Dihydropyrimidine Dehydrogenase Deficiency (DPYD) Genotyping-Guided Fluoropyrimidine-Based Adjuvant Chemotherapy for Breast Cancer. A Cost-Effectiveness Analysis.

To the editor, With interest we read the article by Dr Cubero and colleagues, in which they evaluated the safety of tegafur-uracil (UFT®) in five cases with partial dihydropyrimidine dehydrogenase (DPD) deficiency [Cubero et al. 2012]. Based on our previous experience [Deenen et al. 2010], however, we would like to express our concern about their conclusion that UFT is a safe alternative for the treatment of patients with partial DPD deficiency. Cubero and colleagues make the erroneous and unproven statement that the presence of uracil in UFT creates an artificial DPD deficiency, and that the DPD activity in patients with normal DPD activity would then be similarly as low as in DPD-deficient patients. This assumption, however, is incorrect. As uracil is a competitive inhibitor of DPD, it competes with 5-fluorouracil (5-FU) for DPD-mediated metabolism. This does not mean that the activity of DPD is depleted, as suggested by Cubero and colleagues, in contrast, its activity is fully utilized, as well as for the metabolism of uracil, as for the metabolism of 5-FU. We would like to caution that treating patients with partial DPD deficiency with the standard dose of UFT may unnecessarily lead to severe, potentially lethal toxicity. Unlike the cases described by Cubero and colleagues, we could previously describe four cases presenting with comparable severe toxicity profiles upon treatment with UFT as had previously occurred during treatment with capecitabine or 5-FU. In all subjects an underlying partial DPD deficiency was identified by genotype and phenotype analyses [Deenen et al. 2010]. Furthermore, there are several pharmacological lines of argument that support our clinical observation, i.e. that the standard dose of UFT is not safe in (partial) DPD-deficient patients. First, pharmacokinetic studies have shown that DPD remains essential for the metabolism of UFT, with significantly longer half-lives of 5-FU after administration of UFT compared with 5-FU administered intravenously [Ho et al. 1998]. This is due to the presence of uracil in UFT. Since DPD-deficient patients already have longer half-lives of 5-FU than other patients [Mattison et al. 2006], presence of uracil increases its half-life even further. This in turn leads to prolonged and elevated circulating levels of 5-FU, with a subsequently increased risk of 5-FU-induced severe toxicity. Another argument underscoring the importance of normal DPD function in the safe application of UFT, is the experience with S-1. S-1 is another drug combination of tegafur, consisting of tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate in a molar ratio of 1:0.4:1. CDHP inhibits DPD 200-fold more potently than does uracil [Shirasaka et al. 1996a, 1996b]. Even after administration of S-1, the primary 5-FU metabolite formed by DPD is observed in significant concentrations in plasma [Kim et al. 2007]. Thus, DPD remains an essential detoxification enzyme of 5-FU, even when its activity is strongly inhibited. The ultimate proof of theory is the occurrence of 18 treatment-related deaths in patients with cancer and herpes zoster given UFT plus the antiviral drug sorivudine [Pharmaceutical Affairs Bureau, 1994]. Subsequent studies in rats showed that a metabolite of sorivudine, (E)-5-(2-bromovinyl)uracil, instantly and irreversibly inactivates DPD by covalent binding, which has been identified as the underlying mechanism of these toxic deaths [Ogura et al. 1998; Okuda et al. 1998]. It is for these arguments that the Summary of Product Characteristics of UFT notes a known DPD deficiency as a contra-indication [Merck Serono, 2011]. The fact that the patients described by Cubero and colleagues did not develop significant toxicity might be due to patient selection, the slightly decreased dose intensity of 90%, or despite their DPYD*2A genotype a DPD enzyme activity within the (lower) range of normal. We are not aware of this, because DPD enzyme activity was not determined in these patients. In summary, we would like to state that standard-dose UFT is not a safe treatment in (partial) DPD-deficient patients. Instead, dose reductions of on average 50% of either capecitabine, 5-FU or UFT with careful monitoring of safety and further dose titration are proposed as the standard of care [Deenen et al. 2011].

