Molecular Therapeutics of Non-Small Cell Lung Cancer (NSCLC) and Challenges in Repeat Tissue Biopsy

Abstract

With advances in targeted and personalized treatment for lung cancer, molecular analysis of tumors is routinely performed for sequencing of treatment options in patients with advanced non-small-cell lung cancer (NSCLC). Oncogene addiction due to driver mutations includes EGFR exon 20 insertion mutations, MET amplification, EML4-AL, KRAS G12C point mutations, RET rearrangements, HER2 amplification and mutations, and FGFR amplification and translocations. A re-biopsy at the time of tumor recurrence or progression after first-line treatment failure is important for further molecular assessment and personalized therapy. However, repeat tumor biopsies are fraught with challenges including access to the tumor, sample inadequacy, patient consent, patient performance status, safety, or physician's choice or assessment. Cytological specimens are gaining importance but are limited due to validation difficulties. Liquid biopsies, which are minimally invasive have shown promise to assess dynamic biomarkers using ctDNA analysis and are thus frequently considered in routine clinical practice in advanced NSCLC patients to guide further targeted treatment. Here we present a comprehensive review that emphasizes the significance of performing tumor re-biopsy in advanced stage NSCLC patients following resistance to first-line treatment and simultaneously highlights the current challenges in performing the same and the current status and future perspectives of liquid biopsy in NSCLC.

Towards Machine Learning-Aided Lung Cancer Clinical Routines: Approaches and Open Challenges

“…Tissue biopsy is the current standard procedure for lung cancer classification, consisting of an assessment technique that includes several methods, such as fine needle aspiration, bronchoscopy, endobronchial ultrasound, mediastinoscopy, thoracentesis, thoracoscopy, and electromagnetic navigation. Bronchoscopy is the main diagnosis procedure, with flexible bronchoscopy being more useful for central lesions and navigational bronchoscopy displaying higher sensitivities for peripheral lesions [ 29 , 30 ]. Percutaneous approaches include transthoracic needle aspiration (TTNA) or needle/core biopsy (TTNB) of the primary tumor.…”

“…Moreover, tissue biopsies have some limitations related to tumor heterogeneity, since a single biopsy may not represent the complexity of the entire tumor and its genetic alteration. Thus, there is an inability to carry out a complete therapeutic decision and prognosis, which are the main issue in clinical practices [ 29 , 30 ]. Therefore, although recommendations are clear about the need for a biopsy, its invasive nature limits repetition for treatment response evaluations [ 33 ].…”

“…A liquid biopsy may be viewed as a key strategy to improve lung cancer early diagnosis—either alone or as complementary data for imaging findings. Other clinical applications consist of patient stratification, therapeutic decisions, and disease monitoring [ 29 , 30 ]. Liquid biopsies are shown to be useful in the management of NSCLC in clinical practices.…”

“…Several liquid biopsy-derived biomarkers have been identified, such as circulating tumor cells, circulating cell-free DNA, circulating micro-RNAs, tumor-derived exosomes, and tumor-educated platelets [ 29 , 30 ]. Evidence indicates that a liquid biopsy can be applied to dynamically evaluate resistance mutations during treatment with epidermal growth factor receptor ( EGFR ) and anaplastic lymphoma kinase ( ALK ) inhibitors [ 35 ].…”

“…Thus, the development of more sensitive and specific assays must occur in the following years to allow its standard use in clinical practice. There is also the possibility of combining different biomarkers and other diagnostic techniques, such as imaging techniques, although more robust studies are required to define the best combinations and to validate the clinical role of liquid biopsy in the screening or diagnosis of lung cancer [ 29 , 30 ].…”