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The Genomics of Young Lung Cancer: Comprehensive Tissue Genomic Analysis in Patients Under 40 With Lung Cancer

  • Author Footnotes
    ˆ Affiliated with the Keck School of Medicine, University of Southern California, Los Angeles, California, at the time of this study and currently an employee of Genentech, Inc.
    Barbara J. Gitlitz
    Correspondence
    Corresponding author Address for correspondence: Barbara J. Gitlitz, MD, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080.
    Footnotes
    ˆ Affiliated with the Keck School of Medicine, University of Southern California, Los Angeles, California, at the time of this study and currently an employee of Genentech, Inc.
    Affiliations
    Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
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  • Silvia Novello
    Affiliations
    Department of Oncology, AOU San Luigi-Orbassano, University of Turin, Turin, Italy
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  • Tiziana Vavalà
    Affiliations
    Screening Center of Oncology, Saluzzo Hospital, Saluzzo, Italy
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  • Marisa Bittoni
    Affiliations
    The Ohio State University, Comprehensive Cancer Center, Columbus, Ohio
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  • Author Footnotes
    † Affiliated with the Addario Lung Cancer Medical Institute at the time of the study and currently president of Edwards-Hunt.
    Alicia Sable-Hunt
    Footnotes
    † Affiliated with the Addario Lung Cancer Medical Institute at the time of the study and currently president of Edwards-Hunt.
    Affiliations
    Addario Lung Cancer Medical Institute, San Carlos, California
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  • Dean Pavlick
    Affiliations
    Foundation Medicine, Inc., Cambridge, Massachusetts
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  • Robert Hsu
    Affiliations
    Department of Oncology, Keck School of Medicine, University of Southern California, Los Angeles, California
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  • Author Footnotes
    ‡ Affiliated with the Keck School of Medicine, University of Southern California, Los Angeles, California, at the time of this study and currently an employee of University of Hawaii Cancer Center.
    S. Lani Park
    Footnotes
    ‡ Affiliated with the Keck School of Medicine, University of Southern California, Los Angeles, California, at the time of this study and currently an employee of University of Hawaii Cancer Center.
    Affiliations
    Keck School of Medicine, University of Southern California, Los Angeles, California
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  • Author Footnotes
    § Affiliated with the Dana-Farber Cancer Institute at the time of this study and currently a medical student at the Jacobs School of Medicine and Biomedical Sciences, University at Buffalo.
    Ruthia Chen
    Footnotes
    § Affiliated with the Dana-Farber Cancer Institute at the time of this study and currently a medical student at the Jacobs School of Medicine and Biomedical Sciences, University at Buffalo.
    Affiliations
    Department of Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
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  • Matthew Cooke
    Affiliations
    Foundation Medicine, Inc., Cambridge, Massachusetts
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  • Author Footnotes
    ‖ Affiliated with GO2 Foundation for Lung Cancer at the time of this study and currently an employee of LUNGevity.
    Amy Moore
    Footnotes
    ‖ Affiliated with GO2 Foundation for Lung Cancer at the time of this study and currently an employee of LUNGevity.
    Affiliations
    GO2 Foundation for Lung Cancer, San Carlos, California
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  • Alexa B. Schrock
    Affiliations
    Clinical Development, Foundation Medicine, Inc., Cambridge, Massachusetts
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  • Author Footnotes
    ¶ Affiliated with the Inova Schar Cancer Institute at the time of this study and currently an adjunct professor at the University of Virginia Medical School.
    Joan H. Schiller
    Footnotes
    ¶ Affiliated with the Inova Schar Cancer Institute at the time of this study and currently an adjunct professor at the University of Virginia Medical School.
    Affiliations
    Inova Schar Cancer Institute, Fairfax, Virginia
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  • Bonnie J. Addario
    Affiliations
    Addario Lung Cancer Medical Institute, San Carlos, California

    GO2 Foundation for Lung Cancer, San Carlos, California
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  • Author Footnotes
    # Affiliated with the Dana-Farber Cancer Institute at the time of this study and currently an employee of Foundation Medicine Inc.
    Geoffrey R. Oxnard
    Footnotes
    # Affiliated with the Dana-Farber Cancer Institute at the time of this study and currently an employee of Foundation Medicine Inc.
    Affiliations
    Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
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  • Author Footnotes
    ˆ Affiliated with the Keck School of Medicine, University of Southern California, Los Angeles, California, at the time of this study and currently an employee of Genentech, Inc.
    † Affiliated with the Addario Lung Cancer Medical Institute at the time of the study and currently president of Edwards-Hunt.
    ‡ Affiliated with the Keck School of Medicine, University of Southern California, Los Angeles, California, at the time of this study and currently an employee of University of Hawaii Cancer Center.
    § Affiliated with the Dana-Farber Cancer Institute at the time of this study and currently a medical student at the Jacobs School of Medicine and Biomedical Sciences, University at Buffalo.
    ‖ Affiliated with GO2 Foundation for Lung Cancer at the time of this study and currently an employee of LUNGevity.
    ¶ Affiliated with the Inova Schar Cancer Institute at the time of this study and currently an adjunct professor at the University of Virginia Medical School.
    # Affiliated with the Dana-Farber Cancer Institute at the time of this study and currently an employee of Foundation Medicine Inc.
Open AccessPublished:May 22, 2021DOI:https://doi.org/10.1016/j.jtocrr.2021.100194

      Abstract

      Introduction

      Lung adenocarcinomas in young patients (<40 y) are more likely to harbor targetable genomic alterations. This study aimed to determine whether the prevalence of targetable alterations is greater in young adults with lung carcinoma than in the overall lung cancer population. To reach this rare patient population, a web-based platform was used to recruit and enroll patients remotely.

      Methods

      In this prospective study, patients less than 40 years old at the time of primary lung cancer diagnosis with confirmed lung carcinoma were recruited from four global sites and remotely by means of a website. Genotyping data were collected, if available, or obtained by means of next-generation sequencing using the FoundationOne platform. The prevalence of targetable alterations was quantified across patients with advanced adenocarcinoma.

      Results

      Overall, 133 patients across five continents were included, 41% of whom enrolled online. The mean (SD) age at diagnosis was 34 (5.2) years; 79% had stage IV disease at diagnosis. Among patients with adenocarcinoma (n = 115), 112 entered the study with previous genomic testing results and 86 (77%) had targetable alterations in EGFR, ALK, ROS1, MET, ERBB2, or RET. Among those without targetable alterations, 14 received further testing and a targetable alteration was identified in eight (57%).

      Conclusions

      This study revealed the feasibility of using a web-based platform to recruit young patients with lung cancer and revealed that 94 of 112 (84%) with adenocarcinoma at any stage had targetable genomic alterations. Among patients with stage IV adenocarcinoma, 85% had a targetable alteration, which is higher than historical expectations for the general population.

