REVIEW EDITORIAL For reprint orders, please contact: [email protected]
Tumor heterogeneity-based resistance guides personalized cancer medicine “Notably, effective drugs have not yet been developed to target the wide mutational landscape and cancer-associated genes to kill all primary tumor cancer cell subpopulations. In the near future, we can expect further important steps towards personalized cancer medicine.” Georgios D Lianos1,2, Alberto Mangano3, Stefano Rausei3, Christos Katsios2 & Dimitrios H Roukos*,1,2,4 Recent evidence on tumor heterogeneity shapes a new era in achieving personalized cancer medicine. Indeed, despite advances in modern oncology with standardized single biopsy-based approaches, limitations still exist in predicting resistance to therapies and tumor progression. In this editorial, we will summarize the potential clinical benefits and challenges by translating tumor heterogeneity data into clinical oncology. Interpatient & intratumor heterogeneity Nowadays, accumulating evidence suggests that the present and the future of personalized cancer medicine is represented by interpatient and intratumor heterogeneity status [1] . Different genetic backgrounds and variations among patients with the same tumor, clinical and pathological properties, and staging are defined as interpatient heterogeneity (IPH) [1] . Moreover, different mutations in subpopulations of cancer cells in different geographical regions of the same tumor is known
as intratumor heterogeneity (ITH) [1,2] . Recent genome sequence-based data suggest that these variations may represent a useful tool for predicting the response or resistance of patients to targeted therapies. There is no doubt that cancer is a complex process and, unfortunately, the diversity of the genetic background among patients and tumors cannot be adequately focused by a single biopsy with a surgical resection or even a needle biopsy. IPH and ITH represent a real medical challenge because if they can be ‘characterized’, this may lead to better patient prognosis. To date, tissue diagnosis via histopathology examination has been the current standard of cancer management. But, can this adequately express the interpatient and intratumor diversity or novel methods required? To investigate this, novel next-generation sequencing (NGS) technologies are already being used by investigators in various types of tumors [3] . Currently, much research is focused on IPH with the hope of improving the personalized cancer treatment approach.
KEYWORDS
• cancer • next-generation sequencing analyses • personalized medicine • resistance • tumor
heterogeneity
“...accumulating evidence suggests that the present and the future of personalized cancer medicine is represented by interpatient and intratumor heterogeneity status.”
Centre for Biosystems & Genomic Network Medicine – CBS.GenNetMed University of Ioannina, Ioannina, GR 451 10, Greece 2 Department of Surgery, Ioannina University School of Medicine, Ioannina, GR 451 10, Greece 3 Department of Surgical Sciences & Human Morphology, Insubria University, Varese, Italy 4 Biomedical Research Foundation Academy of Athens (BRFAA), Athens, Greece *Author for correspondence: Tel.: +30 265 100 7423; Fax: +30 265 100 7094; [email protected] 1
10.2217/FON.14.122 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(12), 1889–1892
part of
ISSN 1479-6694
1889
Editorial Lianos, Mangano, Rausei, Katsios & Roukos
“...it is now possible to gain
important information about the genetic background of tumors with a simple patient blood sample and without the need for invasive procedures.”
