tbuckley/cabot-search huggingface dataset:
Novel PET/CT imaging biomarkers of CB-839 in combination with panitumumab and irinotecan in patients with metastatic and refractory RAS wildtype (WT) colorectal cancer: A phase I/II study.
Authors: Satya Das, Dana Backlund Cardin, Laura Williams Goff, Jordan Berlin, Michael Schulte, H. Charles Manning, Robert J. Coffey, Jennifer Whisenant, Rachel Krumsick, Kristen Keon Ciombor
Journal: Journal of Clinical Oncology (2018)

TPS3616 Background: Irinotecan plus panitumumab is active in RAS WT metastatic CRC (mCRC) patients who progress on 5-FU based regimens. Inevitably, patients develop resistance to EGFR inhibition; one such pathway is mediated by the enzyme glutaminase, which converts glutamine to glutamate and is a downstream effector of the EGFR/RAS pathway. Inhibition of this pathway with the selective glutaminase inhibitor CB-839 has stopped growth of cetuximab-sensitive and -resistant HLA-7 CRC cell lines. Greater anti-tumor response with the doublet of cetuximab (or panitumumab) and CB-839 was seen in mouse xenografts of the human CRC line SW48 than with either agent alone. Given this data, we proposed the combination of CB-839 plus panitumumab in RAS WT mCRC patients; to demonstrate on target effect of the therapy, we are utilizing two PET tracers, one which recognizes glutamine and the other glutamate. In addition to safety and efficacy aims, another aim of our study is to correlate SUV changes in pre-treatment and post-cycle 1 carbon-11-labeled glutamine (11C-glutamine) and (4S)-4-(3-[18F]fluoropropyl)-L-glutamate (18F-FSPG) PET with clinical outcome and glutamate levels in plasma. Methods: NCT03263429 is a single arm phase I/II study exploring the combination of CB-839, panitumumab ± irinotecan in RAS WT mCRC patients with at least one prior line of chemotherapy exposure. Phase I has 2 dose levels of CB-839 BID (600 mg and 800 mg) administered with panitumumab 6 mg/kg and irinotecan 180 mg/m2 D1 and D15 each 28-day cycle. Dose escalation is being performed according to a Bayesian continual reassessment method. The Phase II study evaluates CB-839's ability to reverse panitumumab resistance in EGFR inhibitor refractory patients. Irinotecan is included in the phase I for future potential studies in panitumumab-naïve patients. The primary objectives of the phase I and II portions of the study are to demonstrate the maximum tolerated dose and overall response rate of the combination, respectively. A Simon two-stage design is being used in phase II; if ≥ 1 response is seen in the first 10 patients, accrual will continue until 29 patients are enrolled. Clinical trial information: NCT03263429.
PD-L1 expression and TMB status in newly diagnosed metastatic non-small cell lung cancer and their effect on prognosis after EGFR-TKI or platinum-based chemotherapy.
