Kinase Inhibitor Treatment In Patients Research Articles

Outcomes of Therapies and Resistance Mutations Following Non-Covalent Bruton's Tyrosine Kinase Inhibitor Treatment for Patients with Chronic Lymphocytic Leukemia and Richter Transformation

Background: Non-covalent Bruton's Tyrosine Kinase inhibitors (ncBTKi) have shown excellent clinical activity for patients (pts) with relapsed and/or refractory chronic lymphocytic leukemia (CLL) and Richter Transformation (RT). However, some pts treated with ncBTKi develop progressive disease (PD). In addition, acquired BTK mutations (mut) at the time of PD on ncBTKi were recently described, although the frequency at which these mut occur has not been reported. Currently, data regarding treatment sequencing post ncBTKi are lacking but are critical to guide further treatment selection. Methods: We conducted a retrospective, multicenter study of pts treated with any ncBTKi for CLL or RT who have discontinued ncBTKi for any reason. Using a standardized template we collected: pt and disease characteristics (including prior therapies, cytogenetic/molecular characteristics), demographics, clinical response to ncBTKi and subsequent therapies, and survival. Data on 2 lines of therapies (LOT) following ncBTKi were collected for each pt. Primary endpoint was overall response rate (ORR) for therapies following ncBTKi. Progression free survival (PFS) was estimated using the Kaplan Meier method. We also collected next generation sequencing (NGS) data for CLL pts who discontinued ncBTKi. Analyses were performed using STATA 17.0. Results: We identified 63 pts (48 CLL, 15 RT) treated with who then discontinued ncBTKi. Baseline characteristics at ncBTKi start are presented in Table 1. Median number of prior therapies was 4 (1-10), and most pts received prior covalent BTKi (93.7%) and venetoclax (57.1%). At ncBTKi start, 84.8% of patients had unmutated IGHV, 48.8% had a TP53 mut and 37.0% had a complex karyotype. ORR to ncBTKi was 58.8% for the CLL cohort (PR 54.4%, PR-L 4.4%) and 46.7% for the RT cohort (CR 6.7%, PR 40%). Median duration of ncBTKi exposure prior to discontinuation was 9 (1-27) and 4 (1-12) months for CLL and RT, respectively. Overall, 73.7% of the combined cohort progressed on ncBTKi. Specific reasons for ncBTKi discontinuation included: CLL PD (n=26, 41.2%), PD of existing RT (n=7), death not secondary to PD or toxicity (n=6), other reason (n=6), stem cell transplant (SCT, n=5), toxicity (n=4), PD of CLL to RT (n=4), MD/pt preference (n=2), CAR T (n=2), and sudden death on therapy (n=1). Following ncBTKi, 76.2% of pts (n=48) received another LOT. Therapies and responses are presented in Table 1. Common treatment strategies were: chemo+/-immunotherapy (CIT) (n=16, ORR 18.8%), CD19-directed CAR T-cell therapy (n=7, ORR 85.7%), allogeneic SCT (n=6, ORR 83.3%), and venetoclax-based therapy (n=10, ORR 70.0%). 27.3% of therapies administered post ncBTKi were administered on a clinical trial. For CLL pts, median PFS for first LOT following ncBTKi was 14 months (n=25 pts, Figure 1). For the RT cohort, the median PFS for the first LOT following ncBTKi discontinuation was 6 months (median follow-up 2.5 months). Importantly, median PFS for venetoclax following ncBTKi discontinuation for CLL pts was 14 months (8 pts, 87.5% venetoclax-naive, median follow-up 10.5 months). 49.2% of the overall cohort has died, with 58.6% of deaths due to CLL or RT (n=17 of 29 pts with available data). 15 CLL pts who discontinued ncBTKi for PD had end of treatment NGS data available. For these pts, at the start of ncBTKi, BTKC481 mut and PLCG2 mut were present in 38.5% and 33%, respectively. At end of ncBTKi treatment, novel (not C481) BTK mut were identified in 9 of 15 pts (60.0%). These included mut in BTKL528W (n=6), BTKV416L (n=2) and BTKT474I (n=2); 1 pt had mut in both BTKT474I and BTKL528W. Additionally, 4 pts had pre-existing mut in PLCG2 that persisted at PD. Overall, 11 of 15 (73.3%) of CLL pts had a novel BTK mut and/or a persistent PLCG2 mut at PD on ncBTKi. Conclusions: We report results from the first series of CLL and RT pts following ncBTKi discontinuation. CIT for RT and CLL yielded poor outcomes, while CAR T-cell therapy and allogeneic SCT had high ORR warranting further investigation. Most importantly, venetoclax has clinical activity (high ORR, durable PFS) for CLL pts following ncBTKi discontinuation suggesting CLL pts can stay within the BTKi class prior to switching to venetoclax. In addition, at PD 73% of pts had a novel BTK mut and/or the persistence of a PLCG2 mut conferring resistance to ncBTKis. Overall, these results highlight an unmet need for novel therapeutic strategies for pts who require treatment following ncBTKi. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The efficacy and safety of conventional transcatheter arterial chemoembolization combined with PD-1 inhibitor and anti-angiogenesis tyrosine kinase inhibitor treatment for patients with unresectable hepatocellular carcinoma: a real-world comparative study.

