Ductal adenocarcimoma of the prostate is “rare” but aggressive

Pure ductal adenocarcinoma of the prostate (dPC) is thought to be found in just 0.4 to 0.8 percent of men who get diagnosed with prostate cancer each year. However, it can also be found mixed in together with “standard” forms of adenocarcinoma of  the prostate in about 3 to 12 percent of men who are diagnosed with prostate cancer each year. Thus, while rare in the pure form, dPC is also the second most common form of prostate cancer that is identified in men with prostate cancer each year.

We know that dPC is a particularly aggressive form of prostate cancer. We also know that it seems to have limited impact on PSA levels and is not usually detectable by digital rectal examination. A problem with dPC is therefore that it may remain undetected for a considerable period of time, particularly in the pure form.

In a newly published report in JCO Precision Oncology, Schweizer et al. provide data indicating that dPC is associated with a very high occurrence of DNA damage repair or DDR gene alterations (including mismatch repair and homologous repair mutations).

Schweizer and his colleagues carried out next-generation DNA sequencing on tumor tissue from a total of 51 patients, all diagnosed with dPC and with the histopathology confirmed by an expert in genitourinary pathology. These 51 patients had been diagnosed at three highly respected prostate cancer treatment centers (the University of Washington in Seattle, Johns Hopkins in Baltimore, and the University of Calgary in Calgary, Canada).

They were able to show that, among these 51 patients:

  • 25/51 (49 percent) had at least one DNA damage repair gene alteration, including
    • 7/51 (14 percent) with a mismatch repair gene mutation
    • 16/51 (31 percent) with a homologous repair mutation
  • 10/51 (20 percent) had germline autosomal dominant mutations that were either confirmed or suspected in 10 patients (20%).
  • Activating mutations were common in three known pathways:
    • The PI3K pathway (n = 19; 37 percent)
    • The WNT pathway (n = 16; 31 percent)
    • The MAPK pathway (n = 8; 16 percent)

We know that patients with mutations of these types do not respond well to standard forms of treatment for progressive prostate cancer. Schweizer and his colleagues therefore concluded that their study

… strongly suggests that dPCs are enriched for actionable mutations, with approximately 50 percent of patients demonstrating DNA damage repair pathway alteration(s). Patients with dPC should be offered next-generation sequencing to guide standard-of-care treatment (e.g., immune checkpoint inhibitors) or triaged toward an appropriate clinical trial (e.g., poly [ADP-ribose] polymerase inhibitors).

The “New” Prostate Cancer InfoLink would concur with this set of recommendations. Pembrolizumab (Keytruda) has been approved for the treatment of patients with these types of DNA damage repair mutation, and it appears to be highly likely that the so-called PARP inhibitors (olaparib/Lynparza and others) also have benefit in this setting — although conclusive proof of the benefit of the PARP inhibitors in treatment of men with prostate cancer and DNA damage repair mutations is still awaited.

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