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How not to treat cancer
Keynote Comment
How not to treat cancer
Adam Gault/Science Photo Library
A popular American cable television programme called What Not To Wear features expert co-hosts who assess a person’s wardrobe and provide fashion advice. Despite the show’s title, the focus of the programme is to help each guest decide what to wear rather than what not to wear for the best effect. The discrepancy between the stated focus of the programme and its actual theme is reminiscent of the dilemma we currently face in using predictive biomarkers in cancer treatment. Because not all patients benefit from all drugs, we would ideally like to identify those individuals most likely to benefit from particular drugs based on the molecular features of their tumours. Predictive biomarkers that allow us to select the most effective treatment for each individual hold great promise for improving patient outcome, decreasing toxic effects, increasing the efficiency of new drug development, and saving money for the health-care system. Yet, despite all the interest in predictive markers, there are few that have lived up to expectations so far. Arguably, only the oestrogen receptor has achieved the goal of having at least a moderate positive predictive value for those with a positive test result and a high negative predictive value for those with a negative test result. Testing breast tumours for high expression or amplification of ERBB2 is typically given as an example of a useful predictive test, but the ERBB2 test, however done,
Selecting patients who are most likely to benefit from certain drugs is crucial
504
is far more likely to predict which patients will not benefit from ERBB2-directed treatment, rather than which patients will respond. Up to now, no predictive biomarkers have been developed for anti-angiogenic treatments, despite their widespread use, substantial toxic effects, and high cost, and the same can be said of epidermal growth factor receptor (EGFR) inhibitors with the possible exception of screening for rare EGFR mutations or EGFR amplification in non-small-cell lung cancer. The enormous heterogeneity and complex biology of cancer will probably make the identification of a single positive predictive factor for any drug or drug class exceedingly difficult. A better strategy then might be to identify negative predictive factors for drug effects that could be used in the clinic to show how not to treat a particular patient. Several recent studies suggest that this approach might be far more fruitful for both traditional cytotoxic drugs and targeted treatments. For example, temozolomide added to radiotherapy improves survival for an unselected group of patients with glioblastoma, but has no significant effect on survival of those patients whose tumours do not have methyl guanine methyl transferase (MGMT) promoter methylation (that allows high expression of a DNA repair protein that confers resistance to temozolomide).1 Arguably, alternative methods of treatment should be sought for this group of patients. Similarly, adjuvant cisplatin-based chemotherapy seems to confer a small survival benefit for patients with resected non-small-cell lung cancer, but the benefit seems restricted to those patients whose tumours who do not have expression of the excisionrepair cross-complementation group 1 (ERCC1) DNA repair protein.2 Testing for expression of ERCC1 would, therefore, seem to be a reasonable consideration so as to avoid exposing patients with a positive test to the substantial toxic effects of cisplatin chemotherapy. Finally, the addition of paclitaxel to adjuvant chemotherapy with doxorubicin and cyclophosphamide has been shown to improve the survival of women with lymph-node-positive breast cancer, but a recent report suggests that paclitaxel confers no benefit in patients with ERBB2-negative or ER-positive tumours.3 In each of these studies, although the treatment being http://oncology.thelancet.com Vol 9 June 2008
Keynote Comment
tested provided some benefit to an unselected patient population, the companion biomarker study identified a subset of patients who seemed to derive no benefit from the experimental approach. In the case of molecularly-targeted treatments, rapidly emerging data suggest that Kras mutations confer complete resistance to cetuximab and panitumumab in colorectal cancer and might also be associated with no benefit with EGFR tyrosine-kinase inhibitors in non-small-cell lung cancer.4 Indeed, in Europe, panitumumab is approved for use only in those patients with metastatic colorectal cancer that harbours wildtype Ras and the sponsor for this drug has announced plans to seek approval from the US Food and Drug Administration to restrict their label to this group of patients in the USA. Plans are now underway to amend the eligibility criteria of ongoing US colorectalcancer trials