bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of linguistic acculturation on self-efficacy and anxiety in caregivers of Latina breast cancer survivors.
Authors: Schlam Ilana , Campos Claudia , Duron Ysabel , Torres Migdalia , Sampayo Ivis , Graves Kristi D
Published: May 2020

12121

Background: Latina breast cancer survivors and their caregivers face unique challenges. Acculturation is the acquisition of the cultural elements of a dominant society. Higher acculturation in Latino survivors is positively correlated with self-efficacy in patient-provider communication and improved patient-reported outcomes. There is a paucity of research on how language acculturation affects caregiver and patient outcomes. We examined associations over time between linguistic acculturation among caregivers of Latina survivors and outcomes of caregiver self-efficacy and anxiety. Methods: We partnered with four community-based organizations that serve Latino families facing cancer. We enrolled 136 Latina breast cancer survivors and their caregivers for a randomized trial comparing a dyadic coping intervention to usual care (e.g., support groups). Participants completed surveys including demographic and clinical information, the short acculturation scale for Hispanics, caregiver inventory to assess self-efficacy and PROMIS domains of anxiety at baseline and 6-months after the intervention. Results: In multivariate linear regressions models, we examined the effect of acculturation on caregiver self-efficacy and anxiety, controlling for demographics (patient and caregiver age, caregiver education, employment), patient treatment history (chemotherapy and surgery) patient and caregiver language preference (Spanish or English) and intervention arm (intervention vs. usual care). Greater caregiver self-efficacy at 6-months was associated with younger patient age (t=-2.93, p=.004), older caregiver age (t=2.63, p = .01), female caregiver gender (t=2.79, p = .006) and higher acculturation (t=2.01, p=.04), controlling for baseline self-efficacy, patient language and randomization group. Caregiver anxiety was not related to caregiver acculturation or patient language preferences. Conclusions: Caregivers’ language acculturation was significantly associated with their self-efficacy over time, suggesting that caregivers with lower acculturation experience lower confidence in their provision of care for Latina survivors. These findings are particularly salient because participants for this study were enrolled from organizations with bilingual services. Caregivers of Latina survivors without access to these community resources may face even more striking challenges. Future work can explore how caregivers’ confidence relates to survivors’ adherence to care and patient outcomes over time.
Enhanced coping and self-efficacy in caregivers of hematopoietic stem cell transplant (HCT) recipients: Identifying mechanisms of a multimodal psychosocial intervention.
Authors: Elyze Madeleine , Jacobs Jamie M. , Nelson Ashley , Traeger Lara , Jagielo Annemarie , Greer Joseph A. , Temel Jennifer S. , El-Jawahri Areej
Published: May 2020

12122

Background: A brief multimodal psychosocial intervention (BMT-CARE) for caregivers of HCT recipients demonstrated promising efficacy for improving caregiver quality of life (QOL), mood, coping skills, and self-efficacy. We examined whether improvements in coping and self-efficacy mediated the intervention effects on QOL and mood. Methods: We conducted a randomized clinical trial of BMT-CARE for caregivers of patients undergoing autologous or allogeneic HCT at a single institution. Caregivers were randomly assigned to BMT-CARE or usual care. BMT-CARE was tailored to the HCT trajectory and integrated treatment-related education and self-care with cognitive-behavioral skills and caregiving-specific strategies to promote coping. Caregivers completed self-report measures of QOL (CareGiver Oncology QOL), depression and anxiety symptoms (Hospital Anxiety and Depression Scale), coping skills (Measure of Current Status), and self-efficacy (Cancer Self-Efficacy Scale-Transplant) at enrollment and 60 days post-HCT. We used causal mediation regression models to examine whether changes in coping and self-efficacy mediated intervention effects on QOL, depression and anxiety symptoms. Results: Caregivers randomized to BMT-CARE reported improved self-efficacy (adjusted means: 156.20 vs. 147.06, P=0.023) and coping skills (adjusted means: 36.54 vs. 25.41, P<0.001). Improved coping and self-efficacy partially mediated the intervention effects on 60-day QOL (indirect effect=6.93, SE=1.85, 95% CI [3.71, 11.05]). Similarly, improved coping and self-efficacy partially mediated reductions in 60-day depression and anxiety symptoms (indirect effect depression=-1.19, SE=0.42, 95% CI [-2.23, -0.53]; indirect effect anxiety=-1.46, SE=0.55, 95% CI [-2.52, -0.43]). Combined improvements in coping and self-efficacy accounted for 67%, 80%, and 39% of the total intervention effect on QOL and depression and anxiety symptoms, respectively. Conclusions: A brief multimodal intervention for caregivers of HCT recipients may improve QOL and mood by enhancing coping skills and self-efficacy. These findings offer important insights into the mechanisms by which caregiver-directed interventions may enhance caregiver QOL and reduce their psychological distress.
Targeted therapy based on germline analysis of tumor-normal sequencing (MSK-IMPACT) in a pan-cancer population.
Authors: Stadler Zsofia Kinga , Maio Anna , Kemel Yelena , Sheehan Margaret , Salo-Mullen Erin E. , Cadoo Karen Anne , Carlo Maria Isabel , Latham Alicia , Walsh Michael Francis , Drilon Alexander E. , Berger Michael F. , Solit David B. , Birsoy Ozge , Mandelker Diana , Diaz Luis A. , Offit Kenneth , Robson Mark E.
Published: May 2020

