bluuebunny/crossref_metadata_2025 huggingface dataset:
Discovery and validation of a cross-platform 21-gene prognostic signature in neuroblastoma.
Authors: Gupta Mehul , Kannappan Sunand Nageswaran , Narendran Aru , Bose Pinaki
Published: June 2021

10035

Background: Neuroblastoma (NB) is the most common extracranial solid tumor in children. Despite the development of risk stratification tools to improve prognostication, prediction of patient survival outcomes in NB remains poor. In this study we used an unbiased machine-learning algorithm to develop and validate a transcriptomic signature capable of predicting 5-year overall (OS) and event-free survival (EFS) in these patients. Methods: The TARGET-Neuroblastoma dataset (n = 243) was used as the training set. Two independent NB cohorts, E-MTAB-179 (n = 478) and GSE85047 (n = 266) were used as validation sets. Elastic net regression was employed to identify transcripts associated with EFS. Association of the developed signature with EFS and OS was evaluated using univariate Cox proportional hazards (CoxPH), Kaplan-Meier, and 5-year receiver-operator characteristic curves in validation cohorts. Further, the independent prognostic value of the signature was assessed using multivariate CoxPH models with relevant clinicopathologic variables including age, INSS stage, and N-Myc amplification status in both validation sets. Finally, a nomogram was developed to integrate the signature with prognostic clinicopathologic variables to evaluate their combined efficacy for prediction of 5-year EFS and OS. Results: We identified a 21-gene signature that demonstrates significant association with EFS and OS in both E-MTAB-178 and GSE49710 validation cohorts. Moreover, the signature is independent of clinicopathological variables and can be effectively incorporated into a risk model, improving the prognostic performance. Several genes within the signature have been previously implicated in NB, including ECEL1, HOXC9 and ARAF1. Conclusions: To the best of our knowledge, we are the first to use an unbiased machine learning approach to generate a transcriptomic gene signature for neuroblastoma prognosis externally validated in multiple cohorts across platforms. This 21-gene transcriptomic signature significantly associated with EFS and OS in this disease. Combining this signature with current prognostic clinicopathologic variables will improve risk stratification of affected patients and may inform effective clinical decision-making.[Table: see text]
Standardization of fertility preservation discussion amongst pediatric oncology and bone marrow transplant patients.
Authors: Dargan Chandni , Mc Dermott Sarah , Chesbro Shelby , Fulbright Joy M.
Published: June 2021

10051

Background: As treatment for pediatric malignancies improves long term survival, physicians are shifting focus to late effects of therapy such as infertility. Currently, options for fertility preservation include cryopreservation of mature oocytes, sperm, and gonadal tissue, although barriers remain present. Within our division, we lacked a standard approach to discussing fertility preservation options. Methods: Records from 474 pediatric patients with new oncologic diagnoses at CMH from 2014-2020 were retrospectively reviewed. We evaluated the frequency that reproductive health discussions were documented in pubertal males and females requiring chemotherapy or radiation treatment. We implemented a standard fertility preservation note and patient handouts, then surveyed our department to identify diagnoses that place patients at risk for infertility and barriers to formalized fertility consultations. We then provided educational sessions to address these barriers with pre- and post-evaluation to measure efficacy. Our longitudinal assessment, encompassing multiple points of intervention, was compared to results from previous chart review (2010-2013). Results: Of 474 patients diagnosed between 2014-2020, 175 (90 females, 85 males) warranted a fertility discussion per inclusion criteria. 61 (67.8%) females received a fertility discussion and of those 8 (8.9%) completed oocyte or gonadal tissue preservation, all between 2017-2020. 52 (61.2%) males received a fertility discussion and 20 (23.5%) completed sperm cryopreservation, with even distribution pattern between 2014-2020. Following implementation of an electronic fertility consult process and standardized fertility preservation documentation, there was an increase in documented fertility discussions from 30% in 2014 to 63.6% in 2020. Internal department survey responses identified a lack of comfort with knowing fertility preservation options available and diagnoses that should prompt this conversation. Education sessions with pre- and post-provider assessment demonstrated more comfort discussing fertility preservation (average score increase from 3.44 to 4.33) and knowledge regarding diagnoses at higher risk of infertility (average score increase from 3.67 to 4.33). Conclusions: Integration of a standardized fertility preservation process and addressing barriers identified within our division have led to a 33.6% increase in fertility discussions over the last 6 years. While the data shows a promising increase in oocyte and ovarian tissue preservation, sperm banking completion rates remained unchanged. Further steps include incorporation of an automated fertility consultation order into electronic chemotherapy orders, hospital-wide identification of other high-risk patient populations, and continued education of patient, families, and the health care team.
Favorable prognostic factors of oligometastatic breast cancer: A subset analysis of OLIGO-BC1.
Authors: Wang Kun , Bi XiWen , Liu Guangyu , Ueno Takayuki , Takao Shintaro , Sim Sung Hoon , Im Young-Hyuck , Im Seock-Ah , Ahn Sung Gwe , Lee Jeong Eon , Park Yeon Hee , Futamura Manabu , Toi Masakazu , Fujiwara Yasuhiro , Saito-Oba Mari , Kitagawa Yuko , Nishiyama Masahiko , Imoto Shigeru
Published: June 2021

