Cribriform CAP Intraductal Carcinoma Prostate [2022]
Cribriform Prostate Cancer Clinical Trial
I’m here to talk about our recent study, presented at ASTRO’s annual meeting. In this study, the gene expression or transcriptome characteristics of aggressive prostate cancer were looked at and found to be linked. morphologic appearance under the microscope as characterized by our genitor urinary pathologists, who are primary co-authors on the study.
In particular, they were looking at this aggressive morphology or morphology associated with aggressive clinical behavior called cribriform or intraductal cancer of the prostate . The key findings from our study were that in men who harbored this more aggressive microscopic appearance or higher grade disease with these cribriform form features, they had a notable increase in the risk score, genomic classifier risk score, and this gene expression profile of their tumors that seemed to be associated tightly with the appearance of this cribriform feature. In addition to that, what we found was that again, this aggressive microscopic appearance, this honeycombing or cribriform (growth) pattern that the pathologists identified, we know has been associated with more aggressive prostate cancer, more likely to recur, more likely to spread.
It was discovered that specific gene networks were higher or upregulated in cancers with these morphologic features, and that driver oncogene pathways, such as the m oncogene pathway, were up regulated E2F targets, which is a reflection of tumor suppressor RB dysfunction, both of which would have been associated with very aggressive variants of prostate cancer, such as small cell or advanced variant prostate cancer. And one of the inferences we make is that the transcriptomic features of cribriform and intraductal prostate cancer suggest perhaps a mechanism behind the appearance of this more aggressive pathology.
Current SOC in Addition to the Use of Cribriform (Clinical Outcomes)
We know that prostate cancer is a very heterogeneous disease in the sense that there’s a broad spectrum of clinical behavior from indolent disease that we can safely watch that’s unlikely to harm a patient that we should be careful not to overtreat all the way to very aggressive and high-risk localized and metastatic prostate cancers. We oftentimes need to identify, treat more aggressively, and do a better job of developing newer treatments for those gaps where the ones that we have aren’t working. And so, given this spectrum, it’s really important that we classify patients correctly into their risk group (Eg high risk). So we are careful not to over or undertreat any individual’s prostate cancer.
So the idea behind this work, and what I believe drives a lot of current prostate cancer research, is that it is more effective and accurate risk stratification for personalized therapy and clinical significance, and this study certainly falls into that category. We were looking at the combination of microscopic or morphologic features, clinical and pathologic features, things like stage grade grouping, PSA, and combining those for clinical outcome. With molecular and emerging genomic classifiers, the transcriptome classifier we used in this study to more accurately identify patients, in particular at those gaps between, for example, intermediate and high-risk diseases (disease specific survival), where we often don’t fully understand. Exactly which patients need more intensified hormone therapy, for example, or would benefit from surgery instead of radiation therapy, or things like this, are open questions. And so here we are in the sort of cutting edge, modern era of prostate cancer. Therapy is trying to better tie together morphologic features and these transcriptome classifiers, which was at the center of the study that we did.
Could you please tell us about the trial design for Intraductal Prostate Cancer Patients?
The work that was done here was a retrospective study of some 700 patients with prostate cancer who had a commercially available genomic classifier performed on their tumor tissue called the decipher test, for which we also have whole transcripts on the entire genome of genes that are turned on or off, so we can measure those. And so, combining that data with a re-review of these specimens by our expert GEO-focused pathologists like Dr. Nguyen and Dr. Williamson, who are collaborators on the study, We went back and put together the appearance of cribriform features as classified by our pathologist with specific patterns of gene expression and with a genomic classifier score, basically a risk score for more aggressive prostate cancer (Eg high risk).
And we discovered that patients with these features known to be associated with more aggressive prostate cancer, such as cribriform morphology, also had higher decipher scores and higher genomic classifiers. had an increased gene expression network associated with aggressive prostate cancer, like mixed signaling and upregulated E2F targets. In addition to this, we found that the presence of cribriform and intraduct morphology were also associated with a B subtype using the PAM50 classifier, which has been previously shown to be an entity that behaves more aggressively but may indeed have implications for response to hormone therapy.
