Citations

Abstract Background: In vivo synergy with concurrent PI3-Kinase inhibition and PARP inhibition has been observed in BRCA-deficient and BRCA-proficient preclinical models of triple negative breast cancer (TNBC) and ovarian cancer (OC). A phase I trial of the oral pan-class I PI3-Kinase inhibitor BKM120 and the PARP inhibitor olaparib demonstrated anti-cancer activity in TNBC and OC, both in patients with and without germline BRCA1 and BRCA2 (BRCA) mutations. However, CNS toxicity (depression) and liver function test abnormalities limited dose escalation of BKM120 prompting evaluation of the alpha specific PI3-Kinase inhibitor BYL719 (which has no CNS toxicity) in combination with olaparib. Methods: Olaparib was administered twice daily (tablet formulation) and BYL719 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with primary objectives of defining the maximum tolerated dose (MTD) and recommended phase 2 dose of the combination of BYL719 and olaparib, and secondary objectives of defining toxicity, activity, and pharmacokinetic profiles of both agents. Eligibility included recurrent TNBC or high grade serous (HGS) OC, or any histology OC or breast cancer (BC) with presence of a known germline BRCA mutation, performance status of 0-1 and measurable/evaluable cancer. Patients with platinum sensitive or resistant or refractory OC were eligible and prior PARP inhibitor use was allowed. Dose-expansion cohorts at the MTD were enrolled for both BC and OC. Results: 46 patients (16 BC and 30 OC) have been enrolled in the study; 28 patients participated in the dose escalation portion of the study (4 BC and 24 OC). Two patients with OC did not receive study drugs because of ineligibility. MTD was defined as BYL719 200mg once daily and olaparib 200mg twice daily. Dose limiting toxicities included hyperglycemia, rash and fever with decreased neutrophil count. Four patients (3 OC and 1 BC) discontinued protocol therapy because of toxicity (2 for hyperglycemia, 1 for nausea and 1 for allergic reaction). Most common toxicities included nausea, hyperglycemia, fatigue, diarrhea and vomiting. At the MTD, 6 patients with OC and 12 patients with BC were enrolled into a dose expansion cohort. The OC expansion cohort has completed enrollment, while the BC cohort is still enrolling. Among patients with OC who received study drugs (28 patients, 26 (93%) with platinum resistant disease), objective response rate (ORR) by RECIST 1.1 was 36% (10/28 patients, all partial responses (PRs)). Median duration of response was 167 days (range 16-398 days); 5 of 10 patients with PR remain on treatment. ORR was 33% for patients with germline BRCA mutations and 31% for patients without germline BRCA mutations. Among patients without germline BRCA mutations with platinum resistant OC, ORR was 29%. Conclusions: Combined BYL719 and olaparib is feasible, and similar clinical benefit was observed in patients with and without germline BRCA mutations. The activity of this combination in OC patients without germline BRCA mutations and with platinum resistant disease was higher than expected from olaparib monotherapy and warrants further investigation. This work was funded in part by the Stand Up To Cancer Ovarian Dream Team. Clinical trial: NCT01623349. Citation Format: Panagiotis A. Konstantinopoulos, William T. Barry, Michael Birrer, Shannon N. Westin, Sarah Farooq, Karen Cadoo, Christin Whalen, Weixiu Luo, Hui Liu, Carol Aghajanian, David B. Solit, Gordon B. Mills, Barry S. Taylor, Helen Won, Michael F. Berger, Sangeetha Palakurthi, Joyce F. Liu, Lew Cantley, Scott H. Kaufmann, Elizabeth M. Swisher, Alan D. D'Andrea, Eric Winer, Gerburg M. Wulf, Ursula A. Matulonis. Phase I study of the alpha specific PI3-Kinase inhibitor BYL719 and the poly (ADP-Ribose) polymerase (PARP) inhibitor olaparib in recurrent ovarian and breast cancer: Analysis of the dose escalation and ovarian cancer expansion cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT008. doi:10.1158/1538-7445.AM2017-CT008