      Keywords

      Introduction

      Lung cancer is the second most common cancer but remains the most common cause of cancer death, accounting for approximately 24% of cancer deaths in the United States.
      American Cancer Society
      Key statistics for lung cancer.
      The median age at diagnosis is 70 years, with most cases diagnosed in patients older than 65 years.
      American Cancer Society
      Key statistics for lung cancer.
      Fewer than 2% of all cases are found in patients aged younger than 45 years.
      NIH, National Cancer Institute
      Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: lung and bronchus cancer.
      Regardless of patient age, most lung cancer cases are diagnosed at an advanced, incurable stage.
      • Travis W.D.
      • Brambilla E.
      • Riely G.J.
      New pathologic classification of lung cancer: relevance for clinical practice and clinical trials.
      No longer considered a single disease entity, lung cancer is increasingly subdivided into distinct molecular genotypes that are treated with targeted therapies against oncogenic drivers.
      • Sacher A.G.
      • Dahlberg S.E.
      • Heng J.
      • Mach S.
      • Jänne P.A.
      • Oxnard G.R.
      Lung cancer diagnosed in the young is associated with enrichment for targetable genomic alterations and poor prognosis.
      • Sholl L.M.
      • Aisner D.L.
      • Varella-Garcia M.
      • et al.
      Multi-institutional oncogenic driver mutation analysis in lung adenocarcinoma: the lung cancer mutation consortium experience.
      • Konduri K.
      • Gallant J.-N.
      • Chae Y.K.
      • et al.
      EGFR fusions as novel therapeutic targets in lung cancer.
      The identification of genomic alterations sensitive to targeted therapies has transformed the management and survival of NSCLC.
      • Ettinger D.S.
      • Wood D.E.
      • Aisner D.L.
      • et al.
      Non–small cell lung cancer, version 5.2017, NCCN Clinical Practice Guidelines in Oncology.
      The discovery of new molecular targets, mechanisms of resistance, and rare NSCLC genotypes will likely continue, thereby spurring drug development and broadening therapeutic possibilities.
      Multiple retrospective studies have found that genotype prevalence differs by age group and that the likelihood of harboring a targetable alteration in genes, such as EGFR, ALK, or ROS1, is increased in patients diagnosed at a young age.
      • Sacher A.G.
      • Dahlberg S.E.
      • Heng J.
      • Mach S.
      • Jänne P.A.
      • Oxnard G.R.
      Lung cancer diagnosed in the young is associated with enrichment for targetable genomic alterations and poor prognosis.
      ,
      • Bergethon K.
      • Shaw A.T.
      • Ignatius Ou S.-H.
      • et al.
      ROS1 rearrangements define a unique molecular class of lung cancers.
      We hypothesized that lung cancer in young patients—defined as patients younger than 40 years—would be enriched for targetable genomic alterations. We launched the multicenter Genomics of Young Lung Cancer study, the first study to prospectively characterize the clinical characteristics of and somatic genomic alterations in young patients with lung cancer. To best reach this rare population, we adopted a novel approach for consent and enrollment by including patients who enrolled online.

      Materials and Methods

      Study Design and Patient Population

      Given the rarity of lung cancer in young patients, a website was created by the Addario Lung Cancer Medical Institute to provide study information and study personnel contact information and to prospectively recruit patients from a remote global population.
      Addario Lung Cancer Medical Institute
      Genomics of Young Lung Cancer Study.
      Informed consent was obtained from all patients. Remote patients were invited to enroll online by means of a secure portal, OpenMedNet, developed by the Open Medicine Institute
      Open Medicine Institute
      (Mountain View, CA), where they electronically signed an informed consent form. The University of Southern California Institutional Review Board was the governing ethics committee for remote patients and those who enrolled in person at the Norris Comprehensive Cancer Center at the University of Southern California. Local institutional review boards oversaw the following three other physical sites enrolling patients: Dana-Farber Cancer Institute (Boston, MA), Northside Hospital (Atlanta, GA), and University of Turin (Turin, Italy). This study was carried out in accordance with the Declaration of Helsinki.
      Patients eligible for the study were less than 40 years old at the time of primary lung cancer diagnosis and had pathologically confirmed bronchogenic lung carcinoma (SCLC or NSCLC) at any stage and treatment time point. Patients with metastatic nonsquamous NSCLC were required to have EGFR and ALK genotyping by a Clinical Laboratory Improvement Amendments (CLIA)–certified laboratory at the time of enrollment. No genotyping was required before enrollment for patients with early stage NSCLC (stages I–III) or those with SCLC or squamous NSCLC. Patients were excluded if use of their tissue sample for research would compromise the diagnosis or staging of their lung cancer.

      Sample Collection and Clinical Genomics

      Any existing available results from genomic testing performed by a CLIA-certified laboratory were requested from enrolled patients. All patients were required to provide previously collected tumor samples consisting of 16 unstained slides or an adequate formalin-fixed, paraffin-embedded tumor block from a clinically indicated interventional procedure. All eligible participants were asked to complete a questionnaire to obtain demographics, basic lung cancer history, medical and social history, work and environmental exposure history, and family cancer history. A separate questionnaire regarding the patient’s lung cancer diagnosis, staging, and treatment history was completed by the local investigator or mailed to patients to give to their treating physician for completion.
      To investigate additional driver alterations that might guide potential targeted treatment options and to more comprehensively study the genomics of lung cancer in young patients, patients with metastatic nonsquamous NSCLC whose tissue samples had negative results for or had not been tested for all seven protocol-specified mutations or rearrangements (EGFR, KRAS, ERBB2, BRAF, ROS1, ALK, and RET) were offered next-generation sequencing (NGS) by means of the FoundationOne (F1) platform (Foundation Medicine Inc., Cambridge, MA).
      • Frampton G.M.
      • Fichtenholtz A.
      • Otto G.A.
      • et al.
      Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing.
      F1 testing was also performed on samples from patients with SCLC or metastatic squamous NSCLC as an exploratory cohort.
      For patients eligible for F1 testing, Foundation Medicine was notified, and a kit was shipped directly to the patient for CLIA testing. Remote participants were also mailed a kit containing the case report forms for completion by their treating physician and tubes for blood collection for exploratory genotyping.

