Publications by authors named "Kathryn A Gold"

44 Publications

Scirrhous carcinoma: A previously undescribed tumor of the oral cavity.

Clin Case Rep 2021 May 4;9(5):e03864. Epub 2021 May 4.

Department of Surgery Division of Otolaryngology-Head & Neck Surgery University of California San Diego CA USA.

This patient was found to have a scirrhous carcinoma with extensive perineural invasion and without any evidence of minor salivary gland carcinoma. To our knowledge, this is the first report of isolated scirrhous carcinoma of the oral cavity. Treatment was surgery and adjuvant chemoradiation, and there was complete disease response.
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http://dx.doi.org/10.1002/ccr3.3864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142303PMC
May 2021

Biotin-induced thyroid stimulating hormone aberrations in the setting of immunotherapy.

J Oncol Pharm Pract 2021 May 21:10781552211017960. Epub 2021 May 21.

Department of Pharmacy, University of California San Diego Health, San Diego, CA, USA.

Introduction: Immune checkpoint inhibitors are associated with immune-mediated thyroid disease and other endocrinopathies. Biotin is an over-the-counter supplement known to interfere with lab assays, including thyroid function tests. Biotin-induced complications with lab monitoring during immunotherapy have not been previously reported.

Case Report: We present a case of a 68-year old woman with hypothyroidism after initiating immune checkpoint blockade therapy and abnormal laboratory monitoring values while concurrently taking biotin supplements. The patient was initiated on levothyroxine with subsequent dose increases over a period of weeks with resolution of symptoms and normalization of free thyroxine levels. Thyroid stimulating hormone (TSH) levels appeared to remain elevated until biotin supplements were held and levels normalized.

Discussion: The purpose of this report is to provide the first known incidence of biotin complicating the routine monitoring of immune checkpoint inhibitors with elevated TSH levels and to alert providers to elicit accurate medication histories regarding over-the-counter supplements.
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http://dx.doi.org/10.1177/10781552211017960DOI Listing
May 2021

Avelumab and cetuximab as a therapeutic combination: An overview of scientific rationale and current clinical trials in cancer.

Cancer Treat Rev 2021 Jun 2;97:102172. Epub 2021 Mar 2.

Medical Oncology, Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy.

Treatment outcomes have improved with the advent of immune checkpoint inhibitors and small molecule inhibitors. However, many patients do not respond with single agents. Consequently, ongoing research is focused on the use of combination therapies to increase clinical efficacy by potential synergistic effects. Here, we outline ongoing trials and review the rationale and evidence for the combination of avelumab, an anti-programmed death ligand 1 (PD-L1) immunoglobulin G1 (IgG1) monoclonal antibody (mAb), with cetuximab, an anti-epidermal growth factor receptor (EGFR) IgG1 mAb. Avelumab is approved as a monotherapy for the treatment of Merkel cell carcinoma and urothelial carcinoma, and in combination with axitinib for renal cell carcinoma; cetuximab is approved in combination with chemotherapy for the treatment of squamous cell carcinoma of the head and neck (SCCHN) and RAS wild-type metastatic colorectal cancer, and in combination with radiation therapy for SCCHN. Avelumab binds to PD-L1 expressed on tumor cells and immune regulatory cells, thus blocking its interaction with programmed death 1 and reventing T-cell suppression; cetuximab inhibits the EGFR signaling pathway, inhibiting proliferation and inducing apoptosis. Both therapies have complementary mechanisms of action and may also activate the immune system to induce innate effector function through the binding of their Fc regions to natural killer (NK) cells. Furthermore, cetuximab combined with chemotherapy has been shown to induce immunogenic cell death and leads to an increase in tumor-infiltrating CD8+ T and NK cells, which should synergize with the immunostimulatory effects of avelumab. Prospective studies will investigate this combination and inform future treatment strategies.
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http://dx.doi.org/10.1016/j.ctrv.2021.102172DOI Listing
June 2021

Planning for post-pandemic cancer care delivery: Recovery or opportunity for redesign?

CA Cancer J Clin 2021 01 30;71(1):34-46. Epub 2020 Sep 30.

Division of Medical Oncology, Department of Medicine, University of California San Francisco, San Francisco, California.

