Citations

Abstract Background: Preclinical and clinical data indicate a key role for the PI3-kinase (PI3K) pathway in the pathogenesis of resistance to endocrine therapies in hormone receptor-positive (HR) breast cancer (BC) and suggest that combining PI3K inhibitors with endocrine therapy may partially overcome this resistance. FERGI is the first randomized Phase II study testing pictilisib (GDC-0941), a PI3K inhibitor, in combination with fulvestrant to evaluate this hypothesis in MBC patients with and without PIK3CA-mutant tumors. Methods: 168 post-menopausal pts with ER-positive, HER2-negative MBC were randomized (1:1) to receive fulvestrant with either pictilisib 340 mg QD (n=89, "combination" arm) or matching placebo (n=79, "control" arm). To be eligible, pts had to have relapsed during or within 6 mos of completing adjuvant AI treatment or have progressed on an AI for MBC. Pts were stratified based on tumor PIK3CA mutation status, resistance to prior AI therapy and presence of measurable disease. The primary endpoint was PFS by investigator assessment in the intent-to-treat (ITT) group and in pts with centrally confirmed PIK3CA-mutant tumors. The primary analysis was based on a 6 mo median duration follow up. Results: Baseline disease and prior treatment characteristics were similar between study arms. Observed treatment-emergent AEs were consistent with those previously described for single agent pictilisib and fulvestrant (primary toxicities were rash and GI disorders). In the ITT population (84 events) the median PFS (mPFS) was 6.2 mo in the combination arm vs 3.8 months for the control arm (HR, 0.77; 95% CI, 0.50-1.19). For pts with PIK3CA-mutant tumors (37 events), mPFS was 6.2 mo in the combination arm vs 5.1 mo in the control arm (HR, 0.92; 95% CI, 0.48-1.76). For pts without a detectable PIK3CA mutant tumor (43 events), mPFS was 5.8 months in the combination arm vs 3.6 months in the control arm (HR, 0.64; 95% CI, 0.35-1.17). Exploratory post-hoc subgroup analysis suggested improvement in PFS in pts with ER+ and PR+ tumors (centrally confirmed) treated with pictilisib plus fulvestrant. In the ER+/PR+ subgroup (57 events) mPFS was 7.2 mo in the combination arm vs 3.7 mo in the control arm (HR, 0.46; 95% CI, 0.27 to 0.78). This improvement was independent of tumor PIK3CA mutation status. Multivariate analysis suggests that this treatment effect in pts with ER+/PR+ tumors is maintained after adjusting for possible baseline imbalances. A similar analysis on pts with luminal A tumors (per PAM50 analysis) was also consistent with the findings in pts ER+/PR+ disease. Conclusions: This is the first report of a blinded, randomized clinical study evaluating a PI3K inhibitor in pts with MBC. In the ITT population, the addition of pictilisib to fulvestrant was associated with a mPFS improvement of 3.8 mo to 6.2 mo. Exploratory subgroup analyses suggested in pts with ER+/PR+ tumors are more likely to derive benefit from the addition of pictilisib to fulvestrant irrespective of PIK3CA mutation status, though the subgroup analyses are limited by the sample size. Additional biomarker analyses will be reported. Citation Format: Ian Krop, Stephen Johnston, Ingrid A Mayer, Maura Dickler, Vinod Ganju, Andres Forero-Torres, Bohuslav Melichar, Serafin Morales, Richard de Boer, Steven Gendreau, Mika Derynck, Mark Lackner, Jill Spoerke, Ru-Fang Yeh, Gallia Levy, Vivian Ng, Carol O'Brien, Heidi Savage, Yuanyuan Xiao, Timothy Wilson, Soo Chin Lee, Katarina Petrakova, Susanne Vallentin, Denise Yardley, Matthew Ellis, Martine Piccart, Edith A Perez, Eric Winer, Peter Schmid. The FERGI phase II study of the PI3K inhibitor pictilisib (GDC-0941) plus fulvestrant vs fulvestrant plus placebo in patients with ER+, aromatase inhibitor (AI)-resistant advanced or metastatic breast cancer – Part I results [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S2-02.

