New Subtype of mCRPC Refractory to Androgen Receptor Inhibition ID'd

June 1, 2015

Researchers have identified a new histologic subset of metastatic castration-resistant prostate cancer that is refractory to androgen receptor inhibition.

Researchers have identified a new histologic subset of metastatic castration-resistant prostate cancer (mCRPC) that they have labeled intermediate atypical carcinoma (IAC).

According to data (abstract 5003) presented by Eric J. Small, MD, of the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting held May 29 to June 2 in Chicago, IAC is an aggressive subtype of cancer that accounted for about one-fourth of biopsied tumors in their study.

According to Small, the treatment of mCRPC has been revolutionized by the development of highly potent agents targeting the androgen receptor; however, although these agents prolong life, the development of resistant disease is a universal and fatal event.

An increasing number of patients resistant to androgen signaling inhibitors develop small-cell or neuroendocrine prostate cancer (NEPC). Because of this, Small and colleagues from the West Coast Prostate Cancer Dream Team have undertaken a large project designed to help understand the pathologic, clinical, and genomic characteristics of patients who develop resistance to abiraterone and enzalutamide. The project included eligible patients with mCRPC who underwent metastases biopsy and were followed for clinical outcomes.

The researchers used both frozen and formalin-fixed/paraffin-embedded tissue, and independent pathology review was performed by three pathologists. Frozen specimens also underwent laser capture microdissection, RNA isolation, library preparation, and RNA sequencing.

As of May 1, 173 of 300 biopsies have been performed, with a 78% biopsy success rate. Fifty-one percent of the biopsies were from bone metastasis and 27% were from the lymph node.

Of the 124 evaluable biopsies, 35% were classified as pure adenocarcinoma and 13% were classified as pure classical small-cell NEPC.

“A novel subtype was identified in 26% of biopsies that consisted of a pure population of cells distinct from adenocarcinoma and neuroendocrine carcinoma,” Small said. The remaining quarter of samples were mixed.

Looking at this new subtype, the researchers had several questions, including whether IAC possessed unique and reproducible pathologic features and if it was phenotypically and genomically distinct from adenocarcinoma and small-cell NEPC.

When the researchers examined survival, they found that patients with IAC had poor survival, with the Kaplan-Meier curves for survival of IAC tracking with those of patients with small-cell NEPC, and distinct from adenocarcinoma.

“Indeed, when small-cell NEPC and IAC were grouped together, we saw dramatically different survival curve than adenocarcinoma,” Small said.

The presence of IAC and small-cell NEPC subtypes were equally distributed across all tissue types.

The researchers also developed a 50-gene signature with 97% accuracy for NEPC, defined as small-cell or IAC histology.

“Despite being cytologically bland, this is an aggressive cancer similar to that seen with small-cell NEPC,” Small said. “IAC represents 25% of mCRPC biopsies and when combined with small-cell NEPC accounts for 40% of all samples, comprising the single largest group of abiraterone- and enzalutamide-refractory patients.”

Small added that although it can only be conjecture at this point, the increasing use of highly potent androgen receptor–targeted therapy may contribute to the increasing frequency of this entity.