Authors: Yanhui Chen, Yating Wang, Tao Zhou, Wanning Yang, Bohang Yang, Ying Hu, Wenbo Han, Hui Zeng, Henghui Zhang
Journal: Journal of Clinical Oncology (2018)

e24294 Background: Programmed cell death 1 ligand (PD-L1) expression and the tumour mutation burden (TMB) are distinct biomarkers of response to anti-PD-1/PD-L1 therapies. The proportion of PD-L1-positive, high-TMB patients and their overlap in newly diagnosed metastatic non-small cell lung cancer (NSCLC) and their effect on prognosis after receiving epidermal growth factor receptor (EGFR)-TKIs or platinum-based chemotherapy were evaluated. Methods: One hundred eighty-seven NSCLC patients were included. Tumour tissue samples were collected to detect PD-L1 expression and TMB status by immunohistochemistry (using the SP142 antibody) and targeting next-generation sequencing of specific genes, respectively. Correlations between PD-L1 or TMB with clinicopathological characteristics were analysed. Results: The PD-L1-positive rates of tumour cells were 37% (≥1%) and 20% (≥50%) in adenocarcinoma (ADC); 55% (≥1%) and 27% (≥50%) in squamous cell carcinoma (SQCC). PD-L1 in tumour cells was significantly associated with the SQCC subtype (P= 0.030), male sex in ADC (P< 0.001), wild-type ADC (P= 0.049) and survival outcome of ADC (P< 0.0001). The proportion of high TMB (≥13.7 mutations/Mb) in SQCC was higher than that of ADC (P= 0.024). The TMB level did not correlate with survival. There were overlaps between high TMB and PD-L1 expression in patients of SQCC, wild-type ADC and EGFR-mutant ADC (22% vs. 10% vs. 3%, respectively), but the positive degree of PD-L1 did not correlate with TMB. The ADC PD-L1-negative plus low/moderate-TMB group had the longest survival time compared with those that were PD-L1 positive with low/moderate TMB or those that were PD-L1 positive with high TMB (41 mon vs. 8 mon vs. 7 mon, respectively; P< 0.0001); this pattern was similar to that observed in wild-type ADC patients (32 mon vs. 6 mon vs. 8.5 mon, respectively; P= 0.0005). Conclusions: There were overlaps between the high-TMB and PD-L1-positive population, but the positive degree of PD-L1 did not correlate with the TMB value. PD-L1 expression was an independent predictor of poor prognosis in ADC patients, but the effect of TMB level on prognosis was small.
Characterization of the colorectal cancer immune microenvironment using a novel high-plex protein analysis technology.
Authors: Douglas Hinerfeld, Sarah Elizabeth Church, Chris Merritt, Yan Liang, Joseph M Beechem
Journal: Journal of Clinical Oncology (2018)

e15139 Background: Spatial characterization of immune microenvironment within tumors enables a better understanding of immunology and oncology. However, it has proven difficult to perform such studies in a highly multiplexed manner using limited samples. To address this unmet need, we have developed an imaging and tissue-sampling platform designed to simultaneously analyze up to hundreds of tumor and immune proteins in a single FFPE tissue section with spatial resolution. This novel technology, called Digital Spatial Profiling (DSP) was applied to the characterization of therapeutic response of colorectal cancer patients to immunotherapy. Methods: FFPE colorectal tumor specimens were subjected to DSP to determine the spatial expression of 30+ immune-related proteins. Following antigen retrieval, sections were stained with a cocktail of 30+ DNA barcoded antibodies in combination with fluorescently labeled antibodies which were used to define the immune-enriched regions of the tumor. Using the fluorescent signal as a guide, regions of interest (ROI) were delineated followed by UV excitation of the defined ROI’s, which releases the antibody-bound DNA barcodes for downstream quantitation on the NanoString nCounter® technology. Results: Comparing colorectal tumors characterized as Microsatelite stable (MSS), DSP was able to differentiate immune hot and cold tumors despite MSS status. Since there are a subset of patients with MSS colorectal cancer that still responds to immunotherapy, this suggests DSP could ultimately be used to identify unique spatial biology and immune characteristics that might further expand beyond MSS and MSI status to help predict patients' response to therapy. Conclusions: Using this novel approach, we demonstrate multiplexed protein analysis of defined micro regions within a tumor enabling systematic interrogation of the immune microenvironment within the tumor. We demonstrate the ability of this technology to reveal immune biology that can point to novel biomarkers or therapeutic targets.
Active surveillance and deferred medical treatment (ASDT) in metastatic renal cell carcinoma (mRCC): Update of a single center experience and efficacy of medical treatment.