However, the most critical issue in terms of decision-making during tumor progression is represented by intratumor mutational ‘diversity’ of the primary tumor (PT) cancer cells [3,4] . The metastatic progress of a tumor or its resistance to therapy could perhaps be better managed if its heterogeneity was quantified. Tumor biopsies are currently used to provide important information on resistance and recurrence. However, multiple tumor biopsies from the metastatic sites of the disease in the majority of cases are not feasible, are invasive and are more difficult to perform. New molecular profiling NGS analyses are now available and are currently used to examine, analyze and quantify the hetero geneity in many types of PT and metastatic tumors (MT). In early stage tumors and in the absence of metastatic lesions there is no accurate predictive method of resistance to therapy and recurrence. However, it is now possible to gain important information about the genetic background of tumors with a simple patient blood sample and without the need for invasive procedures. In the near future, these novel methods may lead to predicting resistance to therapy or recurrence even in early stage tumors [1,5] . Tumor heterogeneity Tumor heterogeneity had already been extensively studied before the advent of high-throughput sequencing technology. Tumor heterogeneity analysis before and after the introduction of NGS technologies will be discussed in the following sections. ●●Before NGS technologies
There is no doubt that colorectal cancer (CRC) prognosis is strongly correlated with colorectal liver metastases (CRLM). The overall survival rates of these patients are not yet clearly established. Recently, researchers focused on the heterogeneity between PT and MT of patients with CRLM. Using PCR methods, Artale et al. [6] extensively studied mutations of KRAS and BRAF in primary and metastatic cases of CRC and concluded that evaluation of the KRAS and BRAF mutations can be assessed in either primary and metastatic tumors. This finding may help to select ideal patients for anti-EGFR treatment. In the breast cancer setting, an important study was conducted by Ding et al. [7] who studied four samples (PT sample, blood, MT
1890
Future Oncol. (2014) 10(12)
sample and xenograft) from one patient using microarrays. The investigators concluded that secondary tumors may arise from a minority of cells within the PT. By contrast, Barry et al. [8] published the results of 50 core needle biopsies from 18 breast cancer patients and concluded that ITH does not preclude microarray-based predictions of tumor behavior. In the field of melanoma research, Yancovitz et al. [9] performed a BRAF mutant-specific PCR study. For the study, 73 patients were enrolled and 112 tumor samples were collected. By using highly sensitive BRAF mutation detection methods, significant evidence for heterogeneity of the BRAF V600E mutation was observed in melanoma tumor specimens, and evidence for heterogeneity was also revealed among several specimens from individual patients. ●●After NGS technology integration
In the era of individualized cancer treatment, important studies using novel NGS analyses in CRC metastatic settings strongly support ITH. Notably, Miranda et al. [10] recently published a study on 31 primary and metastatic CRCs, which were assessed using NGS analyses. They reported that metastatic lymph nodes were characterized by fewer alterations compared with PT and liver metastases. Moreover, genetic changes found in MT were mostly from the PT. By contrast, epigenetic changes were frequently found de novo. Furthermore, lymph node metastases and CRLM seemed to originate in clonally different processes. In another study, 21 primary and metastatic CRCs were assessed. In total, 6696 known and 1305 new variations were shown in 1174 and 667 genes, respectively. In the metastasis, 83 variations were observed and 70 variations were lost. These results suggest that the genetic pattern of CRLM is perhaps much more heterogeneous than those of the PT [11] . Furthermore, another study conducted on four primary and metastatic CRCs suggested that a very complex interaction between mutations, copy number changes and chromothripsis mechanisms lead to CRC metastasis [12] . In the breast cancer setting, Navin et al. [13] analyzed two PT and matched MT with the latest advanced technologies. In both PT it was found that an abundant subpopulation of genetically diverse cells did not ‘travel’ to the metastatic site. Research on heterogeneity has also been carried out in the field of pancreatic cancer.
future science group
Tumor heterogeneity-based resistance guides personalized cancer medicine Yachida et al. performed whole-exome sequencing (WES) analyses on seven primary and metastatic pancreatic cancers and concluded that clonal populations that give rise to distant metastases are represented within the PT; however, these clones are genetically different and evolved from the original clone [14] . Moreover, Campel et al. [15] analyzed three PT and ten metastatic pancreatic tumors and reported that there is genetic heterogeneity among metastasisinitiating cells. Furthermore, it was reported that metastases may require driver mutations beyond the mutations required for PT. Gerlinger et al. [16] recently published a study examining ITH. The researchers performed exome sequencing, chromosome aberration analysis and ploidy profiling on separated samples obtained from primary renal carcinomas and associated metastatic sites. WES was performed in four primary and metastatic renal cell carcinomas. They concluded that allelic composition and profiling analysis revealed extensive ITH and that ITH can lead to underestimation of tumor genomics pattern when assessed only with single tumor biopsies. These analyses for renal cancer have shown that gene- expression signatures of good and poor prognosis were detected in different regions of the same tumor identifying approximately 64% spatial heterogeneity. The major disadvantage of conducting metastatic site biopsies is its invasive nature. However, this could be overcome with circulating tumor DNA (ctDNA). In 2013, Murtaza et al. [17] published an important article in which WES analyses was performed on 19 PT and MT with ctDNA. Peripheral blood, including two to five plasma samples for six patients with advanced breast, ovarian and lung cancers, was used. Plasma was collected before treatment and at specific time points during the patients’ treatment and follow-up. WES was performed on circulating DNA from plasma at crucial predefined time points. The investigators concluded that WES analysis of ctDNA could significant aid current invasive biopsy procedures to identify mutations associated with acquired drug resistance in patients with advanced tumors. The latest study in this field was published by Bettegowda et al. [18] . The aim of this study was to evaluate the ability of ctDNA to detect tumors. A total of 640 patients with various types of tumors were enrolled in this project and digital PCR-based technologies were used.
