24 results on '"Raghav KPS"'
Search Results
2. Sustained Disease Control in Immune Checkpoint Blockade Responders with Microsatellite Instability-high Colorectal Cancer after Treatment Termination.
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Simmons K, Thomas JV, Ludford K, Willis JA, Higbie VS, Raghav KPS, Johnson B, Dasari A, Kee BK, Parseghian CM, Lee MS, Le PH, Morelli MP, Shen JP, Bent A, Vilar E, Wolff RA, Kopetz S, Overman MJ, and Morris VK
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- Humans, Immune Checkpoint Inhibitors therapeutic use, Retrospective Studies, Microsatellite Instability, Colonic Neoplasms drug therapy, Colorectal Neoplasms drug therapy
- Abstract
Immune checkpoint inhibitors improve survival in patients with mismatch repair deficiency/microsatellite instability-high (MSI-H) colorectal cancer. The recurrence outcomes following discontinuation of immunotherapy after prolonged disease control have not been definitively reported in large series. Records from patients with advanced MSI-H colorectal cancer from The University of Texas - MD Anderson Cancer Center who received immunotherapy between 2014 and 2022 and stopped after prolonged clinical benefit were reviewed. Median progression-free and overall survival were estimated. Associations between the event of recurrence and coexisting mutations (KRAS/NRAS, BRAFV600E), metastatic organ involvement (lung, liver, lymph node, or peritoneum), metastatic timing (synchronous vs. metachronous), prior immunotherapy [anti-PD-(L)1 alone or in combination with anti-CTLA antibodies], etiology of MSI status (sporadic vs. hereditary non-polyposis colorectal cancer), and duration of immunotherapy were assessed. Sixty-four patients with MSI-H colorectal cancer without progression on immunotherapy were reviewed. Of these 48 and 16 received anti-PD(L)1 antibody alone or in combination with anti-CTLA-4 antibody, respectively. Median exposure to immunotherapy was 17.6 months (range, 1.3-51.9). After a median follow-up of 22.6 months (range, 0.3-71.7) after stopping immunotherapy, 56 of 64 patients (88%) remained without disease progression. Lung metastases were associated with recurrence/progression (OR, 6.1; P = 0.04), but coexisting mutation, primary tumor sidedness, and immunotherapy were not. These data provide a retrospective, single-institution analysis that showed that most patients with advanced MSI-H colorectal cancer do not recur after treatment cessation, regardless of the reason for stopping treatment or a variety of patient and disease features, supporting an optimistic prognosis of sustained disease control., Significance: Outcomes for patients with MSI-H colorectal cancer stopping immunotherapy after disease control remain unknown. Sixty-four patients with MSI-H colorectal cancer from our institution stopping treatment for sustained benefit or toxicity were retrospectively assessed. After median follow up of 22 months and median immunotherapy exposure of 18 months, 88% patients remained without progression. All patients who recurred or progressed and were rechallenged with immunotherapy have continued to experience disease control., (© 2023 The Authors; Published by the American Association for Cancer Research.)
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- 2023
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3. Significance of Distinct Liquid Biopsy Compartments in Evaluating Somatic Mutations for Targeted Therapy Selection in Cancer of Unknown Primary.
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Kolbinger FR, Bernard V, Lee JJ, Stephens BM, Branchi V, Raghav KPS, Maitra A, Guerrero PA, and Semaan A
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- Humans, DNA, Neoplasm genetics, Liquid Biopsy, Mutation, Neoplasms, Unknown Primary drug therapy, Neoplasms, Unknown Primary genetics, Cell-Free Nucleic Acids
- Abstract
Purpose: Cancer of unknown primary (CUP) accounts for 2-5% of all cancer diagnoses, wherein standard investigations fail to reveal the original tumor site. Basket trials allocate targeted therapeutics based on actionable somatic mutations, independent of tumor entity. These trials, however, mostly rely on variants identified in tissue biopsies. Since liquid biopsies (LB) represent the overall tumor genomic landscape, they may provide an ideal diagnostic source in CUP patients. To identify the most informative liquid biopsy compartment, we compared the utility of genomic variant analysis for therapy stratification in two LB compartments (circulating cell-free (cf) and extracellular vesicle (ev) DNA)., Methods: CfDNA and evDNA from 23 CUP patients were analyzed using a targeted gene panel covering 151 genes. Identified genetic variants were interpreted regarding diagnostic and therapeutic relevance using the MetaKB knowledgebase., Results: LB revealed a total of 22 somatic mutations in evDNA and/or cfDNA in 11/23 patients. Out of the 22 identified somatic variants, 14 are classified as Tier I druggable somatic variants. Comparison of variants identified in evDNA and cfDNA revealed an overlap of 58% of somatic variants in both LB compartments, whereas over 40% of variants were only found in one or the other compartment., Conclusion: We observed substantial overlap between somatic variants identified in evDNA and cfDNA of CUP patients. Nonetheless, interrogation of both LB compartments can potentially increase the rate of druggable alterations, stressing the significance of liquid biopsies for possible primary-independent basket and umbrella trial inclusion., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2023
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4. Endoscopic and imaging outcomes of PD-1 therapy in localised dMMR colorectal cancer.
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Fox DA, Bhamidipati D, Konishi T, Kaur H, You N, Raghav KPS, Ge PS, Messick C, Johnson B, Morris VK, Thomas JV, Shah P, Bednarski BK, Kopetz S, Chang GJ, Ludford K, Higbie VS, and Overman MJ
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- Humans, DNA Mismatch Repair, Endoscopy, Microsatellite Instability, Neoadjuvant Therapy, Retrospective Studies, Colorectal Neoplasms diagnostic imaging, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics, Programmed Cell Death 1 Receptor antagonists & inhibitors, Immune Checkpoint Inhibitors therapeutic use
- Abstract
Background: Neoadjuvant immune checkpoint blockade (IO) is emerging as a therapeutic option for patients with deficient mismatch repair (dMMR) colorectal cancer (CRC) given high pathological response rates. The aim of the study was to characterise imaging and endoscopic response to IO., Methods: A retrospective analysis of patients with localised dMMR CRC that received at least one cycle of neoadjuvant anti-PD-1 therapy was conducted. Endoscopy, imaging, and pathological outcomes were reviewed to determine response to treatment according to standardised criteria., Results: Thirty-eight patients had received IO for the treatment of localised CRC (median eight cycles). Among evaluable cases (n = 31 for endoscopy and n = 34 for imaging), the best endoscopic response was complete response (CR) in 45% of cases, and the best radiographic response was CR in 23% of cases. Imaging CR rate after ≤4 cycles of IO (n = 1) was 6% compared to 44% after >4 IO cycles (n = 7). Among 28 patients with imaging and endoscopy available, a discrepancy in best response was noted in 15 (54%) cases. At a median follow-up of 28.2 months from IO start, 18 patients underwent surgical resection of which 11 (61%) had pathological CR (pCR). Despite pCR or no evidence of progression ≥6 months after completion of IO among non-operatively managed patients, 72% and 42% of patients had non-CR on imaging and endoscopy, respectively., Conclusions: Discrepancies between imaging and endoscopy are prevalent, and irregularities identified on these modalities can be identified despite pathological remission. Improved clinical response criteria are warranted., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Tsuyoshi Konishi: travel, accommodations, expenses – advent health; Michener Institute of Education at UHN. Kanwal Pratap Singh Raghav: Honoraria - Bayer; Daiichi Sankyo/Astra Zeneca; Eisai; Merck; Seagen. Consulting or advisory role – Bayer; Daiichi Sankyo/Astra Zeneca; Eisai; Merck; Seagen. Research funding – Abbvie (Inst); Abbvie (Inst); Bayer (Inst); Daiichi Sankyo/Astra Zeneca (Inst); Eisai (Inst); Guardant Health (Inst); HiberCell (Inst); Innovent Biologics (Inst); Janssen (Inst); Merck Serono (Inst); Roche/Genentech (Inst); UCB (Inst); Xencor (Inst). Phillip S. Ge: consulting or advisory role – Alira Health; Boston Scientific; Neptune Medical; Ovesco Endoscopy. Benny Johnson: consulting or advisory role – Gritstone Bio; Incyte; Insmed; Pfizer; Taiho Oncology. Research funding – Bristol-Myers Squibb (Inst); Gateway Foundation (Inst); Syntrix Biosystems (Inst). Van K. Morris: consulting or advisory role – Axiom Healthcare Strategies; Bicara Therapeutics; BioMedical Insights; Boehringer Ingelheim; Incyte. Research funding – Bicara Therapeutics (Inst); BioNTech (Inst); Bristol-Myers Squibb (Inst); EMD Serono (Inst); Immatics; Pfizer (Inst). Scott Kopetz: stock and other ownership interests – Frontier Medicines; Iylon; Lutris; Navire; Xilis. Consulting or advisory role – Abbvie; Accademia Nazionale Di Medicina; Amal Therapeutics; Amgen; Astra Zeneca/MedImmune; Bayer Health; Bicara Therapeutics; Black Diamond Therapeutics; Boehringer Ingelheim; Bristol-Myers Squibb/Medarex; Cardiff Oncology; Carina Biotech; CureTeq; EMD Serono; Endeavor BioMedicines; Flame Biosciences; Foundation Medicine; Frontier Medicines; Genentech; Genomic Health; Gilead Sciences; GlaxoSmithKline; HalioDx; Harbinger Oncology, Inc; Holy Stone Healthcare; Inivata; Ipsen; Iylon; Jacobio; Jazz Pharmaceuticals; Johnson & Johnson/Janssen; Lilly; Lutris; Merck; Mirati Therapeutics; NeoGenomics Laboratories; Novartis; Numab; Ono Pharmaceutical; Pfizer; Redx Pharma; Repare Therapeutics; Replimune; Servier; Taiho Pharmaceutical; Takeda; Tempus; Xilis; Zentalis. Research funding – Amgen; Array BioPharma; Biocartis; Daiichi Sankyo; EMD Serono; Genentech/Roche; Guardant Health; Lilly; MedImmune; Novartis; Sanofi. George J. Chang: consulting or advisory role – Medicaroid. Kaysia Ludford: research funding – Merck (Inst). Michael J. Overman: consulting or advisory role – 3D Medicines; Array BioPharma; Bristol-Myers Squibb; Eisai; Gritstone Bio; Janssen; Janssen; MedImmune; Merck; Novartis; Pfizer; Pfizer; Promega; Roche/Genentech; Spectrum Pharmaceuticals. Research funding – Bristol-Myers Squibb; MedImmune; Merck; Roche. The remining authors do not have any disclosures., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2023
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5. Molecular Pathways and Mechanisms of HER2 in Cancer Therapy.
