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

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

10.21203/rs.3.rs-19425/v3 ◽

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 ◽

First Line ◽

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 a 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, and limited information is available regarding genetic diagnostic approaches after EGFR-TKI naïve treatment. This study investigated the characteristics of EGFR-mutated lung cancer patients harboring the T790M substitution resistance to EGFR-TKIs and 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 determined to harbor EGFR mutations. Sixty patients were treated with EGFR-TKIs, among which 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 and 11 of 98 liquid biopsies. If patients displayed an EGFR exon 19 deletion, had new lesions, and were administered gefitinib as first-line therapy, patients harboring an EGFR mutation were suspected of harboring the T790M substitution. Furthermore, the T790M substitution was detected through rebiopsy in patients with co-existing original mutations, brain metastases, tumor enlargement by ≥ 12 mm, or metastases at minor sites. Conclusion: Repeated biopsy can help maximize the detection rate of the T790M substitution. Furthermore, the advantages of repeated tissue or liquid biopsy should be considered among patients with positive T790M factors , and these biopsies can be repeated numerous times .

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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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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/v1 ◽

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 ◽

First Line ◽

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 first-generation EGFR-TKIs used for first-line treatment, their efficacy for long-term patient survival remains unclear even upon administration of a complete sequence of EGFR-TKI therapy, and limited information is available regrading genetic diagnostic approaches after EGFR-TKI naïve treatment. This study aimed to investigate the characteristics of EGFR-mutated lung cancer patients harboring the T790M substitution resistant to EGFR-TKIs and the advantages of rebiopsy and liquid biopsy among 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 harbored EGFR mutations. Sixty patients were treated with EGFR-TKIs, among which 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 and 11 of 98 liquid biopsies. If patients displayed an EGFR exon 19 deletion, displayed a new lesion, and were administered gefitinib as first-line therapy, patients harboring an EGFR mutation were suspected to harbor the T790M substitution. Furthermore, the T790M substitution was detected through rebiopsy in patients with co-existing original mutations, brain metastases, tumor enlargement by ≥ 12 mm, or metastases at rare sites. Conclusion: Repeated biopsy can help maximize the detection rate of the T790M substitution. Furthermore, the advantages of repeated tissue or liquid biopsy should be considered among patients with positive T790M factors, and these biopsies can be repeated numerous times.

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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/v2 ◽

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 ◽

First Line ◽

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, and limited information is available regrading genetic diagnostic approaches after EGFR-TKI naïve treatment. This study investigated the characteristics of EGFR-mutated lung cancer patients harboring the T790M substitution resistant to EGFR-TKIs and 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 determined to harbor EGFR mutations. Sixty patients were treated with EGFR-TKIs, among which 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 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, patients harboring an EGFR mutation were suspected to harbor the T790M substitution. Furthermore, the T790M substitution was detected through rebiopsy in patients with co-existing original mutations, brain metastases, tumor enlargement by ≥ 12 mm, or metastases at minor sites. Conclusion: Repeated biopsy can help maximize the detection rate of the T790M substitution. Furthermore, the advantages of repeated tissue or liquid biopsy should be considered among patients with positive T790M factors , and these biopsies can be repeated numerous times .

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The predictive value of uncommon EGFR mutation in patients with non-small-cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.9028 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 9028-9028

Author(s):

