Exome Sequencing Identifies Carriers of the Autosomal Dominant Cancer Predisposition Disorders Beyond Current Practice Guideline Recommendations.

PURPOSE: The autosomal dominant cancer predisposition disorders hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) are genetic conditions for which early identification and intervention have a positive effect on the individual and public health. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify carriers of HBOC and LS. METHODS: Participants were recruited from three geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; Jacksonville, FL). Participants underwent Exome+ sequencing (Helix Inc, San Mateo, CA) and return of results for specific genetic findings: HBOC (BRCA1 and BRCA1) and LS (MLH1, MSH2, MSH6, PMS2, and EPCAM). Chart review was performed to collect demographics and personal and family cancer history. RESULTS: To date, 44,306 participants have enrolled in Tapestry. Annotation and interpretation of all variants in genes for HBOC and LS resulted in the identification of 550 carriers (prevalence, 1.24%), which included 387 with HBOC (27.2% BRCA1, 42.8% BRCA2) and 163 with LS (12.3% MSH6, 8.8% PMS2, 4.5% MLH1, 3.8% MSH2, and 0.2% EPCAM). More than half of these participants (52.1%) were newly diagnosed carriers with HBOC and LS. In all, 39.2% of HBOC/LS carriers did not satisfy National Comprehensive Cancer Network (NCCN) criteria for genetic evaluation. NCCN criteria were less commonly met in underrepresented minority populations versus self-reported White race (51.5% v 37.5%, P = .028). CONCLUSION: Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have LS and HBOC cancer predisposition syndromes.

Reflections on the state of telehealth and cancer care research and future directions.

Telemedicine has routinely been used in cancer care delivery for the past 3 years. The current state of digital health provides convenience and efficiency for both health-care professional and patient, but challenges exist in equitable access to virtual services. As increasingly newer technologies are added to telehealth platforms, it is essential to eliminate barriers to access through technical, procedural, and legislative improvements. Moving forward, implementation of new strategies can help eliminate disparities in virtual cancer care, facilitate delivery of treatment in the home, and improve real-time data collection for patient safety and clinical trial participation. The ultimate goal will be to extend high-quality survival for all patients with cancer through improved digital delivery of cancer care.

Outcomes in Children, Adolescents, and Young Adults With Down Syndrome and ALL: A Report From the Children's Oncology Group.

PURPOSE: Patients with Down syndrome (DS) and B-ALL experience increased rates of relapse, toxicity, and death. We report results for patients with DS B-ALL enrolled on Children's Oncology Group trials between 2003 and 2019. METHODS: We analyzed data for DS (n = 743) and non-DS (n = 20,067) patients age 1-30 years on four B-ALL standard-risk (SR) and high-risk trials. RESULTS: Patients with DS exhibited more frequent minimal residual disease (MRD) ≥0.01% at end induction (30.8% v 21.5%; P < .001). This difference persisted at end consolidation only in National Cancer Institute (NCI) high-risk patients (34.0% v 11.7%; P < .0001). Five-year event-free survival (EFS) and overall survival (OS) were significantly poorer for DS versus non-DS patients overall (EFS, 79.2% ± 1.6% v 87.5% ± 0.3%; P < .0001; OS, 86.8% ± 1.4% v 93.6% ± 0.2%; P < .0001), and within NCI SR and high-risk subgroups. Multivariable Cox regression analysis of the DS cohort for risk factors associated with inferior EFS identified age >10 years, white blood count >50 × 103/µL, and end-induction MRD ≥0.01%, but not cytogenetics or CRLF2 overexpression. Patients with DS demonstrated higher 5-year cumulative incidence of relapse (11.5% ± 1.2% v 9.1% ± 0.2%; P = .0008), death in remission (4.9% ± 0.8% v 1.7% ± 0.1%; P < .0001), and induction death (3.4% v 0.8%; P < .0001). Mucositis, infections, and hyperglycemia were significantly more frequent in all patients with DS, while seizures were more frequent in patients with DS on high-risk trials (4.1% v 1.8%; P = .005). CONCLUSION: Patients with DS-ALL exhibit an increased rate of relapse and particularly of treatment-related mortality. Novel, less-toxic therapeutic strategies are needed to improve outcomes.

AACR Cancer Centers Alliance: Fostering Collaboration and Innovation to Advance Lifesaving Scientific Discoveries for Patients.