AimWe sought to evaluate the efficacy and safety of conventional transcatheter arterial chemoembolization (cTACE) sequentially combined with systemic treatment by programmed cell death protein 1 (PD-1) inhibitor and anti-angiogenesis tyrosine kinase inhibitor (Anti-angiogenesis TKI) in patients with unresectable hepatocellular carcinoma (HCC).Materials and methodsOne hundred and forty-seven advanced HCC patients who received PD-1 inhibitors and TKIs as first-line systemic treatment between August 2019 and April 2021 were collected retrospectively. Fifty-four patients were finally included and divided into cTACE and no-cTACE groups, according to whether cTACE treatment was performed within 8 weeks before systemic treatment. The tumor objective response ratio (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were compared between the groups. Significant factors affecting PFS and OS were determined by Cox regression.ResultsThirty-one patients received cTACE followed by systemic treatment and 23 patients received systemic treatment only. The ORRs of the cTACE group were 48.4% (after two cycles of systemic treatment) and 51.6% (after four cycles of systemic treatment), while those of the no-cTACE group were only 17.4% and 21.7%. cTACE patients also had a longer median PFS (11.70 vs. 4.00 months, P = 0.031) and median OS (19.80 vs. 11.6 months, P = 0.006) than no-cTACE patients. Regression analyses indicated that cTACE therapy and Eastern Cooperative Oncology Group performance status were independent risk factors for PFS and OS. AEs by type were similar between the cTACE and no-cTACE groups, except for liver function injury, which was more common among cTACE patients. Fourteen patients suffered with grade 1-2 of rash in 21 patients with objective response, while only 10 patients suffered with rash in 33 patients without objective response, the adjusted hazard ratio (HR) was 4.382 (1.297–14.803).ConclusionsThe combination of cTACE and PD-1 inhibitors and anti-angiogenesis TKIs as therapy significantly improved markers of treatment efficacy, including ORR, PFS, and OS, in unresectable HCC patients, while no more serious AEs recorded in this population compared to those receiving systemic treatment alone. Skin rash might be a predict factor to the efficacy of PD-1 inhibitors and TKI treatment.

Characteristics of EGFR Mutations in Plasma Samples in Non-Small Cell Lung Cancer Patients after Treatment with 1st and 2nd Generation of TKI at Bach Mai Hospital

This study aims to describe EGFR mutation status detected in plasma samples and analyze some related factors in non-small cell lung cancer patients after treatment with the generation I and II Tyrosine Kinase inhibitors at Bach Mai Hospital. Patients and methods: A retrospective descriptive study on 75 patients with non-small cell lung cancer tested for EGFR mutations in plasma after treatment with 1st or 2nd EGFR-TKIs in 2019-2020. Results: EGFR mutations were detected in 97.3% plasma samples; the T790M mutation accounted for 37.3% and is accompanied by a sensitive mutation TKI; The T790M mutations ratio after treatment was higher than before treatment with TKIs (p < 0.001); the median total duration of EGFR-TKI treatment was significantly longer in patients with T790M mutation than in those without (16.8 months vs 12.5 months, p = 0.005); the T790M mutation ratio was higher in patients with a deletion on exon 19 than in L858R mutation on exon 21 (p=0.028), in Erlotinib treatment group higher than in Gefitinib and Afatinib treatment group (51.4% vs. with 20.0% and 33.3%, p=0.039). Conclusions: EGFR mutation plasma test helps to monitor disease progression and detect resistance mutations T790M in NSCLC patients after TKI generation I and II.
 Keywords: non-small cell lung cancer, EGFR mutations, T790M mutations, TKIs..
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Genetic Determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo.

