bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of genomic instability test scores used for predicting PARP activity in ovarian cancer.
Authors: Timms Kirsten M , Mills Gordon B. , Perry Michael , Gutin Alexander , Lanchbury Jerry , Brown Robert 
Published: May 2020

1586 Background: Clinical trials have explored the utility of various genomic instability (GI) scores or gene panels to assess deficiencies in the homologous recombination (HR) DNA repair pathway and support PARP inhibitor use in ovarian cancer; however, these methods of assessing homologous recombination deficiency (HRD) may not be equivalent. The myChoice HRD test is the only analytically and clinically validated, FDA-approved HRD test that includes BRCA1/2 mutation status and three measures of GI. We compared the proportion of patients identified as candidates for PARP inhibitor use by two measures of HRD [percent loss of heterozygosity (%LOH), 11-gene panel] to myChoice HRD. Methods: Whole-genome SNP analysis was used to reconstruct ovarian tumor genomic profiles to calculate the myChoice HRD score and %LOH in 2 cohorts (clinical laboratory cohort, N = 3,278; SCOTROC4 trial, N = 248). Mutation screening for a set of 11 genes in the HR pathway ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, MRE11A, NBN, PALB2, RAD51C, RAD51D) was performed for a subset of tumors from the SCOTROC trial (n = 187). Samples were considered positive if the myChoice HRD score was above the threshold (threshold scores of 42 and 33 were assessed), %LOH above the threshold (16%), or a pathogenic variant in one of the 11 HR genes. The correlation between positive results from %LOH and the 11-gene panel were compared to myChoice HRD. Percent positive agreement (PPA) was the proportion of positive test results from myChoice HRD that were also positive by %LOH or the 11-gene panel. Results: The table shows the correlation and PPA between myChoice HRD, %LOH, and the 11-gene panel. Overall, 19%-61% of patients identified as positive by myChoice HRD would have been missed by %LOH or the 11-gene panel in these two cohorts. Conclusions: These data show that HRD tests used in published and ongoing clinical trials are not equivalent, and they should not be considered interchangeable in predicting PARP inhibitor response in clinical practice. [Table: see text]
Effects of initiating in-office germline testing in safety net clinic patients with epithelial ovarian cancer.
Authors: Jordan Scott , Spring Samantha , Schlumbrecht Matthew , Huang Marilyn 
Published: May 2020

1588 Background: Germline genetic mutations occur in approximately 25% of women with epithelial ovarian cancers. Recent advances in frontline maintenance therapy for patients with hereditary breast and ovarian cancer syndrome make timely germline testing critical. Adherence to genetic testing remains low (approximately 30% nationally), including at our safety net hospital where germline testing by a genetic counselor was performed in only 38% of patients. After initiating in-office genetic testing, our aim was to compare current patients with historical controls to determine whether this intervention shortened the time to testing and results. Methods: IRB approval was obtained. Patients seen for a diagnosis of epithelial ovarian cancer between 4/1/2018 and 12/31/2019 were identified. Patients with only one visit or those who received testing elsewhere were excluded. Patient and visit data were abstracted for each visit during the study period. Comparison was made between patients treated before (control cohort) and after in-office testing was initiated (intervention cohort) on 5/21/2019. Categorical variables were compared using Chi Squared and Fisher’s Exact test. Mann Whitney U test was used to compare time from first clinic visit to the date of genetic testing and to the reporting of test results in the chart. All tests were two-sided and significance was set at p = 0.05. Results: 74 patients were identified and 504 clinic visits were analyzed. 57 (77%) patients were White Hispanic, 15 (20.3%) were Black, and 2 (2.7%) were White non-Hispanic. 56 (75.7%) underwent germline testing. Overall median time to testing from the first clinic visit was 21.2 weeks, and median time to reporting of results was 37 weeks. Though there was no significant difference in testing rate between the cohorts, the time to the date of genetic testing in the intervention group was approximately one-third as long as in the control group (9.6 vs 32.1 weeks, p < 0.001). Among the 52 patients with reported genetic results, results were recorded in a clinic note at 4.1 weeks from first visit in the intervention group, compared with 28.8 weeks in the control group (p < 0.001). In the intervention group, during clinic visits without genetics performed to date, testing was performed at that visit 25% of the time. Conclusions: By initiating in-office testing, time to testing and receipt of results were meaningfully shortened. Removing delays to test results will greatly improve the ability of our patients to receive potentially life-saving maintenance therapy following front line treatment.
Cancer risk and overall survival in APC I1307K carriers.
Authors: Gruber Stephen B. , Bonner Joseph D , Lejbkowicz Flavio , Schmit Stephanie , Rennert Hedy , Greenson Joel K , Pinchev Mila , Melas Marilena , Moreno Victor , Tomsho Lynn P , Capella Gabriel , Braun Danielle , Smith Sidney A , McDonnell Kevin , Idos Gregory , Rennert Gad 
Published: May 2020

