Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Advances in Genomics Studies Have Revealed New Etiological and Somatic Genetic Events

As breast cancer specialist George Sledge, M.D., said in his presentation at the Personalized Medicine World Conference last year, “It turns out that we don’t need a magic bullet to cure cancer. We need a magic shotgun.”

Dr. Sledge, professor and chief of medical oncology at Stanford University Medical Center, was referring to the avalanche of genomic studies that have begun to reveal multiple potential drug targets in individual tumors.

In their 2013 Cancer Discovery review (“The Landscape of Breast Cancer as a Therapeutic Roadmap,” Cancer Discov 2013;3:27–34, doi: 10.1158/2159-8290.CD-12-0462), Matthew J. Ellis, M.D., of the Washington University School of Medicine, and Charles M. Perou, Ph.D., at Charles University of North Carolina’s Lineberger Comprehensive Cancer Center, observed that “Deep genomic analysis will drive treatment decisions based on … cell type and pathway-matched therapies.”

The etiological events that drive breast cancer, they said, “Are finally coming into focus and should be used to set priorities for clinical trials.”

The authors noted that during a six-month span in 2012, four papers published in Nature described the application of massively parallel sequencing techniques to hundreds of breast cancer samples providing a comprehensive catalog of somatic mutations that cause this disease.

For example, Christina Curtis, Ph.D., et al.’s 2012 paper in Nature (“The Genomic Transcriptomic Architecture of 2,000 Breast Cancer Tumours Reveals Novel Subgroups,” Nature 486;346–352, doi:10.1038/nature10983) described the genomic and transcriptomic architecture of 2000 breast tumors. It revealed novel subgroups and a highly complex picture of the somatic genetic events driving breast cancer pathogenesis. Their integrated analysis of copy number and gene expression was performed in a discovery and validation set of 997 and 995 primary breast tumors respectively, with long-term clinical follow-up.

Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in ~40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, the investigators identified putative cancer genes, including deletions in PPP2R2A, MTAP, and MAP2K4. Unsupervised analysis of paired DNA–RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort.

Their results, the authors said, provide a novel molecular stratification of the breast cancer population that is derived from the impact of somatic CNAs on the transcriptome.


Next-Generation Sequence Profiling

Next-generation sequencing (NGS) mutational profiling methods have revealed that treatment-naïve triple-negative breast cancers (TNBCs) display a complete spectrum of mutational and clonal evolution, with some patients’ tumors showing only a few somatic coding sequence point mutations involving a limited number of molecular pathways. Other patients’ tumors however exhibit considerable additional mutational involvement.

While primary TNBCs are still treated as if they were a single disease entity, they do not, the investigators say, behave as a single entity in response to current therapies. And as other authors have concluded, understanding the biology and therapeutic responses of patients with TNBC will require the determination of individual tumor clonal genotypes.

Scientists at the MD Anderson Cancer Center, writing in the July 2015 issue of the Journal of the National Cancer Institute in 2015 (“A Decision Framework for Genomically Informed Investigational Cancer Therapy”, JNCI 2015;107:djv098, doi: 10.1093/jnci/djv098) said genomic alterations, including mutations, insertions/deletions, fusions, and copy number changes, need to be “curated” in terms of the likelihood that they alter the function of a “cancer gene” at the level of a specific variant in order to discriminate so-called “drivers” from “passengers.” Alterations that are targetable either directly or indirectly with approved or investigational therapies are potentially “actionable.”

The MD Anderson scientists note that strong evidence linking predictive biomarkers to therapies exists for only a few genomic markers in the context of specific cancer types. For genomic alterations in other diseases and for other genomic alterations, the clinical data are either absent or insufficient to support routine clinical implementation of biomarker-based therapy. However, there is great interest in optimally matching patients to early-phase clinical trials.

Despite the recognition of the need for biomarker-based therapy, Richard Simon, D.Sc., and Eric Polley, Ph.D. (“Clinical Trials for Precision Oncology Using Next-Generation Sequencing,” Personalized Medicine 2013;10:485–495) of the Biometric Research Branch, National Cancer Institute, say moving tumor genomics to clinical oncology entails many practical challenges. They reviewed the challenges and the clinical studies that are being undertaken to translate genomics to clinical oncology. Many recurrently altered genes are not druggable with current approaches, constituting a barrier to improving patient benefit. Surmounting this barrier is too high risk for investigator-initiated research or industry and will require major new government-sponsored, focused initiatives.

