LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition

LKB1/STK11 is a multitasking tumour suppressor kinase. Germline inactivating mutations of the gene are responsible for the Peutz-Jeghers hereditary cancer syndrome. It is also somatically inactivated in approximately 30% of non-small-cell lung cancer (NSCLC). Here, we report that LKB1/KRAS mutant NSCLC cell lines are sensitive to the MEK inhibitor CI-1040 shown by a dose-dependent reduction in proliferation rate, whereas LKB1 and KRAS mutations alone do not confer similar sensitivity. We show that this subset of NSCLC is also sensitised to the mTOR inhibitor rapamycin. Importantly, the data suggest that LKB1/KRAS mutant NSCLCs are a genetically and functionally distinct subset and further suggest that this subset of lung cancers might afford an opportunity for exploitation of anti-MAPK/mTOR-targeted therapies.     

吉非替尼对晚期非小细胞肺癌患者生活质量的改善

Objective  

The aim of this study was to evaluate the effect of gefitinib on improvement of quality of life (QoL) of patients with advanced non-small cell lung cancer (NSCLC).     

Front-line treatment of advanced non-small-cell lung cancer with MTA (LY231514, Pemetrexed disodium, ALIMTATM) and cisplatin: A multicenter phase II trial

Background:To evaluate the activity of MTA plus cisplatin inchemotherapy-naïve patients with non-small cell lung cancer (NSCLC). Patients and methods:Thirty-six chemotherapy-naïve patientswith NSCLC received 500 mg/m² MTA plus 75 mg/m²cisplatin every 21 days, with 4 mg dexamethasone orally twice daily on the daybefore, of, and after MTA administration. Results:Median age was 58 years. WHO performance status was0–2. Eighteen patients each had stage IIIB and IV disease. Seventeenpatients each had squamous-cell and adenocarcinoma; two had undifferentiateddisease. Fourteen patients (39%; 95% confidence interval:23%–57%) showed partial response; seventeen (47%)had stable disease. Median survival was 10.9 months. Twenty-one patients(59%) experienced grade 3 or 4 granulocytopenia without fever orinfection. Five (14%) and six (17%) patients experienced grade3 anemia and grade 3 or 4 thrombocytopenia, respectively. Nonhematologicaltoxicities included grade 3 nausea in two patients (6%), and grade 3and 4 diarrhea in one patient (3%) each. One patient each experiencedgrade 4 ALT and grade 3 bilirubin and AST elevations. Conclusions:MTA plus cisplatin is well tolerated and activeagainst NSCLC. Further studies of this combination are warranted.     

Trastuzumab Emtansine in HER2+ Recurrent Metastatic Non–Small-Cell Lung Cancer: Study Protocol

The treatment outcome has been unsatisfactory for patients with non–small-cell lung cancer (NSCLC) refractory to standard first-line chemotherapy. Trastuzumab emtansine (T-DM1), an anti-HER2 antibody conjugated with a vinca alkaloid, has been approved for clinical use in HER2+ breast cancer in many countries. Approximately 5% of NSCLC tumors possess HER2 alterations, and T-DM1 has shown excellent antitumor effects against HER2+ lung cancer cell lines in preclinical models. Therefore, we hypothesized that T-DM1 could significantly inhibit the growth of HER2+ lung cancers. We have launched a nonrandomized phase II trial of T-DM1 monotherapy for patients with HER2+ lung cancers. The major eligibility criteria are as follows: age ≥ 20 years, pathologically diagnosed NSCLC with documented HER2 positivity (immunohistochemistry 3+, both immunohistochemistry 2+ and fluorescence in situ hybridization positive, or exon 20 insertion mutation), and previous chemotherapy. Thirty patients will receive T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint is the overall response rate. This trial will provide information on whether T-DM1 monotherapy is effective against HER2+ lung cancer.     

Advances in the management of acquired resistance to EGFR-TKI in non-small cell lung cancer

Drugs that specifically target the tyrosine kinase domain of epidermal growth factor receptor(EGFR), such as erlotinib or gefitinib, have exhibited striking efficacy in non-small cell lung cancer(NSCLC) patients harboring activating EGFR mutations. However, acquired resistance inevitably develops and remains a serious barrier for the successful management of patients with this disease. Multiple mechanisms are reportedly involved in the process of acquired resistance, which provide new insights into the management of EGFRtyrosine kinase inhibitor(EGFR-TKI) resistance. Here, we provide an overview of the emerging treatment approaches for patients with EGFR-TKI resistance.     

Duration of immunotherapy – should we continue ad infinitum?

The optimal duration of immunotherapy treatment for cancer patients is unknown. As the survival data from early immunotherapy trials mature we are beginning to appreciate how durable responses can be post‐discontinuation. The purpose of this brief communication is to comment on treatment duration of immunotherapy in patients with melanoma and non‐small cell lung cancer and to provide practice guidance in support of discontinuation.     

Lymphangiosis carcinomatosa independently affects long-term survival of Non-Small Cell Lung Cancer patients

ObjectiveThe significance of postoperatively diagnosed Lymphangiosis Carcinomatosa (L1) as an independent risk factor for long-term survival in Non-Small Cell Lung Cancer (NSCLC) remains controversial. We analyzed the effect of L1 on postoperative survival in stage I, II and III NSCLC-patients.MethodsWe investigated all consecutive patients with NSCLC between January 2012 and December 2019 who underwent an anatomical resection and radical lymphadenectomy at our institute. L1-were compared to L0-patients. All patients received adjuvant chemotherapy in accordance with European guidelines. 3- and 5- year survival rates and median-survival were assessed. To investigate whether L1 is an independent risk factor, we carried out a multivariate cox regression and a pair-match analysis looking at different properties such as TNM.ResultsA total of 641 patients (L0: 74%; L1: 26%) were analyzed. Baseline characteristics were comparable between groups. The mean age was 65.3 ± 10.2 years and 64.9 ± 9.4 years in the L0 and L1-groups respectively (p-value = 0.703). 58.5% of L0-patients were male (L1: 62.7%; p-value = 0.351). Overall survival in the L1-group was significantly shorter compared to the L0-group (L1: 42.3 ± 2.8; L0: 67.6 ± 2.1 months; p-value<0.0001). We confirmed this finding in a pair-matched analysis (L0: 73.9 ± 4.7 months; L1: 42.2 ± 4.2; p-value = 0.009). 3- and 5-year survival were significantly shorter for L1-patients (3-year: L0: 65.9%; L1: 35.9%; p-value<0.0001) (5-year: L0: 34.9%; L1: 7.5%; p-value<0.0001).ConclusionL1 is an independent risk factor for long-term survival of patients with NSCLC. This cohort supports that the L0/L1 status should be included in pathological reports. We suggest to further include L0/L1-status in guideline recommendations for NSCLC patients.