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Imaging of Lung Cancer in the Era of Molecular Medicine

Posted Mar 31, 2011 Updated Apr 10, 2023
By Mizuki Nishino MD , David M. Jackman MD , Hiroto Hatabu MD PhD , Pasi A. Jänne MD PhD , Bruce E. Johnson MD , Annick D. Van den Abbeele MD
23 min read

Recent discoveries characterizing the molecular basis of lung cancer brought fundamental changes in lung cancer treatment. The authors review the molecular pathogenesis of lung cancer, including genomic abnormalities, targeted therapies, and resistance mechanisms, and discuss lung cancer imaging with novel techniques. Knowledge of the molecular basis of lung cancer is essential for radiologists to properly interpret imaging and assess response to therapy. Quantitative and functional imaging helps assessing the biologic behavior of lung cancer.

Lung cancer remains the leading cause of cancer deaths for both men and women in the United States and worldwide, accounting for 30% of estimated cancer deaths in men and 26% of estimated cancer deaths in women in the United States in 2009 ( Fig 1 ) . In addition, the mortality rate of lung cancer is much higher than that of other top three causes of cancer death, including breast, prostate, and colon cancer ( Fig 2 ) . Eighty-five percent of patients with lung cancer have non-small-cell lung cancer (NSCLC), for which the 5-year survival rate is only 15% . Two thirds of patients with NSCLC present with advanced disease and are considered incurable by surgery or radiotherapy. Platinum-based doublet chemotherapy, the standard of care for these patients, is also marginally effective. It has been clear in the past decades that more effective systemic therapy is needed for patients with advanced lung cancer .

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Figure 1

Estimated cancer deaths in women in the United States in 2009.

Modified from American Cancer Society .

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Figure 2

Incidence and mortality rates for four leading causes of cancer death.

Modified from American Cancer Society .

Recent advances in molecular biology have elucidated the different molecular mechanisms of lung cancer development and progression. Some of these genetic abnormalities are specific to lung cancer, while others are present in other cancers. One of the major discoveries was the identification of somatic activating mutations of the epidermal growth factor receptor (EGFR) tyrosine kinase domain in NSCLC. The somatic mutations of EGFR are associated with a dramatic clinical response to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib . The discovery of EGFR mutations and the clinical application of this finding for the selection of therapy have transformed the way oncologists approach lung cancer and plan treatment. It is also a pragmatic example of the contributions that advances in basic molecular research have made to patient care in clinical oncology. As radiologists involved in imaging of patients with lung cancer, we should be familiar with these molecular bases of determining therapies and applications that our oncology colleagues are using. Radiologists should become familiar with the molecular background of lung cancer and its new molecular-targeted treatment approach, to properly validate, use, and apply our advanced imaging technology to diagnose, assess response, and define progressive disease. This will help radiologists contribute in a clinically significant manner as cancer imaging specialists to the management and further progress of care for patients with lung cancer.

In this review article, we describe different molecular mechanisms of the pathogenesis of lung cancer, initially focusing on EGFR mutations in NSCLC, their therapeutic application, and current challenges. The role of histology in lung cancer assessment in current clinical oncology is also discussed. We present information on different imaging approaches to lung cancer, including conventional response assessment methods and their limitations, newer quantitative and functional imaging with multi–detector row computed tomographic (CT) imaging, dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI), and combined positron emission tomographic (PET) and CT imaging. The current status of these advanced imaging techniques in lung cancer is described, their current challenges are outlined, and future directions are proposed.

Molecular mechanisms of lung cancer

EGFR Mutation and Its Inhibitors in NSCLC

The EGFR is a transmembrane tyrosine kinase receptor involved in signaling pathways of cells, and it regulates important tumorigenic processes, including proliferation, apoptosis, angiogenesis, and invasion ( Fig 3 ) . Overexpression of EGFR is frequently noted in the development and progression of NSCLC, and its presence is associated with shortened survival . To specifically target this EGFR pathway in NSCLC, small-molecule inhibitors of the tyrosine kinase domain of EGFR were developed, and erlotinib and gefitinib have been approved for therapy of patients with advanced NSCLC in different parts of the world . Subsequently, activating EGFR mutations were discovered in cancer cells from patients with NSCLC who responded to the targeted therapy with gefitinib and erlotinib .