Abstract Purpose: The relevance of inherited pathogenic variants in cancer predisposition genes to pancreatic cancer (PC) is not well understood. Several small studies have identified pathogenic variants in 4% to 14% of unselected PC patients using multigene panels of predisposition genes, but only BRCA2, ATM, and PALB2 have been clearly implicated in this disease. We aimed to assess the clinical and molecular characteristics of PC patients referred for hereditary cancer genetic testing, and to estimate the risk of PC associated with pathogenic variants in panel-based cancer predisposition genes. Methods: PC patients (n=1,819) were ascertained from a large cohort of over 140,000 patients undergoing multigene panel testing (MGPT) of predisposition genes between March 2012 and June 2016 at a single diagnostic laboratory. Clinical histories and molecular results were reviewed and summarized. Gene-level variant frequencies among PC cases were compared to those from the Exome Aggregation Consortium (ExAC) to calculate gene-specific pancreatic cancer risk ratios. Results: PC patients were predominantly Caucasian (76.5%) and female (58.9%), with a median age at diagnosis of 61 years (51.7). Of these, 33.5% reported additional cancer primaries, and 44.8% reported a family history of PC. Overall, 15.4% of PC patients were found to have at least one pathogenic/likely pathogenic variant in panel-based predisposition genes. Genes with the highest frequencies of pathogenic/likely pathogenic variants included BRCA2 (3.9%), ATM (3.6%), CHEK2 (excluding p.Ile157Thr) (2.0%), PALB2 (1.5%), VHL (1.4%), CDKN2A (1.2%), BRCA1 (0.8%), and MSH6 (0.8%). 21.8% of BRCA1 and BRCA2 carriers did not meet BRCA1/2 testing criteria and 61.5% of MSH6 carriers did not meet Lynch syndrome testing criteria. No CDKN2A families met diagnostic criteria for familial atypical multiple mole melanoma syndrome, and 44% did not report any personal or family history of melanoma. To estimate associations between pathogenic variants and pancreatic cancer, Caucasian PC cases were compared to non-Finnish European, non-TCGA ExAC reference controls. Pathogenic variants in ATM, BRCA2, CDKN2A, MSH6, and PALB2 were significantly associated with high PC risks. Pathogenic variants in BRCA1 were associated with a moderate risk of PC (RR=2.7). Conclusions: These findings shed light on the spectrum of mutations that can be expected for PC patients referred for cancer predisposition testing. The results confirm the associations of CDKN2A and BRCA2 variants with PC, and expand on the phenotypic spectrum associated with these variants. Furthermore, these results suggest that ATM, PALB2, and MSH6 may be high-risk PC genes, warranting further investigation in case-control and family-based studies. Citation Format: Holly LaDuca, Chunling Hu, Hermela Shimelis, Eric Polley, Jenna Lilyquist, Mary Helen Black, Brigette Tippin Davis, David E. Goldgar, Jill Dolinsky, Fergus J. Couch. What have we learned from pancreatic cancer patients undergoing multigene panel testing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4286. doi:10.1158/1538-7445.AM2017-4286