that include cetuximab, to include only patients with Ras wild-type tumours. Doing so requires the ready availability of a clinical test to assess the Ras genotype in paraffin-embedded fixed tissues. Even multiplex genetic tests might be more useful in establishing who not to treat than who should receive treatment. The ongoing Trial Assigning Individualized Options for Treatment (TAILORx)5 in the USA will assess whether molecular profiling can be used to predict the risk of recurrence in women with hormone-receptor positive, lymph-node-negative breast cancer, and to assign them to hormone-treatment, with or without chemotherapy, accordingly. The primary objective of the study is to establish whether hormone treatment alone is non-inferior to hormone treatment plus
http://oncology.thelancet.com Vol 9 June 2008
chemotherapy in women with intermediate risk of recurrence. 10 000 women will be enrolled and tested so that 4500 women can be randomly assigned to treatment groups. Thus, if successful, the trial will show that a molecular prognostic test can be used to establish who not to treat. To be sure, oncologists naturally focus on trying to establish the best treatment for each patient under their care. All of us hope for better drugs and predictive biomarkers that will enable us to use those drugs in the most effective way by selecting patients most likely to benefit. We should not forget, however, that foregoing the use of a toxic and expensive treatment that is not beneficial will also serve our patients well. Biomarkers that reliably tell us how not to treat cancer will likely be extremely valuable, especially as the range of treatment options continues to expand. Richard L Schilsky Section of Hematology-Oncology, University of Chicago, Chicago, IL, USA [email protected] The author declared no conflicts of interest. 1 2
3 4 5
Hegi ME, Diserens A-C, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352: 997–1003. Olaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non small cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006; 355: 983–91. Hayes DF, Thor AD, Dressler LG, et al. Her2 and response to paclitaxel in node positive breast cancer. N Engl J Med 2007; 357: 1496–506. Baselga J, Rosen N. Determinants of RASistance to anti-epidermal growth factor receptor agents. J Clin Oncol 2008; 26: 1582–84. Sparano JA. The TAILORx trial: individualized options for treatment. http://www.communityoncology.net/journal/articles/0308494.pdf (accessed April 17, 2008).
505
How not to treat cancer
Adam Gault/Science Photo Library
A popular American cable television programme called What Not To Wear features expert co-hosts who assess a person’s wardrobe and provide fashion advice. Despite the show’s title, the focus of the programme is to help each guest decide what to wear rather than what not to wear for the best effect. The discrepancy between the stated focus of the programme and its actual theme is reminiscent of the dilemma we currently face in using predictive biomarkers in cancer treatment. Because not all patients benefit from all drugs, we would ideally like to identify those individuals most likely to benefit from particular drugs based on the molecular features of their tumours. Predictive biomarkers that allow us to select the most effective treatment for each individual hold great promise for improving patient outcome, decreasing toxic effects, increasing the efficiency of new drug development, and saving money for the health-care system. Yet, despite all the interest in predictive markers, there are few that have lived up to expectations so far. Arguably, only the oestrogen receptor has achieved the goal of having at least a moderate positive predictive value for those with a positive test result and a high negative predictive value for those with a negative test result. Testing breast tumours for high expression or amplification of ERBB2 is typically given as an example of a useful predictive test, but the ERBB2 test, however done,
Selecting patients who are most likely to benefit from certain drugs is crucial
504
is far more likely to predict which patients will not benefit from ERBB2-directed treatment, rather than which patients will respond. Up to now, no predictive biomarkers have been developed for anti-angiogenic treatments, despite their widespread use, substantial toxic effects, and high cost, and the same can be said of epidermal growth factor receptor (EGFR) inhibitors with the possible exception of screening for rare EGFR mutations or EGFR amplification in non-small-cell lung cancer. The enormous heterogeneity and complex biology of cancer will probably make the identification of a single positive predictive factor for any drug or drug class exceedingly difficult. A better strategy then might be to identify negative predictive factors for drug effects that could be used in the clinic to show how not to treat a particular