Cytotoxic Chemotherapy Treatment Research Articles

Abstract 937: Prioritizing treatment targets for an adolescent with metastatic processive malignancy using proteomics and personalized xenograft models within an actionable timeframe

Abstract Translation of precision oncology data into feasible precision therapies for hard-to-cure childhood, adolescent and young adult malignancies remains a significant challenge. Identifying therapeutic targets at the protein and pathway level and demonstrating treatment response in personalized models hold great promise, particularly for combination therapies, but may be considered complex and time consuming. Here, we present the case of an adolescent with metastatic, progressive spindle epithelial tumor with thymus-like differentiation (SETTLE) and evaluate how proteomics combined with rapid patient-derived models can identify treatment options not apparent at the genome or transcript level. Mass spectrometric proteome analysis of macro-dissected tumor and adjacent normal from formalin fixed paraffin embedded sections was completed within two weeks of biopsy and identified key proteins involved in one-carbon metabolism, including SHMT2 and DHFR as possible targets for single or combination therapy. Elevated SHMT2 levels were validated by immunohistochemistry and compared to levels across AYA tumors. Based on the suitability for an innovative therapy trial, we prioritized single-agent sertraline, a commercially available anti-depressant medication that inhibits SHMT2, and confirmed a positive drug response in both chicken chorioallantoic membrane (CAM) and larval zebrafish xenografts generated from the patient. Retrospective expansion in a murine xenograft enabled metabolic tracing on isolated SETTLE- patient-derived xenograft cells using 13C6-glucose confirming SHMT2 activity and response to in vitro treatment. Following failure of cytotoxic chemotherapy and second-line sorafenib treatment, a monotherapy trial of sertraline was initiated by the patient but stopped after 8 weeks after evidence of progressive disease. Possible combination therapies were evaluated further in the patient-derived models. Combining sertraline with the common antibiotic trimethoprim, resulted in enhanced growth inhibition of SETTLE cells in the larval zebrafish xenografts. Significance: Overall, we demonstrate that proteomics and personalized xenograft models may provide supportive pre-clinical data in a clinically meaningful timeframe to support medical decision-making and impact clinical practice. Citation Format: Georgina D. Barnabas, Tariq A. Bhat, Verena Goebeler, Pascal Leclair, Nadine Azzam, Nicole Melong, Jason N. Berman, Jennifer A. Chan, Donna L. Senger, Seth Parker, Christopher A. Maxwell, Gregor S. Reid, Jonathan Bush, Caron Strahlendorf, Rebecca Deyell, C James Lim, Philipp F. Lange. Prioritizing treatment targets for an adolescent with metastatic processive malignancy using proteomics and personalized xenograft models within an actionable timeframe [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 937.

Tumor-Stroma Proportion to Predict Chemoresistance in Patients With Ovarian Cancer

Platinum-based chemotherapy is the backbone of standard-of-care treatment for patients with advanced-stage, high-grade serous carcinoma (HGSC), the most common form of ovarian cancer; however, one-third of patients have or acquire chemoresistance toward platinum-based therapies. To demonstrate the utility of tumor-stroma proportion (TSP) as a predictive biomarker of chemoresistance of HGSC, progression-free survival (PFS), and overall survival (OS). This prognostic study leveraged tumors from patients with HGSC in The Cancer Genome Atlas (TCGA) cohort (1993-2013) and an independent cohort of resected clinical specimens from patients with HGSC (2004-2014) available in diagnostic and tissue microarray formats from the University of Tübingen in Germany. Data analysis was conducted from January 2021 to January 2024. Diagnosis of HGSC. Principal outcome measures were the ability of TSP to predict platinum chemoresistance, PFS, and OS. Using hematoxylin and eosin-stained slides from the Tübingen cohort (used for routine diagnostic assessment from surgical specimens) as well as tissue microarrays, representative sections of tumors for scoring of TSP were identified using previously evaluated cutoffs of 50% stroma or greater (high TSP) and less than 50% stroma (low TSP). Digitized slides from the TCGA Cohort were analyzed and scored in a similar fashion. Kaplan-Meier time-to-event functions were fit to estimate PFS and OS. The study included 103 patients (mean [SD] age, 61.6 [11.1] years) from the TCGA cohort and 192 patients (mean [SD] age at diagnosis, 63.7 [11.1] years) from the Tübingen cohort. In the TCGA cohort, there was no significant association of TSP levels with chemoresistance, PFS, or OS. However, in the Tübingen cohort, high TSP was associated with significantly shorter PFS (HR, 1.586; 95% CI, 1.093-2.302; P = .02) and OS (hazard ratio [HR], 1.867; 1.249-2.789; P = .002). Patients with chemoresistant tumors were twice as likely to have high TSP as compared to patients with chemosensitive tumors (HR, 2.861; 95% CI, 1.256-6.515; P = .01). In tissue microarrays from 185 patients from the Tübingen cohort, high TSP was again associated with significantly shorter PFS (HR, 1.675; 95% CI, 1.012-2.772 P = .04) and OS (HR, 2.491; 95% CI, 1.585-3.912; P < .001). In this prognostic study, TSP was a consistent and reproducible marker of clinical outcome measures of HGSC, including PFS, OS, and platinum chemoresistance. Accurate and cost-effective predictive biomarkers of platinum chemotherapy resistance are needed to identify patients most likely to benefit from standard treatments, and TSP can easily be implemented and integrated into prospective clinical trial design and adapted to identify patients who are least likely to benefit long-term from conventional platinum-based cytotoxic chemotherapy treatment at the time of initial diagnosis.

