- Email: [email protected]
Routine molecular profiling of patients with NSCLC
Correspondence
BDA, DOM, RM, MW, and MRM are funded by WHO and VA is funded by the Bill & Melinda Gates foundation. We declare no competing interests.
*Bartholomew D Akanmori, David O Mukanga, Richard Mihigo, Michael Ward, Vincent Ahonkhai, Matshidiso R Moeti [email protected] Immunization and Vaccines Development Programme, Family and Reproductive Health Cluster, WHO Regional Office for Africa, Brazzaville Box 03 Djoue, Republic of the Congo (BDA, DOM, RM); Department of Essential Medicines and Health Products, Health Innovation Systems, WHO Headquarters, Geneva, Switzerland (MW); Global Health Division, Bill & Melinda Gates Foundation, Seattle, WA, USA (VA); and Regional Director’s Office, WHO Regional Office for Africa, Brazzaville, Republic of the Congo (MRM) 1
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Rappuoli R, Aderem A. A 2020 vision for vaccines against HIV, tuberculosis and malaria. Nature 2011; 473: 463–69. Hotez PJ, Pecoul B, Rijal S, et al. Eliminating the neglected tropical diseases: translational science and new technologies. PLoS Negl Trop Dis 2016; 10: e0003895. Butler D. Ebola drug trials set to begin amid crisis. Nature 2014; 513: 13–14. Ndebele P, Blanchard-Horan C, Shahkolahi A, Sanne I. Regulatory challenges associated with conducting multicountry clinical trials in resource-limited settings. J Acquir Immune Defic Syndr 2014; 65 (suppl 1): S29–31. Preston C, Valdez ML, Bond K. Strengthening medical product regulation in low- and middle-income countries. PLoS Med 2012; 9: e1001327. Maiga D, Akanmori BD, Chocarro L. Joint reviews and inspections: strategic forms of collaboration for strengthening the regulatory oversight of vaccine clinical trials in Africa. Vaccine 2009; 28: 571–75. Akanmori BD, Bellah A, Ward M, Rago L. Regulatory collaboration. WHO Drug Information 2015; 29: 127–32.
Routine molecular profiling of patients with NSCLC Fabrice Barlesi and co-workers (April 2, p 1415) presented results of the first French nationwide observational study of therapy relevant driver mutations in non-small-cell lung cancer (NSCLC) reflecting routine diagnostic care. This type of study was influenced by diagnostic guidelines of the reimbursement systems, and could not take into account all contingencies (unlike designed clinical trials, in 1
1054
which highly selected patient cohorts encounter restrictive inclusion criteria of a pharmaceutical study protocol). The authors identified only a small percentage of patients who had combined genetic alterations of therapeutic relevance, but the study focused on only six genes that were not completely analysed in all patients because of stepwise diagnostic algorithms. In the future, next-generation sequencing techniques will reduce this bias by doing all-embracing screenings rather than following stepwise diagnostic algorithms, which detect such alterations only by chance. The therapeutic outcome of the patients was not discussed in the paper, which is unfortunate because double mutations might influence the therapeutic outcome, as recently described in a case report from our group.2 The question of whether therapy success is specific for individual mutation patterns also applies for ALK translocations, including more than 15 variants with EML4 in addition to other fusion partners such as KIF5B. Patients harbouring these translocations are eligible for crizotinib therapy (an ALK and ROS1 inhibitor), but the overall survival for ALK-positive patients ranges from non-responder to complete remission. The study would have been informative if it had also shed light on the correlation between therapeutic outcome and distinct ALK translocations. We declare no competing interests.
*Verena Schildgen, Oliver Schildgen [email protected] Department of Pathology, gGmbH Clinic of Cologne, Hospital of University of Witten/Herdecke, Cologne, Germany 1
2
Barlesi F, Mazieres J, Merlio JP, et al. Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT). Lancet 2016; 387: 1415–26. Jurgens J, Engel-Riedel W, Stoelben E, Schildgen V, Schildgen O, Brockmann M. The (Con-) fusion in ALK diagnostics: when Food and Drug Administration– approved algorithms fail. J Clin Oncol 2016; published online April 25. DOI: 10.1200/ JCO.2015.65.4871.
Authors’ reply We thank Verena Schildgen and Oliver Schildgen for their thoughtful and critical comment on our report.1 We agree that our paper mainly reflects the French national programme for biomarkers in lung cancer and thus cannot be extensively extrapolated to other countries and other health systems. Our aim was to provide basic data for a large number of patients (the largest cohort published so far) rather than in-depth analysis for selected patients. We provide a clear and unbiased picture of the incidence of six major biomarkers in daily practice patients. The fact that only a small proportion of patients were enrolled in clinical trials, that the reported incidence was slightly lower than in previously published series, and that many patients only received supportive care makes us confident that our study reflects routine (that is, daily) practice. The question of concomitant molecular alterations is of great interest because many platforms have designed algorithms based on the dogma of mutually exclusive oncogenic events. In our series, we identified 162 double mutations and three triple mutations in 17 664 patients. We thus considered that double mutations are not an exceptional event and agree that all biomarkers of interest should be screened for each patient. We will release more details soon concerning the population of patients with multiple genetic alterations with a dedicated analysis, including data for response to treatment. Our findings are in line with other smaller series, in which genetic alterations ranged from 1% in Europe or North America to 3% in Asia. These percentages will increase with the development of next-generation sequencing with larger panels of biomarkers. We agree that fusion partners in rearrangement of ALK, ROS1, or RET genes are of therapeutic importance and might impact both prognosis and www.thelancet.com Vol 388 September 10, 2016
BDA, DOM, RM, MW, and MRM are funded by WHO and VA is funded by the Bill & Melinda Gates foundation. We declare no competing interests.
