scholarly journals Detection of TP53 Mutations in Tissue or Liquid Rebiopsies at Progression Identifies ALK+ Lung Cancer Patients with Poor Survival

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 124 ◽  
Author(s):  
Petros Christopoulos ◽  
Steffen Dietz ◽  
Martina Kirchner ◽  
Anna-Lena Volckmar ◽  
Volker Endris ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Resistance Mechanisms ◽  
Wild Type ◽  
Tp53 Mutations ◽  
Lung Cancer Patients ◽  
Anaplastic Lymphoma ◽  
Nsclc Patients

Anaplastic lymphoma kinase (ALK) sequencing can identify resistance mechanisms and guide next-line therapy in ALK+ non-small-cell lung cancer (NSCLC), but the clinical significance of other rebiopsy findings remains unclear. We analysed all stage-IV ALK+ NSCLC patients with longitudinally assessable TP53 status treated in our institutions (n = 62). Patients with TP53 mutations at baseline (TP53mutbas, n = 23) had worse overall survival (OS) than patients with initially wild-type tumours (TP53wtbas, n = 39, 44 vs. 62 months in median, p = 0.018). Within the generally favourable TP53wtbas group, detection of TP53 mutations at progression defined a “converted” subgroup (TP53mutconv, n = 9) with inferior OS, similar to that of TP53mutbas and shorter than that of patients remaining TP53 wild-type (TP53wtprogr, 45 vs. 94 months, p = 0.043). Progression-free survival (PFS) under treatment with tyrosine kinase inhibitors (TKI) for TP53mutconv was comparable to that of TP53mutbas and also shorter than that of TP53wtprogr cases (5 and 8 vs. 13 months, p = 0.0039). Fewer TP53wtprogr than TP53mutbas or TP53mutconv cases presented with metastatic disease at diagnosis (67% vs. 91% or 100%, p < 0.05). Thus, acquisition of TP53 mutations at progression is associated with more aggressive disease, shorter TKI responses and inferior OS in ALK+ NSCLC, comparable to primary TP53 mutated cases.

Training and validation study for sequential monitoring of CAMLs in circulation to predict ongoing progression in lung cancer patients undergoing definitive radiotherapy.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3053-3053
Author(s):  
Daniel Adams ◽  
Jianzhong He ◽  
Yawei Qiao ◽  
Ting Xu ◽  
Hui Gao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Radiation Therapy ◽  
Cancer Patients ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Training Set ◽  
Lung Cancer Patients ◽  
Therapeutic Decisions ◽  
Validation Set ◽  
Nsclc Patients

3053 Background: Cancer Associated Macrophage-Like cells (CAMLs) are a recently described circulating stromal cell common in the peripheral blood of cancer patients that are prognostic for progressive disease. Further, it has been shown that changes in CAML size (i.e. enlargement above 50µm) can predict progression free survival (PFS) in thoracic cancers (e.g. lung). We enrolled 104 unresectable non-small cell lung cancer (NSCLC) patients, with an initial training set review of 54 patients, to determine if change in CAML size after radiation therapy was predictive PFS. Methods: A 2 year single blind prospective study was undertaken to test the relationship of ≥50µm CAMLs to PFS based on imaging in lung patients before and after induction of chemo radiation, or radiation therapy. To achieve a 2-tailed 90% power (α = 0.05) we recruited a training set of 54 patients and validation set of 50 patients all with pathologically confirmed unresectable NSCLC: Stage I (n = 14), Stage II (n = 16), Stage III (n = 61) & Stage IV (n = 13). Baseline (BL) blood samples were taken prior to start of therapy & a 2nd blood sample (T1) was taken after completion of radiotherapy (~30 days). Blood was filtered by CellSieve filtration and CAMLs quantified. Analysis by CAML size of < 49 µm or ≥50 µm was used to evaluate PFS hazard ratios (HRs) by censored univariate & multivariate analysis. Results: CAMLs were found in 95% of samples averaging 2.7 CAMLs/7.5mL sample at BL, with CAMLs ≥50 µm having reduced PFS (HR = 2.2, 95%CI1.3-3.8, p = 0.003). At T1, 18 patients had increased CAML size ≥50 µm with PFS (HR = 4.6, 95%CI2.5-8.3, p < 0.001). In total, ≥50 µm CAMLs at BL was 76% accurate at predicting progression within 24 months while ≥50 µm CAMLs at T1 was 83% accurate at predicting progression. Conclusions: In unresectable NSCLC patients, enlargement of CAMLs during treatment is an indicator active progression. We identify that a single ≥50 µm CAML after induction of radiotherapy, in our training set and confirmed in our validation set, is an indicator of poor prognosis. We suggest that changes in CAML size during therapy may indicate the efficacy of therapy and could potentially help shape subsequent therapeutic decisions.

