Demographic disparities in receipt of care at a comprehensive cancer center.

BACKGROUND: National Cancer Institute cancer centers (NCICCs) provide specialized cancer care including precision oncology and clinical treatment trials. While these centers can offer novel therapeutic options, less is known about when patients access these centers or at what timepoint in their disease course they receive specialized care. This is especially important since precision diagnostics and receipt of the optimal therapy upfront can impact patient outcomes and previous research suggests that access to these centers may vary by demographic characteristics. Here, we examine the timing of patients' presentation at Moffitt Cancer Center (MCC) relative to their initial diagnosis across several demographic characteristics. METHODS: A retrospective cohort study was conducted among patients who presented to MCC with breast, colon, lung, melanoma, and prostate cancers between December 2008 and April 2020. Patient demographic and clinical characteristics were obtained from the Moffitt Cancer Registry. The association between patient characteristics and the timing of patient presentation to MCC relative to the patient's cancer diagnosis was examined using logistic regression. RESULTS: Black patients (median days = 510) had a longer time between diagnosis and presentation to MCC compared to Whites (median days = 368). Black patients were also more likely to have received their initial cancer care outside of MCC compared to White patients (odds ratio [OR] and 95% confidence interval [CI] = 1.45 [1.32-1.60]). Furthermore, Hispanics were more likely to present to MCC at an advanced stage compared to non-Hispanic patients (OR [95% CI] = 1.28 [1.05-1.55]). CONCLUSIONS: We observed racial and ethnic differences in timing of receipt of care at MCC. Future studies should aim to identify contributing factors for the development of novel mitigation strategies and assess whether timing differences in referral to an NCICC correlate with long-term patient outcomes.

A scoping review on patient heterogeneity in economic evaluations of precision medicine based on basket trials.

INTRODUCTION: Considerable challenges in the economic evaluation of precision medicines have been mentioned in previous studies. However, they have not addressed how an economic assessment would be conducted based on basket trials (novel studies for evaluation of precision medicine effects) in which the included populations have specific biomarkers and various cancers. Since basket trial populations have remarkable heterogeneity, this study aims to investigate the concept of heterogeneity and specific method(s) for considering it in economic evaluations through guidelines and studies that could be applicable in economic evaluation based on basket trials. AREA COVERED: We searched PubMed, Web of Science, Scopus, Google Scholar, and Google to find studies and pharmacoeconomics guidelines. The inclusion criteria included subjects of patient heterogeneity and suggested explicit method(s). Thirty-nine guidelines and 43 studies were included and evaluated. None of these materials mentioned disease types in a target population as a factor causing heterogeneity. Moreover, in economic evaluations, patient heterogeneity has been considered with four general approaches subgroup analysis, individual-based models, sensitivity analysis, and regression models. EXPERT OPINION: Type of disease is not considered a contributing factor in population heterogeneity, and the probable appropriate method for this issue could be individual-based models.

Investigating the Role of Image Fusion in Brain Tumor Classification Models Based on Machine Learning Algorithm for Personalized Medicine.

Image fusion can be performed on images either in spatial domain or frequency domain methods. Frequency domain methods will be most preferred because these methods can improve the quality of edges in an image. In image fusion, the resultant fused images will be more informative than individual input images, thus more suitable for classification problems. Artificial intelligence (AI) algorithms play a significant role in improving patient's treatment in the health care industry and thus improving personalized medicine. This research work analyses the role of image fusion in an improved brain tumour classification model, and this novel fusion-based cancer classification model can be used for personalized medicine more effectively. Image fusion can improve the quality of resultant images and thus improve the result of classifiers. Instead of using individual input images, the high-quality fused images will provide better classification results. Initially, the contrast limited adaptive histogram equalization technique preprocess input images such as MRI and SPECT images. Benign and malignant class brain tumor images are applied with discrete cosine transform-based fusion method to obtain fused images. AI algorithms such as support vector machine classifier, KNN classifier, and decision tree classifiers are tested with features obtained from fused images and compared with the result obtained from individual input images. Performances of classifiers are measured using the parameters accuracy, precision, recall, specificity, and F1 score. SVM classifier provided the maximum accuracy of 96.8%, precision of 95%, recall of 94%, specificity of 93%, F1 score of 91%, and performed better than KNN and decision tree classifiers when extracted features from fused images are used. The proposed method results are compared with existing methods and provide satisfactory results.

