bluuebunny/crossref_metadata_2025 huggingface dataset:
Low-dose metronomic topotecan and pazopanib in children with recurrent or refractory solid tumors: A C17 Canadian phase I trial (TOPAZ).
Authors: Manji Arif , Morgenstern Daniel A. , Samson Yvan , Deyell Rebecca , Johnston Donna , Lewis Victor Anthony , Zorzi Alexandra Patricia , Berman Jason N. , Brodeur-Robb Kathy , Morrison Ellen , Baruchel Sylvain , Whitlock James A.
Published: June 2021

10020

Background: Low-dose metronomic topotecan (mTP) represents a novel approach to chemotherapy delivery which, in preclinical models, may work synergistically with pazopanib (PZ) in targeting angiogenesis. This study was designed to determine the recommended phase 2 dose (RP2D) of mTP/PZ in pediatric patients with solid tumors, while describing the safety and toxicity of this regimen. Methods: A phase I dose-escalation, pharmacokinetic (PK) and pharmacodynamic (PD) study of mTP/PZ was conducted at ten sites across Canada, enrolling pediatric patients aged 2-21 years with relapsed/refractory solid tumors. Patients were treated with oral mTP and PZ suspension daily without interruption in 28-day cycles, with dose escalation in accordance with the rolling-six design. Five dose levels (0.12/125, 0.16/125, 0.22/125, 0.22/160, and 0.3/160 mg/m2/day of mTP/PZ) were evaluated. PK studies were performed on day 1 and at steady state, and PD studies included circulating angiogenic factors VEGFR1, VEGFR2, VEGF, endoglin and placental growth factor. Results: Thirty patients (pts) were enrolled, of whom 26 were evaluable for dose-limiting toxicity (DLT), with median age 12 years (3-20). The most common diagnoses included osteosarcoma (8), neuroblastoma (NB, 7), Ewing sarcoma/PNET (4), and rhabdomyosarcoma (4). The most common grade 3/4 adverse events (AEs) related to protocol therapy were neutropenia (18%), thrombocytopenia (11%), lymphocytopenia (11%), AST elevation (11%), and lipase elevation (11%). Only 2 cycle-1 DLTs were observed on study, both at the 0.3/160 mg/m2 mTP/PZ dose level (2/5 pts) comprising persistent grade 3 thrombocytopenia and grade 3 ALT elevation. No AEs experienced beyond cycle-1 required treatment discontinuation. Best response was stable disease in 10/25 pts (40%) for a median duration of 6.4 months (1.7-45.1). One patient with refractory NB achieved stable disease for 45 months and continued on mTP/PZ via compassionate access after study closure. PK and PD results are pending at this time. Conclusions: The combination of oral mTP and PZ is safe and tolerable in pediatric patients with solid tumors, with a RP2D of mTP 0.22 mg/m2/day and PZ suspension 160 mg/m2/day. Ten patients achieved stable disease for a median of 6 months. The lack of objective responses suggests that this combination is likely of limited benefit for relapsed disease, but may play a role as maintenance therapy. Clinical trial information: NCT02303028.
Health-related quality of life (HRQoL) among pediatric patients with neurofibromatosis type 1 (NF1) and plexiform neurofibroma (PN) in the United States (U.S.).
Authors: Yang Xiaoqin , Yoo Hyun Kyoo , Amin Suvina , Cheng Wendy Y. , Sipsma Heather , Sundaresan Sanjana , Zhang Lujia , Duh Mei Sheng
Published: June 2021

10042

Background: PNs occur in 30-50% of pediatric patients with NF1, often resulting in debilitating pain and dysfunction. Children with NF1 PN report significantly worse HRQoL than the general population, though real-world evidence is limited. Research is needed to better characterize HRQoL among this patient population in the US. Methods: Patients ages 8-18 years with NF1 PN in the US who were treatment naïve or new users of selumetinib (≤1 month of use) were recruited through the Children’s Tumor Foundation to participate with their caregivers in an online cross-sectional survey in December 2020 and January 2021. Caregivers of similar patients ages 2-7 years also participated. Measures included the Pediatric Quality of Life Inventory (PedsQL; Acute version), EQ-5D-Y, Pain Interference Index (PII), Numeric Rating Scale (NRS-11), and the Patient-Reported Outcomes Measurement Information System (PROMIS) mobility and upper extremity functioning subscales. Patients provided self-reported responses; caregivers provided proxy responses and patient demographic and clinical characteristics. Results: 61 patients and 82 caregivers responded to the survey. Median (range) age of patients was 12.0 (8-14) years, and 53.7% were female. Most were treatment naïve (97.6%), white/Caucasian (85.4%), and had an NF1 and PN diagnosis for > 5 years (80.5% and 68.3%, respectively). On the PedsQL (range: 0-100; higher = better; mean scores typically > 80 among healthy patients), mean patient scores were 50.3 (school functioning), 56.1 (emotional functioning), 60.7 (social functioning), and 63.7 (physical functioning); the mean total score was 58.5.Caregiver-proxy mean scores were similar, ranging from 54.0 for school functioning to 65.0 for physical functioning, with a mean total score of 59.1. On the EQ-5D-Y, more than half of patients reported experiencing “some” or “a lot” of problems with pain or discomfort (65.6%) and with feeling worried, sad or unhappy (62.3%). Among patients with pain in the last 7 days, mean scores on the PII (range: 0-6; higher = more interference) were 3.0 for patients and 2.7 for caregiver proxies. Almost 75% of them reported moderate or severe pain on the NRS-11. Among patients with movement difficulty in the past 7 days, mean t-scores from the PROMIS scales (distribution mean = 50; higher = better) were 40.2 for mobility and 39.5 for upper extremity functioning among patients and 36.0 and 29.1, respectively, among caregivers. Within dyads, patients generally reported better functioning, on average, than their caregiver proxies. Conclusions: The humanistic burden of NF1 PN among this pediatric patient population is substantial, especially regarding pain, emotional functioning, and physical functioning. Results highlight an unmet need to be addressed for improving HRQoL in pediatric patients with NF1 and PN.
PALOMAGE, a French real-world cohort of elderly women beyond age 70 with advanced breast cancer receiving palbociclib: Baseline characteristics and safety evaluation.
Authors: Caillet Philippe , Pulido Marina , Brain Etienne , Falandry Claire , Desmoulins Isabelle , Ghebriou Djamel , Soubeyran Pierre-Louis , Paillaud Elena , Rifi Nada , Vauthier Jean Michel , Tassy Louis , Carola Elisabeth
Published: June 2021

