bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive molecular assessment of mismatch repair deficiency in Lynch-associated ovarian cancers using next-generation sequencing (NGS) panel.
Authors: Kim Rachel Soyoun , Oldfield Leslie E. , Tone Alicia , Pollett Aaron , Van de Laar Emily , Pedersen Stephanie , Wellum Johanna , Clarke Blaise , Pugh Trevor J , Ferguson Sarah
Published: May 2020

1523

Background: Abnormalities in mismatch repair (MMR) gene may be the result of pathogenic germline (Lynch syndrome) and somatic mutations as well as epigenetic events. Abnormalities in MMR have been described in non-serous/non-mucinous ovarian cancer (OC) but few studies have examined the causes of these MMR defects (MMRd). To address this, we have completed targeted mutational and methylation sequencing on MMRd OC cases. Methods: Women with newly diagnosed non-serous/mucinous OC (N = 215) were prospectively recruited from three cancer centers in Ontario, Canada between 2015-18. Tumors were reflexively assessed for MMR protein expression by immunohistochemistry. Tumor DNA was extracted from macrodissected MMRd cases and MMR-intact (MMRi) controls following pathology review. Matched tumor-normal samples were run on a custom NGS panel to identify germline and somatic mutations, copy number variants, rearrangements and promoter methylation in MMR and associated genes. Results: Of the 215 women enrolled in our study, 185 (86%) had OC alone and 30 (14%) had synchronous OC and endometrial cancer. Twenty-eight (13%) cases were MMRd, 11 of which were synchronous. The MMRd cohort had median age of 52.5 years, with mostly stage I (N = 14; 50%), grade 1 or 2 disease (N = 18; 64%) with endometrioid histotype (N = 18; 64%). One patient had recurrence after median follow-up of 33.6 months (13.2-93.6). There was no significant difference in overall/progression-free survival between the MMRd and MMRi patients. Using the NGS panel, Lynch syndrome (LS) was detected in 39% of MMRd cases (11/28; 7 OC and 4 synchronous): 7 MSH6, 2 MLH1, 1 PMS2, and 1 MSH2. Clinical germline sequencing was performed on all cases and verified panel findings. An explanation for the observed MMR phenotype was available for 18/20 deficient cases, including 9/10 MLH1−/PMS2− (7 somatic methylation, 1 bi-allelic somatic deletion, 1 germline mutation), 0/1 PMS2−, 6/7 MSH6− (6 germline mutations) and 2/2 MSH2−/MSH6− (1 germline mutation, 1 bi-allelic somatic mutation). Concordance between clinical and research panel sequencing results was 90%. None of the germline mutations were missed by the panel. Conclusions: Use of our custom NGS panel allows for the streamlined assessment of hereditary and somatic causes of MMR deficiency in OC and may be an attractive screening strategy for LS in this population.
Urgent cancer genetic counseling and testing for young, premenopausal women with breast cancer (BC): Impact on surgical decision-making for contralateral risk-reducing mastectomy.
Authors: Mai Phuong L. , Dettwyler Shenin , Johnson Ronald , McAuliffe Priscilla F. , Steiman Jennifer G. , Thull Darcy , Diego Emilia
Published: May 2020

1533

Background: In women newly diagnosed with unilateral breast cancer (BC), contralateral risk-reducing mastectomy (CRRM) to decrease risk for additional primary BC is an appropriate option for some individuals, such as those with significantly increased risk due to a pathogenic variant (PV) in a breast cancer predisposition gene. Genetic testing at the time of BC diagnosis for young women has become more available and could aid in the decision-making process. We evaluated the trends for CRRM in a cohort of women diagnosed with BC at age ≤45 years who were seen in a multidisciplinary clinic where genetic counseling and testing is offered to each patient. Methods: A single institution, prospectively maintained database of patients seen in a BC multidisciplinary clinic between November 2014 and June 2019 was reviewed. Patients were included if they had non-metastatic, unilateral BC diagnosed ≤45 years of age, and underwent genetic testing at the time of BC diagnosis. Associations between surgical treatment (lumpectomy, mastectomy, or mastectomy with CRRM) and age at diagnosis, BC stage, family history, and genetic testing results were evaluated. Results: 184 patients were included in the analysis. The prevalence of a PV in a breast cancer predisposition gene was 15.8% (29/184; 1 in ATM, 12 in BRCA1, 8 in BRCA2, 5 in CH EK2, 2 in NBN, and 1 in NF1). 69% of the PV were in BRCA1 and BRCA2. 126 (68.4%) tested negative, and 29 (15.8%) had a variant of uncertain significance (VUS) in various genes. Overall, 63 patients (34.2%) elected to have CRRM. Of the 29 patients with a PV, 24 (82.8%) had CRRM. Women who chose CRRM were younger, more likely to test positive for a PV in a breast cancer predisposition gene, and more likely to have a significant family history of breast and/or ovarian cancer. Among the 155 patients who tested negative or had a VUS, there was no statistically significant association between CRRM and age (p = 0.58), test result (negative vs. VUS. p = 0.12), or family history (p = 0.32). Conclusions: For young women with BC seen in a multidisciplinary clinic, a younger age, significant family history, and positive genetic testing result were found to be associated with the decision to undergo CRRM. Among those without a genetic predisposition, having a VUS result was not associated with choosing CRRM. Incorporation of genetic services in the initial evaluation of young patients newly diagnosed with BC could add relevant information in surgical decision making and promote risk-appropriate management.
Heterozygous germline ATM mutations in breast cancer: A single academic center experience.
Authors: Konde Anish S , Ivan Kristina , Klavanian Jeannie , Rangarajan Tara , Jaiyesimi Ishmael A. , Zakalik Dana
Published: May 2020

