Changing how breast cancer is treated: An interview with Cambridge oncologist Dr Charlotte Coles
Breast cancer survival rates in the UK have almost doubled in the last 40 years, and 78 per cent of those diagnosed now survive the disease for a decade or more.
“We are doing pretty well in terms of cure rates with breast cancer and a lot of that is because it is caught early and we’ve got a really good multi-disciplinary team approach in treating it,” says Dr Charlotte Coles, a consultant clinical oncologist at Addenbrooke’s Hospital.
“We have very good treatments in terms of surgery, radiotherapy and drug treatments. So one of the aims now is to see whether we can claw back on treatment to reduce the side effects of patients.
“We are curing a lot more patients - they are living longer and we want them to have the best possible quality of life. We just want them to live normal lives.”
Dr Coles dovetails her clinical work, which she began in 2005, with research, which she took up in recent years. A University of Cambridge Reader in breast radiation oncology, at Cancer Research UK Cambridge Centre, she now leads national trials that influence how breast cancer patients are treated.
One key study that has reached the follow-up stage is IMPORT LOW, which explored the best way to deliver radiotherapy to early-stage, low-risk breast cancer patients after they had undergone surgery to remove a tumour. IMPORT stands for intensity modulated and partial organ radiotherapy.
“The idea for IMPORT LOW came more than 10 years ago,” recalls Dr Coles. “We were developing much better radiotherapy equipment and better imaging so we could target the area that we were treating better.
“We worked with surgeons so they could start putting little titanium clips around the area where they took the tumour out to guide our radiotherapy.
“What we had noticed was that if a cancer is going to come back in the breast, it was most likely to come back around where the original tumour was, in that quadrant.
“The idea was to select a group of patients with low-risk cancer and treat a smaller volume of the breast, targeting that area rather than the whole breast. The hope was they would get fewer side effects.
“Radiotherapy is well-tolerated on the whole but it’s not without its side effects. They can be physical in terms of hardness in the breast and discomfort, but they can also affect the appearance of the breast.
“It can cause psychological distress because it is a constant reminder of the cancer and it’s also about women’s femininity and sexuality, and we want that to be normal.”
IMPORT LOW was a large, randomised study funded by Cancer Research UK and sponsored by the Institute of Cancer Research, involving 2,018 patients across the country with early stage breast cancer. They were all aged over 50 because younger women have a higher chance of a relapse. They were put into three groups:
a third of the patients received the standard whole breast radiotherapy;
a third were given partial breast radiotherapy; and
a third received standard dose radiotherapy to the area where the tumour was removed and reduced-dose radiotherapy to the rest of
the breast.
The study found there was no statistical difference in relapse rates between the groups over five years. Of the 641 receiving partial breast radiotherapy, only six had a local relapse, where the cancer returned to the same site as the original tumour, compared to nine women out of the 666 who had whole breast radiotherapy.
The research paper, published in The Lancet last year, also concluded that those receiving partial breast radiotherapy experienced fewer side effects than those receiving whole breast radiotherapy.
Such side effects can include breast hardening, shrinking of the breast or skin changes.
“When we looked at the side effects after five years, they were really low across all of the groups. It was about one per cent, which was fantastic,” says Dr Coles.
“The clinicians assessed them very carefully, but also we asked patients a series of validated questions. We tailored it, working closely with our patient advocates and used questions important to them, such as ‘Do you have any difficulty finding a bra to fit?’ in case they had breast shrinkage. That is important to patients.”
Last week, a new follow-up paper was published in the Journal of Clinical Oncology looking at patients’ reports.
“It’s the largest breast radiotherapy trial with patient-reported outcomes that there has ever been,” says Dr Coles. “More than 1,000 women in the group carried out serial questionnaires over the five-year period.
“Rather than what doctors think, it’s really about what patients think of the outcome that is important.
“It mirrored the results reported last year in that there were fewer side effects with partial breast radiotherapy. But it also showed reassuringly that the vast majority of symptoms that patients get in the first year or so resolve, which hasn’t always been the case in the past.
“By five years, around half of patients didn’t have any significant side effects and that was across the board, with all the treatment arms, which goes to show how radiotherapy has improved.”
Women who are younger, have larger breasts or suffer from anxiety or depression are more likely to report problems.
“We can target these patients early on and individualise the treatment,” says Dr Coles.
Analysis of the quality of life feedback from patients is ongoing, but those who received partial breast radiotherapy reported better breast appearance.
“We know that breast appearance relates to how people feel in terms of psychological wellbeing. The texture of the breast is better with partial breast radiotherapy. There is less hardening and fewer changes,” explains Dr Coles.
Thanks to IMPORT LOW, partial breast radiotherapy has now become the standard of care for low-risk, early stage breast cancer patients.
“It has gone through NICE guidelines this year,” says Dr Coles. “It’s incredibly easy to do and it’s very simple. It just uses the existing kit we’ve got. It can be done in any radiotherapy centre around the world. Internationally, there are changes happening as well.”
The standard of care remains 15 treatments over three weeks, but that could also change depending on the findings of another study that Dr Coles is involved in, although not leading, called FAST-Forward, which is due to report in 2020.
