Clinicians who treat patients with high-grade serous ovarian cancer (HGSOC) may soon have a better way to decide whether the patient could respond to the anti-angiogenesis antibody bevacizumab (Avastin).
In a presentation at the American Society of Clinical Oncology (ASCO) annual meeting, held May 30-June 3 in Chicago, Charlie Gourley, MD, PhD, of Edinburgh Cancer Research Centre, Edinburgh, United Kingdom, showed that a gene expression test could identify a subgroup of HGSOC patients who had a relatively good prognosis following first-line chemotherapy. The study also showed that this same group did not benefit from, and actually showed a worse progression-free survival (PFS) and overall survival (OS) after the addition of bevacizumab.
Gourley and colleagues analyzed the gene expression from 256 tissue samples from patients in Scotland who were treated with primary debulking followed by standard of care platinum-based chemotherapy. The researchers then repeated the same analysis using 283 samples of patients from the United Kingdom who took part in the international ICON7 phase III clinical trial that tested whether the addition of bevacizumab as either a concurrent therapy or maintenance therapy for 12 months following first-line platinum-based chemotherapy would improve PFS and OS in HGSOC patients.
The test used, called the AADx assay by Almac Group Ltd, analyzes the expression of 63 genes, involved in angiogenesis and immune gene regulation.
Using the test, the researchers identified three main molecular subgroups of patients-two that had increased angiogenesis gene activity ("pro-angiogenic" groups)--and a third subgroup that had increased immune gene expression, as well as repression of angiogenesis related genes. This "immune" subgroup (approximately 40% of all patients in this study), had a better OS compared to the other two subgroups (hazard ratio of 0.66).
The 63-gene test was used prospectively to identify the immune subgroup, validating the prognostic ability of the test. Using the test on samples from the ICON7 study, Gourley and colleagues demonstrated that adding bevacizumab to chemotherapy resulted in a worse PFS (hazard ratio of 1.73) and a worse OS (hazard ratio of 2.00) compared to those patients with this signature who received chemotherapy alone.
Those patients who fell into either of the two pro-angiogenic molecular categories had a non-significant improvement in PFS with the addition of bevacizumab (median 17.4 vs 12.3 months).
“These data suggest a mechanism for stratification of bevacizumab therapy and should be validated in additional datasets,” according to Gourley and co-authors.
This study is interesting, but it is still a research study with small numbers, Michael Birrer, MD, PhD, director of the Gillette Center for Gynecologic Oncology at the Massachusetts General Hospital in Boston, told CancerNetwork. “A complete independent validation study, and preferably by an independent group is needed,” said Birrer.
The investigators of the GOG-218 trial are currently performing a similar gene expression analysis of samples from women treated in the three-arm trial that tested the efficacy of platinum-based chemotherapy, plus or minus the addition of either concurrent or concurrent and maintenance bevacizumab.
Birrer added that it is not really clear why women in the "immune expression group" cohort fared better when treated with bevacizumab. “There is data showing VEGF itself has interactions with the immune system, but this is poorly described and does not provide an adequate explanation for this effect.” This is the reason, according to Birrer, that there is a healthy skepticism about this current study.
Bevacizumab is currently not approved by the FDA for HGSOC patients, but is approved in Europe, based on the ICON7 results, as a first-line therapy for late-stage ovarian cancer. Still, some advanced cancer patients in the U.S. who recur after front-line chemotherapy do receive bevacizumab, said Birrer.
U.K.-based Almac, the company that is developing the AADx assay, is currently performing additional studies to validate these results in ovarian cancer and in other cancers for bevacizumab, as well as other anti-angiogenic agents. According to a press release issued by Almac, the company is currently working with both the FDA and regulatory authorities in Europe to bring this gene expression test to market.