Citations

Background: Invasive hemodynamic evaluation through right heart catheterization plays an essential role in the diagnosis, categorization, and risk stratification of patients with pulmonary hypertension. Methods: Subjects enrolled in the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) program undergo an extensive invasive hemodynamic evaluation that includes repeated measurements at rest and during several provocative physiological challenges. It is a National Institutes of Health/National Heart, Lung, and Blood Institute initiative to reclassify pulmonary hypertension groups based on clustered phenotypic and phenomic characteristics. At a subset of centers, participants also undergo an invasive cardiopulmonary exercise test to assess changes in hemodynamics and gas exchange during exercise. Conclusions: When coupled with other physiological testing and blood -omic analyses involved in the PVDOMICS study, the comprehensive right heart catheterization protocol described here holds promise to clarify the diagnosis and clustering of pulmonary hypertension patients into cohorts beyond the traditional 5 World Symposium on Pulmonary Hypertension groups. This article will describe the methods applied for invasive hemodynamic characterization in the PVDOMICS program. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02980887.

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]

Abstract Eating disorders and substance use disorders frequently co‐occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [ r g ], twin‐based = 0.23‐0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome‐wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance‐use‐related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism‐based genetic correlations between eating disorder‐ and substance‐use‐related phenotypes. Significant positive genetic associations emerged between AUD and AN ( r g = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN ( r g = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating ( r g = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating ( r gs = −0.19 to −0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co‐varying for major depressive disorder loci. The patterns of association between eating disorder‐ and substance‐use‐related phenotypes highlights the potentially complex and substance‐specific relationships among these behaviors.

Treatment of polycythemia vera (PV) with the Murine Double Minute 2 (MDM2) antagonist, idasanutlin, in a phase 1 trial was reported by our group to be well tolerated with a high overall response rate (Mascarenhas et al, Blood. 2019 Jun 5). A global, phase 2 trial is currently underway evaluating idasanutlin in hydroxyurea (HU) resistant/intolerant PV patients (NCT03287245). MDM2, a negative regulator of TP53 is upregulated in PV CD34+ cells and inhibition of MDM2 targets PV hematopoietic stem/progenitor cells (HSPC) (Lu et al, Blood. 2014;124(5):771-90). Additional trials of MDM2 antagonists have shown promise, however, there is concern that these agents have the potential to induce TP53 mutations or promote expansion of TP53 mutated clones. Resistance to MDM2 inhibitors has been evaluated in solid tumor cell lines and attributed to either the emergence of de novoTP53 mutations or the selection of TP53 mutated clones. (Michaelis et al, Cell Death Dis. 2011;2:e243; Skalniak et al, Cancers. 2018;10(11)). The effect of MDM2 inhibition on TP53 mutant clones is of particular interest in myeloproliferative neoplasms (MPNs). TP53 mutations have been reported with a low allele burden in ~15% of chronic MPN patients (Kubesova et al, Leukemia. 2018;32(2):450-61), however, TP53 loss of heterozygosity and rapid expansion of TP53 mutant clones is associated with transformation to blast phase (Lundberg et al, Blood 2014,123:2220-8). As reported, in the idasanutlin PV trial, 1/13 patients were identified to have a baseline pathogenic TP53 mutation in hematopoietic cells (VAF 5.5%), using a deep sequencing assay with a limit of detection (LOD) of VAF 0.5%. This patient was a non-responder to idasanutlin and upon treatment had an increasing JAK2V617F and TP53 mutant VAF. End of study hematopoietic cell specimens of all patients were deep sequenced (LOD 0.1%) and revealed that 4 additional patients harbored detectable TP53 mutations after idasanutlin treatment with VAF ranging from 1-12%. In each sample, 1-5 unique TP53 mutations were identified, all within the hotspot domain of the TP53 gene. Deeper sequencing of baseline and follow-up samples revealed these mutations were present at a subclonal level (VAF 0.1-5.5%) and increased over time, indicating that treatment with the MDM2 antagonist promoted expansion of already existing TP53 mutant clones (Table 1, Figure 1). None of the patients who lacked a TP53 mutation at baseline developed a TP53 mutant clone with idasanutlin treatment. There was no clear association of presence of TP53 mutations with prior HU, anagrelide or interferon exposure. There has been careful monitoring of patients to determine whether the expanding TP53 clone has clinical ramifications. Patients were on study for a median of 54 weeks (23-131). The only patient who exemplified resistance to idasanutlin was the single patient with a high burden TP53 mutation (37%). All other patients were taken off study due to patient choice/toxicity. Furthermore, all TP53 mutant and non-mutant patients have had stable disease with no evidence of progression to MF or AML. Sequencing of 2 patients post-discontinuation of idasanutlin revealed that the VAF of the TP53 mutant clones decreased since the agent was discontinued. Updated patient molecular data post-treatment discontinuation will be reported at the meeting. To investigate whether idasanutlin induces de novo TP53 mutations in PV myeloid cells we performed long term HSPC cultures. Mononuclear cells from 6 distinct PV patients were treated continuously with idasanutlin (500 nM) over ~6 weeks and DNA from both treated and untreated colonies were analyzed using next generation sequencing with a LOD of 2% VAF and no TP53 mutations were detected. The combined in vitro and clinical data reveals that treatment with an MDM2 antagonist is not associated with the emergence of de novoTP53 mutations but rather the expansion of prior existing TP53 clones. This does not appear to have clinical repercussions, however, close monitoring of these patients is essential. We recommend that patients be screened for TP53 mutations prior to treatment with an MDM2 antagonist and that if present the TP53 mutant VAF be followed during their treatment course. Resistance to MDM2 inhibition is likely dependent on the TP53 mutant VAF and further studies will need to clarify the ideal dosing schedule of MDM2 antagonists and/or combinatorial therapy to prohibit TP53 mutant clonal expansion. Disclosures Houldsworth: Cancer Genertics: Other: stock in; Sema4: Employment. Rossi:Sema4: Employment. Kiladjian:AOP Orphan: Honoraria, Research Funding; Celgene: Consultancy; Novartis: Honoraria, Research Funding. Rampal:Agios, Apexx, Blueprint Medicines, Celgene, Constellation, and Jazz: Consultancy; Constellation, Incyte, and Stemline Therapeutics: Research Funding. Mascarenhas:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: Consultancy, Research Funding; Merck: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Promedior: Research Funding; Merus: Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hoffman:Merus: Research Funding.