1026

Background: The Federation of Asian Clinical Oncology (FACO) conducted an international retrospective cohort study of oligometastatic breast cancer (BC) (OLIGO-BC1) (UMIN No.000030047). At ASCO2020, we demonstrated that locoregional and systemic therapy prolonged overall survival (OS) for patients with oligometastatic BC, especially for cases with some type of systemic therapy, younger age, ECOG performance status 0, stage I BC, non-triple negative subtype, fewer metastatic sites, local recurrence and longer disease-free interval from a multivariate analysis (#1025). Although BC is heterogeneous and a retrospective dataset has many kinds of bias, we attempted a subset analysis based on intrinsic subtype and several prognostic factors. Methods: Oligometastatic BC patients diagnosed from 2007 to 2012 were registered from CSCO, KSMO and JSCO. OS period was measured from the diagnosis of oligometastases to the latest follow-up. ER, PgR and HER2 status were determined by immunohistochemistry and/or in situ hybridization. A hazard ratio (HR) of OS was calculated by using a univariate analysis. Results: In 1200 eligible cases, one oligometastatic site was found in 578 cases, two in 289, three in 154, four in 102 and five in 77. Bone metastases were recorded in 301 cases, visceral metastases in 387, locoregional recurrence in 25, local recurrence in 83 and multiple metastatic sites in 404. Luminal subtype was recorded in 526 cases (44%), luminal-HER2 in 189 (16%), HER2 in 154 (13%), triple-negative in 166 (14%) and others in 165 (13%). In any subtype, locoregional and systemic therapy and ECOG performance status 0 were beneficial for OS. Stage I BC, one oligometastatic site and longer disease-free interval were also related to favorable prognosis in luminal and HER2 subtype. However, triple-negative subtype had no survival advantage with these 3 factors. On the other hand, pathological negative or micrometastatic lymph nodes at primary BC and one oligometastatic site of lymph node, lung, liver and bone were favorable prognostic factors. In addition, cases treated locally with surgical resection and conventional radiation therapy were expected to prolong OS. Discussions: Locoregional therapy for oligometastatic BC may be considered in luminal and HER2 subtype with some conditions. As reported in ASCO2020, triple-negative BC should be managed with systemic therapy. Conclusions: Oligometastatic BC is diagnosed by chance, but some cases seem to survive with multidisciplinary treatment. It is worthwhile to consider locoregional therapy in oligometastatic BC after evaluating favorable prognostic factors.
Characterization of long-term responders following treatment with talazoparib (TALA) or physician’s choice of chemotherapy (PCT) in the phase 3 embraca trial.
Authors: Ettl Johannes , Rugo Hope S. , Hurvitz Sara A. , Martin Miguel , Roche Henri , Lee Kyung-Hun , Goodwin Annabel , Usari Tiziana , Lanzalone Silvana , Guenzel Carolin , Blum Joanne Lorraine , Litton Jennifer Keating
Published: June 2021

1029

Background: In the EMBRACA trial (NCT01945775), the poly(ADP-ribose) polymerase inhibitor (PARPi) TALA significantly improved progression-free survival (PFS) versus PCT in patients (pts) with germline BRCA1/2-mutated HER2-negative locally advanced/metastatic breast cancer (BC) (8.6 vs 5.6 months [mo]; hazard ratio [HR, 95% CI] 0.54 [0.41-0.71]; P < 0.0001). Predictive markers for response to PARPi, other than germline BRCA1/2 mutational status, are largely unknown. A previous analysis investigated biomarkers associated with long and short responders in EMBRACA. Here, we report the clinical characteristics of long and short responders. Methods: Pts were randomized 2:1 to TALA or PCT. In this retrospective analysis, pts in the intent-to-treat (ITT) population were mapped into two groups based on response: LONG (pts in TALA arm with overall survival [OS] ≥30 mo and duration of treatment ≥24 mo; pts in PCT arm with OS ≥30 mo); SHORT (pts in either arm with a PFS event [progressive disease by Independent Radiological Facility or death] ≤12 wks). Data cutoff date was Sept 30, 2019. Results: Of 431 pts randomized, 412 pts were treated (286 received TALA; 126 received PCT). In the ITT population, 37 pts receiving TALA and 34 pts receiving PCT were identified as LONG responders; 40 pts receiving TALA and 32 pts receiving PCT were SHORT responders. The Table shows a summary of pt characteristics for LONG and SHORT responders. More pts with HR+ BC and no prior CT for ABC were associated with LONG response; more pts with TNBC and ≥2 prior CT regimens or platinum were associated with SHORT response (Table). Median treatment duration for LONG responders (n = 37, TALA; n = 31, PCT) was 33.5 (24.0-61.4) mo for TALA and 7.6 (1.1-36.3) mo for PCT; 51.4% receiving TALA and 91.2% receiving PCT had subsequent therapy. In SHORT responders, median treatment duration was 2.0 (0.1-5.5) mo (TALA) and 1.4 (0.2-5.6) mo (PCT); 67.5% and 68.8% received subsequent therapy following TALA or PCT, respectively. Conclusions: In this clinical characterization of responders from the EMBRACA study, a higher number of LONG responders had HR+ BC and received no prior CT for ABC. A greater proportion of SHORT responders had TNBC and received ≥2 prior CT regimens or platinum. Further investigation is warranted in a larger number of pts. Clinical trial information: NCT01945775 .[Table: see text]
Cyclin-dependent kinase 4/6 (CDK4/6) inhibitor SHR6390 combined with pyrotinib and letrozole in patients with human epidermal growth factor receptor 2-positive (HER2+), hormone receptor positive (HR+) metastatic breast cancer (MBC): Phase Ib study results.
Authors: Zhang Jian , Meng Yanchun , Wang Biyun , Wang Leiping , Cao Jun , Tao Zhonghua , Li Ting , Yao Wenqing , Hu Xichun
Published: June 2021

