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Special issue editorial—Cancer Genetics
Cancer Genetics 209 (2016) 535–536
Special issue editorial—Cancer Genetics Meaningful progress in survival with pancreatic cancer has been difficult to come by to date; progress is slow and underwhelming. Operations for pancreatic cancer have become more frequent, safer, and less invasive with the advent of robotic surgery. Preoperative and postoperative cares have steadily improved over the past decades. Diagnostic and staging modalities have come “light years” over the past decades with the introduction of and refinements in CT scanning, MR imaging, and endoscopic ultrasound (EUS). Now improvements in adjunctive therapies must occur (1). The considerable majority of patients with pancreatic cancer have metastases detected at the time of their initial diagnosis and staging; these metastases preclude resection and lead to chemotherapy, generally gemcitabine based regimens or combination therapy with FOLFURINOX (i.e., 5-FU, irinotecan, leucovorin, oxaliplatin) (2). For patients without detectable metastases at their initial workup, operations with resection are the only hope for cure and, given appropriate health, pancreaticoduodenectomy or distal pancreatectomy is undertaken (3). However, better than 80% of these patients undergoing resection have occult metastatic disease at the time of their proposed operations, based upon the appearance of metastatic disease after resection. In sum, little improvement in survival has been seen for patients with pancreatic cancer, either overall or adjusted for stage (3). Something needs to be added to this equation. The chemotherapeutic approach to pancreatic cancer has not appreciably changed in nearly a decade, with the last meaningful advance being the application of FOLFURINOX (4). Many drugs and drug combinations have been studied over the past decade to no avail; no new drugs have found a role in treating pancreatic cancer and no new drugs seem forthcoming. The focus of improving survival for pancreatic cancer seems to lie now in improving diagnosis (e.g., making it earlier) and improving adjunctive therapy, either neoadjuvant or adjuvant (5,6). To this end, understanding the genetics of pancreatic cancer is essential. Family history and genetic profiling can identify patients at risk for pancreatic cancer, but can’t tell when or where in the pancreas the cancer will occur (7). Imaging studies alone can identify changes in the architectural makeup of the pancreas, but unless diagnostic for cancer they often cannot tell where a given change falls along the spectrum from early, early genetic predisposition for cancer to “outright” malignancy. Genetic alterations are the causes of malignant degeneration of the ductal tissue of the pancreas. Identification of 2210-7762/$ - see front matter © 2016 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.cancergen.2016.11.003
sentinel genetic changes could “make” the diagnosis of pancreatic cancer. As well, recognition of patterns of genetic changes could “make” the diagnosis, much in the way ancestral heritage can be determined, or provide genetic evidence of a premalignant state, thereby identifying patients at very, very high risk for developing pancreatic cancer (5–7). Once the diagnosis of pancreatic cancer is made, then the focus of genetic testing should be to identify genetic targets for therapy. For many cancers, genetic targets, for which there are commercially available and efficacious drugs, have been identified. The application of the monoclonal antibody trastuzumab for genetically aberrant HER-2 (human epidermal growth factor receptor 2 or also called the ERBB2 [Erb-B2 receptor tyrosine kinase 2] gene) positive breast cancer is a telling example, one not replicated with pancreatic cancer to date. Breast cancers with HER2 gene amplification or HER2 protein overexpression are called “HER2positive”. HER2-positive breast cancers tend to grow faster and are more likely to recur and spread relative to HER2negative breast cancers. But there are now gene-targeting drugs specifically for HER2-positive breast cancers, such as trastuzumab. Furthermore, combining trastuzumab with the chemotherapy drug emtansine may provide enhanced efficacy for emtansine as the combination may deliver emtansine to HER2-positive cancer cells in a targeted manner (5–7). Unfortunately, identifying genetic targets specific for pancreatic cancer that genetic therapies have access to remains a “black box”. The articles herein are designed to begin to get our arms around the enigma of genetic alterations, markers, and targets of pancreatic, hepatobiliary, and esophageal cancers. In the vernacular of baseball, we are in the early innings, arguably the first inning. Much is to be done. For clinicians the work ahead is additionally vexing because it requires a knowledge base and vocabulary not generally associated with clinical medicine, particularly surgery. The articles herein are a start. Reading them will raise many questions, as is appropriate. We are not at the destination we seek; we are at the beginning of what will prove to be a long journey. Let us hope the journey is not endless.
References 1. Bond-Smith G, Banga N, Hammond TM, et al. Pancreatic adenocarcinoma. BMJ 2012;344:1–10.
536 2. Infante JR, Matsubayashi H, Sato N, et al. Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. J Clin Oncol 2007;25:319–325. 3. Hidalgo M, Cascinu S, Kleeff J, et al. Addressing the challenges of pancreatic cancer: future directions for improving outcomes. Pancreatology 2015;15:8–18. 4. Marthey L, Sa-Cunha A, Blanc JF, et al. FOLFIRINOX for locally advanced pancreatic adenocarcinoma: results of an AGEO Multicenter Prospective Observational Cohort. Ann Surg Oncol 2014;22:295–301.
Special issue editorial 5. Frank TS, Sun X, Zhang Y, et al. Genomic profiling guides the choice of molecular targeted therapy of pancreatic cancer. Cancer Lett 2015;363:1–6. 6. Hartley ML, Bade NA, Prins PA, et al. Pancreatic cancer, treatment options, and GI-4000. Hum Vac Immunothe 2015;11:931–937. 7. Muniraj T, Jamidar PA, Aslanian HR. Pancreatic cancer: a comprehensive review and update. Dis Mon 2013;59:368–402. http://dx.doi.org/10.1016/j.disamonth.2013.08.001. ISSN 0011-5029.
