Citations

7086 Background: The HRQOL of patients (pts) with chronic lymphocytic leukemia (CLL) has not been adequately delineated across patient, disease and treatment characteristics. We evaluated HRQOL of CLL pts undergoing treatment in the United States (US) by age, gender and line of therapy. Methods: Data were collected in Connect CLL, a prospective observational US registry. Physicians provided data on demographics, clinical characteristics and line of therapy at enrollment. HRQOL was self-reported by pts at enrollment using the Functional Assessment of Cancer Therapy-Leukemia, an instrument that yields a leukemia-specific total HRQOL score (FACT-Leu) and a cancer-specific total HRQOL score (FACT-G). Mean total scores were analyzed by line of therapy, age and gender. Statistical significance was ascertained by ANOVA using SAS 9.2. Multivariate analyses were conducted to assess the relative association of line of therapy, age and gender with HRQOL. Results: Among 1,252 pts enrolled from 161 geographically diverse centers (90% community, 8% academic, 2% veterans/military), pts were predominantly male (63%), white (89%) with mean age 69 yrs. Pts were categorized by line of therapy at enrollment: First 61%, Second 18%, Third 11%, Higher 9%; and by age group: <65 33%, 65-74 35%, 75+ 32%. Univariate analyses suggested that the total FACT-Leu score was significantly better in men than women (P=0.004); in pts aged 65-74 vs younger or older pts (P=0.033); and in pts initiating first-line treatment vs pts receiving subsequent treatments (P=0.0002). Similar results were found with the FACT-G score except that gender differences were not statistically significant. Multivariate analysis confirmed that line of therapy (P=0.007), gender (P<0.0001), and age group (P=0.039) were each associated with significant differences in the FACT-Leu total score. Conclusions: Results from the Connect CLL Registry indicate that HRQOL is better among pts initiating first-line therapy compared to pts initiating subsequent treatments, and that this remains true when age and gender are considered. Future analyses should determine how HRQOL may change over time relative to treatment and treatment response.

8600 Background: The prognosis of stage IV melanoma patients remains poor. Published results have suggested that components of the complete blood count have significant prognostic value in several malignancies. Among the most studied were the absolute lymphocyte count (ALC), and absolute monocyte count (AMC) on clinical outcomes of patients with lymphoid malignancies. Thus, we sought to investigate if the pre-operative ALC (ALC-PO), AMC (AMC-PO) and ALC/AMC ratio (ALC/AMC-PO) affects the risk of disease recurrence and survival after complete surgical resection of metastatic melanoma. Methods: We studied 66 stage IV, resected melanoma patients followed at Mayo Clinic from 2000 to 2010. Log rank chi-square analysis was used to determine the best cut-off values for each pre-operative variable, while proportional hazards models were used to compared survival. Results: The median follow-up of the cohort was 24 months (range: 2.3 – 117 months). ALC-PO, AMC-PO and ALC/AMC-PO, as continuous variables, were all identified as prognostic factors for both relapse-free survival (RFS) and overall survival (OS). The best cut-off values for ALC-PO, AMC-PO and ALC/AMC-PO were 1.9; 0.62; and 2.05, respectively. Using Kaplan-Meier analysis, patients with an ALC-PO ≥ 1.9 x 109/L experienced superior OS and RFS compared with ALC-PO < 1.9 x 109/L patients [median OS of 58 months vs. 34 months, p < 0.04; median RFS of 14 months vs. 5 months, p < 0.009]. Conversely, a low AMC-PO (<0.62 x 109/L) was associated with better OS and RFS compared with higher AMC-PO (≥ 0.62 x 109/L): [median OS of 47 months vs. 14 months, p < 0.007; median RFS of 9 months vs. 5 months, p < 0.02]. When the ALC-PO and AMC-PO were combined as an ALC/AMC ratio, the group with an ALC/AMC-PO ≥ 2.05 experienced a superior OS and RFS compared to patients with ALC/AMC-PO < 2.05: [median OS of 49 months vs. 12 months, p < 0.0001; median RFS of 10 months vs. 4 months, p < 0.0001]. Multivariate analysis showed ALC/AMC-PO to be an independent prognostic factor for RFS and OS (HR = 0.32, p < 0.003; HR = 0.23, p < 0.002). Conclusions: Our study showed, that ALC/AMC-PO ratio is an independent prognostic factor for RFS and OS in patients undergoing resection of metastatic (stage IV) melanoma.

