tbuckley/cabot-search huggingface dataset:
Comparing programmed death ligand-1 expression on tumor cells before and after acquiring resistance to tyrosine kinase inhibitor in EGFR harbouring non-small cell lung cancer.
Authors: Siwat Sakdejayont, Poonchavist Chantranuwat, Nattaya Poovorawan, Piyada Sitthideatphaiboon, Napa Parinyanitikul, Chanida Vinayanuwattikun, Suebpong Tanasanvimon, Virote Sriuranpong
Journal: Journal of Clinical Oncology (2017)

11617 Background: Although anti-PD1/PD-L1-targeting immunotherapy has been successful in the treatment of non-small cell lung cancer (NSCLC) patients, the benefit is unclear in EGFR mutation(mEGFR) NSCLC. To date, there are several clones of anti-PD-L1 antibody which provide different predictive values and the level of expression also dynamically changed after treatment. The study examined changes of PD-L1 expression in mEGFR harbouring NSCLC tissues, comparing between before and after treatment with tyrosine kinase inhibitors(TKIs) using an FDA-approved PD-L1 assay. Methods: We retrospectively reviewed tumor specimen from 24 patients with mEGFR NSCLC who had been treated with gefitinib, erlotinib, afatinib and received second tissue biopsy after acquiring resistance to TKIs. The collected FFPE specimens were stained with commercial anti-PD-L1 22C3 assay monoclonal antibody. Tumor proportion score(TPS) and H-score were measured before and after TKIs. Results: Of the study patients,54.2% patients were exon 19 deletion(n = 13), 41.7% were exon 21 point mutation(L858R) (n = 10), and 1 case was L858R/S761I. After TKIs resistance 10/13 (76.9%) of exon 19del and 8/10 (80%) of L858R revealed presence of +T790M. Pretreatment PD-L1 expression was positive(TPS≥1%) in 6 cases (25%). Mean TPS of positive cases was 34.0% and H-score was 78.2, All except 2 of 6 positive cases had adequate specimens from second biopsy(n = 22). Among 4 positive cases,PD-L1 expression tended to be higher after TKIs; mean TPS changed from 23.9 to 40.9 (p = 0.171) and H-score were from 49.3 to 91.1 (p = 0.172). 18/24 patients with TPS and H-score zero at the beginning remained zero after progression. Median TTP were similar in patients with positive PD-L1 expression and negative,13.8 m vs 14.5 m (n = 24,p = 0.644) with TKIs and 3.9 m vs 2.5 m (n = 14, p = 0.560) with chemotherapy. Conclusions: Prevalence of PD-L1 expression in mEGFR NSCLC was low. PD-L1 expression tended to be higher after TKIs for this with positive cases which may guide the sequences of treatment. Nevertheless no changes of PD-L1 expression for those with negative, hence re-biopsy may not be necessary.
The use of cardiovascular disease states as exclusion criteria in breast cancer trials: A 4-decade perspective.
Authors: Michal Oren, Ohad Oren, David M. Mintzer
Journal: Journal of Clinical Oncology (2017)

e18053 Background: At the time of diagnosis, patients with breast cancer have a higher prevalence of cardiovascular risk factors than the general population. It is likely that the prevalence of actual cardiac disease is also increased, although no published data is available to support this claim. Individuals with breast cancer who also have heart disease are typically disqualified from clinical trials. We attempted to define the evolution of cardiovascular exclusion criteria in clinical trials of breast cancer over the decades. Methods: We searched the NEJM for original research in “breast cancer” published from 01/1980 to 12/2016. We reviewed the nature of cardiovascular disease as exclusion parameters as well as trends over time. Results: 20 RCTs were analysed, 5 from each decade (total # of patients 21,231). Mean number of cardiac exclusion criteria per study increased over the decades (1980s: 0; 1990s: 0.2; 2000s: 1; 2010s: 7). The most common cardiac exclusion criteria were CHF and recent MI (35% and 25% of studies, respectively). Factors associated with a higher likelihood of having a cardiac exclusion criteria were source of funding (industry vs. university: 77.7% vs. 18.1%, P-value 0.005) and study’s country of origin (U.S versus non-U.S: 57.1% versus 16.6%, P-value 0.02). Prior to 2010, the complete list of exclusion criteria was available with the manuscript. From 2010, it became embedded within the study’s protocol file (and not printed). Cardiovascular AEs were infrequent (1980s: 0.02%; 1990s: 0%, 2000s: 0.08%; 2010: 0.29%). Before 2000, studies described the significant cardiac toxicity in the manuscript. After 2000, a comprehensive registry of AEs contained within supplementary files became the norm. Conclusions: The use of cardiovascular exclusion criteria in clinical trials in breast cancer has become common over the past decades. Currently, it is almost impossible for a woman to enter a trial with even a single cardiac condition. Given that a sizeable fraction of breast cancer patients has cardiac disease, consideration should be given to narrowing the scope of cardiac exclusion criteria to allow more patients to participate, while making the results of those trials more broadly generalisable.
An update on the randomized phase III POST trial: S-1 based doublet as an adjuvant chemotherapy for curatively resected stage III gastric cancer.
Authors: Choong-kun Lee, Minkyu Jung, Hyo Song Kim, Inkyung Jung, Dong Bok Shin, Seok Yun Kang, Dae Young Zang, Ki Hyang Kim, Moon Hee Lee, Bong-Seog Kim, Kyung Hee Lee, Ji Yeong An, Hyoung-Il Kim, Jae-Ho Cheong, Woo Jin Hyung, Sung Hoon Noh, Hyun Cheol Chung, Sun Young Rha
Journal: Journal of Clinical Oncology (2016)