The delivery of cancer care has never changed as rapidly and dramatically as we have seen with the coronavirus disease 2019 (COVID-19) pandemic. During the early phase of the pandemic, recommendations for the management of oncology patients issued by various professional societies and government agencies did not recognize the significant regional differences in the impact of the pandemic. California initially experienced lower than expected numbers of cases, and the health care system did not experience the same degree of the burden that had been the case in other parts of the country. In light of promising trends in COVID-19 infections and mortality in California, by late April 2020, discussions were initiated for a phased recovery of full-scale cancer services. However, by July 2020, a surge of cases was reported across the nation, including in California. In this review, the authors share the response and recovery planning experience of the University of California (UC) Cancer Consortium in an effort to provide guidance to oncology practices. The UC Cancer Consortium was established in 2017 to bring together 5 UC Comprehensive Cancer Centers: UC Davis Comprehensive Cancer Center, UC Los Angeles Jonsson Comprehensive Cancer Center, UC Irvine Chao Family Comprehensive Cancer Center, UC San Diego Moores Cancer Center, and the UC San Francisco Helen Diller Family Comprehensive Cancer Center. The interventions implemented in each of these cancer centers are highlighted, with a focus on opportunities for a redesign in care delivery models. The authors propose that their experiences gained during this pandemic will enhance pre-pandemic cancer care delivery.
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http://dx.doi.org/10.3322/caac.21644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537198PMC
January 2021

Safety and Efficacy of Pembrolizumab With Chemoradiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: A Phase IB Study.

J Clin Oncol 2020 07 1;38(21):2427-2437. Epub 2020 Jun 1.

Sanford Cancer Center, Sanford Health, Sioux Falls, SD.

Purpose: Pembrolizumab is a humanized monoclonal antibody that blocks interaction between programmed death receptor-1 (PD-1) and its ligands (PD-L1, PD-L2). Although pembrolizumab is approved for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), its role in the management of locally advanced (LA) disease is not defined. We report a phase IB study evaluating the safety and efficacy of adding pembrolizumab to cisplatin-based chemoradiotherapy in patients with LA HNSCC.

Patients And Methods: Eligible patients included those with oral cavity (excluding lip), oropharyngeal, hypopharyngeal, or laryngeal stage III to IVB HNSCC (according to American Joint Committee on Cancer, 7th edition, staging system) eligible for cisplatin-based, standard-dose (70 Gy) chemoradiotherapy. Pembrolizumab was administered concurrently with and after chemoradiotherapy with weekly cisplatin. Safety was the primary end point and was determined by incidence of chemoradiotherapy adverse events (AEs) and immune-related AEs (irAEs). Efficacy was defined as complete response (CR) rate on end-of-treatment (EOT) imaging or with pathologic confirmation at 100 days postradiotherapy completion. Key secondary end points included overall (OS) and progression-free survival (PFS).

Results: The study accrued 59 patients (human papillomavirus [HPV] positive, n = 34; HPV negative, n = 25) from November 2015 to October 2018. Five patients (8.8%) required discontinuation of pembrolizumab because of irAEs, all of which occurred during concurrent chemoradiotherapy; 98.3% of patients completed the full planned treatment dose (70 Gy) of radiotherapy without any delays ≥ 5 days; 88.1% of patients completed the goal cisplatin dose of ≥ 200 mg/m. EOT CR rates were 85.3% and 78.3% for those with HPV-positive and -negative HNSCC, respectively.

Conclusion: Pembrolizumab in combination with weekly cisplatin-based chemoradiotherapy is safe and does not impair delivery of curative radiotherapy or chemotherapy in HNSCC. Early efficacy data support further investigation of this approach.
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http://dx.doi.org/10.1200/JCO.19.03156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365766PMC
July 2020

Circulating Tumor DNA Profiling in Small-Cell Lung Cancer Identifies Potentially Targetable Alterations.

Clin Cancer Res 2019 10 12;25(20):6119-6126. Epub 2019 Jul 12.

Washington University School of Medicine, Saint Louis, Missouri.

Purpose: Patients with SCLC rarely undergo biopsies at relapse. When pursued, tissue obtained can be inadequate for molecular testing, posing a challenge in identifying potentially targetable alterations in a clinically meaningful time frame. We examined the feasibility of circulating tumor DNA (ctDNA) testing in identifying potentially targetable alterations in SCLC.

Experimental Design: ctDNA test results were prospectively collected from patients with SCLC between 2014 and 2017 and analyzed. ctDNA profiles of SCLC at diagnosis and relapse were also compared.

Results: A total of 609 samples collected from 564 patients between 2014 and 2017 were analyzed. The median turnaround time for test results was 14 days. Among patients with data on treatment status, there were 61 samples from 59 patients and 219 samples from 206 patients collected at diagnosis and relapse, respectively. The number of mutations or amplifications detected per sample did not differ by treatment status. Potentially targetable alterations in DNA repair, MAPK and PI3K pathways, and genes such as MYC and ARID1A were identifiable through ctDNA testing. Furthermore, our results support that it may be possible to reconstruct the clonal relationship between detected variants through ctDNA testing.