Alterations to DNA methylation patterns induced by chemotherapy treatment are associated with negative impacts on the olfactory pathway

BackgroundExposure to cytotoxic chemotherapy treatment may alter DNA methylation (DNAm) in breast cancer patients.MethodsWe performed DNAm analysis in 125 breast cancer patients with blood drawn before and after chemotherapy, using the Illumina MethylationEPIC array. DNAm changes of 588,798 individual CpGs (including 41,207 promoter regions) were evaluated using linear regression models adjusted for monocyte proportion. Gene set enrichment analyses (GSEA) were conducted to identify key Gene Ontology (GO) biological processes or Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with chemotherapy. Results were validated in a separate cohort of breast cancer patients who were treated (n = 1273) and not treated (n = 872) by chemotherapy (1808 blood, 337 saliva).ResultsA total of 141 differentially methylated CpGs and 11 promoters were significantly associated with chemotherapy after multiple testing corrections in both the paired sample and single time point analyses. GSEA of promoter regions (pre-ranked by test statistics) identified six suppressed biological processes (p < 4.67e−8) related to sensory perception and detection of chemical stimuli, including smell perception (GO:0007606, GO:0007608, GO:0009593, GO:0050906, GO:0050907, and GO:0050911). The same six biological processes were significantly suppressed in the validation dataset (p < 9.02e−14). The KEGG pathway olfactory transduction (hsa04740) was also found to be significantly suppressed (ppaired-samples = 1.72e−9, psingle-timepoint-blood = 2.03e−15 and psingle-timepoint-saliva = 7.52e−56).ConclusionThe enrichment of imprinted genes within biological processes and pathways suggests a biological mechanism by which chemotherapy could affect the perception of smell.

Results of a Phase Ib Study Investigating Durvalumab in Combination with Eribulin in Patients with HER2-Negative Metastatic Breast Cancer and Recurrent Ovarian Cancer

Introduction: The release of tumor-associated antigens with cytotoxic chemotherapy treatment may enhance the response to immune checkpoint blockade. Eribulin is a microtubule inhibitor with proven overall survival (OS) benefit in metastatic breast cancer (MBC), which may also enhance intratumoral vascular remodeling. Durvalumab, a humanized monoclonal antibody, targets the programmed cell death ligand-1 (PD-L1) receptor. This study sought to determine the maximum tolerated dose and recommended phase II dose (RP2D) of eribulin in combination with durvalumab, as well as the safety and preliminary antitumor activity of the combination in patients with previously treated HER2-negative (HER2−) MBC and recurrent ovarian cancer (ROC). Methods: Cohorts of 3–6 patients with HER2− MBC and ROC were treated in a modified 3+3 design. Eligible patients received escalating doses of eribulin (1.1 mg/m2 or 1.4 mg/m2 IV on day 1 and day 8) with durvalumab (1.12 g IV on day 1) in 21-day cycles until dose-limiting toxicity (DLT), intolerable adverse events (AEs), disease progression, or other reasons for withdrawal. Primary endpoint: the rate of DLTs during cycles 1 and 2 of therapy. Secondary endpoints: AE rate, objective response rate (ORR), progression-free survival (PFS), and OS. Results: Nine patients with a median of 4 prior therapies for advanced disease were treated: 5 patients with HER2− MBC (1 with triple-negative disease and 4 with hormone-positive disease) and 4 patients with ROC. The RP2D of eribulin was 1.4 mg/m2 in combination with durvalumab. There were no DLTs experienced during the first two cycles of therapy. The most common treatment-related AEs (>50%) were fatigue, neutropenia, decreased white blood cell count, anemia, AST and alkaline phosphatase elevation, hyperglycemia, and nausea; most were grade 1 or 2. There was one immune-related AE of grade 3 (hepatitis) after 5 cycles of treatment, for which patient came off study. Two other patients discontinued study drug related to toxicity (neutropenia [n = 1], hepatic toxicity [n = 1]). ORR was 55%, and 4 additional patients experienced stable disease. All MBC patients exhibited a response to therapy. Median PFS was 6.2 months. Median OS was 15.0 months. Conclusion: The combination of eribulin at a dose of 1.4 mg/m2 with standard dose durvalumab had a favorable AE profile in patients with previously treated HER2− MBC and ROC. The early antitumor activity observed in all MBC patients enrolled in the study suggests that further investigation of this combination is warranted.

Neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy

Small cell lung cancers (SCLCs) rapidly resist cytotoxic chemotherapy and immune checkpoint inhibitor (ICI) treatments. New, non-cross-resistant therapies are thus needed. SCLC cells are committed into neuroendocrine lineage then maturation arrested. Implicating DNA methyltransferase 1 (DNMT1) in the maturation arrests, we find (1) the repression mark methylated CpG, written by DNMT1, is retained at suppressed neuroendocrine-lineage genes, even as other repression marks are erased; (2) DNMT1 is recurrently amplified, whereas Ten-Eleven-Translocation 2 (TET2), which functionally opposes DNMT1, is deleted; (3) DNMT1 is recruited into neuroendocrine-lineage master transcription factor (ASCL1, NEUROD1) hubs in SCLC cells; and (4) DNMT1 knockdown activated ASCL1-target genes and released SCLC cell-cycling exits by terminal lineage maturation, which are cycling exits that do not require the p53/apoptosis pathway used by cytotoxic chemotherapy. Inhibiting DNMT1/corepressors with clinical compounds accordingly extended survival of mice with chemorefractory and ICI-refractory, p53-null, disseminated SCLC. Lineage commitment of SCLC cells can hence be leveraged into non-cytotoxic therapy able to treat chemo/ICI-refractory SCLC.

Abstract P6-01-44: Alteration of DNA methylation landscape in breast patients treated with adjuvant chemotherapy

Abstract Background Exposure to cytotoxic chemotherapy treatment may alter DNA methylation (DNAm) in treated patients. Methods We performed DNAm analysis in 1,244 and 897 breast cancer patients treated and not treated by adjuvant chemotherapy using the Illumina MethylationEPIC array (1,804 blood, 337 saliva). DNAm changes of 620,095 individual CpGs and 41,581 promoters were evaluated using linear regression models, adjusting for age at diagnosis, ethnicity, years between sample collection and diagnosis and cell-type heterogeneity. Results from datasets normalized separately were combined by meta-analysis (random effects model). Gene set enrichment analyses were conducted to identify key processes or pathways associated with chemotherapy treatment. Results A total of 425 differentially methylated CpGs and 20 promoters were significantly associated with chemotherapy treatment (p&amp;lt; 5e-8). Enriched gene sets among 3,495 chemotherapy-associated promoters (unadjusted p&amp;lt; 0.05, preranked by Z scores) included three suppressed Gene Ontology (GO) terms that survived Bonferroni correction (GO:0002376, immune system process; GO:0009605, response to external stimulus; and GO:1903034: regulation of response to wounding). Using meta-analysis regression coefficients for all promoters as a ranking metric, olfactory transduction (KEGG, hsa04740) was found to be significantly suppressed (unadjusted p=6.38e-06, adjusted p=0.002). Taste transduction (hsa04742, unadjusted p=1.73e-03, adjusted p=0.565) was the next most significantly suppressed pathway. Conclusion The enrichment of imprinted genes within biological processes and pathways suggests a biological mechanism by which chemotherapy treatment could affect immune response, wound healing and changes in the perceptions of smell and taste. Citation Format: Peh Joo Ho, Alexis Jiaying Khng, Benita Kiat Tee Tan, Ern Yu Tan, Geok hoon Lim, Su-Ming Tan, Veronique Kiak Mien Tan, Elaine Hsuen Lim, Mikael Hartman, Jingmei Li. Alteration of DNA methylation landscape in breast patients treated with adjuvant chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-44.

277MO Filgrastim versus pegfilgrastim as primary prevention for reduction of chemotherapy induced febrile neutropenia in Nepal

Chemotherapy-induced neutropenia is a frequent complication of cytotoxic chemotherapy treatment. It increases the risk of infection and often leads to febrile neutropenia (FN). Development of FN may compromise the treatment response with substantial economic burden. Granulocyte colony-stimulating factor (GCSF) administration could prevent episodes of FN and its related complications. Filgrastim and pegfilgrastim are GCSFs approved for the reduction of neutropenia-related outcomes. This study compares filgrastim and pegfilgrastim as primary prevention for reduction of chemotherapy induced FN and its direct cost to the patients.

