Melbourne scientists have revealed a better way to identify which patients should respond to powerful ovarian cancer drugs called PARP inhibitors, resolving an important question in ovarian cancer care about why some patients respond to the drugs, while others do not.

The findings add to a vital ‘checklist’ that helps match ovarian cancer patients with the right therapy for their cancer. Being able to offer targeted treatment is crucial for patient survival rates, which have seen little improvement over the past 30 years.

The study, published in Nature Communications, was led by Professor Clare Scott, Dr. Olga Kondrashova, Dr. Matthew Wakefield, and Dr. Monique Topp from the Walter and Eliza Hall Institute; in collaboration with Associate Professor Alexander Dobrovic from the Olivia Newton-John Cancer Research Institute and LaTrobe University ­­­School of Medicine.

Subtle yet significant differences

Professor Scott said it was well-documented that PARP inhibitors could only work when the cancer’s DNA repair process wasn’t functioning as it should.

“For the past two decades, it was thought that ovarian cancer patients whose cancer’s BRCA1 genes are ‘silenced’—or methylated—had faulty DNA repair and therefore were good candidates for PARP inhibitor treatment. Yet the puzzling thing was we were unable to predict the patients for whom the drugs would work,” she said.

Dr. Kondrashova said the ‘Eureka moment’ came when the researchers discovered epigenetic differences in some BRCA1 methylated cancers. These subtle yet significant differences explained why some patients would respond to the drug, while others would not.

“It was suddenly clear that all patients in the group could not be treated the same way. We discovered that some of the patients had what could be described as ‘incomplete’ BRCA1 methylation where not every gene copy was ‘switched off.’”

“As it turns out, incomplete methylation isn’t enough to cause faulty DNA repair in cancer cells which explains why PARP inhibitor isn’t going to be effective.”

“At the same time, those in the group who had ‘complete’ BRCA1 methylation in their cancer were responsive to PARP inhibitors confirming to us that the treatment should not be discounted,” Dr Kondrashova said.

‘Snap shots’ at key points

Professor Scott said the findings were a result of methodologies developed by Associate Professor Dobrovic at the Olivia Newton-John Cancer Resarch Institute that could accurately determine the degree of BRCA1 methylation, as well as quality datasets and sophisticated laboratory models called patient derived xenografts (PDX models).

“PDX models are powerful because they mimic the complexity of human tumors at key stages as the cancer progresses. Our models are developed with cancerous tissue donated by patients from the Royal Women’s Hospital, the Royal Melbourne Hospital, and the Peter Mac at the time of their cancer diagnosis, or prior to and after treatment with PARP inhibitors.”

"Like ‘snap shots’ in time, PDX models allow us to accurately track how each patient’s cancer is changing or responding to treatment. The success of this approach shows that a long-term, detailed analysis is invaluable for providing better patient care.”

No ‘one size fits all’

Professor Scott said understanding the various reasons for PARP inhibitor resistance was an invaluable approach for developing better, more personalized patient care.

“There is no ‘one size fits all’ approach for ovarian cancer care. We need to keep making these strides in understanding so we can better match patients with the right treatment for their cancer,” she said.