Tumor clone dynamics in lethal prostate cancer Carreira, Suzanne; Romanel, Alessandro; Goodall, Jane ...
Science translational medicine,
2014-Sep-17, Letnik:
6, Številka:
254
Journal Article
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It is unclear whether a single clone metastasizes and remains dominant over the course of lethal prostate cancer. We describe the clonal architectural heterogeneity at different stages of disease ...progression by sequencing serial plasma and tumor samples from 16 ERG-positive patients. By characterizing the clonality of commonly occurring deletions at 21q22, 8p21, and 10q23, we identified multiple independent clones in metastatic disease that are differentially represented in tissue and circulation. To exemplify the clinical utility of our studies, we then showed a temporal association between clinical progression and emergence of androgen receptor (AR) mutations activated by glucocorticoids in about 20% of patients progressing on abiraterone and prednisolone or dexamethasone. Resistant clones showed a complex dynamic with temporal and spatial heterogeneity, suggesting distinct mechanisms of resistance at different sites that emerged and regressed depending on treatment selection pressure. This introduces a management paradigm requiring sequential monitoring of advanced prostate cancer patients with plasma and tumor biopsies to ensure early discontinuation of agents when they become potential disease drivers.
While most testicular germ cell tumours (TGCTs) exhibit exquisite sensitivity to platinum chemotherapy, ~10% are platinum resistant. To gain insight into the underlying mechanisms, we undertake whole ...exome sequencing and copy number analysis in 40 tumours from 26 cases with platinum-resistant TGCT, and combine this with published genomic data on an additional 624 TGCTs. We integrate analyses for driver mutations, mutational burden, global, arm-level and focal copy number (CN) events, and SNV and CN signatures. Albeit preliminary and observational in nature, these analyses provide support for a possible mechanistic link between early driver mutations in RAS and KIT and the widespread copy number events by which TGCT is characterised.
Several definitions have attempted to stratify metastatic castrate-sensitive prostate cancer (mCSPC) into low and high-volume states. However, at this time, comparison of these definitions is ...limited. Here we aim to compare definitions of metastatic volume in mCSPC with respect to clinical outcomes and mutational profiles.
We performed a retrospective review of patients with biochemically recurrent or mCSPC whose tumors underwent somatic targeted sequencing. 294 patients were included with median follow-up of 58.3 months. Patients were classified into low and high-volume disease per CHAARTED, STAMPEDE, and two numeric (≤3 and ≤5) definitions. Endpoints including radiographic progression-free survival (rPFS), time to development of castration resistance (tdCRPC), and overall survival (OS) were evaluated with Kaplan-Meier survival curves and log-rank test. The incidence of driver mutations between definitions were compared.
Median OS and tdCRPC were shorter for high-volume than low-volume disease for all four definitions. In the majority of patients (84.7%) metastatic volume classification did not change across all four definitions. High volume disease was significantly associated with worse OS for all four definitions (CHAARTED: HR 2.89; p < 0.01, STAMPEDE: HR 3.82; p < 0.01, numeric ≤3: HR 4.67; p < 0.01, numeric ≤5: HR 3.76; p < 0.01) however, were similar for high (p = 0.95) and low volume (p = 0.79) disease across all four definitions. Those with discordant classification tended to have more aggressive clinical behavior and mutational profiles. Patients with low-volume disease and TP53 mutation experienced a more aggressive course with rPFS more closely mirroring high-volume disease.
The spectrum of mCSPC was confirmed across four different metastatic definitions for clinical endpoints and genetics. All definitions were generally similar in classification of patients, outcomes, and genetic makeup. Given these findings, the simplicity of numerical definitions might be preferred, especially when integrating metastasis directed therapy. Incorporation of tumor genetics may allow further refinement of current metastatic definitions.
Abstract Abiraterone acetate is a novel CYP17A1 inhibitor demonstrated to prolong survival in castration-resistant prostate cancer (CRPC). This review explores key stages in the almost 20-year ...history of abiraterone acetate׳s development, starting with a program aiming to develop inhibitors of androgen synthesis at the Institute of Cancer Research, London. Clinical development was initially slow owing to insufficient data supporting targeting of androgen synthesis as a therapeutic approach in CRPC and safety concerns of adrenocortical insufficiency from suppression of cortisol. Regulatory authorities approved abiraterone acetate in 2011 after a survival benefit was demonstrated when given in combination with prednisone as compared with prednisone alone in docetaxel-treated men. Licensing approval extended to include chemotherapy-naive patients with CRPC in 2012 following a significant increase in radiographic progression-free survival. Ongoing research focuses on identifying predictive biomarkers and understanding mechanisms of resistance to improve its administration.