1500

Background: Tumor mutational profiling for identification of somatic alterations for targeted treatment is increasingly being performed in advanced cancer patients (pts). We sought to assess the clinical utility of germline mutation profiling for targeted therapeutic interventions in a pan-cancer patient population. Methods: All pts who had germline genetic testing through a prospective protocol via a next-generation sequencing panel (MSK-IMPACT) were identified (N=11,975) from 2015-5/2019. The medical record of pts with likely pathogenic/pathogenic germline (LP/P) alterations in genes with known therapeutic targets were reviewed to identify germline-targeted treatment either in a clinical or research setting. Results: We identified 2,043 (17.1%) pts who harbored LP/P variants in a cancer predisposition genes including 777 (6.5%) in genes with potentially targetable therapeutic implications: 416 BRCA1/2, 149 DNA mismatch repair genes (Lynch syndrome, LS), 122 ATM, 45 PALB2, 26 RAD51C/D, 7 RET, 4 TSC, 3 PTCH1, 2 ALK, 1 EGFR, 1 MET and 1 KIT. Of those with advanced disease (n=554), 45.3% received targeted therapeutic treatment (Table) including 50.9% BRCA1/2, 58.3% LS (67.4% of microsatellite-high LS cases), 41.7% PALB2, 36.8% RAD51C/D and 19.3% ATM carriers. Of patients receiving a poly (ADP-ribose) polymerase inhibitor (PARP-I) in the setting of a BRCA1/2 mutation, 55.1% had breast or ovarian cancer; however, 44.8% had other tumors, including pancreas, prostate, bile duct, gastric, wherein the drug was given in a research setting. Among PALB2 pts receiving PARP-Is, 53.3% (8/15) had breast or pancreas cancer; 46.7% had cancer of the prostate, ovary or unknown primary. Conclusions: In our pan-cancer analysis, 6.5% of pts harbored a targetable germline variant highlighting the importance of germline analysis in advanced cancer pts for selection of both FDA-approved treatments and clinical trial participation with germline-targeted therapeutics. [Table: see text]
Comprehensive breast cancer (BC) risk assessment for CHEK2 carriers incorporating a polygenic risk score (PRS) and the Tyrer-Cuzick (TC) model.
Authors: Gallagher Shannon , Hughes Elisha , Kurian Allison W. , Domchek Susan M. , Garber Judy Ellen , Probst Braden , Morris Brian , Tshiaba Placede , Rosenthal Eric Thomas , Roa Benjamin , Wagner Susanne , Gutin Alexander , Weitzel Jeffrey N. , Lanchbury Jerry , Robson Mark E.
Published: May 2020

1504

Background: Women with pathogenic variants in the moderate penetrance CHEK2 gene have on average an estimated > 20% lifetime risk for breast cancer, thereby meeting an established threshold for more aggressive screening, including consideration of breast magnetic resonance imaging (MRI). However, we previously showed that CHEK2 penetrance is modified by an 86-SNP PRS. CHEK2 risk is further modified by family history (FH) and other TC model variables. Here, we describe development of a comprehensive risk prediction model for women of European ancestry to more precisely estimate risk by incorporating CHEK2, PRS and TC V7.02. The number of CHEK2 carriers with low ( < 20%), moderate (20%-50%) and high ( > 50%) remaining lifetime risk based on the combined model was examined in an independent study cohort. Methods: This IRB-approved study included de-identified clinical records from 358,471 women of European ancestry who were tested clinically for hereditary cancer risk with a multi-gene panel. Model development was based on analysis of CHEK2 PV carriers ( N= 4,331) and women negative for BC gene PV ( N =353,681) who were tested between September 2013 and July 2019. Risk estimates incorporating CHEK2, PRS and TC were calculated using a fixed-stratified (FS) method that accounts for correlations between risk factors in a manner equivalent to multivariable co-estimation. Risk stratification was assessed in an independent cohort of CHEK2 carriers ( N= 459) who were tested after July 2019 and not included in model development. Results: We detected significant correlation of CHEK2 status with FH ( p= 4.1 × 10−17) and of PRS with FH among CHEK2 carriers ( p= 1.7× 10−5). For these factors, joint effects were co-estimated using the FS method. In an independent cohort, 24.0% of CHEK2 carriers were categorized as low risk ( < 20%), and 62.6% were categorized as moderate risk (20-50%). For 13.4% of CHEK2 carriers, risk estimation incorporating PRS and TC generated BC risks of greater than 50%, consistent with genes recognized as highly penetrant. Conclusions: In CHEK2 PV carriers, comprehensive risk assessment could inform individualized decision-making and may lead to improved targeting of screening and prevention strategies.
Uptake of oophorectomy in women with findings on multigene panel testing: Results from the Prospective Registry of Multiplex Testing (PROMPT).
Authors: Domchek Susan M. , Brower Jamie , Symecko Heather , Marcell Vanessa , Walsh Michael Francis , Hamilton Jada G. , Couch Fergus , Offit Kenneth , Garber Judy Ellen , Robson Mark E.
Published: May 2020