1537

Background: Heterozygous germline ATM mutation carriers have an increased risk of developing breast, pancreas, and other cancers. The clinical and pathologic characteristics of ATM-associated breast cancers have not been well defined. Methods: Patients who underwent multigene panel testing (MGPT) between 2013-2019 and identified to harbor ATM mutations were included in the study. We evaluated demographics, pathology, and surgical management of our ATM mutation carriers with breast cancer. Results: At total of 319 individuals were identified to have variants in ATM, of which 114 were pathogenic/likely pathogenic. The majority of patients were female (82%) and Caucasian (88%). A total of 56 patients (49%) had a personal cancer diagnosis, the most common of which was breast cancer (n = 39). Nine individuals had more than one primary malignancy. The mean age at breast cancer diagnosis was 52, with a range of 25-82. The majority of patients had invasive ductal carcinoma (74%), grade 2 or 3 (90%), and ER and /or PR positive (87%). Of those with known HER2 status, 24% were positive. Thirty-nine percent of patients were lymph node positive, and 42% had lymphovascular invasion. The most common stage at diagnosis was 2 (53%). Of the 39 mutation carriers with breast cancer, 16 (42%) received radiation therapy, and 16 underwent bilateral mastectomy. Of 114 ATM positive patients, there were 55 distinct variants. Sixteen (14%) individuals had a mutation in additional cancer predisposition genes. One variant, c.5015delG, was identified in ten patients in a large, consanguineous Iraqi family with an extensive history of pancreatic and other cancers. Eight individuals were identified to have the known high-penetrance variant, c.7271T > G. Conclusions: Our study describes the clinical and pathological characteristics of ATM mutations carriers with breast cancer. The majority of patients had intermediate to high grade disease, hormone receptor positive, with a suggestion of a higher rate of HER2 positivity and lymph node involvement. Additional studies are needed to elucidate the unique characteristics of ATM-associated breast cancer, which may have implications for personalized management.
First year outcomes of an initiative to increase BRCA testing among NCCN guideline-eligible breast cancer patients within a large community OCM practice.
Authors: Waterhouse David Michael , Guinigundo Andrew , Brown Aimee , Davies Dan , Jones Lauren , Mendenhall Molly
Published: May 2020

1540

Background: Pathogenic variants in BRCA1/BRCA2 can affect a breast CA pts care: preventative interventions, surgical decisions, medical treatments, screening, and family counseling. National data suggests significant non-adherence to NCCN testing guidelines, with only 1/3 of eligible pts referred for genetic services. In 2018, OHC (Cincinnati) launched an APP-centric genetics program. Specially trained APPs carry out genetic counseling and order NCCN-compliant testing. Early data suggested a significant deficit in physician-driven referrals. From 1/01/18 - 07/31/18, 138 new breast pts were estimated to be NCCN guideline-eligible. Only 28 (20%) pts received genetic services. Methods: In 2019, the OHC genetics team implemented a standardized screening process for every new breast CA pt. An EMR template (iKnowMed G2) that included NCCN guidelines was created for initial breast CA consultation and Oncology Care Model (OCM) treatment planning. All pts, not just OCM pts, are subject to OCM treatment planning. This automated screening method ensured all breast CA pts were screened, drastically increasing compliance. Through integration of genetics screening into the templates, pts meeting NCCN criteria for testing are reflexively referred for genetic counseling. With USON/McKesson, integrated data fields were developed in the EMR to automate data collection. Results: From 01/01/19 – 12/31/19, 717 new breast CA pts were seen at OHC. 676/717 (94%) were screened. Of those screened, 279 new breast CA pts met NCCN criteria for BRCA testing. 140 (50%) eligible new pts had appts with the genetics team. Another 50 (18%) had confirmed testing outside of OHC. 57 (20%) refused appts and/or testing. 32 (11%) did not have appts, representing screen fails. Referrals in non-breast CA pts also increased by 127%; 604 (2019) vs 264 (2018) suggesting a halo effect. Analyses suggest the program to be economically viable, with a financial growth rate of 127%. Conclusions: EMR templates embedded with the NCCN guidelines for reflex genetics referral can appropriately increase the utilization of genetic services. Breast genetics screening and resultant appt/testing rates increased significantly 2019 vs 2018. Success in BRCA testing in breast CA will lead to expansion to other cancers and genes. Implementation of structured EMR genetics data fields can automate data collection and measure compliance. Integration of genetics screening into universal OCM treatment planning is feasible, economically viable and scalable.
Relationship between CYP2D6 genotype, tamoxifen metabolites, and adverse events, tumor biomarkers and breast cancer recurrence in a low-dose phase III trial in noninvasive disease.
Authors: De Censi Andrea , Johansson Harriet Ann , Helland Thomas , Puntoni Matteo , Buttiron Webber Tania , Macis Debora , Aristarco Valentina , Briata Irene Maria , Serrano Davide , D'Amico Mauro , Bifulco Ersilia , Hustad Steinar , Søiland Håvard , Bonanni Bernardo , Mellgren Gunnar
Published: May 2020