In lung adenocarcinoma, oncogenic EGFR mutations co-occur with many tumor suppressor gene alterations; however, the extent to which these contribute to tumor growth and response to therapy in vivo remains largely unknown. By quantifying the effects of inactivating 10 putative tumor suppressor genes in a mouse model of EGFR-driven Trp53-deficient lung adenocarcinoma, we found that Apc, Rb1, or Rbm10 inactivation strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2-the strongest drivers of growth in a KRAS-driven model-reduced EGFR-driven tumor growth. These results are consistent with mutational frequencies in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, KEAP1 inactivation reduced the sensitivity of EGFR-driven tumors to the EGFR inhibitor osimertinib, and mutations in genes in the KEAP1 pathway were associated with decreased time on tyrosine kinase inhibitor treatment in patients. Our study highlights how the impact of genetic alterations differs across oncogenic contexts and that the fitness landscape shifts upon treatment. SIGNIFICANCE: By modeling complex genotypes in vivo, this study reveals key tumor suppressors that constrain the growth of EGFR-mutant tumors. Furthermore, we uncovered that KEAP1 inactivation reduces the sensitivity of these tumors to tyrosine kinase inhibitors. Thus, our approach identifies genotypes of biological and therapeutic importance in this disease.This article is highlighted in the In This Issue feature, p. 1601.

RNA-Based Multiplexing Assay for Routine Testing of Fusion and Splicing Variants in Cytological Samples of NSCLC Patients.

The detection of ALK receptor tyrosine kinase (ALK), ROS proto-oncogen1, receptor tyrosine kinase (ROS1), ret proto-oncogen (RET), and MET proto-oncogen exon 14 skipping (METΔex14) allows for the selection of specific kinase inhibitor treatment in patients with non-small cell lung cancer (NSCLC). Multiplex technologies are recommended in this setting. We used nCounter, a multiplexed technology based on RNA hybridization, to detect ALK, ROS1, RET, and METΔex14 in RNA purified from cytological specimens (n = 16) and biopsies (n = 132). Twelve of the 16 cytological samples (75.0%) were evaluable by nCounter compared to 120 out of 132 (90.9%) biopsies. The geometrical mean (geomean) of the housekeeping genes of the nCounter panel, but not the total amount of RNA purified, was significantly higher in biopsies vs. cytological samples. Among cytological samples, we detected ALK (n = 3), METΔex14 (n = 1) and very high MET expression (n = 1) positive cases. The patient with METΔex14 had a partial response to tepotinib, one of the patients with ALK fusions was treated with crizotinib with a complete response. Cell blocks and cytological extensions can be successfully used for the detection of fusions and splicing variants using RNA-based methods such as nCounter.

Comparison of the characteristics of uncommon epidermal growth factor receptor (EGFR) mutations and EGFR-tyrosine kinase inhibitor treatment in patients with non-small cell lung cancer from different ethnic groups.

Patients with epidermal growth factor receptor (EGFR)-sensitive mutations generally have a significantly higher objective response rate (ORR) and longer progression-free survival (PFS) after EGFR-tyrosine kinase inhibitor (TKI) treatment. However, the efficacy of EGFR-TKIs in the case of uncommon EGFR mutations has remained elusive. In the present study, the characteristics of uncommon EGFR mutations and EGFR-TKI treatments were compared in patients with non-small cell lung cancer (NSCLC) from different ethnic groups. A total of 2,984 patients with pathologically confirmed NSCLC encountered between February 2012 to February 2017 at the Affiliated Tumor Hospital of Xinjiang Medical University (Urumqi, China) were enrolled in the present study. The Amplification Refractory Mutation System was adopted to determine EGFR gene expression, compare the ethnic differences in EGFR mutations between Xinjiang Uygur and Han people, analyze the distribution of uncommon mutation types and evaluate the link between clinicopathological features associated with uncommon mutations and the efficacy of EGFR-TKI treatment. There were significant differences in EGFR mutations in lung adenocarcinoma and lung squamous cell carcinoma between patients from the Xinjiang Uygur group and the Han group (P<0.001). The differences in the uncommon EGFR mutations were significant in patients with lung adenocarcinoma (P<0.05). The most common site of lymph node metastasis in patients with uncommon mutations was the hilar lymph node, supraclavicular/subclavian lymph node, cervical lymph node and mediastinal lymph node; the most common distant metastatic organs were the lung, bone, brain, liver and adrenal gland. Of the uncommon mutations, the most common single mutations were L861Q, G719X and 20ins mutations; the most common double mutation was the S768I and 20ins mutation. The incidence rate of EGFR gene mutations was significantly higher in Han people from Xinjiang than in Uygur people. There were marked differences between individuals regarding the efficacy of EGFR-TKI treatment and the survival time of patients with uncommon EGFR mutations, second-line EGFR-TKIs had a lower ORR and DCR while had a longer mPFS. All of these could provide a basis for the exploration of different regimens for patients with different types of uncommon mutations.

