Citations

Abstract Background: Roughly 7–10% of patients with pancreatic ductal adenocarcinoma (PDAC) have a deleterious germline variant. Although identification of germline variants in family members has implications for cancer surveillance and can lead to early cancer detection and interception for PDAC, as well as other cancers, cascade genetic testing rates are low. The GENetic Education, Risk Assessment and TEsting (GENERATE) study evaluates novel methods of providing genetic education and testing for individuals at risk for hereditary PDAC. Methods: Eligible participants had: (1) a first- or second-degree relative with a diagnosis of PDAC and a known familial germline variant in APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, or TP53 (Known Familial Mutation (KFM)), (2) or were first-degree relatives of PDAC patients (no KFM). Participants were recruited through six academic centers, patient advocacy organizations and online outreach. Enrollment occurred through the study website (www.GENERATEstudy.org). All study participation, including genetic testing via a at home saliva sample kit, was done remotely. Participants were cluster randomized at the family level into one of two arms. Arm 1 (Doxy.me plus Color Genomics) included remote genetic education and testing through a video-based telemedicine platform (Doxy.me) and physician-mediated testing through Color Genomics. Arm 2 included remote genetic education and testing through Color Genomics only. Results: Between 5/8/2019–6/01/2021, 423 families were randomized, comprising 595 participants. Recruitment occurred through patient invitation via healthcare providers (n=128, 21.5%), family members (n=271, 45.5%), friends, advocacy groups, and online outreach (n=223, 37.5%). Participants were referred from the six GENERATE academic centers (n=270, 45.4%) and other institutions (n=325, 54.6%). Study participants were 52.5 years on average, primarily identified as White (n=577, 97%) and from the Northeast (n=184, 30.9%), Midwest (n=154, 25.9%), South (n=158, 26.6%) and West (n=99, 16.6%). Participants were randomized into each arm (n=296 Doxy.me plus Color Genomics; n=299 Color Genomics only). To date, 527 (88.6%) participants have ordered genetic testing. The uptake of genetic testing was 253/296 (85.5%) in the Doxy.me plus Color Genomics arm and 274/299 (91.6%) in the Color Genomics only arm (p=0.049, generalized mixed-effects model). A total of 82 PDAC associated pathogenic variants were identified. The most frequently detected variants were BRCA2 (n=32), ATM (n=25) and PALB2 (n=6). Additionally, 13 non-PDAC associated pathogenic variants and 20 low penetrance variants were detected. Conclusions: Remote methods of genetic education and testing are successful alternatives to traditional cascade testing, with genetic testing rates nearly 90%. Participant follow up will assess if satisfaction with decision making, cancer-risk distress, knowledge gained, family communication, and uptake of surveillance were impacted by the mode of delivery of pre-test genetic education. Citation Format: Nicolette J. Rodriguez, Constance S. Furniss, Matthew B. Yurgelun, Chinedu Ukaegbu, Pamela E. Constantinou, Alison N. Schwartz, Jill Stopfer, Meghan Underhill-Blazey, Barbara Kenner, Scott Nelson, Sydney Okumura, Sherman Law, Alicia Y. Zhou, Tara B. Coffin, Hajime Uno, Allyson Ocean, Florencia McAllister, Andrew M. Lowy, Scott M. Lippman, Alison P. Klein, Lisa Madlensky, Gloria M. Petersen, Judy E. Garber, Michael G. Goggins, Anirban Maitra, Sapna Syngal. Comparison of novel healthcare delivery models on the uptake of genetic education and testing in families with a history of pancreatic cancer: The GENetic Education, Risk Assessment and TEsting (GENERATE) study [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-013.

