The Role of the Liquid Biopsy in Decision-Making for Patients with Non-Small Cell Lung Cancer

Liquid biopsy is a rapidly emerging tool of precision oncology enabling minimally invasive molecular diagnostics and longitudinal monitoring of treatment response. For the clinical management of advanced stage lung cancer patients, detection and quantification of circulating tumor DNA (ctDNA) is now widely adopted into clinical practice. Still, interpretation of results and validation of ctDNA-based treatment decisions remain challenging. We report here our experience implementing liquid biopsies into the clinical management of lung cancer. We discuss advantages and limitations of distinct ctDNA assay techniques and highlight our approach to the analysis of recurrent molecular alterations found in lung cancer. Moreover, we report three exemplary clinical cases illustrating the complexity of interpreting liquid biopsy results in clinical practice. These cases underscore the potential and current limitations of liquid biopsy, focusing on the difficulty of interpreting discordant findings. In our view, despite all current limitations, the analysis of ctDNA in lung cancer patients is an essential and highly versatile complementary diagnostic tool for the clinical management of lung cancer patients in the era of precision oncology.

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Emerging Lab-on-a-Chip Approaches for Liquid Biopsy in Lung Cancer: Status in CTCs and ctDNA Research and Clinical Validation

Cancers ◽

10.3390/cancers13092101 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2101

Author(s):

Ângela Carvalho ◽

Gabriela Ferreira ◽

Duarte Seixas ◽

Catarina Guimarães-Teixeira ◽

Rui Henrique ◽

...

Keyword(s):

Lung Cancer ◽

Liquid Biopsy ◽

Residual Disease ◽

Lab On A Chip ◽

Microfluidic Devices ◽

Early Recurrence ◽

Circulating Tumor Dna ◽

Clinical Validation ◽

Liquid Biopsies ◽

Lung Cancer Patients

Despite the intensive efforts dedicated to cancer diagnosis and treatment, lung cancer (LCa) remains the leading cause of cancer-related mortality, worldwide. The poor survival rate among lung cancer patients commonly results from diagnosis at late-stage, limitations in characterizing tumor heterogeneity and the lack of non-invasive tools for detection of residual disease and early recurrence. Henceforth, research on liquid biopsies has been increasingly devoted to overcoming these major limitations and improving management of LCa patients. Liquid biopsy is an emerging field that has evolved significantly in recent years due its minimally invasive nature and potential to assess various disease biomarkers. Several strategies for characterization of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have been developed. With the aim of standardizing diagnostic and follow-up practices, microfluidic devices have been introduced to improve biomarkers isolation efficiency and specificity. Nonetheless, implementation of lab-on-a-chip platforms in clinical practice may face some challenges, considering its recent application to liquid biopsies. In this review, recent advances and strategies for the use of liquid biopsies in LCa management are discussed, focusing on high-throughput microfluidic devices applied for CTCs and ctDNA isolation and detection, current clinical validation studies and potential clinical utility.

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Genetic diagnostic features after failure of initial treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors among non-small-cell lung cancer patients harboring EGFR mutations

10.21203/rs.3.rs-19425/v4 ◽

2020 ◽

Author(s):

