tbuckley/cabot-search huggingface dataset:
Multi-gene hereditary cancer testing, family history and prognosis in men with prostate cancer.
Authors: Panagiotis J. Vlachostergios, Ariel Schaap, Michael Sun, Cora N. Sternberg, Ana M. Molina, David M. Nanus, Christopher Barbieri, Scott T. Tagawa
Journal: Journal of Clinical Oncology (2019)

5073 Background: Multi-gene hereditary cancer testing is common in prostate cancer (PC). We assessed the frequency of pathogenic mutations (mt) and examined associations with family history (FH), cancer recurrence, and overall survival (OS). Methods: Men with clinically localized or metastatic PC consented to germline DNA testing using a validated panel of 30 genes associated with elevated risk for common cancers (Color Genomics). Chi-square test and Fisher’s exact test were used to compare pathogenic mt and clinical characteristics. The Kaplan-Meier method was used to evaluate the associations of mt status with PSA recurrence and OS. Results: 315 men (median age 69, range 38-89) were included; 140 (44.4%) with localized and 175 (55.6%) with metastatic PC. 215 (68.3%) reported a FH of any cancer in one and 101 (32.1%) in ≥ 2 first-degree relatives. Genomic testing detected 12.1% of pts possessed a pathogenic mt (39 mt in 38 pts): BRCA2 (n = 12, 3.8%), CHEK2 (n = 10, 3.2%), APC (n = 7, 2.2%), MUTYH (n = 3, 0.9%), ATM (n = 2, 0.6%), and 1 each (0.3%) with NBN, PALB2, RAD51D, MSH2, and PMS2. Variants of uncertain significance were detected in 52 (16.5%). Men with FH of prostate, breast, ovarian, pancreatic cancer or/and melanoma (182/315, 58%), were more likely to have BRCA2 pathogenic mt (P = 0.049). Median age of diagnosis was 55 with BRCA2 versus 62 in non-carriers (P = 0.01). No association was found between FH of Lynch-associated cancers (colon, endometrial, gastric) and mismatch repair gene variants. The prevalence of pathogenic mt was significantly higher with visceral metastases (P = 0.001) but did not differ between localized and advanced PC pts (P = 0.602). In men with clinically localized PC at diagnosis (n = 226, 71.7%), pathogenic mt were associated with a shorter time to recurrence (30 vs 53 months, P = 0.004). Men with advanced PC (n = 175) and germline APC or MUTYH mt had worse median OS (44 vs 318 months, P = 0.004). Conclusions: Our findings confirm the incidence of men with non-PC FH associated with DNA repair gene mt and support testing in early stage pts. Further, our data support the prognostic significance of germline genetic alterations which deserves study in a larger cohort of pts.
Phase I trial of a modified vaccinia ankara (MVA) priming vaccine followed by a fowlpox virus (FPV) boosting vaccine modified to express brachyury and costimulatory molecules in advanced solid tumors.
