Breast cancer patients could be spared unnecessary chemotherapy thanks to a new gene test. Karen Southern chats to surgical oncologist, Prof Simon Holt, about how genomic breakthroughs like Oncotype DX are transforming UK cancer care.

As of 2019, the UK ranked 33rd out of 41 developed nations for cancer mortality. 

And it’s been nearly a decade since the NHS last met its target of treating patients within two months of referral.

Several well-publicised factors lie behind these sad statistics, not least the backlog caused by Covid, which resulted in increasingly late presentations and delays in diagnosis.

The prospect of lengthy chemotherapy post-surgery only adds to patient stress and aftercare pressures. But is it always necessary? 

Prof Holt – retired lead clinician at Prince Philip Hospital breast cancer unit in Llanelli – is a leading force on the research frontline, specifically gene expression in breast cancer.

He is also Honorary Professor at the Faculty of Medicine at Swansea University and has spent over 15 years evaluating the Oncotype DX Breast Recurrence Score (ODX) in independent UK trials.

With trials involving more than 100,000 patients, ODX is the only genomic test to predict chemotherapy benefits after surgery for early-stage cancer patients with fewer than three affected lymph nodes.  It also predicts risk of recurrence. 

The results, he says, have been extraordinarily consistent. They show that optimal quality of care for all patients is still guaranteed by only offering chemotherapy to those who will genuinely benefit.

 “In fact, 85 per cent of postmenopausal patients could be spared chemotherapy using the test.” 

The chemotherapy dilemma

“The reality is that most patients are cured of breast cancer by surgery alone,” Prof Holt explains. 

He cites research by The Oxford Group, which examined an aggregation of all trials where chemotherapy was used as an adjuvant to stop a recurrence of breast cancer after surgery.

Their 2005 study concluded that chemotherapy was only beneficial to 15 per cent of premenopausal women and about six per cent of postmenopausal women.

“The dilemma is giving chemotherapy to everyone, knowing that many genuinely won’t benefit from it.”

So why is it still considered a ‘catch-all’ solution, and how can it be best directed to the women for whom it is a literal lifesaver?

“Basically, until recently there was no way to distinguish who needed it,” he says. “The view was, ‘Well, we should give it to everyone who is fit enough to tolerate it, to prevent some from relapsing. 

 “After all, it’s only natural that most people want to play safe. Although if the cancer reappears in the breast, it can be improved by further surgery or radiotherapy. 

“However, if the tumour appears elsewhere in the body, chemo only works if the tumour is very small. If applied when the recurring cancer can only be detected on a CT scan, for instance, then it is usually too late. The treatment will have benefits in terms of lifespan but is very unlikely to be a cure.”

It’s up to the oncologist and patient to decide if the side effects justify the benefits. “Broadly speaking these aren’t too bad for most patients, but there are also obvious long-term implications for finances, work, mental health and the family. There is also a one per cent risk of developing another malignancy as the treatment particularly affects the bone marrow, plus a probable increased risk of dementia in old age.” 

While the tests are only suitable for women with a particular form of the most common type of breast cancer – who test positive for oestrogen receptors and negative for the HER2 gene – this still amounts to 80 per cent of all diagnoses.

It is not applicable to the 10 per cent of patients who don’t have these receptors on their gene surface, or for the 10% of patients with HER2 positivity as these more active forms of breast cancer require chemotherapy.

Recurrence score indicators

Around 250 candidate genes are currently associated with cancer. Exact Sciences (previously known as Genomic Health) is the company behind Oncotype DX. Initially, they looked at 670 stored samples from women diagnosed with breast cancer in the previous 10 to 15 years to study outcomes.

The team looked at the expression of each gene in individual tumours and tested them for correlation in survival rates. Sixteen genes were found to independently predict survival. 

These findings were combined into a weighted formula to calculate the Oncotype DX Recurrence Score, based on 0 to 100. The lower the number, the more likely hormone therapy will work without chemotherapy, and vice versa. 

And, in the latest trials featuring 680 women undergoing NHS treatment, more than half were spared chemotherapy through testing.

Different outcomes

The Oncotype DX test is also extremely reliable. “If you take one bit of the tumour and test it with the Oncotype DX test and take another bit to test on a different day, or even test it ten years later, the result will be pretty much the same.

“The problem with histology – examining a tumour through a microscope – is that findings are subjective. Two pathologists looking at the same tumour or different bits of it may come up with slightly different answers, which of course will influence treatment.”

During trials based on histology, most doctors and patients opted for chemotherapy; when based on the Oncotype DX tests, their confidence in making a decision on opting out “were greatly increased”.

And economic analysis also showed significant cost savings, amounting to £1.7million. “The tests aren’t cheap at around £2,500 each, and while the NHS gets a large bulk discount, our calculations have to use list prices. But the test still saved around £700 per patient.”

Some health authorities have already adopted the test, but the final decision on a national rollout lies with the National Institute for Health and Care Excellence (NICE). It’s hoped recommendations will be made early next year.

Harnessing the power of our immune system

And so, to the future of cancer care in the UK. Prof Holt concludes, “While I don’t have a crystal ball, this type of gene expression analysis is clearly going to be the way forward, and lots of tests for numerous different cancers are being developed along the same lines.

In reality, we need to stop using chemotherapy and harness the power of the patient’s own immune system instead. We all actually develop cancers continuously, but our immunity recognises and eliminates them; it’s certain cancers that have found a way around our defences.

“The cancer develops because of a gene change in cancer tissue compared to normal tissue. If we can identify one protein produced in the cancer which is different to normal cells, we can direct the immune system to recognise and eliminate the cell containing the rogue protein.

“Work is being done on an individual basis, and this is where artificial intelligence will be very useful in identifying the protein in the first place and we can learn to target it. I think that chemotherapy will then actually become a thing of the past.”