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  • 1
    Online-Ressource
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    Noninvasive Early Identification of Therapeutic Benefit from Immune Checkpoint Inhibition
    Elsevier BV ; 2020
    In:  Cell Vol. 183, No. 2 ( 2020-10), p. 363-376.e13
    Details
    In: Cell, Elsevier BV, Vol. 183, No. 2 ( 2020-10), p. 363-376.e13
    Materialart: Online-Ressource
    ISSN: 0092-8674
    URL: Article
    DOI: 10.1016/j.cell.2020.09.001
    RVK:
    XA 36269
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Elsevier BV
    Publikationsdatum: 2020
    ZDB Id: 187009-9
    ZDB Id: 2001951-8
    SSG: 12
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  • 2
    Online-Ressource
    Online-Ressource
    KEAP1/NFE2L2 Mutations Predict Lung Cancer Radiation Resistance That Can Be Targeted by Glutaminase Inhibition
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Discovery Vol. 10, No. 12 ( 2020-12-01), p. 1826-1841
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 10, No. 12 ( 2020-12-01), p. 1826-1841
    Kurzfassung: Tumor genotyping is not routinely performed in localized non–small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in tumors with KEAP1/NFE2L2 mutations, indicating that they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes KEAP1-mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations. Significance: This study shows that mutations in KEAP1 and NFE2L2 predict for LR after radiotherapy but not surgery in patients with NSCLC. Approximately half of all LRs are associated with these mutations and glutaminase inhibition may allow personalized radiosensitization of KEAP1/NFE2L2-mutant tumors. This article is highlighted in the In This Issue feature, p. 1775
    Materialart: Online-Ressource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-20-0282
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2020
    ZDB Id: 2607892-2
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  • 3
    Online-Ressource
    Online-Ressource
    Abstract 5666: A noninvasive approach for early prediction of therapeutic benefit from immune checkpoint inhibition for lung cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5666-5666
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5666-5666
    Kurzfassung: Although treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICI) can produce remarkably durable responses, most patients develop early disease progression. Furthermore, initial response assessment by conventional imaging is often unable to identify which patients will achieve durable clinical benefit (DCB). Here, we analyze 211 samples from 99 patients and demonstrate that pre-treatment circulating tumor DNA (ctDNA) and circulating immune profiles are independently associated with DCB. We further show that ctDNA dynamics after a single ICI infusion can identify the majority of patients who will achieve DCB. Integrating these determinants, we describe an entirely noninvasive multi-analyte assay (DIREct-On, Durable Immunotherapy Response Estimation by immune profiling and ctDNA- On-treatment) that robustly predicted DCB, and that was validated in two independent cohorts (AUC = 0.89-0.93, PPV = 92-100%, HR = 0.04-0.11). Taken together, these results demonstrate that integrated ctDNA and circulating immune cell profiling can provide accurate, noninvasive, and early forecasting of ultimate outcomes for NSCLC patients receiving ICI. Citation Format: Barzin Y. Nabet, Mohammad S. Esfahani, Emily G. Hamilton, Jacob J. Chabon, Everett J. Moding, Hira Rizvi, Chloe B. Steen, Aadel A. Chaudhuri, Chih Long Liu, Angela B. Hui, Henning Stehr, Linda Goljenola, Michael C. Jin, Young-Jun Jeon, Diane Tseng, Taha Merghoub, Joel W. Neal, Heather A. Wakelee, Sukhmani K. Padda, Kavitha J. Ramchandran, Millie Das, Rene F. Bonilla, Christopher Yoo, Emily L. Chen, Ryan B. Ko, Aaron M. Newman, Matthew D. Hellmann, Ash A. Alizadeh, Maximilian Diehn. A noninvasive approach for early prediction of therapeutic benefit from immune checkpoint inhibition for lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5666.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-5666
    RVK:
