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Numerous social, economic and academic pressures can have a negative impact on representations of biomedical research. We review several of the forces playing an increasingly pernicious role in how health and science information is interpreted, shared and used, drawing discussions towards the role of narrative. In turn, we explore how aspects of narrative are used in different social contexts and communication environments, and present creative responses that may help counter the negative trends. As traditional methods of communication have in many ways failed the public, changes in approach are required, including the creative use of narratives.

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p‐value = 3.5 × 10−6) and rs2189517 (in RAD51B) with rectal cancer risk (p‐value = 5.7 × 10−6). The results had statistical significance close to the Bonferroni corrected p‐value of 5.8 × 10−6. Ninety‐four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis‐eQTL suggesting possible mechanisms of carcinogenesis.

Background:Mutations in isocitrate dehydrogenase 1 (IDH1) occur in ∼4% of patients with myelodysplastic syndrome (MDS) and have been linked with increased transformation to acute myeloid leukemia (AML). Ivosidenib (IVO; AG‐120) is an oral, potent, targeted inhibitor of the mutant IDH1 protein (mIDH1) that is approved for the treatment of adults with mIDH1 relapsed or refractory (R/R) AML. Through inhibition of mIDH1, IVO suppresses production of the oncometabolite 2‐hydroxyglutarate, leading to clinical responses via differentiation of malignant cells.Aims:To report safety and efficacy data from patients with R/R MDS enrolled in the first‐in‐human, phase 1, dose escalation and expansion study of IVO in patients with mIDH1 advanced hematologic malignancies (NCT02074839).Methods:This ongoing study is evaluating the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of IVO. Enrollment was completed on May 8, 2017. In dose escalation, patients received single‐agent IVO orally (dose range, 200–1200 mg daily) in 28‐day cycles. The MTD was not reached and 500 mg QD was selected as the dose for expansion. The overall response rate (ORR) for MDS was defined as complete remission (CR) + partial remission + marrow CR (mCR) according to International Working Group 2006 criteria for MDS. Exploratory biomarker assessments included baseline co‐occurring mutations (next‐generation sequencing panel for hematologic malignancies) and mIDH1 variant allele frequency (VAF) in bone marrow mononuclear cells (BEAMing Digital PCR; lower limit of detection for mIDH1, 0.02–0.04%).Results:Baseline characteristics of the 12 patients with R/R MDS who received 500 mg IVO once daily were: 9 men/3 women; median age 72.5 years (range 52–78), and 42% were ≥75 years of age; median number of prior therapies 1 (range 1–3). As of Nov 2, 2018, 3 of 12 (25.0%) patients remained on treatment; 9 (75.0%) had discontinued (one for allogeneic stem cell transplantation). Median duration of exposure to IVO was 11.4 months (range 3.3–42.5). Adverse events (AEs) of any grade, irrespective of causality, occurring in ≥20% of the 12 patients were diarrhea, fatigue, back pain, rash (n = 4 each, 33.3%), anemia, urinary tract infection, decreased appetite, hypokalemia, arthralgia, dyspnea, pruritus, and hypotension (n = 3 each, 25.0%). No AEs led to permanent discontinuation of treatment. IDH differentiation syndrome was observed in 1 of 12 (8.3%) patients (grade 2). Electrocardiogram QT prolonged was reported in 2 of 12 patients (17%; grade 1 in 1 patient and grade 2 in 1 patient). Five of 12 patients achieved CR (41.7%; 95% CI 15.2%, 72.3%), 1 achieved PR (8.3%), and 5 achieved mCR (41.7%), resulting in an ORR of 91.7% (95% CI 61.5%, 99.8%). The median duration of CR was not estimable (NE) at the time of datacutoff and the median duration of response was 21.4 months (95% CI 2.3, NE). At 12 months, 60.0% of patients remained in CR. Among 5 patients who were transfusion dependent at baseline, 4 became transfusion independent for ≥56 consecutive days on treatment. Baseline co‐occurring mutations and changes in mIDH1 VAF levels will be presented.Summary/Conclusion:In patients with mIDH1 R/R MDS, IVO monotherapy was well tolerated and induced durable remissions and transfusion independence. These findings support the role of IVO as an effective, oral, targeted treatment for patients with mIDH1 R/R MDS.