1035

Background: The combining of HER2 targeted therapy and endocrine therapy (ET) has been demonstrated to be a reasonable therapeutic approach and recommended for highly selected patients (pts) with HR+/HER2+ MBC. CDK4/6 inhibitors could sensitize HER2 targeted therapies in multiple patient-derived xenograft models and delay tumor recurrence in a transgenic model of HER2+ breast cancer. The aim of this phase Ib/II study was to investigate the safety and efficacy of adding a CDK 4/6 inhibitor to the combination. Primary phase Ib results were reported. Methods: Patients with HR+/HER2+ MBC who were eligible for first- or second-line treatment were enrolled, and orally received letrozole, pyrotinib, and a novel CDK4/6 inhibitor SHR6390. In the “3+3” dose-exploring phase, letrozole was given at a fixed dose of 2.5mg/d. Pyrotinib and SHR6390 were initially given at a dose of 400mg/d and 125 mg/d respectively (Level I). If the initial dose level could be tolerated, subsequent pts were assigned to the higher level (Level H) with pyrotinib 400 mg/d and SHR6390 150mg/d; otherwise, simultaneously to Level L1 with pyrotinib 400 mg/d, and SHR6390 100 mg/d, or Level L2 with pyrotinib 320mg/d, and SHR6390 125 mg/d. Primary endpoints of phase Ib included dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety and efficacy. Results: As of 4 Jan 2021, a total of 15 pts (Level I 5 pts, Level L1 6 pts, and Level L2 4 pts) were enrolled in phase Ib and received the study treatment. 6 of them had received systemic therapies in the advanced stage, and 10 of them had been previously treated with trastuzumab. The most frequent grade 3/4 adverse events included neutrophil count decreased (n = 6), white blood cell count decreased (n = 4), stomatitis (n = 4) and diarrhea (n = 3). 3 pts (2 in Level I, and 1 in Level L1) had experienced DLTs, all of which were grade 3 stomatitis. Of the 15 pts evaluable for response, 7 pts（46.7%） had achieved confirmed partial responses (1 in Level I, 3 in Level L1, and 3 in Level L2) and 7 pts (46.7%) had stable disease. Based on DLTs and clinical efficacy, pyrotinib 320mg/d, SHR6390 125mg/d, and letrozole 2.5mg/d was declared as RP2D. Conclusions: Data from phase Ib showed the triplet combination of pyrotinib, letrozole, and SHR6390 had an acceptable safety profile and encouraging preliminary efficacy, potentially offering a chemotherapy sparing treatment option for patients with HR+/HER2+ MBC. Enrollment on phase II is ongoing. Clinical trial information: NCT03772353 .
Phase I study of LZM005, a HER2 antibody, as monotherapy or in combination with trastuzumab and docetaxel in patients with HER2-positive metastatic breast cancer.
Authors: Xue Cong , Yao Herui , Lin Ying , An Xin , Chen Meiting , Dong Yugang , Li Su , Shi Yanxia
Published: June 2021

1042

Background: LZM005 is a novel anti-HER2 antibody that binds with elevated affinity to the domain II of HER2. This phase I study assessed the safety, tolerability, pharmacokinetics (PK) and activity of LZM005, as monotherapy or combined with trastuzumab and docetaxel in patients with HER2-positive metastatic breast cancer. Methods: The phase I trial included phase Ia and Ib. Phase Ia was the monotherapy dosage escalation design. LZM005 was administered intravenously with 5mg/kg, 10mg/kg, 15mg/kg and 20mg/kg. The endpoints were dose limited toxicity (DLT) and maximum-tolerated dose (MTD), safety, tolerability and PK analysis. In phase Ib, LZM005 was combined with trastuzumab and docetaxel with MTD. The endpoints included safety and tolerability, response, PK and biomarker analysis. Results: From Jan 2017 to Feb 2020, 35 patients received LZM005 (15 monotherapy, 20 combination). No DLT was observed from 5mg/kg to 20mg/kg. In phase Ib two arms were set: 420mg arm and 525mg arm. The pharmacokinetics of LZM005 were similar to pertuzumab (Table). Common adverse events included increased transaminases, diarrhea and anemia in monotherapy and combination therapy. The common AE in phase Ia trial included diarrhea (21.4%), anemia (14.3%), elevated transaminase (14.3%). The common AE in phase Ib trial included anemia (44.1%), diarrhea (41.2%), fatigue (26.5%), elevated transaminases (23.5%), nausea (20.6%), rash (17.6%) and asymptomatic urinary tract infection (11.7%). All adverse events were manageable. No treatment-related death occurred. The clinical benefit rate and objective response rate was respectively 42.90% (6/14) and 7.14% (1/14) with monotherapy, with combination cohort was 100% (8/8) and 62.5% (5/8) in trastuzumab-naive, 83.3% (11/12) and 41.7% (5/12) in trastuzumab-pretreated patients. The median progression free survival was 22.5 weeks. Conclusions: LZM005 was well tolerated and showed potent activity in patients with HER2-positive metastatic breast cancer. Further evaluation was warranted. Clinical trial information: CTR20191921 .[Table: see text]
Gene methylation and cytological atypia in random fine needle aspirates for assessment of breast cancer risk: 10-year follow up in average risk women.
Authors: Wrubel Erica , Fackler Mary Jo , Huang Peng , Pulliam Natalie , Montanari Amanda , Zalles Carola Maria , Sukumar Saraswati , Stearns Vered , Khan Seema Ahsan
Published: June 2021