1553

Background: Low dose tamoxifen (T, 5 mg/d) given for 3 years halved recurrence in 500 women with non-invasive disease (DeCensi et al. JCO 2019). Retrospective studies with 20 mg/d have shown an association between low levels of endoxifen (9-16 nM) or Z-4OHtam (3.26 nM) and recurrence, but recent prospective studies have not confirmed these findings. We measured CYP2D6 genotype and 8 metabolite levels to determine their associations with adverse events, tumor biomarkers (IGF-I, SHBG, C-reactive protein, CRP) and breast cancer recurrence. Methods: CYP2D6 genotyping was performed in the T arm (n = 183) as previously described (Johansson H et al. BCRT 2016). T and metabolites were measured at 1 (n = 169) and 3 y (n = 152) as previously described (Helland T et al. BCR 2017). We tested linear relationships between metabolite levels and biomarkers, adjusting for age, BMI, treatment compliance and baseline biomarker levels. Cumulative incidence of recurrence according to endoxifen levels was calculated by the Cox model. Results: Endoxifen concentrations were associated to CYP2D6 metabolizer status (p < 0.001). Median (IQR) endoxifen levels were 8.4 (5.2-11.3) and 8.8 (5.8-11.5) at 1 and 3 y, with only 42% and 47% of subjects reaching 9 nM. Median endoxifen levels were related to pill count (5.5, 7.1 and 9.0 nM/L for medication possession rate < 83.3%, 83.4-99.9%, 100%, respectively). There was no difference in metabolite levels and menopausal symptoms. There was an inverse relationship between endoxifen and endometrial thickness at 3 y (p = 0.04), and between endoxifen or tamoxifen levels and IGF-I levels at 3 y (p = 0.001). T levels were positively associated with SHBG levels in postmenopausal women (p-interaction = 0.04). Endoxifen, T and 4OHtam decreased CRP, with a greater effect in premenopausal women (p-interaction = 0.02). An increase in CRP after 3 years was associated with a HR of 4.37 (95% CI, 1.14-16.73, P = 0.03) of recurrence compared to women with no increase of CRP. Median (IQR) endoxifen levels at year 1 were 8.4 (5.3-11.4) in patients who recurred vs 7.5 (5.1-10.2) in those who did not recur (p = 0.6), although this comparison was underpowered. Conclusions: T levels themselves may contribute to clinical activity by decreasing IGF-I and increasing SHBG. Elevated CRP is a predictive factor for recurrence which is down-regulated by T and metabolites. Endoxifen is below 9 nM in the majority of subjects treated with 5 mg/day, although this threshold was obtained in studies up to 20 years. Clinical trial information: NCT01357772.
Adoption of opportunistic salpingectomy for ovarian cancer prevention: Results from a nationwide sample of privately insured women.
Authors: Karia Pritesh S , Joshu Corinne E , Rosenshein Neil B. , Visvanathan Kala
Published: May 2020

1561

Background: Recent evidence indicates that the Fallopian tube is the site of origin for many high-grade serous ovarian cancers, particularly in BRCA carriers. This has led to the emergence of opportunistic salpingectomy (OS) as a novel ovarian cancer prevention strategy. Despite limited data, some national societies now recommend OS for ovarian cancer prevention during benign hysterectomy or in place of tubal ligation for sterilization in average-risk women. We assessed patient characteristics associated with increased likelihood of OS and national trends in OS adoption before and after release of recommendations. Methods: Data from MarketScan were used to identify women who underwent hysterectomy, tubal ligation, and OS from 2010-2017. Rates of OS were compared and interrupted time series analysis with segmented Poisson regression was used to examine immediate and persistent changes in OS rates before and after recommendations. Rates were calculated quarterly and models were adjusted for age and seasonality. Results: A total of 309,574 tubal ligations, 13,574 OS for sterilization, 293,000 hysterectomies, 22,798 hysterectomies with OS were included. Quarterly rates of OS for sterilization and hysterectomy with OS were 3.13 and 4.82 per 100,000 women, respectively. About 92% of OS for sterilization and 56% of hysterectomy with OS were performed in women < 45 years. The most common indication for hysterectomy with OS was uterine fibroids (46%). About 8% of OS for sterilization and 10% of hysterectomy with OS were performed in women with a family history of breast or ovarian cancer. After adjusting for age and seasonality, there was a 250% immediate increase (RR: 3.50; 95% CI: 2.59-4.72) followed by a 14% (RR: 1.14; 95% CI: 1.10-1.18) persistent increase in the quarterly rate of OS for sterilization after versus before recommendation release. There was a 109% immediate increase (RR: 2.09; 95% CI: 1.15-3.81) in the quarterly rate of hysterectomy with OS after versus before recommendation release. No persistent change in the rate of hysterectomy with OS was observed. Significant declines in hysterectomy and tubal ligation rates were observed and these declines were temporally associated with the release of recommendations. Conclusions: OS for ovarian cancer prevention has rapidly diffused into clinical practice with the speed of adoption bolstered by recommendations from national societies. Future studies evaluating the overall efficacy and long-term complications of OS are needed to support its continued widespread use.
Dietary advanced glycation end products (AGEs) and breast cancer mortality in the women’s health initiative (WHI).
Authors: Peterson Lindsay Leuthen , Omofuma Omonefe , Turner David P , Merchant Anwar , Zhang Jiajia , Neuhouser Marian L. , Snetselaar Linda , Caan Bette Jane , Shadyab Aladdin H. , Saquib Nazmus , Thomson Cynthia A. , Uribarri Jaime , Steck Susan
Published: May 2020

