Cells that move from tumors into the bloodstream can help physicians monitor resistance to therapeutic drugs.Credit: Gunilla Elam / SPL
To make confident cancer treatment decisions in the age of precision medicine, clinicians need a precise diagnosis, one that includes details of the tumour’s genetics and its biology. They need the same sort of information to monitor how the cancer responds to therapy, and how the disease progresses. But tumours can be difficult or impossible to access via conventional tissue biopsy.
Liquid biopsies offer an answer that’s becoming increasingly popular among clinicians.
Liquid biopsies are blood tests that allow the rapid analysis of tumour cells and fragments of their DNA that are circulating in the bloodstream, avoiding the need for an invasive tumour biopsy. They are easily obtained from a minimally invasive blood draw, and provide valuable insights into the tumour’s biology.
“Liquid biopsies are an impressive tool,” says Christian Rolfo, a medical oncologist who directs clinical trials at the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center. They may improve clinical care by helping physicians to monitor patient response over time, and may identify therapeutic resistance earlier.
Comprehensive cancer profiling
Researchers developing or testing targeted therapies rely on an ability to identify specific biomarkers, as do clinicians considering targeted therapies for their patients. The analysis of circulating tumour DNA (ctDNA) can help. This DNA, from dying cancer cells, usually represents just a small fraction of the circulating DNA, but it can aid in the detection of tumour-specific genomic alterations. It can also be associated with targeted therapies for multiple tumour types, including breast cancer, non-small cell lung cancer, prostate cancer, ovarian cancer, as well as other cancers.1
Analysis of ctDNA alone cannot clearly reveal a tumour’s clonality — whether it’s derived from a single somatic cell or multiple cells. Nor can it reveal its heterogeneity, a measure of cellular diversity within the tumour. (The more heterogeneous the cells, the more likely the occasional cell will resist a drug, multiply, and produce a drug-resistant tumour.)
To obtain a more complete picture of a tumour’s evolutionary status, researchers have begun complementing ctDNA analysis by obtaining genomic and expression signatures from circulating tumour cells (CTCs). This combined assessment can offer a more complete clinical and biological picture of a patient’s tumour status, and therefore more relevant information on treatment strategy.
Cancers often spread to other locations via the bloodstream, and therefore CTCs are recognized as the likely source of deadly metastatic disease. As such, CTCs are a critical target for liquid biopsy because they provide information about the molecular makeup of cells within a tumour. They also carry significant phenotypic information regarding tumour clonality, which can help oncologists select an appropriate treatment.
Metastatic prostate cancer is a case in point. At this stage of the disease, which is also called advanced prostate cancer, the cancer has spread from the prostate gland to other tissues. Such patients are often treated with drugs that inhibit the androgen receptor growth pathway.
But patients who have been previously treated by these drugs often express an altered version of the receptor called the truncated androgen receptor splice variant-7 (AR-V7). In 2020, a European team reported that patients with CTCs that expressed AR-V7 had lowered survival benefits to a targeted drug that blocked androgen receptor signaling, compared with taxane-based chemotherapy.2
Enumerating CTCs can also help monitor how patients are responding to treatment. For example, several large clinical trials have validated CTC counts and features as prognostic biomarkers of overall survival in breast, colorectal and prostate cancer.3
Combined analysis improves prediction
Combining CTCs and ctDNA analysis makes clinical predictions more powerful, says Jim Walther, who spearheads business development at Epic Sciences, a San Diego-based medical diagnostics company. By analyzing results from a randomized clinical trial, U.S. researchers reported last year in JAMA Oncology that in patients with early-stage triple negative breast cancer — a particularly aggressive form of the disease with limited treatment options — the presence of ctDNA and CTCs following neoadjuvant chemotherapy was associated with significantly inferior disease-free survival and overall survival.4
“Combined analysis of CTCs and ctDNA provides a more accurate prediction of survival than either entity alone,” says Robert McCormack, an independent consultant on liquid biopsies for medical diagnostics and biopharma companies, including Epic Sciences. “Molecular characterization of the patient’s tumour and the immune response around it can help biopharma companies select the drug most appropriate for the patient cohort,” McCormack adds.
An even more sophisticated analysis is on the horizon. Epic Sciences is developing liquid biopsy tests that comprehensively profile ctDNA, CTCs and immune cells from a single blood draw.
As liquid biopsies develop, their benefit looks assured, Walther says. “We are uncovering so many treatment opportunities and understanding more about cancer and patients through liquid biopsies than we’ve ever been able to before,” he adds.
Nevertheless, challenges remain for liquid biopsy technologies to reach their full potential. McCormack notes that many companies are developing different technologies to detect the same biomarker, and not all of their results align with tissue biopsies. Validation could help persuade companies running clinical trials to use liquid biopsies to screen and monitor patients. “Targeted medicines are tied to diagnostic tests, so the more evidence a company sees, the more likely they are to commit to partner a technology with their drug,” McCormack says.
Rolfo hopes that initiatives such as the International Liquid Biopsy Standardization Alliance will help establish consensus around how blood samples for liquid biopsies should be handled and analysed.5 To use the tests effectively to optimize cancer care, healthcare professionals need to stay abreast of the clinical significance of the “tsunami of information” that these biopsies can provide. “The field of cancer genomics is advancing so fast, it can be overwhelming,” Rolfo says.
Epic Sciences is collaborating with pharmaceutical companies to help identify and measure prognostic and predictive biomarkers that can be embedded into clinical trial design. “Our goal is to develop endpoints that could be used as a measure of efficacy in the development of investigational drugs for prostate, breast, lung cancer and other solid tumours,” Walther concludes.