Conclusions: Patients with relapsed SCLC rarely undergo biopsies for molecular testing and often require prompt treatment initiation. ctDNA testing is less invasive and capable of identifying alterations in relapsed disease in a clinically meaningful timeframe. ctDNA testing on an expanded gene panel has the potential to advance our knowledge of the mechanisms underlying treatment resistance in SCLC and aid in the development of novel treatment strategies.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373320PMC
October 2019

Immune Modulation of Head and Neck Squamous Cell Carcinoma and the Tumor Microenvironment by Conventional Therapeutics.

Clin Cancer Res 2019 07 27;25(14):4211-4223. Epub 2019 Feb 27.

Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, California.

Head and neck squamous cell carcinoma (HNSCC) accounts for more than 600,000 cases and 380,000 deaths annually worldwide. Although human papillomavirus (HPV)-associated HNSCCs have better overall survival compared with HPV-negative HNSCC, loco-regional recurrence remains a significant cause of mortality and additional combinatorial strategies are needed to improve outcomes. The primary conventional therapies to treat HNSCC are surgery, radiation, and chemotherapies; however, multiple other targeted systemic options are used and being tested including cetuximab, bevacizumab, mTOR inhibitors, and metformin. In 2016, the first checkpoint blockade immunotherapy was approved for recurrent or metastatic HNSCC refractory to platinum-based chemotherapy. This immunotherapy approval confirmed the critical importance of the immune system and immunomodulation in HNSCC pathogenesis, response to treatment, and disease control. However, although immuno-oncology agents are rapidly expanding, the role that the immune system plays in the mechanism of action and clinical efficacy of standard conventional therapies is likely underappreciated. In this article, we focus on how conventional and targeted therapies may directly modulate the immune system and the tumor microenvironment to better understand the effects and combinatorial potential of these therapies in the context and era of immunotherapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635035PMC
July 2019

Immunotherapeutic Approaches to the Management of Head and Neck Cancer.

Oncology (Williston Park) 2018 12;32(12):617-9, 625-6

The two programmed death 1 checkpoint inhibitors nivolumab and pembrolizumab are approved by the US Food and Drug Administration as second-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Based on the existing data, the effectiveness of these two drugs is similar in this setting. When choosing between them, the decision should be individualized and can be determined by patient and provider preferences, as well as scheduling. Testing for tumor programmed death ligand 1 (PD-L1) and human papillomavirus status is not required for use of these checkpoint inhibitors in the second-line setting, but the level of tumor PD-L1 expression can be useful for decision making in special situations. There are many ongoing trials that are studying immunotherapy as frontline treatment for recurrent or metastatic HNSCC, as well as trials combining immunotherapy with definitive chemoradiation in locally advanced disease. Based on the updated results of the KEYNOTE-048 trial, checkpoint inhibitors will likely be a part of first-line therapy in the near future.
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December 2018

Exploratory Analysis of Brigatinib Activity in Patients With Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer and Brain Metastases in Two Clinical Trials.

J Clin Oncol 2018 09 16;36(26):2693-2701. Epub 2018 May 16.

D. Ross Camidge, University of Colorado Cancer Center, Aurora, CO; Dong-Wan Kim, Seoul National University Hospital; Myung-Ju Ahn, Samsung Medical Center; Dae Ho Lee, Asan Medical Center, Seoul, South Korea; Marcello Tiseo, University Hospital of Parma, Parma, Italy; Corey J. Langer, University of Pennsylvania, Philadelphia, PA; Alice T. Shaw, Massachusetts General Hospital, Boston; William Reichmann, Jeff Haney, Tim Clackson, and David Kerstein, ARIAD Pharmaceuticals, Cambridge, MA; Rudolf M. Huber, University Hospital of Munich, Munich, Germany; Maximilian J. Hochmair, Otto Wagner Hospital, Vienna, Austria; Lyudmila A. Bazhenova and Kathryn A. Gold, University of California San Diego Moores Cancer Center, La Jolla; Sai-Hong Ignatius Ou, University of California Irvine School of Medicine, Irvine, CA; Howard L. West, Swedish Cancer Institute, Seattle, WA; and Scott N. Gettinger, Yale Cancer Center, New Haven, CT.