      Study Objective and Statistical Analysis

      The primary objective of this study was to determine whether the prevalence of targetable alterations is greater in young adults (<40 y old) with lung carcinoma than in the overall lung cancer population. Patients with stage IV adenocarcinoma were also compared with the historical experience of the Lung Cancer Mutation Consortium. Patients with SCLC or metastatic squamous NSCLC were included as an exploratory cohort.
      A targetable alteration was defined as any alteration in a driver oncogene for which a U.S. Food and Drug Administration–approved therapy existed at the time of study enrolment (e.g., crizotinib for ALK rearrangement)
      or for which an off-label therapy existed at the time of enrollment (e.g., crizotinib for MET amplification).
      • Ettinger D.S.
      • Wood D.E.
      • Aisner D.L.
      • et al.
      Non–small cell lung cancer, version 5.2017, NCCN Clinical Practice Guidelines in Oncology.
      Alterations that exclude certain targeted therapies (e.g., erlotinib for KRAS mutations)
      • Ettinger D.S.
      • Wood D.E.
      • Aisner D.L.
      • et al.
      Non–small cell lung cancer, version 5.2017, NCCN Clinical Practice Guidelines in Oncology.
      or mutations in tumor-suppressor genes (e.g., PTEN)
      • Gkountakos A.
      • Sartori G.
      • Falcone I.
      • et al.
      PTEN in lung cancer: dealing with the problem, building on new knowledge and turning the game around.
      were not considered targetable.
      The Lung Cancer Mutation Consortium
      • Sholl L.M.
      • Aisner D.L.
      • Varella-Garcia M.
      • et al.
      Multi-institutional oncogenic driver mutation analysis in lung adenocarcinoma: the lung cancer mutation consortium experience.
      was formed to enable a collaborative multi-institutional analysis of potential oncogenic driver alterations in patients of any age with advanced lung adenocarcinoma. In the Lung Cancer Mutation Consortium experience, the prevalence of alterations in EGFR, ALK, BRAF, ERBB2, ROS1, or MET was 35% (36% if ROS1 rearrangements were included). With a one-sided 0.07-level exact binomial test, 60 patients were needed to provide 82% power to detect a difference in the rate of targetable genotypes from the historical rate of 35% to 50% among young patients with lung adenocarcinoma. This is equivalent to observing greater than or equal to 27 patients with a targetable alteration among the cohort of 60 patients.
      The prevalence of targetable alterations was quantified across all patients with adenocarcinoma, and alterations in EGFR, ALK, ROS1, and others (RET, ERBB2, and MET) were summarized across all patients. For patients with adenocarcinoma, chi-square tests were used to determine the overall association of targetable alterations in EGFR, ALK, ROS1, and others (KRAS, ERBB2, and RET) by smoking history, marijuana use, race, and family history of lung cancer. A chi-square test was also used to determine the significance of stage by adenocarcinoma and association between cigarette smoking and marijuana use. Unique cases of clinical interest are highlighted in the patient spotlights section.

      Results

      Demographics

      This study enrolled 133 young patients with lung cancer across 5 continents, including North America, South America, Europe, Asia, and Australia, between July 2014 and July 2017. The mean (SD) age at diagnosis was 34 (5.2) years with a range of 16 to 39 years; 57% were female and 73% were white (Table 1). Overall, 79% of patients had stage IV disease at diagnosis, and 86% had adenocarcinoma. Of the 121 patients with documented smoking status, 33 patients (27%) were or had been smokers and 88 patients (73%) were nonsmokers; among nonsmokers, 79 (90%) had adenocarcinoma. Overall, 62% reported no known exposure to secondhand smoke.
      Table 1Demographics and Mutations by Sex and Tumor Type
      CharacteristicAdenocarcinoma (n = 115)Nonadenocarcinoma (n = 18)Both (N = 133)
      Female (n = 68)Male (n = 47)Total (n = 115)Female (n = 8)Male (n = 10)Total (n = 18)Total (N = 133)
      Age, mean (SD), y34 (5.0)34 (5.5)34 (5.2)33 (4.3)34 (4.9)34 (4.6)34 (5.2)
       Range, y17–3916–3916–3924–3825–3924–3916–39
       Race, n (%)
      Race was self-identified.
       White49 (72.1)36 (74.4)85 (73.9)6 (75.0)6 (60.0)12 (66.7)97 (72.9)
       Asian13 (19.1)4 (8.5)17 (14.8)0 (0.0)0 (0.0)0 (0.0)17 (12.8)
       Other
      Five patients were black, nine were Hispanic, four were South Asian, and one was North African.
      6 (8.8)7 (17.1)13 (11.3)2 (25.0)4 (40.0)6 (33.3)19 (14.3)
      Stage, n (%)
      A chi-square test was used to determine significance of stage by adenocarcinoma (p = 0.02).
       N67471147916130
       I–III15 (22.4)3 (6.4)18 (15.8)4 (57.1)5 (55.6)9 (56.3)27 (20.8)
       IV52 (77.6)44 (93.6)96 (84.2)3 (42.9)4 (44.4)7 (43.8)103 (79.2)
      Mutations, n (%)
       N6547112
      There were 115 patients with adenocarcinoma, but only 112 received genomic testing.
      7916
      There were 18 patients with nonadenocarcinoma, but only 16 received genomic testing.
      128
      ALK21 (32.3)20 (42.6)41 (36.6)0 (0.0)1 (11.1)1 (6.3)42 (32.8)
      EGFR23 (35.4)13 (27.7)36 (32.1)0 (0.0)0 (0.0)0 (0.0)36 (28.1)
      ROS17 (10.8)1 (2.1)8 (7.1)0 (0.0)0 (0.0)0 (0.0)8 (6.3)
       Other14 (21.5)13 (27.7)27 (24.1)
      Includes four patients with a RET rearrangement, three with ERBB2 mutations, and two with MET amplification.
      7 (100.0)8 (88.9)15 (93.8)
      Includes one patient with a MET amplification.
      42 (32.8)
      Family history of lung cancer, n (%)
       N604210271017119
       Yes18 (30.0)6 (14.3)24 (23.5)1 (14.3)3 (30.0)4 (23.5)28 (23.5)
       No42 (70.0)36 (85.7)78 (76.5)6 (85.7)7 (70.0)13 (76.5)91 (76.5)
      Ever smoked, n (%)
       N614310471017121
       Yes14 (23.0)11 (25.6)25 (24.0)2 (28.6)6 (60.0)8 (47.1)33 (27.3)
       No47 (77.0)32 (74.4)79 (76.0)5 (71.4)4 (40.0)9 (52.9)88 (72.7)
      Ever used marijuana, n (%)
       N604310371017120
       Yes14 (23.3)13 (30.2)27 (26.2)2 (28.6)6 (60.0)8 (47.1)35 (29.2)
       No46 (76.7)30 (69.8)76 (73.8)5 (71.4)4 (40.0)9 (52.9)85 (70.8)
      Exposure to secondhand smoke, n (%)
       N604310371017120
       Yes24 (40.0)13 (30.2)37 (35.9)3 (42.9)6 (60.0)9 (52.9)46 (38.3)
       No36 (60.0)30 (69.8)66 (64.1)4 (57.1)4 (40.0)8 (47.1)74 (61.7)
      Note: Denominators changed for several of the variables owing to missing data. Percentages may not add up to 100% owing to rounding.
      a Race was self-identified.
      b Five patients were black, nine were Hispanic, four were South Asian, and one was North African.
      c A chi-square test was used to determine significance of stage by adenocarcinoma (p = 0.02).
      d There were 115 patients with adenocarcinoma, but only 112 received genomic testing.
      e There were 18 patients with nonadenocarcinoma, but only 16 received genomic testing.
      f Includes four patients with a RET rearrangement, three with ERBB2 mutations, and two with MET amplification.
      g Includes one patient with a MET amplification.
      A total of 54 patients (41%) enrolled online. Their mean (SD) age was 34 years (5.2) (range: 17–39 y); 54% were female and 46% were male; 78% were white and 22% were minorities (Asian, n = 5; black, n = 1; Hispanic, n = 3; South Asian, n = 3). Most (81%) had stage IV disease at diagnosis, and 83% had adenocarcinoma. In comparison, among patients who enrolled at the study centers, 60% were female and 30% were minorities.

