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Background Genomic testing of somatic and germline DNA has transformed cancer care. However, low genetic knowledge among patients may compromise care and health outcomes. Given the rise in genomic testing, we sought to understand patients’ knowledge of their genetic test results. Materials and Methods We conducted a survey‐based study with 85 patients at a comprehensive cancer center. We compared self‐reported recall of (a) having had somatic/germline testing and (b) their specific somatic/germline results to the genomic test results documented in the medical record. Results Approximately 30% of patients did not recall having had testing. Of those who recalled having testing, 44% of patients with pathogenic/likely pathogenic germline mutations and 57% of patients with reported somatic alterations did not accurately recall their specific gene or variant‐level results. Conclusion Given significant knowledge gaps in patients’ recall of genomic testing, there is a critical need to improve patient‐directed education and return‐of‐results strategies., Considering the increase in genomic testing for cancer care, this study aimed to better understand patients’ knowledge of their genetic test results.

Peritoneal metastases (PM) from ovarian, gastric, appendiceal, or colorectal origin can be treated via cytoreductive surgery with or without the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) for selected patients. Unfortunately, not all patients are candidates for aggressive surgical debulking. For these patients, pressurized intraperitoneal aerosolized chemotherapy (PIPAC) has emerged as an alternative method for intraperitoneal (IP) chemotherapy administration. This report presents the design and implementation of the first phase 1 trial to evaluate the safety and efficacy of PIPAC in the United States. This is an ongoing prospective phase 1 clinical trial of PIPAC for patients who have histologically confirmed ovarian, uterine, gastric, appendiceal, or colorectal cancer with PM and have progressed to at least one evidence-based chemotherapeutic regimen. The trial has two clinical arms. The patients in arm 1 have gynecologic and gastric malignancies treated with IP cisplatin and doxorubicin, and the arm 2 patients have colorectal and appendiceal malignancies treated with intravenous fluorouracil and leucovorin followed by IP oxaliplatin. All the patients are monitored for dose-limiting toxicities and adverse events. Practical and technical considerations for the phase 1 PIPAC trial are presented. These considerations include patient selection, operating room setup, and technical details for successful aerosolized chemotherapy delivery. The phase 1 study results will be reported separately at completion of the trial. The PIPAC treatment is a feasible, minimally invasive approach that permits IP delivery of chemotherapy. Once completed, the ongoing phase 1 trial will help to provide safety and initial efficacy data.

Background To identify additional at-risk groups for lung cancer screening, which targets persons with a long history of smoking and thereby misses younger or nonsmoking cases, the authors evaluated germline pathogenic variants (PVs) in patients with lung adenocarcinoma for an association with an accelerated onset. Methods The authors assembled a retrospective cohort (1999-2018) of oncogenetic clinic patients with lung adenocarcinoma. Eligibility required a family history of cancer, data on smoking, and a germline biospecimen to screen via a multigene panel. Germline PVs (TP53/EGFR, BRCA2, other Fanconi anemia [FA] pathway genes, and non-FA DNA repair genes) were interrogated for associations with the age at diagnosis via an accelerated failure time model. Results Subjects (n = 187; age, 28-89 years; female, 72.7%; Hispanic, 11.8%) included smokers (minimum of 5 pack-years; n = 65) and nonsmokers (lighter ever smokers [n = 18] and never smokers [n = 104]). Overall, 26.7% of the subjects carried 1 to 2 germline PVs: TP53 (n = 5), EGFR (n = 2), BRCA2 (n = 6), another FA gene (n = 11), or another DNA repair gene (n = 28). After adjustment for smoking, sex, and ethnicity, the diagnosis of lung adenocarcinoma was accelerated 12.2 years (95% confidence interval [CI], 2.5-20.6 years) by BRCA2 PVs, 9.0 years (95% CI, 0.5-16.5 years) by TP53/EGFR PVs, and 6.1 years (95% CI, -1.0 to 12.6 years) by PVs in other FA genes. PVs in other DNA repair genes showed no association. Germline associations did not vary by smoking. Conclusions Among lung adenocarcinoma cases, germline PVs (TP53, EGFR, BRCA2, and possibly other FA genes) may be associated with an earlier onset. With further study, the criteria for lung cancer screening may need to include carriers of high-risk PVs, and findings could influence precision therapy and reduce lung cancer mortality by earlier stage diagnosis.

Objective Epithelial ovarian carcinoma (EOC) is diagnosed at advanced stage in the majority of women and, despite being initially chemosensitive, eventually recurs and develops resistance to known therapies. SC-003 is a pyrrolobenzodiazepine-based antibody-drug conjugate targeting dipeptidase 3 (DPEP3), a membrane-bound dipeptidase associated with tumor-initiating cells in patient-derived EOC xenograft models. This first-in-human phase 1a/1b study evaluated the safety/tolerability, pharmacokinetics, and preliminary antitumor activity of SC-003 alone or in combination with budigalimab (formerly ABBV-181), an antibody targeting PD-1, in patients with platinum-resistant/refractory EOC ( NCT02539719 ). Methods Patients received SC-003 at 1 of 6 dose levels (0.025–0.4 mg/kg) every 3 weeks (Q3W), utilizing a standard 3 + 3 design (dose-limiting toxicity [DLT] period: 21 days). Patients with DPEP3-positive tumors were enrolled in the dose-expansion phase of the study and treated with SC-003 monotherapy or in combination with budigalimab. Results Seventy-four patients (n = 29, dose escalation; n = 45, dose expansion; n = 3 budigalimab combination) were enrolled and received ≥ 1 dose of study drug. One DLT occurred (grade 3 ileus) but was considered unrelated to study drug. The MTD for the Q3W schedule was 0.3 mg/kg and the SC-003 doses selected for the dose-expansion phase of the study were 0.3 mg/kg and 0.2 mg/kg. The most common treatment-emergent adverse events were fatigue, nausea, decreased appetite, pleural effusion, abdominal pain, and peripheral edema. The overall response rate was low (4%), and responses were not durable. Post-hoc examination of antitumor activity suggested a higher response rate in patients with higher DPEP3 expression. Conclusions SC-003 lacked the requisite safety profile and antitumor activity to warrant further development.

PURPOSE: The reported maximum tolerated dose (MTD) of single agent belinostat is 1000 mg/m(2) given days 1-5, every 21 days. Pre-clinical evidence suggests histone deacetylase inhibitors enhance retinoic acid signaling in a variety of solid tumors. We conducted a phase I study of belinostat combined with 50-100 mg/m(2)/day 13-cis-retinoic acid (13-cRA) in patients with advanced solid tumors. METHODS: Belinostat was administered days 1-5 and 13-cRA days 1-14, every 21 days. Dose limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity grade ≥3 not resolving to grade ≤1 within 1 week or non-hematologic toxicity grade ≥3 (except controlled nausea and vomiting and transient liver function abnormalities) attributable to belinostat. RESULTS: Among 51 patients, two DLTs were observed: grade 3 hypersensitivity with dizziness and hypoxia at 1700 mg/m(2)/day belinostat with 100 mg/m(2)/day 13-cRA, and grade 3 allergic reaction at 2000 mg/m(2)/day belinostat with 100 mg/m(2)/day 13-cRA. The MTD was not reached. Pharmacokinetics of belinostat may be non-linear at high doses. Ten patients had stable disease, including one with neuroendocrine pancreatic cancer for 56 cycles, one with breast cancer for 12 cycles, and one with lung cancer for 8 cycles. Partial responses included a patient with keratinizing squamous cell carcinoma of the tonsils, and a patient with lung cancer. CONCLUSIONS: The combination of belinostat 2000 mg/m(2) days 1-5 and 13-cRA 100 mg/m(2) days 1-14, every 21 days, was well-tolerated and an MTD was not reached despite doubling the established single agent MTD of belinostat.