Authors: Philipp Ivanyi, Maria-Luisa Tiemann, Viktor GrÃ¼nwald, Hendrik Eggers, Arnold Ganser, Christoph Reuter
Journal: Journal of Clinical Oncology (2018)

4581 Background: ASDT is applicable to a fraction of mRCC patients (pts). We investigated clinical outcome of ASDT and report on efficacy of medical treatment (Rx). Methods: Between 4/2000-3/2016 patients (pts) with mRCC were identified from medical records, retrospectively. Pts alive ≥3 months after diagnosis of metastatic disease without Rx for ≥6 months were grouped as ASDT(+), all other pts were deemed ASDT(-). Overall survival (OS) and clinical progression free survival (cPFS) of administered Rx were analysed, as well as time from diagnosis mRCC to initiation of 2nd line treatment or death ( = time to failure of treatment strategy [TTFS]). Descriptive statistics, Kaplan-Meier and Log-rank analyses were applied. Results: 142/370 (38.4%) mRCC received ASDT for a median duration of 24.1 (95%CI:20.2-28.1) months (mo). ASDT pts showed a superior OS: 67.3 (95%CI:50-84.6) mo vs. ASDT(-): 30.4 (95%CI:25-35.9) mo (p < .001). ASDT pts received a median of 1 (range(r): 0-8) lines of Rx compared to ASDT(-) with median 3 (r:1-10) lines of Rx (p < 0.001). cPFS in either 1st (p = .052), 2nd (p = .062) and 3rd (p. = .067) line Rx tends to be superior in in ASDT(+) pts compared to ASDT(-). TTFS compared favourably in ASDT(+) vs. ASDT(-) pts with 37.3 (95%CI: 28.2-46.4) mo vs. 10.0 (95%CI: 8.8-11.2) mo. (p < .001). Conclusions: Clinical selection by expert opinion was able to identify pts with indolent disease and favorable OS. Deferred treatment did not impact efficacy of subsequent Rx in ASDT(+) pts. ASDT is a feasible approach in selected pts in high-volume centers.
Macrophages of distinct origins contribute to tumor development in the lung
Authors: Pierre-Louis Loyher, Pauline Hamon, Marie Laviron, Aïda Meghraoui-Kheddar, Elena Goncalves, Zihou Deng, Sara Torstensson, Nadège Bercovici, Camille Baudesson de Chanville, Béhazine Combadière, Frederic Geissmann, Ariel Savina, Christophe Combadière, Alexandre Boissonnas
Journal: The Journal of Experimental Medicine (2018)

Tissue-resident macrophages can self-maintain without contribution of adult hematopoiesis. Herein we show that tissue-resident interstitial macrophages (Res-TAMs) in mouse lungs contribute to the pool of tumor-associated macrophages (TAMs) together with CCR2-dependent recruited macrophages (MoD-TAMs). Res-TAMs largely correlated with tumor cell growth in vivo, while MoD-TAMs accumulation was associated with enhanced tumor spreading. Both cell subsets were depleted after chemotherapy, but MoD-TAMs rapidly recovered and performed phagocytosis-mediated tumor clearance. Interestingly, anti-VEGF treatment combined with chemotherapy inhibited both Res and Mod-TAM reconstitution without affecting monocyte infiltration and improved its efficacy. Our results reveal that the developmental origin of TAMs dictates their relative distribution, function, and response to cancer therapies in lung tumors.
c15-148: Phase I/II trial of concurrent chemohormonal therapy using enzalutamide and cabazitaxel in patients with metastatic castration resistant prostate cancer (mCRPC).