Authors: Julie Marie Collins, Renee Nicole Donahue, Yo-Ting Tsai, Claudia Palena, Jennifer L. Marte, Ravi Amrit Madan, Fatima Karzai, Christopher Ryan Heery, Julius Strauss, Margaret Elena Gatti-Mays, Lisa M. Cordes, Jeffrey Schlom, James L. Gulley, Marijo Bilusic
Journal: Journal of Clinical Oncology (2019)

2640 Background: Brachyury, a transcription factor, plays an integral role in epithelial-to-mesenchymal transition, metastasis, poor prognosis, and resistance to chemotherapy. It is expressed in many tumor types, and rare in normal tissue, making it an ideal immunologic target. BN-Brachyury comprises heterologous vaccination with recombinant MVA priming followed by FPV boosting, each encoding transgenes for brachyury and three costimulatory molecules (B7-1, ICAM1, and LFA-3). Heterologous prime boost approach is intended to optimize immunogenicity, as previously observed. Methods: Pts with metastatic solid tumors were treated with 2 monthly doses of MVA-brachyury SC at the previously tested dose, 2.2 x 10 9 infectious units (IU), followed by FPV-brachyury SC, 1 x 10 9 IU, for 6 monthly doses and then every 3 months for up to 2 years. The primary objective was to determine safety and tolerability and establish the RP2D. Immune assays were conducted to evaluate immunogenicity. Results: In 10 pts (3 chordoma, 6 GI, 1 papillary thyroid), no dose-limiting toxicities or serious treatment-related adverse events (TRAEs) were observed. The only Grade 3 TRAE was sedation associated with fever, which resolved spontaneously and did not recur with subsequent cycles. All other TRAEs were Grade 1 or 2; the most common was injection-site reaction in all patients. Five pts have had stable disease for &gt; 24 wks (per RECIST v1.1) and remain on treatment. One pt with chordoma, for which BN-Brachyury was granted orphan drug designation, has had a 13.2% reduction in tumor size. As previously demonstrated, brachyury-specific T cell responses were observed, as were responses against cascade antigens (non-encoded antigens) CEA and MUC-1. Conclusions: Heterologous MVA- and FPV-brachyury is well tolerated and induced immune responses to brachyury and cascade antigens, suggesting induction of immunologically relevant tumor cell destruction. These data have informed combining BN-Brachyury with checkpoint inhibition (NCT03493945) and radiation (NCT03595228) to evaluate potential for synergetic activity in selected populations. Clinical trial information: NCT03349983.
Impact of clinical risk category on prognosis and prediction of chemotherapy benefit in early breast cancer (EBC) by age and the 21-gene recurrence score (RS) in TAILORx.
Authors: Joseph A. Sparano, Robert James Gray, Della F. Makower, Tracy G. Lively, Thomas James Saphner, Maccon M. Keane, Henry Leonidas Gomez, Pavan S. Reddy, Timothy F. Goggins, Ingrid A. Mayer, Deborah Toppmeyer, Adam Brufsky, Matthew P. Goetz, Daniel F. Hayes, Elizabeth Claire Dees, Kathleen I. Pritchard, Charles E. Geyer, John A. Olson, Kathy S. Albain, George W. Sledge
Journal: Journal of Clinical Oncology (2019)

503 Background: TAILORx established that endocrine therapy (ET) alone is non-inferior to adjuvant chemotherapy (CT) plus ET in EBC and a 21-gene RS of 11-25, with some benefit if ≤50 years (y) with RS 16-25 (PMID: 29860917). We evaluated whether clinical risk (tumor size &amp; histologic grade) provides additional prognostic information to RS, a secondary trial objective. Methods: Clinical risk by was assessed by Adjuvant! (version 8.0) using MINDACT criteria (PMID 27557300), defined as low clinical risk (LCR - tumor ≤3 cm and low grade, &lt;2 cm and intermediate grade, or ≤1 cm and high grade) or high clinical risk (HCR -not meeting LCR criteria). Results: Of 9427 women with RS and clinical risk information, 70% were LCR and 30% HCR, with comparable distribution by age ( ≤50 vs. &gt;50). The RS was 26-100 in 9% of LCR and 27% of HCR patients, with similar distributions by age. Although LCR/HCR provided additional prognostic information in each RS category for iDFS, including RS 0-10 (9-year rates 86.7% vs. 75.7% LCR vs. HCR), 11-25 (85.4% vs. 78.9%), and 26-100 (82.0% vs. 70.4%), iDFS rates were similar irrespective of CT (no vs. yes) in the entire RS 11-25 cohort whether LCR (85.8% vs. 85.1%) or HCR (79.8% vs. 77.9%). DRFI rates were also similar irrespective of CT in the RS 11-25 cohort or &gt; 50y group whether LCR (96.0% vs. 96.1% overall; 96.5% vs. 96.0% &gt; 50y) or HCR (92.3% vs. 89.9% overall; 91.7% vs. 90.7% &gt;50y). For women ≤50y, the absolute reduction in distant recurrence from CT with a RS of 16-20 (N=923) was -0.2% (standard error [SE]±2.1%) for LCR vs. 6.5%(SE±4.9%) for HCR (vs. 1.6%[SE±1.9%] overall), whereas for a RS 21-25 (N=492) it was 6.4% (SE±4.9%) for LCR vs. 8.6% (SE±6.2%) for HCR (vs. 6.5%[SE±3.7%] overall). Conclusions: Clinical risk stratification provides additional prognostic information to the 21-gene RS, but not prediction of CT benefit in the overall TAILORx population or those &gt; 50y, and facilitates more refined estimates of absolute CT benefit for women ≤50y with a RS 16-25. (Funded by National Cancer Institute, Komen Foundation, Breast Cancer Research Foundation). Clinical trial information: NCT00310180.