Developments in systemic therapies beyond traditional cytotoxic chemotherapy have resulted in an unparalleled number of US Food and Drug Administration approvals in the past 5 years for ovarian, endometrial, and cervical cancer. In this review, we highlight registration trials leading to recent Food and Drug Administration approvals for targeted systemic therapies in advanced gynecologic malignancies, encompassing three classes of agents: the antiangiogenic anti-vascular endothelial growth factor antibody bevacizumab in ovarian and cervical cancer, poly (ADP-ribose) polymerase inhibitors in ovarian cancer, and the immune checkpoint inhibitor pembrolizumab in cervical and endometrial cancer. The addition of bevacizumab to chemotherapy has been approved in frontline and relapsed advanced ovarian cancer, in both platinum-resistant and platinum-sensitive settings. Three poly (ADP-ribose) polymerase inhibitors are approved for women with ovarian cancer. Olaparib and rucaparib are utilized in recurrent germline or somatic BRCA mutated ovarian cancer. Along with a third poly (ADP-ribose) polymerase inhibitor, niraparib, they are also Food and Drug Administration approved as maintenance therapy regardless of BRCA mutation status for patients with recurrent ovarian cancer in complete or partial response to platinum-based chemotherapy. More recently, olaparib was approved as maintenance therapy for BRCA mutated ovarian cancer following first-line platinum-based chemotherapy. Pembrolizumab has been approved for relapsed cervical cancer with programmed death ligand 1 positivity and relapsed solid tumors with mismatch repair deficiency, which applies to 30% of endometrial cancers. Together, these therapies represent the advent of personalized medicine in gynecologic malignancies. Additional information is required to determine cost-effective strategies for incorporating these therapies and rational means of sequencing these agents.

Research shows that displaying face time—being observed by others at work—leads to many positive outcomes for employees. Drawing on this prior work, we argue that face time helps employees to receive better work and leads to career advancement because it is a strong signal of their commitment to their job, their team, and their organization. But when employees are geographically distributed from managers who control the assignment of work, they are often unable to display face time. To compensate, employees must engage in other behaviors that signal commitment. Our study of two large, globally distributed, product-development companies demonstrates that employees who engage in certain behaviors can effectively signal their commitment to the organization and, as a consequence, will receive better work assignments. But because they operate in a competitive signaling environment, they have to continually engage in the behaviors that produce desired signals to the point where they often feel that they are sacrificing their personal lives for their job. We induct a model from our data that explains why simple behaviors that signal commitment eventually turn into feelings of sacrifice and why employees at headquarters who have the power to assign better work fail to notice the sacrifice behind the signals. We discuss the implications of this model and the signal misalignment it explains for theories of distributed work and signaling in organizations. The online appendix is available at https://doi.org/10.1287/orsc.2018.1265 .

Antibody drug conjugates (ADC) are a novel class of cancer therapeutics, delivering cytotoxic therapy directly to cancer cells, and show promise in the management of platinum-resistant ovarian cancer. Herein we summarize the ADC landscape currently in clinical study.Mirvetuximab Soravtansine, IMGN853, is an ADC targeting the folate receptor alpha (FRα) and has demonstrated promising single agent activity and a favorable toxicity profile in FRα-positive, platinum-resistant, epithelial ovarian cancer (EOC). The antitumor effect is seen primarily in less heavily pretreated EOC patients with moderate-to-high FRα tumor expression. A phase III study, randomizing patients to either IMGN853 or the physician's choice of single-agent chemotherapy has completed accrual. Additional ADC are being evaluated in ovarian cancer including agents that target NaPiB2, Trop2, mesothelin, and MUC16 are in phase 1 clinical trials.ADC bind antigens overexpressed on cancer cells and provide site-selective drug delivery, with the goal to increase therapeutic efficacy of cytotoxics while decreasing the off-target toxicity of the payloads. With appropriate antigen selection and adequate, measurable antigen threshold targets, these new agents may provide an improved strategy for overcoming resistance to standard chemotherapy in ovarian cancer.

The risk of non-competitiveness is a problem that companies face because anticipating changes can improve their market position. The characteristics of the branch often determine particularities at the level of technology evolution, and later, through the appropriate combination of factors, sources, and the effect of progressive changes in technology, there are possibilities to improve the company’s position in the market. The research carried out allowed us to determine an analysis of the risk of non-competitiveness through the evolution of indicators that measure this risk compared to the main competitor and the market average.

Number of involved lymph nodes (LNs) is a crucial stratification factor in staging of numerous disease sites, but has not been incorporated for endometrial cancer. We evaluated whether number of involved LNs provide improved prognostic value.Patients diagnosed with node-positive endometrial adenocarcinoma without distant metastasis were identified in the National Cancer Database. We trained a machine-learning based model of overall survival. Shapley additive explanation values (SHAP) based on the model were used to identify cutoffs of number of LNs involved. Results were validated using a Cox proportional hazards regression model.We identified 11,381 patients with endometrial cancer meeting the inclusion criteria. Using the SHAP values, we selected the following thresholds: 1-3 LNs, 4-5 LNs, and 6+ LNs. The 3-year OS was 82.0% for 1-3 LNs, 74.3% for 4-5 LNs (hazard ratio [HR] 1.38; p 0.001), and 59.9% for 6+ LNs (HR 2.23; p 0.001). On univariate Cox regression, PA nodal involvement was a significant predictor of OS (HR 1.20; p 0.001) but was not significant on multivariate analysis when number of LNs was included (HR 1.05; p = 0.273). Additionally, we identified an interaction between adjuvant therapy and number of involved LNs. Patients with 1-3 involved LNs had 3-year OS of 85.2%, 78.7% and 74.2% with chemoradiation (CRT), chemotherapy, and radiation, respectively. Patients with 6+ involved LNs had 3-yr OS of 67.8%, 49.6%, and 48.9% with CRT, chemotherapy, and radiation, respectively (p 0.001).Number of involved LNs is a stronger prognostic and predictive factor compared to PA node involvement.

BackgroundWe conducted a2-part study to evaluate the incorporation of veliparib, a PARP inhibitor, into chemoradiotherapy (CRT) for stage III non-small-cell lung cancer.Patients and methodsIn the phase I part, patients were treated successivelyat3dose levels of veliparib(40,80, and120mg) twice daily during CRT. In the phase II part, patients were randomized to receive veliparib or placebo during thoracic radiotherapy with concurrent weekly carboplatin andpaclitaxel, followed by 2 cycles of consolidation carboplatin and paclitaxel with veliparib or placebo. The study was prematurely discontinued owing to the emergence of adjuvant immunotherapy as standard of care.ResultsOf 21 patients enrolled in phase I, 2 patients developed dose-limiting toxicities (DLTs): 1 grade 3 esophagitis with dysphagia (at 40 mg) and 1 grade 3 esophagitis with dehydration (at 80 mg). No DLTs were seen at veliparib dose of 120 mg twice daily, which was selected for the phase II part that enrolled 31 eligible patients. Progression-free survival (PFS) was not different between the 2 arms (P=.20). For the veliparib and placebo arms, response rates were 56% and 69%, PFS at 1 year 47% and 46%, and overall survival at 1 year 89% and 54%, respectively.ConclusionVeliparib with CRT was feasible and well tolerated. Efficacy could not accurately be determined because of early study closure. Nonetheless, there is enthusiasm for the evaluation of PARP inhibitors in lung cancer as predictive biomarkers are being developed and combinations with immunotherapy are attractive.