Association Between Glutathione-S-Transferase Gene Polymorphisms and Responses to Tyrosine Kinase Inhibitor Treatment in Patients with Chronic Myeloid Leukemia: A Meta-analysis.

Although many earlier studies revealed an effect of glutathione-S-transferase (GST) gene polymorphisms on tyrosine kinase inhibitor (TKI) treatment responses in chronic myeloid leukemia (CML) patients, the significance of this relationship remains controversial. This study aimed to review and meta-analyze treatment responses to TKIs in patients with CML and GST gene polymorphisms, including GSTT1, GSTM1, and GSTP1. We searched four medical databases, PubMed, Web of Science, the Cochrane Library, and Embase, by using keywords related to GST gene polymorphisms and clinical responses in CML patients receiving TKI treatment. The meta-analysis was performed using RevMan version 5.3 and Comprehensive Meta-Analysis software version 3.0. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to examine the association between GSTT1, GSTM1, and GSTP1 polymorphisms and TKI treatment responses in patients with CML. The null polymorphisms of GSTT1 and GSTM1 did not affect TKI treatment responses, while the GSTP1 Ile105Val polymorphism had a significant impact on responses to TKI. Patients who were GSTP1 variant allele carriers (AG + GG) had poor responses to TKI treatment compared to patients who were wild-type homozygote carriers (AA) (OR 1.85, 95% CI 1.31-2.62; p < 0.001). This meta-analysis of patients with CML showed that G allele carriers with GSTP1 Ile105Val polymorphism had significantly worse responses to TKI treatment than wild-type homozygote carriers.

Multiple-line Chemotherapy and Tyrosine Kinase Inhibitor Treatment in Patients with Advanced Lung Cancer.

To analyse the clinical outcomes of patients with lung cancer treated with first and multiple-line chemotherapy and tyrosine kinase inhibitor (TKI). The present study included a total of 89 patients of whom lung cancer was histologically confirmed between July 2016 and September 2017. Patients' demographics, chemotherapy/TKI treatment details and clinical outcomes were retrieved. The progression-free survivals (PFS) after first-line and multiple-line treatments were evaluated using Kaplan-Meier analysis with log-rank test. Risk factors for progressive disease (PD) were identified using Cox multivariate regression model. A total of 50 males and 39 females were enrolled. About 90% of the tumors were histologically classified as adenocarcinoma, and 77/89 cases (86.5%) were at TNM stage IV. The median PFS for the first-line treatment was 6.17 months. After first-line treatment, more favourable PFS was observed in patients who had prior surgery of lung cancer (P = 0.002). Multivariate analysis showed that patients who had received no prior surgical treatment for lung cancer were at higher risk of PD (OR, 4.311; 95% CI, 1.836 to 10.120; P = 0.0008). Besides, in patients with driver mutations, those who received no TKI treatment were under higher risk of PD compared to those who had been treated with TKI (OR, 4.876; 95% CI, 1.877 to 12.666; P = 0.0011). The median PFS for the multiple-line treatment was 24.67 months. After multiple-line treatments, favourable PFS was associated with tumor histological types of adenocarcinoma (P = 0.041), genetic lesions at exon 19 of EGFR (P = 0.001) and fourth-line treatment (P = 0.001). Risk factors for PD after multiple-line treatments were no prior surgery for lung cancer (OR, 3.335; 95% CI, 1.158 to 9.605; P = 0.0256), no TKI use in multiple-line treatment (OR, 10.095; 95% CI, 2.405 to 42.378; P = 0.0016), and being treated by first-line treatment alone (OR, 30.421; 95% CI, 4.813 to 192.269; P = 0.0003). The present study demonstrated the benefits of TKI in patients with advanced lung cancer, providing insights into the refinement of the management strategy.

Plasma ctDNA monitoring during epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor treatment in patients with EGFR-mutant non-small cell lung cancer (JP-CLEAR trial).