Comparison of Short Acting versus Long Acting Filgrastim for Reduction of Chemotherapy Induced Febrile Neutropenia

Introduction: Febrile neutropenia (FN) is the most frequent complications reported during cytotoxic chemotherapy treatment. Granulocyte colony stimulating factor (GCSF) is used to reduce neutropenia and related complications. This study compares short versus long acting filgrastim for reduction of chemotherapy induced FN. Methods: Histologically confirmed solid cancer patients (n=112) receiving either high risk or intermediate risk chemotherapy regimens for FN were randomized into two groups. Group one received filgrastim 300 mcg subcutaneously for five days and group two received pegfilgrastim 6 mg subcutaneously single dose, starting after 24 hours after completion of chemotherapy during each chemotherapy cycle. The primary end point was the occurrence of FN. The secondary end points were number of hospital visits, duration of hospital stay and total direct costs of filgrastim and pegfilgrastim. Results: Fifty six patients were analyzed in each group. The incidence of FN was significantly lower in pegfilgrastim group (42.90%) than filgrastim group (69.6%), p&lt;0.004. The mean hospital visits were 1.84±1.93 in filgrastim group and 0.84±1.19 in pegfilgrastim group with 58.90% and 33.90% hospital admission respectively in both groups. The mean duration of stay was 4.14±3.69 days in filgrastim group and 2.36±3.35 days in pegfilgrastim group. The mean cost (Nepali rupees) of filgrastim and pegfilgrastim was 20162.50+6645.37 (US$168.17±55.42) and 32210.71±10429.43($268.67±86.99) respectively. Conclusion: Single dose of pegfilgrastim was significantly better than multiple doses of filgrastim for reducing FN incidence in cancer patients receiving chemotherapy.

Traditional Systemic Treatment Options in Advanced Low-Grade Serous Ovarian Cancer after Successful Cytoreduction: A Systematic Review and Meta-Analysis.

Simple SummaryLow-Grade Serous Ovarian cancer (LGSOC) is considered less sensitive to traditional chemotherapy than its high-grade counterpart. Guidelines are still inconsistent around the use and value of cytotoxic and antihormonal agents in the adjuvant setting. Traditional cytotoxic or antihormonal systemic treatment option is not associated with a significant OS or PFS benefit in this Meta-analysis.Objective: We performed a systematic literature review and a subsequent meta-analysis to compare traditional treatment options, i.e., antihormonal and cytotoxic, in LGSOC. Methods: We conducted a systematic literature review in MEDBASE and MEDLINE between September 2000 and June 2021 for women who received cytotoxic chemotherapy and/or antihormonal treatment after primary cytoreduction due to stage II–IV LGSOC and also at relapse. PFS and OS were calculated depending on the type of their adjuvant treatment. For each endpoint in the meta-analysis, pooled HR was calculated using the random effect model with the inverse variance weighted method. Only primary patients were included in the subsequent meta-analysis due to the small number of studies in the relapsed setting. Results: Five eligible first-line studies were included. Systemic chemotherapy failed to provide a significant OS benefit when compared to no systemic treatment (pooled HR = 1.01, 95% CI [0.79, 1.29]) after successful cytoreduction. Moreover, systemic chemotherapy followed by antihormonal treatment also did not result to a significant PFS or OS benefit when compared to systemic chemotherapy alone (for PSF: pooled HR = 0.59, 95% CI [0.33, 1.04]; for OS: pooled HR = 0.83, 95% CI [0.50, 1.39]). There were insufficient data from studies in the recurrent setting to allow their inclusion in the meta-analysis. Conclusions: In this meta-analysis, we failed to identify a traditional cytotoxic or antihormonal systemic treatment option that was associated with a significant OS or PFS benefit when administered following successful cytoreduction for advanced LGSOC. Prospective randomized studies are urgently warranted to define optimal adjuvant options in this challenging disease.

Managing Side Effects of Cytotoxic Chemotherapy in Patients With High Grade Gliomas.

Cytotoxic chemotherapy has been a mainstay of cancer treatment since the 1940s. In the recent era of emergent targeted therapies and immunotherapies, many cytotoxic chemotherapy agents including temozolomide are still one of main weapons for the treatment of high grade gliomas. However, cytotoxic chemotherapy often causes side effects. Proper management of chemotherapy-induced toxicity can have a significant impact on a patient’s quality of life and clinical outcomes. Many supportive care advances have transformed our ability to give full doses of chemotherapy, which is important for achieving their full efficacy. Prevention and treatment strategies have been developed for many chemotherapy-related toxicities. This review focused on managing gastrointestinal toxicity, chemotherapy-induced nausea and vomiting, and hematologic toxicities such as thrombocytopenia during cytotoxic chemotherapy treatment in high-grade brain tumors.

Understanding the Role of Autophagy in Cancer Formation and Progression Is a Real Opportunity to Treat and Cure Human Cancers.

