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1.
Gastroenterology ; 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33524400

RESUMO

BACKGROUND AND AIMS: Homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC), remains poorly defined beyond germline (g) alterations in BRCA1, BRCA2, and PALB2. METHODS: We interrogated whole genome sequencing (WGS) data on 391 patients, including 49 carriers of pathogenic variants (PVs) in gBRCA and PALB2. HRD classifiers were applied to the dataset and included (1) the genomic instability score (GIS) used by Myriad's MyChoice HRD assay; (2) substitution base signature 3 (SBS3); (3) HRDetect; and (4) structural variant (SV) burden. Clinical outcomes and responses to chemotherapy were correlated with HRD status. RESULTS: Biallelic tumor inactivation of gBRCA or PALB2 was evident in 43 of 49 germline carriers identifying HRD-PDAC. HRDetect (score ≥0.7) predicted gBRCA1/PALB2 deficiency with highest sensitivity (98%) and specificity (100%). HRD genomic tumor classifiers suggested that 7% to 10% of PDACs that do not harbor gBRCA/PALB2 have features of HRD. Of the somatic HRDetecthi cases, 69% were attributed to alterations in BRCA1/2, PALB2, RAD51C/D, and XRCC2, and a tandem duplicator phenotype. TP53 loss was more common in BRCA1- compared with BRCA2-associated HRD-PDAC. HRD status was not prognostic in resected PDAC; however in advanced disease the GIS (P = .02), SBS3 (P = .03), and HRDetect score (P = .005) were predictive of platinum response and superior survival. PVs in gATM (n = 6) or gCHEK2 (n = 2) did not result in HRD-PDAC by any of the classifiers. In 4 patients, BRCA2 reversion mutations associated with platinum resistance. CONCLUSIONS: Germline and parallel somatic profiling of PDAC outperforms germline testing alone in identifying HRD-PDAC. An additional 7% to 10% of patients without gBRCA/PALB2 mutations may benefit from DNA damage response agents.

2.
Cancer Med ; 10(3): 1155-1165, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33372414

RESUMO

BACKGROUND: RNA-sequencing-based classifiers can stratify pancreatic ductal adenocarcinoma (PDAC) into prognostically significant subgroups but are not practical for use in clinical workflows. Here, we assess whether histomorphological features may be used as surrogate markers for predicting molecular subgroup and overall survival in PDAC. METHODS: Ninety-six tissue samples from 50 patients with non-resectable PDAC were scored for gland formation, stromal maturity, mucin, necrosis, and neutrophil infiltration. Prognostic PDAC gene expression classifiers were run on all tumors using whole transcriptome sequencing data from the POG trial (NCT02155621). Findings were validated using digital TCGA slides (n = 50). Survival analysis used multivariate Cox proportional-hazards tests and log-rank tests. RESULTS: The combination of low gland formation and low neutrophil infiltration was significantly associated with the poor prognosis PDAC molecular subgroup (basal-like or squamous) and was an independent predictor of shorter overall survival, in both frozen section (n = 47) and formalin-fixed paraffin-embedded (n = 49) tissue samples from POG patients, and in the TCGA samples. This finding held true in the subgroup analysis of primary (n = 17) and metastatic samples (n = 79). The combination of high gland formation and high neutrophils had low sensitivity but high specificity for favorable prognosis subgroups. CONCLUSIONS: The assessment of gland formation and neutrophil infiltration on routine histological sections can aid in prognostication and allow inferences to be made about molecular subtype, which may help guide patient management decisions and contribute to our understanding of heterogeneity in treatment response.