Patient-derived organoids for personalized gallbladder cancer modelling and drug screening.

BACKGROUND: Gallbladder carcinoma (GBC) is a relatively rare but highly aggressive cancer with late clinical detection and a poor prognosis. However, the lack of models with features consistent with human gallbladder tumours has hindered progress in pathogenic mechanisms and therapies. METHODS: We established organoid lines derived from human GBC as well as normal gallbladder and benign gallbladder adenoma (GBA) tissues. The histopathology signatures of organoid cultures were identified by H&E staining, immunohistochemistry and immunofluorescence. The genetic and transcriptional features of organoids were analysed by whole-exome sequencing and RNA sequencing. A set of compounds targeting the most active signalling pathways in GBCs were screened for their ability to suppress GBC organoids. The antitumour effects of candidate compounds, CUDC-101 and CUDC-907, were evaluated in vitro and in vivo. RESULTS: The established organoids were cultured stably for more than 6 months and closely recapitulated the histopathology, genetic and transcriptional features, and intratumour heterogeneity of the primary tissues at the single-cell level. Notably, expression profiling analysis of the organoids revealed a set of genes that varied across the three subtypes and thus may participate in the malignant progression of gallbladder diseases. More importantly, we found that the dual PI3K/HDAC inhibitor CUDC-907 significantly restrained the growth of various GBC organoids with minimal toxicity to normal gallbladder organoids. CONCLUSIONS: Patient-derived organoids are potentially a useful platform to explore molecular pathogenesis of gallbladder tumours and discover personalized drugs.

Novel Fibroblast Activation Protein Inhibitor-Based Targeted Theranostics for Radioiodine-Refractory Differentiated Thyroid Cancer Patients: A Pilot Study.

Background: This exploratory study was meant to assess clinical and safety data with a novel fibroblast activation protein inhibitor-based targeted theranostics as a salvage treatment option in radioiodine-refractory differentiated thyroid cancer (RR-DTC) patients who had progressed on tyrosine kinase inhibitors. Methods: Patients with metastatic RR-DTC who progressed on sorafenib/lenvatinib were prospectively recruited. If [68Ga]Ga-DOTA.SA.FAPi positron emission tomography/computed tomography scan demonstrated moderate-to-excellent uptake in metastases, and patients had given informed consent, they received intravenous [177Lu]Lu-DOTAGA.(SA.FAPi)2 as therapy at eight-weekly intervals. The primary endpoints were thyroglobulin (Tg) response and functional imaging response. The secondary endpoints were visual analog score (VAS) and Eastern Cooperative Oncology Group (ECOG) performance status. The grading of toxicities was performed by using Common Terminology Criteria for Adverse Events (CTCAEV5.0). The sequential images were acquired by a dual-headed gamma camera, and dosimetric calculations were performed by using OLINDA/EXM V2.1. Results: Fifteen patients were recruited [age: 55 ± 9 years (range: 39-67)]. [177Lu]Lu-DOTAGA.(SA.FAPi)2 had median whole-body Teff of 88.06 hours (interquartile range [IQR]: 86.6-99). The colon was identified as a critical organ. The whole-body effective dose was 1.62E-01 ± 1.53E-02 mSv/MBq. A total of 45 cycles were administered, and the median cumulative administered activity was 8.2 ± 2.7 GBq (range 5.5-14 GBq). The median absorbed doses to the tumor lesions were 1.08E+01 (IQR: 4.16E+00 to 8.97E+01) mSv/MBq per cycle. The Serum Tg level significantly decreased after treatment [(median Tg: baseline-10,549 ng/mL (IQR: 3066.5-39,450) versus at the time of assessment: 5649 ng/mL (IQR: 939.5-17,099), p = 0.0005)]. Molecular response assessment revealed no complete response; however, partial response was documented in four, and stable disease in three patients. The VASmax scores [pre-therapy: 9 (IQR: 8-10) versus follow-up: 6 (3-6) (p-0.0001)], and ECOG [3, (IQR: 2-3 vs. 2, (IQR: 2-3) (p-0.0078)] performance scores significantly improved after treatment. None of the patients experienced grade III/IV hematological, renal, or hepatotoxicity. Conclusion: These preliminary data suggest that the novel molecule [177Lu]Lu-DOTAGA.(SA.FAPi)2 is safe, seems effective, and, most importantly, opens up a new avenue for the treatment of aggressive RR-DTC patients who have exhausted all standard line of treatments.

