Analysis Helps Distinguish the Molecular Profile of Intraductal Carcinoma of the Prostate

Benjamin Miron, MD

Patients with intraductal carcinoma of the prostate harbored several alterations in DNA damage repair (DDR) genes that may be clinically actionable, and they had high frequency of alterations associated with poor disease prognosis, according to a molecular analysis presented at the 2023 ASCO Annual Meeting.

Better understanding the genetic profile of intraductal carcinoma of the prostate could help guide treatment selection and support the development of novel agents, fueling the rationale for further research regarding the incidence and molecular biology of this novel histological classification, according to Benjamin Miron, MD.

According to a molecular analysis of available tissue from patients with intraductal carcinoma of the prostate throught RNA and DNA sequencing, the most frequently detected alterations were in TMPRSS2 fusions (38.7%), TP53 (38.7%), FOXA1 (16.1%), SPOP (9.7%), CDK12 (9.7%), and PIK3CA (9.7%). Alterations in cell cycle regulatory, DRR, and PI3K/AKT/MTOR pathways were present in 49.9%, 22.7%, and 22.8% of patients, respectively. Oncogenic FOXA1 mutations—which are commonly associated with disease progression and the development of castration resistance— were enriched in this population. Moreover, intraductal carcinoma of the prostate was found to have a molecular profile more similar to that of metastatic castration-sensitive prostate cancer (mCSPC) compared with localized disease.

“[Intraductal carcinoma of the prostate] is clearly a high-risk entity. Right now, we're just starting to learn about the molecular landscape [of this histology] and how that might guide us future treatment decisions and strategies…[but] for now, we still follow the standard of care,” said Miron, who is a medical oncologist and researcher at Fox Chase Cancer Center in Philadelphia, Pennsylvania.

In an interview with OncLive®, Miron explained the purpose of studying the molecular profile of intraductal carcinoma of the prostate, expanded on the potential prognostic and targetable alterations identified in patients with this histology, and discussed the planned cohort expansion and analysis of RNA signatures in this population.

OncLive: Could you discuss the rationale for investigating the molecular profile of intraductal carcinoma of the prostate? What information is currently known or suspected about this emerging disease characterization?

Miron: Intraductal carcinoma of the prostate is a relatively new addition to the World Health Organization’s criteria. Pathologists have only been officially diagnosing it since about 2016. It has been associated with higher volume tumors and more aggressive tumors that are more likely to spread. It's got some important clinical characteristics.

Because of what we know about the clinical phenotype, we wanted to learn more about the molecular landscape and some of the drivers of what might be different about intraductal carcinoma. We worked with Caris Life Sciences to look into their database of thousands of samples. We specifically took prostatectomy specimens and identified those that had intraductal carcinoma. [We then] performed sequencing and looked at the sequencing data from those samples.

Could you expand on the patient population included in this study?

We identified 31 cases [of intraductal carcinoma of the prostate]. Because it's a relatively new addition to the diagnostic criteria, we have to go through and try to identify more cases. In those 31 cases, all patients were men, since they were prostate cancer specimens, and there was a predominance of high-grade group [5] disease; 84% [of patients in] the whole cohort were grade group 5. That fit with what we think we know about intraductal carcinoma of the prostate.

What findings from this study were presented at the 2023 ASCO Annual Meeting?

We presented the molecular landscape of intraductal carcinoma [of the prostate]. We saw a number of different alterations that are interesting, but a few that are clinically actionable. We found some BRCA1/2 mutations in the cohort, [as well as] CDK12 mutations. Those are [markers] that you could use now for clinical decision making with PARP inhibitors [according to] their approved indications.

We also [conducted] another analysis comparing the intraductal cases from our cohort to a different published study for localized prostate cancer and mCSPC. Visually, when you look at the 2 distributions, the distribution of mutations [in] intraductal carcinoma of the prostate was more similar to that of metastatic disease than it was to the other localized disease cohort. I thought that was interesting based on the risk of metastasis with this entity.

What are the implications of these findings?

This warrants further investigation on the molecular landscape. We want to do some RNA sequencing comparisons with a pure adenocarcinoma cohort. For now with clinical testing, patients with prostate cancer [will] benefit [from] getting comprehensive [RNA] sequencing up-front or early on. There are some actionable mutations that we've already found in these patients. As far as germline testing, there are guidelines for who to test, and we should still follow those.

Are any next steps planned for this research?

We have a team of pathologists that [has] worked on the project with us so far and [will] continue to work with us. [We plan to] go through more cases using digital pathology slides, [potentially to] identify more intraductal cases to increase our cohort and identify a pure adenocarcinoma cohort for comparison. Once we have that, we'll have a much more robust study. We'll hopefully put that in a manuscript.

This [research] is a work in progress. If anyone's interested in this type of entity and they want to contact us to collaborate, [I encourage them to do so]. We want to be as inclusive as possible and [involve] people who are interested in studying this. Hopefully we'll report back with some more interesting results.

Disclosures: Dr Miron serves as a consultant or in an advisory role for Intellisphere and Seattle Genetics/Astellas; he has stock or ownership interests with Guardant Health.

Reference

Miron B, Wei S, Baca Y, et al. Clinical implications of molecular alterations in intraductal carcinoma of the prostate. J Clin Oncol. 2023;41(suppl 16):5024. doi:10.1200/JCO.2023.41.16_suppl.5024