3.
Int J Cancer ; 148(2): 481-491, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32955725

RESUMO

The mixture of epithelial and stromal components in pancreatic ductal adenocarcinoma (PDAC) may confound sequencing-based studies of tumor gene expression. Virtual microdissection has been suggested as a bioinformatics approach to segment the aforementioned components, and subsequent prognostic gene sets have emerged from this research. We examined the prognostic signature from the epithelial gene set of one such study using laser capture microdissected (LCM) epithelial samples. We also examined this gene set in matched stromal samples to determine whether prognostic findings were specific to the epithelium. LCM samples from 48 long-term and 48 short-term PDAC survivors were obtained. The resultant epithelial and stromal components were subjected to direct mRNA quantification using a 49 gene published PDAC classifier. Component-specific unsupervised hierarchical clustering was used to derive groups and survival differences were quantified. Immunohistochemical validation of particular genes was performed in an independent cohort. Clustering in the epithelial component yielded prognostic differences in univariable analysis (P = .02), but those differences were not significant when controlled for other clinicopathologic covariates (P = .06). Clustering in the stromal component yielded prognostic differences that persisted in the presence of other clinicopathologic covariates (P = .0005). Validation of selected genes in the epithelium (KRT6A-negative prognostic [P = .004]) and stroma (LY6D-improved prognostic [P = .01] and CTSV-negative prognostic [P = .0002]) demonstrated statistical independence in multivariable analysis. Although the genes used in this study were originally identified as being representative of the epithelial component of PDAC, their expression in the stroma appears to provide additional information that may aid in improved prognostication.

4.
Cell Rep Med ; 1(8): 100131, 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33294856

RESUMO

Activating KRAS mutations are found in over 90% of pancreatic ductal adenocarcinomas (PDACs), yet KRAS has remained a difficult target to inhibit pharmacologically. Here, we demonstrate, using several human and mouse models of PDACs, rapid acquisition of tumor resistance in response to targeting KRAS or MEK, associated with integrin-linked kinase (ILK)-mediated increased phosphorylation of the mTORC2 component Rictor, and AKT. Although inhibition of mTORC1/2 results in a compensatory increase in ERK phosphorylation, combinatorial treatment of PDAC cells with either KRAS (G12C) or MEK inhibitors, together with mTORC1/2 inhibitors, results in synergistic cytotoxicity and cell death reflected by inhibition of pERK and pRictor/pAKT and of downstream regulators of protein synthesis and cell survival. Relative to single agents alone, this combination leads to durable inhibition of tumor growth and metastatic progression in vivo and increased survival. We have identified an effective combinatorial treatment strategy using clinically viable inhibitors, which can be applied to PDAC tumors with different KRAS mutations.

5.
Can J Gastroenterol Hepatol ; 2020: 5104082, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33299824

RESUMO

Background: Yttrium-90 (Y-90) can be an effective liver-directed therapy for patients with metastatic neuroendocrine tumors (NETs), but population-based data are limited. We characterized the use of Y-90 in NET patients and identified factors associated with response. Methods: We identified 49 patients with metastatic liver-dominant NETs across BC Cancer's six regional centres who received Y-90 between June 2011 and January 2017 in British Columbia, Canada. Baseline characteristics, radiographic responses, and outcomes were summarized. Results: Of the 49 patients who received Y-90, the median age was 56 years (range 21-78), 49% were male, and 94% had an ECOG performance status of 0-1. The primary location of the NET included pancreas (31%), small bowel (41%), large bowel (6%), unknown (14%), and others (12%). 69% of these patients had liver metastases alone, and tumors were graded as G1 (61%), G2 (25%), G3 (2%), and unknown (12%). Prior therapies included surgery (63%), local ablative therapy (25%), somatostatin analogue (69%), and systemic therapy (35%). The median Y-90 dose was 2.2 GBq (range 0.8-3.6), as SIR-spheres (69%) or TheraSpheres (29%). Median time to Y-90 from diagnosis of metastases measured 1.54 years. 88% received segmental Y-90, with 1 (69%), 2 (29%), and 3 (2%) treatments. Y-90 resulted in partial response (53%), stable disease (33%), and progressive disease (12%). Y-90 was well-tolerated, with infrequent grade 3-4 biochemical toxicities (2%) and grade 3 abdominal pain (6%). Longer overall survival (OS) was associated with resection of primary tumor, well-differentiated histology, and low Ki-67. Median OS was 27.2 months (95% CI 8.0-46.5). Conclusions: In our population-based cohort, Y-90 was well-tolerated in patients with metastatic liver-dominant NETs. Prior surgical resection was an important predictor of OS.