1508

Background: With the expansion of multigene panel testing for cancer susceptibility, increasing numbers of patients are identified with pathogenic/likely pathogenic variants (P/LP V) in genes which do not have a clearly actionable increased risk of ovarian cancer (OC) (lifetime risk of OC >5%). However, there is concern that patients and/or providers may ascribe OC risk to such genetic findings with the potential for unnecessary oophorectomy (ooph). Methods: The Prospective Registry of Multiplex Testing (PROMPT) is an online registry for individuals with a genetic alteration detected on multiplex panel testing for cancer susceptibility. Participants self-enroll and complete baseline and annual follow-up questionnaires. PROMPT has enrolled 7388 participants (6936; 93.9% women) since September 2014. Results: 1566 women in the PROMPT registry reported ooph, the indications for which were reported as either cancer treatment (n=481, 30.7%) or benign disease (n=432, 27.6%). An additional 186 (12.8%) reported PV in genes associated with lifetime OC risk >5% ( BRCA1, BRCA2, RAD51C, RAD51D, BRIP, or Lynch syndrome genes). The remaining 467 did not have guideline based indications for ooph due to OC risk and are described further here. 92 (19.7%) had a variant of uncertain significance (VUS) in genes associated with OC, 241 (51.6%) had a personal history of breast cancer (BC) and no VUS in OC genes, and 119 (25.5%) had no personal history of BC and no VUS in OC genes. The majority of women had no family history (FH) of OC in first or second degree relatives (Table). Most ooph occurred prior to age 50. Of the 405 women with CHEK2 P/LP, 11.4% reported ooph (59% under age 50 when age known), as did 13.2% (of 228) with CHEK2 VUS, 8.8% (of 261) with ATM P/LP (66.7% under age 50), and 8.3% (of 387) with ATM VUS. In addition, of the 184 women with PALB2 P/LP, 14.1% reported ooph (35.3% under age 50) as did 11.6% (of 198) with PALB2 VUS. Of those who reported provider discussions, 47.2% stated “my provider recommended this” (including >60% in the OC gene VUS group) and an additional 25.2% stated “my provider presented this as an option, but not a requirement”. In those with no FH of OC, 45.8% stated that their provider recommended ooph. Conclusions: 10-15% of women with PV/VUS in genes not associated with a high risk of OC reported ooph without a clear indication. [Table: see text]
The impact of tumor NGS testing on hereditary cancer risk assessment and population management in an integrated community health care system.
Authors: Thomas Sachdev P. , Suga Jennifer Marie , Truong Thach-Giao , Sundaresan Tilak Kumar , Pan Minggui , Kim Won , Jiang Chen , Hoodfar Elizabeth , Chung Elaine , Tse Pamela , Achacoso Ninah , Cheng Lirong , Habel Laurel A.
Published: May 2020

1517

Background: Next-generation sequencing (NGS) for tumor molecular profiling is used in Oncology to identify ‘actionable alterations’ for clinical trials or on/ off-label therapy. Tumor NGS can also reveal potentially heritable germline mutations. The frequency of such incidental germline mutations has been estimated to be 4-15%. The 2015 ASCO Statement supports communication of medically relevant incidental germline findings from somatic mutation profiling to patients (PTS). The impact of tumor NGS testing on hereditary cancer risk assessment programs in the context of a wider population management strategy is unknown. We sought to evaluate this within our Kaiser Permanente Northern California (KPNC) population with ready access to tumor NGS and an ongoing hereditary cancer risk assessment program. Methods: Kaiser Permanente Northern California (KPNC) is part of a large, integrated health care system. NGS at KPNC is performed in collaboration with STRATA Oncology, a precision oncology partnership. All NGS results are reviewed by a multidisciplinary KPNC Genomic Oncology Committee (GOC)which also includes genetic counselors and pathologists. We examined all NGS reports between November 2017 through December 2019 to determine the types of cancers tested, number with a possible germline mutation and number referred for genetic counseling and testing (GCT). Results: 4,825 PTS with advanced cancer underwent STRATA NGS testing. A total of 207 PTS (4.3%) were identified as potential germline mutation carriers, all 207 were recommended for GCT referral. Of these, 92 (45.0%) separately met 2020 NCCN Criteria for Genetic/Familial High-Risk Assessment (2020NG/FA), prior to tumor NGS; 115 (53.6%) did not and 3 (1.4%) had insufficient information. The cancers most frequently meeting NCCN criteria were pancreatic, breast and colon. Of the 92 PTS who met 2020NG/FA, 60 (65%) underwent GCT and 34 (57%) were confirmed to have a germline mutation. Of the 115 PTS that did not meet 2020NG/FA, 47 (41%) underwent GCT and 19 (40%) were confirmed to have a germline mutation. Overall germline mutations were confirmed in 16.5% of patients who did not meet 2020NG/FA and 37% who did. Conclusions: In our community-based integrated healthcare system, systematic review of next-generation sequencing results by an expert GOC led to more robust identification of germline mutation carriers and navigated them to appropriate GCT. Ongoing work will clarify data on cascade testing. We are currently developing automated workflows for GCT.
Characterization of clonal hematopoiesis of indeterminate potential mutations from germline whole exome sequencing data.
Authors: Wu Hsin-Ta , Kalashnikova Ekaterina , Mehta Samay , Salari Raheleh , Sethi Himanshu , Zimmermann Bernhard , Billings Paul R. , Aleshin Alexey
Published: May 2020