The evolution of resistance in high-grade serous ovarian cancer (HGSOC) cells following chemotherapy is only partially understood. To understand the selection of factors driving heterogeneity before and through adaptation to treatment, we profile single-cell RNA-sequencing (scRNA-seq) transcriptomes of HGSOC tumors collected longitudinally during therapy. We analyze scRNA-seq data from two independent patient cohorts to reveal that HGSOC is driven by three archetypal phenotypes, defined as oncogenic states that describe the majority of the transcriptome variation. Using a multi-task learning approach to identify the biological tasks of each archetype, we identify metabolism and proliferation, cellular defense response, and DNA repair signaling as consistent cell states found across patients. Our analysis demonstrates a shift in favor of the metabolism and proliferation archetype versus cellular defense response archetype in cancer cells that received multiple lines of treatment. While archetypes are not consistently associated with specific whole-genome driver mutations, they are closely associated with subclonal populations at the single-cell level, indicating that subclones within a tumor often specialize in unique biological tasks. Our study reveals the core archetypes found in progressive HGSOC and shows consistent enrichment of subclones with the metabolism and proliferation archetype as resistance is acquired to multiple lines of therapy., High-grade serous ovarian cancer (HGSOC) is prone to developing resistance to treatment. Here, the authors use single-cell RNA-seq and an analysis of archetypes, and find that shifts in metabolism and proliferation are associated with the response to treatment and clonal heterogeneity in HGSOC.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and is the country’s fifth most common cause of cancer mortality in women. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. These NCCN Guidelines discuss cancers originating in the ovary, fallopian tube, or peritoneum, as these are all managed in a similar manner. Most of the recommendations are based on data from patients with the most common subtypes─high-grade serous and grade 2/3 endometrioid. The NCCN Guidelines also include recommendations specifically for patients with less common ovarian cancers, which in the guidelines include the following: carcinosarcoma, clear cell carcinoma, mucinous carcinoma, low-grade serous, grade 1 endometrioid, borderline epithelial, malignant sex cord-stromal, and malignant germ cell tumors. This manuscript focuses on certain aspects of primary treatment, including primary surgery, adjuvant therapy, and maintenance therapy options (including PARP inhibitors) after completion of first-line chemotherapy.

5579 Background: Adavosertib (AZD-1775) is a potent small molecule inhibitor of Wee-1, currently in clinical development. In a double-blind, placebo-controlled, phase 2 trial (NCT02151292), adavosertib and gemcitabine significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with recurrent platinum-resistant or platinum-refractory high grade serous ovarian cancer (HGSOV) compared to gemcitabine alone. We investigated whether plasma and intra-tumoral adavosertib concentrations correlated with survival in these patients. Methods: Adavosertib was administered orally on Days 1, 2, 8, 9, 15 and 16 at 175 mg per day, and gemcitabine was administered on Days 1, 8 and 15 at 1000 mg/m2 every 28 days. Serial blood samples were collected on Day 1 of cycle 1 after adavosertib administration. Tumor biopsies were taken 1-2 weeks after initiation of study treatments. Plasma and tumor adavosertib concentrations were determined using validated HPLC-MS/MS. Patients were divided into groups with plasma or tumor adavosertib concentrations above or below the biologically active concentration (BAC) of 125 ng/ml (Leijen et al, J Clin Onco 2016). Survival was described using the Kaplan-Meier method. Results: Among 61 HGSOV patients who received adavosertib, plasma samples were available in 47, and tumor samples were available in 31 patients. Among 25 non-HGSOV patients (exploratory cohort), plasma and tumor samples were available in 21 and 17 patients respectively. The mean maximum adavosertib concentration (Cmax) was 355.3 ± 120.9 ng/ml and 358.6 ± 117.9 ng/ml respectively. Cmax was above BAC in all patients. The mean tumor adavosertib concentration was 609.2 ± 1129.2 ng/ml (range: 0.47 – 5501 ng/ml) for HGSOV patients, and 964.2 ± 1611.2 ng/ml (range: 0.22 – 6116 ng/ml) for non-HGSOV patients. There was no correlation between Cmax and tumor adavosertib concentrations. In HGSOV, the median PFS was 5.8 months for patients with tumor concentrations above BAC, and 3.5 months for those with tumor concentrations below BAC (Hazard ratio (HR): 0.46, 95% confidence interval: 0.19 – 1.14, p = 0.06). No difference in PFS was seen in non-HGSOV patients according to tumor adavosertib concentration. Tumor adavosertib concentration did not correlate with OS. Conclusions: Although Cmax was above BAC in all patients, there was a high variability in tumor adavosertib concentrations. In HGSOV, higher tumor adavosertib concentration was associated with a trend towards improved PFS, but not OS. Our results indicate that the current adavosertib dosing regimen may not produce the desired concentrations in tumors for some patients, and further optimization may be needed.

5570 Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin confers a survival benefit in epithelial ovarian cancer (EOC). Unfortunately, cisplatin is associated with significant renal toxicities. Sodium thiosulfate (ST) has been suggested as a nephroprotectant for patients undergoing HIPEC with cisplatin. Methods: A feasibility trial ( ClinicalTrials.gov: NCT01970722) evaluated safety outcomes of HIPEC with cisplatin 75 mg/m2 during optimal cytoreductive surgery (CRS) in patients with EOC and endometrial cancer (n = 40), with or without ST. Twenty-one patients received no sodium-thiosulfate (nST group), and nineteen patients received sodium thiosulfate (ST group). Toxicities were reported according to CTCAE v. 5. Progression-free survival was followed. Normal tissue biopsies were collected intra-operatively immediately following HIPEC and cisplatin exposure in a subset of patients (n = 21), and profiled with transcriptomic sequencing to identify RNAseq signatures correlating with toxicities. Hierarchical cluster analyses identified distinct transcriptomic signatures in post-HIPEC normal samples of patients with renal AEs (rAEs) compared to no renal AEs (nrAEs). KEGG pathway analysis identified up- or downregulated gene sets using GSEA. Results: Forty patients had HIPEC at time of optimal CRS. Renal toxicities were higher in the nST group (no sodium thiosulfate) compared to the ST group. nST patients had 17% any grade, and 9% Grade 3 AEs for acute and chronic kidney injuries. In contrast, ST patients suffered 0% renal AEs. rAE patients demonstrated upregulation of immune signaling pathways (Toll-like receptor, Natural killer cell, Nod-like receptor); and downregulation of metabolic pathways. Top upregulated genes in rAE patients included immune (e.g. neutrophil) related genes, while downregulated genes included metabolism genes. Kaplan-Meier curves demonstrated improved PFS in primary ovarian cancer patients undergoing HIPEC who were treated with ST vs no ST (p = 0.04, NR vs 13.4 mo). Conclusions: HIPEC with cisplatin results in significant renal toxicities. The mechanisms of cisplatin-induced nephrotoxicity in HIPEC are immune-related and reflect reduced metabolism. Sodium thiosulfate abrogated renal toxicities and did not decrease PFS. Clinical trial information: NCT01970722.

e17555 Background: The prognosis of ovarian cancer worsens markedly with age. Yet few data are available to explain this phenomenon. Two hypotheses can be made. Changes in pharmacokinetics (PK) and treatment tolerance limit the dosing of chemotherapy, and/or changes in tumor and host-tumor biology limit treatment efficacy. Objective:To identify PK, body composition, and biologic changes with age that may impact prognosis. We reported PK findings in a previous abstract (Extermann et al., ASCO 2021) In this abstract we focus on the biologic findings. Methods: We conducted a prospective cohort study of women with stage III/IV high-grade serous ovarian cancers treated with neoadjuvant intravenous carboplatin (C) AUC 5 every 3 weeks and paclitaxel (P) dosed either weekly at 80 mg/m2 or every 3 weeks at 175 mg/m2. Body composition was assessed using baseline CT scans at the L3 level. Pre- and post-chemotherapy plasma samples were assayed by ELISA for CRP, IL-6, TNF alpha, TNF-receptor 1 and 2, d-dimers, vitamins B12 and D, methylmalonic acid, and cortisol levels. Tissue samples pre- and post-chemotherapy were analyzed for gene expression, gene methylation, and immunohistochemistry for inflammatory markers and senescence. Toxicity was assessed as first cycle nadir ANC and G4 hematologic (H) or grade 3-4 non-hematologic (NH) toxicity by CTCAE 4.0 criteria over a 3 cycles follow-up. The correlation between continuous measures was assessed by Spearman correlation coefficient, and the association with toxicity was evaluated by Wilcoxon rank sum test. The association with relapse-free survival (RFS) and overall survival (OS) was calculated by Log-rank and Cox regression analyzes. Results: Seventeen patients, ages 38 to 86 (median 61) were eligible, 14 underwent surgery. Treatment delivery was high with a median relative dose intensity of 100%. The mean percentage of senescent cells (CAV-1 +) was 49.5% in the stroma, vs 12.8% in the tumor (p < 0.001) prechemotherapy, and 15.7% in the stroma vs 21.4% in the tumor post-chemotherapy (pre-post stroma p < 0.01). The percentage of PD-L1 positive cells and CTLA-4 positive cells was very low: mean < 1% both pre-and post-chemotherapy. The results from gene expression and methylation showed an increase in the inflammatory pathways and a decrease in the apoptosis pathways over time. Vitamin D levels decreased with age. Prechemotherapy CD8 percentage in the stroma and post chemotherapy d-dimers were associated with RFS. Conclusions: Neoadjuvant treatment delivery was high in an academic setting. Our results provide insights in the underexplored area of biologic response to chemotherapy in patients with ovarian cancer. Although our results did not provide clear candidates to explain the worsening of prognosis with age, they offer clues to develop future research on this issue.