      Genomic Results

      Adenocarcinoma

      Among the 115 patients with adenocarcinoma, 112 had previous genomic testing results on study entry. Three patients did not have previous genomic testing at study entry owing to early stage disease. Of the 112 patients entering the study with genomic testing results, tumor samples from 86 (77%) harbored a targetable driver alteration. Of the 26 patients without a targetable alteration, 14 received further on-protocol F1 testing. For the remaining 12 patients, the reasons for no further on-protocol testing were as follows: not eligible owing to early stage disease (n = 4), tissue not available or not submitted (n = 6), KRAS+ (n = 1), and previous negative F1 test results on trial entry (n = 1) (Supplementary Fig. 1).
      Of the 14 patients with adenocarcinoma who underwent on-protocol F1 testing, a targetable driver alteration was identified in eight (57%), consisting two with a RET rearrangement, two with ERBB2 point mutations, two with MET amplification, one with an ALK rearrangement who had previous negative results from fluorescence in situ hybridization testing for ALK, and one with a novel EGFR-RAD51 fusion
      • Konduri K.
      • Gallant J.-N.
      • Chae Y.K.
      • et al.
      EGFR fusions as novel therapeutic targets in lung cancer.
      who had previous negative hotspot testing results for EGFR mutation.
      In summary, of 112 patients with adenocarcinoma who had previous genomic testing, 86 patients had previously identified targetable driver alterations, whereas 14 patients received on-protocol F1 testing that identified targetable alterations in an additional eight patients. Overall, of these 112 patients, 94 (84%) had a targetable driver alteration, with 85 (76%) harboring an ALK (n = 41; 37%), EGFR (n = 36; 32%), or ROS1 (n = 8; 7%) mutation or rearrangement (Fig. 1). Other drivers included RET rearrangement (n = 4; 4%), ERBB2 mutations (n = 3; 3%), and MET amplification (n = 2; 2%). Of patients who enrolled online with adenocarcinoma, 36 (80%) had one of the following targetable driver alterations: ALK rearrangement (n = 14), EGFR mutation (n = 15), ROS1 rearrangement (n = 4), RET rearrangement (n = 2), and ERBB2 mutation (n = 1).
      Figure thumbnail gr1
      Figure 1Targetable driver mutations in patients with lung adenocarcinoma. n = 112. ex19del, exon 19 deletion; ex20ins, exon 20 insertion.
      Of the 115 patients with adenocarcinoma, 84% had stage IV disease and were the focus of the comparison to historical expectations of the Lung Cancer Mutation Consortium (Table 1). In this study, 82 (85%) of these patients had tumors harboring a targetable driver alteration in ALK (n = 37), EGFR (n = 30), ERBB2 (n = 4), BRAF (n = 1), ROS1 (n = 6), or RET (n = 4). In comparison, the consortium found that the prevalence of ALK, EGFR, ERBB2, BRAF, ROS1, and MET alterations in patients with advanced lung adenocarcinoma was 35%.
      • Sholl L.M.
      • Aisner D.L.
      • Varella-Garcia M.
      • et al.
      Multi-institutional oncogenic driver mutation analysis in lung adenocarcinoma: the lung cancer mutation consortium experience.
      Among patients with adenocarcinoma, targetable alterations were analyzed by smoking status (n = 104), marijuana use (n = 103), race (n = 115), and family history of lung cancer (n = 102) (Fig. 2). Because of small cell counts, statistical significance could not be determined for these analyses. The analysis by smoking status included 79 nonsmokers and 25 smokers (Fig. 2A). Most patients with an alteration in a driver oncogene were nonsmokers versus smokers (ALK rearrangement, 77% versus 23%; EGFR mutation, 80% versus 20% versus genomic aberrations in other genes described in our study population [i.e., KRAS, ERBB2, TP53, RET, NF1], 64% versus 36%). None of the patients with ROS1+ were smokers. Cigarette smoking and marijuana use were significantly associated (p < 0.0001). Most marijuana users, approximately 70%, did not have targetable alterations. Alteration prevalence in ALK, EGFR, and other genes was similar among users (25%, 29%, and 31%, respectively) and among nonusers (75%, 71%, and 69%, respectively) (Fig. 2B). When analyzed by white (n = 85), Asian (n = 17), or other race (n = 13), most patients with alterations in ALK, EGFR, ROS1, and other were white (50%–80%). The ROS1+ group had the highest proportion of Asian patients (38%), followed by EGFR (22%) (Fig. 2C). Among patients with a family history of lung cancer (n = 24) versus without (n = 78), most patients with alterations did not have a family history of lung cancer. The ROS1+ and other groups had the highest proportion of patients with a family history of lung cancer (43% and 32%, respectively) (Fig. 2D).
      Figure thumbnail gr2
      Figure 2Genetic mutation by (A) cigarette smoking, (B) marijuana use, (C) race, and (D) family history of lung cancer. Because of small cell counts, statistical significance could not be determined for these analyses. ∗Other includes KRAS, ERBB2, TP53, RET, and NF1.

      Nonadenocarcinoma

      The 18 patients with nonadenocarcinoma consisted of nine with squamous cell carcinoma, six with SCLC, one with pulmonary blastoma, and two not otherwise specified. Among these 18 patients, 13 entered the trial with previous genomic testing results; one patient with stage IV squamous cell carcinoma harbored an ALK rearrangement. Four patients received further on-protocol F1 testing; one of these patients had a MET amplification. For the remaining patients, the reasons for no further on-protocol testing were previous negative F1 test results on trial entry (n = 4), no tissue (n = 3), and tissue not sent (n = 1) (Supplementary Fig. 1).