Background: Obesity is a risk factor for complications in breast reconstruction. Thus, implant-based immediate breast reconstruction in obese women may be controversial. The authors analyzed obese patients who underwent skin-sparing mastectomy using Wise-pattern incisions (Goldilocks procedure) and compared outcomes between two groups: Goldilocks with immediate breast reconstruction and Goldilocks only. Methods: A retrospective review was performed of patients with a body mass index of 30 kg/m2 or higher who underwent the Goldilocks procedure at the Mayo Clinic Health System from 2012 to 2019. Data were extracted from electronic medical records. Minor complications (partial-thickness wound dehiscence or flap necrosis, or tissue expander/implant malposition) and major complications (full-thickness wound dehiscence or flap necrosis, capsular contracture, tissue expander/implant explantation, or unplanned reoperation or readmission) were compared between groups. Patient-reported outcomes using BREAST-Q questionnaires were also assessed. Results: One hundred five patients (181 breasts) were included. Mean ± SEM age and body mass index were 57.1 ± 10.4 years and 37.9 ± 5.8 kg/m2 for the Goldilocks-only group and 51.5 ± 1.1 years and 35.5 ± 0.4 kg/m2 for the Goldilocks with immediate breast reconstruction group, respectively. Median follow-up time was 15.1 months (interquartile range, 10.0 to 28.6 months). Overall, 96 breasts underwent the Goldilocks-only procedure and 85 Goldilocks with immediate breast reconstruction. Multivariable analyses revealed a higher rate of minor complications (adjusted hazard ratio, 2.83; 95 percent CI, 1.22 to 7.02) and major complications (adjusted hazard ratio, 2.26; 95 percent CI, 1.25 to 4.24) in the Goldilocks with immediate breast reconstruction group compared with the Goldilocks-only group, at any given time. Patient satisfaction was not statistically different between groups. Conclusions: The Goldilocks procedure is a feasible breast reconstructive option in obese patients; however, when it is performed with immediate breast reconstruction, it is associated with higher rates of complications. For patients with a body mass index of 40 kg/m2 or greater, the authors recommend the Goldilocks-only procedure or delayed reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Abstract Up to 10% of patients with pancreatic ductal adenocarcinoma (PDAC) carry underlying germline pathogenic variants in cancer susceptibility genes. The GENetic Education Risk Assessment and TEsting (GENERATE) study aimed to evaluate novel methods of genetic education and testing in relatives of patients with PDAC. Eligible individuals had a family history of PDAC and a relative with a germline pathogenic variant in APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, or TP53 genes. Participants were recruited at six academic cancer centers and through social media campaigns and patient advocacy efforts. Enrollment occurred via the study website (https://GENERATEstudy.org) and all participation, including collecting a saliva sample for genetic testing, could be done from home. Participants were randomized to one of two remote methods that delivered genetic education about the risks of inherited PDAC and strategies for surveillance. The primary outcome of the study was uptake of genetic testing. From 5/8/2019 to 5/6/2020, 49 participants were randomized to each of the intervention arms. Overall, 90 of 98 (92%) of randomized participants completed genetic testing. The most frequently detected pathogenic variants included those in BRCA2 (N = 15, 17%), ATM (N = 11, 12%), and CDKN2A (N = 4, 4%). Participation in the study remained steady throughout the onset of the Coronavirus disease (COVID-19) pandemic. Preliminary data from the GENERATE study indicate success of remote alternatives to traditional cascade testing, with genetic testing rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for PDAC interception approaches. Prevention Relevance: Preliminary data from the GENERATE study indicate success of remote alternatives for pancreatic cancer genetic testing and education, with genetic testing uptake rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for pancreatic cancer interception.

