Editorial
Genetic Variants and Response to Cancer Treatments Janindra Warusavitarne, B Med, FRACS, PhD1; Justin Stebbing, FRCP, FRCPath, PhD2; and Omar Faiz, BSc(Hons), MBBS, FRCS(GenSurg), MS1
Stremitzer and colleagues have demonstrated that single nucleotide polymorphisms (SNPs) in several genes involved in an alternate pathway of angiogenesis are predictive of prognosis in patients with colorectal liver metastases who receive treatment with bevacizumab before undergoing liver resection, as reported in this issue of Cancer.1 These findings have particular relevance, because most patients experience disease relapse, from which they die; and there are no biomarkers to date that can predict a cure. In their report, the authors’ hypothesis is that genes involved in the angiopoietin and pericyte pathways are escape mechanisms for antivascular endothelial growth factor (anti-VEGF) treatments and that variants in these alternate pathway genes may help determine outcomes. To demonstrate this, they evaluated SNPs in 9 genes involved in the pathway and identified several SNPs that were associated with disease-free survival, overall survival, histologic response, radiologic, response, and cure. The study raises several issues with regard to our understanding of biomarkers and how we translate genetic studies into clinical practice. Perhaps the most important point is the apparent dissociation between genes associated with recurrence-free survival, overall survival, and achieving a cure. Genes that were associated with a cure in this cohort were not associated with overall or recurrence-free survival. The authors explain that the markers predicting tumor growth are not necessarily the same as those predicting tumor shrinkage, which would account for the dissociation. Although this appears to be a plausible hypothesis, it warrants further investigation, because it raises relevant issues regarding translational studies and how we draw conclusions from them. Many attempts to identify markers that would make certain tumors more responsive to particular therapies have been unable to identify which tumors are likely to respond prospectively and, instead, have only served to highlight the complex interactions that exist. Another hypothesis is that the toxicity of chemotherapy and its potential associated morbidities may outweigh the benefits of the drugs; conceivably, the drugs may unintentionally target separate genes that could cause an imbalance (and, thus, progression) in the tumor instead of destroying it. This explains why the survival benefits may not be as dramatic as expected from “curing” a tumor and is all the more reason to identify which tumors are most likely to benefit from the drug to minimize collateral damage from the treatment. The concept of biomarker-based assessment of response to chemotherapy is important. Earlier studies that assessed response to chemotherapy in microsatellite-unstable colon cancers produced conflicting results. For example, although some studies have demonstrated that 5-fluorouracil–based chemotherapy may be associated with a poor response to treatment in tumors with microsatellite instability, not all population-based studies have supported this hypothesis.2,3 This is mainly because microsatellite instability was not a part of the randomization in many chemotherapy trials at the time. Similarly, in their study, Stremitzer’s group reports that, although some SNPs are relevant for the overall population, others may be important only for a subgroup of patients based on their biologic function. It has been demonstrated that tumor location influences the biologic behavior of colorectal cancer and, similarly, that biomarker-based evaluation of colorectal cancer according to disease site is important; however, these issues are not addressed by Stremitzer and colleagues. Although it is assumed that blocking aspects of the VEGF pathway may lead to tumor destruction, as observed in a recent meta-analysis, the effects of targeted drugs like bevacizumab may reach beyond the expected target.4 This adds a level of complexity to determining who is most likely to benefit from treatment and also makes it difficult to identify alternate
Corresponding author: Justin Stebbing, FRCPath, FACP, PhD, Imperial College Centre for Translational and Experimental Medicine, Hammersmith Hospital, Du Cane Road, London, W12 0NN; Fax: (011) 4420 331114-33; [email protected] 1 Department of Surgery, St. Mark’s Hospital and Imperial College, London, United Kingdom; 2Imperial College Centre for Translational and Experimental Medicine, Hammersmith Hospital, London, United Kingdom
The authors discuss new findings that single nucleotide polymorphisms in genes associated with off-target effects of antiangiogenesis agents have a bearing on clinical outcomes. This, in turn, reveals potential new targets for drug development. See related original article on pages 1898-905, this issue. DOI: 10.1002/cncr.29257, Received: October 7, 2014; Revised: December 23, 2014; Accepted: December 24, 2014, Published online February 17, 2015 in Wiley Online Library (wileyonlinelibrary.com)
