Pharmacogenomics News & Views in ...
Highlighting the latest news in pharmacogenomics
New strategies could lead to more personalized therapies for cancer
part of
10.2217/PGS.14.77 © 2014 Future Medicine Ltd
Hundreds or even thousands of DNA mutations can accumulate in tumor cells which induce growth and spread of cancer. Different tumors harbor a different number and pattern of mutations, even between those that are classed as the same type of tumor. Researchers discovered the extent of this complexity just a few years ago. In order to target the specific characteristics of each tumor, new tools are required to filter relevant genetic information, which will allow for the development of personalized therapies. A new strategy to personalize medicine in advanced cancer patients with a poor prognosis has been developed by researchers led by Manuel Hidalgo, Vice-Director of Translational Research at CNIO (Madrid, Spain). Treatments induced clinical responses in up to 77% of patients when this new tool was applied, either through stabilization of their condition of through partial clinical response. The first phase of the study involved analysis of the genetic signature of the tumors, specifically the exome in 23 patients with advanced cancer, including pancreatic adenocarcinomas and colon cancer. Researchers identified mutations that could play a role in the growth and spread of the tumors through the use of whole-exome sequencing and bioinformatic analysis. In the second phase, avatar mice were used to match potential effective treatments to the patient’s genetic signature. Elena Garralda, a predoctoral researcher in
Pharmacogenomics (2014) 15(7), 901–904
Hidalgo’s group said that avatar mice are “one of the key aspects of our research.” In order to study the effectiveness of drugs under real conditions, avatar mice are used, with each patient having their own equivalent animal. The likelihood of the drug working in the patient if it has been seen to be effective in the avatar is very high. Patients were therefore given the treatments that worked best in avatar mice. Clinical benefit, either the stabilization of disease or partial clinical response, was seen in up to 77% of patients. “We have demonstrated that it is possible to apply our personalized cancer treatment strategy to the clinic,” says Garralda, adding: “as we learn more about the genetic information obtained from cancer-exome sequencing, future clinical trials will allow for the inclusion of patients with specific genetic alterations, and therefore a better access to cancer drugs.”
ISSN 1462-2416
901
News & Views News The team is currently studying the efficiency of the techniques in a larger number of patients with advanced pancreatic cancer in order to compare them to standard treatments. Pancreatic cancer, which often has a poor prognosis, often has survival
rates of less that a year. As it is a complex and heterogeneous disease, the personalized study of relevant mutations in tumor growth could be a promising avenue of research in the development of new t reatments.
– Written by Sarah Jones Source: Garralda E, Paz K, Lopez-Casas PP et al. Integrated next-generation sequencing and avatar mouse models for personalized cancer treatment. Clin. Cancer Res. 20(9), 2476–2484 (2014).
Importance of keeping patients well informed key to gene-based drug dosing The need for a lot more education around pharmacogenetics is highlighted by a new study out of Western University (London, Canada). This is the first study to investigate how patients perceive pharmacogenetic information, which promises to optimize patient response to therapy, and whether those perceptions differ when it comes to parents and their children. The study published in the journal Pediatrics is led by Michael Rieder of Western’s Schulich School of Medicine and Dentistry. “Pharmacogenetic testing has become widely used and gene-based drug dosing is becoming a reality for a number of common health problems. This study confirms what we suspected; whether or not you’re a parent, your degree of acceptability of genetic testing was determined by your knowledge of it. That is to say – if you understand what the test is for, and the concept of gene-based drug dosing, you’re far more open to it, than if you don’t understand it,” said Rieder, a Professor in the Departments of Paediatrics, and Physiology and Pharmacology. Three groups were surveyed by the researchers: 236 medical students who represented those who have greater educational exposure to pharmacogenomics, 1226 lay parents and 105 lay people without children. A second group was made up of 229 parents who completed a different survey. Rather then using the term
pharmacogenetics the surveys asked about ‘DNA testing to guide therapy’. It was concluded by the study that the acceptability of pharmacogenomics testing, either for oneself or one’s child, was dependent on baseline pharmacogenomics knowledge but not parenthood. For all respondents the main concern was the need for informed consent. Other findings included: • More acceptance for PGx when the disease was severe • Strong desire/demand for separate for pharmacogenomics testing
consent
• More education about pharmacogenomics needed in medical schools • Acceptability of genetic testing didn’t differ whether for the parent or the child Rieder said that pediatric oncology provides a good example as healthcare workers in this division do well at framing discussions around care, treatment and consent: “when they have to make a diagnosis, they spend a lot of time explaining what tests they’re going to do, the risks and what therapies are available, and they’re successful. Their patients comply with treatment, they get involved in studies, they’re informed, and they want to know what’s going on.”
