Shijia Zhang

EML4-ALK Fusion Detected by RT-PCR Confers Similar Response to Crizotinib as Detected by FISH in Patients with Advanced Non-Small-Cell Lung Cancer.

Introduction: Reverse transcriptase polymerase chain reaction (RT-PCR) assay has been proved to have high sensitivity and specificity to detect anaplastic lymphoma kinase (ALK) rearrangements. The aim of this study was to investigate the response to crizotinib in patients of advanced non–small-cell lung cancer (NSCLC) with ALK rearrangements detected by RT-PCR. Methods: Only patients with advanced NSCLC who had their ALK rearrangement status detected by RT-PCR were included in this analysis. The utility of RT-PCR and fluorescence in situ hybridization (FISH) assay were compared in patients who were treated with crizotinib based on their positive ALK rearrangements. Results: One thousand ten patients were included in this study. Among them, 104 patients were ALK RT-PCR positive and 53 of them received crizotinib treatment. Among 255 tumors simultaneously analyzed by FISH and RT-PCR, the latter successfully detected all the 25 tumors with arrangements, including two cases that were missed by FISH. The overall response rate and median progression-free survival of the 53 patients with ALK rearrangements who received crizotinib treatment were 60.4% (95% confidence interval [CI], 47.2–73.6) and 8.4 months (95% CI, 6.75–10.05), respectively, which were similar to the 21 patients detected by FISH with overall response rate of 57.1% (95% CI, 33.3–76.2; p = 0.799) and median progression-free survival of 7.4 months (95% CI, 4.43–10.38; p = 0.833) after crizotinib treatment. Interestingly, there were two patients responded to crizotinib had their ALK rearrangement detected by RT-PCR but not FISH. Conclusions: RT-PCR should be considered as an alternative/supplemental approach to detect ALK fusion oncogene in NSCLC patients who might benefit from crizotinib treatment.

The role of endobronchial ultrasound elastography in the diagnosis of mediastinal and hilar lymph nodes

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been widely used for diagnosis and mediastinal lymph nodes staging in patients with suspicious lung cancer. Ultrasound elastography is a novel sonographical technique that can evaluate tissue compressibility. The aim of the present study was to investigate the diagnostic yield of elastography for differentiating malignant and benign mediastinal lymph nodes. Conventional EBUS B-mode features, including size, shape, border distinction, echogenicity, central hilar structure with central blood vessel and coagulation necrosis were also evaluated. The ultrasonic features were compared with the pathological results from EBUS-TBNA. 133 lymph nodes in 60 patients were assessed. Elastography displayed the highest area under the curve (AUC) (type 3 versus type 1: AUC, 0.825; 95% confidence interval [CI], 0.707-0.910) with an impressive sensitivity (100%) and an acceptable specificity (65%). The combined model covering the four positive criteria (elastography, heterogeneity, size, and shape) showed that the odds ratio for malignance is 9.44 with a 95% CI of 3.99 to 22.32 (p <0.0001). The combined model was superior to elastography alone (AUC, 0.851; sensitivity, 89.89%; specificity, 72.73%; p <0.0001). This prospective study showed that elastography is a feasible technique for classifying mediastinal lymph nodes, especially in combination with conventional EBUS imaging.Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been widely used for diagnosis and mediastinal lymph nodes staging in patients with suspicious lung cancer. Ultrasound elastography is a novel sonographical technique that can evaluate tissue compressibility. The aim of the present study was to investigate the diagnostic yield of elastography for differentiating malignant and benign mediastinal lymph nodes. Conventional EBUS B-mode features, including size, shape, border distinction, echogenicity, central hilar structure with central blood vessel and coagulation necrosis were also evaluated. The ultrasonic features were compared with the pathological results from EBUS-TBNA. 133 lymph nodes in 60 patients were assessed. Elastography displayed the highest area under the curve (AUC) (type 3 versus type 1: AUC, 0.825; 95% confidence interval [CI], 0.707-0.910) with an impressive sensitivity (100%) and an acceptable specificity (65%). The combined model covering the four positive criteria (elastography, heterogeneity, size, and shape) showed that the odds ratio for malignance is 9.44 with a 95% CI of 3.99 to 22.32 (p <0.0001). The combined model was superior to elastography alone (AUC, 0.851; sensitivity, 89.89%; specificity, 72.73%; p <0.0001). This prospective study showed that elastography is a feasible technique for classifying mediastinal lymph nodes, especially in combination with conventional EBUS imaging.