Authors: Julie Nicole Graff, Tomasz M. Beer, Joshi J. Alumkal, Dustin Kreitner, Delia Petreaca, George V. Thomas, Heather H. Cheng
Journal: Journal of Clinical Oncology (2018)

TPS5097 Background: The management of mCRPC has been both enhanced and complicated by the rapid emergence of at least five new agents that can lengthen survival. While great strides have been made in developing new agents for mCRPC, response rates and duration have remained modest, and men ultimately succumb to their disease. Historically, combined chemo-hormonal therapy has not improved outcomes for patients with prostate cancer, but earlier trials were hindered by lack of efficacious chemotherapy and weaker hormonal agents. In this study, we aim to determine if potential synergistic effects between two newer and more effective agents can be identified and exploited for therapeutic effect, and to obtain correlative biological information that may offer predictive and response value. Methods: An initial 3-12 study subjects will be treated with cabazitaxel at 25 mg/m2 on day 1 and enzalutamide 160 mg daily every 21 days. These subjects will be permitted to continue on cabazitaxel and enzalutamide until progression and will be included in the final analysis of efficacy. The trial will proceed to phase II stage at the dose of 25 mg/m2 if 0/3 or 1/6 patients receiving 25 mg/m2 had DLT. The dose de-escalation will happen if ≥2/3 or ≥2/6 patients receiving 25 mg/m2 had DLT. The trial will proceed to Phase II stage at the dose of 20 mg/m2 if 0/3 or 1/6 patients receiving 20 mg/m2 had DLT. In the absence of treatment delays due to adverse events, treatment with cabazitaxel and enzalutamide will continue for 6-10 cycles. Patients may then continue enzalutamide monotherapy on a 28-day cycle until progression or limiting toxicity. For the phase I portion of this trial an initial 3 study subjects were treated with cabazitaxel at 25 mg/m2 on day 1 and enzalutamide 160 mg daily every 21 days; no DLTs occurred. These subjects will be permitted to continue on cabazitaxel and enzalutamide until progression and will be included in the final analysis of efficacy. The phase II patients are treated with 25 mg/m2 cabazitaxel and 160 mg enzalutamide. The trial is open at 2 sites and managed by the Prostate Cancer Clinical Trials Consortium (PCCTC). Clinical trial information: NCT02522715.
Barriers to adherence in hematologic malignancies in a rural regional hospital network.
Authors: Darla K. Liles, C. Suzanne Lea, Tiffanie Nicole Moore, Chelsea Passwater, Bryan Dangott, Larrin Stewart, Charles Knupp
Journal: Journal of Clinical Oncology (2016)

e18189 Background: Adherence to complex oral medication regimens is important to achieving optimal clinical outcomes in patients with Multiple Myeloma (MM) and Chronic Myeloid Leukemia (CML). As part of an educational grant initiative, we provided education about MM and CML therapies to our regional oncology physicians and nurses at five clinics and assessed patient adherence as a marker of programmatic success. Methods: The ASK-12 survey, a validated, 12-question medication adherence survey, was administered to 42 MM and CML patients during routine visits to regional oncology clinics. Initial and follow-up surveys were administered between March-2015 and January-2016, with an average of five months between surveys. The survey, measured on a Likert scale (1=strongly disagree, 5=strongly agree) assessed inconvenience/forgetfulness, treatment beliefs, and behaviors, summing from 12 – 60. Lower scores indicate fewer barriers to adherence. Mean initial and follow-up ASK-12 scores were computed as paired t-tests in SPSS. Results: Thirty-onerespondents were majority MM (65%), African American (68%), and female (58%). Median years since diagnosis among MM and CML patients were 4 and 5 years, respectively. We saw significant improvement in mean adherence scores between 2 surveys across categories. Best category improved was inconvenience/forgetfulness. Behavioral factors scored weakest, with the least change. Conclusions: While based on a small group,patients reported greatest change in ‘not forgetting, getting re-fills, and taking pills >1 time per day’. Physician and nurse interaction with patients about medication adherence improved measures in forgetfulness category. More evaluation of behavioral factors influencing adherence is needed. While information bias cannot be eliminated, our patients consistently improved medication adherence with intentional education to providers. Improvement in medication adherence in rural oncology clinics, 2015-2016. Category Mean Adherence Score (n=31) p-value Initial Follow-Up Inconvenience/ Forgetfulness 6.23 5.68 .002 Treatment Beliefs 7.48 7.23 .023 Behavior 7.90 7.29 .044 Total Survey Score 21.61 20.03 <.001
Evaluation of the prognostic value of the lymph-node ratio in patients with colon cancer in the oxaliplatin era.
