Lung Cancer

Exploring dysfunctional pathways, mechanisms, and biomarkers in lung cancer to discover new insights into the progression of the disease.

0

of the total number of cancer-related deaths worldwide are caused by lung cancer1

0

5-year survival rate of NSCLC from diagnosis2,3

Incidence & Mortality

Lung cancer is the leading cause of overall cancer-related mortality throughout the world.1

  • Lung cancer accounts for 19.8% of the total number of cancer-related deaths.1
  • In the United States, lung cancer has the second-highest incidence in both men and women.4

Overview

NSCLC comprise 80% of all lung cancers and are associated with poor prognosis and limited treatment options beyond platinum chemotherapy.5-7

  • Three major morphologic subtypes of NSCLC2,8-10:
    • Squamous cell NSCLC (sqNSCLC) - ~25% to 31%
    • Non-squamous cell NSCLC (NsqNSCLC) adenocarcinoma - ~37% to 50%
    • Other NsqNSCLC (including adenosquamous carcinomas, large cell carcinomas, and neuroendocrine tumors) - ~19% to 25%

Mechanism of Disease

sqNSCLC arise centrally in thin, flat squamous cells within the large bronchi and are usually associated with smoking.10

NsNsqNSCLC adenocarcinomas arise in the peripheral epithelial tissue and primarily have a lepidic, acinar, papillary, or mucinous morphology.8 Approximately 75% of adenocarcinomas are associated with smoking.10

Large cell carcinomas lack morphologic or immunohistochemistry evidence of clear lineage.2,8

Adenosquamous carcinomas are tumors with mixed adenocarcinoma and squamous cell carcinoma components, each being at least 10% of the tumor.2,8

Development involves a multistep process that includes multiple genetic and epigenetic alterations, particularly activation of growth-promoting pathways and inhibition of tumor-suppressing pathways.11-13

  • Mutations in KRAS, EGFR, MEK, and HER2 genes
  • Alterations in BRAF, PIK3, and PARP pathways
  • Amplification of FGFR1 and DDR2 genes
  • Structural rearrangements in ALK, ROS1, and RET

Dysregulation of DNA repair is also associated with platinum resistance in NSCLC.14,15

  • Significantly correlates with the relative risk of death in patients with NSCLC who are treated with chemotherapy

Diagnosis & Staging

All NSCLC should be classified into specific pathologic subtypes based on the specific histologic and genetic characteristics of the patient's tumor using the 2015 WHO Guidelines8 In the era of personalized medicine and targeted therapies, this can determine eligibility for certain types of molecular testing and therapeutic strategies.8

Challenges in Treatment

More than 75% of patients are diagnosed at an advanced stage (III or IV).16

  • Advanced-stage NSCLC at diagnosis is a strong predictor of poor prognosis and high mortality.16,17
  • Advanced lung cancer patients typically have poor performance status at diagnosis and cannot tolerate aggressive chemotherapy18
  • Choice of treatment is often driven by biomarkers associated with the patient's specific tumor biology.
  • In patients for whom targeted agents are unavailable, platinum-based chemotherapy is the recommended first-line therapy.18

Squamous and non-squamous histologies may react differently to similar therapies.

  • Some therapies may have different safety profiles and clinical outcomes depending on the histologic subtype of NSCLC present.

Five-year survival in patients with NSCLC is <20%.17

  • Patients with sqNSCLC have worse overall survival (OS) than patients with adenocarcinoma.9,10

Overview

SCLC is classified as a high-grade pulmonary neuroendocrine tumor (NET).19,20 It is among the 20% of lung tumors that exhibit neuroendocrine differentiation.19,20

  • SCLC accounts for approximately 13% of all lung cancers.21
  • Large cell neuroendocrine carcinoma (LCNEC) accounts for 3% of all lung cancers.

