However, there are inaccuracies in this terminology. Neuroendocrine prostate cancer is reflective of a poor clinical course reminiscent of a small cell variant, but this is a confusing term in that there are neuroendocrine pathologic features not associated with an aggressive (Paneth cell-like differentiation) phenotype. “Aggressive variants of prostate cancer” is less confusing, but potentially a more contaminated definition. “Therapy-related neuroendocrine prostate cancer” is better, but the concern is that clinicians may withhold potentially effective hormonal therapies. “Androgen indifferent prostate cancer” is reasonable according to Dr. Efstathiou. However, some tumors may still respond to novel androgen signaling inhibition and bias should not be introduced. Finally, “AR negative prostate cancer” is too limiting, and “Anaplastic prostate cancer” is a term used to denote pleomorphic cytology.
This aggressive variant prostate cancer may be increasing in incidence (~20%), which may be secondary to greater awareness of this entity, patients living longer, and the development of aggressive variant prostate cancer as a resistance to novel therapies. To try and further characterize this entity, the National Cancer Institute conducted a workshop on lineage plasticity and androgen receptor-independent prostate cancer to identify unmet needs. This led to a better understanding of how lineage plasticity occurs by determining the temporal contribution and cooperation of emerging drivers, identifying preclinical models that recapitulate biology/recognized phenotypes, and identifying therapeutic targets and novel trial designs dedicated to the entity as it is defined.
According to Dr. Efstathiou, first, small cell prostate carcinoma was present with an aggressive course and atypical clinical features. This was followed by the realization of an intense clinical presentation of aggressive variant prostate cancer that had a clinical course similar to small cell prostate cancer. The clinicopathologic criteria for aggressive variant prostate cancer includes (i) small cell prostate carcinoma, (ii) visceral metastases only, (iii) lytic bone metastases, (iv) bulky nodes or prostate mass, (v) low PSA relative to volume of disease, (vi) elevated neuroendocrine markers and serum CEA or LDH, (vii) primary castration-resistance.
Dr. Efstathiou’s group's main hypothesis for a phase II trial was that shared clinical features of small cell prostate carcinoma predict for shared platinum-based chemotherapy combination sensitivity. For this trial, 120 patients were assessed with first-line carboplatin and docetaxel, followed by second-line etoposide and cisplatin. There were 74 of 113 (65.4%) patients that were progression-free after four cycles of carboplatin and docetaxel, and 24 of 71 (33.8%) patients that were progression-free after four cycles etoposide and cisplatin. The median overall survival (OS) was 16 months (95% CI 13.6-19.0 months), and among seven patients with "anaplastic" criteria, bulky tumor mass was significantly associated with poor outcome. Furthermore, serum CEA concentration strongly predicted OS but not rapid progression. Presenting data that is currently in press, Dr. Efstathiou reports that carboplatin added to cabazitaxel (median 7.3 months, 95% CI 5.5-8.2) improves the median PFS among these at-risk men compared to cabazitaxel alone (median 4.5 months, 95% CI 3.5-5.7).
The current state of aggressive variant prostate cancer from a practical perspective according to Dr. Efstathiou is as follows:
- Clinical criteria help identify the aggressive variant of prostate cancer, however, the caveat is that there may be contamination by other molecular subtypes.
- Regarding morphology, several groups now recommend sampling metastases.
- Molecular subtyping data is immature and requires validation.
- Treatment considerations should include platinum-based combinatorial chemotherapy, although the evidence remains weak.
Presented by: Eleni Efstathiou, MD, PhD, Associate Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md, at the 2019 Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 - 31, 2019 in Basel, Switzerland
- Aparicio AM, Harzstark AL, Corn PG, et al. Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clin Cancer Res 2013 Jul 1;19(13):3621-3630.