Solid Predominant Histologic Subtype in Resected Stage I Lung Adenocarcinoma Is an Independent Predictor of Early, Extrathoracic, Multisite Recurrence and of Poor Postrecurrence Survival.

PURPOSE To examine the significance of the proposed International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) histologic subtypes of lung adenocarcinoma for patterns of recurrence and, among patients who recur following resection of stage I lung adenocarcinoma, for postrecurrence survival (PRS). PATIENTS AND METHODS We reviewed patients with stage I lung adenocarcinoma who had undergone complete surgical resection from 1999 to 2009 (N = 1,120). Tumors were subtyped by using the IASLC/ATS/ERS classification. The effects of the dominant subtype on recurrence and, among patients who recurred, on PRS were investigated. RESULTS Of 1,120 patients identified, 188 had recurrent disease, 103 of whom died as a result of lung cancer. Among patients who recurred, 2-year PRS was 45%, and median PRS was 26.1 months. Compared with patients with nonsolid tumors, patients with solid predominant tumors had earlier (P = .007), more extrathoracic (P < .001), and more multisite (P = .011) recurrences. Multivariable analysis of primary tumor factors revealed that, among patients who recurred, solid predominant histologic pattern in the primary tumor (hazard ratio [HR], 1.76; P = .016), age older than 65 years (HR, 1.63; P = .01), and sublobar resection (HR, 1.6; P = .01) were significantly associated with worse PRS. Presence of extrathoracic metastasis (HR, 1.76; P = .013) and age older than 65 years at the time of recurrence (HR, 1.7; P = .014) were also significantly associated with worse PRS. CONCLUSION In patients with stage I primary lung adenocarcinoma, solid predominant subtype is an independent predictor of early recurrence and, among those patients who recur, of worse PRS. Our findings provide a rationale for investigating adjuvant therapy and identify novel therapeutic targets for patients with solid predominant lung adenocarcinoma.

[1]  R. Gray,et al.  Annual hazard rates of recurrence for breast cancer after primary therapy. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  C. Sima,et al.  Patterns of recurrence and second primary lung cancer in early-stage lung cancer survivors followed with routine computed tomography surveillance. , 2013, The Journal of thoracic and cardiovascular surgery.

[3]  Michael Thomas,et al.  The novel histologic International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification system of lung adenocarcinoma is a stage-independent predictor of survival. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  Tae Min Kim,et al.  Heterogeneity of Genetic Changes Associated with Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancer , 2013, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[5]  William Pao,et al.  Comprehensive Histologic Assessment Helps to Differentiate Multiple Lung Primary Nonsmall Cell Carcinomas From Metastases , 2009, The American journal of surgical pathology.

[6]  Kotaro Kameyama,et al.  Postrecurrence survival in patients with stage I non-small cell lung cancer. , 2008, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[7]  M Zelen,et al.  Exploratory data analysis and the use of the hazard function for interpreting survival data: an investigator's primer. , 1985, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  W. Hsu,et al.  Post-recurrence survival in completely resected stage I non-small cell lung cancer with local recurrence , 2009, Thorax.

[9]  Masahiro Tsuboi,et al.  International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma , 2011, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[10]  H. Müller,et al.  Hazard rate estimation under random censoring with varying kernels and bandwidths. , 1994, Biometrics.

[11]  Akihiko Yoshizawa,et al.  Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases , 2011, Modern Pathology.

[12]  M E Burt,et al.  Incidence of local recurrence and second primary tumors in resected stage I lung cancer. , 1995, The Journal of thoracic and cardiovascular surgery.

[13]  C. Berg,et al.  Targeting of low-dose CT screening according to the risk of lung-cancer death. , 2013, The New England journal of medicine.

[14]  Robert Gray,et al.  A Proportional Hazards Model for the Subdistribution of a Competing Risk , 1999 .

[15]  Prasad S Adusumilli,et al.  Associations Between Mutations and Histologic Patterns of Mucin in Lung Adenocarcinoma: Invasive Mucinous Pattern and Extracellular Mucin Are Associated With KRAS Mutation , 2014, The American journal of surgical pathology.

[16]  C. Sima,et al.  FDG-PET SUVmax Combined with IASLC/ATS/ERS Histologic Classification Improves the Prognostic Stratification of Patients with Stage I Lung Adenocarcinoma , 2012, Annals of Surgical Oncology.

[17]  Yang Zhang,et al.  The prognostic and predictive value of solid subtype in invasive lung adenocarcinoma , 2014, Scientific Reports.