1525

Background: Clonal hematopoiesis of Indeterminate Potential (CHIP) is an age-related phenomenon where somatic mutations accumulate in cells of the blood or bone marrow. It is a source of biological noise that causes false-positives in ctDNA analysis and is present in up to 20% of individuals over the age of 70. The presence of CHIP has been linked to an increased risk of hematologic cancers and cardiovascular disease. The Signatera assay filters CHIP mutations through tumor tissue and germline sequencing thereby reducing false-positive results and focuses on tumor-specific mutations for each patient. Methods: Whole exome sequencing data (average depth ~250x) analyzed from patients’ buffy coat (n = 159) was used to characterize CHIP mutations. Variant calling was performed using Freebayes variant caller with allele frequency threshold between 1% and 10%. Following which variant annotation and selection was performed based on the top 54 genes that are most implicated in myeloid disorders. The selected variants were further screened based on the reported variants in the literature and/or the Catalog of Somatic Mutations in Cancer (COSMIC). Results: The analysis revealed an average of 0.14 (0-2) CHIP mutations per patient with an average variant allele frequency of 3.49% (1%-8.5%). The most common CHIP mutations were observed in DNMT3A, (n = 17), TET2 (n = 7) and TP53 (n = 7) genes. The percentage of patients with at least 1 mutation found in DNMT3A, TET2, and TP53 were 4.2%, 1.94%, and 1.38%, respectively. Other genes containing CHIP mutation included CEBPA, ETV6, HRAS, PDGFRA, NRAS, KMT2A, EZH2, GATA2, GNAS at a frequency below 1%. CHIP mutations were not observed in patients younger than 40 years, but they increased in frequency with every decade of life thereafter. The incidence of CHIP increased from 0.04 for the 40-50 yrs age group to 0.18 for individuals older than 60. Further analysis of associations between incidence of CHIP and cancer type, prior exposure to chemotherapy as well as longitudinal evolution of CHIP mutations during cytotoxic treatment are underway and will be presented. Conclusions: CHIP, a common finding in the elderly population is an important factor to consider in ctDNA analysis and most frequently involves DNMT3A, TET2, and TP53 genes. The frequency of CHIP can be impacted by a number of other factors such as cytotoxic chemo- or radiotherapy.
Evaluating the association between clonal hematopoiesis and germline pathogenic and likely pathogenic variants in cancer predisposition genes.
Authors: Comen Elizabeth Anne , Razavi Pedram , Patel Parth Bhargav , Martin Axel , Seshan Venkatraman E. , Mandelker Diana , Ptashkin Ryan , Kemel Yelena , Stadler Zsofia Kinga , Ladanyi Marc , Berger Michael F. , Zehir Ahmet , Robson Mark E. , Reis-Filho Jorge S. , Norton Larry , Levine Ross L.
Published: May 2020

1535

Background: Clonal hematopoiesis (CH) is most commonly associated with mutations in genes with a known or putative role in leukemia and with an increased risk for hematologic malignancies. Nearly 50% of primary breast cancers contain leukocytes with CH mutations and CH mutations can be found in breast cancer (BC) tumor infiltrating leukocytes years prior to the development of secondary leukemia. It is currently not known whether CH is more prevalent among BC patients with both germline pathogenic variants and likely pathogenic variants (collectively referred to as PV) in cancer predisposition genes. Here we evaluated the relationship of CH to PV in 546 BC patients (pts). Methods: 546 BC pts underwent targeted capture sequencing of tumor and peripheral blood (PB) samples using MSK-IMPACT. Sequencing results from PB were used for identifying PV affecting up to 89 cancer predisposition genes and somatic mutations in 15 genes commonly associated with CH using previously validated methods. All pts consented via an IRB-approved protocol. Results: The majority (82.3%) of pts had non-metastatic disease. 59.7% of the 546 pts received chemotherapy and 42.7% received radiation. Of the 546 pts, 90 patients had germline PV in a cancer predisposition gene for a total of 98 germline PV identified (8 patients had 2 germline PV). Mutations in DNMT3A followed by TET2 were the most common CH mutations identified. CHEK2 PV were statistically significantly associated with CH in a multivariate analysis after controlling for age, prior chemotherapy and radiation therapy (OR: 3.94, CI: 1.51-10.26, p-value ≤0.005). Age by decade was significantly associated with the presence of CH in that model (OR: 1.93, CI: 1.53-2.42, p value ≤0.001). Of the 8 patients with CHEK2 germline PV and CH, the most common mutated CH genes were DNMT3A (4 pts), followed by TET2 (2 pts), although our sample size is too small to test for significant enrichment for any specific CH gene, type of CH mutation, or trinucleotide context. Further, CH was not associated with germline PV in other cancer predisposition genes. Conclusions: Our findings provide evidence of an association between CHEK2 germline PV with CH in BC pts, which will be further tested in an expanded cohort. If this association is confirmed, it might have theoretical and practical implications, including cancer prevention strategies.
Test of an online tool to facilitate NCCN guideline-compliant access to cancer genetics care.
Authors: Milliron Kara J. , Cook Amanda , Keren David , McCain Lynn A. , Schroeder Lee , Hulswit Bailey , Arthurs James , Harper Diane M , Ernst Susan , Zazove Philip , Parvaz Jasmine , Merajver Sofia
Published: May 2020

