tbuckley/cabot-search huggingface dataset:
Understanding biological driver mutations and mechanism of resistance to EGFR-tyrosine kinase inhibitors in lung cancer patients using a novel translational platform.
Authors: Govind K. Babu, Padmaparna Chaudhuri, Deepak Koppak, Manjusha Biswas
Journal: Journal of Clinical Oncology (2019)

e20555 Background: Lung cancer causes ~1.69 million deaths globally and 5-year survival rate is &lt; 20%. Surgery is preferred for patients with early stage NSCLC, however, in &gt; 50% cases lung cancers are diagnosed at an advanced stage. EGFR-TKIs, erlotinib and gefitinib have shown benefit in patients harboring sensitizing EGFR mutations, although 20-30% of NSCLC patients do not show good clinical response to EGFR-TKIs despite having the mutations. Several factors have been identified for de novo and acquired resistance to first generation EGFR-TKIs, including secondary mutations such as T790M, aberrant activation of bypass pathways such as amplification of c-MET, or other abnormalities in downstream pathways including KRAS mutations or loss of PTEN among others. There exist significant inter-patient variations in response profiles and mechanisms of resistance, which often confounds treatment selection on a personalized level, especially if first-line therapy fails. Methods: We have developed a patient tumor derived ex vivo platform technology using multi-disciplinary systems biology-based approach that recreates a patient’s tumor microenvironment by preserving the tumor-stromal architecture and immune contexture. Fresh tumor biopsies and 10-ml blood were collected from patients with IRB approval and patient consent. Tumors obtained from 21 lung cancer patients were grown ex vivo on our platform in presence of PBMC and autologous sera. The tumors were treated with standard of care chemotherapies and EGFR inhibitors, and drug efficacy on tumors were measured. Results: Of 18 tumor samples treated with EGFR-TKIs, 4 were predicted responders to gefitinib and 14 were predicted non-responders to EGFR-TKIs (erlotinib or gefitinib). Of the 14 non-responders, 7 were predicted responders to carboplatin/pemetrexed and/or carboplatin/docetaxel. Patients were followed, and clinical data was captured. Whole genome sequencing and mutational analysis was done on the tumors. Hits were validated by immunohistochemical assays. Data from molecular signatures of the tumors with functional, phenotypic assays, were used to delineate mechanism of resistance in individual lung cancer patients to EGFR-TKIs. Conclusions: We have developed an ex vivo, personalized platform, which enables prediction of treatment response on an individual level, and also aids in capturing resistance mechanisms for identifying actionable targets.
Metformin treatment of locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients induces an anti-tumorigenic immune response.
Authors: Vidhya Karivedu, Benyamin Yaniv, Melissa Asman, Sarah Palackdharry, Shuchi Gulati, Roman Jandarov, Nooshin Hashemi Sadraei, Vinita Takiar, Trisha Michel Wise-Draper
Journal: Journal of Clinical Oncology (2019)

6037 Background: Metformin is a biguanide, widely used oral hypoglycemic agent. Metformin has also shown to inhibit tumor growth and progression in a wide variety of cancers including Head and Neck Squamous Cell Carcinoma (HNSCC). Metformin activates AMP protein kinase (AMPK) related pathways leading to inactivation of mammalian target of rapamycin (mTOR) and suppression of its downstream effectors. In addition, metformin is postulated to alter immune regulation in the tumor microenvironment leading to increased tumor cell killing. Here, we report our findings on the impact of metformin on T cells, NK cells and cytokines from patient peripheral blood mononuclear cells (PBMCs) from a phase I open-label single site dose escalation study combining metformin and chemoradiation (CRT) in HNSCC (NCT02325401). Methods: In this study, we evaluated the immune cell phenotypes and cytokine profiles of peripheral blood in patients before and after metformin treatment on trial by using flow cytometry and cytokine magnetic bead assays (Luminex). Cytokine profiles were further studied in co-culture experiments combining PBMCs, HNSCC cell lines, and metformin. Results: Patients who received metformin developed expanded NK cell populations, increased NKG2D expression, and a shift in their CD8+ T-cell memory phenotypes. Patient serum ELISA examination revealed increased anti-tumorigenic cytokine profiles. Metformin treatment of HNSCC cell lines in vitro as well as HNSCC PBMCs ex vivo resulted in downregulation of STAT3 compared to healthy controls. Downregulation of STAT3 may be a potential mechanism in which metformin stimulates NK cells. Conclusions: Here we show evidence that metformin treatment has a direct effect on the innate immune system in patients with HNSCC, inducing an anti-tumorigenic immune response suggesting that metformin continues to be a good candidate to yield improved clinical outcomes in patients with advanced stage HNSCC. Clinical trial information: NCT02325401.
A plasma miRNA signature classifier identifies PD-L1 ≥ 50% NSCLC nonresponders to immune checkpoint inhibitors.
Authors: Claudia Proto, Arsela Prelaj, Carla Verri, Diego Signorelli, Giuseppe Lo Russo, Roberto Ferrara, Giulia Galli, Benedetta Trevisan, Mensah Mavis, Filippo G. De Braud, Marina Chiara Garassino, Gabriella Sozzi, Mattia Boeri
Journal: Journal of Clinical Oncology (2019)