[18]  R. Gelber,et al.  Patterns of Recurrence and outcome according to breast cancer subtypes in lymph node-negative disease: results from international breast cancer study group trials VIII and IX. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  Arash Naeim,et al.  Cost-effectiveness of CT screening in the National Lung Screening Trial. , 2014, The New England journal of medicine.

[20]  Akihiko Yoshizawa,et al.  A Grading System of Lung Adenocarcinomas Based on Histologic Pattern is Predictive of Disease Recurrence in Stage I Tumors , 2010, The American journal of surgical pathology.

[21]  T. Chou,et al.  Prognostic factors of postrecurrence survival in completely resected stage I non-small cell lung cancer with distant metastasis , 2010, Thorax.

[22]  J. Crowley,et al.  The IASLC Lung Cancer Staging Project: Proposals for the Revision of the TNM Stage Groupings in the Forthcoming (Seventh) Edition of the TNM Classification of Malignant Tumours , 2007, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[23]  J. Usuda,et al.  Prognostic factors and the significance of treatment after recurrence in completely resected stage I non-small cell lung cancer. , 2013, Chest.

[24]  David R. Jones,et al.  Differences in patterns of recurrence in early-stage versus locally advanced non-small cell lung cancer. , 2014, The Annals of thoracic surgery.

[25]  Prasad S Adusumilli,et al.  A grading system combining architectural features and mitotic count predicts recurrence in stage I lung adenocarcinoma , 2012, Modern Pathology.

[26]  C. Sima,et al.  Visceral pleural invasion does not affect recurrence or overall survival among patients with lung adenocarcinoma ≤ 2 cm: a proposal to reclassify T1 lung adenocarcinoma. , 2013, Chest.

[27]  R. Gray A Class of $K$-Sample Tests for Comparing the Cumulative Incidence of a Competing Risk , 1988 .

[28]  M. Ladanyi,et al.  KRAS mutations are associated with solid growth pattern and tumor-infiltrating leukocytes in lung adenocarcinoma , 2013, Modern Pathology.

[29]  David R. Jones,et al.  Tumor Spread through Air Spaces is an Important Pattern of Invasion and Impacts the Frequency and Location of Recurrences after Limited Resection for Small Stage I Lung Adenocarcinomas , 2015, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[30]  K R Hess,et al.  Hazard function estimators: a simulation study. , 1999, Statistics in medicine.

[31]  Akihiko Yoshizawa,et al.  Prognostic Significance of Adenocarcinoma In Situ, Minimally Invasive Adenocarcinoma, and Nonmucinous Lepidic Predominant Invasive Adenocarcinoma of the Lung in Patients With Stage I Disease , 2014, The American journal of surgical pathology.

[32]  C. Gatsonis,et al.  Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening , 2012 .

[33]  T. Chou,et al.  Prognostic Value of the New International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Lung Adenocarcinoma Classification on Death and Recurrence in Completely Resected Stage I Lung Adenocarcinoma , 2013, Annals of surgery.

[34]  J. Dignam,et al.  The Use and Interpretation of Competing Risks Regression Models , 2012, Clinical Cancer Research.

[35]  C. Sima,et al.  Thyroid transcription factor‐1 expression is an independent predictor of recurrence and correlates with the IASLC/ATS/ERS histologic classification in patients with stage I lung adenocarcinoma , 2013, Cancer.

[36]  P. Russell,et al.  The Clinical Relevance of Pathologic Subtypes in Metastatic Lung Adenocarcinoma , 2014, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[37]  Sukki Cho,et al.  Prognostic factors for post-recurrence survival in patients with completely resected Stage I non-small-cell lung cancer. , 2014, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[38]  J. Roth,et al.  Predictors for Locoregional Recurrence for Clinical Stage III-N2 Non-small Cell Lung Cancer with Nodal Downstaging After Induction Chemotherapy and Surgery , 2012, Annals of Surgical Oncology.

[39]  Prasad S Adusumilli,et al.  Impact of micropapillary histologic subtype in selecting limited resection vs lobectomy for lung adenocarcinoma of 2cm or smaller. , 2013, Journal of the National Cancer Institute.

[40]  Haiquan Chen,et al.  Protein expression of programmed death 1 ligand 1 and ligand 2 independently predict poor prognosis in surgically resected lung adenocarcinoma , 2014, OncoTargets and therapy.

[41]  Mickael Guedj,et al.  Clinically Relevant Characterization of Lung Adenocarcinoma Subtypes Based on Cellular Pathways: An International Validation Study , 2010, PloS one.