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Raghav KPS and Moasser MM
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- Humans, Female, Receptor, ErbB-2 metabolism, Signal Transduction, Oncogenes, Breast metabolism, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Neoplasms drug therapy, Neoplasms genetics, Breast Neoplasms drug therapy
- Abstract
The oncogene ERBB2 encoding the receptor tyrosine-protein kinase erbB-2 (HER2) is frequently overexpressed or amplified and occasionally mutated in a variety of human cancers. The early discovery of this oncogene, its established oncogenic relevance in diverse cancers, its substantial expression on the surface of cancer cells, and its druggable catalytic activity have made it one of the most pursued targets in the history of cancer drug development. Initiatives targeting HER2 provided the early stimulus for several transformational pharmaceutical technologies, including mAbs, tyrosine kinase inhibitors, antibody-drug conjugates, and others. The seismic impact of these efforts has been felt in treatment of many cancers, including breast, gastroesophageal, lung, colorectal, and others. This impact continues to broaden with increasing indications on the horizon and a plethora of novel agents in development. However, implementation of these therapeutic strategies has been complex. The clinical translation of every one of these classes of agents has been notable for underperformance or overperformance characteristics that have informed new lines of research providing deeper insights into the mechanistic complexities and unrealized opportunities provided by this molecular target. Despite all the successes to date, the preponderance of scientific evidence indicates that the full potential of HER2 as a target for cancer therapeutics is far greater than currently realized, and numerous lines of investigation are ongoing to deepen and broaden the scope of impact of HER2 as a signaling, homing, or immunologic target. In this review, we explore the existing data and evolving paradigms surrounding this remarkable target for cancer therapy., (©2022 American Association for Cancer Research.)
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- 2023
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6. Neoadjuvant Pembrolizumab in Localized Microsatellite Instability High/Deficient Mismatch Repair Solid Tumors.
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Ludford K, Ho WJ, Thomas JV, Raghav KPS, Murphy MB, Fleming ND, Lee MS, Smaglo BG, You YN, Tillman MM, Kamiya-Matsuoka C, Thirumurthi S, Messick C, Johnson B, Vilar E, Dasari A, Shin S, Hernandez A, Yuan X, Yang H, Foo WC, Qiao W, Maru D, Kopetz S, and Overman MJ
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- Humans, DNA Mismatch Repair, Microsatellite Instability, Neoadjuvant Therapy, Tumor Microenvironment, Antineoplastic Agents, Immunological adverse effects, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics, Neoplasms drug therapy
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Purpose: Pembrolizumab significantly improves clinical outcomes in advanced/metastatic microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) solid tumors but is not well studied in the neoadjuvant space., Methods: This is a phase II open-label, single-center trial of localized unresectable or high-risk resectable MSI-H/dMMR tumors. Treatment is pembrolizumab 200 mg once every 3 weeks for 6 months followed by surgical resection with an option to continue therapy for 1 year followed by observation. To continue on study, patients are required to have radiographic or clinical benefit. The coprimary end points are safety and pathologic complete response. Key secondary end points are response rate and organ-sparing at one year for patients who declined surgery. Exploratory analyses include interrogation of the tumor immune microenvironment using imaging mass cytometry., Results: A total of 35 patients were enrolled, including 27 patients with colorectal cancer and eight patients with noncolorectal cancer. Among 33 evaluable patients, best overall response rate was 82%. Among 17 (49%) patients who underwent surgery, the pathologic complete response rate was 65%. Ten patients elected to receive one year of pembrolizumab followed by surveillance without surgical resection (median follow-up of 23 weeks [range, 0-54 weeks]). An additional eight did not undergo surgical resection and received less than 1 year of pembrolizumab. During the study course of the trial and subsequent follow-up, progression events were seen in six patients (four of whom underwent salvage surgery). There were no new safety signals. Spatial immune profiling with imaging mass cytometry noted a significantly closer proximity between granulocytic cells and cytotoxic T cells in patients with progressive events compared with those without progression., Conclusion: Neoadjuvant pembrolizumab in dMMR/MSI-H cancers is safe and resulted in high rates of pathologic, radiographic, and endoscopic response, which has implications for organ-sparing strategies.
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- 2023
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7. Regorafenib plus nivolumab in patients with mismatch repair-proficient/microsatellite stable metastatic colorectal cancer: a single-arm, open-label, multicentre phase 2 study.
