Exploring dysfunctional pathways, mechanisms, and biomarkers in lung cancers
to discover new insights into the progression of the disease.
INCIDENCE & MORTALITY
Lung cancer (including tracheal and bronchus cancers) is the leading cause of overall cancer-related mortality throughout the world, accounting for 18.0% of the total number of cancer-related deaths.1 In the United States, lung cancer has the second-highest incidence of all cancers in both men and women.4
There are two main categories of lung cancer: non-small cell lung cancer and small cell lung cancer.3
NSCLC comprises ~85% of all lung cancers and are associated with poor prognosis and limited treatment options beyond platinum chemotherapy.5-7 NSCLC has different morphologic subtypes, defined by the type of cancerous cells and the unique growth and spread of the malignancy: 2,8-10, 39
- Squamous cell carcinoma (also called epidermoid carcinoma), represents ~25% to 31% of NSCLC
- Large cell (undifferentiated) carcinoma: Cancer that may begin in several types of large cells, represents ~5-10% of NSCLC
- Adenocarcinoma: Cancer that begins in the cells that line the alveoli and make substances such as mucus, represents ~40% to 50% of NSCLC
- Other less common subtypes of NSCLC: adenosquamous carcinoma, sarcomatoid carcinoma, neuroendocrine tumors
Mechanism of Disease
Squamous NSCLC arise centrally in thin, flat squamous cells within the large bronchi and are usually associated with smoking.10
- 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.2,11-13
- Alterations in RAS, PI3K/AKT, and RTK pathways
- Mutations in BRAF, KRAS, P53, NRF2, PTEN, EGFR, MET, and HER2 genes
- Amplification of FGFR1, SOX, and PIK3CA 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 Guidelines.8 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 chemotherapy.18
- 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 has typically been the recommended first-line therapy.2,18
- With encouraging clinical activity, immune checkpoint inhibitors are evolving to play a key role in treatment, especially in patients who are PD-L1-positive (TPS ≥ 50%) or have disease without a targetable mutation.7
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.
The 5-year survival rate for patients with NSCLC is <20%.3
- Patients with sqNSCLC have worse overall survival (OS) than patients with adenocarcinoma.9,10
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 development.22
- ASCL1, NEUROD1, SOX2, TTF1, Myc family
- Expression of ASCL1 and NEUROD1 are mutually exclusive in SCLC cell lines.22
- PARP1 and EZH2 were the most overexpressed proteins in SCLC in a study comparing significant differences in signaling pathways between SCLC and NSCLC.22
Tumor suppressors TP53 and RB1 (loss of function) and proto-oncogene Myc family members (upregulation) appear mutated in nearly all SCLC tumors.22,25
- Inactivating mutations in NOTCH family genes have been observed in 25% of human SCLC.22,25 Studies have shown DLL3, a NOTCH ligand, may be associated with the neuroendocrine phenotype and contribute to neuroendocrine tumorigenesis.22
- High DLL3 protein expression was found in approximately two-thirds of SCLC patients and was associated with long lasting stable disease.22
- KRAS mutations are rare or non-existent.22
Diagnosis & Staging
TNM system for staging SCLC is used in clinical trials. Veterans Administration Lung Study Group's (VALG) system of limited-stage disease (LD) vs. extensive-stage disease (ED) is most commonly used for clinical decision-making.26,27
- LD-SCLC: disease confined to the ipsilateral hemithorax (can be safely encompassed within a radiation field)
- ED-SCLC: disease spread beyond the ipsilateral hemithorax and cannot be included in a single radiation field
- Approximately two-thirds of patients present with ED-SCLC
- ED-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
Overall, the 5-year relative survival for patients with SCLC is only 6.4%.21
Most patients present with ED-SCLC at diagnosis.27,28
- Median survival for ED-SCLC: 8 to 13 months
- Median survival for LD-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 ED-SCLC has only improved by 2.2% (from 3.4% to 5.6%) between 1973 and 2002.30
Although SCLC is characterized by a high mutation rate, typically it harbors loss of function mutations or deletions in tumor suppressor genes and is not susceptible to selective targeted inhibition.22,25
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, while the majority of the patients with advanced NSCLC do not harbor a targetable driver mutation.32 For these patients, strategies to improve the efficacy of chemotherapy is an unmet need.35
