Source: web.musc.edu
Author: Leslie Cantu

Every once in a while, oncologist John Kaczmar, M.D., will have a patient following a course of immunotherapy whose cancer just seems to vanish.

“In your heart of hearts, you’re like, ‘Man, I kind of think we might have cured this person,’” said the MUSC Hollings Cancer Center researcher.

“Cure” is a word that cancer doctors tend to shy away from, especially in those who have metastatic cancer he said. But Kaczmar is curious about whether those people whose cancer is quickly knocked down – he terms them “extraordinary responders” – could potentially stop immunotherapy treatments sooner.

Right now, he said, immunotherapy treatments typically last two years, though there isn’t strong research indicating what the proper length of treatment should be. If doctors and patients were confident that the cancer was gone, they could stop treatment sooner.

“Side effects are random in immune therapy. They can happen six months out. They can happen nine months out,” Kaczmar said. “Perhaps some can have a shorter treatment course and avoid immunotherapy toxicity and reduce financial toxicity.”

To begin to pull together data, Kaczmar is running a pilot study to look at circulating tumor DNA (ctDNA) in these extraordinary responders. Circulating tumor DNA is DNA from the cancer that can be found in the patient’s blood.

Once a specialized lab has a sample of the tumor, collected either from a biopsy or during surgery, the tumor tissue can be sequenced to find the likely cancer mutations and develop a “fingerprint” of that specific tumor, Kaczmar said. That fingerprint can then be tested against the patient’s blood samples to see if cancer is still circulating, even if it has disappeared from scans. In this study, Kaczmar will be working with the Signatera ctDNA assay developed by clinical genetic testing company Natera.

Kaczmar said a ctDNA study involving stage 2 colon cancer patients was the talk of the American Society of Clinical Oncology meeting this summer. In that clinical trial, investigators used ctDNA to determine whether to give patients chemotherapy after surgery. Chemotherapy used for stage 2 colon cancer patients is generally at the doctor’s discretion; there isn’t a bright line indicating when it’s called for. However, in this trial, the people who didn’t get chemotherapy after being identified as negative for ctDNA were alive and cancer-free at the same rates as people who did get chemotherapy.

The results of that trial, Kaczmar explained, were so attention-grabbing that one of the investigators presented at a recent meeting of the Head and Neck Recurrent and Metastatic Task Force at the National Cancer Institute.

“We don’t know exactly how it applies to head and neck cancer, but it’s a big deal when a totally different field is saying, ‘Hey, we’d like to hear about this because it seems like it’s going to be practice-changing,’” he said.

For his pilot study, Kaczmar is seeking Hollings patients who showed a strong response to immunotherapy to see if they test as ctDNA-negative. All cancer types are eligible for the study, though Kaczmar expects to see patients with the types of cancers that usually respond best to immunotherapy – melanoma and cutaneous squamous cell cancer, along with kidney, head and neck, lung, gynecologic and certain types of breast and colon cancers. He hypothesizes that these extraordinary responders will test negative for ctDNA.

“What does being ctDNA-negative mean, or, if it stays at a low, stable amount, maybe that’s just as good?” he said. “I think it will give us a lot of qualitative information about the cancer kinetics in these extraordinary responders. And I don’t know – maybe we’ll find a lot of people are positive and few are negative. Maybe we’ll find most of them are negative. I don’t know the answer to that. But I think understanding the kinetics and understanding how that interplays with their scans will hopefully help us improve treatment decisions in the future.”

Kaczmar noted that sometimes patients, whose scans appeared clean, will have their cancer reappear after a number of years. Perhaps, he said, ctDNA will show that those patients always had the cancer circulating in very low but stable numbers. Then, when the patient’s immune system weakens – either because of aging or because of an illness or another event – the cancer escapes and appears to have returned.

Kaczmar said it’s one thing to see good results based on a scan, but the ctDNA results could indicate how long-lasting that good result is likely to be.

The data from this pilot study could then be used to design a larger prospective study that could examine halting immunotherapy treatments for patients who test negative for ctDNA, much as the colon cancer study used ctDNA to decide whether to give chemotherapy.