Purpose In patients with crizotinib-treated, anaplastic lymphoma kinase gene ( ALK)-rearranged non-small-cell lung cancer (ALK-positive NSCLC), initial disease progression often occurs in the CNS. We evaluated brigatinib, a next-generation ALK inhibitor, in patients with ALK-positive NSCLC with brain metastases. Patients and Methods Patients with ALK-positive NSCLC received brigatinib (90 to 240 mg total daily) in a phase I/II trial (phI/II; ClinicalTrials.gov identifier: NCT01449461) and in the subsequent randomized phase II trial ALTA (ALK in Lung Cancer Trial of AP26113; ClinicalTrials.gov identifier: NCT02094573; patients in arm A received 90 mg once daily; patients in arm B received 180 mg once daily with 7-day lead-in at 90 mg). Primary end points (systemic objective response rates [ORRs]) were previously reported. Independent review committees assessed intracranial efficacy in patients with baseline brain metastases. Results Most patients with ALK-positive NSCLC had baseline brain metastases (50 of 79 [63%], phI/II; 80 of 112 [71%] and 73 of 110 [66%] in ALTA arms A and B, respectively), many of whom had no prior brain radiotherapy (23 of 50 [46%], phI/II; 32 of 80 [40%], ALTA arm A; 30 of 73 [41%], arm B). All patients, except four in phI/II, had received crizotinib. Among patients with measurable (≥ 10 mm) brain metastases, confirmed intracranial ORR was 53% (eight of 15; 95% CI, 27% to 79%) in phI/II, 46% (12 of 26; 95% CI, 27% to 67%) in ALTA arm A, and 67% (12 of 18; 95% CI, 41% to 87%) in arm B. Intracranial ORRs were similar in subsets without prior radiation or progression postradiation. Among patients with any baseline brain metastases, median intracranial progression-free survival (iPFS) was 14.6 months (95% CI, 12.7 to 36.8 months), phI/II; 15.6 months (95% CI, 9.0 to 18.3 months), ALTA arm A; 18.4 months (95% CI, 12.8 months to not reached), ALTA arm B. Conclusion Brigatinib yielded substantial intracranial responses and durable iPFS in ALK-positive, crizotinib-treated NSCLC, with highest iPFS in patients receiving 180 mg once daily (with lead-in).
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http://dx.doi.org/10.1200/JCO.2017.77.5841DOI Listing
September 2018

Erlotinib in the treatment of recurrent or metastatic cutaneous squamous cell carcinoma: A single-arm phase 2 clinical trial.

Cancer 2018 05 26;124(10):2169-2173. Epub 2018 Mar 26.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Cutaneous squamous cell carcinoma (CSCC) is a very common malignancy in which most patients present with localized disease. Recurrent and metastatic disease is rare, and there is no standard therapy. These tumors frequently overexpress the epidermal growth factor receptor (EGFR). We conducted a phase 2 trial to determine the response rate to therapy with erlotinib, an EGFR tyrosine kinase inhibitor, in patients with locoregionally recurrent or metastatic CSCC that was not amenable to curative treatment (NCT01198028).

Methods: Eligible patients had CSCC not amenable to curative intent therapy. Patients who had previously received anti-EGFR targeted therapy were excluded. All patients received oral therapy with erlotinib 150 mg daily. Response was assessed every 8 weeks, and treatment continued until progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was overall response rate according to RECIST 1.1 criteria.

Results: A total of 39 patients received treatment during the trial; 29 of these patients were evaluable for response. The overall response rate was 10% (3/29); all responses were partial responses. The disease control rate (partial response + stable disease) was 72% (21/29). The median progression-free survival was 4.7 months (95% confidence interval, 3.5-6.2 months); the median overall survival was 13 months (95% confidence interval, 8.4-20.5 months). No unexpected toxicities were seen.

Conclusion: Erlotinib therapy was feasible for most patients with incurable CSCC and was associated with expected toxicities. However, only a modest response rate of 10% was observed. Further study of EGFR tyrosine kinase inhibitors in this patient population is not warranted. Cancer 2018;124:2169-73. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935588PMC
May 2018

Induction Cisplatin Docetaxel Followed by Surgery and Erlotinib in Non-Small Cell Lung Cancer.

Ann Thorac Surg 2018 Feb 6;105(2):418-424. Epub 2017 Dec 6.

Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Background: Data from meta-analyses support the use of induction or adjuvant platinum-based chemotherapy for locally advanced non-small cell lung cancers (NSCLCs). This phase 2 study assessed the role of induction cisplatin and docetaxel followed by surgery in patients with resectable stage I to III NSCLCs, followed by 12 months of adjuvant erlotinib.

Methods: Patients with resectable stage I to III NSCLCs received cisplatin 80 mg/m, docetaxel 75 mg/m every 21 days for 3 cycles, followed by surgery, followed by adjuvant erlotinib for 12 months. The primary endpoint included safety. Long-term efficacy outcomes and exploratory analysis of intermediary endpoints are also reported (NCT00254384).

Results: Forty-seven eligible patients received a median of 3 cycles of induction treatment, 37 underwent surgical resection, and only 21 received adjuvant erlotinib. Two patients died in the perioperative period (1 sepsis during chemotherapy, 1 acute respiratory distress syndrome postoperatively). Most common grade 3 to 5 toxicities during chemotherapy included hypokalemia (8%), infection (7%), and granulocytopenia (25%). During adjuvant erlotinib, 14% of patients experienced grade 2 rash. Median overall survival was 3.4 years. Major pathologic responses in the primary tumor were observed in 19% (7 of 37) of patients and correlated with improved long-term overall survival. Complete pathologic response in mediastinal/hilar nodes also correlated with superior survival.