SUMMARY: Basic and clinical cancer research discoveries stemming from the nation's cancer centers have markedly improved outcomes for many cancer patients. Despite this forward momentum in our progress against this complex disease, cancer in all its forms remains a major public health challenge that touches the lives of nearly every American, either directly or indirectly. The newly formed AACR Cancer Centers Alliance will accelerate the pace of discovery by providing an ongoing mechanism for transferring new knowledge, sharing resources, developing national demonstration projects, and driving innovation that impacts cancer science, cancer care delivery, and science and health policy.

AACR Cancer Centers Alliance: Fostering Collaboration and Innovation to Advance Lifesaving Scientific Discoveries for Patients.

Basic and clinical cancer research discoveries stemming from the nation's cancer centers have markedly improved outcomes for many cancer patients. Despite this forward momentum in our progress against this complex disease, cancer in all its forms remains a major public health challenge that touches the lives of nearly every American, either directly or indirectly. The newly formed AACR Cancer Centers Alliance will accelerate the pace of discovery by providing an ongoing mechanism for transferring new knowledge, sharing resources, developing national demonstration projects, and driving innovation that impacts cancer science, cancer care delivery, and science and health policy.

AACR Cancer Centers Alliance: Fostering Collaboration and Innovation to Advance Lifesaving Scientific Discoveries for Patients.

Basic and clinical cancer research discoveries stemming from the nation's cancer centers have markedly improved outcomes for many cancer patients. Despite this forward momentum in our progress against this complex disease, cancer in all its forms remains a major public health challenge that touches the lives of nearly every American, either directly or indirectly. The newly formed AACR Cancer Centers Alliance will accelerate the pace of discovery by providing an ongoing mechanism for transferring new knowledge, sharing resources, developing national demonstration projects, and driving innovation that impacts cancer science, cancer care delivery, and science and health policy.

AACR Cancer Centers Alliance: Fostering Collaboration and Innovation to Advance Lifesaving Scientific Discoveries for Patients.

Basic and clinical cancer research discoveries stemming from the nation's cancer centers have markedly improved outcomes for many cancer patients. Despite this forward momentum in our progress against this complex disease, cancer in all its forms remains a major public health challenge that touches the lives of nearly every American, either directly or indirectly. The newly formed AACR Cancer Centers Alliance will accelerate the pace of discovery by providing an ongoing mechanism for transferring new knowledge, sharing resources, developing national demonstration projects, and driving innovation that impacts cancer science, cancer care delivery, and science and health policy.

AACR Cancer Centers Alliance: Fostering Collaboration and Innovation to Advance Lifesaving Scientific Discoveries for Patients.

Basic and clinical cancer research discoveries stemming from the nation's cancer centers have markedly improved outcomes for many cancer patients. Despite this forward momentum in our progress against this complex disease, cancer in all its forms remains a major public health challenge that touches the lives of nearly every American, either directly or indirectly. The newly formed AACR Cancer Centers Alliance will accelerate the pace of discovery by providing an ongoing mechanism for transferring new knowledge, sharing resources, developing national demonstration projects, and driving innovation that impacts cancer science, cancer care delivery, and science and health policy.

AACR Cancer Centers Alliance: Fostering Collaboration and Innovation to Advance Lifesaving Scientific Discoveries for Patients.

SUMMARY: Basic and clinical cancer research discoveries stemming from the nation's cancer centers have markedly improved outcomes for many cancer patients. Despite this forward momentum in our progress against this complex disease, cancer in all its forms remains a major public health challenge that touches the lives of nearly every American, either directly or indirectly. The newly formed AACR Cancer Centers Alliance will accelerate the pace of discovery by providing an ongoing mechanism for transferring new knowledge, sharing resources, developing national demonstration projects, and driving innovation that impacts cancer science, cancer care delivery, and science and health policy.

AACR Cancer Centers Alliance: Fostering Collaboration and Innovation to Advance Lifesaving Scientific Discoveries for Patients.

Basic and clinical cancer research discoveries stemming from the nation's cancer centers have markedly improved outcomes for many cancer patients. Despite this forward momentum in our progress against this complex disease, cancer in all its forms remains a major public health challenge that touches the lives of nearly every American, either directly or indirectly. The newly formed AACR Cancer Centers Alliance will accelerate the pace of discovery by providing an ongoing mechanism for transferring new knowledge, sharing resources, developing national demonstration projects, and driving innovation that impacts cancer science, cancer care delivery, and science and health policy.