1592 Background: The germline variant APC I1307K is one of the most commonly identified pathogenic variants on germline genetic testing panels. The purpose of the Molecular Epidemiology of Colorectal Cancer study was to quantify the risk of colorectal cancer among carriers, characterize the clinical, pathologic, and molecular features of colorectal cancers arising in patients with APC I1307K, and to describe the overall and disease-specific survival of carriers with colorectal cancer. Here, the final results of the Molecular Epidemiology of Colorectal Cancer Study are reported with respect to APC I1307K. Methods: We consented 6,006 incident, pathologically confirmed cases of colorectal adenocarcinoma and 5,023 age, sex, and ethnicity matched controls without colorectal cancer between March 31, 1998 and July 1, 2017 within a geographically defined area of Northern Israel. Comprehensive, in-person epidemiologic interviews were conducted for cases and controls, with uniform histopathologic review, detailed molecular analysis, medical record review and clinical follow-up for up to 21 years. Results: The demographic and clinical features of incident colorectal cancer cases matched the population distribution of colorectal cancer in Israel. APC I1307K was identified in 429 (7.1%) of cases and 201 (4.0%) of controls. The estimated relative risk of colorectal cancer among carriers was 1.89 (95% confidence interval, 1.59 - 2.24), p < 0.0001. The prevalence and odds ratios differed by ethnic group. Homozygous carriers were at especially high risk, with an odds ratio of 3.90 (95% confidence interval 1.11–13.71). APC I1307K carriers were significantly less likely to have microsatellite instable tumors (p = 0.04). Overall survival of APC I1307K carriers was not significantly different than survival of non-carriers, after adjustment for age, stage, sex, ethnicity, and microsatellite instability. Conclusions: APC I1307K is an actionable germline mutation that confers meaningful lifetime risk of colorectal cancer in heterozygous and homozygous carriers. APC I1307K is not an independent prognostic factor for overall survival or disease specific survival and is not associated with the MSI phenotype. Cumulative lifetime risk estimates inform genetic counseling and provide data for policies regarding the timing and frequency of screening and other preventive strategies.
Relative and absolute risk of second primary neoplasms of the central nervous system.
Authors: Liu Elisa , Oh Cheongeun , Sulman Erik P. 
Published: May 2020

1593 Background: Cranial radiation is known to increase the relative risk for developing a second primary neoplasm, but existing analyses do not take into account differential survival or follow-up. The absolute risk, or true incidence, of developing a second primary neoplasm in the central nervous system (CNS) is not well characterized. Methods: Patients diagnosed with cancer from between 1976 and 2016 were sampled using the Surveillance, Epidemiology, and End Results (SEER) Program. Relative risks were estimated using standardized incidence ratios (SIRs) and absolute risks were estimated using cumulative incidence (CI) functions with death as a competing risk. Among CNS primaries, comparison groups were matched by age, sex, year of diagnosis, primary histology, and lesion location. Results: Over 3.8 million patient records, including 13,167 second primary CNS tumors, were extracted from SEER. The relative risk of developing a second primary CNS neoplasm is elevated in all patients diagnosed with a CNS primary cancer (SIR = 9.6), but higher in those who received radiation (SIR = 13.1) or chemotherapy (SIR = 12.6). The absolute risk of developing a second primary CNS neoplasm at 25-years is highest in CNS and endocrine cancers (CI 1.0% and 0.50%, respectively). Among long-term ( > 10-year) survivors of CNS primaries, the 25-year CI of a second primary CNS neoplasm was 4.4%. Cranial radiation increased the incidence of second primary tumors in pediatric patients (25-year CI 4.8% vs 1.2%, p = 0.007), but not adults (25-year CI 5.1% vs 4.9%, p = 0.85). Chemotherapy did not increase CI in either pediatric (25-year CI 7.0% vs 5.4%, p = 0.87) or adult (25-year CI 3.6% vs 5.8%, p = 0.11) populations. Meningiomas (39.3% vs 22.0%, p = 1e-6) and glioblastomas (21.1% vs 14.6%, p = 0.03) represent a greater proportion of the second primary CNS tumors in those who received cranial irradiation. Conclusions: The risk of developing a second primary CNS neoplasm is elevated in patients with a prior CNS cancer. Cranial irradiation increased the CI of second primary tumors in pediatric patients but did not affect adult patients. The association between radiation therapy and risk for subsequent cancers may be limited to the pediatric population.
Changes in cancer mortality rates after the adoption of the Affordable Care Act.
Authors: Lee Anna , Shah Kanan , Chino Junzo P. , Chino Fumiko 
Published: May 2020