Characterization of distinct types of KRAS mutation and its impact on first‑line platinum‑based chemotherapy in Chinese patients with advanced non‑small cell lung cancer

We performed this retrospective study to investigate whether the KRAS mutation status and its subtypes could predict the effect of first-line platinum-based chemotherapy in Chinese patients with non-small cell lung cancer (NSCLC). Patients received who had KRAS mutations were enrolled. Correlations between KRAS mutations, specific mutant subtypes and responses to chemotherapy were analyzed using Kaplan-Meier and Cox proportional hazard methods. A total of 2,183 cases who received KRAS mutation detection were included. A total of 218 of these cases were indicated to have KRAS mutations. KRAS mutations were identified more commonly in males compared with females (P=0.035). The most common subtypes were G12C, G12D and G12V. Among 73 KRAS mutant patients and 100 EGFR/ALK/KRAS wild-type patients with advanced NSCLC, KRAS-mutant NSCLC patients had a significantly shorter progression-free survival (P=0.007) compared with NSCLC patients with KRAS wild-type. In addition, there was a shorter but marginally statistically significant progression-free survival (PFS) in KRAS mutant patients with adenocarcinoma compared with those with non-adenocarcinoma (P=0.051). In the KRAS mutant group, patients with the KRAS G12V mutation had the poorest PFS compared with non-G12V mutant cases (P=0.045). In conclusion, KRAS mutation was a negative predictive factor of PFS in Chinese patients with advanced NSCLC who received first platinum-based chemotherapy. Patients with KRAS G12V mutations exhibited the poorest PFS compared with those with other KRAS mutant types.

Continuation of gefitinib plus chemotherapy prolongs progression- free survival in advanced non-small cell lung cancer patients who get acquired resistance to gefitinib without T790M mutations

Background Aimed to identify the benefit population from continuation of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), this study investigated the efficacy of continuation of EGFR-TKIs plus chemotherapy beyond the response evaluation criteria in solid tumors-progressive disease (RECIST-PD) according to different progression modes and T790M mutational status. Methods From November 2009 to July 2015, 630 patients with advanced non-small cell lung cancer (NSCLC) receiving gefitinib as initial EGFR-TKI treatment were screened in Shanghai Pulmonary Hospital. A total of 170 patients with documented gradual or dramatic progression after gefitinib treatment who received chemotherapy alone or in combination with gefitinib were included. Post-RECIST-PD progression-free survival (PPFS) between continuation of gefitinib plus chemotherapy and chemotherapy alone was assessed. Results The incidence of T790M mutation was 42.9% (63/147) in patients who got acquired resistance in this study. Median PPFS was 4.0 months [95% confidence interval (CI), 3.1-4.9 months] in the chemotherapy group and 5.0 months (95% CI, 3.6-6.4 months) in the combination group with a borderline statistical significance (P=0.071). Continuation of gefitinib plus chemotherapy resulted in a significant improvement in PPFS compared with chemotherapy alone in patients with EGFRT790M-negative tumors [median PPFS: 6.6 vs. 3.5 months, hazard ratio (HR) 0.50, 95% CI, 0.29-0.88; P=0.011], especially in pemetrexed-based chemotherapy (HR 0.45, 95% CI, 0.24-0.86; P=0.011). PPFS was similar in patients with EGFRT790M-positive tumors (median PPFS: 5.0 vs. 5.5 months, HR 0.80, 95% CI, 0.40-1.61; P=0.520) or EGFRT790M-unknown tumors (median PPFS: 2.0 vs. 3.0 months, HR 1.40, 95% CI, 0.69-2.81; P=0.323). Conclusions Our study showed that continuous gefitinib plus chemotherapy, especially pemetrexed-based therapy, significantly improved PPFS in patients with EGFRT790M-negative tumors as compared with chemotherapy alone, suggesting that this subtype of patients may derive clinical benefit from continuation of gefitinib treatment beyond progression.

Feasibility of cytological specimens for ALK fusion detection in patients with advanced NSCLC using the method of RT-PCR.

