ONCOLOGY UPDATE

Experts from the Dr Rosell Oncology Institute, co-authors of research presented at the World Conference on Lung Cancer (WCLC)

31/10/2013

Barcelona, October 2013. Expert investigators from the Dr Rosell Oncology Institute are co-authors of results presented at the 2013 annual meeting of the International Association for the Study of Lung Cancer (IASLC). Results presented include analyses of predictive biomarkers and novel mechanisms of resistance to targeted therapies, as well as the early results of whole exome and transcriptome sequencing in collaboration with the US Cancer Therapeutics Innovation Group (GTIC). Results of the studies were presented during the congress in the form of oral presentations and posters.



The Spanish Lung Cancer Group (SLCG) BRCA1-RAP80 Expression Customization (BREC) randomized phase III trial of customized chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients with wild-type epidermal growth factor receptor (EGFR) (NCT00617656/GECP-BREC)

Rafael Rosell et al.

Abstract #1157 Oral


The Spanish Lung Cancer Group and the French Lung Cancer Group performed a prospective, randomized phase III trial in metastatic NSCLC patients to compare non-customized cis/doc with customized therapy customized according to BRCA1 and RAP80 mRNA expression levels. The primary endpoint was progression-free survival (PFS). Based on the negative results for PFS at the interim analysis, accrual was closed on this study. The negative results may be due to the poor predictive capacity of RAP80 and/or to the inclusion of doc alone as a treatment in the experimental arm. Customized chemotherapy could be further encouraged in oncogene-driven pan-negative patients with PS 0.



 



The concomitant presence of echinoderm microtubule associated protein like 4 – anaplastic lymphoma kinase (EML4-ALK) EML4-ALK fusion gene in EGFR-mutant non-small-cell lung cancer (NSCLC) patients treated with erlotinib or chemotherapy in the EURTAC trial

Niki Karachaliou et al.

Abstract #1109 Mini Oral


Activating mutations in the epidermal growth factor receptor (EGFR) confer sensitivity to gefitinib and erlotinib in patients with NSCLC. The EML4-ALK fusion gene has recently been identified in a subset of NSCLCs harboring EGFR mutations. We evaluated the frequency and impact of the concomitant presence of EML4-ALK in patients included in the randomized phase III EURTAC trial. Our findings indicate that the EML4-ALK rearrangement is concomitant with EGFR mutations in a considerable number of NSCLC patients and may favorably affect outcome.



Integrated genomic analysis by whole exome and transcriptome sequencing of tumor samples from EGFR-mutant non-small-cell lung cancer (NSCLC) patients with acquired resistance to erlotinib

Trever Bivona et al.

Abstract #1426 Mini Oral


NSCLC patients with EGFR mutations initially respond to EGFR tyrosine kinase inhibitors (TKIs) but ultimately relapse. Sub-genomic molecular studies indicate that the EGFR T790M mutation and the activation of MET, PI3K, AXL, HER2 and MAPK can lead to acquired resistance to EGFR TKIs. To date, no integrated comprehensive genomic investigation of EGFR TKI resistance has been reported. We conducted the first ever comprehensive integrated genomic analysis of EGFR TKI resistant NSCLC patients, and identified both known and potentially novel drivers of EGFR TKI resistance. This study demonstrated the feasibility and utility of comprehensive genomic analysis in the clinical management of NSCLC receiving targeted therapy. Together, our data provide unprecedented insight into the molecular pathogenesis of escape from EGFR oncogene inhibition in NSCLC. We are now conducting a prospective observational study in additional NSCLC patients on targeted therapy



Integrated genomic analysis of EGFR-mutant non-small cell lung cancer immediately following erlotinib initiation in patients

Petros Giannikopoulos et al.

Abstract 1003 Poster


Major obstacles limiting the clinical success of EGFR TKI therapy in EGFR mutant non-small cell lung cancer (NSCLC) patients are heterogeneity and variability in the initial anti-tumor response to treatment. The underlying molecular basis for this heterogeneity has not been explored in patients immediately after initiation of therapy. This study is the first reported longitudinal integrated genomic analysis of EGFR-mutant NSCLC in a patient treated with an EGFR TKI. We documented the feasibility, safety and utility of this strategy to establish initial drug efficacy at the molecular level prior to any radiographic evidence of response (6 days), as well as evidence that acquired resistance can emerge early in the course of TKI therapy. Serial integrated genomic analysis is ongoing in other TKI treated patients to enhance the management of NSCLC patients on targeted therapy.



