Correspondence
Refining Prognosis in Non–Small-Cell Lung Cancer
N Engl J Med 2007; 356:189-191January 11, 2007
- Article
To the Editor:
Potti et al. (Aug. 10 issue)1 apply a metagene model to the profiling of non–small-cell lung cancer (NSCLC) and demonstrate superior performance in predicting tumor recurrence and survival, as compared with a clinical model. We believe that the impressively contrasting results could be partially due to the incompleteness of the clinical model the authors used. Classifying NSCLC into squamous-cell carcinoma and adenocarcinoma has not been predictive for prognosis in general. However, subtypes of adenocarcinoma — bronchioloalveolar carcinoma and mixed adenocarcinoma with a bronchioloalveolar component, which account for approximately 20% of cases of early-stage NSCLC — have a much better prognosis than do other subtypes.2 Potti et al. did not consider these adenocarcinoma subtypes.
In addition, the literature3 and our recent work demonstrate that the histologic grade is a significant predictor of both tumor recurrence and survival,4 and there is a high correlation between histologic features and gene-expression profiles.5 Our work also shows that incorporating the adenocarcinoma subtype and histologic grade into clinical models would provide a prediction very similar to that of a well-validated, 50-gene panel for survival.5
5 ReferencesZhifu Sun, M.D.
Ping Yang, M.D., Ph.D.
Mayo Clinic, Rochester, MN 55905
sun.zhifu@mayo. edu 1
Potti A ,Mukherjee S ,Petersen R , et al. A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med 2006;355:570-580
Full Text | Web of Science | Medline2
Travis WD, Brambilla E, Müller-Hermelink HK, Harris CC, eds. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Vol. 10 of World Health Organization classification of tumours. Lyon, France: IARC Press, 2004.
3
Goldstein NS ,Mani A ,Chmielewski G ,Welsh R ,Pursel S . Prognostic factors in T1 NO MO adenocarcinomas and bronchioloalveolar carcinomas of the lung. Am J Clin Pathol 1999;112:391-402
Web of Science | Medline4
Sun Z ,Aubry MC ,Deschamps C , et al. Histologic grade is an independent prognostic factor for survival in non-small cell lung cancer: an analysis of 5018 hospital- and 712 population-based cases. J Thorac Cardiovasc Surg 2006;131:1014-1020
CrossRef | Web of Science | Medline5
Sun Z ,Yang P . Gene expression profiling on lung cancer outcome prediction: present clinical value and future premise. Cancer Epidemiol Biomarkers Prev 2006;15:2063-2068
CrossRef | Web of Science | Medline
To the Editor:
Potti et al. mention that adjuvant chemotherapy is beneficial in patients with stages IB, II, or IIIA NSCLC. We think the question regarding the benefit of adjuvant chemotherapy in patients with stage IB disease is still open. Analysis of the Cancer and Leukemia Group B (CALGB) 9633 trial, which was presented at the 2006 meeting of the American Society of Clinical Oncology, showed no survival benefit at 5 years in patients with stage IB disease who received adjuvant chemotherapy.1
These results mirror the findings of two previous trials, which did not show any survival benefit of adjuvant chemotherapy for patients with stage IB disease. The Adjuvant Navelbine International Trialist Association (ANITA) study2 and the National Cancer Institute of Canada's JBR.10 trial3 also showed no significant survival advantage with the administration of adjuvant chemotherapy for patients with stage IB disease.
3 ReferencesTejvir Singh, M.D.
Reno Oncology Consultants, Reno, NV 89502
tejasam@hotmail.com Jasmine Dhindsa, M.D.
Washoe Medical Center, Reno, NV 895021
Strauss GM ,Herndon JE ,Maddaus MA , et al. Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): update of Cancer and Leukemia Group B (CALGB) protocol 9633. J Clin Oncol 2006;24:Suppl:7007-70072
Douillard J-Y ,Rosell R ,Delena M ,Legroumellec A ,Torres A ,Carpagnano F . ANITA: phase III adjuvant vinorelbine (N) and cisplatin (P) versus observation (OBS) in completely resected (stage I-III) non-small-cell lung cancer (NSCLC) patients (pts): final results after 70-month median follow-up. J Clin Oncol 2005;23:Suppl:7013-7013
CrossRef | Web of Science | Medline3
Winton TL ,Livingston R ,Johnson D , et al. A prospective randomised trial of adjuvant vinorelbine (VIN) and cisplatin (CIS) in completely resected stage 1B and II non small cell lung cancer: (NSCLC) Intergroup JBR.10. J Clin Oncol 2004;22:Suppl:7018-7018
To the Editor:
Potti et al. report on a model consisting of nine metagenes (the dominant factors in a cluster of genes) for predicting the recurrence of lung cancer. Such a model can influence treatment decisions substantially. We reasoned that it should be possible to replicate the predictive ability of these metagenes independently, regardless of the microarray platform or biostatistical methods used.