Abstract BACKGROUND: Incidence of glioma varies significantly by sex, and most glioma histologies occur with greater incidence in males. Previous analyses have examined the impact of estrogen exposure as a risk factor for these tumors, but have found results of varying significance and low effect size. There may be differences in effect of previously discovered risk alleles that contribute to sex differences. METHODS: Using data collected for three previous glioma GWAS in European-ancestry populations (MD Anderson Cancer Center, the San Francisco Adult Glioma Study, and the Glioma International Case Control Study) we assessed sex-specific effects for 14 previously identified and 13 newly identified glioma risk SNPs (27 total) overall and for glioblastoma (GBM) and non-GBM tumors separately. There were 3,892 male cases (59% GBM), 4,522 male controls, 2,500 female cases (52% GBM) and 4,940 female controls. Sex-specific odds ratios (ORM and ORF), 95% confidence intervals (95% CI) and p values (pM and pF) were generated using stratified logistic regression models. Data from each study were analyzed separately and combined using inverse variance weighted meta-analysis. Results were considered statistically significant at p<6.2x10-4. RESULTS: In GBM, rs11979158 (7p11.2, pM=1.01x10-10, ORM=1.43 [95% CI: 1.28-1.59]; pF=3.43x10-3, ORF=1.22 [95% CI: 1.07-1.39]) and rs2562152 (16p13.3, pM=5.59x10-4, ORM=1.23 [95% CI: 1.09-1.39]; pF=1.22x10-1, ORF=1.12 [95% CI: 0.97-1.29]) had significant effect in males only. In non-GBM gliomas, rs12076373 (1q44, pM=3.56x10-7, ORM=1.41, 95% CI: 1.23-1.61; pF=1.76x10-2, ORF=1.20, 95% CI: 1.03-1.38), rs11979158 (7p11.2, pM=1.77x10-5, ORM=1.32 [95% CI: 1.16-1.49]; pF=2.73x10-1, ORF=1.08 [95% CI: 0.94-1.24]), and rs3751667 (16p13.3, pM=9.44x10-7, ORM=1.30 [95% CI: 1.17-1.44]; pF=5.18x10-2, ORF=1.13 [95% CI: 1.00-1.28]) had significant effect in males only. Effect size for rs55705857 (8q24.21) varied significantly by sex, with ORM=2.63 (95% CI: 2.24-3.09, pM=4.42x10-32), as compared to ORF=3.95 (95% CI: 3.28-4.76, pF=1.82x10-47). A sensitivity analysis was performed due to allele frequency heterogeneity by study and results did not change. CONCLUSIONS: Sex differences and other demographic differences in cancer susceptibility can provide important clues to etiology, and these differences can be leveraged for discovery in genetic association studies. Significant differences in effect size may suggest variation in genetic effect of risk alleles or in unidentified risk factors that vary in prevalence or effect by sex. There may also be differences in the distribution of molecular subtypes within each histology by sex. Further investigation using an agnostic approach may further elucidate the relationship between effect of risk alleles and sex. Citation Format: Quinn T. Ostrom, Ben Kinnersley, Margaret Wrensch, Jeanette E. Eckel-Passow, Georgina Armstrong, Terri Rice, Yanwen Chen, John Wiencke, Lucie McCoy, Helen Hansen, Christopher Amos, Jonine L. Bernstein, Elizabeth B. Claus, Dora Il'yasova, Christoffer Johansen, Daniel Lachance, Rose Lai, Ching C. Lau, Ryan T. Merrell, Sara H. Olson, Siegal Sadetzki, Joellen Schildkraut, Sanjay Shete, Richard S. Houlston, Robert B. Jenkins, Beatrice Melin, Melissa Bondy, Jill S. Barnholtz-Sloan. Estimating sex-specific effects of genetic loci associated with glioma risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1315. doi:10.1158/1538-7445.AM2017-1315

AbstractBackgroundWhile limited data suggest that the fecal microbiota in healthy people is stable over time, the intraindividual variability of the fecal microbiota in constipated patients is unknown.MethodsThis study evaluated the intraindividual reproducibility of fecal microbiota analyzed with 16S rRNA gene sequencing in two stool samples collected without and after a laxative, respectively, in 25 healthy people and 25 constipated women. Participants completed a food record for 3 d before the stool collection. Colonic transit was measured with scintigraphy.Key ResultsThe constipated patients were older (48±15 vs 39±10 y, P=.02) than healthy participants but had a similar BMI. The total daily caloric intake was less (P=.005) in constipated (1265±350 kcal) than healthy participants (1597±402 kcal). Fourteen patients but only two controls (P<.005), had delayed colonic transit. For most measures of alpha (eg, Observed OTU number, Shannon index) and beta diversity (eg, Bray‐Curtis dissimilarity, UniFrac, phyla level abundance), the ICCs between two stool samples were high, indicating moderate or strong agreement, and similar in healthy people and constipated patients. The ICC for the weighted UniFrac distance, which is weighted by abundance, was lower than its unweighted counterpart, indicating that the unweighted measure is more robust and reproducible.Conclusions and InferencesThe intraindividual reproducibility of fecal microbiota in constipated patients is high and comparable to healthy participants. For most purposes, evaluating the fecal microbiota in a single stool sample should generally suffice in adequately powered studies of healthy and constipated patients.