1618 Background: DPD deficiency is the most important risk factor for developing fluoropyrimidine-related adverse events. Genetic variants causing DPD deficiency are found in 6-8% of Caucasian patients. However, there is limited information on their prevalence in underrepresented ethnic groups, such as Hispanics and Latinos, and testing for these variants is not routinely recommended in Latin America. Our goal was to assess the allele frequency of clinically actionable dihydropyrimidine dehydrogenase ( DPYD) risk variants defined by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the European Medicines Agency (EMA) among admixed Mexican patients with GI malignancies. Methods: Patients with recently diagnosed GI cancer candidates for fluropyrimidine therapy were recruited from a single institution in Mexico City. After providing informed consent, a blood sample and clinical characteristics were collected. We utilized the Illumina Infinium Global Screening Array (GSA)-to genotype 34 DPYD variants, six of which are known to lead to an increased risk of fluoropyrimidine toxicity and are considered clinically actionable. Results: Two hundred and eight patients with a mean age of 62 years (SD 13.2) were included. 47% were female. The most common type of cancer was colorectal (38%) followed by pancreas (22%) and biliary tract (18%). DNA samples from 192 patients passed quality control, of which 156 (62%) received fluoropyrimidines during follow-up. Only 2 patients (1%) were heterozygous for actionable DPYD intermediate metabolizer risk variant alleles: one with c.2846A > T ( rs67376798 , D949V) and one with c.1129–5923C > G [ rs75017182; HapB3 SNP c.1236G > A; rs56038477]. No patients were found to have other CPIC-listed DPYD risk variants . Additionally, we investigated the allele frequencies of other 30 DPYD variants and observed low-frequency variation (between 0.260 and 0.0032) in rs56038477, rs1801160, rs17376848, rs1801159, rs1801158, rs45589337, rs2297595, rs200562975, and rs1801265. Several of these may be related to decreased DPYD activity and warrant further analysis regarding their impact on adverse drug reactions. Conclusions: In contrast with reports from Caucasic populations, we found a very low allele frequency of DPYD actionable variants. Our findings highlight the limitation of current pharmacogenomic testing recommendations and panels, which may not be appropriate for admixed ethnic populations such as Hispanics/Latinos due to disparities in representation. There is a need to study the role of other DPYD variants in larger patient samples to understand their role in the toxicity risk of admixed populations in Mexico and Latin America, to explore the use of novel techniques such as Next Generation Sequencing, and to investigate the effect of other related genes on toxicity risk.

Monocyte activation in cancer patients may be reflective of anticancer activity. However, studies indicate that recruitment of macrophages can actually promote tumor growth and angiogenesis. Assessment of other microenvironmental cells such as circulating endothelial cells (CECs) may provide additional information regarding disease progression. The objective of this study was to assess monocyte activation and CECs in breast cancer patients and determine the potential clinical relevance during disease progression. Patients (n = 41) with localized or metastatic breast cancer who were not currently receiving treatment were eligible for study inclusion. Peripheral blood was collected and analyzed by flow cytometry for monocyte activation (Leuko64 assay kit), and for CECs (CD146(+)CD45(-) phenotype). Metastatic breast cancer patients demonstrated a higher monocyte CD64 index relative to normal donors and localized breast cancer patients (P < 0.05). Furthermore, breast cancer patients had a lower monocyte CD163 index relative to normal donors (P = 0.008). Localized breast cancer patients demonstrated higher levels of CD146(+)CD45(-) cells CECs relative to metastatic breast cancer patients and normal donors. Within the localized breast cancer population, levels of CD146(+)CD45(-) cells increased with disease stage (P < 0.05). These results suggest that monocyte activation and CECs may play a role in breast cancer progression. We speculate that monocyte activation may reflect a reaction to metastatic cells and/or response to tissue damage caused by metastatic growth in distant organs. Furthermore, the observation that CECs increase with disease stage in localized breast cancer suggests that CECs could be a useful surrogate marker for disease progression in this patient population.