6.
Clin Cancer Res ; 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33148671

RESUMO

PURPOSE: Gene fusions are important oncogenic drivers and many are actionable. Whole-genome and transcriptome (WGS and RNA-seq, respectively) sequencing can discover novel clinically relevant fusions. EXPERIMENTAL DESIGN: Using WGS and RNA-seq, we reviewed the prevalence of fusions in a cohort of 570 patients with cancer, and compared prevalence to that predicted with commercially available panels. Fusions were annotated using a consensus variant calling pipeline (MAVIS) and required that a contig of the breakpoint could be constructed and supported from ≥2 structural variant detection approaches. RESULTS: In 570 patients with advanced cancer, MAVIS identified 81 recurrent fusions by WGS and 111 by RNA-seq, of which 18 fusions by WGS and 19 by RNA-seq were noted in at least 3 separate patients. The most common fusions were EML4-ALK in thoracic malignancies (9/69, 13%), and CMTM8-CMTM7 in colorectal cancer (4/73, 5.5%). Combined genomic and transcriptomic analysis identified novel fusion partners for clinically relevant genes, such as NTRK2 (novel partners: SHC3, DAPK1), and NTRK3 (novel partners: POLG, PIBF1). CONCLUSIONS: Utilizing WGS/RNA-seq facilitates identification of novel fusions in clinically relevant genes, and detected a greater proportion than commercially available panels are expected to find. A significant benefit of WGS and RNA-seq is the innate ability to retrospectively identify variants that becomes clinically relevant over time, without the need for additional testing, which is not possible with panel-based approaches.

7.
World J Gastroenterol ; 26(39): 6027-6036, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33132652

RESUMO

BACKGROUND: Over the last decade, multiple agents have demonstrated efficacy for advanced esophagogastric cancer (EGC). Despite the availability of later lines of therapy, there remains limited real-world data about the treatment attrition rates between lines of therapy. AIM: To characterize the use and attrition rates between lines of therapy for patients with advanced EGC. METHODS: We identified patients who received at least one cycle of chemotherapy for advanced EGC between July 1, 2017 and July 31, 2018 across six regional centers in British Columbia (BC), Canada. Clinicopathologic, treatment, and outcomes data were extracted. RESULTS: Of 245 patients who received at least one line of therapy, median age was 66 years (IQR 58.2-72.3) and 186 (76%) were male, Eastern Cooperative Oncology Group (ECOG) performance status 0/1 (80%), gastric vs GEJ (36% vs 64%). Histologies included adenocarcinoma (78%), squamous cell carcinoma (8%), and signet ring (14%), with 31% HER2 positive. 72% presented with de novo disease, and 25% had received previous chemoradiation. There was a high level of treatment attrition, with patients receiving only one line of therapy n = 122, 50%), two lines n = 83, 34%), three lines n = 34, 14%), and four lines n = 6, 2%). Kaplan-Meier analysis demonstrated improved survival with increasing lines of therapy (median overall survival 7.7 vs 16.6 vs 22.8 vs 40.4 mo, P < 0.05). On multivariable Cox regression, improved survival was associated with better baseline ECOG and increased lines of therapy (P < 0.05). CONCLUSION: The steep attrition rates between therapies highlight the unmet need for more efficacious early-line treatment options for patients with advanced EGC.

8.
Mol Genet Genomic Med ; : e1554, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33237632

RESUMO

BACKGROUND: Randomized controlled trials (RCTs) are uncommon in precision oncology. We provide an introduction and illustrative example of matching methods for evaluating precision oncology in the absence of RCTs. We focus on British Columbia's Personalized OncoGenomics (POG) program, which applies whole-genome and transcriptome analysis (WGTA) to inform advanced cancer care. METHODS: Our cohort comprises 230 POG patients enrolled between 2014 and 2015 and matched POG-naive controls. We generated our matched cohort using 1:1 propensity score matching (PSM) and genetic matching prior to exploring survival differences. RESULTS: We find that genetic matching outperformed PSM when balancing covariates. In all cohorts, overall survival did not significantly differ across POG and POG-naive patients (p > 0.05). Stratification by WGTA-informed treatment indicated unmatched survival differences. Patients whose WGTA information led to treatment change were at a reduced hazard of death compared to POG-naive controls in all cohorts, with estimated hazard ratios ranging from 0.33 (95% CI: 0.13, 0.81) to 0.41 (95% CI: 0.17, 0.98). CONCLUSION: These results signal that clinical effectiveness of precision oncology approaches will depend on rates of genomics-informed treatment change. Our study will guide future evaluations of precision oncology and support reliable effect estimation when RCT data are unavailable.

