Genomic heterogeneity of multiple synchronous lung cancer

Liu, Yu; Zhang, Jianjun; Lin, Li; Yin, Guangliang; Zhang, Jianhua; Zheng, Shan; Cheung, Hannah; Wu, Ning; Lü, Ning; Mao, Xizeng; Yang, Lingzhi; Zhang, Li; Seth, Sahil; Huang, Chen; Song, Xingzhi; Liu, Kan; Xie, Yu; Zhou, Lina; Zhao, Chenyang; Han, Ning; Chen, Wenting; Zhang, Susu; Chen, Longyun; Cai, Wenjun; Shen, Miaozhong; Xu, Nuo; Cheng, Shujun; Yang, Huanming; Lee, John; Correa, Arlene M.; Fujimoto, Junya; Behrens, Carmen; Chow, Chi Wan; William, William N.; Heymach, John V.; Hong, Waun Ki; Swisher, Stephen G.; Wistuba, Ignacio I.; Wang, Jun; Lin, Dongmei; Li, Xiangyang; Futreal, P. Andrew; Gao, Yanning

doi:10.1038/ncomms13200

Cited by 151 publications

(158 citation statements)

References 42 publications

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“…16 Additional merits to whole genome structural profiling of MFLC nodules for measures of tumor lineage arise from the ability to clinically assess the level of relatedness in metastatic lesions. While two MFLC nodules may be demonstrated to be related, progressive mutations of each distal lesion could lead to a scenario where despite shared clonal lineage, the repertoire of distinct mutations could result in differential responses to systemic therapies.…”

Section: Discussionmentioning

confidence: 99%

Management of Multifocal Lung Cancer: Results of a Survey

Leventakos

Peikert

Midthun

et al. 2017

Journal of Thoracic Oncology

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Introduction Multifocal lung cancer (MFLC) is an increasingly common clinical scenario but there is lack of high-level evidence for its optimal treatment. Thus, we surveyed members of the interdisciplinary International Association for the Study of Lung Cancer (IASLC) on their therapeutic approaches and analyzed the resultant practice patterns. Methods We described the clinical scenario of an otherwise healthy 60 years old man with bilateral pulmonary nodules and asked the 6373 IASLC members whether they would recommend surgery, and if so, the extent of surgery. We also asked what other measures would be recommended to complete the staging, and whether radiation therapy or chemotherapy would be suggested. Results We received 221 (3.5%) responses from multiple specialists. Most respondents recommended surgery (n=140, 63%) for this scenario. Surgeons were significantly more likely to recommend surgery than other specialties. Of those who recommended surgery, most would obtain a PET/CT to rule out distant metastases and an MRI to rule out brain metastases; but in the absence of radiographic lymph node involvement, most would not stage the mediastinum by bronchoscopy or mediastinoscopy prior to resection. When surgery was not recommended or declined, respondents commonly recommended radiation. Conclusions This survey suggests that therapeutic recommendations for MFLC are influenced to a large extent by physicians’ specialty training, probably due to the lack of high-level evidence for its standard treatment. Ongoing systematic and multidisciplinary approaches with robust short-term and long-term patient outcomes may improve the quality of evidence for the optimal management of this clinical entity.

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Section: Discussionmentioning

confidence: 99%

Management of Multifocal Lung Cancer: Results of a Survey

Leventakos

Peikert

Midthun

et al. 2017

Journal of Thoracic Oncology

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“…But then again, there is insufficient knowledge when or how often the molecular genetic profile can be used as the sole diagnostic tool to determine if two tumours are related or not. Liu and co-workers argued that a case with three lung cancers, all with the same EGFR mutation, still were likely to be synchronous tumours based on about 40 discordant non-driver mutations found with WES [58]. However, given the number of mutations typically found with WES in lung cancers, [26] it is difficult to be certain, and WES is maybe not more helpful than targeted sequencing for comparison of molecular genetic profiles in these situations.…”

Section: Discussionmentioning

confidence: 99%

Targeted sequencing may facilitate differential diagnostics of pulmonary tumours: a case series

et al. 2017

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BackgroundHistopathological diagnosis is important for prognostication and choice of treatment in patients with cancer in the lung. Metastases to the lungs are common and need to be distinguished from primary lung cancer. Furthermore, cases with synchronous or metachronous primary lung cancers (although infrequent) are often handled differently than cases with lung cancer with intrapulmonary metastasis or relapse, respectively. In some cases, morphology and immunohistochemical staining is not sufficient for certain diagnosis.MethodsThe present study included six cases where molecular genetic analysis in form of pyrosequencing or targeted next-generation sequencing was of value for certain diagnosis of selected tumours in the lung.ResultsTwo of the included cases were rare metastases to the lung; colorectal cancer with IHC profile consistent with primary lung cancer and malignant adenomyoepithelioma of the breast, respectively, where molecular genetic analysis was of aid for proving the relationship to the primary tumour. The other four cases were multiple lung adenocarcinomas where molecular genetic analysis was of aid to distinguish between intrapulmonary metastasis and synchronous tumour.ConclusionsComparison of molecular genetic profile may be an important tool for determination of relationship between tumours in some situations and should always be considered in unclear cases. Further studies on concordance and discordance of molecular genetic profiles between spatially or temporally different tumours with common origin may be helpful for improved diagnostics of pulmonary tumours.