future science group
It was revealed that ctDNA was detectable in more than 75% of patients with advanced cancers (pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, head and neck cancers), but in less than 50% of primary brain, renal, prostate or thyroid cancers. The most critical point to be highlighted is that in patients with early-stage tumors, ctDNA was detected in 73, 57, 48 and 50% of patients with colorectal, gastroesophageal, pancreatic and breast cancer, respectively [18] . All these data suggest that ctDNA can be used as a specific biomarker and may shape a novel noninvasive pathway towards new genomic personalized cancer therapies. Taken together, IPH and intratumor diversity now represent the most credible explanation of the observed resistance to systemic therapy and metastatic recurrence in the adjuvant setting or tumor progression in the metastatic setting [19] . Although older array-based technologies have supported tumor heterogeneity, high-throughput sequencing technologies now provide a better approach to reveal the extent and magnitude of tumor heterogeneity in the emerging resistance to therapy. Therefore, new large-scale clinical trial data are required to establish the clinical utility of tumor heterogeneity. The rapid drop in the cost of human genome sequencing (meeting the US$1000 goal [20]) this year provides optimism for accurate cancer genome sequencing and guidelines based on data for accurate assessment of ITH. Although NGS-based ITH assessment could be used as a biomarker to predict therapeutic response, new clinical trials will be required to study the efficacy of targeted drugs combinations to eliminate all cancer cell subpopulations of ITH. Notably, effective drugs have not yet been developed to target the wide mutational landscape and cancer-associated genes to kill all PT cancer cell subpopulations. In the near future, we can expect further important steps towards personalized cancer medicine.
Editorial
“...interpatient heterogeneity and intratumor diversity now represent the most credible explanation of the observed resistance to systemic therapy and metastatic recurrence in the adjuvant setting or tumor progression in the metastatic setting.”
Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
www.futuremedicine.com
1891
Editorial Lianos, Mangano, Rausei, Katsios & Roukos microarray-based predictors of breast cancer biology and clinical outcome. J. Clin. Oncol. 28, 2198–2206 (2010).
References 1
2
Bedard PL, Hansen AR, Ratain MJ, Siu LL. Tumour heterogeneity in the clinic. Nature 501(7467), 355–364 (2013). Tran B, Dancey JE, Kamel-Reid S et al. Cancer genomics: technology, discovery, and translation. J. Clin. Oncol. 30, 647–660 (2012).
3
Klein CA. Selection and adaptation during metastatic cancer progression. Nature 501(7467), 365–372 (2013).
4
Polzer B, Klein CA. Metastasis awakening: the challenges of targeting minimal residual cancer. Nat. Med. 19, 274–275 (2013).
5
Greaves M, Maley CC. Clonal evolution in cancer. Nature 481, 306–313 (2012).
6
Artale S, Sartore-Bianchi A, Veronese SM et al. Mutations of KRAS and BRAF in primary and matched metastatic sites of colorectal cancer. J. Clin. Oncol. 26, 4217–4219 (2008).