Simple SummaryThe modulation of autophagy represents a potential therapeutic strategy for cancer. More than one hundred clinical trials have been conducted or are ongoing to explore the efficacy of autophagy modulators to reduce the tumor growth and potentiate the anti-cancer effects of conventional therapy. Despite this, the effective role of autophagy during tumor initiation, growth, and metastasis remains not well understood. Depending on the cancer type and stage of cancer, autophagy may have tumor suppressor properties as well as help cancer cells to proliferate and evade cancer therapy. The current review aims to summarize the current knowledge about the autophagy implications in cancer and report the therapeutic opportunities based on the modulation of the autophagy process.The malignant transformation of a cell produces the accumulation of several cellular adaptions. These changes determine variations in biological processes that are necessary for a cancerous cell to survive during stressful conditions. Autophagy is the main nutrient recycling and metabolic adaptor mechanism in eukaryotic cells, represents a continuous source of energy and biomolecules, and is fundamental to preserve the correct cellular homeostasis during unfavorable conditions. In recent decades, several findings demonstrate a close relationship between autophagy, malignant transformation, and cancer progression. The evidence suggests that autophagy in the cancer context has a bipolar role (it may act as a tumor suppressor and as a mechanism of cell survival for established tumors) and demonstrates that the targeting of autophagy may represent novel therapeutic opportunities. Accordingly, the modulation of autophagy has important clinical benefits in patients affected by diverse cancer types. Currently, about 30 clinical trials are actively investigating the efficacy of autophagy modulators to enhance the efficacy of cytotoxic chemotherapy treatments. A deeper understanding of the molecular pathways regulating autophagy in the cancer context will provide new ways to target autophagy for improving the therapeutic benefits. Herein, we describe how autophagy participates during malignant transformation and cancer progression, and we report the ultimate efforts to translate this knowledge into specific therapeutic approaches to treat and cure human cancers.

Clinical and Pathologic Features Associated With Invasive Breast Carcinoma With 2018 American Society of Clinical Oncology/College of American Pathologists In Situ Hybridization Group 2 Results (Human Epidermal Growth Factor Receptor 2 [HER2]/Chromosome 17 Centromere [CEP17] Ratio ≥2.0 and Average HER2 Copy Number

The American Society of Clinical Oncology/College of American Pathologists updated the human epidermal growth factor receptor 2 (HER2) breast carcinoma testing guideline in 2018 to address issues from uncommon HER2 fluorescence in situ hybridization (FISH) results. Based on the 2013 American Society of Clinical Oncology/College of American Pathologists guideline, cases wherein the HER2/chromosome 17 centromere (CEP17) ratio of 2.0 or more with an average HER2 copy number of less than 4.0 were considered in situ hybridization (ISH) positive. Under the 2018 guideline, such cases are classified as ISH Group 2 and are no longer considered eligible for anti-HER2 therapy when the corresponding HER2 immunohistochemistry result is 0, 1+, or 2+. To assess the clinical, pathologic, and treatment aspects of patients with ISH Group 2 results. We retrospectively reviewed HER2 FISH results at our center between January 2012 and December 2014 and identified and characterized cases with ISH Group 2 results. Thirty-nine cases with ISH Group 2 results from 39 patients were reviewed. Twenty of 39 (51%) patients received anti-HER2 therapy. Patients treated with HER2-targeted therapy were less likely to have hormone receptor-positive tumors, compared with patients without anti-HER2 treatment, though not significantly (P = .30). The only significant difference between the 2 patient groups was receipt of cytotoxic chemotherapy treatment (P < .001). Overall, clinical outcome was similar between the 2 groups (P > .99). This retrospective study with median follow-up of at least 6 years shows patients with ISH Group 2 tumors had similar clinical outcomes, irrespective of HER2-targeted therapy. Further analysis in the prospective setting would provide valuable data that would potentially inform clinical decision making.

Microbes exploit death-induced nutrient release by gut epithelial cells.

Regulated cell death is an integral part of life, and has broad effects on organism development and homeostasis1. Malfunctions within the regulated cell death process, including the clearance of dying cells, can manifest in diverse pathologies throughout various tissues including the gastrointestinal tract2. A long appreciated, yet elusively defined relationship exists between cell death and gastrointestinal pathologies with an underlying microbial component3-6, but the direct effect of dying mammalian cells on bacterial growth is unclear. Here we advance a concept that several Enterobacteriaceae, including patient-derived clinical isolates, have an efficient growth strategy to exploit soluble factors that are released from dying gut epithelial cells. Mammalian nutrients released after caspase-3/7-dependent apoptosis boosts the growth of multiple Enterobacteriaceae and is observed using primary mouse colonic tissue, mouse and human cell lines, several apoptotic triggers, and in conventional as well as germ-free mice in vivo. The mammalian cell death nutrients induce a core transcriptional response in pathogenic Salmonella, and we identify the pyruvate formate-lyase-encoding pflB gene as a key driver of bacterial colonization in three contexts: a foodborne infection model, a TNF- and A20-dependent cell death model, and a chemotherapy-induced mucositis model. These findings introduce a new layer to the complex host-pathogen interaction, in which death-induced nutrient release acts as a source of fuel for intestinal bacteria, with implications for gut inflammation and cytotoxic chemotherapy treatment.

Plasma Cytokeratin 18 and fecal Alpha-1 Antitrypsin concentrations in dogs with osteosarcoma receiving carboplatin chemotherapy.