Conclusions: Induction cisplatin and docetaxel was well tolerated. Adjuvant erlotinib did not improve outcomes compared with historical controls. Major pathologic response predicted for improved long-term survival and is a suitable intermediary endpoint for future phase 2 studies.
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http://dx.doi.org/10.1016/j.athoracsur.2017.08.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783769PMC
February 2018

Modulation of Biomarker Expression by Osimertinib: Results of the Paired Tumor Biopsy Cohorts of the AURA Phase I Trial.

J Thorac Oncol 2017 10 24;12(10):1588-1594. Epub 2017 Jul 24.

Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, Massachusetts. Electronic address:

Introduction: Osimertinib is an oral, potent, irreversible EGFR tyrosine kinase inhibitor (TKI) selective for EGFR TKI and T790M resistance mutations. To enhance understanding of osimertinib's mechanism of action, we aimed to evaluate the modulation of key molecular biomarkers after osimertinib treatment in paired clinical samples from the phase I AURA trial.

Methods: Paired tumor biopsy samples were collected before the study and after 15 plus or minus 7 days of osimertinib treatment (80 or 160 mg daily). Clinical efficacy outcomes were assessed according to whether viable paired biopsy samples could be collected; safety was also assessed. Immunohistochemical analyses assessed key pathway and tumor/immune-relevant markers (phospho-EGFR, phospho-S6, phospho-AKT, programmed death ligand 1, and CD8), with samples scored by image analysis or a pathologist blinded to treatment allocation.

Results: Predose tumor biopsy samples were collected from 61 patients with EGFR T790M tumors; 29 patients had no viable postdose biopsy sample because of tumor regression or insufficient tumor sample. Evaluable predose and postdose tumor biopsy samples were collected from 24 patients. Objective response rate (ORR) and median progression-free survival (mPFS) were improved in patients from whom a postdose biopsy sample could not be collected (ORR 62% and mPFS 9.7 months [p = 0.027]) compared with those from whom paired samples were collected (ORR 29% and mPFS 6.6 months). Osimertinib modulated key EGFR signaling pathways and led to increased immune cell infiltration.

Conclusions: Collection of paired biopsy samples was challenging because of rapid tumor regression after osimertinib treatment, highlighting the difficulties of performing on-study biopsies in patients treated with highly active drugs.
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http://dx.doi.org/10.1016/j.jtho.2017.07.011DOI Listing
October 2017

The Influence of Body Mass Index on Overall Survival Following Surgical Resection of Non-Small Cell Lung Cancer.

J Thorac Oncol 2017 08 25;12(8):1280-1287. Epub 2017 May 25.

Department of Thoracic/Head and Neck Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas. Electronic address:

Background: Population studies suggest that high body mass index (BMI) correlates with a reduced risk for death from lung cancer. The aim of our study was to evaluate definitively the influence of BMI on long-term overall survival (OS) in surgical patients with NSCLC.

Methods: The study population consisted of 1935 patients who underwent surgical resection for lung cancer at M. D. Anderson Cancer Center (2000-2014). Study variables included both patient- and treatment-related characteristics. Univariate and multivariate Cox regression analyses were performed to identify variables associated with OS.

Results: On univariate analysis, significant predictors of improved survival were higher BMI, pathologic tumor stage (stage I versus stage II, III, or IV), type of surgical procedure (lobectomy/pneumonectomy versus wedge resection/segmentectomy), younger age, female sex, and adenocarcinoma histologic subtype (versus squamous) (all p < 0.05). Morbidly obese patients (BMI ≥ 35) demonstrated a trend toward better outcomes than those classified as obese (BMI ≥30 and <35 kg/m) (p = 0.05), overweight (BMI ≥ 25 and <30 kg/m) (p = 0.13), or healthy weight (BMI <25 kg/m) (p = 0.37) (hazard ratio = 0.727, 0.848, 0.926, and 1, respectively). On multivariate analysis, BMI remained an independent predictor of survival (p = 0.02). Propensity matching analysis demonstrated significantly better OS (p = 0.003) in patients with a BMI of 30 kg/m or higher as compared with a BMI of 25 kg/m.

Conclusions: In this large, retrospective, single-center series, after control for disease stage and other variables, higher BMI was associated with improved OS after surgical resection of NSCLC. Further studies are necessary to elucidate the precise relationship between BMI and treatment outcomes.
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http://dx.doi.org/10.1016/j.jtho.2017.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532070PMC
August 2017

Cancer Genomics and Important Oncologic Mutations: A Contemporary Guide for Body Imagers.

