Yutao Liu

The Molecular Detection and Clinical Significance of ALK Rearrangement in Selected Advanced Non-Small Cell Lung Cancer: ALK Expression Provides Insights into ALK Targeted Therapy

Background This study aimed to elucidate clinical significance of anaplastic lymphoma kinase (ALK) rearrangement in selected advanced non-small cell lung cancer (NSCLC), to compare the application of different ALK detection methods, and especially evaluate a possible association between ALK expression and clinical outcomes in crizotinib-treated patients. Methods ALK status was assessed by fluorescent in situ hybridization (FISH), immunohistochemistry (IHC) and quantitative RT-PCR (qRT-PCR) in 173 selected advanced NSCLC patients. Clinicopathologic data, genotype status and survival outcomes were analyzed. Moreover, the association of ALK expression with clinical outcomes was evaluated in ALK FISH-positive crizotinib-treated patients including two patients with concurrent epidermal growth factor receptor (EGFR) mutation. Results The positivity detection rate of ALK rearrangement by FISH, IHC and qRT-PCR was 35.5% (59/166), 35.7% (61/171), and 27.9% (34/122), respectively. ALK rearrangement was observed predominantly in young patients, never or light smokers, and adenocarcinomas, especially with signet ring cell features and poor differentiation. Median progression-free survival (PFS) of crizotinib-treated patients was 7.6 months. The overall survival (OS) of these patients was longer compared with that of crizotinib-naive or wild-type cohorts, but there was no significant difference in OS compared with patients with EGFR mutation. ALK expression did not associate with PFS; but, when ALK expression was analyzed as a dichotomous variable, moderate and strong ALK expression had a decreased risk of death (P = 0.026). The two patients with concomitant EGFR and ALK alterations showed difference in ALK expression, response to EGFR and ALK inhibitors, and overall survival. Conclusions Selective enrichment according to clinicopathologic features in NSCLC patients could highly improve the positivity detection rate of ALK rearrangement for ALK-targeted therapy. IHC could provide more clues for clinical trial design and therapeutic strategies for ALK-positive NSCLC patients including patients with double genetic aberration of ALK and EGFR.

Randomize Trial of Cisplatin plus Gemcitabine with either Sorafenib or Placebo as First-line Therapy for Non-small Cell Lung Cancer

BACKGROUND AND OBJECTIVE Platinum-based chemotherapy doublets reached an efficacy plateau in nonsmall-cell lung cancer (NSCLC). This randomized controlled study prospectively assessed the efficacy and safety of cisplatin plus gemcitabine with either Sorafenib or placebo as first-line therapy for NSCLC. METHODS Thirty patients, which were confirmed advanced NSCLC histologically or cytologically, were randomly assigned to receive up to six cycles of cisplatin plus gemcitabine with sorafenib or placebo. The maintenance of sorafenib or placebo after chemotherapy will continued in patients with response or stable disease until disease progression or unacceptable adverse events. RESULTS Overall demographics were balanced between experimental group (sorafenib+chemotherapy) and controlled group (chemotherapy only). Overall response (OS) rate was 55.6% and 41.7% in experimental arm and controlled arm, respectively (P=0.905). Median progressive-free survival (PFS) and median overall survival were similar (5 months vs 4 months, P=0.75; 18 months vs 18 months, P=0.68). Adverse events were tolerable, though the risk of hypertension and diarrhea was increase in experimental arm. Since patients with ECOG PS 0, stage IIIb, no liver metastasis and tyrasine kinasis inhibitor treatment after study had longer survive, these factors seemed to be predictive factors favor of survival in Cox regression analyses. CONCLUSIONS No additional benefit of response rate, PFS or OS were observed from adding targeted agent-sorafenib to regular cisplatin plus gemcitabine chemotherapy. Selecting aproper patients is needed in further study.

Survival of patients with advanced lung adenocarcinoma before and after approved use of gefitinib in China

To compare the overall survival (OS) of patients with advanced lung adenocarcinoma in China before and after the approved use of gefitinib, and analyze clinical factors that may affect OS.

Suitability of Surgical Tumor Tissues, Biopsy, or Cytology Samples for Epidermal Growth Factor Receptor Mutation Testing in Non–Small Cell Lung Carcinoma Based on Chinese Population

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation status is crucial in treatment selection for non–small cell lung cancer (NSCLC) patients; however, the detection materials’ availability remains challenging in clinical practice. In this study, we collected surgical resection tissues, lymph node biopsy, and cytological samples for EGFR mutation testing and investigated the associations between gene mutation and clinical characteristics. METHODS: Two hundred and seventy-six NSCLC adenocarcinoma specimens were collected, and highly sensitive amplification refractory mutation system method was implemented for EGFR mutation detection, with clinicopathologic characteristics involved in the final analysis. RESULTS: In the total of 276 samples, 96% (265/276) of tumors obtained evaluable EGFR mutation status, the frequency of mutation was 55.8% (148/265) in all specimens, and three different type samples shared a comparable successful testing rate: 97.4% (38/39) in surgical tumor tissues, 100% (108/108) in lymph node biopsy samples, and 92.2% (119/129) in cytological samples. EGFR mutation was significantly associated with sex, smoking history, lymph node metastasis status (N stage), primary tumor size, testing tissues origin, and sample type (P < .05). Multivariate analysis reconfirmed that smoking history and primary tumor size shared significant correlation with EGFR mutation after adjustment. CONCLUSIONS: Both lymph node biopsy and cytological samples were suitable surrogates for EGFR mutation detection in NSCLC compared with tumor tissues, gene status should be detected widely considering the high EGFR mutation rate, and nonsmoking history together with smaller primary tumor size was an independent indicator of EGFR mutation status.

