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Clinical Cancer Research
Journal Prestige (SJR): 4.929
Citation Impact (citeScore): 8
Number of Followers: 50  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1078-0432 - ISSN (Online) 1557-3265
Published by AACR Homepage  [8 journals]
  • Selected Articles from This Issue

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      Pages: 5441 - 5441
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-27-20-HI
      Issue No: Vol. 27, No. 20 (2021)
       
  • Consolidating Radiotherapy with Immunotherapy

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      Authors: Rodriguez-Ruiz, M. E; Sanmamed, M. F, Serrano-Mendioroz, I, Melero, I.
      Pages: 5443 - 5445
      Abstract: Radiotherapy and immunotherapy can be concomitantly or sequentially combined seeking synergistic effects in terms of control of irradiated tumors and abscopal effects on nonirradiated lesions. Clinical-trial testing of such combinations faces several obstacles to demonstrate efficacy and needs improvements in trial design, patient selection, evaluation of results and biomarker discovery.See related article by Foster et al., p. 5510
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-2335
      Issue No: Vol. 27, No. 20 (2021)
       
  • Interpreting the Complex Landscape of Immune-Tumor Interface

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      Authors: Symmans W. F.
      Pages: 5446 - 5448
      Abstract: Predictive biomarkers for immune therapy must address a complex interface between the immune system and triple-negative breast cancer and still be technically reliable for diagnostic use. Two recent articles describe the assessment of spatial heterogeneity using digital methods that promise to improve the quantification of immune infiltrate or molecular targets.See related articles by Bai et al., p. 5557 and Carter et al., p. 5628
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-2208
      Issue No: Vol. 27, No. 20 (2021)
       
  • Going with the Flow: The Promise of Plasma-Only Circulating Tumor DNA
           Assays

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      Authors: Bent, A; Kopetz, S.
      Pages: 5449 - 5451
      Abstract: Circulating tumor DNA (ctDNA) has emerged as a noninvasive diagnostic and prognostic tool for colorectal cancer. Here, we discuss studies that evaluate the ability of plasma-only ctDNA assays to detect minimal residual disease and the potential benefit of integration of methylation into ctDNA assays.See related articles by Parikh et al., p. 5586 and Taieb et al., p. 5638
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-2181
      Issue No: Vol. 27, No. 20 (2021)
       
  • FDA Approval Summary: Pralsetinib for the Treatment of Lung and Thyroid
           Cancers With RET Gene Mutations or Fusions

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      Authors: Kim, J; Bradford, D, Larkins, E, Pai-Scherf, L. H, Chatterjee, S, Mishra-Kalyani, P. S, Wearne, E, Helms, W. S, Ayyoub, A, Bi, Y, Sun, J, Charlab, R, Liu, J, Zhao, H, Liang, D, Ghosh, S, Philip, R, Pazdur, R, Theoret, M. R, Beaver, J. A, Singh, H.
      Pages: 5452 - 5456
      Abstract: The FDA granted accelerated approval for pralsetinib on September 4, 2020 for non–small cell lung cancer (NSCLC) and December 1, 2020 for thyroid cancer, for: (i) adult patients with metastatic RET fusion–positive NSCLC, (ii) adult and pediatric patients ≥12 years of age with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy, and (iii) adult and pediatric patients ≥12 years of age with advanced or metastatic RET fusion–positive thyroid cancer who require systemic therapy and who are radioactive iodine refractory (if radioactive iodine is appropriate). Approval was based on the results of a multicenter, open-label, multi-cohort clinical trial (ARROW, NCT03037385), demonstrating substantial overall response rates (ORR) and durable responses in patients with RET-altered tumors. ORRs within the approved patient populations ranged from 57% [95% confidence interval (CI), 46–68] in patients with RET fusion–positive NSCLC previously treated with platinum chemotherapy to 89% (95% CI, 52–100) in patients with RET fusion–positive thyroid cancer, with response duration of at least 6 months in most responders. The product label includes warnings and precautions for pneumonitis, hypertension, hepatotoxicity, hemorrhagic events, tumor lysis syndrome, risk of impaired wound healing, and embryo-fetal toxicity. This article summarizes the major considerations during FDA review leading to the approval of pralsetinib.
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-0967
      Issue No: Vol. 27, No. 20 (2021)
       
  • Bispecific Immunomodulatory Antibodies for Cancer Immunotherapy

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      Authors: Blanco, B; Dominguez-Alonso, C, Alvarez-Vallina, L.
      Pages: 5457 - 5464
      Abstract: The recent advances in the field of immuno-oncology have dramatically changed the therapeutic strategy against advanced malignancies. Bispecific antibody-based immunotherapies have gained momentum in preclinical and clinical investigations following the regulatory approval of the T cell–redirecting antibody blinatumomab. In this review, we focus on emerging and novel mechanisms of action of bispecific antibodies interacting with immune cells with at least one of their arms to regulate the activity of the immune system by redirecting and/or reactivating effector cells toward tumor cells. These molecules, here referred to as bispecific immunomodulatory antibodies, have the potential to improve clinical efficacy and safety profile and are envisioned as a second wave of cancer immunotherapies. Currently, there are more than 50 bispecific antibodies under clinical development for a range of indications, with promising signs of therapeutic activity. We also discuss two approaches for in vivo secretion, direct gene delivery, and infusion of ex vivo gene-modified cells, which may become instrumental for the clinical application of next-generation bispecific immunomodulatory antibodies.
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-20-3770
      Issue No: Vol. 27, No. 20 (2021)
       
  • MRN Complex and Cancer Risk: Old Bottles, New Wine

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      Authors: Elkholi, I. E; Foulkes, W. D, Rivera, B.
      Pages: 5465 - 5471
      Abstract: The MRN complex, composed of MRE11A, RAD50, and NBN, mediates vital molecular functions to maintain genomic stability and hence protect against related disorders. Germline mutations in the MRN genes predispose to three different syndromes: ataxia-telangiectasia-like disorder (MRE11A deficiency), Nijmegen breakage syndrome (NBS; NBN deficiency), and NBS-like disorder (RAD50 deficiency). The potential cancer component of these syndromes in addition to the close physical and functional proximity of the MRN complex to BRCA1 has promoted the MRN genes as candidate risk genes for developing breast cancer. This notion has been challenged by independent large-scale population-based studies. Despite having their two-decade old candidacy as breast cancer genes close to being refuted, it has recently been reported that the MRN genes rise to have potential new roles in clonal hematopoiesis. In this article, we discuss the history and current status of MRN genes' clinical utility in breast cancer and then focus on their recently uncovered and less understood roles in clonal hematopoiesis that likely predispose to health-related disorders such as hematologic malignancies and/or cardiovascular morbid events.
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-1509
      Issue No: Vol. 27, No. 20 (2021)
       
  • A Grant-Based Experiment to Train Clinical Investigators: The AACR/ASCO
           Methods in Clinical Cancer Research Workshop

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      Authors: Von Hoff, D. D; Clark, G. M, Coltman, C. A, Disis, M. L, Eckhardt, S. G, Ellis, L. M, Foti, M, Garrett-Mayer, E, Gönen, M, Hidalgo, M, Hilsenbeck, S. G, Littlefield, J. H, LoRusso, P. M, Lyerly, H. K, Meropol, N. J, Patel, J. D, Piantadosi, S, Post, D. A, Regan, M. M, Shyr, Y, Tempero, M. A, Tepper, J. E, Von Roenn, J, Weiner, L. M, Young, D. C, Vu, N. V.
      Pages: 5472 - 5481
      Abstract: To address the need for clinical investigators in oncology, American Association for Cancer Research (AACR) and American Society for Clinical Oncology (ASCO) established the Methods in Clinical Cancer Research Workshop (MCCRW). The workshop's objectives were to: (i) provide training in the methods, design, and conduct of clinical trials; (ii) ensure that clinical trials met federal and international ethical guidelines; (iii) evaluate the effectiveness of the workshop; and (iv) create networking opportunities for young investigators with mentoring senior faculty. Educational methods included: (i) didactic lectures, (ii) Small Group Discussion Sessions, (iii) Protocol Development Groups, and (iv) one-on-one mentoring. Learning focused on the development of an Institutional Review Board (IRB)-ready protocol, which was submitted on the last day of the workshop. Evaluation methods included: (i) pre- and postworkshop tests, (ii) students' workshop evaluations, (iii) faculty's ratings of protocol development, (iv) students' productivity in clinical research after the workshop, and (v) an independent assessment of the workshop. From 1996 to 2014, 1,932 students from diverse backgrounds attended the workshop. There was a significant improvement in the students' level of knowledge from the pre- to the postworkshop exams (P < 0.001). Across the classes, student evaluations were very favorable. At the end of the workshop, faculty rated 92% to 100% of the students' protocols as ready for IRB submission. Intermediate and long-term follow-ups indicated that more than 92% of students were actively involved in patient-related research, and 66% had implemented five or more protocols. This NCI-sponsored MCCRW has had a major impact on the training of clinicians in their ability to design and implement clinical trials in cancer research.
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-1799
      Issue No: Vol. 27, No. 20 (2021)
       