55 Background: Fluoropyrimidine chemotherapy agents, including 5-fluorouracil and capecitabine, are the backbone of adjuvant treatment for colon cancer, and adjuvant chemotherapy substantially reduces recurrence and mortality after surgical resection of stage 3 colon cancer. While fluoropyrimidine chemotherapy is generally safe, the risk of severe, potentially fatal chemotherapy toxicity is substantially increased for the 2-3% of U.S. patients with DPD deficiency caused by pathogenic variants in the DPYD gene. DPYD genotype testing is readily available in the U.S. but has not been widely adopted. We evaluated the cost effectiveness of DPYD genotyping prior to adjuvant chemotherapy for colon cancer in the U.S. Methods: We constructed a Markov model to simulate screening for DPD deficiency with DPYD genotyping (versus no screening) among patients receiving fluoropyrimidine-based adjuvant chemotherapy for stage 3 colon cancer. Screen-positive patients were modeled to receive dose-reduced fluoropyrimidine chemotherapy. Model transition probabilities for treatment-related toxicities were derived from published clinical trial data with annotation of DPYD genotype and chemotherapy dosing strategy. Our analysis is from the healthcare perspective, with a time horizon of five years and an annual discount rate of 3% for future costs and benefits. Direct healthcare costs and health utilities were estimated from published sources and converted to 2020 US dollars, and post-treatment survival was modeled from SEER data. The primary outcome was the incremental cost-effectiveness ratio (ICER), defined as dollars per quality-adjusted life year (QALY). We used a value of $100,000/QALY as the cost-effectiveness threshold. One-way sensitivity analyses were used to examine model uncertainty. Results: Compared with no screening, screening for DPD deficiency with DPYD genotyping increased per-patient costs by $106 and improved quality-adjusted survival by 0.0028 QALYs, leading to an ICER of $37,300/QALY. In one-way sensitivity analyses, the ICER exceeded $100,000/QALY when the carrier frequency of pathogenic DPYD gene variants was less than 1.17%, and when the specificity of DPYD genotyping was less than 98.9%. Cost-effectiveness estimates were not sensitive to the cost of DPYD genotyping, the cost of toxicity-related hospitalizations, or the health utility associated with grade 3-4 toxicity. Conclusions: Among patients receiving adjuvant chemotherapy for stage 3 colon cancer, screening for DPD deficiency with DPYD genotyping is a cost-effective strategy for preventing infrequent but severe, sometimes fatal toxicities of fluoropyrimidine chemotherapy.

Short-course regimens are currently explored to improve multidrug-resistant tuberculosis effects, reduce costs, as well as enhance patient adherence. Currently, we are determining the most cost-effective shorter regimen out of seven short-course regimens (6-9months) to treat drug-resistant tuberculosis (DR-TB) compared to the current standard of care (SoC) 9- to 11-month regimen. Cost-effectiveness of various short-course DR-TB treatment regimens, namely BEAT, BPaL, BPaLM, BPaLC, mBPaL1, mBPaL2, and mBPaL3, was compared to the current SoC in India. Decision tree model was used from a health system perspective. The information on various costs - such as preinvestigations, regimens, adverse drug reactions (ADRs) management, inpatient treatment - and on effect - such as clinical outcomes and ADRs - was collected from different published sources. It estimated costs, quality-adjusted life years, and incremental cost-effectiveness ratios (ICERs). Sensitivity analyses were performed to validate outcomes against the willingness-to-pay threshold. When all the short-course regimens were compared with the current SoC regimen, the ICERs were ₹5,385, ₹2,014, ₹2,008, ₹2,435, ₹1,462, ₹1,159, and ₹1,895 for BEAT, BPaL, BPaLM, BPaLC, mBPaL1, mBPaL2, and mBPaL3, respectively. Among the short-course regimens, mBPaL2 is the dominant strategy, and mBPaL1 has extended dominance. For all Bedaquiline-containing regimens, the cost of the drug is a crucial factor in determining cost effectiveness. The cost-effectiveness acceptability curve showed that all shorter regimens were 100 percent cost-effective. The implementation of Bedaquiline-based regimen to treat DR-TB has become more effective, shorter in duration, and less burdensome to the health system.

