Liquid biopsy for cancer recurrence creates a new kind of patient-in-waiting

My husband’s cancer came back this summer after not being evident for almost two years.

With advances in cancer surveillance, we now speak of cancer survivors being cancer-free far less frequently. If you are among the luckiest unlucky who survive treatment for metastatic cancer and receive clear scans, you simply have “no evidence of disease.”

Jesse was diagnosed with metastatic colon cancer in June 2021 after a routine colonoscopy, his first. His cancer was considered curable because his metastases were limited to two tumors in his liver that were surgically resected, along with the primary tumor, with clear margins. He underwent six months of adjuvant chemotherapy, and none of his surveillance scans have revealed any evidence of disease.

But in June, he received a positive result on a Signatera test, which predicts disease recurrence in patients with some types of cancer months before it shows up on a scan. Signatera is a novel personalized assay designed around the patient’s tumor profile that can identify circulating tumor DNA (ctDNA) in the blood. It’s also known as a liquid biopsy. A positive result signals minimal residual disease (MRD), an accumulation of cancer cells too small to be detected on imaging.

Until Jesse’s positive result, which followed two negatives earlier this year, I had assumed that his cancer had been eradicated. The five-year survival rate for stage 4 colon cancer, at 13%, is grim, but the more time passed, the more his odds improved.

After a recurrence, however, one’s odds drop precipitously. For the first time since his diagnosis, I let my mind wander to a future without my 45-year-old husband.

We are both academics, so we immediately launched into research mode. There is no clear standard of care for colon cancer patients with positive ctDNA results but no radiologic evidence of disease. Some start oral chemotherapy prophylactically, but most oncologists — including Jesse’s — will not begin treatment until something appears on a scan. Pushing up scans and bloodwork, which we decided to do, is common. I also started investigating MRD clinical trials, some of which are quite promising.

The main thing to do, though, is wait. Typically, the values will creep up on repeat testing until a tumor eventually appears on a scan.

In Jesse’s case, however, six weeks after the positive result, a repeat Signatera test returned negative. What did this mean? The Signatera test is highly accurate for colorectal cancer — the risk of cancer recurrence after a positive result is 97%. Still, Jesse’s oncologist thought his positive result was likely a false positive in part because the test value, at .05, was extremely low.

On the other hand, a low positive result followed by a negative could also suggest that Jesse had trace cancer cells hovering at the threshold of detectability, which his immune system cleared, at least temporarily, on its own.

Which of these scenarios is more likely may become clearer with time. Jesse will undergo Signatera testing every three months for the foreseeable future. If he continues to test negative and evidence of cancer never returns on scans, the false positive hypothesis may be justified. If, on the other hand, a test returns positive and the value rises, a false positive is less likely.

I am incredibly grateful for the negative result and the way that it shifted Jesse’s prospects for long-term survival. But merely receiving a single positive result flooded us with uncertainty that cannot be easily dissipated. I felt relieved by the negative result, but at the same time, I also felt something closer to grief.

As a medical anthropologist who has studied new genetic technologies and their impact on patients and society, I am very familiar with how scientific advances such as Signatera can have unintended consequences for patients and caregivers. Thirteen years ago, my colleague Stefan Timmermans and I introduced the concept of patients-in-waiting to describe how new genetic technologies create new categories of patients who are not quite sick yet nevertheless not healthy. The cases we wrote about include people who undergo genetic susceptibility testing for cancer or Alzheimer’s disease.

CtDNA testing had not yet been developed at the time of our study, but if it had, it would have offered us an ideal case. Jesse’s Signatera result instantly switched him from being a cancer survivor to a patient-in-waiting whose cancer might never be considered fully eliminated. It was a subtle shift, one that was imperceptible to friends and relatives who were understandably ecstatic to hear about the negative result. Yet simply receiving the lone positive result opened the door to a persistent new type of uncertainty. This, then, was the source of my grief: the loss of an easier time in which I knew less and had less reason to worry.

Jesse’s oncologist had warned him before ordering the first Signatera test that the wait following a positive result can be distressing. Despite our best efforts, the news cast a dark shadow over our summer. Had Jesse never undergone ctDNA testing, on July 2 we would have celebrated two years with no evidence of disease — after which, his oncologist had advised us, his survival odds would increase substantially. Instead, I spent the two-year mark consumed by apprehension over a looming recurrence.

Of course, it wasn’t a recurrence, or at least isn’t one yet. But as a caregiver, I found that the worry, fear, and uncertainty were not that much different than they were with actual disease — just as Stefan and I found in our interviews with parents whose children had been diagnosed through newborn screening with genetic anomalies of ambiguous significance.

I don’t regret this knowledge, and neither does Jesse. It has enabled us to move up his scans and consider therapeutic options that were not previously on the table.

But we have also lost something here. When a person becomes a patient-in-waiting, their world is irrevocably altered. Every patient-in-waiting stands in for a life interrupted, a blissful innocence lost.

With applications for both surveillance and monitoring the efficacy of ongoing treatment, Signatera and other ctDNA assays are poised to change the landscape of cancer management. As the biomedical sciences continue their inevitable onward march, we must remember these ambiguous losses as well the triumphs.

Mara Buchbinder is professor and vice chair of the Department of Social Medicine at the University of North Carolina at Chapel Hill.