Osimertinib, a third generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), is active against EGFR-mutant non-small cell lung cancer (NSCLC) resistant to first-/second-generation EGFR-TKIs with the T790M mutation. T790M monitoring in plasma circulating tumor DNA (ctDNA) in patients receiving EGFR-TKIs is less invasive than re-biopsy and could provide valuable clinical information. Patients with advanced or postoperative recurrent NSCLC with sensitizing EGFR mutations who were planned to receive or were receiving first-/second-generation EGFR-TKI treatment without disease progression were eligible for enrollment. Plasma samples at baseline and every 1-2 months thereafter were analyzed for EGFR mutation status using the cobas®EGFR Mutation Test v2. Between September 2016 and March 2017, 122 patients at 15 Japanese institutions were enrolled. In August 2018, 1291 plasma samples from 121 patients were analyzed for EGFR mutation status. At baseline, a sensitizing EGFR mutation was detected in 29 (23.9%) of 121 patients and T790M mutation was detected in three (2.5%). At follow-up, 66 (54.5%) patients experienced disease progression and 64 (52.9%) discontinued first-line EGFR-TKI treatment. Twenty-two (18.2%) patients showed T790M in plasma ctDNA, of which 15(68.2%) received osimertinib. Although 31 patients received re-biopsy to examine EGFR status at disease progression, T790M was detected in only nine (22.0%) patients, of which 7 (77.8%) received osimertinib. ctDNA monitoring during EGFR-TKI treatment is useful for detecting T790M mutation. The efficacy of osimertinib treatment based on T790M status in plasma ctDNA remains to be established, warranting further research.

Factors associated with improvement in symptoms and quality of life for first-line EGFR-tyrosine kinase inhibitor treatment in patients with EGFR-mutated non-small-cell lung cancer - A multicenter prospective SMILE study

Introduction: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are a standard first-line treatment for advanced EGFR-mutated NSCLC patients. Factors associated with symptoms and quality of life (QOL) improvements have not been investigated.Methods: We conducted a multicenter, prospective study to evaluate improvements in QOL and symptoms in NSCLC patients treated with first-line EGFR-TKIs. QOL was assessed using the instrument of Functional Assessment of Cancer Therapy-Lung questionnaire (FACT-L) and Treatment Outcome Index (TOI). Assessment of symptoms was evaluated using the Lung cancer subscale (LCS).Results: Eligible subjects included 280 patients for endpoint analyses. The mean FACT-L score increased by 4.0 ± 15.56 at Week 2 (p<0.001), 5.1 ± 18.48 at Week 4 (p<0.001), and 4.2 ± 20.27 at Week 12 (p=0.001). Similarly, a 2.3 ± 11.65 (p<0.001), 3.2 ± 13.59 (p<0.001), and 2.4 ± 14.34 (p=0.009) increase in mean TOI score were observed at Weeks 2, 4 and 12, respectively. For LCS, it was slightly increased by 1.7 ± 4.61, 2.0 ± 5.50, and 2.0 ± 5.36 at Weeks 2, 4, and 12 (all p<0.001), respectively. Subgroup analyses showed patients who were ex-smokers or with at least 3 metastatic sites were associated with symptoms improvement. Patients who were ex-smokers, with at least 3 metastatic sites, a PS of 1, or treated with gefitinib were associated with QOL improvement.Conclusions: In EGFR -mutated NSCLC patients who were treated with first-line EGFR-TKIs, these ex-smokers or with 3 or more metastatic sites were associated with improvements in symptoms and QOL.

Changeable Conditional Survival Rates and Associated Prognosticators in Patients with Metastatic Renal Cell Carcinoma Receiving First Line Targeted Therapy

In this study we evaluated conditional survival probabilities in patients with metastatic renal cell carcinoma who underwent first line tyrosine kinaseinhibitor therapy. We also identified predictors of conditional survival with time. We retrospectively reviewed clinical data on 1,659 individuals with metastatic renal cell carcinoma in the Korean Renal Cancer Study Group database, of whom the records of 1,131 were finally analyzed. The primary end point was conditional overall survival. Kaplan-Meier survival analysis was used to calculate conditional overall survival probabilities using the formula, conditional survival (α│β) = S(α + β)/S(β), indicating the likelihood of additional α years survivorship in person who has already survived for β years after initial therapy. S(χ) represents the actual survival rate. Multivariate Cox regression model was used to identify predictors of conditional survival with time. Six, 12, 18, 24 and 36-month conditional overall survival gradually increased in patients at all additional survival times after initial treatment compared to patient baseline survival estimations. While the actual overall survival rate decreased with time, the 36-month conditional overall survival rate was calculated as 7.3% higher in patients who had already survived 36 months compared to baseline estimations at the time of initial tyrosine kinase inhibitor treatment. Furthermore, predictors of conditional overall survival changed with time. Only previous metastasectomy remained a key prognosticator of conditional overall survival until 36 months of survival following initial tyrosine kinase inhibitor treatment. Conditional survival improved with time after initial tyrosine kinase inhibitor treatment in patients with metastatic renal cell carcinoma. Our study offers valuable information for practical survival estimations and relevant prognosticators in patients with metastatic renal cell carcinoma who receive first line tyrosine kinase inhibitor.

Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience

AbstractWe previously reported durable responses and manageable safety of ibrutinib from a 3-year follow-up of treatment-naïve (TN) older patients (≥65 years of age) and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We now report on long-term efficacy and safety with median follow-up of 5 years in this patient population with TN (N = 31) and R/R (N = 101) CLL/SLL. With the current 5-year follow-up, ibrutinib continues to yield a high overall response rate of 89%, with complete response rates increasing over time to 29% in TN patients and 10% in R/R patients. The median progression-free survival (PFS) was not reached in TN patients. The 5-year PFS rate was 92% in TN patients and 44% in R/R patients. Median PFS in R/R patients was 51 months; in those with del(11q), del(17p), and unmutated IGHV, it was 51, 26, and 43 months, respectively, demonstrating long-term efficacy of ibrutinib in some high-risk subgroups. Survival outcomes were less robust for R/R patients with del(17p) and those who received more prior therapies. The onset of grade ≥3 cytopenias, such as neutropenia and thrombocytopenia, decreased over time. Treatment--limiting adverse events were more frequent during the first year compared with subsequent periods. These results demonstrate sustained efficacy and acceptable tolerability of ibrutinib over an extended time, providing the longest experience for Bruton tyrosine kinase inhibitor treatment in patients with CLL/SLL. These trials were registered at www.clinicaltrials.gov as #NCT01105247 and #NCT01109069.

Circulating plasma microRNAs as potential markers to identify EGFR mutation status and to monitor epidermal growth factor receptor-tyrosine kinase inhibitor treatment in patients with advanced non-small cell lung cancer.

We aimed to identify a panel of circulating plasma microRNAs that can predict EGFR mutation status and monitor epidermal growth factor receptor-tyrosine kinase inhibitor treatment in patients with non-small cell lung cancer. Microarrays were performed for the preliminary screening of dysregulated microRNAs in 9 EGFR mutation-positive patients versus healthy controls. MiR-107 was upregulated and miR-195 was downregulated in the exon 19 deletion versus wild-type group. The areas under the receiver operating characteristic curves for miR-107, miR-195, and a panel of these 2 microRNAs were 0.72, 0.75, and 0.74, with sensitivities and specificities of 64.7% and 76.6%, 71.8% and 69.1%, and 71.7% and 78.9%, respectively. MiR-122 was significantly upregulated in the p.L858R versus wild-type group. An area under the receiver operative characteristic curve of 0.75 suggests that miR-122 might be a specific biomarker for patients with the p.L858R mutation. In addition, dynamic changes in these 3 microRNAs were also found to correlate with responses to epidermal growth factor receptor-tyrosine kinase inhibitor treatment, indicating that circulating plasma microRNAs may represent potential biomarkers for monitoring epidermal growth factor receptor-tyrosine kinase inhibitor treatment. This study demonstrates the prospective application of circulating plasma microRNAs as potential non-invasive, convenient biomarkers for patients with EGFR-sensitive mutations.

EGFR mutation testing in blood for guiding EGFR tyrosine kinase inhibitor treatment in patients with nonsmall cell lung cancer

Epidermal growth factor receptor (EGFR) mutation testing in tumor tissue is now a common practice in selecting non-small cell lung cancer (NSCLC) patients for EGFR tyrosine kinase inhibitor (TKI) treatment. However, tumor tissues are often absent or insufficient for the testing. Blood is a potential substitute providing a noninvasive, easily accessible and repeatedly measureable source of genotypic information. However which is the best blood EGFR mutation testing method remains unclear. We undertake this study to investigate the best blood EGFR mutation testing method for selecting EGFR TKI treatment in patients with NSCLC. This study was registered in PROSPERO (CRD42017055263). PubMed, EMBASE, Cochrane library, and NIHR Health Technology Assessment program will be searched. Studies fulfill the following criteria will be eligible: (1) randomized controlled trials or cohort studies; (2) included patients with NSCLC; (3) reported response, progression-free survival, or overall survival for EGFR TKI by the EGFR mutation status in blood sample. Diagnostic accuracy of blood EGFR mutation tests for predicting response to TKI will be pooled. Tumor response, progression-free survival, and overall survival according to different blood EGFR mutation testing methods will be evaluated and compared. Based published data and combined analysis, this study will quantitatively compare the blood EGFR mutation testing methods according to their accuracy for predicting treatment response and relationship with clinical outcome in NSCLC patients treated with EGFR TKIs. This protocol will determine the best blood EGFR mutation testing method.

