New research indicates that a greater number of women could benefit from targeted therapies for breast and ovarian cancer, following a landmark study that mapped mutations within tumours. Experts from the Manchester Cancer Research Centre and the Institute of Cancer Research have achieved a significant first, decoding the complete spectrum of mutations that drive tumour growth. This breakthrough is poised to usher in a new era of precision medicine, offering more effective treatments to thousands of individuals battling cancer.
The findings also present a potential key to understanding the recent rise in bowel cancer cases among younger adults. Over a six-year period, a dedicated team of scientists meticulously examined the genetic make-up of tumours across 16 distinct cancer types. Their comprehensive analysis involved processing an “enormous” volume of data, drawn from 10,983 cancer patients who participated in the 100,000 Genomes Project.
Using whole-genome sequencing, the research team catalogued 370 million mutations and assigned them to 134 distinct mutational “signatures” – patterns of DNA damage that act like fingerprints of the processes that caused the cancer.
Of these, 26 signatures were identified which were not previously included in the database of known signatures used by many scientists – the Catalogue of Somatic Mutations in Cancer (Cosmic) – according to the study published in the journal Nature Genetics.
The researchers said the findings indicate many more patients may benefit from precision therapies.
The study identified large numbers of tumours with evidence of homologous recombination deficiency (HRD)- a weakness in DNA repair that makes cancers vulnerable to targeted cancer drugs PARP inhibitors and platinum-based chemotherapy.
It said HRD was identified in 16% of breast cancer tumours and 14% of ovarian cancer tumours, so based on UK figures, researchers estimated more than 7,700 breast cancer patients and 1,000 ovarian cancer patients could benefit from HRD-targeted therapies – much more than currently identified through standard genetic testing for mutations in genes such as BRCA1/BRCA2 alone.
While the researchers stressed that clinical trials are needed to ascertain that patients with HRD signatures respond to PARP inhibitors, the finding could lead to a significantly higher number of patients benefitting from precision medicine for cancer.
Experts said the study also lends support to a theory that toxins produced by particular strains of E. coli, a bacteria in the gut, could be linked to the rise in bowel cancer in younger people.
Many strains of the bacteria are harmless to humans but others can make people sick with diarrhoea, urinary tract infections and pneumonia, among other illnesses.
The team found this signature from these toxins occurs more in younger patients than older ones, in contrast with several other signatures that tend to increase with a patient’s age.
Data from Cancer Research UK suggests one in 20 bowel cancers is diagnosed in people aged under 50.
Figures provided by the charity up to 2019 show a 52% increase in incidence rates for adults aged 25 to 49 since the early 1990s.
David Wedge, professor of cancer genomics and data science at the University of Manchester, said: “Every cancer develops because DNA is damaged over time.
“Different causes such as ultraviolet light, tobacco smoke or inherited gene faults leave different patterns in the genome.
“By reading these patterns we can now understand, in a larger proportion of cancers, what caused the cancer, when key mutations occurred, and which treatments are most likely to work.
“Until now, most testing has focused on mutations of a single base (or ‘letter’) in a cancer’s DNA. By analysing the entire genome and examining more complex mutations that affect multiple bases, I hope our research contributes to better predictions of which treatment might benefit specific patients.
“This could enable better targeting of treatment to those patients most likely to benefit, given the genetic make-up of their tumours.”
Professor Richard Houlston, head of cancer genomics at the Institute of Cancer Research in London, said: “The scale of this study was very large as we analysed samples from almost every tumour type.
“The quantity of data was enormous, and although laborious to work through, we have been rewarded with a very exciting outcome.
“This study provides one of the clearest demonstrations yet that reading the full genetic history of a tumour can unlock clues to better patient care. The future of cancer treatment lies not just in finding mutations, but in understanding the story they tell.”
Commenting on the study, Simon Vincent, chief scientific officer at Breast Cancer Now, said: “This research demonstrates the potential of whole-genome sequencing in helping to ensure more people diagnosed with breast cancer receive the most effective treatment for them.
“By analysing the entire genetic make-up of thousands of tumours, the study gives us more insight into what drives each cancer, but most importantly what weaknesses these tumours have that could be targeted with existing treatments.
“These findings suggest that more people with breast cancer might benefit from targeted drugs like PARP inhibitors than current genetic testing identifies.
“Which in practice could mean more precise, effective and personalised treatment options for the 55,000 women and 400 men who are diagnosed with breast cancer every year in the UK.”
Catherine Hart, chief executive of Target Ovarian Cancer, said: “This could be a huge breakthrough in understanding which gene differences can cause ovarian cancer and how to treat it.
“Personalised treatment, based on understanding people’s genes, has become vital in treating ovarian cancer, but still too many women face limited treatment options.
“This research shows that whole genome analysis can reveal critical vulnerabilities in someone’s cancer, making it more responsive to life-saving targeted therapies like PARP inhibitors.
“These findings have the power to transform treatment and, ultimately, improve thousands of women’s chances of survival.”