10520

Background: Alterations in DNA methylation occur early in tumorigenesis, and are a potential breast cancer risk biomarker. We previously reported a study where healthy volunteers underwent random fine needle aspiration (rFNA) of the breasts; cumulative methylation index of eight preselected tumor suppressor genes (CMI) was associated with the presence of cytological atypia in rFNA samples. We now report 10-year follow-up of this population, to evaluate whether increased CMI is associated with subsequent breast cancer development. Methods: 380 women, unselected by breast cancer risk, were enrolled. Demographics, breast cancer risk factors, lifetime Gail model risk estimates (Gail-LR), and %breast density were obtained at baseline. rFNA samples were assessed for cytopathology (Masood Score, MS) and CMI. Patients were contacted annually for 10 years to ascertain development of invasive or non-invasive breast cancer. In univariate analysis, log-rank test was used to compare breast cancer incidence rates between individuals with high and low baseline measures (separated by median). Area under the ROC curve was used to evaluate the cancer prediction accuracy. In multivariate analysis, the effect of CMI (after log-transformation to reduce skewness) was further studied using Cox regression model adjusting for confounding baseline variables. Results: 362 women participated in follow up. At a median follow up time of 9.5 years after rFNA sampling, 16 women developed invasive or non-invasive breast cancer. There were no significant differences between women who developed cancer and those that did not in regard to demographic factors, %breast density, MS, or Gail-LR. On univariate analysis, Gail-LR was higher in women who developed cancer (13.0 vs. 16.5, p=0.08). The largest hazard ratios were observed from high breast density (2.30, 95% CI 0.8, 6.6) and high CMI (2.26, 95% CI 0.8, 6.6, p=0.07). In breast cancer prediction, the AUC for CMI was 0.64 (95% CI 0.51, 0.77). In separate bivariable models that adjusted for age, Gail-LR, MS, and %breast density, the HR for log CMI was consistently above unity, with a p value consistently below 0.1, except for the model that included MS (see Table). Conclusions: Elevated CMI has potential as a robust predictor of future breast cancer occurrence in average risk women, even when adjusted for breast density or cytologic atypia. Our prior analysis established that CMI is not susceptible to variation with menstrual cycle phase and menopausal status. These features support its further evaluation in larger trials. Clinical trial information: NCT00896636 .[Table: see text]
Uptake of genetic counseling and testing in a clinic based population of women with breast cancer.
Authors: Wehbe Alexandra , Manning Mark A. , Assad Hadeel , Purrington Kristen , Simon Michael S.
Published: June 2021

10524

Background: Carriers of pathogenic variants in cancer susceptibility genes have an elevated risk of developing breast, ovarian, and other cancers.We conducted a medical record review to determine the uptake of genetic counseling and testing in a clinic-based population of women with breast cancer. Methods: Medical records of 150 women with breast cancer seen at the Karmanos Cancer Institute between January-December 2018 were reviewed to determine the proportion eligible for genetic testing according to National Comprehensive Cancer Network guidelines. We also assessed genetics referral rates, appointment completion and results of genetic testing. Using chi-square and ANOVA tests, we analyzed the association of demographic and clinical factors with eligibility and referral to genetic counseling. Results: The average age of diagnosis was 57.1 years old, with 68.7% of women diagnosed with stage I-III disease, and 31.3% diagnosed with stage IV disease. There were 91 (60.7%) women who met NCCN criteria for genetic testing, of which 46.2% ultimately underwent genetic testing. Eligible women were more likely to be younger (52.6 vs. 64.0 years old), White (75.0% vs. 54.5%), and have Medicaid (75.0%) or private insurance (72.9%) vs. Medicare (44.8%). Women who met NCCN criteria were 3.5 times more likely to be referred for genetic counseling than those that did not meet eligibility criteria. Women were also more likely to be referred if they had early-stage disease compared to stage IV (67.8% vs. 48.3%), and Medicaid or private insurance compared to Medicare (71.4%, 72.0% and 40.0%, respectively). Of eligible women, 59.3% had a genetic counseling appointment scheduled, and of those, 78.0% attended their appointment. There were no apparent differences in appointment completion based on race with similar percentages of Black and White women completing their appointments (74.0% and 77.0% respectively). Women with stage IV disease were more likely to complete their appointments (83.0%) compared to women with stages I-III (74.0%) and fewer women with Medicare completed their genetic counseling appointment (56.0%) compared to women with Medicaid (83.0%) and women with private insurance (83.0%). Among women who attended their appointment, 95.9% underwent genetic testing. Of women who had genetic testing, 8.5% had a pathogenic variant and 30.4% had a variant of unknown significance. Conclusions: The results of this study indicate that lack of genetic counseling referrals contribute to a gap between the need for and completion of genetic testing. By understanding barriers to genetic counseling and testing, future clinical initiatives could effectively improve accessibility to genetic counseling services.
Closing the gap: Trends in inconclusive rates on hereditary cancer testing across racial/ethnic groups.
Authors: Ademuyiwa Foluso Olabisi , Horton Carrie , LaDuca Holly , Komala Timothy , Profato Jessica , Pesaran Tina , Couch Fergus
Published: June 2021

