Mismatch repair deficiency may be common in ductal adenocarcinoma of the prostate

Abstract

Precision oncology entails making treatment decisions based on a tumor's molecular characteristics. For prostate cancer, identifying clinically relevant molecular subgroups is challenging, as molecular profiling is not routine outside of academic centers. Since histologic variants of other cancers correlates with specific genomic alterations, we sought to determine if ductal adenocarcinoma of the prostate (dPC) - a rare and aggressive histopathologic variant - was associated with any recurrent actionable mutations. Tumors from 10 consecutive patients with known dPC were sequenced on a targeted next-generation DNA sequencing panel. The median age at diagnosis was 59 years (range, 40-73). Four (40%) patients had metastases upon presentation. Archival tissue from formalin-fixed paraffin-embedded prostate tissue samples from nine patients and a biopsy of a metastasis from one patient with castration-resistant prostate cancer were available for analysis. Nine of 10 samples had sufficient material for tumor sequencing. Four (40%) patients' tumors had a mismatch repair (MMR) gene alteration (N = 2, MSH2; N = 1, MSH6; and N = 1, MLH1), of which 3 (75%) had evidence of hypermutation. Sections of the primary carcinomas of three additional patients with known MMR gene alterations/hypermutation were histologically evaluated; two of these tumors had dPC. MMR mutations associated with hypermutation were common in our cohort of dPC patients. Since hypermutation may predict for response to immune checkpoint blockade, the presence of dPC may be a rapid means to enrich populations for further screening. Given our small sample size, these findings require replication.

Keywords: ductal adenocarcinoma; hypermutation; microsatellite instability; mismatch repair; prostate cancer.

Figure 1. Ductal adenocarcinoma component

In this case, approximately 65% of the carcinoma is ductal. Large tumor cell aggregates have a tubulopapillary architecture (100× final magnification). Forming a pseudostratified columnar epithelium the tumor cells have markedly atypical nuclei with clumped chromatin and prominent nucleoli (400× final magnification).

Figure 2. PSA response to checkpoint blockade immunotherapy in a patient with hypermutated prostate cancer

Prior to initiating pembrolizumab, this patient had bone, adrenal and lymph node metastases, and a baseline PSA of 177.35 ng/mL. A total of 3 cycles of pembrolizumab were administered before stopping due to an immune related adverse event (anasarca) requiring corticosteroids. He expired in June 2016. Note: this patient did not have ductal histopathologic features. Enza, enzalutamide; Doc, docetaxel; C, carboplatin; CBZ, cabazitaxel; Pembro, pembrolizumab.