Critical role of neutrophil extracellular traps (NETs) in patients with Behcet’s disease
Authors: Alexandre Le Joncour, Raphael Martos, Stephane Loyau, Nicolas Lelay, Antoine Dossier, Aurelie Cazes, Pierre Fouret, Fanny Domont, Thomas Papo, Martine Jandrot-Perrus, Marie-Christine Bouton, Patrice Cacoub, Nadine Ajzenberg, David Saadoun, Yacine Boulaftali
Journal: Annals of the Rheumatic Diseases (2019)

Objectives Behçet’s disease (BD) is a chronic systemic vasculitis. Thrombosis is a frequent and life-threatening complication. The pathogenesis of BD is poorly understood and evidence supporting a role for primed neutrophils in BD-associated thrombotic risk is scant. To respond to inflammatory insults, neutrophils release web-like structures, known as neutrophil extracellular traps (NETs), which are prothrombotic. We evaluated the role of NETs and markers of NETs in BD. Methods Blood samples were collected from patients with BD, according to the International Study Group Criteria for Behçet's disease, and healthy donors (HD). NET components, including cell-free DNA (CfDNA) and neutrophil enzymes myeloperoxidase (MPO), were assessed in serum or in purified neutrophils from patients with BD and HD. Results Patients with active BD had elevated serum cfDNA levels and MPO-DNA complexes compared with patients with inactive BD and to HD. In addition, levels of cfDNA and MPO-DNA complexes were significantly higher in patients with BD with vascular involvement compared with those without vascular symptoms. Purified neutrophils from patients with BD exhibited spontaneous NETosis compared with HD. Thrombin generation in BD plasma was significantly increased and positively correlated with the levels of MPO-DNA complexes and cfDNA. Importantly, DNAse treatment significantly decreased thrombin generation in BD plasma but not in HD plasma. In addition, biopsy materials obtained from patients with BD showed NETs production in areas of vasculitic inflammation and thrombosis. Conclusions Our data show that NETs and markers of NETS levels are elevated in patients with BD and contribute to the procoagulant state. Targeting NETs may represent a potential therapeutic target for the reduction or prevention of BD-associated thrombotic risk.
Outcomes in MAGE+ cutaneous squamous cell carcinoma with perineural invasion treated with surgery followed by postoperative radiation therapy.
