Molecular analysis of NSCLC patients with acquired resistance to gefitinib or erlotinib

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7078-7078 ◽  
Author(s):  
W. Pao ◽  
M. N. Balak ◽  
G. J. Riely ◽  
A. R. Li ◽  
M. F. Zakowski ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Kinase Domain ◽  
Site Mutation ◽  
Primary Resistance ◽  
Kras Mutations ◽  
T790m Mutation ◽  
Exon 2 ◽  
Nsclc Patients ◽  
Egfr Kinase ◽  
Exon 19

7078 Background: We previously reported that in 2 of 5 non-small cell lung cancer (NSCLC) patients with acquired resistance to the tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, tumors biopsied after disease progression contained a second site mutation (T790M) in the epidermal growth factor receptor (EGFR) kinase domain, in addition to a primary drug-sensitive mutation (exon 19 deletion (del) or exon 21 point mutation (L858R)) (Pao et al, PLoS Med ‘05). No patients had KRAS mutations, which are associated with primary resistance to these TKIs. We sought to determine the frequency of second site EGFR kinase domain and KRAS mutations in tumors from patients with acquired resistance to TKIs, administered either as monotherapy or with chemotherapy. Methods: 18 patients with NSCLC who responded to either TKI alone (n = 14) or TKI plus chemotherapy (n = 4) and then progressed were re-biopsied. Genomic DNA samples from tumors were examined for EGFR (exons 18–24) and KRAS (exon 2) mutations. Results: Sequence analysis was successfully performed on tumors from 17 patients. The T790M EGFR mutation was detected in 6 of 13 (46%, 95% CI 19–75%) on TKI monotherapy, and in 0 of 4 (0%, 95% CI 0–53%) on TKI plus chemotherapy. In one autopsy case, the T790M mutation was detected in 5 of 5 sites, which all harbored the same exon 19 del. No other EGFR or KRAS mutations were detected. Conclusions: Secondary EGFR T790M but not KRAS mutations are commonly associated with acquired resistance to TKI monotherapy. More patients are being studied, and we are trying to elucidate determinants of acquired resistance in the absence of T790M mutations. New therapies are needed to treat and/or suppress the development of acquired resistance to gefitinib or erlotinib. Support: Joan’s Legacy, DDCF, K08-CA097980, R21-CA115051. [Table: see text]

scholarly journals Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer

2021 ◽  
Author(s):  
Danish Memon ◽  
Hira Rizvi ◽  
George Fromm ◽  
Jayon Lihm ◽  
Adam J Schoenfeld ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Acquired Resistance ◽  
Interferon Signaling ◽  
Molecular Phenotype ◽  
Primary Resistance ◽  
Molecular Features ◽  
Survival Patterns ◽  
Nsclc Patients ◽  
Whole Transcriptome

Although cancer immunotherapy with PD-(L)1 blockade is now routine treatment for patients with lung cancer, remarkably little is known about acquired resistance. We examined 1,201 patients with NSCLC treated with PD-(L)1 blockade to clinically characterize acquired resistance, finding it to be common (occurring in more than 60% of initial responders), with persistent but diminishing risk over time, and with distinct metastatic and survival patterns compared to primary resistance. To examine the molecular phenotype and potential mechanisms of acquired resistance, we performed whole transcriptome and exome tumor profiling in a subset of NSCLC patients (n=29) with acquired resistance. Systematic immunogenomic analysis revealed that tumors with acquired resistance generally had enriched signals of inflammation (including IFNγ signaling and inferred CD8+ T cells) and could be separated into IFNγ upregulated and stable subsets. IFNγ upregulated tumors had putative routes of resistance with signatures of dysfunctional interferon signaling and mutations in antigen presentation genes. Transcriptomic profiling of cancer cells from a murine model of acquired resistance to PD-(L)1 blockade also showed evidence of dysfunctional interferon signaling and acquired insensitivity to in vitro interferon gamma treatment. In summary, we characterized clinical and molecular features of acquired resistance to PD-(L)1 blockade in NSCLC and found evidence of ongoing but dysfunctional IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance informs therapeutic strategies to effectively reprogram and reverse acquired resistance.

scholarly journals Efficacy and Acquired Resistance of EGFR-TKI Combined with Chemotherapy as First-Line Treatment for Chinese Patients with Advanced Non-Small Cell Lung Cancer in a Real-world Setting

2020 ◽  
Author(s):  
Qianqian Wang ◽  
Wen Gao ◽  
Fangyan Gao ◽  
Shidai Jin ◽  
Tianyu Qu ◽  
...  
Keyword(s):  
Egfr Mutation ◽  
Advanced Nsclc ◽  
Acquired Resistance ◽  
Small Cell ◽  
Combination Group ◽  
Monotherapy Group ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Nsclc Patients ◽  
Egfr Tki