Verification of prognostic expression biomarkers is improved by examining enriched leukemic blasts rather than mononuclear cells from acute myeloid leukemia patients.

BACKGROUND: Studies have not systematically compared the ability to verify performance of prognostic transcripts in paired bulk mononuclear cells versus viable CD34-expressing leukemic blasts from patients with acute myeloid leukemia. We hypothesized that examining the homogenous leukemic blasts will yield different biological information and may improve prognostic performance of expression biomarkers. METHODS: To assess the impact of cellular heterogeneity on expression biomarkers in acute myeloid leukemia, we systematically examined paired mononuclear cells and viable CD34-expressing leukemic blasts from SWOG diagnostic specimens. After enrichment, patients were assigned into discovery and validation cohorts based on availability of extracted RNA. Analyses of RNA sequencing data examined how enrichment impacted differentially expressed genes associated with pre-analytic variables, patient characteristics, and clinical outcomes. RESULTS: Blast enrichment yielded significantly different expression profiles and biological pathways associated with clinical characteristics (e.g., cytogenetics). Although numerous differentially expressed genes were associated with clinical outcomes, most lost their prognostic significance in the mononuclear cells and blasts after adjusting for age and ELN risk, with only 11 genes remaining significant for overall survival in both cell populations (CEP70, COMMD7, DNMT3B, ECE1, LNX2, NEGR1, PIK3C2B, SEMA4D, SMAD2, TAF8, ZNF444). To examine the impact of enrichment on biomarker verification, these 11 candidate biomarkers were examined by quantitative RT/PCR in the validation cohort. After adjusting for ELN risk and age, expression of 4 genes (CEP70, DNMT3B, ECE1, and PIK3CB) remained significantly associated with overall survival in the blasts, while none met statistical significance in mononuclear cells. CONCLUSIONS: This study provides insights into biological information gained/lost by examining viable CD34-expressing leukemic blasts versus mononuclear cells from the same patient and shows an improved verification rate for expression biomarkers in blasts.

Leadership Diversity and Development in the Nation's Cancer Centers.

The capacity and diversity of the oncology leadership workforce has not kept pace with the emerging needs of our increasingly complex cancer centers and the spectrum of challenges our institutions face in reducing the cancer burden in diverse catchment areas. Recognizing the importance of a diverse workforce to reduce cancer inequities, the Association of American Cancer Institutes conducted a survey of its 103 cancer centers to examine diversity in leadership roles from research program leaders to cancer center directors. A total of 82 (80%) centers responded, including 64 National Cancer Institute-designated and 18 emerging centers. Among these 82 respondents, non-Hispanic White individuals comprised 79% of center directors, 82% of deputy directors, 72% of associate directors, and 72% of program leaders. Women are underrepresented in all leadership roles (ranging from 16% for center directors to 45% for associate directors). Although the limited gender, ethnic, and racial diversity of center directors and perhaps deputy directors is less surprising, the demographics of current research program leaders and associate directors exposes a substantial lack of diversity in the traditional cancer center senior leadership pipeline. Sole reliance on the cohort of current center leaders and leadership pipeline is unlikely to produce the diversity in cancer center leadership needed to facilitate the ability of those centers to address the needs of the diverse populations they serve. Informed by these data, this commentary describes some best practices to build a pipeline of emerging leaders who are representative of the diverse populations served by these institutions and who are well positioned to succeed.

A Framework for Promoting Diversity, Equity, and Inclusion in Genetics and Genomics Research.

IMPORTANCE: Research into the genetic and genomic ("genomics") foundations of disease is central to our understanding of disease prevention, early detection, diagnostic accuracy, and therapeutic intervention. Inequitable participation in genomics research by historically excluded populations limits the ability to translate genomic knowledge to achieve health equity and ensure that findings are generalizable to diverse populations. OBSERVATIONS: We propose a novel framework for promoting diversity, equity, and inclusion in genomics research. Building on principles of community-based participatory research and collective impact frameworks, the framework can guide our understanding of the social, cultural, health system, policy, community, and individual contexts in which engagement and genomics research are being done. Our framework highlights the involvement of a multistakeholder team, including the participants and communities to be engaged, to ensure robust methods for recruitment, retention, return of genomic results, quality of engagement, follow-up, and monitoring of participants. CONCLUSIONS AND RELEVANCE: The proposed engagement framework will guide investigators in optimizing equitable representation in research and enhancing the rigor of genomics investigation.