Characterizing biomarker testing over time in lung cancer patients using oncology electronic medical records (EMR).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20056-e20056
Author(s):  
Jennifer Christian ◽  
Joe Wagner ◽  
Gregory Mastrogiovanni ◽  
Andrew David Norden ◽  
Ian Kurashige
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Cell Lung Cancer ◽  
Stage Iv ◽  
Lung Cancer Patients ◽  
Anaplastic Lymphoma ◽  
Biomarker Testing ◽  
Nsclc Patients ◽  
The Impact ◽  
Over Time

e20056 Background: This study characterizes biomarker testing over time in Non-Small Cell Lung Cancer (NSCLC) patients treated within a clinical setting. There have been tremendous advances in treatments for NSCLC that target specific biomarkers such as epithelial growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and the Programmed cell death-ligand 1 (PD-L1) pathway. As we consider using oncology EMR records for future studies, it is critical to understand the extent to which biomarker testing is conducted in routine care, the extent to which testing has increased, and the types of patients for which it is done. Methods: This is a retrospective observational analysis derived from the COTA Oncology EHR database from January 1, 2015 through December 31, 2017. The data sets generated for the study included all relevant, retrospective patient-level, de-identified data available for patients with lung cancer, including EGFR, ALK, and PD-L1 testing regardless of age, gender, and stage at diagnosis. We examined characteristics associated with each type of test received as well as by those who had received all 3 biomarker tests, 1-2 of the tests, or no biomarker testing. Analyses were conducted using SAS V. 9.1 and stratified by data source. Results: There were 1,891 patients in the COTA database. Among newly diagnosed NSCLC patients, EGFR testing has been consistently conducted in patients during the study period (76 – 86%), while ALK testing [44% in 2015Q1 to 74% in 2017Q4] and PD-L1 testing [12% in 2015Q1 to 77% in 2017Q4] have steadily increased each quarter. Overall, testing was more likely to be conducted in non-squamous cell lung cancer patients, Stage IV lung cancer, and those without a history of smoking. For EGFR, testing was more prevalent among women and young age groups ( < 64 years vs. 65 and older). Conclusions: Biomarker testing has rapidly increased for ALK and PD-L1, which correlates with the uptake of new targeted therapies. Further research could be conducted to understand clinical outcomes associated with this increase in testing as well as the impact on healthcare resource utilization.

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

BMC Cancer ◽  
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.

The role of PTEN and TP53 co-mutations in immunotherapy of lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21161-e21161
Author(s):  
Xiaolong Ma ◽  
Ding Zhang ◽  
Shiqing Chen
Keyword(s):  
Lung Cancer ◽  
Small Sample Size ◽  
Case Reports ◽  
Progression Free Survival ◽  
Small Sample ◽  
Wild Type ◽  
Tp53 Mutations ◽  
Pathogenic Mutations ◽  
Nsclc Patients

e21161 Background: Patients with non-small cell lung cancer (NSCLC) harboring PTEN mutations have a worse prognosis of immunotherapy in research with small sample size and case reports. However, the role of PTEN and TP53 co-mutations in immunotherapy of NSCLC has not been fully studied. Methods: Patients with NSCLC from our dataset were enrolled in this study. For the genomic profiling, only the pathogenic mutations and likely pathogenic mutations in clinical significance were rolled. The efficiency of immunotherapy was analyzed in a public cohort of 240 NSCLC patients by Rizvi. Patients with EGFR/ALK mutation were excluded in our analysis. Results: In our dataset, 1,428 patients were included in the analysis. 25 (1.75%) patients have PTEN mutations and 429 (30.04%) patients have TP53 mutations. In all patients with PTEN mutations, 84% with TP53 co-mutations. Median tumor mutational burden (TMB) was 12.29 mutations/MB (range, 3.35-36.87) and 6.98mutations/MB (range, 0.56-9.50) in patients harboring PTEN mutations with TP53 co-mutations and without TP53 co-mutations, respectively ( p= 0.02). In 240 NSCLC patients of Rizvi, the overall response rate (ORR) of the PTEN and TP53 co-mutations group, the PTEN mutations without TP53 mutations group and PTEN wild-type group was 33.33%, 0% and 20.26%, respectively. The disease control rate (DCR) was 83.33%, 0% and 54.74%, respectively. The median progression-free survival (PFS) in the PTEN and TP53 co-mutations group was the longest (7.5 months), while the median PFS in the PTEN mutations without TP53 mutations group was only 2.5 months. However, No significant differences of PFS were observed. Conclusions: Our findings suggested that patients with NSCLC harboring PTEN and TP53 co-mutations might benefit more from immunotherapy compare to those harboring PTEN mutation without TP53 mutations and PTEN wild-type. TMB may be an important factor that lead to the results. Further studies need to be explore in cohorts with larger sample sizes.