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Fakih M, Raghav KPS, Chang DZ, Larson T, Cohn AL, Huyck TK, Cosgrove D, Fiorillo JA, Tam R, D'Adamo D, Sharma N, Brennan BJ, Wang YA, Coppieters S, Zebger-Gong H, Weispfenning A, Seidel H, Ploeger BA, Mueller U, Oliveira CSV, and Paulson AS
- Abstract
Background: Anti-programmed cell death protein 1 antibodies plus multikinase inhibitors have shown encouraging activity in several tumour types, including colorectal cancer. This study assessed regorafenib plus nivolumab in patients with microsatellite stable/mismatch repair-proficient metastatic colorectal cancer., Methods: This single-arm, open-label, multicentre phase 2 study enrolled adults from 13 sites in the USA with previously treated advanced microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Eligible patients had known extended RAS and BRAF status, progression or intolerance to no more than two (for extended RAS mutant) or three (for extended RAS wild type) lines of systemic chemotherapy and an Eastern Cooperative Oncology Group performance status of 0 or 1. Regorafenib 80 mg/day was administered orally for 3 weeks on/1 week off (increased to 120 mg/day if 80 mg/day was well tolerated) with intravenous nivolumab 480 mg every 4 weeks. Primary endpoint was objective response rate. Secondary endpoints included safety, overall survival, and progression-free survival. Exploratory endpoints included biomarkers associated with antitumour activity. Patients who received at least one dose of study intervention were included in the efficacy and safety analyses. Tumour assessments were carried out every 8 weeks for the first year, and every 12 weeks thereafter until progressive disease/end of the study, and objective response rate was analysed after all patients had met the criteria for primary completion of five post-baseline scans and either 10-months' follow-up or drop out. This trial is registered with ClinicalTrials.gov, number NCT04126733., Findings: Between 14 October 2019 and 14 January 2020, 94 patients were enrolled, 70 received treatment. Five patients had a partial response, yielding an objective response rate of 7% (95% CI 2.4-15.9; p = 0.27). All responders had no liver metastases at baseline. Median overall survival (data immature) and progression-free survival were 11.9 months (95% CI 7.0-not evaluable) and 1.8 months (95% CI 1.8-2.4), respectively. Most patients (97%, 68/70) experienced a treatment-related adverse event; 51% were grade 1 or 2, 40% were grade 3, 3% were grade 4, and 3% were grade 5. The most common (≥20%) events were fatigue (26/70), palmar-plantar erythrodysesthesia syndrome (19/70), maculopapular rash (17/70), increased blood bilirubin (14/70), and decreased appetite (14/70). Higher baseline expression of tumour biomarkers of immune sensitivity correlated with antitumour activity., Interpretation: Further studies are warranted to identify subgroups of patients with clinical characteristics or biomarkers that would benefit most from treatment with regorafenib plus nivolumab., Funding: Bayer/Bristol Myers Squibb., Competing Interests: YAW, AW, and HS report employment with Bayer. BP and BB report employment and stock ownership with Bayer. CO and SC report previous employment with Bayer. HZG report previous employment and stock or stock options with Bayer. DDA reports employment and stock ownership from Bristol Myers Squibb. MF reports research funding (to institution) from Amgen, Bristol Myers Squibb, Genentech, Verastem, and Novartis, consulting fees from AstraZeneca, Bristol Myers Squibb, Incyte, PsiOxus, Zhuhai Yufan Biotech, and Taiho Pharmaceutical, honoraria from Guardant360, and advisory roles from Amgen, Bayer, Array Biopharma, Eisai, GSK, Merck, Mirati, Nouscom, Roche/Genentech, and Xenthera. NS reports employment, support for attending meetings and stock ownership with Bayer. ASP reports research funding (to institution) from Ipsen, Bristol Myers Squibb, Exelixis, Hutchison MediPharma, Taiho Pharmaceutical, Lilly, AstraZeneca, Incyte, Deciphera, G1 Therapeutics, Zentalis, Tempus, Camurus, Relay Therapeutics, Nucana, Merck, Bayer, Seattle Genetics, Sotio, Innovative Cellular Therapeutics, Camurus, Regenxbio, Gilead Sciences, Gritstone Bio, BioNTech S, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Cardinal Health and Ideo Oncology, leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from Amgen, Bristol Myers Squibb, Eisai, Ipsen, Advanced Accelerator Applications, Incyte, Exelixis, Pfizer, QED Therapeutics, Lilly, Mirati Therapeutics, Hutchison MediPharma, Astellas Pharma, AADi, Stromatis Pharma, EMD Serono, AstraZeneca, and Servier, and stock or stock options from Actinium Pharmaceuticals, Aptose Biosciences, Alexion Pharmaceuticals, Lynx Health, and Stromatis Pharma. KPSR reports research funding to institution from Bayer, Daiichi Sankyo, Merck, Hibercell, UCB Biosciences, Janssen, Eisai, AbbVie, Guardant, Innovent, and Xencor, payment or honoraria for educational events from Bayer, Daiichi Sankyo, and Seagen, and participation on advisory board of Daiichi Sankyo, Eisai, Merck, SAGA Diagnostics, Bayer, Seagen, Pfizer, and AstraZeneca. RT reports employment and stock ownership with Bristol Myers Squibb. UM reports consulting fees from Bayer as a statistician for ClinStat. AC, DZC, DC, TH, TL, and JF have nothing to disclose., (© 2023 The Authors.)
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- 2023
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8. Definitive Liver Radiotherapy for Intrahepatic Cholangiocarcinoma with Extrahepatic Metastases.
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De B, Upadhyay R, Liao K, Kumala T, Shi C, Dodoo G, Abi Jaoude J, Corrigan KL, Manzar GS, Marqueen KE, Bernard V, Lee SS, Raghav KPS, Vauthey JN, Tzeng CD, Tran Cao HS, Lee G, Wo JY, Hong TS, Crane CH, Minsky BD, Smith GL, Holliday EB, Taniguchi CM, Koong AC, Das P, Javle M, Ludmir EB, and Koay EJ
- Abstract
Introduction: Tumor-related liver failure (TRLF) is the most common cause of death in patients with intrahepatic cholangiocarcinoma (ICC). Though we previously showed that liver radiotherapy (L-RT) for locally advanced ICC is associated with less frequent TRLF and longer overall survival (OS), the role of L-RT for patients with extrahepatic metastatic disease (M1) remains undefined. We sought to compare outcomes for M1 ICC patients treated with and without L-RT., Methods: We reviewed ICC patients that found to have M1 disease at initial diagnosis at a single institution between 2010 and 2021 who received L-RT, matching them with an institutional cohort by propensity score and a National Cancer Database (NCDB) cohort by frequency technique. The median biologically effective dose was 97.5 Gy (interquartile range 80.5-97.9 Gy) for L-RT. Patients treated with other local therapies or supportive care alone were excluded. We analyzed survival with Cox proportional hazard modeling., Results: We identified 61 patients who received L-RT and 220 who received chemotherapy alone. At median follow-up of 11 months after diagnosis, median OS was 9 months (95% confidence interval [CI] 8-11) and 21 months (CI: 17-26) for patients receiving chemotherapy alone and L-RT, respectively. TRLF was the cause of death more often in the patients who received chemotherapy alone compared to those who received L-RT (82% vs. 47%; p = 0.001). On multivariable propensity score-matched analysis, associations with lower risk of death included duration of upfront chemotherapy (hazard ratio [HR] 0.82; p = 0.005) and receipt of L-RT (HR: 0.40; p = 0.002). The median OS from diagnosis for NCDB chemotherapy alone cohort was shorter than that of the institutional L-RT cohort (9 vs. 22 months; p < 0.001)., Conclusion: For M1 ICC, L-RT associated with a lower rate of death due to TRLF and longer OS versus those treated with chemotherapy alone. Prospective studies of L-RT in this setting are warranted., Competing Interests: BD reports consulting honoraria from Sermo Inc. EBH reports research funding from Merck Serono. CT reports a consulting/advisory role with Accuray. EJK reports grants from National Institutes of Health, Stand Up 2 Cancer, MD Anderson Cancer Center, Philips Healthcare, Elekta, and GE Healthcare; personal fees from RenovoRx and Taylor and Francis; and a consulting/advisory role with Augmenix. ACK reports ownership of shares in Aravive, Inc. PD reports consulting/advisory relationships with the American Society for Radiation Oncology and the National Cancer Institute. All reported conflicts are outside of the submitted work., (© 2023 The Author(s). Published by S. Karger AG, Basel.)
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- 2023
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9. Ablative liver radiotherapy for unresected intrahepatic cholangiocarcinoma: Patterns of care and survival in the United States.
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De B, Tran Cao HS, Vauthey JN, Manzar GS, Corrigan KL, Raghav KPS, Lee SS, Tzeng CD, Minsky BD, Smith GL, Holliday EB, Taniguchi CM, Koong AC, Das P, Javle M, Ludmir EB, and Koay EJ
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- Bile Ducts, Intrahepatic, Humans, Retrospective Studies, United States epidemiology, Bile Duct Neoplasms therapy, Cholangiocarcinoma therapy
- Abstract
Background: Single-institution studies have shown the oncologic benefit of ablative liver radiotherapy (A-RT) for patients with unresectable intrahepatic cholangiocarcinoma (ICC). However, adoption of A-RT across the United States and its associated outcomes are unknown., Methods: We queried the National Cancer Data Base for nonsurgically managed patients with ICC diagnosed between 2004 and 2018. Patients were labeled A-RT for receipt of biologically effective doses (BED
10 ) ≥ 80.5 Gy and conventional RT (Conv-RT) for lower doses. Associations with A-RT use and overall survival were identified using logistic and Cox regressions, respectively., Results: Of 27,571 patients, the most common treatments were chemotherapy without liver RT (45%), no chemotherapy or liver RT (42%), and liver RT ± chemotherapy (13%). Use of liver RT remained constant over time. Of 1112 patients receiving liver RT with known doses, RT was 73% Conv-RT (median BED10 , 53 Gy; median, 20 fractions) and 27% A-RT (median BED10 , 100 Gy; median, 5 fractions). Use of A-RT increased from 5% in 2004 to 48% in 2018 (Ptrend < .001). With a median follow-up of 52.3 months, median survival estimates for Conv-RT and A-RT were 12.8 and 23.7 months (P < .001), respectively. On multivariable analysis, stage III and IV disease correlated with a higher risk of death, whereas chemotherapy and A-RT correlated with a lower risk., Conclusions: Although A-RT has been increasingly used, use of liver RT as a whole in the United States remained constant despite growing evidence supporting its use, suggesting continued unmet need. A-RT is associated with longer survival versus Conv-RT., Lay Summary: Bile duct cancer is a rare, deadly disease that often presents at advanced stages. Single-institution retrospective studies have demonstrated that use of high-dose radiotherapy may be associated with longer survival, but larger studies have not been conducted. We used a large, national cancer registry of patients diagnosed between 2004 and 2018 to show that liver radiotherapy use remains low in the United States, despite growing evidence that patients who receive it live longer. Furthermore, we showed that patients who received high-dose radiotherapy lived longer than those who received lower doses. Greater awareness of the benefits of liver radiotherapy is needed to improve patient outcomes., (© 2022 American Cancer Society.)- Published
- 2022
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10. Benchmarking Outcomes for Definitive Treatment of Young-Onset, Locally Advanced Rectal Cancer.