Cancer
June 1, 2015
1735
Editorial
pathways of resistance to treatment. The new genes studied here may represent therapeutic targets for overcoming resistance to bevacizumab-based therapeutics or at least may hint at the mechanisms involved with regard to offtarget drug effects. Mutational analysis of K-Ras (v-Ki–ras2 Kirsten rat sarcoma viral oncogene homolog) is now commonly performed to identify treatment pathways for colorectal cancer. The current analysis predicts resistance to treatment rather than response. Both in vivo and in vitro studies have demonstrated that KRAS G13D mutations (glycine to aspartic acid change at position 13) are associated with sensitivity to both cetuximab and panitumumab compared with KRAS glycine to valine change at position 12 (G12V) mutations,5 which, in turn, simply highlights the point that simple mutational analysis alone may not be adequate, and the same may apply to SNPs. With the increasing use of genome-wide sequencing, it may be possible to identify a tumor signature or footprint that could best identify which patients most likely would benefit from these treatments. The possible explanation for the conflicting gene information in different publications is that there are interactions between genes in a pathway that are not necessarily explained by investigating the pathways in isolation but perhaps by investigating the difference between genetics and genomics. The hypothesis proposed by Stremitzer and colleagues may be too simplistic, and this could offer us some explanation regarding why the results from many such translational studies are inconsistent. Thus, an issue with whole-genome sequencing is the handling of such a vast quantity of data, which, in turn, calls out for international collaboration between centers that already collect such information. The outcomes measured in these studies determine the conclusions, and 5-year survival traditionally has been used as the measure in cancer-related publications. Although this still remains a good measure of treatment efficacy, it does not always take treatment-related complications into account. Perhaps the same pathways that promote apoptosis and, thus, a cure may be involved in promoting apoptosis in other dividing cells, and any survival benefit observed with a “cure” can be negated or reduced as a result. The authors should be congratulated on their article and their attempt to tease out the pathways and tailor treatment to those who are most likely to benefit. Although this may appear to be the tip of the iceberg
1736
in individualized treatment, perhaps someday soon we will move away from the current practice, in which colorectal cancer is largely treated based on stage, and chemotherapy protocols are relatively standard. For example, despite comments about our era of personalized therapies, we still do not know how to treat third-line, K-Ras– mutated, metastatic colon cancer. Proangiogenic factors like interleukin 8, fibroblast growth factor, hepatocyte growth factor, and others, as pointed out, have been associated with compensatory up-regulation during antiVEGF–targeted therapy, which, in turn, may facilitate alternative angiogenic signaling. However, none are established clinical biomarkers: we still do not have a marker that can predict response to bevacizumab, let alone resistance, and it is pretty clear that investigators (let alone Roche/Genentech) have tried to identify one. Thus, the real question is how to target treatments in such a way that the toxicity of the treatment does not outweigh the benefits. In other words, we would like to give treatments to those who would most likely benefit as opposed to simply predicting resistance. Therefore, as the story on biomarkers and chemotherapy slowly unravels, we should pursue the genetic signature that determines an individual’s treatment. The article by Stremitzer and colleagues is an important step in this direction. FUNDING SUPPORT No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.
REFERENCES 1. Stremitzer S, Zhang W, Yang D, et al. Genetic variations in angiopoietin and pericyte pathways and clinical outcome in patients with resected colorectal liver metastases. Cancer. 2015;121:1898-1905. 2. Warusavitarne J, Ramanathan P, Kaufman A, Robinson BG, Schnitzler M. 5-Fluorouracil (5FU) treatment does not influence invasion and metastasis in microsatellite unstable (MSI-H) colorectal cancer. Int J Colorectal Dis. 2006;21:625-631. 3. Warusavitarne J, Schnitzler M. The role of chemotherapy in microsatellite unstable (MSI-H) colorectal cancer. Int J Colorectal Dis. 2007; 22:739-748. 4. de Haas S, Delmar P, Bansal A, et al. Genetic variability of VEGF pathway genes in six randomized phase III trials assessing the addition of bevacizumab to standard therapy. Angiogenesis. 2014;17:909-920. 5. Mao C, Huang Y-F, Yang Z-Y, Zheng D-Y, Chen J-Z, Tang J-L. KRAS p.G13D mutation and codon 12 mutations are not created equal in predicting clinical outcomes of cetuximab in metastatic colorectal cancer. Cancer. 2013;119:714-721.