scholarly journals Novel MRPS9-ALK Fusion Mutation in a Lung Adenocarcinoma Patient: A Case Report

2021 ◽  
Vol 11 ◽  
Author(s):  
Huamiao Zhou ◽  
Binyue Xu ◽  
Jili Xu ◽  
Guomeng Zhu ◽  
Yong Guo
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Inhibitors ◽  
Clinical Symptoms ◽  
Progression Free Survival ◽  
Anaplastic Lymphoma ◽  
Lung Adenocarcinoma Patient ◽  
Tki Treatment ◽  
Nsclc Patients ◽  
First And Second Generation

Anaplastic lymphoma kinase (ALK) rearrangements account for approximately 5–6% of non–small-cell lung cancer (NSCLC) patients. In this study, a case of lung adenocarcinoma harboring a novel MRPS9-ALK fusion is reported. The patient responded well to the first and second generation of ALK-tyrosine kinase inhibitors (ALK-TKIs) (crizotinib then alectinib), as her imaging findings and clinical symptoms significantly improved. At last follow-up, over 21 months of overall survival (OS) has been achieved since ALK-TKI treatment. The progression-free survival (PFS) is already ten months since alectinib. The adverse effects were manageable. The case presented here provides first clinical evidence of the efficacy of ALK-TKIs in NSCLC patients with MRPS9-ALK fusion.

Epithelial to mesenchymal markers and clinical outcomes on erlotinib in stage IV non-small cell lung cancer patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19117-e19117
Author(s):  
Mark Pool ◽  
Mary J. Fidler ◽  
Sanjib Basu ◽  
Brett Mahon ◽  
Lela Buckingham ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Advanced Nsclc ◽  
Stage Iv ◽  
Difference Score ◽  
Lung Cancer Patients ◽  
Resected Nsclc ◽  
Epithelial Phenotype ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Tissue Specimens ◽  
Nsclc Patients

e19117 Background: An epithelial phenotype in NSCLC is associated with improved sensitivity to EGFR tyrosine kinase inhibitors (TKI). The best method to identify this subset is unknown (Richardson Anticancer Research 2012, Byers Clin Cancer Res 2012). This retrospective study correlates E-cadherin (Ecad) and vimentin (vim) immunohistochemistry (IHC) expression with outcomes in advanced NSCLC patients (pts) treated with erlotinib (E). Methods: Advanced NSCLC pts that received E were included if sufficient tumor was available from diagnosis. IHC scores for E-cad and vim were generated by multiplying frequency (0-4) by intensity (0-4). Log Rank was used to correlate IHC expression with progression free and overall survival (PFS, OS). Results were compared to a subset of pts with tissue from primary surgical NSCLC resection who later received E for recurrent disease. Results: 159 advanced NSCLC pts treated with E had tissue from diagnosis and IHC analysis. There was no correlation with PFS or OS on E and high/low vim or Ecad expression. Subtracting the IHC scores (vim minus ecad) created a difference score. A low difference score (n = 62) correlated with prolonged PFS (2.6 vs 1.9 months, p = .014 HR 1.52) compared with a high score, n = 97. Low difference score trended toward prolonged OS (p=.46) 33 of the patients had tissue available from primary surgical resection. The invasive front was examined for membranous E-cad and cytoplasmic vim (Allred score 0-8). Patients with low vim (< 4) and Ecad (>5), n= 19, trended toward prolonged PFS and OS on E compared with patients with high vim (>5) and low Ecad (<6), n=10 (4.2 vs 1.6 months and 15.5 vs 6.5 months, respectively, p=NS). Conclusions: In this retrospective analysis, using unselected, frequently small tissue specimens, the expression of ecad or vim alone by IHC did not correlate with outcomes for E treated patients. A complicated difference score (vimentin score minus ecadherin score) did correlate with PFS on E. Examining EMT markers at the invasive edge of resected NSCLC tumors might more accurately assess EMT activity and its relationship to outcomes when these pts are recommended EGFR-TKIs.

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