– Written by Sarah Jones Source: Zhang SC, Bruce C, Hayden M, Rieder MJ. Public perceptions of pharmacogenetics. Pediatrics 133(5), e1258 (2014).
About the News & Views
The News highlights some of the most important events and research in pharmacogenomics. If you have newsworthy information, please contact: Sarah Jones, Commissioning Editor, Pharmacogenomics, Future Medicine Ltd, Unitec House, 2 Albert Place, London, N3 1QB, UK; Tel.: +44 (0)20 8371 6090; [email protected]
902
Pharmacogenomics (2014) 15(7)
future science group
News
News & Views
Huge emphasis placed on gene-expression profiling test by breast cancer patients New research suggests that although many women with early-stage breast cancer take into account geneexpression profiling (GEP) when deciding whether to have chemotherapy, many do not fully understand what some of the test results mean. Currently, guidelines result in thousands of women with early-stage breast cancer receiving chemotherapy with no benefit. Those who might benefit from chemotherapy versus those who might not can be differentiated using a GEP test. By analyzing the patterns of 21 different genes within cancer cells, the test helps predict how likely it is that a women’s cancer will recur within 10 years of initial treatment and how much benefit chemotherapy will have. Yvonne Bombard, a genomics and health services researcher in the Li Ka Shing Knowledge Institute of St Michael’s Hospital (Toronto, Canada), who interviewed a group of women with early-stage breast cancer said that they understood that the test would indicate whether they would benefit from chemotherapy. However, many did not realize that the test result was based on larger population statistics and did not reflect their individual unique circumstances. “Patients often viewed their GEP results as providing information that was more scientifically valid, uniquely personalized and emotionally significant than any other information they had received,” Bom-
bard said. “For many, the test was a transformational element that empowered them, allowed them to feel confident in their decisions and may even have rescued them from unnecessary chemotherapy.”
“
Currently, guidelines result in thousands of women with early-stage breast cancer receiving
”
chemotherapy with no benefit.
Despite misunderstandings around the test and it’s validity, the GEP test was a main determinant of patients’ decisions regarding chemotherapy. “GEP is one of many factors that women in consultation with their oncologists, should consider when choosing treatment for early-stage breast cancer,” said Maureen Trudeau, a medical oncologist of the Breast Care team and head of the Medical Oncology Program at Sunnybrook’s Odette Cancer Center (Toronto, Canada), and study coauthor. “The GEP test does not replace standard prognostic information but adds one more piece of information.” Current clinical guidelines suggest that the majority of patients whose breast cancer tests negative for human HER2 should be offered chemotherapy, which amounts to 22,600 Canadian women each year. However, only about 15% of these cancers will recur, which could mean that about 8500 Canadian breast cancer patients are treated without benefit.
– Written by Sarah Jones Source: Bombard Y, Rozmovits L, Trudeau ME, Leighl NB, Deal K, Marshall DA. Patients’ perceptions of gene expression profiling in breast cancer treatment decisions. Curr. Oncol. 21(2), e203–e211 (2014).