K-RAS mutation and resistance to epidermal growth factor receptor-tyrosine kinase inhibitor treatment in patients with nonsmall cell lung cancer.

The aim of this study was to evaluate the relationship between k-RAS gene mutation and the resistance to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment in patients with nonsmall-cell lung cancer (NSCLC). Forty-five pathologies confirmed NSCLC patients who received EGFR-TKI (Gefitinib) treatment were retrospectively included in this study. The mutation of codon 12 and 13, located in exon1 and exon 2 of k-RAS gene were examined by polymerase chain reaction (PCR) and DAN sequencing in tumor samples of the included 45 NSCLC patients. The correlation between Gefitinib treatment response and k-RAS mutation status was analyzed in tumor samples of the 45 NSCLC patients. Eight tumor samples of the 45 NSCLC patients were found to be mutated in coden 12 or 13, with an mutation rate of 17.8% (8/45); the objective response rate (ORR) was 29.7%(11/37) with 1 cases of complete response (CR) and 10 cases of partial response in k-RAS mutation negative patients. Furthermore, the ORR was 0.0% in k-RAS mutation positive patients with none CR. The ORR between k-RAS mutation and nonmutation patients were significant different (P < 0.05). k-RAS gene mutation status was associated with the response of Gefitinib treatment in patients with NSCLC.

A survey on tyrosine kinase inhibitor treatment in patients with chronic myeloid leukemia in China: from patients'perspective

目的评估中国慢性髓性白血病（CML）患者接受酪氨酸激酶抑制剂（TKI）治疗的现状，并分析相关影响因素。方法2014年5月至11月，在全国范围内向正在接受TKI治疗的成年CML患者发放并收集无记名调查问卷。结果共收集1 038份问卷，949份可供评估。949例受访者中，男549例（58%），中位年龄41(18~88）岁，623例（66%）为城镇户籍，449例（47%）具有大学及以上学历。888例（94%）的受访者初诊时处于慢性期，其中690例（78%）在诊断1年内开始用TKI治疗。794例（84%）服用伊马替尼，768例（81%）服用原研药。TKI中位治疗时间为3（<1~13）年，可评估TKI治疗反应的受访者中，85%（708/834）获得完全细胞遗传学反应（CCyR），46%（397/859）获得完全分子学反应（CMR）。多因素分析显示，女性（OR=1.8, 95% CI 1.1~2.8，P=0.019和OR=1.5, 95% CI 1.1~2.0，P=0.015）、TKI治疗时间>3年（OR=4.1，95% CI 2.6~6.5，P<0.001和OR=3.7, 95% CI 2.7~5.1，P<0.001）和服用伊马替尼（OR=2.1, 95% CI 1.2~3.7，P=0.007和OR=3.3, 95% CI 2.1~5.1，P<0.001）是有利于获得CCyR和CMR的共同独立因素。此外，大学及以上学历（OR=2.0, 95% CI 1.3~3.1，P=0.003）、确诊1年内开始TKI治疗（OR=2.4, 95% CI 1.5~3.8，P<0.001）和服用原研药（OR=2.4, 95% CI 1.4~4.0，P=0.001）是有利于获得CCyR的独立因素。787例（83%）受访者付费服用TKI，每年TKI中位自付金额为7.20（0.24~37.00）万元。884例报告了TKI治疗中的最大障碍的受访者中，534例（62%）报告“经济负担”，仅152例（17%）报告“不良反应影响生活质量”。结论在当今中国，绝大多数CML患者服用伊马替尼，TKI治疗结果满意，但经济负担重是TKI治疗中的主要障碍。

Analysis of Intratumor Heterogeneity of EGFR Mutations in Mixed Type Lung Adenocarcinoma