1012

Background: Advanced breast cancer (ABC) is common in older patients, resulting from the high incidence of breast cancer beyond age 70. This population is often limited in clinical trials. Endocrine therapy (ET) combined with a CDK4/6 inhibitor is the standard of care in ABC overexpressing hormonal receptors (HR+). Data specific to older patients are scarce in the literature, deserving further research. Methods: PALOMAGE is an ongoing French prospective study evaluating palbociclib (PAL) + ET in real life setting in women aged ≥70 with HR+ HER2- ABC, split in 2 cohorts: ET sensitive patients with no prior systemic treatment for ABC (cohort A), and ET resistant patients and/or with prior systemic treatment for ABC (cohort B). Data collected include clinical characteristics, quality of life (EORTC QLQ-C30 and ELD14) and geriatric description [G8 and Geriatric-COre DatasEt (G-CODE)]. This analysis reports on baseline characteristics and safety data for the whole population. Results: From 10/2018 to 10/2020, 400 and 407 patients were included in cohort A and B, respectively. The median age was 79 years (69-98), 15.1% with an age > 85. ECOG performance status (PS) was ≥2 in 17.9% patients, 68.3% had a G8 score ≤14 suggesting frailty, 32.1% had bone only metastasis, and 44% had visceral disease. 35.8% of patients in cohort B had no prior treatment for ABC. Safety data were available for 787 patients. The median follow-up was 6.7 months (IC95% = 6.1-7.6). At start of treatment, full dose of PAL (125 mg) was used in 76% of the patients: 62.6%, 68.7% and 71.6% of patients aged ≥ 80, those with ECOG PS ≥2 and those with a G8 score ≤14, respectively. In the safety population, 70% had ≥1 adverse event (AE), including 43.1% grade 3/4 AE, and 22.9% ≥ 1 serious AE. Most frequent AE reported were neutropenia (43.2%), anemia (17.5%), asthenia (16.3%) and thrombocytopenia (13.6%). Grade 3/4 neutropenia was observed in 32.3% of patients, with febrile neutropenia in 1.1%. Grade 3/4 AE PAL-related were reported in 40.1%, 31.4% of patients aged < 80, ≥80, respectively. Regarding PAL, 23.4% of patients had a dose reduction and 41.8% had a temporary or permanent discontinuation due to AE. Safety data were similar in both cohorts. Geriatric data and impact on safety will be presented. Conclusions: PALOMAGE is a unique large real-world cohort focusing on older patients treated with PAL in France. These preliminary data do not suggest any new safety signal, matching data derived from PALOMA trials. The occurrence of less grade3/4 AE related to PAL in patients aged 80 and beyond might reflect the 30% decrease of PAL dose upfront. Effectiveness analyses are eagerly awaited. Clinical trial information: EUPAS23012 .
Identification of pathogenic CDK12 alterations in cell-free DNA (cfDNA) from patients with breast cancer.
Authors: Taylor Mary Love , Dada Hiba I. , Florian Hannah , Marcom Paul Kelly , Anders Carey K. , Drusbosky Leylah , Force Jeremy Meyer
Published: June 2021

