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  • 1
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    Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer
    Elsevier BV ; 2021
    In:  Cell Vol. 184, No. 25 ( 2021-12), p. 6119-6137.e26
    Details
    In: Cell, Elsevier BV, Vol. 184, No. 25 ( 2021-12), p. 6119-6137.e26
    Type of Medium: Online Resource
    ISSN: 0092-8674
    URL: Article
    DOI: 10.1016/j.cell.2021.11.017
    RVK:
    XA 36269
    RVK:
    WA 15000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
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  • 2
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    Diminished Efficacy of Programmed Death-(Ligand)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma Is Affected by KRAS Mutation Status
    Elsevier BV ; 2022
    In:  Journal of Thoracic Oncology Vol. 17, No. 3 ( 2022-03), p. 399-410
    Details
    In: Journal of Thoracic Oncology, Elsevier BV, Vol. 17, No. 3 ( 2022-03), p. 399-410
    Type of Medium: Online Resource
    ISSN: 1556-0864
    URL: Article
    DOI: 10.1016/j.jtho.2021.10.013
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
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  • 3
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    Mammalian SWI/SNF Complex Genomic Alterations and Immune Checkpoint Blockade in Solid Tumors
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Immunology Research Vol. 8, No. 8 ( 2020-08-01), p. 1075-1084
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 8, No. 8 ( 2020-08-01), p. 1075-1084
    Abstract: Prior data have variably implicated the inactivation of the mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) complex with increased tumor sensitivity to immune checkpoint inhibitors (ICI). Herein, we examined the association between mSWI/SNF variants and clinical outcomes to ICIs. We correlated somatic loss-of-function (LOF) variants in a predefined set of mSWI/SNF genes (ARID1A, ARID1B, SMARCA4, SMARCB1, PBRM1, and ARID2) with clinical outcomes in patients with cancer treated with systemic ICIs. We identified 676 patients from Dana-Farber Cancer Institute (DFCI, Boston, MA) and 848 patients from a publicly available database from Memorial Sloan Kettering Cancer Center (MSKCC, New York, NY) who met the inclusion criteria. Multivariable analyses were conducted and adjusted for available baseline factors and tumor mutational burden. Median follow-up was 19.6 (17.6–22.0) months and 28.0 (25.0–29.0) months for the DFCI and MSKCC cohorts, respectively. Seven solid tumor subtypes were examined. In the DFCI cohort, LOF variants of mSWI/SNF did not predict improved overall survival (OS), time-to-treatment failure (TTF), or disease control rate. Only patients with renal cell carcinoma with mSWI/SNF LOF showed significantly improved OS and TTF with adjusted HRs (95% confidence interval) of 0.33 (0.16–0.7) and 0.49 (0.27–0.88), respectively, and this was mostly driven by PRBM1. In the MSKCC cohort, where only OS was captured, LOF mSWI/SNF did not correlate with improved outcomes across any tumor subtype. We did not find a consistent association between mSWI/SNF LOF variants and improved clinical outcomes to ICIs, suggesting that mSWI/SNF variants should not be considered as biomarkers of response to ICIs.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-19-0866
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 4
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    Molecular Characterization and Therapeutic Targeting of Colorectal Cancers Harboring Receptor Tyrosine Kinase Fusions
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 6 ( 2021-03-15), p. 1695-1705
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 6 ( 2021-03-15), p. 1695-1705
    Abstract: Receptor tyrosine kinase fusions in colorectal cancers are rare, but potentially therapeutically relevant. We describe clinical, molecular, and pathologic attributes of RTK fusion–associated colorectal cancer. Experimental Design: We identified all cases with RTK fusions in patients with colorectal cancer seen at Dana-Farber Cancer Institute (Boston, MA) who underwent OncoPanel testing between 2013 and 2018. Clinical, histologic, and molecular features were extracted from the patient charts and molecular testing results. Results: We identified 12 driver oncogenic fusions in various RTKs. These fusions occurred exclusively in BRAF and RAS wild-type tumors and were enriched in right-sided and mismatch repair–deficient (MMR-D) colorectal cancers. All of the MMR-D colorectal cancers with RTK fusions were found in tumors with acquired MMR-D due to MLH1 promoter hypermethylation and one was associated with a sessile serrated polyp. Molecular profiles of MMR-D colorectal cancer with RTK fusions largely resembled BRAF V600E–mutated MMR-D colorectal cancer, rather than those secondary to Lynch syndrome. We