Gastrointestinal (GI) toxicosis is a common side effect of cytotoxic chemotherapy treatment in humans and dogs. Measurement of cytokeratin 18 (CK18), an intracellular structural protein released during epithelial apoptosis, and Alpha1‐Antitrypsin (A1AT) in faeces provides a mechanism for evaluating damage to the intestinal mucosa secondary to cytotoxic chemotherapy. Our goal was to evaluate the clinical utility of plasma CK18 and faecal A1‐AT levels as non‐invasive biomarkers of cytotoxic chemotherapy induced GI toxicity. We conducted a prospective cohort study in dogs (N = 10) with osteosarcoma undergoing amputation followed by carboplatin chemotherapy. We hypothesized that plasma CK18 and faecal A1‐AT levels would increase following carboplatin administration due to drug‐induced GI epithelial damage/apoptosis, and that plasma CK18 and faecal A1‐AT levels would correlate with severity of GI toxicity. Mean baseline plasma CK18 concentration was variable amongst patients; however, CK18 concentration prior to carboplatin chemotherapy treatment was not significantly different from CK18 levels after treatment. There was significant intra and inter‐patient variability in mean faecal A1‐AT levels at baseline. Mean A1‐AT concentration did not change significantly from day 0 to day 21. Gastrointestinal toxicity was minimal; therefore, we were unable to determine the association of plasma CK18 and faecal A1‐AT concentrations with development of GI toxicosis. In this study population, plasma CK18 and faecal A1‐AT concentration were not clinically useful biomarkers for the detection of GI toxicosis secondary to carboplatin administration. Further prospective evaluation of CK18 and A1‐AT as biomarkers of drug‐induced GI toxicity is warranted in a larger cohort of dogs receiving cytotoxic chemotherapy.AVMA clinical trial registration number: AAHSD004827.

Small-Molecule Inhibitors (SMIs) as an Effective Therapeutic Strategy for Endometrial Cancer.

Simple SummaryPatients diagnosed with endometrial cancer (EC), the most common gynaecological malignancy in women worldwide, cope with a disease associated with poor prognosis and limited treatment options after first-line therapy when it reaches an advanced or metastatic stage. Lately, small-molecule inhibitors have emerged as an alternative targeted therapy, renewing hope in the fight against this disease. The aim of this review is to shed light into the current state and future prospects of small-molecule inhibitors on EC treatment by summarizing the extensive number of clinical trials that have been performed during the last years, and to provide a comprehensive up-to-date document with the most remarkable results. Despite the great effort researchers are making to improve the molecular characterization of tumours, to unravel the underlying mechanism of EC progression, and to increase the efficacy of targeted therapy, we might say that there is still a long way to pave to efficiently treat EC patients.Endometrial cancer (EC) is the sixth most common cancer in women. A continued number of low-risk EC patients at diagnosis, as well as patients diagnosed with advanced-stage disease, will experience an aggressive disease. Unfortunately, those patients will present recurrence or overt dissemination. Systemic cytotoxic chemotherapy treatment on advanced, recurrent, or metastatic EC patients has shown poor results, with median survival rates of less than one year, and median progression-free survival rates of four months. Therefore, the search for innovative and alternative drugs or the development of combinatorial therapies involving new targeted drugs and standard regimens is imperative. Over the last few decades, some small-molecule inhibitors have been introduced in the clinics for cancer treatment, but only a few have been approved by the Food and Drug Administration (FDA) for EC treatment. In the present review, we present the current state and future prospects of small-molecule inhibitors on EC treatment, both alone and in combination.

1677MO COVID-19 mortality in hospitalized cancer patients is not significantly affected by chemotherapy or other anti-cancer treatments

Individuals with cancer, particularly those who are receiving systemic anti-cancer treatments, have been postulated to be at increased risk of mortality from SARS-CoV-2 related coronavirus disease (COVID-19). This conjecture has considerable impact on the treatment of cancer patients and large, multi-centre data to support this assumption is lacking due to the contingencies of the pandemic. The cancer community of the United Kingdom (UK) has launched the UK Coronavirus Cancer Monitoring Project (UKCCMP). The UKCCMP is the first COVID-19 clinical registry that enables near real-time reports to frontline doctors about the effect of COVID-19 on cancer patients. An analysis of the first 800 cancer patients with symptomatic COVID-19 disease entered into the UKCCMP registry has been performed. Approximately half of these patients have a mild COVID-19 disease course (52%). Mortality was observed in 226 patients (28%) and risk of death was significantly associated with advancing patient age, sex (M>F) and the presence of other co-morbidities. Approximately one third had received cytotoxic chemotherapy within 4 weeks prior to testing positive for COVID-19. After adjusting for age, sex and comorbidities, recent receipt of chemotherapy had no significant effect on mortality from COVID-19 disease, when compared to cancer patients who had not received recent chemotherapy. No significant effect on mortality was also observed for patients with recent immunotherapy, hormonal therapy, targeted therapy or radiotherapy use. Mortality from COVID-19 in cancer patients appears to be principally driven by age, sex and co-morbidities. We are not able to identify evidence that cancer patients on cytotoxic chemotherapy or other anti-cancer treatment are at significantly increased risk of mortality from COVID-19 disease compared to those not on active treatment.