*Bartholomew D Akanmori, David O Mukanga, Richard Mihigo, Michael Ward, Vincent Ahonkhai, Matshidiso R Moeti [email protected] Immunization and Vaccines Development Programme, Family and Reproductive Health Cluster, WHO Regional Office for Africa, Brazzaville Box 03 Djoue, Republic of the Congo (BDA, DOM, RM); Department of Essential Medicines and Health Products, Health Innovation Systems, WHO Headquarters, Geneva, Switzerland (MW); Global Health Division, Bill & Melinda Gates Foundation, Seattle, WA, USA (VA); and Regional Director’s Office, WHO Regional Office for Africa, Brazzaville, Republic of the Congo (MRM) 1
2
3 4
5
6
7
Rappuoli R, Aderem A. A 2020 vision for vaccines against HIV, tuberculosis and malaria. Nature 2011; 473: 463–69. Hotez PJ, Pecoul B, Rijal S, et al. Eliminating the neglected tropical diseases: translational science and new technologies. PLoS Negl Trop Dis 2016; 10: e0003895. Butler D. Ebola drug trials set to begin amid crisis. Nature 2014; 513: 13–14. Ndebele P, Blanchard-Horan C, Shahkolahi A, Sanne I. Regulatory challenges associated with conducting multicountry clinical trials in resource-limited settings. J Acquir Immune Defic Syndr 2014; 65 (suppl 1): S29–31. Preston C, Valdez ML, Bond K. Strengthening medical product regulation in low- and middle-income countries. PLoS Med 2012; 9: e1001327. Maiga D, Akanmori BD, Chocarro L. Joint reviews and inspections: strategic forms of collaboration for strengthening the regulatory oversight of vaccine clinical trials in Africa. Vaccine 2009; 28: 571–75. Akanmori BD, Bellah A, Ward M, Rago L. Regulatory collaboration. WHO Drug Information 2015; 29: 127–32.
Routine molecular profiling of patients with NSCLC Fabrice Barlesi and co-workers (April 2, p 1415) presented results of the first French nationwide observational study of therapy relevant driver mutations in non-small-cell lung cancer (NSCLC) reflecting routine diagnostic care. This type of study was influenced by diagnostic guidelines of the reimbursement systems, and could not take into account all contingencies (unlike designed clinical trials, in 1
1054
which highly selected patient cohorts encounter restrictive inclusion criteria of a pharmaceutical study protocol). The authors identified only a small percentage of patients who had combined genetic alterations of therapeutic relevance, but the study focused on only six genes that were not completely analysed in all patients because of stepwise diagnostic algorithms. In the future, next-generation sequencing techniques will reduce this bias by doing all-embracing screenings rather than following stepwise diagnostic algorithms, which detect such alterations only by chance. The therapeutic outcome of the patients was not discussed in the paper, which is unfortunate because double mutations might influence the therapeutic outcome, as recently described in a case report from our group.2 The question of whether therapy success is specific for individual mutation patterns also applies for ALK translocations, including more than 15 variants with EML4 in addition to other fusion partners such as KIF5B. Patients harbouring these translocations are eligible for crizotinib therapy (an ALK and ROS1 inhibitor), but the overall survival for ALK-positive patients ranges from non-responder to complete remission. The study would have been informative if it had also shed light on the correlation between therapeutic outcome and distinct ALK translocations. We declare no competing interests.
*Verena Schildgen, Oliver Schildgen [email protected] Department of Pathology, gGmbH Clinic of Cologne, Hospital of University of Witten/Herdecke, Cologne, Germany 1
2
Barlesi F, Mazieres J, Merlio JP, et al. Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT). Lancet 2016; 387: 1415–26. Jurgens J, Engel-Riedel W, Stoelben E, Schildgen V, Schildgen O, Brockmann M. The (Con-) fusion in ALK diagnostics: when Food and Drug Administration– approved algorithms fail. J Clin Oncol 2016; published online April 25. DOI: 10.1200/ JCO.2015.65.4871.
Authors’ reply We thank Verena Schildgen and Oliver Schildgen for their thoughtful and critical comment on our report.1 We agree that our paper mainly reflects the French national programme for biomarkers in lung cancer and thus cannot be extensively extrapolated to other countries and other health systems. Our aim was to provide basic data for a large number of patients (the largest cohort published so far) rather than in-depth analysis for selected patients. We provide a clear and unbiased picture of the incidence of six major biomarkers in daily practice patients. The fact that only a small proportion of patients were enrolled in clinical trials, that the reported incidence was slightly lower than in previously published series, and that many patients only received supportive care makes us confident that our study reflects routine (that is, daily) practice. The question of concomitant molecular alterations is of great interest because many platforms have designed algorithms based on the dogma of mutually exclusive oncogenic events. In our series, we identified 162 double mutations and three triple mutations in 17 664 patients. We thus considered that double mutations are not an exceptional event and agree that all biomarkers of interest should be screened for each patient. We will release more details soon concerning the population of patients with multiple genetic alterations with a dedicated analysis, including data for response to treatment. Our findings are in line with other smaller series, in which genetic alterations ranged from 1% in Europe or North America to 3% in Asia. These percentages will increase with the development of next-generation sequencing with larger panels of biomarkers. We agree that fusion partners in rearrangement of ALK, ROS1, or RET genes are of therapeutic importance and might impact both prognosis and www.thelancet.com Vol 388 September 10, 2016