1542

Background: Minority populations experience inequities of access to cancer genetics. We developed and tested an online family history collection and interpretation tool, InheRET, to determine acceptability, validity and utility.Patients are mostly unable to recall accurate family history in clinic and providers have little time to collect the 3-generation pedigree. Thus, ~90% of high risk patients remain unidentified. We evaluated the impact InheRET has on facilitating National Comprehensive Cancer Network (NCCN) Guideline-compliant referrals for cancer genetic counseling. Methods: Patients from 3 clinics were consented online to participate. A user experience survey for patients and providers followed the health history questionnaire. Results: 628 patients were consented over a year, 555 (>88%) completed the tool. 439 (79%) completed the post-questionnaire user experience. Review of Inheret's recommendations by a genetic counselor found 100% accuracy. Ease of Use: 84-87% of patients reported tool was easy to use. Understandability: 92-97% of patients reported tool was easy to understand. No significant differences were reported between those with high school (n=28, avg age 50.1 yrs) compared to those with advanced degrees (n=139, avg age 45.4 yrs); patients age 70+ experienced increased difficulties. Among primary care patients (n=135), 43 established patients were newly identified as meeting NCCN referral criteria. Healthcare providers found InheRET useful, did not require extra clinical time, and all wish to continue to use it. The patient provided data were more complete and encompassed more family members than with paper forms. Turn-around-times to receive the patient’s information were decreased from 4-6 weeks to ~ 72 hours. A patient scheduling backlog of 400 patients was cleared using InheRET. Previously, 40% of cancer genetics patients were lost to follow up, due to not completing their intake forms. This number was reduced to 6.5%. Conclusions: Patients find InheRET to be easy to use and understand and they complete this health history tool more frequently and in greater detail than by paper forms. InheRET provides accurate results, verified by in person interviews, in a timely fashion, saving clinical time, possibly enabling increase in earned clinical revenues (under analysis), and improving patient care overall. Importantly, the 43 primary care patients identified to be at increased risk were already established patients, who had not been previously identified as such by their healthcare providers as being at increased risk.
Potential germline findings identified during somatic tumor testing: Room for improvement.
Authors: Khan Sundas , Wright Heather , Cuke Melissa , Folefac Edmund , Verschraegen Claire F. , Wood Marie
Published: May 2020

1543

Background: Genomic testing, useful for treatment planning and identification of patients for clinical trials, may indicate the presence of a germline mutation. We sought to evaluate the incidence of potentially actionable germline mutations detected via genomic testing and determined rates of germline testing among patients with potential germline mutations. Methods: This was a retrospective review of patients undergoing genomic testing at The University of Vermont Cancer Center (UVMCC) between 03/02-11/19. Testing was reviewed for mutations in 60 genes associated with hereditary cancer and recognized as clinically actionable by the American College of Medical Genetics. Records were reviewed for clinical follow-up. Positive (pathogenic or likely pathogenic) genomic test results were evaluated with descriptive analyses. Proportions with 95% confidence intervals are presented and comparisons made using a χ2 test. Results: 342 patients underwent genomic testing at UVMCC over the study period, with a median age of 61. Common tumor types include: CNS (19%), NSCLCA (17%), ovarian (8%), and sarcoma (7%). 59% (203/342) had a mutation in ≥ 1 gene associated with hereditary cancer. Most common tumor types with potential germline mutations include: NSCLCA (25%), CNS (18%), ovarian (8%), sarcoma (8%), and endometrial (7%). Potential germline mutations were most commonly identified in TP53, CDKN2A, PTEN, and RB1 (each with mutations in >6% of patients). 58 patients in the cohort have undergone germline testing, of which 19% were positive for germline mutations. Of patients with mutations in the highly penetrant BRCA, PALB2, and Lynch genes, 71% were positive for germline mutations. Young age ( < 50) did not enrich for germline mutations (p > 0.05). Only 18% (36/203) of patients with potential germline results were referred for genetic counseling. Conclusions: Genomic testing can reveal hereditary cancer syndromes. While the majority of patients with tumor mutations in genes associated with hereditary cancer will not have germline mutations, genetic testing is the only way to confirm this. 19% of patients who underwent genetic testing in this cohort had a pathogenic germline mutation. This was enriched to 71% when considering genes rarely mutated in tumors (BRCA, PALB2, and Lynch genes). Only 17% of this cohort underwent genetic testing, representing a significant missed opportunity given the implications of these findings for both patients and families. Patients and their providers should be aware of the potential for germline findings when genomic testing is performed.
Outcome of patients with breast cancer and a germline BRCA mutation in a prospective cohort.
Authors: Arun Banu , Gutierrez Barrera Angelica , Layman Rachel M. , Gruschkus Stephen K. , Bedrosian Isabelle , Albarracin Constance T. , Barcenas Carlos Hernando , Valero Vicente , Litton Jennifer Keating , Tripathy Debu
Published: May 2020