Of the 133 genes in the 9 metagenes, 120 were represented in our data set (Operon-HuV2) of resected lung tumors from patients with stage I, II, or III disease (51 squamous-cell tumors and 48 adenocarcinomas), classified according to whether the patient was disease-free for more than 3 years or had a recurrence within 1.5 years. We generated a principal component score for each metagene and classified the tumors using axis-parallel decision trees with leave-one-out cross-validation. The metagenes predicted recurrence with an accuracy of 53% for squamous-cell tumors and 75% for adenocarcinomas. In contrast, the mean accuracy of 100 random permutations was 49% (P<0.05).
Our lower overall predictive accuracy, as compared with that of Potti et al., may be due to the profiling of incomplete metagenes on nonidentical microarray platforms. Nevertheless, in this “real world” test, the nine metagenes retained the ability to predict recurrence in an independent cohort of adenocarcinomas, attesting to the potential of this model for clinical use.
Jill E. Larsen, B.Sc.
Kwun M. Fong, M.B., B.S., Ph.D.
Prince Charles Hospital, Brisbane 4035, Australia
kwun_fong@health.qld. gov. au Nicholas K. Hayward, Ph.D.
Queensland Institute of Medical Research, Brisbane 4029, AustraliaAuthor/Editor Response
Although pathological differentiation of lung tumors has been shown to be beneficial in understanding the underlying biology, very few subtypes are considered to be standard prognostic indicators, with the exception of the bronchioloalveolar phenotype. The study cited by Sun and Yang1 describes hazard ratios of approximately 2.0 for undifferentiated tumors. In contrast, the odds ratios for the genomic predictor of recurrence in our study were 16.1 and 35.0 in the two independent validation cohorts. Thus, although inclusion of the histologic grade may enhance the predictive capability of a model, it is unlikely to have a significant effect on the difference seen between the prognostic abilities of clinicopathological variables and genomic data.
Singh and Dhindsa are correct in stating that the recent results of the CALGB 9633 trial suggest that there was no absolute survival benefit for patients with stage IB disease who were treated with adjuvant chemotherapy.2 This result was reported after our article went to press. Although this finding does not affect the results of our study, it does suggest that the clinical benefit of a refined prognosis could be extended to all patients with stage I disease, rather than just those with stage IA disease. Indeed, Kaplan–Meier survival analysis of all patients with stage I disease, stratified as high risk or low risk on the basis of the gene-expression model, revealed a subgroup with significantly poorer survival (Figure 1Figure 1
Kaplan–Meier Survival Analysis of 138 Patients with Stage I Non–Small-Cell Lung Cancer.), a result similar to that seen when the analysis was restricted to patients with stage IA disease.Larsen et al. suggest that independent replication of the genes that were identified in our analysis should be possible, regardless of the microarray platform and biostatistical methods used. We disagree. The platform will clearly affect absolute measures of gene activity, and the method of analysis that is used to generate a predictive model will also have a substantial effect on the selection of genes. In addition, many studies now point to the complexity of cancer phenotypes and the capacity of multiple gene sets to serve as predictive models.3 The critical question in any of these studies is not the specific set of genes developed to predict an outcome but, rather, the ability to replicate any given model in multiple sample sets. We demonstrated replication of our original finding in three independent data sets.
3 ReferencesAnil Potti, M.D.
Duke Institute for Genome Sciences and Policy, Durham, NC 27708David H. Harpole, Jr., M.D.
Duke University Medical Center, Durham, NC 27705Joseph R. Nevins, Ph.D.
Duke Institute for Genome Sciences and Policy, Durham, NC 27708
nevin001@mc.duke. edu 1
Sun Z ,Aubry MC ,Deschamps C , et al. Histologic grade is an independent prognostic factor for survival in non-small cell lung cancer: an analysis of 5018 hospital- and 712 population-based cases. J Thorac Cardiovasc Surg 2006;131:1014-1020
CrossRef | Web of Science | Medline2
Strauss GM ,Herndon JE ,Maddaus MA , et al. Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): update of Cancer and Leukemia Group B (CALGB) protocol 9633. J Clin Oncol 2006;24:Suppl:7007-70073
Fan C ,Oh DS ,Wessels L , et al. Concordance among gene-expression-based predictors for breast cancer. N Engl J Med 2006;355:560-569
Full Text | Web of Science | Medline
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Alberto M. Marchevsky. 2010. Pathologic Classification of Lung Malignancies and Special Pathologic Procedures. , 213-237.
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Joo Sung Sun, Kyung Joo Park, Seung Soo Sheen, Joon-Kee Yoon, Seok Nam Yoon, Kyi Beom Lee, Sung Chul Hwang. (2009) Clinical usefulness of the fluorodeoxyglucose (FDG)-PET maximal standardized uptake value (SUV) in combination with CT features for the differentiation of adenocarcinoma with a bronchioloalveolar carcinoma from other subtypes of non-small cell lung cancers. Lung Cancer 66:2, 205-210
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F. Barlési, J.-M. Bréchot, G. Zalcman. (2007) La biologie moléculaire permettra peut-être dans l’avenir de mieux évaluer le risqué de rechute des cancers bronchiques opérés. Revue des Maladies Respiratoires 24, 57
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