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Taku N, Yi-Qian YN, Chang GJ, Ludmir EB, Raghav KPS, Rodriguez-Bigas MA, Holliday EB, Smith GL, Minsky BD, Overman MJ, Messick C, Boyce-Fappiano D, Koong AC, Skibber JM, Koay EJ, Dasari A, Taniguchi CM, Bednarski BK, Morris VK, Kopetz S, and Das P
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- Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Benchmarking, Chemoradiotherapy, Disease-Free Survival, Humans, Middle Aged, Neoplasm Staging, Retrospective Studies, Treatment Outcome, Young Adult, Neoadjuvant Therapy, Rectal Neoplasms epidemiology, Rectal Neoplasms pathology, Rectal Neoplasms therapy
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Purpose: There has been an increase in the incidence of rectal cancer diagnosed in young adults (age < 50 years). We evaluated outcomes among young adults treated with pre-operative long course chemoradiation (CRT) and total mesorectal excision (TME)., Methods: The medical records of 219 patients, age 18-49, with non-metastatic, cT3-4, or cN1-2 rectal adenocarcinoma treated from 2000 to 2017 were reviewed for demographic and treatment characteristics, as well as pathologic and oncologic outcomes. The Kaplan-Meier test, log-rank test, and Cox regression analysis were used to evaluate survival outcomes., Results: The median age at diagnosis was 44 years. CRT followed by TME and post-operative chemotherapy was the most frequent treatment sequence (n = 196), with FOLFOX (n = 115) as the predominant adjuvant chemotherapy. There was no difference in sex, stage, MSS/pMMR, or pCR by age (< 45 years [n = 111] vs. ≥ 45 years [n = 108]). The 5-year rates of DFS were 77.2% for all patients, 69.8% for age < 45 years and 84.7% for age ≥ 45 years (P = .01). The 5-year rates of OS were 89.6% for all patients, 85.1% for patients with age < 45 years and 94.3% for patients with age ≥ 45 years (P = .03). Age ≥ 45 years was associated with a lower risk of disease recurrence or death on multivariable Cox regression analysis (HR = 0.55, 95% CI 0.31-0.97, P = .04)., Conclusion: Among young adults, patients with age < 45 years had lower rates of DFS and OS, compared to those with age ≥ 45 years. These outcomes could serve as a benchmark by which to evaluate newer treatment approaches., (Copyright © 2021. Published by Elsevier Inc.)
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- 2022
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11. Cancer of Unknown Primary Presenting as Bone-Predominant or Lymph Node-Only Disease: A Clinicopathologic Portrait.
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Huey RW, Smaglo BG, Estrella JS, Matamoros A, Overman MJ, Varadhachary GR, and Raghav KPS
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- Humans, Kaplan-Meier Estimate, Lymph Nodes, Paclitaxel, Prognosis, Neoplasms, Unknown Primary therapy
- Abstract
Background: Cancer of unknown primary (CUP) presenting as bone-predominant (BCUP) or lymph node-only disease (LNCUP) represents two clinically distinct subsets of nonvisceral CUP. These present a diagnostic challenge with a large differential of putative primary cancers and defy the "one-treatment-fits-all" approach., Materials and Methods: We identified patients with BCUP (n = 29) and LNCUP (n = 63) using a prospectively collected CUP database and tumor registry of patients seen at MD Anderson Cancer Center between 2001 to 2017. Clinicopathological characteristics, treatments, and outcomes were abstracted. A control group of non-BCUP/LNCUP cases (n = 443) from the database was used for comparison. Kaplan-Meier method was used to estimate overall survival and compared using log-rank test., Results: In this cohort, 64% and 60% patients had disseminated disease at diagnosis and 39% and 23% had Culine poor-risk disease in BCUP and LNCUP, respectively. Median overall survival (OS) for BCUP was 14.5 months and for LNCUP was 32.6 months. For BCUP, gemcitabine plus platinum was the most common initial chemotherapy (54%). For LNCUP, carboplatin plus paclitaxel was the most common initial chemotherapy (38%). Radiation was given to 74% of patients with BCUP and 37% of those with LNCUP. On multivariate analysis, poor-risk Culine group (hazard ratio [HR], 1.76; p < .001) and high neutrophil-to-lymphocyte ratio (HR, 2.38, p < .001) were associated with worse OS., Conclusion: BCUP and LNCUP are rare subsets within CUP with varying prognosis. Poor-risk Culine group and high neutrophil-to-lymphocyte ratio are associated with poor survival. Select patients with limited metastases can have long-term survival with aggressive multimodality treatment. Careful clinicopathological review can facilitate chances of site-directed therapy., Implications for Practice: Cancer of unknown primary (CUP) rarely presents as bone-predominant (BCUP) or lymph node-only (LNCUP) disease. This article describes a cohort of each and compares with a larger CUP cohort. Patients with BCUP have unique issues with fractures and pain, often receiving radiation. Overall survival of 14.5 months was similar to a larger CUP comparison cohort. Patients with LNCUP had improved overall survival at 32.6 months, with longer survival in patients without disseminated disease. Culine poor-risk group and neutrophil-to-lymphocyte ratio were associated with worse overall survival. Tips regarding diagnosis and management of these rare malignant subsets are provided., (© 2021 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)
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- 2021
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12. Molecular Profiling-Based Assignment of Cancer Therapy (NCI-MPACT): A Randomized Multicenter Phase II Trial.