Authors: Mary Stevenson, Alexis Santana, Nicole Adell Doudican, Theresa N Canavan, Anna C. Pavlick, John Carucci
Journal: Journal of Clinical Oncology (2019)

e21043 Background: Perineural invasion (PNI) is associated with a high risk for recurrence and metastasis from cutaneous squamous cell carcinoma (cSCC). Recommendations vary regarding use of post-operative radiation therapy (PORT). Biomarkers for poor outcome from cSCC with PNI are lacking. We aimed to evaluate outcomes in high-risk cSCC with PNI treated surgically +/- PORT and to evaluate tissue from the primary tumor to identify biomarkers for highest risk. Methods: We conducted a retrospective chart review of PNI SCC patients seen between 2005 and 2014. We compared outcomes for surgery vs. surgery plus PORT. Gene expression from tumor debulk was evaluated via Nanostring. MAGEA3 function was evaluated using PAM 212 SCC cells in a BALB/c mouse model. CRISPR-Cas9 MAGEA3 PAM 212 knockouts were developed to assess role of MAGEA3 in SCC growth. Results: Thirty-two patients with PNI SCC were identified. All were treated surgically, and 18/32 elected to undergo PORT. Nodal metastases were noted in 5/14 patients who did not undergo PORT, whereas no metastases were noted in any patient who underwent PORT. Thus, surgery plus PORT was associated with better outcome than surgery alone (P &lt; 0.01). Local recurrence was not observed in any patients treated by surgery, including 30 patients treated by Mohs micrographic surgery (MMS). MAGEA3 was highly expressed in PNI SCC. MAGEA3 expression in PAM 212 SCC was associated with tumor growth and increased expression of cyclins A, B, and E. CRISPR-Cas9 MAGEA3 PAM 212 knockouts exhibited reduced growth in BALB/c mice. Conclusions: MAGEA3 expression is increased in human PNI SCC. We can mitigate against worst case outcome with surgery plus PORT. MAGEA3 merits further investigation as a potential biomarker for best candidates for surgery plus PORT.
Phase 1b/2, open label, multicenter, study of the combination of SD-101 and pembrolizumab in patients with advanced/metastatic melanoma resistant to anti-PD-1/PD-L1 therapy.
Authors: Asim Amin, Mohammed M. Milhem, Georgina V. Long, Christopher J. Hoimes, Theresa Michelle Medina, Robert Martin Conry, Christopher D. Lao, Gregory A. Daniels, Sunil A. Reddy, Robert Hans Ingemar Andtbacka, Minal A. Barve, Montaser F. Shaheen, Thomas Tueting, Michael Jon Chisamore, Emmett V. Schmidt, Albert Candia, Cynthia Chinedu Obiozor, Erick Gamelin, Robert Janssen, Antoni Ribas
Journal: Journal of Clinical Oncology (2019)

9555 Background: SD-101 is a synthetic CpG-ODN agonist of TLR9 that stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells - activating T cell anti-tumor responses. Pembrolizumab has demonstrated activity in melanoma. SYNERGY-001/KEYNOTE-184 study assesses the safety and preliminary efficacy of the combination of intratumoral SD-101 and intravenous pembrolizumab in PD1/PDL 1 resistant unresectable stage IIIC- IV melanoma. A prior phase 2 study with SD-101 at 8 mg per injection resulted in a 21.4% ORR in this population (Abstract 3781, ESMO 2018). We report preliminary data in this ongoing phase 2 trial evaluating efficacy at a lower SD-101 dose of 2 mg per injection. Methods: PD1/PDL 1 resistant melanoma patients received 2 mg of SD-101 intratumorally per lesion in 1-4 lesions (weekly x 4 doses followed by Q3W x 7). Pembrolizumab was administered at a dose of 200 mg intravenously Q3W. Scans were performed Q9W. Responses were assessed per RECIST v1.1. Results: 23 patients have been enrolled with baseline characteristics: median age 65 years; male: 77%; stage at screening: IIIC = 26%; IV = 57%, unknown = 17%; LDH &gt; ULN: 36%. Lines of prior therapy: 1: 52%; 2: 22%; &gt; 2: 26%. Prior anti CTL-A4 therapy: 39%. Best overall response on prior antiPD-1/PD-L1: PD: 88%, PR/CR: 8%, SD: 4%. Safety: Grade ≥3 treatment-related AEs: pneumonia and constipation (8%). No immune-related AEs reported. 2 non-treatment related SAEs reported from 2 patients: pneumonia and intussusception. 4 patients discontinued treatment early: 1 post SAE, per patient’s request, 3 due to PD. 1 patient died due to malignant pleural effusion after 1 dose of SD 101 and Pembrolizumab. No treatment related deaths. Efficacy: Mean duration on treatment: 39 days (1 - 169). mITT population: six patients at time of first CT scan at day 64: PR: 1, SD: 1, PD:3; non-evaluable: 1. 17 patients on study have not yet had first CT scan. Conclusions: The TLR9 innate immune stimulant, SD-101, in combination with pembrolizumab is well tolerated. Mature efficacy data, with additional first and second follow-up CT scans, will be presented at the meeting. Clinical trial information: NCT02521870.
