In a small, proof-of-concept study, researchers have identified molecular changes in tumors that may partially explain why some cancer patients respond to treatments far outside the expected norm.
Using modern genomic tools, scientists at the National Cancer Institute collaborated with investigators from around the country to analyze the tumor samples of 111 patients with various types of advanced cancer-all identified as "exceptional responders." In roughly a fourth of them, the researchers found that distinct molecular features seemed to provide a rare survival edge after cancer treatment, with a few patients surviving many years past diagnosis.
"We all know a metastatic stage IV patient who's alive 7 years later and that this shouldn't happen," said Louis Staudt, MD, PhD, Director of the NCI's Center for Cancer Genomics, who co-led the study, along with Percy Ivy, MD, of NCI's Division of Cancer Treatment and Diagnosis.
To understand why such outliers occur, researchers developed stringent study criteria, classifying molecular mechanisms into four different categories: 1) the ability to repair DNA damage, 2) intracellular signaling pathway activity, 3) immune responses, and 4) prognostic genetics, in which a "nasty" tumor seen under the microscope proved less aggressive upon genomic analysis, with a known favorable outcome.
In all, the final analysis focused on 26 patients whose results appeared in a recent issue of Cancer Cell (2020; https://doi.org/10.1016/j.ccell.2020.10.015). Although that number might seem small, Staudt conceded, "it's actually large with respect to the difficulty in identifying these types of patients," usually studied one at a time. And, eventually, as further data accumulates about them, he said routine molecular analysis "will inform the care of a great number of cancer patients we would not know about," without benefit of a clinical trial.
However, because cancer is so heterogeneous a disease, he said "it's literally impossible to do all the clinical trials we would need to do," especially when a genetic mutation may be a "one-off"-useful, perhaps, to only a few patients.
"We would never do a clinical trial of the 1 percent of patients in whom PARP inhibitors work," for example, he said, so the NCI analysis provides a different type of evidence: better guidance in clinical decision-making and more precise personalized medicine in the future.
The investigators defined exceptional responders in the study as patients who had partial or complete responses to treatment-primarily combination chemotherapy-that ordinarily would be effective in less than 10 percent of those on similar drugs. They defined an exceptional response as a treatment response lasting at least 3 times longer than the median response to the same cancer drugs, before a cancer's return.
No gender, racial, or age distinctions have yet emerged in the NCI initiative. Most exceptional responders in the study skewed older-"not vastly different from the general demographics of cancer patients," Ivy said, ruling out the notion that youth alone might explain an exceptional response.
And using the NCI criteria, established through a review of medical literature and input from experts familiar with patient responses "way outside the norm," she noted investigators in many other countries now have begun their own studies of exceptional responders. Unlike the NCI focus, however, scientists in the United Kingdom, France, and Italy, among others, are looking at exceptional responders in specific cancers, such as breast cancers in France and ovarian cancer in Australia.
Only six patients in the NCI analysis underwent treatment with immunotherapy before being classified as exceptional responders, primarily because the study predated the immunotherapy era, according to the investigators.
But one case, Staudt suggested, illustrates how immunotherapy already has changed the treatment landscape in cancer and future studies will include them. A bladder cancer patient, for example, who was placed on a checkpoint inhibitor after failing other treatments had a longer-than-expected response time, he said, with his cancer cells recruiting T-cell cytokines to attack his tumors. While such an unusual response, seen in only about 3 percent of bladder cancer patients, likely is one of those "one offs" he described, Staud said it underscores the importance of the immune system in cancer surveillance.
Other findings, highlighted in the study, included rare combinations of genomic errors that resulted in the death of tumor cells during treatment, known as synthetic lethality. In one instance, the researchers identified genetic mutations in the DNA repair genes of two cancer patients-one with bile duct cancer and the other with rectal cancer. Mutations in their BRCA1 or BRCA2 genes-rarely seen in these cancers-may have thwarted the tumors' ability to repair damaged DNA, the researchers theorized, allowing platinum-based chemotherapy drugs to kill cancer cells more efficiently.
The new NCI research, part of the institute's Exceptional Responders Initiative, was first launched in 2014. The hypotheses developed since then about the molecular underpinnings of exceptional responders will need to be validated by larger studies going forward, Staudt said, with a number of groups expected to publish in the next few years.
Susan Jenks is a contributing writer.