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Has genetic profiling finally come of age in NSCLC?
Leading Edge
Has genetic profiling finally come of age in NSCLC? One of the major goals in cancer research nowadays is personalisation of treatment. Numerous approaches have been used to achieve this goal—from identifying physiological characteristics to mining the genome—and many tests have been developed to predict prognosis. However, none of these predictive tests has been used in a prospective trial as the sole method to stratify patients for treatment. Now, however, such a trial is being planned in which individual patients with early-stage non-small-cell lung cancer (NSCLC) will be selected for treatment on the basis of their genomic profile—an exciting and urgently needed advance if treatment is to be truly and confidently personalised. The assay, called the Lung Metagene Predictor, has been developed by researchers in the USA, and includes a series of about 2070 genes, many of which are known carcinogenic factors that, when clustered together into nine metagenes predict with about 80% certainty whether an individual patient with NSCLC will respond to cytotoxic chemotherapy. The researchers used mRNA from tumour tissue taken during surgery in a trial set of 89 patients from their institution, and then validated the model in two independent datasets of 106 patients. The predictor was more accurate than the current method of assigning treatment, which is based on clinical characteristics such as disease stage, tumour diameter, nodal status, age, sex, histological subtype, and smoking history, and the accuracy of the model did not improve when these data were included. The Cancer and Leukemia Group B (CALGB) 30506 trial will be the first to use genomics to define treatment, and aims to recruit more than 1000 patients from several centres in the USA and Canada. Although few details are available about the trial, it seems to be restricted to patients with stage IA NSCLC, a population for which chemotherapy is not thought to be sufficiently effective. The model could then be used to determine which patients are likely respond to conventional chemotherapy, potentially saving many lives. However, the implications go much further. The genomic approach could be applied to all patients with early-stage NSCLC, not only redefining
http://oncology.thelancet.com Vol 7 September 2006
eligibility for chemotherapy, but also identifying those who are currently eligible but are unlikely to respond, thereby shielding them from unnecessary side-effects. Furthermore, although many new drugs have been developed that have varying success in treatment of metastatic NSCLC, most trials in early-stage NSCLC have shown frustratingly small improvements. Methods such as genomic profiling that have the potential to identify which drug or drug combinations will work best very early in the development process are therefore eagerly awaited. They could help reduce the number of patients needed in clinical trials, saving huge costs in drug development, which should translate to cheaper treatments for patients. Perhaps they will even offer insight into why some patients with specific genes or mutations do not respond to drugs targeted to these characteristics. The use of genomics to personalise treatment to individuals will raise important new issues. Participation in such trials will probably need a leap of faith: adjuvant chemotherapy has been proven to be of benefit in populations, although not necessarily individual patients, with later stages of NSCLC. With the new tests, some patients who would have been offered treatment will now not be eligible. Until the effectiveness of genomic profiling is better established, patients might find it difficult to accept not receiving treatment, especially when others with similar characteristics do. However, this is the nature of randomised controlled trials, and such calculated risks are essential if medicine is to progress and patients and clinicians are to become confident of the options. Use of genetics to guide treatment decisions requires a fundamental shift in thinking, from assessing risk for populations, to risks for individuals. However, with the huge burden placed on society from lung cancer, and with the idea that patients could one day be much more confident of whether these highly toxic treatments are going to benefit them as individuals, such advances are very welcome. After many promises, a new era in personalised treatment might truly be just around the corner. ■ The Lancet Oncology
For more information on the Lung Metagene Predictor, see N Engl J Med 2006; 355: 570–80
For more information on the benefits of adjuvant chemotherapy, see Articles page 719 and Reflection and Reaction page 701
699
Has genetic profiling finally come of age in NSCLC? One of the major goals in cancer research nowadays is personalisation of treatment. Numerous approaches have been used to achieve this goal—from identifying physiological characteristics to mining the genome—and many tests have been developed to predict prognosis. However, none of these predictive tests has been used in a prospective trial as the sole method to stratify patients for treatment. Now, however, such a trial is being planned in which individual patients with early-stage non-small-cell lung cancer (NSCLC) will be selected for treatment on the basis of their genomic profile—an exciting and urgently needed advance if treatment is to be truly and confidently personalised. The assay, called the Lung Metagene Predictor, has been developed by researchers in the USA, and includes a series of about 2070 genes, many of which are known carcinogenic factors that, when clustered together into nine metagenes predict with about 80% certainty whether an individual patient with NSCLC will respond to cytotoxic chemotherapy. The researchers used mRNA from tumour tissue taken during surgery in a trial set of 89 patients from their institution, and then validated the model in two independent datasets of 106 patients. The predictor was more accurate than the current method of assigning treatment, which is based on clinical characteristics such as disease stage, tumour diameter, nodal status, age, sex, histological subtype, and smoking history, and the accuracy of the model did not improve when these data were included. The Cancer and Leukemia Group B (CALGB) 30506 trial will be the first to use genomics to define treatment, and aims to recruit more than 1000 patients from several centres in the USA and Canada. Although few details are available about the trial, it seems to be restricted to patients with stage IA NSCLC, a population for which chemotherapy is not thought to be sufficiently effective. The model could then be used to determine which patients are likely respond to conventional chemotherapy, potentially saving many lives. However, the implications go much further. The genomic approach could be applied to all patients with early-stage NSCLC, not only redefining
http://oncology.thelancet.com Vol 7 September 2006
eligibility for chemotherapy, but also identifying those who are currently eligible but are unlikely to respond, thereby shielding them from unnecessary side-effects. Furthermore, although many new drugs have been developed that have varying success in treatment of metastatic NSCLC, most trials in early-stage NSCLC have shown frustratingly small improvements. Methods such as genomic profiling that have the potential to identify which drug or drug combinations will work best very early in the development process are therefore eagerly awaited. They could help reduce the number of patients needed in clinical trials, saving huge costs in drug development, which should translate to cheaper treatments for patients. Perhaps they will even offer insight into why some patients with specific genes or mutations do not respond to drugs targeted to these characteristics. The use of genomics to personalise treatment to individuals will raise important new issues. Participation in such trials will probably need a leap of faith: adjuvant chemotherapy has been proven to be of benefit in populations, although not necessarily individual patients, with later stages of NSCLC. With the new tests, some patients who would have been offered treatment will now not be eligible. Until the effectiveness of genomic profiling is better established, patients might find it difficult to accept not receiving treatment, especially when others with similar characteristics do. However, this is the nature of randomised controlled trials, and such calculated risks are essential if medicine is to progress and patients and clinicians are to become confident of the options. Use of genetics to guide treatment decisions requires a fundamental shift in thinking, from assessing risk for populations, to risks for individuals. However, with the huge burden placed on society from lung cancer, and with the idea that patients could one day be much more confident of whether these highly toxic treatments are going to benefit them as individuals, such advances are very welcome. After many promises, a new era in personalised treatment might truly be just around the corner. ■ The Lancet Oncology
For more information on the Lung Metagene Predictor, see N Engl J Med 2006; 355: 570–80
For more information on the benefits of adjuvant chemotherapy, see Articles page 719 and Reflection and Reaction page 701
699