Abstract Background To compare the benefits and explore the cause of acquired resistance of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and its combination with chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients harboring EGFR mutation in a real-life setting.Methods This retrospective analysis included 117 advanced NSCLC patients with EGFR mutation who underwent next-generation sequencing (NGS) prior to treatment. The combination group included 50 patients who received the regimen of EGFR-TKI combined with chemotherapy, while the EGFR-TKI monotherapy group included 67 patients treated with TKI only. The primary endpoint of this study was progression-free survival (PFS); the secondary endpoints were overall survival (OS), response rate, and toxicity.Results The median PFS was significantly longer in the combination group than in the EGFR-TKI monotherapy group (19.00 months [95% CI, 14.674-23.326] vs. 11.70 months [95% CI, 10.807-12.593], p = 0.000). Subgroup analysis showed a similar trend of results. The median OS was not reached in the combination group and was 38.50 (95% CI, 35.300-41.700) months in the EGFR-TKI monotherapy group (p = 0.586). Patients in the combination group were more likely to experience adverse events, most of which showed the severity of grade 1 or 2. T790M mutation remains the main reason for acquired resistance, and the frequency of T790M mutation was similar between the two groups (p = 0.898). Conclusions Compared with EGFR-TKI monotherapy, EGFR-TKI combined with chemotherapy significantly improved PFS in advanced NSCLC patients with EGFR mutation, with acceptable toxicity.

scholarly journals Histological transformation of lung adenocarcinoma to small cell lung cancer with mutant C797S conferring acquired resistance to osimertinib

2020 ◽  
Vol 48 (6) ◽  
pp. 030006052092791 ◽  
Author(s):  
Xiaohui Ren ◽  
Xinfeng Cai ◽  
Jing Li ◽  
Xia Zhang ◽  
Jianfei Yu ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Acquired Resistance ◽  
Small Cell ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Exon 19 Deletion ◽  
Exon 19

Epidermal growth factor receptor (EGFR) gene-mutated non-small cell lung cancer may initially respond to EGFR tyrosine kinase inhibitors (TKIs), but may subsequently become resistant; however, the resistance mechanisms remain unclear. We report a rare case of acquired resistance to osimertinib associated with transformation to small cell lung cancer (SCLC) with cis-C797S mutation. A man with recurrent lung adenocarcinoma harboring an EGFR exon 19 deletion received erlotinib for 10 months following curative surgery and adjuvant chemotherapy. However, he switched to osimertinib after repeat biopsy showed EGFR exon 19 deletion and T790M mutation leading to erlotinib resistance. His disease progressed after 15 months and repeat biopsy showed SCLC. Next-generation sequencing of peripheral blood detected EGFR exon 19 deletion, T790M mutation, cis-C797S mutation, and RB1 inactivation. The tumor was reduced after four cycles of etoposide and cisplatin and his respiratory symptoms improved. However, computed tomography after six cycles of chemotherapy showed multiple bilateral lung lesions, and single-photon emission computed tomography showed bone metastasis. The patient received paclitaxel plus cisplatin for two cycles with partial response. Because heterogeneous genetic and phenotypic mechanisms of TKI-resistance may occur at different times and locations, histopathological and molecular testing both provide evidence to support appropriate treatment.

A retrospective analysis of the prevalence of EGFR or KRAS mutations in patients (pts) with crizotinib-naïve and crizotinib-resistant, ALK-positive non-small cell lung cancer (NSCLC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8083-8083
Author(s):  
Justin F. Gainor ◽  
Anna M. Varghese ◽  
Sai-Hong Ignatius Ou ◽  
Sheheryar Kabraji ◽  
Mark M Awad ◽  
...  
Keyword(s):  
Direct Sequencing ◽  
Acquired Resistance ◽  
Kinase Domain ◽  
Repeat Biopsy ◽  
Egfr Mutations ◽  
Tyrosine Kinase Domain ◽  
Kras Mutations ◽  
Anaplastic Lymphoma ◽  
Biopsy Specimens ◽  
Alk Positive