7
8
Ding L, Ellis MJ, Li S et al. Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464, 999–1005 (2010). Barry WT, Kernagis DN, Dressman HK et al. Intratumor heterogeneity and precision of
1892
9
Yancovitz M, Litterman A, Yoon J et al. Intra- and inter-tumor heterogeneity of BRAF mutations in primary and metastatic melanoma. PLoS ONE 7, e29336 (2012).
10 Miranda E, Bianchi P, Destro A et al. Genetic
and epigenetic alterations in primary colorectal cancers and related lymph node and liver metastases. Cancer 119(2), 266–276 (2013). 11 Vermaat JS, Nijman IJ, Koudijs MJ et al.
Primary colorectal cancers and their subsequent hepatic metastases are genetically different: implications for selection of patients for targeted treatment. Clin. Cancer Res. 18(3), 688–699 (2012). 12 Kloosterman WP, Hoogstraat M, Paling O
et al. Chromothripsis is a common mechanism driving genomic rearrangements in primary and metastatic colorectal cancer. Genome Biol. 12(10), R103 (2011). 13 Navin N, Kendall J, Troge J et al. Tumour
evolution inferred by single-cell sequencing. Nature 472, 90–94 (2011).
Future Oncol. (2014) 10(12)
14 Yachida S, Jones S, Bozic I et al. Distant
metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467, 1114–1117 (2010). 15 Campbell PJ, Yachida S, Mudie LJ et al. The
patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467, 1109–1113 (2010). 16 Gerlinger M, Rowan AJ, Horswell S et al.
Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366(10), 883–892 (2012). 17 Murtaza M, Dawson SJ, Tsui DW et al.
Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497(7447), 108–112 (2013). 18 Bettegowda C, Sausen M, Leary R et al.
Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci. Transl. Med. 6(224), 224ra24 (2014). 19 Swanton C. Intratumor heterogeneity:
evolution through space and time. Cancer Res. 72(19), 4875–4882 (2012). 20 Hayden EC. Technology: the $1,000 genome.
Nature 507(7492), 294–295 (2014).
future science group
Tumor heterogeneity-based resistance guides personalized cancer medicine “Notably, effective drugs have not yet been developed to target the wide mutational landscape and cancer-associated genes to kill all primary tumor cancer cell subpopulations. In the near future, we can expect further important steps towards personalized cancer medicine.” Georgios D Lianos1,2, Alberto Mangano3, Stefano Rausei3, Christos Katsios2 & Dimitrios H Roukos*,1,2,4 Recent evidence on tumor heterogeneity shapes a new era in achieving personalized cancer medicine. Indeed, despite advances in modern oncology with standardized single biopsy-based approaches, limitations still exist in predicting resistance to therapies and tumor progression. In this editorial, we will summarize the potential clinical benefits and challenges by translating tumor heterogeneity data into clinical oncology. Interpatient & intratumor heterogeneity Nowadays, accumulating evidence suggests that the present and the future of personalized cancer medicine is represented by interpatient and intratumor heterogeneity status [1] . Different genetic backgrounds and variations among patients with the same tumor, clinical and pathological properties, and staging are defined as interpatient heterogeneity (IPH) [1] . Moreover, different mutations in subpopulations of cancer cells in different geographical regions of the same tumor is known
as intratumor heterogeneity (ITH) [1,2] . Recent genome sequence-based data suggest that these variations may represent a useful tool for predicting the response or resistance of patients to targeted therapies. There is no doubt that cancer is a complex process and, unfortunately, the diversity of the genetic background among patients and tumors cannot be adequately focused by a single biopsy with a surgical resection or even a needle biopsy. IPH and ITH represent a real medical challenge because if they can be ‘characterized’, this may lead to better patient prognosis. To date, tissue diagnosis via histopathology examination has been the current standard of cancer management. But, can this adequately express the interpatient and intratumor diversity or novel methods required? To investigate this, novel next-generation sequencing (NGS) technologies are already being used by investigators in various types of tumors [3] . Currently, much research is focused on IPH with the hope of improving the personalized cancer treatment approach.