1570

Background: Breast cancer (BrCa) is the second leading cause of cancer death and constitutes about 14% of total cancer deaths among US women. Advanced glycation end-products (AGEs) are implicated in chronic diseases including cancer and cardiovascular diseases (CVD). AGEs are naturally found in animal products and processed foods, and preparing food at high temperatures increases AGE formation. Our goal was to assess the association between post-diagnosis dietary NƐ-carboxymethyl-lysine (CML)-AGE intake, a common measure of AGE, and mortality from all-causes, BrCa and CVD among participants with invasive BrCa in the Women’s Health Initiative (WHI). Methods: The WHI enrolled postmenopausal women aged 50 to 79 years from 1993-1998 into randomized controlled trials and a prospective observational study to examine causes of morbidity and mortality. In this analysis, we included 2,073 women diagnosed with invasive BrCa during follow-up who completed a food frequency questionnaire (FFQ) after diagnosis, had energy intakes between ≥600 kcal/day and ≤5000 kcal/day, and had CML-AGE intake data available. Women were followed from BrCa diagnosis until death or censoring through March 2018. Cox proportional hazards regression models estimated the hazard ratios (HR) and 95% CIs of mortality risk from all-causes, BrCa and CVD by tertiles of dietary CML-AGE intake with adjustment for age, income, race/ethnicity, study arm, time from diagnosis to FFQ completion, education, physical activity, smoking, BMI, ER/PR status, diagnosis stage, postmenopausal hormone use, intake of energy, alcohol, fat, red and processed meats. Results: After a median 15.1 years of follow-up, 642 deaths were reported including 198 BrCa-specific and 129 CVD-specific deaths. The average time from BrCa diagnosis to FFQ completion was 1.5 years. Compared to the lowest tertile of CML-AGE intake, there was an increased risk in the highest tertile for all-cause mortality (HR: 1.51, 95% CI: 1.17-1.94), BrCa (HR: 1.86, 95% CI: 1.19-2.91) and CVD (HR: 2.14, 95% CI: 1.19-3.84) mortality. Conclusions: Higher dietary AGE intake after BrCa diagnosis in postmenopausal women was associated with increased risk of mortality from all-causes, BrCa and CVD. Exposure to AGEs could be modified through dietary counseling and evaluated in relation to reduced mortality risk after BrCa diagnosis.
Burden of genetic testing in an academic biobank by pathological and family history-based criteria in prostate cancer (PCa).
Authors: Ding James , Feld Emily , Le Anh , Sanchez Pauleen , Powers Jacquelyn , Doucette Abigail , Gabriel Peter Edward , McLaughlin Michael , Kember Rachel , Weaver Joellen , Judy Renae , Rader Daniel , Damrauer Scott , Lee Daniel , Narayan Vivek , Domchek Susan M. , Schwartz Lauren , Maxwell Kara Noelle
Published: May 2020

1576

Background: Approximately 5% of localized PCa and 12% of metastatic PCa are associated with germline mutations in DNA repair genes. The National Comprehensive Cancer Network (NCCN) issued genetic testing guidelines to identify PCa patients (pts) likely to harbor a germline DNA repair mutation. The overall burden of this guideline-based, resource-intensive genetic testing is unknown. Using supervised phenotype-genotype information extraction algorithms, we determined the projected genetic testing burden at a single institution adhering to NCCN PCa genetic testing guidelines. Methods: A PCa cohort of 2127 pts was identified from the Penn Medicine BioBank via ICD 9/10 codes. Phenotypic data were extracted from the Penn Medicine Cancer Registry and electronic health record systems via natural language processing and manual chart review. Pts were classified based on 9 germline genetic testing criteria outlined in the NCCN PCa guidelines (Version 4.2019). Results: 895/2127 pts met at least 1 of the 9 NCCN genetic testing criteria, corresponding to a 42.1% overall genetic testing burden. 35.2% qualified for testing via high-risk localized PCa and 6.4% qualified via metastatic disease. Of the pts with localized PCa (n=2014), 15.1% qualified for genetic testing via high Gleason score, 5.1% via high-risk family history, 3.7% via PSA>20ng/mL, 8.7% via Ashkenazi Jewish descent, and 0.8% via intraductal/ductal histology. Conclusions: In this single-center PCa cohort, germline genetic testing was NCCN-guideline recommended for a larger proportion of pts than would otherwise be expected based on previously published reports. Future studies are needed to validate the sensitivity and specificity of these criteria for identifying germline mutations. Our study also highlights a need for novel methods to improve the efficiency of genetic testing for a large cohort. [Table: see text]
Diagnostic yield of germline genetic testing following tumor testing in prostate cancer patients.
Authors: Das Kingshuk , Lincoln Stephen E , Ngo Nhu , Pineda Alvarez Daniel Esteban , Yang Shan , Michalski Scott T. , Nielsen Sarah M. , Esplin Edward D. , Nussbaum Robert Luke
Published: May 2020

1591

Background: NCCN guidelines recommend germline testing for patients with localized or advanced prostate cancer meeting family history or clinical/pathologic criteria. However, the guidelines for somatic molecular analysis generally consider advanced disease only, primarily to inform therapy. As the analytical and clinical specifications of both testing modalities differ accordingly, we examined the results of germline testing following prior somatic testing. Methods: We reviewed somatic and germline variants in an otherwise unselected consecutive series of patients who: (a) had a current or previous diagnosis of prostate cancer; (b) had undergone tumor sequencing; and (c) were referred for germline testing. Indications for germline testing included: potential germline origin of somatic test result, treatment or surgical planning, personal or family history, and patient concern. Results: 208 patients met study criteria of whom 81 (39%) harbored a pathogenic germline variant (PGV) in a cancer predisposition gene. Certain genes were more likely to harbor germline variants, and 98% (81) of PGVs were potentially actionable (Table). 9.6% of PGVs were not reported by somatic testing, reflecting analytical limitations of the somatic testing. Of note, 11 patients (14%) had PGVs identified after diagnosis of a subsequent primary malignancy. Conclusions: The high PGV rate of 39% was unexpected, given reported rates of 11.8% in patients with metastatic prostate cancer and 6% in high-risk localized disease (NCCN)--even considering potential clinician ascertainment bias. This finding, the potential clinical utility of 98% of PGVs identified, the significant proportion unreported by somatic testing, and the fraction of patients diagnosed with a PGV after a subsequent malignancy all suggest that germline testing is an underutilized tool in the care of prostate cancer patients and their families. [Table: see text]
Outcomes of lung cancer screening among cancer survivors: An NCCN institution experience.
Authors: Maller Bradley , Simmons Vani Nath , Byrne Margaret M , Tanvetyanon Tawee
Published: May 2020