The most aggressive form of lung cancer, SCLC has an overall 5-year survival rate of <7%.21

Mechanism of Disease (SCLC)

Normal adult lung epithelium contains several distinct progenitor and stem cell populations.22 High-grade pulmonary neuroendocrine tumors (NETs) are believed to develop from neuroendocrine progenitor cells that have acquired mutations.22

  • These most often develop from exposure to carcinogens in cigarette smoke.22
  • High-grade NETs are characterized by a rapid doubling time, high growth fraction, and early development of metastases.23,25

SCLC has one of the highest mutation rates compared to other tumor types, per comprehensive sequencing studies.24

  • SCLC tumor cells overexpress transcription factors critical for normal primary neuroendocrine cell development22
    • ASCL1, NEUROD1, SOX2, TTF1, Myc family
  • Tumor suppressors TP53 and RB1 (loss of function) and proto-oncogene Myc family members (upregulation) appear mutated in nearly all SCLC tumors.22
    • Inactivating mutations in NOTCH family genes have been observed in 25% of human SCLC.25
    • KRAS mutations are rare or non-existent.22

High-grade NETs are characterized by a rapid doubling time, high growth fraction, and early development of metastases25

Diagnosis & Staging

TNM system for staging SCLC is used in clinical trials. Veterans Administration Lung Study Group's (VALG) system of limited stage (LS) vs. extensive stage (ES) is most commonly used for clinical decision-making.26,27

  • LS-SCLC: disease confined to the ipsilateral hemithorax (can be safely encompassed within a radiation field)
  • ES-SCLC: disease spread beyond the ipsilateral hemithorax and cannot be included in a single radiation field
    • Approximately two-thirds of patients present with ES-SCLC
    • ES-SCLC is an aggressive, rapidly progressing disease with a poor prognosis

Accurate staging is critical to provide important prognostic information and determine appropriate treatment approach.26,27

Treatment Challenges

Overall, the 5-year relative survival for patients with SCLC is only 6.4%.21

  • Most patients present with ES-SCLC at diagnosis.27,28
    • Median survival for ES-SCLC: 8 to 13 months
    • Median survival for LS-SCLC: 15 to 20 months
  • First-line therapeutic options have remained largely unchanged for more than 40 years.27,29
    • The 2-year survival rate for ES-SCLC has only improved by 2.2% (from 3.4% to 5.6%) between 1973 and 2002.30
  • Most patients develop chemoresistance and will suffer relapse within months of completing platinum-based chemotherapy.19,29 For patients who relapse <3 months after first-line therapy, treatment options are usually limited to palliative care.30,31
    • Median survival for these patients is only 4 to 5 months after treatment.

Non-Small Cell Lung Cancer

Targeted therapies are presently available for about 25% of adenocarcinoma patients.32 Additional targeted therapies that may be effective for more patients and therapies that overcome chemoresistance are primary clinical needs for patients with NSCLC.

Small Cell Lung Cancer

Despite the advances in personalized medicine in recent years, there are no biomarker-guided therapies currently available to target SCLC tumor cells.27

Recent technological advances, such as patient-derived xenografts (PDX) and next-generation sequencing, will allow the study of expressed biomarkers and the identification of potential targets.33,34

