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Prostacyclin infusion for pulmonary arterial hypertension (PAH) is an effective therapy with varied dosing requirements and clinical response. The major aim of this study was to determine new biologically-based predictors of prostacyclin treatment response heterogeneity.Ninety-eight patients with hemodynamically defined PAH at two academic medical centers volunteered for registry studies. A stable dose of treprostinil was the quantitative phenotype for the genome-wide association study (GWAS). Candidate genes with the largest effect sizes and strongest statistical associations were further characterized with in silico and in-vitro assays to confirm mechanistic hypotheses. The clinical significance of these candidate predictors was assessed for mechanistically consistent physiologic effects in an independent cohort of patients.GWAS identified three loci for association with P 10-6. All three loci had clinically significant effect sizes. Specific single-nucleotide polymorphisms (SNPs) at two of the loci: rs11078738 in phosphoribosylformylglycinamidine synthase and rs10023113 in CAMK2D encoded sequence changes with clear predicted consequences. Production of the primary mediator of prostacyclin-induced vasodilation, cyclic AMP, was reduced in human cell lines by the missense variant rs11078738 (p.L621P). Located in the promoter of CAMK2D, the allele of rs10023113 associated with a higher treprostinil dose has higher ventricular transcription of CAMK2δ. At initial diagnostic catheterization in a separate cohort of patients, the same allele of rs10023113 was associated with elevated right mean atrial and ventricular diastolic pressures.The quantitative phenotype of stable treprostinil dose identified two gene loci associated with pharmacodynamic response and right ventricular function in PAH worth further investigation.

Evolutionary biology-based methods to characterize human cancer increasingly inform screening, surveillance, and early stage disease treatment strategies. Advanced metastatic disease presents distinct challenges in research and effective treatment. We have established the Advanced Solid Tumor Registry at the Inova Schar Cancer Institute to systematically track quantitative behavior of advanced solid tumors in a “real world” treatment setting. The study supports collection of serial: plasma samples for ctDNA analysis, computed tomography digital images and semi-automated segmentation of lesions for tumor burden volume measurement, and collection of tumor marker measures among patients receiving routine, longitudinal treatment in a community oncology practice. At submission, the study has enrolled 53 patients, 6 with recurrent metastatic endometrial cancer. Study operations have been enhanced by development of R code and workflow to enable graphical display for individual patients in clinically relevant time. In addition to enhancing clinical decision-making for the individual patients, the collective endometrial cancer patient data currently cover 207 patient-months of observation, 119 circulating marker time-points, 73 CT scans, 27 individual lesions, and 20 different courses of treatment. Treatments included palliative radiation, and: cytotoxic, hormonal, immune-, and targeted therapeutics. We propose this registry represents a new tool to support application of evolutionary science-based methods to clinical care and reciprocally to collect “real world” data with sufficient detail to inform computational science assumptions and inferences in multi-scale modeling projects. In this pilot study, individual cases effectively display multiple observations relevant to understanding treatment response in advanced metastatic disease in the clinical care environment. This project was supported, in part, by R01-CA194783. Citation Format: Erik Dvergsten, Sanja Karovic, Vasiliki Thomeas-McEwing, Danielle Kimble, Pingzhen Guo, Hao Yang, Binsheng Zhao, Lawrence H. Schwartz, Michael L. Maitland. Multidimensional longitudinal assessment of patients under treatment for advanced endometrial cancer: a new tool to advance research on human disease [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO022.

Combined use of new molecular diagnostic and imaging methods could improve care of individual patients with rare cancers. A 57-year-old developed apocrine adenocarcinoma of the left axilla with regional lymph node metastasis detected at initial surgery. After adjuvant regional radiotherapy, metastases developed and over the subsequent 7 years he received serial systemic therapy with 11 different regimens. Expression of 128 proteins/phosphoproteins was evaluated in 8 tissue samples from diagnosis, progressive adenopathy at 45 months, brain metastases at 60 months, and abdominal metastases at 63 months by CLIA-standardized reverse phase phosphoprotein arrays (RPPA). Tumor burden was estimated by quantifying the volume of individual lesions with semi-automated segmentation algorithms on serially collected CT images. Next-generation sequencing (NGS) revealed a PIK3CA K111T mutation, prompting treatment with sirolimus 28 months after diagnosis. Seventeen months later, new neoplastic adenopathy emerged. NGS revealed a new PIK3CA M610V mutation. Semiquantitative scoring of RPPA demonstrated relative increase in AKT (from 0.72 to 0.9) and mTOR (from 0.55 to 0.8) pathway activation. The relative estimated tumor burden (RETB) was 21,145 mm3. Over 6 months of docetaxel therapy the RETB decreased to 12,077 mm3. The patient subsequently received pembrolizumab with increased RETB (71,308 mm3). Gemcitabine appeared to stabilize the RETB (73,168 mm3), but brain metastases emerged. The patient underwent craniotomy, began paclitaxel therapy, and then RETB declined to 35,623 mm3. But new symptomatic abdominal metastases prompted surgical resection. The patient then received the PI3K inhibitor taselisib; however, after an initial decrease, RETB rose to 31,208 mm3. At this point, the patient began bicalutamide therapy. NGS of the primary mass and the initial metastatic adenopathy revealed no amplification of the androgen receptor (AR). But RPPA demonstrated inversion of the ratio of measured phosphorylated AR S81 to AR S650, suggesting primarily cytoplasmic AR in tumor through 45 months but nuclear AR in samples resected at 60 and 63 months. Immunohistochemistry revealed 3+ nuclear AR expression in the latter metastatic tissue. After 9 months of bicalutamide, enzalutamide and leuprolide were administered for 7 months (final RETB = 1,555 mm3). Treatment continued beyond the study period. Tumor burden assessment by new CT imaging measurement methods, combined with RPPA could improve adaptive, responsive, therapy for patients with rare tumors. We identified the phenotypic evolution of androgen-driven growth of apocrine adenocarcinoma after cytotoxic and PI3K-mTOR inhibitor therapy. Protein-based diagnostics revealed an effective treatment strategy in late metastatic disease that was not indicated by NGS testing. Citation Format: Erik Dvergsten, Anthony Serritella, Danielle Kimble, Malcom McIver, Sanja Karovic, Vasiliki Thomeas-McEwing, Hao Yang, Manish R. Sharma, Thomas P. Conrads, Mariaelena Pierobon, Peter Pytel, Binsheng Zhao, Lawrence H. Schwartz, Emanuel F. Petricoin, Russell Szmulewitz, Michael L. Maitland. Longitudinal proteomic assessment of patient with metastatic apocrine adenocarcinoma reveals evolutionary selection for androgen-receptor-dependence and therapeutic response [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5451.