Abstract Background: Although the spectrum of genomic alterations in primary, treatment-naïve breast tumors has been described, the genomic landscape of HER2+ MBC remains underexplored. Furthermore, tumor genomic alterations that arise after progression on anti-HER2 therapy are largely unknown. Methods: We prospectively collected metastatic tumor biopsies from patients (pts) enrolled on TBCRC003 (NCT00470704), a phase II study evaluating the combination of lapatinib (L) and T in pts with HER2+ MBC who had varying degrees of prior T exposure. We performed WES on baseline metastatic biopsies and normal DNA from 57 pts. In 36 pts, we also performed WES on pre-treatment primary tumors. Tumors were analyzed for point mutations, insertions/deletions, and copy number alterations. Results: Total accrual was 116 pts. 87 pts were registered in one of two efficacy cohorts: Cohort 1 included pts w no prior T for MBC. Pts with prior adjuvant T were included if the interval from last T to 1st recurrence > 12 months. Cohort 2 included pts with 1-2 prior lines of T for MBC or recurrence within 12 months of adjuvant T. An additional 29 pts were enrolled in a biomarker cohort (Cohort 3). Per-protocol efficacy analyses for 85 pts deemed evaluable are shown below: Objective Response RateClinical Benefit RateMedian Time to ProgressionCohort 150% (90% CI 33.8-66.2%)57.5% (95% CI 40.9-73.0)7.4 monthsCohort 222.2% (90% CI 11.2-37.1%)42.2% (95% CI 27.7-57.8)5.3 months As we previously reported (Wagle et al, ASCO 2014), across 57 metastatic tumors, significant recurrently mutated genes were TP53 (n=30; 53%) and PIK3CA (n=19; 33%). The frequency of mutant TP53 and PIK3CA was not significantly different from 119 primary, treatment-naïve HER2+ tumors sequenced in the TCGA study (50%, p=0.8 and 27%, p=0.5, respectively). Recurrent copy number alterations were also similar to TCGA data. Comparing the 38 pts who received any prior T with the 19 pts who did not, there was no significant difference in the incidence of mutant TP53 (53% vs 53%, p=1.0) and PIK3CA (37% vs 26%, p=0.6). We identified mutations in the HER2 kinase domain in 4/38 pts who received prior T (11%), as compared to 0/19 T-naïve pts. HER2 kinase domain mutations have been identified in ∼2% of HER2-negative cancers but <1% of primary HER2+ cancers. 3 of the mutations were L755S, which has been shown to be resistant to L and sensitive to irreversible HER2 inhibitors. The 4th mutation was D742N, a novel kinase domain mutation. None of the 4 pts with HER2 kinase domain mutations had an objective response, though 1 pt had stable disease for 29 weeks. An analysis comparing paired archival primary tumors and baseline metastatic biopsies from 36 pts to identify genomic alterations acquired or enriched in the metastatic tumors will be presented. Conclusions: We present an analysis of the genomic landscape of HER2+ MBC, including comparisons between matched primary tumors and metastatic biopsies. Somatic HER2 kinase mutations in pts with HER2+ MBC treated with prior T suggests that these mutations may be involved in resistance to T, and may predict poor response to additional anti-HER2 therapy with combined L and T. Novel therapeutic approaches may be required for these pts. Citation Format: Nikhil Wagle, Nancy U Lin, Andrea L Richardson, Ignaty Leshchiner, Ingrid A Mayer, Andres Forero-Torres, Timothy J Hobday, Elizabeth C Dees, Rita Nanda, Mothaffar F Rimawi, Hao Guo, William T Barry, Ron Bose, Wei Shen, Antonio C Wolff, Stacey B Gabriel, Levi A Garraway, Eric P Winer, Ian E Krop. Whole exome sequencing (WES) of HER2+ metastatic breast cancer (MBC) from patients with or without prior trastuzumab (T): A correlative analysis of TBCRC003 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD3-5.

Intracardiac thrombosis (ICT) during orthotopic liver transplantation (OLT) is an uncommon event. However, it is a devastating complication with high mortality when it occurs. This study aimed to identify possible predisposing factors for ICT during OLT. We retrospectively identified the cases of all patients with ICT during OLT at our institution from 1998 to 2014. Of 2750 OLTs performed, 10 patients had ICT intraoperatively. The patients' immediate prethrombosis intraoperative hemodynamic and coagulation values and thromboelastography (TEG) data were reviewed. Preexisting venous thrombosis, atrial fibrillation, and the prior placement of a transjugular intrahepatic portosystemic shunt for portal hypertension were noted in several patients and may be related to ICT during OLT. A high Model of End‐Stage Liver Disease score, low cardiac output, and sepsis did not appear to be associated with ICT. ICT occurred in some patients without the administration of antifibrinolytic agents. TEG and coagulation parameters did not appear to be helpful in predicting the onset of ICT. Four patients had ICT in both right‐ and left‐sided heart chambers; none of these 4 patients survived. All 6 patients with only right‐sided thrombus survived. In those who survived, improved hemodynamics and clot disappearance on transesophageal echocardiography (TEE) occurred over time, even without the use of thrombolytics. Whether this is because of endogenous thrombolysis or distal clot propagation into the pulmonary vasculature, or both, is unclear. Tissue plasminogen activator may have a role in the resuscitation procedure. In conclusion, without the routine use of TEE during OLT, the incidence of ICT will remain an under‐recognized event. Liver Transpl 21:1280‐1285, 2015. © 2015 AASLD.