9096 Background: A sizable proportion of PD-L1≥50% NSCLC patients (pts) do not respond to single agent immune checkpoint inhibitors (ICI) and no biomarker is able to identify non responders. A three levels plasma microRNA signature classifier (MSC), reflecting an immunosuppressive profile of immune cell subsets, has already shown its ability to identify pts treated with ICI with a worse prognosis independently from PD-L1 expression. Aim of this trial is to prospectively test the ability of MSC to identify at diagnosis PD-L1≥50% non responders to ICI. Methods: we prospectively collected baseline plasma samples from 41 consecutive advanced EGFR/ALK/ROS1 wild-type NSCLC pts with PD-L1 TPS ≥50% treated with ICI as first (n = 28) or further line treatment to run the MSC molecular test. Pts were stratified in high (H) vs intermediate/low (I/L) risk levels. Overall response rate (ORR) and the relative risk of response (RR) were evaluated by 2x2 contingency table using Fisher exact test. Cox proportional hazard models were used to define crude and adjusted hazard ratio (HR). Results: According to RECIST 1.1 criteria, 14 (34%) pts respond to ICIs. With a global median follow-up of 9.8 months, median progression free survival (PFS) and overall survival (OS) were 7.9 months and not reached, respectively. Ten (24%) NSCLC pts were MSC H risk level. ORR was 0% in MSC H vs 45% in MSC I/L risk pts (RR = 0.10; 95%CI = 0.00-0.90; p = 0.0080). Median PFS was 11.4 months for MSC I/L pts vs 2.3 months for MSC H risk (HR = 0.26 95%CI = 0.11-0.62; p = 0.0021). Median OS was not reached for MSC I/L vs 2.7 months for MSC H risk pts (HR = 0.17 95%CI = 0.06-0.48; p = 0.0008). Data remained significant adjusting for age, sex, pack-years and ECOG performance status at the baseline: PFS HR = 0.24 (95%CI = 0.09-0.66; p = 0.0054) and OS HR = 0.15 (95%CI = 0.05-0.51; p = 0.0023). Conclusions: plasma MSC shows promising results for treatment selection with ICI. So far, MSC is the only molecular test able to identify a group of NSCLC pts with PD-L1≥50% who do not respond to single agent immunotherapy. Ongoing trials are validating these results and testing the possible predictive effect of MSC in chemotherapy plus immunotherapy combinations.
Effect of subcutaneous multipeptide active antigen-specific immunotherapy at lymph nodes and tumor sites on clinical outcomes in progressive tumors.
Authors: Juan Pablo Marquez-Manriquez, Pedro Alejandro Lucero-Diaz, Jose Antonio Matute-Briseno, Alejandro Camacho-Hernandez, Dolores Gallardo-Rincon
Journal: Journal of Clinical Oncology (2019)