1028

Background: Cyclin dependent kinase 12 ( CDK12) has both tumor suppressive and proto-oncogenic potential in metastatic breast cancers (MBC). CDK12 may be an important biomarker and target in MBC. However, a comprehensive genomic analysis of CDK12 alterations from cfDNA in MBC has not been investigated and the genomic impact of CDK12 alterations across the MBC spectrum is unknown. The purpose of this study was to identify the incidence of CDK12 genomic alterations occurring in cfDNA from patients with MBC and elucidate which CDK12 alterations may impact CDK12 kinase activity. Methods: We queried 13,070 MBC samples from the Guardant Health database between April 2019 – November 2020 to identify the incidence of CDK12 alterations detected in cfDNA. We classified each alteration type as: missense mutations, indels, or truncations. Amino acid changes occurring at conserved regions across multiple species were identified. Three-dimensional biochemical in silico analyses with ChimeraX were used to determine which CDK12 alterations may impact CDK12 kinase activity. To gain further biologic insights into CDK12 altered MBC we made associations with CDK12 alterations and co-occurring mutated genes. Results: Nonsynonymous CDK12 alterations from the Guardant Health database were found in 317 samples from a cohort of 13,070 patients indicating an overall incidence of 2.43%. Alterations included: 239 (75.4%) missense mutations; 26 (8.2%) indels; and 52 (16.4%) truncations. We identified 62 alterations within the kinase domain with all occurring at highly conserved regions across species. The most frequent hotspot mutation identified was I76M/T, occurring in 11 unique breast cancers. Three-dimensional analyses indicate that CDK12 alterations within the hinge, HRD, DFG, catalytic spine, and regulatory spine may impact CDK12 kinase activity. The significantly co-occurring mutations from the Guardant Health breast cancer database in samples with CDK12 alterations were ARID1A, APC, RB1, and PTEN. Conclusions: A modest incidence of CDK12 genomic alterations occur in cfDNA from patients with breast cancer. Novel somatic alterations in CDK12 were identified from Guardant Health that were not detected in the public domain. A portion of these occurred at highly conserved regions across species suggesting these specific CDK12 mutations may impact CDK12 kinase expression and be actionable therapeutic targets in breast cancers. Three dimensional analyses of the CDK12 gene further illustrate which specific alterations may induce CDK12 kinase expression or lead to inactivation. Co-occurring mutations reveal a unique genotype associated with CDK12 alterations that may play a biologic role in CDK12-mediated breast cancer pathogenesis. Preclinical studies to determine the prognostic and therapeutic implication of CDK12 alterations in MBC are warranted.
Efficacy of CDK4/6i in the visceral crisis setting: Result from a real-world database.
Authors: Dawood Shaheenah S. , Brzozowski Kaylen
Published: June 2021

1047

Background: The combination of the CDK4/6 inhibitors(CDK4/6i) and endocrine therapy has improved overall survival(OS) in patients(pts) with either endocrine sensitive or resistant disease who are not in visceral crisis. The goal of this retrospective analysis of a real world database was to look at the efficacy of CDK4/6i among pts with hormone receptor positive (HR+ve)/HER2-ve metastatic breast cancer(MBC) who present with visceral crisis at diagnosis. Methods: For this analysis, we utilized a federated network of de-identified health data representing approximately 64 million patient lives available through the TriNetX Platform. We identified 5966 pts who had HR+ve/HER2-ve MBC diagnosed between 2015 and 2020. OS was computed using the Kaplan Meier product limit method. Propensity score matching was performed on all comparisons of survival. Visceral crisis was defined as either liver metastases with liver dysfunction, lymphangitis with dyspnea or the presence of pancytopenia. Results: 906(15%) pts received CDK4/6i. OS any time after treatment among pts who did and did not receive CDK4/6i was significantly different (p=0.0002) favoring the group receiving CDK4/6i, with median OS at 59.6 months and 46.2 months and 2-year OS at 71.6% and 61.4% respectively. Among pts who received CDK4/6i versus another treatment as first line therapy, OS was significantly different(HR 0.7, 95%CI 0.57 – 0.86, p<0.0001), and median OS was 59.6 months and 41.5 months respectively. 336 pts with HR+ve mbc presented with visceral crisis at the time of diagnosis of whom 61(18%) received CDK4/6i therapy as first line therapy. Median OS among pts who did and did not have visceral crisis at diagnosis and received treatment was 8.1 months and 210 months respectively. OS any time after initial treatment was significantly different among pts with visceral crisis who did and did not receive CDK4/6i (p=0.01), with 2-year OS at 26.1% and 8.1% and median OS at 11 months and 6 months respectively Conclusions: The use of CDK4/6i in the presence of visceral crisis at diagnosis was associated with a 5 month improvement in OS compared to chemotherapy. Future clinical trials should explore the use of CDK4/6i in the setting of visceral crisis.
Germline mutations in DNA damage repair genes and HOXB13 among African American men diagnosed with early-onset prostate cancer.
Authors: Beebe-Dimmer Jennifer Lynn , Sample Christopher , Baird Tara , Sadeghpour Azita , Ruterbusch Julie J. , Cooney Kathleen A.
Published: June 2021

10505

Background: Inherited defects in DNA damage repair (DDR) genes (e.g. ATM, BRCA1/2) and the tumor suppresser gene HOXB13 are rare in the general population, but have been observed at a higher rate among men with early-onset and advanced prostate cancer. However, most studies include few, if any, African American men, highlighting the need to understand the contribution of mutations in these genes in this high-risk population. Methods: A population-based cohort of 757 African American men diagnosed with prostate cancer at age 62 years or younger were identified and enrolled through the Metropolitan Detroit Cancer Surveillance System (MDCSS), one of NCI’s founding members of the SEER program. Participants completed a short survey to collect information on family history, medical history (including cancer-related treatment), surveillance, and health behaviors. Each participant submitted a saliva or blood sample for genetic analyses and consent for tumor tissue if available. All clinical data were collected through linkage with the MDCSS registry. Full exome sequencing was performed and herein, we report the mutation patterns observed in a panel of DNA repair genes and HOXB13. All variants were ranked according to frequency (MAF < 1%); REVEL, SIFT and PolyPhen scores for pathogenic potential; evidence from existing literature; and prevalence in the cohort. Results: Among the 744 African American prostate cancer cases with adequate DNA for sequencing and thus included in this analysis, the mean age at diagnosis was 55.6 years, 29% reported a family history of prostate cancer in a first degree family member, and 40% were initially diagnosed with intermediate- to high-risk disease (stage T3/T4 and/or Gleason 4+3 and higher at diagnosis). We identified 20 variants that were either known or predicted to be pathogenic in 11 candidate genes ( ATM, ATR, BRCA1/2, BRIP1, CHEK2, FANCA, HOXB13, MSH2, PALB2, and PMS2). These particular variants were more common among men diagnosed before age 55 and in men with high grade cancer in this cohort. Conclusions: Our results suggest that mutations in DDR genes and HOXB13 may be important cancer risk factors for African American men diagnosed with early-onset and intermediate- to high-risk disease. Further study is necessary to describe the spectrum and prevalence of genetic mutations in this population including the characterization of variants of unknown significance.
Dietary intervention influence on physical activity in the Women’s Health Initiative randomized Dietary Modification trial.
Authors: Pan Kathy , Aragaki Aaron K. , Michael Yvonne , Thomson Cynthia A. , Shadyab Aladdin H. , Snetselaar Linda , Wactawski-Wende Jean , Garcia David O. , Saquib Nazmus , Chlebowski Rowan T.
Published: June 2021