Abstract An ovarian cancer Genome Wide Association Study (GWAS) identified 9p22.2 as a novel susceptibility locus with the most statistically significant single nucleotide polymorphisms (SNPs) located in an intergenic region near the Basonuclin 2 (BNC2) gene, which codes for a putative transcription regulator containing three pairs of zinc finger (ZF) domains. The minor alleles are protective in terms of ovarian cancer susceptibility. However, the molecular mechanisms by which these SNPs modify susceptibility remain largely unknown. The significant SNPs in the 9p22.2 locus lie in non-coding regions and therefore are hypothesized to affect the activity of regulatory elements and modify the expression of a target gene(s). In order to test this hypothesis we conducted fine mapping for the locus which delimited a ∼74kb region containing SNPs with a p-value less than 10-8. FAIRE-Seq and ChIP-Seq experiments for histone markers conducted in immortalized ovarian surface epithelial cells (IOSE) and fallopian tube epithelial cells (IFTE) were used to prioritize functional SNP candidates which overlap with regulatory elements. Luciferase assays tested the ability of these regulatory elements to activate transcription. Chromosome conformation capture (3C) experiments demonstrate a physical interaction between the BNC2 promoter and candidate regulatory elements containing risk-associated SNPs. Methylation Quantification at Trait Loci (mQTL) revealed an association between decreased methylation at the BNC2 promoter and the protective minor alleles. Expression analysis shows decreased expression of BNC2 in cancer versus normal tissue implicating tumor suppressor function of BNC2. Therefore the protective minor allele likely increases expression of BNC2 which in turn contains tumor suppressing properties that decrease ovarian cancer risk. BNC2 protein is in complex with transcriptional regulatory proteins, in particular the NURD complex components. Moreover, BNC2 acts as a transcriptional repressor in in vitro transfection assays indicating that it functions in transcriptional repression. We then used protein binding microarrays and CHIP-Seq experiments to identify its putative DNA binding motifs and its downstream target genes. Analysis of this data suggests that BNC2 functions in a regulatory transcription network that impacts on genes implicated in ovarian cancer with enrichment for genes in the TGF-beta response pathway. Citation Format: Melissa A. Buckley, Howard C. Shen, Gustavo A. Mendoza-Fandino, Nicholas T. Woods, Anxhela Gjyshi, Juliet French, Kate Lawrenson, Honglin Song, Jonathan Tyrer, Renato S. Carvalho, Alexandra Valle, Ann Chen, Sean Yoder, Gregory Bloom, Ya-Yu Tsai, Ally Yang, Timothy R. Hughes, Xiaotao Qu, Mine Cicek, Melissa Larson, Ellen Goode, Brooke Fridley, Susan Ramus, Georgia Chenevix-Trench, Paul Pharoah, Thomas A. Sellers, Simon Gayther, Alvaro N.A. Monteiro, Ovarian Cancer Association Consortium. Functional analysis of the 9p22 locus implicates the transcriptional regulation of BNC2 as a mechanism in ovarian cancer predisposition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3285. doi:10.1158/1538-7445.AM2014-3285

BACKGROUND Although hypogammaglobulinemia is a well recognized complication in patients with chronic lymphocytic leukemia (CLL), its prevalence at the time of CLL diagnosis, and association with novel prognostic markers and clinical outcome is not well understood. METHODS All patients at the Mayo Clinic between January 1999 and July 2013 who had newly diagnosed CLL and had a baseline assessment of serum immunoglobulin G (IgG) were included. The relation between hypogammaglobulinemia at diagnosis and the novel prognostic parameters time to first treatment (TFT) and overall survival (OS) were evaluated. RESULTS Of 1485 patients who met the eligibility criteria, 382 (26%) had hypogammaglobulinemia (median IgG, 624 mg/dL), whereas the remaining 1103 patients (74%) had normal serum IgG levels (median IgG, 1040 mg/dL). Patients who had hypogammaglobulinemia at diagnosis were more likely to have advanced Rai stage (III‐IV; P = .001) and higher expression of CD49d ( P < .001) compared with patients who had normal IgG levels. Although the median TFT for patients who had hypogammaglobulinemia was shorter compared with that for patients who had normal IgG levels (3.8 years vs 7.4 years; P < .001), on multivariable analysis, there was no difference in OS between these 2 groups (12.8 years vs 11.3 years, respectively; P = .73). Of 1103 patients who had CLL with normal IgG levels at diagnosis and who did not receive CLL therapy, the risk of acquired hypogammaglobulinemia was 11% at 5 years and 23% at 10 years. CONCLUSIONS Hypogammaglobulinemia is present in 25% of patients with newly diagnosed CLL. Approximately 25% of patients who have CLL with normal IgG levels at diagnosis will subsequently develop hypogammaglobulinemia on long‐term follow‐up. The presence of hypogammaglobulinemia does not appear to impact overall survival. Cancer 2015;121:2883–2891. © 2015 American Cancer Society .