4042 Background: We report an updated results from a randomized, multicenter, phase III trial to compare S-1 plus docetaxel (DS) with S-1 plus cisplatin (SP) as an adjuvant chemotherapy for stage III gastric cancer (GC) patients. (ClinicalTrials.gov: NCT01283217). Methods: Stage III GC patients received curative gastrectomy with D2 lymphadenectomy were randomized into equal groups to receive adjuvant chemotherapy of 8 cycles of DS (S-1 70mg/m2/day on days 1-14, docetaxel 35mg/m2 on days 1 and 8) or SP (S-1 70mg/m2/day on days 1-14, cisplatin 60mg/m2 on day 1) every 3 weeks. The primary endpoint was 3-year disease-free survival (DFS) rate. Results: Between November 2010 and July 2013, 153 patients (75 patients to DS and 78 patients to SP) were enrolled from 8 institutions in Korea. After the capecitabine plus oxaliplatin was approved based on the CLASSIC study, it was decided to close the study early. With a median follow up duration of 37 (range, 1–57) months, the 3-year DFS rate was 49.3% in DS group (median DFS: 27.7 months) and 56.4% in SP group (median DFS: 44.0 months). Both group did not reach median OS with 29 (38.7%) and 27 (34.6%) deaths in DS and SP groups, respectively. There was no statistically significant difference in DFS (Hazard Ratio [HR], 1.251; 95% confidence interval [CI], 0.787–1.989; P = 0.343) or OS (HR, 1.200; 95% CI, 0.709–2.030; P = 0.497) between two groups. The most common grade 3 or 4 adverse event was neutropenia (42.7% in DS and 38.5% in SP, P= 0.351). SP group had more grade 3 or 4 anemia (1.3% vs. 11.5%, P= 0.037), whereas grade 3 or 4 hand-foot syndrome (4.1% vs. 0%, P= 0.025) and mucositis (10.7% vs. 2.6%, P= 0.001) were more common in DS group. Fifty-one patients (68%) in DS group and 52 (66.7%) in SP groups finished planned treatment. The median relative dose intensity (RDI) was 0.86 for both docetaxel and S-1 in DS group, while 0.83 for cisplatin and 0.86 for S-1 in SP group. Conclusions: Our results suggest that S-1 plus cisplatin or docetaxel is an effective and tolerable option for patients with curatively resected stage III gastric cancer. Clinical trial information: NCT01283217.
The impact of lenalidomide exposure on response and outcomes in patients with lower-risk myelodysplastic syndromes and del(5q)
Authors: Mikkael A. Sekeres, Arlene S. Swern, Aristoteles Giagounidis, Alan F. List, Dominik Selleslag, Moshe Mittelman, Brigitte Schlegelberger, Gudrun Göhring, Jack Shiansong Li, Mary M. Sugrue, Pierre Fenaux
Journal: Blood Cancer Journal (2018)
Phase 1/2 study of combination therapy with pexidartinib and sirolimus to target tumor-associated macrophages in malignant peripheral nerve sheath tumors.
Authors: Gulam Abbas Manji, Parag Patwardhan, Shing Mirn Lee, Nanette Matos, Edward Bentlyewski, Brian Andrew Van Tine, Khanh Tu Do, Suzanne George, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2016)