OBJECTIVES Histological tissues are preferred for anaplastic lymphoma kinase (ALK) fusion detection in non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the feasibility of cytological sample as an alternative specimen for ALK fusion testing in patients with advanced NSCLC. MATERIALS AND METHODS Advanced NSCLC patients with cytological specimens or tumor tissue who had their ALK fusion status detected by the method of reverse transcriptase polymerase chain reaction (RT-PCR) in Shanghai Pulmonary Hospital, Tongji University were included into this study. The efficacy was evaluated in those with ALK fusion positive and received the therapy of crizotinib. RESULTS 1274 patients were included in this study. Among them, 108 patients were ALK RT-PCR positive and 69 of them received crizotinib treatment. Among 1002 patients with cytological specimens, the average concentration of RNA extracted from cytological specimens was 60.99 ng/μl (95% confidence interval [CI], 55.56-66.60) and the incidence rate of ALK fusion was 8.3% (83/1002), which were similar to 63.16 ng/μl (95% CI, 51.88-76.34) (p=0.727) and 9.2% (25/272, p=0.624) in 272 patients with tumor tissue. Also, there were no statistically significant differences regarding to the objective response rate (ORR) (62.0% vs. 42.1%, p=0.177) and the median progression free survival (mPFS) [8.6 months (95% CI 7.30-9.84) vs. 7.0 months (95% CI 4.54-9.47), p=0.736] in patients of cytological group and tissue group after the treatment of crizotinib. CONCLUSION Cytological specimens showed a high feasibility to detect ALK fusion status, which could be regarded as alternative samples for ALK fusion detection by the method of RT-PCR in patients with advanced NSCLC.

Successful treatment using apatinib with or without docetaxel in heavily pretreated advanced non-squamous non-small cell lung cancer: a case report and literature review

ABSTRACT Although targeted therapy directed toward driver mutations has produced a significant efficacy benefit for patients with non-small cell lung cancer (NSCLC), many patients do not possess mutations associated with the approved targeted drugs. Angiogenic agents play an important role in the therapeutic strategy for advanced NSCLC. Apatinib is a novel tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor-2. A phase II clinical trial demonstrated the survival benefit of apatinib monotherapy in advanced NSCLC. Moreover, addition of anti-angiogenic agents to chemotherapy showed robust efficacy in advanced NSCLC, regardless of tumor histology. Here, we present the case of a heavily pretreated lung adenocarcinoma patient who was treated with apatinib and apatinib continuation plus docetaxel re-challenge. He was negative for several driver genes, including EGFR, ALK, KRAS, ROS1, HER2, RET and BRAF. The previous treatment included platinum-based doublets, pemetrexed monotherapy, docetaxel plus bevacizumab, gefitinib monotherapy, nab-paclitaxel monotherapy, irinotecan plus oxaliplatin and radiotherapy. He obtained a partial response after both apatinib monotherapy and apatinib plus docetaxel treatment, with progression-free survival durations of 5 months and 6 months, respectively. This case indicated that apatinib monotherapy or apatinib plus docetaxel might be regarded as a therapeutic option for heavily pretreated patients with advanced non-squamous NSCLC.

Hepatic metastasis is a poor predictive marker for erlotinib in lung adenocarcinoma

Lung cancer is the leading cause of cancer related death worldwide and most of lung cancer patients have had metastases when they are diagnosed. With respect to chemotherapy, target therapy is a more effective and less toxic treatments. The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib or erlotinib, are one of the representatives of targeted therapy which have been widely used in first line, maintenance and 2nd/3rd line therapy among advanced non-small cell lung cancer (NSCLC). But those with hepatic metastases may insensitive to EGFR-TKIs due to MET activation by hepatocyte growth factor (HGF). In our retrospective analysis, 164 lung adenocarcinoma patients with known epidermal growth factor receptor (EGFR) mutation status who received the treatment of erlotinib as 2nd/3rd line setting were reviewed. The disease control rate (DCR) in patients without hepatic metastases group was higher than that in patients with hepatic metastases (66.1% vs 54.5%, p<0.001). In EGFR mutation-positive patients, median PFS was significantly longer in patients without hepatic metastases than that in those with hepatic metastases (9.9months 95% CI 7.74-12.06months vs. 7.9months 95% CI 5.88-9.92months; p=0.017). Therefore, we assume that hepatic metastasis may be a poor predictive marker for erlotinib in lung adenocarcinoma.