Background Immunogenic cell death has been suggested as a mechanism for HIPEC, through the release of heat shock proteins, and resulting in activation of tumor-specific T cells. Methods This is a subgroup analysis of a Phase I trial using HIPEC with cisplatin 75 mg/m2 at time of optimal cytoreduction. Metastatic tumors from nine ovarian cancer patients were collected intraoperatively before and after HIPEC. Differentially expressed genes and pathways of pre- and post-HIPEC tumors were analyzed via whole-transcriptome sequencing (WTS). Immunofluorescent (IF) staining and multispectral imaging were used to determine composition and PD-1 expression of CD8+ and conventional CD4+ tumor-infiltrating lymphocytes (TILs), using antibodies against CD8, FOXP3, PD-1, and pancytokeratin (to distinguish cancer islands from stroma). Kaplan-Meier and log-rank tests compared the overall and progression free survivals (PFS) of patients with low versus high%PD-1 changes, based on dichotomization with respect to the median%PD-1 change. Results Heatshock proteins comprised the top differentially upregulated genes in HIPEC-treated tumors. Gene set enrichment analysis revealed significant upregulation of immune pathways, including antigen processing/presentation. IF staining demonstrated increased%PD-1 in cancer islands of CD8+ and CD4+ TILs after HIPEC. In stroma, the largest%PD-1 change occurs in an exceptional responder (PFS, OS 5 years), while the lowest%PD-1 change occurred in a poor responder. Kaplan-Meier curves demonstrate superior PFS in patients with high stromal PD-1 changes in TILs after HIPEC. Conclusions Increased PD-1 expression after HIPEC suggests early HIPEC-induced T cell activation, and is associated with improved survival, implicating a potential future role for PD-1 inhibitors following HIPEC in ovarian cancer.

Background RPTR-147 is a novel autologous non-genetically modified multi-clonal T cell product loaded with an IL15-Fc nanogel. The product was derived from rare peripherally-derived anti-tumor T cell clones that were primed against a multi-antigen cassette containing tumor associated antigens (TAA), known to be over-expressed in specific tumor types. We describe preliminary results from the ongoing first-in-human Phase 1 trial. Methods Autologous anti-TAA T cells are generated with a proprietary dendritic cell priming process and then loaded with an IL15-Fc nanogel. TAAs used in cassette: PRAME, NY-ESO-1, SSX2, Survivin and WT1. Thawed RPTR-147 is delivered by infusion. Pre- and post-treatment biopsies were collected for biomarker analysis by immunohistochemistry (IHC) and transcriptome sequencing. Serial blood collections were obtained for measuring IL-15 pharmacokinetics and pharmacodynamic parameters including plasma cytokine levels and immunophenotyping by flow cytometry. T cell receptor sequencing (TCRSeq) was used to characterize the T cell repertoire from manufactured T cell product and the patient‘s blood. Results Interim clinical and biomarker data from 17 patients with advanced metastatic disease refractory to SOC who received monthly infusions of 20-360 million cells/m², were reviewed (table 1). There were no dose-limiting toxicities and no evidence of cytokine-release syndrome. The 360M/m² dose contained 3X more IL15-Fc than the MTD of systemically administered IL15-Fc,1 but produced less than a tenth of the systemic exposure to free IL15-Fc. Currently, 360M cells/m² is considered safe and well-tolerated. Further dose escalation is planned. Matched evaluable biopsies were obtained in 7 patients. Tumor-infiltrating T cell lymphocytes was observed in 5 cases for CD8 T cells and 4 cases for CD4 T cells. A dose dependent increase in both inflammatory cytokines and NK & CD8+ T cells was observed, consistent with expected MOA and PK. TCRSeq analysis demonstrated that product specific T cell clones could be tracked in both patient‘s blood and tumor over time. Further analysis to decode the specificity of those cells and demonstrate that tumor antigen specific T cells can be found in patient‘s blood and tumor biopsies is ongoing. Of the 17 patients who received RPTR-147 infusions 10 were noted to have stable disease (SD) and in 4 patients SD lasted > 6 months. Conclusions Interim results with RPTR-147 have shown it to be well-tolerated and have a favorable safety profile. Dose-escalation is proceeding. Ongoing biomarker analysis will inform future clinical strategies in matching patients to an optimized PRIME IL-15 T cell product. Trial Registration NCT03815682 Ethics Approval The study was approved by local institutional IRBs after acceptance of the IND by the FDA. Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal. Reference Romee R, Cooley S, Berrien-Elliott MM, et al. First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation. Blood 2018;131(23):2515-2527.

Summary Background The Wee1 (WEE1hu) inhibitor adavosertib and gemcitabine have shown preclinical synergy and promising activity in early phase clinical trials. We aimed to determine the efficacy of this combination in patients with ovarian cancer. Methods In this double-blind, randomised, placebo-controlled, phase 2 trial, women with measurable recurrent platinum-resistant or platinum-refractory high-grade serous ovarian cancer were recruited from 11 academic centres in the USA and Canada. Women were eligible if they were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0–2, a life expectancy of more than 3 months, and normal organ and marrow function. Women with ovarian cancer of non-high-grade serous histology were eligible for enrolment in a non-randomised exploratory cohort. Eligible participants with high-grade serous ovarian cancer were randomly assigned (2:1), using block randomisation (block size of three and six) and no stratification, to receive intravenous gemcitabine (1000 mg/m2 on days 1, 8, and 15) with either oral adavosertib (175 mg) or identical placebo once daily on days 1, 2, 8, 9, 15, and 16, in 28-day cycles until disease progression or unacceptable toxicity. Patients and the team caring for each patient were masked to treatment assignment. The primary endpoint was progression-free survival. The safety and efficacy analysis population comprised all patients who received at least one dose of treatment. The trial is registered with ClinicalTrials.gov , NCT02151292 , and is closed to accrual. Findings Between Sept 22, 2014, and May 30, 2018, 124 women were enrolled, of whom 99 had high-grade serous ovarian cancer and were randomly assigned to adavosertib plus gemcitabine (65 [66%]) or placebo plus gemcitabine (34 [34%]). 25 women with non-high-grade serous ovarian cancer were enrolled in the exploratory cohort. After randomisation, five patients with high-grade serous ovarian cancer were found to be ineligible (four in the experimental group and one in the control group) and did not receive treatment. Median age for all treated patients (n=119) was 62 years (IQR 54–67). Progression-free survival was longer with adavosertib plus gemcitabine (median 4·6 months [95% CI 3·6–6·4] with adavosertib plus gemcitabine vs 3·0 months [1·8–3·8] with placebo plus gemcitabine; hazard ratio 0·55 [95% CI 0·35–0·90]; log-rank p=0·015). The most frequent grade 3 or worse adverse events were haematological (neutropenia in 38 [62%] of 61 participants in the adavosertib plus gemcitabine group vs ten [30%] of 33 in the placebo plus gemcitabine group; thrombocytopenia in 19 [31%] of 61 in the adavosertib plus gemcitabine group vs two [6%] of 33 in the placebo plus gemcitabine group). There were no treatment-related deaths; two patients (one in each group in the high-grade serous ovarian cancer cohort) died while on study medication (from sepsis in the experimental group and from disease progression in the control group). Interpretation The observed clinical efficacy of a Wee1 inhibitor combined with gemcitabine supports ongoing assessment of DNA damage response drugs in high-grade serous ovarian cancer, a TP53-mutated tumour type with high replication stress. This therapeutic approach might be applicable to other tumour types with high replication stress; larger confirmatory studies are required. Funding US National Cancer Institute Cancer Therapy Evaluation Program, Ontario Institute for Cancer Research, US Department of Defense, Princess Margaret Cancer Foundation, and AstraZeneca.