Targeted treatment for lung cancer could be possible due to identification of nonuniform genetic mutations New research published in Oncotarget has examined tumor heterogeneity (when different cells within the same cancer have different appearances or their own DNA signatures). These differences mean it could be difficult to design effective, targeted treatments. First it was confirmed that the EGFR and either KRAS or BRAF mutations are mutually exclusive. Second, it was found that in lung cancers driven by the EGFR mutation, the mutation can be found uniformly throughout the tumor, regardless of microscopic
future science group
appearance. In contrast to this, they found that tumors with either the KRAS or BRAF mutation do not have the mutation present throughout the tumor. It was said by lead researcher Associate Professor Gavin Wright from the University of Melbourne (Australia), that this is good news for patients whose tumors contain treatable mutations in the EGFR gene. Occurring most commonly in women and nonsmokers, lung adenocarcinomas with the EGFR gene mutation are effectively treated by the oral drug gefi-
www.futuremedicine.com
903
News & Views News tinib. This makes it vital that the mutation is accurately detected. “Because we found that this particular EGFR mutation was present throughout all areas of such tumors tested, patients with this mutation will be easily identified, even by small needle biopsies.” “This means they will always be offered the appropriate targeted treatment drug, which is more effective than standard chemotherapy for these cases.” Wright continues: “Fortunately, the diagnostic accuracy for biopsies of lung cancers with this mutation is only dependent on there being sufficient tumor cells for testing.”
However, things are a little more complicated for other types of lung cancer. It was found that KRAS and BRAF, less common mutations in lung cancer, could be missed in small biopsy samples. The mutation was only present in one subtype of the tumor in a quarter of cases tested and not necessarily uniformly. “These genetic mutations cannot be so confidently biopsied due to the possibility of being absent in a significant component but present in only the more aggressive part of the cancer,” Wright said. “These findings have significance for diagnostics and for precision medicine in lung adenocarcinoma and may lead to similar studies in other tumor types.”
– Written by Sarah Jones Source: Wright GM, Do H, Weiss J et al. Mapping of actionable mutations to histological subtype domains in lung adenocarcinoma: implications for precision medicine. Oncotarget 5(8), 2107–2115 (2014).
904
Pharmacogenomics (2014) 15(7)
future science group
Highlighting the latest news in pharmacogenomics
New strategies could lead to more personalized therapies for cancer
part of
10.2217/PGS.14.77 © 2014 Future Medicine Ltd
Hundreds or even thousands of DNA mutations can accumulate in tumor cells which induce growth and spread of cancer. Different tumors harbor a different number and pattern of mutations, even between those that are classed as the same type of tumor. Researchers discovered the extent of this complexity just a few years ago. In order to target the specific characteristics of each tumor, new tools are required to filter relevant genetic information, which will allow for the development of personalized therapies. A new strategy to personalize medicine in advanced cancer patients with a poor prognosis has been developed by researchers led by Manuel Hidalgo, Vice-Director of Translational Research at CNIO (Madrid, Spain). Treatments induced clinical responses in up to 77% of patients when this new tool was applied, either through stabilization of their condition of through partial clinical response. The first phase of the study involved analysis of the genetic signature of the tumors, specifically the exome in 23 patients with advanced cancer, including pancreatic adenocarcinomas and colon cancer. Researchers identified mutations that could play a role in the growth and spread of the tumors through the use of whole-exome sequencing and bioinformatic analysis. In the second phase, avatar mice were used to match potential effective treatments to the patient’s genetic signature. Elena Garralda, a predoctoral researcher in
Pharmacogenomics (2014) 15(7), 901–904
Hidalgo’s group said that avatar mice are “one of the key aspects of our research.” In order to study the effectiveness of drugs under real conditions, avatar mice are used, with each patient having their own equivalent animal. The likelihood of the drug working in the patient if it has been seen to be effective in the avatar is very high. Patients were therefore given the treatments that worked best in avatar mice. Clinical benefit, either the stabilization of disease or partial clinical response, was seen in up to 77% of patients. “We have demonstrated that it is possible to apply our personalized cancer treatment strategy to the clinic,” says Garralda, adding: “as we learn more about the genetic information obtained from cancer-exome sequencing, future clinical trials will allow for the inclusion of patients with specific genetic alterations, and therefore a better access to cancer drugs.”
