Transformation to small cell lung cancer is irrespective of EGFR and accelerated by SMAD4-mediated ASCL1 transcription independently of RB1 in non-small cell lung cancer.

OBJECTIVES: Histological transformation to small cell lung cancer (SCLC) has been identified as a mechanism of TKIs resistance in EGFR-mutant non-small cell lung cancer (NSCLC). We aim to explore the prevalence of transformation in EGFR-wildtype NSCLC and the mechanism of SCLC transformation, which are rarely understood. METHODS: We reviewed 1474 NSCLC patients to investigate the NSCLC-to-SCLC transformed cases and the basic clinical characteristics, driver gene status and disease course of them. To explore the potential functional genes in SCLC transformation, we obtained pre- and post-transformation specimens and subjected them to a multigene NGS panel involving 416 cancer-related genes. To validate the putative gene function, we established knocked-out models by CRISPR-Cas 9 in HCC827 and A549-TP53-/- cells and investigated the effects on tumor growth, drug sensitivity and neuroendocrine phenotype in vitro and in vivo. We also detected the expression level of protein and mRNA to explore the molecular mechanism involved. RESULTS: We firstly reported an incidence rate of 9.73% (11/113) of SCLC transformation in EGFR-wildtype NSCLC and demonstrated that SCLC transformation is irrespective of EGFR mutation status (P = 0.16). We sequenced 8 paired tumors and identified a series of mutant genes specially in transformed SCLC such as SMAD4, RICTOR and RET. We firstly demonstrated that SMAD4 deficiency can accelerate SCLC transition by inducing neuroendocrine phenotype regardless of RB1 status in TP53-deficient NSCLC cells. Further mechanical experiments identified the SMAD4 can regulate ASCL1 transcription competitively with Myc in NSCLC cells and Myc inhibitor acts as a potential subsequent treatment agent. CONCLUSIONS: Transformation to SCLC is irrespective of EFGR status and can be accelerated by SMAD4 in non-small cell lung cancer. Myc inhibitor acts as a potential therapeutic drug for SMAD4-mediated resistant lung cancer. Video Abstract.

Precision oncology strategy in cetuximab-resistant ERRFI1-mutant colon cancer: case report of disease progression on afatinib.

Despite the existence of effective first and second line therapy options for patients with colorectal cancer, heavily treated patients have limited additional therapies. Genomic profiling is a promising tool for guiding subsequent treatment selection. Here, we describe the results of treating a colorectal cancer patient with molecularly-matched therapy based on the results of genomic profiling. The patient received a combination of afatinib and bevacizumab due to the presence of ERRFI1 variant. To our knowledge, this is the first report on the effect of EGFR inhibitors in patients with ERRFI1-altered RAS/BRAF wild-type colorectal adenocarcinoma.

EGFR Tyrosine Kinase Inhibitor (TKI) Combined With Concurrent or Sequential Chemotherapy for Patients With Advanced Lung Cancer and Gradual Progression After First-Line EGFR-TKI Therapy: A Randomized Controlled Study.

INTRODUCTION: Continuing tyrosine kinase inhibitor (TKI) therapy may be beneficial when patients with non-small-cell lung cancer and EGFR mutations experience gradual disease progression after initial EGFR-TKI treatment. We aimed to compare the efficacy of simultaneous EGFR-TKI and chemotherapy with that of sequential treatment after patients' disease gradually progressed after first-line EGFR-TKI treatment. PATIENTS AND METHODS: Patients with gradual progression who were EGFR-T790M mutation negative were randomly divided into two groups. In the concurrent group, patients were treated with pemetrexed plus cisplatin along with the same EGFR-TKI. In the sequential group, patients continued with EGFR-TKI until the disease progressed again, according to RECIST, then switched to chemotherapy. We evaluated the patients' progression-free survival (PFS) and overall survival times. RESULTS: Ninety-nine patients were enrolled: 49 in the concurrent group and 50 in the sequential group. The median PFS (mPFS) was 7.7 months (95% confidence interval [CI], 3.6-11.7) in the concurrent group and 5.7 months (95% CI, 3.5-7.9) in the sequential group (hazard ratio = 0.66; 95% CI, 0.44-1.00; P = .026), respectively. For the sequential group, the mPFS1 and mPFS2 were 1.8 months (95% CI, 1.4-2.3) and 3.8 months (95% CI, 3.1-4.5), respectively. The median overall survival of the concurrent group was longer than that of the sequential group (20.0 vs. 14.7 months; hazard ratio = 0.52; 95% CI, 0.32-0.85; P = .038). CONCLUSION: For patients with advanced non-small-cell lung cancer and gradual progression who are EGFR-T790M mutation negative after initial EGFR-TKI therapy, EGFR-TKI combined with chemotherapy confers longer PFS and overall survival than sequential EGFR-TKI and chemotherapy does.