      Patient Spotlights

      Patient 1

      A 33-year-old white male patient with stage IV lung adenocarcinoma was tested on the F1 platform. He had never smoked and had no family history of lung cancer. F1 testing detected a 12-fold amplification of EGFR and EGFR kinase domain duplication of exons 18 to 25 (Supplementary Table 1). Similar to the more canonical L858R mutation or exon 19 deletions, this lesser-described, tandem, in-frame duplication of the EGFR tyrosine kinase is expected to be pathogenic, and the functional and therapeutic implications are being explored.
      • Gallant J.N.
      • Sheehan J.H.
      • Shaver T.M.
      • et al.
      EGFR kinase domain duplication (EGFR-KDD) is a novel oncogenic driver in lung cancer that is clinically responsive to afatinib.
      • Wang J.
      • Li X.
      • Xue X.
      • et al.
      Clinical outcomes of EGFR kinase domain duplication to targeted therapies in NSCLC.
      • Du Z.
      • Brown B.P.
      • Kim S.
      • et al.
      Structure-function analysis of oncogenic EGFR kinase domain duplication reveals insights into activation and a potential approach for therapeutic targeting.
      Of note, this patient and others have revealed response to EGFR tyrosine kinase inhibitors. Other alterations detected by F1 testing included amplifications of GNAS and ZNF217 (Supplementary Table 1).

      Patient 2

      A 36-year-old black male patient with stage IV lung adenocarcinoma was tested only for EGFR and ALK at study entry, and both were negative. The patient had never smoked and had no family history of lung cancer. Per protocol, F1 testing was performed revealing two missense alterations in ERBB2 (T862A and L869R), highlighting the importance of deeper genomic testing (Supplementary Table 1). Further analysis of NGS data revealed that both T862A and L869R, described as pathogenic mutations, were located in cis (Supplementary Table 1). Other alterations detected by F1 testing included amplification of EMSY, NFKBIA, and NKX2-1 (Supplementary Table 1). Although both testing methodologies were ERBB2-amplification negative, activating base substitutions of ERBB2 have been found to respond to anti–ERBB2-targeted therapies.
      • Chuang J.C.
      • Stehr H.
      • Liang Y.
      • et al.
      ERBB2-mutated metastatic non-small cell lung cancer: response and resistance to targeted therapies.

      Patient 3

      A 27-year-old white female patient with stage IV lung adenocarcinoma was tested with both standard genomics and the F1 platform (per protocol). The patient was a 2-pack-year smoker and had no family history of lung cancer. Both testing methodologies detected a Y163C alteration in TP53 (Supplementary Table 1). F1 testing further revealed a 36-fold amplification of MET (Supplementary Table 1). Other alterations detected by F1 testing include MAP2K4 Q93∗ and amplifications in CDK8, FLT3, and PIK3CG (Supplementary Table 1). Response to MET inhibitors has been found with focal, high copy number amplifications, albeit more often with exon 14 skipping events.
      • Wolf J.
      • Seto T.
      • Han J.
      • et al.
      Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer.
      ,
      • Camidge D.
      • Otterson G.
      • Clark J.
      • et al.
      Crizotinib in patients with MET-amplified NSCLC.