6122 Background: Clinicians and investigators commonly use ECOG PS and clinician-reported patient (pt) fatigue as surrogates for HRQOL, a multi-faceted construct that comprehensively looks at the pt perspective on disease and well-being. Because limited data exist on the relationships between PS, fatigue, and HRQOL for CLL pts, we examined the associations between these measures, and 3 validated HRQOL instruments: the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu), EQ-5D, and Brief Fatigue Inventory (BFI). Methods: Data were collected in CONNECT CLL, a prospective US observational registry initiated in 2010. Patient demographics and clinical characteristics were provided by clinicians. Patient HRQOL was self-reported at enrollment using the FACT-Leu, EQ-5D, and BFI. Scores were analyzed by ECOG PS (0, 1, 2-4) and clinician-reported fatigue (yes, no). Differences in HRQOL scores were assessed by ANOVA. Results: HRQOL data were reported by 899 pts from 148 community, 10 academic, and 3 government centers. ECOG PS was available on 711 pts. Overall HRQOL, measured by mean FACT-Leu, FACT-G and EQ-5D Visual Analogue Scale (VAS), worsened with ECOG PS severity and was worse in pts with fatigue (all p<0.0001). All FACT-Leu domains except social/family were worse in pts with fatigue and those with higher ECOG PS. Mean EQ-5D pain/discomfort, mobility, self care and usual activities domain scores worsened in severity as ECOG worsened and for pts with fatigue (all p<0.011). BFI data indicated that global fatigue, fatigue severity and fatigue-related interference worsened by ECOG severity and were associated with clinician-reported fatigue (all p<0.0001). Conclusions: Initial CONNECT CLL results confirm that HRQOL worsens with worsening ECOG PS and was worse among pts with fatigue, especially in physical/functioning domains, pain/discomfort, and mobility. These results indicate that baseline ECOG PS and physician-rated fatigue are rapid assessments that predict robust measures of HRQOL. Future analyses are planned to examine how HRQOL, ECOG PS and fatigue change over time with changes in treatment and CLL disease status.

PURPOSE To determine the sensitivity and specificity of genetic testing criteria for the detection of germline pathogenic variants in women with breast cancer. MATERIALS AND METHODS Women with breast cancer enrolled in a breast cancer registry at a tertiary cancer center between 2000 and 2016 were evaluated for germline pathogenic variants in 9 breast cancer predisposition genes ( ATM , BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, and TP53). The performance of the National Comprehensive Cancer Network (NCCN) hereditary cancer testing criteria was evaluated relative to testing of all women as recommended by the American Society of Breast Surgeons. RESULTS Of 3,907 women, 1,872 (47.9%) meeting NCCN criteria were more likely to carry a pathogenic variant in 9 predisposition genes compared with women not meeting criteria (9.0% v 3.5%; P < .001). Of those not meeting criteria (n = 2,035), 14 (0.7%) had pathogenic variants in BRCA1 or BRCA2. The sensitivity of NCCN criteria was 70% for 9 predisposition genes and 87% for BRCA1 and BRCA2, with a specificity of 53%. Expansion of the NCCN criteria to include all women diagnosed with breast cancer at ≤ 65 years of age achieved > 90% sensitivity for the 9 predisposition genes and > 98% sensitivity for BRCA1 and BRCA2. CONCLUSION A substantial proportion of women with breast cancer carrying germline pathogenic variants in predisposition genes do not qualify for testing by NCCN criteria. Expansion of NCCN criteria to include all women diagnosed at ≤ 65 years of age improves the sensitivity of the selection criteria without requiring testing of all women with breast cancer.

Abstract Purpose: The purpose of this study was to qualitatively analyze metacommunication during the digital storytelling (DST) workshop process for patients undergoing hematopoietic cell transplantation (HCT). Methods: HCT survivors who had undergone transplant within the past 2 years were recruited at a cancer center in the Phoenix Metropolitan area. Participants (M age = 51.5 years) attended a 3-day DST workshop telling and creating digital stories around their HCT experiences. Using a constructivist grounded theory approach, line by line coding and content analysis were conducted with four research team members. Results: Four themes emerged from the data: (1) communal connection; (2) expressing and processing emotions; (3) self-empowerment; and (4) multi-dimensional coping. Participants described telling and sharing their story with other HCT patients as therapeutic. Conclusion: DST shows promise as a potential coping tool and offers multiple dimensions of the role of narrative as a coping technique, in community building, and in patient-centered contexts within HCT.