9.
Clin Cancer Res ; 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33051307

RESUMO

PURPOSE: RNA-sequencing-based subtyping of pancreatic ductal adenocarcinoma (PDAC) has been reported by multiple research groups, each using different methodologies and patient cohorts. "Classical" and "basal-like" PDAC subtypes are associated with survival differences, with basal-like tumors associated with worse prognosis. We amalgamated various PDAC subtyping tools to evaluate the potential of such tools to be reliable in clinical practice. EXPERIMENTAL DESIGN: Sequencing data for 574 PDAC tumors was obtained from prospective trials and retrospective public databases. Six published PDAC subtyping strategies (Moffitt regression tools, clustering-based Moffitt, Collisson, Bailey, and Karasinska subtypes) were used on each sample, and results were tested for subtype call consistency and association with survival. RESULTS: Basal-like and classical subtype calls were concordant in 88% of patient samples, and survival outcomes were significantly different (P < 0.05) between prognostic subtypes. Twelve percent of tumors had subtype-discordant calls across the different methods, showing intermediate survival in univariate and multivariate survival analyses. Transcriptional profiles compatible with that of a hybrid subtype signature were observed for subtype-discordant tumors, in which classical and basal-like genes were concomitantly expressed. Subtype-discordant tumors showed intermediate molecular characteristics, including subtyping gene expression (P < 0.0001) and mutant KRAS allelic imbalance (P < 0.001). CONCLUSIONS: Nearly 1 in 6 patients with PDAC have tumors that fail to reliably fall into the classical or basal-like PDAC subtype categories, based on two regression tools aimed toward clinical practice. Rather, these patient tumors show intermediate prognostic and molecular traits. We propose close consideration of the non-binary nature of PDAC subtypes for future incorporation of subtyping into clinical practice.

10.
Clin Cancer Res ; 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020056

RESUMO

PURPOSE: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of solid tumors with dramatic and durable responses seen across multiple tumor types. However, identifying patients who will respond to these drugs remains challenging, particularly in the context of advanced and previously treated cancers. EXPERIMENTAL DESIGN: We characterized fresh tumor biopsies from a heterogeneous pan-cancer cohort of 98 patients with metastatic predominantly pretreated disease through the Personalized OncoGenomics program at BC Cancer (Vancouver, Canada) using whole genome and transcriptome analysis (WGTA). Baseline characteristics and follow-up data were collected retrospectively. RESULTS: We found that tumor mutation burden, independent of mismatch repair status, was the most predictive marker of time to progression (P = 0.007), but immune-related CD8+ T-cell and M1-M2 macrophage ratio scores were more predictive for overall survival (OS; P = 0.0014 and 0.0012, respectively). While CD274 [programmed death-ligand 1 (PD-L1)] gene expression is comparable with protein levels detected by IHC, we did not observe a clinical benefit for patients with this marker. We demonstrate that a combination of markers based on WGTA provides the best stratification of patients (P = 0.00071, OS), and also present a case study of possible acquired resistance to pembrolizumab in a patient with non-small cell lung cancer. CONCLUSIONS: Interpreting the tumor-immune interface to predict ICI efficacy remains challenging. WGTA allows for identification of multiple biomarkers simultaneously that in combination may help to identify responders, particularly in the context of a heterogeneous population of advanced and previously treated cancers, thus precluding tumor type-specific testing.

11.
Am J Clin Oncol ; 43(11): 788-791, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32868523

RESUMO

INTRODUCTION: With an increasing number of systemic therapy options for hepatocellular carcinoma (HCC), optimal sequencing is an important consideration. There remains limited real-world data about the eligibility of patients for second-line therapies in advanced HCC. We characterized real-world eligibility and use of second-line therapies post sorafenib. MATERIALS AND METHODS: We identified all patients with advanced HCC who received ≥1 cycle of first-line sorafenib between January 1, 2014 and December 31, 2017 in British Columbia, Canada. All patients were Child-Pugh class A for initiation of sorafenib. Baseline characteristics and clinical outcomes were reviewed. Eligibility for second-line therapy was determined using the RESORCE and CELESTIAL study entry criteria. RESULTS: Of 144 patients with advanced HCC who received ≥1 cycle of first-line sorafenib, median age was 65.3 years (range, 32.2 to 83.4 y) and 85% were male. Median duration of sorafenib was 2.6 months. Twelve patients (8%) received second-line treatment but 37 patients (26%) were eligible for second-line therapies based on inclusion criteria from recent registration trials. Primary reasons for ineligibility included ECOG ≥2 (58%), and deterioration to Child-Pugh status B (28%). On Cox regression, improved survival was associated with better ECOG and recurrent disease after initial locoregional therapy. Eligibility for second-line treatment was associated with improved median overall survival from end of first-line treatment (8.5 vs. 5.1 mo; P<0.01). CONCLUSIONS: Only a minority of real-world patients with advanced HCC were eligible for second-line therapies based on trial criteria. Given the high rate of attrition, improved first-line treatment options are urgently needed.