KEYWORDS
• cancer • next-generation sequencing analyses • personalized medicine • resistance • tumor
heterogeneity
“...accumulating evidence suggests that the present and the future of personalized cancer medicine is represented by interpatient and intratumor heterogeneity status.”
Centre for Biosystems & Genomic Network Medicine – CBS.GenNetMed University of Ioannina, Ioannina, GR 451 10, Greece 2 Department of Surgery, Ioannina University School of Medicine, Ioannina, GR 451 10, Greece 3 Department of Surgical Sciences & Human Morphology, Insubria University, Varese, Italy 4 Biomedical Research Foundation Academy of Athens (BRFAA), Athens, Greece *Author for correspondence: Tel.: +30 265 100 7423; Fax: +30 265 100 7094; [email protected] 1
10.2217/FON.14.122 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(12), 1889–1892
part of
ISSN 1479-6694
1889
Editorial Lianos, Mangano, Rausei, Katsios & Roukos
“...it is now possible to gain
important information about the genetic background of tumors with a simple patient blood sample and without the need for invasive procedures.”
However, the most critical issue in terms of decision-making during tumor progression is represented by intratumor mutational ‘diversity’ of the primary tumor (PT) cancer cells [3,4] . The metastatic progress of a tumor or its resistance to therapy could perhaps be better managed if its heterogeneity was quantified. Tumor biopsies are currently used to provide important information on resistance and recurrence. However, multiple tumor biopsies from the metastatic sites of the disease in the majority of cases are not feasible, are invasive and are more difficult to perform. New molecular profiling NGS analyses are now available and are currently used to examine, analyze and quantify the hetero geneity in many types of PT and metastatic tumors (MT). In early stage tumors and in the absence of metastatic lesions there is no accurate predictive method of resistance to therapy and recurrence. However, it is now possible to gain important information about the genetic background of tumors with a simple patient blood sample and without the need for invasive procedures. In the near future, these novel methods may lead to predicting resistance to therapy or recurrence even in early stage tumors [1,5] . Tumor heterogeneity Tumor heterogeneity had already been extensively studied before the advent of high-throughput sequencing technology. Tumor heterogeneity analysis before and after the introduction of NGS technologies will be discussed in the following sections. ●●Before NGS technologies
There is no doubt that colorectal cancer (CRC) prognosis is strongly correlated with colorectal liver metastases (CRLM). The overall survival rates of these patients are not yet clearly established. Recently, researchers focused on the heterogeneity between PT and MT of patients with CRLM. Using PCR methods, Artale et al. [6] extensively studied mutations of KRAS and BRAF in primary and metastatic cases of CRC and concluded that evaluation of the KRAS and BRAF mutations can be assessed in either primary and metastatic tumors. This finding may help to select ideal patients for anti-EGFR treatment. In the breast cancer setting, an important study was conducted by Ding et al. [7] who studied four samples (PT sample, blood, MT
1890
Future Oncol. (2014) 10(12)
sample and xenograft) from one patient using microarrays. The investigators concluded that secondary tumors may arise from a minority of cells within the PT. By contrast, Barry et al. [8] published the results of 50 core needle biopsies from 18 breast cancer patients and concluded that ITH does not preclude microarray-based predictions of tumor behavior. In the field of melanoma research, Yancovitz et al. [9] performed a BRAF mutant-specific PCR study. For the study, 73 patients were enrolled and 112 tumor samples were collected. By using highly sensitive BRAF mutation detection methods, significant evidence for heterogeneity of the BRAF V600E mutation was observed in melanoma tumor specimens, and evidence for heterogeneity was also revealed among several specimens from individual patients. ●●After NGS technology integration
In the era of individualized cancer treatment, important studies using novel NGS analyses in CRC metastatic settings strongly support ITH. Notably, Miranda et al. [10] recently published a study on 31 primary and metastatic CRCs, which were assessed using NGS analyses. They reported that metastatic lymph nodes were characterized by fewer alterations compared with PT and liver metastases. Moreover, genetic changes found in MT were mostly from the PT. By contrast, epigenetic changes were frequently found de novo. Furthermore, lymph node metastases and CRLM seemed to originate in clonally different processes. In another study, 21 primary and metastatic CRCs were assessed. In total, 6696 known and 1305 new variations were shown in 1174 and 667 genes, respectively. In the metastasis, 83 variations were observed and 70 variations were lost. These results suggest that the genetic pattern of CRLM is perhaps much more heterogeneous than those of the PT [11] . Furthermore, another study conducted on four primary and metastatic CRCs suggested that a very complex interaction between mutations, copy number changes and chromothripsis mechanisms lead to CRC metastasis [12] . In the breast cancer setting, Navin et al. [13] analyzed two PT and matched MT with the latest advanced technologies. In both PT it was found that an abundant subpopulation of genetically diverse cells did not ‘travel’ to the metastatic site. Research on heterogeneity has also been carried out in the field of pancreatic cancer.
