[Show abstract][Hide abstract] ABSTRACT: Background: Activation of bypass signaling pathways, impairment of apoptosis and mutation of epidermal growth factor receptor (EGFR) to a drug-resistant state are well known mechanisms of resistance to singleagent erlotinib therapy in non-small-cell lung cancer (NSCLC) driven by EGFR mutations. Orphan receptor 1 (ROR1) knockdown inhibited the growth of NCI-H1975 cells (harboring EGFR L858R and T790M mutations). A pro-survival function for ROR1/MEK/ERK signaling in cooperation with AKT has been demonstrated.
Methods: We have assessed ROR1 expression in 45 patients from the EURTAC trial (clinicaltrials.gov NCT00446225), 27 of whom harbored pretreatment concomitant EGFR T790M mutations, and correlated results with outcome.
Results: Progression-free survival (PFS) was 11.8 months for erlotinib-treated patients with low/ intermediate and 5.8 months for those with high ROR1 levels. PFS for chemotherapy-treated patients was 5.6 and 9 months, respectively (P=0.0165). A total of 15 erlotinib-treated patients harbored concomitant T790M mutations; for these patients, PFS was 10.8 months for those with low/intermediate compared to 2.7 months for those with high ROR1 levels. In contrast, among 12 chemotherapy-treated patients with concomitant T790M mutations, PFS was 5.8 months for those with low/intermediate, compared to 14.2 months for those with high ROR1 levels (P=0.0138).
Conclusions: ROR1 expression has a differential effect on outcome to erlotinib and chemotherapy in EGFR-mutant NSCLC patients. High ROR1 expression significantly limits PFS in erlotinib-treated patients with T790M mutations and ROR1-directed therapies can enhance the efficacy of treatment. In contrast, high ROR1 expression confers longer PFS to chemotherapy in the same group of patients. The role of chemotherapy and erlotinib in EGFR-mutant NSCLC patients with high ROR1 expression warrants further investigation.
Translational Lung Cancer Research. 06/2014; 3(3):122-130.
[Show abstract][Hide abstract] ABSTRACT: Over a short period of time, translational research has described a new clinically relevant molecular subset of non-small-cell lung cancer (NSCLC) that is defined by EGFR mutations or EML4-ALK fusions. Today, patients with metastatic disease can achieve survival rates at least double that of patients with wild-type tumors. Through the rational dissection of the mechanisms of drug sensitivity and resistance, promising strategies have been defined to further improve the outcomes of patients with NCSLC. This review adds to a growing body of knowledge into mechanisms of resistance that can be interrogated in NSCLC patients with EGFR mutations or EML4-ALK fusions, as well as strategies to overcome resistance to TKIs.
Expert Review of Anti-infective Therapy 03/2014; · 2.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Concomitant genetic alterations could account for transient clinical responses to tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR) in patients harboring activating EGFR mutations.
We have evaluated the impact of pretreatment somatic EGFR T790M mutations, TP53 mutations and BIM mRNA expression in 95 patients with EGFR-mutant NSCLC included in the EURTAC trial (trial registration: NCT00446225).
T790M mutations were detected in 65.26% of patients using our highly sensitive method based on laser microdissection and PNA-clamping PCR, which can detect the mutation at an allelic dilution of 1 in 5000. Progression-free survival (PFS) to erlotinib was 9.7 months for those with T790M mutations and 15.8 months for those without, while among patients receiving chemotherapy, it was 6 and 5.1 months, respectively (P<0.0001). PFS to erlotinib was 12.9 months for those with high and 7.2 months for those with low/intermediate BIM expression levels, while among chemotherapy-treated patients, it was 5.8 and 5.5 months, respectively (P=0.0003). Overall survival was 28.6 months for patients with high BIM expression and 22.1 months for those with low/intermediate BIM expression (P=0.0364). Multivariate analyses showed that erlotinib was a marker of longer PFS (hazard ratio [HR]=0.35; P=0.0003), while high BIM expression was a marker of longer PFS (HR=0.49; P=0.0122) and overall survival (HR=0.53; P=0.0323).
Low-level pretreatment T790M mutations can frequently be detected and can be used for customizing treatment with T790M-specific inhibitors. BIM mRNA expression is a biomarker of survival in EGFR-mutant NSCLC and can potentially be used for synthetic lethality therapies.