Abstract Background Fentanyl is a synthetic opioid associated with illicit drug use and overdose deaths. The SEFRIA Immunalysis (IAL) and ARK fentanyl assays are both FDA-cleared, open channel immunoassays for fentanyl detection in urine. However, limited data are available in the literature comparing these assays. The objective of this study was to perform a direct comparison of these two fentanyl immunoassays. Methods IAL and ARK fentanyl immunoassays were performed on a Roche Cobas e602 automated chemistry analyzer. Repeatability and total imprecision were compared by diluting fentanyl into urine at concentrations above, below, and at the manufacturers’ cutoffs of 1.0 ng/mL. Cross-reactivity was assessed for norfentanyl and the fentanyl analogs acetylfentanyl, acrylfentanyl, and furanylfentanyl. Concordance was assessed in 90 patient samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS) as the gold standard. Results Repeatability varied from 11.4%–17.8% on the IAL assay and 2.8%–5.5% on the ARK assay. Total imprecision was 18.9%–40.7% on the IAL assay and 2.9%–6.4% on the ARK assay. Both assays cross-reacted with acetylfentanyl (∼100%), acrylfentanyl (∼100%), and furanylfentanyl (∼20%), but only the ARK assay cross-reacted with norfentanyl (∼3%). An admixture of 0.5 ng/mL fentanyl and 6 ng/mL norfentanyl produced a positive result on the ARK assay. Total concordance between IAL and ARK for 90 tested patient samples was 93% (kappa = 0.85). Relative to LC-MS/MS, the IAL assay had a concordance of 90% (kappa = 0.79) and the ARK assay had a concordance of 94% (kappa = 0.88). Including norfentanyl in the LC-MS/MS confirmation increased the concordance of the ARK to 96% (kappa = 0.90). Conclusions The ARK assay recognized the metabolite norfentanyl, demonstrated superior precision, and had better concordance with LC-MS/MS compared to the IAL assay.

Background: The National Comprehensive Cancer Network and American Society of Clinical Oncology recommend consideration of the use of echocardiography 6 to 12 months after completion of anthracycline-based chemotherapy in at-risk populations. Assessment of BNP (B-type natriuretic peptide) has also been suggested by the American College of Cardiology/American Heart Association/Heart Failure Society of America for the identification of Stage A (at risk) heart failure patients. The real-world frequency of the use of these tests in patients after receipt of anthracycline therapy, however, has not been studied previously. Methods and Results: In this retrospective study, using administrative claims data from the OptumLabs Data Warehouse, we identified 31 447 breast cancer and lymphoma patients (age ≥18 years) who were treated with an anthracycline in the United States between January 1, 2008 and January 31, 2018. Continuous medical and pharmacy coverage was required for at least 6 months before the initial anthracycline dose and 12 months after the final dose. Only 36.1% of patients had any type of cardiac surveillance (echocardiography, BNP, or cardiac imaging) in the year following completion of anthracycline therapy (29.7% echocardiography). Surveillance rate increased from 37.5% in 2008 to 42.7% in 2018 (25.6% in 2008 to 40.5% echocardiography in 2018). Lymphoma patients had a lower likelihood of any surveillance compared with patients with breast cancer (odds ratio, 0.79 [95% CI, 0.74–0.85]; P <0.001). Patients with preexisting diagnoses of coronary artery disease and arrhythmia had the highest likelihood of cardiac surveillance (odds ratio, 1.54 [95% CI, 1.39–1.69] and odds ratio, 1.42 [95% CI, 1.3–1.53]; P <0.001 for both), although no single comorbidity was associated with a >50% rate of surveillance. Conclusions: The majority of survivors of breast cancer and lymphoma who have received anthracycline-based chemotherapy do not undergo cardiac surveillance after treatment, including those with a history of cardiovascular comorbidities, such as heart failure.