Impact of EGFR T790M mutations and BIM mRNA expression on progression-free survival (PFS) and overall survival (OS) in patients with EGFR-mutant non-small-cell lung cancer (NSCLC) treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial

Rafael Rosell et al.

Abstract #1167 Poster


Activating EGFR mutations confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs) in patients with NSCLC, but responses are transient, with delay in disease progression but no impact on survival. Concomitant genetic alterations could account for these incomplete clinical responses. Erlotinib-treated EGFR-mutant NSCLC patients harboring the EGFR T790M mutation had shorter PFS than those without the mutation (12 vs 18 months [m]). Low BIM levels were associated with gefitinib resistance in EGFR-mutant NSCLC. BIM mRNA expression is a biomarker of PFS and OS in EGFR-mutant NSCLC. T790M mutations and BIM mRNA expression can potentially be used for designing combination therapeutic strategies for use in lieu of EGFR TKI monotherapy.



 



ROR1 as a novel therapeutic target for EGFR-mutant non-small-cell lung cancer (NSCLC) patients with the EGFR T790M mutation

Niki Karachaliou et al.

Abstract #1395 Poster


Molecular cross-talk between EGFR and other signaling pathways creates alternative means of tumor cell proliferation and promotes resistance to single-agent erlotinib therapy in NSCLC driven by EGFR mutations. 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. 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. 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.



Outcome in pemetrexed/cisplatin-treated non-small-cell lung cancer (NSCLC) patients according to mRNA expression levels of BRCA1, TS, AEG1 and REV3

Bartomeu Massuti et al.

Abstract #1170 Poster


REV3, the catalytic subunit of the translesion synthesis (TLS) polymerase x, can continue replication past DNA adducts. Depletion of REV3 sensitizes A549 lung cancer cells to cisplatin. REV3 expression is part of a gene signature that predicted pemetrexed sensitivity in 17 NSCLC cell lines. BRCA1, TS, AEG1 and RAP80 are involved in DNA damage repair through homologous recombination. The homologous recombination and TLS pathways have non-redundant functions in response to cisplatin. We hypothesized that low mRNA expression of these genes – either alone or in combination – could confer improved outcome to cisplatin/pemetrexed in NSCLC patients. Low BRCA1 expression predicts longer PFS and OS in pemetrexed/cisplatin-treated NSCLC p. Low TS and AEG1 levels have similar predictive value. The combination of low BRCA1 and REV3 expression confers longer PFS and OS. Analysis of these genes could be useful for customizing pemetrexed/platinum chemotherapy.



MED12, a component of the transcriptional MEDIATOR complex, and STAT3 influence outcome to platinum-based chemotherapy in patients (p) with advanced non-small-cell lung cancer (NSCLC)

Daniela Morales-Espinosa et al.

Abstract #323 Poster




Chinese randomized phase II trial of customized chemotherapy based on BRCA1-RAP80 mRNA expression in advanced non-small-cell lung cancer (NSCLC) patients (p) (ChiCTR-TRC-12001860/BREC-CHINA)

Jia Wei et al.

Abstract #1883 Poster


BRCA1 serves as a differential modulator of chemosensitivity to docetaxel (doc) and cisplatin (cis). RAP80 targets the BRCA1-BARD1 E3 ligase at double-strand breaks. A Spanish Lung Cancer Group (SLCG) phase II customized chemotherapy trial (NCT00883480) indicated that RAP80 and BRCA1 jointly influenced outcome in NSCLC p treated with cis- or doc-based chemotherapy. Based on these findings, the SLCG initiated a randomized phase III trial (NCT00617656/GECP-BREC), and we have performed a parallel phase II trial comparing non-customized cis/doc with customized therapy in metastatic NSCLC p in China. In the multivariate analysis including PS, treatment arm, BRCA1, RAP80, histology and smoking status, only ex-smokers were associated with an increased risk of progression (HR, 1.906; P=0.029). Customized chemotherapy based on BRCA1/RAP80 expression does not improve PFS. The predictive value of BRCA1 alone seems to be stronger than that of BRCA1/RAP80 combined.


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