The Liquid Biopsy: A Noninvasive Tumor Tracker.

To date, the “liquid biopsy,” a blood test that detects evidence of cancer in the circulation, has generated a lot of excitement in the lab but little in the clinic.

The only liquid biopsy currently approved by the US Food and Drug Administration (FDA) for clinical use is a prognostic survival tool with no potential to guide treatment decisions (CellSearch, Janssen Diagnostics).

But research published in the February 19 issue of Science Translational Medicine shows how liquid biopsies can provide a noninvasive, ongoing picture of a patient’s cancer, offering valuable insight into how best to fight it.

Work from 2 different groups shows how liquid biopsies are being used in the lab to identify tumors at a very early stage, monitor them for metastasis, and even pick up signs of early treatment resistance.

In the future, instead of extensive imaging and invasive tissue biopsies, liquid biopsies could be used to guide cancer treatment decisions and perhaps even screen for tumors that are not yet visible on imaging.

“I think early detection is the Holy Grail of cancer research,” said Luis Diaz Jr., MD, from Johns Hopkins University School of Medicine in Baltimore. Liquid biopsies will likely offer a screening method for most cancers one day, he told Medscape Medical News.

However, this exciting potential is probably furthest from being ready for the clinic, he acknowledged; other potential applications include genotyping, detection of minimal residual disease, and detection of treatment resistance.

In their research, Dr. Diaz and colleagues show that a liquid biopsy measuring the serum level of circulating tumor (ct)DNA could one day be a very useful tool in cancer decision-making, giving clues about what type of cancer a patient has and whether it has spread.

“Mutant DNA fragments are found at relatively high concentrations in the circulation of most patients with metastatic cancer and at lower but detectable concentrations in a substantial fraction of patients with localized cancers,” they write.

The team found this to be particularly true in cases of breast, colon, pancreas, and gastroesophageal tumors, where “detectable levels of ctDNA were present in 49% to 78% of patients with localized tumors and 86% to 100% of patients with metastatic tumors.”

They evaluated 136 metastatic tumors in 14 different tumor types, and found that “most patients with stage III ovarian and liver cancers and metastatic cancers of the pancreas, bladder, colon, stomach, breast, liver, esophagus, and head and neck, as well as neuroblastoma and melanoma, harbored detectable levels of ctDNA. In contrast, less than 50% of patients with medulloblastomas or metastatic cancers of the kidney, prostate, or thyroid, and less than 10% of patients with gliomas, harbored detectable ctDNA.”

In addition to offering clues about stage and spread, liquid biopsies can be used to monitor the effects of cancer treatment, give an early warning about possible recurrence, and offer clues to the reasons for treatment resistance.

A second team of researchers used liquid biopsies in colorectal cancer patients to show that early resistance to treatment with epidermal growth-factor receptor (EGFR) inhibitors could be identified by the presence of certain mutations in the blood.

In their research, Sandra Misale, a PhD student from the Department of Oncology at the University of Torino in Italy, and colleagues showed that this resistance can be overcome by concomitant treatment with mitogen-activated protein kinase (MEK) inhibitors.

“We reasoned that tissue biopsies would only offer a snapshot of the overall tumor mass and might therefore be ill suited to capture the multiclonal feature of the resistant disease,” the researchers note, explaining that liquid biopsies are “more likely to capture the overall genetic complexity of tumors in patients with advanced disease.”

In fact, Dr. Diaz’s team found the same mutations in treatment-resistant colorectal cancer patients, suggesting a future clinical application for liquid biopsies. “These data therefore strongly suggest that patients being considered for treatment with EGFR blockading agents should be tested for these additional mutations,” they advise. Patients harboring such mutations “are unlikely to benefit from these agents and would be better served by other therapeutic approaches.”

Tissue Biopsy Can Be Challenging

There is good reason to want to learn about cancer through the blood, said Terence Friedlander, MD, from the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco. “For most tumors, a tissue biopsy is quite challenging, in that it’s costly, painful, and potentially risky for the patient,” he explained.

The research by both teams illustrates that there is “a lot of reason to be excited” about liquid biopsies, he told Medscape Medical News. “Together, both of these papers show that you can detect resistance as it’s happening in real time.”

Although the current FDA-approved liquid biopsy measures intact circulating tumor cells (CTC) to give a prognosis of overall survival, the potential predictive value of ctDNA is much more exciting, he said.

“Predictive markers are better because they help guide treatment decisions. In a sense, the ctDNA liquid biopsy allows us to understand specifically what kind of molecular changes are happening in the tumor in real time, which is a very big step beyond where CTCs are today, clinically.”

World’s oldest example of metastatic cancer discovered on a human skeleton in Sudan

One of the world’s oldest examples of a human cancer has been found in Sudan by British-based researchers.

Because cancers are mainly a consequence of pollution, obesity, smoking and longevity (all major features of our modern world), evidence of them is only very rarely found on the skeletons of ancient populations.

From a medical research perspective, the new discovery, dating from 1200 BC, is therefore of considerable scientific significance. It is the oldest proven case of metastatic (“organ-originating”) cancer ever found.

“This find is of critical importance, as it allows us to explore possible underlying causes of cancer in ancient populations, before the onset of modernity, and it could provide important new insights into the evolution of cancer in the past,” said the lead researcher, bioarchaeologist Michaela Binder of Durham University.

The ancient cancer discovery and other disease-related finds from the site – Amara West, on the left bank of the Nile in the far north of Sudan – are also revealing the poor general health of the population there at that period, a time of climatic change and environmental stress.

This photo depicts the sternum of the skeleton, the arrows pointing to lytic lesions in the bone


This photo depicts the sternum of the skeleton, the arrows pointing to lytic lesions in the bone .

Of the 180 skeletons examined by the British team, a quarter had chronic lung disease, all had often severe dental disease, at least half had various unidentifiable infectious diseases – and 75  per cent died before the age of 35. What’s more, half the individuals had sustained fractures, often multiple ones, to their bones – and some 20 per cent of the children probably had scurvy.

The individual who died of cancer was a young man aged between 25 and 35. As well as suffering cancerous damage to his pelvis, ribs, spine, shoulder blades, breast bone and collar bones, he also had severe tooth decay and chronic sinusitis.

Buried in a painted wooden coffin, he was accompanied to the next world by a model scarab beetle made of blue faience – and supplies of food (placed in several still surviving pottery vessels). His cancer may have been caused by an infection, potentially something like the predominantly African parasitic water-borne worm disease bilharzia, or by wood smoke from hearths in small poorly ventilated houses.

The research into the 180 skeletons from Amara West has been carried out by Michaela Binder of Durham University, as part of a detailed archaeological research project on the ancient settlement and landscape of Amara West, led by Dr. Neal Spencer, Keeper of the British Museum’s Department of Ancient Egypt and Sudan.