Racial and Ethnic Disparities Among Participants in Precision Oncology Clinical Studies.

Importance: Precision oncology is revolutionizing cancer care, allowing for personalized treatments to improve outcomes. Cancer research has benefitted from well-designed studies incorporating precision medicine objectives, but it is unclear if these studies are representative of the diverse cancer population. Objective: To evaluate racial and ethnic representation in breast, prostate, lung, and colorectal cancer studies incorporating precision oncology objectives in the Clinicaltrials.gov registry and compare with the incidence of these cancer types in racial and ethnic minority groups in the US population. Design, Setting, and Participants: This cross-sectional study identified US-based breast, prostate, lung, and colorectal cancer studies incorporating precision oncology objectives for reporting of race and ethnicity. The Surveillance, Epidemiology, and End Results and US Census databases were used to determine cancer incidence by race and ethnicity, linked with cancer type and median year of enrollment for each trial. Data were collected and analyzed between December 2020 and April 2021. Main Outcomes and Measures: The expected number of participants per study by each racial and ethnic group was calculated based on the corresponding US-based proportion. Under- and overrepresentation was defined as the ratio of the actual number of enrolled cases to the expected number of cases for each trial by cancer type. Ratios above 1 indicated overrepresentation while a ratio below 1 indicated underrepresentation. Random-effects meta-analysis of representation ratios of individual trials was performed to weigh each individual study. Results: Of 93 studies encompassing 5867 enrollees with race and ethnicity data; 4826 participants (82.3%) were non-Hispanic White, 587 (10.0%) were Black, and 238 (4.1%) were Asian. Per observed-to-expected ratios, White participants were overrepresented in all studies, with a ratio of 1.35 (95% CI, 1.30-1.37), as well as Asian participants, with a ratio of 1.46 (95% CI, 1.28-1.66), while Black participants (ratio, 0.49; 95% CI, 0.45-0.54), Hispanic participants (ratio, 0.24; 95% CI, 0.20-0.28), and American Indian and Alaskan Native participants (ratio, 0.43; 95% CI, 0.24-0.78) were underrepresented. By individual cancer site, White participants were consistently overrepresented in all studies, while Black and Hispanic participants were underrepresented. Conclusions and Relevance: This analysis found that precision oncology studies for breast, lung, prostate, and colorectal cancers vastly underrepresent racial and ethnic minority populations relative to their cancer incidence in the US population. It is imperative to increase diversity among enrollees so that all individuals may benefit from cancer research breakthroughs and personalized treatments.

Perspectives on emerging technologies, personalised medicine, and clinical research for cancer control in Latin America and the Caribbean.

Challenges of health systems in Latin America and the Caribbean include accessibility, inequity, segmentation, and poverty. These challenges are similar in different countries of the region and transcend national borders. The increasing digital transformation of health care holds promise of more precise interventions, improved health outcomes, increased efficiency, and ultimately reduced health-care costs. In Latin America and the Caribbean, the adoption of digital health tools is in early stages and the quality of cancer registries, electronic health records, and structured databases are problematic. Cancer research and innovation in the region are limited due to inadequate academic resources and translational research is almost fully dependent on public funding. Regulatory complexity and extended timelines jeopardise the potential improvement in participation in international studies. Emerging technologies, artificial intelligence, big data, and cancer research represent an opportunity to address the health-care challenges in Latin America and the Caribbean collectively, by optimising national capacities, sharing and comparing best practices, and transferring scientific and technical capabilities.

Rationale and design of the preserved versus reduced ejection fraction biomarker registry and precision medicine database for ambulatory patients with heart failure (PREFER-HF) study.

