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The pecan nut is a nutrient-rich part of a healthy diet full of beneficial fatty acids and antioxidants, but can also cause allergic reactions in people suffering from food allergy to the nuts. The transcriptome of a developing pecan nut was characterized to identify the gene expression occurring during the process of nut development and to highlight those genes involved in fatty acid metabolism and those that commonly act as food allergens. Pecan samples were collected at several time points during the embryo development process including the water, gel, dough, and mature nut stages. Library preparation and sequencing were performed using Illumina-based mRNA HiSeq with RNA from four time points during the growing season during August and September 2012. Sequence analysis with Trinotate software following the Trinity protocol identified 133,000 unigenes with 52,267 named transcripts and 45,882 annotated genes. A total of 27,312 genes were defined by GO annotation. Gene expression clustering analysis identified 12 different gene expression profiles, each containing a number of genes. Three pecan seed storage proteins that commonly act as allergens, Car i 1, Car i 2, and Car i 4, were significantly up-regulated during the time course. Up-regulated fatty acid metabolism genes that were identified included acyl-[ACP] desaturase and omega-6 desaturase genes involved in oleic and linoleic acid metabolism. Notably, a few of the up-regulated acyl-[ACP] desaturase and omega-6 desaturase genes that were identified have expression patterns similar to the allergen genes based upon gene expression clustering and qPCR analysis. These findings suggest the possibility of coordinated accumulation of lipids and allergens during pecan nut embryogenesis.

Background: SAR439859 has antitumor activity in patients (pts) with wild type (WT) and mutated ESR1 mBC. Here we describe tumor molecular features and evidence of on target activity in SAR439859-treated pts. abstracts Annals of OncologyVolume 31 -Issue S4 -2020 S351period, and at the end of treatment. Samples were analyzed using the Guardant360 platform.Results: Currently, 58 pts have been evaluated at baseline, with 44 pts (75.9%) harboring at least one somatic single nucleotide variant (mutation) in the genes evaluated. Seventeen pts (29.3%) harbored mutations in PIK3CA, with H1047R being the most common (8/17, 47.1%). Seven pts (12.1%) harbored mutations in ESR1, with D583G being the most common (4/7, 57.1%). No pts had mutations in both ESR1 and PIK3CA at baseline. Additionally, 3 pts (5.2%), 2 pts (3.4%), and 1 pt (1.7%) had mutations in genes at baseline associated with CDK4/6 resistance (RB1, CCND1, and CCNE1, respectively). Additional analyses of cfDNA (cycle 1 day 15 and end of treatment) along with correlation of cfDNA dynamics with clinical response are ongoing and will be presented. Conclusions:The most common baseline mutations detected were PIK3CA and ESR1. Additional analyses, including cycle 1 day 15 change from baseline and correlation with clinical response, are anticipated to help elucidate predictors of response and/or resistance to the combination of lerociclib and fulvestrant in patients with HR+ ABC.

Background: Rintodestrant is an orally bioavailable, potent and selective estrogen receptor degrader (SERD) that inhibits estrogen receptor (ER) gene transcription, degrades the ER, and delays tumor proliferation in preclinical models. Preliminary results from Part 1 dose escalation (200-1000 mg once daily) demonstrated that rintodestrant has a favorable safety profile and encouraging antitumor activity in patients (pts) with heavily pretreated ER+/HER2- advanced breast cancer (ABC) (Dees et al., ESMO 2019 [abstract #3587]). Here, we report the pharmacodynamic (PD) analysis in peripheral blood and tumor biopsies from pts who received rintodestrant in Part 1 and 2 (600 and 1000 mg dose expansion) to characterize the pt population and mechanisms of response. Methods: This Phase 1, first-in-human, open-label study evaluated rintodestrant in women with ER+/HER- ABC after progression on endocrine therapy. PD analysis included inhibition of ER target engagement with 18F-fluoroestradiol positron emission tomography (FES-PET), mutational profiling (cell-free DNA [cfDNA]), and circulating tumor cell (CTC) enumeration. Tumor biopsies sampled at baseline and 6 weeks on treatment were evaluated for ER degradation (immunohistochemistry [IHC]) and proliferation (Ki67, IHC) to understand the on-target effects of rintodestrant. Results: As of May 13, 2020, 67 pts had been treated. FES-PET data were obtained in 14 pts and showed a decrease in all pts, with maximum standard uptake values (SUVmax) ranging from 70% to 98% after 4 weeks of rintodestrant monotherapy across all doses. Fifty-nine pts were tested for cfDNA at baseline; 95% (n = 56) harbored ≥1 somatic variant (median = 3 mutations per pt). Among pts with somatic variants, 41% had ESR1 mutations, with D538G being the most common (58%). Additionally, 46% and 42% of pts harbored mutations in TP53 and PIK3CA, respectively, and 10% had mutations in both ESR1 and PIK3CA. Similar clinical benefit rates were observed in wild-type vs ESR1 and/or PIK3CA mutant tumors. An analysis of change of variant allele fraction (VAF) in 55 pts between baseline and 2 weeks of treatment revealed that 58% had a decrease in mean VAF, with a decrease in ESR1 VAF in 16/20 pts that had ESR1 mutations at baseline. Furthermore, of 24 pts who had samples collected at baseline and progression, 16 (67%) developed additional variants (median [range]: 2 [1, 15]), including EGFR, ERBB2, TP53, and ESR1. CTC analysis (n = 45) showed the mean value of Epi+CD45- CTCs decreased from 2.8 cells/mL to 1.8 cells/mL after 8 weeks of treatment. Tumor biopsies were collected in 9 pts (5 received 600 mg and 4 received 1000 mg) at baseline and 6 weeks on treatment. Of the 7/9 pts that had a decrease in the ER H-score (median [range]: -27.8% [-33.8%, -3.4%]), 4 had ≥1 variant in ESR1 at baseline. Overall, 4 pts had a decrease in Ki67, with reductions mostly observed in pts who received 600 mg rintodestrant. Additional analyses, including correlations with clinical response, are ongoing and will be presented. Conclusions: Rintodestrant demonstrated robust ER target engagement on FES-PET, as well as substantial decreases in ER H-score, cfDNA VAF, and Epi+CD45- CTCs. These data, along with promising clinical benefit in pts with heavily pretreated ER+/HER2- ABC, regardless of ESR1 or PIK3CA mutation status, warrant additional investigation of rintodestrant (NCT03455270). Citation Format: Philippe Aftimos, Marina Maglakelidze, Andor WJM Glaudemans, Erika Hamilton, Linnea Chap, Elisabeth de Vries, Catharina Willemien Menke-van der Houven van Oordt, Agnes Jager, E. Claire Dees, Massimo Cristofanilli, Mark Pegram, Susanna Ulahannan, Patrick Neven, Iurie Bulat, Ruhi Rai, Wenli Tao, Sarika Jain, Andrew P Beelen, Jessica A Sorrentino. Pharmacodynamic analysis from a phase 1 study of rintodestrant (G1T48), an oral selective estrogen receptor degrader, in ER+/HER2- locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD8-07.