10511

Background: In the Women’s Health Initiative (WHI) Dietary Modification (DM) randomized trial, after 8.5 years dietary intervention and 19.5 years cumulative (median) follow-up, dietary intervention participation was associated with a statistically significantly 22% lower breast cancer mortality (P = 0.02). In observational studies, physical activity has been associated with lower breast cancer risk with emerging results now indicating, compared to inactivity, any increase in physical activity has health benefits. Currently, longitudinal data on whether an intervention targeting dietary change influences other health-related behaviors as a gateway effect is limited. To evaluate whether randomization to a dietary intervention was associated with self-directed change in physical activity. Methods: In the WHI DM trial, 48,835 postmenopausal women, ages 50-79 years, with no prior breast cancer and baseline normal mammogram were randomized at 40 US clinical centers to a dietary intervention (19,541) or a comparison group. Dietary goals were to reduce fat intake to 20% of energy and increase intake of vegetable, fruit, and grains addressed in 18 group sessions in year 1 then quarterly. Neither randomization group received specific or ongoing instructions to increase physical activity, but physical activity was referenced in written materials given to the intervention groups in 7 of the 56 sessions. Episodes per week of moderate or vigorous recreational physical activity (MVPA) were collected at baseline and serially through 15.9 years follow-up by self-report questionnaire. Marginal longitudinal logistic regression models were used to assess physically inactive (MVPA = 0) or physically active (MVPA > 0) participants by randomization group. Marginal Poisson regression models estimated mean weekly MVPA by randomization group. Results: 45.6% of participants reported 0 MVPA at baseline which largely persisted throughout follow-up. During cumulative follow-up, relative to the comparison group, dietary intervention group participation was associated with 7% lower physical inactivity rate (odds ratio [OR] 0.93 95% confidence interval [CI] 0.91, 0.95, P < 0.001) and a 4% higher mean MVPA (ratio of means [RM] 1.04 95% CI 1.02, 1.06, P < 0.001). The association between dietary intervention participation with higher physical activity level was stronger with increasing BMI (P-interaction 0.01) and for women with waist circumference ≥ 88 cm (P-interaction 0.02). Conclusions: In conclusion, in a randomized trial setting, a low-fat dietary pattern intervention was associated with a significantly lower physical inactivity rate and significantly higher moderate and vigorous physical activity level which could be associated with health benefits. Clinical trial information: NCT00000611 .
The impact of socioeconomic status on stage at presentation, receipt of diagnostic imaging, receipt of treatment, and overall survival in colorectal cancer patients.
Authors: Shah Rajan , Chan Kelvin K.
Published: June 2021

10565

Background: Socioeconomic factors have been identified to influence patterns of care in colorectal cancer yet current literature findings are sparse, conflicting, and often incomplete. As such, this study investigates the impact of socioeconomic status (SES) on stage at presentation, receipt of diagnostic imaging, receipt of treatment, and overall survival (OS) in a universal healthcare system. Methods: The Ontario Cancer Registry was accessed to identify a cohort of patients diagnosed with colorectal adenocarcinoma from 2007-2016 in Ontario, Canada. Linkage to administrative datasets allowed study of the impact of SES, measured by mean neighbourhood household income divided into quintiles (Q1-Q5; Q1 = lowest income), on stage, imaging, treatments, and OS. Multivariable regression analyses of all endpoints were adjusted for age, sex, comorbidity, and rurality with OS models also adjusting for imaging and treatment. Results: 39,802 colon and 13,164 rectal patients were identified. Lower SES patients were more likely to present at a higher stage in both cohorts. Lower SES colon patients were less likely to receive magnetic resonance imaging (MRI) of the abdomen, liver resection, adjuvant oxaliplatin, and all palliative systemic therapies studied. In rectal patients, lower SES was associated with decreased receipt of MRI pelvis, rectal cancer resection in early stages, adjuvant oxaliplatin, and most palliative chemotherapies studied. All OS models found that lower SES was associated with poorer OS. Conclusions: These findings suggest disparities across the continuum of cancer care persist even within a universal healthcare system. Further efforts should be directed towards temporal research, identifying barriers, and subsequently applying this information to actionable policies.
Outcomes for hospitalized cancer patients with COVID-19 during the height of pandemic in New York City.
Authors: Sawyers Amelia , Chou Margaret , Johannet Paul , Gulati Nicholas , Qian Yingzhi , Zhong Hua , Osman Iman
Published: June 2021