INTRODUCTION: Patients with heart failure (HF) are classically categorised by left ventricular ejection fraction (LVEF). Efforts to predict outcomes and response to specific therapy among LVEF-based groups may be suboptimal, in part due to the underlying heterogeneity within clinical HF phenotypes. A multidimensional characterisation of ambulatory patients with and without HF across LVEF groups is needed to better understand and manage patients with HF in a more precise manner. METHODS AND ANALYSIS: To date, the first cohort of 1313 out of total planned 3000 patients with and without HF has been enroled in this single-centre, longitudinal observational cohort study. Baseline and 1-year follow-up blood samples and clinical characteristics, the presence and duration of comorbidities, serial laboratory, echocardiographic data and images and therapy information will be obtained. HF diagnosis, aetiology of disease, symptom onset and clinical outcomes at 1 and 5 years will be adjudicated by a team of clinicians. Clinical outcomes of interest include all-cause mortality, cardiovascular mortality, all-cause hospitalisation, cardiovascular hospitalisation, HF hospitalisation, right-sided HF and acute kidney injury. Results from the Preserved versus Reduced Ejection Fraction Biomarker Registry and Precision Medicine Database for Ambulatory Patients with Heart Failure (PREFER-HF) trial will examine longitudinal clinical characteristics, proteomic, metabolomic, genomic and imaging data to better understand HF phenotypes, with the ultimate goal of improving precision medicine and clinical outcomes for patients with HF. ETHICS AND DISSEMINATION: Information gathered in this research will be published in peer-reviewed journals. Written informed consent for PREFER-HF was obtained from all participants. All study procedures were approved by the Mass General Brigham Institutional Review Board in Boston, Massachusetts and performed in accordance with the Declaration of Helsinki (Protocol Number: 2016P000339). TRIAL REGISTRATION NUMBER: PREFER-HF ClinicalTrials.gov identifier: NCT03480633.

The Design of Individual Orthopedic Insoles for the Patients with Diabetic Foot Using Integral Curves to Describe the Plantar Over-Pressure Areas.

Identification of over-pressure areas in the plantar side of the foot in patients with diabetic foot and reduction of plantar pressure play a major role in clinical practice. The use of individual orthopedic insoles is essential to reduce the over-pressure. The aim of the present study is to mark the over-pressure areas of the plantar part of the foot on a pedogram and describe them with high accuracy using a mathematical research method. The locally over-pressured areas with calluses formed due to repeated injuries were identified on the patients' pedograms. The geometric shapes of the over-pressure areas were described by means of the integral curves of the solutions to Dirichlet singular boundary differential equations. Based on the mathematical algorithm describing those curves, the computer programs were developed. The individual orthopedic insoles were produced on a computer numerical control milling machine considering the locally over-pressured areas. The ethylene vinyl acetate polymers of different degrees of hardness were used to produce the individual orthopedic insoles. For the over-pressure areas, a soft material with a hardness of 20 Shore A was used, which reduces the pressure on the plantar side of the foot and increases the contact area. A relatively hard material with a hardness of 40 Shore A was used as the main frame, which imparts the stability of shape to the insole and increases its wear life. The individual orthopedic insoles produced by means of such technology effectively reduce the pressure on the plantar side of the foot and protect the foot from mechanical damage, which is important for the treatment of the diabetic foot.

Identification of novel and rare variants associated with handgrip strength using whole genome sequence data from the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program.

Handgrip strength is a widely used measure of muscle strength and a predictor of a range of morbidities including cardiovascular diseases and all-cause mortality. Previous genome-wide association studies of handgrip strength have focused on common variants primarily in persons of European descent. We aimed to identify rare and ancestry-specific genetic variants associated with handgrip strength by conducting whole-genome sequence association analyses using 13,552 participants from six studies representing diverse population groups from the Trans-Omics in Precision Medicine (TOPMed) Program. By leveraging multiple handgrip strength measures performed in study participants over time, we increased our effective sample size by 7-12%. Single-variant analyses identified ten handgrip strength loci among African-Americans: four rare variants, five low-frequency variants, and one common variant. One significant and four suggestive genes were identified associated with handgrip strength when aggregating rare and functional variants; all associations were ancestry-specific. We additionally leveraged the different ancestries available in the UK Biobank to further explore the ancestry-specific association signals from the single-variant association analyses. In conclusion, our study identified 11 new loci associated with handgrip strength with rare and/or ancestry-specific genetic variations, highlighting the added value of whole-genome sequencing in diverse samples. Several of the associations identified using single-variant or aggregate analyses lie in genes with a function relevant to the brain or muscle or were reported to be associated with muscle or age-related traits. Further studies in samples with sequence data and diverse ancestries are needed to confirm these findings.

