NCI-MATCH Arms N & P: Phase II study of PI3K beta inhibitor GSK2636771 in patients (pts) with cancers (ca) with PTEN mutation/deletion (mut/del) or PTEN protein loss

Background: The NCI-MATCH trial is the largest national study (1173 sites) for ptswith relapsed/ refractory solid tumors, lymphomas and myeloma, which assigns tar-geted therapies based on individual tumor molecular alterations detected using theadapted Oncomine AmpliSeq panel (143 genes) and immunohistochemistry (IHC).We hypothesized that patients with PTEN-deficient cancers enrolled to Arms N and Pmay benefit from treatment with the PI3K beta-selective inhibitor GSK2636771. Methods: Eligibility: relapsed/refractory ca, good end-organ function, and ECOG PS ≤ 1. Pts were screened for molecular alterations by centralized testing on fresh tumor biopsy and had deleterious PTEN mut/del without loss of expression (Arm N) or complete loss of cytoplasmic and nuclear PTEN staining on IHC (Arm P), and no other aberrations activating the PI3K/MTOR and MAPK pathways (mut in PIK3CA, PIK3R1, BRAF, KRAS, AKT1, TSC1/2, mTOR, RHEB, NF2, NRAS, HRAS). Pts received GSK2636771 400mg/day (28-days cycles). RECIST 1.1 overall response rate (ORR) was the primary endpoint. Results: Of 59 enrolled pts, 56 were eligible and received treatment. Of 22 pts with PTEN mut/del (Arm N: 6 uterine, 2 breast, 2 prostate, 2 head/neck ca, 10 other), all are off treatment as of analysis (14 disease progression, 4 for adverse events [AEs], 4 other). One pt (4.5%) with prostate ca (PTEN deletion, MPRSS2-ERG fusion) attained a partial response (-42%). Of 7 (32%) pts with stable disease (SD), 2 had SD \u3e 6 months (uterine leiomyosarcoma; endometrial carcinoma). Of 34 pts with loss of PTEN protein by IHC (Arm P: 7 prostate, 6 breast, 3 squamous anal ca, 2 cholangiocarcinoma, 16 other), all are off treatment as of analysis (26 disease progression, 4 for AE, 4 other). Of 9 (37.5%) pts with SD, 3 had SD \u3e 6 months (prostate cancer; squamous bladder cancer, squamous anal cancer). Median progression-free survival was 1.8 months for both arms. Gr ≥ 3 treatment-related (tr) reversible toxicities were experienced by 30% (7) and 20% (7) of pts in arms N and P, respectively. No tr Gr 5 toxicities were observed in either arm. Conclusions: Single agent GSK2636771 has very modest activity in ca with PTEN gene mutation/deletion and/or PTEN protein loss

Targeted Mutation Detection in Advanced Breast Cancer Using MammaSeq Identifies RET as a Potential Contributor to Breast Cancer Metastasis

The lack of any reported breast cancer specific diagnostic NGS tests inspired the development of MammaSeq, an amplicon based NGS panel built specifically for use in advanced breast cancer. In a pilot study to define the clinical utility of the panel, 46 solid tumor samples, plus an additional 14 samples of circulating-free DNA (cfDNA) from patients with advanced breast cancer were sequenced and analyzed using the OncoKB precision oncology database. We identified 26 clinically actionable variants (levels 1-3) annotated by the OncoKB precision oncology database, distributed across 20 out of 46 solid tumor cases (40%), and 4 clinically actionable mutations distributed across 4 samples in the 14 cfDNA sample cohort (29%). The mutation allele (MAF) frequencies of ESR1-D538G and FOXA1-Y175C mutations correlated with CA.27.29 levels in patient-matched blood, indicating that MAF may be a reliable marker for disease burden. Interestingly, 4 of the mutations found in metastatic samples occurred in the gene RET, an oncogenic receptor tyrosine kinase. In an orthogonal study, the lab has recently identified RET as one of the most recurrently upregulated genes in breast cancer brain metastases. Interestingly, the ligand for RET is the family of glial-cell derived neurotrophic factors (GDNF), a growth factor secreted by glial cells of the central nervous system. This lead to the hypothesis that RET overexpression facilitates breast cancer brain metastasis in response to the high levels of GDNF, while RET activating point mutations increase metastatic capacity without specific organ tropism. While the effect of GDNF treatment on proliferation in 2D was limited, in ultra-low attachment (ULA) plates we saw a significant increase in anchorage independent growth of MCF-7 cells. To determine if GDNF acts as a chemoattractant for RET positive BrCa cells, we utilized a transwell migration assay, with GDNF as the sole chemoattractant. When RET was overexpressed, there was a visual increase in cell migration. Together, these studies demonstrate the clinical feasibility of using MammaSeq to detect clinically actionable mutations in breast cancer patients, and provides provisional data supporting the investigation of RET signaling as a potentially targetable mediator of breast cancer brain metastasis