Radiology 2017 05;283(2):314-340

From the Department of Radiology, Abdominal Imaging Section (V.L.C., P.B., N.W.B., A.Q.), Department of Gastrointestinal Medical Oncology (G.R.V.), Department of Melanoma Medical Oncology (I.C.G.), Department of Thoracic and Head & Neck Medical Oncology (K.A.G.), Department of Gynecologic Oncology (P.T.S.), Department of Investigational Cancer Therapeutics (J.T.A., D.S.H.), University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030.

The field of cancer genomics is rapidly evolving and has led to the development of new therapies. Knowledge of commonly involved cellular pathways and genetic mutations is now essential for radiologists reading oncology cases. Radiogenomics is an emerging area of research that seeks to correlate imaging features with cancer genotypes. Such knowledge may extend the utility of multiparametric imaging to yield information regarding cancer prognosis and likelihood of therapeutic response. To date, only a handful of radiogenomics studies have been performed to evaluate solid tumors of the body, and there is much to explore. Before doing so, however, it behooves us to have adequate background knowledge of clinical cancer genomics to design meaningful radiogenomics projects and explore imaging phenotypes. Herein, an up-to-date, detailed overview is provided of well-known and common mutations of solid body tumors (such as human epithelial growth factor receptor 2, breast cancer susceptibility protein), newer genomic alterations with potential for clinical relevance, and a discussion of known related imaging findings, including existing radiogenomics data and other radiologic patterns of disease. RSNA, 2017 Online supplemental material is available for this article.
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http://dx.doi.org/10.1148/radiol.2017152224DOI Listing
May 2017

Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial.

Lancet Oncol 2016 Dec 8;17(12):1683-1696. Epub 2016 Nov 8.

University of Colorado Cancer Center, Aurora, CO, USA.

Background: Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers of non-small-cell lung cancer (NSCLC). Brigatinib (AP26113) is an investigational ALK inhibitor with potent preclinical activity against ALK mutants resistant to crizotinib and other ALK inhibitors. We aimed to assess brigatinib in patients with advanced malignancies, particularly ALK-rearranged NSCLC.

Methods: In this ongoing, single-arm, open-label, phase 1/2 trial, we recruited patients from nine academic hospitals or cancer centres in the USA and Spain. Eligible patients were at least 18 years of age and had advanced malignancies, including ALK-rearranged NSCLC, and disease that was refractory to available therapies or for which no curative treatments existed. In the initial dose-escalation phase 1 stage of the trial, patients received oral brigatinib at total daily doses of 30-300 mg (according to a standard 3 + 3 design). The phase 1 primary endpoint was establishment of the recommended phase 2 dose. In the phase 2 expansion stage, we assessed three oral once-daily regimens: 90 mg, 180 mg, and 180 mg with a 7 day lead-in at 90 mg; one patient received 90 mg twice daily. We enrolled patients in phase 2 into five cohorts: ALK inhibitor-naive ALK-rearranged NSCLC (cohort 1), crizotinib-treated ALK-rearranged NSCLC (cohort 2), EGFR-positive NSCLC and resistance to one previous EGFR tyrosine kinase inhibitor (cohort 3), other cancers with abnormalities in brigatinib targets (cohort 4), and crizotinib-naive or crizotinib-treated ALK-rearranged NSCLC with active, measurable, intracranial CNS metastases (cohort 5). The phase 2 primary endpoint was the proportion of patients with an objective response. Safety and activity of brigatinib were analysed in all patients in both phases of the trial who had received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT01449461.

Findings: Between Sept 20, 2011, and July 8, 2014, we enrolled 137 patients (79 [58%] with ALK-rearranged NSCLC), all of whom were treated. Dose-limiting toxicities observed during dose escalation included grade 3 increased alanine aminotransferase (240 mg daily) and grade 4 dyspnoea (300 mg daily). We initially chose a dose of 180 mg once daily as the recommended phase 2 dose; however, we also assessed two additional regimens (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg) in the phase 2 stage. four (100% [95% CI 40-100]) of four patients in cohort 1 had an objective response, 31 (74% [58-86]) of 42 did in cohort 2, none (of one) did in cohort 3, three (17% [4-41]) of 18 did in cohort 4, and five (83% [36-100]) of six did in cohort 5. 51 (72% [60-82]) of 71 patients with ALK-rearranged NSCLC with previous crizotinib treatment had an objective response (44 [62% (50-73)] had a confirmed objective response). All eight crizotinib-naive patients with ALK-rearranged NSCLC had a confirmed objective response (100% [63-100]). Three (50% [95% CI 12-88]) of six patients in cohort 5 had an intracranial response. The most common grade 3-4 treatment-emergent adverse events across all doses were increased lipase concentration (12 [9%] of 137), dyspnoea (eight [6%]), and hypertension (seven [5%]). Serious treatment-emergent adverse events (excluding neoplasm progression) reported in at least 5% of all patients were dyspnoea (ten [7%]), pneumonia (nine [7%]), and hypoxia (seven [5%]). 16 (12%) patients died during treatment or within 31 days of the last dose of brigatinib, including eight patients who died from neoplasm progression.