    XA 36000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2020
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
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  • 4
    Online-Ressource
    Online-Ressource
    Circulating tumor DNA dynamics predict benefit from consolidation immunotherapy in locally advanced non-small-cell lung cancer
    Springer Science and Business Media LLC ; 2020
    In:  Nature Cancer Vol. 1, No. 2 ( 2020-01-20), p. 176-183
    Details
    In: Nature Cancer, Springer Science and Business Media LLC, Vol. 1, No. 2 ( 2020-01-20), p. 176-183
    Materialart: Online-Ressource
    ISSN: 2662-1347
    URL: Article
    DOI: 10.1038/s43018-019-0011-0
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2020
    ZDB Id: 3005299-3
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  • 5
    Online-Ressource
    Online-Ressource
    Abstract PO-069: Circulating tumor DNA kinetics to identify genomic predictors of rapid response to chemoradiation in non-small cell lung cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 8_Supplement ( 2021-04-15), p. PO-069-PO-069
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 8_Supplement ( 2021-04-15), p. PO-069-PO-069
    Kurzfassung: Introduction: Despite evidence that a subset of patients with locoregionally advanced non-small cell lung cancer (NSCLC) can be cured with radiation doses less than 60 Gy, there are currently no validated approaches to identify patients that could benefit from radiation dose de-escalation. Normal tissue changes including inflammation and fibrosis can be difficult to distinguish from residual disease on standard imaging during and following chemoradiation therapy (CRT), making assessment of treatment response and identification of favorable responders challenging. We hypothesized that circulating tumor DNA (ctDNA) kinetics during CRT could be used as a surrogate of response to identify genomic predictors of rapid response to treatment. Methods: We applied cancer personalized profiling by deep sequencing (CAPP-Seq) ctDNA analysis to 61 patients treated with CRT for Stage II-III NSCLC. We quantified ctDNA concentrations pre-CRT and a median of 21 days into CRT (mid-CRT) to determine the log-fold change in ctDNA concentration and identify “rapid responders.” The association between ctDNA log-fold change as a continuous variable with progression-free survival (PFS) was analyzed using univariable and multivariable regression, including gender, age, and stage as co-variables. The prevalence of driver gene single nucleotide variants in rapid responders versus slow responders was compared for each gene using Fisher’s exact tests with P-values adjusted using the Benjamini-Hochberg procedure. Results: Mid-CRT ctDNA log-fold change was significantly associated with progression-free survival as a continuous variable on both univariable (P=0.02) and multivariable analysis (P=0.03). Among patients whose ctDNA log-fold change was more negative than -2.15, 10/11 (91%) did not recur within the radiation field. We defined ctDNA rapid responders as the 10 patients with the largest decrease in ctDNA concentration mid-CRT without local progression. Compared with slow responders, ctDNA rapid responders had a trend towards more TP53 mutations (P=0.12), but no driver mutations were significantly enriched in rapid responders. Notably, mutations in common driver genes KEAP1, NFE2L2, KRAS, and EGFR were observed in 36% of slow responders and 0% of rapid responders (P=0.03). Conclusions: Our results suggest that ctDNA kinetics during CRT can identify patients responding favorably to treatment. Additional molecular characterization of ctDNA rapid responders may enable identification of patients who could benefit from treatment de-escalation. Citation Format: Everett J. Moding, Yufei Liu, Angela B. Hui, Jianzhong He, Yawei Qiao, Ting Xu, Luyang Yao, Saumil Gandhi, Zhongxing Liao, Millie Das, Kavitha J. Ramchandran, Sukhmani K. Padda, Joel W. Neal, Heather A. Wakelee, Billy W. Loo, Steven H. Lin, Ash A. Alizadeh, Maximilian Diehn. Circulating tumor DNA kinetics to identify genomic predictors of rapid response to chemoradiation in non-small cell lung cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-069.