      Discussion

      This study is the first prospective, multicenter, web-based investigation of the genomics of young patients with lung cancer. In our series, patients aged less than 40 years who were diagnosed with primary NSCLC tended to be never-smokers and have stage IV adenocarcinoma. Most adenocarcinomas occurred in female patients (59%), whereas most nonadenocarcinomas occurred in male patients (56%).
      Notably, 94 of 112 patients (84%) with adenocarcinoma at any stage harbored a targetable driver alteration: 86 patients entered the study with evidence of targetable driver alterations, whereas 8 patients were found to have targetable alterations during further on-study testing. Among the patients with adenocarcinoma who underwent additional on-study comprehensive testing, more than half (8 of 14) were found to harbor an actionable alteration, including a RET rearrangement, a novel actionable EGFR fusion, and an ALK rearrangement. One of our patients with squamous NSCLC was found to harbor an ALK rearrangement on testing before study consent only after a second opinion consultation suggested testing owing to his young age and never-smoking status. This underscores the need for genomic testing with comprehensive panels that include ROS1, RET, and ERBB2 alteration in young patients with adenocarcinoma or nonadenocarcinoma, particularly as the landscape of diverse targetable alterations and approved therapies continues to expand. Among patients with stage IV adenocarcinoma, 85% had a targetable alteration, which is higher than historical expectations on the basis of the Lung Cancer Mutation Consortium and warrants further investigation.
      We observed differences and similarities between our prospective study and previous retrospective studies of young patients with lung cancer. These studies revealed a similar predominance of adenocarcinoma, but with variations in disease stages and specific targetable driver alterations (Table 2). One study had a subset of 81 patients who were younger than 40 years, with similar proportions of adenocarcinoma and female predominance.
      • Sacher A.G.
      • Dahlberg S.E.
      • Heng J.
      • Mach S.
      • Jänne P.A.
      • Oxnard G.R.
      Lung cancer diagnosed in the young is associated with enrichment for targetable genomic alterations and poor prognosis.
      Our prospective cohort had a slightly higher percentage of patients with stage IV disease (79% versus 65%) and a similar percentage of EGFR mutations in all patients (28% versus 32%) but a higher percentage of ALK rearrangements (33% versus 19%). Compared with retrospective studies, our study reveals a similar percentage of never-smokers (73%; Table 2)
      • Sacher A.G.
      • Dahlberg S.E.
      • Heng J.
      • Mach S.
      • Jänne P.A.
      • Oxnard G.R.
      Lung cancer diagnosed in the young is associated with enrichment for targetable genomic alterations and poor prognosis.
      ,
      • Liu B.
      • Quan X.
      • Xu C.
      • et al.
      Lung cancer in young adults aged 35 years or younger: a full-scale analysis and review.
      • Chen Z.
      • Teng X.
      • Zhang J.
      • et al.
      Molecular features of lung adenocarcinoma in young patients.
      • Wang Y.
      • Chen J.
      • Ding W.
      • Yan B.
      • Gao Q.
      • Zhou J.
      Clinical features and gene mutations of lung cancer patients 30 years of age or younger.
      • Tanaka K.
      • Hida T.
      • Oya Y.
      • et al.
      Unique prevalence of oncogenic genetic alterations in young patients with lung adenocarcinoma.
      • Pan X.
      • Lv T.
      • Zhang F.
      • Fan H.
      • Liu H.
      • Song Y.
      Frequent genomic alterations and better prognosis among young patients with non-small-cell lung cancer aged 40 years or younger.
      • Galvez-Nino M.
      • Ruiz R.
      • Pinto J.A.
      • et al.
      Lung cancer in the young.
      ; however, we saw greater percentages of EGFR and ALK alterations in nonsmokers.
      Table 2Comparison With Retrospective Studies
      ParameterGoYLC2020Galvez-Nino et al.25Chen et al.21Liu et al.20Pan et al.24Tanaka et al.23Sacher et al.4Wang et al.22
      Patient age evaluated<40<40<35<35<40<40
      Patients less than 40 were a subgroup within the study.
      <40
      Patients less than 40 were a subgroup within the study.
      <30
      Tumor type
       N1331668982270818141
       Adenocarcinoma, n (%)115 (86.5)105 (63.3)89 (100)37 (45.1)194 (71.8)81 (100)68 (84.0)32 (78.0)
       SCLC, n (%)6 (4.5)21 (25.9)18 (6.7)2 (4.9)
       Squamous cell, n (%)9 (6.8)13 (7.8)9 (11.0)42 (15.6)3 (3.7)1 (2.4)
      Stage
       N130137
      Patients with NSCLC only.
      8963252818139
      Patients with NSCLC only.
       I-III, n (%)27 (20.8)10 (7.3)74 (83.1)32 (50.8)84 (33.3)23 (28.4)28 (34.6)19 (48.7)
       IV, n (%)103 (79.2)116 (84.7)15 (16.9)31 (49.2)159 (63.1)58 (71.6)53 (65.4)20 (51.2)
       Unknown/other, n (%)11 (8.1)9 (3.6)
      Mutations
       N12808918
      Patients with adenocarcinoma only.
      ,
      Number of patients with data available for EGFR and ALK mutations differed between groups.
      81
      Number of patients with data available for EGFR and ALK mutations differed between groups.
      22
      Patients with adenocarcinoma only.
      EGFR, n (%)36 (28.1)19 (21.4)10 (55.6)29 (39.7)
      n = 73.
      24 (29.6)25 (32.1)
      n = 78.
      5 (22.7)
      ALK, n (%)42 (32.8)15 (16.9)5 (27.8)25 (33.8)
      n = 74.
      33 (40.7)13 (19.1)
      n = 68.
      6 (27.2)
       Mutation negative, n (%)13 (10.2)29 (32.6)3 (16.7)22 (27.1)7 (31.8)
      Smoking, n (%)
       N121137
      Patients with NSCLC only.
      8981252818141
       Smoking, n (%)33 (27.2)17 (14.4)9 (10.1)23 (28.4)48 (19.0)36 (44.4)27 (33.3)5 (12.2)
       Nonsmoking, n (%)88 (72.8)101 (73.7)80 (89.9)58 (71.6)196 (77.8)45 (55.6)54 (66.7)36 (87.8)
       Unknown/not registered, n (%)19 (13.9)8 (3.2)
      a Patients less than 40 were a subgroup within the study.
      b Patients with NSCLC only.
      c Patients with adenocarcinoma only.
      d Number of patients with data available for EGFR and ALK mutations differed between groups.
      e n = 73.
      f n = 78.
      g n = 74.
      h n = 68.
      Our study revealed a predominance of EGFR exon 19 deletions in patients with EGFR mutations (81%; Fig. 1). Retrospective studies have revealed a similar majority of EGFR exon 19 deletions, with 66% reported by Pan et al.
      • Pan X.
      • Lv T.
      • Zhang F.
      • Fan H.
      • Liu H.
      • Song Y.
      Frequent genomic alterations and better prognosis among young patients with non-small-cell lung cancer aged 40 years or younger.
      and 75% reported by Tanaka et al.
      • Tanaka K.
      • Hida T.
      • Oya Y.
      • et al.
      Unique prevalence of oncogenic genetic alterations in young patients with lung adenocarcinoma.
      Conversely, our study revealed a smaller proportion of EGFR L858R mutations (8%) compared with 31% reported by Pan et al.
      • Pan X.
      • Lv T.
      • Zhang F.
      • Fan H.
      • Liu H.
      • Song Y.
      Frequent genomic alterations and better prognosis among young patients with non-small-cell lung cancer aged 40 years or younger.
      and 17% reported by Tanaka et al.
      • Tanaka K.
      • Hida T.
      • Oya Y.
      • et al.
      Unique prevalence of oncogenic genetic alterations in young patients with lung adenocarcinoma.
      Subgroup analysis by race revealed variations within the driver alterations, with 38% of Asians having a ROS1 rearrangement and 22% having an EGFR mutation (Fig. 2C). Multiple single-center retrospective studies have evaluated the molecular features of lung cancer in young patients (Table 2).
      • Sacher A.G.
      • Dahlberg S.E.
      • Heng J.
      • Mach S.
      • Jänne P.A.
      • Oxnard G.R.
      Lung cancer diagnosed in the young is associated with enrichment for targetable genomic alterations and poor prognosis.
      ,
      • Liu B.
      • Quan X.
      • Xu C.
      • et al.
      Lung cancer in young adults aged 35 years or younger: a full-scale analysis and review.
      • Chen Z.
      • Teng X.
      • Zhang J.
      • et al.
      Molecular features of lung adenocarcinoma in young patients.
      • Wang Y.
      • Chen J.
      • Ding W.
      • Yan B.
      • Gao Q.
      • Zhou J.
      Clinical features and gene mutations of lung cancer patients 30 years of age or younger.
      • Tanaka K.
      • Hida T.
      • Oya Y.
      • et al.
      Unique prevalence of oncogenic genetic alterations in young patients with lung adenocarcinoma.
      • Pan X.
      • Lv T.
      • Zhang F.
      • Fan H.
      • Liu H.
      • Song Y.
      Frequent genomic alterations and better prognosis among young patients with non-small-cell lung cancer aged 40 years or younger.
      • Galvez-Nino M.
      • Ruiz R.
      • Pinto J.A.
      • et al.
      Lung cancer in the young.
      The predominant alterations in these studies are EGFR mutations and ALK rearrangements, although our study revealed fewer ALK rearrangements in the Asian population. Nevertheless, across all age groups, Asians have consistently been found to have higher EGFR mutation rates.
      • Han B.
      • Tjulandin S.
      • Hagiwara K.
      • et al.
      EGFR mutation prevalence in Asia-Pacific and Russian patients with advanced NSCLC of adenocarcinoma and non-adenocarcinoma histology: the IGNITE study.
      A previous study by Sacher et al.
      • Sacher A.G.
      • Dahlberg S.E.
      • Heng J.
      • Mach S.
      • Jänne P.A.
      • Oxnard G.R.
      Lung cancer diagnosed in the young is associated with enrichment for targetable genomic alterations and poor prognosis.
      found a higher prevalence of driver alterations in young patients (<40 y of age) with lung cancer than in an older population (>70 y of age): EGFR, 32% versus 23%; ALK, 19% versus 1%; ROS, 6% versus 1%.
      • Sacher A.G.
      • Dahlberg S.E.
      • Heng J.
      • Mach S.
      • Jänne P.A.
      • Oxnard G.R.
      Lung cancer diagnosed in the young is associated with enrichment for targetable genomic alterations and poor prognosis.
      Similarly, Tanaka et al.
      • Tanaka K.
      • Hida T.
      • Oya Y.
      • et al.
      Unique prevalence of oncogenic genetic alterations in young patients with lung adenocarcinoma.
      reported that patients less than 40 years of age had significant increases in EGFR exon 19 deletions (75% versus 43%; p = 0.002) and exon 20 insertions (8% versus 1%; p = 0.002) and a significant decrease in EGFR L858R mutations (17% versus 48%; p = 0.002), compared with patients more than 40 years of age. Tanaka et al.
      • Tanaka K.
      • Hida T.
      • Oya Y.
      • et al.
      Unique prevalence of oncogenic genetic alterations in young patients with lung adenocarcinoma.
      also found that the percentage of ALK rearrangements increased in patients less than 40 years of age compared with all other age groups.
      Given the rare incidence of lung cancer in young patients, we developed a website to expand our recruitment efforts. The 54 patients who enrolled by means of the website included patients from multiple states in the United States and multiple countries in Europe; a few patients were from the South Pacific, South America, and Afghanistan. This concept of “bringing the research to the patient” demonstrated in our study reveals the feasibility of using the internet to recruit patients internationally. We observed differences in enrollment demographics in the web-based population versus the study center, with slightly fewer female patients enrolling online than in study centers (54% versus 60%). The web-based population was also predominantly white (78%), with fewer minorities enrolling by means of the web compared with study centers (22% versus 30%), which may indicate unequal access to technology in some regions.
      Approximately 30% of our patients learned of the trial from patient advocacy groups. This successful foray into web-based informed consent and remote collection of data and specimens has motivated additional partnerships with patient advocacy groups for individuals with rare oncogenes (the ROS1ders,
      The ROS1ders
      Welcome to the The ROS1ders.
      EGFR Resisters,
      EGFR Lung Cancer Resisters Group
      and ALK Positive
      ALK positive.
      ). These partnerships are supporting the creation of cancer models (ROS1ders and EGFR Resisters), informing surveys on adverse effects (ROS1ders and ALK Positive) and accelerating studies on resistance mechanisms (EGFR Resisters and ALK Positive).
      Our study has several limitations. Not all patients received genomic testing from the same platform, as some genomic results were available from previous testing and some patients were given additional testing by means of the F1 platform; however, previous studies have revealed consistency of results for mutational profiling across diverse platforms.
      • Sholl L.M.
      • Aisner D.L.
      • Varella-Garcia M.
      • et al.
      Multi-institutional oncogenic driver mutation analysis in lung adenocarcinoma: the lung cancer mutation consortium experience.
      At the time of protocol development, evaluating alteration status in early stage disease was not standard of care, and we did not require this testing at study entry for these patients; however, among the 27 patients with stages I to III disease, 22 entered with study with standard genomic testing. Since this study, additional biomarkers have been identified as actionable, several with associated approved targeted therapies (e.g., NTRK, BRAF, METex14, and tumor mutational burden).
      • Stencel K.
      • Chmielewska I.
      • Milanowski J.
      • Ramlau R.
      Non-small-cell lung cancer: new rare targets-new targeted therapies-state of the art and future directions.
      ,
      Disparate access to technology in some countries may have resulted in a biased patient population for those who participated remotely. Even in the United States, access to NGS can be harder for younger patients with cancer owing to variable insurance coverage, whereas Medicare routinely covers Food and Drug Administration–approved NGS tests for older patients. Lastly, our study has limited generalizability: assessments of alteration prevalence depended on those who participated; 30% of patients were recruited by means of patient advocacy groups, although many of these groups were forming at the time of the study, and it was not necessarily established that patients had mutations in known oncogenes. Nevertheless, the alteration prevalence found in this study may not reflect a real-world population.
      In summary, we adopted a unique, web-based, patient-engaged trial design, which enabled us to recruit and enroll more young patients with lung cancer, a rare subset. Genomic testing revealed that a high percentage of these patients (84%) harbored a targetable genomic alteration. The results of our study highlight the need to prioritize comprehensive genomic testing, as targeted treatment increases patient survival.
      • Aisner D.L.
      • Sholl L.M.
      • Berry L.D.
      • et al.
      The impact of smoking and TP53 mutations in lung adenocarcinoma patients with targetable mutations—the Lung Cancer Mutation Consortium (LCMC2).
      ,
      • Kris M.G.
      • Johnson B.E.
      • Berry L.D.
      • et al.
      Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs.
      Genomics of Young Lung Cancer lays the groundwork for a planned future study, Epidemiology of Young Lung Cancer, which will build on our unique web-based, patient-engaged trial design and seek to identify risk factors related to specific genomic alterations.