10572

Background: Several reports have suggested that cancer patients are at increased risk for contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and suffering worse coronavirus disease 2019 (COVID-19) outcomes. However, little is known about the impact of cancer status on presentation and outcome. Here, we report on the association between cancer status and survival in hospitalized patients who tested positive for SARS-CoV-2 during the height of pandemic in New York City. Methods: Of the 6,724 patients who were hospitalized at NYU Langone Health (3/16/20 - 7/31/20) and tested positive for SARS-CoV-2, 580 had either active cancer (n = 221) or a history of cancer (n = 359). Patients were classified as having active malignancy if they either received treatment within six months of their COVID-19 diagnosis or they had measurable disease documented at the time of their hospitalization. Patients were categorized as having a history of cancer if there was no evidence of measurable disease or there were no treatments administered within six months of their COVID-19 diagnosis. We compared the baseline clinicodemographic characteristics and hospital courses of the two groups, and the relationship between cancer status and the rate of admission to the intensive care unit (ICU), use of invasive mechanical ventilation (IMV), and all-cause mortality. Results: There was no differences between the two groups in their baseline laboratory results associated with COVID-19 infection, incidence of venous thromboembolism, or incidence of severe COVID-19. Active cancer status was not associated with the rate of ICU admission ( P = 0.307) or use of IMV ( P = 0.236), but was significantly associated with worse all-cause mortality in both univariate and multivariate analysis with ORs of 1.48 (95% CI: 1.04-2.09; P = 0.028) and 1.71 (95% CI: 1.12-2.63; P = 0.014), respectively. Conclusions: Active cancer patients had worse survival outcomes compared to patients with a history of cancer despite similar COVID-19 disease characteristics in the two groups. Our data suggest that cancer care should continue with minimal interruptions during the pandemic to bring about response and remission as soon as possible. Additionally, these findings support the growing body of evidence that malignancy portends worse COVID-19 prognosis, and demonstrate that the risk may even apply to those without active disease.
The global burden of 29 cancer groups from 2010 to 2019: A systematic analysis for the Global Burden of Disease study 2019.
Authors: Kocarnik Jonathan M , Compton Kelly , Dean Franny , Fu Weijia , Gaw Brian , Harvey James , Henrikson Hannah , Lu Dan , Pennini Alyssa , Xu Rixing , Lisa Force
Published: June 2021

10577

Background: Cancer is a major cause of morbidity and mortality worldwide, and global efforts to reduce health loss from cancer require systematic estimates that can measure progress from national to global levels. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019), we examined global cancer burden in order to highlight areas where cancer burden is inequitably distributed and to inform cancer control efforts around the world. Methods: Using estimation methods from GBD 2019, we analyzed the incidence, mortality, years lived with disability, years of life lost (YLLs), and disability-adjusted life years (DALYs) for 29 cancer groups and 204 countries and territories from 2010 to 2019. Cancer burden was compared to health burden from other categories of diseases and injuries in the GBD. Results were assessed globally and by socio-demographic index (SDI), a summary measure of income per capita, average educational attainment, and total fertility rate. Point estimates and 95% Uncertainty Intervals (UIs) are reported. Results: There were 23.6 million (95% UI 22.2-24.9 million) incident cancer cases globally in 2019 (17.2 [15.9-18.5] million excluding non-melanoma skin cancer), and 10.0 (9.36-10.6) million cancer deaths. There were 250 (235-264) million DALYs globally due to cancer, 97% of which came from years of life lost. The leading five cancers by DALYs in 2019 were: tracheal, bronchus, and lung cancer (45.9 [42.3-49.3] million); colon and rectum cancer (24.3 [22.6-25.7] million); stomach cancer (22.2 [20.3-24.1] million); breast cancer (20.6 [19.0-22.2] million; and liver cancer (12.5 [11.4-13.7] million). Compared to other diseases and injuries in the GBD, cancer was responsible for the second-highest number of deaths, YLLs, and DALYs globally in 2019. These rankings of cancer burden differed by SDI quintile: cancer was the leading cause of absolute DALYs in high SDI countries but was ranked 10th in low SDI countries. From 2010-2019, the number of global cancer cases increased by 26.3% (20.3-32.3%), deaths by 20.9% (14.2-27.6%), and DALYs by 16.0% (9.29-22.8%). The largest annualized rate of change in absolute cases and deaths over this period occurred in the low and low-middle SDI quintiles. Conclusions: Cancer cases and deaths are growing globally, with the largest relative growth over the last decade occurring in low to middle SDI countries. Improvements in cancer prevention efforts and ensuring access to timely diagnosis and care will be necessary to make equitable progress in reducing the global burden of cancer.
Germline pathogenic variants in cancer predisposition genes among women with invasive lobular cancer of breast.
Authors: Yadav Siddhartha , Hu Chunling , Domchek Susan M. , Weitzel Jeffrey N. , Goldgar David , Kraft Peter , Nathanson Katherine L. , Karam Rachid , Chao Elizabeth , Yussuf Amal , Pesaran Tina , Dolinsky Jill S. , Hart Steven , LaDuca Holly , Polley Eric , Couch Fergus ,   The CARRIERS Consortium
Published: June 2021