Clinical and economic impact of current ALK rearrangement testing in Spain compared with a hypothetical no-testing scenario.

BACKGROUND: Currently biomarkers play an essential role in diagnosis, treatment, and management of cancer. In non-small cell lung cancer (NSCLC) determination of biomarkers such as ALK, EGFR, ROS1 or PD-L1 is mandatory for an adequate treatment decision. The aim of this study is to determine the clinical and economic impact of current anaplastic lymphoma kinase testing scenario in Spain. METHODS: A joint model, composed by decision-tree and Markov models, was developed to estimate the long-term health outcomes and costs of NSCLC patients, by comparing the current testing scenario for ALK in Spain vs a hypothetical no-testing. The current distribution of testing strategies for ALK determination and their sensitivity and specificity data were obtained from the literature. Treatment allocation based on the molecular testing result were defined by a panel of Spanish experts. To assess long-term effects of each treatment, 3-states Markov models were developed, where progression-free survival and overall survival curves were extrapolated using exponential models. Medical direct costs (expressed in €, 2019) were included. A lifetime horizon was used and a discount rate of 3% was applied for both costs and health effects. Several sensitivity analyses, both deterministic and probabilistic, were performed in order test the robustness of the analysis. RESULTS: We estimated a target population of 7628 NSCLC patients, including those with non-squamous histology and those with squamous carcinomas who were never smokers. Over the lifetime horizon, the current ALK testing scenario produced additional 5060 and 3906 life-years and quality-adjusted life-years (QALY), respectively, compared with the no-testing scenario. Total direct costs were increased up to € 51,319,053 for testing scenario. The incremental cost-effectiveness ratio was 10,142 €/QALY. The sensitivity analyses carried out confirmed the robustness of the base-case results, being the treatment allocation and the test accuracy (sensitivity and specificity data) the key drivers of the model. CONCLUSIONS: ALK testing in advanced NSCLC patients, non-squamous and never-smoker squamous, provides more than 3000 QALYs in Spain over a lifetime horizon. Comparing this gain in health outcomes with the incremental costs, the resulting incremental cost-effectiveness ratio reinforces that testing non-squamous and never-smoker squamous NSCLC is a cost-effective strategy in Spain.

Precision medicine testing in ovarian cancer: The growing inequity between patients with commercial vs medicaid insurance.

INTRODUCTION: Precision medicine technologies have significant impact in the care of patients with ovarian cancer. Compared to affluent patients, socioeconomically vulnerable patients are less likely to have access to this testing. There is little data that demonstrate this inequity over time. METHODS: We used the IBM Truven Health MarketScan Research Database to identify patients in the United States who underwent surgery for ovarian cancer between 2011 and 2017. The presence of claims for precision medicine testing within six months of surgery was assessed for each patient. Precision medicine testing included both molecular genetic testing (BRCA limited or full sequencing, somatic and germline testing) as well as ancillary pathology tests (immunohistochemistry, microsatellite instability). Demographic data was extracted. RESULTS: We identified 27,181 patients who met eligibility. Of these, 88.6% had commercial insurance, and 11.4% had Medicaid. While the proportion of patients who underwent precision medicine testing increased over time for both cohorts (47.0% to 66.6% for commercially insured, 41.4% to 57.6% for Medicaid insured, p < 0.0001), the inequity in testing rates widened (5.6% disparity to 9.0%, p < 0.0001). This was driven by growing inequity in germline and somatic genetic testing (7.6% disparity to 21.3%, p < 0.0001). CONCLUSIONS: There is widening inequity in precision medicine testing rates between commercially insured and Medicaid insured poate patients with ovarian cancer.

Applying methods for personalized medicine to the treatment of alcohol use disorder.