Figure 3, Epidermal growth factor receptor (EGFR) signaling pathways and development of cancer. EGFR signaling pathways regulate important tumorigenic processes, including proliferation, apoptosis, angiogenesis, and invasion. EGF, epidermal growth factor; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homologue; RAS, rat sarcoma; STAT, signal transducer and activator of transcription; TGF-α, transforming growth factor α.

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Figure 4, Epidermal growth factor receptor ( EGFR ) and its mutations in lung cancer. Note that common mutations in adenocarcinomas, exon 19 deletions, or L858R point mutation are in the intracellular catalytic domain. ATP, adenosine triphosphate; ca., carcinoma; del, deletion; L858R, substitution of arginine for leucine at amino acid position 858; T790M, substitution of methionine for threonine at amino acid position 790.

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Figure 5, A 52-year-old female nonsmoker with lung adenocarcinoma treated with erlotinib. (a) Baseline computed tomographic scan prior to erlotinib therapy demonstrated a dominant mass in the right upper lobe with innumerable metastatic nodules. Epidermal growth factor receptor ( EGFR ) gene sequencing of the tumor showed EGFR mutation with exon 19 deletion. (b) After one cycle (2 months) of therapy, the mass was significantly decreased in size, and the nodules were markedly decreased in size and number, representing partial response. (c) After two cycles (4 months) of therapy, a further decrease in size of the mass was noted. The nodules had mostly resolved. The patient remained progression free after 2.5 years, with a minimal amount of residual disease at the site of the dominant mass.

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Rat Sarcoma ( RAS ) Mutations in NSCLC

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Figure 6, Rat sarcoma ( RAS ) mutation in non-small-cell lung cancer. RAS mutations result in inhibition of this guanosine-5′-triphosphate (GTP)–ase activity, which normally switches off RAS-GTP and leads to the constitutive activation of RAS protein and subsequent tumor cell proliferation. EGFR, epidermal growth factor receptor. EGFR, epidermal growth factor receptor; Grb-2, growth factor receptor-bound protein 2; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; STAT, signal transducer and activator of transcription; SOS, son of sevenless homolog; RAS, rat sarcoma.

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Figure 7, A 77-year-old woman with poorly differentiated adenocarcinoma of the lung. (a) An irregular and heterogeneous left upper lobe mass with invasion to the mediastinal fat was noted on the baseline study. (b) Follow-up computed tomographic scan of the chest after one cycle of erlotinib therapy demonstrated marked increase in size with new pleural effusion, representing progressive disease. Genomic testing of the tumor was negative for epidermal growth factor receptor mutation and positive for Vi-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutation.

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Table 1

Predictors of Sensitivity to Erlotinib Therapy in Non-Small-Cell Lung Cancer

Modified from Mol Oncol Rep .

Positive Predictors Clinical Molecular Nonsmoker status_EGFR_ mutations (exon 19 deletions, L858R point mutations) Asian ethnicity_EGFR_ gene amplification (FISH or CISH) Female gender EGFR protein expression on immunohistochemistry Adenocarcinoma/BAC histology MALDI-ToF algorithm

Negative predictors_KRAS_ mutations T790M mutations Exon 20 insertion mutations

BAC, bronchioloalveolar cell carcinoma; CISH, chromogenic in situ hybridization; FISH, fluorescence in situ hybridization; KRAS , Vi-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; L858R, substitution of arginine for leucine at amino acid position 858; MALDI-ToF, matrix-assisted laser desorption/ionization–time of flight; T790M, substitution of methionine for threonine at amino acid position 790.

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Acquired Resistance to Erlotinib

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Figure 8, Mechanism of acquired resistance to erlotinib: mesenchymal-epithelial transition factor (MET) amplification. Amplification of MET provides redundant signaling, and tumor cells survive despite epidermal growth factor receptor (EGFR) inhibition. EGFR, epidermal growth factor receptor; ERK, extracellular-signal-regulated kinase; MET, mesenchymal-epithelial transition factor; PI3K, phosphatidylinositol 3-kinase; STAT, signal transducer and activator of transcription.