Despite well-established clinical guidelines for breast cancer treatment, Standard of Care (SOC) is not universal in the U.S. The purpose of this study was to describe the extent to which patients receive guideline-based, stage-specific treatments for localized female breast cancer in Oklahoma. Data were obtained from the Oklahoma Central Cancer Registry for the period 2003–2006. We included localized, invasive female breast cancers and analyzed both treatment and demographic factors. We used the National Comprehensive Cancer Network (NCCN) treatment guidelines to determine SOC. Among women who received breast conserving surgery (BCS), we used logistic regression to evaluate factors related to SOC. In Oklahoma, 92 percent of the 4,177 localized breast cancer patients were treated with recognized SOC. In women aged ≥65 years with BCS, those ≥75 years had a lower adjusted odds of meeting SOC than did those without insurance, with comorbid conditions, or whose comorbid status was unknown. Among women aged <65 years, those with Medicare/Medicaid, Medicare only, or without insurance, along with comorbid conditions, had a lower adjusted odds of meeting SOC. Overall, 92 percent of women met SOC. Factors such as age, insurance type, and comorbid conditions were associated with meeting SOC.

Background: Circulating tumor cells (CTCs) and circulating free plasma DNA (FPDNA) have been proposed as biomarkers predictive of outcome and response to therapy in solid tumors. We investigated the multiple associations of the presence of CTC and the levels of FPDNA with the outcome and/or the response to chemotherapy in patients with localized breast cancer (LBC), metastatic breast cancer (MBC) and advanced ovarian cancer (AOC). Experimental Design: Blood samples were collected before (baseline), during and after therapy in 40 LBC and 50 AOC patients treated with neo-adjuvant chemotherapy. In 20 MBC patients blood was sampled at baseline and every each cycle of adjuvant chemotherapy. Real time PCR was applied to quantify FPDNA using the Quantifiler Human Quantification kit and CTCs through the detection of tumor-cell specific mRNA levels with or without epithelial enrichment. Results: At baseline CTCs were detected in 90% MBC, 42.5% LBC and 33% AOC patients respectively. The presence of baseline CTC was significantly associated with shorter overall survival (OS) in MBC and AOC patients, and shorter progression free survival (PFS) in LBC patients. Presence of CTCs at the end of neo-adjuvant chemotherapy was detected in 42% LBC and 18% AOC patients and was associated with shorter PFS and OS only in LBC. Increased FPDNA levels at baseline were found in 65% MBC, 17.5% LBC and 76% AOC patients but never related to OS. Baseline FPDNA high levels were associated with shorter PFS only in LBC patients. High FPDNA levels after neo-adjuvant chemotherapy were detected in 57% LBC and 48% AOC patients. Increased FPDNA after neo-adjuvant was associated with response to therapy and shorter PFS in AOC patients. Conclusions: Detection of CTCs may represent a prognostic and predictive biomarker in LBC, MBC and AOC. Quantification of FPDNA could be useful for monitoring response to therapy in AOC patients.