Immune checkpoint inhibitors have demonstrated distinctly durable responses and represent the advent of a new treatment approach for patients with NSCLC, especially for those whose tumors are PD-L1-positive (TPS ≥ 1%) and lack targetable mutations.7
Combination therapies also hold promise to address the unmet need of treatment for patients unfit or resistant/refractory to current treatment options for NSCLC.36
Small Cell Lung Cancer
Chemotherapy improves the survival of patients with limited-stage disease (LD) or extensive-stage disease (ED), but it is curative in only a minority of patients. Immune checkpoint inhibitors in combination with chemotherapy have also demonstrated improved outcomes in SCLC patients. Despite treatment advances, most patients with SCLC die of their tumor even with the best available therapy. Most of the improvements in the survival of patients with SCLC are attributable to clinical trials that have attempted to improve on the best available and most accepted therapy.37
Given that immunotherapy drugs, targeted therapy drugs, and chemotherapy drugs act on different targets and cells, synergistic or combined treatment of these drugs may achieve greater therapeutic effects for SCLC; the success of this strategy will require the use of validated biomarkers to select patients most likely to benefit from such strategy.38
- Global Burden of Disease Cancer Collaboration; Sung H; Ferlay J, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: Cancer J. Clin. 2021;71(3):209-249.
- NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.5.2019. ©2019 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.
- 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 2018. Accessed September 2021.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.
- 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.
- 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.
- Brahmer JR, et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC). Journal for ImmunoTherapy of Cancer. (2018) 6:75.
- 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.
- 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.
- Pandiri A. Comparative pathobiology of environmentally induced lung cancers in humans and rodents. Toxicol Pathol. 2015;43(1):107-114.
- 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.
- Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489(7417):519-525.
- Heist RS, Sequist LV, Engelman JA. Genetic changes in squamous cell lung cancer: a review. J Thorac Oncol. 2012;7(5):924-933.
- 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.
- 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.
- 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.
- 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. (remove?)
- 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.
- 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.
- 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.
- 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.
- 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.
- Gustafsson BI, Kidd M, Chan A, Malfertheiner MV, Modlin IM. Bronchopulmonary neuroendocrine tumors. Cancer. 2008;113(1):5-21.
- Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Cancer genome landscapes. Science. 2013;339(6127):1546-1558.
- George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524(7563):47-53.
- Kalemkerian GP, Gadgeel SM. Modern staging of small cell lung cancer. J Natl Compr Canc Netw. 2013;11(1):99-104.
- Byers LA, Rudin CM. Small cell lung cancer: where do we go from here? Cancer. 2015;121(5):664-672.
- van Meerbeeck JP, Fennell DA, De Ruysscher DKM. Small-cell lung cancer. Lancet. 2011;378:1741-1755.
- 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.
- 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.
- Codony-Servat J, Verlicchi A, Rosell R. Cancer stem cells in small cell lung cancer. Transl Lung Cancer Res. 2016;5(1):16-25.
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- Ramalingam SS, et al. Randomized, Placebo-Controlled, Phase II Study of Veliparib in Combination with Carboplatin and Paclitaxel for Advanced/Metastatic Non–Small Cell Lung Cancer. Clin Cancer Res. 2017;23(8).
- Zhang et al. Emerging therapies for non-small cell lung cancer. Journal of Hematology & Oncology. (2019) 12:45.
- Liu SV, et al. Updated Overall Survival and PD-L1 Subgroup Analysis of Patients With Extensive-Stage Small-Cell Lung Cancer Treated With Atezolizumab, Carboplatin, and Etoposide (IMpower133). J Clin Oncol. 2021;39(6):619-630.
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- Zappa C, et al. Non-small cell lung cancer: current treatment and future advances. Transl Lung Cancer Res. 2016 Jun; 5(3): 288–300.