Guided by precision oncology, researchers at the Ohio State University Comprehensive Cancer Center used "rapid autopsy" in a recent study to show promising clinical activity in a second-line therapy for a rare bile duct cancer. The study-part of a growing trend in the use of these procedures-found that the drug, infigratinib, worked well against a fusion gene, which acts as a known spur to cancer progression in cholangiocarcinoma and several other difficult-to-treat cancers.
Of the 108 patients who carried these fusion errors, "progression-free survival improved a lot," on average 6.5 months compared with a benefit of just 1-2 months on prior therapy, according to Sameek Roychowdhury, MD, PhD, Associate Professor of Medical Oncology and one of the study's principal investigators.
"The drug proved very effective," he noted, which ultimately lead to FDA approval last May for patients who harbor these distinctive genetic markers and fail earlier treatments. Results of the study were published in Lancet's Gastroenterology and Hepatology last fall (2021; https://doi.org/10.1016/S2468-1253(21)00196-5).
Ohio's rapid autopsy program is one of an estimated 15-20 programs nationwide that exist today, almost all housed at major universities, where investigators study cancer's molecular disruptions as tumors spread and grow. All of these programs rely on the selfless contributions of patients and their families who consent to participate in these studies once treatments have been exhausted and death occurs or seems near.
While the exact number of programs has changed little in recent years, cancer investigators' interest and collaborative efforts in this work have grown, rekindled in part by autopsy's success in understanding COVID-19, noted Jody Hooper, MD, Associate Professor of Pathology and Director of Autopsy at Stanford University School of Medicine. Stanford, under her direction, is expected to launch a new autopsy research program, possibly by late spring.
"One of the powers of autopsy is that you can focus on multiple tissue samples (for study) at the same time and in large volumes," not possible when a patient is still alive, she explained. And, that capability provides not only insight into the genetic mutations acquired in the tumor itself, but also in the surrounding tumor environment as well.
By definition, time is of the essence in rapid autopsy, to define molecular clues in every organ of the body before tissue degradation sets in. Ideally, Hooper noted that autopsies should be performed as quickly as possible, usually within 6-8 hours of a patient's death. But, the exact time frame for autopsy differs, depending on what researchers want to do-whether growing tissues in mice for further study or some other investigative pursuit.
Also, even though the rapid window might close, she said other types of research remain possible with tissue cryopreservation allowing study 12-24 hours after patients succumb to their disease.
Hooper described the Ohio study as important to improving cancer treatment and an example of how autopsy actually contributes at "both ends" of an evaluation. These procedures provide preclinical insights that can improve patient care before death, she said, as well as postmortem results that can help others receive better care in the future. Because of this breadth of promise, she stressed, "autopsies should be integrated into clinical trials of all kinds."
Encouraged by results in the single-arm Phase II trial of infigratinib, Roychowdhury and his colleagues have begun enrolling patients with other types of cancer in further studies at the cancer center in Columbus. All carry the same genetic rearrangements known to fuel malignancy. The hope is these patients, much as the bile duct patients have, will benefit either from infigratinib or another targeted therapy that inhibits their fusion genes.
Roychowdhury said he chose to focus initially on patients with bile duct cancers in part, because of sparse treatment options available to them, and in part because of the failure of earlier novel therapies, tested in 2014 and 2015, to bring lasting benefit. Patients wanted to know why their drugs stopped working, and so did Roychowdhury.
That decision, as it turned out, proved to be a "great example of how precision oncology and genetic-guided therapy can work together to further understanding of drug resistance," allowing for better drug design, he said.
Meanwhile, as these and other studies move forward, investigators continue to rely on the willingness of patients and their families to participate in autopsy research programs to help others. Many patients who agree to undergo these procedures at death are already organ donors, investigators say, or participate in clinical trials and see autopsy as a continuation of that process. Or they've begun asking questions about hospice care, so they're thinking about end-of-life issues, and want to advance cancer research in some way, even if it won't help them.
"Doctors think families are more troubled about talking about autopsy than they actually are," Hooper said.
The wife of Jeff Gibbs, an Ohio patient of Roychowdhury with an aggressive cancer of unknown origin, reflects that view. In a recent podcast, in which she described her late husband, as a "scientist at heart," she noted that he wanted to do whatever he could to help others.
"The idea of an autopsy gave purpose to his pain," she said. "He would have loved to have known what was found out about his cancer."
Susan Jenks is a contributing writer.