tbuckley/cabot-search huggingface dataset:
Phase 1b/2, open label, multicenter study of intratumoral SD-101 in combination with pembrolizumab in anti-PD-1 treatment naïve patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).
Authors: Ezra E.W. Cohen, Lisle Nabell, Deborah J.L. Wong, Terry A Day, Gregory A. Daniels, Mohammed M. Milhem, Sanjeev Deva, Michael B. Jameson, Orlando Guntinas-Lichius, Mohammed Almubarak, Robert Matthew Strother, Eric D. Whitman, Michael Jon Chisamore, Cynthia Chinedu Obiozor, Teresa Bagulho, Albert Candia, Erick Gamelin, Robert Janssen, Alain Patrick Algazi
Journal: Journal of Clinical Oncology (2019)

6039 Background: SD-101, a synthetic CpG-ODN agonist of TLR9, stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells - activating T cell anti-tumor responses. Pembrolizumab has demonstrated activity in HNSCC. Study DV3-MEL-01 (NCT02521870) assesses safety and efficacy of SD-101 in combination with pembrolizumab in patients with recurrent/metastatic HNSCC. We have previously reported a 27.3% ORR in 22 patients receiving 8 mg SD-101/injection in the modified ITT after at least 2 CT scans due to late responses (Abstract 3560, ESMO 2018). Higher efficacy at a lower SD-101 dose, 2 mg/injection, has been reported in advanced melanoma patients (LBA 45, ESMO 2018). Consequently, this dose is now being assessed in HNSCC. We report preliminary data with the 2 mg/injection dose in 23 patients in mITT at the first CT scan. Methods: Anti-PD-1/PD-L1 naïve patients received 2 mg SD-101 intratumorally in 1 - 4 lesions (weekly x 4 doses then Q3W x 7 doses). Pembrolizumab is was administered IV at 200 mg Q3W. Responses were assessed per RECIST v1.1. Results: 28 patients enrolled: median age 63 y/o, male 68%; ECOG PS 0-1 (18%/82%); mean prior lines of systemic therapy 1 (0-3); mean treatment duration 70 days (1-253). Primary tumors: 19 (68%) oropharyngeal; 3 (10%) laryngeal; 2 (7%) hypopharyngeal; 4 (14%) unknown. Mean number of target lesions: 1.82 (1 to 5). HPV status: 7 (25%) +, 9 (32%) -, 12 (43%) unknown. 18 (64 %) discontinued treatment: 12 (42%) due to PD, 4 (16%) deaths, 1 (3%) consent withdrawn, 1 (3%) went to hospice. Mean follow up 2.70 months. Safety: 16 non-treatment-related SAEs in 9 patients. 2 treatment-related Grade ≥3 AEs: sepsis (4%) and lymphopenia (4% ). No treatment-related deaths. Efficacy: 23 patients in the mITT population with first CT scan at day 64: ORR: CR: 2, PR: 3 (22%); SD: 6 (26%), PD: 7 (30%), non-evaluable: 5 (22%). Disease control rate (48%). 5 patients on study have not had a CT scan. Conclusions: SD-101 with Pembrolizumab shows early promising data and is well tolerated. Additional follow-up scans from both dose cohorts are being evaluated and will be presented. Clinical trial information: NCT02521870.
First results of a prospective registry in unresectable locally advanced or metastatic breast cancer patients: GEICAM/2014-03 (RegistEM).