2636 Background: The tumor and lymph nodes (LN) microenvironment clinically speaking are mainly unexplored and there are limited clinical studies of immunotherapeutic approaches manipulating those in progressive cancer patients. The tumor and LN microenvironment offers an opportunity to treat locally with multi-peptide immunotherapy in challenging clinical situations where we can have still a potential safe and effective therapeutic approach using the concept treat locally treat systemically. Methods: N = 11 patients were enrolled after the local IRB ethic committee approved the pilot clinical study number CICS/SS/0035. Previous identified targets such as FAP, b-2-microglobulin, Fascin, RCAS1/EBAG9, Bcl-2, survivin, Sox2, Ape-1, Valosin containing-protein (VCP) and EGFR were analyzed by IHC, Th1 and CD8 long-peptides were predicted, immune assays using PBMCs including tumor microenvironment were performed to detect Granzyme B by ELISPOT, naturally processed epitopes by T-cell expansion and cytokines. Patients were treated subcutaneously (S.C.) eight times in the axillary and inguinal LN area one week apart. Afterwards we treated S.C. as well but now in the areas with tumor activity according with the CT or PET every week 10 times. Initial DTH and at the end of the treatment was performed. Pathological, clinical and immunological correlations were made using multivariate analysis. Results: Despite progressive disease 100% of the patients responded to the treatment. 80% had CR and 20% pseudo-progression and then CR. 100% of the patients increased the levels of Granzyme B against Bcl-2 (p = 0.001), VCP (p = 0.0001), Ape-1 (p = 0.005) and RCAS1 (P = 0.0001) and this correlated with the scans post-treatment. The patients showed more CD8 infiltration in the DTH test at the tumor site (p = 0.002) than in the non-tumor site (p = 0.01). The number of metastatic lesions in lungs (p = 0.004) and hepatic tissue (p = 0.001) disappeared and correlated with increased levels of IL-12 production in vivo. Conclusions: Treating immunologically the LN and the microenvironment of the areas with tumor activity is a feasible and safe approach to limit systemic toxicity and improve the clinical outcomes in patients with progressive cancer including bone sarcoma, epithelial ovarian cancer, PDAC, pediatric sarcomas and TNBC.
Distinct resistant mechanism and genomic evolution during TKI treatment in non-small cell lung cancer patients with or without acquired T790M mutation.
Authors: Ying Jin, Hua Bao, Xiuning Le, Xiaojun Fan, Ming Tang, Yun Fan, Yiping Zhang, Yang Xu, Xue Wu, Yang Shao, Junrong Yan, Jiachen He, Ming Chen, Jianjun Zhang, Xinmin Yu
Journal: Journal of Clinical Oncology (2019)

e20603 Background: EGFR-mutant non-small-cell lung cancer (NSCLC) patients inevitably develop drug resistance when treated with EGFR tyrosine kinase inhibitors (TKIs). Clonal and clinical analyses of genetic alterations at baseline and progressive disease (PD), as well as differences between acquired T790M and T790M-negative patients in drug-resistant mechanisms, have not been systematically studied. Methods: We performed targeted sequencing of pre-treatment and PD tumor samples from 54 EGFR-mutant NSCLC patients. Correlation between genomic features and patients’ progression-free survival (PFS) was evaluated. Ten additional patients were sequenced using whole exome sequencing to infer the clonal evolution patterns. Results: We observed new pathways limiting EGFR-inhibitor response, including NOTCH1/ STK11 co-deletion, and TGF-beta alterations. Besides acquired T790M mutation, chromosomal instability (CIN) related genes including AURKA and TP53 alterations were the most frequently acquired events. CIN significantly increased with TKI treatment in T790M-negative patients. Transcriptional regulators including HNF1A, ATRX and NKX2-1 acquired alterations were enriched in T790M-positive patients, and diverse oncogenic pathway alterations were more common in T790M-negative patients. T790M-positive patients had improved PFS compared to T790M-negative patients. We identified subgroups within T790M-positive or T790M-negative patients with distinct PFS. Interestingly, we observed a death-and-birth process of RTK-RAS mutations during TKI treatment, and baseline and acquired RTK-RAS mutations had opposite effects on PFS. Clonal evolution analysis indicated progression of T790M-positive patients depends on competition between T790M and non-T790M resistant subclones. Conclusions: T790M-positive and T790M-negative patients display divergent landscape of acquired somatic events. Subgroups of patients were identified within T790M-positive and T790M-negative patients with distinct survival. Our results point the importance of clonal competition between T790M and non-T790M resistant subclones.
A novel model of controlling PD-L1 expression in ALK+ anaplastic large cell lymphoma revealed by CRISPR screening
Authors: Jing-Ping Zhang, Zhihui Song, Hong-Bo Wang, Lang Lang, Yuan-Zhong Yang, Wenming Xiao, Daniel E. Webster, Wei Wei, Stefan K. Barta, Marshall E. Kadin, Louis M. Staudt, Masao Nakagawa, Yibin Yang
Journal: Blood (2019)
CD161 contributes to prenatal immune suppression of IFN-γ–producing PLZF+ T cells
Authors: Joanna Halkias, Elze Rackaityte, Sara L. Hillman, Dvir Aran, Ventura F. Mendoza, Lucy R. Marshall, Tippi C. MacKenzie, Trevor D. Burt
Journal: Journal of Clinical Investigation (2019)