10525

Background: Several groups have described disparities in genetic test results for inherited breast cancer predisposition, with a disproportionate number of variants of unknown significance (VUS) reported in non-Caucasian individuals. These disparities are due in part to the underrepresentation of non-Caucasians in reference databases and clinical genetic testing cohorts. Over the past few years, diversification efforts have been made however, little data exists on how ethnicity- and gene-specific VUS rates have changed over time and whether such disparities have improved or worsened. Methods: We retrospectively reviewed demographic information and test results for individuals who underwent hereditary cancer multigene panel testing between March 2012 and September 2020 at a single laboratory. Individuals who self-reported as African American, Asian, Caucasian, or Hispanic on the test requisition form and whose testing included ATM, BRCA1, BRCA2, CHEK2 and PALB2 (five commonly tested breast cancer predisposition genes with management guidelines) were included in the study (n = 284,130). The frequency of germline variants of unknown significance (VUS) in the five genes was assessed in September 2015 and September 2020. Results: Amongst patients tested between March 2012 and September 2015, 82.8% of the study cohort self-reported as Caucasian and 17.2% were not Caucasian (6.5% African American, 6.0% Hispanic, and 4.6% Asian). The proportion of non-Caucasian individuals in the study cohort increased slightly by September 2020 to 22.8% (77.2% Caucasian, 9.2% African American, 8.4% Hispanic, and 5.3% Asian). Consistent with previous reports, Caucasians had the lowest VUS rate overall in both 2015 and 2020. This was also true at the individual gene level, with the exception of CHEK2. Over time, we observed a relative decrease in VUS rates across all ethnicities. Between 2015 and 2020, the overall VUS rate for the five included genes in non-Caucasian individuals was reduced by 32.0% in non-Caucasians compared to 23.6% in Caucasians. The absolute difference in VUS rate between non-Caucasians and Caucasians decreased from 7.9% in 2015 to 4.5% in 2020. Conclusions: While VUS rates for commonly tested breast cancer predisposition genes remain higher in non-Caucasians relative to Caucasians, our results demonstrate that this gap has been reduced over a five-year time period. These findings may be indicative of efforts by clinicians and laboratories to reduce these disparities. Further studies are necessary to improve the clinical utility of genetic testing in under-represented populations.[Table: see text]
Rare BAP1 variant of unknown significance (VUS) and analysis of BAP1 codon 146 genomics: Potential germline and therapeutic implications.
Authors: Murphy Jo-Ellen , Sadan Sara , Lee Jessica Kim , Pruski-Clark Jana , Sutphen Rebecca , McGregor Kimberly
Published: June 2021

10533

Background: The BAP1 gene ( B RCA1-Associated Protein) encodes a protein ubiquitin carboxyl-terminal hydrolase (BAP1), which removes ubiquitin moieties and regulates various cellular functions including DNA repair. This association has driven interest in defining if BAP1 variants confer susceptibility to PARP inhibitors (PARPi). Germline and somatic BAP1 alterations are both rare, mostly unique, often classified as VUS’s, and associated with a broad range of overlapping tumor types. Based on the identification of a BAP1 R146K VUS variant in tumor, also previously identified as germline, an analysis of BAP1 codon 146 alterations was initiated to explore potential genetic and therapeutic implications. Methods: 394,756 tumor specimens were tested using hybrid capture-based genomic profiling (Foundation Medicine) for all variant types and Tumor Mutational Burden (TMB). BAP1 codon 146 cases were analyzed for clinicogenomic features and germline results when available. Results: BAP1 codon 146 variants were identified in 23 unique patients across the following tumor types: cholangiocarcinoma (CCA) (4), mesothelioma (4), NSCLC (3), RCC (2), ocular melanoma (2), and carcinoma of unknown primary (CUP) (3); many of which overlap with known and suspected germline associated BAP1 syndromic tumor types. BAP1 R146 mutations were classified as VUS in 16 patients and 7 were likely or known pathogenic. In 20 of the 23 cases where zygosity could be determined 16 (80%) were homozygous and 4 (20%) were heterozygous. In 2 of the 3 NSCLC cases, the BAP1 variant appeared likely somatic and/or associated with a high TMB. A previously reported germline BAP1 variant in a RCC patient, R146K, occurred 5 times in our tumor database. One case which was homozygous in tumor and confirmed in germline occurred in a patient who had both breast and CCA. She also had a sibling with RCC who shared the germline BAP1 R146K variant along with multiple 1st and 2nd degree relatives with RCC, mesothelioma, melanoma, liver cancer, colon cancer, and a cancer of unknown primary. Conclusions: Codon 146 of BAP1 localizes to the UCH (ubiquitin carboxyl hydrolase) domain, which includes the BARD1 interaction region. Loss of BAP1 activity as a consequence of germline or somatic mutation likely impacts ubiquitination status and activity of downstream proteins, such as those involved in DNA repair. For patients with suspected BAP1 inactivating alterations, often seen in non-homologous recombination deficiency related tumor types, PARPi therapy may be relevant. As demonstrated here, variants identified through tumor testing may also aid in re-classification of germline VUS’s. These results support the further investigation and validation of BAP1 alterations for germline risk stratification and therapeutic strategies with either PARPi and/or other therapies specific to tumors with impaired chromatin remodeling.
Genetic ancestry and clinical outcomes to immune checkpoint inhibitors among seven common cancers.
Authors: Nassar Amin , Adib Elio , Abou Alaiwi Sarah , Akl Elie , El Zarif Talal , Nuzzo Pier Vitale , Mouhieddine Tarek H. , El-Khoury Habib , Groha Stefan , Sonpavde Guru P. , Haddad Robert I. , Mouw Kent William , Giannakis Marios , Ananda Guruprasad , Freedman Matthew L. , Kwiatkowski David J. , MacConaill Laura E , Choueiri Toni K. , Gusev Alexander
Published: June 2021