Authors: Carlos Jara, Isabel Alvarez, Mireia Margeli Vila, Cesar Augusto Rodriguez, Purificacion Martinez, J. Norberto Batista, Jose Luis Alonso Romero, Silvia Antolín Novoa, Sofía Ruíz, Angel Guerrero, Ignasi Tusquets, Antonio Anton, Jose Ignacio Chacon, Álvaro Rodríguez-Lescure, Ariadna Tibau Martorell, Silvia Varela Ferreiro, Juan José Miralles, Susana Bezares, Federico Rojo, Sara López-Tarruella
Journal: Journal of Clinical Oncology (2019)

1077 Background: In Spain there is limited prospective data for unresectable locally advanced breast cancer (ULABC) or metastatic breast cancer (MBC) patients (pts) treated as per clinical practice. RegistEM study will provide epidemiological, pathological and clinical data, including treatments given for different disease stages. Understanding the real distribution of the different BC subtypes is the primary objective. Methods: This is a non-interventional cohort study enrolling approximately 1,400 pts with advanced disease diagnosed from January 2016 to December 2018, either after recurrence or as first diagnosis, in 38 Spanish sites. Biological samples (primary tumor, metastatic lesions, blood) are currently being collected. In this first analysis, we include 489 pts who met study criteria before October 31, 2017. All data are described in two subgroups: on the most recent tumor lesion or on the primary breast tumor. Results: At first diagnosis, 67.9%, 31.5% and 0.6% of pts had early BC (EBC), MBC and ULABC, respectively. In the total analysis population, median age at diagnosis of advanced disease was 59.6 years, most of pts were white (98.2%), female (99.4%) and postmenopausal (70%). Family history of BC and ovarian cancer was reported in 5.7% pts. In ~390 pts BC clinical subtypes distribution was luminal B(HER2-)-like (~55%), luminal B(HER2+)-like (~16%), luminal A-like or triple negative (TN) (~10% each) and HER2 enriched-like (~8%). Median time to recurrence (years) in EBC pts was: luminal A-like 5.8, luminal B(HER2-)-like 5.1, luminal B(HER2+)-like 3.9, HER2 enriched-like 2.7 and TN 1.7. Bone (59%), visceral (58%) and lymph node (27%) lesions were the most frequent metastatic locations. The two most frequent therapies in first line consisted in: endocrine therapy (ET) (47%) and ET+biological therapy (BT) (29%) for luminal A-like; ET (32%) and ET+BT (32%) for luminal B(HER2-)-like; chemotherapy (CT)+ET+BT (43%) and CT+BT (24%) for luminal B(HER2+)-like; CT+BT (68%) and CT (16%) for HER2 enriched-like; CT (59%) and CT+BT (34%) for TN. Conclusions: These first data confirm that luminal B (HER2-)-like subtype is the most predominant in MBC.
Association of BAP1 alterations with malignant pleural mesothelioma treated with trimodality therapy.
Authors: Marjorie Glass Zauderer, Hira Rizvi, Mariel A. DuBoff, Prasad S. Adusumilli, Valerie W. Rusch, Jennifer L. Sauter, Marc Ladanyi, Andreas Rimner
Journal: Journal of Clinical Oncology (2019)

8552 Background: Trimodality therapy with pleurectomy/decortication, cytotoxic chemotherapy, and adjuvant pleural intensity modulated radiation therapy (IMPRINT) is an emerging standard of care for locally advanced epithelioid mesothelioma (Rimner, Zauderer et al. JCO 2016). Some patients, however, progress rapidly and we therefore sought to identify potential predictive markers of response to this treatment. Given the putative role of BAP1 in DNA damage repair, we hypothesized that alteration in BAP1 would be associated with improved local control after radiation therapy. Methods: We identified patients previously treated at our institution with IMPRINT to a median dose of 4680cGy in 26 fractions. Targeted next generation sequencing was performed with MSK-IMPACT on archival tissue samples. Chart review was undertaken for clinicopathologic features and outcome data. Results: MSK-IMPACT testing was successfully performed on 58 patients who completed IMPRINT. The majority were male with a median age of 70 years. Ninety-seven percent had epithelioid subtype while 3% were biphasic with predominantly epithelioid histology. Median overall survival was 30.2 months with a median follow-up of 45.3 months, consistent with prior reports. Somatic BAP1 mutations were identified in 34% of the specimens. Those with BAP1 mutant tumors had a median time to local failure of 22.4 months (IQR 10.9 – 36.9 months) while those with BAP1 wild type tumors only had a median of 12.1 months (IQR 8.7-15.85 months) to local failure (p = 0.057). We identified a trend towards improved overall survival among those with BAP1 altered tumors compared to those with BAP1 wild type (HR = 0.61, p = 0.14). Conclusions: BAP1 alteration may be associated with improved duration of local control and improved overall survival after IMPRINT therapy. Further analysis and validation in a large data set is needed and a platform for identifying and validating predictive biomarkers should be included in the planned NRG randomized trial of IMPRINT.