12.
Clin Cancer Res ; 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958704

RESUMO

PURPOSE: With the rising incidence of early-onset pancreatic cancer (EOPC), molecular characteristics that distinguish early-onset pancreatic ductal adenocarcinoma (PDAC) tumors from those arising at a later age are not well understood. EXPERIMENTAL DESIGN: We performed bioinformatic analysis of genomic and transcriptomic data generated from 269 advanced (metastatic or locally advanced) and 277 resectable PDAC tumor samples. Patient samples were stratified into EOPC (age of onset ≤55 years; n = 117), intermediate (age of onset 55-70 years; n = 264), and average (age of onset ≥70 years; n = 165) groups. Frequency of somatic mutations affecting genes commonly implicated in PDAC, as well as gene expression patterns, were compared between EOPC and all other groups. RESULTS: EOPC tumors showed significantly lower frequency of somatic single-nucleotide variant (SNV)/insertions/deletions (indel) in CDKN2A (P = 0.0017), and were more likely to achieve biallelic mutation of CDKN2A through homozygous copy loss as opposed to heterozygous copy loss coupled with a loss-of-function SNV/indel mutation, the latter of which was more common for tumors with later ages of onset (P = 1.5e-4). Transcription factor forkhead box protein C2 (FOXC2) was significantly upregulated in EOPC tumors (P = 0.032). Genes significantly correlated with FOXC2 in PDAC samples were enriched for gene sets related to epithelial-to-mesenchymal transition (EMT) and included VIM (P = 1.8e-8), CDH11 (P = 6.5e-5), and CDH2 (P = 2.4e-2). CONCLUSIONS: Our comprehensive analysis of sequencing data generated from a large cohort of PDAC patient samples highlights a distinctive pattern of biallelic CDKN2A mutation in EOPC tumors. Increased expression of FOXC2 in EOPC, with the correlation between FOXC2 and EMT pathways, represents novel molecular characteristics of EOPC.

13.
Gut ; 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32933947

RESUMO

OBJECTIVE: To describe the clinical, pathological and genomic characteristics of pancreatic cancer with DNA mismatch repair deficiency (MMRD) and proficiency (MMRP). DESIGN: We identified patients with MMRD and MMRP pancreatic cancer in a clinical cohort (N=1213, 519 with genetic testing, 53 with immunohistochemistry (IHC)) and a genomic cohort (N=288 with whole-genome sequencing (WGS)). RESULTS: 12 out of 1213 (1.0%) in the clinical cohort were MMRD by IHC or WGS. Of the 14 patients with Lynch syndrome, 3 (21.4%) had an MMRP pancreatic cancer by IHC, and 4 (28.6%) were excluded because tissue was unavailable for testing. MMRD cancers had longer overall survival after surgery (weighted HR after coarsened exact matching 0.11, 95% CI 0.02 to 0.78, p=0.001). One patient with an unresectable MMRD cancer has an ongoing partial response 3 years after starting treatment with PD-L1/CTLA-4 inhibition. This tumour showed none of the classical histopathological features of MMRD. 9 out of 288 (3.1%) tumours with WGS were MMRD. Despite markedly higher tumour mutational burden and neoantigen loads, MMRD cancers were significantly less likely to have mutations in usual pancreatic cancer driver genes like KRAS and SMAD4, but more likely to have mutations in genes that drive cancers with microsatellite instability like ACV2RA and JAK1. MMRD tumours were significantly more likely to have a basal-like transcriptional programme and elevated transcriptional markers of immunogenicity. CONCLUSIONS: MMRD pancreatic cancers have distinct clinical, pathological and genomic profiles. Patients with MMRD pancreatic cancer should be considered for basket trials targeting enhanced immunogenicity or the unique genomic drivers in these malignancies.