Cancer
June 1, 2015
Copyright of Cancer (0008543X) is the property of John Wiley & Sons, Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Genetic Variants and Response to Cancer Treatments Janindra Warusavitarne, B Med, FRACS, PhD1; Justin Stebbing, FRCP, FRCPath, PhD2; and Omar Faiz, BSc(Hons), MBBS, FRCS(GenSurg), MS1
Stremitzer and colleagues have demonstrated that single nucleotide polymorphisms (SNPs) in several genes involved in an alternate pathway of angiogenesis are predictive of prognosis in patients with colorectal liver metastases who receive treatment with bevacizumab before undergoing liver resection, as reported in this issue of Cancer.1 These findings have particular relevance, because most patients experience disease relapse, from which they die; and there are no biomarkers to date that can predict a cure. In their report, the authors’ hypothesis is that genes involved in the angiopoietin and pericyte pathways are escape mechanisms for antivascular endothelial growth factor (anti-VEGF) treatments and that variants in these alternate pathway genes may help determine outcomes. To demonstrate this, they evaluated SNPs in 9 genes involved in the pathway and identified several SNPs that were associated with disease-free survival, overall survival, histologic response, radiologic, response, and cure. The study raises several issues with regard to our understanding of biomarkers and how we translate genetic studies into clinical practice. Perhaps the most important point is the apparent dissociation between genes associated with recurrence-free survival, overall survival, and achieving a cure. Genes that were associated with a cure in this cohort were not associated with overall or recurrence-free survival. The authors explain that the markers predicting tumor growth are not necessarily the same as those predicting tumor shrinkage, which would account for the dissociation. Although this appears to be a plausible hypothesis, it warrants further investigation, because it raises relevant issues regarding translational studies and how we draw conclusions from them. Many attempts to identify markers that would make certain tumors more responsive to particular therapies have been unable to identify which tumors are likely to respond prospectively and, instead, have only served to highlight the complex interactions that exist. Another hypothesis is that the toxicity of chemotherapy and its potential associated morbidities may outweigh the benefits of the drugs; conceivably, the drugs may unintentionally target separate genes that could cause an imbalance (and, thus, progression) in the tumor instead of destroying it. This explains why the survival benefits may not be as dramatic as expected from “curing” a tumor and is all the more reason to identify which tumors are most likely to benefit from the drug to minimize collateral damage from the treatment. The concept of biomarker-based assessment of response to chemotherapy is important. Earlier studies that assessed response to chemotherapy in microsatellite-unstable colon cancers produced conflicting results. For example, although some studies have demonstrated that 5-fluorouracil–based chemotherapy may be associated with a poor response to treatment in tumors with microsatellite instability, not all population-based studies have supported this hypothesis.2,3 This is mainly because microsatellite instability was not a part of the randomization in many chemotherapy trials at the time. Similarly, in their study, Stremitzer’s group reports that, although some SNPs are relevant for the overall population, others may be important only for a subgroup of patients based on their biologic function. It has been demonstrated that tumor location influences the biologic behavior of colorectal cancer and, similarly, that biomarker-based evaluation of colorectal cancer according to disease site is important; however, these issues are not addressed by Stremitzer and colleagues. Although it is assumed that blocking aspects of the VEGF pathway may lead to tumor destruction, as observed in a recent meta-analysis, the effects of targeted drugs like bevacizumab may reach beyond the expected target.4 This adds a level of complexity to determining who is most likely to benefit from treatment and also makes it difficult to identify alternate
Corresponding author: Justin Stebbing, FRCPath, FACP, PhD, Imperial College Centre for Translational and Experimental Medicine, Hammersmith Hospital, Du Cane Road, London, W12 0NN; Fax: (011) 4420 331114-33; [email protected] 1 Department of Surgery, St. Mark’s Hospital and Imperial College, London, United Kingdom; 2Imperial College Centre for Translational and Experimental Medicine, Hammersmith Hospital, London, United Kingdom
The authors discuss new findings that single nucleotide polymorphisms in genes associated with off-target effects of antiangiogenesis agents have a bearing on clinical outcomes. This, in turn, reveals potential new targets for drug development. See related original article on pages 1898-905, this issue. DOI: 10.1002/cncr.29257, Received: October 7, 2014; Revised: December 23, 2014; Accepted: December 24, 2014, Published online February 17, 2015 in Wiley Online Library (wileyonlinelibrary.com)