Case 27-1988
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Marshall M. Kaplan, Carolyn C. Compton
Journal: New England Journal of Medicine (1988)

Presentation of CaseA 25-year-old man was admitted to the hospital because of hematemesis.He was well until one year earlier, when upper gastrointestinal tract bleeding developed, and the patient was informed of hepatic enlargement; no medical follow-up was arranged. The patient was well thereafter except for fatigue during the several weeks preceding entry. One day before admission the patient became nauseated. That evening he vomited brightred clots of blood. He was taken by ambulance to another hospital; he continued to vomit large volumes of fresh blood en route and was lethargic but arousable; saline solution was infused by vein. . . .
A multicenter phase II trial of rucaparib in combination with nivolumab as maintenance therapy for patients with advanced biliary tract cancer.
Authors: Vaibhav Sahai, Nguyen H. Tran, Kent A. Griffith, Mark Zalupski
Journal: Journal of Clinical Oncology (2019)

TPS4153 Background: Patients (pts) with advanced biliary tract cancers (BTC) have a poor prognosis with a median overall survival (OS) less than 12 months. Using whole exome NGS, 26 (49%) pts in a 53 pt cohort had either DNA damage repair (DDR) pathway mutations (somatic and/or germline, n = 18), or isocitrate dehydrogenase 1 (IDH1) mutations (n = 8), and may have potentially benefited from PARP inhibition. Further, disruption of the mutated DDR pathways with a PARP inhibitor may result in increased mutational burden and neoantigens leading to immunogenicity, thus providing the rationale for combination with a PD-1 antibody. This phase 2 trial is designed to investigate the role of a PARP inhibitor in combination with a PD-1 antibody in pts with advanced BTC. Methods: Key eligibility criteria include histologically confirmed advanced, unresectable biliary adenocarcinoma (intra- or extra-hepatic, and gallbladder) without progression after 4-6 months of 1 st line platinum-based systemic chemotherapy, measurable disease per RECIST v1.1, ECOG PS 0-1, Child-Pugh A or B7, and absence of autoimmune disease or chronic steroid use. Primary objective is to evaluate progression-free survival (PFS) rate at 4 months. Secondary objectives include evaluation of objective response rate per immune related (ir)RECIST criteria, median PFS and OS, and safety in this patient population. Exploratory objectives include identification of predictive biomarkers of response and mechanisms of resistance through serial biopsies and blood collection (pre, on and post therapy), including sequential whole exome/transcriptomic analysis with immune cell subset analysis. Treatment includes rucaparib 600 mg PO BID on days 1-28 with nivolumab 240 mg on days 1, 15 Q4 weeks. In absence of disease progression, pts may continue therapy up to 2 years. Accrual goal is 32 evaluable pts. Using a null hypothesis value of a 63% PFS rate at 4 months, and an 85% alternative hypothesis, this ongoing study has 80% power, with a one-sided alpha of 0.05 to identify treatment efficacy in the study arm. Clinical trial information: NCT03639935.
Unselected germline screening in pancreatic adenocarcinoma yields high rates of pathogenic and likely pathogenic variants (PV) in hereditary cancer susceptibility genes.