Alexander Rosemurgy
Special issue editorial—Cancer Genetics Meaningful progress in survival with pancreatic cancer has been difficult to come by to date; progress is slow and underwhelming. Operations for pancreatic cancer have become more frequent, safer, and less invasive with the advent of robotic surgery. Preoperative and postoperative cares have steadily improved over the past decades. Diagnostic and staging modalities have come “light years” over the past decades with the introduction of and refinements in CT scanning, MR imaging, and endoscopic ultrasound (EUS). Now improvements in adjunctive therapies must occur (1). The considerable majority of patients with pancreatic cancer have metastases detected at the time of their initial diagnosis and staging; these metastases preclude resection and lead to chemotherapy, generally gemcitabine based regimens or combination therapy with FOLFURINOX (i.e., 5-FU, irinotecan, leucovorin, oxaliplatin) (2). For patients without detectable metastases at their initial workup, operations with resection are the only hope for cure and, given appropriate health, pancreaticoduodenectomy or distal pancreatectomy is undertaken (3). However, better than 80% of these patients undergoing resection have occult metastatic disease at the time of their proposed operations, based upon the appearance of metastatic disease after resection. In sum, little improvement in survival has been seen for patients with pancreatic cancer, either overall or adjusted for stage (3). Something needs to be added to this equation. The chemotherapeutic approach to pancreatic cancer has not appreciably changed in nearly a decade, with the last meaningful advance being the application of FOLFURINOX (4). Many drugs and drug combinations have been studied over the past decade to no avail; no new drugs have found a role in treating pancreatic cancer and no new drugs seem forthcoming. The focus of improving survival for pancreatic cancer seems to lie now in improving diagnosis (e.g., making it earlier) and improving adjunctive therapy, either neoadjuvant or adjuvant (5,6). To this end, understanding the genetics of pancreatic cancer is essential. Family history and genetic profiling can identify patients at risk for pancreatic cancer, but can’t tell when or where in the pancreas the cancer will occur (7). Imaging studies alone can identify changes in the architectural makeup of the pancreas, but unless diagnostic for cancer they often cannot tell where a given change falls along the spectrum from early, early genetic predisposition for cancer to “outright” malignancy. Genetic alterations are the causes of malignant degeneration of the ductal tissue of the pancreas. Identification of 2210-7762/$ - see front matter © 2016 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.cancergen.2016.11.003
sentinel genetic changes could “make” the diagnosis of pancreatic cancer. As well, recognition of patterns of genetic changes could “make” the diagnosis, much in the way ancestral heritage can be determined, or provide genetic evidence of a premalignant state, thereby identifying patients at very, very high risk for developing pancreatic cancer (5–7). Once the diagnosis of pancreatic cancer is made, then the focus of genetic testing should be to identify genetic targets for therapy. For many cancers, genetic targets, for which there are commercially available and efficacious drugs, have been identified. The application of the monoclonal antibody trastuzumab for genetically aberrant HER-2 (human epidermal growth factor receptor 2 or also called the ERBB2 [Erb-B2 receptor tyrosine kinase 2] gene) positive breast cancer is a telling example, one not replicated with pancreatic cancer to date. Breast cancers with HER2 gene amplification or HER2 protein overexpression are called “HER2positive”. HER2-positive breast cancers tend to grow faster and are more likely to recur and spread relative to HER2negative breast cancers. But there are now gene-targeting drugs specifically for HER2-positive breast cancers, such as trastuzumab. Furthermore, combining trastuzumab with the chemotherapy drug emtansine may provide enhanced efficacy for emtansine as the combination may deliver emtansine to HER2-positive cancer cells in a targeted manner (5–7). Unfortunately, identifying genetic targets specific for pancreatic cancer that genetic therapies have access to remains a “black box”. The articles herein are designed to begin to get our arms around the enigma of genetic alterations, markers, and targets of pancreatic, hepatobiliary, and esophageal cancers. In the vernacular of baseball, we are in the early innings, arguably the first inning. Much is to be done. For clinicians the work ahead is additionally vexing because it requires a knowledge base and vocabulary not generally associated with clinical medicine, particularly surgery. The articles herein are a start. Reading them will raise many questions, as is appropriate. We are not at the destination we seek; we are at the beginning of what will prove to be a long journey. Let us hope the journey is not endless.
References 1. Bond-Smith G, Banga N, Hammond TM, et al. Pancreatic adenocarcinoma. BMJ 2012;344:1–10.
536 2. Infante JR, Matsubayashi H, Sato N, et al. Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. J Clin Oncol 2007;25:319–325. 3. Hidalgo M, Cascinu S, Kleeff J, et al. Addressing the challenges of pancreatic cancer: future directions for improving outcomes. Pancreatology 2015;15:8–18. 4. Marthey L, Sa-Cunha A, Blanc JF, et al. FOLFIRINOX for locally advanced pancreatic adenocarcinoma: results of an AGEO Multicenter Prospective Observational Cohort. Ann Surg Oncol 2014;22:295–301.
Special issue editorial 5. Frank TS, Sun X, Zhang Y, et al. Genomic profiling guides the choice of molecular targeted therapy of pancreatic cancer. Cancer Lett 2015;363:1–6. 6. Hartley ML, Bade NA, Prins PA, et al. Pancreatic cancer, treatment options, and GI-4000. Hum Vac Immunothe 2015;11:931–937. 7. Muniraj T, Jamidar PA, Aslanian HR. Pancreatic cancer: a comprehensive review and update. Dis Mon 2013;59:368–402. http://dx.doi.org/10.1016/j.disamonth.2013.08.001. ISSN 0011-5029.
Alexander Rosemurgy