Authors: Darragh Connell, Brian Richard Bird, Derbrenn O'Connor
Journal: Journal of Clinical Oncology (2018)

e15666 Background: N stage for colon cancer is based on the absolute number of cancer-positive lymph nodes removed at surgery. Lymph-node ratio (LNR) is the ratio of the number of cancer-positive lymph nodes to the total number of nodes removed. In patients receiving adjuvant 5-fluorouracil (5FU), LNR has been shown to be a superior prognostic indicator than N stage. However, adjuvant 5FU/oxaliplatin has now become the new standard of care. There is limited evidence to show LNR retains its prognostic significance in this setting. The aim of this work is to determine whether LNR retains its prognostic significance when colon cancer patients are treated with oxaliplatin. Methods: Data was collected for all patients with stage 3 colon cancer treated with adjuvant oxaliplatin at a single institution between 2000 and 2015. End points were overall survival (OS) and disease-free survival (DFS). Based on previous work patients were stratified into three groups according to LNR (LNR1 < 0.11; LNR2 0.11 - 0.27; LNR3 > 0.27). These categories were related to the endpoints using Kaplan-Meier curves and Cox regression analysis. Results: 142 patients met the inclusion criteria. Using LNR1 as the reference category, the hazard ratios for OS were 1.54 (p = 0.26) for LNR2 and 0.53 (p = 0.23) for LNR3. The hazard ratios for DFS were 1.95 (p = 0.68) and 1.12 (p = 0.79) for LNR2 and LNR3, respectively. The Kaplan-Meier curves did not show a statistically significant relationship between LNR and OS (p = 0.10) or DFS (p = 0.13). Conclusions: LNR is not a useful prognostic indicator for colon cancer treated with 5FU/oxaliplatin.
Frequency and factors predictive of aberrant drug behavior in patients presenting to outpatient supportive care center at a comprehensive cancer center.
Authors: Sriram Yennu, Tonya Edwards, Joseph Anthony Arthur, Janet L. Williams, Zhanni Lu, Suresh Reddy, Eduardo Bruera
Journal: Journal of Clinical Oncology (2017)

10118 Background: Opioid misuse is a growing crisis in cancer patients. Cancer patients at risk of aberrant drug behaviors (ADB) are frequently underdiagnosed in routine cancer care. The aim of this study was to determine the frequency and factors associated with ADB using the “Screener and Opioid Assessment for Patients tool” (SOAPP-14) in cancer patients seen at the outpatient supportive care center. We also examined the screening performance of Cut Down, Annoyed, Guilty, and Eye Opener (CAGE-AID) as compared to The SOAPP-14 as a gold standard. Methods: In this retrospective study, 1108 consecutive patients referred to supportive care clinic were reviewed. Patients were eligible if they were ≥18 yrs, have a diagnosis of cancer, and were on opioids for pain for atleast a week. Patients’ demographics, the Edmonton Symptom Assessment Scale (ESAS), SOAPP-14, and CAGE-AID scores were analyzed. ADB+ was defined as SOAPP-14 score ≥7. Descriptive statistics, spearman correlation coefficient, multivariate, and ROC analysis were performed. Results: 703/1108 consults were eligible. A total of 153/703 (22%) were ADB +ve. SOAPP-14 scores were positively correlated with CAGE-AID r = .38, p &lt; 0.001; male gender r = 0.11, p = 0.003; ESAS pain r = 0.11, p = 0.005; ESAS depression r = 0.22, p &lt; 0.001; ESAS anxiety r = 0.22, p &lt; 0.001, and ESAS financial distress r = 0.23, p &lt; 0.001. Multivariate analysis indicated that the odds ratio for ADB +ve was 6.18 in patients with CAGE-AID+ (p &lt; 0.001), 1.8 for male gender (p = 0.007), 1.1/pt. for ESAS anxiety (p = 0.044), and 1.1/pt. for ESAS financial distress (p = 0.007). A CAGE-AID score of 1/4 has a sensitivity of 47%, specificity of 89% positive predictive value 63.6% and negative predictive value 69.2%. Conclusions: Our study suggests that 22% of cancer patients on opioids presenting to supportive care center are at risk of aberrant drug behavior (ADB). Male patients with anxiety, financial distress, and prior alcoholism/illicit drug use are significant predictors of ADB’s. A cut off score of ≥1 out 4 on CAGE-AID questionnaire allows better screening of ADB in outpatient advanced cancer patients. Further research to effectively manage these patients is needed.