So we learned a lot on the preclinical side by looking at these tumor samples retrospectively. And what we hope to do with this data is to get prospective validation around this correlation that may inform the way we select patients for For instance, more tailored treatments, such as intensifying hormone therapy in the correct patients or, for instance, deescalating with radiation alone instead of combined radiation and hormone therapy for patients who are potentially at lower risk, who may harbor the presence of cribriform features but have lower genomic risk scores (genomic instability) or vice versa. And. I think that’s the ultimate goal of this work. But what we’re describing here in the currently presented and recently published study is really this association, which we think reveals the biologic underpinnings of these morphologic features.
Read and Share the Article Here: https://oncologytube.com/v/41382
What Led You to Study Prostate Cancer?
Thanks for asking. I’ve always been interested in cancer biology and cancer medicine, but like many people, prostate cancer is a common disease, often thought of as an indent disease, but can have very aggressive variants. My family and I have been very personally touched by prostate cancer. My father had an aggressive prostate cancer and ultimately lost his life to prostate cancer. And as you might imagine, that had a big influence on my choice of career and the work that I do. I think it’s an incredibly exciting time to be studying prostate cancer.
As a biologist and a physician scientist, this is a disease for which we have a broad spectrum of new and emerging treatments. There’s the incorporation, as you’re hearing now, of molecular profiling into clinical decision making, which I think is something that me and my colleagues are very excited about. It’s been the goal of personalized medicine for some time, and we’re seeing it actually working, which is terrific. And in addition, I think that as a radiation oncologist, I see many patients with prostate cancer, both those who do well and sometimes patients.
We just don’t have effective treatments and don’t have the right combinations to offer them to treat their disease (specific survival). And so that, as you might imagine, is an incredibly frustrating thing and drives me and my many colleagues here in urology, medical oncology, and radiation oncology like myself to work really hard to identify better and better treatments so that we can do a better job of caring for our patients.
Final Thoughts
I think the key takeaway point from our study is that even though we don’t think this work is at the point yet where we’ll use it for clinical decision making, This kind of study is very important if we want to learn more about the biological causes of aggressive prostate cancer and find better biomarkers for more accurate risk assessment. And I think the key point is pre-clinical studies, early phase clinical investigations like these investigator-initiated studies, the kind of work that will take our findings forward and validate them, bringing them closer to the clinic where they can help our patients. They’re so important, and I think it’s critical to support that.
I think one of the things I would love for folks to know about the Cleveland Clinic is that our medicine here is really driven by the cutting-edge scientists that work here and elsewhere that help us develop the next generation of therapies. As a result, I believe that these clinical trials and preclinical studies like the one we presented are really the engine of innovation in cancer medicine. And I think it’s incredibly exciting to be a part of that. I am so looking forward to what I think will be many exciting developments in the months and years ahead for prostate cancer patients.
What Future Studies Are Being Done?
We have several very exciting clinical trials and early-phase investigational studies. And registries that have come out of this and related work here at the Cleveland Clinic. So we’re currently looking at a number of things, one of which is germline biomarkers for response to combined radiation therapy and androgen deprivation therapy, and men with high-risk (intraductal) prostate cancer. Based on the work of my group as well as my colleague Nima Sharifi, who’s really a world expert in steroid hormone biology and initially discovered an enzyme that has two different variants and depending on which one is inherited, patients’ risk for progressing to hormone therapy may be very different.
Both tumors have a genetic basis, so these types of things exist. And the patient’s genetic risk in the disease is determined by the genes and genetics that they inherited. These are critical to understand, both from the perspective of the effectiveness of our treatments and of avoiding side effects from either over or under treatment or using the wrong treatment for the wrong patient. And so I think that in a disease where we have many options for treatment, where there are many risk groups, this is the challenge for clinicians for prostate cancer: to match the right treatments to the right patient at the right time. That’s really the whole promise of personalized and tailored medicine and cancer therapy. But what does it do for disease specific survival?
Once again, I am very excited about the implications of this work, the emerging or the clinical studies that will emerge from these types of molecular profiling efforts that have already moved into the clinic here at our center, and what this means for better and better treatments for prostate cancer patients in the future.
Omar Mian, MD, PhD – About The Author, Credentials, and Affiliations
Dr. Mian is a radiation oncologist and physician/scientist at the Cleveland Clinic who specializes in treating genitourinary cancer. He holds appointments at the Lerner Research Institute, the Cleveland Clinic Lerner College of Medicine, and Case Western Reserve University, where he is an assistant professor of medicine. He participates in the Case Comprehensive Cancer Center’s Genitourinary Malignancies Research Program and he worked on the cribriform prostate cancer clinical trial.