1595

Background: In 2013, the USPTF recommended low-dose CT (LDCT) screening for individuals at high risk of lung cancer based on data from the National Lung Screening Trial. However, the trial excluded participants with cancer diagnosis < 5 years except for non-melanoma skin cancer, making it unclear whether the data will be generalizable to cancer survivors. This population, while at increased risk of secondary lung cancer, may be prone to false positive results due to anatomic defects or recurrent cancers. Our NCCN institution serves a large number of cancer survivors. We evaluated the outcomes of LDCT screening and the adherence to annual screening among cancer survivors, compared with individuals without cancer history (IWC). Methods: Prospectively maintained database of LDCT screening participants was analyzed. Eligibility was per NCCN criteria and cancer survivors needing regular chest CT were not offered LDCT. Participants were asked to complete a self-administered questionnaire on risk factors. Positive result was defined as Lung-RADS ≥3, corresponding to nodule ≥6 mm. Adherence to LDCT screening was defined as having T1 screening, excluding those < 18 months from T0 at time of analysis. Predicted risk of lung cancer was calculated per PLCOm2012 model. Results: To date, 454 subjects have undergone LDCT screening. Positive results occurred in 60 subjects (13.2%) at T0; lung cancer was diagnosed in 10 subjects (2.2%); and other cancers were diagnosed in 5 subjects (1.1%). There were 152 cancer survivors, including survivors of breast (52), prostate (26), bladder or kidney (19), lung (14), and head and neck cancer (13). The median time from cancer treatment to LDCT screening was 6 years (range 0-55). Cancer survivors were older than IWC: median age 67.4 vs. 63.5 years ( p< 0.001) and more likely to be active smokers: 37.5% vs. 29.5%, ( p= 0.09). The median predicted risk of lung cancer at 6 year was 5.5% vs. 3.2%, ( p= 0.15). No significant difference in the screening outcomes was found between groups. Among cancer survivors (N = 152), positive screening occurred in 15 (9.9%); lung cancer was diagnosed in 1 (0.7%); and other cancers were diagnosed in 3 subjects (1.9%). Non-adherence to LDCT screening occurred in 31 out of 152 cancer survivors (20.4%), compared with 81 out of 262 (30.9%) IWC, ( p= 0.02). Conclusions: About one-third of LDCT screenings at this NCCN institution occurred among cancer survivors. We found no evidence of increased false positive results. However, a higher rate of adherence to annual screening was observed among cancer survivors than IWC.
Methodology, results, and publication of oncology clinical trials: Insights from all the world’s randomized controlled trials (RCTs) 2014-2017.
Authors: Sharma Shubham , Wells Connor , Del Paggio Joey C. , Hopman Wilma M. , Gyawali Bishal , Pramesh C S. , Sullivan Richard , Booth Christopher M.
Published: May 2020

2019

Background: Clinical cancer research is now a global effort. Most published overviews of oncology trials are restricted to a specific disease site or cohort of high-profile journals. Here we describe authorship, trial characteristics, design, and results of all oncology RCTs published globally during 2014-2017. Methods: A structured literature search was designed using PUBMED to identify all RCTs evaluating anti-cancer therapies published during 2014-2017. Data were captured regarding authorship, participants, study characteristics, design, and results. Among superiority RCTs that met the primary endpoint (i.e. statistically “positive”), we calculated the ESMO-MCBS to identify trials with substantial clinical benefit (MCBS scores 4/5 or A/B). Outcomes were compared with Chi Square or Fisher’s Exact tests. Results: The study cohort included 694 RCTs. The most common cancers evaluated were breast (17%, 121/694), lung (15%, 104/694) and colorectal (8%, 58/694). Treatment intent was curative, adjuvant/neoadjuvant, and palliative in 10% (68/694), 25% (176/694), and 65% (448/694) of trials respectively. Median sample size was 443 (IQR 246-718). Seventy percent (488/694) of RCTs were supported by industry; 87% (601/694) of experimental arms tested systemic therapy. Ninety-two percent (636/694) of RCTs were led by investigators in 28 high-income countries; the most common countries leading these trials were US (27%, 174/636), France (10%, 64/636), Germany (10%, 62/636), Japan (9%, 59/636), and UK (9%, 57/636). The most common primary endpoints were PFS (32%, 220/694), OS (31%, 215/694), and DFS (11%, 79/694); Forty-six percent of all trials (318/694) met their primary endpoint. Among superiority trials with “positive” results, 33% met ESMO-MCBS threshold for substantial clinical benefit. The median impact factor (IF) of journals which published the overall study cohort of trials was 21 (IQR 7-27); trials meeting their primary endpoint were published in higher profile journals (median IF 25 vs 18, p < 0.001). Conclusions: At the global level, oncology clinical trials are dominated by high-income countries and study diseases which do not necessarily reflect the global burden of cancer. The vast majority of trials are funded by industry and only one third of “positive” trials meet ESMO-MCBS threshold for substantial clinical benefit.
Association of hospital type and patient volume growth with timely cancer treatment.
Authors: Frosch Zachary AK , Illenberger Nicholas , Mitra Nandita , Boffa Daniel J. , Facktor Matthew A. , Nelson Heidi , Bekelman Justin E. , Shulman Lawrence N. , Takvorian Samuel U
Published: May 2020