10581

Background: The prevalence of germline pathogenic variants (PVs) in cancer predisposition genes among women with invasive lobular breast cancer (ILC) and the risk of ILC in PV carriers is not well-defined. Methods: The study included 2,999 women with ILC and 32,544 unaffected controls from a population-based cohort; 3,796 women with ILC and 20,323 women with invasive ductal carcinoma (IDC) undergoing clinical multigene panel testing (clinical cohort); and 125,748 exome sequences from unrelated women without a cancer diagnosis in the gnomAD 3.0 dataset. Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected controls in both cohorts and between women with ILC and IDC in the clinical cohort. Results: The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analyses, CDH1 and BRCA2 PVs were associated with high risks of ILC (Odds ratio (OR) > 4), and CHEK2, ATM and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. PV frequencies in these genes in ILC and IDC were similar except for PV frequencies in BRCA1 and CDH1. Conclusions: The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2 and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. While, multigene panel testing may be appropriate for women with ILC, CDH1 should be specifically discussed in the context of low prevalence and attendant gastric cancer risk.
Oncologists’ (ONCs) perceptions of tumor genomic profiling (TGP) and barriers to communicating secondary hereditary risk to African American (AA) patients.
Authors: Hall Michael J. , Bass Sarah Bauerle , Chertock Yana , Brajuha Jesse A , D'Avanzo Paul
Published: June 2021

10592

Background: TGP identifies targets for precision cancer treatments. TGP may also identify secondary hereditary cancer risks, necessitating complex decision support during informed consent. ONCs are poorly trained in the communication of genetic information, particularly for patients with low health literacy, poor knowledge of genetics, and high medical mistrust. AA patients are especially vulnerable in this setting. Methods: We conducted semi-structured interviews with 10 ONCs to assess perceived barriers related to communication of secondary hereditary risks of TGP, probing barriers unique to AA patients. Informed by results, an Internet-based survey was developed/distributed to a convenience sample of 50 ONCs nationwide to assess TGP knowledge, genomics confidence, and perceptions related to communication of secondary hereditary risk. Results: Six themes emerged from interviews: risk/benefits of TGP, knowledge of genetics, discussing hereditary risk, value/harm of TGP, unique risks in AA, and training needs. Most ONCs felt uncomfortable discussing hereditary risks of TGP w/patients. Seven out of 10 identified socio-economic status, medical mistrust, discrimination, genetic counseling non-compliance, low health literacy and family relationships as factors important to consider with AA patients. Online survey participants were 52% White, 66% male, with median age of 42 years. Education in the interpretation/communication of TGP was largely informal (56% reported only informal training) and 46% reported perceived gaps in their education. Genomic confidence was associated w/higher use of TGP (p = 0.05), but was not associated w/knowledge or years in practice; however, low knowledge was associated w/more perceived barriers to TGP and w/negative attitudes toward the value of TGP and the challenge of communication of possible hereditary risks (p = 0.05). Early-career ONCs were more likely to endorse perceived barriers to communication of genetic risk information from TGP to AA patients. Overall 86% ONCs felt additional online training in communication of secondary hereditary risks of TGP would be useful. Conclusions: ONCs recognize unique needs and barriers for AAs related to communication of secondary hereditary genetic information from TGP. Many feel uncertain about how/whether to address barriers and recognize the need to improve their skillset to do so. Training is critical to ensure informed decision making in vulnerable populations.
Impact of race on biomarker testing among HER2- advanced breast cancer (ABC) patients (pts) in the United States: Results from a real-world study.
Authors: Mahtani Reshma L. , Niyazov Alexander , Lewis Katie , Massey Lucy , Rider Alex , Arondekar Bhakti , Lux Michael P
Published: June 2021

10598

Background: African Americans (AA) have the highest breast cancer (BC) mortality rate. Access to treatment is a known contributing factor. In the past 4 years, several targeted therapies for HER2- BC have become available which require testing for specific biomarkers. This study assessed the impact of race on biomarker testing rates in HER2- ABC pts receiving treatment in the US. Methods: Oncologists were recruited to abstract data from medical charts for the next 8-10 pts receiving treatment with HER2- ABC during Sept 2019-Apr 2020. Pts records were stratified by race and categorized into 3 mutually exclusive cohorts [White/Caucasian (White), AA, Other]. The other race cohort was excluded from this analysis due to small sample size. Differences in pt demographics/clinical characteristics were analyzed via Fisher’s exact tests. Testing rates for actionable biomarkers (i.e. BRCA1/2, PIK3CA, PD-L1) were compared between White and AA pts utilizing logistic regressions controlling for age, known family history of a BRCA-related cancer, hormone receptor (HR) status and practice setting (academic vs. community). Further analyses by age will be presented. Results: This analysis included 378 pts records, provided by 40 oncologists. Mean age was 64 years; 77% had HR+/HER2- ABC; 20% had advanced triple negative breast cancer (TNBC), 3% had ABC with an unknown HR status. Compared to White pts, AA pts were significantly more likely to have advanced TNBC (27% vs. 18%, p<0.05). Compared to White pts, AA pts had significantly lower BRCA1/2 mutation (mut) testing rates (Table). Numerically lower rates of PIK3CAmut and PD-L1 testing were observed among AA pts (Table). BRCA1/2mut positivity rate (germline [g] and/or somatic [s]) was higher among AA vs. White pts (30% vs. 22%). Positivity rate for PIK3CAmut was lower for AA vs. White pts (8% vs. 11%). Conclusions: A higher than expected BRCA1/2mut positivity rate was observed than previously reported in the literature. This is likely because this analysis included s BRCA1/2mut and represented a high risk pt population. Across all biomarkers assessed, AA pts had lower testing rates than White pts. This suggests racial disparities in testing rates of actionable biomarkers. Consistent with guidelines, and with the increased availability of targeted therapies, focused efforts should be developed to increase biomarker testing in AA pts. Funding: Pfizer Biomarker Testing Rates by Race.[Table: see text]
Metastasectomy versus radiation of secondary sites in stage IV breast cancer.
Authors: Bilani Nadeem , Elson Leah , Elimimian Elizabeth Blessing , Liang Hong , Saravia Diana , Nahleh Zeina A.
Published: June 2021

