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At ESMO, experts assess the clinical use of genome sequencing

Vienna—Should oncologists begin using deep genome sequencing in their clinical practice? Next-generation sequencing (NGS) technologies have come a long way since 1977 when Frederick Sanger developed chain-termination sequencing, but are they ready for prime time? At the annual meeting of the European Society for Medical Oncology, two key opinion leaders battled it out over this topic in a debate.

The Argument for Deep Genome Sequencing

Arguing the pro position, Fabrice Andre, MD, PhD, of the Institut Gustave Roussy in Villejuif, France, said that embracing deep sequencing in daily clinical practice is not only the right thing to do, it is a necessity. The number of genetic biomarkers known to influence patient outcomes and care has risen dramatically in recent years and is only expected to grow, he said.

“The current system is not sustainable for hospitals and academic centers,” said Dr. Andre. “It’s not possible for [them] to run more than 10 bioassays per patient. We need to move to multiplex technology.”

For breast cancer, he said, clinicians can run tests for ER/HER2, TOP2A, FGR1, IGFR1R, EGFR, PAK1, BRCA1, CYP2D6, PTEN and PI3KCA among others. With whole genome sequencing, “you can assess all the genes that you want,” said Dr. Andre. “When you do one test for each biomarker, each biomarker has a cost. Keep in mind that three FISH [fluorescence in situ hybridization] is equal to the same cost of one whole genome CGH [comparative genomic hybridization] array.”

Whole genome sequencing also offers a number of other potential advantages. High throughput approaches can identify a large number of rare targetable gene alterations. This is increasingly important as researchers find genetic alterations that exist in 1% or 2% of patients. The technology also can capture minority clones that may be hard to identify when there is a low percentage of tumor cells in a sample. The next-generation sequencers have been proven to be accurate and they do not need large samples of tissue. Dr. Andre pointed out that some protein-based assays, which are used because they are less expensive than FISH, are not reliable. One study found that the immunohistochemistry test for the HER2 protein was accurate only 81.6% of the time (J Clin Oncol 2006;24:3032-3038, PMID: 16809727).

The “robust” deep sequencing technology is already being used for patient care at academic centers. One such example is the MOSCATO trial, which began in fall 2011. This trial enrolled 120 patients with difficult-to-treat cancers and is using whole genome sequencing to identify potential therapeutic targets. Once a target has been identified, patients receive targeted therapy in a clinical trial if one is available. The turnover time for sequencing is 15 days and the total cost is 1,500 euros, or roughly $2,000 per patient.

The cost of technology is expected to decrease dramatically in the next few years. By the end of 2012, Oxford Nanopore Technology is expected to launch a technology that is the size of a USB drive and will offer whole genome sequencing in 15 minutes for less than $1,000. Dr. Andre argued that deep sequencing will be less expensive than a multiplicity of tests.

He pointed to a case study recently described in the Journal of Thoracic Oncology as an example of a success story (2012;7:e14-e16). In the case report, a 43-year-old never smoker with lung cancer had tested negative for EML4-ALK on the approved companion genetic test for crizotinib (Xalkori, Pfizer). Sensing that an oncogenic genetic driver was spurring the patient’s cancer, clinicians ordered deep sequencing and identified a novel ALK fusion. The patient was treated with crizotinib and was recently reported to have had a complete response.

“In the context of prospective cohorts, but not clinical trials, I think we need to deliver NGS in order to detect a high number of rare, relevant genomic alterations and then treatment can be done in the context of Phase I trials or drug access programs,” said Dr. Andre.

The Argument Against Deep Genome Sequencing

According to Kenneth O’Byrne, MD, a consultant medical oncologist at St. James Hospital and Trinity College Dublin, Ireland, Dr. Andre is jumping the gun. “He makes the fundamental error that all people who are enthusiastic about new technologies always make and that is the non-application of evidence-based medicine,” Dr. O’Byrne said. “Deep sequencing is a fantastic tool, but it is a research toy and an expensive toy at the moment. For day-to-day practical medicine, we have to go by evidence base.”

Dr. O’Byrne cast doubt on Dr. Andre’s success story example. “They treated the patient with crizotinib and made the false conclusion that the ALK rearrangement they detected was responsible for the response. Do we know if that patient expressed MET? Is there any other reason [he] may have responded to crizotinib?” Dr. O’Byrne said.

He agreed that the cost of the sequencing technology was decreasing, but argued that analysis would remain expensive. He argued that the clinical benefit of identifying genetic drivers is still uncertain.

“I would argue that in lung cancer, and indeed in almost every other tumor, there are only a few proven genetic alterations that can be identified that actually affect the way we treat our patients in clinic,” Dr. O’Byrne said. “EGFR [epidermal growth factor receptor] mutations and ALK rearrangements are the only validated predictive biomarkers in NSCLC [non-small cell lung cancer].” He pointed out that these affect only 15% of lung cancer patients, and although there are targeted agents available, the jury is still out on whether the drugs that target these mutations improve survival.

As an example of this, he pointed out that an interim analysis of the PROFILE 007 trial presented at the ESMO meeting (abstract LBA1) showed that although crizotinib increased progression-free survival by 4.7 months compared with chemotherapy, there was no difference in overall survival. “If you look at all of the EGFR TKI [tyrosine kinase inhibitor] randomized controlled trials versus cytotoxic chemotherapy in EGFR mutation–positive disease, there has yet to be a proven [overall] survival benefit, despite obvious clinical benefits,” Dr. O’Byrne said. Researchers say the lack of overall survival advantage in many of these trials can be blamed on the large numbers of patients who cross over to the experimental therapy. “The argument is crossover, but we don’t know that yet,” he said.

Dr. O’Byrne urged caution, as several years ago, it was thought that tumor angiogenesis inhibitors would be the salvation of lung cancer patients and that did not happen. There was clear evidence that new blood tumor vessels were associated with poor outcome, but when researchers tested a slew of antiangiogenic TKIs in patients with lung cancer, none of them worked. These included apatinib, axitinib, cedarinib, motesanib, pazopanib, sorafenib, sunitinib and vandetanib. “There is still some promise that some of these might break through,” Dr. O’Byrne said, pointing to Boehringer Ingelheim’s BIBF1120. “But to date, we’ve spent billions of euros proving that many of these are of no value.

“In my view, and I feel this quite strongly, predictive biomarker tests must undergo validation and quality assurance before they are used rou- tinely in clinical practice,” Dr. O’Byrne said. “Deep DNA sequencing holds huge promise … but it is a research tool, and I do genuinely believe that a lot of clinically irrelevant data is generated that actually confuses the clinician and the patient.”

Clinical Oncology News Issue: December 2012 | Volume: 07:12