2022

Background: Studies have suggested superior outcomes for patients with cancer treated at National Cancer Institute (NCI) and academic hospitals, leading some to advocate for complex cancer care to be delivered at regional referral centers. However, growing demand at such centers may exceed their capacity to provide timely treatment, which could be detrimental to patient outcomes. We evaluated the relationship between hospital type, the average annual growth rate in patient volume (PV), and time to treatment initiation (TTI) trends. Methods: We used the National Cancer Database to identify patients undergoing initial treatment for a new diagnosis of cancer (breast, lung, prostate, colorectal, melanoma, bladder, non-Hodgkin lymphoma, renal, uterine or pancreatic) in 2007-2016. The exposure was hospital type (NCI, academic, community or integrated network). The primary outcome was TTI over time. We estimated both the average annual growth rate for PV and adjusted TTI trends by hospital type using linear mixed effects models, including a hospital type-by-time interaction and, when modeling TTI, a patient volume-by-time interaction. Results: We identified 4,218,577 patients treated at 1351 hospitals (49% at 897 community, 23% at 177 academic, 14% at 50 NCI and 14% at 227 integrated network hospitals). Over the study period, PV grew by 40% at NCI and 25% at academic hospitals, compared to 8% at community hospitals (p-value for trend both < 0.001). Meanwhile, mean TTI increased by 3.2 days at community, remained stable at academic (+0.3 days) and decreased by 4.3 days at NCI hospitals (p-value for trend both < 0.001 vs community). A higher annual PV growth rate was associated with a statistically but not clinically significant TTI increase (0.05 days for each 100 patient/year increase in the growth rate, p = 0.001). Conclusions: Patients with newly diagnosed cancer are increasingly receiving treatment at NCI and academic hospitals. While TTI at NCI and academic hospitals is longer than in the community, PV growth has been possible without delaying cancer treatment. Further study is needed to determine whether continued growth at this rate is sustainable. [Table: see text]
Impact of an immuno-oncology (IO) education/monitoring program on patient’s self-efficacy and adverse event reporting from immune checkpoint inhibitors (ICIs).
Authors: Cheema Parneet Kaur , Nematollahi Massey , Berco FeRevelyn , Papadakos Janet , Kaushik Deepanjali , Matthews Priscilla , Iafolla Marco , Perdrizet Kirstin , Balcewicz Margaret , Raskin William , Reingold Stephen , Husain Juhi , Kuruvilla Philip , Conter Henry Jacob
Published: May 2020

2032

Background: ICIs have unique side effects of immune related adverse events (irAEs). For early detection and management of irAEs, at a large community hospital we implemented a standard IO nursing baseline assessment, education and monitoring program. We studied it’s impact on a patient’s irAE reporting and self-efficacy (confidence to manage symptoms) of ICIs. Methods: Prospective study conducted at William Osler Health System, Brampton, Canada from May 2018-December 2019. Patients aged > = 18, English speaking that received an ICI for cancer were included. Patients underwent a standardized baseline nursing assessment and education class. Patients identified at the assessment as high risk (risk of grade 3/4 irAE >20%) had weekly nurse proactive calls. Cancer Behaviour Inventory – Brief Version (CBI-B) (Heitzmann et al, 2011) was used to evaluate patient’s self-efficacy. Results: Eighty patients were enrolled. Median follow up of 4.1 months. Baseline demographics: median age 69, 70% males, 77% Caucasian, 81% ECOG 0/1, 66% had English as their first language and 19% highest education was elementary, 30% high school, 26% trade diploma and 21% post-secondary. Fourty-one percent had limited cancer health literacy (measured by CHLT6 (Dumenci et al, 2014)). ICIs prescribed were 70% monotherapy anti-PD1/PDL1, 13% combination nivolumab/ipilimumab, 17% anti-PD1/PDL1 + chemotherapy/other therapies. Majority had a diagnosis of non-small cell lung cancer (55%), melanoma (19%) and renal cell carcinoma (9%). A statistically significant improvement in the average CBI-B scores were found pre and post baseline assessment/education (p < 0.001) and this improvement was maintained over time at follow-up visits (non-significant change in scores from post education results). Fourty-three percent of patient’s experienced > 1 irAE. Most were grade 1/2 at time of detection (65%). Method of detection was mainly by patient self-reporting (62%), followed by proactive calls (27%). Only 3 patients had detection of an irAE with an ER visit. Rate of discontinuation of ICIs due to toxicity was 8.8%. Conclusions: In this diverse patient population with almost half of patients having limited cancer health literacy, a standardized IO baseline assessment, education and monitoring program resulted in improved patient self-efficacy with most irAEs detected by self-reporting and proactive calls. Our IO program can be a model for other oncology programs.
Affordable Care Act Medicaid expansion does not reduce guideline concordant cancer care disparities in vulnerable populations.
Authors: Ju Michelle , Blackwell James-Michael , Polanco Patricio , Mansour John C. , Wang Sam C. , Porembka Matthew R. , Zeh Herbert , Yopp Adam Charles
Published: May 2020