      CRediT Authorship Contribution Statement

      Barbara J. Gitlitz: Conceptualization, Methodology, Supervision, Investigation, Writing—original draft preparation, Writing—reviewing and editing.
      Silvia Novello, Alicia Sable-Hunt, Tiziana Vavalà: Investigation, Writing—reviewing and editing.
      Marisa Bittoni: Investigation, Formal analysis, Visualization, Writing—original draft preparation, Writing—reviewing and editing.
      Dean Pavlick: Investigation, Formal analysis, Writing—Reviewing and Editing
      Robert Hsu, S. Lani Park: Investigation, Writing—original draft preparation, Writing—reviewing and editing.
      Ruthia Chen, Matthew Cooke, Amy Moore, Alexa B. Schrock: Investigation, Writing—reviewing and editing.
      Joan H. Schiller: Writing—reviewing and editing.
      Bonnie J Addario, Geoffrey R. Oxnard: Funding acquisition, Supervision, Writing—reviewing and editing.

      Acknowledgments

      Support for third-party writing assistance, furnished by Sarah Nordquist, PhD, and Claire Stedden, PhD, of Health Interactions, Inc., was provided by Foundation Medicine, Inc. Furthermore, this study was supported in part by the Addario Lung Cancer Medical Institute, The GO2 Foundation for Lung Cancer (includes the former Bonnie J. Addario Lung Cancer Foundation), Foundation Medicine, Inc., The Peter Barker Foundation, Beth Longwell Foundation, Schmidt Legacy Foundation, and Upstage Lung Cancer. Foundation Medicine, Inc., and the Addario Lung Cancer Medical Institute were involved in the study design and in the collection, analysis, and interpretation of the data. Clinical Trials Registry: #NCT02273336.