Abstract Objective: The perceptions and attitudes of menopause shared by men are largely unknown. This analysis characterized men's awareness and their understanding of their partner's menopausal transition. Methods: A 35-question, online survey was used to assess men's perceptions and attitudes toward menopause. Men were recruited from an online research marketplace and were eligible to participate if their female partners (45-64 years old) experienced ≥1 of the following symptoms: hot flashes, night sweats, sleepless nights, difficulty sleeping, low libido, mood swings, pain during sex, or vaginal dryness. Couples either lived together full time, or, if living separately, resided together regularly two or more times a week. Results: Of the 1,356 surveys sent to eligible men, 450 (33%) were completed. Most men were between 50 and 69 years (80%), married and not separated (90%), and lived with their partner full time (97%). Men were aware of the symptoms regularly experienced by their partner, with difficulty sleeping (54%) and lack of energy (49%) being frequently identified; these symptoms were attributed to menopause (26%) and/or aging (22%). Of those who were affected by symptoms (63%), most men reported they negatively impacted them (77%), their partners (70%), and relationships (56%). Men engaged in discussions with their partners regarding menopausal symptoms (72%) and believed they were somewhat/very influential (75%) in their partner's decision to seek treatment or make lifestyle adjustments. Conclusions: Overall, men are aware of their partner's menopausal transition and may influence decisions relating to symptom management. Educational interventions would further benefit men's awareness of menopause and available treatment options. Video Summary: http://links.lww.com/MENO/A424.

Abstract Background: Patients with DNA-damage response genes (DDR)-related pancreas cancer (BRCA1/2 or other DNA-damage related genes) may have improved outcomes secondary to increased sensitivity to DNA-damaging drugs (platinum chemotherapy/ poly ADP ribose polymerase (PARP)-inhibitors). However, data is scarce pertaining to outcomes in this subset of patients. Our objective was to retrospectively identify DDR-related pancreas cancer patients and report on clinical outcomes. Methods: Pancreas cancer patients with either a somatic or germline BRCA1/2 or other DDR genes were identified retrospectively through review of medical records (medical genetics/oncology), germline and tumor-based genetic testing results at our institution. Data regarding clinical outcomes, therapy received, and survival was subsequently extracted. Results: A total of 11 patients with pancreas cancer were identified. Pathogenic DDR-variants detected were within BRCA1 (3), ATM (4), BRCA2 (2), PALB2 (1) and FANCC (1). Five of these individuals had prior history of other cancers. Clinically these tumors were localized (4), locally advanced (3), and metastatic (4) at diagnosis. Seven out of 11 patients were still alive at time of data review. Survival in the 3 patients who had died in the metastatic/advanced cohort was 23.5, 25.8 and 111.5 months. All patients with advanced disease had exposure to platinum chemotherapy. Conclusions: Historical survival in patients with advanced and metastatic pancreas cancer is poor. Results of this DDR-subset of patients do show significantly superior outcomes, likely secondary to exposure to platinum drugs. This data, alongside other similar cohorts, would favor the DDR-genes being a predictive marker with improved survival if exposed to these drugs and the new class of drugs, PARP-inhibitors.