Cancer
June 1, 2015
1735
Editorial
pathways of resistance to treatment. The new genes studied here may represent therapeutic targets for overcoming resistance to bevacizumab-based therapeutics or at least may hint at the mechanisms involved with regard to offtarget drug effects. Mutational analysis of K-Ras (v-Ki–ras2 Kirsten rat sarcoma viral oncogene homolog) is now commonly performed to identify treatment pathways for colorectal cancer. The current analysis predicts resistance to treatment rather than response. Both in vivo and in vitro studies have demonstrated that KRAS G13D mutations (glycine to aspartic acid change at position 13) are associated with sensitivity to both cetuximab and panitumumab compared with KRAS glycine to valine change at position 12 (G12V) mutations,5 which, in turn, simply highlights the point that simple mutational analysis alone may not be adequate, and the same may apply to SNPs. With the increasing use of genome-wide sequencing, it may be possible to identify a tumor signature or footprint that could best identify which patients most likely would benefit from these treatments. The possible explanation for the conflicting gene information in different publications is that there are interactions between genes in a pathway that are not necessarily explained by investigating the pathways in isolation but perhaps by investigating the difference between genetics and genomics. The hypothesis proposed by Stremitzer and colleagues may be too simplistic, and this could offer us some explanation regarding why the results from many such translational studies are inconsistent. Thus, an issue with whole-genome sequencing is the handling of such a vast quantity of data, which, in turn, calls out for international collaboration between centers that already collect such information. The outcomes measured in these studies determine the conclusions, and 5-year survival traditionally has been used as the measure in cancer-related publications. Although this still remains a good measure of treatment efficacy, it does not always take treatment-related complications into account. Perhaps the same pathways that promote apoptosis and, thus, a cure may be involved in promoting apoptosis in other dividing cells, and any survival benefit observed with a “cure” can be negated or reduced as a result. The authors should be congratulated on their article and their attempt to tease out the pathways and tailor treatment to those who are most likely to benefit. Although this may appear to be the tip of the iceberg
1736
in individualized treatment, perhaps someday soon we will move away from the current practice, in which colorectal cancer is largely treated based on stage, and chemotherapy protocols are relatively standard. For example, despite comments about our era of personalized therapies, we still do not know how to treat third-line, K-Ras– mutated, metastatic colon cancer. Proangiogenic factors like interleukin 8, fibroblast growth factor, hepatocyte growth factor, and others, as pointed out, have been associated with compensatory up-regulation during antiVEGF–targeted therapy, which, in turn, may facilitate alternative angiogenic signaling. However, none are established clinical biomarkers: we still do not have a marker that can predict response to bevacizumab, let alone resistance, and it is pretty clear that investigators (let alone Roche/Genentech) have tried to identify one. Thus, the real question is how to target treatments in such a way that the toxicity of the treatment does not outweigh the benefits. In other words, we would like to give treatments to those who would most likely benefit as opposed to simply predicting resistance. Therefore, as the story on biomarkers and chemotherapy slowly unravels, we should pursue the genetic signature that determines an individual’s treatment. The article by Stremitzer and colleagues is an important step in this direction. FUNDING SUPPORT No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.
REFERENCES 1. Stremitzer S, Zhang W, Yang D, et al. Genetic variations in angiopoietin and pericyte pathways and clinical outcome in patients with resected colorectal liver metastases. Cancer. 2015;121:1898-1905. 2. Warusavitarne J, Ramanathan P, Kaufman A, Robinson BG, Schnitzler M. 5-Fluorouracil (5FU) treatment does not influence invasion and metastasis in microsatellite unstable (MSI-H) colorectal cancer. Int J Colorectal Dis. 2006;21:625-631. 3. Warusavitarne J, Schnitzler M. The role of chemotherapy in microsatellite unstable (MSI-H) colorectal cancer. Int J Colorectal Dis. 2007; 22:739-748. 4. de Haas S, Delmar P, Bansal A, et al. Genetic variability of VEGF pathway genes in six randomized phase III trials assessing the addition of bevacizumab to standard therapy. Angiogenesis. 2014;17:909-920. 5. Mao C, Huang Y-F, Yang Z-Y, Zheng D-Y, Chen J-Z, Tang J-L. KRAS p.G13D mutation and codon 12 mutations are not created equal in predicting clinical outcomes of cetuximab in metastatic colorectal cancer. Cancer. 2013;119:714-721.
Cancer
June 1, 2015
Copyright of Cancer (0008543X) is the property of John Wiley & Sons, Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
