A Systematic Review and Meta-Analysis of the Effectiveness of Neuroprotectants for Paclitaxel-Induced Peripheral Neuropathy

10.3389/fonc.2021.763229Frontiers in Oncology11763229

Abstract P4-06-13: <i>BRCA1/2</i> mutations identified by screening a large unselected breast cancer cohort in Sweden

Abstract Background Treatment options for BRCA1/2 breast cancer include new therapeutic agents, such as poly (ADP-ribose) polymerase (PARP) inhibitors, which selectively target BRCA defective cells. According to current Swedish screening guidelines, eligibility for clinical BRCA1/2 hereditary mutation testing is mainly based on family history of breast or ovarian cancer and early age onset. We aimed at examining the prevalence and characteristics of BRCA1/2 mutation carriers by screening a large unselected breast cancer cohort in Sweden, and comparing our results with BRCA mutation carriers already identified through the national BRCA testing program. Methods Germline DNA (blood) from 5122 women diagnosed with breast cancer between 2001-2008 (LIBRO1 study) were analysed for BRCA1/2 mutations by targeted sequencing (next generation sequencing, NGS), of which 5099 samples passed quality control. All patients provided informed consent. Information on patient and tumor characteristics was collected from the LIBRO1 database. Clinical BRCA testing information was obtained from the BRCA Lab (Lund University, Sweden), which carries out mutation screening for all oncogenetic clinics in Sweden. Multinomial logit models were used to compare tumor characteristics of BRCA1 and BRCA2 versus non-BRCA carriers. Multivariable logistic regression models were used to examine for differences between BRCA carriers identified through the national BRCA testing program and additional BRCA carriers found by sequencing the entire study population (not tested or not identified under current screening guidelines). Results In total, 92 (1.8%) BRCA1/2 mutation carriers were identified retrospectively by NGS. The prevalence of BRCA1/2 mutations was 1.6% (38/2363) between years 2001-2004; and 2.0% (54/2736) between years 2005-2008. After controlling for age and year of diagnosis, BRCA2 mutation carriers were in general similar to non-BRCA carriers regarding tumor characteristics (hormone receptor status, grade, tumor size and proliferation index), except for nodal involvement. BRCA1 mutation carriers, however, had more aggressive tumor characteristics than non-BRCA breast cancer patients. Overall, 55/92 BRCA1/2 mutation carriers (59.8%) found by NGS were not already identified through the national clinical BRCA testing program. The BRCA carriers identified by clinical testing were more likely high-risk individuals, i.e. younger, less likely to have experienced menopause, and more likely to be associated with a familiar ovarian cancer compared to those not identified through clinical testing, after adjusting for year of diagnosis. A larger proportion of BRCA2 (34/42, 80%) than BRCA1 mutations (25/50, 50%) were missed by selectively testing, mainly high-risk individuals. Conclusion BRCA1/2 mutations were found in approximately 2.0% of unselected BC patients. Six out of ten BRCA mutation carriers were not identified through the national testing program, which follows the screening guidelines. Revised guidelines might be needed for the effective identification of BRCA1/2 germline mutations. Citation Format: Li J, Wen SWX, Eriksson M, Kvist A, Christensen HN, Torstensson A, Easton DF, Teo S-H, Borg Å, Grönberg H, Czene K. BRCA1/2 mutations identified by screening a large unselected breast cancer cohort in Sweden [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-06-13.</jats:p

Abstract P4-06-15: Targeted sequencing of <i>BRCA1/2</i> across a large unselected breast cancer cohort in Sweden