  • Niraparib for Advanced Breast Cancer with Germline BRCA1 and BRCA2
           Mutations: the EORTC 1307-BCG/BIG5-13/TESARO PR-30-50-10-C BRAVO Study

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      Authors: Turner; N. C., Balmana, J., Poncet, C., Goulioti, T., Tryfonidis, K., Honkoop, A. H., Zoppoli, G., Razis, E., Johannsson, O. T., Colleoni, M., Tutt, A. N., Audeh, W., Ignatiadis, M., Mailliez, A., Tredan, O., Musolino, A., Vuylsteke, P., Juan-Fita, M. J., Macpherson, I. R. J., Kaufman, B., Manso, L., Goldstein, L. J., Ellard, S. L., Lang, I., Jen, K. Y., Adam, V., Litiere, S., Erban, J., Cameron, D. A., on behalf of the BRAVO Steering Committee the BRAVO investigators
      Pages: 5482 - 5491
      Abstract: Purpose:To investigate the activity of niraparib in patients with germline-mutated BRCA1/2 (gBRCAm) advanced breast cancer.Patients and Methods:BRAVO was a randomized, open-label phase III trial. Eligible patients had gBRCAm and HER2-negative advanced breast cancer previously treated with ≤2 prior lines of chemotherapy for advanced breast cancer or had relapsed within 12 months of adjuvant chemotherapy, and were randomized 2:1 between niraparib and physician's choice chemotherapy (PC; monotherapy with eribulin, capecitabine, vinorelbine, or gemcitabine). Patients with hormone receptor–positive tumors had to have received ≥1 line of endocrine therapy and progressed during this treatment in the metastatic setting or relapsed within 1 year of (neo)adjuvant treatment. The primary endpoint was centrally assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), PFS by local assessment (local-PFS), objective response rate (ORR), and safety.Results:After the pre-planned interim analysis, recruitment was halted on the basis of futility, noting a high degree of discordance between local and central PFS assessment in the PC arm that resulted in informative censoring. At the final analysis (median follow-up, 19.9 months), median centrally assessed PFS was 4.1 months in the niraparib arm (n = 141) versus 3.1 months in the PC arm [n = 74; hazard ratio (HR), 0.96; 95% confidence interval (CI), 0.65–1.44; P = 0.86]. HRs for OS and local-PFS were 0.95 (95% CI, 0.63–1.42) and 0.65 (95% CI, 0.46–0.93), respectively. ORR was 35% (95% CI, 26–45) with niraparib and 31% (95% CI, 19–46) in the PC arm.Conclusions:Informative censoring in the control arm prevented accurate assessment of the trial hypothesis, although there was clear evidence of niraparib's activity in this patient population.
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-0310
      Issue No: Vol. 27, No. 20 (2021)
       
  • A Phase II Trial of the Bruton Tyrosine-Kinase Inhibitor Zanubrutinib
           (BGB-3111) in Patients with Relapsed/Refractory Waldenstro╠łm
           Macroglobulinemia

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      Authors: An, G; Zhou, D, Cheng, S, Zhou, K, Li, J, Zhou, J, Xie, L, Jin, J, Zhong, L, Yan, L, Guo, H, Du, C, Zhong, J, Yu, Y, Wu, B, Qiu, L.
      Pages: 5492 - 5501
      Abstract: Purpose:Although Bruton tyrosine kinase (BTK) inhibitors have demonstrated promising efficacy in patients with Waldenström macroglobulinemia (WM), data in Asian populations are scarce. This trial is the first to investigate the effect of a BTK inhibitor in Chinese patients with relapsed/refractory (R/R) WM.Patients and Methods:Patients with R/R WM with at least one prior regimen were enrolled into this single-arm, multicenter, phase II study (NCT03332173) and received zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. The primary endpoint was major response rate (MRR), as assessed by an independent review committee. Secondary endpoints included progression-free survival, overall response rate, duration of major response, and safety.Results:Forty-four patients were enrolled. After a median follow-up of 33.0 (range, 3.2–36.5) months, MRR in all patients was 69.8%, with very good partial response or better in 32.6% of patients. All mutation groups benefited from zanubrutinib treatment (MRR in patients with MYD88L265P mutation, 73%; MRR in patients with MYD88 wild type mutation, 50%). A higher response rate was seen in the MYD88L265P/CXCR4WT population, compared with the other populations. Median progression-free survival and median duration of major response were not reached. The most frequently reported grade ≥3 treatment-emergent adverse events (AEs) were neutrophil count decreased (31.8%), and platelet count decreased and pneumonia (20.5% each). No case of atrial fibrillation/flutter occurred.Conclusions:Zanubrutinib achieved a high rate of response that was durable and deep in patients with R/R WM across all subgroups, and potentially confers a positive benefit–risk profile for WM.
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-0539
      Issue No: Vol. 27, No. 20 (2021)
       
  • A Randomized, Phase III Study of Lenvatinib in Chinese Patients with
           Radioiodine-Refractory Differentiated Thyroid Cancer

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      Authors: Zheng, X; Xu, Z, Ji, Q, Ge, M, Shi, F, Qin, J, Wang, F, Chen, G, Zhang, Y, Huang, R, Tan, J, Huang, T, Li, S, Lv, Z, Lin, Y, Guo, Z, Kubota, T, Suzuki, T, Ikezawa, H, Gao, M.
      Pages: 5502 - 5509
      Abstract: Purpose:Lenvatinib has shown efficacy in treating radioiodine-refractory differentiated thyroid cancer (RR-DTC) in the multinational phase III SELECT study; however, it has not been tested in Chinese patients with RR-DTC.Patients and Methods:Chinese patients with confirmed RR-DTC (n = 151) were randomly assigned 2:1 to receive lenvatinib 24 mg/day or placebo in 28-day cycles. The primary endpoint was progression-free survival, and key secondary endpoints included objective response rate and safety. Analyses for progression-free survival and objective response rate were conducted using Response Evaluation Criteria in Solid Tumors v1.1 and confirmed by independent imaging review. All adverse events were assessed and monitored.Results:Progression-free survival was significantly longer with lenvatinib treatment [n = 103; median 23.9 months; 95% confidence interval (CI), 12.9–not estimable] versus placebo (n = 48; median 3.7 months; 95% CI, 1.9–5.6; hazard ratio = 0.16; 95% CI, 0.10–0.26; P < 0.0001). The objective response rate was 69.9% (95% CI, 61.0–78.8) in the lenvatinib arm and 0% (95% CI, 0–0) in the placebo arm. At data cutoff, 60.2% of patients receiving lenvatinib remained on treatment; treatment-emergent adverse events led to lenvatinib discontinuation in 8.7% of patients. Overall, treatment-emergent adverse events of grade ≥3 occurred in 87.4% of patients in the lenvatinib arm, the most common being hypertension (62.1%) and proteinuria (23.3%).Conclusions:Lenvatinib at a starting dose of 24 mg/day significantly improved progression-free survival and objective response rate in Chinese patients with RR-DTC versus placebo. There were no new or unexpected toxicities. Results are consistent with those from SELECT involving patients with RR-DTC.
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-0761
      Issue No: Vol. 27, No. 20 (2021)
       
  • Phase I Study of Stereotactic Body Radiotherapy plus Nivolumab and
           Urelumab or Cabiralizumab in Advanced Solid Tumors