10536

Background: Prior studies and clinical trials report associations between self-reported race and clinical outcomes to Immune Checkpoint Inhibitors (ICIs). However, comprehensive studies of ancestry-associated differences in clinical outcomes have not been performed. We derived genetic ancestry scores and assessed clinical outcomes in 1341 patients with cancer treated with ICIs. Methods: Patients at the Dana-Farber Cancer Institute treated with ICIs only and with relevant cancer types and targeted exome sequencing data (Oncopanel) were included. Relevant cancer types included colorectal adenocarcinoma (CRC), esophagogastric adenocarcinoma (EGC), head and neck squamous cell carcinoma (HNSCC), melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and urothelial carcinoma (UC). We developed a bioinformatics pipeline to infer fine-scale genetic ancestry for each patient (n=1341) directly from tumor sequencing data by leveraging off and on-target sequenced reads and external ancestry reference panels. Three ancestry scores were determined (African, East Asian, European). Overall survival (OS) and time-to-treatment failure (TTF) were compared by Cox logistic regression between ancestral populations. Hazard ratio (HR) was derived using multivariable analysis, adjusted for single versus combination therapy, prior lines of therapy, and tumor mutational burden (TMB, as percentiles). Results: Median follow-up was 37.8 months (m; interquartile range: 35.7-39.5m). Common cancer types included CRC (n=52), EGC (n=114), HNSCC (n=88), melanoma (n=274), NSCLC (n=571), RCC (n=99), and UC (n=143). A higher East Asian ancestry (EAS) was significantly associated with worse OS ( p=0.03) and TTF ( p=0.002) in patients with RCC, independent of the histologic subtype (Table). There was no significant association between any of the three ancestral populations and clinical outcomes in the other 6 cancer types. Conclusions: We described clinical outcomes to ICIs across three global populations in 7 cancers. As the medical field re-evaluates the use of self-reported race in clinical decision-making, we utilize a novel ancestry pipeline that can be readily applied to tumor-only sequencing panels and better characterize non-white populations. We find no ancestry differences in clinical outcomes except in patients with RCC treated with ICIs which will require future validation. We plan to analyze genomic correlates of response by ancestry in each of the cancer types to better understand these diverge clinical behaviors.[Table: see text]
Analysis of breast cancer screening results in urban areas of Henan Province.
Authors: Lan-Wei Guo
Published: June 2021

10543

Background: Breast cancer is the most common female cancer in China. Reasonable and effective screening is an important means to reduce the mortality of breast cancer. This study was to evaluate the compliance and efficacy of breast cancer screening in urban areas of Henan province from 2013 to 2019. Methods: A cluster sampling method was used to select the residents of 40-74 years old in Henan province to investigate the risk factors and breast cancer risk assessment. For subjects with high risk of breast cancer, those aged 40-44 conduct breast ultrasound examination; those aged over 45 conduct breast ultrasound combined with mammography examination. BI-RADs classification was used as the evaluation standard in both examinations. BI-RADS 3 class was defined as suspicious and BI-RADS≥4 class was defined as positive. Chi-square test was used to analyze the compliance rate and breast cancer detection rate among different groups. Results: A total of 29 111 residents at high risk for breast cancer were recruited in this study. They were 55.03 ± 7.91 years old, of which 13 760 took the following breast ultrasound or mammography examination, yielding a participation rate of 47.27% (13 760/29 111). The detection rates of suspected positive patients, positive patients and breast cancer patients were 23.40% (3 220/13 760), 2.55% (351/13 760) and 0.30% (41/13 760), respectively. Among the screening population, the highest detection rate of suspected positive patients was found in the 45-49 age group [27.79% (935/3 365)], the highest detection rate of positive patients was found in the 50-54 age group [2.98% (97/3 257)], and the highest detection rate of breast cancer was found in the 65-69 age group [0.49% (5/1 012)]. The detection rate of breast cancer positive patients by breast ultrasound combined with mammography examination was 2.95% (316/10 728), which was significantly higher than that of breast ultrasound alone [1.99% (213/10 728)] or mammography examination alone [1.25% (134/10 728)]. Conclusions: Breast ultrasound combined with mammography examination as a means of screening for breast cancer can significantly increase the detection rate of breast cancer positive patients. The next step should be to improve the compliance of the population, as well as the organization's implementation and service capabilities of the screening provider, to improve screening effectiveness.
Interactive online skin cancer training game “Whack-a-Mole” assesses training strategies and real-time feedback on melanoma identification among U.S. adults.
Authors: Sanchez Margaret , Carcioppolo Nicholas , Kim Soyoon , Lun Di , Malova Kate , Mao Bingjing , Reynolds Ashley Renee , Ewing Clay , Hu Shasa
Published: June 2021