Abstract Background Observed BRCA1/2 mutation frequencies can vary depending on the population screened, screening criteria, founder effects, and methods used for testing. We aimed at examining BRCA1/2 germline mutations, identified through targeted sequencing, in a large unselected breast cancer population in Sweden. Methods Sequencing libraries of germline DNA from 5122 breast cancer patients diagnosed between 2001-2008 (LIBRO1) were prepared (48.48 Fluidigm Access Array system, Fluidigm Corp, USA) and sequenced (Next-generation sequencing [NGS], Illumina HiSeq 2500, v2 chemistry, University of Cambridge, UK). A total of 5099 samples (97.8%) passed quality control and were analysed. BRCA1/2 carriers identified by NGS were compared with those who were already identified by clinical BRCA screening (n=418) performed by the BRCA Lab (Lund University). This unit carries out mutation screening for all oncogenetic clinics in Sweden using denaturing high performance liquid chromatography (DHPLC) and multiple ligation-dependent probe amplification (MLPA). Results A total of 50 BRCA1 mutation carriers were identified, of which 28 were unique pathogenic germline mutations. Frameshift insertions and deletions made up 34/50 (68%) of the BRCA1 mutations. Exon 11 harbored 33/50 (66%) of the BRCA1 mutations. The most common mutation was c.3048_3052dupTGAGA (n=8), which is a founder mutation originating from the West coast of Sweden. Three other Swedish founder mutations were also identified (c.1082_1092del [n=5], c.3626delT [n=3] and c.2475delC [n=2]). For BRCA2, 42 mutation carriers were identified; 33 unique deleterious BRCA2 mutations (27 frameshift deletions, 3 frameshift insertions, 9 truncating and 3 splice sites). More than half of the mutations (24/42, 57%) were found on exon 11. Of the 418 women who had attended clinical BRCA testing, 38 deleterious mutations were found. Our screening method confirmed 34 of these mutations, as two each of BRCA1 and BRCA2 mutations were missed, since NGS was proven unsuitable for the detection of large exon duplications. NGS did, however, identify three more carriers not previously identified by clinical testing (c.3048_3052dup, c.2577delA and c.7442delT). Overall, 55/92 BRCA1/2 mutation carriers (59.8%) identified in the present study by NGS were not clinically tested. Conclusion NGS is comparable with current BRCA testing tools for the identification of BRCA1/2 germline mutations, suggesting that the technology has the potential to be used in BRCA1/2 clinical testing in unselected breast cancer patients. Citation Format: Li J, Wen SWX, Eriksson M, Kvist A, Christensen HN, Torstensson A, Easton DF, Teo S-H, Borg Å, Grönberg H, Czene K. Targeted sequencing of BRCA1/2 across a large unselected breast cancer cohort in Sweden [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-06-15.</jats:p

Association between infectious diseases consultation and mortality in hospitalized patients with Gram-negative bloodstream infection: a retrospective population-wide cohort study.

OBJECTIVES: Data supporting routine infectious diseases (ID) consultation in Gram-negative bloodstream infection (GN-BSI) are limited. We evaluated the association between ID consultation and mortality in patients with GN-BSI in a retrospective population-wide cohort study in Ontario using linked health administrative databases. METHODS: Hospitalized adult patients with GN-BSI between April 2017 and December 2021 were included. The primary outcome was time to all-cause mortality censored at 30 days, analyzed using a mixed effects Cox proportional hazards model with hospital as a random effect. ID consultation 1-10 days after the first positive blood culture was treated as a time-varying exposure. RESULTS: Of 30,159 patients with GN-BSI across 53 hospitals, 11,013 (36.5%) received ID consultation. Median prevalence of ID consultation for patients with GN-BSI across hospitals was 35.0% with wide variability (range 2.7-76.1%, interquartile range 19.6-41.1%). 1041 (9.5%) patients who received ID consultation died within 30 days, compared to 1797 (9.4%) patients without ID consultation. In the fully-adjusted multivariable model, ID consultation was associated with mortality benefit (adjusted HR 0.82, 95% CI 0.77-0.88, p < 0.0001; translating to absolute risk reduction of -3.8% or NNT of 27). Exploratory subgroup analyses of the primary outcome showed that ID consultation could have greater benefit in patients with high-risk features (nosocomial infection, polymicrobial or non-Enterobacterales infection, antimicrobial resistance, or non-urinary tract source). CONCLUSIONS: Early ID consultation was associated with reduced mortality in patients with GN-BSI. If resources permit, routine ID consultation for this patient population should be considered to improve patient outcomes