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      Authors: Foster, C. C; Fleming, G. F, Karrison, T. G, Liao, C.-Y, Desai, A. V, Moroney, J. W, Ratain, M. J, Nanda, R, Polite, B. N, Hahn, O. M, O'Donnell, P. H, Vokes, E. E, Kindler, H. L, Hseu, R, Janisch, L. A, Dai, J, Hoffman, M. D, Weichselbaum, R. R, Pitroda, S. P, Chmura, S. J, Luke, J. J.
      Pages: 5510 - 5518
      Abstract: Purpose:CD137 agonism and CSF1R blockade augment stereotactic body radiotherapy (SBRT) and anti-programmed death-1 in preclinical models. We evaluated the safety and efficacy of SBRT with nivolumab+urelumab (CD137 agonist) or nivolumab+cabiralizumab (CSF1R inhibitor).Patients and Methods:This phase I clinical trial enrolled patients with advanced solid tumors that had progressed on standard therapies. SBRT was delivered to 1–4 metastases with nivolumab+urelumab or nivolumab+cabiralizumab given concurrently and following SBRT. Dose-limiting toxicity (DLT) was the primary endpoint with anatomic location-specific SBRT doses deemed safe if ≤33% DLT frequency was observed. Secondary endpoints included RECISTv1.1 response, progression-free survival (PFS), overall survival (OS), and molecular correlative studies.Results:Sixty patients were enrolled, and median follow-up for living patients is 13.8 months. Of these, 23 (38%) received SBRT+nivolumab+urelumab and 37 (62%) received SBRT+nivolumab+cabiralizumab. Seven patients (12%) experienced a DLT (n = 3 grade 3, n = 4 grade 4) in the following anatomic cohorts: abdominal/pelvic (3/17, 18%), liver (1/13, 8%), central lung (2/14, 14%), and peripheral lung (1/12, 8%). Of 41 patients radiographically evaluable for best overall response including 55 radiated and 23 unirradiated RECIST target lesions, 2 had complete responses (5%), 7 had partial responses (17%), 12 had stable disease (29%), and 20 had progression (49%). Median estimated PFS and OS are 3.0 months [95% confidence interval (CI), 2.9–4.8] and 17.0 months (95% CI, 6.8–undetermined), respectively. No patients with elevated pre-SBRT serum IL8 experienced a response.Conclusions:SBRT to ≤4 sites with nivolumab+urelumab or nivolumab+cabiralizumab for treating advanced solid tumors is feasible with acceptable toxicity and modest antitumor activity.See related commentary by Rodriguez-Ruiz et al., p. 5443
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-0810
      Issue No: Vol. 27, No. 20 (2021)
       
  • A Phase I Study of the Combination of Pexidartinib and Sirolimus to Target
           Tumor-Associated Macrophages in Unresectable Sarcoma and Malignant
           Peripheral Nerve Sheath Tumors

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      Authors: Manji, G. A; Van Tine, B. A, Lee, S. M, Raufi, A. G, Pellicciotta, I, Hirbe, A. C, Pradhan, J, Chen, A, Rabadan, R, Schwartz, G. K.
      Pages: 5519 - 5527
      Abstract: Purpose:To evaluate the safety and tolerability in phase I first-in-human combination therapy with pexidartinib, an inhibitor of colony-stimulating factor-1 receptor, and sirolimus, an mTOR inhibitor, to target tumor-associated macrophage (TAM) polarization in soft tissue sarcomas (STS).Patients and Methods:This multicenter phase I study used the time-to-event continual reassessment method (TITE-CRM) to study the combination of sirolimus, doses ranging from 2 to 6 mg, with pexidartinib, doses ranging from 600 to 1,000 mg, both provided continuously on a 28-day cycle, in patients with advanced sarcoma. A total of 24 patients [8 malignant peripheral nerve sheath tumor, 3 tenosynovial giant cell tumor (TGCT), 5 leiomyosarcoma, and 8 with other sarcoma subtypes] were enrolled. The median age was 46 years, 56% were male, and 61% had>2 prior lines of therapy.Results:The recommended phase II dose was 2 mg of sirolimus combined with 1,000 mg of pexidartinib daily. Of the 18 evaluable subjects, 5 experienced dose-limiting toxicities (2 elevated aspartate aminotransferase/alanine aminotransferase, 2 elevated sirolimus trough levels, and 1 grade 5 dehydration). Most common grade 2 or higher treatment-related adverse events included anemia, fatigue, neutropenia, and lymphopenia. Clinical benefit was observed in 12 of 18 (67%) evaluable subjects with 3 partial responses (all in TGCT) and 9 stable disease. Tissue staining indicated a decreased proportion of activated M2 macrophages within tumor samples with treatment.Conclusions:Pexidartinib can be safely administered with sirolimus. These findings support further investigation of this combination to determine clinical efficacy. Clinicaltrials.gov identifier NCT02584647.
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-1779
      Issue No: Vol. 27, No. 20 (2021)
       
  • Intratumoral Delivery of STING Agonist Results in Clinical Responses in
           Canine Glioblastoma

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      Authors: Boudreau, C. E; Najem, H, Ott, M, Horbinski, C, Fang, D, DeRay, C. M, Levine, J. M, Curran, M. A, Heimberger, A. B.
      Pages: 5528 - 5535
      Abstract: Purpose:Activation of STING (stimulator of interferon genes) can trigger a robust, innate antitumor immune response in immunologically "cold" tumors such as glioblastoma.Patients and Methods:A small-molecule STING agonist, IACS-8779, was stereotactically administered using intraoperative navigation intratumorally in dogs with spontaneously arising glioblastoma. The phase I trial used an escalating dose design, ascending through four dose levels (5–20 μg). Treatment was repeated every 4–6 weeks for a minimum of two cycles. Radiographic response to treatment was determined by response assessment in neuro-oncology (RANO) criteria applied to isovoxel postcontrast T1-weighted MR images obtained on a single 3T magnet.Results:Six dogs were enrolled and completed ≥1 cycle of treatment. One dog was determined to have an abscess and was removed from further analysis. One procedure-related fatality was observed. Radiographic responses were dose dependent after the first cycle. The first subject had progressive disease, whereas there was 25% volumetric reduction in one subject and greater than 50% in the remaining surviving subjects. The median progression-free survival time was 14 weeks (range: 0–22 weeks), and the median overall survival time was 32 weeks (range: 11–39 weeks).Conclusions:Intratumoral STING agonist (IACS-8779) administration was well tolerated in dogs with glioblastoma to a dose of 15 μg. Higher doses of IACS-8779 were associated with radiographic responses.
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-1914
      Issue No: Vol. 27, No. 20 (2021)
       
  • GEN-1 in Combination with Neoadjuvant Chemotherapy for Patients with
           Advanced Epithelial Ovarian Cancer: A Phase I Dose-escalation Study

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      Authors: Thaker, P. H; Bradley, W. H, Leath, C. A, Gunderson Jackson, C, Borys, N, Anwer, K, Musso, L, Matsuzaki, J, Bshara, W, Odunsi, K, Alvarez, R. D.
      Pages: 5536 - 5545
      Abstract: Purpose:GEN-1 (phIL-12-005/PPC), an IL12 plasmid formulated with polyethyleneglycol-polyethyleneimine cholesterol lipopolymer, has preclinical activity when combined with platinum-taxane intravenous chemotherapy and administered intraperitoneally in epithelial ovarian cancer (EOC) models. OVATION I was a multicenter, nonrandomized, open-label phase IB trial to evaluate the safety, preliminary antitumor activity, and immunologic response to GEN-1 in combination with neoadjuvant chemotherapy (NACT) carboplatin-paclitaxel in patients with advanced EOC.Patients and Methods:A total of 18 patients with newly diagnosed stage IIIC and IV EOC were enrolled. A standard 3+3 dose-escalation design tested four GEN-1 doses (36, 47, 61, 79 mg/m2) to determine the maximum tolerated dose and dose-limiting toxicities (DLTs). GEN-1 was administered in eight weekly intraperitoneal infusions starting at cycle 1 week 2 in combination with three 21-day cycles of NACT carboplatin AUC 6 and weekly paclitaxel 80 mg/m2.Results:The most common treatment-emergent adverse events at least possibly related were nausea, fatigue, abdominal pain/cramping, anorexia, diarrhea, and vomiting. Eight patients experience grade 4 neutropenia attributed to NACT. No DLTs occurred. A total of 14 patients were evaluable for response and 12 (85.7%) had radiological response (two complete response and 10 partial response) prior to debulking; nine were R0 at debulking and one patient had complete pathologic response. IL12 and its downstream cytokine, IFN, increased in peritoneal washings but not as much in blood. Increased levels of myeloid dendritic cells and T-effector memory cells in peritoneal fluid, plus elevated CD8+ T cells and reduced immunosuppression within the tumor microenvironment were found. A median time to treatment failure of 18.4 months (95% confidence interval, 9.2–24.5) was observed in the intention-to-treat population.Conclusions:Adding GEN-1 to standard NACT is safe, appears active, and has an impact on the tumor microenvironment.
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-0360
      Issue No: Vol. 27, No. 20 (2021)
       
  • Phase 2 Trial of Oncolytic H-1 Parvovirus Therapy Shows Safety and Signs
           of Immune System Activation in Patients With Metastatic Pancreatic Ductal
           Adenocarcinoma