OBJECTIVE: Numerous behavioral treatments for alcohol use disorder (AUD) are effective, but there are substantial individual differences in treatment response. This study examines the potential use of new methods for personalized medicine to test for individual differences in the effects of cognitive behavioral therapy (CBT) versus motivational enhancement therapy (MET) and to provide predictions of which will work best for individuals with AUD. We highlight both the potential contribution and the limitations of these methods. METHOD: We performed secondary analyses of abstinence among 1,144 participants with AUD participating in either outpatient or aftercare treatment who were randomized to receive either CBT or MET in Project MATCH. We first obtained predicted individual treatment effects (PITEs), as a function of 19 baseline client characteristics identified a priori by MATCH investigators. Then, we tested for the significance of individual differences and examined the predicted individual differences in abstinence 1 year following treatment. Predictive intervals were estimated for each individual to determine if they were 80% more likely to achieve abstinence in one treatment versus the other. RESULTS: Results indicated that individual differences in the likelihood of abstinence at 1 year following treatment were significant for those in the outpatient sample, but not for those in the aftercare sample. Individual predictive intervals showed that 37% had a better chance of abstinence with CBT than MET, and 16% had a better chance of abstinence with MET. Obtaining predictions for a new individual is demonstrated. CONCLUSIONS: Personalized medicine methods, and PITE in particular, have the potential to identify individuals most likely to benefit from one versus another intervention. New personalized medicine methods play an important role in putting together differential effects due to previously identified variables into one prediction designed to be useful to clinicians and clients choosing between treatment options. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Assessment of the Implementation of Pharmacogenomic Testing in a Pediatric Tertiary Care Setting.

Importance: Pharmacogenomic (PGx) testing provides preemptive pharmacotherapeutic guidance regarding the lack of therapeutic benefit or adverse drug reactions of PGx targeted drugs. Pharmacogenomic information is of particular value among children with complex medical conditions who receive multiple medications and are at higher risk of developing adverse drug reactions. Objectives: To assess the implementation outcomes of a PGx testing program comprising both a point-of-care model that examined targeted drugs and a preemptive model informed by whole-genome sequencing that evaluated a broad range of drugs for potential therapy among children in a pediatric tertiary care setting. Design, Setting, and Participants: This cohort study was conducted at The Hospital for Sick Children in Toronto, Ontario, from January 2017 to September 2020. Pharmacogenomic analyses were performed among 172 children who were categorized into 2 groups: a point-of-care cohort and a preemptive cohort. The point-of-care cohort comprised 57 patients referred to the consultation clinic for planned therapy with PGx targeted drugs and/or for adverse drug reactions, including lack of therapeutic benefit, after the receipt of current or past medications. The preemptive cohort comprised 115 patients who received exploratory whole-genome sequencing-guided PGx testing for their heart conditions from the cardiac genome clinic at the Ted Rogers Centre for Heart Research. Exposures: Patients received PGx analysis of whole-genome sequencing data and/or multiplex genotyping of 6 pharmacogenes (CYP2C19, CYP2C9, CYP2D6, CYP3A5, VKORC1, and TPMT) that have established PGx clinical guidelines. Main Outcomes and Measures: The number of patients for whom PGx test results warranted deviation from standard dosing regimens. Results: A total of 172 children (mean [SD] age, 8.5 [5.6] years; 108 boys [62.8%]) were enrolled in the study. In the point-of-care cohort, a median of 2 target genes (range, 1-5 genes) were investigated per individual, with CYP2C19 being the most frequently examined; genotypes in 21 of 57 children (36.8%) were incompatible with standard treatment regimens. As expected from population allelic frequencies, among the 115 children in the whole-genome sequencing-guided preemptive cohort, 92 children (80.0%) were recommended to receive nonstandard treatment regimens for potential drug therapies based on their 6-gene pharmacogenetic profile. Conclusions and Relevance: In this cohort study, among both the point-of-care and preemptive cohorts, the multiplex PGx testing program provided dosing recommendations that deviated from standard regimens at an overall rate that was similar to the population frequencies of relevant variants.

Molecular Profiling Practices in Pancreatic Adenocarcinoma: Academic vs Community Physicians.