describe two patients with fusion-associated microsatellite stable (MSS) colorectal cancer who derived clinical benefit from therapeutic targeting of their translocation. The first harbored an ALK-CAD fusion and received sequential crizotinib and alectinib therapy for a total of 7.5 months until developing an ALK L1196Q gatekeeper mutation. The second patient, whose tumor contained an ROS1-GOPC fusion, continues to benefit from entrectinib after 9 months of therapy. Conclusions: RTK fusions in colorectal cancer are a rare, but important disease subgroup that occurs in RAS and BRAF wild-type tumors. Despite enrichment in acquired MMR-D tumors, RTK fusions also occur in MSS colorectal cancer and provide an important therapeutic target.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-20-4073
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 5
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    Abstract 5705: Mechanisms and therapeutic implications of hypermutation in gliomas
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5705-5705
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5705-5705
    Abstract: High tumor mutational burden (hypermutation) is observed in some gliomas; however, its mechanisms of development and whether it predicts immunotherapy response are poorly understood. Here, we comprehensively analyze the molecular determinants of mutational burden and signatures in 10,294 gliomas including AACR Project GENIE and institutional datasets. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after temozolomide treatment. Experimentally, the mutational signature of post-treatment hypermutated gliomas was only recapitulated by temozolomide-induced damage in cells harboring MMR deficiency. MMR-deficient gliomas exhibited unique features including the lack of prominent T-cell infiltrates, extensive intratumoral heterogeneity, poor survival and low response rate to PD-1 blockade. Moreover, while microsatellite instability in MMR-deficient gliomas was not detected by bulk analyses, single-cell whole-genome sequencing of post-treatment hypermutated glioma cells demonstrated microsatellite mutations. This study shows that chemotherapy can drive acquisition of hypermutated populations without promoting response to PD-1 blockade and supports diagnostic use of mutational burden and signatures in cancer. Citation Format: Mehdi Touat, Yvonne Y. Li, Adam N. Boynton, Liam F. Spurr, Bryan Iorgulescu, Craig L. Bohrson, Isidro Cortes-Ciriano, Jack E. Geduldig, Kristine Pelton, Mary J. Lim-Fat, Sangita Pal, Shakti H. Ramkissoon, Frank Dubois, Charlotte Bellamy, Naomi Currimjee, Kenin Qian, Seth Malinowski, Aniket Shetty, Kin-Hoe Chow, Maïté Verreault, Erell Guillerm, Samy Ammari, Frédéric Beuvon, Karima Mokhtari, Agusti Alentorn, Caroline Dehais, Caroline Houillier, Florence Laigle-Donadey, Dimitri Psimaras, Alexandre Carpentier, Philippe Cornu, Laurent Capelle, Bertrand Mathon, Jill S. Barnholtz-Sloan, Arnab Chakravarti, Wenya L. Bi, Garrett M. Frampton, Marc Sanson, Brian M. Alexander, Andrew Cherniack, Patrick Y. Wen, David A. Reardon, Aurelien Marabelle, Peter J. Park, Ahmed Idbaih, Rameen Beroukhim, Pratiti Bandopadhayay, Franck Bielle, Keith L. Ligon. Mechanisms and therapeutic implications of hypermutation in gliomas [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 5705.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-5705
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 6
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    Abstract 5668: Genomic correlates of PD-L1 expression are associated with response to immunotherapy in non-small cell lung cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5668-5668
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5668-5668
    Abstract: PD-L1 expression is the primary clinical biomarker of immune checkpoint blockade (ICB) response in non-small cell lung cancer (NSCLC); patients with tumors that express higher levels of PD-L1 tend to have better responses. However, somatic genomic events correlating with PD-L1 expression are not fully defined. To investigate this, we utilized a DFCI cohort of 909 non-squamous NSCLC samples grouped into 3 categories of PD-L1 expression based on immunohistochemistry (IHC): & lt;1% (negative, n=304), 1-49% (low, n=326), and ≥50% (high, n=279) expression. All samples were sequenced by hybrid capture for over 300 cancer-associated genes (OncoPanel), and we assessed somatic mutations and copy number (CN) variations for correlation with PD-L1 expression. Compared to PD-L1 high tumors, PD-L1 neg. cases were more likely to have mutations in STK11 (Permutation test, q=7e-4), EGFR (q=7e-4), CTNNB1 (q=0.04), APC (q=0.17), and SMARCA4 (q=0.2). CN losses that more significantly occurred in PD-L1 neg. tumors included deletions of PD-L1, PD-L2, and JAK2 (Fisher exact test, q & lt;1e-3) as well as 9p chromosomal