e21005 Background: Tumor pathophysiological conditions depending on tumor cell metabolism and tumor microenvironment offer an opportunity to better characterize tumors by providing metabolic signature. Metabolomics is the combination of analytical techniques such as Nuclear Magnetic Resonance (NMR) spectroscopy with statistical data analysis methods aimed to evaluate the metabolic status of biofluids. This technology may be relevant for breast cancer prognosis. Therefore, the first objective of this study was to provide evidence that metabolomics from patients' (pts) blood sample is able to distinguish between metastatic and localized breast cancer. Methods: Serum samples from 2 cohorts of pts were analyzed using 1H NMR spectroscopy on a Bruker Avance III spectrometer operating at 800 MHz and equipped with a triple resonances automated TXI probe. Fasting blood sample were drawn from 30 pts with localized breast cancer (before surgery), and from 25 pts with metastatic breast cancer (before the first chemotherapy injection). For each sample, a 1D NMR spectrum was acquired, showing a large number of resonances corresponding to protons belonging to different classes of metabolites. A spectral database was generated, and bioinformatic tools were used to analyze the results using supervised multivariate analysis (Partial Least Square Regression). Results: The use of very high-field NMR allows the acquisition of resolved spectra with a reliable assignment of resonances based on multidimensional homo- and heteronuclear experiments. We identify metabolic signature of metastatic breast cancer, which is statistically different from the metabolic signature of localized breast cancer. Target analysis is on going to have further quantitative analysis of a class of metabolites that are related to the metastatic condition. Conclusions: Metabolomics may become a novel biomarker for cancer prognosis. Prospective studies to validate metabolomics as a prognostic/predictive tool are planed. No significant financial relationships to disclose.

An agenda for research on adverse drug reactions

PDB24 An EARLY Cost-Utility MODEL of Mrna-Based Therapies Compared with Standard of Care in EARLY-Onset Propionic Acidaemia in the United Kingdom

PDB40 An EARLY Cost-Utility MODEL of Mrna-Based Therapies Compared with Standard of Care in EARLY-Onset Methylmalonic Acidaemia in the United Kingdom

The CHANCE-2 study compared 3 weeks of aspirin-ticagrelor to aspirin-clopidogrel in CYP2C19 loss-of-function (LOF) allele carriers following a transient ischemic attack (TIA)/minor stroke and demonstrated a modestly lower risk of stroke recurrence with aspirin-ticagrelor. This stroke protection was largely for minor stroke and came at an increased risk of bleeding. The cost-effectiveness of implementing testing for LOF allele status to personalize antiplatelet regimen for secondary stroke prevention after a TIA/minor stroke in the Canadian health care context is unknown. Cost-effectiveness analysis using a decision-analytic Markov cohort model with a lifetime horizon was performed to determine the costs and health benefits of testing for LOF allele status compared with no testing (current standard of care). The population of interest was patients living in Canada who suffered a TIA/minor stroke. Outcomes of interest were life-years gained (LYG), quality-adjusted life years (QALY) gained, costs (reported in 2022 Canadian dollars), and the incremental cost-effectiveness ratio (ICER). We adopted the perspective of the Federal, Provincial, and Territorial Ministries of Health and used a 1.5% annual discount rate. Sensitivity analyses were performed to assess uncertainty. Compared to standard of care, LOF allele testing leads to 0.14 LYG (undiscounted), 0.12 QALYs gained (undiscounted), and additional lifetime costs of CAD$432 (discounted) per patient. The ICER of the LOF allele testing strategy is CAD$4310 per QALY gained compared with standard of care. The probabilistic sensitivity analyses demonstrated that LOF allele testing was cost-effective in more than 99.99% of simulations using a willingness-to-pay threshold of CAD$50,000 per QALY. Based on available evidence, testing for LOF allele followed by short duration 3 weeks of aspirin-ticagrelor compared to standard-of-care aspirin-clopidogrel can lead to prolonged life and improved quality of life and can be considered very cost-effective when compared with other well-accepted technologies in health and medicine.

Cost Effectiveness of Nivolumab for the Treatment of Relapsed/Refractory Classical Hodgkin Lymphoma (cHL) after Failure of Autologous Stem Cell Transplantation (ASCT) and Treatment with Brentuximab Vedotin (BV) Treatment in Australia

Time to Invest in the Future: Assessing the Cost-Effectiveness of Empagliflozin in Diabetic Kidney Disease

Cost-Effectiveness of Axicabtagene Ciloleucel for Adult Patients with Relapsed or Refractory Follicular Lymphoma in the United States