2003 Background: The Affordable Care Act (ACA) was designed to improve health status in the US primarily through improving access to health insurance. As adoption of Medicaid expansion varied at the state level, this study aims to compare cancer mortality rates over time between states who did (EXP) and did not adopt (NonEXP) Medicaid expansion. Methods: Age-adjusted mortality rates per 100,000 were gathered from the National Center for Health Statistics from 1999-2017 to establish trends. Only deaths due to cancer in patients less than 65 were included. Absolute change in cancer mortality was calculated from 2011-2013 and then from 2015-2017 with 2014 as washout year. Changes within subpopulations (gender, race, ethnicity) were also assessed. Mortality changes between EXP and NonEXP groups were via “difference in differences” analysis. Results: Overall age-adjusted cancer mortality in the US fell from 1999-2017 from 66.9 to 48.8 per 100,000. EXP states had higher population (157 vs 118 million) with less black/African Americans (19.2 vs 21.8 million) and more Hispanics (33.0 vs 21.7 million) than NonEXP states (all examples from 2017). The overall age-adjusted cancer mortality was consistently worse in NonEXP states, cancer mortality fell from 64.7 to 46.0 per 100,000 in EXP states and from 69.0 to 51.9 per 100,000 in NonEXP states from 1999-2017 (both trends p < 0.001, comparison p < 0.001). Comparing the mortality changes in the peri-ACA years (2011-2013 vs 2015-2017) between the 2 cohorts, the difference in differences between EXP and NonEXP states was -1.1 and -0.6 per 100,000 respectively (p = 0.006 EXP, p = 0.14 NonEXP). The estimated overall cancer mortality benefit gained in EXP states after Medicaid expansion (∆∆∆) is -0.5 per 100,000 (p = NS). In EXP states, this translates to an estimated 785 less cancer deaths in 2017. Age-adjusted cancer mortality per 100,000 was worse in NonEXP states for black patients (58.5 EXP vs 63.4 NonEXP in 2017) however there was no differential mortality benefit after ACA expansion when comparing between the peri-ACA years. Of the subpopulations assessed, Hispanics in EXP states had the highest differential cancer mortality benefit at -2.1 per 100,000 (p = 0.07). Conclusions: This is the first study to show a directly measured cancer survival benefit from the ACA on a national scale using a comprehensive database. Hispanic populations appear to have the highest differential cancer mortality benefit after Medicaid expansion. Further study is needed to elucidate why other populations like black patients did not appear to reap the same mortality decrease.
Prospective study of an AI enabled online intervention to increase delivery of guideline compliant cancer care, on the ground.
Authors: Pramesh C S. , Sirohi Bhawna , Nag Shona Milon , Gupta Sudeep , Anderson Benjamin O. , Feldman Nancy Renee , Thaker Premal H. , Beriwal Sushil , Badwe Rajendra A. 
Published: May 2020