1544

Background: There are limited large prospective single institution studies on outcome of breast cancer in patients with germline BRCA1 and BRCA2 mutation. The primary aim of this study was to determine the effect of a germline BRCA1 or BRCA2 mutation on recurrence-free survival (RFS) and overall survival (OS) in patients with breast cancer. Methods: This is a prospective cohort study of patients with invasive breast cancer recruited from the UT MD Anderson Cancer Center Breast Medical Oncology and Clinical Cancer Genetics Center. For the purpose of this analysis, newly diagnosed breast cancer patients who have had germline BRCA1 and BRCA2 testing within 12 months were included. Clinical and pathological data, and data regarding outcomes were collected in this prospective cohort. The Kaplan-Meier method and corresponding log-rank test were used to estimate OS and RFS and to compare survival by mutation status. Results: Between 1996 and 2015, 3026 patients were recruited. Median age at diagnosis was 45 (19-87) years. A germline BRCA mutation was detected in 361 (11.9%) patients (207 with BRCA1, 154 with BRCA2). After a median follow-up time of 5.3 (0.04-20.7) years, 437 (14.4%) patients recurred and 340 (11.2%) were deceased. At median follow-up time 5 years, 79.3% of BRCA1, 91.4% of BRCA2 and 89.6% of BRCA negative patients were disease free; this difference was significant (p = 0.0001). Difference in OS between BRCA1/2-positive and BRCA-negative patients was also significant (p = 0.0001), with 81.2% of BRCA1, 93.4% of BRCA2 and 90% of BRCA negative patients being alive at 5 years. Amongst 600 patients with triple negative breast cancer (TNBC) patients, DFS and OS were not significantly different between the 3 groups. Of those patients diagnosed under 40 years (n = 937), RFS and OS was significantly different between 3 groups at 5 years (0.001 for RFS and OS); 75% BRCA1, 92% BRCA2 and 86% BRCA negative patients were disease free and 77% BRCA1, 94% BRCA2 and 88% BRCA negative patients were alive. Conclusions: Patients with BRCA1 or BRCA2 mutations have different survival outcomes. The prognosis of the first cancer needs to be taken into consideration when deciding for preventive surgeries to prevent second primary breast cancers in these patients. Furthermore, for BRCA1 mutation carriers more effective therapy strategies need to be evaluated to improve outcome.
Tumor detection rates in screening carriers with SDHx-related hereditary paraganglioma-pheochromocytoma syndrome based on prior tumor history.
Authors: Greenberg Samantha , Jacobs Michelle , Wachtel Heather , Anson Amanda , Buchmann Luke , Cohen Debbie , Bonnani Maria , Bennett Bonita , Naumer Anne , Schaefer Amanda , Kohlmann Wendy , Nathanson Katherine , Else Tobias , Fishbein Lauren
Published: May 2020

1545

Background: Patients with germline pathogenic variants (PVs) in the SDHx genes have increased risk for paragangliomas/pheochromocytomas (PGL/PCC), renal cell carcinomas, and gastrointestinal stromal tumors. Expert recommendation suggests individuals with SDHx PVs undergo biennial whole-body imaging and annual biochemical testing. This study aimed to evaluate tumor detection rate using standard biochemical and imaging protocols for individuals with SDHx PVs, particularly in those with and without SDHx-related tumor history, and in those with biochemical testing data. Methods: A retrospective longitudinal observational study at the Universities of Michigan, Pennsylvania, and Utah Huntsman Cancer Institute was conducted from the start of each center’s screening program through March 1, 2018. Individuals with SDHx PVs had clinical imaging with whole body MRI/CT and biochemical testing per expert recommendation. SDHx-related tumors identified during clinical screening were measured. Results: A total of 263 individuals with SDHx PVs completed 491 screens. Individuals with SDHB PVs were the most prevalent (n = 188, 71.5%). The average number of screens per subject was 1.87 (range 1-7). A majority (n = 194, 73.7%) of individuals did not have a prior history of PGL/PCC. Overall, SDHx-related tumors were detected in 17.1% (n = 45) of the cohort. Of the 46 scans that identified an SDHx-related tumor, 85% of them (n = 39) were baseline scans. SDHx-related tumors were identified in 18.6% (n = 36/194) of individuals that did not have a prior history of PGL/PCC, whereas they were identified in 13.0% (n = 9/69) of individuals that did have a prior history of PGL/PCC (p = 0.39). Biochemical testing was available for 70% (n = 343) of imaging screens, of which 18% (n = 61) had positive biochemistry. Of those with positive biochemistry, 19 tumors were identified on imaging (6%). Sixteen tumors were identified on imaging with negative biochemistry (5%) with a sensitivity of 54% and a specificity of 94%. Utilizing a cut-off of two times the upper limit of normal, 9.91% (n = 34) biochemical tests were positive, and 15 (44.12%) had an SDHx-related tumor on corresponding imaging. Conclusions: Current SDHx screening protocols are effective at identifying SDHx-related tumors. Tumors were detected in subjects with a prior history of PGL/PCC and those with no prior history. This suggests life-long screening is important for all SDHx carriers. Imaging is a crucial piece of SDHx screening given biochemical testing’s sensitivity and specificity.
Non-invasive detection of urothelial carcinoma (UC) by cost-effective low-coverage whole genome sequencing from urine exfoliated cells DNA.
Authors: Zeng Shuxiong , Nai Dongxing , Ye Yingdie , Ji Jiatao , Zhou Zunlin , Wang Baiyun , Ziliang Qian , Xu Changliang
Published: May 2020