Yuichiro Takeda ◽

Go Naka ◽

Yoh Yamaguchi ◽

Masao Hashimoto ◽

Manabu Suzuki ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Patients ◽

Liquid Biopsy ◽

Growth Factor Receptor ◽

Egfr Mutations ◽

Liquid Biopsies ◽

Lung Cancer Patients ◽

Epidermal Growth ◽

Egfr Tki ◽

Egfr Tkis

Abstract Background: Osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), can be used as second-line treatment for lung cancer patients harboring the T790M substitution. Although osimertinib is more effective than the first-generation EGFR-TKIs used for first-line treatment, its efficacy with respect to long-term patient survival remains unclear even upon the administration of a complete sequence of EGFR-TKI therapy. Moreover, limited information is available regarding genetic diagnostic approaches after the treatment of EGFR-TKI–naïve patients. This study investigated the clinical characteristics of EGFR -mutated lung cancer patients harboring the T790M substitution resistant to EGFR-TKIs, as well as the advantages of rebiopsy and liquid biopsy for these patients. Methods: The medical records of patients screened for EGFR mutations were reviewed. Upon failure of naïve treatment with EGFR-TKIs, except for osimertinib, single-plexus cobas version 2 was repeatedly used to detect the T790M substitution in EGFR via tissue or liquid biopsy. Results: From April 2016 through May 2019, 113 patients were found to harbor EGFR mutations. Sixty patients were treated with EGFR-TKIs, among whom 46 underwent tissue or liquid biopsy. Twenty-nine of these 46 (63%) patients harbored the T790M substitution. In total, 141 rebiopsies were performed. The T790M substitution was detected in 24 of 43 tissue biopsies and 11 of 98 liquid biopsies. If patients displayed an EGFR exon 19 deletion, had a new lesion, and were administered gefitinib as first-line therapy, they were suspected to harbor the T790M substitution. Furthermore, the T790M substitution was detected through rebiopsy in patients with coexisting original mutations, brain metastases, tumor enlargement by ≥ 12 mm, or metastases at minor sites. Conclusion: Among patients with positive factors associated with the T790M mutation, repeated tissue or liquid biopsies are useful to maximize the detection rate of the T790M substitution. Furthermore, these biopsies need to be repeated numerous times in order to reduce “detection overlook” among such patients.

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Genetic diagnostic features after failure of initial treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors among non-small-cell lung cancer patients harboring EGFR mutations

BMC Cancer ◽

10.1186/s12885-020-07424-w ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Yuichiro Takeda ◽

Go Naka ◽

Yoh Yamaguchi ◽

Masao Hashimoto ◽

Manabu Suzuki ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Patients ◽

Liquid Biopsy ◽

Growth Factor Receptor ◽

First Line ◽

Liquid Biopsies ◽

Lung Cancer Patients ◽

Epidermal Growth ◽

Egfr Tki ◽

Egfr Tkis

Abstract Background Osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), can be used as second-line treatment for lung cancer patients harboring the T790M substitution. Although osimertinib is more effective than the first-generation EGFR-TKIs used for first-line treatment, its efficacy with respect to long-term patient survival remains unclear even upon the administration of a complete sequence of EGFR-TKI therapy. Moreover, limited information is available regarding genetic diagnostic approaches after the treatment of EGFR-TKI–naïve patients. This study investigated the clinical characteristics of EGFR-mutated lung cancer patients harboring the T790M substitution resistant to EGFR-TKIs, as well as the advantages of rebiopsy and liquid biopsy for these patients. Methods The medical records of patients screened for EGFR mutations were reviewed. Upon failure of naïve treatment with EGFR-TKIs, except for osimertinib, single-plexus cobas version 2 was repeatedly used to detect the T790M substitution in EGFR via tissue or liquid biopsy. Results From April 2016 through May 2019, 113 patients were found to harbor EGFR mutations. Sixty patients were treated with EGFR-TKIs, among whom 46 underwent tissue or liquid biopsy. Twenty-nine of these 46 (63%) patients harbored the T790M substitution. In total, 141 rebiopsies were performed. The T790M substitution was detected in 24 of 43 tissue biopsies and 11 of 98 liquid biopsies. If patients displayed an EGFR exon 19 deletion, had a new lesion, and were administered gefitinib as first-line therapy, they were suspected to harbor the T790M substitution. Furthermore, the T790M substitution was detected through rebiopsy in patients with coexisting original mutations, brain metastases, tumor enlargement by ≥12 mm, or metastases at minor sites. Conclusion Among patients with positive factors associated with the T790M mutation, repeated tissue or liquid biopsies are useful to maximize the detection rate of the T790M substitution. Furthermore, these biopsies need to be repeated numerous times in order to reduce “detection overlook” among such patients.