14.
Oncologist ; 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32852072

RESUMO

BACKGROUND: Neuregulin 1 (NRG1) fusions, which activate ErbB signaling, are rare oncogenic drivers in multiple tumor types. Afatinib is a pan-ErbB family inhibitor that may be an effective treatment for NRG1 fusion-driven tumors. PATIENTS AND METHODS: This report summarizes pertinent details, including best tumor response to treatment, for six patients with metastatic NRG1 fusion-positive tumors treated with afatinib. RESULTS: The six cases include four female and two male patients who ranged in age from 34 to 69 years. Five of the cases are patients with lung cancer, including two patients with invasive mucinous adenocarcinoma and three patients with nonmucinous adenocarcinoma. The sixth case is a patient with colorectal cancer. NRG1 fusion partners for the patients with lung cancer were either CD74 or SDC4. The patient with colorectal cancer harbored a novel POMK-NRG1 fusion and a KRAS mutation. Two patients received afatinib as first- or second-line therapy, three patients received the drug as third- to fifth-line therapy, and one patient received afatinib as fifteenth-line therapy. Best response with afatinib was stable disease in two patients (duration up to 16 months when combined with local therapies) and partial response (PR) of >18 months in three patients, including one with ongoing PR after 27 months. The remaining patient had a PR of 5 months with afatinib 40 mg/day, then another 6 months after an increase to 50 mg/day. CONCLUSION: This report reviews previously published metastatic NRG1 fusion-positive tumors treated with afatinib and summarizes six previously unpublished cases. The latter include several with a prolonged response to treatment (>18 months), as well as the first report of efficacy in NRG1 fusion-positive colorectal cancer. This adds to the growing body of evidence suggesting that afatinib can be effective in patients with NRG1 fusion-positive tumors. KEY POINTS: NRG1 fusions activate ErbB signaling and have been identified as oncogenic drivers in multiple solid tumor types. Afatinib is a pan-ErbB family inhibitor authorized for the treatment of advanced non-small cell lung cancer that may be effective in NRG1 fusion-driven tumors. This report summarizes six previously unpublished cases of NRG1 fusion-driven cancers treated with afatinib, including five with metastatic lung cancer and one with metastatic colorectal cancer. Several patients showed a prolonged response of >18 months with afatinib treatment. This case series adds to the evidence suggesting a potential role for afatinib in this area of unmet medical need.

15.
J Oncol Pharm Pract ; : 1078155220951845, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32847480

RESUMO

INTRODUCTION: Carcinogenesis is driven by an array of complex genomic patterns; these patterns can render an individual resistant or sensitive to certain chemotherapy agents. The Personalized Oncogenomics (POG) project at BC Cancer has performed integrative genomic analysis of whole tumour genomes and transcriptomes for over 700 patients with advanced cancers, with an aim to predict therapeutic sensitivities. The aim of this study was to utilize the POG genomic data to evaluate a discrete set of biomarkers associated with chemo-sensitivity or-resistance in advanced stage breast and colorectal cancer POG patients. METHODS: This was a retrospective multi-centre analysis across all BC CANCER sites. All breast and colorectal cancer patients enrolled in the POG program between July 1, 2012 and November 30, 2016 were eligible for inclusion. Within the breast cancer population, those treated with capecitabine, paclitaxel, and everolimus were analyzed, and for the colorectal cancer patients, those treated with capecitabine, bevacizumab, irinotecan, and oxaliplatin were analyzed. The expression levels of the selected biomarkers of interest (EPHB4, FIGF, CD133, DICER1, DPYD, TYMP, TYMS, TAP1, TOP1, CKDN1A, ERCC1, GSTP1, BRCA1, PTEN, ABCB1, TLE3, and TXNDC17) were reported as mRNA percentiles. RESULTS: For the breast cancer population, there were 32 patients in the capecitabine cohort, 15 in the everolimus cohort, and 12 in the paclitaxel cohort. For the colorectal cancer population, there were 29 patients in the bevacizumab cohort, 12 in the oxaliplatin cohort, 29 in the irinotecan cohort, and 6 in the capecitabine cohort. Of the biomarkers evaluated, the strongest associations were found between Bevacizumab-based therapy and DICER1 (P = 0.0445); and between capecitabine therapy and TYMP (P = 0.0553). CONCLUSIONS: Among breast cancer patients, higher TYMP expression was associated with sensitivity to capecitabine. Among colorectal cancer patients, higher DICER1 expression was associated with sensitivity to bevacizumab-based therapy. This study supports further assessment of the potential predictive value of mRNA expression of these genomic biomarkers.