Authors: Carol Cremin, Michael Lee, Quan Hong, Carolyn Hoeschen, Steve Kalloger, Joanna Karasinska, Anna Mackenzie, Mary McCullum, Jennifer E Nuk, James Thomas Topham, Sophie Sun, David F. Schaeffer, Daniel John Renouf, Kasmintan A Schrader
Journal: Journal of Clinical Oncology (2019)

1582 Background: Recent literature cites a germline mutation rate of 3.9-15.1% in patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) depending on breadth of genes tested, pre-selection of high-risk history and population substructure. True incidence of germline mutations in PDAC is unknown in unselected population. Methods: All patients (pts) diagnosed with PDAC in the province of British Columbia, Canada and referred to the Hereditary Cancer Program, were eligible to undergo 30 gene Color saliva kit testing under a research protocol, or clinical multigene testing if they met existing local criteria regardless of whether they signed on to the protocol. Any healthcare provider or patients themselves could refer. Results: 243 pts were referred between August 2016 and October 2018 but 25.1% (61) declined and 9.1% (22) died before testing. Of the 141 pts who consented to research protocol and completed germline testing, median age was 64 (46.1-81.0), 68.8% were European, 1.4% Ashkenazi Jewish heritage, 42% male, 61% non-smoker, 24.1% had personal history of a second cancer and 39% had metastatic disease. Baseline characteristics were similar between the PV positive and uninformative group. 20/25 PV were in known PDAC susceptibility genes with cascade screening implications (ATM (9), BRCA2 (4), BRCA2/ATM (1), CDKN2A (4), and MSH2 (2)). Excluding the 3 PV identified through carrier testing (1) and prior research identification (2), the rate of PV in unselected, unrelated PDAC cohort is 22/138 (15.9%). Utilizing previous NCCN criteria for BRCA1/BRCA2 testing or for familial pancreatic cancer did not appear to select for patients with higher risk of PV positive (12/65 (18.4%) PV positive rate versus 13/76 (17.1%) in those that didn’t meet criteria). Previous criteria would have missed 52% (13/25) PV in ATM (6), BRCA2/ATM (1), BRCA2 (2), MSH2 (2), NBN (1), CHEK2 (1). To date, a third of families with PV identified have accessed cascade testing in 38 relatives. Conclusions: Given the high incidence of 15.9% PV in hereditary cancer susceptibility genes, our data support recommendations for universal germline genetic testing of PDAC pts.
Final results of early non-invasive gastric cancer detection study using the serum pepsinogen test method in Croatian patients.
Authors: Dragan Trivanovic, Stjepko Plestina, Lorena Honovic, Renata Dobrilla-Dintinjana, Jelena Vlasic Tanaskovic
Journal: Journal of Clinical Oncology (2019)

e15551 Background: Gastric cancer (GC) is the 8th most common cancer cause of cancer deaths in Croatia and 2nd most common cause of cancer deaths worldwide. GC of the intestinal type is usually preceded by a chronic atrophic gastritis which is a precancerous change in the stomach. Methods: A reliable diagnostic tool for the early detection of the GC is essential. Screening programs have led to an improvement of overall 5-y survival rate for GC in Japan and Pepsinogen test method was suggested to reduce mortality from gastric cancer. The gold standard for the diagnosis of GC is the pathohistological study of biopsies obtained during an upper GI endoscopy, an invasive method that is too complicated for use in population screening and patients with comorbidity. We have conducted a prospective single center clinical study over a period of &gt; 2 years to evaluate sensitivity and specificity of reagents, and to determine if these reagents can be part of routine. Inclusion criteria for the study were: signed informed consent, life expectancy &gt; 12, and exclusion criteria were: previous treatments for any malignancy, current usage of IPP or NSAIDs medication, poor ECOG performance status ≥3, known history of H. pylori eradication treatment or gastric surgery. We previously reported preliminary results of PG test method in Croatian population. Here, we present mature data after median follow-up of 26 months. Statistical analyses were performed by using a Mann-Whitney U test, multiple logistic regression and the receiver operating characteristics (ROC) to evaluate the predictive power of biomarkers. Results: Blood samples have been collected from patients with suspicious to GC attending for endoscopy or surgery. We used cut off points to evaluate gastric cancer risk: PGI ≤ 70 and PGI/II ratio ≤ 3.0. Of the 116 patients, 25 patients had GC and 91 had non-malignant pathology on tissue biopsy (like atrophic gastritis). Based on an optimal cut-off value calculated by ROC curve analysis had accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of 86.2%, 60.0%, 93.4%, 65.2%and 89.47%, respectively, for the diagnosis of GC. AUC was 0.767 (95% CI 64.0-89.0). Conclusions: The single use of pepsinogen tests is not sufficient for stomach cancer detection; however, it provides a valuable test for selecting a population that needs further diagnosing. Meanwhile, its high specificity could also help to avoid unnecessary endoscopy, especially in older population or patients with heavy burden of comorbidity. Clinical trial information: 2016-0019-34.