8083 Background: Anaplastic lymphoma kinase (ALK) gene rearrangements define a distinct molecular subset of NSCLC. Recently, several studies have reported that ALK+ pts occasionally harbor concomitant mutations in other oncogenic drivers. Methods: We retrospectively analyzed tumor genotyping data from 1,683 pts with NSCLC seen at 3 U.S. centers from 2009 – 2012 to determine rates of overlapping alterations in EGFR, KRAS and ALK. Mutations in EGFR and KRAS were mainly identified using the SNaPshot multiplexed assay (>95% of cases). ALK FISH was performed in all cases. To determine if this prevalence is impacted by crizotinib, we also updated our earlier analysis (Katayama et al., Sci Transl Med, 2012) of a series of repeat biopsy specimens from 34 crizotinib-resistant, ALK+ pts. Resistant specimens were examined using ALK FISH, SNaPshot, and direct sequencing of the ALK tyrosine kinase domain (TKD). Results: Screening identified 301 (17.8%) EGFR mutations, 465 (27.6%) KRAS mutations, and 75 (4.4%) ALK rearrangements. EGFR mutations and ALK rearrangements were mutually exclusive. 4 pts with KRAS mutations also had abnormal ALK FISH patterns, involving isolated 5’ green probes (3/4 cases) and an isolated 3’ red probe that was unusually small (1/4 cases). Sufficient tissue was available for confirmatory ALK immunohistochemistry (clone 5A4, Novacastra, UK) in 3 of these cases, all of which were negative for ALK expression. Among pts with ALK+ NSCLC and acquired crizotinib resistance, repeat biopsy specimens remained ALK fusion positive in 28/28 (100%) cases. Secondary mutations in the ALK TKD (1151Tins, L1196M, G1202R, S1206Y, and G1269A) were identified in 7/34 (20.6%) cases. L1196M was the most common secondary mutation (3/34, 8.8% cases). ALK gene amplification was present in 3/28 (10.71%) pts. No EGFR or KRAS mutations were identified in 23 crizotinib-resistant, ALK+ pts with sufficient tissue for testing. Conclusions: Functional ALK rearrangements were mutually exclusive with EGFR and KRAS mutations in a large Western patient population. This lack of overlap was also observed in ALK+ pts with acquired resistance to crizotinib.

Emergence of KRAS mutations and acquisition of resistance to EGFR blockade.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3598-3598
Author(s):  
Takeshi Yamada ◽  
Goro Takahashi ◽  
Takuma Iwai ◽  
Kohki Takeda ◽  
Kohji Ueda ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Braf V600e ◽  
Braf Mutations ◽  
Primary Resistance ◽  
Kras Mutations ◽  
Primary Tumors ◽  
Ras Mutation ◽  
Epidermal Growth ◽  
Digital Polymerase Chain Reaction

3598 Background: Epidermal growth factor receptor (EGFR) blockade can effectively shrink tumors in patients with metastatic colorectal cancer (CRC). However, most patients who benefit from EGFR blockade acquire resistance. Although RAS mutation is established as a main cause of primary resistance, the mechanisms of this acquired resistance remain unclear. Here, we aimed to identify the mechanisms underlying acquired resistance to EGFR blockade by using circulating cell-free (ccf)DNA to track emerging KRAS, BRAF and S492R mutations during chemotherapy. Methods: We enrolled 33 patients with metastatic CRC and no RAS mutations in their primary tumors. Patients were treated with first-line systemic chemotherapy that included EGFR blockade. We obtained ccfDNA from each patient before they started chemotherapy, and every 2–3 months during chemotherapy until disease progression. We detected KRAS (codons 12, 13, 61, and 146), BRAF (V600E) and S492R mutations using digital polymerase chain reaction. Results: KRAS mutations were detected in the ccfDNA of 4 of the 33 patients (12%) before chemotherapy. The response rate was 88% (29/33); all four non-responders had KRAS mutations in their ccfDNA and one of the four had both KRAS and BRAF mutations before starting chemotherapy. A response was detected in all patients (29/29) with no KRAS or BRAF mutations in their ccfDNA before chemotherapy. Of the 29 initial responders, 14 (48%) acquired resistance. Emerging KRAS mutations were detected in the ccfDNA of 13 of these 14 patients (93%); eight of these patients had multiple mutations (e.g. G12D and G12V; G13D and Q61H). BRAF mutations were also detected in six patients (43%); none of the patients had solo BRAF mutations. Six patients (43%) had S492R mutations; none of the patients had solo S492R mutations. Only one patient had no KRAS, BRAF or S492R mutations. Conclusions: Emergence of KRAS, BRAF or S492R mutations that were undetectable before the start of chemotherapy may be a mechanism underlying acquisition of resistance to EGFR blockade. Notably, emerging KRAS mutations were detected in most of the patients (93%) who acquired resistance. This indicates that KRAS mutation emergence may play a major role in the acquisition of resistance to EGFR blockade.

Does CNS metastases reduce systemic therapy lines for NSCLC patients with EGFR mutation?