1094

Background: Prospective trials have yielded mixed results on the utility of surgery in metastatic breast cancer (mBC). Thus far, however, studies have focused primarily on the impact of lumpectomy or mastectomy. We previously showed that a combined approach involving resection of primary and secondary sites (i.e. ‘metastasectomy’) in patients with limited mBC was associated with improved overall survival (OS). We sought to evaluate the effect on OS of two approaches to loco-regional therapy (LRT) at secondary sites: metastasectomy versus radiation therapy. Methods: This is a retrospective analysis of patients diagnosed with mBC from 2010-2017 using the National Cancer Database. We identified 5 cohorts of patients by site of metastasis: mBC involving only 1) bone, 2) brain, 3) liver, or 4) lung; and 5) patients with metastasis involving >1 site. For each cohort, we used Kaplan-Meier (KM) models with log-rank testing to evaluate differences in OS, by the LRT approach at secondary sites (radiation versus metastasectomy). Prior to KM modeling, chi-squared statistics were used in each cohort to assess whether age, race, Charlson/Deyo score (CDS) for comorbidity, and receptor subtype were potential confounders of survival. The KM models were adjusted accordingly, as per the table below. Results: 53.4%) were between 50-70 years old, White (n=53,409, 78.9%), and had hormone receptor (HR)-positive/HER2 receptor-negative breast cancer. N=12,362 patients received radiation therapy at either the bone, brain, liver, or lung; while n=2674 underwent surgical resection of a metastatic site. Of patients with metastasis to 1 site (n=44,451), n=30,341(68.3%) involved the bone, n=1,119 (2.5%) involved the brain, n=5,227 (11.8%) involved the liver, and n=7,764 (17.5%) involved the lung. N=24,017 patients had metastatic disease involving > 1 site. KM modeling revealed superior OS of patients undergoing metastasectomy versus radiation of secondary sites in all 5 cohorts (p<0.05). The difference in median OS (ΔmOS) by LRT approach was more pronounced when metastasis involved only the liver (41.6 months) or lung (48.6 months), versus only the brain (9.7 months) or bone (8.7 months). Conclusions: Metastasectomy appears to confer a superior benefit for OS compared to radiation of secondary sites, particularly in patients with secondary site involvement limited to the liver or lung. More research is needed from prospective trials investigating surgical resection of metastatic sites.[Table: see text]
Self-reported gender bias encountered by hematology and oncology fellows.
Authors: Balanchivadze Nino , Passalacqua Karla D. , Askar Sally , Kuriakose Philip , Duma Narjust , Nambudiri Vinod E. , Springer Kylie , Divine George , Donthireddy Vijayalakshmi
Published: June 2021

11017

Background: Gender-related bias and discrimination have been well documented, particularly in male-dominated fields such as surgery, and have been associated with increased risk for physician burnout. In hematology/medical oncology, women make up between 41% and 49% of first-year fellows, but represent less than 40% of the academic hematology/oncology workforce. We aimed to study current hematology/oncology fellow perceptions about gender-related bias and challenges to inform interventions that promote gender equity. Methods: An anonymous 18-question survey was sent online to 165 adult and 75 pediatric hematology/oncology fellowship programs. Two group comparisons to analyze survey responses between genders were performed using chi-square, or Fisher’s test (if cell counts < 5), and Wilcoxon Rank Sum tests. Results: A total of 133 fellows completed the survey, where 88 self-identified as female (66%) and 45 (33.83%) self-identified as male. Most participants were White (52%), followed by Asian (29%), Hispanic (9%), Middle Eastern (5%), and Black (3%). Most respondents (n = 100; 75%) were age 31-40 years. More than half (54%) were enrolled in adult hematology/oncology fellowships, 24% were enrolled in pediatric hematology/oncology fellowship programs, and 88% practiced in University-based programs. Compared to male respondents, female fellows were more likely to report experiencing gender bias (p < 0.001), felt more insecure in their job (p = 0.043), felt second-guessed by colleagues (p < 0.001), and were more likely to believe that they had been unfairly denied a promotion (p = 0.003). In addition, female respondents were more likely to report having been mistaken as a non-physician (p < 0.001) and were more concerned about perceived gender bias. Female respondents reporting gender bias used techniques such as wearing a white coat (p < 0.0001), emphasizing a professional look (p < 0.0001), and ensuring “Doctor” (p < 0.0001) was clearly written on their badge more often than male fellows. When asked about how to combat gender-related challenges, female fellows more often recommended formal lectures and instruction about gender bias for attending physicians and non-physician staff. Suggestions about mitigating gender-related bias included encouraging same-sex mentors and open discussions about existing bias. Conclusions: Female hematology/oncology fellows reported facing gender-related bias and challenges in daily practice and often used specific techniques to face these challenges. Transparency and directed education about gender bias may help mitigate these challenges to create better working environments for fellows.
Gender disparities in National Institute of Health funding for hematologic malignancies, hematopoietic stem cell transplantation, and cellular therapeutics.
Authors: Siddiqui Raheel Sufian , Shahzad Moazzam , Majeed Mahrukh , Hussain Ali , Murtaza Faryal , Khalid Farhan , Habib Ayesha , Aijaz Zobia , Bukhari Syeda Sadia , Anwar Iqra , Altaf Sehar , Anwer Faiz , Chaudhary Sibgha Gull , Balusu Ramesh , Ahmed Nausheen , Ganguly Siddhartha , Abhyankar Sunil H. , McGuirk Joseph , Khosa Faisal , Mushtaq Muhammad Umair
Published: June 2021