10564

Background: Cutaneous melanoma is a deadly form of skin cancer. Several studies have shown that early melanoma detection is associated with decreased mortality through self-examination and dermatology full-body skin exams. ABCD rule and the ugly duckling sign (UDS) are used to identify melanomas, but little research has explored the comparative efficacy of these approaches. This investigation compares the effectiveness of different mole identification training strategies and explores the effect of real-time feedback on decision-making. Methods: We developed an online melanoma identification game that tests differences between training types and expert feedback on mole identification. This online RCT tests a 4 (training: ABCD, UDS, both, control) X 3 (feedback: standard, motivational, control) factorial design on melanoma identification, skin cancer beliefs (perceived susceptibility and self-efficacy), and skin cancer prevention intentions. Standard feedback included expert evaluations of moles, whereas motivational feedback added statements grounded in fear appeals theory to encourage skin self-examination. An online research panel service was used to recruit 1025 US adults. Participants were randomly assigned to condition, completed a pretest, participated in the game intervention, and completed a posttest. Gameplay incorporates the same mechanics as Tinder (swipe left on benign moles and swipe right on malignant moles). Results: In total, participants reviewed 48 moles, 12 of which were melanomas. We used two-way ANCOVA for the analysis. ABCD training resulted in significantly higher melanoma identification than the control ( p =.011). Every training type resulted in significantly higher self-efficacy than the control ( p =.007). Additionally, there was a significant main effect of feedback on self-efficacy ( p =.001), where both standard and motivational feedback elicited significantly higher levels of self-efficacy than the control condition. Around 88% of participants intend to conduct skin self-exams and wear sunscreen. Conclusions: Our data suggests that “Whack a Mole” is an efficacious tool for melanoma training. ABCD and UDS training with interactive feedback are important to improve accuracy and ability for melanoma identification.
Outcomes for cancer patients on systemic anti-cancer therapies during the COVID-19 pandemic from the CAPITOL (COVID-19 Cancer PatIenT Outcomes in North London) cohort study.
Authors: Crolley Valerie , Hanna Daire , Joharatnam-Hogan Nalinie , Chopra Neha , Bamac Ekin , Desai Meera , Lam Yuk-Chun , Dipro Sabiq , Kanani Ruhi , Benson Jack , Wilson William , Fox Thomas Andrew , Shiu Kai-Keen , Forster Martin , Bridgewater John A. , Hochhauser Daniel , Khan Khurum Hayat
Published: June 2021

10567

Background: One of the major challenges with COVID-19 has been the changes to cancer services, including changes to the type of systemic anti-cancer treatment being delivered to patients. There needs to be a better understanding of which cancer patients are at the greatest amount of risk to make informed decisions on how cancer treatment can be altered to protect patients from COVID-19 infection. The CAPITOL (COVID-19 CAncer PatIenT Outcomes in North London) study investigated the outcomes of patients receiving systemic anti-cancer therapies (SACT) with regards to COVID-19 infection, as patients with cancer are hypothesised to be at higher risk. Methods: CAPITOL collected data from all patients receiving SACT at two cancer centres. The effect of clinical characteristics on the incidence and severity of COVID-19 infection in patients on SACT was the primary outcome, and we used univariable and multivariable models in our analysis, adjusting for age, gender and comorbidities. Results: 2871 patients were analysed from 2nd March to 31st May 2020, all of whom received SACT; during this time period 68 (2.4%) were diagnosed with COVID-19. Receiving SACT increased the risk of death when contracting COVID-19 (adjusted (adj.) OR 9.84; 95% CI 5.73 – 16.9). The risk of contracting COVID-19 was increased by receiving chemotherapy (adj. OR 2.99; 95% CI = 1.72 - 5.21), with the risk significantly increased by high dose chemotherapy (adj. OR 2.36, 95% CI 1.35 – 6.48). Patients with comorbidities (adjusted OR 2.29; 95% CI 1.19 - 4.38), or with a respiratory or intrathoracic neoplasm (adj. OR 2.12; 95% CI 1.04 - 4.36) were also at increased risk of contracting COVID-19. Cancer patients who received targeted treatment had a reduced risk of contracting COVID-19 (adj. OR 0.53; 95% CI 0.30 – 0.95), while there was no significant change in risk caused by treatment intent (curative versus palliative), hormonal- or immunotherapy and solid versus haematological cancers. Conclusions: To the best of our knowledge, this is one of the first investigations into the risk of contracting COVID-19 in a cohort of all cancer patients on SACT. We found that patients on SACT are more likely to die if they contract COVID-19. The type of SACT received by cancer patients can affect their likelihood of contacting COVID-19, with chemotherapy increasing risk, targeted therapy decreasing risk and a potential protective effect for hormonal and immunotherapy.
Trends in incidence and mortality of squamous cell carcinoma of the skin: An observational analysis of the Global Burden of Disease database from 1990 to 2017.
Authors: Yang Dorothy , Jani Chinmay , Crowley Conor , Goodall Richard , Shalhoub Joseph , Salciccioli Justin D , Marshall Dominic C
Published: June 2021