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Chen AP, Kummar S, Moore N, Rubinstein LV, Zhao Y, Williams PM, Palmisano A, Sims D, O'Sullivan Coyne G, Rosenberger CL, Simpson M, Raghav KPS, Meric-Bernstam F, Leong S, Waqar S, Foster JC, Konaté MM, Das B, Karlovich C, Lih CJ, Polley E, Simon R, Li MC, Piekarz R, and Doroshow JH
- Subjects
- Adult, Aged, Aged, 80 and over, Benzimidazoles therapeutic use, Carboplatin therapeutic use, DNA, Neoplasm analysis, Double-Blind Method, Everolimus therapeutic use, Female, Gene Expression Profiling, Humans, Male, Middle Aged, Molecular Diagnostic Techniques, Neoplasms diagnosis, Pyrazoles, Pyridones therapeutic use, Pyrimidinones therapeutic use, Temozolomide therapeutic use, Young Adult, Antineoplastic Agents therapeutic use, Neoplasms drug therapy, Neoplasms genetics
- Abstract
This trial assessed the utility of applying tumor DNA sequencing to treatment selection for patients with advanced, refractory cancer and somatic mutations in one of four signaling pathways by comparing the efficacy of four study regimens that were either matched to the patient's aberrant pathway (experimental arm) or not matched to that pathway (control arm)., Materials and Methods: Adult patients with an actionable mutation of interest were randomly assigned 2:1 to receive either (1) a study regimen identified to target the aberrant pathway found in their tumor (veliparib with temozolomide or adavosertib with carboplatin [DNA repair pathway], everolimus [PI3K pathway], or trametinib [RAS/RAF/MEK pathway]), or (2) one of the same four regimens, but chosen from among those not targeting that pathway., Results: Among 49 patients treated in the experimental arm, the objective response rate was 2% (95% CI, 0% to 10.9%). One of 20 patients (5%) in the experimental trametinib cohort had a partial response. There were no responses in the other cohorts. Although patients and physicians were blinded to the sequencing and random assignment results, a higher pretreatment dropout rate was observed in the control arm (22%) compared with the experimental arm (6%; P = .038), suggesting that some patients may have had prior tumor mutation profiling performed that led to a lack of participation in the control arm., Conclusion: Further investigation, better annotation of predictive biomarkers, and the development of more effective agents are necessary to inform treatment decisions in an era of precision cancer medicine. Increasing prevalence of tumor mutation profiling and preference for targeted therapy make it difficult to use a randomized phase II design to evaluate targeted therapy efficacy in an advanced disease setting., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Shivaani KummarStock and Other Ownership Interests: PathomIQ, Arxeon Consulting or Advisory Role: Corvus Pharmaceuticals, MedTree, Nodus Therapeutics, Genentech, ShangPharma Innovation, Seattle Genetics, Bayer, Boehringer Ingelheim, Mundipharma EDO GMBH, Harbour BioMed, Cadila Pharmaceuticals Research Funding: Bristol Myers Squibb, Dynavax Technologies, Pfizer, Loxo, Corvus Pharmaceuticals, Plexxikon, Jounce Therapeutics, ADC Therapeutics, Advenchen Laboratories, Incyte, Taiho Pharmaceutical, Bayer, Astex Pharmaceuticals, Seattle Genetics, Amgen, Genome & Company Travel, Accommodations, Expenses: BayerNancy MoorePatents, Royalties, Other Intellectual Property: Nestle NutritionP. Mickey WilliamsResearch Funding: Illumina Patents, Royalties, Other Intellectual Property: I was a co-inventor of the DLBCL cell of origin patent recently filed by the NIHKanwal P. S. RaghavConsulting or Advisory Role: AstraZeneca, Bayer, Eisai, Daiichi SankyoFunda Meric-BernstamEmployment: MD Anderson Cancer Center Honoraria: Mayo Clinic, Rutgers Cancer Institute of New Jersey Consulting or Advisory Role: Genentech, Inflection Biosciences, Samsung Bioepis, Spectrum Pharmaceuticals, Aduro Biotech, OrigiMed, Xencor, Debiopharm Group, Mersana, Seattle Genetics, Silverback Therapeutics, Immunomedics, IBM, Roche, PACT Pharma, eFFECTOR Therapeutics, Jackson Laboratory for Genomic Medicine, Kolon Life Sciences, Parexel International, Pfizer, Tyra Biosciences, Zymeworks, Puma Biotechnology, Zentalis, Alkermes Speakers' Bureau: Chugai Pharma Research Funding: Novartis, AstraZeneca, Taiho Pharmaceutical, Genentech, Calithera Biosciences, Debiopharm Group, Bayer, Aileron Therapeutics, Puma Biotechnology, CytomX Therapeutics, Jounce Therapeutics, Zymeworks, Curis, Pfizer, eFFECTOR Therapeutics, Abbvie, Boehringer Ingelheim, Guardant Health, Daiichi Sankyo, GlaxoSmithKline, Seattle Genetics, Millennium Travel, Accommodations, Expenses: Taiho Pharmaceutical, Beth Israel Deaconess Medical CenterStephen LeongEmployment: Merck Sharp & Dohme Stock and Other Ownership Interests: Antares Pharmaceuticals, Spectrum Pharmaceuticals Consulting or Advisory Role: Bristol Myers Squibb Research Funding: Deciphera, Karyopharm Therapeutics, Bristol Myers Squibb, Lilly Travel, Accommodations, Expenses: Genentech/RocheSaiama WaqarResearch Funding: Spectrum Pharmaceuticals, Lilly, Pfizer, Genentech/Roche, Daiichi Sankyo, Newlink Genetics, EMD Serono, Puma Biotechnology, Novartis, Xcovery, Synermore Biologics, Celgene, Vertex, Bristol Myers Squibb, Stemcentrx, Hengrui Therapeutics, Checkpoint Therapeutics, Ignyta, AstraZeneca, ARIAD, Roche, MerckBiswajit DasResearch Funding: IlluminaChris KarlovichStock and Other Ownership Interests: Clovis Oncology Research Funding: Illumina Travel, Accommodations, Expenses: IlluminaChih-Jian LihEmployment: Exelixis Stock and Other Ownership Interests: ExelixisEric PolleyResearch Funding: GRAILRichard SimonConsulting or Advisory Role: AbbVie, Amgen, Janssen, Bristol Myers Squibb, Pfizer, Onco-Nano Travel, Accommodations, Expenses: Amgen No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)
- Published
- 2021
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13. Malignant Mesothelioma of the Peritoneum in Women: A Clinicopathologic Study of 164 Cases.
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Malpica A, Euscher ED, Marques-Piubelli ML, Ferrufino-Schmidt MC, Miranda RN, Sams R, Royal RE, Raghav KPS, Fournier KF, and Ramalingam P
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Female, Humans, Mesothelioma, Malignant mortality, Mesothelioma, Malignant therapy, Middle Aged, Peritoneal Neoplasms mortality, Peritoneal Neoplasms therapy, Young Adult, Mesothelioma, Malignant pathology, Peritoneal Neoplasms pathology
- Abstract
Malignant mesothelioma of the peritoneum in women is an uncommon tumor. In this study, we present the clinicopathologic features of 164 such cases seen in our institution over a period of 42 years (1974-2016). Clinical information, pathologic findings, immunohistochemical results, and follow-up were recorded. Hematoxylin and eosin-stained slides were reviewed in all cases. Patients ranged in age from 3 to 85 years, median: 49 years. Most patients presented with abdominal/pelvic pain, although some were asymptomatic, presented with paraneoplastic syndromes or cervical lymphadenopathy. Overall, 9% of patients had a history of direct or indirect exposure to asbestos. In total, 31% and 69% of patients had either a personal or family history of other tumors; most of these tumors are currently recognized as part of a syndrome. Genetic testing information was available in 5 patients: BAP-1 germline mutation (1), type 2 neurofibromatosis (1), Lynch syndrome (1), McCune-Albright syndrome (1), no BAP-1 or TP53 mutation (1). Most cases had gross and microscopic features typical of malignant mesothelioma of the peritoneum in women; however, some had confounding features such as gelatinous appearance, signet ring or clear cells, and well-differentiated papillary mesothelioma-like areas. Calretinin and WT-1 were the markers more frequently expressed, and up to 23% of the cases showed PAX-8 expression. Patients' treatments predominantly included: chemotherapy, cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy. On multivariate analysis, the predominance of deciduoid cells, nuclear grade 3, and the absence of surgical treatment were associated with worse overall survival (OS). For all patients, the 3- and 5-year OS were 74.3% and 57.4%, respectively. The 3- and 5-year OS for patients treated with cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy were 88.9% and 77.8%, respectively.
- Published
- 2021
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14. CUP-AI-Dx: A tool for inferring cancer tissue of origin and molecular subtype using RNA gene-expression data and artificial intelligence.