ISSN 1462-2416
901
News & Views News The team is currently studying the efficiency of the techniques in a larger number of patients with advanced pancreatic cancer in order to compare them to standard treatments. Pancreatic cancer, which often has a poor prognosis, often has survival
rates of less that a year. As it is a complex and heterogeneous disease, the personalized study of relevant mutations in tumor growth could be a promising avenue of research in the development of new t reatments.
– Written by Sarah Jones Source: Garralda E, Paz K, Lopez-Casas PP et al. Integrated next-generation sequencing and avatar mouse models for personalized cancer treatment. Clin. Cancer Res. 20(9), 2476–2484 (2014).
Importance of keeping patients well informed key to gene-based drug dosing The need for a lot more education around pharmacogenetics is highlighted by a new study out of Western University (London, Canada). This is the first study to investigate how patients perceive pharmacogenetic information, which promises to optimize patient response to therapy, and whether those perceptions differ when it comes to parents and their children. The study published in the journal Pediatrics is led by Michael Rieder of Western’s Schulich School of Medicine and Dentistry. “Pharmacogenetic testing has become widely used and gene-based drug dosing is becoming a reality for a number of common health problems. This study confirms what we suspected; whether or not you’re a parent, your degree of acceptability of genetic testing was determined by your knowledge of it. That is to say – if you understand what the test is for, and the concept of gene-based drug dosing, you’re far more open to it, than if you don’t understand it,” said Rieder, a Professor in the Departments of Paediatrics, and Physiology and Pharmacology. Three groups were surveyed by the researchers: 236 medical students who represented those who have greater educational exposure to pharmacogenomics, 1226 lay parents and 105 lay people without children. A second group was made up of 229 parents who completed a different survey. Rather then using the term
pharmacogenetics the surveys asked about ‘DNA testing to guide therapy’. It was concluded by the study that the acceptability of pharmacogenomics testing, either for oneself or one’s child, was dependent on baseline pharmacogenomics knowledge but not parenthood. For all respondents the main concern was the need for informed consent. Other findings included: • More acceptance for PGx when the disease was severe • Strong desire/demand for separate for pharmacogenomics testing
consent
• More education about pharmacogenomics needed in medical schools • Acceptability of genetic testing didn’t differ whether for the parent or the child Rieder said that pediatric oncology provides a good example as healthcare workers in this division do well at framing discussions around care, treatment and consent: “when they have to make a diagnosis, they spend a lot of time explaining what tests they’re going to do, the risks and what therapies are available, and they’re successful. Their patients comply with treatment, they get involved in studies, they’re informed, and they want to know what’s going on.”
– Written by Sarah Jones Source: Zhang SC, Bruce C, Hayden M, Rieder MJ. Public perceptions of pharmacogenetics. Pediatrics 133(5), e1258 (2014).
About the News & Views
The News highlights some of the most important events and research in pharmacogenomics. If you have newsworthy information, please contact: Sarah Jones, Commissioning Editor, Pharmacogenomics, Future Medicine Ltd, Unitec House, 2 Albert Place, London, N3 1QB, UK; Tel.: +44 (0)20 8371 6090; [email protected]
902
Pharmacogenomics (2014) 15(7)
future science group
News
News & Views
Huge emphasis placed on gene-expression profiling test by breast cancer patients New research suggests that although many women with early-stage breast cancer take into account geneexpression profiling (GEP) when deciding whether to have chemotherapy, many do not fully understand what some of the test results mean. Currently, guidelines result in thousands of women with early-stage breast cancer receiving chemotherapy with no benefit. Those who might benefit from chemotherapy versus those who might not can be differentiated using a GEP test. By analyzing the patterns of 21 different genes within cancer cells, the test helps predict how likely it is that a women’s cancer will recur within 10 years of initial treatment and how much benefit chemotherapy will have. Yvonne Bombard, a genomics and health services researcher in the Li Ka Shing Knowledge Institute of St Michael’s Hospital (Toronto, Canada), who interviewed a group of women with early-stage breast cancer said that they understood that the test would indicate whether they would benefit from chemotherapy. However, many did not realize that the test result was based on larger population statistics and did not reflect their individual unique circumstances. “Patients often viewed their GEP results as providing information that was more scientifically valid, uniquely personalized and emotionally significant than any other information they had received,” Bom-
bard said. “For many, the test was a transformational element that empowered them, allowed them to feel confident in their decisions and may even have rescued them from unnecessary chemotherapy.”