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      Authors: Hajda, J; Leuchs, B, Angelova, A. L, Frehtman, V, Rommelaere, J, Mertens, M, Pilz, M, Kieser, M, Krebs, O, Dahm, M, Huber, B, Engeland, C. E, Mavratzas, A, Hohmann, N, Schreiber, J, Jäger, D, Halama, N, Sedlaczek, O, Gaida, M. M, Daniel, V, Springfeld, C, Ungerechts, G.
      Pages: 5546 - 5556
      Abstract: Purpose:To investigate the safety, clinical efficacy, virus pharmacokinetics, shedding, and immune response after administration of an oncolytic parvovirus (H-1PV, ParvOryx) to patients with metastatic pancreatic ductal adenocarcinoma (PDAC) refractory to first-line therapy.Patients and Methods:This is a noncontrolled, single-arm, open-label, dose-escalating, single-center clinical trial. Seven patients with PDAC and at least one liver metastasis were included. ParvOryx was administered intravenously on 4 consecutive days and as an intralesional injection, 6 to 13 days thereafter. Altogether, three escalating dose levels were investigated. In addition, gemcitabine treatment was initiated on day 28.Results:ParvOryx showed excellent tolerability with no dose-limiting toxicities. One patient had a confirmed partial response and one patient revealed an unconfirmed partial response according to RECIST criteria. Both patients showed remarkably long surivial of 326 and 555 days, respectively. Investigation of pharmacokinetics and virus shedding revealed dose dependency with no excretion of active virus particles in saliva or urine and very limited excretion in feces. H-1PV nucleic acids were detected in tumor samples of four patients. All patients showed T-cell responses to viral proteins. An interesting immunologic pattern developed in tumor tissues and in blood of both patients with partial response suggesting immune activation after administration of ParvOryx.Conclusions:The trial met all primary objectives, revealed no environmental risks, and indicated favorable immune modulation after administration of ParvOryx. It can be considered a good basis for further systematic clinical development alone or in combination with immunomodulatory compounds.
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-1020
      Issue No: Vol. 27, No. 20 (2021)
       
  • An Open-Source, Automated Tumor-Infiltrating Lymphocyte Algorithm for
           Prognosis in Triple-Negative Breast Cancer

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      Authors: Bai, Y; Cole, K, Martinez-Morilla, S, Ahmed, F. S, Zugazagoitia, J, Staaf, J, Bosch, A, Ehinger, A, Nimeus, E, Hartman, J, Acs, B, Rimm, D. L.
      Pages: 5557 - 5565
      Abstract: Purpose:Although tumor-infiltrating lymphocytes (TIL) assessment has been acknowledged to have both prognostic and predictive importance in triple-negative breast cancer (TNBC), it is subject to inter and intraobserver variability that has prevented widespread adoption. Here we constructed a machine-learning based breast cancer TIL scoring approach and validated its prognostic potential in multiple TNBC cohorts.Experimental Design:Using the QuPath open-source software, we built a neural-network classifier for tumor cells, lymphocytes, fibroblasts, and "other" cells on hematoxylin–eosin (H&E)–stained sections. We analyzed the classifier-derived TIL measurements with five unique constructed TIL variables. A retrospective collection of 171 TNBC cases was used as the discovery set to identify the optimal association of machine-read TIL variables with patient outcome. For validation, we evaluated a retrospective collection of 749 TNBC patients comprised of four independent validation subsets.Results:We found that all five machine TIL variables had significant prognostic association with outcomes (P ≤ 0.01 for all comparisons) but showed cell-specific variation in validation sets. Cox regression analysis demonstrated that all five TIL variables were independently associated with improved overall survival after adjusting for clinicopathologic factors including stage, age, and histologic grade (P ≤ 0.0003 for all analyses).Conclusions:Neural net-driven cell classifier-defined TIL variables were robust and independent prognostic factors in several independent validation cohorts of TNBC patients. These objective, open-source TIL variables are freely available to download and can now be considered for testing in a prospective setting to assess clinical utility.See related commentary by Symmans, p. 5446
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-0325
      Issue No: Vol. 27, No. 20 (2021)
       
  • TP53 Mutations with Low Variant Allele Frequency Predict Short Survival in
           Chronic Lymphocytic Leukemia

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      Authors: Bomben, R; Rossi, F. M, Vit, F, Bittolo, T, D'Agaro, T, Zucchetto, A, Tissino, E, Pozzo, F, Vendramini, E, Degan, M, Zaina, E, Cattarossi, I, Varaschin, P, Nanni, P, Berton, M, Braida, A, Polesel, J, Cohen, J. A, Santinelli, E, Biagi, A, Gentile, M, Morabito, F, Fronza, G, Pozzato, G, D'Arena, G, Olivieri, J, Bulian, P, Pepper, C, Hockaday, A, Schuh, A, Hillmen, P, Rossi, D, Chiarenza, A, Zaja, F, Di Raimondo, F, Del Poeta, G, Gattei, V.
      Pages: 5566 - 5575
      Abstract: Purpose:In chronic lymphocytic leukemia (CLL), TP53 mutations are associated with reduced survival and resistance to standard chemoimmunotherapy (CIT). Nevertheless, the clinical impact of subclonal TP53 mutations below 10% to 15% variant allele frequency (VAF) remains unclear.Experimental Design:Using a training/validation approach, we retrospectively analyzed the clinical and biological features of TP53 mutations above (high-VAF) or below (low-VAF) the previously reported 10.0% VAF threshold, as determined by deep next-generation sequencing. Clinical impact of low-VAF TP53 mutations was also confirmed in a cohort (n = 251) of CLL treated with fludarabine-cyclophosphamide-rituximab (FCR) or FCR-like regimens from two UK trials.Results:In the training cohort, 97 of 684 patients bore 152 TP53 mutations, while in the validation cohort, 71 of 536 patients had 109 TP53 mutations. In both cohorts, patients with the TP53 mutation experienced significantly shorter overall survival (OS) than TP53 wild-type patients, regardless of the TP53 mutation VAF. By combining TP53 mutation and 17p13.1 deletion (del17p) data in the total cohort (n = 1,220), 113 cases were TP53 mutated only (73/113 with low-VAF mutations), 55 del17p/TP53 mutated (3/55 with low-VAF mutations), 20 del17p only, and 1,032 (84.6%) TP53 wild-type. A model including low-VAF cases outperformed the canonical model, which considered only high-VAF cases (c-indices 0.643 vs. 0.603, P < 0.0001), and improved the prognostic risk stratification of CLL International Prognostic Index. Clinical results were confirmed in CIT-treated cases (n = 552) from the retrospective cohort, and the UK trials cohort.Conclusions:TP53 mutations affected OS regardless of VAF. This finding can be used to update the definition of TP53 mutated CLL for clinical purposes.
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-0701
      Issue No: Vol. 27, No. 20 (2021)
       
  • Improving Risk Stratification for Pediatric Patients with Rhabdomyosarcoma
           by Molecular Detection of Disseminated Disease

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      Authors: Lak, N. S. M; Voormanns, T. L, Zappeij-Kannegieter, L, van Zogchel, L. M. J, Fiocco, M, van Noesel, M. M, Merks, J. H. M, van der Schoot, C. E, Tytgat, G. A. M, Stutterheim, J.
      Pages: 5576 - 5585
      Abstract: Purpose:Survival of children with rhabdomyosarcoma that suffer from recurrent or progressive disease is poor. Identifying these patients upfront remains challenging, indicating a need for improvement of risk stratification. Detection of tumor-derived mRNA in bone marrow (BM) and peripheral blood (PB) using reverse-transcriptase qPCR (RT-qPCR) is a more sensitive method to detect disseminated disease. We identified a panel of genes to optimize risk stratification by RT-qPCR.Experimental Design:Candidate genes were selected using gene expression data from rhabdomyosarcoma and healthy hematologic tissues, and a multiplexed RT-qPCR was developed. Significance of molecular disease was determined in a cohort of 99 Dutch patients with rhabdomyosarcoma (72 localized and 27 metastasized) treated according to the European pediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 protocol.Results:We identified the following 11 rhabdomyosarcoma markers: ZIC1, ACTC1, MEGF10, PDLIM3, SNAI2, CDH11, TMEM47, MYOD1, MYOG, and PAX3/7-FOXO1. RT-qPCR was performed for this 11-marker panel on BM and PB samples from the patient cohort. Five-year event-free survival (EFS) was 35.5% [95% confidence interval (CI), 17.5%–53.5%] for the 33/99 RNA-positive patients, versus 88.0% (95% CI, 78.9%–97.2%) for the 66/99 RNA-negative patients (P < 0.0001). Five-year overall survival (OS) was 54.8% (95% CI, 36.2%–73.4%) and 93.7% (95% CI, 86.6%–100.0%), respectively (P < 0.0001). RNA panel positivity was negatively associated with EFS (Hazard Ratio = 9.52; 95% CI, 3.23–28.02), whereas the RMS2005 risk group stratification was not, in the multivariate Cox regression model.Conclusions:This study shows a strong association between PCR-based detection of disseminated disease at diagnosis with clinical outcome in pediatric patients with rhabdomyosarcoma, also compared with conventional risk stratification. This warrants further validation in prospective trials as additional technique for risk stratification.
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-1083
      Issue No: Vol. 27, No. 20 (2021)
       