Interpretation: Brigatinib shows promising clinical activity and has an acceptable safety profile in patients with crizotinib-treated and crizotinib-naive ALK-rearranged NSCLC. These results support its further development as a potential new treatment option for patients with advanced ALK-rearranged NSCLC. A randomised phase 2 trial in patients with crizotinib-resistant ALK-rearranged NSCLC is prospectively assessing the safety and efficacy of two regimens assessed in the phase 2 portion of this trial (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg).

Funding: ARIAD Pharmaceuticals.
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http://dx.doi.org/10.1016/S1470-2045(16)30392-8DOI Listing
December 2016

Sleep and Breathing … and Cancer?

Cancer Prev Res (Phila) 2016 11 7;9(11):821-827. Epub 2016 Sep 7.

Division of Pulmonary, Critical Care and Sleep Medicine, University of California San Diego, La Jolla, California.

Sleep, like eating and breathing, is an essential part of the daily life cycle. Although the science is still emerging, sleep plays an important role in immune, cardiovascular, and neurocognitive function. Despite its great importance, nearly 40% of U.S. adults experience problems with sleep ranging from insufficient total sleep time, trouble initiating or maintaining sleep (Insomnia), circadian rhythm disorders, sleep-related movement disorders, and sleep-related breathing disorders such as obstructive sleep apnea (OSA). Herein, we discuss new evidence that suggests that sleep may also affect carcinogenesis. Specifically, we review recent epidemiologic data suggesting links between cancer and OSA. As OSA is a common, underdiagnosed, and undertreated condition, this has public health implications. Intriguing animal model data support a link between cancer and sleep/OSA, although mechanisms are not yet clear. Leaders in the fields of sleep medicine, pulmonology, and oncology recently met to review and discuss these data, as well as to outline future directions of study. We propose a multidisciplinary, three-pronged approach to studying the associations between cancer and sleep, utilizing mutually interactive epidemiologic studies, preclinical models, and early-phase clinical trials. Cancer Prev Res; 9(11); 821-7. ©2016 AACR.
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http://dx.doi.org/10.1158/1940-6207.CAPR-16-0092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353979PMC
November 2016

The microRNA-200/Zeb1 axis regulates ECM-dependent β1-integrin/FAK signaling, cancer cell invasion and metastasis through CRKL.

Sci Rep 2016 Jan 5;6:18652. Epub 2016 Jan 5.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Tumor cell metastasis is a complex process that has been mechanistically linked to the epithelial-mesenchymal transition (EMT). The double-negative feedback loop between the microRNA-200 family and the Zeb1 transcriptional repressor is a master EMT regulator, but there is incomplete understanding of how miR-200 suppresses invasion. Our recent efforts have focused on the tumor cell-matrix interactions essential to tumor cell activation. Herein we utilized both our Kras/p53 mutant mouse model and human lung cancer cell lines to demonstrate that upon miR-200 loss integrin β1-collagen I interactions drive 3D in vitro migration/invasion and in vivo metastases. Zeb1-dependent EMT enhances tumor cell responsiveness to the ECM composition and activates FAK/Src pathway signaling by de-repression of the direct miR-200 target, CRKL. We demonstrate that CRKL serves as an adaptor molecule to facilitate focal adhesion formation, mediates outside-in signaling through Itgβ1 to drive cell invasion, and inside-out signaling that maintains tumor cell-matrix contacts required for cell invasion. Importantly, CRKL levels in pan-cancer TCGA analyses were predictive of survival and CRKL knockdown suppressed experimental metastases in vivo without affecting primary tumor growth. Our findings highlight the critical ECM-tumor cell interactions regulated by miR-200/Zeb1-dependent EMT that activate intracellular signaling pathways responsible for tumor cell invasion and metastasis.
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http://dx.doi.org/10.1038/srep18652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4700473PMC
January 2016

Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial.

Lancet Oncol 2016 Feb 19;17(2):234-242. Epub 2015 Dec 19.

Chao Family Comprehensive Cancer Center, University of California, Irvine School of Medicine, Orange, CA, USA.