2039

Background: The receipt of timely, guideline concordant cancer amongst racial/ethnic and socioeconomic vulnerable populations remains a significant health policy issue. The Affordable Care Act (ACA) with implementation of Medicaid Expansion sought to reduce cancer disparities by reducing uninsured rates, theoretically improving healthcare access and delivery. We assessed the impact of Medicaid expansion on racial/ethnic disparities in the receipt of timely guideline concordant cancer care. Methods: We identified patients between 40-64 years of age with all stages of cancer (lung, colorectal, breast, uterine, and cervical) in the National Cancer Database, 2012-2015. Patients were assigned to Medicaid expansion cohort based on state of residence and whether Medicaid expansion was enacted at date of diagnosis in that state. Guideline concordant care was defined based on NCCN guidelines. We constructed an ecological model with multivariate regression analysis on rate of guideline concordant care receipt with covariates including race/ethnicity, Medicaid expansion, SES, gender, Charlson-Deyo score, and treatment facility type. Results: We identified 445,952 patients, 12% Black, 6% Hispanic white, median age 55 years. Patients in the lowest SES quartile following Medicaid expansion had the greatest increase in rates of insured status, although all SES quartiles had increased insured rates compared to non-Medicaid expansion regardless of race/ethnicity. In our ecological model, the rate of receipt of guideline concordant care declined by 0.5% per year between 2012-2015. After adjusting for covariates, Asians were 2.8% less likely to receive guideline concordant care than non-Hispanic whites, Blacks 3.8% less likely, and Hispanics 6.3% less likely (p < 0.0001). Racial/ethnic disparities in receipt of guideline concordant cancer care remained after Medicaid expansion with no differential benefit. Conclusions: Insurance gains under the ACA Medicaid expansion did not affect the rate of guideline concordant care receipt. Significant racial disparities persist in the likelihood of receiving guideline concordant care, particularly among Hispanics. Further studies are needed to determine additional barriers to cancer care access/delivery and identify key targets aimed at improving equity.
Novel artificial intelligence (AI)-based technology to improve oncology clinical trial fulfillment.
Authors: Bowen TJ , Stephens Laura , Vance Mark , Huang Yancui , Fridman Deborah , Nabhan Chadi
Published: May 2020

2052

Background: Less than 5% of US adult cancer pts are enrolled on clinical trials. Challenges in clinical trial fulfillment limit available treatment options, slow enrollment and ultimately delay new therapies from reaching market. Pt screening requires multiple clinical team members to find pts that meet strict inclusion/exclusion criteria. We evaluated the impact of new technology, Deep Lens VIPER, in identifying more qualified pts for clinical studies, and reduction of staff burden. Methods: We implemented Deep Lens VIPER at Hoag Hospital (Newport Beach, California), accessing the electronic medical records and pathology systems (EMR/LIS) to effectively identify pts who are candidates for 20 ongoing recruiting clinical studies. VIPER was fed pt data from 5,706 surgical pathology pts over a 4-month period (October 1, 2019 - January 31, 2020). Proprietary AI identification and matching technology was configured to align cancer pts with those 20 clinical studies, each with unique study criteria. Following an initial machine-assisted triage step, a research coordinator was alerted when pts who met protocol criteria were ready for final approval steps. Results were analyzed and a qualitative assessment of usability was also performed. Results: VIPER was able to triage all 5,706 surgical pathology cases (100%), identifying 1,045 pts (18.3%) with malignant neoplasms that would qualify for further analysis for clinical trials enrollment. Further triage based on inclusion and exclusion criteria led to the identification of 150 previously unidentified pts for 16 of the 20 studies. The 16 different studies for which potential pts were identified, included 11 tumor types, 12 biomarkers and 3 basket studies. Working with the VIPER system, 1 novice care team member performed initial identification of all 150 previously unidentified pts. The VIPER system increased monthly candidate pt catchment for 16 of the 20 studies under investigation, which is approximately 600 patients annually added for final triage for studies being conducted. Conclusions: We demonstrate the use of an AI-based platform to identify pts for clinical trial enrollment who would be missed using traditional recruiting methods. One staff member effectively triaged participants from 20 different studies with unique inclusion/exclusion criteria. These studies were previously managed by 6 different care team members with limited time for recruitment. Scaling this platform to additional institutions and more studies is ongoing to validate these findings.
Trends in FDA cancer registration trial design over time, 1969-2020.
Authors: Warner Jeremy Lyle , Sethi Tarsheen Kaur , Rivera Donna R , Venepalli Neeta K. , Osterman Travis John , Khaki Ali Raza , Rubinstein Sam
Published: May 2020

2060

Background: The FDA has issued hundreds of cancer drug indications, with many new drugs, expanded indications, and biosimilars approved in recent years. While the gold standard for regulatory approval is the randomized controlled trial (RCT), RCT design including selection of control arms can differ considerably. We sought to investigate trends and patterns in RCT trial design used to support FDA approvals in oncology. Methods: We reviewed the available FDA package inserts of oncology drugs (N=258) for RCTs cited to support initial and expanded indication approvals as of January 2020; biosimilars were excluded. RCTs were linked to the HemOnc ontology, which contains trial-level metadata including publication year, endpoints, and trial design. Log-linear regression was performed to evaluate trends in approvals over time by endpoint. Study drugs were categorized as cytotoxic therapy, targeted therapy, or immunotherapy. RCTs were categorized by four designs: escalation (adding a drug or increasing the drug dose in an established regimen), in-class comparison (comparing two drugs in the same therapeutic class), out-of-class switch (comparing drugs in distinct therapeutic classes), and de-escalation (removing a drug or reducing the drug dose in an established regimen). Results: We identified 556 registration trials, 372 (67%) of which were RCTs. Approvals have been increasing exponentially over time (R2 0.9, p<0.001), both for RCTs reporting overall survival (OS) endpoints (R2 0.77, p<0.001), and non-OS endpoints (R2 0.67, p<0.001). Of the three most common trial designs (Table), in-class comparisons were least likely to report OS (28%; escalations 47%; out-of-class switches 43%, p=0.01 by Chi-squared). Class switches were common in immunotherapy trials compared to targeted or cytotoxic therapy. Conclusions: Despite growth in FDA approvals, a minority of registration trials report paradigmatic shifts in therapeutic approach (out-of-class switches), with the relative exception of immunotherapy trials. Escalation is the most common route to FDA approval, even though this design inevitably increases cost and toxicity. This suggests that new oncology drug approvals are not alone a useful metric of practice-changing innovation. [Table: see text]
Self-reported overall wellbeing (OWb), physical function (PFn), and PRO-CTCAE symptom scores in post-operative and chemotherapy patients.
Authors: Hazard Hannah , Osarogiagbon Raymond U. , Wong Sandra L. , Bian Jessica J , Dizon Don S. , Wedge Jason , Mallow Jennifer , Basch Ethan M. , Enzinger Andrea Catherine , Wright Alexi A. , Remick Scot C. , Bradford Leslie Siriya , Cass Ilana , Phillips Joseph D. , Ivatury Srinivas J , Bandera Christina A. , Faris Nicholas Ryan , Cronin Christine , Hassett Michael J. , Schrag Deborah ,   eSyM Project Managers
Published: May 2020