Clinical Cancer Research 02/2014; · 7.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Non-small-cell lung cancer is often diagnosed at the metastatic stage, with median survival of just 1 year. The identification of driver mutations in the epidermal growth factor receptor (EGFR) as the primary oncogenic event in a subset of lung adenocarcinomas led to a model of targeted treatment and genetic profiling of the disease. EGFR tyrosine kinase inhibitors confer remission in 60% of patients, but responses are short-lived. The pre-existing EGFR Thr790Met mutation could be a subclonal driver responsible for these transient responses. Overexpression of AXL and reduced MED12 function are hallmarks of resistance to tyrosine kinase inhibitors in EGFR-mutant non-small-cell lung cancer. Crosstalk between signalling pathways is another mechanism of resistance; therefore, identification of the molecular components involved could lead to the development of combination therapies cotargeting these molecules instead of EGFR tyrosine kinase inhibitor monotherapy. Additionally, novel biomarkers could be identified through deep sequencing analysis of serial rebiopsies before and during treatment.
The Lancet 08/2013; 382(9893):720-31. · 39.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: : Lung adenocarcinoma patients harboring EGFR activating mutations attain improved progression-free survival (PFS) with treatment with epidermal growth factor receptor tyrosine kinase inhibitors. However, patients ultimately relapse, indicating that other genetic factors could influence outcome in such patients. We hypothesized that PFS could be influenced by the expression of genes in DNA repair pathways.
: We examined the mRNA expression of C terminus-binding protein-interacting protein and Lin11, Isl-1, and Mec-3 domain only 4 (LMO4) in pretreatment tumor samples from 91 erlotinib-treated advanced non-small-cell lung cancer patients with EGFR mutations in whom breast cancer gene 1 (BRCA1) expression and the concomitant presence of the EGFR T790M mutation had previously been assessed. Gene expression was analyzed by polymerase chain reaction, using β-actin as endogenous gene. Results were correlated with PFS and overall survival.
: In patients with low LMO4 levels, PFS was 13 months, whereas it was not reached for those with high LMO4 levels (p = 0.03). In patients with low levels of both BRCA1 and LMO4, PFS was 19 months whereas it was not reached in those with low BRCA1 and high LMO4 mRNA levels (p = 0.04). In patients with high BRCA1 and low LMO4 levels, PFS was 8 months, whereas it was 18 months in those with high levels of both genes (p = 0.03).
: Low BRCA1 and high LMO4 levels were associated with longer PFS to erlotinib. Baseline assessment of BRCA1 and LMO4 mRNA expression can help predict outcome to erlotinib.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 03/2013; 8(3):295-300. · 4.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of the study was to evaluate the predictive value of genes involved in the action of cisplatin-etoposide in Small Cell Lung Cancer (SCLC).
184 SCLC patients' primary tumour samples were analyzed for ERCCI, BRCA1, ATP7B, PKM2 TOPOI, TOPOIIA, TOPOIIB and C-MYC mRNA expression. All patients were treated with cisplatin-etoposide.
The patients' median age was 63 years and 120 (65%) had extended stage, 75 (41%) had increased LDH serum levels and 131 (71%) an ECOG performance status was 0-1. Patients with limited stage, whose tumours expressed high ERCC1 (p=0.028), PKM2 (p=0.046), TOPOI (p=0.008), TOPOIIA (p=0.002) and TOPOIIB (p<0.001) mRNA had a shorter Progression Free Survival (PFS). In limited stage patients, high expression of ERCC1 (p=0.014), PKM2 (p=0.026), TOPOIIA (p=0.021) and TOPOIIB (p=0.019) was correlated with decreased median overall survival (mOS) while in patients with extended stage, only high TOPOIIB expression had a negative impact on Os (p=0.035). The favorable expression signature expression signature (low expression of ERCC1, PKM2, TOPOIIA and TOPOIIB) was correlated with significantly better PFS and Os in both LS-SCLC (p<0.001 and p=0.007, respectively) and ES-SCLC (p=0.007 and (p=0.011, respectively) group. The unfavorable expression signature was an independent predictor for poor PFS (HR: 3.18; p=0.002 and HR: 3.14; p=0.021) and Os (HR: 4.35; p=0.001and HR: 3.32; p=0.019) in both limited and extended stage, respectively.
Single gene's expression analysis as well as the integrated analysis of ERCC1, PKM2, TOPOIIA and TOPOIIB may predict treatment outcome in patients with SCLC. These findings should be further validated in a prospective study.
PLoS ONE 01/2013; 8(9):e74611. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epidermal growth factor receptor (EGFR) gene mutations and increased EGFR copy numbers have been associated with a favorable response to EGFR tyrosine kinase inhibitors (TKI) in patients with non-small-cell lung cancer (NSCLC), and several markers have been identified that predict response to treatment. Lung adenocarcinomas also harbor activating mutations in the downstream GTPase, v-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS), and mutations in EGFR and KRAS appear to be mutually exclusive. Even though KRAS mutations were identified in NSCLC tumors more than 20 years ago, we have only just begun to appreciate the clinical value of determining KRAS tumor status. Recent studies indicate that patients with mutant KRAS tumors fail to benefit from adjuvant chemotherapy and do not respond to EGFR inhibitors. There is a clear need for therapies specifically developed for patients with KRAS-mutant NSCLC. In this review, we summarize the clinical and pathologic characteristics of patients with NSCLC and with KRAS mutations, describe work that explores the predictive and prognostic influence of KRAS mutations, and provide an overview of the "synthetic lethal" interactions and current approaches to targeting KRAS-mutant NSCLC.