  • Minimal Residual Disease Detection using a Plasma-only Circulating Tumor
           DNA Assay in Patients with Colorectal Cancer

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      Authors: Parikh, A. R; Van Seventer, E. E, Siravegna, G, Hartwig, A. V, Jaimovich, A, He, Y, Kanter, K, Fish, M. G, Fosbenner, K. D, Miao, B, Phillips, S, Carmichael, J. H, Sharma, N, Jarnagin, J, Baiev, I, Shah, Y. S, Fetter, I. J, Shahzade, H. A, Allen, J. N, Blaszkowsky, L. S, Clark, J. W, Dubois, J. S, Franses, J. W, Giantonio, B. J, Goyal, L, Klempner, S. J, Nipp, R. D, Roeland, E. J, Ryan, D. P, Weekes, C. D, Wo, J. Y, Hong, T. S, Bordeianou, L, Ferrone, C. R, Qadan, M, Kunitake, H, Berger, D, Ricciardi, R, Cusack, J. C, Raymond, V. M, Talasaz, A, Boland, G. M, Corcoran, R. B.
      Pages: 5586 - 5594
      Abstract: Purpose:Detection of persistent circulating tumor DNA (ctDNA) after curative-intent surgery can identify patients with minimal residual disease (MRD) who will ultimately recur. Most ctDNA MRD assays require tumor sequencing to identify tumor-derived mutations to facilitate ctDNA detection, requiring tumor and blood. We evaluated a plasma-only ctDNA assay integrating genomic and epigenomic cancer signatures to enable tumor-uninformed MRD detection.Experimental Design:A total of 252 prospective serial plasma specimens from 103 patients with colorectal cancer undergoing curative-intent surgery were analyzed and correlated with recurrence.Results:Of 103 patients, 84 [stage I (9.5%), II (23.8%), III (47.6%), IV (19%)] had evaluable plasma drawn after completion of definitive therapy, defined as surgery only (n = 39) or completion of adjuvant therapy (n = 45). In "landmark" plasma drawn 1-month (median, 31.5 days) after definitive therapy and>1 year follow-up, 15 patients had detectable ctDNA, and all 15 recurred [positive predictive value (PPV), 100%; HR, 11.28 (P < 0.0001)]. Of 49 patients without detectable ctDNA at the landmark timepoint, 12 (24.5%) recurred. Landmark recurrence sensitivity and specificity were 55.6% and 100%. Incorporating serial longitudinal and surveillance (drawn within 4 months of recurrence) samples, sensitivity improved to 69% and 91%. Integrating epigenomic signatures increased sensitivity by 25%–36% versus genomic alterations alone. Notably, standard serum carcinoembryonic antigen levels did not predict recurrence [HR, 1.84 (P = 0.18); PPV = 53.9%].Conclusions:Plasma-only MRD detection demonstrated favorable sensitivity and specificity for recurrence, comparable with tumor-informed approaches. Integrating analysis of epigenomic and genomic alterations enhanced sensitivity. These findings support the potential clinical utility of plasma-only ctDNA MRD detection.See related commentary by Bent and Kopetz, p. 5449
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-0410
      Issue No: Vol. 27, No. 20 (2021)
       
  • Prevalence and Landscape of Actionable Genomic Alterations in Renal Cell
           Carcinoma

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      Authors: Attalla, K; DiNatale, R. G, Rappold, P. M, Fong, C. J, Sanchez-Vega, F, Silagy, A. W, Weng, S, Coleman, J, Lee, C.-H, Carlo, M. I, Durack, J. C, Solomon, S. B, Reuter, V. E, Russo, P, Chan, T. A, Motzer, R. J, Schultz, N. D, Reznik, E, Voss, M. H, Hakimi, A. A.
      Pages: 5595 - 5606
      Abstract: Purpose:We report our experience with next-generation sequencing to characterize the landscape of actionable genomic alterations in renal cell carcinoma (RCC).Experimental Design:A query of our institutional clinical sequencing database (MSK-IMPACT) was performed that included tumor samples from 38,468 individuals across all cancer types. Somatic variations were annotated using a precision knowledge database (OncoKB) and the available clinical data stratified by level of evidence. Alterations associated with response to immune-checkpoint blockade (ICB) were analyzed separately; these included DNA mismatch repair (MMR) gene alterations, tumor mutational burden (TMB), and microsatellite instability (MSI). Data from The Cancer Genome Atlas (TCGA) consortium as well as public data from several clinical trials in metastatic RCC were used for validation purposes. Multiregional sequencing data from the TRAcking Cancer Evolution through Therapy (TRACERx) RENAL cohort were used to assess the clonality of somatic mutations.Results:Of the 753 individuals with RCC identified in the MSK-IMPACT cohort, 115 showed evidence of targetable alterations, which represented a prevalence of 15.3% [95% confidence interval (CI), 12.7%–17.8%). When stratified by levels of evidence, the alterations identified corresponded to levels 2 (11.3%), 3A (5.2%), and 3B (83.5%). A low prevalence was recapitulated in the TCGA cohort at 9.1% (95% CI, 6.9%–11.2%). Copy-number variations predominated in papillary RCC tumors, largely due to amplifications in the MET gene. Notably, higher rates of actionability were found in individuals with metastatic disease (stage IV) compared with those with localized disease (OR, 2.50; 95% CI, 1.16–6.16; Fisher's P = 0.01). On the other hand, the prevalence of alterations associated with response to ICB therapy was found to be approximately 5% in both the MSK-IMPACT and TCGA cohorts and no associations with disease stage were identified (OR, 1.35; 95% CI, 0.46–5.40; P = 0.8). Finally, multiregional sequencing revealed that the vast majority of actionable mutations occurred later during tumor evolution and were only present subclonally in RCC tumors.Conclusions:RCC harbors a low prevalence of clinically actionable alterations compared with other tumors and the evidence supporting their clinical use is limited. These aberrations were found to be more common in advanced disease and seem to occur later during tumor evolution. Our study provides new insights on the role of targeted therapies for RCC and highlights the need for additional research to improve treatment selection using genomic profiling.
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-20-4058
      Issue No: Vol. 27, No. 20 (2021)
       
  • Copy Number Aberration Analysis to Predict Response to Neoadjuvant
           Anti-HER2 Therapy: Results from the NeoALTTO Phase III Clinical Trial

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      Authors: Venet, D; Rediti, M, Maetens, M, Fumagalli, D, Brown, D. N, Majjaj, S, Salgado, R, Pusztai, L, Harbeck, N, El-Abed, S, Wang, Y, Saura, C, Gomez, H, Semiglazov, V. F, de Azambuja, E, Huober, J, Nuciforo, P, Di Cosimo, S, Piccart, M, Loi, S, Rothe, F, Sotiriou, C.
      Pages: 5607 - 5618
      Abstract: Purpose:The heterogeneity of response to anti-HER2 agents represents a major challenge in patients with HER2-positive breast cancer. To better understand the sensitivity and resistance to trastuzumab and lapatinib, we investigated the role of copy number aberrations (CNA) in predicting pathologic complete response (pCR) and survival outcomes in the NeoALTTO trial.Experimental Design:The neoadjuvant phase III NeoALTTO trial enrolled 455 patients with HER2-positive early-stage breast cancer. DNA samples from 269 patients were assessed for genome-wide copy number profiling. Recurrent CNAs were found with GISTIC2.0.Results:CNA estimates were obtained for 184 patients included in NeoALTTO. Among those, matched transcriptome and whole-exome data were available for 154 and 181 patients, respectively. A significant association between gene copy number and pCR was demonstrated for ERBB2 amplification. Nevertheless, ERBB2 amplification ceased to be predictive once ERBB2 expression level was considered. GISTIC2.0 analysis revealed 159 recurrent CNA regions. Lower copy number levels of the 6q23-24 locus predicted absence of pCR in the whole cohort and in the estrogen receptor–positive subgroup. 6q23-24 deletion was significantly more frequent in TP53 wild-type (WT) compared with TP53-mutated, resulting in copy number levels significantly associated with lack of pCR only in the TP53 WT subgroup. Interestingly, a gene-ontology analysis highlighted several immune processes correlated to 6q23-24 copy number.Conclusions:Our analysis identified ERBB2 copy number as well as 6q23-24 CNAs as predictors of response to anti–HER2-based treatment. ERBB2 expression outperformed ERBB2 amplification. The complexity of the 6q23-24 region warrants further investigation.
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-1317
      Issue No: Vol. 27, No. 20 (2021)
       