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Zhao Y, Pan Z, Namburi S, Pattison A, Posner A, Balachander S, Paisie CA, Reddi HV, Rueter J, Gill AJ, Fox S, Raghav KPS, Flynn WF, Tothill RW, Li S, Karuturi RKM, and George J
- Subjects
- Algorithms, Computational Biology standards, Databases, Genetic, Genomics methods, Humans, Machine Learning, Neoplasm Metastasis diagnosis, Neoplasm Metastasis genetics, Neural Networks, Computer, Reproducibility of Results, Workflow, Artificial Intelligence, Biomarkers, Tumor genetics, Computational Biology methods, Neoplasms, Unknown Primary diagnosis, Neoplasms, Unknown Primary genetics, RNA, Software
- Abstract
Background: Cancer of unknown primary (CUP), representing approximately 3-5% of all malignancies, is defined as metastatic cancer where a primary site of origin cannot be found despite a standard diagnostic workup. Because knowledge of a patient's primary cancer remains fundamental to their treatment, CUP patients are significantly disadvantaged and most have a poor survival outcome. Developing robust and accessible diagnostic methods for resolving cancer tissue of origin, therefore, has significant value for CUP patients., Methods: We developed an RNA-based classifier called CUP-AI-Dx that utilizes a 1D Inception convolutional neural network (1D-Inception) model to infer a tumor's primary tissue of origin. CUP-AI-Dx was trained using the transcriptional profiles of 18,217 primary tumours representing 32 cancer types from The Cancer Genome Atlas project (TCGA) and International Cancer Genome Consortium (ICGC). Gene expression data was ordered by gene chromosomal coordinates as input to the 1D-CNN model, and the model utilizes multiple convolutional kernels with different configurations simultaneously to improve generality. The model was optimized through extensive hyperparameter tuning, including different max-pooling layers and dropout settings. For 11 tumour types, we also developed a random forest model that can classify the tumour's molecular subtype according to prior TCGA studies. The optimised CUP-AI-Dx tissue of origin classifier was tested on 394 metastatic samples from 11 tumour types from TCGA and 92 formalin-fixed paraffin-embedded (FFPE) samples representing 18 cancer types from two clinical laboratories. The CUP-AI-Dx molecular subtype was also independently tested on independent ovarian and breast cancer microarray datasets FINDINGS: CUP-AI-Dx identifies the primary site with an overall top-1-accuracy of 98.54% in cross-validation and 96.70% on a test dataset. When applied to two independent clinical-grade RNA-seq datasets generated from two different institutes from the US and Australia, our model predicted the primary site with a top-1-accuracy of 86.96% and 72.46% respectively., Interpretation: The CUP-AI-Dx predicts tumour primary site and molecular subtype with high accuracy and therefore can be used to assist the diagnostic work-up of cancers of unknown primary or uncertain origin using a common and accessible genomics platform., Funding: NIH R35 GM133562, NCI P30 CA034196, Victorian Cancer Agency Australia., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2020
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15. Modified gemcitabine plus nab-paclitaxel regimen in advanced pancreatic ductal adenocarcinoma.
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Rogers JE, Mizrahi JD, Xiao L, Mohindroo C, Shroff RT, Wolff R, Varadhachary GR, Javle MM, Overman M, Fogelman DR, Raghav KPS, Pant S, and McAllister F
- Subjects
- Aged, Albumins pharmacology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Deoxycytidine pharmacology, Deoxycytidine therapeutic use, Female, Humans, Male, Paclitaxel pharmacology, Retrospective Studies, Gemcitabine, Adenocarcinoma drug therapy, Albumins therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Pancreatic Ductal drug therapy, Deoxycytidine analogs & derivatives, Paclitaxel therapeutic use
- Abstract
Background: Gemcitabine (GEM) plus nab-paclitaxel (NabP) (GEM 1000 mg/m
2 IV over 30 minutes + NabP 125 mg/m2 IV given days 1, 8, and 15 every 28 days) is one of the two standard of care combination therapies for metastatic pancreatic ductal adenocarcinoma (PDAC). Our cancer center has utilized GEM-NabP given every two-weeks due to tolerability and patient convenience. Here, we review the safety and efficacy of this modified regimen., Methods: Metastatic PDAC patients (pts) who initiated front-line or second-line GEM-NabP during 2013-2017 were retrospectively reviewed. Primary objective was overall survival. Secondary objectives were disease control rate, progression-free survival, and the incidence of dose delays and/or adjustments., Results: From a total of 235 patients, 140 pts received GEM-NabP front-line while 95 pts received GEM-NabP second-line. Median dosing was 600 mg/m2 at fixed-dose rate for GEM and 125 mg/m2 for NabP given predominantly (~90%) every two-weeks. Eastern Cooperative Group performance status of 0 and 1 pts had front-line OS of 12.7 and 9.6 months and when given second-line had OS of 8 months and 7.3 months, respectively. ECOG 0 and 1 pts had front-line progression-free survival (PFS) of 5.3 months and 2.8 months and second-line PFS was 3.5 months and 2.4 months, respectively. Treatment was well tolerated with limited dose modifications., Conclusion: Our analysis revealed safety with every two-week low dose GEM-NabP while maintaining efficacy. Patient schedule convenience should factor into metastatic incurable malignancies. We suggest the use of every two-week GEM-NabP particularly in patients desiring a modified schedule., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)- Published
- 2020
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16. Modified FOLFIRINOX in pancreatic cancer patients Age 75 or older.
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Mizrahi JD, Rogers JE, Hess KR, Wolff RA, Varadhachary GR, Javle MM, Shroff RT, Ho L, Fogelman DR, Raghav KPS, Overman MJ, and Pant S
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- Aged, Aged, 80 and over, Antimetabolites, Antineoplastic administration & dosage, Antineoplastic Agents administration & dosage, Antineoplastic Agents, Phytogenic administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Disease-Free Survival, Female, Fluorouracil administration & dosage, Fluorouracil adverse effects, Fluorouracil therapeutic use, Humans, Irinotecan administration & dosage, Irinotecan adverse effects, Irinotecan therapeutic use, Kaplan-Meier Estimate, Leucovorin adverse effects, Leucovorin therapeutic use, Male, Oxaliplatin administration & dosage, Oxaliplatin adverse effects, Oxaliplatin therapeutic use, Retrospective Studies, Survival Analysis, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Pancreatic Neoplasms drug therapy
- Abstract
Background: Although FOLFIRINOX (5-Fluorouracil + leucovorin + irinotecan + oxaliplatin) is now the standard of care for patients (pts) with metastatic pancreatic cancer (PC) based on the 2011 study by Conroy et al. which demonstrated improved median overall survival (mOS), pts > 75 yrs old were excluded from this study. The purpose of this study was to assess the safety and efficacy of modified FOLFIRINOX (mFOLFIRINOX) in this population., Methods: We retrospectively analyzed unresectable PC pts, age ≥ 75, treated with mFOLFIRINOX at MD Anderson from 2011 to 2017. Primary outcome was rate of grade 3 or 4 hematologic toxicity (HT)., Results: 24 pts were included. Grade 3 or 4 HT occurred in 11 pts 6 pts required hospitalization for any toxicity, and 10 stopped mFOLFIRINOX due to toxicity. The most frequently used starting doses of infusional 5-FU, irinotecan and oxaliplatin were 2400, 150 and 75 mg/m
2 , respectively. Median PFS was 3.7 months (95% CI: 3.0-5.7) with a median OS of 11.6 months (95% CI: 6.14-15.7). For first line pts, median PFS and OS were 5.1 (95% CI: 2.0-12.8) and 12.2 months (95% CI: 4.8-30.8), respectively., Conclusions: In this single-center retrospective analysis of unresectable PC pts age 75 or older given mFOLFIRINOX, toxicities and survival outcomes were similar to those reported in the initial study. These data indicate that the use of modified dosing FOLFIRINOX in advanced PC pts older than 75 appears to maintain similar toxicity and efficacy when compared to younger pts., Competing Interests: Declaration of competing interest The authors report no conflicts of interest relevant to this research., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)- Published
- 2020
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17. Molecular Profiling of Hepatocellular Carcinoma Using Circulating Cell-Free DNA.
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Kaseb AO, Sánchez NS, Sen S, Kelley RK, Tan B, Bocobo AG, Lim KH, Abdel-Wahab R, Uemura M, Pestana RC, Qiao W, Xiao L, Morris J, Amin HM, Hassan MM, Rashid A, Banks KC, Lanman RB, Talasaz A, Mills-Shaw KR, George B, Haque A, Raghav KPS, Wolff RA, Yao JC, Meric-Bernstam F, Ikeda S, and Kurzrock R
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers, Tumor blood, Carcinoma, Hepatocellular blood, Carcinoma, Hepatocellular therapy, Circulating Tumor DNA blood, Clinical Decision-Making methods, Cohort Studies, DNA Mutational Analysis, Female, Gene Frequency, High-Throughput Nucleotide Sequencing, Humans, Liver Neoplasms blood, Liver Neoplasms therapy, Male, Middle Aged, Mutation, Patient Selection, Prognosis, United States, Young Adult, Biomarkers, Tumor genetics, Carcinoma, Hepatocellular genetics, Circulating Tumor DNA genetics, Genetic Testing methods, Liver Neoplasms genetics
- Abstract
Purpose: Molecular profiling has been used to select patients for targeted therapy and determine prognosis. Noninvasive strategies are critical to hepatocellular carcinoma (HCC) given the challenge of obtaining liver tissue biopsies., Experimental Design: We analyzed blood samples from 206 patients with HCC using comprehensive genomic testing (Guardant Health) of circulating tumor DNA (ctDNA)., Results: A total of 153/206 (74.3%) were men; median age, 62 years (range, 18-91 years). A total of 181/206 patients had ≥1 alteration. The total number of alterations was 680 (nonunique); median number of alterations/patient was three (range, 1-13); median mutant allele frequency (% cfDNA), 0.49% (range, 0.06%-55.03%). TP53 was the common altered gene [>120 alterations (non-unique)] followed by EGFR, MET, ARID1A, MYC, NF1, BRAF, and ERBB2 [20-38 alterations (nonunique)/gene]. Of the patients with alterations, 56.9% (103/181) had ≥1 actionable alterations, most commonly in MYC, EGFR, ERBB2, BRAF, CCNE1, MET, PIK3CA, ARID1A, CDK6, and KRAS . In these genes, amplifications occurred more frequently than mutations. Hepatitis B (HBV)-positive patients were more likely to have ERBB2 alterations, 35.7% (5/14) versus 8.8% HBV-negative ( P = 0.04)., Conclusions: This study represents the first large-scale analysis of blood-derived ctDNA in HCC in United States. The genomic distinction based on HCC risk factors and the high percentage of potentially actionable genomic alterations suggests potential clinical utility for this technology., (©2019 American Association for Cancer Research.)