Clinical Lung Cancer 10/2012; · 2.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate the efficacy and safety of docetaxel plus capecitabine (DC) combination as salvage treatment in anthracycline- and taxane-pretreated patients with metastatic breast cancer (MBC).
Patients with MBC who had disease progression after initial chemotherapy with anthracyclines (n = 29; 100 %) and taxanes (n = 11; 37.9 %) were treated with oral capecitabine 950 mg/m(2) twice daily on days 1-14 and docetaxel 75 mg/m(2) on day 1 every 3 weeks. Nineteen (65.5 %) patients received this regimen as second line and 10 (34.5 %) as ≥3rd line of therapy. All patients were evaluable for response and toxicity.
Complete response occurred in two (6.9 %) patients and partial response in eleven (37.9 %) for an overall response rate of 44.8 % (95 % CI 26.7-62.9 %). Eleven women (37.9 %) had stable disease and five (17.2 %) progressive disease. Of the eleven patients previously treated with anthracyclines and taxanes, five (45.5 %) responded to DC combination. The median duration of response was 5.7 months (range 3.4-64.2), the median time to disease progression 9.3 months (range 1.2-58), and the median overall survival 25.5 months. No toxic death occurred. Neutropenia grade 4 occurred in 58.6 % of patients and three of them (10.3 %) developed neutropenic fever. Non-hematological toxicities were manageable with grade 3 hand-foot syndrome occurring in 6.9 % of the patients, fatigue in 3.4 %, and neurotoxicity in 3.4 %.
The DC combination is a valuable regimen as salvage treatment in anthracycline- or anthracycline and taxane-pretreated patients with MBC.
Cancer Chemotherapy and Pharmacology 06/2012; 70(1):169-76. · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Therapeutic options for patients with relapsed, chemo-resistant small-cell lung cancer (SCLC) are limited. Since paclitaxel has demonstrated single-agent activity in the second-line setting of SCLC and angiogenesis seems to play an important role in the pathogenesis of the disease, a phase II trial was conducted in order to evaluate the efficacy and the tolerance of their combination in patients with relapsed, chemo-resistant SCLC.
Patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 who experienced relapse within 3 months after completion of 1st line chemotherapy for SCLC were eligible. Patients were treated with paclitaxel (90 mg/m(2), days 1, 8 and 15) along with bevacizumab (10mg per kg of body weight, days 1 and 15) in cycles of 28 days.
Thirty patients (male/female: 27/3) with a median age of 64 years and ECOG performance status 0/1/2: 2/25/3 were enrolled. Nineteen patients (63.3%) had received at least two lines of prior treatment, 17 (56.7%) had undergone prior radiotherapy and nine (30%) had brain metastases at the time of study entry. The overall objective response rate was 20% (95% CI: 5.69-34.31%), including one complete remission, whereas the disease control rate was 36.7%. The median duration of response was 2.5 months (range, 1.5-5.7), the median progression-free survival 2.7 months (range, 0.5-9.2) and the median overall survival 6.3 months (range, 0.5-17.9). Grades 3 and 4 toxicities were limited in neutropenia, diarrhea and fatigue. There was one case of non-fatal pulmonary embolism.
The combination of paclitaxel with bevacizumab was feasible and active in this poor prognosis and heavily pretreated population of patients with advanced, chemoresistant SCLC, representing a valid therapeutic alternative which merits further evaluation.
Lung cancer (Amsterdam, Netherlands) 03/2012; 77(1):146-50. · 3.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate the docetaxel-gemcitabine (DG) combination administered every 2 weeks as salvage therapy in anthracycline- and taxane-pretreated patients with metastatic breast cancer (MBC).
Thirty women with MBC who had disease progression after chemotherapy with anthracyclines, or anthracyclines and taxanes were treated with docetaxel 50 mg/m² and gemcitabine 1,500 mg/m² on days 1 and 14 in cycles of 28 days. All patients had received prior anthracyclines, and fourteen (46.6%) had also received prior taxanes. All patients were evaluable for toxicity and 24 for response to treatment.