Abstract Background: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk. Methods: Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined. Results: Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [ORLA = 0.96; 95% confidence interval (CI) = 0.93–0.98; P = 5.2 × 10−4] and α-linolenic acid (ORALA = 0.95; 95% CI = 0.92–0.97; P = 5.4 × 10−5), whereas modest increased risks were observed for arachidonic (ORAA = 1.06; 95% CI = 1.03–1.08; P = 3.3 × 10−5), eicosapentaenoic (OREPA = 1.04; 95% CI = 1.01–1.07; P = 2.5 × 10−3), and docosapentaenoic acids (ORDPA = 1.03; 95% CI = 1.01–1.06; P = 1.2 × 10−2). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses. Conclusions: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk. Impact: The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.

PURPOSEThe phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer.PATIENTS AND METHODSI-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week.RESULTSMK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform).CONCLUSIONThe Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.

Abstract Introduction Infections of cardiac implantable electronic devices remain a prevalent health concern necessitating the advent of novel preventative strategies. Based on the observation that bacterial infections of the Micra transcatheter pacemaker device are extremely rare, we examine the effect of parylene coating on bacterial adhesion and growth. Methods Bacterial growth was compared on polyurethane coated, bare, or parylene coated titanium surfaces. Eight test samples per bacterial species and material combination were incubated with Staphylococcus Aureus or Pseudomonas aeruginosa for 24 hours and then assayed for bacterial growth. The surface contact angle was also characterized by measuring the angle between the tangent to the surface of a liquid droplet made with the surface of the solid sample. Results The mean bacterial colony counts were significantly reduced for both parylene coated titanium versus bare samples (3.69 ± 0.27 and 4.80 ± 0.48 log[CFU/mL] respectively for S. aureus [ P < .001] and 5.51 ± 0.27 and 6.08 ± 0.11 log[CFU/mL] respectively for P. aeruginosa [ P < .001]), and for parylene coated titanium versus polyurethane samples (4.27 ± 0.42 and 5.40 ± 0.49 log[CFU/mL] respectively for S. aureus [ P < .001] and 4.23 ± 0.42 and 4.84 ± 0.32 log[CFU/mL] respectively for P. aeruginosa [ P = .006]). Parylene coated titanium samples had a higher contact angle compared with bare titanium, but lower compared with polyurethane (mean contact angle 87.5 ± 3.1 degrees parylene, 73.3 ± 3.7 degrees titanium [ P < .001 vs parylene], and 94.8 ± 3.7 degrees polyurethane [ P = .002 vs parylene]). Conclusions Parylene coating significantly reduced the ability of bacteria to grow in colony count assays suggesting that this could contribute to the reduction of bacterial infections of Micra transcatheter pacemakers.