Furthermore, they say, single-agent, molecularly targeted treatment of metastatic disease will provide only limited patient benefit, more “substantial” gains requiring better understanding of crosstalk among signaling pathways, ability to combine drugs, and use of targeted drugs at initial diagnosis.

Early-phase discovery clinical trials in which patients will have genome-wide tumor characterization at diagnosis and at critical retreatment points will provide datasets for learning how to match therapeutics to genomic alterations effectively. Such studies can also provide a setting for identifying drug combinations that are highly active against tumors bearing specific genomic alterations.


IMPACT Trial

One such trial is the National Cancer Institute (NCI)-sponsored IMPACT trial (ClinicalTrials.gov Identifier: NCT01827384), initiated in March 2013 with a projected completion date of March 2017. According to the NCI, the trial will determine whether targeted therapies for people whose tumors have specific gene mutations will be effective regardless of their cancer type.

NCI-MATCH will incorporate more than 20 different study drugs or drug combinations, each targeting a specific gene mutation, to match each patient in the trial with a therapy that targets a molecular abnormality in their tumor. The study was co-developed by the NCI and the Eastern Cooperative Oncology Group and American College of Radiology Imaging Network (ECOG-ACRIN) Cancer Research Group, part of the NCI-sponsored National Clinical Trials Network (NCTN). It is being led by ECOG-ACRIN.

But, says Hope S. Rugo, M.D., who spoke at the 2015 Miami Breast Cancer Conference, while tumor genome profiling identifies driver mutations in breast tumors, it is still too early to use this information in clinical decision making. Dr. Rugo, professor of medicine and director of breast oncology and clinical trials education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, said that “the role of next-generation sequencing remains unclear, and I feel it should be primarily a research tool.”

For most patients, according to Dr. Rugo, the clinical value of targeting specific markers has proven to be uncertain and, at this point, does not seem to justify the risks. She was specifically commenting on sequencing results from a FoundationOne genomic test to illustrate the gap between the prognostic and the predictive science. Reported genomic alterations among 1,445 invasive breast cancers showed that the most common mutations were TP53 and PI3K.

“TP53 mutations are seen in 60% of these cancers. But we don’t have anything to target those cancers with. [At this point] getting that information doesn’t help you in managing your patient,” said Dr. Rugo, adding that “having patients have toxicity as well as cost with unclear benefit is really an ethical dilemma.”

But Dr. Rugo has higher hopes for studies designed like the AURORA trial, already underway in Europe.

Demitrios Zardavas, M.D. (Institut Jules Bordet, Brussels), et al., writing in the British Journal of Cancer (“The AURORA Initiative for Metastatic Breast Cancer,” Br J Cancer. 2014;111:1881–1887, doi: 10.1083/bjc.2014.341), noted that most research efforts have focused on the molecular analysis of the primary tumor to dissect breast cancer genotypes. But accumulating evidence supports, they say, a molecular evolution of breast cancer during its life cycle, with metastatic lesions acquiring new molecular aberrations.

The AURORA initiative for metastatic breast cancer, as described in the British Journal of Cancer, began to enroll patients in 2014 in a European pilot study.

Positive results from a pilot study that aimed to determine the feasibility of large-scale molecular screening, including targeted gene sequencing to detect changes in tumor markers in patients with metastatic breast cancer, were presented at the IMPAKT Breast Cancer Conference held in May 2015 in Brussels. Marion Maetens, M.D., from the Breast Cancer Translational Research Laboratory, Institut Jules Bordet, discussed the findings on behalf of the Breast International Group (BIG) from the AURORA molecular screening program during a conference session.

According to the study authors, results from the pilot study showed that conducting an international molecular screening program for patients with metastatic breast cancer is “feasible and can be carried out across Europe.” As a result, BIG officials say they are proceeding with the AURORA initiative and intend to enroll 1,300 patients with metastatic breast cancer from more than 80 centers throughout Europe.

During the trial, patients with genetic aberrations that are being targeted by new drugs in development will be offered the opportunity to participate in clinical trials, when approved and available in their countries. Ultimately, the aim of AURORA is to improve the outcomes of all patients diagnosed with metastatic breast cancer, the authors said. 








































This article was originally published in the April 2016 issue of Clinical OMICs. For more content like this and details on how to get a free subscription to this digital publication, go to www.clinicalomics.com.