future science group
Tumor heterogeneity-based resistance guides personalized cancer medicine Yachida et al. performed whole-exome sequencing (WES) analyses on seven primary and metastatic pancreatic cancers and concluded that clonal populations that give rise to distant metastases are represented within the PT; however, these clones are genetically different and evolved from the original clone [14] . Moreover, Campel et al. [15] analyzed three PT and ten metastatic pancreatic tumors and reported that there is genetic heterogeneity among metastasisinitiating cells. Furthermore, it was reported that metastases may require driver mutations beyond the mutations required for PT. Gerlinger et al. [16] recently published a study examining ITH. The researchers performed exome sequencing, chromosome aberration analysis and ploidy profiling on separated samples obtained from primary renal carcinomas and associated metastatic sites. WES was performed in four primary and metastatic renal cell carcinomas. They concluded that allelic composition and profiling analysis revealed extensive ITH and that ITH can lead to underestimation of tumor genomics pattern when assessed only with single tumor biopsies. These analyses for renal cancer have shown that gene- expression signatures of good and poor prognosis were detected in different regions of the same tumor identifying approximately 64% spatial heterogeneity. The major disadvantage of conducting metastatic site biopsies is its invasive nature. However, this could be overcome with circulating tumor DNA (ctDNA). In 2013, Murtaza et al. [17] published an important article in which WES analyses was performed on 19 PT and MT with ctDNA. Peripheral blood, including two to five plasma samples for six patients with advanced breast, ovarian and lung cancers, was used. Plasma was collected before treatment and at specific time points during the patients’ treatment and follow-up. WES was performed on circulating DNA from plasma at crucial predefined time points. The investigators concluded that WES analysis of ctDNA could significant aid current invasive biopsy procedures to identify mutations associated with acquired drug resistance in patients with advanced tumors. The latest study in this field was published by Bettegowda et al. [18] . The aim of this study was to evaluate the ability of ctDNA to detect tumors. A total of 640 patients with various types of tumors were enrolled in this project and digital PCR-based technologies were used.
future science group
It was revealed that ctDNA was detectable in more than 75% of patients with advanced cancers (pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, head and neck cancers), but in less than 50% of primary brain, renal, prostate or thyroid cancers. The most critical point to be highlighted is that in patients with early-stage tumors, ctDNA was detected in 73, 57, 48 and 50% of patients with colorectal, gastroesophageal, pancreatic and breast cancer, respectively [18] . All these data suggest that ctDNA can be used as a specific biomarker and may shape a novel noninvasive pathway towards new genomic personalized cancer therapies. Taken together, IPH and intratumor diversity now represent the most credible explanation of the observed resistance to systemic therapy and metastatic recurrence in the adjuvant setting or tumor progression in the metastatic setting [19] . Although older array-based technologies have supported tumor heterogeneity, high-throughput sequencing technologies now provide a better approach to reveal the extent and magnitude of tumor heterogeneity in the emerging resistance to therapy. Therefore, new large-scale clinical trial data are required to establish the clinical utility of tumor heterogeneity. The rapid drop in the cost of human genome sequencing (meeting the US$1000 goal [20]) this year provides optimism for accurate cancer genome sequencing and guidelines based on data for accurate assessment of ITH. Although NGS-based ITH assessment could be used as a biomarker to predict therapeutic response, new clinical trials will be required to study the efficacy of targeted drugs combinations to eliminate all cancer cell subpopulations of ITH. Notably, effective drugs have not yet been developed to target the wide mutational landscape and cancer-associated genes to kill all PT cancer cell subpopulations. In the near future, we can expect further important steps towards personalized cancer medicine.