The molecular landscape of premenopausal breast cancer

Introduction: Breast cancer in premenopausal women (preM) is frequently associated with worse prognosis compared to that in postmenopausal women (postM), and there is evidence that preM estrogen receptor-positive (ER+) tumors may respond poorly to endocrine therapy. There is, however, a paucity of studies characterizing molecular alterations in premenopausal tumors, a potential avenue for personalizing therapy for this group of women. Methods: Using TCGA and METABRIC databases, we analyzed gene expression, copy number, methylation, somatic mutation, and reverse-phase protein array data in breast cancers from >2,500 preM and postM women. Results: PreM tumors showed unique gene expression compared to postM tumors, however, this difference was limited to ER+ tumors. ER+ preM tumors showed unique DNA methylation, copy number and somatic mutations. Integrative pathway analysis revealed that preM tumors had elevated integrin/laminin and EGFR signaling, with enrichment for upstream TGFβ-regulation. Finally, preM tumors showed three different gene expression clusters with significantly different outcomes. Conclusion: Together these data suggest that ER+ preM tumors have distinct molecular characteristics compared to ER+ postM tumors, particularly with respect to integrin/laminin and EGFR signaling, which may represent therapeutic targets in this subgroup of breast cancers

Understanding how sporting characteristics and behaviours influence destination selection: a grounded theory study of golf tourism

Sports tourism has received growing attention in academic research over the past two decades (Weed and Bull, 2009, Gibson, 2005) but greater understanding of the consumer is needed, particularly the factors influencing decisions to include sport as part of a leisure trip. This paper provides, through a focus on the sport of golf, insight into the characteristics of the sports tourist and how sports tourist behaviours influence the selection of locations deemed suitable for sports participation. This qualitative research employs a grounded theory methodology, underpinned by a constructivist epistemology, to evaluate twenty-six in-depth interviews with golf tourists. The findings propose a model which explains the relationship between golf tourist behaviours and destination selection. This identifies six strands which determine the relationship between the golf tourist, golf behaviours and destination selection (constructing the golf holiday, emotional rewards of taking a trip, total trip spend, amenities and support facilities, course characteristics and reputation of the destination). Furthermore it illuminates the complexity of these relationships through recognition of four spheres of influence (group dynamics, competition and ability, golfing capital and intermediaries). Discussion elucidates how this increased understanding of the golf tourist behaviours and destination selection might be applied to other sports, with conclusions exploring implications for the sports tourism industry and destinations

Transmission of Fusarium boothii Mycovirus via Protoplast Fusion Causes Hypovirulence in Other Phytopathogenic Fungi

There is increasing concern regarding the use of fungicides to control plant diseases, whereby interest has increased in the biological control of phytopathogenic fungi by the application of hypovirulent mycoviruses as a possible alternative to fungicides. Transmission of hypovirulence-associated double-stranded RNA (dsRNA) viruses between mycelia, however, is prevented by the vegetative incompatibility barrier that often exists between different species or strains of filamentous fungi. We determined whether protoplast fusion could be used to transmit FgV1-DK21 virus, which is associated with hypovirulence on F. boothii (formerly F. graminearum strain DK21), to F. graminearum, F. asiaticum, F. oxysporum f. sp. lycopersici, and Cryphonectria parasitica. Relative to virus-free strains, the FgV1-DK21 recipient strains had reduced growth rates, altered pigmentation, and reduced virulence. These results indicate that protoplast fusion can be used to introduce FgV1-DK21 dsRNA into other Fusarium species and into C. parasitica and that FgV1-DK21 can be used as a hypovirulence factor and thus as a biological control agent

Interspecific comparisons of C\u3csub\u3e3\u3c/sub\u3e turfgrass for tennis use: I. Wear tolerance and carrying capacity under actual match play

Previous studies in the evaluation of wear tolerance have been conducted using wear simulators. Research to investigate wear tolerance of C3 turfgrasses under actual playing conditions and their carrying capacity is limited. Three grass tennis courts (replicates) maintained as official size (single) courts were constructed. Eight species and cultivars were randomized within the three courts (blocks): (1) ‘Keeneland’ Kentucky bluegrass (KB, Poa pratensis L.), (2) ‘Rubix’ KB, (3) ‘Villa’ velvet bentgrass (VBG, Agrostis canina L.), (4) ‘Puritan’ colonial bentgrass (CL, Agrostis capillaris L.), (5) ‘007’ creeping bentgrass (CB, Agrostis stolonifera L.), (6) fine fescue (FF, Festuca spp.) mixture, (7) ‘Karma’ perennial ryegrass (PR, Lolium perenne L.), and (8) ‘Wicked’ PR. Injury at the baseline was measured by counting healthy grass on four dates in 2017 and 2019 using an intersect grid. Carrying capacity at the baseline was derived as hours of play to sustain 90, 80, 70, and 60% grass cover. After 6 wk of actual tennis play involving \u3e120 participating players in 2017 and 2019, KB and PR were superior to other C3 turfgrass for wear tolerance and carrying capacity. These two species exhibited four times the carrying capacity of FF species and nearly 60% more carrying capacity than bentgrass (BG) species. Species of BG afforded higher shoot density and better traction than KB and PR, with VBG exhibiting the best traction, and FF and PR exhibiting the poorest traction. In 2017, greater cell wall content increased wear tolerance and carrying capacity. Velvet bentgrass was as good as KB and PR in overall wear tolerance and carrying capacity under actual match play

