Accepted Manuscript. Risk stratification for distant recurrence of resected early stage NSCLC is under construction. Michael Lanuti, MD

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1 Accepted Manuscript Risk stratification for distant recurrence of resected early stage NSCLC is under construction Michael Lanuti, MD PII: S (17) DOI: /j.jtcvs Reference: YMTC To appear in: The Journal of Thoracic and Cardiovascular Surgery Received Date: 13 October 2017 Accepted Date: 24 October 2017 Please cite this article as: Lanuti M, Risk stratification for distant recurrence of resected early stage NSCLC is under construction, The Journal of Thoracic and Cardiovascular Surgery (2017), doi: / j.jtcvs This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Risk stratification for distant recurrence of resected early stage NSCLC is under construction Michael Lanuti MD Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA. Running Head: Word count: 480 words Conflicts of Interest: Author has nothing to disclose with regard to commercial support. CORRESPONDENCE: Michael Lanuti MD 55 Fruit Street, Founders 7 Boston, MA USA mlanuti@mgh.harvard.edu Tel: , Fax:

3 COMMENTARY: In our efforts to offer curative pulmonary resection for patients who harbor stage I nonsmall cell lung cancer, we fall short on identifying patients deemed high risk for distant recurrence and offering adjuvant treatment. Independent prognostic histopathologic factors have been published and include tumor size (1), visceral pleural invasion (2), lympho-vascular invasion (3), large cell neuroendocrine phenotype (4), and micropapillary adenocarcinoma subtype (5). Some investigators have moved to tumor molecular profiling and validated gene expression assays to risk stratify patients.(6) Others have assessed the predictive role of common driver mutations in resected early stage NSCLC.(7) Despite this knowledge (albeit limited), the enthusiasm to further understand and implement adjuvant strategies to mitigate risk in stage I NSCLC is lackluster. In this retrospective series of the Journal, Brandt and colleagues (8) reviewed a large number (893) of patients who underwent lobectomy with curative intent for T1-3N0 adenocarcinoma (which included stage IA, IB, IIA and IIB) over a 16-year period ( ). All patients with non-adenocarcinoma histology, sublobar resection, and death within 90 days were excluded. Tumor genomic data was collected on a fraction of patients. Primary outcome was distant recurrence, disease-free survival and overall survival. Recurrence was defined by distant, locoregional or both. Median follow-up was short, just under 3 years. Thirteen percent (115/893) developed recurrence, 85% (99/115) were distant, and (16/893) developed isolated local recurrence. The recurrence rate in this cohort was astonishingly low (13%) compared to what is understood for stage I and II disease in the 7th edition lung cancer staging system. This speaks to a highly-selected patient population or a consequence of excluding nonadenocarcinoma histology. The analysis is vulnerable to changes in treatment over time where adjuvant therapy became more accepted for stage IB (tumors > 4cm), stage IIA and IIB disease.(9) The study cohort was enriched for less aggressive disease by excluding patients who may have received adjuvant therapy from 2006 on. Lastly, the 1.8% (16/893) observed rate of local recurrence in this cohort was also impressively low in contrast 6% local recurrence reported in the Lung Cancer Study Group where tumors were < 5cm. The authors conclude that tumor size and lymphovascular invasion are independent predictors of recurrence. The observations reported in this study are not novel, but further corroborate the importance of these specific histopathologic parameters when assessing recurrence risk in completely resected, node negative NSCLC. The authors should be congratulated on analyzing a large cohort and including only patients undergoing lobectomy, which is the most potent oncologic modality for node negative NSCLC. Prediction of recurrence in early stage NSCLC is in its infancy and should be further refined by enhanced molecular profiling, circulating tumors cells and perhaps circulating tumor DNA. As molecular fingerprinting of NSCLC expands, it is my strong conviction that Thoracic Surgeons have a leadership role in the development of adjuvant therapy trials, since we have the most impact on early stage NSCLC.

4 1. Goldstraw P, Chansky K, Crowley J, Rami-Porta R, Asamura H, Eberhardt WE, et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2016;11(1): Yang X, Sun F, Chen L, Shi M, Shi Y, Lin Z, et al. Prognostic value of visceral pleural invasion in non-small cell lung cancer: A propensity score matching study based on the SEER registry. J Surg Oncol. 2017;116(3): Mollberg NM, Bennette C, Howell E, Backhus L, Devine B, Ferguson MK. Lymphovascular invasion as a prognostic indicator in stage I non-small cell lung cancer: a systematic review and meta-analysis. Ann Thorac Surg. 2014;97(3): Cattoni M, Vallieres E, Brown LM, Sarkeshik AA, Margaritora S, Siciliani A, et al. Improvement in TNM staging of pulmonary neuroendocrine tumors requires histology and regrouping of tumor size. J Thorac Cardiovasc Surg Hung JJ, Yeh YC, Wu YC, Chou TY, Hsu WH. Prognostic Factors in Completely Resected Node-Negative Lung Adenocarcinoma of 3 cm or Smaller. J Thorac Oncol Kratz JR, He J, Van Den Eeden SK, Zhu ZH, Gao W, Pham PT, et al. A practical molecular assay to predict survival in resected non-squamous, non-small-cell lung cancer: development and international validation studies. Lancet. 2012;379(9818): Izar B, Sequist L, Lee M, Muzikansky A, Heist R, Iafrate J, et al. The impact of EGFR mutation status on outcomes in patients with resected stage I non-small cell lung cancers. Ann Thorac Surg. 2013;96(3): Brandt, W et al. Factors associated with distant recurrence in R0 lobectomy for pn0 Lung Adenocarcinoma. 9. Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J, et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004;350(4):

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