A Phase II Clinical Trial of Apatinib in Pretreated Advanced Non-squamous Non–small-cell Lung Cancer

&NA; Apatinib is an oral multi‐tyrosine kinase inhibitor that has been effective in treating many solid tumors. This phase II clinical trial evaluated the efficacy and safety of apatinib in cases of previously heavily treated non‐squamous non–small‐cell lung cancer. Apatinib showed promising efficacy and manageable toxicity, and thus represents a therapeutic option for patients with non‐squamous non–small‐cell lung cancer. Objectives: Apatinib exhibits broad‐spectrum antitumor activities by selectively inhibiting vascular endothelial growth factor receptor‐2. This study evaluated the efficacy and safety of apatinib in patients with advanced non‐squamous non–small‐cell lung cancer who were heavily pretreated or not suitable to receive standard second‐line chemotherapy. Patients and Methods: This was an open‐label, single‐arm phase II clinical trial (ClinicalTrials.gov NCT02515435). Patients received 500 or 750 mg apatinib daily until progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was the objective response rate. The secondary endpoints included disease control rate, progression‐free survival, overall survival, and side effects. Apatinib administration was allowed beyond disease progression. Results: Between March 2015 and August 2016, 40 patients were enrolled. Among them, 6 (15.0%), 16 (40.0%), and 18 (45.0%) received apatinib as the second‐, third‐, and fourth‐line or beyond treatment, respectively. The mean dosage of apatinib was 477.0 ± 85.3 mg/day. Thirty‐eight patients were available for response evaluation; the objective response rate and disease control rate were 13.2% and 63.2%, respectively. The median progression‐free survival was 3.06 months (95% confidence interval [CI], 2.20‐4.14 months). The median overall survival was 7.69 months (95% CI, 5.36 months to not estimable). The most common treatment‐related adverse events were hand‐foot‐skin reaction (30.0%), proteinuria (27.5%), oral mucositis (22.5%), fatigue (20.0%), and hypertension (17.5%). Nine patients received apatinib after progression, and the median duration of apatinib therapy beyond progression was 5.13 months (95% CI, 4.27‐7.82 months). Conclusion: Apatinib shows promising efficacy and manageable toxicity in patients with advanced non‐squamous non–small‐cell lung cancer. Apatinib therapy beyond progression could provide further benefits in specific subpopulations.

Uncommon EGFR mutations in a cohort of Chinese NSCLC patients and outcomes of first-line EGFR-TKIs and platinum-based chemotherapy

Objective Data on the clinical activity of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer (NSCLC) and uncommon EGFR mutations remain insufficient. This study aimed to investigate the effect of first-line EGFR-TKIs or platinum-based chemotherapy in NSCLC patients with uncommon EGFR mutations. Methods We retrospectively enrolled 504 patients with EGFR-mutant NSCLC. The clinical characteristics and treatment outcomes were collected and compared between patients with common and uncommon EGFR-mutant NSCLC. Results Seventy patients (13.9%) harboring uncommon EGFR mutations were included. Thirty of these patients received EGFR-TKIs and 40 received platinum-based chemotherapy as first-line therapy. The objective response rate (ORR) and median progression-free survival (mPFS) of patients treated with TKIs in the uncommon mutation group was significantly inferior to that in the common mutation group (ORR: 23.3% vs. 51.8%, P=0.003; mPFS: 7.1 vs. 10.9 months, P<0.001). In the uncommon group, mPFS was similar between first-line EGFR-TKIs treatment and platinum-based chemotherapy (7.1vs. 6.1 months, P=0.893). In patients with EGFR G719X or L861Q mutations, the mPFS was longer in the first-line EGFR-TKIs treatment group than in the chemotherapy group, but the difference was not statistically significant (G719X: 8.2 vs. 5.8 months, P=0.061; L861Q: 7.6 vs. 4.1 months, P=0.872). Multivariate analyses identified adenocarcinoma (P=0.003) as the independent predictive factor for PFS in patients with uncommon EGFR mutations who were treated with first-line EGFR-TKIs. Conclusions The current study demonstrated that the effect of first-line EGFR-TKIs was similar to that of platinum-based chemotherapy in patients with uncommon EGFR-mutant NSCLC. Adenocarcinoma was the independent predictive factor for PFS in uncommon EGFR-mutant NSCLC patients treated with first-line EGFR-TKIs.