• Promising results from a Phase II study evidence the clinical gains of combinatorial therapy with BRAF inhibitors for patients with advanced BRAF-mutated colorectal cancer
• Pioneering research led by VHIO for the very first time establishes the clinical relevance of clonal mutations in colorectal cancer
Many Vall d´Hebron Institute of Oncology (VHIO) leading physician-researchers are currently participating at the Annual Meeting of the American Society of Clinical Oncology (ASCO), Chicago, 03 -07 June. From among the numerous posters and oral presentations accepted to first outing during this annual meeting that convenes over 30.000 oncologists from across the globe as the international reference event in clinical oncology, several will be presented by VHIO experts – to name but two in colorectal cancer: one study led by Josep Tabernero, VHIO´s Director and Head of the Medical Oncology Department at the Vall d’Hebron University Hospital, revealed the results of a Phase II clinical trial exploring novel combinatorial therapy in patients with BRAF-mutated colorectal cancer and a second, to be delivered by Rodrigo Dienstmann, Principal Investigator of VHIO´s Oncology Data Science (ODysSey) Group, as an oral presentation during The Clone Wars Session of the Clinical Science Symposium, will center on: Clonality patterns of driver mutations (mut) to reveal spatial-temporal genomic heterogeneity in colorectal cancer (CRC).
Rodrigo´s research focuses on the study of gene mutations that drive colorectal cancer development, which is fundamental in gaining essential insights into tumor biology, disease evolution, and response to targeted therapies – all decisive factors in the survival of patients. Mirroring the purely translational and multidisciplinary research model for which VHIO is famed, Rodrigo´s data showcasing this week during ASCO, also derives from close collaboration and connectivity with researchers belonging to VHIO´s Cancer Genomics Group led by Ana Vivancos. The particularly innovative aspect of this study is the exploration of gene alterations based on the number of cells within the tumor that present a given mutation and thus, consequently determine tumor heterogeneity — as opposed to a ´black or white´ approach (mutated or non mutated).
The principal aim of this research was to establish whether multiple mutations in a tumor can determine a patient´s prognosis as well as response to treatment targeted at cells with BRAF gene mutations.
After studying a collection of more than 700 colorectal patient samples used for essential research carried out by VHIO scientists from 2010 to 2015, Rodrigo and his team have evidenced the existence of tumors presenting a gene mutation in all cells — so-called clonal, and others that do not: heterogeneous tumors or those with subclonal alterations. For the very first time, this VHIO collaboration led by Rodrigo has shown the clinical relevance of clonal mutations in colorectal cancer.
This subclonal heterogeneity is most prevalent in tumors with BRAF and PI3K (PIK3CA) mutations, while KRAS and NRAS mutations tend to be homologous and clonal. VHIO researchers also discovered a greater molecular heterogeneity in colorectal cancer metastases than in primary tumor metastases — representing evolutionary changes that drive the development of metastasis or the selection of clones resistant to standard therapy.
The importance of this study, reflected by ASCO´s hand-pick as an oral presentation during its prestigious annual meeting, lies in the fact that mutations implicated in the development of colorectal cancer in a large number of patient samples have been comprehensively studied, thanks to VHIO´s leading pre-screening program that currently performs molecular profiling in over 1500 patients per year across several tumor types.
“In order to assess the importance of clonality, we looked at patient survival. We found that both clonal and subclonal mutations impact on survival,” explains Rodrigo. “We also studied whether the presence of clonal mutations increased efficacy of mutation-targeted therapies. Again, we found that the number of mutated cells in the tumor didn’t alter the likelihood of response to precision therapies. Our results also highlight the importance of using sensitive sequencing techniques. While a tumor may only present a small number of cells with mutations in a key gene, this could have a major impact on its biology,” he concludes.
Data from a Phase II study led by Josep Tabernero, also benefiting from the molecular profiling of samples from VHIO´s pre-screening program, were presented at ASCO last Saturday June 04 during the Gastrointestinal (Colorectal) Cancer Poster Session.
Results from this multi-center, international Phase 2 clinical trial with Array Biopharma, evidence the efficacy of combination therapy using BRAF (encorafenib), EGFR (cetuximab) and PI3K (alpelisib) inhibitors for patients with advanced BRAF-mutated colorectal cancer.
Tabernero and study collaborators explored the efficacy and safety of this combined trio of inhibitors either as a triple regimen of encorafenib, cetuximab and alpelisib; or as a double regimen with encorafenib and cetuximab. The results of both combinations show promising clinical activity in patients with BRAF-mutated colorectal cancer. Crucially, without these targeted therapies, these patients tend to have a very poor prognosis, as also evidenced in Rodrigo Dienstmann´s study.
“The BRAF mutation carries a poor prognosis for patients with advanced colorectal cancer who fail to respond to first-line therapy,” explains Josep Tabernero, Head of the Medical Oncology Service of the Vall d’Hebron University Hospital and Director of the Vall d’Hebron Institute of Oncology (VHIO). “Both treatment regimens showed a substantial improvement in progression-free survival and overall survival in this phase II trial. Patients with this difficult-to-treat cancer may therefore stand to benefit from the combination of encorafenib-based regimens.”
To discover more about the final results presented at ASCO, please consult Array Biopharma´s press release attached.
These two studies are representative of the translational research carried out at VHIO and are connected by its strong pre-screening program through which VHIO scientists routinely assess the molecular make-up of patients, affording not only the vital insights into the biology and evolution of tumors but also important data surrounding the suitability for enrolment of patients in clinical studies aimed at testing the efficacy of novel anti-cancer therapeutics.
ASCO´s Annual Meeting, Chicago, 03-07 June 2016
Clonality patterns of driver mutations (mut) to reveal spatial-temporal genomic heterogeneity in colorectal cancer (CRC)
Session: The Clone Wars
Type: Clinical Science Symposium
Time: Monday 06 June, 11.30 – 13:00h
Location: Hall D2
Phase 2 results: Encorafenib (ENCO) and cetuximab (CETUX) with or without alpelisib (ALP) in patients with advanced BRAF-mutant colorectal cancer (BRAFm CRC)
Session: Gastrointestinal (Colorectal) Cancer
Type: Poster Session
Time: Saturday 04 June, 08:00 – 11:30h
Location: Hall A
For additional information please contact Amanda Wren, Director of International Communications, Vall d´Hebron Institute of Oncology (VHIO), Email: firstname.lastname@example.org, Tel. +34 695207886.