Elsevier

Human Pathology

Volume 45, Issue 12, December 2014, Pages 2379-2387
Human Pathology

Original contribution
Molecular alterations in non–small cell lung carcinomas of the young

https://doi.org/10.1016/j.humpath.2014.08.005Get rights and content

Summary

Lung cancer is the leading cause of cancer death in the United States. Gene alterations are significant in lung tumorigenesis, with certain genes (Kristen rat sarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], and B-Raf proto-oncogene, serine/threonine kinase (BRAF)) possessing alterations important in the prognosis and treatment of lung adenocarcinoma. Mutation frequencies are affected by different patient factors, such as smoking history, age, and race. Because most lung cancers occur in patients older than age of 50 years, few studies have examined molecular alterations present in these younger patients. The pathology database was searched for patients age of 50 years or younger with non–small cell lung carcinomas (NSCLCs) tested for EGFR, ALK, KRAS, and/or BRAF alterations. A total of 53 cases were identified. The mean patient age was 44.4 years old, and there were 19 men and 34 women. Of the tumors, 11.6% had ALK rearrangements, 25.5% had KRAS mutations, and 20.0% had EGFR mutations. No BRAF mutations were identified in the 28 cases tested. All but 1 (92% [12/13]) tumor with KRAS mutation were from women patients. A smoking history of greater than 5 pack-years was associated with KRAS mutations and negatively associated with EGFR mutations and ALK translocation. The frequencies of EGFR mutation and ALK translocation in the study cohort are greater than the reported frequencies among NSCLC from adults of all ages in the United States but less than the reported frequencies among NSCLC from East Asian young adults. The frequency of KRAS mutation is significantly greater than what was previously found in young Japanese patients.

Introduction

Lung cancer is the leading cause of cancer death in the United States. Non–small cell lung carcinoma (NSCLC) constitutes 85% to 90% of all lung carcinomas with a median patient age of 70 years old [1]. Mutations in epidermal growth factor receptor (EGFR), KRAS, anaplastic lymphoma kinase (ALK), and BRAF affect the prognosis and treatment of lung adenocarcinoma. The frequencies of these alterations are associated with different patient factors, such as smoking history, sex, race, and age [2], [3], [4], [5], [6], [7]. However, because most lung cancers occur in patients older than age of 50 years, few studies have examined molecular alterations present in a younger cohort [2], [3].

Malignancies affecting young adults can differ significantly from those that arise in older adults. These include differences in tumor morphology, molecular alterations, prognosis, and response to treatment [2], [3], [8], [9], [10], [11]. Excluding pediatric malignancies, a significant risk factor for many cancers is age, and malignancy is rare in adults below the age of 50 years [1]. However, a cancer diagnosis in this group can be particularly devastating, often leading to a greater loss of longevity and quality of life for a given individual [12]. Although inherited genetic syndromes can result in malignancy at an earlier age, for many malignancies, it is unknown which factors contribute most to their early development.

The recently established molecular alterations in lung adenocarcinoma not only provide an understanding of tumorigenesis but are also strongly connected with patient prognosis and treatment. In this retrospective study, we examine the frequency of ALK, KRAS, EGFR, and BRAF mutations in 53 patients who developed NSCLC at or below the age of 50 years.

Section snippets

Database search

Permission to conduct the study and an informed consent waiver were obtained from the institutional review board. The pathology database was searched for patients below the age of 50 years old with NSCLC who underwent testing for EGFR, ALK, KRAS, and/or BRAF gene alterations. A total of 57 cases were identified, 53 of which were ultimately diagnosed as NSCLC. The cases spanned a period of approximately 4 years, from January 2010 to 2014.

Molecular testing before February 2013

All specimens were clinical samples submitted to our

Description of the study population

Fifty-three cases of NSCLC in patients age of 50 years or younger were identified in the pathology database (Table 1, Table 2). There was a predominance of women (64%). The average patient age at the time of diagnosis was 44.4 years, with a range between ages of 28 and 50 years old. Most patients were white (60%) or black (28%), with only 1 Asian patient (2%) and 5 patients of another or unknown race (10%). Patients with a greater than 5 pack-year history of smoking comprised 53% of all

Discussion

Activating EGFR mutations are most commonly found in nonsmokers, women, and patients of Asian descent. EGFR mutations are often associated with lepidic growth and a micropapillary pattern on histology [16], but histology is a poor predictor of mutation (Fig. 2C and D). Patients with activating EGFR mutations can be treated with EGFR tyrosine kinase inhibitors (TKI) [17]. When patients of all ages are considered, various studies have demonstrated EGFR mutation frequencies between 2% and 20% in

References (46)

  • S.Y. Lee et al.

    Somatic mutations in epidermal growth factor receptor signaling pathway genes in non-small cell lung cancers

    J Thorac Oncol

    (2010)
  • A. Helland et al.

    EGFR gene alterations in a Norwegian cohort of lung cancer patients selected for surgery

    J Thorac Oncol

    (2011)
  • B. Gao et al.

    Spectrum of LKB1, EGFR, and KRAS mutations in chinese lung adenocarcinomas

    J Thorac Oncol

    (2010)
  • K. Shinmura et al.

    EML4-ALK fusion transcripts, but no NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts, in non-small cell lung carcinomas

    Lung Cancer

    (2008)
  • N. Howlader et al.

    SEER Statistics Review, 1975–2010

    (2013)
  • O. Nagashima et al.

    High prevalence of gene abnormalities in young patients with lung cancer

    J Thorac Dis

    (2013)
  • G.J. Riely et al.

    Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma

    Clin Cancer Res

    (2008)
  • Y. Sun et al.

    Lung adenocarcinoma from East Asian never-smokers is a disease largely defined by targetable oncogenic mutant kinases

    J Clin Oncol

    (2010)
  • J.G. Paez et al.

    EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy

    Science

    (2004)
  • P.K. Paik et al.

    Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations

    J Clin Oncol

    (2011)
  • R. Gryfe et al.

    Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer

    N Engl J Med

    (2000)
  • R. Alvarado et al.

    Biology, Treatment, and Outcome in Very Young and Older Women with DCIS

    Ann Surg Oncol

    (2012)
  • N.E. Avis et al.

    Quality of life among younger women with breast cancer

    J Clin Oncol

    (2005)
  • Cited by (0)

    Competing interests: Dr Ettinger is a consultant for Gilead, Foster city, CA, USA, Roche/Genetech, San Francisco, CA, USA, Boehringer Ingelheim, Fremont, CA, USA, Biodesix, Boulder, CO, USA, Lilly, Indianapolis, IN, USA, and Helsinn Pharmaceutical, Mulhuddart, Dublin, Germany. There are no additional current financial disclosures from any other authors. No payment or support was received for any aspect of the submitted work. The authors have no conflicts of interest to report.

    View full text