Analysis of clinicopathological features of the echinoderm microtubule-associated protein-like-4-anaplastic lymphoma kinase fusion gene in Chinese patients with advanced non-small-cell lung cancer

The echinoderm microtubule‐associated protein‐like‐4‐anaplastic lymphoma kinase (EML4‐ALK) fusion gene defines a novel molecular subset of non‐small‐cell lung cancer (NSCLC). However, the clinicopathological features of patients with the EML4‐ALK fusion gene have not been defined completely.

Heterogeneity-based, multiple mechanisms in the resistance to osimertinib (AZD9291): A case report: Heterogeneity-induced resistance to osimertinib

Osimertinib is a novel, irreversible, mutant‐selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor targeting EGFR mutations and the EGFR T790 mutation. Here, we report a woman with EGFR‐mutated lung adenocarcinoma who, after 23‐month treatment with gefitinib, developed the EGFR T790M mutation, which converted the T790M status from positive to negative before osimertinib treatment and developed MET amplification, leading to rapid progression on osimertinib in two months. Subsequent treatment with crizotinib and c‐Met inhibitor plus gefitinib also failed to improve the clinical outcome, suggesting the potential existence of another resistance mechanism. Our findings revealed the underlying multiple and heterogeneous mechanisms in resistance to osimertinib, suggesting combination strategies should be considered post‐osimertinib progression.

Combination TS-1 plus EGFR-tyrosine kinase inhibitors (TKIs) for the treatment of non-small cell lung cancer after progression on first-line or further EGFR-TKIs: A phase II, single-arm trial: TS-1 plus EGFR-TKIs for resistant NSCLC

EGFR‐tyrosine kinase inhibitors (TKIs) combined with TS‐1 might overcome EGFR‐TKI resistance, which has been indicated by several preclinical studies. We investigated the synergistic efficacy and safety of the combination therapy of EGFR‐TKIs and TS‐1 in non‐small cell lung cancer (NSCLC) patients with acquired resistance to previous EGFR‐TKI therapy.

Impact of platinum/pemetrexed combination versus other platinum-based regimens on adjuvant chemotherapy in resected lung adenocarcinoma

For advanced non-squamous non-small cell lung cancer (NSCLC), although platinum/pemetrexed is known to result in a longer survival compared with other regimens, the outcome in the adjuvant setting is still unknown. In this study, the difference of the disease-free survival (DFS) between lung adenocarcinoma patients treated with platinum/pemetrexed and with other platinum-based doublets was concerned. A total of 389 radically resected lung adenocarcinoma patients received adjuvant chemotherapy with platinum/pemetrexed chemotherapy (Group A, n = 143) or other third generation platinum-based regimens (Group B, n = 246) were analyzed in terms of DFS. Propensity score matching (PSM) allowed generation of best matched pairs for the two categories. DFS was proved to be considerably better in pemetrexed doublets group (P = 0.0079); and platinum/pemetrexed was found to be associated with lower rates of several hematological and non-hematological adverse events (AEs), when compared with gemcitabine containing chemotherapy (leukopenia: RR 0.514, p = 0.001; neutropenia: RR 0.688, p = 0.002), or taxanes-doublets treatment (leukopenia: RR 0.685, p = 0.019; neutropenia: RR 0.805, p = 0.032). For patients with radically resected pulmonary adenocarcinoma, adjuvant chemotherapy with platinum/pemetrexed results in a better DFS and a less clinical toxicity in comparison with non-pemetrexed based doublets.

Is there an optimal time to initiate adjuvant chemotherapy to predict benefit of survival in non-small cell lung cancer?

Objective Adjuvant chemotherapy (AC) after curative resection is known to improve the survival of patients with non-small cell lung cancer (NSCLC); however, few studies have reported the correlation between the time to initiation of AC (TTAC) and survival in NSCLC patients. Methods The clinical data of 925 NSCLC patients who received curative resection and post-operative AC at the Cancer Hospital of Chinese Academy of Medical Sciences between 2003 and 2013 were retrospectively analyzed. TTAC was measured from the date of surgery to the initiation of AC. Disease-free survival (DFS) was defined as the duration from surgery to the time of tumor recurrence or last follow-up evaluation. The optimal cut-off value of TTAC was determined by maximally selected log-rank statistics. The DFS curve was estimated using the Kaplan-Meier method, and the Cox proportional hazards regression model was used to identify risk factors independently associated with DFS. Propensity score matching (PSM) was performed for survival analysis using the match data. Results The optimal discriminating cut-off value of TTAC was set at d 35 after curative resection based on which the patients were assigned into two groups: group A (≤35 d) and group B (>35 d). There was no significant difference in the DFS between the two groups (P=0.246), indicating that the TTAC is not an independent prognostic factor for DFS. A further comparison continued to show no significant difference in the DFS among 258 PSM pairs (P=0.283). Conclusions There was no significant correlation between the TTAC and DFS in NSCLC patients. Studies with larger samples are needed to further verify this conclusion.

Body mass index and exon 19 mutation as factors predicting the therapeutic efficacy of gefitinib in patients with epidermal growth factor receptor mutation-positive non-small cell lung cancer.

Many randomized clinical trials have demonstrated that epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) are advantageous over standard chemotherapy, either as front‐line treatment or as further management of patients with EGFR mutation‐positive non‐small‐cell lung cancer (NSCLC). However, which subgroup of these patients could benefit more from EGFR‐TKIs needs to be further explored. In the present study, we explored the predictive factors in such cohorts of patients who received gefitinib.