TPS11070 Background: Malignant peripheral nerve sheath tumors (MPNSTs) are generally resistant to chemotherapy. Receptor tyrosine kinases (RTKs) play a role in MPNST growth and include c-KIT, PDGFR, and CSF1R, all of which are inhibited by pexidartinib (PLX3397, PEX). We reported that the combination of PEX and the mTOR inhibitor sirolimus (S) synergistically inhibited MPNST growth (Patwardhan P. et al CCR 20: 3146, 2014). Inhibiting CSF1R resulted in a marked depletion of tumor-associated macrophages (TAMs) in MPNST xenografts and a shift from M2 (tumor promoting) to M1 (tumor inhibiting) TAMs within tumors. This effect on TAMs was enhanced and sustained by mTOR inhibition with S. Therefore, this drug combination, by potently blocking RTKs and by altering tumor macrophage infiltration, represents a novel drug combination. The goal of this first-in-man trial is to prove safety and test efficacy of PEX and S in sarcomas and MPNST. Methods: This is an open label, multicenter, investigator-initiated study testing PEX in combination with S in patients with advanced sarcomas (phase 1, N = 24) and MPNST (phase 2, N = 25). The primary objective of the phase 1 component is to determine the safety, tolerability, and the recommended phase 2 dose (RP2D) using the time-to-event continual reassessment method. The phase 1 component enrolls patients with sarcoma who have progressed on standard of care therapy or for whom no standard treatment exists. The primary outcome for phase 2 is progression free survival (PFS). Assuming a median PFS of 6 weeks in patients treated with standard of care, we have 90% power to detect a difference of 12 weeks in median PFS given a 2-sided test with an alpha of 0.05. Secondary objectives include response rate and overall survival. Patients enrolled to the phase 2 component will undergo mandatory biopsies at baseline and at end of cycle 1 and an optional biopsy on progression. Exploratory studies include analysis of RTK activity and assessment of TAMs within the tumor samples. This trial has started in December 2015 and has enrolled 4 patients to the phase Ib (2 PVNS, 1 MPNST, and 1 Epithelioid sarcoma) as of January 2016. Clinical trial information: NCT02584647.
The impact of sample storage time on calculating tumor mutation burden (TMB).
Authors: Shifu Chen, Ming Liu, Yanqing Zhou, Mingyan Xu, Charles E. Melançon, Jeremy Edwards
Journal: Journal of Clinical Oncology (2018)

e24022 Background: Tumor mutation burden (TMB) has recently been recognized as an independent predictor of response to immunotherapy in diverse cancers. However, there is a lack of standardized methods for calculating TMB values determined from high-throughput sequencing data obtained under distinct conditions. Many factors, including sequencing method, target capture panel used, sequencing coverage, and sample storage time can affect the TMB value. Methods: We re-analyzed sequencing data obtained from all 8,136 patient samples sequenced using the same 410 gene MSK-IMPACT panel. We found that TMB value was strongly impacted by the sample storage time. Data from these samples was grouped by tissue sample storage time, and the mean mutation number of each group was recorded and compared. Results: We found that the mean mutation number decreased as the sample storage time increased. Samples sequenced within 1 week (N = 608) had a mean mutation number of 9.58, samples sequenced within 1 week to 3 months (N = 3,825) had a mean mutation number of 8.06, samples sequenced within 3 months to 1 year (N = 1,728) had a mean mutation number of 7.22, samples sequenced within 1 to 3 years (N = 1,102) had a mean mutation number of 6.94, and samples sequenced after > 3 years (N = 1,975) had a mean mutation number of 5.23. Conclusions: We found that fewer mutations are found in samples with longer sample storage time. We suggest that this may be due to sample degradation or other storage time-dependent factors. We suggest that, in clinical practice, sample storage time should be taken into account when setting TMB cut-off values; and that tissue samples older than three years should be avoided due to a propensity to miss key driver mutations and to underestimate TMB value.
Optical topography of cognitive tasks-based hemodynamic responses in the prefrontal cortex.
Authors: Pascal Jean-Pierre, Hansley Bobo, Harisa Saphic, Temple Robinson, Brian Omar Johnson
Journal: Journal of Clinical Oncology (2018)