While the human fetal immune system defaults to a program of tolerance, there is concurrent need for protective immunity to meet the antigenic challenges encountered after birth. Activation of T cells in utero is associated with the fetal inflammatory response with broad implications for the health of the fetus and of the pregnancy. However, the characteristics of the fetal effector T cells that contribute to this process are largely unknown.We analyzed primary human fetal lymphoid and mucosal tissues and performed phenotypic, functional, and transcriptional analysis to identify T cells with pro-inflammatory potential. The frequency and function of fetal-specific effector T cells was assessed in the cord blood of infants with localized and systemic inflammatory pathologies and compared to healthy term controls.We identified a transcriptionally distinct population of CD4+ T cells characterized by expression of the transcription factor Promyelocytic Leukemia Zinc Finger (PLZF). PLZF+ CD4+ T cells were specifically enriched in the fetal intestine, possessed an effector memory phenotype, and rapidly produced pro-inflammatory cytokines. Engagement of the C-type lectin CD161 on these cells inhibited TCR-dependent production of IFNγ in a fetal-specific manner. IFNγ-producing PLZF+ CD4+ T cells were enriched in the cord blood of infants with gastroschisis, a natural model of chronic inflammation originating from the intestine, as well as in preterm birth, suggesting these cells contribute to fetal systemic immune activation.Our work reveals a fetal-specific program of protective immunity whose dysregulation is associated with fetal and neonatal inflammatory pathologies.
Methylated circulating tumor DNA (Met-DNA) as an independent prognostic factor in metastatic pancreatic adenocarcinoma (mPAC) patients.
Authors: Daniel Pietrasz, Shufang Wang-Renault, Laetitia Dahan, Julien Taieb, Karine Le Malicot, Yves Rinaldi, Solene Doat, Jean-Marc Phelip, Valerie Taly, Jean-Baptiste Bachet, Pierre Laurent-Puig
Journal: Journal of Clinical Oncology (2019)

4136 Background: Circulating tumor DNA has emerged as prognostic biomarker in oncology. Many different genes can be mutated within a tumor, complicating procedures, even with highly sensitive next-generation sequencing (NGS). DNA methylation in promotor of specific genes is an early key epigenetic change during oncogenesis. Specific methylated genes could be a potential relevant cancer biomarker that may substitute for NGS panels. The aim of this study was to assess the prognostic value of Met-DNA in mPAC. Methods: Prognostic value of Met-DNA was assessed in a prospective cohort (PLAPAN) of mPAC (training cohort), correlated with NGS, then in two prospective independent validation cohorts from two randomized phase II trials (PRODIGE 35 and 37). Plasma samples were collected before chemotherapy on EDTA-coated tubes. Met-DNA was quantified using two specific markers of pancreatic DNA methylation by digital droplet PCR and correlated with prospectively registered patient (pts) characteristics and oncologic outcomes (progression free survival (PFS) and overall survival (OS)). Results: 330 patients (pts) were enrolled. 60% (n = 58) of the 96 pts of the training cohort had at least one Met-DNA marker. The correlation with NGS assessment was R = 0.93 (Pearson; p &lt; 0.001). 59.5% (n = 100/168) and 59% (n = 39/66) of pts had detectable Met-DNA in the 2 validation cohorts. In the training cohort, Met-DNA was correlated with poor OS (HR = 1.82; 95%CI 1.07-2.42; p = 0.026). In validation cohorts, Met-DNA was a prognostic factor of PFS (HR = 1.62; 95%CI 1.17-2.25, p = 004) and OS (HR = 1.79; 95%CI 1.28-2.49, p &lt; 0.001) in PRODIGE 35, as in PRODIGE 37: PFS HR = 1.79 (95%CI 1.07-2.99; p = 0.026) and OS HR = 2.08 (95%CI [1.18-3.68], p = 0.01), respectively. In multivariate analysis adjusted on gender, age, CA19-9 &gt; 40UI.mL, treatment arm, number of metastatic sites and stratified on center, Met-DNA was independently associated with poor OS in both trials: HR = 1.81 (95%CI 1.10-2.98; p = 0.02) and HR = 3.62 (95%CI: 1.32-9.93; p = 0.01). Conclusions: This study demonstrates that Met-DNA is a strong independent prognostic factor in mPAC. These results argue for patient’s stratification on ctDNA status for further randomized trials. Clinical trial information: NCT02827201 and NCT02352337.
Reversion and non-reversion mechanisms of resistance (MoR) to PARP inhibitor (PARPi) or platinum chemotherapy (chemotx) in patients (pts) with <i>BRCA1/2</i>-mutant metastatic breast cancer (MBC).
Authors: Adrienne Gropper Waks, Ofir Cohen, Bose Kochupurakkal, Dewey Kim, Seth Andrew Wander, Jorge Buendia-Buendia, Karla Helvie, Ursula A. Matulonis, Ian E. Krop, Sara M. Tolaney, Eric P. Winer, Alan D. D'Andrea, Geoffrey Shapiro, Nancy U. Lin, Nikhil Wagle
Journal: Journal of Clinical Oncology (2019)

