How can liquid biopsies help capture the full spectrum of breast cancer heterogeneity?

Written by Andrew Newland (ANGLE plc; UK)
Breast Emerging technologies Genetics and genomics Opinion Prevention and screening

Traditional tissue biopsies, while standard in breast cancer diagnosis, present significant limitations and provide only a static snapshot of a dynamic disease. In this interview, Andrew Newland (ANGLE plc, UK) discusses the potential of liquid biopsies in capturing the full picture of tumor heterogeneity through analysis of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). Newland also shares findings from the ongoing INFORM clinical study, which is evaluating these approaches in 1,000 cancer patients across six NHS Trusts.

Can you explain the challenges with traditional tissue biopsies in diagnosing and treating breast cancer?

Under NCCN, ESMO, and NICE clinical guidelines, core tissue biopsy is one of the approaches used after clinical examination and imaging in the current standard of care for the diagnosis of breast cancer. Tissue biopsies are also utilized for the simultaneous assessment of critical biomarkers to guide treatment, including estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2).

However, tissue biopsy is an invasive surgical procedure that is associated with clinical risks and high costs. Tissue biopsies are also limited to a single point in space and time, are challenging or impossible to repeat and may fail to reflect tumor heterogeneity. Moreover, they provide only a static snapshot of a dynamic and rapidly evolving disease.

For example, we know that HER2 status can change significantly over time, with studies reporting HER2 discordance between primary and recurrent tumors in approximately 40% of breast cancer patients. This means that many patients are missing new therapeutic opportunities, such as HER2 antibody drug conjugates (ADCs), which could significantly improve treatment outcomes.

How can liquid biopsies help to address these challenges?

Liquid biopsies offer a minimally invasive, cost-effective and repeatable method to overcome many limitations associated with traditional tissue biopsies. By analyzing CTCs, ctDNA and other tumor-derived components in a blood sample, liquid biopsies provide a real-time and comprehensive view of the tumor’s molecular profile.

This is particularly valuable in metastatic breast cancer, where over 50% of patients have two or more metastatic sites and may not be suitable for repeat tissue biopsy due to tumor inaccessibility or procedural risks. Liquid biopsies can detect genetic alterations across multiple tumor sites simultaneously, capturing tumor heterogeneity that a single tissue biopsy might miss. This includes identifying resistance mutations in genes such as ESR1 or PIK3CA, or changes in HER2 status, which could guide timely and more effective treatment decisions.

Moreover, liquid biopsies enable dynamic monitoring of disease progression and response to therapy, offering clinicians the opportunity to adjust treatment strategies based on evolving molecular information. As the technology matures and becomes more widely integrated into clinical practice, liquid biopsies could significantly improve personalized care in breast cancer, particularly in the metastatic and recurrent settings where clinical decisions are most complex.  This is evidenced by research demonstrating that genomic information from a liquid biopsy can be available more than 3 weeks before the results of a tissue biopsy, accelerating the commencement of targeted treatment. Liquid biopsies can also detect early signs of cancer progression before scans and identify genetic mutations associated with treatment resistance. This enables timely adjustments to treatment strategies and reduces healthcare costs associated with ineffective treatment.

What are the key clinical questions or hypotheses that the INFORM study was designed to address?

INFORM is ANGLE’s largest clinical study and is based in the UK across six NHS Trusts. Enrolling up to 1,000 breast, prostate, lung and ovarian cancer patients over a 3-to-5-year period, participants will have blood drawn across multiple (up to six) time points during diagnosis, treatment and follow-up. The objectives of this study are to:

  • Evaluate and characterize CTCs from cancer patients using multiple downstream techniques such as immunofluorescence, fluorescent in-situ hybridization (FISH), multiplex gene expression analyses, mutational analyses and sequencing.
  • Evaluate changes in CTCs and other rare cells in cancer patients over the course of their treatment.
  • Develop and validate novel CTC-based imaging and molecular assays, with the long-term potential to improve cancer care.

As of 31 December 2024, 543 patients had been enrolled into the INFORM study, with a total of 1,962 blood draws performed and 5,426 tubes of blood processed using ANGLE’s Parsortix® system for the isolation and harvest of CTCs.

How are you hoping the results of the INFORM study will impact clinical practice?

Blood samples collected for the INFORM clinical study have supported the development of multiple assays that could impact clinical practice by enabling real-time, repeatable assessment of a cancer’s mutational status. This could be used to inform targeted treatment selection, identify emerging treatment resistance and monitor treatment response. CTC presence is also validated as a prognostic biomarker and has the potential to be used for recurrence monitoring or to identify the presence of residual disease.

At ANGLE, we are particularly excited about the development of our Next Generation Sequencing (NGS) workflow, which enables concurrent DNA dual analysis of CTCs and ctDNA from a single blood sample. Data from our latest lung cancer cohort, using INFORM study blood samples, showed substantial mutational differences between the two analytes, with 53% of mutations found in CTCs alone, 36% in ctDNA alone and 11% found in both analytes. These findings mirror our earlier work in breast, prostate, lung and ovarian cancers, and provide further evidence that CTC-DNA and ctDNA provide distinct and complementary information, with many druggable targets found in CTC-DNA only. These findings support numerous other independent studies using the Parsortix system and drive our belief that a multi-analyte approach is key to unlocking the true potential of liquid biopsies in precision medicine.

How might the integration of liquid biopsies into cancer care pathways evolve over the next 5-10 years?

With significant technological advances, including AI, machine learning, high-sensitivity, high-throughput sequencing, and multiomics, complex molecular data can now be translated into actionable clinical insights. In the UK, this is supported by the Department of Health and Social Care which aims to integrate genomics into 50% of all healthcare interactions by 2035.

These technologies are dependent on the quality of the sample — and as intact, viable cancer cells with metastatic relevance — CTCs provide a high-quality analyte for longitudinal monitoring and therapeutic guidance. Unlike traditional tissue biopsies, liquid biopsies — particularly those analyzing CTCs — offer dynamic, real-time insights into tumor heterogeneity, enabling personalized, timely treatment decisions, and tailored follow-up.

The adoption of liquid biopsy to improve cancer care and monitoring aligns with the NHS Long Term Plan and the Cancer Strategy for Scotland 2023–2033, which prioritize the expansion of community-based care. By enabling improved accessibility via the provision of local and mobile healthcare services and leveraging innovative technologies, liquid biopsy may help alleviate pressure on traditional outpatient and hospital services, ultimately enhancing accessibility to cancer care.

At ANGLE, we aim to revolutionize cancer care by facilitating the integration of liquid biopsies across the treatment continuum, improving outcomes for the 18.7 million people diagnosed annually and the 49 million people living with the disease. We believe that as sequencing becomes increasingly affordable and accurate, CTC-based multiomics will be broadly adopted, ushering in a new era of adaptive, precise and effective cancer care.

Interviewee profile:

Andrew Newland is Chief Executive of ANGLE plc, having founded the Company in 1994 with the goal of developing and commercializing technologies that enable precision medicine and translational research. He has an MA in Engineering Science from the University of Cambridge (UK) and is a qualified Chartered Accountant. He has over 20 years of medical diagnostics experience and has specialized in liquid biopsy technologies for the past 14 years. Andrew has also led the development of technology-based businesses and has been on the Board of several specialist medical technology companies.

The opinions expressed in this article are those of the author and do not necessarily reflect the views of Oncology Central or Taylor & Francis Group.