Personalised therapy has been the Holy Grail of cancer research since scientists first sequenced the human genome more than a decade ago. Yet the initial impact of the discovery of faulty genes (BRCA1 and BRCA2) that raise significantly the risk of breast cancer, seem to be a mixed blessing.
Few women can have envied Angelina Jolie when she decided to have her perfectly healthy breasts surgically removed after discovering that she had inherited the BRCA1 gene that caused her mother’s death from ovarian cancer at 57.
Indeed, with this mutation significantly raising the risk of ovarian as well as breast cancer, the 38-year-old Hollywood superstar has already made public her plan to have a hysterectomy. The operation will trigger an early menopause, while the combined surgery will reduce, but not eliminate, Jolie’s risk of breast cancer. So it’s good to know that more recent breakthroughs in genetic medicine aim to improve the efficacy of cancer treatment and could lead to therapies that leave patients’ healthy tissue intact.
The key to this new-style personalised cancer therapy is the recognition that once breast cancer tumours are surgically removed, one-size treatment does not necessarily fit all. ‘We’re discovering that these tumours may look very similar under the microscope but can be genetically very different and may require different treatment strategies,’ leading breast cancer expert Dr Martine Piccart, director of Medicine at the Bordet Institute in Brussels, told a conference on breast cancer therapy in Belgium in May this year.
A highly desirable consequence of this discovery is that cancer patients will be less therapeutically dependent on chemotherapy. First introduced as a ‘cure’ for cancer in the Sixties, the medication is sufficiently toxic to knock out any cancer cells that can cause the disease to recur. But it also knocks out every speedily dividing cell throughout the body, resulting in a series of unpleasant side effects: hair loss, nausea and vomiting and loss of immunity as the bone marrow is suppressed.
Doctors have known for years that chemotherapy is not always needed – and that many, if not most, breast cancer patients manage just as well by taking tamoxifen, a hormonal drug not dissimilar to the Pill. The problem is that the conventional method of deciding whether or not patients require chemotherapy, by examining the tumour post-surgery, is inexact.
‘We know that while the external appearance of the tumour can be a fairly good guide to how dangerous it is, it can sometimes hide the extent of the cell proliferation that is responsible for the cancer spreading,’ explains Simon Holt, a breast cancer surgeon at Prince Philip Hospital, Llanelli, who has an international reputation for research in this field. ‘It’s rather like judging a red BMW as more likely to be involved in an accident because it will be driven more aggressively than, for instance, a grey Rover. To really assess that risk, you have to check the skills of the driver.’
Indeed, NICE (the National Institute for Health and Clinical Excellence) issued draft guidelines in February covering the use of chemotherapy. One section said that some patients ‘are over-treated, resulting in unnecessary use of expensive chemotherapy with its associated adverse effects, while others are under-treated, resulting in avoidable deaths’.
Now that should all change. A genetic test, Oncotype DX, is used to sequence the genes within the tumour itself, usually carried out after either a lumpectomy or a full mastectomy. Technicians then assess the cancer’s genome – how many of the 16 genes known to be responsible for the proliferation of cancer cells are present in the lump.
The test has been shown in a series of major clinical trials to change the advice about the need for chemotherapy in one in three patients. Most are advised they need not undergo chemotherapy, while a smaller number learn that, contrary to earlier advice, they do.
For the past two years the test has been available to private patients at around £3,700, and it is set to become available on the NHS before the end of the year – at least for the 30,000 women, mostly over 50, who are diagnosed every year with the most common type of tumour, oestrogen-receptor-positive cancer.
Karen Krukowski, a 63-year-old retired civil servant with two children and three grandchildren, was diagnosed with this type of breast cancer in 2010. She underwent surgery and faced six weeks of chemotherapy, so ‘I leapt at the chance of undergoing the test when my surgeon suggested it’.
When the test confirmed that she was a borderline case and unlikely to benefit, she was relieved. ‘My sister had chemo and suffered terribly. Of course if I’d needed the treatment, I would have had it, but I certainly didn’t want to put myself through it unnecessarily.’ She remains confident that she made the right decision. ‘I did require radiotherapy and had a significant reaction to it, which made me feel strongly that I would have had an even worse reaction to chemo.’
The opportunity for NHS breast cancer patients to get ‘the inside knowledge’ to which so many private patients have had access is welcomed by cancer specialists.
‘Going through chemotherapy is bad enough, but knowing there’s a high chance it is doing no good whatsoever is far worse,’ says Dr Susan Cleator of Charing Cross Hospital in London. ‘I was always worried about explaining to patients that Oncotype DX could help them make this decision, then finding that they couldn’t afford the test. I always feared that it would make the chemotherapy even more difficult to endure.’
Alongside the test offering the opportunity for tamoxifen only, for some women with oestrogen-receptor-positive cancers, there are already other options for breast cancer with far fewer side effects than chemotherapy. The best known is Herceptin, a relatively new drug that targets cancer cells in patients who are found to have abnormalities in the HER2 protein within the tumour. But the quest for ever more personalised cancer treatments is among the most active in pharmaceutical research today –not least because the approach looks so promising. In an ongoing study of breast cancer tumours removed from 230 women over 50, described at the Belgian conference in May, researchers reported finding a series of different mutations ‘for which targeted therapies could potentially be used’, according to Dr Piccart.
Above all, there is a feeling that this approach is healthier than preventive treatment that involves cutting out healthy tissue. ‘I worry that future generations will look back in horror at the practice of cutting off a woman’s breasts in the belief that it will prevent cancer, especially as, for some, this may prove a vain hope,’ commented Ian Fentiman, professor of surgical oncology at Guy’s Hospital, London.
However, there is recognition that NHS funding may simply not be available for these new approaches. Charlie Chan, a breast cancer surgeon at Cheltenham General Hospital, has been among the vanguard of clinicians to recognise the value of the Oncotype DX test and says he has often felt isolated. ‘There has been concern in Britain that the test is expensive and the results are not certain. Having seen the impact on patients, it’s not a concern that I share and it’s a view that has been dismissed by NICE,’ he says. ‘It’s to be hoped that the benefits of genetic medicine for breast cancer patients will continue to be used in full in the long term.’
How genetics can improve breast cancer care
October is Breast Cancer Awareness month. For details, visit www.breastcancercare.org.uk. The helpline number is 0808 800 6000.
Scientists now know that there are at least ten sub-types of breast cancer – each with a unique genetic fingerprint that should in future determine a patient’s tailor-made treatment or cure.
This recent finding has shown that current ‘blanket’ treatment –chemotherapy – frequently serves no benefit for the patient, while causing damaging and distressing side effects.
The Government’s drug regulatory body, NICE, is this month set to approve Oncotype DX, a genetic test of the cancer (rather than the cancer patient) that will decide if chemotherapy is helpful.
The biggest breakthroughs are still to come. The finding has triggered a major research initiative, backed by the pharmaceutical industry, to find custom-designed ‘silver bullets’ to treat cancer sub-types.
Scientists predict the imminent development of a new range of anti-cancer drugs that will be used effectively and appropriately, with fewer adverse side effects and speedier recovery.