Chronic health conditions (CHC) and late mortality in survivors of acute lymphoblastic leukemia (ALL) in the Childhood Cancer Survivor Study.
Authors: Stephanie Dixon, Yan Chen, Yutaka Yasui, Ching-Hon Pui, Stephen Hunger, Lewis B. Silverman, Daniel M. Green, Nina S. Kadan-Lottick, Kirsten K. Ness, Wendy Leisenring, Rebecca M. Howell, Kevin C. Oeffinger, Joseph Philip Neglia, Kevin R. Krull, Melissa M. Hudson, Leslie L. Robison, Ann C. Mertens, Gregory T. Armstrong, Paul C. Nathan
Journal: Journal of Clinical Oncology (2019)

10016 Background: The impact of evolving risk-stratified therapy on long-term morbidity and mortality in survivors of childhood ALL remains largely unknown. Methods: All-cause and health-related late mortality (HRM; captures death from late-effects occurring &gt; 5 yrs from diagnosis), subsequent (malignant) neoplasm [S(M)N], CTCAE graded CHC and neurocognitive outcomes were assessed in 5-yr survivors of ALL diagnosed &lt; 21 yrs of age from 1970-99. Therapy combinations defined 6 groups: 1970s-like ( 70s), standard and high risk 1980s- and 1990s-like ( 80sSR, 80sHR, 90sSR, 90sHR), relapse/transplant ( R/BMT). Cumulative incidence and standardized mortality ratios (SMR) were calculated. Piecewise exponential and log-binomial models estimated rate ratios (RR) with 95% confidence intervals (CI). Results: Among 6148 survivors (median age 31.5 yrs), 15-yr cumulative incidence of all-cause mortality was 5.8% (CI 5.3-6.2) and HRM was 1.5% (1.2-1.7). Compared to 70s, HRM was lower for 90sSR and 90sHR (RR 0.1, CI 0.0-0.3; 0.2, 0.1-0.7), similar to that in the US population (SMR; CI: 90sSR 1.1; 0.6-1.9, 90sHR 1.9; 0.8-3.7). 20-yr cumulative incidence of SN was 3.5% (CI 3.1-3.9). Compared to 70s, 90sSR had lower risk of benign meningioma (RR 0.1, CI 0.0-0.3) and SMN (0.3, 0.1-0.6) with no absolute excess risk compared to the US population. 90sSR was associated with a lower risk of CHCs (Table). Conclusions: More recent risk-stratified therapy has succeeded in reducing risk of late mortality and CHCs among long-term survivors of ALL. [Table: see text]
Phase II trial of nivolumab with chemotherapy as neoadjuvant treatment in inflammatory breast cancer.