Figure 9, A 55-year-old lifelong female nonsmoker with advanced lung adenocarcinoma. (a) Baseline computed tomographic (CT) scan of the chest demonstrated a spiculated mass in the right upper lobe. (b) CT scan after 2 months of erlotinib therapy showed a significant decrease in size of the lesion, demonstrating response to erlotinib. (c) The patient continued on erlotinib therapy. After 38 months, a slight increase in size of the tumor was noted. However, the change in tumor size did not meet the criteria for progressive disease by the Response Evaluation Criteria in Solid Tumors (RECIST). (d) After 44 months of therapy, the size increase of the lesion met the criteria for progressive disease of RECIST. Genomic testing of the recurrent tumor showed T790M (substitution of methionine for threonine at amino acid position 790) mutation.

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Histology and genomic mutation as markers for therapy

Assessment of Lung Cancer in the New Era of Molecular Medicine

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Figure 10, Assessment of lung cancer in the era of molecular medicine. (a) Conventional assessment was based on histology, simply dividing tumors into small-cell and non-small-cell categories. For advanced non-small-cell cancer, the therapeutic regimen was essentially the same despite various subtypes. (b) In the current era of molecular medicine, the assessment of lung cancer starts with mutation testing to determine if the patient can be treated with specific targeted therapy. EGFR , epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.

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Histology as a Marker for Therapy

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Table 2

Histology and Genomic Mutations in Lung Cancer

Histology Genomic Mutations Adenocarcinoma (50%)EGFR , KRAS , TP53 , STK11 , CDKN2A , ERBB-2 Squamous cell carcinoma (20%) SOX2 amplification , EGFR VIII Small-cell lung cancer (15%)TP53 , RB1 , Myc gene amplification , nontargetable oncogene

CDKN2A , cyclin-dependent kinase inhibitor 2A; ERBB-2 , erythroblastic leukemia viral oncogene homolog 2; RB1 , retinoblastoma 1; SOX2, sex-determining region Y–box 2; STK11 , serine/threonine kinase 11; TP53 , tumor protein 53.

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Genomewide Approach to Characterize Lung Cancer Genomes

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Lung cancer imaging in assessment of response to therapy

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Response Assessment on the Basis of Size Measurement

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Figure 11, Tumor measurement by World Health Organization (WHO) criteria and Response Evaluation Criteria in Solid Tumors (RECIST). Computed tomographic scan of the chest demonstrates a lobulated mass in the left lower lobe representing lung cancer. Using the WHO criteria, the measurement for the lesion would be A × B cm 2 . Using RECIST, the measurement would be A cm, the longest diameter of the lesion.

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Tumor Volume Measurement Using Multidetector CT Imaging

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Figure 12, Computed tomographic (CT) volume measurement in non-small-cell lung cancer. (a) CT scan of the chest demonstrated an irregular mass in the left lower lobe. Using three-dimensional segmentation algorithm of a commercially available volume analysis software (Vitrea; Vital Images, Minnetonka, MN), the lesion was segmented from the rest of the structures. (b,c) The segmented lesion is displayed in three-dimensional manner, and the volume and CT attenuation of the tumor are obtained.

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Figure 13, Irregular lung mass abutting vessels and bronchi. Computed tomographic scans of the chest in a patient with advanced non-small-cell lung cancer demonstrate an irregular mass closely abutting vessels and bronchi in the lung. To measure the volume of the mass, it is necessary to separate the tumor from adjacent vessels and bronchi.

Figure 14, Cavitary lung lesion. Cavitation in lung lesions can be seen at the baseline or after therapy and presents significant technical challenges for volume measurement software.

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DCE MRI

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Figure 15, Dynamic contrast-enhanced magnetic resonance imaging of a lung nodule representing non-small-cell lung cancer. (a) Sequential images of the nodule were acquired on sagittal plane (1 image/2 s). (b) Enhancement measured on signal intensity was plotted over time as a time-intensity curve.

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PET/CT Imaging

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Figure 16, An 82-year-old man with squamous cell lung cancer. (a,b) Baseline 18 F–fluorodeoxyglucose (FDG) positron emission tomographic (PET)/computed tomographic (CT) imaging demonstrated a spiculated mass in the left upper lobe with intense FDG uptake. (c,d) Follow-up 18 F-FDG PET/CT imaging after CyberKnife therapy showed significant decreases in size and FDG uptake of the lesion.

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Multiparametric Approach for Tumor Response Assessment

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Conclusions

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Academic Radiology, Volume 18, Issue 4
Journals General Radiology
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