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Nicolas Girard, MD, PhD
Author and Funding Information

From the Service de Pneumologie, Hôpital Louis Pradel, Hospices Civils de Lyon; and Unité Mixte de Recherche (UMR) 754, Université Claude Bernard.

Correspondence to: Nicolas Girard, MD, PhD, Service de Pneumologie, Hôpital Louis Pradel, Hospices Civils de Lyon, 28 ave doyen Lépine, 69677 Lyon (Bron) cedex, France; e-mail: nicolas.girard@chu-lyon.fr


Financial/nonfinancial disclosures: The author has reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;144(2):715-716. doi:10.1378/chest.13-1021
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To the Editor:

I thank Dr Leuzzi and colleagues for their insightful comment on our article in CHEST.1 Based on the study of seven patients with multiple lung adenocarcinomas harboring distinct EGFR and KRAS mutations, we demonstrated the limits of the Martini-Melamed and American College of Chest Physicians criteria to distinguish multiple primary tumors from metastases.1 As reported in our article, only one of the three patients with synchronous multiple tumors presented with nodal involvement; all four metachronous tumors were N0 at the time of recurrence, precluding us to answer Dr Leuzzi and colleagues about the potential interest of mutation genotyping on tumor lymph node specimens to assess clonality. Of note, another published surgical series stressed the low frequency of nodal involvement in synchronous multiple lung cancers.2

Contrary to Takamochi and colleagues,3 we actually believe that EGFR and KRAS genotyping is not sufficiently informative to assess clonality in multiple lung cancers, considering both the variable probability of a match in independent tumors that may be high for frequent mutations (eg, 5.2% for KRAS G12D) and, conversely, the infrequency of the occurrences of each specific mutation overall.4 Thus, in a subsequent study from our group on 20 patients with 42 multiple lung cancers, no mutations were observed in either tumor for seven patients (35%), despite the sequencing (using mass spectrometry-based genotyping) of nine genes frequently harboring oncogenic mutations.4 In this study, we reported the use of array-based comparative genomic hybridization to assess clonality.4 By identifying precise regions of allelic gains and losses, this technique has a far higher potential to establish whether tumors are independent (ie, lack matching gains/losses) or clonal (ie, contain matching gains/losses) as compared with mutation profiling. Again, none of the 42 multiple lung tumors included in this analysis presented with nodal involvement.

Ultimately, a major issue when interpreting reported data on intratumor or intertumor or tumor node molecular heterogeneity is the variable technical sensitivity of genotyping techniques, which may explain most reported discrepancies. Next-generation sequencing technology may then be of great interest to further explore clonality of multiple lung cancers. A recent study showed that pyrosequencing of multiple tumor specimens from metastatic renal carcinomas leads to the identification of mutations not detectable across every tumor region or metastatic lymph nodes in >60% of cases.5 Another avenue is genotyping of circulating tumor cells that may allow the identification of different tumor clones in single or multiple tumors; EGFR T790M mutant circulating cells may then be identified in EGFR-mutant lung adenocarcinomas at time of diagnosis, before the occurrence of acquired resistance to epidermal growth factor receptor inhibitors.6 At this level of analysis, unexpected biologic mechanisms have to be considered. Dissemination of cancer cells is conventionally viewed as a unidirectional process that leads to metastatic colonization of distant organs, but circulating tumor cells have been reported in mice to be able to colonize back their tumors of origin, in a process called “tumor self-seeding.”7 Such a process remains to be explored in multiple lung cancers and, besides clonal relationships, may play a major role in the clinical outcome of patients.

References

Girard N, Deshpande C, Azzoli CG, et al. Use of epidermal growth factor receptor/Kirsten rat sarcoma 2 viral oncogene homolog mutation testing to define clonal relationships among multiple lung adenocarcinomas: comparison with clinical guidelines. Chest. 2010;137(1):46-52. [CrossRef]
 
Finley DJ, Yoshizawa A, Travis W, et al. Predictors of outcomes after surgical treatment of synchronous primary lung cancers. J Thorac Oncol. 2010;5(2):197-205. [CrossRef]
 
Takamochi K, Oh S, Matsuoka J, Suzuki K. Clonality status of multifocal lung adenocarcinomas based on the mutation patterns of EGFR and K-ras. Lung Cancer. 2012;75(3):313-320. [CrossRef]
 
Girard N, Ostrovnaya I, Lau C, et al. Genomic and mutational profiling to assess clonal relationships between multiple non-small cell lung cancers. Clin Cancer Res. 2009;15(16):5184-5190. [CrossRef]
 
Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883-892. [CrossRef]
 
Maheswaran S, Sequist LV, Nagrath S, et al. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med. 2008;359(4):366-377. [CrossRef]
 
Kim MY, Oskarsson T, Acharyya S, et al. Tumor self-seeding by circulating cancer cells. Cell. 2009;139(7):1315-1326. [CrossRef]
 

Figures

Tables

References

Girard N, Deshpande C, Azzoli CG, et al. Use of epidermal growth factor receptor/Kirsten rat sarcoma 2 viral oncogene homolog mutation testing to define clonal relationships among multiple lung adenocarcinomas: comparison with clinical guidelines. Chest. 2010;137(1):46-52. [CrossRef]
 
Finley DJ, Yoshizawa A, Travis W, et al. Predictors of outcomes after surgical treatment of synchronous primary lung cancers. J Thorac Oncol. 2010;5(2):197-205. [CrossRef]
 
Takamochi K, Oh S, Matsuoka J, Suzuki K. Clonality status of multifocal lung adenocarcinomas based on the mutation patterns of EGFR and K-ras. Lung Cancer. 2012;75(3):313-320. [CrossRef]
 
Girard N, Ostrovnaya I, Lau C, et al. Genomic and mutational profiling to assess clonal relationships between multiple non-small cell lung cancers. Clin Cancer Res. 2009;15(16):5184-5190. [CrossRef]
 
Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883-892. [CrossRef]
 
Maheswaran S, Sequist LV, Nagrath S, et al. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med. 2008;359(4):366-377. [CrossRef]
 
Kim MY, Oskarsson T, Acharyya S, et al. Tumor self-seeding by circulating cancer cells. Cell. 2009;139(7):1315-1326. [CrossRef]
 
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