2064

Background: A standardized, validated tool for capturing symptoms from cancer patients, PRO-CTCAE, has been used to reduce symptom burden, decrease acute care needs, and preserve quality of life. The association between specific PRO-CTCAE symptom scores and single item measures of OWb and PFn were characterized to understand symptom constellations. Methods: A novel Epic-based symptom management program (eSyM) was deployed for GI, GYN, and thoracic cancer patients starting chemotherapy (Memphis Baptist) or having surgery (WVU Medicine). Patients received automated prompts to complete surveys via the patient portal (MyChart) on a fixed schedule, approximately twice/week. Each survey included one OWb item, one PFn item, and at least 6 PRO-CTCAE items (pain, nausea, vomiting, fatigue, anxiety, insomnia). The OWb and PFn items, which were created de novo, included 5 ordinal response options with corresponding pictograms (emojis from very happy to very sad for OWb; a figure walking to one prone in bed for PFn). Composite scores were generated: 0 for no symptoms, 1-2 for mild/moderate symptoms, and 3 for severe symptoms. We describe OWb and PFn and analyze associations between these items and PRO-CTCAE symptom scores. Results: Between 9/10/19-1/22/20, we collected 908 eSyM responses from 166 chemotherapy patients at Baptist (Age, M = 65), and 480 eSyM responses from 97 postoperative patients at WVU (Age, M = 57). The OWb and PFn scores demonstrated moderate correlation with PRO-CTCAE symptom scores (Baptist r = 0.63; WVU r = 0.75), and moderate correlation with mean symptom scores among surgery patients at WVU (r = 0.74); but lower correlation among chemotherapy patients at Baptist (r = 0.53-0.55). Scores improved over time following surgery, but not after initiation of chemotherapy. Among the 730 eSyM responses with none/mild values for both OWb and PFn (52.9% of all responses), only 4.5% reported any severe symptom; among 651 responses with impairment of OWb and/or PFn, 45.2% reported at least one severe symptom. Conclusions: Integration of eSyM into the Epic EHR enabled tracking of OWb, PFn, and PRO-CTCAE items. When asked alongside PRO-CTCAE symptom items, two single item OWb and PFn measures provided distinct information and correlated with symptom burden. These results demonstrate the feasibility of integrating ePRO collection into routine post-operative and medical oncology care and that PRO-CTCAE items provide information that is distinct from that obtained from global metrics of well-being. Clinical trial information: NCT03850912.
Administration of immune checkpoint inhibitors using teleoncology model of care in Far North Queensland: A multicenter review of safety outcomes.
Authors: Fletcher James , Kang Sebastian , Brown Amy , Sabesan Sabe S. , Lyle Megan , Pandey Ritwik , Lui Andrew , Rainey Natalie , Kelly Barbara , Schmidt Andrew Lachlan , Joshi Abhishek Jagdish
Published: May 2020

2084

Background: The Teleoncology model of care, as developed and implemented across health services in Far North Queensland (Australia), improves access to specialist oncology services, including telehealth supervised administration of Oncology drugs for patients in rural/remote towns. There is limited published data regarding the safety of checkpoint inhibitor immunotherapy when it is administered via Teleoncology. Aim: Evaluate safety of immunotherapy administration via Teleoncology, including immune-related adverse events (irAE), treatment delays, hospital admissions and interhospital transfers, in comparison to a retrospective control population. Methods: Retrospective review of all patients treated with immunotherapy via Teleoncology as part of Cairns and Hinterland Hospital and Health Service (CHHHS) and the Townsville Teleoncology Network (TTN) between January 2015 and April 2019. A retrospective cohort treated at Townsville Cancer Centre over the same time period was used as a control group. Results: Fifty-one patients received a total of 624 cycles of immunotherapy (all single agent anti-PD-1/L-1) via Teleoncology. The control population included 142 patients who received 1697 cycles of immunotherapy. Baseline characteristics were well matched between groups. Compared to the control population, patients treated via telehealth did not have statistically significant differences in the rate of Grade 3+ irAE (13.7% v 8%), hospital admissions (13.7% v 7.4%) or protocol suspensions due to immune toxicity (16% v 10%). One patient with Grade 3+ irAE required interhospital transfer for investigation and management, which occurred within 24 hours of presentation to hospital. There were no treatment-related mortalities in either group. Conclusions: Checkpoint inhibitor immunotherapy can safely be delivered using the Teleoncology model of care in rural and remote centres. The incidence of toxicity for single agent immunotherapy was predictably low and not significantly different between groups, however the numbers in this retrospective study were small. The time to recognition and management of immune mediated toxicity in rural and remote centres is an important factor that was not assessed in this study and will be considered in future work.