TBCRC 002: A phase II, randomized, open-label trial of preoperative letrozole with or without bevacizumab in postmenopausal women with newly diagnosed stage 2/3 hormone receptor-positive and HER2-negative breast cancer

Background: In preclinical studies, the expression of vascular endothelial growth factor (VEGF) in hormone receptor-positive breast cancer is associated with estrogen-independent tumor growth and resistance to endocrine therapies. This study investigated whether the addition of bevacizumab, a monoclonal antibody against VEGF, to letrozole enhanced the antitumor activity of the letrozole in the preoperative setting. Methods: Postmenopausal women with newly diagnosed stage 2 or 3 estrogen and/or progesterone receptor-positive, HER2-negative breast cancer were randomly assigned (2:1) between letrozole 2.5 mg PO daily plus bevacizumab 15 mg/kg IV every 3 weeks (Let/Bev) and letrozole 2.5 mg PO daily (Let) for 24 weeks prior to definitive surgery. Primary objective was within-arm pathologic complete remission (pCR) rate. Secondary objectives were safety, objective response, and downstaging rate. Results: Seventy-five patients were randomized (Let/Bev n = 50, Let n = 25). Of the 45 patients evaluable for pathological response in the Let/Bev arm, 5 (11%; 95% CI, 3.7-24.1%) achieved pCR and 4 (9%; 95% CI, 2.5-21.2%) had microscopic residual disease; no pCRs or microscopic residual disease was seen in the Let arm (0%; 95% CI, 0-14.2%). The rates of downstaging were 44.4% (95% CI, 29.6-60.0%) and 37.5% (95% CI, 18.8-59.4%) in the Let/Bev and Let arms, respectively. Adverse events typically associated with letrozole (hot flashes, arthralgias, fatigue, myalgias) occurred in similar frequencies in the two arms. Hypertension, headache, and proteinuria were seen exclusively in the Let/Bev arm. The rates of grade 3 and 4 adverse events and discontinuation due to adverse events were 18% vs 8% and 16% vs none in the Let/Bev and Let arms, respectively. A small RNA-based classifier predictive of response to preoperative Let/Bev was developed and confirmed on an independent cohort. Conclusion: In the preoperative setting, the addition of bevacizumab to letrozole was associated with a pCR rate of 11%; no pCR was seen with letrozole alone. There was additive toxicity with the incorporation of bevacizumab. Responses to Let/Bev can be predicted from the levels of 5 small RNAs in a pretreatment biopsy. Trial registration: This trial is registered with ClinicalTrials.gov (Identifier: NCT00161291), first posted on September 12, 2005, and is completed

Efficacy and tolerability of veliparib (V; ABT-888) in combination with carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer: A randomized, phase 2 study

Background: Poly(ADP-ribose) polymerase (PARP) inhibitors block DNA damage repair and may thereby enhance the clinical activity of DNA-damaging chemotherapy. Homologous recombination is defective in BRCA1/2-mutated tumors, leading to more error-prone mechanisms of DNA repair and increased sensitivity to PARP inhibition. V is a potent PARP inhibitor that enhances the antitumor activity of platinum agents in preclinical models. This phase 2 trial (NCT01506609) investigated the safety and efficacy of V+C/P or V+ temozolomide (TMZ) vs Plc+C/P in pts with locally recurrent or metastatic breast cancer harboring a BRCA1 or BRCA2 mutation. Results of the V+C/P and Plc+C/P arms are presented; V+TMZ results will be presented separately. Methods: Pts ≥18 years with histologically confirmed locally recurrent or metastatic breast cancer were randomized 1:1:1 to: 1) V 40 mg BID D1–7+TMZ, 28-D cycle; 2) V 120 mg BID D1–7+C AUC 6, D3 and P 175 mg/m2, D3, 21-D cycle; or 3) Plc BID D1–7+C/P. Key eligibility criteria included deleterious BRCA1/2 mutation, ≤2 prior chemotherapies for metastatic disease, no prior platinum agent, and no CNS metastases. Randomization was stratified by hormone receptor status..

Evaluation of veliparib (V) and temozolomide (TMZ) in a phase 2 randomized study of the efficacy and tolerability of V+TMZ or carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer

DOI: 10.1158/1538-7445.SABCS16-P4-22-02 Published February 201