5082
Background: Enrichment of germline PVs in metastatic castration resistant prostate cancer (mCRPC), compared to localized disease, has directly informed genetic testing guidelines. The prevalence ...and prognostic/predictive associations of such variants are not well characterized in the mHSPC state, in particular the effect of susceptibility mutations related to DNA damage and repair (DDR) pathways. Methods: We performed whole exome sequencing of germline DNA derived from whole blood available from patients (pts) in the phase III CHAARTED trial (NCT00309985) of androgen deprivation therapy (ADT) versus ADT plus docetaxel (ADT+D). After filtering for low coverage, variant annotation and effect prediction, PVs from a curated list of 588 prostate cancer-associated genes were reviewed. The prognostic effect of PVs was evaluated within each treatment arm. Endpoints of time to CRPC (ttCRPC), time to clinical progression (ttClinPD), and overall survival (OS) were estimated by Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated by Cox models evaluating association of endpoints with biomarkers/arm. Multivariable analysis adjusted for metastatic timing and volume. Results: Of 137 pts, 135 had unique germline exomes that passed downstream analysis. Most pts had synchronous (66.7%) and high-volume (62.2%) disease. This biomarker cohort showed benefit of adding docetaxel to ADT (ttCRPC: HR 0.55, 95% CI 0.37-0.82; OS: HR 0.68, 95% CI 0.44-1.07). In total, 61 PVs were detected; 49 pts (36.3%) harbored at least 1 PV in 41 different genes. The most frequently-mutated gene was BRCA2 (6.67%). In addition, PVs were found in DDR-associated genes including PALB2 (1.48%), CHEK2 (1.48%), BRCA1 (0.74%) and PMS2 (0.74%) for an overall prevalence of 11.1% (15/135). Pts with BRCA2 PV on ADT alone had shorter ttCRPC compared with men without the PV (UVA: HR 2.67, 95% CI 0.93-7.63, log rank p=0.057; MVA: HR 2.59, 95% CI 0.91-7.39, p=0.074). There was no evidence of a difference in the ADT+D arm (UVA: HR 1.00, 95% CI 0.31-3.25, log rank p=0.1). Supportive data was observed for ttClinPD in ADT arm (HR 2.85, 95% CI 1.01-8.08, log rank p=0.04). Metastatic volume and timing were not significantly associated with germline BRCA1/2 or DDR PVs. Conclusions: The prevalence of germline BRCA1/2 and DDR PVs in mHSPC is similar to mCRPC and BRCA2 PV may confer worse outcomes on ADT alone. This supports the need for genetic testing at diagnosis of mHSPC. Table: see text
Pancreaticoduodenectomy is the standard treatment for localised neoplasms of the pancreatic head. The operation can be performed safely in specialist units but good outcome is compromised if ...postoperative blood flow to the liver and biliary tree is inadequate. Coeliac artery occlusion with blood supply to the liver arising from the superior mesenteric artery via the gastroduodenal artery is difficult to recognise, especially intraoperatively. Recognition of absent hepatic artery pulsation after occlusion of the gastroduodenal artery opens a dilemma: should the resection be abandoned or should vascular reconstruction be undertaken, adding risk to an already complex procedure? We describe two cases with a resectable pancreatic endocrine tumour in which coeliac artery occlusion caused by median arcuate ligament compression was identified from cross-sectional imaging and reconstructions. We highlight two different strategies to correct the vascular insufficiency and allow safe pancreatic resection.
Patients diagnosed with advanced prostate cancer starting long term ADT follow a highly variable clinical course. Treatment intensification improves outcome overall, but without biomarkers we ...overtreat some subgroups and we are unable to direct the most effective treatment strategy to others. I developed a protocol for biomarker discovery and evaluation, leveraging the STAMPEDE trial, in which donated clinical samples are associated with prospective clinical data. Genomic copy number alterations commonly occur in prostate cancer, however the clinical implication of copy number change in advanced HSPC is unknown. I generated low coverage WGS data from FFPE tissue from participants in the control group of STAMPEDE and copy number profiled 688 tumour regions from 300 participants to describe the association between the burden of copy number alteration and outcome. The burden of copy number alteration positively associated with radiologically-evident distant metastases at diagnosis (P value=0.00006) and showed a non-linear relationship with clinical outcome on univariable and multivariable analysis, characterised by a sharp increase in the relative risk of progression (P value=0.003) and death (P value=0.045) for each unit increase, stabilising into more modest increases with higher burdens. This association between copy number burden and outcome was similar in each of the metastatic states. Copy number loss occurred significantly more frequently than gain at the lowest copy number burden quartile (q=4.1X10-6). Loss of segments in chromosome 5q21-22 and gains at 8q21-24, respectively including CHD1 and cMYC, occurred more frequently in cases with higher copy number alteration. Intra-patient burden of copy number alteration variance associated with increased risk of distant metastases (Kruskal-Wallis test P value=0.037). In conclusion, copy number alteration at diagnosis in advanced prostate cancer associates with increased risk of metastases and accumulation of a limited number of copy number alterations associates with most of the increased risk of disease progression and death.