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“…Recently, first-generation immune checkpoint inhibitors have become a second-line standard option in patients with advanced or metastatic NSCLC. 59,60 Because both tumor response to immune checkpoint inhibitors and tumor genomics are extremely heterogeneous, 61,62 further development of biomarker research and rational combinational strategies are critical to select the molecular subsets of NSCLC patients suitable for different treatment options alone and in combination in the era of precision oncology. Thus, to validate our results, a future prospective study of PDS of pemetrexed and intercalated erlotinib as maintenance or second-line therapy against new second-line standards might be warranted in patients with EGFR wild-type NSCLC tumors using a multiplex cancer biomarker assay containing EGFR genotyping.…”

Section: Discussionmentioning

confidence: 99%

Randomized Phase 2 Trial of Pharmacodynamic Separation of Pemetrexed and Intercalated Erlotinib Versus Pemetrexed Alone for Advanced Nonsquamous, Non–small-cell Lung Cancer

Piperdi

Walsh

et al. 2017

Clinical Lung Cancer

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This randomized phase 2 study demonstrated promising clinical synergism between pemetrexed and intercalated erlotinib in patients with unselected nonsquamous non–small-cell lung cancer (NSCLC) as second-line therapy. EGFR (epidermal growth factor receptor) genotyping by Sequenom multiplex oncogenotyping assay was feasible in 79% of eligible patients using tumor DNA from either archival specimens and/or plasma. Because patients with EGFR-mutant NSCLC respond well to EGFR tyrosine kinase inhibitor monotherapy alone or in combination with bevacizumab, the combination might merit further evaluation as second-line or maintenance therapy against new standards in patients with EGFR wild-type advanced NSCLC. Background Pharmacodynamic separation of pemetrexed and erlotinib avoids negative cellular interactions and results in antitumor synergy in erlotinib-resistant non–small-cell lung cancer (NSCLC) cells, independent of EGFR (epidermal growth factor receptor) genotype. Patients and Methods Patients with platinum-treated metastatic nonsquamous NSCLC were randomly assigned 1:2 to pemetrexed alone (500 mg/m2 provided intravenously on day 1) or pemetrexed followed by erlotinib (150 mg provided orally once daily on days 2–17) every 21 days. EGFR genotype was centrally confirmed by Sequenom multiplex oncogenotyping assay. The primary end point was progression-free survival (PFS), which would be considered promising for future study if median PFS was ≥ 4.5 months. Results Of 83 patients enrolled, 79 were randomized to either pemetrexed alone (n = 27) or in combination (n = 52). Fifty-nine (79%) of 75 eligible patients had tumors with confirmed EGFR genotype: 7 with activating mutations and 52 wild type. Median PFS was 4.7 and 2.9 months in the combination and pemetrexed-alone groups, respectively. In patients with EGFR wild-type tumors, median PFS was 5.3 and 3.5 months in the combination and pemetrexed-alone groups, respectively. Objective response rate (29% vs. 10%, P = .17), 6-month PFS (45% vs. 29%, P = .26), and 12-month PFS (23% vs. 10%, P = .28) were all higher in the combination arm. Rash (67% vs. 26%, P = .0007) and diarrhea (44% vs. 11%, P = .003) were significantly more common in the combination arm. Conclusion In patients with unselected or EGFR wild-type advanced nonsquamous NSCLC, pharmacodynamic separation of pemetrexed and intercalated erlotinib had promising antitumor activity without new safety concerns. The combination merits further evaluation as maintenance or second-line therapy against new standards in patients with EGFR wild-type advanced NSCLC.

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Genomic heterogeneity of multiple synchronous lung cancer

Cited by 151 publications

References 42 publications

Management of Multifocal Lung Cancer: Results of a Survey

Management of Multifocal Lung Cancer: Results of a Survey

Targeted sequencing may facilitate differential diagnostics of pulmonary tumours: a case series

Randomized Phase 2 Trial of Pharmacodynamic Separation of Pemetrexed and Intercalated Erlotinib Versus Pemetrexed Alone for Advanced Nonsquamous, Non–small-cell Lung Cancer

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