BackgroundEpidermal growth factor receptor mutations are predictive of the success of EGFR tyrosine kinase inhibitor treatment in patients with advanced non–small-cell lung cancer. As with other solid tumors, lung cancer is thought to be the result of an accumulation of genetic alterations after exposure to carcinogens. The aim of the present study was to clarify the relationship between multistep carcinogenesis and the accumulation of EGFR mutations. Patients and MethodsThe intratumor heterogeneity of EGFR mutations was analyzed in 38 patients with resected mixed-type lung adenocarcinoma according to histological patterns, and the clinical features of the patients harboring intratumor heterogeneity of EGFR mutations were evaluated. ResultsIntratumor heterogeneity of EGFR mutations was detected in 9 of 38 tumors. EGFR mutations were more common in the bronchioloalveolar (lepidic) carcinoma pattern than in the papillary and acinar patterns, although this difference was not significant. However, there was a significant correlation between intratumor heterogeneity of EGFR mutations and smoking history (P < .043). ConclusionIntratumor heterogeneity of EGFR mutations correlates with the distribution of histological subtype in mixed type adenocarcinoma and is associated with smoking history.

Serum Heparan Sulfate Concentration is Correlated with the Failure of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Treatment in Patients with Lung Adenocarcinoma

The epidermal growth factor receptor (EGFR) mutation status is a validated biomarker for the stratification of EGFR-tyrosine kinase inhibitor (EGFR-TKIs) treatment in patients with non-small cell lung cancer (NSCLC); however, its use is limited in patients with wild-type EGFR, and new biomarkers are needed. We hypothesized that the serum concentration of heparan sulfate (HS), which activates oncogenic growth factor receptor signaling through EGFR and non-EGFR signaling pathways, may be a novel glycobiological biomarker for EGFR-TKIs treatment in NSCLC. The pretreatment serum HS concentrations were determined using enzyme-linked immunosorbent assay in 83 patients with stage IV non-small cell lung adenocarcinoma who received EGFR-TKIs treatment. The relationship between the serum HS concentrations and patient characteristics, tumor response, progression-free survival (PFS), and overall survival (OS) were analyzed. Patient sex, performance status, smoking history, and EGFR mutation status were associated with tumor response. The serum HS concentrations were significantly higher among patients with progressive disease than among those without progressive disease (p = 0.003). Furthermore, the serum HS concentrations were strongly associated with a poor PFS and OS in a univariate Cox analysis (p = 0.0022 and p = 0.0003, respectively). A stratified multivariate Cox model according to the EGFR mutation status showed that higher HS concentrations were significantly associated with a shorter PFS and OS (p = 0.0012 and p = 0.0003). We concluded that a high-serum HS concentration was strongly related to a poor treatment outcome of EGFR-TKIs and may be a promising noninvasive and repeatable glycobiological biomarker in cancer treatment.

An analysis of serum heparan sulfate concentration and EGFR tyrosine kinase inhibitor treatment in patients with non-small cell lung adenocarcinoma.

10601 Background: The EGFR mutation status is a validated biomarker for the stratification of EGFR-tyrosine kinase inhibitor (EGFR-TKIs) treatment in patients with non-small-cell lung cancer (NSCLC); however, its use is limited in patients with wild-type EGFR, and new biomarkers are needed. We hypothesized that the serum concentration of heparan sulfate (HS), which activates oncogenic growth factor receptor signaling through EGFR and non-EGFR signaling pathways, may be a novel glycobiological biomarker for EGFR-TKIs treatment in NSCLC. Methods: The pre-treatment serum HS concentrations were determined using ELISA in 83 patients with stage IV non-small-cell lung adenocarcinoma who received EGFR-TKIs treatment. The relationship between the serum HS concentrations and patient characteristics, tumor response, progression-free survival (PFS) and overall survival (OS) were analyzed. Results: Patient sex, performance status, smoking history, and EGFR mutation status were associated with tumor response. The serum HS concentrations were significantly higher among patients with progressive disease (PD) than among those without PD (P=0.003). Furthermore, the serum HS concentrations were strongly associated with a poor PFS and OS in a univariate Cox analysis (P=0.0022 and P=0.0003, respectively). A stratified multivariate Cox model according to the EGFR mutation status showed that higher HS concentrations were significantly associated with a shorter PFS and OS (P=0.0012 and P=0.0003). Conclusions: We concluded that a high serum HS concentration was strongly related to a poor treatment outcome of EGFR-TKIs and may be a promising non-invasive and repeatable glycobiological biomarker in cancer treatment.