5518 Background: Platinum resistant ovarian cancer (OC) remains a therapeutic challenge. High grade serous OC (HGSOC) harbors TP53 mutations leading to increased dependency on S- and G2-phase checkpoints. Wee1 inhibition with Adavosertib (AZD 1775) (A) induces G2 checkpoint escape. Gemcitabine (G) is an antimetabolite therapy and blocks the progression of cells through the G1/S phase. We hypothesized that combining G+A would be synergistic and overcome resistance. Methods: We conducted a multicentre double-blind 2:1 randomized phase 2 trial to assess the progression free survival (PFS) in women with recurrent platinum-resistant/refractory HGSOC receiving G+A or G+placebo (P) (NCT02151292). Eligibility required measurable disease and feasibility of paired tumor biopsies; no limitation in prior lines of therapy. Non HGSOC histologic subtypes were enrolled in a separate non-randomized exploratory cohort. A/P was given orally at 175mg QD on D1-2, D8-9 and D15-16 with G 1000mg/m² IV D1, D8 and D15 in a 28-day cycle until progression or unacceptable AE. Tumor staging was scheduled every 8 weeks. TP53 mutations were analyzed on archival tissue with Sanger sequencing, TAm-Seq and IHC. TP53 mutation will be also assessed in circulating tumor DNA (ctDNA). Whole exome and RNA sequencing were performed on paired tumor tissues. Results: 124 patients (pts) with median of 3 prior lines of therapy (range 1-10) from 12 centres across Canada and US were enrolled between Sep 2014 to May 2018, with 99 pts randomized (65 in Arm G+A and 34 in G+P). 5 pts were ineligible; 64 pts have died. The median follow-up was 14.3 months. Main related AE was hematologic toxicity (Anemia G≥3: 31% in G+A vs 18% in G+P; Thrombocytopenia G≥3: 31% vs 6%; Neutropenia G≥3: 62% vs 30%). PFS was significantly improved from 3.0 to 4.6 months (HR 0.56 (95%CI: 0.35-0.90, p=0.015 Log rank). There was a significant improvement in overall survival (OS) from 7.2 to 11.5 months (HR 0.56 (95%CI: 0.34-0.92, P=0.022). Partial response by RECIST 1.1 was observed in 13 (21%) and 1 (3%) pts for Arms G+A and G+P, respectively (p=0.02). From the 25 pts in the exploratory cohort, 3 (12%) partial responses were observed. Final results will be reported at the meeting. Conclusion: Addition of adavosertib to gemcitabine in women with platinum resistant/refractory OC improved response rate, PFS and OS with manageable toxicity. Clinical trial information: NCT02151292.

1514 Background: The prevalence of germline mutations in non-white patients with breast cancer and the germline genetic drivers of breast cancer risk in non-white populations are largely unknown. Methods: The study population included 77,900 women with breast cancer (Non-Hispanic white: 57,003; Black: 6,722; Asian: 4,183; Hispanic: 5,194; Ashkenazi-Jewish: 4,798) who underwent germline multigene panel testing of cancer predisposition genes from March 2012 to December 2016. The prevalence of predisposition gene mutations in racial and ethnic populations relative to non-Hispanic Whites was assessed while accounting for age at diagnosis of breast cancer, family history of breast and ovarian cancer, and estrogen receptor status of breast tumors. Associations between mutations in each gene and breast cancer risk were evaluated using reference controls. Results: The overall frequency of pathogenic mutations in known breast cancer predisposition genes was 9.1% for non-Hispanic Whites, 9.8% for African Americans, 10.2% for Hispanics, 7.6% for Ashkenazi-Jewish, and 7.5% for Asians. BRCA1 mutations were enriched (p < 0.05) and CHEK2 mutations were under-represented in all racial and ethnic populations relative to non-Hispanic Whites. BRCA2 and BARD1 mutations were enriched in African Americans and Hispanics relative to non-Hispanic Whites, whereas PALB2 and RAD51C mutations were enriched in Hispanics. Among genes with mutation counts large enough for assessment, mutations in BARD1, BRCA1, BRCA2, PALB2 and TP53 were significantly associated with clinically relevant increased risks (odds ratio (OR) > 2) of breast cancer across all ethnicities and races. Rates of variants of uncertain significance were highest among Asians (29%), followed by blacks (27%), Hispanics (21%), non-Hispanic whites (16%) and Ashkenazi-Jews (14%). Conclusions: While there is some similarity across ethnic groups, substantial heterogeneity exists in the prevalence of mutations in breast cancer predisposition genes across major racial and ethnic groups in the US population. These findings contribute to our understanding of breast cancer risk and have significant implications for genetic testing, screening, and management of patients with an inherited predisposition to breast cancer, with a need for continued analysis with increased cohort size in ethnic minority groups.