e22066 Background: Cancer/treatment-related neurocognitive dysfunction (CRND) is a significant adverse condition. We examined the feasibility of using functional near-infrared spectroscopy (fNIRS) to assess CRND-related brain hemodynamics/neuronal activities. Methods: We used fNIRS to assess prefrontal-cortex (PFC) hemodynamic during cognitive stimuli: Stroop, n-Back, Go/NoGo in 18 adults (18-74 years). We used a general linear model to extract channel-wise activation responses, and plotted β values as a topological map for cognitive tasks to identify significantly activated regions. We used linear-mixed-effects models (LMEM) to represent the covariance structure associating common random effects to observations with similar levels as the grouping variable. Fixed effects were fNIRS channel locations, age groups, sex, and cognitive tasks. Results: We found significant task sub-levels and location “12” activations for the Stroop (p< 0.05). We found significant group differences on channels 2, 4, 6, and 16 for the n-Back (p < 0.05), and bilateral activations in the right ventrolateral prefrontal cortex (R-VLPFC) for older adults and mild deactivations in the R-VLPFC for younger adults. All participants showed increased PFC activations with increasing working-memory load (0-3Back). Younger adults showed a slight right hemispheric dominance for the lower n-Back condition, whereas older adults used both hemispheres. The LMEM showed no differences in age, sex, and task sub-levels for the n-Back (p> 0.05). The Go/No-Go showed diffuse and bilateral patterns of activation in VLPFC for older adults. Only channel 14 (R-VLPFC) was significant for the Go tasks (p< 0.05), indicating possible VLPFC support for inhibitory control. Overall, there were significant differences between cancer and healthy participants on channels 14 and 1 for NoGo tasks, and channel 4 for Go tasks. Greater VLPFC deactivation and DLPFC activation were observed in cancer patients. Conclusions: The findings support the use of fNIRS to assess CRND. Increasing working memory load showed that DLPFC and VLPFC were negatively correlated. The R-VLPFC could be used as a biomarker of CRND. Decreased activation in cancer patients may also reflects CRND.
Effect of pre-treatment sleep disturbance on radiation therapy (RT)-induced pain in 676 women with breast cancer.
Authors: Anita Roselyn Peoples, Wilfred R. Pigeon, Dongmei Li, Joseph A. Roscoe, Sheila N. Garland, Michael L. Perlis, Vincent Vinciguerra, Thomas Anderson, Lisa Smith Evans, James Lloyd Wade, Deborah J. Ossip, Gary R. Morrow, Julie Ryan-Wolf
Journal: Journal of Clinical Oncology (2018)

10100 Background: Pain is a debilitating side effect that remains poorly controlled in ~50% of cancer patients. Data from the general population has shown a strong bi-directional relationship between sleep disturbance and pain; however, little is known about this relationship in cancer patients. The present secondary analyses examine the effect of pre-RT moderate-severe cancer-related sleep disturbance (CRSD) on subsequent RT-induced pain. Methods: Analyses were performed on 676 female breast cancer patients (mean age 58) scheduled to receive RT from a previously completed multicenter, phase II RCT examining the efficacy of oral curcumin on radiation dermatitis. The trial was conducted at 21 community oncology practices throughout the U.S. affiliated with the URCC NCORP Research Base. CRSD and total pain as well as the subdomains: sensory pain (SP), affective pain (AP), and perceived pain intensity (PPI) were assessed at pre-RT (baseline) and post-RT by the modified MD Anderson Symptom Inventory and the short-form McGill Pain Questionnaire, respectively. Patients were dichotomized into 2 groups: those with moderate-severe CRSD at baseline (N = 101) vs. those with mild or no CRSD (control; N = 575). Results: Spearman rank correlations showed that changes in CRSD from baseline to post-RT were significantly correlated with concurrent changes in total pain, SP, AP, and PPI (r = 0.21–0.38; all p’s < 0.001). Generalized linear estimating equations, after controlling for baseline pain and other covariates (baseline fatigue and distress, age, sleep medications, anti-anxiety/depression medications, prescription pain medications, and depression or anxiety disorder), showed that patients with moderate-severe CRSD at baseline had significantly higher mean values of post-RT total pain (by 39%; p = 0.033), SP (by 41%; p = 0.046), and AP (by 55%; p = 0.035) than the control group, but not for PPI (p = 0.066). Conclusions: These findings suggest that moderate-severe disturbed sleep prior to RT is an important predictor of pain at post-RT in breast cancer patients. Further research is needed to confirm these findings. NCI UG1CA189961, NCATS TL1 TR002000. Clinical trial information: NCT01246973.
Uncommon ALK fusion partners in advanced ALK-positive non-small-cell lung cancer.
Authors: Jin Kang, Xuchao Zhang, Huajun Chen, Qing Zhou, Haiyan Tu, Wen-Feng Li, Yi-Long Wu, Jinji Yang
Journal: Journal of Clinical Oncology (2018)