    Materialart: Online-Ressource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.RADSCI21-PO-069
    RVK:
    XA 36791
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2021
    ZDB Id: 1225457-5
    ZDB Id: 2036787-9
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  • 6
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    Online-Ressource
    Abstract PO-059: Investigating gene expression profiles associated with clinical radiation resistance in KEAP1/NFE2L2 wildtype lung cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 8_Supplement ( 2021-04-15), p. PO-059-PO-059
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 8_Supplement ( 2021-04-15), p. PO-059-PO-059
    Kurzfassung: Background: We previously reported that approximately half of local recurrences (LR) after radiotherapy for localized NSCLC harbor mutations in KEAP1 or NFE2L2. Here we sought to explore factors associated with LR after radiotherapy in KEAP1/NFE2L2 wildtype NSCLC. Methods: We identified consecutive patients with stage IA1-IIIC NSCLC treated at our institution with chemoradiotherapy (CRT) or stereotactic ablative radiotherapy (SABR) from 2009-2018 and who had genotyping performed on tumor tissue with full coverage of common recurrent lung cancer driver genes including TP53, KRAS, KEAP1, and NFE2L2. We defined LR as tumor regrowth within the prescription dose radiotherapy volume. Our primary objective was to identify factors associated with LR in KEAP1/NFE2L2WT tumors. We performed RNA-seq on a subset of cases with available tissue using the SMARTer Stranded total RNA-seq Kit v2 (Takara Bio USA, Inc.). Statistical analysis was performed using R (version 3.6) with differential gene expression performed using ‘DESeq2’. All P-values were two-sided and considered significant at P & lt;0.05 with adjustment for multiple hypothesis testing when appropriate. Results: We identified 139 consecutive patients with localized NSCLC who received tumor genotyping and were treated with CRT for stage IIB-IIIC NSCLC (n=58) or SABR for stage I-IIB NSCLC (n=81). 26 (18.7%) of these patients harbored KEAP1/NFE2L2WT tumors. Clinical factors such as tumor volume (P=0.18), histology (P=0.87), and radiation dose (P=0.3) were not associated with LR in this subset. Similarly, somatic mutation analysis did not reveal association of any recurrent driver mutations with LR in these KEAP1/NFE2L2WT tumors, including in TP53 (n=19; P=0.73) or KRAS (n=9; P=0.98). Tissue was available for RNA-seq analysis of 38 KEAP1/NFE2L2WT tumors, of which the majority were adenocarcinomas (n=25, 65.8%) and approximately half each received CRT (n=20, 52.6%) and SABR (n=18, 47.4%). Gene set enrichment analysis revealed a trend for association of LR with expression of hypoxia genes (P=0.07, Q=0.28). Similarly, a previously reported 10-gene radiation sensitivity index (RSI) was not associated with LR (P=0.34). Individual gene analysis identified KRT14 as being significantly less expressed in cases with LR (adjusted P=2.2e-9). In a validation cohort of 24 stage I-IIA KEAP1/NFE2L2WT patients from the TCGA who were treated with radiotherapy, those who died had lower expression of KRT14 than those who did not (P=0.0003). Conclusions: In summary, we identify low expression of KRT14, a squamous cell carcinoma differentiation gene, as a potential biomarker for increased risk of LR after definitive radiotherapy of KEAP1/NFE2L2WT NSCLC. Validation in larger cohorts and biological characterization will be required to determine if this biomarker could be useful for guiding precision radiotherapy approaches. Citation Format: Michael S. Binkley, Young-Jun Jeon, Monica Nesselbush, Everett J. Moding, Barzin Nabet, Diego Almanza, Christopher Yoo, David M. Kurtz, Susie Grant Owen, Leah M. Backhus, Mark F. Berry, Joseph B. Shrager, Kavitha J. Ramchandran, Sukhmani K. Padda, Millie Das, Joel W. Neal, Heather A. Wakelee, Ash A. Alizadeh, Billy W. Loo, Maximilian Diehn. Investigating gene expression profiles associated with clinical radiation resistance in KEAP1/NFE2L2 wildtype lung cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-059.
    Materialart: Online-Ressource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.RADSCI21-PO-059
    RVK:
    XA 36791
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2021
    ZDB Id: 1225457-5
    ZDB Id: 2036787-9
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  • 7
    Online-Ressource
    Online-Ressource
    A mid-chemoradiation dynamic risk model integrating tumor features and ctDNA analysis for lung cancer outcome prediction.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 9046-9046
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 9046-9046
    Kurzfassung: 9046 Background: Circulating tumor DNA (ctDNA) molecular residual disease after curative intent therapy predicts disease progression in localized lung cancer. We hypothesized that integrating pre-CRT features and ctDNA levels during chemoradiation therapy (CRT) can predict patient outcomes earlier to enable response-adapted therapy. Methods: We identified pre-CRT features prognostic of disease progression after CRT for Stage II-III non-small cell lung cancer (NSCLC) in a historical “pre-CRT” training cohort of 109 patients. In addition, we applied CAPP-Seq ctDNA analysis pre-CRT and a median of 21 days into CRT (mid-CRT) to a “ctDNA” training cohort of 42 patients treated at MD Anderson and an independent validation cohort of 21 patients treated at Stanford. Prognostic pre-CRT features and mid-CRT ctDNA concentration were integrated using a Bayesian proportional hazards approach to generate a Continuous Individualized Risk Index (Kurtz et al. Cell 2019) for NSCLC (CIRI-NSCLC) to predict freedom from progression (FFP). Results: Adenocarcinoma histology (HR 2.6, P = 0.0005) and KEAP1 mutation (HR 2.7, P = 0.002) but not stage (P = 0.16), age (P = 0.60), or gender (P = 0.98) were significantly associated with FFP in the pre-CRT training cohort. Mid-CRT ctDNA concentration as a continuous variable was significantly associated with FFP in the ctDNA training cohort (HR 1.6, P = 0.04), and applying an optimal threshold identified in the training cohort (3.2 hGE/ml) significantly stratified FFP in the independent ctDNA validation cohort (HR 4.8, P = 0.02). CIRI-NSCLC enabled individualized real-time updating of the probability of FFP as model features became available over the course of CRT. CIRI-NSCLC outperformed individual model features in the independent validation cohort when compared by C-statistic (CIRI-NSCLC: 0.85; mid-CRT ctDNA: 0.76; histology: 0.66; KEAP1: 0.60). Across the whole cohort, patients with a greater than 66% risk of progression predicted by CIRI-NSCLC (n = 10) had an FFP of 10.0% at 12 months while patients with a less than 33% risk of progression predicted by CIRI-NSCLC (n = 22) had an FFP of 79.7% at 12 months (HR 15.0, P 〈 0.001). Conclusions: Our results suggest that CIRI-NSCLC can identify patients at very high and low risk of progression. Prospective evaluation will be necessary to test the potential utility of adapting treatment based on CIRI-NSCLC.
