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MD Anderson Implements Tiered Cancer Sequencing to Personalize Treatment


This story was originally published Oct. 8.

Researchers at MD Anderson Cancer Center's Institute for Personalized Cancer Therapy have begun a two-tiered sequencing protocol for cancer patients in order to guide treatment and identify eligible clinical trials.

Patient samples are initially sequenced in a CLIA-certified setting on the Ion Torrent PGM, Funda Meric-Bernstam, the medical director of MD Anderson's Institute for Personalized Cancer Therapy, explained at BGI's International Conference of Genomics meeting in Philadelphia this month.

The team uses the Ion AmpliSeq Cancer panel, which targets hotspot mutations across 46 known cancer genes, as a quick first pass to identify known druggable mutations to help place patients in clinical trials, she said.

Next, broader sequencing, targeting the exons of about 200 genes, is done within a research setting using Nimblegen capture technology and the Illumina HiSeq 2000. While oncologists have access to this data, they cannot act on it without first confirming the actionable mutations in a CLIA setting.

The advantage of doing both, said Meric-Bernstam, is that the AmpliSeq panel allows the obvious, clinically actionable mutations to be identified quickly so patients can receive appropriate therapy or be placed into a clinical trial as soon as possible.

However, the 200-gene protocol is more comprehensive and may pick up mutations not seen by the AmpliSeq panel, but that are still relevant. Additionally, the 200-gene panel screens entire exons, rather than hotspots, said Meric-Bernstam.

This "gives insight into copy number variation" and also enables the team to evaluate tumor-suppressor genes in which mutations are not limited to hotspots, she said.

Currently, the protocol is open to patients with metastatic disease, since those are the ones most likely to be eligible for clinical trials. The center has already enrolled 600 patients and hopes to expand to around 3,000 next year, Meric-Bernstam said.

Initially, the team focused on colon and breast cancer, but has expanded the program to all solid tumors and will eventually open it up to hematological cancers, she added.

When possible, the team sequences samples from both the primary tumor and the metastatic tumor to "give insight into molecular evolution."

The next step is to begin implementing whole-exome or whole-genome sequencing in the cases where the targeted sequencing does not uncover anything actionable. Similar to the 200-gene test, this would be done on a research basis, but the oncologist would have access to the data and would have to verify it before making treatment decisions based on the results.

As the project moves forward, Meric-Bernstam said, it will give the center the ability "to deliver more effective therapies to patients" and "the ability to do high-quality clinical trials by having patients with cohorts of known aberrations in advance to assist in the … marker-based trials."

One of the major challenges has been developing a genomic decision-support system. "We need better algorithms to identify actionable aberrations," Meric-Bernstam said.

From the sequencing data it has been collecting, the team is building a database that includes molecular aberrations, as well as all existing approved drugs, investigational drugs, and available clinical trials so that after sequencing is done, mutations can be linked to drugs. Investigational drugs will link to a clinical trial search engine so that the oncologist can identify an appropriate trial for the patient.

The project is currently being funded through a philanthropic grant, but Meric-Bernstam hopes that "as more evidence builds, it will transition to standard of care."

Additionally, she said that the center is considering moving more of the sequencing into a CLIA-certified lab. The team is looking at validating the 200-gene sequencing protocol on the HiSeq and is also evaluating the Ion Proton.

The center is also launching an "unusual responder program" to identify predictive biomarkers from patients with a "surprising response." These would include patients who have complete response to a drug, patients with unexpected rapid progression, or patients who respond initially but then progress. The goal here is to identify mechanisms of drug sensitivity, resistance, and acquired resistance.

Because the "unusual responder" project is more research oriented, the team will start with the 200-gene panel, rather than the more targeted AmpliSeq panel, and expand to more comprehensive sequencing as funding allows, she said.