2011 Background: Despite survival benefits of guideline compliant cancer care, under treatment and over treatment are prevalent. Navya is an AI enabled online intervention that matches a patient’s medical record with NCCN and NCG guidelines (National Cancer Grid, India) and layers live multidisciplinary expert review to recommend actionable treatment plans. It was developed to standardize care and mitigate morbidity and mortality, by delivering on-t ime, guideline based expert treatment plans. Methods: From July 2019 to January 2020, all patients who received a Navya treatment plan based on guidelines and live expert review were included. Intended treatment plans were prospectively collected from the patient. Compliance of intended plans with NCCN (including Resource Stratified Framework) or NCG was measured. Noncompliant intended plans were categorized as overtreatment or undertreatment. After delivery of Navya plan, prospective phone follow up assessed whether noncompliant intended plans were changed to guideline compliant care. Results: Of 1707 consecutive patients who received a Navya plan, 1549 intended plans were available. Patients were diverse with respect to geographic, socioeconomic, and primary tumor distribution: West of India: 28%, North: 26%, East: 21%, South: 15%, Central: 7%, International: 3%; 35% of patients with income < $300/month; GI: 23%, Breast: 14%, Head & Neck: 11%, Thoracic: 10%. Of the 1549 intended plans, 441 (28.47% (95% CI ± 0.26%)) were not compliant with NCCN or NCG. Undertreatment was 35%, overtreatment 26%, incomplete staging workup 28% and 11% could not be categorized. Of 441 patients with noncompliant intended plans, 80.19% (± 0.97%) shared the Navya plan with their treating oncologists and 50.40% (± 0.88%) changed their intended plan to receive the Navya treatment plan. Intervention with Navya increased on-the -ground guideline compliance by ~15% (from 71.53% ±0.42% to 85.87% ± 1.73%). Conclusions: Guideline compliant care ensures best achievable clinical outcomes with existing therapies. A technological earthshot that significantly increases adoption of guideline based care is the first step towards cancer moonshots.
Mapping PRO-CTCAE responses to clinician-graded adverse events, dose reductions, interruptions, and discontinuations in phase I cancer trials.
Authors: Watson Geoffrey Alan , Veitch Zachary William Neil , Shepshelovich Daniel , Liu Zhihui (Amy) , Spreafico Anna , Abdul Razak Albiruni Ryan , Bedard Philippe L. , Siu Lillian L. , Minasian Lori M. , Hansen Aaron Richard 
Published: May 2020

2014 Background: Typically symptomatic adverse events (sy-AEs) on clinical trials are reported by clinicians using the CTCAE. To complement clinician collected sy-AEs and understand tolerability better, the patient report outcome version of the CTCAE (PRO-CTCAE) has been developed to provide the patient (pt) perspective on severity of AEs (graded scale 0-4) and their interference in daily life (scale 0-4). The aim of this study was to correlate PRO responses with the grade (G) of AEs, dose interruptions/reductions and dose limiting toxicities (DLTs). Methods: Pts enrolled on phase 1 clinical trials at Princess Margaret were surveyed electronically on tablet using the full library of items for PRO-CTCAE. The PRO-CTCAE was administered at baseline (prior to therapy), mid-cycle 1, and mid-cycle 2. AEs on study were recorded by physicians using the CTCAE. The electronic medical records were analyzed for an association between reported sy-AEs and PRO score. Summary statistics were used to describe patient and disease characteristics, as well as the outcomes. Spearman’s method was used to correlate PRO severity and interference responses. Logistic regression was used to assess which factors were associated with CTCAE G 3-4 vs G 2 AEs. Results: We analyzed 158 pts: median age 60yrs, 77 (49%) were male; all were ECOG ≤1 and 22, 55 and 81 pts completed 1, 2 and 3 surveys, respectively. Clinician reported G2, 3 and 4 sy-AEs occurred in 81, 47 and 3 pts, respectively and all of these were related to a PRO item except 5% (4/81), 9% (4/47) and 33% (1/3), respectively because either the AE occurred after 3rd time point or patient not able to complete the PRO (encephalitis). Sy-AEs causing dose interruptions, reductions, DLTs and discontinuations occurred in 45 (28%), 12 (7.5%), 5 (3%) and 12 (7.5%) pts, respectively; with a corresponding PRO item in 40 (89%), 12 (100%), 4 (80%) and 11(92%) pts, respectively. For patients who had CTCAE G2, G3/4 AEs, interruptions and discontinuations, their severity and inference levels were positively correlated (coefficient 0.49, p < 0.001; 0.45, p < 0.001 0.59, p < 0.001, 0.86, p < 0.001). Dose interruptions (p = 0.0027) and reductions (p = 0.0061) were significantly associated with G3-4 compared to G2 AEs. Conclusions: This is the first time an association between PRO-CTCAE severity and interference; and CTCAE G2, 3, 4 AEs, dose interruptions and discontinuations has been demonstrated. Additional modelling and more patient data are being analyzed to explore the relationship.
Post-hoc power of clinical trials supporting anticancer drug approval by FDA.
Authors: Nadler Michelle , Desnoyers Alexandra , Saleh Ramy , Amir Eitan 
Published: May 2020