patient. Several recent studies suggest that this approach might be far more fruitful for both traditional cytotoxic drugs and targeted treatments. For example, temozolomide added to radiotherapy improves survival for an unselected group of patients with glioblastoma, but has no significant effect on survival of those patients whose tumours do not have methyl guanine methyl transferase (MGMT) promoter methylation (that allows high expression of a DNA repair protein that confers resistance to temozolomide).1 Arguably, alternative methods of treatment should be sought for this group of patients. Similarly, adjuvant cisplatin-based chemotherapy seems to confer a small survival benefit for patients with resected non-small-cell lung cancer, but the benefit seems restricted to those patients whose tumours who do not have expression of the excisionrepair cross-complementation group 1 (ERCC1) DNA repair protein.2 Testing for expression of ERCC1 would, therefore, seem to be a reasonable consideration so as to avoid exposing patients with a positive test to the substantial toxic effects of cisplatin chemotherapy. Finally, the addition of paclitaxel to adjuvant chemotherapy with doxorubicin and cyclophosphamide has been shown to improve the survival of women with lymph-node-positive breast cancer, but a recent report suggests that paclitaxel confers no benefit in patients with ERBB2-negative or ER-positive tumours.3 In each of these studies, although the treatment being http://oncology.thelancet.com Vol 9 June 2008
Keynote Comment
tested provided some benefit to an unselected patient population, the companion biomarker study identified a subset of patients who seemed to derive no benefit from the experimental approach. In the case of molecularly-targeted treatments, rapidly emerging data suggest that Kras mutations confer complete resistance to cetuximab and panitumumab in colorectal cancer and might also be associated with no benefit with EGFR tyrosine-kinase inhibitors in non-small-cell lung cancer.4 Indeed, in Europe, panitumumab is approved for use only in those patients with metastatic colorectal cancer that harbours wildtype Ras and the sponsor for this drug has announced plans to seek approval from the US Food and Drug Administration to restrict their label to this group of patients in the USA. Plans are now underway to amend the eligibility criteria of ongoing US colorectalcancer trials that include cetuximab, to include only patients with Ras wild-type tumours. Doing so requires the ready availability of a clinical test to assess the Ras genotype in paraffin-embedded fixed tissues. Even multiplex genetic tests might be more useful in establishing who not to treat than who should receive treatment. The ongoing Trial Assigning Individualized Options for Treatment (TAILORx)5 in the USA will assess whether molecular profiling can be used to predict the risk of recurrence in women with hormone-receptor positive, lymph-node-negative breast cancer, and to assign them to hormone-treatment, with or without chemotherapy, accordingly. The primary objective of the study is to establish whether hormone treatment alone is non-inferior to hormone treatment plus
http://oncology.thelancet.com Vol 9 June 2008
chemotherapy in women with intermediate risk of recurrence. 10 000 women will be enrolled and tested so that 4500 women can be randomly assigned to treatment groups. Thus, if successful, the trial will show that a molecular prognostic test can be used to establish who not to treat. To be sure, oncologists naturally focus on trying to establish the best treatment for each patient under their care. All of us hope for better drugs and predictive biomarkers that will enable us to use those drugs in the most effective way by selecting patients most likely to benefit. We should not forget, however, that foregoing the use of a toxic and expensive treatment that is not beneficial will also serve our patients well. Biomarkers that reliably tell us how not to treat cancer will likely be extremely valuable, especially as the range of treatment options continues to expand. Richard L Schilsky Section of Hematology-Oncology, University of Chicago, Chicago, IL, USA [email protected] The author declared no conflicts of interest. 1 2
3 4 5
Hegi ME, Diserens A-C, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352: 997–1003. Olaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non small cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006; 355: 983–91. Hayes DF, Thor AD, Dressler LG, et al. Her2 and response to paclitaxel in node positive breast cancer. N Engl J Med 2007; 357: 1496–506. Baselga J, Rosen N. Determinants of RASistance to anti-epidermal growth factor receptor agents. J Clin Oncol 2008; 26: 1582–84. Sparano JA. The TAILORx trial: individualized options for treatment. http://www.communityoncology.net/journal/articles/0308494.pdf (accessed April 17, 2008).
505