1552

Background: Urothelial carcinoma (UC) is a malignancy with frequent chromosomal aberrations. The FISH assays were more sensitive as compared to cytology tests. Here we investigated cost-effective whole genome sequencing technology, which is able to detect all chromosomal aberrations for UC diagnoses. Methods: UC patients and control group are prospectively recruited in trial NCT03998371. First-morning-voided urine were freshly collected before TURBT or cystectomy. Urine Exfoliated Cells DNA was analyzed by illumina HiSeq X10, followed by genotyping by bioinformatics workflow UCAD. Results: 195 individuals were prospectively recruited. 121 UC patients and 67 non-tumor diseases were included in this study. 7 other malignancies as confirmed by pathological testing were excluded. Frequent chromosome copy number changes were found in cancer patients as compared non-tumor controls, including chromosome 3 gain, 17 gain, 7 gain and 9p loss used in FISH assays were found. In addition to that, chr9q loss, 8q gain, 5q loss, 17p loss, 11p loss, 1q gain, 8p loss, 10q loss, 6q loss, 4q loss and 11q loss were also frequent in cancer patients (AUC > 0.65). Metacentric chromosomes showed better AUC compared to acrocentric and telocentric chromosomes (P = 1.7e-03). A novel diagnosis model UCAD was built by incorporating all the chromosomal changes. The model reached performance of AUC = 0.933. At the optimal cutoff |Z| > = 3.16, the sensitivity, specificity and accuracy were 84.7%, 97.9% and 89.0% respectively. The prediction positivity was found correlated with urine microscopy visible epithelial cells (P = 0.00069), tumor invasiveness (Ta/Tis vs the other, P = 0.0048) and tumor grade (P = 0.0030), but not microscopy RBC/WBC findings, urine culture findings, smoke and drinking history. The UCAD model outperformed cytology tests by predicting all 16-cytology positive and 12 cytology negative tumors with comparable specificity. The model found 75.0% more tumors. And UCAD identified more upper urinary tract cancer (P = 0.012) and smaller tumors ( < 3cm, P = 5.9e-04). The adding of cytology to UCAD did not improve diagnosing sensitivity and specificity. UCAD reproduce the diagnoses among morning - void urine, morning, afternoon urine samples with correlation coefficient R2> 0.98. All the urine samples showed high concordances with matched tumor samples (R2> 0.85). Conclusions: UCAD could be a high specific, robust UC diagnoses method with improved sensitivity as compared to cytology tests. Clinical trial information: NCT03998371.
Mammography adherence among medically underserved women undergoing cancer genetic risk assessment.
Authors: Schwartz Candice , Chukwudozie Ifeanyi Beverly , Tejeda Silvia , Vijayasiri Ganga , Abraham Ivy , Remo Mylene Hernandez , Shah Hiral A. , Ferrans Carol Estwing , Warnecke Richard , Hoskins Kent
Published: May 2020

1554

Background: Medically underserved women bear a disproportionate burden of breast cancer (BC) mortality. Early detection is vital for reducing BC deaths. Cancer genetic risk assessment (CGRA) provides an opportunity to identify women at highest risk so that risk-adapted screening can be implemented. The effect of CGRA on mammography adherence among underserved women is unknown. Methods: We conducted a study to test the feasibility of performing cancer genetic risk assessment (CGRA) as part of standard primary healthcare at two Federally Qualified Health Centers in Chicago, IL. Racial/ethnically diverse women age 25-69 without a personal history of BC underwent CGRA at the time of an annual well-visit and received the result from their PCP. Medical record review provided data on mammography adherence. Demographic data and measures of perceived BC risk, BC cultural beliefs, fatalism, and BC worry were collected with an enrollment survey. McNemar’s test compared the rate of adherence to screening mammography before and after implementation of CGRA, defined as completing a screening mammogram within 18 months prior to or following CGRA, resp., among women eligible for screening (age > 40 at study enrollment). Logistic regression models tested for associations between mammography adherence and demographic characteristics/health beliefs. Results: Data was available for 90 participants with increased BC risk (IR) who were eligible for screening and 98 eligible, average risk (AR) participants (in total, 61% black and 37% Latina). Overall, adherence improved from 38% at baseline to 49% following CGRA (p = 0.03). Adherence increased from 35% to 51% among IR participants (p = 0.04), and from 40% to 47% among AR participants (p = 0.39). Data on predictors of adherence will be presented. Conclusions: Implementing CGRA as a standard component of primary healthcare improved adherence to screening mammography among racial/ethnically diverse underserved women. The effect was seen primarily in those with increased risk. This intervention could be used to improve uptake of mammography in the subgroup of underserved women who benefit the most from screening.
Evaluation of a mobile cervical cancer screening program in São Luis, Maranhão, Brazil: Impact and challenges.
Authors: Cossetti Leal Rachel Jorge Dino , Pereira Emanuel Cabral , Ribeiro Thamires Sales , Machado Monalisa Leal Matta , de Carvalho Roseline Braga , Neme Larisa Machado , Alves Deborah Costa , Leal Plinio da Cunha , Brito Luciane Maria Oliveira , Chein Maria Bethânia da Costa
Published: May 2020

1558

Background: Cervical cancer (CC) still represents a public health priority in Brazil, with estimated incidence of 15,43 cases per 100.000 women. CC is the most frequent cause of cancer and cancer-related mortality in women in the state of Maranhão. The Brazilian national screening program recommends cervical cytology (Pap test) every 3 years in women 25-64 years old. Although of public access, the screening program continues to be non-organized. This was a real-life CC screening intervention through a mobile screening unit (MSU) in communities of São Luis, Maranhão. Methods: Prospective, intervention-based, analytic study, from April to August, 2018. Women in the assisted communities were offered Pap tests. Tests were collected and results were retrieved within 4 weeks along with further screening recommendations. Quality control and monitoring of the test were done. A structured questionnaire was applied. Results: 960 tests were collected and 545 women answered the questionnaire. Median age: 43 (34 – 52), with 88.2% of women within the target age. Socioeconomic charachteristics: 47.3% completed high school education; 37.8% were housewives, 16.1% were unemployed; 56.3% were married; 59.8% had a monthly family-income up to 1 minimum wage ($ 250,00). Previous Pap tests and difficulties: 94.1% had at least one previous test; 78,2% had a test within the past 3 years; 48.4% referred to dificculties to scheduling, 23.3% time constraints, 11.2% being ashamed, and 10.4% financial restrains. There were 65 (6.9%) abnormal results (LSIL in 3%, HSIL in 0.7%, and in situ adenocarcinoma in 1 case), for whom further investigation was recommended. Follow-up was possible in 31 of these cases. More than 50% were still awaiting for additional screening tests at time of contact (>6 month interval). Conclusions: MSU strategy faccilitated the access to Pap tests, their results and recommendations. Although Pap test was easily available, the non-organized process of invitation, follow-up and referal of positive cases for further investigation, as offered by the Brazilian public health services, limit screening efficacy and CC control.
Epigenetic control of breast cancer susceptibility.
Authors: Marino Natascia , German Rana , Harikrishna Nakshatri , Podicheti Ram , Vode Ashley , Liu Jun , Huang Jie , Rusch Douglas B , Cao Sha , Storniolo Anna Maria
Published: May 2020