Acquired NF2 mutations confer resistance to HER2 targeted therapy in HER2-mutant breast cancer.
Authors: Xuelu Li, Jing Ma, Bo Pan, Zuowei Zhao, Man Li
Journal: Journal of Clinical Oncology (2019)

e12518 Background: Preclinical studies suggest that HER2 mutations lead to constitutive HER2 activation, but knowledge about effective treatment options and clinical resistance mechanisms remain uncharacterized. Methods: We performed dynamic monitoring of &gt;300 serial plasma samples collected from 49 metastatic breast cancer patients used targeted sequencing of 425 clinically relevant genes, to detect HER2 mutations and track resistance to HER2-targeted treatments in HER2-mutant breast cancer. Results: We identified activating HER2 mutations (S310F、D769Y、V777L、778insGSP) in ctDNA and paired tissue samples from four patients with ER positive/HER2-amplification negative metastatic breast cancer, who had developed resistance to multi-line (&gt;3) endocrine therapy. Two patients achieved a durable partial response (approximately 1 years) to trastuzumab combined with everolimus. Intriguingly however, analysis of ctDNA revealed that the NF2 mutation was acquired from a patient with HER2 S310F/V777L who had developed resistance to HER2-targeted treatments. We showed that HER2 S310F / D769Y/V777L/778insGSP mutations were constitutively active, and T47D and MCF7 overexpressing HER2 S310F/V777L/778insGSP were sensitive to HER2 targeted therapies combined with everolimus. Consistent with our clinical findings, NF2 knockdown in HER2 S310F/V777L/778insGSP overexpressing T47D and MCF7 contributed to HER2-targeted therapy resistance. Furthermore, MEK inhibitor remarkably sensitized NF2 knockdown and HER2 mutations co-expressing T47D and MCF7 cells to trastuzumab. Conclusions: Dynamic monitoring of ctDNA could provide the candidate resistance genes for metastatic HER2-mutant breast cancer. Our findings validated NF2 mutations as a potential mechanism of resistance to HER2-targeted therapy, and the combined use of HER2 and ERK inhibitors may overcome resistance to HER2 targeted therapy in HER2-mutant breast cancer.
Quantitative assessment of immune cell populations and associations with clinical outcomes in African-American (AA) versus Caucasian triple-negative breast cancer (TNBC).