Background: Pancreatic adenocarcinoma (PDAC) is relatively rare but highly aggressive, with most patients diagnosed once they have metastatic or locally invasive disease. Molecular profiling is being explored as a tool for selecting patients for targeted therapy clinical trials and for assessing whether targeted therapies may be effective in PDAC. Whether molecular profiling is being performed at both academic and community oncology clinics has yet to be examined. Here, we characterized the molecular profiling practice patterns in patients with PDAC in academic versus community practices in Denver, Colorado. Methods: We retrospectively reviewed records of all patients with refractory, metastatic PDAC who were referred to a tertiary clinical trials drug development unit in Denver between 2014 and 2019. Results: Of 77 patients, 41 (55%) were men with a mean age of 65 years (SD, 9.3). Fifty-three patients (69%) were referred from the community and 20 (26%) from academic centers; 4 (5%) were self-referred. A total of 51% received profiling prior to referral; 29 of 50 (58%) were from the community and 10 of 21 (47%) from academic settings. Guardant was the most commonly ordered test (47 of 77; 61%); FoundationOne was the second most common (40 of 77; 52%). Twenty-three of 77 patients (30%) received both Guardant and FoundationOne testing, and 3 of 77 (4%) received Caris MI Profile. One patient received a Mocha assay and another received Ascend/Clarient fluorescence in situ hybridization (FISH). Four patients were self-referred, 2 of whom underwent both Guardant and FoundationOne, 1 who underwent Guardant testing only, and 1 who did not receive any molecular profiling testing. Conclusions: This study characterizes molecular profiling practice patterns in individuals with advanced PDAC who were referred to a tertiary clinical trials drug development unit. Both academic and community physicians were found to order profiling about 50% of the time. Further research is needed to determine impact on clinical trial enrollment and detection of PDAC.

Real-world genetic testing patterns in metastatic castration-resistant prostate cancer.

Aim: To assess the patterns of genetic testing for homologous recombination repair mutations in patients with metastatic castration-resistant prostate cancer (mCRPC) pre-PARP inhibitors approval. Patients & methods: mCRPC patients were selected in an oncology electronic medical records database. Patterns and predictors of testing for ATM, BRCA1/2, CDK12, PALB2 and FANCA gene alterations were assessed. Results: Of 5213 mCRPC patients, 674 (13%) had a documented genetic test. The number of tested patients increased from 1 in 2013 to 313 in 2018 (out of 3161 and 3010 clinically active patients, respectively). Receiving care in an academic oncology center (versus a community-based center) strongly predicted genetic testing (hazard ratio = 2.41). Conclusion: The use of and access to genetic testing pre-PARP inhibitor approval was suboptimal.

Lay abstract In 2017, US guidelines recommended the use of genetic testing in patients with metastatic castration-resistant prostate cancer (mCRPC). While the initial goal of genetic testing was to guide referral to genetic counselling and clinical trial enrollment, it is now also used to identify patients who could benefit from new drugs that target specific molecular defects. Using medical record data of US patients with mCRPC, we found that the rates of genetic testing and the breadth of molecular defects tested were suboptimal from 2013 to 2019. We also found lower rates of genetic testing in patients treated in community-based centers compared with those treated in academic oncology centers. These results underscore the importance of increasing the take up rate of genetic testing in patients with mCRPC to help guide treatment decisions.

An evaluation of RAS testing among metastatic colorectal cancer patients in the USA.

Background: Data on RAS testing practices prior to metastatic colorectal cancer (mCRC) treatment initiation are lacking in the USA. Materials & methods: Flatiron data were utilized for patients diagnosed with mCRC between 2011 and 2017. Flatiron is a longitudinal, demographically and geographically diverse database representing data from over 1.5 million active US patients treated at 255 community and hospital-affiliated oncology clinics. Results: Among 17,387 mCRC patients 69% were RAS tested and 31% were never tested. Timing of RAS testing was as follows: 23% were tested at the time of their initial CRC diagnosis, 60% following mCRC diagnosis but prior to first line of treatment, 3% prior to third line, the remaining 14% were tested following third line. Conclusion: A third (31%) of patients failed to receive RAS testing, therefore all treatment options were unavailable to them. These data highlight how universal testing has not been achieved.

Impact of pretreatment dihydropyrimidine dehydrogenase genotype-guided fluoropyrimidine dosing on chemotherapy associated adverse events.

