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Why Cambridge research gives grounds for optimism that ovarian cancer survival rates will finally improve

Ovarian cancer statistics currently make for grim reading.

About 7,500 women are diagnosed each year in the UK with the disease – and about 5,000 of them will have the most aggressive form. Only 43 per cent of women in England survive five years beyond their diagnosis.

This compares very poorly to survival rates for more common cancers such as breast (85 per cent) and prostate cancer (87 per cent).

Prof James Brenton, senior group leader at the Cancer Research UK Cambridge Institute
Prof James Brenton, senior group leader at the Cancer Research UK Cambridge Institute

But there are grounds to be hopeful that the poor record on ovarian cancer is set to change, with a pioneering new approach to treatment that was created and developed here in Cambridge, which is now helping patients.

The leaders of the ovarian cancer programme at the Cancer Research UK Cambridge Centre, Prof James Brenton and Prof Paul Pharoah, will discuss the challenges and innovations in this field in an upcoming free virtual talk on July 1.

Ahead of it, Prof Brenton explained to the Cambridge Independent: “When most people talk about ovarian cancer, they are talking about high-grade serous ovarian cancer, although there are other types.

“Ovarian cancer remains a challenge first of all because it’s a cancer that almost always has spread widely by the time of diagnosis.

“High-grade serous ovarian cancer arises from the fallopian tube. It has nothing to do with the ovary per se.

“The fallopian tube is a finger-like structure that sits close to the ovary so the ovulated egg comes out of the ovary, goes into the fallopian tube, where it can be fertilised and be carried down to the uterus for implantation.

“Malignant change towards the end of the tube quickly has no physical barrier to spread – it’s an open tube. It goes on to the surface of the ovary, goes down on the low tummy – the pelvis – and is circulated around the abdomen long before a patient has any symptoms whatsoever. It’s called the silent killer, which is not a phrase I like very much.”

Like all cancers, it is the acquisition of genetic damage that can lead to ovarian cancer.

Prof Paul Pharaoh, professor of cancer epidemiology, University of Cambridge
Prof Paul Pharaoh, professor of cancer epidemiology, University of Cambridge

But the absence of a barrier in ovarian cancer contrasts with, for example, colon cancer, which has to grow through the wall of the tube and spread to nodes and the blood supply in order to spread elsewhere.

“Because of where it arises from and the symptoms it causes, ovarian cancer is very challenging to diagnose early,” said Prof Brenton, who is professor of ovarian cancer medicine in the University of Cambridge’s Department of Oncology,

“Patients present unwell, with large amounts of cancer throughout most of their abdomen and sometimes in their chest. Often they have become malnourished and have other reasons why they are unwell because of the cancer.

“The second major challenge is that out of all the cancers we have studied in science, it is the most complex in terms of its wiring diagram. By that I mean the pattern of genetic damage in these tumours. We don’t see easy to identify changes in genes that allow you to easily choose a treatment

“In lung cancer, we know changes, faults or mutations in genes like EGFR activate that protein and make those cells grow too quickly and lose control and become cancer cells. So if you can make a medicine that targets the EGFR protein, made by the gene, then you can switch off that cancer drive.

“And that is the basis of cancer treatments today. We’re not just trying to kill dividing cells with cytotoxic chemotherapy from the 1960s. We are trying to bring in medicines that precisely target something that switches off a key portion of that cancer cell’s machinery.

“In high-grade serous ovarian cancer, we just don’t have those types of changes. We see chaos – a lot of damage and many genes are not over-active. They have simply stopped working. So trying to find medicines for genes or proteins that don’t exist anymore is a lot harder.”

But there have been some important breakthroughs, notably the development of olaparib.

Based on the work of Prof Steve Jackson, head of Cancer Research UK laboratories at the University of Cambridge’s Gurdon Institute, this drug is known as a PARP inhibitor as it prevents a protein – PARP – from doing its job of helping damaged cells to repair themselves. Some cancer cells rely on this protein to keep their DNA healthy, meaning inhibiting it can cause cancer cells to die.

Prof Steve Jackson, of The Gurdon Institute at the University of Cambridge
Prof Steve Jackson, of The Gurdon Institute at the University of Cambridge

Cambridge-based AstraZeneca sells this drug under the brand name Lynparza, and it is now being given to individuals with a faulty BRCA1 or BRCA2 gene as a targeted therapy.

“We are seeing dramatic improvements for these individuals because PARP inhibitors have become a targeted therapy for them,” says Prof Brenton.

“I think we are going to see cures in patients who would never have been cured previously, by those medicines.

“I think that sets a paradigm for other approaches that exploit our understanding of the mechanism behind the chaos.”

[Read more: Ovarian cancer drug developed with University of Cambridge research can now be used in combination]

Encouragingly, data from the SOLO-1 trial suggests olaparib used as a maintenance treatment more than doubles the five-year disease-free survival time for patients who have newly diagnosed advanced ovarian cancer with BRCA mutations. After five years, 48 per cent of these patients given olaparib were progression-free, compared with 21 per cent given a placebo.

Whole genome sequencing is providing further insight.

Prof Brenton and colleagues have just published research in Nature that, he explained, describes the approach of looking at “the wood, not the trees” – in other words, examining the detail of the genetic changes.

“There is so much chaos, but trying to see patterns in the DNA damage might tell us the way to treat patients. We do a lot of whole genome sequencing and our approach is to take the patterns across the entire genome and start building signatures.

“By looking at that, we understand the cause, and that may tell us the best way to treat a patient.”

Prof James Brenton
Prof James Brenton

Unlike in cervical or breast cancer, screening trials for ovarian cancer have yet to prove successful at saving lives, nor has immunotherapy proved successful for patients with it.

“What we’ve got to really focus on is prevention,” explained Prof Brenton, who is a senior group leader at the Cancer Research UK Cambridge Institute and honorary consultant in medical oncology at Addenbrooke’s.

“Individuals with higher risk – women with BRCA1 or BRCA2 mutations – can undergo prophylactic surgery. In other words they have their uterus and fallopian tubes removed.

“PARP medicines might mean there are different ways of preventing the cancer. If you took a PARP medicine for a period of time, would that be a way of preventing the disease by clearing out from the fallopian tube the altered cells that were destined to become cancer?”

Cascade testing means family members are checked for BRCA mutations when a woman is diagnosed with ovarian cancer.

“There are many medicines coming, getting to the heart of these DNA damage effects,” added Prof Brenton, who noted that while the best effects of PARP inhibitors are seen in those with BRCA mutations, these drugs can also help others.

“We’ve been in the wilderness for a long time with ovarian cancer. PARP inhibitors are tremendously powerful at indicating the strategy of using synthetic lethality as an approach and finding the medicines that make a tumour cell vulnerable.”

You can learn more at the talk - part of the CBC On Virtual Tour series, for which the Cambridge Independent is media partner. It runs from 12.30-1.30pm on Friday, July 1 online.

Register free via Eventbrite at https://bit.ly/3OMVeTe.

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