Metastatic prostate cancer resistant to castration (mCRPC) can be classified as either basal or luminal, and, as with primary tumors, the distinction has important prognostic as well as therapeutic implications, concludes the new report in JAMA Oncology.
In addition the classification is “an important step towards individualizing treatment for men suffering from mCRPC,” write investigators led by Rahul Aggarwal, MD, a Genitourinary Oncologist from the University of California, San Francisco.
They also point out that even though the classification is of clinical importance in the context of localized diseases to determine prognosis, it hasn’t been examined in mCRPC.
The team suggests that this could be due to the difficulty of biopsying prostate metastases which typically are located in the bone.
The team retrospectively looked at genetic information as well as clinical data from 634 men participating in four clinical trial cohorts. 45percent of the tumors were classified as luminal while 55% were classified as basal based upon increased or decreased expressions of luminal gene signatures. The treatment for the cohorts was at physicians discretion.
The team’s findings are similar to those of localized disease. Aggarwal and his colleagues wrote that patients suffering from luminal cancer should be considered for androgen signaling inhibitor [ASI] therapy. Patients with basal tumors should be considered be chemotherapeutic due the similarities to small cell/neuroendocrine prostate cancer and the decreased benefit of androgen signaling inhibitors.
Amazingly, and consistent with the importance of oncogenic estrogen receptor signaling in luminal cancers, patients had significantly better survival rates when they were treated using ASIs rather than chemotherapy (hazard ratio [HR], 0.27, P >.001).
Notably, luminal tumors demonstrated an increase in the expression of androgen signaling genes and obtained preferential benefit from ASI treatment over basal tumors.
The basal subtype contained but was not limited to prostate cancers that are small cell/neuroendocrine (SCNC), “which raises the possibility that non-SCNC basal tumors (the majority) could share enough similarities with their SCNC counterparts that similar chemotherapy-based treatments could be effective, especially given the less benefit of ASI treatment,” the team writes.
The investigators agree that the results merit more validation in larger prospective groups or clinical trials.
Possibly Practice Modifying
Rodwell Mabaera, MD, PhD Medical Oncologist at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire, agreed with investigators on the potential impact of the luminal and basal classifications in an accompanying editorial.
“These subtypes represent a potentially powerful tool for personalized therapeutic decision-making that could improve outcomes for patients with mCRPC,” he writes.
Mabaera noted that luminal cancer patients treated with chemotherapy had the lowest survival rates, suggesting the possibility of a negative effect from chemotherapy in this particular group.
“The authors concluded that ASI should be considered for this patient …..” If the results are confirmed, could alter the method of selecting treatment in the luminal subtype mCRPC.
Basal tumors were discovered by the researchers as having genetic mutations that result in resistance to antagonists of androgen receptors. They also had increased dependence on DNA damage repair pathways. That opens “the possibility that PARP inhibitors,” which block cancer cells from repairing DNA “may be effective in this subgroup of patients,” Mabaera said.
The basal/luminal treatment duality may not be fully applicable, however.
This is because there was a trend toward an increase in survival after ASI treatment in basal tumors (HR, 0.62; P = .07), which suggests that there could be a subset of basal tumors dependent on the androgen pathway and could benefit from ASI therapy, he said.
Regarding the difficulty of biopsying mCRPC metastases, the investigators noted that the limited intraindividual variation in biopsy results suggests “the feasibility of classifying patients on the basis of a single biopsy of an metastatic tumor.”
The research was aided by the US Department of Defense Prostate Cancer Research Program as well as the National Cancer Institute, and others. Aggarwal has been a consultant for a fee and/or has received research funding from a number of companies including Janssen, Merck, and AstraZeneca. Mabaera has not disclosed any relevant financial connections.
M. Alexander Otto is a physician assistant who holds a master’s degree in medical science. He is also an award-winning medical journalist who worked for various major news outlets prior to joining Medscape. He is a Knight Science Journalism Fellow at the MIT. Email: [email protected]
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