Molecular Discoveries Yield Many Personalized Treatment Targets in Ovarian Cancer

Michael J. Birrer, MD, PhD

Translating current and emerging knowledge of the molecular drivers of ovarian cancer is yielding promising new insights into potential clinical targets, moving treatment away from historical paradigms in favor of more personalized therapeutic approaches.

This was the focus of a talk Thursday by Michael J. Birrer, MD, PhD, a professor at Harvard Medical School and director of Gynecologic Medical Oncology at Massachusetts General Hospital. He told his audience at the gynecologic malignancies session yesterday that although “pathologists have been telling us for years that ovarian cancer doesn’t look the same under the microscope.…We ignored them and they were right.”

“These tumors look different, and they behave differently, and that has important biologic consequences and, more importantly, clinical consequences,” he said.

Birrer provided the audience with an overview of research currently under way that draws on these new understandings, gleaned from the work of The Cancer Genome Atlas (TCGA) project and individual laboratories. This work has informed approaches to difficult-to-treat clear-cell cancers of the ovary, among others. One clear cell—specific trial highlighted by Birrer (GOG 268), is an upfront trial which just closed; the study uses standard-of-care carboplatin and paclitaxel, which, Birrer noted, “we don’t think works very well.” In this trial, the regimen was combined with the mTOR inhibitor temsirolimus, and “we’re awaiting those results with a lot of excitement,” he added.

Tumor cell analyses have also yielded insights into how high- and low-grade ovarian tumors are related, Birrer explained. Investigators have studied where low malignant—potential and borderline tumor cells fall on the spectrum and found that they are closer to normal cells than they are to cancer.

“This is the first data—along with a lot of data from Johns Hopkins—that suggests that, in fact, low-grade tumors of the ovary are a completely separate disease,” and thus, “should be approached in a completely different fashion, we believe, than high-grade tumors.”

High-Grade Serous Ovarian Cancers

GOG 239 builds on this knowledge, looking at an investigational MEK inhibitor in recurrent, low-grade tumors. Early results from this study have led to two randomized phase III registration trials, as well as a randomized phase II trial that Birrer is leading. These trials are looking at three other MEK inhibitors in low-grade patients. “I suspect that within about 2 or 3 years, we’ll have an improved MEK inhibitor for recurrent, low-grade tumors, and potentially, you’ll begin to see MEK inhibitors being brought upfront in the treatment of low-grade tumors of the ovary.”Birrer explained that when compared with lung cancer, glioblastoma, breast cancer, and a variety of other epithelial tumors, the mutation rate in high-grade serous ovarian tumors is quite low outside of p53 andBRCA1andBRCA2.

“What you do see, though, is huge areas of chromosomal gain and loss, shifting of DNA,” he continued. “These are tumors of genomic chaos.” Researchers are looking at how they might exploit this DNA repair deficiency to develop clinical targets—deploying such agents as PARP inhibitors (eg, olaparib), which, Birrer noted, are especially active in patients with platinum-resistant ovarian cancer.

“It’s very impressive, we’re back on track, and it’s likely we will have a PARP inhibitor approved in this country in a couple of years,” said Birrer. “We think that probably somewhere between 30% and 50% of high-grade serous tumors are going to have homologous recombination deficiency and be candidates for PARP inhibitors.”

Agents targeting PI3K are also being investigated in serous ovarian cancer, as well as the folate receptor, Birrer said. Agents in development for that target include IMGN853, a humanized antibody, which he noted is a “very potent chemotherapeutic agent, and has already shown substantial response in platinum-resistant disease without a lot of toxicity.”

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