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The Role of Tissue and Liquid Biopsy in the Clinical Management of Adult Lung Cancer Patients in King Abdul-Aziz Medical City in Riyadh, Saudi Arabia

Cureus ◽

10.7759/cureus.20914 ◽

2022 ◽

Author(s):

Lafi Alanazi ◽

Ryan N Alqahtani ◽

Nazish Masud ◽

Meshal M Zuraie ◽

Abdulrahman A Bin Afif ◽

...

Keyword(s):

Lung Cancer ◽

Saudi Arabia ◽

Cancer Patients ◽

Liquid Biopsy ◽

Clinical Management ◽

Lung Cancer Patients ◽

Adult Lung ◽

Medical City

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Detection of low abundant mutants from circulating tumor DNA of plasma, pleural effusion, and cerebrospinal fluid of lung cancer patients using a novel mutant-capture enrichment approach.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14520 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14520-e14520

Author(s):

Rui Lin ◽

Yue Pu ◽

Li Mao

Keyword(s):

Lung Cancer ◽

Cerebrospinal Fluid ◽

Pleural Effusion ◽

Cancer Patients ◽

Liquid Biopsy ◽

High Sensitivity ◽

Circulating Tumor Dna ◽

Lung Cancer Patients ◽

Egfr Tki ◽

Tumor Dna

e14520 Background: In the era of precision medicine, liquid biopsy analysis is well accepted based on advantages including availability, non-invasiveness, and non-heterogeneity. However, the circulating tumor DNA (ctDNA) in liquid biopsy is diluted by a large excess of wild-type alleles, which necessitates high sensitivity approach for ctDNA detection. In addition, ctDNA analysis from different liquid biopsy samples need to be evaluated. Methods: We have developed a novel mutant-capture based method, termed PErsonalized Analysis of Cancer (PEAC), for high sensitivity detection of cancer driver mutants at abundance as low as 0.01-0.1% for circulating free DNA (cfDNA) standards. ctDNA samples were extracted from body fluids of lung cancer patients including plasma, pleural effusion and cerebrospinal fluid. EGFR mutants predictive of EGFR tyrosine kinase activity were enriched using PEAC technology, and analyzed using Sanger sequencing. Results: Plasma ctDNA samples B7110003, B7110010, and B7112012 had no or barely detectable L858R mutation, which was enriched to 50-90% after PEAC and readily detected by Sanger. T790M was undetectable before PEAC in plasma sample B7112052 and became 50% after PEAC enrichment. Pleural effusion samples E8106029 and E8111305 had dominated L858R and T790M peaks, respectively, in Sanger chromatograms after PEAC, which was almost to the background levels prior to PEAC. Interestingly, both EGFR L858R and T790M mutants were detected in pleural effusion sample E8106029 after PEAC; the sample was from a patient who had previously treated with an EGFR tyrosine kinase inhibitor (TKI), suggestive of resistance developed after target therapy and the utility of PEAC in monitoring patient’s response to EGFR TKI. In addition to enriching point mutations, we also established enrichment of the most frequently occurred EGFR 19 deletion, E746_A750del (c. 2235_2249 del15), which were dominant after PEAC enrichment of ctDNA from plasma samples (B8101186 and B8101241), pleural effusion (E8108088) and cerebrospinal fluid (C8108095); the mutants were undetectable without PEAC enrichment. Conclusions: PEAC technology can enrich ctDNA from body fluids in lung cancer patients and allow detection of low abundant mutants predictive for EGFR TKI therapy. With further validation, the technology may improve current detection methods used in clinical practice.

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Selecting a PRO-CTCAE based subset for patient reported symptom monitoring during lung cancer treatment (Preprint)

10.2196/preprints.26574 ◽

2020 ◽

Author(s):

Evalien Veldhuijzen ◽

Iris Walraven ◽

Jose Belderbos

Keyword(s):

