Change in Mutation Characteristics of NSCLC Detected by Liquid Biopsy – Case Study

Using Liquid Biopsy to Guide Targeted Therapy in NSCLC Patients

Significant progress has been made in lung cancer treatment in recent years. Studies have shown that targeted therapy according to biomarkers is associated with better outcomes. Detection of mutations in EGFR,BRAF, and MET genes and rearrangements in ALK, ROS1, RET, and NTRK genes has been included in NSCLC diagnostic recommendations, and inhibitors of these pathways are recommended in therapy. Analysis of PD-L1 protein expression is also performed to decide on administering immune checkpoint inhibitors.

However, the presence of gene mutations and alterations may change during NSCLC treatment and progression. Repeated tissue biopsy is technically challenging and risky for lung cancer patients, so liquid biopsy, which captures circulating tumor DNA, is increasingly used. This minimally invasive and easily repeatable method can be effectively used to monitor changes and guide targeted therapy of NSCLC.

Case Description

A 71-year-old man was referred to an oncology clinic for evaluation of a 2 × 3 cm lesion in the upper lobe of the left lung and a large left-sided pleural effusion, which were found during an examination in the emergency department. The patient described left-sided back pain radiating to the left and to the epigastrium starting in early July 2020. He underwent comprehensive gastroenterological examination, including esophagogastroduodenoscopy and abdominal MRI, with negative results.

Later, he developed unbearable chest pain on the left side, radiating to the shoulder and neck and worsening with deep breaths. His primary care physician ordered a chest x-ray and CT scan with contrast, which showed a peribronchial lesion with distal obstructive atelectasis and pleural effusion, and referred the patient to the emergency department.

Biopsy performed in August 2020 revealed adenocarcinoma. Fluorescence in situ hybridization (FISH) found 16% of cells in the tumor tissue with ALK gene rearrangement. PET imaging showed a 3.1 × 2.2 cm tumor mass in the apex of the left lung (stage T2a) with involvement of para-aortic lymph nodes and left hilum nodes (N2) and multiple pleural metastases (M1a). Brain MRI revealed no central nervous system (CNS) metastases. This was stage IVA adenocarcinoma, and given the identified ALK rearrangement, the patient was started on the tyrosine kinase inhibitor (TKI) alectinib at a dose of 600 mg twice daily orally.

PET scan after 2 months of alectinib use showed disease progression and new bone metastases. Treatment was switched to a combination of bevacizumab/atezolizumab/carboplatin/paclitaxel. PET performed after completing 4 cycles of this therapy showed progression with > 20% increase in disease extent. Liquid biopsy found the KRAS^G12C mutation and absence of ALK rearrangement. Circulating tumor DNA was examined using next-generation sequencing (NGS) with an 83-gene panel. At that time, targeted therapy for this mutation was not yet approved. Upon further disease progression, the patient was started on the newly registered sotorasib in July 2021. In September, a mixed response to treatment was achieved. However, the disease gradually progressed, and after 4 months of sotorasib therapy, the patient was referred to hospice palliative care.

Conclusion

This case study demonstrates the clinical utility of liquid biopsy for identifying mechanisms of failure in targeted therapy of NSCLC and predicting clinical outcomes, mentioning the newly registered targeted treatment modality for patients with tumors with the KRAS^G12C mutation – sotorasib.

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Source: Sama S., Le T., Ullah A. et al. The role of serial liquid biopsy in the management of metastatic non-small cell lung cancer (NSCLC). Clin Pract 2022 Jun 10; 12 (3): 419−424, doi: 10.3390/clinpract12030046.