“FAST-Forward is for a different patient population, including intermediate and higher risk patients.
“It will compare three weeks of treatment with one week of whole breast radiotherapy,” says Dr Coles.
If one week of treatment proves equally effective, it could be mirrored for those receiving partial breast radiotherapy too.
Dr Coles’ successful nomination for Researcher of the Year at the 2018 Cambridge Independent Science and Technology Awards was put forward by Richard Gilbertson, director of the Cancer Research UK (CRUK) Cambridge Centre, and Greg Hannon, director of the CRUK Cambridge Institute. The award was sponsored by AstraZeneca and MedImmune,
And Dr Coles is running two other trials with CRUK in partnership with the Institute of Cancer Research Clinical Trials and Statistics Unit, led by Prof Judith Bliss.
“IMPORT HIGH, with 2,600 higher risk patients, looks at very technical radiotherapy to see whether we can vary the dose across the breast according to the risk of relapse across the breast, using intensity-modulated and image-guided radiotherapy,” explains Dr Coles.
“Instead of having four and a half weeks of treatment, the aim is to have three weeks of treatment. These patients normally have an extra boost treatment. In some countries, it can be as long as six and a half week of treatments.
“We’ve got it down to three weeks, using something called simultaneous integrated boost. This is much more technical radiotherapy.”
Dr Coles recently visited the United States, where she reported some of the early findings to the San Antonio Breast Cancer Symposium in Texas.
“The three-year toxicity results are really promising. We’re going to report the local relapse rates in 2020,” she explains.
The IMPORT team is collaborating with Prof Carlos Caldas at the CRUK Cambridge Institute to look at whole genome sequencing of recurrences, work similar to the Personalised Breast Cancer Programme, co-led by Prof Caldas and Dr Jean Abraham.
The programme uses whole genome sequencing to read DNA and RNA information in patients’ tumours to tailor treatment, and is being rolled out to 2,000 patients, following on from the initial 250.
“With IMPORT LOW in Cambridge, we’re looking at the molecular clonality, or make-up, of the cancers that have come back, which tells us whether they are truly recurrences of the original cancer or whether they are new cancers and that makes a big difference to how we treat them,” says Dr Coles.
“It uses whole genome sequencing and that hasn’t been done before in radiotherapy trials. That will give us a better idea as to how we select patients in future based on the genetics of their cancer.”
It has been known for some years that breast cancer is not one disease, but multiple. Currently though, patients’ disease type is not yet routinely determined through genome sequencing.
“At the moment we use fairly standard immunohistochemistry markers, looking to see if they are oestrogen-receptor positive, and look at the grade of the cancer along with clinical details like the age of the patient, the size of the tumour and whether it has spread to the lymph nodes,” explains Dr Coles, who said she expects genome sequencing of cancers to become routine.
She is leading another study called PRIMETIME that seeks to learn whether there is a group of patients who are at such low risk of a relapse that they do not need to be given any radiotherapy at all after surgery.
“It looks at extra information in the tumour sample using a biomarker called IHC4+C,” she says. “It is a simple, cheap biomarker to see whether they are in a very low risk group for whom the side effects of radiotherapy outweigh the benefits.
“We’ll also look at genome sequencing to see if we can fine-tune the type of treatment a patient has based on the molecular and genetic make-up of their cancer. It is all about individualised treatment. In the past it used to be one size fits all.”
Surgery is not always the first treatment stage for breast cancer patients.
“With fast proliferating tumours, we would give chemotherapy first,” says Dr Coles.
“We can see how it responds to treatment to see what it is sensitive too and change the treatment if we need to. Then they have surgery afterwards.”
In October, Breast Cancer Now awarded a grant worth almost £195,000 to Dr Coles to investigate whether treating women with radiotherapy and hormone therapy could help avoid extensive surgery such as mastectomies.
“It looks at patients who don’t respond well to chemotherapy because they have slower-growing tumours and the patients who would normally have bigger operations – mastectomies – to see whether having radiotherapy up front followed by hormone treatment shrinks the tumour and makes the surgery easier,” says Dr Coles.
The three-year study will involve 43 patients who will receive three weeks of radiotherapy followed by 20 weeks of hormone therapy.
“The exciting thing is that there is lots of translational research we’re doing,” says Dr Coles, explaining that this includes taking liquid biopsies – blood samples – to examine circulating tumour DNA, the genetic material from a tumour that passes into the bloodstream.
The biopsies, along with tissue samples, and novel imaging scans taken before and after radiotherapy, will help the research team discover if there are biomarkers that may indicate – at an early stage – how tumours are responding to radiotherapy.
“The other exciting thing we’ve found out about radiotherapy in recent years is that it affects the immune system and we can exploit that with various drugs to attack the tumour as well. So we are looking at the immune response to radiotherapy in that study. There is lots of interesting science in here,” says Dr Coles.
With about 55,000 new cases of breast cancer in the UK each year, making it the most common cancer in the country, and 11,563 deaths from the disease in 2016, the importance of these studies is hard to underestimate.
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