VIENNA, Austria – The genomic landscape of lung cancer is becoming clearer as new mutations are identified in different types of cancers. Two studies presented at the European Cancer Congress (ECC) 2015 in Vienna report new insights into this expanding area. Dr David Planchard, Pulmonary Oncologist at the Gustave Roussy Cancer Campus in Villejuif, France, explains how new technologies, such as next-generation sequencing, offer the possibility of rapid identification of actionable oncogenic alterations and targeted treatment options.
What are the latest findings in the genetics of lung cancer?
Planchard: The last few decades have witnessed significant strides in defining the molecular pathogenesis of lung cancers, and in particular, the detection of critical oncogenic drivers which have led to the development of specific targeted agents. The two studies presented at ECC in Vienna report gene alteration profile of lung cancer through multiplex testing. In the first study (abstract 3001) gene mutations were assessed in resected stage I–III NSCLC (48.3% adenocarcinoma, 7.2% non-smokers), included with biomaterial in the ETOP Lungscape iBiobank. An important number of resected patients were included in this trial (2,709 cases) with 76.7% analysis done by the time of data reporting (a complete mutations panel was possible for 95.1% of patients). The most common mutations reported were KRAS (23.2%, G12C in 45%), MET (6.3%), EGFR (5.1%, mainly females and never smokers, Exon 19 deletion in 56.8%), PIK3CA (4.9%), NRAS (0.7%) and BRAF (0.6%). Rare mutations like AKT1 and MYD were reported in one case.
The second study (abstract 3007) brings data on the BRAF pathway which was evaluated by studying 3,300 consecutive lung cancer cases for molecular alterations. A BRAF mutation was observed in 4.9% of NSCLC. BRAF mutations were found in less than 1% of squamous cell carcinoma (3/385 patients) but no alterations were detected in small cell lung cancer (SCLC). The most frequent type of BRAF mutation was V600 in adenocarcinomas (2.5%) which included 50% V600E. Other types of BRAF mutations (like G469, G466 or D594) were really rare (0 to 1.3%). Two adenocarcinomas harboured interestingly novel fusions, namely DOCK4-BRAF and PTPN13-BRAF.
What strategies have been recently tested to identify driver mutations in different types of lung cancers with prognostic or predictive roles?
Planchard: Among the targetable genetic abnormalities in NSCLC, the presence of activating mutations of the EGFR gene and of chromosomic rearrangements in the ALK proto-oncogene, have been the first reported to enter the clinical arena. Recent genomic studies identified several genetic aberrations with a potential prognostic or predictive role, mainly in the adenocarcinoma histological subtype, including ROS1 rearrangements, RET fusions, MET amplification, HER2 amplification and insertions, and activating mutations in BRAF and KRAS. Oncogenic drivers, such as DDR2 mutations, FGFR1 amplification and PI3KCA mutations, have been characterised in squamous cell lung carcinoma. The key challenge will be developing efficient assays for identifying these genomic alterations such that appropriate targeted therapies can be delivered.
New technologies, such as next-generation sequencing, offer the possibility of rapid identification of actionable oncogenic alterations and targeted treatment options. Few large scale data are currently available in resected NSCLC, like in the ETOP study, in which ~150 (13 genes) mutations were covered in a multiplex test. Results presented focus on KRAS, HRAS, MET, EGFR, PIK3CA, BRAF, AKT1, MYD88, ERBB2, FLT3, JAK2 and KIT abnormalities. The authors reported no significant difference in overall survival according to the EGFR, KRAS, MET or PIK3CA status (mutated or not). The strength of the second study is the number of tumours studied (3,300 lung cancer cases) including 201 SCLC (histological type with no specific identification of actionable oncogenic alterations) by sequencing 3769 exons of 315 cancer-related genes and selected introns (28 genes). Only results concerning BRAF abnormalities are presented.
Are we getting closer to novel targeted strategies?
Planchard: Preclinical data and early clinical findings suggest that ROS1, RET and BRAF may be viable therapeutic targets. Opposite efforts to target some mutated genes like KRAS have been unsuccessful and further efforts to develop therapies for patients with KRAS mutant NSCLCs are urgently needed. The ETOP trial demonstrated the feasibility of performing multiplex molecular profiling on archival NSCLC material but unfortunately did not identify specific prognostic factors in resected NSCLC.
These results do not change current clinical practice but encourage continuing molecular screening in this population. Concerning the screening of a BRAF abnormality in lung cancer it appears to be important notably in adenocarcinoma of the lung. This trial confirmed the low frequency of BRAF alteration that has been previously reported either in retrospective or prospective trials. Responses of patients with BRAF inhibitors will be interesting to see, particularly in non V600E mutations and in patients with the two fusion genes reported.
While awaiting the results of ongoing phase II trials, BRAF V600E mutations could potentially be considered as a predictive factor for response to a specific BRAF inhibitor like vemurafenib or dabrafenib. As demonstrated in metastatic melanoma with a BRAF V600 mutation, combining a BRAF inhibitor with a MEK inhibitor provides clear evidence for the benefit of this combination therapy over BRAF monotherapy. Preliminary clinical data of a phase II study suggest similar benefit in BRAF V600E-mutated NSCLC and might lead to a new standard of care in this sub-population.
Abstracts presented at ECC 2015, held 25–29 September in Vienna, Austria:
3001: Prevalence and clinical association of gene mutations through Multiplex Mutation Testing in patients with NSCLC: Results from the ETOP Lungscape Project. K. Kerr, UK. Saturday 26th September 2015 – 10:30-12:20 Proffered Paper Session STRAUSS
3007: Comprehensive genomic profiling characterizes the cpectrum of non-V600E activating BRAF alterations Including BRAF fusions in lung cancer. S. Ali, USA. Monday 28th September 2015 – 09:00-11:10 Proffered Paper Session STRAUSS
Information contained in this commentary was provided by the interviewee.