16.
Mol Cancer Ther ; 19(9): 1889-1897, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32518206

RESUMO

Next-generation sequencing of solid tumors has revealed variable signatures of immunogenicity across tumors, but underlying molecular characteristics driving such variation are not fully understood. Although expression of endogenous retrovirus (ERV)-containing transcripts can provide a source of tumor-specific neoantigen in some cancer models, associations between ERV levels and immunogenicity across different types of metastatic cancer are not well established. We performed bioinformatics analysis of genomic, transcriptomic, and clinical data across an integrated cohort of 199 patients with metastatic breast, colorectal, and pancreatic ductal adenocarcinoma tumors. Within each cancer type, we identified a subgroup of viral mimicry tumors in which increased ERV levels were coupled with transcriptional signatures of autonomous antiviral response and immunogenicity. In addition, viral mimicry colorectal and pancreatic tumors showed increased expression of DNA demethylation gene TET2 Taken together, these data demonstrate the existence of an ERV-associated viral mimicry phenotype across three distinct metastatic cancer types, while indicating links between ERV abundance, epigenetic dysregulation, and immunogenicity.

17.
Clin Cancer Res ; 26(17): 4599-4605, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32571791

RESUMO

PURPOSE: BRAF V600E mutations portend poor prognosis in metastatic colorectal cancer (mCRC); however, the true prevalence and prognosis are unknown, as unwell patients may not undergo BRAF sequencing. EXPERIMENTAL DESIGN: We reviewed a population-based cohort of 1,898 patients with colorectal cancer that underwent reflexive IHC mismatch repair (MMR) and BRAF V600E testing. Outcomes among IHC-detected BRAF V600E mCRC (BRAF IHC) were compared with patients with next-generation sequencing (NGS)-identified BRAF V600E-mutated mCRC from two institutions (BRAF NGS) with patients spanning from 2004 to 2018. RESULTS: All-stage population prevalence of BRAF V600E was 12.5% (238/1,898) and did not differ between early and metastatic stages (P = 0.094). Prevalence among mCRC was 10.6% (61/575), of whom 51 (83.6%) were referred to oncology and 26 (42.6%) had NGS testing. BRAF IHC had worse median overall survival (mOS) than BRAF NGS [5.5 vs. 20.4 months; HR, 2.90; 95% confidence interval (CI), 1.89-4.45; P < 0.0001], which persisted in multivariate analysis (P < 0.0001). Across a combined NGS and IHC cohort, BRAF V600E tumors with deficient MMR showed worse mOS compared with MMR proficient tumors (8.9 vs. 17.2 months; HR, 1.46; 95% CI, 0.96-2.27; P = 0.043). In this combined cohort, first-line progression-free survival was 5.9 months, with minimal differences between regimens. Within the population-based cohort, attrition between treatment lines was high with only 60.7% receiving first-line chemotherapy and 26.2% receiving second line. CONCLUSIONS: Patients with BRAF V600E-mutated mCRC have a worse prognosis than previously suggested, potentially arising from referral bias for testing. High attrition between lines of therapy suggests efficacious therapies need to be prioritized early for patients to benefit.

