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Roche Shares New Data on Cell-Free DNA Kits, Anticipates US Availability This Month

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CHICAGO (GenomeWeb) – After Launching its suite of Avenio circulating cell-free DNA assays last month for users outside the US, Roche now plans to make the panels available to American customers in about two weeks, and said it is anticipating strong interest after presenting two new posters at the American Society of Clinical Oncology annual meeting here this week.

Last November, Roche previewed two of the research-use-only panels at a meeting of the Association for Molecular Pathology — a 17-gene 'focused' panel and a 77-gene 'expanded' panel.

Both of these, and the third panel, are based on the CAPP-Seq technology developed by Stanford University's Max Diehn and Ash Alizadeh, and acquired by Roche in 2015.

In one of the new studies presented at ASCO, a team led by Diehn and Alizadeh shared results using the Avenio technology to identify patients who had lingering cancer mutations in their blood (a sign of what clinicians call minimal residual disease) and to assess how these mutations corresponded to the risk of relapse.

This particular application of liquid biopsy is a growing target for research and commercial development, because of the significant potential to impact clinical practice and improve pharmaceutical trials in the adjuvant space.

In colorectal cancer for example, adjuvant chemotherapy is offered to most patients with stage III disease, and to some with Stage II cancers. However many of these patients would be cured with surgery alone.

The great promise of ctDNA is that it could pick out patients with residual disease and consequent high risk much more sensitively than current clinical measures, and help physicians personalize additional or adjuvant treatment plans. It could also help drug companies improve trials for new adjuvant drugs by avoiding stacking their cohorts with patients who might be cured by surgery alone.

And indeed, a few groups have now begun to show that this is possible, starting with researchers at Johns Hopkins University and the Institute of Medical Research in Melbourne, Australia, which showed last year that circulating tumor DNA can be used to identify patients whose colorectal cancer is more likely to recur after surgical tumor resection.

More recently, Hopkins investigator Ben Park has begun a study using circulating tumor DNA to predict breast cancer recurrence. The study is tracking whether tumor DNA lingers or disappears in the blood of triple negative breast cancer patients treated with neoadjuvant chemotherapy and whether this can predict which patients will go on to recur and which will not.

In their new study at ASCO this week, Diehn and colleagues used Roche's third Avenio assay, the 'surveillance kit', which identifies variants in regions of nearly 200 genes, testing both tumor and blood samples from a cohort of 145 Stage II and III colorectal cancer patient whose tumors were surgically removed.

Based on the blood results, the investigators classified patients as either ctDNA-positive or ctDNA-negative based on detection of any variant that was present in a patient's corresponding tumor sequencing results.

Overall, 12 patients were positive for ctDNA after surgery. These 12 subjects had both shorter relapse-free survival and shorter overall survival compared to the 132 ctDNA-negative patients. More than 90 percent of the ctDNA-positive patients (11 of 12) developed recurrence, while only 7 percent of ctDNA-negative patients (9 of 132) recurred.

Diehn said during a separate podium presentation at the ASCO meeting that while other groups have also used ctDNA in this manner, most other tests have relied on tissue sequencing to pick out a single DNA biomarker to track in patient's blood, rather than using a broad panel.

In the study with Roche, he and his colleagues calculated what their results would have been if they had tracked only a single mutation, rather than using the full Avenio assay. According to the team's abstract, the broader method appears to double the sensitivity of looking for single alterations.

Sushma Selvarajan, head of disease areas for Roche Sequencing Solutions, said that when it launched the three Avenio kits earlier this year, Roche anticipated that the largest interest would be in the smaller targeted panel, at least among community oncologists looking for a test limited to the most clinically validated markers. But in actuality many users seem to want the broader panel, and are interested in research using the surveillance assay.

"As we look around the globe we will be tracking how things take off, but the idea is that we've provided flexibility and a level of choice depending on what the user wants but also in light of things like reimbursement," Roche Sequencing Solutions Head Neil Gunn added.

"With the two therapy prediction kits, we know that some markets are very sensitive to what is reimbursed, so the 17-gene kit can allow more compliance with reimbursement and with rules for reporting in certain areas," Selvariajan said.

"We thought community oncologists are going to get the 17-gene panel, and that's kind of true," she said. "But in reality most of the interest we are seeing is in the expanded and surveillance kits — the expanded kit for the clinical questions of today and the surveillance kit because that's really where research is turning: to minimal residual disease, surveillance, and monitoring."

Selvarajan and Gunn said that pharmaceutical companies especially have recognized that tools like the CAPP-seq-based Avenio surveillance product may allow them to more effectively and efficiently advance therapies in the adjuvant space, as evidenced by growing research from groups like Diehn's.

According to Selvarajan, Roche has about 22 clinical research studies ongoing in various cancers using one of the three Avenio assays. For surveillance in particular, she said that there has also been a lot of new interest from pharma since the kits were launched last month.

With laboratory-developed tests still outside the regulatory umbrella of the US Food and Drug Administration, clinical labs can and do use RUO technologies to test patients, but Roche has stressed that the Avenio assays are still research tools.

However, Gunn and Selvarajan said that the ultimate goal is to advance CAPP-seq based liquid biopsy tests for clinical, not just research use.

"At the end of the day Roche is an IVD company, so we built the RUO products so that we could allow the research community to answer the questions that will get us there," Selvarajan said.

Aside from minimal residual disease, liquid biopsy assays also appear to be entering wide use in drug trials to stratify patient responses. In the other new study at ASCO, a team from Roche, Genentech, and several collaborating academic centers evaluated patient clinical outcomes from the completed STEAM trial in metastatic colorectal cancer, looking for links between drug response and blood-based mutations.

STEAM assessed the efficacy of either concurrent or sequential FOLFOXIRI-bevacizumab versus FOLFOX with bevacizumab for first-line treatment of metastatic CRC patients.

Researchers used the Avenio 77-gene 'expanded kit' to measure somatic cancer mutations in both pre- and post-treatment plasma samples from about 180 STEAM subjects, in addition to sequencing tissue samples. Overall, the authors reported that pre-treatment plasma mutations were 83 percent concordant with patients' tissue-based mutation status.

Focusing only on the seven most mutated genes in the panel, concordance ranged from 91 to 100 percent, the team wrote.

More importantly, the researchers saw that both ctDNA and tissue mutations were both predictors of drug response. Patients who were RAS wild type either in tissue or in plasma had significantly longer progression-free survival on either the concurrent or sequential FOLFOXIRI combination. RAS-mutant patients did now show this difference in response.

In contrast, TP53-wild type patients didn't respond much differently to any of the three treatment schemes, but mutated patients went longer without progressing on concurrent FOLFOXIRI-bevacizumab compared to the FOLFOX-based arm.

Beyond liquid biopsy, Gunn said that Roche is also working toward release of new sequencing assays for preserved tissue samples next year, as well as new technology to automate workflows.

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