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- 2019
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18. Signet ring cell colorectal cancer: genomic insights into a rare subpopulation of colorectal adenocarcinoma.
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Korphaisarn K, Morris V, Davis JS, Overman MJ, Fogelman DR, Kee BK, Dasari A, Raghav KPS, Shureiqi I, Trupti M, Wolff RA, Eng C, Menter DG, Hamilton S, and Kopetz S
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma genetics, Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Signet Ring Cell drug therapy, Carcinoma, Signet Ring Cell genetics, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics, DNA Methylation, Female, Follow-Up Studies, Humans, Liver Neoplasms drug therapy, Liver Neoplasms genetics, Liver Neoplasms secondary, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms secondary, Male, Middle Aged, Peritoneal Neoplasms drug therapy, Peritoneal Neoplasms genetics, Peritoneal Neoplasms secondary, Prognosis, Retrospective Studies, Survival Rate, Young Adult, Adenocarcinoma pathology, Biomarkers, Tumor genetics, Carcinoma, Signet Ring Cell pathology, Colorectal Neoplasms pathology, Gene Expression Regulation, Neoplastic, Genomics methods, Mutation
- Abstract
Background: Signet ring cell carcinoma (SRCC) is a rare subtype of colorectal cancer (CRC). The aim of this study was to characterise the genomic alterations and outcomes of SRCC., Methods: Medical records of metastatic CRC (mCRC) patients whose tumours were evaluated by NGS analysis were reviewed. SC-mCRC were classified into two groups: SRCC (>50% signet ring cells) and adenocarcinoma (AC) with SC component (≤50% signet ring cells)., Results: Six hundred and sixty-five mCRC patients were included. Of the 93 mCRC cases with SC features, 63 had slides for review. Of those 63 cases, 35 were confirmed SRCC, and 28 were AC with SC component. Compared with AC group, KRAS and PIK3CA mutations (mts) were found in only 11% (OR: 0.13) and 3% (OR: 0.15) of SRCC cases, respectively. In contrast to the 44% rate of APC mts in AC group, only 3% of SRCC patients had APC mts (OR = 0.04)., Conclusions: SRCC has distinct molecular features, including low rates of KRAS, PIK3CA and APC mts. Further study to identify activation pathways and potential therapeutic targets are needed.
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- 2019
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19. Clinical and molecular characterization of early-onset colorectal cancer.
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Willauer AN, Liu Y, Pereira AAL, Lam M, Morris JS, Raghav KPS, Morris VK, Menter D, Broaddus R, Meric-Bernstam F, Hayes-Jordan A, Huh W, Overman MJ, Kopetz S, and Loree JM
- Subjects
- Adenocarcinoma genetics, Adenocarcinoma pathology, Adolescent, Adult, Age of Onset, Aged, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, DNA Mutational Analysis, Female, Follow-Up Studies, Humans, Incidence, Male, Microsatellite Instability, Middle Aged, Prognosis, Retrospective Studies, United States epidemiology, Young Adult, Adenocarcinoma epidemiology, Biomarkers, Tumor genetics, Colorectal Neoplasms epidemiology, Mutation
- Abstract
Background: Colorectal cancer (CRC) incidence is increasing in adults younger than 50 years. This study evaluated clinical and molecular features to identify those features unique to early-onset CRC that differentiate these patients from patients 50 years old or older., Methods: Baseline characteristics were evaluated according to the CRC onset age with 3 independent cohorts. A fourth cohort was used to describe the impact of age on the consensus molecular subtype (CMS) prevalence., Results: This retrospective review of more than 36,000 patients with CRC showed that early-onset patients were more likely to have microsatellite instability (P = .038), synchronous metastatic disease (P = .009), primary tumors in the distal colon or rectum (P < .0001), and fewer BRAF V600 mutations (P < .001) in comparison with patients 50 years old or older. Patients aged 18 to 29 years had fewer adenomatous polyposis coli (APC) mutations (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.35-0.90; P = .015) and an increased prevalence of signet ring histology (OR, 4.89; 95% CI, 3.23-7.39; P < .0001) in comparison with other patients younger than 50 years. In patients younger than 40 years, CMS1 was the most common subtype, whereas CMS3 and CMS4 were uncommon (P = .003). CMS2 was relatively stable across age groups. Early-onset patients with inflammatory bowel disease were more likely to have mucinous or signet ring histology (OR, 5.54; 95% CI, 2.24-13.74; P = .0004) and less likely to have APC mutations (OR, 0.24; 95% CI, 0.07-0.75; P = .019) in comparison with early-onset patients without predisposing conditions., Conclusions: Early-onset CRC is not only distinct from traditional CRC: special consideration should be given to and further investigations should be performed for both very young patients with CRC (18-29 years) and those with predisposing conditions. The etiology of the high rate of CMS1 in patients younger than 40 years deserves further exploration., (© 2019 American Cancer Society.)
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- 2019
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20. Retrospective Analysis of Taxane-Based Therapy in Small Bowel Adenocarcinoma.
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Aldrich JD, Raghav KPS, Varadhachary GR, Wolff RA, and Overman MJ
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- Adenocarcinoma pathology, Adult, Aged, Carboplatin administration & dosage, Deoxycytidine administration & dosage, Deoxycytidine analogs & derivatives, Etoposide administration & dosage, Female, Follow-Up Studies, Humans, Intestinal Neoplasms pathology, Intestine, Small pathology, Male, Middle Aged, Paclitaxel administration & dosage, Prognosis, Retrospective Studies, Survival Rate, Gemcitabine, Adenocarcinoma drug therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Intestinal Neoplasms drug therapy, Intestine, Small drug effects
- Abstract
Currently, treatment of small bowel adenocarcinoma (SBA) mirrors that of colorectal cancer (CRC). Recent genomic data have demonstrated SBA to be a genetically unique entity, suggesting that therapies not traditionally utilized in CRC should be explored. In order to further characterize the activity of taxanes in this rare cancer, we completed a single-center retrospective study. Twenty patients were found to have been treated with taxane-based regimens (monotherapy in 3, combination therapy in 17). Median time to progression was 3.8 months (95% confidence interval [CI] 2.9-4.6), and median overall survival was 10.7 months (95% CI: 3.1-18.3). The results of this study demonstrate clinical activity from taxane-based therapy in advanced SBA and support further clinical trial investigation., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)
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- 2019
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21. Gemcitabine, Cisplatin, and nab-Paclitaxel for the Treatment of Advanced Biliary Tract Cancers: A Phase 2 Clinical Trial.
