COMMENTARY

What Drives an Exceptional Response to Cancer Treatment?

David J. Kerr, CBE, MD, DSc

Disclosures

February 23, 2021

This transcript has been edited for clarity.

Hello. I'm David Kerr, professor of cancer medicine at the University of Oxford. Today I'd like to talk about exceptional responders.

On my very first day in medical school in 1973 in Glasgow, the dean introduced about 200 of us to the art of medicine and told us two important facts that have remained with me throughout my medical career. The first was that surgeons are the fighter pilots of medicine and physicians are the bomber pilots. I've never forgotten that. The second was to cherish your exceptions. He was an insightful man. The sense was that if you see something unusual — an unusual response, an unusual pattern of disease — try better to understand it.

I'd like to discuss a rather nice paper that's been published recently in Cancer Cell by David Wheeler and colleagues, in which they've tried to undo the intricate molecular mesh that underpins exceptional responders. Let me give you the exact definition of "exceptional responders" that they use. These are patients for whom a complete or partial response was expected in less than 10% of similarly treated patients, or whose duration of response lasted three times the published median or longer. A cohort of these patients has been built up by a group at the National Cancer Institute (NCI) in Bethesda.

These are individuals who have done remarkably well, and we'd have expected them (gloomily, perhaps) to have progressed many moons ago, but here they are, still responding. Or, here is somebody who came with a very large tumor volume, a huge burden, and has a complete response.

In my particular field of colorectal cancer, chemotherapy-induced complete responses are rare. To find one in somebody who has a large, bulky tumor that persists for a long period of time would classify somebody as an exceptional responder. It's somebody in that sort of ilk. All of us can remember those patients. I'm sure at some time we have all thought, I wonder what it was? Was it the immune microenvironment? Was it something about the biology of the patient's tumor? Was it something about their germline capacity to metabolize anticancer drugs? Who knows? It remains an enigma.

Wheeler and colleagues have taken a highly structured approach to try to give us some insights into the mechanisms underpinning these cherished exceptional patients. They've used a multimodal genomic approach in which they've literally thrown the technical kitchen sink at blood and tumor specimens that have been collected by the NCI from these exceptional responders. They've looked at the somatic tumor mutational landscape, epigenetics, chromosomal fusion proteins, and RNA. They've looked at the cellular tumor microenvironment. They've tried to integrate these mathematically, very cleverly, looking for needles in haystacks, which are common across multiple tumor types; this wasn't focused on a single tumor type.

They discovered that in only about a quarter of patients could they detect a plausible signature or a plausible mechanistic event that could explain what they thought was going on. This came around to predominantly DNA repair mechanisms, intercellular signaling pathways, lethality and associated mechanisms, and prognostic markers. It may have just happened that tumors of exceptional responders were tumors that were prognostically good. They may have had a large tumor volume, but they had characteristics of good prognosis. They presented a huge amount of technical information via a complex, well-thought-through analytical approach, and a possibility of categorizing the molecular events into these different fields.

Having an answer in only a quarter of the patients that it will touch — it's a fantastic start; it's a technical tour de force. But isn't it interesting that even despite this fairly high-powered approach, only in a minority of patients could they come up with clues showing the complexity of the Gordian knot that governs tumor responsiveness to the treatments that we offer?

There are a couple of things to remember. This is a cohort of 111 patients across multiple tumor types. Clearly, if one could expand that cohort, perhaps with enough power to look at individual tumor types across the whole, that would be one way of going about it. Technically, I think they used all the methodologies that are currently available. I don't think there's any new technical platform or advance that would allow them to gain any more insights. Perhaps it may just be the old chestnut of statistical power of seeing if one could ramp up the numbers appropriately that would then allow them to detect those rare events that were contributing to these exceptional responders.

What do we take away from this? Well, my dean was right: Cherish your unusual patients. If we go through them with a fine-molecular-tooth comb, we might be able to detect a hint, a strain, a signature, or a distant melody as to why these tumors are responsive.

The idea of looking across different tumor types for common themes is attractive. In terms of statistical power, though, it makes it more difficult to detect rare events. I think if we could increase the number of individual tumor types in the cohort, that would just allow us to look at the ontogeny within a discrete tumor type. That still seems important.

I know we want to move as far away from tissue in talking about colorectal cancer or breast cancer. We want to be able to talk about cancer, which is driven by pathway X or pathway Y. We're not even remotely there yet. Therefore, the tissue of origin still seems to be terribly important in driving it forward. Perhaps if there was more of an international, collected effort for us to build up the biobank around these exceptional responders, that could be a truly important resource for all of us to help interrogate and come to understand better.

What are the benefits to patients? If we can come up with some of the thematics that identify sensitive individuals, there may be new pathways for drug development, for prognostic biomarkers or predictive markers, and so on.

This is a very well-conducted study, standing, as always, in the foothills of understanding more and being able to develop better treatments.

Thanks again for listening. For the time being, from David Kerr, over and out.

David J. Kerr, CBE, MD, DSc, is a professor of cancer medicine at the University of Oxford. He is recognized internationally for his work in the research and treatment of colorectal cancer and has founded three university spin-out companies: COBRA Therapeutics, Celleron Therapeutics, and Oxford Cancer Biomarkers. In 2002, he was appointed Commander of the British Empire by Queen Elizabeth II.

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