Radiofrequency Ablation with Continued EGFR Tyrosine Kinase Inhibitor Therapy Prolongs Disease Control in EGFR-Mutant Advanced Lung Cancers with Acquired Resistance to EGFR Tyrosine Kinase Inhibitors: Two Case Reports.

OBJECTIVE: Lung cancer remains the leading cause of malignant tumor-related death globally. There is mounting evidence that a large proportion of patients harboring epidermal growth factor receptor (EGFR) mutation and treated with EGFR TKI experience oligoprogressive disease. The optimal treatment strategy for these patients is undetermined. Thus, in this article, we report two cases of EGFR-mutant NSCLC patients with locally resistant lesions achieving disease control via combination therapy. PATIENTS AND METHODS: We present two cases of lung adenocarcinoma patients that developed oligoprogressive disease during TKI treatment. For further treatment, the patient then received radiofrequency ablation. RESULTS: Through follow-up observation, we found that the addition of radiofrequency ablation might provide the clinical benefit of these two NSCLC patients. CONCLUSION: Our two cases provide a promising treatment for oligoprogressive disease during the first-line EGFR-TKI therapy.

Real-world use of osimertinib in non-small cell lung cancer: ASTRIS study Korean subgroup analysis.

Objective: ASTRIS is a large real-world, open-label, multinational clinical study of osimertinib in patients with epidermal growth factor receptor (EGFR) T790M mutation-positive advanced non-small cell lung cancer (NSCLC) who have previously received a tyrosine kinase inhibitor (TKI). We report data from the Korean ASTRIS subgroup.Methods: Adult patients with locally advanced or metastatic NSCLC with a confirmed T790M mutation, WHO performance status of 0-2 and prior EGFR-TKI therapy, received osimertinib 80 mg once daily. Efficacy outcomes were overall survival (OS), investigator-assessed response rate (RR) and progression-free survival (PFS), and time to treatment discontinuation (TTD).Results: At data cut-off (20 October 2017), 466 Korean patients were enrolled. Baseline EGFR molecular testing was mainly performed on biopsied tissue (75.1%). Baseline mutations co-occurring with T790M included exon 19 deletions (60.7%) and L858R (32.8%). 1-year OS was 82.7% (OS data not matured at data cut-off). Overall, RR was 71.0%, median PFS was 12.4 months and median TTD was 15.0 months. In patients with/without CNS metastases, RR was 68.0% and 79.6%, respectively; median PFS, 10.8 and 11.0 months, respectively; and median TTD, 11.2 and 14.7 months, respectively. Overall, 31.1% of patients experienced ≥1 adverse event (AE), leading to dose modification (12.0%), discontinuation (5.2%) or death (2.8%). Serious AEs (24.9%) included pulmonary embolism (1.7%), pleural effusion (1.7%), and pneumonia (1.5%).Conclusion: In this real-world subgroup analysis of Korean patients in the ASTRIS study, osimertinib demonstrated comparable clinical efficacy to that attained in the global ASTRIS study and other clinical trials, with no new safety concerns.

Osimertinib Administration as the Primary Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy for Brain Metastasis of De Novo T790M-positive Lung Cancer.