Relevant Biomarker Pathways

  1. Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, Barber RM, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability adjusted life-years for 32 cancer groups, 1990 to 2015: A systematic analysis for the Global Burden of Disease Study. JAMA Oncol. 2017;3(4):524-548.
  2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.1.2018. ©2017 National Comprehensive Cancer Network, Inc. All rights reserved. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org.
  3. Cancer Stat Facts: Lung and Bronchus Cancer. National Cancer Institute: Surveillance, Epidemiology, and End Results Program. https://seer.cancer.gov/statfacts/html/lungb.html. Updated April 2017. Accessed November 2017.
  4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7-30.
  5. Ardizzoni A, Boni L, Tiseo M, et al. Cisplatin- versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis. J Natl Cancer Inst. 2007;99:847-857.
  6. Cheng H, Zhang Z, Borczuk A, et al. PARP inhibition selectively increases sensitivity to cisplatin in ERCC1-low non-small cell lung cancer cells. Carcinogenesis. 2013;34(4):739-749.
  7. Johnson DH, Schiller JH, Bunn PA. Recent clinical advances in lung cancer management. J Clin Oncol. 2014;32(10):973-982.
  8. Travis WD, Brambilla E, Nicholson AG, et al. The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol. 2015;10(9):1243-1260.
  9. Cetin K, Ettinger ES, Hei Y, O'Malley CD. Survival by histologic subtype in stage IV nonsmall cell lung cancer based on data from the Surveillance, Epidemiology and End Results Program. Clin Epidemiol. 2011;3:139-148.
  10. Pandiri A. Comparative pathobiology of environmentally induced lung cancers in humans and rodents. Toxicol Pathol. 2015;43(1):107-114.
  11. Stead LF, Egan P, Devery A, et al. An integrated inspection of the somatic mutations in a lung squamous cell carcinoma using next-generation sequencing. PLoS One. 2013;8(11):1-8.
  12. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489(7417):519-525.
  13. Heist RS, Sequist LV, Engelman JA. Genetic changes in squamous cell lung cancer: a review. J Thorac Oncol. 2012;7(5):924-933.
  14. Bosken CH, Wei Q, Amos CI, Spitz MR. An analysis of DNA repair as a determinant of survival in patients with non-small-cell lung cancer. J Natl Cancer Inst. 2002;94(14):1091-1099.
  15. Zeng-Rong N, Paterson J, Alpert L, et al. Elevated DNA repair capacity is associated with intrinsic resistance of lung cancer to chemotherapy. Cancer Res. 1995;55:4760-4764.
  16. Slatore CG, Gould MK, Deffeback ME, White E. Lung cancer stage at diagnosis: individual associations in the prospective VITamins and lifestyle (VITAL) cohort. BMC Cancer. 2011;11:228.
  17. Kelsey CR, Werner-Wasik M, Marks LB. Stage III lung cancer: two or three modalities? The continued role of thoracic radiotherapy. Oncology (Williston Park). 2006;20(10):1210-1219; discussion 1219, 1223, 1225.
  18. Lwin Z, Weirss JR, Gandara D. The continuing role of chemotherapy for advanced non-small cell lung cancer in the targeted therapy era. J Thorac Dis. 2013;5(S5):S556-S564
  19. Koinis F, Kotsakis A, Georgoulias V. Small cell lung cancer (SCLC): no treatment advances in recent years. Transl Lung Cancer Res. 2016;5(1):39-50.
  20. Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas. 2010;39(6):707-712.
  21. Howlader N, Noone AM, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975-2012. National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2012/, based on November 2014 SEER data submission, posted to the SEER website, April 2015.
  22. Karachaliou N, Pilotto S, Lazzari C, Bria E, de Marinis F, Rosell R. Cellular and molecular biology of small cell lung cancer: an overview. Transl Lung Cancer Res. 2016;5(1):2-15.
  23. Gustafsson BI, Kidd M, Chan A, Malfertheiner MV, Modlin IM. Bronchopulmonary neuroendocrine tumors. Cancer. 2008;113(1):5-21.
  24. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Cancer genome landscapes. Science. 2013;339(6127):1546-1558.
  25. George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524(7563):47-53
  26. Kalemkerian GP, Gadgeel SM. Modern staging of small cell lung cancer. J Natl Compr Canc Netw. 2013;11(1):99-104.
  27. Byers LA, Rudin CM. Small cell lung cancer: where do we go from here? Cancer. 2015;121(5):664-672.
  28. van Meerbeeck JP, Fennell DA, De Ruysscher DKM. Small-cell lung cancer. Lancet. 2011;378:1741-1755.
  29. Pietanza MC, Byers LA, Minna JD, Rudin CM. Small cell lung cancer: will recent progress lead to improved outcomes? Clin Cancer Res. 2015;21(10):2244-2255.
  30. Alvarado-Luna G, Morales-Espinosa D. Treatment for small cell lung cancer, where are we now? A review. Transl Lung Cancer Res. 2016;5(1):26-38.
  31. Codony-Servat J, Verlicchi A, Rosell R. Cancer stem cells in small cell lung cancer. Transl Lung Cancer Res. 2016;5(1):16-25.
  32. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014;311(19):1998-2006.
  33. Codony-Servat J, Rosell R. Cancer stem cells and immunoresistance: clinical implications and solutions. Transl Lung Cancer Res. 2015;4(6):689-703.
  34. Valent P, Bonnet D, De Maria R, et al. Cancer stem cell definitions and terminology: the devil is in the details. Nat Rev Cancer. 2012;12(11):767-775.

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