Background: The Afirma ® Gene Expression Classifier (GEC) risk stratifies The Bethesda System for the Reporting of Thyroid Cytopathology class III/IV (indeterminate) thyroid nodules (ITNs) as suspicious for malignancy or benign. Several authors have published studies describing the diagnostic accuracy of the GEC. However, the quality of these methods has not been rigorously examined. Summary: In this study, MEDLINE and EMBASE were searched for studies published between January 1, 2010, and June 30, 2016, examining the sensitivity, specificity, negative predictive value, and positive predictive value of the GEC. The Quality of Diagnostic Accuracy Studies 2 was customized to evaluate the methods of included studies in each of four domains: nodule selection, index test execution, reference standard assignment, and flow and timing. Signaling questions were used to identify sources of potential bias in calculation of diagnostic accuracy, and issues of applicability were assessed. Three panelists applied the Quality of Diagnostic Accuracy Studies 2 tool to each study included, and divergence was resolved in conference. In 12 studies evaluated, the most common methodologic flaw was lack of reference standard diagnosis assignment to un-excised GEC-benign ITNs. Exclusion of these ITNs from the analyses resulted in unreliable estimates of specificity and negative predictive value. Other flaws identified included restriction to ITNs that had already been selected for referral for thyroidectomy or lobectomy. Conclusions: Future studies should define and assign a “true negative” label to GEC-benign nodules that do not develop malignant signs or symptoms during a pre-specified period of follow-up, and these nodules should be included in calculations of diagnostic accuracy.

In this study, we present a simple and effective process that integrates hydrogels with drugs + ceramics via physical crosslinks resulting in improved mechanical properties. These cryogels have the potential for controlled drug release and stimulus responsive behavior. The hydrogels were produced from polyvinyl alcohol (PVA) and polyacrylic acid by varying the molecular weight of the polymers, via freeze‐thawing technique. The cryogels were combined with two ceramics: (1) a combination of beta‐tricalcium phosphate, wollastonite, magnesium silicate and (2) titanium dioxide nanopowder. Theophylline, a model drug, was incorporated into the structure to analyze the drug release behavior. A layered structure was produced by adding both hydrogels + ceramics into a mold where a PVA dried film acted as a barrier and reinforcing structure. The results showed that the barrier integrated between both hydrogels by a physically crosslinking mechanism. This adhesion was demonstrated using Fourier‐transform infrared spectroscopy and scanning electron microscopy. Swelling of this composite showed the profile of drug release from both hydrogels + ceramics while simultaneously releasing the drug independently without diffusing via the opposite layer. Finally, mechanical properties were improved with the addition of the ceramics, which demonstrates the potential approach in terms of modification of weak hydrogel systems. POLYM. COMPOS., 39:E210–E220, 2018. © 2017 Society of Plastics Engineers

Purpose Treatment options for neuroendocrine tumors (NETs) remain limited. This trial assessed the progression-free survival (PFS) of bevacizumab or interferon alfa-2b (IFN-α-2b) added to octreotide among patients with advanced NETs. Patients and Methods Southwest Oncology Group (SWOG) S0518, a phase III study conducted in a US cooperative group system, enrolled patients with advanced grades 1 and 2 NETs with progressive disease or other poor prognostic features. Patients were randomly assigned to treatment with octreotide LAR 20 mg every 21 days with either bevacizumab 15 mg/kg every 21 days or 5 million units of IFN-α-2b three times per week. The primary end point was centrally assessed PFS. This trial is registered with ClinicalTrials.gov as NCT00569127. Results A total of 427 patients was enrolled, of whom 214 were allocated to bevacizumab and 213 to IFN-α-2b. The median PFS by central review was 16.6 months (95% CI, 12.9 to 19.6 months) in the bevacizumab arm and was 15.4 months (95% CI, 9.6 to 18.6 months) in the IFN arm (hazard ratio [HR], 0.93; 95% CI, 0.73 to 1.18; P = .55). By site review, the median PFS times were 15.4 months (95% CI, 12.6 to 17.2 months) for bevacizumab and 10.6 months (95% CI, 8.5 to 14.4 months) for interferon (HR, 0.90; 95% CI, 0.72 to 1.12; P = .33). Time to treatment failure was longer with bevacizumab than with IFN (HR, 0.72; 95% CI, 0.58 to 0.89; P = .003). Confirmed radiologic response rates were 12% (95% CI, 8% to 18%) for bevacizumab and 4% (95% CI, 2% to 8%) for IFN. Common adverse events with bevacizumab and octreotide included hypertension (32%), proteinuria (9%), and fatigue (7%); with IFN and octreotide, they included fatigue (27%), neutropenia (12%), and nausea (6%). Conclusion No significant differences in PFS were observed between the bevacizumab and IFN arms, which suggests that these agents have similar antitumor activity among patients with advanced NETs.