18.
Cancer Med ; 9(11): 4004-4013, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32255556

RESUMO

BACKGROUND: Recent guidelines recommend consideration of germline testing for all newly diagnosed pancreatic ductal adenocarcinoma (PDAC). The primary aim of this study was to determine the burden of hereditary cancer susceptibility in PDAC. A secondary aim was to compare genetic testing uptake rates across different modes of genetic counselling. PATIENTS AND METHODS: All patients diagnosed with PDAC in the province of British Columbia, Canada referred to a population-based hereditary cancer program were eligible for multi-gene panel testing, irrespective of cancer family history. Any healthcare provider or patients themselves could refer. RESULTS: A total of 305 patients with PDAC were referred between July 2016 and January 2019. Two hundred thirty-five patients attended a consultation and 177 completed index germline genetic testing. 25/177 (14.1%) of unrelated patients had a pathogenic variant (PV); 19/25 PV were in known PDAC susceptibility genes with cancer screening or risk-reduction implications. PDAC was significantly associated with PV in ATM (OR, 7.73; 95% CI, 3.10 to 19.33, P = 6.14E-05) when comparing age and gender and ethnicity-matched controls tested on the same platform. The overall uptake rate for index testing was 59.2% and was significantly higher with 1-on-1 consultations and group consultations compared to telehealth consultations (88.9% vs 82.9% vs 61.8%, P < .001). CONCLUSION: In a prospective clinic-based cohort of patients with PDAC referred for testing irrespective of family history, germline PV were detected in 14.1%. PV in ATM accounted for half of all PVs and were significantly associated with PDAC. These findings support recent guidelines and will guide future service planning in this population.

19.
Am J Clin Oncol ; 43(7): 484-490, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32251122

RESUMO

OBJECTIVES: SLC-0111 is an ureido-substituted benzenesulfonamide small molecule inhibitor of carbonic anhydrase IX. The objectives of this first-in-human Phase 1 study were to determine the safety and tolerability of SLC-0111 in patients with advanced solid tumors and to establish the recommended Phase 2 dose for future clinical investigations. MATERIALS AND METHODS: Using a 3+3 design, dose escalation started at 500 mg oral daily dosing of SLC-0111 in cohort 1 and increased to 1000 and 2000 mg in cohorts 2 and 3. Drug-related adverse events (AEs) were monitored to determine safety and tolerability. Pharmacokinetic analyses assessed plasma concentrations of single and repeated doses of SLC-0111. RECIST 1.1 criteria were used to assess disease progression. RESULTS: No dose-limiting toxicities were reported and patients dosed at ≤1000 mg exhibited fewer drug-related AEs ≥ grade 3 and fewer AEs such as nausea and vomiting, compared with the 2000-mg cohort. Forty-one percent of patients experienced dose interruptions or discontinuation and the majority (71%) of these occurred in the 2000-mg cohort. Mean Cmax and AUC(0-24) values for single doses were similar at the 1000-mg and 2000-mg dose levels. Mean Tmax and T1/2 values of SLC-0111 were similar after single and repeated dosing. Power-law analysis of Cmax and AUC0-24 showed that exposure to SLC-0111 was generally dose proportional. No objective responses were observed, but stable disease >24 weeks was observed in 2 patients. CONCLUSIONS: SLC-0111 was safe in patients with previously treated, advanced solid tumors. The safety and pharmacokinetic data support 1000 mg/d as the recommended phase 2 dose for SLC-0111.


Assuntos
Antineoplásicos/uso terapêutico , Anidrase Carbônica IX/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Antígenos de Neoplasias , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
20.
Br J Cancer ; 122(8): 1158-1165, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32147671

RESUMO

BACKGROUND: The majority of patients with advanced gastrointestinal stromal tumours (GISTs) develop resistance to imatinib and sunitinib, the standard of care for these patients. This study evaluated the combination of buparlisib, an oral phosphoinositide 3-kinase (PI3K) inhibitor, with imatinib in patients with advanced GIST, who have failed prior therapy with imatinib and sunitinib. METHODS: This Phase 1b, multicentre, open-label study aimed to determine the maximum tolerated dose (MTD) and/or a recommended Phase 2 dose of buparlisib in combination with 400 mg of imatinib through a dose-escalation part and a dose-expansion part, and also evaluated the clinical profile of the combination. RESULTS: Sixty patients were enrolled, including 25 in the dose-escalation part and 35 in the dose-expansion part. In the combination, MTD of buparlisib was established as 80 mg. No partial or complete responses were observed. The estimated median progression-free survival was 3.5 months in the expansion phase. Overall, 98.3% of patients had treatment-related adverse events (AEs), including 45% with grade 3 or 4 AEs. CONCLUSIONS: Buparlisib in combination with imatinib provided no additional benefit compared with currently available therapies. Due to the lack of objective responses, further development of this combination was not pursued for third-line/fourth-line advanced/metastatic GIST. TRIAL REGISTRATION NUMBER: NCT01468688.

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