Lung Cancer ◽

Clinical Practice ◽

Cancer Patients ◽

Treatment Modalities ◽

European Organization ◽

Specific Patient ◽

Symptom Monitoring ◽

Lung Cancer Patients ◽

Wide Range ◽

Patient Reported

BACKGROUND The Patient Reported Outcomes Version of the Common Terminology Criteria of Adverse Events (PRO-CTCAE) item library covers a wide range of symptoms relevant for oncology care. To enable implementation of PRO-CTCAE-based symptom monitoring in clinical practice, there is a need to select a subset of items relevant for specific patient populations. OBJECTIVE The aim of this study was to develop a PRO-CTCAE subset relevant for patients with lung cancer. METHODS The PRO-CTCAE-based subset for lung cancer patients was generated using a mixed methods approach based on the European Organization for Research and Treatment of Cancer (EORTC) guidelines for developing questionnaires, consisting of a literature review and semi-structured interviews with both lung cancer patients and health care practitioners (HCPs). Both patients and HCPs were queried on the relevance and impact of all PRO-CTCAE items. Results were summarized and, after a final round of expert review, a selection of clinically relevant items for lung cancer patients was made. RESULTS A heterogeneous group of lung cancer patients (n=25) from different treatment modalities and HCPs (n=22) participated in the study. A final list of eight relevant PRO-CTCAE items was created: decreased appetite, cough, shortness of breath, fatigue, constipation, nausea, sadness, and pain (general). CONCLUSIONS Based on literature and both professional and patient input, a subset of PRO-CTCAE items has been identified for use in lung cancer patients in clinical practice. Future work is needed to confirm the validity and effectiveness of this PRO-CTCAE lung cancer subset internationally, and in the real-world clinical practice setting.

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Efficacy and Safety of Lipegfilgrastim in Lung Cancer Patients Receiving Myelosuppressive Chemotherapy in a Real-World Setting: Results of an Analysis of Pooled Data from Two Non-Interventional European Studies

Oncology Research and Treatment ◽

10.1159/000512594 ◽

2021 ◽

pp. 1-9

Author(s):

Christian Gessner ◽

Karin Potthoff ◽

Nikolaj Frost

Keyword(s):

Lung Cancer ◽

Clinical Practice ◽

Cancer Patients ◽

Adverse Drug Reactions ◽

Real World ◽

Secondary Prophylaxis ◽

Drug Reactions ◽

Myelosuppressive Chemotherapy ◽

Lung Cancer Patients ◽

Chemotherapy Induced Neutropenia

Background/Aim: Chemotherapy-induced neutropenia is a common and serious complication in cancer patients receiving myelosuppressive chemotherapy. This analysis was undertaken to evaluate the effectiveness and safety of prophylaxis with lipegfilgrastim, a glycoPEGylated granulocyte colony-stimulating factor, in lung cancer patients undergoing chemotherapy in real-world clinical practice. Methods: Data from two European non-interventional studies (NIS NADIR and NIS LEOS) investigating lipegfilgrastim for primary and secondary prophylaxis were pooled. Outcomes included the incidence of chemotherapy-induced neutropenia and febrile neutropenia (FN), use of anti-infectives and antimycotics, and adverse events and their relationship to lipegfilgrastim. Results: The safety population included 361 patients with lung cancer (median age, 66 years [range, 36–88]), of whom 322 had received 2 or more consecutive cycles of lipegfilgrastim (efficacy population [primary prophylaxis, 75.5%; secondary prophylaxis, 16.5%]). Almost 40% of the patients were considered to have a high risk (>20%) of FN, and around 60% had an intermediate risk (10–20%). For all cycles, FN was reported in 3 patients (0.9%), neutropenia in 14 (4.3%), and grade 4 neutropenia in 9 (2.8%). Anti-infectives were used in 27 patients (8.4%) and antimycotics in 6 (1.9%). The incidence rates were lower for the patients’ first cycle (FN, 0.4%; neutropenia, 0.8%; grade 4 neutropenia, 0.8%; anti-infectives, 0.6%; antimycotics, 0.6%). Adverse drug reactions considered lipegfilgrastim related were reported in 35 patients (9.7%), and serious adverse drug reactions in 10 (2.8%). None of the fatal events reported in 28 patients (7.8%) were lipegfilgrastim related. Conclusion: Lipegfilgrastim administered to patients with lung cancer undergoing chemotherapy in real-world clinical practice showed similar effectiveness and safety to that reported in published pivotal trials.

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