Oncologists say that there is beginning to be a paradigm shift in how they approach advanced breast cancer. Photo / Rebekah Vos, Unsplash
From novel vaccines which train the immune system to attack pancreatic cancer to new forms of precision medicine which work on particular types of breast cancer, the landscape of treatment is rapidly transforming to become ever more personalised.
In some forms of the disease, this is already having a remarkable impact – especially in advanced breast cancer, which is now moving from being a lethal killer to a chronic illness which patients can often live with for many years.
Last week, scientists presented the results of a groundbreaking clinical trial which found that a drug called Enhertu doubled the average survival rates in women with breast cancer which has spread to other organs.
Many patients on Enhertu reported seeing tumours rapidly shrinking or even disappearing altogether.
For cancer specialists around the world, the results were particularly eye-catching because the drug was not expected to work on these patients. Enhertu was previously only thought to be useful for women where the cancer is driven by high levels of a protein called HER2, which occurs in 25 per cent of metastatic breast cancers. Right now, it is only available on the NHS for these patients and when all other treatment options have failed.
However, this latest trial found Enhertu to be effective in breast cancer patients who have low or even negligible levels of the HER2 protein, meaning that a much wider range of patients could now benefit from the treatment.
Scientists are hopeful that it will soon become far more widely available on the NHS, perhaps even by the end of 2022, while clinical trials are also investigating the potential of Enhertu in lung and gastric cancers.
"Given the clear survival advantage, it would be very odd for it not to be licensed," says David Cameron, professor of medical oncology at the University of Edinburgh. "I think it's most likely to be available next year, but you never know. Sometimes it goes through quickly."
Enhertu is the latest example of a form of targeted chemotherapy known as antibody-drug conjugates. It uses an antibody to pinpoint the HER2 protein on the surface of cancer cells, and delivers high doses of a toxin directly to the tumour.
Denise Scott, who has stage IV breast cancer, has already reported an improvement in her condition after just three months of treatment. "April 6 was my first infusion and my latest scan showed one tumour completely gone and the other down from 11mm to 4mm," she says. "This gives me so much hope."
Oncologists say there is beginning to be a paradigm shift in how they approach advanced breast cancer. As well as Enhertu, the introduction of drugs called CDK4/6 inhibitors, which interrupt the process through which tumours divide and multiply, has helped greatly extend life in almost all subtypes of the disease.
Cameron describes another recent clinical trial where the use of CDK4/6 inhibitors, in combination with hormone therapy, helped push the average survival rate beyond five years. "More and more are living for longer," he says. "It's becoming more of a chronic disease, and it's only a small minority, but we have a few people who are on these drugs for eight or 10 years. So we start to wonder whether a small group of them are even being cured."
One of the benefits of Enhertu is that its more targeted approach means it is less toxic to the body than standard chemotherapy, and in other cancers, scientists are having success in developing personalised immunotherapies which have fewer side effects than conventional treatments.
Oncologists at the UNC School of Medicine in North Carolina have published a study on 12 patients with a particular subtype of advanced colorectal cancer, characterised by a genetic mutation known as mismatch repair deficiency, which occurs in 5 to 10 per cent of patients with the disease.
By using an immunotherapy called Dostarlimab, which trains the immune system to recognise these mutated tumour cells, all 12 patients had entered remission after six months. While it is too soon to say whether they are cured, and much larger trials need to be done before it can be considered for regulatory approval, Naureen Starling, a consultant medical oncologist at the Royal Marsden hospital, described it as a potential way of replacing existing treatments in future.
"The standard approach for many of these patients is currently to offer pre-operative radiation combined with chemotherapy, then surgery," she says. "That has a good chance of curing the patient of cancer, but the radiation can have long-term effects on bladder function, fertility and sexual function. That can be very psychologically distressing."
There is also hope that training the immune system to recognise the patient's particular tumours could offer new hope in pancreatic cancer, which remains one of the deadliest forms of the disease. According to Cancer Research UK, just 7.3 per cent of patients survive five years after diagnosis.
Oncologists have long been at a loss for how to treat pancreatic cancer because it does not tend to be diagnosed until it is at a more advanced stage, by which time it has spread to the liver. "Surgery doesn't tend to work and there's not much you can do," says Chris Scott, director of the Patrick G Johnston Centre for Cancer Research at Queen's University Belfast. "The big issue is that the tumours that form are exceptionally dense fibrous tissues. That actually acts as a barrier and you can't get drugs into them."
But while chemotherapy has struggled to make a difference, reprogramming the immune system may offer a new way forward. In a new Phase I trial from German biotechnology company BioNTech, scientists used messenger RNA (mRNA) to create personalised vaccines which can train the patient's own white blood cells to recognise and attack pancreatic cancer cells.