      Supplementary Data

      Data Sharing Statement

      Data will be made available to researchers on request.

      References

        • American Cancer Society
        Key statistics for lung cancer.
        • NIH, National Cancer Institute
        Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: lung and bronchus cancer.
        • Travis W.D.
        • Brambilla E.
        • Riely G.J.
        New pathologic classification of lung cancer: relevance for clinical practice and clinical trials.
        J Clin Oncol. 2013; 31: 992-1001
        • Sacher A.G.
        • Dahlberg S.E.
        • Heng J.
        • Mach S.
        • Jänne P.A.
        • Oxnard G.R.
        Lung cancer diagnosed in the young is associated with enrichment for targetable genomic alterations and poor prognosis.
        JAMA Oncol. 2016; 2: 313-320
        • Sholl L.M.
        • Aisner D.L.
        • Varella-Garcia M.
        • et al.
        Multi-institutional oncogenic driver mutation analysis in lung adenocarcinoma: the lung cancer mutation consortium experience.
        J Thorac Oncol. 2015; 10: 768-777
        • Konduri K.
        • Gallant J.-N.
        • Chae Y.K.
        • et al.
        EGFR fusions as novel therapeutic targets in lung cancer.
        Cancer Discov. 2016; 6: 601-611
        • Ettinger D.S.
        • Wood D.E.
        • Aisner D.L.
        • et al.
        Non–small cell lung cancer, version 5.2017, NCCN Clinical Practice Guidelines in Oncology.
        J Natl Compr Canc Netw. 2017; 15: 504-535
        • Bergethon K.
        • Shaw A.T.
        • Ignatius Ou S.-H.
        • et al.
        ROS1 rearrangements define a unique molecular class of lung cancers.
        J Clin Oncol. 2012; 30: 863-870
        • Addario Lung Cancer Medical Institute
        Genomics of Young Lung Cancer Study.
        https://alcmi.net/research/goylc-study/
        Date accessed: October 19, 2020
        • Open Medicine Institute
        https://www.openmedicineinstitute.org/
        Date accessed: October 19, 2020
        • Frampton G.M.
        • Fichtenholtz A.
        • Otto G.A.
        • et al.
        Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing.
        Nat Biotechnol. 2013; 31: 1023-1031
      1. XALKORI (crizotinib) [prescribing information]. Pfizer Inc, New York, NY2019
        • Gkountakos A.
        • Sartori G.
        • Falcone I.
        • et al.
        PTEN in lung cancer: dealing with the problem, building on new knowledge and turning the game around.
        Cancers. 2019; 11: 1141
        • Gallant J.N.
        • Sheehan J.H.
        • Shaver T.M.
        • et al.
        EGFR kinase domain duplication (EGFR-KDD) is a novel oncogenic driver in lung cancer that is clinically responsive to afatinib.
        Cancer Discov. 2015; 5: 1155-1163
        • Wang J.
        • Li X.
        • Xue X.
        • et al.
        Clinical outcomes of EGFR kinase domain duplication to targeted therapies in NSCLC.
        Int J Cancer. 2019; 144: 2677-2682
        • Du Z.
        • Brown B.P.
        • Kim S.
        • et al.
        Structure-function analysis of oncogenic EGFR kinase domain duplication reveals insights into activation and a potential approach for therapeutic targeting.
        Nat Commun. 2021; 12: 1382
        • Chuang J.C.
        • Stehr H.
        • Liang Y.
        • et al.
        ERBB2-mutated metastatic non-small cell lung cancer: response and resistance to targeted therapies.
        J Thorac Oncol. 2017; 12: 833-842
        • Wolf J.
        • Seto T.
        • Han J.
        • et al.
        Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer.
        N Engl J Med. 2020; 383: 944-957
        • Camidge D.
        • Otterson G.
        • Clark J.
        • et al.
        Crizotinib in patients with MET-amplified NSCLC.
        J Thorac Oncol. 2021; 16: 1017-1029
        • Liu B.
        • Quan X.
        • Xu C.
        • et al.
        Lung cancer in young adults aged 35 years or younger: a full-scale analysis and review.
        J Cancer. 2019; 10: 3553-3559
        • Chen Z.
        • Teng X.
        • Zhang J.
        • et al.
        Molecular features of lung adenocarcinoma in young patients.
        BMC Cancer. 2019; 19: 777
        • Wang Y.
        • Chen J.
        • Ding W.
        • Yan B.
        • Gao Q.
        • Zhou J.
        Clinical features and gene mutations of lung cancer patients 30 years of age or younger.
        PLoS One. 2015; 10e0136659
        • Tanaka K.
        • Hida T.
        • Oya Y.
        • et al.
        Unique prevalence of oncogenic genetic alterations in young patients with lung adenocarcinoma.
        Cancer. 2017; 123: 1731-1740
        • Pan X.
        • Lv T.
        • Zhang F.
        • Fan H.
        • Liu H.
        • Song Y.
        Frequent genomic alterations and better prognosis among young patients with non-small-cell lung cancer aged 40 years or younger.
        Clin Transl Oncol. 2018; 20: 1168-1174
        • Galvez-Nino M.
        • Ruiz R.
        • Pinto J.A.
        • et al.
        Lung cancer in the young.
        Lung. 2020; 198: 195-200
        • Han B.
        • Tjulandin S.
        • Hagiwara K.
        • et al.
        EGFR mutation prevalence in Asia-Pacific and Russian patients with advanced NSCLC of adenocarcinoma and non-adenocarcinoma histology: the IGNITE study.
        Lung Cancer. 2017; 113: 37-44
        • The ROS1ders
        Welcome to the The ROS1ders.
        https://ros1cancer.com/
        Date accessed: October 19, 2020
        • EGFR Lung Cancer Resisters Group
        https://egfrcancer.org/
        Date accessed: October 19, 2020
      2. ALK positive.
        https://www.alkpositive.org
        Date accessed: October 19, 2020
        • Stencel K.
        • Chmielewska I.
        • Milanowski J.
        • Ramlau R.
        Non-small-cell lung cancer: new rare targets-new targeted therapies-state of the art and future directions.
        Cancers (Basel). 2021; 13: 1829
      3. KEYTRUDA (pembrolizumab) [package insert]. Merk Sharp & Dohme Crop, Whitehouse Station, NJ2020
        • Aisner D.L.
        • Sholl L.M.
        • Berry L.D.
        • et al.
        The impact of smoking and TP53 mutations in lung adenocarcinoma patients with targetable mutations—the Lung Cancer Mutation Consortium (LCMC2).
        Clin Cancer Res. 2018; 24: 1038-1047
        • Kris M.G.
        • Johnson B.E.
        • Berry L.D.
        • et al.
        Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs.
        JAMA. 2014; 311: 1998-2006