Background— After left ventricular assist device (LVAD) placement for advanced heart failure, increased cerebral perfusion should result in improved cognitive function. However, stroke (a well-known LVAD complication) and subclinical cerebral ischemia may result in transient or permanent cognitive decline. We sought to describe the incidence and predictors of cognitive decline after LVAD using a valid, sensitive assessment tool. Methods and Results— Among 4419 patients in the Interagency Registry for Mechanically Assisted Circulatory Support who underwent LVAD implantation between May 2012 and December 2013, cognitive function was assessed in 1173 patients with the Trail Making B Test before LVAD and at 3, 6, and 12 months. The test detects several forms of cognitive impairment, including subclinical stroke. Cognitive decline was defined as a clinically important increase during follow-up using a moderate Cohen d effect size of 0.5×baseline SD (32 s). The cumulative incidence of cognitive decline in the year after LVAD implantation, treating death and transplantation as competing risks, was 29.2%. In adjusted analysis, older age (≥70 versus <50 years; hazard ratio, 2.24; 95% confidence interval 1.46–3.44; P trend <0.001) and destination therapy (hazard ratio, 1.42; 95% confidence interval, 1.05–1.92) were significantly associated with greater risk of cognitive decline. Conclusions— Cognitive decline occurs commonly in patients in the year after LVAD and is associated with older age and destination therapy. These results could have important implications for patient selection and improved communication of risks before LVAD implantation. Additional studies are needed to explore the association between cognitive decline and subsequent stroke, health status, and mortality in patients after LVAD.

Ischemia-reperfusion injury (IRI) due to hypotension is a common cause of human acute kidney injury (AKI). Hypoxia-inducible transcription factors (HIFs) orchestrate a protective response in renal endothelial and epithelial cells in AKI models. As human mucin 1 (MUC1) is induced by hypoxia and enhances HIF-1 activity in cultured epithelial cells, we asked whether mouse mucin 1 (Muc1) regulates HIF-1 activity in kidney tissue during IRI. Whereas Muc1 was localized on the apical surface of the thick ascending limb, distal convoluted tubule, and collecting duct in the kidneys of sham-treated mice, Muc1 appeared in the cytoplasm and nucleus of all tubular epithelia during IRI. Muc1 was induced during IRI, and Muc1 transcripts and protein were also present in recovering proximal tubule cells. Kidney damage was worse and recovery was blocked during IRI in Muc1 knockout mice compared with congenic control mice. Muc1 knockout mice had reduced levels of HIF-1α, reduced or aberrant induction of HIF-1 target genes involved in the shift of glucose metabolism to glycolysis, and prolonged activation of AMP-activated protein kinase, indicating metabolic stress. Muc1 clearly plays a significant role in enhancing the HIF protective pathway during ischemic insult and recovery in kidney epithelia, providing a new target for developing therapies to treat AKI. Moreover, our data support a role specifically for HIF-1 in epithelial protection of the kidney during IRI as Muc1 is present only in tubule epithelial cells.

Hypoglycemia results in a reduction in cardiac baroreflex sensitivity and a shift in the baroreflex working range to higher heart rates. This effect is mediated, in part, by the carotid chemoreceptors. Therefore, we hypothesized hypoglycemia-mediated changes in baroreflex control of heart rate would be blunted in carotid body–resected patients when compared with healthy controls. Five patients with bilateral carotid body resection for glomus tumors and 10 healthy controls completed a 180-minute hyperinsulinemic, hypoglycemic (≈3.3 mmol/L) clamp. Changes in heart rate, blood pressure, and spontaneous cardiac baroreflex sensitivity were assessed. Baseline baroreflex sensitivity was not different between groups ( P >0.05). Hypoglycemia resulted in a reduction in baroreflex sensitivity in both the groups (main effect of time, P <0.01) and responses were lower in resected patients when compared with controls (main effect of group, P <0.05). Hypoglycemia resulted in large reductions in systolic (−17±7 mm Hg) and mean (−14±5 mm Hg) blood pressure in resected patients that were not observed in controls (interaction of group and time, P <0.05). Despite lower blood pressures, increases in heart rate with hypoglycemia were blunted in resected patients (interaction of group and time, P <0.01). Major novel findings from this study demonstrate that intact carotid chemoreceptors are essential for increasing heart rate and maintaining arterial blood pressure during hypoglycemia in humans. These data support a contribution of the carotid chemoreceptors to blood pressure control and highlight the potential widespread effects of carotid body resection in humans.