A 69-year-old woman underwent left upper lobectomy for left upper lobe lung adenocarcinoma. She later perceived a left visual field defect, and a brain metastasis was detected on head magnetic resonance imaging (MRI). Epidermal growth factor receptor (EGFR) testing identified two separate EGFR mutations: an L858R mutation in exon 21 and a de novo T790M mutation in exon 20. Treatment with osimertinib was started. After one month, head MRI showed that the brain metastasis had shrunk, and the visual field defect had also improved. In this case, first-line osimertinib was effective for treating brain metastasis of de novo T790M-positive lung cancer.

Clinical outcome of epidermal growth factor receptor-tyrosine kinase inhibitors therapy for patients with overlapping kirsten rat sarcoma 2 viral oncogene homolog and epidermal growth factor receptor gene mutations.

BACKGROUND: Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) is the second most common mutated gene following epidermal growth factor receptor (EGFR) mutation in Chinese lung adenocarcinoma (LADC) patients. Investigating the clinical characteristics and outcomes of patients with co-existing KRAS and EGFR mutations can provide significant information for suitable therapies. METHODS: We retrospectively investigated 2106 LADC patients who had undergone EGFR and KRAS mutation tests at the Peking University Cancer Hospital. Only advanced LADC patients who carried KRAS and/or EGFR mutations, received EGFR-tyrosine kinase inhibitors (TKIs) and/or chemotherapy, and had completed follow-up analysis were analyzed further. KRAS and EGFR mutations were tested by denaturing high-performance liquid chromatography. RESULTS: A KRAS mutation was detected in 123 out of 2106 LADC patients (5.8%) and 38 (1.8%) had a concurrent EGFR mutation. Seventy-two of 123 patients were advanced cases, which were divided into two sub-groups according to EGFR mutation status: overlapping KRAS and EGFR mutations (n = 24) and KRAS mutation alone (n = 48). Clinical characteristics of the two subgroups were similar. A greater ratio of patients with double mutations received EGFR-TKIs compared to KRAS mutation alone (75% vs. 43.8%, P = 0.012), and obtained a better objective response rate (38.9% vs. 9.5%, P = 0.027) and longer progression-free survival (8.0 vs. 1.5 months, P = 0.028) following EGFR-TKIs therapy. However, these differences were not observed in patients treated with platinum-based chemotherapy. CONCLUSIONS: Overlapping KRAS and EGFR mutations occurred in 1.8% of Chinese LADC patients studied. The co-presence of EGFR mutations could predict a clinical benefit from EGFR-TKIs treatment for patients with KRAS mutations.

Programmed Death-Ligand 1 Expression Predicts Tyrosine Kinase Inhibitor Response and Better Prognosis in a Cohort of Patients With Epidermal Growth Factor Receptor Mutation-Positive Lung Adenocarcinoma.

BACKGROUND: The immune checkpoint proteins programmed death-1/ligand (PD-1/PD-L1) play a critical role in immune escape of tumor cells. In models of epidermal growth factor receptor (EGFR)-driven non-small-cell lung cancer (NSCLC), EGFR signal upregulates PD-1/PD-L1. However, data on the clinical significance of PD1/PD-L1 expression in patients with the subtype of NSCLC carrying EGFR mutations remain limited. MATERIALS AND METHODS: Immunohistochemistry was performed to evaluate the expression of PD-1, PD-L1, and CD4+ and CD8+ tumor-infiltrating T lymphocytes (TILs). RESULTS: In a cohort of 56 patients, PD-L1 and PD-1 was positive in 53.6% and 32.1% of tumor specimens, respectively. PD-L1(+) patients had a significantly greater disease-control rate (P = .004), in association with longer progression-free survival (P = .001) after EGFR-tyrosine kinase inhibitor (TKI) therapy and overall survival (P = .004), and no correlation between PD-1 positivity and clinical outcomes was observed. PD-L1 expression was not significantly associated with either clinicopathologic features or TILs. CONCLUSIONS: These findings suggest that this subtype of EGFR mutation-positive NSCLC is highly eligible for PD-1/PD-L1 immunotherapy. PD-L1 might represent a favorable biomarker candidate for the response to EGFR-TKIs and outcomes of these patients with NSCLC.