PARP inhibitor (PARPi) monotherapy treatment in non-BRCA and/or non-serous gynaecological cancers
Authors: A. Ryan, S.M. Cruz, R. Miller, R. Kristeleit
Journal: Annals of Oncology (2018)

Background: The vast majority of PARPi clinical trial experience in gynaecological cancer is for patients with platinum sensitive high grade serous ovarian carcinoma (HGSOC) and deleterious BRCA1/2 mutations. It is known that other homologous recombination deficiency (HRD) associated mutations exist eg RAD51, BRIP1 that can potentially sensitise to PARPi. Extremely limited clinical data exists on the use of PARPi in HGSOC with HRD mutations other than BRCA1/2; or in BRCA-mutated gynaecological cancers excluding HGSOC. We investigated the role of PARPi in a cohort of patients with non-BRCA and/or non-high grade serous (HGS) gynaecological cancer. Methods: Retrospective case series from two tertiary referral centres. Results: Ten cases were identified. Non-HGS cohort included large cell neuroendocrine carcinoma (LCNEC) of the cervix, small cell ovarian cancer, low grade ovarian cancer (LGSOC) and endometrial carcinoma. Non-BRCA patients were affected by alterations of RAD51, ATM and EMSY. Median number of cycles of PARPi received was 2 (range 1-16). CA125 response was seen in 75% (6 of 8 cases with minimum three CA125 results) with a median reduction of 53.3%. Overall radiological response rate 28.6% (2 of 7 cases with minimum one restaging scan). Progression free survival (PFS) was greater for non-HGS BRCA mutant patients (median PFS 10.5m, range 2-15m), than for HGSOC non-BRCA patients (median PFS 1.2m, range 1-2m). Legend: Abbreviations as in text, germline (g), somatic (s). Conclusions: In this series, deleterious BRCA mutation or variant of unknown significance (VUS) remains the single strongest predictor for response to PARPi irrespective of histology. It may be difficult to classify a BRCA mutation as deleterious or VUS in rarer gynaecological cancer populations. Non-BRCA mutations in HRD related genes eg RAD51/ATM may also sensitise to treatment with PARPi. Four patients remain on treatment and updated results will be presented. Legal entity responsible for the study: Dr R Kristeleit. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.Table: 109PSiteBRCA 1/2Other mutsNumber cyclesCA125 ResponseRadiological ResponsePFSEndometrialBRCA1 mut (g)16yesyes15.5LCNEC cervixBRCA2 VUS (s)8yesN10.7LGSOCBRCA2 VUS (g)13yes (<50%)yes (on treatment)7.9Small cell ovarianBRCA2 VUS (g)2no dataN2.2HGSOCWTEMSY (s)4yes (<50%)N2.7HGSOCWTATM (s)2NN1.2HGSOCWTRAD51L3 (s)2NN1.0HGSOCWTRAD51C (g)2Nno data (on treatment)NAPP (as HGSOC)WTRAD51D (g)1yes (<50%)no data (on treatment)NAHGSOCWTRAD51C (g)2yesno data (on treatment)NA Open table in a new tab