Authors: Maryann J. Kwa, Nancy Tray, Francisco J. Esteva, Yelena Novik, James L. Speyer, Ruth Oratz, Marleen Iva Meyers, Franco Muggia, Victor Ty, Andrea Troxel, Robert Schneider, Sylvia Adams
Journal: Journal of Clinical Oncology (2019)

TPS604 Background: Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer with poor prognosis and is often resistant to neoadjuvant chemotherapy with risk of early recurrence and systemic spread of disease. PD-L1 expression in IBC is frequent (Bertucci et al. Oncotarget 2015), and blockade of the PD-1/PD-L1 axis with checkpoint inhibitors has emerged as a promising treatment to enhance anti-tumor immunity and clinical response. We hypothesize that PD-1 blockade with nivolumab in combination with neoadjuvant (primary) chemotherapy will increase the rate of pathologic complete response (pCR) and reduce risk of recurrence in patients with IBC. Methods: This is a single-arm open-label multicenter phase II study of nivolumab with neoadjuvant chemotherapy in patients with non-metastatic IBC (n = 52) (ClinicalTrials.gov: NCT03742986). All breast cancer subtypes (based on ER/PR/HER2) will be allowed. Patients will receive nivolumab 360 mg IV on day 1 (21-day cycle) for four cycles in addition to standard chemotherapy. Cohort 1 (patients with triple negative breast cancer or hormone receptor-positive (HR)/HER2-negative IBC) will receive nivolumab in combination with paclitaxel followed by doxorubicin and cyclophosphamide (AC). Cohort 2 (patients with HER2-positive IBC) will receive nivolumab in combination with a taxane (docetaxel or paclitaxel), trastuzumab, and pertuzumab followed by AC. All patients will then undergo mastectomy followed by radiation. The primary study objective is pCR rate (ypT0/Tis ypN0). Secondary objectives will be safety, tolerability and invasive recurrence-free interval. Association of correlative biomarkers with pCR and sensitivity or resistance to therapy with the combination of nivolumab and chemotherapy will be evaluated. Analyses will include mutational and neoantigen load, tumor-infiltrating lymphocytes (TILs) by histopathological assessment, T-cell receptor (TCR) by immunosequencing, and immune gene profiles in the tumor. PD-L1 expression in tumor tissue is not required for enrollment but will be assessed as a predictive marker. Clinical trial information: NCT03742986.
<i>PMEPA1</i> gene isoforms to indicate disease progression in solid tumors.
Authors: Shashwat Sharad, ZsÃ£Â³fia Sztupinszki, Zoltan Szallasi, Inger L. Rosner, Shiv Srivastava, Albert Dobi, Jennifer Cullen, Hua Li
Journal: Journal of Clinical Oncology (2019)

e16580 Background: Dysfuncitons of androgen and TGF-β signaling play important roles in prostate tumorigenesis. PMEPA1 gene has been defined as an androgen and TGF-β responsive gene which inhibits androgen and TGF-β signaling via negative feed-back loops. Our previous data has established that PMEPA1 distinct isoforms ( PMEPA1-a and PMEPA1-b) with disparities within N-terminus protein sequences navigate different androgen/TGF-β signaling regulations. In this study, the roles of PMEPA1 isoforms in disease progressions were investigated in solid tumors of prostate (CaP), breast, lung and colon. Methods: RNA seq data from total 2479 solid tumor samples in the TCGA dataset were used to study the correlation between expressions of PMEPA1 isoforms and disease progression including Gleason score, pathology stages, progression free survival rate (PFS) and overall survival rate (OS). The cohort is composed of 482 prostate, 1049 breast, 499 lung and 449 colon cancer patients. Results: In CaP, the TCGA data analysis showed that lower transcript level of PMEPA1-b isoform associated with higher Gleason scores and lower progression free survival rate (PFS) (P = 0.014) and worse overall survival rate (OS) (P &lt; 0.01). The ratio of mRNA levels of PMEPA1-a versus PMEPA-b indicated higher Gleason score, lower PFS rate (P = 0.0063) and worse OS rate (P = 0.0042). In contrast, higher expression of both PMEPA1-a and PMEPA- b associated with lower PFS (P = 0.023 and 0.028, respectively) in breast cancer. And the enhanced ratio of PMEPA1-a/ b was also found to indicate lower PFS (P = 0.016) and worse OS (P = 0.016) in breast cancer. Similarly, the increased transcript levels of PMEPA1-a and PMEPA1-b isoforms significantly associated with lower PFS and worse OS rates in lung and colon cancer. The expression of PMEPA1 isoforms was not found to associate with pathology stages of diseases. Conclusions: Our data establish the biomarker potential of PMEPA1 gene isoforms ( a and b) indicating more aggressive disease progressions in 4 solid tumors, further underscoring the PMEPA1 isoform specific biological functions to differentiate regulation of androgen and TGF-β signaling in cancer cells.