An excerpt from Race for a Remedy: The Science and Scientists Behind the Next Life-Saving Cancer Medicine.
I like to compare diabetes and cancer. Both are chronic illnesses with a trend of increasing new cases globally over the past decades, and both are expected to be among the leading diagnoses in the world with an estimated one-half billion people living with either diabetes or cancer by 2040.
The similarities don’t end there. Cancer and diabetes share risk factors: smoking, obesity, poor diet, and physical inactivity, to name a few. The risk of getting cancer increases with a diagnosis of diabetes—with some cancers the risk almost doubles. Diabetes damages the immune cells, B- and T-lymphocytes, that are key players in several lymphomas. Thus, the risk of T-cell lymphoma and leukemia increases with having diabetes.
Despite many similarities, one thing that distinguishes the two drives me crazy. In a job interview a few years ago I was going off on a tirade about cancer and diabetes when the professor stopped my rant and asked, “What’s your point? That we oncologists don’t do a good job of detection and screening?” “No, they [diabetologists] have something we don’t: a glucometer!” I replied. “They can measure blood glucose instantly and plan treatment accordingly. I dream of the day when we’ll have a matchbox-size device that can test my blood and tell me in real time if I have cancer in my blood!” He laughed. “A single drop of blood to run hundreds of tests in the office and diagnose cancer—sounds very familiar!”
The professor was alluding to the bold claims made by the Silicon Valley biotech Theranos and its charismatic, nineteen-year-old founder Elizabeth Holmes. She claimed that a portable device Theranos made could run dozens of diagnostic medical tests on a single drop of blood and detect disease. It could not. The disgraced company, which at one point was valued at $10 billion, closed its labs in 2018. Holmes, along with the former president of Theranos Ramesh Balwani, were both indicted for fraud and later convicted by juries. I joined in the laughter with the professor. Indeed, my outlandish vision of real-time cancer detection in blood—a tumor-meter, sounded very similar to what Theranos had promised.
Except this is becoming a reality in cancer now through a technique called liquid biopsy. No, it’s not from a single drop of blood nor does it have a matchbox-size meter to display the results at the bedside. It’s done through laboratory tests and the results are interpreted and reported by a medical team with expertise in oncology, pathology and genomics. Nonetheless this method is beginning to allow oncologists to search for remnants of cancer cells in the blood when conventional imaging—X-rays, CT scans—can’t detect it. This method of tracking cancer is known as minimal residual disease (MRD) detection, and it’s taking the cancer world by storm. To me, MRD tracking by liquid biopsy represents a tremendous tool for overcoming drug resistance in cancer. We all agree that the best way to address drug resistance is to detect cancer early when the burden of tumor is low and when the cancer cells haven’t quite deployed their evasion strategies through mutations. MRD detection methods can identify precancerous conditions, which can be treated before they become full-blown cancers. It can also tell a patient and his or her medical team after a course of therapy how deep the patient’s response is to the therapy.
Conventional ways of cancer monitoring are based on serial radiographic imaging to measure the change in size of a tumor. While it can detect progression of disease, imaging is not useful in monitoring how the tumor is changing in response to therapy. But real-time tracking of MRD can offer a heads-up that a patient may relapse soon. That in turn gives us an opportunity to modify or change treatment approaches. There are several ways to detect MRD, but one of these captivated me most due to its sheer ingenuity: it is called circulating tumor DNA (ctDNA) tracking.
Once again, genomics is at play here. It started with a New York-based scientist S.A. Leon and his colleagues’ assumptions that in cancer patients’ blood, higher levels of DNA might be expected given there are growing tumor cells in their system. Cells suffer from injury all the time both in normal conditions and at times of disease. DNA resides inside cells, and when a cell is destroyed, pieces of its DNA are released into the bloodstream. These DNA remnants are cell-free DNA floating in the plasma. While cell-free DNA could also be from non-cancer cells, patients with any one of several cancer types—lung, breast, colon, and lymphoma, among others—have greater amounts of cell-free DNA in their blood than expected.
Leon and colleagues suggested in 1977 that if cell-free DNA persists at a higher level after cancer treatment, this can mean the patient had a poor response to it. On the other hand, if cell-free DNA level decreases after treatment, it likely means a good response to the treatment. “We hope, therefore, that sequential measurements of DNA concentrations may be a useful tool for monitoring the effects of the therapy,” they concluded in their paper. But at the time they didn’t have the technology to distinguish between tumor DNA and normal cell-free DNA. Serial measurements of cell-free DNA wasn’t feasible.
The challenge was to determine whether the cell-free DNA had come from tumor cells or normal cells. That’s where newer developments in human genome sequencing have proved to be very useful. By comparing a patient’s normal tissue with their tumor biopsies, we can compare the two DNA sequences.
Once that is done, the cell-free DNA bathing in the patient’s blood is magnified through established method like polymerase chain reaction (PCR), and researchers can then determine if any ominous calling cards of the patient’s former tumor are present. All of this happens at the molecular level. This can be measured on multiple occasions since it only requires a blood sample from the patient, and the burden of cancer can be monitored over time this way. There are limitations and challenges to circulating tumor DNA tracking
mostly because of the technically demanding way the blood samples need to be collected, prepared, and analyzed. But there is no denying that real-time monitoring of drug response will allow oncologists to modify dose or schedule or even pick an alternative treatment plan for their patient. By monitoring ctDNA we can pick up mutations in cancer cells earlier, and this can save valuable time when patients need to receive an alternate treatment before it’s too late.
I am convinced I see my tumor-meter already. Well, yes, it’s not quite a meter per se, but I think MRD detection is as close to it as possible. Like the father of vaccines, Edward Jenner, who predicted what was in store for smallpox after his vaccine discovery, I would like to do the same by saying the annihilation of drug resistance in cancer, the most dreadful outcome of a therapy, must be the final result of MRD monitoring!
Makhdum Ahmed is a physician-scientist and author of Race for a Remedy: The Science and Scientists Behind the Next Life-Saving Cancer Medicine.