While mRNA made headlines through its use in the Covid-19 vaccines produced by BioNTech and Pfizer, it was originally designed for use in cancer. In the study, eight out of 16 pancreatic cancer patients displayed promising immune responses against their tumours.
Scott describes these forms of precision medicine as being the way forward in many types of cancer, with BioNTech also looking to target melanoma and brain cancer with their vaccines. However, he fears that even if larger clinical trials reveal promising results, the technology will prove too expensive for the NHS to be able to afford it.
Cancer vaccines involve an injection of lipid nanoparticles containing strands of mRNA which are specifically designed to instruct the immune system to recognise proteins on the patient's own cancer. Because they are so personalised, it is currently very difficult to manufacture them in a cost-effective manner, meaning that there is a risk that only patients who can afford them privately will be able to access them.
"It is very, very expensive," says Scott. "I am confident that long term, we will be able to see the prices of these things come down, but I remain unconvinced whether an entirely personalised vaccine approach could be delivered in our NHS."
But at the same time, the rise of other new technologies could help save the NHS many millions of pounds, which could then be invested in newer treatments.
Starling and others at the Royal Marsden are launching a clinical trial to examine the efficacy of a new diagnostic test which looks for tiny fragments of DNA from bowel cancer tumours circulating in the bloodstream.
Nine out of 10 patients with early-stage bowel cancer undergo surgery, but doctors have no way of telling whether all the cancer has been completely removed, meaning that many patients then undergo potentially unnecessary chemotherapy as a precaution.
An early trial of the test by the University of Melbourne involving 455 bowel cancer patients found that it halved the number who required post-surgery chemotherapy without increasing the risk of relapse.
Starling and her colleagues are now looking to see whether that remains the case in an even larger patient cohort.
"Eventually we will have a tool that will help us select who does and who doesn't need chemotherapy," she says. "From a patient's perspective this is great because some of the drugs can give horrible lasting effects, while if we can reduce unnecessary chemotherapy, that has the potential to save the NHS millions of pounds a year."
In January 2021, Lanette Davy received the news she had been dreading. Having been first diagnosed with breast cancer in early 2019, and then given the all-clear at the end of the year after a round of chemotherapy, she was told that it had returned in a far more aggressive way.
"I had a scan and there were tumours in my lungs, my liver and my lymph nodes, and they were developing quite fast," says Davy, 50.
As a former nurse, she began looking for possible clinical trials which she might be eligible for, and she was soon enrolled on an experimental study examining a much more targeted chemotherapy called Enhertu.
A few years earlier, Davy would not have been considered for Enhertu, a drug which was previously thought to only work in breast cancer patients with high levels of the HER2 protein. Her tumours had low levels of HER2, but to the surprise of doctors, they soon began to rapidly fade away.
"By June 2021, the tumours in my liver and most of my other ones were gone," she says. "And I think by October I was classed as having no evidence of disease. When they told me that, I did have a little cry because of the hope it's given me that I might actually get to see my kids grow up."
Davy says the impact of her illness and the ongoing uncertainty has been particularly hard on her two sons, 14 and 11. But now she is in remission, she is learning to see her disease as more of a chronic condition than something which is potentially terminal.
"When you've got secondary cancer you know that you always live with the feeling of, is it going to come back?" she says. "That fear is always there but I'm starting to take the mindset of managing this as a chronic disease, keep it at bay, and live your best life around it."
She admits that if she had not received Enhertu as part of a trial, she is not sure she would still be alive. "I don't know where I would be without it because there were so few treatment options that were open to someone with the type of cancer I had," she says. "But I'm here, I'm well and I can spend time with my kids."
For decades, the promise of mRNA was consigned largely to the "scientific desert". Numerous breakthroughs paved the way for the new vaccine technology, but three stand out:
• In 2004, Katalin Kariko and Drew Weissman found that by substituting U, one of the four building blocks of mRNA, with a naturally occurring alternative, they could put the molecule into "stealth mode" – meaning it wouldn't provoke a dangerous inflammatory reaction.
• By around 2006, Ugur Sahin and Ozlem Tureci establish how to hack mRNA to trigger a 5000-fold increase in the immune response prompted by a single strand of the molecule, making mRNA treatments and vaccines viable.
• More gradually, scientists discovered the protective power of lipids – fatty casings that encase and protect the delicate mRNA until it reaches human cells. In 2014, BioNTech became the first organisation to use lipid-enveloped mRNA, delivered intravenously, in a clinical trial.
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