  • Circulating Tumor DNA Analysis Detects FGFR2 Amplification and Concurrent
           Genomic Alterations Associated with FGFR Inhibitor Efficacy in Advanced
           Gastric Cancer

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      Authors: Jogo, T; Nakamura, Y, Shitara, K, Bando, H, Yasui, H, Esaki, T, Terazawa, T, Satoh, T, Shinozaki, E, Nishina, T, Sunakawa, Y, Komatsu, Y, Hara, H, Oki, E, Matsuhashi, N, Ohta, T, Kato, T, Ohtsubo, K, Kawakami, T, Okano, N, Yamamoto, Y, Yamada, T, Tsuji, A, Odegaard, J. I, Taniguchi, H, Doi, T, Fujii, S, Yoshino, T.
      Pages: 5619 - 5627
      Abstract: Purpose:FGFR2 amplification is associated with poor prognosis in advanced gastric cancer and its subclonal heterogeneity has been revealed. Here, we examined whether circulating tumor DNA (ctDNA) was useful for detecting FGFR2 amplification and co-occurring resistance mechanisms in advanced gastric cancer.Experimental Design:We assessed genomic characteristics of FGFR2-amplified advanced gastric cancer in a nationwide ctDNA screening study. We also analyzed FGFR2 amplification status in paired tissue and plasma samples with advanced gastric cancer. In addition, we examined patients with FGFR2-amplified advanced gastric cancer identified by ctDNA sequencing who received FGFR inhibitors.Results:FGFR2 amplification was more frequently detected by ctDNA sequencing in 28 (7.7%) of 365 patients with advanced gastric cancer than by tissue analysis alone (2.6%–4.4%). FGFR2 amplification profiling of paired tissue and plasma revealed that FGFR2 amplification was detectable only by ctDNA sequencing in 6 of 44 patients, which was associated with a worse prognosis. Two patients in whom FGFR2 amplification was detected by ctDNA sequencing after tumor progression following previous standard chemotherapies but not by pretreatment tissue analysis had tumor responses to FGFR inhibitors. A third patient with FGFR2 and MET co-amplification in ctDNA showed a limitation of benefit from FGFR inhibition, accompanied by a marked increase in the MET copy number.Conclusions:ctDNA sequencing identifies FGFR2 amplification missed by tissue testing in patients with advanced gastric cancer, and these patients may respond to FGFR inhibition. The utility of ctDNA sequencing warrants further evaluation to develop effective therapeutic strategies for patients with FGFR2-amplified advanced gastric cancer.
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-1414
      Issue No: Vol. 27, No. 20 (2021)
       
  • Characteristics and Spatially Defined Immune (micro)landscapes of
           Early-stage PD-L1-positive Triple-negative Breast Cancer

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      Authors: Carter, J. M; Polley, M.-Y. C, Leon-Ferre, R. A, Sinnwell, J, Thompson, K. J, Wang, X, Ma, Y, Zahrieh, D, Kachergus, J. M, Solanki, M, Boughey, J. C, Liu, M. C, Ingle, J. N, Kalari, K. R, Couch, F. J, Thompson, E. A, Goetz, M. P.
      Pages: 5628 - 5637
      Abstract: Purpose:Programmed death ligand 1 [PD-(L)1]-targeted therapies have shown modest survival benefit in triple-negative breast cancer (TNBC). PD-L1+ microenvironments in TNBC are not well characterized and may inform combinatorial immune therapies. Herein, we characterized clinicopathologic features, RNA-based immune signatures, and spatially defined protein-based tumor–immune microenvironments (TIME) in early-stage PD-L1+ and PD-L1– TNBC.Experimental Design:From a large cohort of chemotherapy-naïve TNBC, clinicopathologic features, deconvoluted RNA immune signatures, and intraepithelial and stromal TIME (Nanostring GeoMX) were identified in subsets of PD-L1+ and PD-L1– TNBC, as defined by FDA-approved PD-L1 companion assays.Results:228 of 499 (46%) TNBC were PD-L1+ (SP142: ≥1% immune cells-positive). Using PD-L1 22C3, 46% had combined positive score (CPS) ≥ 1 and 16% had CPS ≥10. PD-L1+ TNBC were higher grade with higher tumor-infiltrating lymphocytes (TIL; P < 0.05). PD-L1 was not associated with improved survival following adjustment for TILs and other variables. RNA profiles of PD-L1+ TNBC had increased dendritic cell, macrophage, and T/B cell subset features; and decreased myeloid-derived suppressor cells. PD-L1+ stromal and intraepithelial TIMEs were highly enriched in IDO-1, HLA-DR, CD40, and CD163 compared with PD-L1-TIME, with spatially specific alterations in CTLA-4, Stimulator of Interferon Genes (STING), and fibronectin. Macrophage- and antigen presentation–related proteins correlated most strongly with PD-L1 protein.Conclusions:In this early-stage TNBC cohort, nearly 50% were PD-L1+ (SP142 companion assay) while 16% were PD-L1+ with the 22C3 companion assay. PD-L1+ TNBC had specific myeloid-derived and lymphoid features. Spatially defined PD-L1+ TIME were enriched in several clinically actionable immune proteins. These data may inform future studies on combinatorial immunotherapies for patients with PD-L1+ TNBC.See related commentary by Symmans, p. 5446
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-0343
      Issue No: Vol. 27, No. 20 (2021)
       
  • Prognostic Value and Relation with Adjuvant Treatment Duration of ctDNA in
           Stage III Colon Cancer: a Post Hoc Analysis of the PRODIGE-GERCOR
           IDEA-France Trial

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      Authors: Taieb, J; Taly, V, Henriques, J, Bourreau, C, Mineur, L, Bennouna, J, Desrame, J, Louvet, C, Lepere, C, Mabro, M, Egreteau, J, Bouche, O, Mulot, C, Hormigos, K, Chaba, K, Mazard, T, de Gramont, A, Vernerey, D, Andre, T, Laurent-Puig, P.
      Pages: 5638 - 5646
      Abstract: Purpose:Circulating tumor DNA (ctDNA) has been suggested as a major prognostic factor in resected stage-III colon cancer. We analyzed ctDNA of patients randomized in the phase III IDEA-France trial.Experimental Design:ctDNA was tested for WIF1 and NPY by droplet digital PCR with method developed and validated for colorectal cancer. Disease-free survival (DFS) and overall survival (OS) were analyzed via multivariable analysis in patients with ctDNA samples and in sub-groups according to treatment duration (3/6 months) and disease stage (high/low-risk stage III).Results:Of 2,010 randomized patients, 1,345 had available ctDNA samples (1,017 collected both post-surgery and pre-chemotherapy). More Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 (78% versus 69%) and T4 and/or N2 (40% versus 36%) were observed in patients studied (n = 1017) versus not analyzed (n = 993). There were 877 ctDNA-negative (86.2%) and 140 ctDNA-positive (13.8%) patients; their baseline characteristics were similar. With a median follow-up of 6.6 years, the 3-year DFS rate was 66.39% for ctDNA-positive patients and 76.71% for ctDNA-negative patients (P = 0.015). ctDNA was confirmed as an independent prognostic marker for DFS (adjusted HR = 1.55, 95% CI 1.13–2.12, P = 0.006) and OS (HR = 1.65, 95% CI 1.12–2.43, P = 0.011). ctDNA was prognostic in patients treated for 3 months and with T4 and/or N2 tumors, but not in those treated for 6 months and with T1–3/N1 tumors.Conclusions:In this first ctDNA assessment of a large series of patients with stage III colon cancer enrolled in phase III trial, post-surgery ctDNA was found in 13.8% of them and was confirmed as an independent prognostic marker.See related commentary by Bent and Kopetz, p. 5449
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-0271
      Issue No: Vol. 27, No. 20 (2021)
       
  • Kinobead Profiling Reveals Reprogramming of BCR Signaling in Response to
           Therapy within Primary CLL Cells