BackgroundAcute myeloid leukemia (AML) is fatal in elderly patients who are unfit for standard induction chemotherapy. The objective of this study was to evaluate the survival benefit of administering sapacitabine, an oral nucleoside analogue, in alternating cycles with decitabine, a low‐intensity therapy, to elderly patients with newly diagnosed AML.MethodsThis randomized, open‐label, phase 3 study (SEAMLESS) was conducted at 87 sites in 11 countries. Patients aged ≥70 years who were not candidates for or chose not to receive standard induction chemotherapy were randomized 1:1 to arm A (decitabine in alternating cycles with sapacitabine) received 1‐hour intravenous infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 8 weeks (first cycle and subsequent odd cycles) and sapacitabine 300 mg twice daily on 3 consecutive days per week for 2 weeks every 8 weeks (second cycle and subsequent even cycles) or to control arm C who received 1‐hour infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 4 weeks. Prior hypomethylating agent therapy for preexisting myelodysplastic syndromes or myeloproliferative neoplasms was an exclusion criterion. Randomization was stratified by antecedent myelodysplastic syndromes or myeloproliferative neoplasms, white blood cell count (<10 × 109/L and ≥10 × 109/L), and bone marrow blast percentage (≥50% vs <50%). The primary end point was overall survival (OS). Secondary end points were the rates of complete remission (CR), CR with incomplete platelet count recovery, partial remission, hematologic improvement, and stable disease along with the corresponding durations, transfusion requirements, number of hospitalized days, and 1‐year survival. The trial is registered at ClinicalTrials.gov (NCT01303796).ResultsBetween October 2011 and December 2014, 482 patients were enrolled and randomized to receive decitabine administered in alternating cycles with sapacitabine (study arm, n = 241) or decitabine monotherapy (control arm, n = 241). The median OS was 5.9 months on the study arm versus 5.7 months on the control arm (P = .8902). The CR rate was 16.6% on the study arm and 10.8% on the control arm (P = .1468). In patients with white blood cell counts <10 × 109/L (n = 321), the median OS was higher on the study arm versus the control arm (8.0 vs 5.8 months; P = .145), as was the CR rate (21.5% vs 8.6%; P = .0017).ConclusionsThe regimen of decitabine administered in alternating cycles with sapacitabine was active but did not significantly improve OS compared with decitabine monotherapy. Subgroup analyses suggest that patients with baseline white blood cell counts <10 × 109/L might benefit from decitabine alternating with sapacitabine, with an improved CR rate and the convenience of an oral drug. These findings should be prospectively confirmed.

Abstract Purpose: Programmed death ligand 1 [PD-(L)1]-targeted therapies have shown modest survival benefit in triple-negative breast cancer (TNBC). PD-L1+ microenvironments in TNBC are not well characterized and may inform combinatorial immune therapies. Herein, we characterized clinicopathologic features, RNA-based immune signatures, and spatially defined protein-based tumor–immune microenvironments (TIME) in early-stage PD-L1+ and PD-L1− TNBC. Experimental Design: From a large cohort of chemotherapy-naïve TNBC, clinicopathologic features, deconvoluted RNA immune signatures, and intraepithelial and stromal TIME (Nanostring GeoMX) were identified in subsets of PD-L1+ and PD-L1− TNBC, as defined by FDA-approved PD-L1 companion assays. Results: 228 of 499 (46%) TNBC were PD-L1+ (SP142: ≥1% immune cells-positive). Using PD-L1 22C3, 46% had combined positive score (CPS) ≥ 1 and 16% had CPS ≥10. PD-L1+ TNBC were higher grade with higher tumor-infiltrating lymphocytes (TIL; P &lt; 0.05). PD-L1 was not associated with improved survival following adjustment for TILs and other variables. RNA profiles of PD-L1+ TNBC had increased dendritic cell, macrophage, and T/B cell subset features; and decreased myeloid-derived suppressor cells. PD-L1+ stromal and intraepithelial TIMEs were highly enriched in IDO-1, HLA-DR, CD40, and CD163 compared with PD-L1-TIME, with spatially specific alterations in CTLA-4, Stimulator of Interferon Genes (STING), and fibronectin. Macrophage- and antigen presentation–related proteins correlated most strongly with PD-L1 protein. Conclusions: In this early-stage TNBC cohort, nearly 50% were PD-L1+ (SP142 companion assay) while 16% were PD-L1+ with the 22C3 companion assay. PD-L1+ TNBC had specific myeloid-derived and lymphoid features. Spatially defined PD-L1+ TIME were enriched in several clinically actionable immune proteins. These data may inform future studies on combinatorial immunotherapies for patients with PD-L1+ TNBC. See related commentary by Symmans, p. 5446