arm loss (q=0.04) and homozygous deletions in CDKN2A/B (q=0.05). We assessed the association of these somatic alterations with PD-L1 mRNA expression in an independent cohort of 529 TCGA primary lung tumors. STK11 mutation (Mann-Whitney test, q & lt;1e-3), CN loss of PD-L1, PD-L2, and/or JAK2 (q & lt;1e-3), and CN loss of chromosome arm 9p (q & lt;1e-3) were all associated with decreased PD-L1 mRNA expression. Conversely, CN gain of PD-L1, PD-L2, and/or JAK2 and 9p were significantly (q & lt;1e-3) associated with increased PD-L1 expression. Next, we examined if somatic alterations associated with PD-L1 expression were also correlated with progression free (PFS) or overall survival (OS) using a partially-overlapping DFCI cohort of 468 advanced stage NSCLCs. STK11 mutation (Log-rank test, q=0.1), EGFR mutation (q & lt;1e-3), and CN loss of PD-L1, PD-L2, and/or JAK2 (q=0.02) were all significantly associated with worse PFS after ICB. EGFR mutation was significantly associated with worse OS after ICB (q=0.19). We observed the previously identified (Schabath, et al 2016) mutual exclusivity between EGFR and STK11 mutations. We further show that they may indicate distinct subtypes of PD-L1 neg. tumors with STK11 mutant tumors exhibiting strikingly worse prognosis after ICB (med. PFS 52 vs 64 days, p & lt;1e-3; med. OS 212 vs 299 days, p=5e-3). In summary, we confirm the findings that STK11 and EGFR mutations are associated with reduced PD-L1 expression and worse prognosis after ICB (Rizvi, et al 2018) and identify CN loss of the PD-L1 locus as a potential novel biomarker of lower PD-L1 expression and worse ICB outcomes. In addition, we show a novel anticorrelation between Wnt pathway alterations and PD-L1 expression by IHC. Taken together, this work suggests a role of specific mutations and CNVs in affecting PD-L1 expression and response to ICB. Citation Format: Liam F. Spurr, Giuseppe Lamberti, Yvonne Y. Li, Biagio Ricciuti, Gonzalo Recondo, Renato Umeton, Lynette M. Sholl, Matthew L. Meyerson, Andrew D. Cherniack, Mark M. Awad. Genomic correlates of PD-L1 expression are associated with response to immunotherapy in non-small cell 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 5668.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-5668
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 7
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    Molecular Mechanisms of Acquired Resistance to MET Tyrosine Kinase Inhibitors in Patients with MET Exon 14–Mutant NSCLC
    American Association for Cancer Research (AACR) ; 2020
    In:  Clinical Cancer Research Vol. 26, No. 11 ( 2020-06-01), p. 2615-2625
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 26, No. 11 ( 2020-06-01), p. 2615-2625
    Abstract: Molecular mechanisms of acquired resistance to MET tyrosine kinase inhibitors (TKI) are poorly understood. We aimed to characterize the genomic mechanisms of resistance to type I and type II MET TKIs and their impact on sequential MET TKI therapy outcomes in patients with metastatic MET exon 14–mutant NSCLC. Experimental Design: Genomic alterations occurring at the time of progression on MET TKIs were studied using plasma and tissue next-generation sequencing (NGS). Results: A total of 20 patients had tissue or plasma available for analysis at the time of acquired resistance to a MET TKI. Genomic alterations known or suspected to be mechanisms of resistance were detected in 15 patients (75%). On-target acquired mechanisms of resistance, including single and polyclonal MET kinase domain mutations in codons H1094, G1163, L1195, D1228, Y1230, and high levels of amplification of the MET exon 14–mutant allele, were observed in 7 patients (35%). A number of off-target mechanisms of resistance were detected in 9 patients (45%), including KRAS mutations and amplifications in KRAS, EGFR, HER3, and BRAF; one case displayed both on- and off-target mechanisms of resistance. In 2 patients with on-target resistant mutations, switching between type I and type II MET TKIs resulted in second partial responses. Conclusions: On-target secondary mutations and activation of bypass signaling drive resistance to MET TKIs. A deeper understanding of these molecular mechanisms can support the development of sequential or combinatorial therapeutic strategies to overcome resistance.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-19-3608
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    detail.hit.zdb_id: 2036787-9
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  • 8
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    Mechanisms and therapeutic implications of hypermutation in gliomas
    Springer Science and Business Media LLC ; 2020
    In:  Nature Vol. 580, No. 7804 ( 2020-04-23), p. 517-523
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 580, No. 7804 ( 2020-04-23), p. 517-523
