Clinical trial data for AR-directed therapies consistently show that between 20% and 30% of men with prostate cancer do not respond to secondary hormone therapy. But that does not necessarily mean that those patients had AR-indifferent tumors, Dr Aparicio acknowledged: “You could argue that it’s not AR indifference — are those people who have truly AR-indifferent disease, or are the drugs not inhibiting the particular flavor of AR that is driving their disease?”

When investigating small-cell carcinoma-morphology prostate cancers, however, Dr Aparicio and her colleagues found something unexpected.

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“When we were investigating small-cell carcinomas, we took to biopsying anything that looked atypical in the hope that we could identify the morphology of small-cell cancers and apply chemotherapy earlier to improve patients’ outcomes,” she said. “We were surprised by the fact that we often did not find the small-cell carcinoma morphology, although we might find adenocarcinoma morphology in tumors that clinically behaved very much like small-cell carcinomas.”

Clinical research showed that among men with aggressive prostate cancer features, adding platinum-based chemotherapy to treatment improved outcomes.2

Traditionally, prostate cancer progression was seen through the prism of clinical state evolution, Dr Aparicio noted: lobe and aggressive localized disease, then castration-resistant disease, then metastatic disease. “It’s almost like trying to define leukemia based on the number of blasts in a blood smear.”

But that may change: biological classification — including drug response and resistance mechanisms — is set to overturn a strictly anatomic-distribution understanding of prostate cancer classification.

The importance of a biological classification is that will offer insights into how to apply combination therapies. “I think it takes a whole therapeutic strategy, not just one drug,” Dr Aparicio said. “We have to think about controlling the primary tumor in the metastatic setting, how to affect the immune system in different tumor subsets, and how different AR programs are manipulated in different settings.”

Small-cell carcinomas substitute an AR-epithelial lineage with neurodevelopmental pathways, Dr Aparicio noted. One mechanism that appears to underlie the transition to neuroendocrine-like AR-indifferent tumor cell phenotypes is the combined loss P53 and RB. P53 and RB loss may serve as a biomarker of the AR-indifferent disease, although not all RB and p53 deficient tumors take on this phenotype.5 There is clearly more to understand with regard to RB and p53 function, noted Karen E. Knudsen, PhD, director of the NCI-designated Sidney Kimmel Cancer Center and Chair of Cancer Biology at Thomas Jefferson University in Philadelphia, Pennsylvania, and the prostate tumor progression panel’s chair at the Genitourinary Cancers Symposium.  

“Genomic analysis of prostate cancer has identified recurrent mutations and copy number alterations in androgen signaling, DNA repair, PI3K pathway among others,” said Joshua Armenia, PhD, a computational biologist at Memorial Sloan Kettering Cancer Center in New York, New York. Nevertheless, prostate cancer harbors significant interpatient genomic heterogeneity, and statistical power analysis “indicates that aggregation and uniform genomic analysis of considerably larger cohorts may reveal significantly mutated genes and pathways in the ‘long tail’ of prostate cancer occurring in 1% to 5% of cases.”

Dr Armenia and colleagues performed uniform whole-exome analyses of 918 prostate cancer primary and metastatic tumor samples and matched noncancerous prostate tissue.