11020

Background: Gender inequality in research funding has been studied extensively; however, the literature lacks evidence in Hematology. We investigated trends in National Institutes of Health (NIH) funding for hematologic malignancies (HM), hematopoietic stem cell transplantation (HSCT), and cellular therapeutics (CT). Methods: The data on Hematology funding was retrieved from NIH Research Portfolio Online Reporting Tools (RePORT) Categorical Spending for fiscal years 2018 and 2019. A total of 6351 entries were reported. Only grants (n=1834) that were related to HM, HSCT, and CT were included. After excluding non-relevant, 975 principal investigators (PIs) were included in the analysis. Additional data regarding PIs was ascertained from the Scopus database, LinkedIn, Doximity, and departmental websites, including the number of publications, number of years of active research, H-index, highest degree, gender, and institution. Data were analyzed using SPSS version 21. Bivariate analyses, using chi-square and t-test, and linear regression analyses were performed. Results: In 2018 and 2019, 1834 grants totaling $799.4 million were awarded by the NIH for malignant hematology research (men 1301, 71% vs women 533, 29%). Of 975 PIs, 680 (70%) were men and 295 (30%) were women. Table highlights gender disparities in NIH funding and associated factors. Most of the grant recipients were Ph.D. or M.D./Ph.D. About 70% of total funding was awarded to male PIs. There were no gender differences in the mean number of grants and mean grant amount. Women had significantly lower years of active research and academic productivity. Conclusions: Although the gender gap in academic hematology has decreased in recent years, the latest trend suggests significant gender inequality in NIH funding for malignant hematology, transplantation, and cellular therapy.[Table: see text]
Cancer specialists in the VA as early adopters of clinical genetic services.
Authors: Scheuner Maren Theresa , Sales Paloma , Whooley Mary , Hoggatt Katherine , Kelley Michael
Published: June 2021

11029

Background: Genetic testing has become essential to delivery of cancer treatment, risk assessment, surveillance, and prevention. We sought to understand the use of genetic tests by clinicians in the Department of Veterans Affairs (VA). Methods: We administered a web-based survey to clinicians at 20 VA facilities with precision oncology programs. We excluded respondents if they were: not at one of the 20 VA facilities; not seeing patients in VA; not a physician, nurse practitioner (NP), physician assistant (PA), or pharmacist; a medical geneticist or specialty was not reported; or if the survey was incomplete. Using multiple logistic regression, we assessed the association between genetic test ordering, genetics referral, and clinician characteristics. Results: There were 909 (909/11,442, 8%) eligible respondents with 61% women and 64% under age 55. There were 571 physicians (63%), 200 NPs (22%), 93 pharmacists (10%), and 45 PAs 5(%). There were 361 (40%) primary care providers (PCPs), 90 (10%) cancer specialists, and 458 (50%) non-cancer specialists. Only 21% of clinicians reported feeling prepared to use genetic tests in their practice. In the past year, only 8% had ordered at least one multi-gene cancer test (germline, tumor or both), 12% a pharmacogenetic test, and 0.2%, an exome. Compared to physicians, NPs were 60% less likely (OR = 0.42, 0.23-0.77, p = 0.005), pharmacists, 80% less likely (OR = 0.22, 0.08-0.62, p = 0.005), and PAs, 90% less likely (OR = 0.08, 0.01-0.58, p = 0.01) to have ordered a genetic test. Compared to PCPs, cancer specialists were almost 5 times more likely to order a genetic test (OR = 4.74, 2.57-8.73, p < 0.0001); there was no difference in genetic test ordering between PCPs and non-cancer specialists. Among clinicians (n = 72) who had ordered cancer genetic tests, only about two-thirds were confident in knowing the indications for testing; discussing the potential benefits, harms and limitations of testing; understanding the test report; and knowing implications of results on disease management and prevention. Clinicians (n = 106) who had ordered pharmacogenetic tests had lower frequencies of confidence in these tasks. About half (52%) of the cancer specialists had referred patients to genetics in the past year; they were 1.8 times more likely than PCPs to refer (OR = 1.82, 1.10-3.03, p = 0.02), and non-cancer specialists were about 50% less likely than PCPs to refer (OR = 0.46, 0.33-0.64, p < 0.0001). Conclusions: In the VA, cancer specialists are integrating genetic testing and genetics referral into their practice more than PCPs and other specialists. However, genetic testing is underutilized, and many clinicians remain unprepared to use genetic tests in their practice. These results will inform workforce planning, clinician education, and development of clinical decision support to facilitate genetic risk assessment, informed consent, and ordering of genetic tests.