Complete response occurred in four (13.3%) patients and partial response in 10 (33.3%) for an overall response rate of 46.7% (95% CI 28.8-64.5). Seven patients (23.3%) had stable disease and nine (30%) progressive disease. Of the 14 patients previously treated with both anthracyclines and taxanes, seven (50%) responded. The median duration of response was 4.8 months (range 1.9-15.3), the median time to disease progression 6.6 months (range 0.5-16.9) and the median overall survival 16.8 months (range 1.3-53.2). There was no treatment-related toxic death. Neutropenia was the only grade 4 toxicity occurring in three (10%) patients. None of them developed neutropenic fever. Grade 3 thrombocytopenia occurred in two (6.7%) patients. Non-hematological toxicities were manageable.
The DG combination administered biweekly is very well tolerated and effective in anthracycline- and taxane-pretreated patients with MBC. A previous treatment with taxanes does not preclude a good clinical response to this regimen.
Cancer Chemotherapy and Pharmacology 02/2012; 69(5):1345-52. · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study evaluates the activity and toxicity of the paclitaxel/carboplatin (PC) doublet versus vinorelbine/carboplatin (VC) doublet as second-line treatment in patients who have advanced non-small-cell lung cancer (NSCLC).
Patients pretreated with front-line docetaxel and gemcitabine were randomized to receive either PC (n = 75), which consisted of paclitaxel at a dose of 140 mg/m(2) and carboplatin area under the curve (AUC3), or VC (n = 78), which consisted of vinorelbine at a dose of 45 mg/m(2) orally and carboplatin AUC3; both drugs were administered on days 1 and 15.
The overall response rate was 18.6% (95% confidence interval, 9.85%-27.49%; one complete and 13 partial responses) in the PC arm and 7.7% (95% confidence interval, 1.78%-13.61%; one complete and five partial responses) in the VC arm (P = .056). Median time to tumor progression was 3.5 months (range, 0.3 - 23.73 months) and 3.07 months (range, 0.37-18.5) in the PC and VC arm, respectively (P = .287). Median overall survival was 7.83 months (range, 0.3-45.03 months) and 7.60 months (range, 0.5-30.27 months) for PC and VC arms, respectively (P value = .633). Chemotherapy was well-tolerated and grade III/IV toxicities were relatively infrequent. No toxic deaths were observed.
Platinum-based doublets with either paclitaxel or vinorelbine in patients with advanced/metastatic NSCLC pretreated with front-line docetaxel/gemcitabine show comparable efficacy when used in the second-line setting.
Clinical Lung Cancer 03/2011; 12(2):100-5. · 2.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate the efficacy and tolerability of oxaliplatin (L-OHP) in combination with irinotecan (CPT-11) as first-line treatment of advanced biliary tract cancer.
Patients with histologically confirmed nonresectable biliary adenocarcinoma were treated with oxaliplatin (85 mg/m(2)) and irinotecan (200 mg/m(2)) every 3 weeks.
Twenty-eight patients were enrolled between May 2005 and March 2009. The overall objective response rate was 17.9% with an additional 21.4% of patients with stable disease (disease control rate 39.3%). The median overall survival time was 9.2 months (95% CI 5.8-12.5) and the median progression-free survival time 2.7 months (95% CI 2.2-3.2). Grades 3 and 4 neutropenia occurred in 1 (3.6%) and 4 (14.3%) patients, respectively, and febrile neutropenia in 3 (10.7%). Grade 3-4 diarrhea was observed in 2 (7.1%) patients and grade 3 asthenia in 1 (6%). There were no treatment-related deaths.
The combination of oxaliplatin and irinotecan has a modest antitumor activity with manageable toxicity as first-line treatment in metastatic cancer of the biliary tract and therefore it cannot be recommended as front-line treatment for unresectable biliary tract cancer.
[Show abstract][Hide abstract] ABSTRACT: Purpose: To evaluate the efficacy and tolerability of oxaliplatin (L-OHP) in combination with irinotecan (CPT-11) as first-line treatment of advanced biliary tract cancer. Patients and Methods: Patients with histologically confirmed nonresectable biliary adenocarcinoma were treated with oxaliplatin (85 mg/m2) and irinotecan (200 mg/m2) every 3 weeks.Results: Twenty-eight patients were enrolled between May 2005 and March 2009. The overall objective response rate was 17.9% with an additional 21.4% of patients with stable disease (disease control rate 39.3%). The median overall survival time was 9.2 months (95% CI 5.8–12.5) and the median progression-free survival time 2.7 months (95% CI 2.2–3.2). Grades 3 and 4 neutropenia occurred in 1 (3.6%) and 4 (14.3%) patients, respectively, and febrile neutropenia in 3 (10.7%). Grade 3–4 diarrhea was observed in 2 (7.1%) patients and grade 3 asthenia in 1 (6%). There were no treatment-related deaths. Conclusion: The combination of oxaliplatin and irinotecan has a modest antitumor activity with manageable toxicity as first-line treatment in metastatic cancer of the biliary tract and therefore it cannot be recommended as front-line treatment for unresectable biliary tract cancer.