AnCan’s Brains Trust Review Very Recent Seminal Prostate Cancer Work
A couple of weeks ago a prospective seminal paper was published in Nature . Of course, you don’t know if a paper is seminal until it is considered and acclaimed, but this paper is already getting plaudits.
It wouldn’t be the first time some of the paper’s authors have been acclaimed. Back in 2018 several of ‘the usual suspects’, Drs. Small, Aggarwal, Feng, Chi et al published a work in ASCO’s respected Journal of Clinical Oncology. I had first heard about that hypothesis some 3 years earlier at a UCSF Prostate Cancer Research Retreat where Eric Small suggested that advanced prostate cancer morphs into a small cell/neuroendocrine like form as the disease progresses. The significance of this current paper brought the earlier one to mind.
So what is the revelation from this new opus. Well first a tip off – it was published in Nature! That immediately indicates that you need a science background, and maybe even a PhD to even understand the abstract. Not surprisingly, it left me cold so I reached out to our AnCan PCa Brains Trust for a better understadning. Herb Geller and Ben Nathanson independently took the time to reveiw and summarize their understanding in easy-to-understand, patient lingo … and that’s what is presented below.
Oh … and the revelation as I understand it – that in time liquid biopsies will allow us to better define and personally tailor hormone therapy for each man.
Prof. Herb Geller sees this paper clearly identifying that the sum of the parts as greater than the whole ….
Current clinical practice depends upon traditional measures such as serum PSA and scans to stage prostate cancer and determine treatment protocols. More recently, liquid biopsies (from analyzing a blood sample) have begun to provide more information about mutations and cancer progression.
A new paper in Nature from a large group of clinicians and scientists takes the use of liquid biopsies to the next level through the use of whole-genome sequencing and samples taken over time to provide a more detailed picture of cancer progression in metastatic castration resistant prostate cancer (mCRPC) and compare that picture with a similar analysis of a biopsied metastatic site.
One result is that the liquid biopsy can provide a more detailed picture than the surgical biopsy. For example, they find, through the use of sophisticated analytical techniques, that the liquid biopsy shows that different metastatic sites have different mutations, and that sequential liquid biopsies can trace the evolution of the cancer within each site and how it contributes to overall progression. This is in contrast to current methods which only look at the aggregate.
Two observations are of particular interest. One is that they can follow the contribution of the individual sites to cancer progression. Given that some sites may have specific mutations, this may suggest precision treatment protocols that are tailored to each mutation, either separately or in combination. The second is that, while there are many different mutations associated with prostate cancer, they reaffirm that the major driver of cancer progression is the androgen receptor, suggesting, in their view, medicine needs to keep finding new ways to suppress AR signalling.
The overall impact of this paper is that it provides methods that can be implemented more generally. The major current impediments are the cost of whole-genome sequencing, which is decreasing exponentially, and the computational power needed to do the analysis. However, given the huge potential for providing clinical insights, we should expect to see these methods get implemented at major cancer centers.
Ben Nathanson thinks this paper will open the door for Game Theory to play a part in treatment strategy …
A new paper in Nature allows us to witness the day-to-day evolution of a patient’s cancer as its mutations grow and shrink. This level of knowledge is unprecedented, and it can change the face of research and treatment.
Cancer’s guessing game
A drug trial may yield dozens of failures and one miraculous remission. Hormone therapy is indistinguishable from a cure — then stops working. Though we can investigate cancer down to the molecular level, help unraveling these cases is limited because the molecular data is only a snapshot.
We can see what’s different in the genes of the one exceptional responder, but we struggle to identify which differences were significant — and more importantly, why they mattered. We can inventory the mutations in our castrate-resistant cancer, but have no clue how they evolved and how they might be countered.
Instead of snapshots, we need live-action footage. This work provides it.
The very different makeup of five patients’ cancers and their responses over time. A color indicates a cell population with a unique set of mutations. Plots show the details of each individual’s response. Circled numbers are times at which liquid biopsies were taken; AE numbers are patient IDs. The researchers were able to project back before the first measurement to the very start of the cancer. A lot of information was gained from a few measurements. From Herberts et al., Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer.
Evolution of five cancers
The figure above shows the kind of information yielded up by the new work. Each plot is from a different patient; rises and falls are changes in his PSA. A color indicates a unique cell population with its own set of mutations.
We can see what’s happening in each patient’s cancer to cause those changes in PSA.
Based on liquid biopsies
The Nature paper has a lot to be excited about. The molecular information comes from blood samples — “liquid biopsies” — rather than conventional tissue biopsies. Tissue biopsies are impossible when a tumor is too small or inaccessible, and are time-consuming, require high-level medical expertise, and can be painful. Liquid biopsies just require drawing blood.
Convenience aside, a liquid biopsy contains data from every metastasis, not just one.
Samples can be taken again and again during the course of the disease, tracking its evolution in detail.
Liquid biopsies are already used clinically to find treatable mutations in genes like BRCA2. The new results can turn liquid biopsies into the most revealing tool we have ever had to investigate castrate resistance. Ultimately it can make them the tool of choice for assessing patients and monitoring treatment — a requisite for precision medicine.
Real-time results
The work also can strengthen use of game theory and similar novel strategies to head off resistance. Cancer uses Darwin’s playbook: A mutation that improves survival in a hostile environment allows a cell and its children to dominate. If we continuously deprive a tumor of androgens, cells that need androgens will be replaced by mutations that don’t.
Thus one way to prevent resistance may be to modulate treatment so nascent mutations have no chance to grow. Trials are underway that do this, using PSA to monitor the cancer. We gain an advantage if we can lean over and read cancer’s cards. That’s what the research offers: an opportunity to see mutational populations growing and shrinking in real time.
No new equipment
Another exciting aspect of the work is how little it requires. There’s no special assay, no new machinery, no delicate lab procedure. It needs only a state-of-the-art DNA sequencer and public software.
Thus any lab with a good sequencer can join this effort and expand it in countless directions. Part of the software was designed to fit the data in this specific study, but the authors explain their work, and the results are so compelling that other institutions are likely to help generalize the code.
Biological insights
The authors have already made biological discoveries using their methodology, and these dominate the paper. Most require a deeper knowledge of genomics than I can lay claim to, but at least two bear mentioning.
The research confirmed that the DNA in the liquid biopsies showed more diversity than DNA in comparison tissue biopsies – suggesting that tissue biopsies do indeed reveal only part of the story.
And the work sought to determine for the first time whether genes other than the androgen receptor gene change during androgen deprivation. The AR gene was, in fact, the only gene seen to change in every sample. Their conclusion: As long as ADT remains the backbone of prostate therapy, medicine needs to keep finding new ways to suppress AR signaling.
For now this is a tool for insight rather than treatment. Today, although we can see those colors and know exactly what’s in them, we don’t know what to do about them. There’s much we have to learn about cancer dynamics, but we now have a tool that gives us a front-row seat.