10569

Background: Epidemiological data relating to non-melanoma skin cancer (NMSC), including squamous cell carcinoma (SCC), is highly under-reported and under-studied due to its lower metastatic potential. In recent years, incidence and prevalence of SCC has increased in many countries due to earlier detection, increased ultraviolet light exposure, as well as increasing life expectancy. This investigation compared trends in SCC incidence, mortality and disability-adjusted life years (DALYs) in 33 countries. Methods: We utilized the Global Burden of Disease (GBD) database for 33 countries, including the European Union nations as well as other selected high-income countries including the UK and USA. We extracted data including age-standardized incidence rates (ASIRs), age-standardized mortality rates (ASMRs) and DALYs for SCC of the skin from 1990 to 2017. Joinpoint regression analysis was used to describe the trends. Results: For both sexes, the highest ASIRs were seen in the USA and Australia: ASIRs were 362.8/100,000 and 283.7/100,000 respectively for males, and 171.2/100,000 and 152.4/100,000 respectively for females. Males had higher ASIRs than females at the end of the observation period in all countries. In contrast, the highest ASMRs for males were observed in Australia (2.77/100,000) and Latvia (2.44/100,000), while the highest ASMRs for females were observed in Romania (0.95/100,000) and Croatia (0.90/100,000). The highest DALYs for both sexes were seen in Australia and Romania: DALYs were 58.4/100,000 and 43.8/100,000 respectively for males, and 16.9/100,000 and 14.9/100,000 respectively for females. Over the observation period, there were more countries demonstrating decreasing trends in mortality than in incidence. There was also a disparity between which countries had comparatively high mortality rates and which had high incidence rates – for instance, the USA, which had by far the highest SCC incidence rates, had among the lower mortality rates. Overall reductions in DALYs were observed in 24 of 33 countries for males, and 25 countries for females. Conclusions: Over the past 27 years, although trends in SCC incidence have risen in most countries, there is evidence that mortality rates have been decreasing, especially towards the end of the observation period. Overall, burden of disease as assessed using DALYs has decreased in the majority of countries. Future work will explore potential explanatory factors for the observed disparity in trends in SCC incidence and mortality.
A phase Ib study of xentuzumab plus abemaciclib and fulvestrant in patients (pts) with advanced hormone receptor-positive (HR+), HER2-negative breast cancer (BC) with visceral or non-visceral disease.
Authors: Yee Douglas , LoRusso Patricia , Sablin Marie Paule , Prat Aleix , Stradella Agostina , Utriainen Meri , Oliveira Mafalda , Yonemori Kan , Naito Yoichi , Hardebeck Molly Catherine , Puig Marta , Hu Joy , Biyukov Tsvetan Nikolov , Iwata Hiroji
Published: June 2021

1057

Background: Cyclin-dependent kinase (CDK) 4 & 6 inhibitors plus endocrine therapy (ET) are standard of care for advanced HR+ BC. Combining xentuzumab, an insulin-like growth factor (IGF) ligand-neutralizing antibody, with ET and everolimus, suggested progression-free survival (PFS) benefit in pts with advanced HR+ BC and non-visceral disease. Activation of the IGF pathway leads to an increase in cyclin D1, providing a rationale for combining IGF and CDK4 & 6 inhibition. This prospective, open-label study is investigating xentuzumab plus abemaciclib, a CDK4 & 6 inhibitor, with fulvestrant. In dose-finding cohorts, the recommended phase II dose (RP2D) was determined as xentuzumab 1000 mg weekly intravenously plus abemaciclib 150 mg every 12h orally (Q12h). Here, we report preliminary data on disease control rate (DCR) from two expansion cohorts in pts with advanced HR+ BC with visceral (D1) or non-visceral disease (D2). Methods: Postmenopausal women with advanced/metastatic HR+ BC that had progressed on or after ET (including adjuvant ET) were enrolled. Pts could not have received >1 line of ET or any chemotherapy for metastatic disease. No prior CDK4 & 6 inhibitor therapy was permitted. Pts had to have ≥1 documented visceral metastasis in D1 and no visceral metastases in D2. Pts received xentuzumab weekly plus abemaciclib Q12h (at RP2D) plus fulvestrant 500 mg per label. Protocol primary endpoint was PFS rate at 18 months (mos). Secondary endpoints included DCR (complete response [CR], partial response [PR] and non-CR/non-progressive disease [PD] or stable disease [SD] lasting ≥24 weeks [wks]). Results: In D1/D2, 33/31 pts were treated: median age 60/53 years. 19 pts in D2 had bone-only, non-measurable disease. At data cut-off (Jan 2021), median treatment duration was 7.5/9.2 mos in D1/D2; 40 pts remain on treatment. In D1, DCR was 64%: 17 (52%) pts had PR and 4 (12%) had SD lasting ≥24 wks. In D2, DCR was 55%: 5 (16%) pts had PR, 10 (32%) had non-CR/non-PD lasting ≥24 wks and 2 (7%) had SD lasting ≥24 wks. Median duration of disease control was 10.9 mos in each cohort. Some pts had not reached 24 wks; full DCR data will be presented. Most common AEs are shown in the table (≥33% all-grade in either cohort). No hypo/hyperglycemia was reported. Conclusions: Xentuzumab plus abemaciclib and fulvestrant demonstrated encouraging disease control in pts with advanced HR+ BC with visceral and non-visceral disease. The safety profile was manageable, and consistent with the known profiles of the three agents. Clinical trial information: NCT03099174 .[Table: see text]