Mari Nakabayashi

Whole exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer

Comprehensive analyses of cancer genomes promise to inform prognoses and precise cancer treatments. A major barrier, however, is inaccessibility of metastatic tissue. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming the challenges of isolating rare cells and sequencing low-input material. Here we report an integrated process to isolate, qualify and sequence whole exomes of CTCs with high fidelity using a census-based sequencing strategy. Power calculations suggest that mapping of >99.995% of the standard exome is possible in CTCs. We validated our process in two patients with prostate cancer, including one for whom we sequenced CTCs, a lymph node metastasis and nine cores of the primary tumor. Fifty-one of 73 CTC mutations (70%) were present in matched tissue. Moreover, we identified 10 early trunk and 56 metastatic trunk mutations in the non-CTC tumor samples and found 90% and 73% of these mutations, respectively, in CTC exomes. This study establishes a foundation for CTC genomics in the clinic.

SLCO2B1 and SLCO1B3 May Determine Time to Progression for Patients Receiving Androgen Deprivation Therapy for Prostate Cancer

PURPOSE Androgen deprivation therapy (ADT), an important treatment for advanced prostate cancer, is highly variable in its effectiveness. We hypothesized that genetic variants of androgen transporter genes, SLCO2B1 and SLCO1B3, may determine time to progression on ADT. PATIENTS AND METHODS A cohort of 538 patients with prostate cancer treated with ADT was genotyped for SLCO2B1 and SLCO1B3 single nucleotide polymorphisms (SNP). The biologic function of a SLCO2B1 coding SNP in transporting androgen was examined through biochemical assays. RESULTS Three SNPs in SLCO2B1 were associated with time to progression (TTP) on ADT (P < .05). The differences in median TTP for each of these polymorphisms were about 10 months. The SLCO2B1 genotype, which allows more efficient import of androgen, enhances cell growth and is associated with a shorter TTP on ADT. Patients carrying both SLCO2B1 and SLCO1B3 genotypes, which import androgens more efficiently, exhibited a median 2-year shorter TTP on ADT, demonstrating a gene-gene interaction (P(interaction) = .041). CONCLUSION Genetic variants of SLCO2B1 and SLCO1B3 may function as pharmacogenomic determinants of resistance to ADT in prostate cancer.

Inherited Variation in the Androgen Pathway Is Associated With the Efficacy of Androgen-Deprivation Therapy in Men With Prostate Cancer

PURPOSE Androgen-deprivation therapy (ADT) is the most common and effective systemic therapy for advanced prostate cancer. We hypothesized that germline genetic variation in the androgen axis would improve the efficacy of ADT. PATIENTS AND METHODS A cohort of 529 men with advanced prostate cancer treated with ADT was genotyped for 129 DNA polymorphisms distributed across 20 genes involved in androgen metabolism. RESULTS Three polymorphisms in separate genes (CYP19A1, HSD3B1, and HSD17B4) were significantly (P < .01) associated with time to progression (TTP) during ADT, remaining so in multivariate analyses and after correcting for the number of hypotheses tested. Individuals carrying more than one of the polymorphisms associated with improved TTP demonstrated a better response to therapy than individuals carrying zero or one (P < .0001). CONCLUSION This report is the first to examine the influence of inherited variation in the androgen metabolic pathway on the efficacy of ADT, establishing the importance of pharmacogenomics on individuals response to this therapy. At least two potential clinical benefits may be realized from this study. The first is prognostic -genotyping patients at these loci may yield important information that could improve efficacy prediction. The second is therapeutic -these results shed light on the pathways that govern response to ADT. Drugs could be developed (or may already exist) to inhibit or augment these targets to improve ADT efficacy.

Efficacy of androgen deprivation therapy (ADT) in patients with advanced prostate cancer: association between Gleason score, prostate-specific antigen level, and prior ADT exposure with duration of ADT effect.

The purpose of this study was to compare predictive factors for the efficacy of androgen deprivation therapy (ADT) in men with hormone‐sensitive prostate cancer (HSPC) either with (M+) or without (M−) metastases.

Phase II trial of RAD001 and bicalutamide for castration-resistant prostate cancer.

Study Type – Therapy (cohort)

The risk of renal impairment in hormone-refractory prostate cancer patients with bone metastases treated with zoledronic acid†

Bisphosphonates have been used to treat bone metastases in hormone‐refractory prostate cancer (HRPC), but certain agents have been associated with renal toxicity. For this observational study, the authors assessed the risk of renal impairment in patients with HRPC who received zoledronic acid from December 1999 to April 2005.

Response to docetaxel/carboplatin-based chemotherapy as first- and second-line therapy in patients with metastatic hormone-refractory prostate cancer

To evaluate the efficacy of docetaxel/carboplatin (DC)‐based chemotherapy as first‐ and second‐line chemotherapy for patients with hormone‐refractory prostate cancer (HRPC).

Efficacy of nilutamide as secondary hormonal therapy in androgen-independent prostate cancer

To evaluate the activity of nilutamide as secondary hormonal therapy in patients with androgen‐independent prostate cancer (AIPC), as treatment options are limited for these patients and secondary hormonal therapy with antiandrogens has advantages, including low toxicity, oral administration and high patient acceptance.

Patients with Biopsy Gleason 9 and 10 Prostate Cancer Have Significantly Worse Outcomes Compared to Patients with Gleason 8 Disease

PURPOSE We examined differences in outcome in patients with biopsy Gleason score 8 vs 9-10 who received definitive local therapy. MATERIALS AND METHODS Using an institutional database we identified a cohort of 847 patients with biopsy Gleason 8-10 disease who received definitive local therapy with radiation therapy or radical prostatectomy between January 2001 and December 2011. Multivariable Cox modeling was used to assess the association of Gleason score 8 vs 9-10 with time to biochemical recurrence, metastasis and overall survival, and evaluate treatment by Gleason score interaction. Median followup in the cohort was 5.3 years. RESULTS Baseline patient characteristics were similar for biopsy Gleason 8 vs 9-10. Gleason 9-10 disease was associated with higher prostate specific antigen at diagnosis. As local treatment such patients were also more likely to have received radiation therapy (58% vs 46%, p = 0.001) and neoadjuvant/adjuvant androgen deprivation therapy (64% vs 49%, p <0.001). Those with higher grade disease were at increased risk for metastasis (HR 1.41, 95% CI 1.11-1.79). There was a trend toward an increased risk of death in Gleason 9-10 vs 8 cases (HR 1.28, 95% CI 0.98-1.66). The increased risk of death for Gleason 9-10 was mainly observed in patients treated with radical prostatectomy with or without additional radiation therapy (HR 1.74, 95% CI 1.15-2.65). CONCLUSIONS Patients with localized biopsy Gleason 9-10 disease treated with definitive local therapy had worse outcomes than those diagnosed with biopsy Gleason 8 disease. Clinical trials are urgently needed that incorporate newer approaches to Gleason 9-10 cancer.

Elevated IL-8, TNF-α, and MCP-1 in men with metastatic prostate cancer starting androgen-deprivation therapy (ADT) are associated with shorter time to castration-resistance and overall survival.

Chemokines and cytokines have been implicated in progression to castration‐resistant prostate cancer (CRPC).