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21558-e21558
Author(s):  
Danilo Giffoni ◽  
Maria Luisa Romero ◽  
Mark Doherty
Keyword(s):  
Brain Metastases ◽  
Systemic Therapy ◽  
Egfr Mutation ◽  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Administrative Databases ◽  
Cns Metastases ◽  
T790m Mutation ◽  
Nsclc Patients ◽  
The Brain

e21558 Background: The latest generation tyrosine kinase inhibitor (TKI), Osimertinib, targets the epidermal growth factor receptor (EGFR) despite the T790M mutation status in non-small-cell lung cancer (NSCLC). In cases where there is a detected EGFR mutation on the exon 19-deletion and on the exon 21-L858R in the NSCLC population, studies have demonstrated that Osimertinib has a positive benefit in overall survival and delayed progression of central nervous system (CNS) metastases. Methods: From January 2010 to December 2018, 56 patients with the metastatic NSCLC-EGFR mutation, treated with Osimertinib 80 mg once daily, were included in this analysis. Retrospective data was extracted through the internal administrative databases located at Sunnybrook Hospital. All patients had EGFR mutation positivity by cytology, plasma or tissue sampling. The primary endpoint was to evaluate whether NSCLC patients who were exposed to Osimertinib and had brain metastases underwent fewer systemic therapy lines as compared to those who did not have metastases involving the brain. Results: Eligible patients were analyzed and the median age at the initial diagnosis was 65 years old; 50% (n = 28) of the patients had brain metastases. The median of systemic treatment lines for patients without CNS metastasis was two and for those who have metastases to the brain was three. 82,2% of this cohort received Osimertinib in 2nd line, after development of acquired resistance to first or second TKI generation. Conclusions: Results from this study did not demonstrate that EGFR mutated, NSCLC patients with CNS metastases received less systemic therapy lines to those without metastases involving the brain. A larger cohort for further investigation is warranted.

Non-invasive and quantitative analysis for EGFR T790M mutation in the patients with advanced non-small cell lung cancer received EGFR-TKI therapy.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19101-e19101
Author(s):  
Rui Chen ◽  
Tongtong An ◽  
Jie Wang ◽  
Hua Bai ◽  
Zhijie Wang ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Low Frequency ◽  
Digital Pcr ◽  
T790m Mutation ◽  
Frequency Group ◽  
Pre Treatment ◽  
Nsclc Patients ◽  
Wild Group ◽  
Egfr T790m ◽  
Egfr Tkis

e19101 Background: Approximately 50% of advanced non-small cell lung cancer (A-NSCLC) patients with EGFR sensitive mutation who develop acquired resistance to EGFR-TKIs reportedly have a secondary EGFR T790M mutation. Establishing a dynamical, quantitative and noninvasive detection system of EGFR T790M mutation in process of disease therapy for NSCLC is critical to personalized targeted therapy. Methods: 135 A-NSCLC patients with EGFR mutation who received EGFR-TKIs and presented acquired resistance (PFS≥6 months) were included into this study. All patients provided the plasma samples for molecular analysis when disease progressed. 109 patients of them had matched TKI-naive plasma. T790M mutation was measured qualitatively and quantitatively by ARMS and Digital PCR (DggPCR), respectively. Association of T790M mutation with clinical charateristics were evaluated. Results: DgPCR was more sensitive than ARMs to detect T790M mutation in plasma [pre-treatment 29.4% (32/109) VS 5.5% (6/109); post-treatment: 43.0% (58/135) VS 25.2% (34/135)]. 32 patients with pre-treatment T790M mutation predicted shorter PFS and OS compared with 77 T790 M negative patients (PFS, F 12.7 VS 9.2 months, P=0.004, GOS, F 27.0 VS 18.8 months, P=0.002). Patients with or without post-treatment T790M mutation have no significantly different PFS and OS. However, quantified the ratio of copy number of mutant T790M to wild-type by DgPCR, patients were divided into high-frequency groups (≥5%), low-frequency group (0%-5%) and wild-group (0%) according to the number of positive signals observed from DgPCR results. 12 patients in high-frequency group showed shorter PFS and OS compared with wild group and low-frequency group (PFS 9.5 VS 11.9 months, P=0.033, G9.5 VS 13.6 months, P=0.028, GOS, F 18.5 VS 21.2 months, P=0.044, 18.5 VS 28.8 months, P=0.001). Conclusions: Non-invisive and quantitative detection of T790m mutation by digital PCR is feasible in clinical practice. High contents of T790M when disease progression after EGFR-TKIs therapy predicted poor prognosis.

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