“
Currently, guidelines result in thousands of women with early-stage breast cancer receiving
”
chemotherapy with no benefit.
Despite misunderstandings around the test and it’s validity, the GEP test was a main determinant of patients’ decisions regarding chemotherapy. “GEP is one of many factors that women in consultation with their oncologists, should consider when choosing treatment for early-stage breast cancer,” said Maureen Trudeau, a medical oncologist of the Breast Care team and head of the Medical Oncology Program at Sunnybrook’s Odette Cancer Center (Toronto, Canada), and study coauthor. “The GEP test does not replace standard prognostic information but adds one more piece of information.” Current clinical guidelines suggest that the majority of patients whose breast cancer tests negative for human HER2 should be offered chemotherapy, which amounts to 22,600 Canadian women each year. However, only about 15% of these cancers will recur, which could mean that about 8500 Canadian breast cancer patients are treated without benefit.
– Written by Sarah Jones Source: Bombard Y, Rozmovits L, Trudeau ME, Leighl NB, Deal K, Marshall DA. Patients’ perceptions of gene expression profiling in breast cancer treatment decisions. Curr. Oncol. 21(2), e203–e211 (2014).
Targeted treatment for lung cancer could be possible due to identification of nonuniform genetic mutations New research published in Oncotarget has examined tumor heterogeneity (when different cells within the same cancer have different appearances or their own DNA signatures). These differences mean it could be difficult to design effective, targeted treatments. First it was confirmed that the EGFR and either KRAS or BRAF mutations are mutually exclusive. Second, it was found that in lung cancers driven by the EGFR mutation, the mutation can be found uniformly throughout the tumor, regardless of microscopic
future science group
appearance. In contrast to this, they found that tumors with either the KRAS or BRAF mutation do not have the mutation present throughout the tumor. It was said by lead researcher Associate Professor Gavin Wright from the University of Melbourne (Australia), that this is good news for patients whose tumors contain treatable mutations in the EGFR gene. Occurring most commonly in women and nonsmokers, lung adenocarcinomas with the EGFR gene mutation are effectively treated by the oral drug gefi-
www.futuremedicine.com
903
News & Views News tinib. This makes it vital that the mutation is accurately detected. “Because we found that this particular EGFR mutation was present throughout all areas of such tumors tested, patients with this mutation will be easily identified, even by small needle biopsies.” “This means they will always be offered the appropriate targeted treatment drug, which is more effective than standard chemotherapy for these cases.” Wright continues: “Fortunately, the diagnostic accuracy for biopsies of lung cancers with this mutation is only dependent on there being sufficient tumor cells for testing.”
However, things are a little more complicated for other types of lung cancer. It was found that KRAS and BRAF, less common mutations in lung cancer, could be missed in small biopsy samples. The mutation was only present in one subtype of the tumor in a quarter of cases tested and not necessarily uniformly. “These genetic mutations cannot be so confidently biopsied due to the possibility of being absent in a significant component but present in only the more aggressive part of the cancer,” Wright said. “These findings have significance for diagnostics and for precision medicine in lung adenocarcinoma and may lead to similar studies in other tumor types.”
– Written by Sarah Jones Source: Wright GM, Do H, Weiss J et al. Mapping of actionable mutations to histological subtype domains in lung adenocarcinoma: implications for precision medicine. Oncotarget 5(8), 2107–2115 (2014).
904
Pharmacogenomics (2014) 15(7)
future science group