Chemotherapy and COVID-19 Outcomes in Patients With Cancer.

Coronavirus-2019 (COVID-19) mortality is higher in patients with cancer than in the general population, yet the cancer-associated risk factors for COVID-19 adverse outcomes are not fully characterized. We reviewed clinical characteristics and outcomes from patients with cancer and concurrent COVID-19 at Memorial Sloan Kettering Cancer Center until March 31, 2020 (n = 309), and observed clinical end points until April 13, 2020. We hypothesized that cytotoxic chemotherapy administered within 35 days of a COVID-19 diagnosis is associated with an increased hazard ratio (HR) of severe or critical COVID-19. In secondary analyses, we estimated associations between specific clinical and laboratory variables and the incidence of a severe or critical COVID-19 event. Cytotoxic chemotherapy administration was not significantly associated with a severe or critical COVID-19 event (HR, 1.10; 95% CI, 0.73 to 1.60). Hematologic malignancy was associated with increased COVID-19 severity (HR, 1.90; 95% CI, 1.30 to 2.80). Patients with lung cancer also demonstrated higher rates of severe or critical COVID-19 events (HR, 2.0; 95% CI, 1.20 to 3.30). Lymphopenia at COVID-19 diagnosis was associated with higher rates of severe or critical illness (HR, 2.10; 95% CI, 1.50 to 3.10). Patients with baseline neutropenia 14-90 days before COVID-19 diagnosis had worse outcomes (HR, 4.20; 95% CI, 1.70 to 11.00). Findings from these analyses remained consistent in a multivariable model and in multiple sensitivity analyses. The rate of adverse events was lower in a time-matched population of patients with cancer without COVID-19. Recent cytotoxic chemotherapy treatment was not associated with adverse COVID-19 outcomes. Patients with active hematologic or lung malignancies, peri-COVID-19 lymphopenia, or baseline neutropenia had worse COVID-19 outcomes. Interactions among antineoplastic therapy, cancer type, and COVID-19 are complex and warrant further investigation.

Abstract 5467: Outlier analysis to identify determinants of therapeutic resistance in breast cancer

Abstract Tumors are typically characterized by variable responses to targeted therapy driven by the heterogeneity of drivers among tumors. Inter-tumor heterogeneity also results in different resistance determinants to the same therapeutic agent. Outlier analysis has been applied extensively to identify drivers of cancer when comparing a heterogenous population of tumor samples to a relatively homogenous population of normal samples. However, the application of outlier analysis has rarely been applied to identify intrinsic determinants of resistance to targeted cancer therapies. We recently applied outlier analysis to baseline proteomics data collected from HER2/ERBB2 positive breast cancer patients treated with anti-HER2 therapy, comparing protein levels in each patient that did not show pathological complete response (pCR) to the population of patients that did. Three of the five non-pCR patients were outliers for low expression of the ERBB2 protein relative to the pCR patients, suggesting that lack of protein expression of the direct therapeutic target drives resistance in some cases whereas other mechanisms contribute to resistance in other cases. Here, we systematically evaluate the ability of multiple outlier analysis methods, including the method we implemented for the HER2 study (outlieR), to identify molecular genes associated with poor prognosis in estrogen receptor (ESR1) positive patients receiving hormone therapy (targeting ESR1) using a large-scale publicly available dataset which contains baseline gene expression and survival data for ~2000 breast cancer patients (METABRIC). Specifically, we compared expression data from tumors of 72 patients that showed poor prognosis (died of disease within 5 years) to data from 226 tumors from patients with good prognosis (did not die of disease, with at least five years of follow-up time). For this evaluation, we focused on the direct target of hormone therapy, ESR1, and growth factor receptors associated with endocrine therapy resistance. Scores from outlier analysis methods consistently ranked ESR1, EGFR, and genes associated with the ERBB2 locus (amplification of the locus drives ERBB2 gene expression in HER2 positive breast cancer) more highly than the the T-test metric did, with the outlieR method outperforming another established method, Outlier Sums (OS), in most cases. Furthermore, four targets of FDA-approved drugs, including two genes in the MAPK pathway, were amongst the top 200 genes identified by the outlieR method, whereas TOP2A was the only approved target in the top 200 genes identified by the T-test, a target of cytotoxic chemotherapy treatments. Finally, the outlieR method generates outlier scores for each gene in each non-responder relative to the set of non-responders, allowing for the evaluation of genes associated with resistance on a patient-by-patient basis. These observations suggest that outlier analysis can be used to prioritize molecular features as potential mechanisms of resistance and alternative drug targets by accounting for heterogeneity between resistant tumors. Citation Format: Eric James Jaehnig, Meenakshi Anurag, Jonathan T. Lei, Bing Zhang. Outlier analysis to identify determinants of therapeutic resistance in breast cancer [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 5467.

COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study

BackgroundIndividuals with cancer, particularly those who are receiving systemic anticancer treatments, have been postulated to be at increased risk of mortality from COVID-19. This conjecture has considerable effect on the treatment of patients with cancer and data from large, multicentre studies to support this assumption are scarce because of the contingencies of the pandemic. We aimed to describe the clinical and demographic characteristics and COVID-19 outcomes in patients with cancer.MethodsIn this prospective observational study, all patients with active cancer and presenting to our network of cancer centres were eligible for enrolment into the UK Coronavirus Cancer Monitoring Project (UKCCMP). The UKCCMP is the first COVID-19 clinical registry that enables near real-time reports to frontline doctors about the effects of COVID-19 on patients with cancer. Eligible patients tested positive for severe acute respiratory syndrome coronavirus 2 on RT-PCR assay from a nose or throat swab. We excluded patients with a radiological or clinical diagnosis of COVID-19, without a positive RT-PCR test. The primary endpoint was all-cause mortality, or discharge from hospital, as assessed by the reporting sites during the patient hospital admission.FindingsFrom March 18, to April 26, 2020, we analysed 800 patients with a diagnosis of cancer and symptomatic COVID-19. 412 (52%) patients had a mild COVID-19 disease course. 226 (28%) patients died and risk of death was significantly associated with advancing patient age (odds ratio 9·42 [95% CI 6·56–10·02]; p<0·0001), being male (1·67 [1·19–2·34]; p=0·003), and the presence of other comorbidities such as hypertension (1·95 [1·36–2·80]; p<0·001) and cardiovascular disease (2·32 [1·47–3·64]). 281 (35%) patients had received cytotoxic chemotherapy within 4 weeks before testing positive for COVID-19. After adjusting for age, gender, and comorbidities, chemotherapy in the past 4 weeks had no significant effect on mortality from COVID-19 disease, when compared with patients with cancer who had not received recent chemotherapy (1·18 [0·81–1·72]; p=0·380). We found no significant effect on mortality for patients with immunotherapy, hormonal therapy, targeted therapy, radiotherapy use within the past 4 weeks.InterpretationMortality from COVID-19 in cancer patients appears to be principally driven by age, gender, and comorbidities. We are not able to identify evidence that cancer patients on cytotoxic chemotherapy or other anticancer treatment are at an increased risk of mortality from COVID-19 disease compared with those not on active treatment.FundingUniversity of Birmingham, University of Oxford.

Association of tumor mutations with arterial thromboembolism risk in patients with solid cancer.

e13537 Background: Patients with cancer have an increased risk of arterial thromboembolic events (ATE). Clinical characteristics such as medical comorbidities, cancer type, cancer stage and a history of smoking are established risk factors for ATE, but scant data exist about the effect of cancer-specific genomic alterations. We aimed to determine whether individual tumor mutations influence ATE risk. Methods: We performed a retrospective cohort study using tumor mutational data from adults with solid cancers who had MSK-IMPACT testing at Memorial Sloan Kettering Cancer Center between 2014 and 2016. MSK-IMPACT is an FDA-authorized DNA sequencing panel targeting 341+ oncogenes and tumor suppressor genes identifying mutations, copy number alterations, and gene fusions in solid malignancies. The primary ATE outcome was defined as ischemic stroke, myocardial infarction or coronary revascularization and detected by systematic electronic health record assessments. Patients were followed up to one year from the date of tissue-matched blood control sampling to the first ATE or death. We used Cox proportional hazards regression adjusting for age, cancer type, cytotoxic chemotherapy treatment (time-dependent) and tobacco use to determine hazard ratios (HR) of individual genes for ATE risk. We adjusted for multiple comparisons using the Benjamini-Hochberg method. Results: Among 11,317 patients, mean age was 59 years (SD = 14 years) and 55% were women. The most frequent cancers were lung (16%), breast (15%), and colorectal (10%), and 73% were metastatic. During a median follow-up of 253 days, 151 patients had an ATE (1.3%). In multivariable analysis, genomic alterations in KRAS (HR, 2.11; CI, 1.41-3.16), STK11 (HR, 2.62; 95% CI, 1.49-4.59), and ROS1 (HR, 5.3; 95% CI, 1.93-14.58) were independently associated with an increased risk of ATE. Presence of clonal hematopoiesis was not found to be associated with an increased risk of ATE in this cohort (HR, 0.96; 95% CI, 0.63-1.47). Conclusions: In a large genomic tumor-profiling registry of patients with solid cancers, alterations in KRAS, STK11, and ROS1 were associated with an increased risk of ATE independent of cancer type. [Table: see text]