Consensus guidelines exist for genotype-guided fluoropyrimidine dosing based on variation in the gene dihydropyrimidine dehydrogenase (DPYD). However, these guidelines have not been widely implemented in North America and most studies of pretreatment DPYD screening have been conducted in Europe. Given regional differences in treatment practices and rates of adverse events (AEs), we investigated the impact of pretreatment DPYD genotyping on AEs in a Canadian context. Patients referred for DPYD genotyping prior to fluoropyrimidine treatment were enrolled from December 2013 through November 2019 and followed until completion of fluoropyrimidine treatment. Patients were genotyped for DPYD c.1905+1G>A, c.2846A>T, c.1679T>G, and c.1236G>A. Genotype-guided dosing recommendations were informed by Clinical Pharmacogenetics Implementation Consortium guidelines. The primary outcome was the proportion of patients who experienced a severe fluoropyrimidine-related AE (grade ≥3, Common Terminology Criteria for Adverse Events version 5.0). Secondary outcomes included early severe AEs, severe AEs by toxicity category, discontinuation of fluoropyrimidine treatment due to AEs, and fluoropyrimidine-related death. Among 1394 patients, mean (SD) age was 64 (12) years, 764 (54.8%) were men, and 47 (3.4%) were DPYD variant carriers treated with dose reduction. Eleven variant carriers (23%) and 418 (31.0%) noncarriers experienced a severe fluoropyrimidine-related AE (p = 0.265). Six carriers (15%) and 284 noncarriers (21.1%) experienced early severe fluoropyrimidine-related AEs (p = 0.167). DPYD variant carriers treated with genotype-guided dosing did not experience an increased risk for severe AEs. Our data support a role for DPYD genotyping in the use of fluoropyrimidines in North America.

Custom Implants in TKA Provide No Substantial Benefit in Terms of Outcome Scores, Reoperation Risk, or Mean Alignment: A Systematic Review.

BACKGROUND: Failure to accurately replicate the native anatomy and biomechanics of the knee has been suggested to contribute to dissatisfaction after TKA. Custom implants promise a personalized surgical approach, with the aim of improving patient satisfaction and pain as well as lowering revision rates. However, some published research on custom TKA implants has found no clinically important improvements in postoperative validated outcomes scores, risks of revision or reoperation, and implant alignment. In the interest of helping to settle this controversy, a systematic review seems warranted. QUESTION/PURPOSE: In this systematic review, we asked whether custom implants result in clinically important improvements over conventional off-the-shelf implants for anatomically uncomplicated primary TKA in terms of (1) validated outcomes scores, (2) the risk of revision or reoperation, and (3) implant alignment. METHODS: The US National Library of Medicine (PubMed/Medline), Embase, Web of Science, and Cochrane Database of Systematic Reviews were systematically searched to identify publications from the past 10 years relevant to this review. Publications that compared the clinical outcome measures, number of revisions and reoperations, and radiological assessment of implant alignment of custom and standard implants with validated endpoints were eligible for inclusion. In the interest of capturing as much potentially relevant information as possible, we applied no requirement for minimum follow-up duration. Clinical outcomes were assessed using patient-reported outcome (PROM) scores including the Knee Society Score (KSS), Forgotten Joint Score, and Knee Injury and Osteoarthritis Outcome Score. The risk for revision or reoperation were evaluated by the number of early and late manipulations, debridement procedures, and replacement of one or more components. Implant alignment was compared using postoperative deviation from the neutral (0°) mechanical axis of the limb and each component and the posterior tibial slope. All qualified studies were retrospective, and all compared custom implants with standard implants. Data on 1510 patients were reviewed (749 with custom implants and 761 with off-the-shelf implants). The mean follow-up time ranged from 12 to 33 months. RESULTS: There was no apparent advantage to custom implants in terms of PROM scores. Of the five studies evaluating clinical outcomes, only one reported better KSS-Function scores at 3 months; two reported no difference, and two found inferior KSS scores. In several studies, custom implants were associated with more frequent reoperations than standard implants. Although in general there were no differences between custom and standard implants in terms of mean coronal plane limb alignment, one of seven studies found that the proportion of patients whose alignment was outside ± 3° from the neutral axis in the coronal plane was lower in the custom group than in the standard group. CONCLUSION: With generally poorer outcomes scores for pain and function, generally higher risks of reoperation and reintervention, and no overall benefit to alignment, custom implants for primary TKA for the general population currently appear to be inferior to standard implants. Whether the slight reduction in the proportion of patients with alignment outliers observed in a minority of studies will result in a substantial reduction in revision risk over time must be addressed by future studies. However, until or unless such a reduction is proven, we recommend against the routine use of custom implants in practice because of increased costs and the risks associated with their novelty. LEVEL OF EVIDENCE: Level III, therapeutic study.