The Snow Ensemble Uncertainty Project (SEUP) is an effort to establish a baseline characterization of snow water equivalent (SWE) uncertainty across North America with the goal of informing global snow observational needs. An ensemble-based modeling approach, encompassing a suite of current operational models, is used to assess the uncertainty in SWE and total snow storage (SWS) estimation over North America during the 2009&ndashl2017 period. The highest modeled SWE uncertainty is observed in mountainous regions, likely due to the relatively deep snow, forcing uncertainties, and variability between the different models in resolving the snow processes over complex terrain. This highlights a need for high-resolution observations in mountains to capture the high spatial SWE variability. The greatest SWS is found in Tundra regions where even though the spatiotemporal variability in modeled SWE is low, there is considerable uncertainty in the SWS estimates due to the large areal extent over which those estimates are spread. This highlights the need for high accuracy in snow estimations across the Tundra. In mid-latitude boreal forests, large uncertainties in both SWE and SWS indicate that vegetation-snow impacts are a critical area where focused improvements to modeled snow estimation efforts need to be made. Finally, the SEUP results indicate that SWE uncertainty is driving runoff uncertainty and measurements may be beneficial in reducing uncertainty in SWE and runoff, during the melt season at high latitudes (e.g., Tundra and Taiga regions) and in the Western mountain regions, whereas observations at (or near) peak SWE accumulation are more helpful over the mid-latitudes.

Epithelial ovarian cancer (EOC) is the most common histology of ovarian cancer defined as epithelial cancer derived from the ovaries, fallopian tubes, or primary peritoneum. It is the fifth most common cause of cancer-related death in women in the United States. Because of a lack of effective screening and non-specific symptoms, EOC is typically diagnosed at an advanced stage (FIGO stage III or IV) and approximately one third of patients have malignant ascites at initial presentation. The treatment of ovarian cancer consists of a combination of cytoreductive surgery and systemic chemotherapy. Despite the advances with new cytotoxic and targeted therapies, the five-year survival rate for all-stage EOC in the United States is 48.6%. Delivery of up-to-date guideline care and multidisciplinary team efforts are important drivers of overall survival. In this paper, we review our frontline management of EOC that relies on a multi-disciplinary approach drawing on clinical expertise and collaboration combined with community practice and cutting edge clinical and translational research. By optimizing partnerships through team medicine and clinical research, we combine our cancer center clinical expertise, community practice partnership, and clinical and translational research to understand the biology of this deadly disease, advance therapy and connect our patients with the optimal treatment that offers the best possible outcomes.

125 Background: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is being evaluated as a novel minimally invasive palliative treatment of peritoneal metastases (PM). Prior studies have established the feasibility and safety of repeated PIPAC treatments in gastrointestinal and gynecologic cancers. The goal of the present phase 1 trial was to establish the safety and feasibility of PIPAC oxaliplatin in a highly chemotherapy refractory colorectal and appendiceal cancer patient population. Methods: Patients with biopsy-proven peritoneal metastases from colorectal or appendiceal cancer underwent up to three PIPAC treatments using oxaliplatin (92 mg/m2) with a six-week interval at two academic centers. Patients with bowel obstruction, extra-peritoneal metastases, or poor performance status (ECOG>2) were excluded. PIPAC was nebulized over 5 min with a 30 min aerosol dwell time. Apart from the first PIPAC cycle, the patients also received a sensitizing dose of 5FU/LV (400mg/m2) within 24 hours of the procedure. Primary end point was safety as assessed by dose limiting toxicities within 6 weeks of the first PIPAC. Secondary endpoints included safety with the addition of 5FU/LV, efficacy, surgical morbidity, technical failure rate, progression-free and overall survival, pharmacokinetics (PK), and quality of life assessment. Results: A total of 8 patients were included: 5 colorectal; and 3 appendiceal. Median number of prior chemotherapy cycles was 2 (Interquartile range – IQR; 1.5-3.5). All patients were refractory to systemic oxaliplatin-based chemotherapy. Median time from diagnosis to PIPAC was 16 months (IQR; 5.6, 17.5) and Peritoneal Carcinomatosis Index was 29 (IQR; 20.5, 31.5). Five (62.5%) patients completed 3 PIPAC cycles while in 3 (37.5%) patients PIPAC was discontinued due to disease progression within the peritoneal cavity. No surgical complication or dose limiting toxicity was observed. Only one patient developed grade 3 treatment-related toxicity after first PIPAC (anemia), and another patient after second PIPAC (abdominal pain and anemia). At the completion of PIPAC treatment 5 patients had stable disease and 3 had disease progression. Pharmacokinetic, histologic response and preliminary survival data will be presented at the meeting. Conclusions: PIPAC with oxaliplatin is safe and feasible in a highly chemotherapy refractory cohort of appendiceal and colorectal carcinomatosis patients with or without sensitizing 5-FU/ LV. Clinical trial information: NCT04329494.

Thermal infrared sensing from space is a well-developed field, but mixed pixels pose a problem for many applications. We present a field study in Dana Meadows, Yosemite National Park, California to scale from point (~2-m resolution) to aerial (~5-m resolution gridded, 1 km × 6 km extent) to satellite (MODIS, ~1000-m resolution, global extent) observations. We demonstrate how multiple thermal bands on MODIS can be used to separate snow and forest temperatures and determine the fractional snow-covered area (fSCA) over a 3 km × 3 km array of 9 MODIS grid cells. During the day, visible, near-infrared, and shortwave-infrared bands provide a first guess of fSCA and help to constrain the solution. This technique, which has estimated errors

The aim of this paper is to analyse the Agile methods implementation capability within software projects as a more viable alternative to the waterfall model and determine the key factors that guarantee the continuous delivery of software to market at the right and agreed quality level. Two Agile implementation methods were considered: Scrum and Kanban, which were evaluated based on factors like predictability, practicability and complexity. The conclusions show the selected methodologies advantages and disadvantages, and project key attributes can be used to choose the suitable methodology for a project. Regarding the Agile implementation methods, the most straightforward and predictable one was proven to be Scrum. This framework supports frequent delivery of software products that can address complex problems and adapt to the rapid market changes.

