Janis C. Kelly

June 06, 2014

CHICAGO — A new gene expression biomarker test might help guide the treatment of high-grade serous ovarian cancer (HGSOC) and avoid the futile use of an expensive type of targeted therapy.

The AADx assay (Almac Group Ltd) helps clinicians determine which patients with HGSOC are likely to benefit from antiangiogenic drugs such as bevacizumab (Avastin, Genentech/Roche) and which might have worse outcomes with these drugs and do better with standard chemotherapy.

"This is the first assay to convincingly predict sensitivity to anti-angiogenic therapy in any cancer," said lead author Charlie Gourley, MD, PhD, chair of Medical Oncology at Edinburgh Cancer Research Centre, Edinburgh, United Kingdom.

He presented study results on the assay here at the annual meeting of the American Society of Clinical Oncology® (ASCO).

Dr. Gourley also pointed out that bevacizumab is licensed in Europe for first-line treatment of stage IIIB, IIIV, and IV ovarian cancer but has not yet been approved in the United States for treatment of this cancer.

The story of the new test starts with Dr. Gourley and fellow researchers in the UK performing transcriptional analysis on mRNA extracted from tumor tissue samples of a group of 200-plus Scottish patients.

The exercise was repeated on an additional 283 tissue samples from the ICON7 study of HGSOC. ICON7 patients had been randomized to first-line paclitaxel/carboplatin with or without concomitant and maintenance bevacizumab for 12 months.

The team identified 3 subtypes among these HGSOC patients. Two had angiogenic gene upregulation, which means that they had high expression of genes involved in vascular development during angiogenesis. They were combined in most of the subsequent analyses and dubbed the "proangiogenic" subgroup.

The other 1 was a subgroup with no angiogenic gene expression and immune gene upregulation.

This latter "immune response" subgroup had a superior overall survival (OS) compared with the other 2 subgroups (ie, angiogenic gene expression) combined (hazard ratio [HR] = 0.66) in ICON7.

A 63-gene expression signature (ie, the AADx assay) to prospectively identify this immune response subgroup, which had the better survival, was then generated. The gene test was subsequently validated as prognostic for OS in an independent dataset (HR = 0.32 [0.19 - 0.54]).

Next, the team hypothesized that the immune response subgroup, which had no angiogenesis-related gene expression, would benefit less from bevacizumab.

Dr. Gourley put it this way at ASCO: "This immune molecular subtype was characterized by the absence of angiogenic biology. We therefore hypothesized that they would not benefit from anti-angiogenic agents, so we applied our immune assay to 285 HGSOC translational research samples from the ICON7 study,"

Sure enough, in the ICON7 dataset, the gene signature showed a difference in impact of bevacizumab on progression-free survival (PFS) between the immune response and "proangiogenic" (upregulation) subgroups (P = .016).

For the immune group (41% of cases), the addition of bevacizumab conferred a worse PFS (HR = 1.73) and OS (HR = 2.00) compared with chemotherapy alone.

Dr. Gourley summarized the meaning of this finding: "What we found was that in the immune subgroup patients who received bevacizumab had a worse PFS than those in the pro-angiogenic subgroups. The test for interaction, which tells us whether a biomarker distinguishes those who will respond from those who won't respond, had a p=0.015."

The PFS curve split at about 1 month after the start of bevacizumab, with PFS at 36 months of about 50% with carboplatin/paclitaxel and about half that when bevacizumab was added.

On the other hand, in the combined proangiogenic groups, there was a nonsignificant trend to improved PFS for the addition of bevacizumab (median 17.4 vs 12.3 months in controls).

"The immune signature identified patients whose outcome was adversely affected by bevacizumab, and there was a trend toward improved outcomes with bevacizumab outside of this subtype. This is the first assay to convincingly predict sensitivity to anti-angiogenic therapy in any cancer," Dr. Gourley said.

Speaking at a Highlights of the Day Session at ASCO, Rebecca Kristeleit, MD, PhD, medical oncologist at University College of London Cancer Institute, characterized this as a very exciting study because it is the first time that researchers have managed to identify subgroups that will vs will not respond to bevacizumab.

Patients with the immune gene signature could likely be spared the costs and possible side effects of bevacizumab treatment, she added.

"This is a powerful tool to help us refine treatment," Dr. Kristeleit said.

The assay manufacturer, Almac Diagnostics, believes that the test will also work for other antiangiogenic compounds that function in a similar manner. The company is working with the US Food and Drug Administration and European Platform of Regulatory Authorities to bring the novel assay to market, according to a company press release.

Dr. Gourley reported financial ties to industry, including Roche; coauthors include employees of Almac Diagnostics.

J Clin Oncol. 2014;32:5s(suppl; abstr 5502). Abstract

2014 Annual Meeting of the American Society of Clinical Oncology: Abstract 5502. Presented May 31, 2014.

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