Haiyan Tu ◽

Ee Ke ◽

Yue-Li Sun ◽

Ming-Ying Zheng ◽

Jin-Ji Yang ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Patients ◽

Growth Factor Receptor ◽

Small Cell ◽

Egfr Mutations ◽

Small Cell Lung ◽

Lung Cancers ◽

Lung Cancer Patients ◽

Exon 20 ◽

Egfr Tki

9028 Background: Non-small-cell lung cancers with uncommon epidermal growth factor receptor ( EGFR) mutations are regarded as a heterogeneous group with variable responses to EGFR-targeted drugs. Here we designed this retrospective study to describe the epidemiology and clinical outcomes of uncommon EGFR mutations in a Chinese cohort of lung cancer patients. Methods: Between June 2007 and June 2014, 5363 lung cancer patients whose EGFR genotyping was performed successfully at Guangdong Lung Cancer Institute (GLCI, Guangzhou, China) were screened. 1837 patients were included in the epidemiological analysis. The clinical outcome was analyzed in 97 advanced-stage patients harboring uncommon EGFR mutations with follow-up data. Results: 218 patients harbored uncommon EGFR mutations, making up 11.9% of all cancers with documented EGFR mutations. Compared with common mutants, those with uncommon mutations were more commonly found in smokers and male patients. The most frequently detected uncommon mutations were exon 20 insertions, G719X mutations and L858R complex mutations, occurring in 30.7%, 21.1% and 17.0% of all EGFR-uncommon-mutation cases. G719X and L858R complex mutations were associated with similar benefit from EGFR-TKI; median PFS was 15.2 (95% CI 8.7-21.7) and 11.6 (95% CI 3.6-19.6) months, respectively. T790M or 20INS was associated with a poorer EGFR-TKI response; median PFS was 1.0 (95% CI 0.0-2.2) and 3.0 (95% CI 1.3-4.7) months, respectively. Of note, two patients with 23% and 65% tumor shrinkages had N771_P772insN and H773_V774insQ, with PFS of 5.7 and 6.1 months respectively. Conclusions: Favorable responses were observed in specific subtypes including complex L858R and G719X, and our results suggested first-line EGFR-TKI should be preferable in such patients.

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Genetic and treatment profiles of patients with concurrent Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) mutations

BMC Cancer ◽

10.1186/s12885-021-08824-2 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Xiaodan Yang ◽

Jia Zhong ◽

Zhuo Yu ◽

Minglei Zhuo ◽

Min Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Patients ◽

Kinase Inhibitors ◽

Growth Factor Receptor ◽

Progression Free Survival ◽

Egfr Mutations ◽

Resistance Mutations ◽

Lung Cancer Patients ◽

Anaplastic Lymphoma ◽

Egfr Tkis

Abstract Background EGFR and ALK alternations often contribute to human malignancies, including lung cancer. EGFR and ALK mutations are usually sensitive to EGFR-tyrosine kinase inhibitors (TKIs) and ALK-TKIs. Although generally mutually exclusive, these mutations do co-exist in rare cases. This study investigated the frequencies, clinical characteristics, therapeutic efficacies, and genetic profiles of lung cancer patients with EGFR and ALK co-mutations. Methods Patients with concurrent EGFR and ALK mutations were included in this study, which analyzed mutation profiles and treatment histories. SPSS20.0 were used for survival analysis. Results Among 271 ALK-positive (ALK-pos) and 2975 EGFR-positive (EGFR-pos) patients in our database, nine (2.6% of ALK-pos and 0.2% of EGFR-pos) patients had concurrent EGFR and ALK mutations (including three exon19 Indel + EML4-ALK, two exon19 Indel + STRN-ALK, two L858R + L1152R, one L858R + EML4-ALK, and one G719C + S768I + STRN-ALK). Eight patients had at least one type of EGFR-TKIs treatment. The median progression free survival (PFS) of these patients on first-generation EGFR-TKIs was 14.5 months (95% CI: 11 - NR). Of these eight patients, one who progressed on Gefitinib and subsequently on Osimertinib had a T790M + C797G. The other seven EGFR-TKIs resistance patients had no known resistance mutations. No patients had ALK mutations before treatment, so ALK mutations may have developed as resistance mechanisms during EGFR-TKIs therapies. EGFR-TKIs-treated patients with EGFR/ALK L1152R mutations generally had a shorter PFS than patients with other mutation combinations. Conclusions ALK and EGFR mutations coincide at a relatively low frequency in lung cancer patients. ALK mutations developed either synchronously or heterochronously with EGFR mutations. Two ALK mutations (L1152R and STRN-ALK) may co-exist with EGFR mutations at a higher frequency than others. Most EGFR/ALK co-alteration patients (other than the EGFR/ALK L1152R type) can benefit from first line EGFR-TKIs.

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