Objectives: To demonstrate safety and tolerability of HIPEC in ovarian cancer. Methods: A phase I, single-institution feasibility study was designed to evaluate the safety and feasibility of HIPEC at time of optimal cytoreductive surgery (CRS) in ovarian cancer patients, followed by optional normothermic intraperitoneal chemotherapy, at City of Hope National Comprehensive Cancer Center (Duarte, CA). Primary endpoint of the trial was to evaluate the safety and feasibility of HIPEC at time of optimal cytoreductive surgery (CRS). Progression-free survival was a secondary end-point. Exploratory endpoints included the assessment of molecular markers in tumors. Eligibility criteria included epithelial ovarian cancer (stage III or IV), primary or recurrent, ECOG 0-1, and appropriate surgical candidates. 35 patients were enrolled between 2015 and 2019, who underwent optimal CRS (gross residual disease less than 1 cm), and received HIPEC intra-operatively with cisplatin at 75 mg/m2 for 60 minutes immediately following optimal CRS. Patients were stratified as either 1) primary disease (n=19), defined as having received HIPEC at time of interval CRS following neoadjuvant chemotherapy for primary EOC; 2) recurrent disease (n=16), defined as having received HIPEC at time of interval or upfront CRS for recurrent (salvage) EOC. Adjuvant chemotherapy was given at the discretion of the treating oncologist following HIPEC. Results: Median age was 58 years (36-74 years), with a mean BMI of 26. Primary (interval) patients represented 54% of patients, with pretreatment clinical stages III (53%) and IV (47%). Recurrent (salvage) patients represented 45.7%, with platinum-sensitive (75%) and platinum-resistant (25%). The most common histological subtype was high grade serous (69%). All primary (interval) patients underwent neoadjuvant chemotherapy (3-4 cycles) prior to interval CRS and HIPEC. The majority of recurrent patients (81%) did not receive neo-adjuvant chemotherapy. Thirty-three patients underwent closed technique and two underwent laparoscopic technique. Total mean operating time was 8.4 hours (4.6-15.3). Mean length of stay was 10 days (3-30). All patients underwent optimal cytoreduction (69% with complete R0 resection). Peritoneal carcinomatosis index (PCI) ranged 2 to 30 (median of 8). Patients with PCI /= 8 whose PFS was 12.6 (p=0.04). Time to initiation of adjuvant chemotherapy in recurrent patients was 8.4 weeks. 22.9% of the ovarian cancer cohort was gBRCA mutated. Median PFS for primary patients was 12.6 months (95% CI 6.4; NR); with median follow up of 22.1 months (95% CI 12.6, 31.5). Median PFS for recurrent patients was 18.8 months (95% CI 7.2; 28.7), with median follow up of 36.3 months (95% CI 21.1, 51.5). There were no grade 4 or 5 AEs. Anemia was the most common Grade 3 AE (43%), followed by liver dysfunction and electrolyte abnormalities. The most common AE of any grades were abdominal pain (86%), anemia (77%), and nausea (66%). Two patients (6%) had grade 3 acute kidney injury and one patient had grade 3 chronic kidney disease. Sodium thiosulfate was introduced to the trial in January 2018, following which there were no grade 1-4 acute or chronic kidney injuries. Download : Download high-res image (61KB) Download : Download full-size image Conclusions: HIPEC in ovarian cancer was well tolerated, without any grade 4 or 5 AEs. Renal toxicities were mitigated with sodium thiosulfate. Patients with a low PCI ( /= 8.

Reliable maps of snow-covered areas at scales of meters to tens of meters, with daily temporal resolution, are essential to understanding snow heterogeneity, melt runoff, energy exchange, and ecological processes. Here we develop a parsimonious downscaling routine that can be applied to fractional snow covered area (fSCA) products from satellite platforms such as the Moderate Resolution Imaging Spectroradiometer (MODIS) that provide daily ∼500 m data, to derive higher resolution snow presence/absence grids. The method uses a composite index combining both the topographic position index (TPI) to represent accumulation effects and the diurnal anisotropic heat (DAH, sun exposure) index to represent ablation effects. The procedure is evaluated and calibrated using airborne-derived high-resolution datasets across the Tuolumne watershed, CA using 11 scenes in 2014 to downscale to 30-m resolution. The average matching F score was 0.83. We then tested our method's transferability in time and space by comparing against the Tuolumne watershed in water years 2013 and 2015, and over an entirely different site, Mt. Rainier, WA in 2009 and 2011, to assess applicability to other topographic and climatic conditions. For application to sites without validation data, we recommend equal weights for the TPI and DAH indices and close TPI neighborhoods (60 m and 27 m for downscaling to 30 m and 3 m, respectively), which worked well in both our study areas. The method is less effective in forested areas, which still requires site-specific treatment. We demonstrate that the procedure can even be applied to downscale to 3 m resolution, a very fine scale relevant to alpine ecohydrology research.

Background: M5A is a humanized monoclonal antibody (mAb) directed against carcinoembryonic antigen (CEA) The purpose of this first in human phase I dose-escalation trial was to characterize the toxicities and determine the maximum tolerated dose (MTD) of yttrium-90 ((90)Y)-DOTA-M5A as a single agent and in combination with gemcitabine (gem). Methods: Patients with advanced metastatic CEA-producing malignancies who had progressed on standard therapies were first administered indium-111 ((111)In)-DOTA-M5A. If tumor targeting was observed, the patient then received the therapy dose of (90)Y-DOTA-M5A. Serial scans, blood sampling, and 24 h urine collections were then performed to estimate radiation doses to organs and total body. Assays for human antihuman antibody (HAHA) responses were performed out to 6 months. Results: Of the 18 patients who received (111)In-DOTA-M5A, 16 received (90)Y-DOTA-M5A therapy; 1 patient at 14 mCi/m(2) with gem (150 mg/m(2) days 1and 3), 3 patients at 12 mCi/m(2) with gem, 6 patients at 12 mCi/m(2) without gem, and 6 at 10 mCi/m(2) without gem. Prolonged cytopenias resulted in discontinuation of dose escalation with gemcitabine. A single agent MTD of 10 mCi/m(2) was established based on dose-limiting hematopoietic toxicities. HAHA immune response was identified in 2 of 16 patients (12.5%). Stable disease at 3 months was seen in 10 patients and 2 patients demonstrated an 88% and 64% decrease in CEA back to normal levels. In 2 patients (111)In-DOTA-M5A imaging revealed previously unknown brain metastases. Conclusion: This study demonstrates the potential utility of the (90)Y-DOTA-M5A anti-CEA mAb as a therapeutic antibody. There is decreased immunogenicity compared with murine and chimeric mAbs, allowing for the potential of multiple administrations. Combined modality therapy approaches incorporating this agent should continue to be evaluated.

Ovarian cancer is a heterogeneous disease that encompasses a number of different histologic subtypes, including high-grade serous carcinomas (the most frequent), endometrioid, and clear cell, mucinous, and low-grade serous carcinomas. Mutations in the tumor suppressor gene TP53, BRCA mutations, and abnormalities of DNA repair genes are found primarily in high-grade serous carcinomas, while mutations in other key molecular pathways such as Ras/Raf/MEK/ERK, PI3K/AKT/mTOR, and the ErbB family are present in the less common ovarian histologies. Three PARP inhibitors have been FDA approved for the treatment of recurrent OC or for use as maintenance therapy after platinum-based chemotherapy.

Purpose Following promising responses to the DNA methyltransferase (DNMT) inhibitor 5-fluoro-2′-deoxycytidine (FdCyd) combined with tetrahydrouridine (THU) in phase 1 testing, we initiated a non-randomized phase 2 study to assess response to this combination in patients with advanced solid tumor types for which tumor suppressor gene methylation is potentially prognostic. To obtain pharmacodynamic evidence for DNMT inhibition by FdCyd, we developed a novel method for detecting expression of tumor suppressor protein p16/INK4A in circulating tumor cells (CTCs). Methods Patients in histology-specific strata (breast, head and neck [H&N], or non-small cell lung cancers [NSCLC] or urothelial transitional cell carcinoma) were administered FdCyd (100 mg/m2) and THU (350 mg/m2) intravenously 5 days/week for 2 weeks, in 28-day cycles, and progression-free survival (PFS) rate and objective response rate (ORR) were evaluated. Blood specimens were collected for CTC analysis. Results Ninety-three eligible patients were enrolled (29 breast, 21 H&N, 25 NSCLC, and 18 urothelial). There were three partial responses. All strata were terminated early due to insufficient responses (H&N, NSCLC) or slow accrual (breast, urothelial). However, the preliminary 4-month PFS rate (42%) in the urothelial stratum exceeded the predefined goal—though the ORR (5.6%) did not. An increase in the proportion of p16-expressing cytokeratin-positive CTCs was detected in 69% of patients evaluable for clinical and CTC response, but was not significantly associated with clinical response. Conclusion Further study of FdCyd + THU is potentially warranted in urothelial carcinoma but not NSCLC or breast or H&N cancer. Increase in the proportion of p16-expressing cytokeratin-positive CTCs is a pharmacodynamic marker of FdCyd target engagement.