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      Authors: Linley, A. J; Karydis, L. I, Mondru, A. K, D'Avola, A, Al Shmrany, H, Cicconi, S, Griffin, R, Forconi, F, Pettitt, A. R, Kalakonda, N, Rawstron, A. C, Hillmen, P, Steele, A. J, MacEwan, D. J, Packham, G, Prior, I. A, Slupsky, J. R.
      Pages: 5647 - 5659
      Abstract: Purpose:B-cell receptor (BCR) signaling is critical for the pathogenesis of chronic lymphocytic leukemia (CLL), promoting both malignant cell survival and disease progression. Although vital, understanding of the wider signaling network associated with malignant BCR stimulation is poor. This is relevant with respect to potential changes in response to therapy, particularly involving kinase inhibitors. In the current study, we describe a novel high-resolution approach to investigate BCR signaling in primary CLL cells and track the influence of therapy on signaling response.Experimental Design:A kinobead/mass spectrometry–based protocol was used to study BCR signaling in primary CLL cells. Longitudinal analysis of samples donated by clinical trial patients was used to investigate the impact of chemoimmunotherapy and ibrutinib on signaling following surface IgM engagement. Complementary Nanostring and immunoblotting analysis was used to verify our findings.Results:Our protocol isolated a unique, patient-specific signature of over 30 kinases from BCR-stimulated CLL cells. This signature was associated with 13 distinct Kyoto Encyclopedia of Genes and Genomes pathways and showed significant change in cells from treatment-naïve patients compared with those from patients who had previously undergone therapy. This change was validated by longitudinal analysis of clinical trials samples where BCR-induced kinome responses in CLL cells altered between baseline and disease progression in patients failing chemoimmunotherapy and between baseline and treatment in patients taking ibrutinib.Conclusions:These data comprise the first comprehensive proteomic investigation of the BCR signaling response within CLL cells and reveal unique evidence that these cells undergo adaptive reprogramming of this signaling in response to therapy.
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-0161
      Issue No: Vol. 27, No. 20 (2021)
       
  • Sulindac, a Nonselective NSAID, Reduces Breast Density in Postmenopausal
           Women with Breast Cancer Treated with Aromatase Inhibitors

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      Authors: Thompson, P. A; Huang, C, Yang, J, Wertheim, B. C, Roe, D, Zhang, X, Ding, J, Chalasani, P, Preece, C, Martinez, J, Chow, H.- H. S, Stopeck, A. T.
      Pages: 5660 - 5668
      Abstract: Purpose:To evaluate the effect of sulindac, a nonselective anti-inflammatory drug (NSAID), for activity to reduce breast density (BD), a risk factor for breast cancer.Experimental Design:An open-label phase II study was conducted to test the effect of 12 months' daily sulindac at 150 mg twice daily on change in percent BD in postmenopausal hormone receptor–positive breast cancer patients on aromatase inhibitor (AI) therapy. Change in percent BD in the contralateral, unaffected breast was measured by noncontrast magnetic resonance imaging (MRI) and reported as change in MRI percent BD (MRPD). A nonrandomized patient population on AI therapy (observation group) with comparable baseline BD was also followed for 12 months. Changes in tissue collagen after 6 months of sulindac treatment were explored using second-harmonic generated microscopy in a subset of women in the sulindac group who agreed to repeat breast biopsy.Results:In 43 women who completed 1 year of sulindac (86% of those accrued), relative MRPD significantly decreased by 9.8% [95% confidence interval (CI), –14.6 to –4.7] at 12 months, an absolute decrease of –1.4% (95% CI, –2.5 to –0.3). A significant decrease in mean breast tissue collagen fiber straightness (P = 0.032), an investigational biomarker of tissue inflammation, was also observed. MRPD (relative or absolute) did not change in the AI-only observation group (N = 40).Conclusions:This is the first study to indicate that the NSAID sulindac may reduce BD. Additional studies are needed to verify these findings and determine if prostaglandin E2 inhibition by NSAIDs is important for BD or collagen modulation.
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-0732
      Issue No: Vol. 27, No. 20 (2021)
       
  • TOP2B Enzymatic Activity on Promoters and Introns Modulates Multiple
           Oncogenes in Human Gliomas

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      Authors: Gonzalez-Buendia, E; Zhao, J, Wang, L, Mukherjee, S, Zhang, D, Arrieta, V. A, Feldstein, E, Kane, J. R, Kang, S. J, Lee-Chang, C, Mahajan, A, Chen, L, Realubit, R, Karan, C, Magnuson, L, Horbinski, C, Marshall, S. A, Sarkaria, J. N, Mohyeldin, A, Nakano, I, Bansal, M, James, C. D, Brat, D. J, Ahmed, A, Canoll, P, Rabadan, R, Shilatifard, A, Sonabend, A. M.
      Pages: 5669 - 5680
      Abstract: Purpose:The epigenetic mechanisms involved in transcriptional regulation leading to malignant phenotype in gliomas remains poorly understood. Topoisomerase IIB (TOP2B), an enzyme that decoils and releases torsional forces in DNA, is overexpressed in a subset of gliomas. Therefore, we investigated its role in epigenetic regulation in these tumors.Experimental Design:To investigate the role of TOP2B in epigenetic regulation in gliomas, we performed paired chromatin immunoprecipitation sequencing for TOP2B and RNA-sequencing analysis of glioma cell lines with and without TOP2B inhibition and in human glioma specimens. These experiments were complemented with assay for transposase-accessible chromatin using sequencing, gene silencing, and mouse xenograft experiments to investigate the function of TOP2B and its role in glioma phenotypes.Results:We discovered that TOP2B modulates transcription of multiple oncogenes in human gliomas. TOP2B regulated transcription only at sites where it was enzymatically active, but not at all native binding sites. In particular, TOP2B activity localized in enhancers, promoters, and introns of PDGFRA and MYC, facilitating their expression. TOP2B levels and genomic localization was associated with PDGFRA and MYC expression across glioma specimens, which was not seen in nontumoral human brain tissue. In vivo, TOP2B knockdown of human glioma intracranial implants prolonged survival and downregulated PDGFRA.Conclusions:Our results indicate that TOP2B activity exerts a pleiotropic role in transcriptional regulation of oncogenes in a subset of gliomas promoting a proliferative phenotype.
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-0312
      Issue No: Vol. 27, No. 20 (2021)
       
  • Comparative Assessment of Diagnostic Homologous Recombination
           Deficiency-Associated Mutational Signatures in Ovarian Cancer

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      Authors: Sztupinszki, Z; Diossy, M, Borcsok, J, Prosz, A, Cornelius, N, Kjeldsen, M. K, Mirza, M. R, Szallasi, Z.
      Pages: 5681 - 5687
      Abstract: Purpose:Homologous recombination (HR) deficiency (HRD) is one of the key determinants of PARP inhibitor response in ovarian cancer, and its accurate detection in tumor biopsies is expected to improve the efficacy of this therapy. Because HRD induces a wide array of genomic aberrations, mutational signatures may serve as a companion diagnostic to identify PARP inhibitor–responsive cases.Experimental Design:From the The Cancer Genome Atlas (TCGA) whole-exome sequencing (WES) data, we extracted different types of mutational signature–based HRD measures, such as the HRD score, genome-wide LOH, and HRDetect trained on ovarian and breast cancer–specific sequencing data. We compared their performance to identify BRCA1/2-deficient cases in the TCGA ovarian cancer cohort and predict survival benefit in platinum-treated, BRCA1/2 wild-type ovarian cancer.Results:We found that the HRD score, which is based on large chromosomal alterations alone, performed similarly well to an ovarian cancer–specific HRDetect, which incorporates mutations on a finer scale as well (AUC = 0.823 vs. AUC = 0.837). In an independent cohort these two methods were equally accurate predicting long-term survival after platinum treatment (AUC = 0.787 vs. AUC = 0.823). We also found that HRDetect trained on ovarian cancer was more accurate than HRDetect trained on breast cancer data (AUC = 0.837 vs. AUC = 0.795; P = 0.0072).Conclusions:When WES data are available, methods that quantify only large chromosomal alterations such as the HRD score and HRDetect that captures a wider array of HRD-induced genomic aberrations are equally efficient identifying HRD ovarian cancer cases.
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-0981
      Issue No: Vol. 27, No. 20 (2021)
       
  • Prognostic Utility of Breast Cancer Index to Stratify Distant Recurrence
           Risk in Invasive Lobular Carcinoma

