoma and treated with gemcitabine-based therapy. It has been reported that WWOX protein can act as a tumor suppressor through interaction with p53 and modulation of apoptosis in mouse and human cell cultures (4–6). From their laboratory-based studies, the researchers demonstrate that lymphoblastoids harboring the AA genotype and pancreatic cancer cells with RNAi-suppressed WWOX expression are less sensitive to gemcitabine treatment as compared with their controls. In addition, the experimental
results of electrophoretic mobility shift assay indicate that the G-to-A mutation reduces Sp1/3 binding to the promoter of the WWOX gene, leading to low levels of WWOX expression in pancreatic cancer cells. The association of WWOX rs11644322 and low overall survival among patients with metastatic pancreatic cancer treated with gemcitabine-based therapy should be explored to assess if such genomic testing can screen appropriate patients for gemcitabine therapy. After additional clinical trials on large populations of pancreatic cancer patients are performed to confirm this finding, SNP rs11644322 tests could help physicians select patients who would likely respond to and benefit from gemcitabine treatment. However, there are factors that may affect the clinical application of SNP rs11644322 as a major prognostic factor. The WWOX gene is located within one of the fragile regions of the human genome. DNA breakage and deletion of the WWOX gene have been detected in multiple myeloma, breast, and prostate cancer (7–9). Assessment of the association between deletion/breakage of the WWOX gene with gemcitabine-resistant pancreatic cancer and detection of the gene deletion can help screen patients harboring the deleted WWOX gene. However, deletion of the SNP rs11644322–containing region may interfere with the detection of SNP rs11644322. It is possible that the combination of both SNP rs11644322 and gene deletion assessments may be a comprehensive approach for screening gemcitabine-responsive individuals with advanced pancreatic cancer. Apart from rs11644322, other SNPs such as rs763780 and rs505922 have been associated with either gemcitabine responsiveness or the risk of pancreatic cancer (3,10). It is unclear how these SNPs or genes interact amongst each other and whether they can contribute to gemcitabine resistance and/or tumorigenesis of pancreatic cancer. This warrants further investigation. Nevertheless, the development of a multi-SNP panel to predict the responsiveness of pancreatic cancer patients to gemcitabine therapy is expected to be more inclusive and accurate.
Received: December 7, 2015; Accepted: December 14, 2015 © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].
1 of 2
Downloaded from http://jnci.oxfordjournals.org/ at University of California, San Diego on February 11, 2016
Jianliang Zhang, Steven N. Hochwald
2 of 2 | JNCI J Natl Cancer Inst, 2016, Vol. 108, No. 5
The establishment of the association between WWOX rs11644322 and worse overall survival among gemcitabinetreated patients with metastatic pancreatic cancer provides a molecular basis for the development of a simple genomic screening test for tailoring future gemcitabine therapy. Furthermore, the potent tumor suppressor gene WWOX may contribute to gemcitabine-induced apoptosis, which can help better understand drug-specific sensitivity or resistance in pancreatic cancer treatment.
References
Downloaded from http://jnci.oxfordjournals.org/ at University of California, San Diego on February 11, 2016
1. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–1825. 2. Innocenti F, Owzar K, Cox NL, et al. A genome-wide association study of overall survival in pancreatic cancer patients treated with gemcitabine in CALGB 80303. Clin Cancer Res. 2012;18(2):577–584.
3. Schirmer MA, Luske CM, Roppel S, et al. Relevance of Sp binding site polymorphism in WWOX for treatment outcome in pancreatic cancer. J Natl Cancer Inst. 2015;108(5):XXX-XXX. 4. Chang NS, Pratt N, Heath J, et al. Hyaluronidase induction of a WW domaincontaining oxidoreductase that enhances tumor necrosis factor cytotoxicity. J Biol Chem. 2001;276(5):3361–3370. 5. Bednarek AK, Keck-Waggoner CL, Daniel RL, et al. WWOX, the FRA16D gene, behaves as a suppressor of tumor growth. Cancer Res. 2001;61(22):8068–8073. 6. Chang NS, Doherty J, Ensign A. JNK1 physically interacts with WW domaincontaining oxidoreductase (WOX1) and inhibits WOX1-mediated apoptosis. J Biol Chem. 2003;278(11):9195–9202. 7. Mignot C, Lambert L, Pasquier L, et al. WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation. J Med Genet. 2015;52(1):61–70. 8. Finnis M, Dayan S, Hobson L, et al. Common chromosomal fragile site FRA16D mutation in cancer cells. Hum Mol Genet. 2005;14(10):1341–1349. 9. Jiang Y, Lucas I, Young DJ, et al. Common fragile sites are characterized by histone hypoacetylation. Hum Mol Genet. 2009;18(23):4501–4512. 10. Amundadottir L, Kraft P, Stolzenberg-Solomon RZ, et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet. 2009;41(9):986–990.