8561 Background: The variants affect the efficacy of crizotinib in echinoderm microtubule protein-like-4 (EML4)- anaplastic lymphoma kinase (ALK) fusion-positive non–small-cell lung cancers (NSCLCs). Non–EML4-ALK fusions were detected and may have biologic and clinical implications differently. However, few studies focused on the effects of non–EML4-ALK fusions on the efficacy of crizotinib. Methods: Among 182 ALK-positive patients whose ALK rearrangement were confirmed by fluorescence in situ hybridization developing resistance to crizotinib as the initial ALK-TKI between October 2010 and December 2017, 41 patients with sufficient tumor specimens could be evaluated for ALK variants by next-generation sequencing (NGS). Uncommon ALK fusion partners include non-EML4 or EML4-based variants. We retrospectively investigated progression-free survival (PFS), objective response rate (ORR) and overall survival (OS) between the patients with uncommon ALK fusion partners and those with EML4-ALK variants. Results: The frequency of uncommon ALK fusion partners was 34.1% (14/41). Among the 14 patients, there are 9 patients only harboring with one kind of non-EML4 partners. The ALK fusion partners of the other 5 patients included non-EML4 and EML4. The median PFS was longer in patients with uncommon ALK fusion partners than in those with EML4 variants (10.5 months VS 3.7 months [95% CI, 0.85 to 3.06 months], respectively; P = 0.142). The ORR between two groups were 64.3% and 77.8% in the two groups respectively. The median OS was 34.2 months and 21.0 months in the two groups respectively (95% CI, 1.21 to 4.65 months; P = 0.012). Four patients harbored with uncommon ALK fusion partners developed primary resistance to crizotinib and these fusions included DTNB-ALK, NR_110271-ALK, ZC3H8-ALK and STED2-ALK. A emerging FSHR-ALK fusion was found in a patient who had dynamic plasma to be monitored during the treatment of crizotinib. Conclusions: The ALK fusion partners have a profound impact on the efficacy of ALK TKIs. Some partners led to primary resistance to crizotinib and some partners might produce better efficacy of ALK TKIs than EML4 in advanced ALK-positive NSCLCs. The ALK fusion partners should be detected by NGS beforehand.
A phase 1, open-label, multicenter, non-randomized study to assess the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of AZD4573, a potent and selective CDK9 inhibitor, in subjects with relapsed or refractory hematological malignancies.
Authors: Simon Rule, Arnon P. Kater, Tim H. Brümmendorf, Chris Fegan, Martin Kaiser, John A. Radford, Stephan Stilgenbauer, Sabine Kayser, Martin JS Dyer, Peter Brossart, Justin Cidado, Lisa Drew, Joe Birkett, Andrew Davies, Wenlin Shao, Wolfram Brugger
Journal: Journal of Clinical Oncology (2018)

TPS7588 Background: Cyclin-dependent kinase 9 (CDK9) belongs to the group of transcription-regulating CDKs and promotes transcription elongation through phosphorylation of RNA Polymerase II at serine 2 (pSer2-RNAPII). Studies using multi-CDK inhibitors with CDK9 activity demonstrated that transient inhibition of CDK9 can modulate expression of oncogenes with short-lived transcripts and proteins (e.g. MCL1, MYC), providing an intriguing therapeutic rationale. Transient and selective inhibition of CDK9 is key to preferentially kill tumor cells dependent on survival proteins without causing broad toxicity due to prolonged transcription suppression. Multi-CDK inhibitors, e.g. Dinaciclib (Flynn et al., Leukemia 2015) have been progressed in early trials and shown to reduce levels of MCL1 and induced clinical responses attributed to CDK9 inhibition. However, a more potent and selective CDK9 inhibitor that has appropriate pharmacokinetics for tuneable target engagement and an optimal dose/schedule, leading to improved efficacy, is warranted. We developed a selective CDK9 inhibitor, AZD4573, with nanomolar potency that exhibits anticancer activity across a diverse set of hematological models. Pre-clinical experiments demonstrated a rapid, dose-dependent decrease in pSer2 RNAPII with concomitant depletion of MYC and MCL1 mRNA and protein leading to induction of cleaved caspase/PARP. AZD4573 induced significant antitumor activity in xenograft models when given as monotherapy or in combination (Cidado J et al, AACR 2018). These data suggest clinical progression of AZD4573 for treatment of hematological malignancies. Methods: This study is a multicenter, open-label, first in human phase 1 dose-escalation study including an intra-subject ramp-up. The purpose is to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of AZD4573 in subjects with relapsed/refractory haematological malignancies. Study enrolment is ongoing. Clinical trial information: NCT03263637.