Purpose: The relevance of the MET/hepatocyte growth factor pathway in endometrial cancer tumor biology supports the clinical evaluation of cabozantinib in this disease. Patients and Methods: PHL86/NCI#9322 (NCT01935934) is a single arm study that evaluated cabozantinib (60 mg once daily) in women with endometrial cancer with progression after chemotherapy. Coprimary endpoints were response rate and 12-week progression-free-survival (PFS). Patients with uncommon histology endometrial cancer (eg, carcinosarcoma and clear cell) were enrolled in a parallel exploratory cohort. Results: A total of 102 patients were accrued. Among 36 endometrioid histology patients, response rate was 14%, 12-week PFS rate was 67%, and median PFS was 4.8 months. In serous cohort of 34 patients, response rate was 12%, 12-week PFS was 56%, and median PFS was 4.0 months. In a separate cohort of 32 patients with uncommon histology endometrial cancer (including carcinosarcoma), response rate was 6% and 12-week PFS was 47%. Six patients were on treatment for >12 months, including two for >30 months. Common cabozantinib-related toxicities (>30% patients) included hypertension, fatigue, diarrhea, nausea, and hand–foot syndrome. Gastrointestinal fistula/perforation occurred in four of 70 (6%) patients with serous/endometrioid cancer and five of 32 (16%) patients in exploratory cohort. We observed increased frequency of responses with somatic CTNNB1 mutation [four partial responses (PRs) in 10 patients, median PFS 7.6 months] and concurrent KRAS and PTEN/PIK3CA mutations (three PRs in 12 patients, median PFS 5.9 months). Conclusions: Cabozantinib has activity in serous and endometrioid histology endometrial cancer. These results support further evaluation in genomically characterized patient cohorts.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years from diagnosis. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. The best outcomes are observed in patients whose primary treatment includes complete resection of all visible disease plus combination platinum-based chemotherapy. Research efforts are focused on primary neoadjuvant treatments that may improve resectability, as well as systemic therapies providing improved long-term survival. These NCCN Guidelines Insights focus on recent updates to neoadjuvant chemotherapy recommendations, including the addition of hyperthermic intraperitoneal chemotherapy, and the role of PARP inhibitors and bevacizumab as maintenance therapy options in select patients who have completed primary chemotherapy.

Background Oral metronomic chemotherapy, which has low toxicity, has demonstrated promising anti-tumor and anti-angiogenic properties that may lead to prolonged progression-free survival and improved response rates in patients with recurrent epithelial ovarian cancer (EOC). These effects may be enhanced by the co-administration of anti-angiogenic agents. Methods We conducted a randomized phase II clinical trial to evaluate the therapeutic benefit of oral metronomic cyclophosphamide (CTX) alone and with the anti-angiogenic drug celecoxib in patients with gynecological malignancies. 52 patients were randomly assigned to two treatments arms: 50 mg oral CTX daily alone (Arm A) or with 400 mg celecoxib twice daily (Arm B). The primary endpoint was response rate. Secondary endpoints included toxicity, time to treatment failure, and overall survival. Results In Arm A (n = 26), 3 patients (12%) had stable disease >6 months and 1 (4%) had a partial response. In Arm B, 5 (19%) had stable disease >6 months and 1 patient (4%) had a partial response. There were no significant between-group differences in overall survival (9.69 months [95% CI 3.84–13.18] vs. 12.55 months [6.67–17.61]) or in median time to treatment failure (1.84 months [1.68–2.76] vs. 1.92 months [1.64–5.22]). The most common adverse events were nausea, vomiting, and abdominal pain. Conclusions Oral metronomic CTX has activity with no major toxicities in heavily pretreated recurrent gynecological cancers and may be considered in patients with indolent disease. We did not observe any additional benefit of celecoxib treatment, though this may be due to small sample sizes.

Introduction: Mesenchymal epidermal transition and vascular endothelial growth factor pathways are important in mediating non-small cell lung cancer (NSCLC) tumorigenesis and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance. We hypothesized that treatment with cabozantinib plus erlotinib in EGFR mutation-positive NSCLC following progression on EGFR TKI therapy may allow tumors to overcome this resistance or restore sensitivity to therapy regardless of T790M status. Methods: Patients with advanced NSCLC, known EGFR mutation and progressive disease on an EGFR TKI immediately prior to enrollment without intervening therapy were enrolled. Patients received erlotinib 150 mg and cabozantinib 40 mg daily. The primary endpoint was evaluation of efficacy by objective response rate. Secondary endpoints included assessment of progression free survival (PFS), overall survival, change in tumor growth rate, safety and toxicity, and the evaluation of specific EGFR mutations and MET amplification in pre-treatment tissue and plasma. Results: Thirty-seven patients were enrolled at 4 centers. Four patients had partial response (10.8%) and 21 had stable disease (59.5%). A greater than 30% increase in tumor doubling time was observed in 79% of assessable patients (27/34). Median PFS was 3.6 months for all patients. Diarrhea (32%) was the most common grade 3 adverse event; 3 patients had asymptomatic grade 4 elevation of amylase and lipase. Conclusions: Combination erlotinib and cabozantinib demonstrates activity in a highly pretreated population of patients with EGFR mutation and progression on EGFR TKI. Further elucidation of beneficial patient subsets is warranted. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT01866410.

Introduction: Broad application of neoTCR-T cell therapy involves isolation of mutation-targeted CD8 T cells from the blood of patients with different tumor types. An ultra-sensitive process streamlined for high-throughput capture of neoE-specific T cells from blood is leveraged for producing a fully personalized adoptive T cell therapy for trial participants with BC or OC (NCT03970382). Methods: Expressed mutations were identified by comparative sequencing of blood cells and tumor tissue. HLA typing was performed with OpiType. Proprietary algorithms were used to predict and prioritize tumor-exclusive neoE-HLA candidates. A library of barcoded HLA-mutational neoantigen complexes was used to interrogate PBMCs from each patient using imPACT Isolation Technology® (Dalmas et al., 2020). NeoTCRs cloned from captured antigen-experienced CD8 T cells were precision genome engineered into healthy donor T cells for functional characterization, including secretion of cytokines and effector molecules (Jacoby et al., 2019; Sennino et al., 2019). Based on pre-specified prioritization criteria, up to 3 actionable neoTCRs were selected for manufacturing the products for each individual. Results: Six patients (2 BC/4 OC) successfully underwent neoTCR product selection. The median age was 59.5 years (range 38-69). Patients received a median of 5.5 prior regimens for metastatic disease (range 4-9). Median tumor mutational burden (TMB) was 2.7 (range 0.9-13.4). HLA-neoantigen libraries contained a median of 91 snares (range 29-262) and represented 6/6 HLA alleles in 4 patients and 5/6 in the remaining 2. A median of 8.5 distinct neoE-specific T cells (range 5-15) were isolated per patient. Following functional characterization 13 neoTCRs met selection criteria: three patients with 3 TCRs, one with 2 TCRs, and two had a single TCR. The median predicted neoE:HLA affinity of the selected TCRs was 77 nM (range 6.3 - 5866) and the median IFN-g EC50 was 4 ng/mL (range 1-431). Conclusion: Relevant antigen-experienced, tumor mutation-targeted CD8 T cells were isolated from the blood of heavily pre-treated BC and OC patients with low TMB ( Citation Format: Mihaela Cristea, Bartosz Chmielowski, David Y. Oh, Roel P. Funke, Daniela A. Bota, Mehrdad Abedi. Characterization of neoepitope (neoE)-specific T cells from peripheral blood for adoptive neoTCR-T cell therapy for patients with breast cancer (bc) or ovarian cancer (oc) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 331.