1560

Background: Epigenetic mechanisms such as DNA methylation are important regulators of gene expression and are frequently dysregulated early in breast carcinogenesis. The relationship between DNA methylation aberrations in normal breast tissue and breast cancer risk remains unclear. Methods: Disease-free breast tissue cores donated by 71 high-risk (Tyrer-Cuzick lifetime risk ≥20%) and 79 average-risk women were obtained from the Komen Tissue Bank and processed for whole methylome (Diagenode's MethylCap Library and single-end 75-bp sequencing on Illumina Nextseq) and whole transcriptome (Illumina Nextseq) profiling. Reads from RNA-seq data were aligned to the human genome reference, GRCh38.p12 using STAR v.2.5.2b and tested for differential gene expression using DESeq2 ver. 1.24.0. For DNA methylation data, difference of variation in deduplicated read coverage among 250-bp fixed sized bins spanning CpG islands between high- and average-risk libraries was computed as z-ratios to identify differentially methylated regions. Pathway analysis was performed using IPA v06_01. Results: We identified 1355 CpGs that were differentially methylated between high- and average-risk breast tissues (ΔZ > 0.5, FDR < 0.05). Hypomethylated CpGs were overrepresented in high-risk tissue and were found predominantly (68%) in non-coding regions. Hypermethylated CpG sites were found equally in the gene body and non-coding regions. Transcriptomic analysis identified 112 differentially expressed genes (fold change≥2, FDR < 0.05), involved in chemokines signaling, metabolism and estrogen biosynthesis. Among those, FAM83A (logfc = 2.3, FDR = 0.004) was previously described as epigenetically dysregulated in multiple cancers and transforms breast epithelial cell in vitro. Methylation-expression correlations revealed 11 epigenetically regulated genes including cellular transformation-associated BMPR1B. Two hypomethylated/upregulated long non-coding RNAs were also identified in high-risk breasts. Conclusions: This is the first gene expression/DNA methylation analysis of normal breasts from women at either high or average risk of breast cancer. Our discovery of epigenetically regulated genes associated with breast cancer risk provides an opportunity to mechanistically dissect breast cancer susceptibility and risk-associated molecular alterations. Unlike the current focus of identifying germline mutations or single nucleotide polymorphisms responsible for higher risk, our studies reveal an epigenetic mechanism, which is not discernable through simple genomic sequencing.
Mammography utilization among women with a negative circulating tumor DNA-based early cancer detection test.
Authors: Jones Claire , Parker Alex , Warren Andrew , Vanenkevort Erin A , Gupta Mudit , Lagerman Braxton , Honushefsky Ashley M , Cohain Ariella , Leeming Rosemary , O'Broin-Lennon Anne Marie , Buchanan Adam H
Published: May 2020

1563

Background: Blood-based tests may enable minimally invasive detection of multiple cancer types. One such test, CancerSEEK, employs ctDNA and protein biomarkers for this purpose. Test performance has been evaluated in women without a history of cancer in an ongoing prospective study called DETECT-A. The introduction of such blood tests holds promise, and their future utility lies in augmenting, not displacing, standard-of-care (SOC) cancer screening. One important safety concern is that a negative test result could provide false reassurance that discourages adherence to SOC cancer screening. To investigate this possibility, we studied delivery of mammography to DETECT-A participants before and after receipt of a negative CancerSEEK result. Methods: DETECT-A screened 10,000 women aged 65-75 using CancerSEEK. Participants completed a survey about cancer screening at enrollment and at one-year post-enrollment. We analyzed only those participants who had received a negative CancerSEEK result, were insured by Geisinger Health Plan (GHP), and had completed both surveys. GHP claims data were used to identify mammograms performed within one year prior-to and post-enrollment. Overall utilization was determined by combining claims and survey data at enrollment and one-year post-enrollment. In addition to comparing SOC screening rates pre- versus post-testing, we evaluated the impact of primary care physician (PCP) type (Geisinger versus any other institution), as screening reminder mechanisms differ between institutions. Results: Of the 2,241 participants who met analysis criteria, 73.6% (n = 1,650) had a mammogram in the year before enrollment while a significantly great number (79.3%, n = 1,777) did so during the one-year follow-up (χ2(1) = 59.05, p < 0.001). At enrollment, there were 591 participants who had not had a mammogram completed in the previous year, but 404 (68.4%) of them did have a mammogram during the one-year follow-up. The rate of change in mammography utilization did not differ between those who had a Geisinger versus a non-Geisinger PCP (χ2(2) = 1.83, p = 0.40). Conclusions: Participants in a study using a novel blood test for earlier cancer detection had a significantly higher rate of annual mammography after study enrollment and testing. These results indicate that introduction of a minimally invasive ctDNA and protein biomarker-based cancer screening test may engender greater, not lesser, utilization of SOC cancer screening. Further study is required to understand the root causes of increased utilization in this context.