5088 Background: The landscape and clinical impact of genomic variants in mHSPC are incompletely understood. We have shown that deleterious germline BRCA2 alterations (alts) associate with shorter ...time to castration resistant prostate cancer (TTCRPC) on androgen deprivation therapy (ADT), but not on ADT plus docetaxel (ADT+D) (ASCO 2023). Somatic variation from tissue of patients (pts) with mHSPC is not well characterized and may influence therapeutic outcomes. Methods: We performed whole exome sequencing of HSPC specimens obtained at initial diagnosis and germline DNA from whole blood from pts in the CHAARTED trial (NCT00309985) of ADT vs ADT+D. Somatic single nucleotide variants (SNV) and allele-specific copy number alts (CNAs) were identified, including estimation of tumor mutational burden (TMB) and copy number burden (CNB). Prognostic effects were evaluated in both arms. Loss of selected tumor suppressor genes was defined by monoallelic or biallelic loss. TTCRPC and overall survival (OS) were estimated by Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated by Cox models. Results: After quality control, 68 tumor-normal cases were analyzed. The majority of pts had synchronous (51.5%) and high volume (58.8%) disease. Most frequent somatic SNVs were TP53 (33.8%), PTEN (7.4%), PIK3CA (5.9%) and SPOP (5.9%). AR amplification was uncommon (4.4%), however frequent MYC gain (60.3%) was seen as well as monoallelic deletion of NKX3-1, TP53, PTEN and BRCA2. Whole genome doubling occurred in 14.7%. Median TMB and CNB were 4.7 mut/Mb and 9.1%, respectively. CNB was elevated in synchronous (p=0.01) and high volume (p=0.046) disease. CNB greater than median was associated with shorter TTCRPC in the overall cohort (HR 2.06, 95%CI 1.13-3.75, p=0.015) and ADT+D arm (HR 2.98, 95%CI 1.17-7.58, p=0.016). The effect in the overall cohort was reduced after adjustment for volume and presentation (HR 1.72, p=0.091). A compounding effect of PTEN and TP53 alts was seen in the ADT arm where median TTCRPC for wild-type (WT), 1-gene hit, 2-gene hit was 19.6 mos, 8.5 mos, 6.3 mos, respectively. The median OS of WT vs 1-hit/2-hit loss was 47.1 mos vs 26.8 mos (HR 2.05, 95% CI 0.90-4.68, p=0.087). Similar differences in TTCRP and OS by PTEN/ TP53 status were not observed with ADT+D. Conclusions: The genomic landscape of mHSPC is characterized by frequent alts in putative drivers known to be enriched in mCRPC (Table). We observed a low rate of genomic instability and AR amplification/mutation similar to non-metastatic HSPC. Concordant with the STAMPEDE trial, greater CNB confers a higher risk of progression. Combined tumor suppressor gene alts associate with prognosis in mHSPC, which may differ by therapy intensification. Table: see text
Abstract Background Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) occurs frequently in prostate cancers. Preclinical evidence suggests that activation of PI3K/AKT signaling ...through loss of PTEN can result in resistance to hormonal treatment in prostate cancer. Objective To explore the antitumor activity of abiraterone acetate (abiraterone) in castration-resistant prostate cancer (CRPC) patients with and without loss of PTEN protein expression. Design, setting, and participants We retrospectively identified patients who had received abiraterone and had hormone-sensitive prostate cancer (HSPC) and/or CRPC tissue available for PTEN immunohistochemical analysis. Outcome measurements and statistical analysis The primary end point was overall survival from initiation of abiraterone treatment. Relationship with outcome was analyzed using multivariate Cox regression and log-rank analyses. Results and limitations A total of 144 patients were identified who had received abiraterone post-docetaxel and had available tumor tissue. Overall, loss of PTEN expression was observed in 40% of patients. Matched HSPC and CRPC tumor biopsies were available for 41 patients. PTEN status in CRPC correlated with HSPC in 86% of cases. Loss of PTEN expression was associated with shorter median overall survival (14 vs 21 mo; hazard ratio HR: 1.75; 95% confidence interval CI, 1.19–2.55; p = 0.004) and shorter median duration of abiraterone treatment (24 vs 28 wk; HR: 1.6; 95% CI, 1.12–2.28; p = 0.009). PTEN protein loss, high lactate dehydrogenase, and the presence of visceral metastases were identified as independent prognostic factors in multivariate analysis. Conclusions Our results indicate that loss of PTEN expression was associated with worse survival and shorter time on abiraterone treatment. Further studies in larger and prospective cohorts are warranted. Patient summary PTEN is a protein often lost in prostate cancer cells. In this study we evaluated if prostate cancers that lack this protein respond differently to treatment with abiraterone acetate. We demonstrated that the survival of patients with loss of PTEN is shorter than patients with normal PTEN expression.
For the Commission, we established four working groups, each of which examined a different aspect of prostate cancer: epidemiology and future projected trends in cases, the diagnostic pathway, ...treatment, and management of advanced disease, the main problem for most men diagnosed with prostate cancer worldwide. ...novel methods of empowering patients, such as cloud-based medical record systems, should be exploited to enable doctors and patients to make informed, personalised case-management plans. Linking cloud-based records to artificial intelligence systems could allow access to context-sensitive, up-to-date advice for both patients and health professionals, and could be used to drive evidence-based change in all settings. ...resource-sensitive guidelines should be implemented to maximise the effect of available therapies, especially surgery and radiotherapy, use of which is often limited in LMICs.
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