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Shroff RT, Javle MM, Xiao L, Kaseb AO, Varadhachary GR, Wolff RA, Raghav KPS, Iwasaki M, Masci P, Ramanathan RK, Ahn DH, Bekaii-Saab TS, and Borad MJ
- Subjects
- Aged, Albumins adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cisplatin adverse effects, Deoxycytidine adverse effects, Deoxycytidine therapeutic use, Female, Humans, Male, Middle Aged, Paclitaxel adverse effects, Treatment Outcome, Gemcitabine, Albumins therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bile Duct Neoplasms drug therapy, Cisplatin therapeutic use, Deoxycytidine analogs & derivatives, Paclitaxel therapeutic use
- Abstract
Importance: Administration of gemcitabine-cisplatin, the current standard therapy for advanced biliary tract cancers, results in median progression-free survival and overall survival of 8.0 and 11.7 months, respectively. New treatments offering improved survival outcomes are therefore needed., Objective: To evaluate the association between progression-free survival and the addition of nanoparticle albumin-bound (nab)-paclitaxel to gemcitabine-cisplatin for the treatment of patients with advanced biliary tract cancer., Design, Setting, and Participants: This open-label, single-arm, phase 2 clinical trial conducted at the University of Texas MD Anderson Cancer Center and the Mayo Clinic in Phoenix, Arizona, enrolled 62 patients with advanced biliary tract cancers between April 14, 2015, and April 24, 2017., Interventions: Patients initially received gemcitabine, 1000 mg/m2, cisplatin, 25 mg/m2, and nab-paclitaxel, 125 mg/m2, on days 1 and 8 of 21-day cycles. Owing to hematologic adverse events among the first 32 patients enrolled, these starting doses were reduced to 800, 25, and 100 mg/m2, respectively, for the remaining 28 patients., Main Outcomes and Measures: The primary trial end point was investigator-assessed progression-free survival in the intention-to-treat population., Results: Of 60 patients who started treatment, the mean (SD) age was 58.4 (11.0) years, 38 (63%) had intrahepatic cholangiocarcinoma, 9 (15%) had extrahepatic cholangiocarcinoma, 13 (22%) had gallbladder cancer, 47 (78%) had metastatic disease, and 13 (22%) had locally advanced disease. Median follow-up was 12.2 (95% CI, 9.4-19.4) months, and median progression-free survival was 11.8 (95% CI, 6.0 to 15.6) months. The partial response rate was 45%, and the disease control rate was 84%. Median overall survival was 19.2 months (95% CI, 13.2 months to not estimable). Patients in the safety population (n = 57) received a median of 6 (interquartile range, 3-11) cycles of treatment; 26 patients (46%) remained on their starting dose throughout the trial. Grade 3 or higher adverse events occurred in 58% of patients, and 9 patients (16%) withdrew owing to adverse events. Neutropenia was the most common grade 3 or higher adverse event, occurring in 19 patients (33%) overall. Post hoc analyses showed that treatment efficacy was not significantly associated with starting dose, tumor type, or disease status and that tolerability was improved with reduced- vs high-dose treatment., Conclusions and Relevance: Treatment with nab-paclitaxel plus gemcitabine-cisplatin prolonged median progression-free survival and overall survival vs those reported for historical controls treated with gemcitabine-cisplatin alone. These findings will be tested in a phase 3 randomized clinical trial., Trial Registration: ClinicalTrials.gov identifier: NCT02392637.
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- 2019
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22. Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study.
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Meric-Bernstam F, Hurwitz H, Raghav KPS, McWilliams RR, Fakih M, VanderWalde A, Swanton C, Kurzrock R, Burris H, Sweeney C, Bose R, Spigel DR, Beattie MS, Blotner S, Stone A, Schulze K, Cuchelkar V, and Hainsworth J
- Subjects
- Aged, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Drug Resistance, Neoplasm, Female, Gene Amplification, Humans, Male, Middle Aged, Receptor, ErbB-2 antagonists & inhibitors, Treatment Outcome, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents, Immunological therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Colorectal Neoplasms drug therapy, Receptor, ErbB-2 genetics, Trastuzumab therapeutic use
- Abstract
Background: Therapies targeting HER2 have improved clinical outcomes in HER2-positive breast and gastric cancers, and are emerging as potential treatments for HER2-positive metastatic colorectal cancer. MyPathway evaluates the activity of targeted therapies in non-indicated tumour types with potentially predictive molecular alterations. We aimed to assess the activity of pertuzumab and trastuzumab in patients with HER2-amplified metastatic colorectal cancer., Methods: MyPathway is an ongoing, phase 2a, multiple basket study. Patients in this subset analysis were aged 18 years or older and had treatment-refractory, histologically confirmed HER2-amplified metastatic colorectal cancer with measurable or evaluable disease and an Eastern Cooperative Oncology Group performance status score of 2 or less, enrolled from 25 hospitals or clinics in 16 states of the USA. Patients received pertuzumab (840 mg loading dose, then 420 mg every 3 weeks, intravenously) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks, intravenously). The primary endpoint was the proportion of patients who achieved an objective response based on investigator-reported tumour responses. Analyses were done per protocol. This ongoing trial is registered with ClinicalTrials.gov, number NCT02091141., Findings: Between Oct 20, 2014, and June 22, 2017, 57 patients with HER2-amplified metastatic colorectal cancer were enrolled in the MyPathway study and deemed eligible for inclusionin this cohort analysis. Among these 57 evaluable patients, as of Aug 1, 2017, one (2%) patient had a complete response and 17 (30%) had partial responses; thus overall 18 of 57 patients achieved an objective response (32%, 95% CI 20-45). The most common treatment-emergent adverse events were diarrhoea (19 [33%] of 57 patients), fatigue (18 [32%] patients), and nausea (17 [30%] patients). Grade 3-4 treatment-emergent adverse events were recorded in 21 (37%) of 57 patients, most commonly hypokalaemia and abdominal pain (each three [5%] patients). Serious treatment-emergent adverse events were reported in ten (18%) patients and two (4%) of these adverse events (ie, chills and infusion-related reaction) were considered treatment related. There were no treatment-related deaths., Interpretation: Dual HER2-targeted therapy with pertuzumab plus trastuzumab is well tolerated and could represent a therapeutic opportunity for patients with heavily pretreated, HER2-amplified metastatic colorectal cancer., Funding: F Hoffmann-La Roche/Genentech., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
- Full Text
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23. The role of HER2 amplification testing in metastatic colorectal cancer.
- Author
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Raghav KPS
- Subjects
- Humans, Neoplasm Metastasis, Colorectal Neoplasms genetics, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, Gene Amplification, Receptor, ErbB-2 genetics, Receptor, ErbB-2 metabolism
- Published
- 2018
24. FBXW7 missense mutation: a novel negative prognostic factor in metastatic colorectal adenocarcinoma.
- Author
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Korphaisarn K, Morris VK, Overman MJ, Fogelman DR, Kee BK, Raghav KPS, Manuel S, Shureiqi I, Wolff RA, Eng C, Menter D, Hamilton SR, Kopetz S, and Dasari A
- Subjects
- Adenocarcinoma genetics, Adult, Aged, Aged, 80 and over, Colorectal Neoplasms genetics, Female, Follow-Up Studies, Humans, Liver Neoplasms genetics, Lymphatic Metastasis, Male, Middle Aged, Prognosis, Survival Rate, Young Adult, Adenocarcinoma secondary, Biomarkers, Tumor genetics, Colorectal Neoplasms pathology, F-Box-WD Repeat-Containing Protein 7 genetics, Liver Neoplasms secondary, Mutation, Missense
- Abstract
Background: FBXW7 functions as a ubiquitin ligase tagging multiple dominant oncogenic proteins and commonly mutates in colorectal cancer. Data suggest missense mutations lead to greater loss of FBXW7 function than other gene aberrations do. However, the clinicopathologic factors and outcomes associated with FBXW7 missense mutations in metastatic colorectal cancer (mCRC) have not been described., Methods: Data were obtained from mCRC patients whose tumors were evaluated by next-generation sequencing for hotspot mutations at The University of Texas MD Anderson Cancer Center. Alterations in FBXW7 were identified, and their associations with clinicopathologic features and overall survival (OS) were evaluated., Results: Of 855 mCRC patients, 571 had data on FBXW7 status; 43 (7.5%) had FBXW7 mutations, including 37 with missense mutations. R465C mutations in exon 9 were the most common missense mutations (18.6%). PIK3CA mutations were associated with FBXW7 missense mutations (p=0.012). On univariate analysis, patients with FBXW7 missense mutations had significantly worse OS (median 28.7 mo) than those with wild-type FBXW7 (median 46.6 mo; p=0.003). On multivariate analysis including other known prognostic factors such as BRAF mutations, FBXW7 missense mutations were the strongest negative prognostic factor for OS (hazard ratio 2.0; p=0.003)., Conclusions: In the largest clinical dataset of mCRC to date, FBXW7 missense mutations showed a strong negative prognostic association.
- Published
- 2017
- Full Text
- View/download PDF
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