    Materialart: Online-Ressource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.9046
    RVK:
    XA 52760
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Society of Clinical Oncology (ASCO)
    Publikationsdatum: 2020
    ZDB Id: 2005181-5
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  • 8
    Online-Ressource
    Online-Ressource
    KEAP1/NFE2L2 mutations to predict local recurrence after radiotherapy but not surgery in localized non-small cell lung cancer.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 9012-9012
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 9012-9012
    Kurzfassung: 9012 Background: Tumor genotyping in localized non-small cell lung cancer (NSCLC) is not broadly performed due to lack of actionable associations of mutations with treatment or outcome. We sought to identify recurrent mutations in localized NSCLC that are associated with local recurrence (LR) after radiotherapy (RT) or surgery. Methods: We identified consecutive patients with NSCLC treated with chemoradiotherapy (CRT), stereotactic ablative radiotherapy (SABR) or surgery from 2009-2018 at our institution with stage IA1-IIIC NSCLC who had genotyping performed on tumor tissue using a targeted gene panel. Our primary objective was to identify somatic tumor mutations that predicted LR after RT but not surgery. We also performed functional screening assays by expressing open reading frame constructs harboring patient-derived mutations in knock-out cell lines generated by CRISPR-Cas9 and evaluating effects on in vitro radioresistance. Results: We identified 232 consecutive patients with localized NSCLC (87.1% adenocarcinoma, 10.3% squamous, 2.3% other) who received tumor biopsy or resection specimen and underwent tumor genotyping. 47 patients with locally advanced NSCLC received CRT, 50 patients with early stage NSCLC received SABR, and 135 patients with early stage NSCLC underwent surgical resection. Of all recurrent mutations ( 〉 5% mutation frequency), only mutations in Kelch-like ECH-associated protein 1 ( KEAP1) or Nuclear Factor Erythroid 2-Related Factor 2 ( NFE2L2) genes (K/N MUT ) were significantly associated with LR after CRT or SABR, with 2-year LR in the combined RT cohort of 42.4% for K/N MUT versus 12.5% for wildtype (P = 0.005). Furthermore, K/N MUT were present in nearly half of all LR events. Strikingly, there was no significant difference in LR for K/N MUT tumors following CRT versus SABR (P = 0.47). Local recurrence was rare for patients who received surgery (n = 2) and was not associated with K/N mutation status (P = 0.60). Functional evaluation by expression of K/N mutations in knock-out cell lines revealed that LR only occurred in patients with mutations that induced radioresistance (i.e. pathogenic) but not passenger mutations (P = 0.04). In contrast to genotyping, NFE2L2 target gene expression analysis via RNA-seq did not predict LR (P = 0.93). Conclusions: Our findings suggest that KEAP1/NFE2L2 mutations are a predictive biomarker of clinical radioresistance and a dominant cause of LR after RT. Genotyping for KEAP1/NFE2L2 mutations could therefore facilitate treatment personalization in localized NSCLC.
    Materialart: Online-Ressource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.9012
    RVK:
    XA 52760
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Society of Clinical Oncology (ASCO)
    Publikationsdatum: 2020
    ZDB Id: 2005181-5
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