Fentanyl-detected illicit drug overdose deaths in British Columbia (BC) recently increased dramatically from 13 deaths in 2012 to 90 deaths in 2014, signaling an emerging public health concern. Illicit fentanyl is sold as pills or powders, often mixed with other substances like heroin or oxycodone; reports from coroners suggested that fentanyl was frequently taken unknowingly by people who use drugs. This study aimed to assess the prevalence and characteristics of fentanyl use among clients accessing harm reduction (HR) services in BC. Participants attending HR services at 17 sites across BC were invited to complete an anonymous questionnaire describing drugs they have used within the last 3 days and provide a urine sample to test for fentanyl. Data from eligible participants were analyzed using descriptive, bivariate, and multivariate statistical methods. Surveys from 17 HR sites were received, resulting in analysis of responses from 242 eligible participants. Most participants used multiple substances (median = 3), with crystal meth (59 %) and heroin (52 %) use most frequently reported. Seventy participants (29 %) tested positive for fentanyl, 73 % of whom did not report using fentanyl. Controlling for age, gender, and health authority, reported use of fentanyl (odds ratio (OR) = 6.13, 95 % confidence interval (CI) = [2.52, 15.78], p < 0.001) and crystal methamphetamine (OR = 3.82, 95 % CI = [1.79, 8.63], p < 0.001) use were significantly associated with fentanyl detection. The proportion of those testing positive who did not report knowingly using fentanyl represents a considerable public health concern. The risk of overdose among this vulnerable population highlights the need for targeted HR strategies, such as increased accessibility to naloxone, overdose education, and urine screens.

PURPOSE: To assess modified folinic acid/leucovorin, fluorouracil, irinotecan, oxaliplatin (FOLFIRINOX [mFFX]) versus gemcitabine/nab-paclitaxel (GnP) in de novo metastatic pancreatic ductal adenocarcinoma (PDAC) and explore predictive biomarkers. PATIENTS AND METHODS: Patients were randomly assigned 1:1 to mFFX or GnP with exclusion of germline pathogenic variants in BRCA1/2 or PALB2 . The primary end point was progression-free survival (PFS) between arms with 0.3 significance. The per-protocol (PP) population included patients who received one dose of chemotherapy. Pretreatment biopsies underwent whole-genome/transcriptome sequencing and patient-derived organoid (PDO) development, providing correlate recommendations at a molecular tumor board and outcomes assessed according to RNA signatures (basal-like v classical). RESULTS: Of 160 patients randomly assigned (80 mFFX, 80 GnP), 140 patients were in the PP population (71 mFFX, 69 GnP), with median follow-up of 8.3 months. The median PFS was 4.0 months for mFFX versus 5.3 months for GnP (hazard ratio [HR], 1.37 [95% CI, 0.97 to 1.92]; P = .069) in intention-to-treat. Median overall survival (OS) was 8.5 months with mFFX and 9.7 months with GnP (HR, 1.57 [95% CI, 1.08 to 2.28]; P = .017). Genomic data were generated in 94%, transcriptomes in 74%, and PDOs in 50%. The median PFS for those with basal-like was 3.0 (mFFX) and 5.5 (GnP) months ( P = .17), and classical PDAC was 6.3 (mFFX) versus 5.4 (GnP) months ( P = .36). The median OS in basal-like was 7.5 (mFFX) and 8.9 (GnP) months ( P = .75) versus in classical OS was 9.7 (mFFX) and 13.9 (GnP) months ( P = .047). Overall, 75 (54%) of patients received second-line treatment, 33/75 (44%) correlate-guided. The median time on second-line treatment was only 2.1 months with a median OS of 5.4 months for a correlate-guided choice versus 4.4 months on a standard chemotherapy approach ( P = .45). CONCLUSION: In the phase II Pancreatic Adenocarcinoma Signature Stratification for Treatment-01 (PASS-01) trial population, PFS was similar between GnP and mFFX; however, OS and safety trends favored GnP. The second-line setting appears inadequate to offer precision choices, given the short survival observed.

There is emerging evidence about the predictive role of homologous recombination deficiency (HRD), but this is less defined in gastrointestinal (GI) and thoracic malignancies. We reviewed whole genome (WGS) and transcriptomic (RNA-Seq) data from advanced GI and thoracic cancers in the Personalized OncoGenomics trial (NCT02155621) to evaluate HRD scores and single base substitution (SBS)3, which is associated withBRCA1/2mutations and potentially predictive of defective HRD. HRD scores were calculated by sum of loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions scores. Regression analyses examined the association between HRD and time to progression on platinum (TTPp). We included 223 patients with GI (n = 154) or thoracic (n = 69) malignancies. TTPp was associated with SBS3 (p < 0.01) but not HRD score in patients with GI malignancies, whereas neither was associated with TTPp in thoracic malignancies. Tumors with gBRCA1/2mutations and a somatic second alteration exhibited high SBS3 and HRD scores, but these signatures were also present in several tumors with germline but no somatic second alterations, suggesting silencing of the wild-type allele orBRCA1/2haploinsufficiency. Biallelic inactivation of an HR gene, including loss ofXRCC2andBARD1, was identified inBRCA1/2wild-type HRD tumors and these patients had prolonged response to platinum. Thoracic cases with high HRD score were associated with highRECQL5expression (p ≤ 0.025), indicating another potential mechanism of HRD. SBS3 was more strongly associated with TTPp in patients with GI malignancies and may be complementary to using HRD andBRCAstatus in identifying patients who benefit from platinum therapy.