A team of international researchers, led by Australian scientists, has identified why some ovarian cancers become resistant to treatment.
In a world-first study, published today in Nature Genetics, the researchers analysed autopsy samples from women who recently died from ovarian cancer to see how their tumours had evolved to evade drug therapies.
Lead author Elizabeth Christie, a specialist in treatment resistance at Peter MacCallum Cancer Centre in Melbourne, said 70 to 80 per cent of women with the most common type of ovarian cancer — high-grade serous carcinoma — become resistant to treatment over time.
"Ovarian cancer is normally very sensitive to first treatment but unfortunately many women will have disease recurrence," said Dr Christie.
"At that point, it can become more difficult to treat as the cancer becomes resistant."
In Australia, around 1,800 women are diagnosed with ovarian cancer every year.
Most cases are diagnosed at an advanced stage, when the disease has spread, contributing to relatively low overall survival rates.
There is no early detection test for ovarian cancer, and symptoms — which include bloating, difficulty eating or feeling full quickly, frequent or urgent urination, and back, abdominal or pelvic pain — are often absent or misdiagnosed in the cancer's early stages.
Dr Christie said better understanding the way cancer cells develop resistance to treatment would pave the way for new techniques to treat the deadly cancer.
"Uncovering the process that causes treatment resistance in ovarian cancer allows us to focus on finding new therapies that target these resistance mechanisms early and improve outcomes for patients."
Multiple resistance mechanisms identified
Using a combination of genomic sequencing, targeted DNA sequencing, and information about immune cells and proteins, Dr Christie and her colleagues analysed almost 400 tumour samples from 15 patients.
"These women donated their bodies to science after passing away," Dr Christie said.
All patients had been diagnosed with high-grade serous ovarian cancer with a BRCA1/2 gene mutation, and all agreed to undergo an autopsy immediately after their death.
"We focused on patients with BRCA1/2 mutations as they are more common in ovarian cancer than other cancer types, and as these patients will often develop acquired resistance to treatment," Dr Christie said.
Through studying the samples, the researchers identified nine different mechanisms that caused ovarian cancer cells to resist treatment, with one particular mechanism driving resistance in almost half of patients.
"We also identified that, in many patients, the cancers had developed multiple mechanisms to resist treatment."
Despite the small number of patients involved in the study, Dr Christie said the research provided a valuable insight into end-stage disease and the evolution of resistance in response to treatment.
"It's hard to generalise [the findings] across all patients, but it's given us an understanding of how complicated the disease becomes as the cancer becomes more resistant," she said.
"Resistance comes at all different levels — it's not just DNA, but also RNA and proteins."
Paving the way for better treatments
In recent years, drugs known as PARP inhibitors have been successfully used to treat some women with advanced ovarian cancer caused by defective BRCA genes.
PARP is a protein that plays an important role in DNA damage repair. As a cancer treatment, PARP inhibitors block the activity of the protein, meaning cancer cells are unable to repair themselves, and they die.
But patients with recurring cancer can still develop resistance to these drugs, said cancer epidemiologist Penny Webb.
"They work really well until they stop working."
Professor Webb, who leads the Gynaecological Cancers Group at the QIMR Berghofer Medical Research Institute in Queensland, said the study — which she was not involved in — could help to address the limitations of PARP inhibitors and other therapeutics.
"The more we know about why they stop working, the better chance we have of solving that problem," she said.
"[The researchers] found there were a lot of different things going on, even within one woman, so there's not one consistent mechanism that explains why the cancer has become resistant.
"It suggests that if we could stop resistance happening in the first place that would be better, because once it's happened, it's going to be complex to treat. There's probably not one solution."
Dr Christie said the findings would help scientists rethink the way current drug therapies are delivered, as well as contribute to the development of new treatments.
"In an ideal world, we'd use existing treatments but think about new combinations for some patients, or giving them at different times, including earlier in the disease," she said.
"But we also think we'll need to start looking at new drugs that can prevent resistance, or be more effective if it develops."