Editorial
“...interpatient heterogeneity and intratumor diversity now represent the most credible explanation of the observed resistance to systemic therapy and metastatic recurrence in the adjuvant setting or tumor progression in the metastatic setting.”
Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
www.futuremedicine.com
1891
Editorial Lianos, Mangano, Rausei, Katsios & Roukos microarray-based predictors of breast cancer biology and clinical outcome. J. Clin. Oncol. 28, 2198–2206 (2010).
References 1
2
Bedard PL, Hansen AR, Ratain MJ, Siu LL. Tumour heterogeneity in the clinic. Nature 501(7467), 355–364 (2013). Tran B, Dancey JE, Kamel-Reid S et al. Cancer genomics: technology, discovery, and translation. J. Clin. Oncol. 30, 647–660 (2012).
3
Klein CA. Selection and adaptation during metastatic cancer progression. Nature 501(7467), 365–372 (2013).
4
Polzer B, Klein CA. Metastasis awakening: the challenges of targeting minimal residual cancer. Nat. Med. 19, 274–275 (2013).
5
Greaves M, Maley CC. Clonal evolution in cancer. Nature 481, 306–313 (2012).
6
Artale S, Sartore-Bianchi A, Veronese SM et al. Mutations of KRAS and BRAF in primary and matched metastatic sites of colorectal cancer. J. Clin. Oncol. 26, 4217–4219 (2008).
7
8
Ding L, Ellis MJ, Li S et al. Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464, 999–1005 (2010). Barry WT, Kernagis DN, Dressman HK et al. Intratumor heterogeneity and precision of
1892
9
Yancovitz M, Litterman A, Yoon J et al. Intra- and inter-tumor heterogeneity of BRAF mutations in primary and metastatic melanoma. PLoS ONE 7, e29336 (2012).
10 Miranda E, Bianchi P, Destro A et al. Genetic
and epigenetic alterations in primary colorectal cancers and related lymph node and liver metastases. Cancer 119(2), 266–276 (2013). 11 Vermaat JS, Nijman IJ, Koudijs MJ et al.
Primary colorectal cancers and their subsequent hepatic metastases are genetically different: implications for selection of patients for targeted treatment. Clin. Cancer Res. 18(3), 688–699 (2012). 12 Kloosterman WP, Hoogstraat M, Paling O
et al. Chromothripsis is a common mechanism driving genomic rearrangements in primary and metastatic colorectal cancer. Genome Biol. 12(10), R103 (2011). 13 Navin N, Kendall J, Troge J et al. Tumour
evolution inferred by single-cell sequencing. Nature 472, 90–94 (2011).
Future Oncol. (2014) 10(12)
14 Yachida S, Jones S, Bozic I et al. Distant
metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467, 1114–1117 (2010). 15 Campbell PJ, Yachida S, Mudie LJ et al. The
patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467, 1109–1113 (2010). 16 Gerlinger M, Rowan AJ, Horswell S et al.
Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366(10), 883–892 (2012). 17 Murtaza M, Dawson SJ, Tsui DW et al.
Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497(7447), 108–112 (2013). 18 Bettegowda C, Sausen M, Leary R et al.
Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci. Transl. Med. 6(224), 224ra24 (2014). 19 Swanton C. Intratumor heterogeneity:
evolution through space and time. Cancer Res. 72(19), 4875–4882 (2012). 20 Hayden EC. Technology: the $1,000 genome.
Nature 507(7492), 294–295 (2014).
future science group