SWOG 1318: A Phase II Trial of Blinatumomab Followed by POMP Maintenance in Older Patients With Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia.

PURPOSE: Chemotherapy outcomes in older patients with Philadelphia (Ph) chromosome-negative B-acute lymphoblastic leukemia (ALL) are very poor. Here, we evaluated blinatumomab as induction and consolidation therapy followed by prednisone, vincristine, 6-mercaptopurine, and methotrexate (POMP) maintenance chemotherapy in this patient population. PATIENTS AND METHODS: Patients were treated at National Clinical Trial Network sites. Eligibility criteria included age ≥ 65 years and newly diagnosed Ph chromosome-negative B-ALL. Patients received blinatumomab as induction for one-two cycles until attainment of response (complete remission (CR) and CR with incomplete count recovery). Patients then received three cycles of consolidation with blinatumomab followed by 18 months of POMP maintenance chemotherapy. Eight doses of intrathecal methotrexate were administered as central nervous system prophylaxis. RESULTS: Twenty-nine eligible patients were enrolled. The median age was 75 years, and the median bone marrow blast count at diagnosis was 87%. Cytogenetic risk was poor in 10 patients (34%), and five of 14 patients (36%) tested had the Ph-like ALL gene signature. Nineteen patients (66%; 95% CI, 46 to 82) achieved CR. Kaplan-Meier 3-year disease-free survival and overall survival estimates were 37% (95% CI, 17 to 57) and 37% (95% CI, 20 to 55), respectively. CONCLUSION: Blinatumomab was well tolerated and effective in the treatment of older patients with newly diagnosed Ph chromosome-negative B-ALL, including patients with poor-risk cytogenetics. The 3-year disease-free survival and overall survival results are encouraging and suggest that this approach should be further explored.

Molecular classification improves risk assessment in adult BCR-ABL1-negative B-ALL.

Genomic classification has improved risk assignment of pediatric, but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (#NCT00002514) trial accrued 1229 adolescent/adult patients with BCR-ABL1- B-ALL (aged 14 to 65 years). Although 93% of patients achieved remission, 41% relapsed at a median of 13 months (range, 28 days to 12 years). Five-year overall survival (OS) was 42% (95% confidence interval, 39, 44). Transcriptome sequencing, gene expression profiling, cytogenetics, and fusion polymerase chain reaction enabled genomic subtyping of 282 patient samples, of which 264 were eligible for trial, accounting for 64.5% of E2993 patients. Among patients with outcome data, 29.5% with favorable outcomes (5-year OS 65% to 80%) were deemed standard risk (DUX4-rearranged [9.2%], ETV6-RUNX1/-like [2.3%], TCF3-PBX1 [6.9%], PAX5 P80R [4.1%], high-hyperdiploid [6.9%]); 50.2% had high-risk genotypes with 5-year OS of 0% to 27% (Ph-like [21.2%], KMT2A-AFF1 [12%], low-hypodiploid/near-haploid [14.3%], BCL2/MYC-rearranged [2.8%]); 20.3% had intermediate-risk genotypes with 5-year OS of 33% to 45% (PAX5alt [12.4%], ZNF384/-like [5.1%], MEF2D-rearranged [2.8%]). IKZF1 alterations occurred in 86% of Ph-like, and TP53 mutations in patients who were low-hypodiploid (54%) and BCL2/MYC-rearranged (33%) but were not independently associated with outcome. Of patients considered high risk based on presenting age and white blood cell count, 40% harbored subtype-defining genetic alterations associated with standard- or intermediate-risk outcomes. We identified distinct immunophenotypic features for DUX4-rearranged, PAX5 P80R, ZNF384-R/-like, and Ph-like genotypes. These data in a large adult B-ALL cohort treated with a non-risk-adapted approach on a single trial show the prognostic importance of genomic analyses, which may translate into future therapeutic benefits.

AML risk stratification models utilizing ELN-2017 guidelines and additional prognostic factors: a SWOG report.

