15,000 women a year with breast cancer could benefit from whole genome sequencing, say researchers

Whole genome sequencing offered to breast cancer patients is likely to identify unique genetic features that could either guide immediate treatment or help match patients to clinical trials for over 15,000 women a year, say scientists at the University of Cambridge.

In 2022, 2.3 million women were diagnosed with breast cancer worldwide and there were 670,000 related deaths. Despite significant progress in recent years, it remains challenging to accurately identify the best treatments for individual patients and to predict cases with poorer prognosis.

Whole genome sequencing is a powerful technique that involves analysing the DNA of both the patient and their tumour to look for genetic changes, or mutations. This provides information on the underlying cause of the tumour and what is driving it. It can also provide valuable information to guide treatment, for example by identifying vulnerabilities in the tumour’s makeup or spotting signs that a patient might be resistant to a particular treatment.

Although the technology is rapidly becoming cheaper – Ultima Genomics has recently announced that it can sequence a human genome for US$100 – it is not widely used across the NHS. Offered through the NHS Genomic Medicine Service, it is currently available for a few adult cancers, rare cancers, paediatric cancers, and certain metastatic cancers.

Professor Serena Nik-Zainal from the Department of Genomic Medicine and Early Cancer Institute at the University of Cambridge said: “It is becoming increasingly possible to use whole genome sequencing to inform cancer management, but it’s arguably not being used to its full potential, and certainly not for some of the more common types of cancer.

“Part of the reason why is because we lack the clinical studies to support its use, but it’s also in part precisely because the information is so rich – in a sense, the information can be too overwhelming to make sense of.”

To help address these challenges, Professor Nik-Zainal and colleagues used data from almost 2,500 women from across England housed within the National Genomic Research Library – one of the world’s largest and most valuable data assets of its kind and run by Genomics England. The data from the 2,500 women came from their recruitment to the 100,000 Genomes Project and was linked to clinical and/or mortality records, tracking outcomes over five years. The researchers looked for genetic changes that cause or influence breast cancer, including problems in the way cells repair DNA.

The results of their study are published today in The Lancet Oncology.

The researchers found that 27% of breast cancer cases had genetic features that could help guide personalised treatment immediately, either with existing drugs or recruitment to prospective or current clinical trials. This equates to more than 15,000 women a year in the UK.

Among those features identified were: HRD (homology-directed repair deficiency), a DNA repair issue found in 12% of all breast cancers; unique mutations that could be targeted with specific drugs; signs of resistance to hormone therapy; and mutational patterns that suggest weaknesses in the cancer that treatments could exploit.

The team identified an additional 15% of cases that had features that could be useful for future research, such as problems with other DNA repair pathways. This would equate to more than 8,300 women a year.

The analysis also provided insights into prognosis. For example, in the most common subtype of breast cancer, known as ER+HER2- breast cancers, which account for approximately 70% of diagnoses, there were strong genetic indicators of how aggressive the cancer might be. For example, major structural DNA changes were linked to a much higher risk of death, as were APOBEC mutational signatures (a type of DNA damage pattern) and mutations in the cancer gene TP53. These genetic markers were more predictive than traditional measures like age of the patient, stage of their cancer, or tumour grade.

Using the results, the researchers created a framework to help doctors identify which patients need more aggressive treatment and which might safely have less treatment. It also suggested that around 7,500 women a year with low-grade tumours may benefit from more aggressive treatment.

Professor Nik-Zainal said: “The UK is a genuine world-leader in terms of its ability to do whole genome sequencing in the NHS through the Genomic Medicine Service. Now that we have population-level evidence of how impactful whole-genome sequencing could be, we have the potential to make a difference to thousands of patients’ lives every year, helping tailor their care more precisely, giving more treatment to those who need it and less to those who don’t.”

As well as being used to tailor treatments to individual patients, whole genome sequencing data could help transform how we recruit for and run clinical trials, speeding up the development of much needed new treatments.

Professor Nik-Zainal added: “At the moment, we test patients for just a small number of genetic mutations and may invite them to join a clinical trial if the patient has a mutation that matches the trial’s target. But if we have their entire genetic readout instead, we will no longer be restricted to single trials with a specific target. We could massively open up the potential for recruitment, to multiple clinical trials in parallel, making recruitment to clinical trials more efficient, ultimately getting the right therapies to the right patients much faster.”

Professor Nik-Zainal is an Honorary Fellow at Murray Edwards College, Cambridge, and an Honorary Consultant in Clinical Genetics at Cambridge University Hospitals NHS Foundation Trust (CUH).

The study was largely funded by the National Institute for Health and Care Research (NIHR), Breast Cancer Research Foundation, Gray Foundation and Cancer Research UK, with additional support from the NIHR Cambridge Biomedical Research Centre.

The University of Cambridge and Addenbrooke's Charitable Trust (ACT) are fundraising for a new hospital that will transform how we diagnose and treat cancer. Cambridge Cancer Research Hospital, set to be built on the Cambridge Biomedical Campus, will bring together clinical excellence from Addenbrooke’s Hospital and world-leading researchers at the University of Cambridge under one roof in a new NHS hospital. The new hospital will be home to the Precision Breast Cancer Institute, applying the latest genomic advances to tailor treatment for breast cancer patients, maximising treatment efficacy and minimising the risk of debilitating side effects.