Authors: Tess O'Meara, Vesal Yaghoobi, Kim Blenman, Vasiliki Pelekanou, Andrea Silber, David L. Rimm, Lajos Pusztai
Journal: Journal of Clinical Oncology (2019)

e14180 Background: Tumor infiltrating lymphocytes (TILs) are powerful prognostic and predictive factors in TNBC. We hypothesized that survival differences in TNBC by race may be caused by differences in the tumor immune microenvironment. We assessed racial differences in the extent and composition of immune infiltration in TNBC and correlated these differences with clinical characteristics and disease-free survival (DFS). Methods: Formalin fixed paraffin embedded TNBC samples and clinical information were collected for n = 43 AA and n = 43 Caucasian cases, matched by diagnosis date and stage. Stromal TILs were assessed on H&amp;E-stained slides. Multiplexed immunofluorescence was performed to quantify CD68 (macrophage), CD8 (cytotoxic T cell) and PD-L1 protein expression in the whole-section, tumor and stromal compartments. Average expression for each marker was calculated over all fields of view. Cox proportional hazards were used to assess associations between DFS, staining markers and clinical variables. Results: Characteristics of AA and Caucasian cases were not significantly different. There were 14 and 8 recurrences in the AA and Caucasian cohorts, respectively (median follow-up 8.7 vs 9.4 yrs). TIL counts (p = 0.031) and overall CD68 expression (p = 0.005) were higher in AA compared to Caucasian patients. 21% percent of AA cases had TIL predominant phenotype versus 3% of Caucasians, but CD8 expression was similar by race. PD-L1 expression was higher in stroma compared to tumor across all patients (median 401 vs 267 au, p = 0.002) and did not differ by race. Higher overall and stromal PD-L1 expression were associated with better DFS in the entire population (median 3501 vs 1895 days, p = 0.0009) and in each race separately. Higher CD68 expression was also associated with better DFS (median 3015 vs 2111 days, p = 0.0004). In multivariate analysis of DFS, stage at presentation remained significant (p = 0.002) in addition to PD-L1 and CD68 expression. Conclusions: AA TNBC had higher TIL counts and CD68 expression but similar CD8 and PD-L1 expression compared to Caucasians. High CD68 and PD-L1 expression were associated with better DFS in both race cohorts.
The ability of isolated fine needle aspiration of lymph nodes to provide complete diagnostic information without necessitating additional diagnostic procedures: A retrospective cohort study.
Authors: Nathan Tidwell, Taylor Leslie Barnett, Connor H Thrun, Brendan C Graham, Lindsey Jean Graham
Journal: Journal of Clinical Oncology (2019)

e18341 Background: Diagnostic fine needle aspiration (FNA) of pathologically enlarged lymph nodes is a relatively safe, quick, and well-tolerated procedure that can be quickly analyzed to identify the presence of malignant cells. Though proven very useful to assess for the presence or absence of malignancy for staging purposes, the procedure’s ability to provide adequate tissue to appropriately diagnose a new malignancy and perform all necessary predictive and prognostic studies has not been explored. Methods: We retrospectively reviewed clinical records of patients who underwent FNA of a pathologically enlarged lymph node for the purpose of obtaining a tissue diagnosis at our institution between January 2010 and December 2015. We then assessed the percentage of patients that required a second diagnostic procedure independent of the FNA result. Procedures done for therapeutic purposes (such as resection) were not counted as a second procedure. We also collected data on the type of procedure used to obtain FNA, patient history of malignancy, and whether the diagnosis was benign or malignant. Results: We identified 594 FNA procedures that fit the study criteria. Of these, 277 (46.6%) required an additional diagnostic procedure. Among the 277 that required a second procedure, 237 (85.6%) were benign and 40 (14.4%) were malignant on primary FNA (P &lt; 0.0001). Of the 237 benign FNAs that required a second procedure, 84 (35.5%) had the diagnosis changed to malignant after the second procedure (P &lt; 0.001). There was no difference between procedure used to obtain the FNA (bronchoscopy, endoscopy, percutaneous) or patient age in the need for a second procedure. Conclusions: Though fine needle aspiration is a useful procedure for establishing the presence or absence of metastatic disease, our analysis suggests that the ability of the procedure to reliably diagnose or provide sufficient tissue for ancillary testing is limited. Nearly half of the patients in this study were subjected to the risks, cost, and diagnostic delay associated with a second procedure.