BACKGROUND: The recently updated European LeukemiaNet risk stratification guidelines combine cytogenetic abnormalities and genetic mutations to provide the means to triage patients with acute myeloid leukemia for optimal therapies. Despite the identification of many prognostic factors, relatively few have made their way into clinical practice. METHODS: In order to assess and improve the performance of the European LeukemiaNet guidelines, we developed novel prognostic models using the biomarkers from the guidelines, age, performance status and select transcript biomarkers. The models were developed separately for mononuclear cells and viable leukemic blasts from previously untreated acute myeloid leukemia patients (discovery cohort, N = 185) who received intensive chemotherapy. Models were validated in an independent set of similarly treated patients (validation cohort, N = 166). RESULTS: Models using European LeukemiaNet guidelines were significantly associated with clinical outcomes and, therefore, utilized as a baseline for comparisons. Models incorporating age and expression of select transcripts with biomarkers from European LeukemiaNet guidelines demonstrated higher area under the curve and C-statistics but did not show a substantial improvement in performance in the validation cohort. Subset analyses demonstrated that models using only the European LeukemiaNet guidelines were a better fit for younger patients (age < 55) than for older patients. Models integrating age and European LeukemiaNet guidelines visually showed more separation between risk groups in older patients. Models excluding results for ASXL1, CEBPA, RUNX1 and TP53, demonstrated that these mutations provide a limited overall contribution to risk stratification across the entire population, given the low frequency of mutations and confounding risk factors. CONCLUSIONS: While European LeukemiaNet guidelines remain a critical tool for triaging patients with acute myeloid leukemia, the findings illustrate the need for additional prognostic factors, including age, to improve risk stratification.

Association of immunophenotype with expression of topoisomerase II α and ß in adult acute myeloid leukemia.

Anthracyclines used in the treatment of acute myelogenous leukemia (AML) inhibit the activity of the mammalian topoisomerase II (topo II) isoforms, topo II α and topo IIß. In 230 patients with non-M3 AML who received frontline ara-C/daunorubicin we determined expression of topo IIα and topo IIß by RT-PCR and its relationship to immunophenotype (IP) and outcomes. Treatment outcomes were analyzed by logistic or Cox regression. In 211 patients, available for analysis, topo IIα expression was significantly lower than topo IIß (P < 0.0001). In contrast to topo IIα, topo IIß was significantly associated with blast percentage in marrow or blood (P = 0.0001), CD7 (P = 0.01), CD14 (P < 0.0001) and CD54 (P < 0.0001). Event free survival was worse for CD56-negative compared to CD56-high (HR = 1.9, 95% CI [1.0-3.5], p = 0.04), and overall survival was worse for CD-15 low as compared to CD15-high (HR = 2.2, 95% CI [1.1-4.2], p = 0.02). Ingenuity pathway analysis indicated topo IIß and immunophenotype markers in a network associated with cell-to-cell signaling, hematological system development/function and inflammatory response. Topo IIß expression reflects disease biology of highly proliferative disease and distinct IP but does not appear to be an independent variable influencing outcome in adult AML patients treated with anthracycline-based therapy.

At three years, patients with acute lymphoblastic leukaemia are still at risk for relapse. Results of the international MRC UKALLXII/ECOG E2993 trial.

Late relapse [>3 years from complete remission (CR)] in acute lymphoblastic leukaemia (ALL), is unusual. Data from the MRC UKALLXII/ECOG E2993 trial are presented to evaluate the incidence and characteristics of late relapse in adult ALL. Of 1,909 patients, 1,752 (92%) achieved CR and among these 757 (43·2%) relapsed; 691 (91·3%) within three years and 66 (8·7%) beyond. Among these 66 patients, median time to relapse was 47 (37-144) months. Relapse beyond three years occurred in 3·8% of all who achieved CR. The cumulative risk of relapse was 40%, 43% and 45% at three, five and ten years respectively. Out of the 1 752 patients who achieved CR, 11·7% underwent autologous and 40·6% allogeneic transplant, while in CR1. Of the autologous patients, 43·2% relapsed early and 3·4% relapsed late. However, among the allogeneic patients, 13·2% relapsed early and only 1·3% late. The five-year overall survival from relapse was 5·8% and 20% in the early and late relapse patients respectively. In conclusion, late relapse in adults with ALL is not uncommon, and is associated with better outcome after relapse compared to early relapse.