The evolution of resistance in high-grade serous ovarian cancer (HGSOC) cells following chemotherapy is only partially understood. To uncover phenotypic changes associated with chemotherapy resistance, we profiled single-cell RNA-sequencing (scRNA-seq) transcriptomes of HGSOC tumors collected longitudinally during patient treatment. Analysis of scRNA-seq data from two independent patient cohorts revealed that HGSOC is driven by three core archetypal phenotypes, defined as oncogenic tasks that describe the majority of the transcriptome variation. A multi-task learning approach to identify the biological tasks of each archetype identified metabolism and proliferation, cellular defense response, and DNA repair signaling. The metabolism and proliferation archetype evolved during treatment and was enriched in cancer cells from patients that received multiple-lines of treatment and had elevated tumor burden indicated by CA-125 levels. The emergence of archetypes was not consistently associated with specific whole-genome driver mutations. However, archetypes were closely associated with subclonal populations at the single-cell level, indicating that subclones within a tumor often specialize in unique biological tasks. Our study reveals the core archetypes found in progressive HGSOC and shows consistent enrichment of subclones with the metabolism archetype as resistance is acquired to multiple lines of therapy. Citation Format: Aritro Nath, Patrick Cosgrove, Benjamin Copeland, Hoda Mirsafian, Elizabeth Christie, Lance Pflieger, Sumana Majumdar, Mihaela Cristea, Ernest Han, Stephen Lee, Edward Wang, Sian Fereday, Nadia Traficante, Ravi Salgia, Theresa Werner, Adam Cohen, Phillip Moos, Jeffrey Chang, David Bowtell, Andrea Bild. Evolution of core archetypal phenotypes in progressive high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3141.

Snow cover affects a diverse array of physical, ecological, and societal systems. As such, the development of optical remote sensing techniques to measure snow-covered area (SCA) has enabled progress in a wide variety of research domains. However, in many cases, the spatial and temporal resolutions of currently available remotely sensed SCA products are insufficient to capture SCA evolution at spatial and temporal resolutions relevant to the study of fine-scale spatially heterogeneous phenomena. We developed a convolutional neural network-based method to identify snow covered area using the ~3 m, 4-band PlanetScope optical satellite image dataset with ~daily, near-global coverage. By comparing our model performance to snow extent derived from high-resolution airborne lidar differential depth measurements and satellite platforms in two North American sites (Sierra Nevada, CA, USA and Rocky Mountains, CO, USA), we show that these emerging image archives have great potential to accurately observe snow-covered area at high spatial and temporal resolutions despite limited radiometric bandwidth and band placement. We achieve average snow classification F-Scores of 0.73 in our training basin and 0.67 in a climatically-distinct out-of-sample basin, suggesting opportunities for model transferability. We also evaluate the performance of these data in forested regions, suggesting avenues for further research. The unparalleled spatial and temporal coverage of CubeSat imagery offers an excellent opportunity for satellite remote sensing of snow, with real implications for ecological and water resource applications.

e17553 Background: The prognosis of ovarian cancer worsens markedly with age. Yet few data are available to explain this phenomenon. Two hypotheses can be made. Changes in pharmacokinetics and treatment tolerance limit the dosing of chemotherapy. And/or changes in tumor and host-tumor biology limit treatment efficacy. Methods: We conducted a prospective cohort study of women with stage III/IV high-grade serous ovarian cancers treated with neoadjuvant intravenous carboplatin(C) AUC 5 every 3 weeks and paclitaxel(P) dosed either weekly at 80 mg/m2 or every 3 weeks at 175 mg/m2. Body composition was assessed using baseline CT scans at the L3 level. Total muscle mass, total fat mass, skeletal muscle index (SMI) and fat index were computed. Plasma concentrations were collected at pre-established time points for both C1D1 of C and P and concentration-time data was analyzed by non-compartmental methods. Area under the curve (AUC)0-INF, volume of distribution(Vd), clearance (Cl), half-life, and mean residence time were calculated. Free C concentrations were determined in plasma ultrafiltrate and assayed, along with P plasma concentrations, by liquid chromatography-tandem mass spectrometry. Toxicity was assessed as first cycle nadir ANC and G4 hematologic(H) or grade 3-4 non-hematologic(NH) toxicity by CTCAE 4.0 criteria over a 3 cycles follow-up. The correlation between continuous measures was assessed by Spearman correlation coefficient, and the association with toxicity was evaluated by Wilcoxon rank sum test. Results: Seventeen patients, ages 38 to 86 (median 61) were eligible. All patients but one received 3 cycles of chemotherapy and median dose intensity was 100% (range 33.3-100%). Mean 1st cycle nadir ANC was 1.29 (range 0.06-9.0). 10/17 (59%) patients experienced G4 H and/or G3-4 NH toxicity. SMI was associated with C AUC (r -0.50, p < 0.05), and both total muscle (r = 0.61) and total fat (r = 0.53) were associated with C Vd. We did not find a correlation of P pharmacokinetics with body composition. A lower SMI was associated with 1st cycle G4H toxicity (p = 0.02), while C AUC had a borderline trend only (p = 0.15). Age was associated with a lower Vd (r -0.63, p = 0.009) and Cl (r -0.67, p = 0.004) of C. There was no significant age trend in the body composition parameters. Conclusions: Neoadjuvant treatment delivery was high in an academic setting. Toxicity appeared driven by low skeletal muscle index, in part via affecting carboplatin pharmacokinetics, and showed no significant age trend. The explanation for age-related changes in prognosis is more likely to lay with changes in tumor and host-tumor biology, which are being analyzed.

Purpose In 2010, a randomized clinical trial demonstrated noninferior survival for patients with advanced ovarian cancer who were treated with neoadjuvant chemotherapy (NACT) compared with primary cytoreductive surgery (PCS). We examined the use and effectiveness of NACT in clinical practice. Patients and Methods A multi-institutional observational study of 1,538 women with stages IIIC to IV ovarian cancer who were treated at six National Cancer Institute–designated cancer centers. We examined NACT use in patients who were diagnosed between 2003 and 2012 (N = 1,538) and compared overall survival (OS), morbidity, and postoperative residual disease in a propensity-score matched sample of patients (N = 594). Results NACT use increased from 16% during 2003 to 2010 to 34% during 2011 to 2012 in stage IIIC disease ( Ptrend < .001), and from 41% to 62% in stage IV disease ( Ptrend < .001). Adoption of NACT varied by institution, from 8% to 30% for stage IIIC disease (P < .001) and from 27% to 61% ( P = .007) for stage IV disease during this time period. In the matched sample, NACT was associated with shorter OS in stage IIIC disease (median OS: 33 v 43 months; hazard ratio [HR], 1.40; 95% CI, 1.11 to 1.77) compared with PCS, but not stage IV disease (median OS: 31 v 36 months; HR, 1.16; 95% CI, 0.89 to 1.52). Patients with stages IIIC and IV disease who received NACT were less likely to have ≥ 1 cm postoperative residual disease, an intensive care unit admission, or a rehospitalization (all P ≤ .04) compared with those who received PCS treatment. However, among women with stage IIIC disease who achieved microscopic or ≤ 1 cm postoperative residual disease, NACT was associated with decreased OS (HR, 1.49; 95% CI, 1.01 to 2.18; P = .04). Conclusion Use of NACT increased significantly between 2003 and 2012. In this observational study, PCS was associated with increased survival in stage IIIC, but not stage IV disease. Future studies should prospectively consider the efficacy of NACT by extent of residual disease in unselected patients.

Regions of complex topography and remote wilderness terrain have spatially-varying patterns of temperature and streamflow, but due to inherent difficulties of access, are often very poorly sampled. Here we present a dataset of distributed stream stage, streamflow, stream temperature, barometric pressure, and air temperature from the Tuolumne River Watershed in Yosemite National Park, Sierra Nevada, California, U.S.A. for water years 2002 to 2015, as well as a quality-controlled hourly meteorological forcing time series for use in hydrologic modeling. We also provide snow data and daily inflow to the Hetch Hetchy Reservoir for 1970 to 2015. This paper describes data collected using low-visibility and low-impact installations for wilderness locations and can be used alone or as a critical supplement to ancillary datasets collected by cooperating agencies, referenced herein. This dataset provides a unique opportunity to understand spatial patterns and scaling of hydroclimatic processes in complex terrain and can be used to evaluate downscaling techniques or distributed modeling. The paper also provides an example methodology and lessons learned in conducting hydroclimatic monitoring in remote wilderness. This article is protected by copyright. All rights reserved.