Abstract Glioblastoma multiforme (GBM) and other solid malignancies are heterogeneous and contain subpopulations of tumor cells that exhibit stem-like features. Our recent findings point to a dedifferentiation mechanism by which reprogramming transcription factors Oct4 and Sox2 drive the stem-like phenotype in glioblastoma, in part, by differentially regulating subsets of miRNAs. Currently, the molecular mechanisms by which reprogramming transcription factors and miRNAs coordinate cancer stem cell tumor-propagating capacity are unclear. In this study, we identified miR-486-5p as a Sox2-induced miRNA that targets the tumor suppressor genes PTEN and FoxO1 and regulates the GBM stem-like cells. miR-486-5p associated with the GBM stem cell phenotype and Sox2 expression and was directly induced by Sox2 in glioma cell lines and patient-derived neurospheres. Forced expression of miR-486-5p enhanced the self-renewal capacity of GBM neurospheres, and inhibition of endogenous miR-486-5p activated PTEN and FoxO1 and induced cell death by upregulating proapoptotic protein BIM via a PTEN-dependent mechanism. Furthermore, delivery of miR-486-5p antagomirs to preestablished orthotopic GBM neurosphere-derived xenografts using advanced nanoparticle formulations reduced tumor sizes in vivo and enhanced the cytotoxic response to ionizing radiation. These results define a previously unrecognized and therapeutically targetable Sox2:miR-486-5p axis that enhances the survival of GBM stem cells by repressing tumor suppressor pathways. Significance: This study identifies a novel axis that links core transcriptional drivers of cancer cell stemness to miR-486-5p–dependent modulation of tumor suppressor genes that feeds back to regulate glioma stem cell survival.

176 Background: Multiple tumour tissue studies have demonstrated the prognostic utility of CNVs in mCRPC. However, accurate assessment of CNVs in plasma cfDNA remains challenging, and prognostic significance has not been well characterized. Using a large customized panel, we correlated plasma CNVs with clinical outcomes in a contemporary cohort of mCRPC patients. Methods: Deep targeted sequencing was performed using a 180-gene cfDNA panel (Predicine) in 56 patients commencing AR pathway inhibitors (enzalutamide or abiraterone; n = 34) or taxane chemotherapy (n = 22) at two Australian institutions. Kaplan-Meier estimates and Cox proportional-hazards models were used to correlate CNVs with progression-free survival (PFS) and overall survival (OS). Significant results were validated in an independent cohort (Mayo Clinic, n = 144). Results: Median follow-up was 19.4 months (mo; IQR 11.3-31.9). The most common CNVs in the Australian cohort are shown (Table). OS was significantly decreased in patients with PI3KCA gain (median 21.7 mo vs 6.6 mo, p < 0.0001), PTEN loss (24.8 mo vs 11.7 mo, p = 0.0019) and AR gain (21.7 mo vs 12.0 mo, p = 0.0083). Furthermore, all three alterations independently predicted for poor survival in multivariable analyses (MVA; Table). Findings in the independent cohort showed similar OS results in MVA: PIK3CA gain (HR 2.0, p = 0.07), PTEN loss (HR 1.7, p = 0.08) and AR gain (HR 1.7, p = 0.03). Conclusions: Sequencing of plasma cfDNA revealed that PTEN loss, and PIK3CA and AR gain are associated with inferior clinical outcomes in patients commencing contemporary systemic treatment. These data support therapeutic strategies co-targeting the PI3K and AR pathways in mCRPC.[Table: see text]

Background: Palate re-repair has been proposed as an effective treatment for velopharyngeal insufficiency (VPI) with a low risk of obstructive sleep apnea (OSA). The authors conducted a systematic review and meta-analysis to determine the proportion of patients achieving normal speech resonance following palate re-repair for VPI, the proportion developing OSA, and the criteria for patient selection that are associated with increased effectiveness. Methods: PubMed, Embase, and Scopus were searched from inception through April 2018 for English language articles evaluating palate re-repair for the treatment of VPI in patients with a repaired cleft palate. Inclusion criteria included reporting of hypernasality, nasal air emission, nasometry, additional VPI surgery, and/or OSA outcomes. Meta-analysis was conducted using random effects models. Risk of bias was assessed regarding criteria for patient selection, blinding of outcome assessors, and validity of speech assessment scale. Results: Eighteen studies met inclusion criteria. The incidence of achieving no consistent hypernasality follow palate re-repair was 61% (95% confidence interval [CI]: 44%-75%). The incidence of additional surgery for persistent VPI symptoms was 21% (95% CI: 12%-33%). The incidence of OSA was 28% (95% CI: 13%-49%). Criteria for selecting patients to undergo re-repair varied, with anterior/sagittal position of palatal muscles (33%) and small velopharyngeal gap (22%) being the most common. No specific patient selection criteria led to superior speech outcomes ( P = .6572). Conclusions: Palate re-repair achieves normal speech resonance in many but not all patients with VPI. Further research is needed to identify the specific examination and imaging findings that predict successful correction of VPI with re-repair.