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-020-2209-9
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
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    detail.hit.zdb_id: 1413423-8
    SSG: 11
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  • 9
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    FGFR2 Extracellular Domain In-Frame Deletions Are Therapeutically Targetable Genomic Alterations That Function as Oncogenic Drivers in Cholangiocarcinoma
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Discovery Vol. 11, No. 10 ( 2021-10-01), p. 2488-2505
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 11, No. 10 ( 2021-10-01), p. 2488-2505
    Abstract: We conducted next-generation DNA sequencing on 335 biliary tract cancers and characterized the genomic landscape by anatomic site within the biliary tree. In addition to frequent FGFR2 fusions among patients with intrahepatic cholangiocarcinoma (IHCC), we identified FGFR2 extracellular domain in-frame deletions (EID) in 5 of 178 (2.8%) patients with IHCC, including two patients with FGFR2 p.H167_N173del. Expression of this FGFR2 EID in NIH3T3 cells resulted in constitutive FGFR2 activation, oncogenic transformation, and sensitivity to FGFR inhibitors. Three patients with FGFR2 EIDs were treated with Debio 1347, an oral FGFR1/2/3 inhibitor, and all showed partial responses. One patient developed an acquired L618F FGFR2 kinase domain mutation at disease progression and experienced a further partial response for 17 months to an irreversible FGFR2 inhibitor, futibatinib. Together, these findings reveal FGFR2 EIDs as an alternative mechanism of FGFR2 activation in IHCC that predicts sensitivity to FGFR inhibitors in the clinic. Significance: FGFR2 EIDs are transforming genomic alterations that occur predominantly in patients with IHCC. These FGFR2 EIDs are sensitive to FGFR inhibition in vitro, and patients with these alterations benefited from treatment with FGFR inhibitors in the clinic. This article is highlighted in the In This Issue feature, p. 2355
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-20-1669
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 10
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    Characterizing the landscape of genomic variants in high-risk pediatric osteosarcoma.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 11530-11530
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 11530-11530
    Abstract: 11530 Background: Survival rates for patients with metastatic and/or recurrent osteosarcoma are poor, and treatment strategies have remained unchanged for more than three decades. Genomic characterization can identify new treatment strategies and improve risk stratification. To date, sequencing studies of osteosarcoma have focused on newly diagnosed patients. We present one of the first reports of osteosarcoma genomics in a high-risk cohort. Methods: 92 samples from 92 patients were sequenced in a CLIA/CAP laboratory with a targeted NGS panel test. Patients were enrolled in one of two studies. The PROFILE study enrolls all patients seen at Dana-Farber Cancer Institute, and the GAIN study enrolls patients with metastatic and/or recurrent cancer at 11 institutions. Sequencing was performed using primary tumor samples at biopsy and/or from sites of metastasis when available. Results: 33 patients were enrolled on the PROFILE study, and 59 were enrolled on GAIN. Diagnostic stage was available for 65 (67%) of patients. 37% had metastatic disease at diagnosis. The 3-year overall survival (OS) was 71% for the entire study population, 56% for patients with metastatic disease at diagnosis, and 81% for patients with initially localized disease. The presence of metastases at diagnosis was significantly associated with poor outcome (p 〈 0.0087) and was the only independent clinical prognostic factor identified. Genomic analysis revealed frequent alterations in TP53 (37%), RB1 (15%), CDKN2A (13%), MYC (12%), CDKN1A (12%), ATRX (10%), and CCND3 (8%). Patients whose tumors had MYC amplification (defined as ≥ 6 copies) had a 3-year OS of 39% compared with a 3-year OS of 76% in the absence of MYC amplification, a difference with borderline statistical significance (p = 0.051). Conclusions: In the first study to examine genomic alterations detected by targeted gene panel sequencing in a CAP-certified laboratory in a large population of pediatric patients with higher risk osteosarcoma, the most frequently occurring events were similar to those found in prior reports. MYC amplification, reported as a possible poor prognostic factor in other studies, was present in 12% of patients and was associated with a worse OS, though this finding did not reach statistical significance.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.11530
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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