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      Authors: Nunes, R; Sella, T, Treuner, K, Atkinson, J. M, Wong, J, Zhang, Y, Exman, P, Dabbs, D, Richardson, A. L, Schnabel, C. A, Sgroi, D. C, Oesterreich, S, Cimino-Mathews, A, Metzger, O.
      Pages: 5688 - 5696
      Abstract: Purpose:The prognostic utility of Breast Cancer Index (BCI) for risk assessment of overall (0–10 years), early (0–5 years), and late (5–10 years) distant recurrence (DR) in hormone receptor–positive (HR+) invasive lobular carcinoma (ILC) was evaluated.Experimental Design:BCI gene expression analysis was performed blinded to clinical outcome utilizing tumor specimens from patients with HR+ ILC from a multi-institutional cohort. The primary endpoint was time to DR. Kaplan–Meier analyses of overall, early, and late DR risk were performed, and statistical significance was evaluated by log-rank test and Cox proportional hazards regression. The prognostic contribution of BCI in addition to clinicopathologic factors was evaluated by likelihood ratio analysis.Results:Analysis of 307 patients (99% ER+, 53% T1, 42% N+, 70% grade II) showed significant differences in DR over 10 years based on BCI risk categories. BCI low- and intermediate-risk patients demonstrated similar DR rates of 7.6% and 8.0%, respectively, compared with 27.0% for BCI high-risk patients. BCI was a significant independent prognostic factor for overall 10-year DR [HR = 4.09; 95% confidence interval (CI), 2.00–8.34; P = 0.0001] as well as for both early (HR = 8.19; 95% CI, 1.85–36.30; P = 0.0042) and late (HR = 3.04; 95% CI, 1.32–7.00; P = 0.0224) DR. In multivariate analysis, BCI remained the only statistically significant prognostic factor for DR (HR = 3.49; 95% CI, 1.28–9.54; P = 0.0150).Conclusions:BCI is an independent prognostic factor for ILC and significantly stratified patients for cumulative risk of 10-year, early, and late DR. BCI added prognostic value beyond clinicopathologic characteristics in this distinct subtype of breast cancer.
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-0733
      Issue No: Vol. 27, No. 20 (2021)
       
  • KRAS Inhibitor Resistance in MET-Amplified KRASG12C Non-Small Cell Lung
           Cancer Induced By RAS- and Non-RAS-Mediated Cell Signaling Mechanisms

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      Authors: Suzuki, S; Yonesaka, K, Teramura, T, Takehara, T, Kato, R, Sakai, H, Haratani, K, Tanizaki, J, Kawakami, H, Hayashi, H, Sakai, K, Nishio, K, Nakagawa, K.
      Pages: 5697 - 5707
      Abstract: Purpose:Treatment with KRASG12C inhibitors such as sotorasib can produce substantial regression of tumors in some patients with non–small cell lung cancer (NSCLC). These patients require alternative treatment after acquiring resistance to the inhibitor. The mechanisms underlying this acquired resistance are unclear. The purpose of this study was to identify the mechanisms underlying acquired sotorasib resistance, and to explore potential treatments for rescuing patients with sotorasib-resistant KRASG12C NSCLC cells.Experimental Design:Clones of sotorasib-sensitive KRASG12C NSCLC H23 cells exposed to different concentrations of sotorasib were examined using whole-genomic transcriptome analysis, multiple receptor kinase phosphorylation analysis, and gene copy-number evaluation. The underlying mechanisms of resistance were investigated using immunologic examination, and a treatment aimed at overcoming resistance was tested in vitro and in vivo.Results:Unbiased screening detected subclonal evolution of MET amplification in KRASG12C NSCLC cells that had developed resistance to sotorasib in vitro. MET knockdown using small interfering RNA (siRNA) restored susceptibility to sotorasib in these resistant cells. MET activation by its amplification reinforced RAS cycling from its inactive form to its active form. In addition to RAS-mediated MEK–ERK induction, MET induced AKT activation independently of RAS. Crizotinib, a MET inhibitor, restored sensitivity to sotorasib by eliminating RAS–MEK–ERK as well as AKT signaling. MET/KRASG12C dual inhibition led to tumor shrinkage in sotorasib-resistant xenograft mice.Conclusions:MET amplification leads to the development of resistance to KRASG12C inhibitors in NSCLC. Dual blockade of MET and KRASG12C could be a treatment option for MET-amplified, KRASG12C-mutated NSCLC.
      PubDate: 2021-10-15T00:05:45-07:00
      DOI: 10.1158/1078-0432.CCR-21-0856
      Issue No: Vol. 27, No. 20 (2021)
       
  • Circulating Protein Disulfide Isomerase Is Associated with Increased Risk
           of Thrombosis in JAK2-Mutated Myeloproliferative Neoplasms

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      Authors: Sharda, A. V; Bogue, T, Barr, A, Mendez, L. M, Flaumenhaft, R, Zwicker, J. I.
      Pages: 5708 - 5717
      Abstract: Purpose:Thromboembolic events (TE) are the most common complications of myeloproliferative neoplasms (MPN). Clinical parameters, including patient age and mutation status, are used to risk-stratify patients with MPN, but a true biomarker of TE risk is lacking. Protein disulfide isomerase (PDI), an endoplasmic reticulum protein vital for protein folding, also possesses essential extracellular functions, including regulation of thrombus formation. Pharmacologic PDI inhibition prevents thrombus formation, but whether pathologic increases in PDI increase TE risk remains unknown.Experimental Design:We evaluated the association of plasma PDI levels and risk of TE in a cohort of patients with MPN with established diagnosis of polycythemia vera (PV) or essential thrombocythemia (ET), compared with healthy controls. Plasma PDI was measured at enrollment and subjects followed prospectively for development of TE.Results:A subset of patients, primarily those with JAK2-mutated MPN, had significantly elevated plasma PDI levels as compared with controls. Plasma PDI was functionally active. There was no association between PDI levels and clinical parameters typically used to risk-stratify patients with MPN. The risk of TE was 8-fold greater in those with PDI levels above 2.5 ng/mL. Circulating endothelial cells from JAK2-mutated MPN patients, but not platelets, demonstrated augmented PDI release, suggesting endothelial activation as a source of increased plasma PDI in MPN.Conclusions:The observed association between plasma PDI levels and increased risk of TE in patients with JAK2-mutated MPN has both prognostic and therapeutic implications.
      PubDate: 2021-10-15T00:05:46-07:00
      DOI: 10.1158/1078-0432.CCR-21-1140
      Issue No: Vol. 27, No. 20 (2021)
       
  • Therapeutic Targeting of Mesothelin with Chimeric Antigen Receptor T Cells
           in Acute Myeloid Leukemia

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      Authors: Le, Q; Castro, S, Tang, T, Loeb, A. M, Hylkema, T, McKay, C. N, Perkins, L, Srivastava, S, Call, L, Smith, J, Leonti, A, Ries, R, Pardo, L, Loken, M. R, Correnti, C, Fiorenza, S, Turtle, C. J, Riddell, S, Tarlock, K, Meshinchi, S.
      Pages: 5718 - 5730
      Abstract: Purpose:We previously identified mesothelin (MSLN) as highly expressed in a significant fraction of acute myeloid leukemia (AML) but entirely silent in normal hematopoiesis, providing a promising antigen for immunotherapeutic targeting that avoids hematopoietic toxicity. Given that T cells genetically modified to express chimeric antigen receptors (CAR) are effective at eradicating relapsed/refractory acute lymphocytic leukemia, we developed MSLN-directed CAR T cells for preclinical evaluation in AML.Experimental Design:The variable light (VL) and heavy (VH) sequences from the MSLN-targeting SS1P immunotoxin were used to construct the single-chain variable fragment of the standard CAR containing 41-BB costimulatory and CD3Zeta stimulatory domains. The preclinical efficacy of MSLN CAR T cells was evaluated against AML cell lines and patient samples expressing various levels of MSLN in vitro and in vivo.Results:We demonstrate that MSLN is expressed on the cell surface of AML blasts and leukemic stem cell–enriched CD34+CD38– subset, but not on normal hematopoietic stem and progenitor cells (HSPC). We further establish that MSLN CAR T cells are highly effective in eliminating MSLN-positive AML cells in cell line– and patient-derived xenograft models. Importantly, MSLN CAR T cells can target and eradicate CD34+CD38– cells without impacting the viability of normal HSPCs. Finally, we show that CAR T-cell functionality can be improved by inhibition of the ADAM17 metalloprotease that promotes shedding of MSLN.Conclusions:These findings demonstrate that MSLN is a viable target for CAR T-cell therapy in AML and that inhibiting MSLN shedding is a promising approach to improve CAR T-cell efficacy.
      PubDate: 2021-10-15T00:05:46-07:00
      DOI: 10.1158/1078-0432.CCR-21-1546
      Issue No: Vol. 27, No. 20 (2021)
       
 
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