1085 Background: Little is known about MoR to PARPi and platinum chemotx in MBC pts with BRCA1/2 mutations. Biomarkers predictive of response/resistance have not been identified, but could have clinical utility. Methods: We obtained 8 BRCA-mutant metastatic tumor biopsies from MBC pts with acquired resistance to DNA-damaging tx (PARPi/platinum) on a prospective tissue collection protocol. In 7/8 patients, we also obtained pre-tx biopsies. Whole exome sequencing (WES) was performed on each tumor and on germline DNA from blood. We performed immunohistochemical (IHC) staining for RAD51 foci for functional assessment of intact homologous recombination (HR). Results: 4/7 pts with complete WES analysis acquired a somatic reversion mutation likely to result in functional BRCA1/2 protein in the post-tx tumor specimen after platinum (2 pts) or PARPi (2 pts; Table). 4/7 pts had plausible non-reversion MoR identified by WES, including alterations in genes involved in replication fork protection and DNA end resection. As expected, in all pts with genomic reversion, RAD51 foci were acquired in the post-resistance tumor, consistent with reconstitution of HR. In 2 pts without reversion, presence of RAD51 foci post-resistance was mixed. Reversion mutations occurred both with and without other alterations that could possibly lead to fork protection, suggesting &gt; 1 MoR could occur in the same tumor. 3 pts whose tumors demonstrated RAD51 foci post-resistance were later re-exposed to DNA-damaging tx, to which all had intrinsic resistance. Conclusions: BRCA1/2 reversion was identified as a MoR in the majority of pts. WES identified potential novel MoR in fork protection and end resection genes. The presence of RAD51 foci by IHC was consistent with BRCA protein functional status from genomic data and predicted response to later DNA-damaging tx, suggesting RAD51 IHC may be a clinically useful biomarker. [Table: see text]
Should pregnancy testing during chemotherapy be standardized?
Authors: Natalie S Berger, Katherine FitzPatrick, Paula Klein
Journal: Journal of Clinical Oncology (2019)

e18314 Background: The incidence of cancer diagnosed during pregnancy is 0.1-0.2%. The incidence of women who become pregnant while on chemotherapy is less clear. As the initiative to improve awareness about the risks of infertility in premenopausal women receiving chemotherapy improves, it is also important to reinforce the risk of pregnancy during chemotherapy. Treating patients with chemotherapy, especially during the first trimester, is an absolute contraindication and a serious adverse event. Pregnancy testing prior to the initiation of chemotherapy is recommended by the NCCN and ASCO. However, recommendations on how to monitor for pregnancy after an initial screen are inconsistent and lack standardization. Methods: We surveyed five breast medical oncologists and six infusion nurses at a busy urban breast center to determine their baseline practices for pregnancy counseling and testing. We then initiated a quality improvement project over a six month period to routinely screen premenopausal patients ( &lt; 55 years) diagnosed with breast cancer for pregnancy prior to each cycle of chemotherapy. Results: Of physicians and nurses surveyed, 40% and 33% respectively have diagnosed a pregnancy during chemotherapy. All physicians surveyed check a pregnancy test prior to the initiation of chemotherapy, 60% check urine and 40% check serum. Counseling patients on the risk of pregnancy varies with 80% of physicians counseling patients prior to initiation of chemotherapy. Half of the infusion nurses ask patients if they are concerned they may be pregnant intermittently during chemotherapy and 50% do not ask again after the initial screen. During routine screening over a 6 month period no pregnancies were detected. One patient missed a baseline screening prior to initiating chemotherapy. Two patients had a borderline result ( &lt; 1%) on urine pregnancy testing but reflex serum testing was negative. Compliance for testing by nurses was 93%. Conclusions: Results of the survey demonstrate that pregnancy counseling and screening practices vary even within the same institution. We must improve and standardize educating patients and healthcare providers on the risks of pregnancy during chemotherapy in order to prevent unwanted pregnancies, and identify pregnancies in a timely manner. Given the very small risk of pregnancy, we would not recommend routine screening prior to each cycle of chemotherapy, but we do recommend asking all premenopausal patients if there is a chance they may be pregnant prior to each treatment and test based on the individual risk.