2018 Background: Regulatory approval of drugs is based typically on randomized control trials (RCTs) observing statistically significant superiority of an experimental agent over a prior standard. Statistical significance can result from large effect size and/or over-sampling (as a result of large sample size or long follow-up). Here we explore the source(s) of statistically significant results in trials supporting anti-cancer drug approval by the FDA. Methods: We searched Drugs@FDA to identify anti-cancer drug approvals for solid tumors (excluding lymphoma) from 2015-2019. We retrieved corresponding manuscripts and associated appendices and extracted data on study characteristics, statistical plan, primary outcomes and accrual and follow-up times. Post-hoc power was calculated based on observed results and was compared to expected effect size and power in the statistical plan. We explored associations with higher than expected power resulting from over-sampling using binary logistic regression. Results: We identified 75 unique drug-approvals reporting 94 endpoints. The most common tumour types were lung, breast, melanoma, and renal cell carcinoma. The most common endpoints were progression free survival and overall survival (OS). In 74 endpoints (79%), observed power was greater than expected power. The magnitude of higher than expected power ranged from 0.1 to > 20%. Of these, 59 (80%) had an effect size greater than predicted in the statistical plan. In 44/74 over-powered endpoints (60%), post-trial power was 100%. When post-hoc power was calculated based on expected effect size rather than observed effect size, 50 endpoints (85%) remained over-powered. Higher than expected power resulting from over-sampling was associated with OS compared to other endpoints (OR 3.03), with targeted agents compared to immunotherapy (OR 1.63) and inversely associated with year of approval (OR 0.57). Conclusions: Most cancer drug approvals result from statistically significant studies which are over-powered due to greater than anticipated effect size. Approximately 1 in 5 studies are over-powered likely due to over-sampling. In this setting, benefit observed in RCTs may not translate to the real-world setting.
Evaluating barriers to uptake of comprehensive genomic profiling (CGP) in advanced cancer patients (pts).
Authors: Smith Kortnye Maureen , O Haire Sophie , Khuong-Quang Dong Anh , Markman Ben , Gan Hui Kong , Ekert Paul G , O'Byrne Kenneth John , Millward Michael , Solomon Benjamin J. , Tran Ben , Scott Clare L. , Kee Damien , McArthur Grant A. , Fellowes Andrew , Weerasuriya Rona , Lynch Elly , Martyn Melissa , Gaff Clara , Fox Stephen B. , Desai Jayesh 
Published: May 2020

2033 Background: Despite increasing evidence of benefit supporting CGP in personalizing cancer therapy, its widespread uptake remains limited. Barriers include low patient understanding, unmet patient expectations related to low utility, clinician concerns over cost-effectiveness, perceived value, and discomfort in management of complex genomic results. Methods: This prospective cross-institutional demonstration study was designed to evaluate implementation of CGP in the care of adult and paediatric advanced cancer pts, incorporating pt reported outcomes (PROMs), discrete choice experiment (DCE), ongoing process optimization and clinician evaluations. DNA sequencing of FFPE tumor and matched blood was completed with CGP (PMCC Comprehensive Cancer Panel; 391 genes) via central laboratory. A tumor board reported results weekly with emphasis on therapeutic relevance. Oncologists performed consent and results delivery. Pts completed pre-and post-test surveys, including validated and study-specific questions, DCE and if eligible, semi-structured interviews. Qualitative interviews were undertaken with study clinicians and laboratory staff to evaluate processes. Results: 86% (315) of 365 enrolled pts had successful CGP; of these 63% (199) had relevant therapeutic, diagnostic or germline results. 50 (16%) had treatment change at 6m, 49 (16%) had germline mutations. 293 (88% of adult pts) completed PROMs. 17 of 19 clinicians/laboratory staff approached consented to an interview. At consent pts cited multifaceted value in testing, showed good understanding of basic concepts, but most (69%) overestimated the likelihood of result-led change. Post-test pts remained consistently satisfied with accessing CGP; valuing research contribution, taking opportunities and information for family. 21% struggled with understanding results but there were low levels of decisional regret following participation (89% had nil/mild regret). Pt-elicited preferences (via DCE) indicated priority for high rates of clinical utility and timeliness. Clinicians sited collaboration and communication as critical to delivery of CGP. Conclusions: Pts undergoing CGP are generally satisfied, and derive value on its use beyond potential therapeutic benefit. Our results suggest that to improve test utility and delivery of CGP with value to pts and investing institution, focus must be placed on addressing the additional barriers to its wider implications including efforts to improve process efficiencies, clinician genomic literacy and decision-making support.