Background: Alectinib--a highly selective, CNS-active, ALK inhibitor-showed promising clinical activity in crizotinib-naive and crizotinib-resistant patients with ALK-rearranged (ALK-positive) non-small-cell lung cancer (NSCLC). We aimed to assess the safety and efficacy of alectinib in patients with ALK-positive NSCLC who progressed on previous crizotinib.

Methods: We did a phase 2 study at 27 centres in the USA and Canada. We enrolled patients aged 18 years or older with stage IIIB-IV, ALK-positive NSCLC who had progressed after crizotinib. Patients were treated with oral alectinib 600 mg twice daily until progression, death, or withdrawal. The primary endpoint was the proportion of patients achieving an objective response by an independent review committee using Response Evaluation Criteria in Solid Tumors, version 1.1. Response endpoints were assessed in the response-evaluable population (ie, patients with measurable disease at baseline who received at least one dose of study drug), and efficacy and safety analyses were done in the intention-to-treat population (all enrolled patients). This study is registered with ClinicalTrials.gov, number NCT01871805. The study is ongoing and patients are still receiving treatment.

Findings: Between Sept 4, 2013, and Aug 4, 2014, 87 patients were enrolled into the study (intention-to-treat population). At the time of the primary analysis (median follow-up 4·8 months [IQR 3·3-7·1]), 33 of 69 patients with measurable disease at baseline had a confirmed partial response; thus, the proportion of patients achieving an objective response by the independent review committee was 48% (95% CI 36-60). Adverse events were predominantly grade 1 or 2, most commonly constipation (31 [36%]), fatigue (29 [33%]), myalgia 21 [24%]), and peripheral oedema 20 [23%]). The most common grade 3 and 4 adverse events were changes in laboratory values, including increased blood creatine phosphokinase (seven [8%]), increased alanine aminotransferase (five [6%]), and increased aspartate aminotransferase (four [5%]). Two patients died: one had a haemorrhage (judged related to study treatment), and one had disease progression and a history of stroke (judged unrelated to treatment).

Interpretation: Alectinib showed clinical activity and was well tolerated in patients with ALK-positive NSCLC who had progressed on crizotinib. Therefore, alectinib could be a suitable treatment for patients with ALK-positive disease who have progressed on crizotinib.

Funding: F Hoffmann-La Roche.
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http://dx.doi.org/10.1016/S1470-2045(15)00488-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752892PMC
February 2016

New strategies in immunotherapy for non-small cell lung cancer.

Transl Lung Cancer Res 2015 Oct;4(5):553-9

1 Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA ; 2 The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Treatment for the most common form of cancer (lung cancer) has historically involved use of cytotoxic chemotherapy. With the advent of mutation analysis, more therapies beyond traditional cytotoxics have been discovered. Most recently, the use of immunotherapy has entered the treatment arsenal of non-small cell lung cancer (NSCLC). This review aims to summarize the current and future use of immunotherapy in the treatment of NSCLC.
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http://dx.doi.org/10.3978/j.issn.2218-6751.2015.06.05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630527PMC
October 2015

Comparison of systemic therapies used concurrently with radiation for the treatment of human papillomavirus-associated oropharyngeal cancer.

Head Neck 2016 04 23;38 Suppl 1:E1554-61. Epub 2015 Nov 23.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: This was a retrospective study of patients with human papillomavirus (HPV)-associated oropharyngeal cancer treated with concurrent systemic therapy and radiation.

Methods: Data were extracted through chart review, and statistical analyses included frequency tabulation, chi-square, and Kaplan-Meier tests.

Results: Three hundred thirty-nine patients were analyzed; 166 received neoadjuvant chemotherapy. One hundred thirty-six patients were treated with cisplatin, 123 with cetuximab, and 59 with carboplatin. The 2-, 3-, and 5-year actuarial overall survival rates were 92%, 88%, and 78%, respectively. There were no significant differences in survival or disease control when analyzed by systemic agent. Platin-treated patients had greater hematologic toxicity, and required more intravenous hydration. The incidence of confluent mucositis was highest among patients treated with cetuximab.

Conclusion: Platin and cetuximab seem to have similar efficacy when delivered concurrently with radiation in our retrospective population study. Although platin did cause greater hematologic toxicity, radiation-specific side effects seemed relatively comparable. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1554-E1561, 2016.
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http://dx.doi.org/10.1002/hed.24278DOI Listing
April 2016

Relation between the level of lymph node metastasis and survival in locally advanced head and neck squamous cell carcinoma.

Cancer 2016 Feb 10;122(4):534-45. Epub 2015 Nov 10.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: The current head and neck squamous cell carcinoma (HNSCC) staging system may not capture the full prognostic implications of regional lymph node involvement. This study investigated the impact of the level of lymph node metastasis (LNM) on survival.

Methods: The Surveillance, Epidemiology, and End Results registry was queried for oral cavity (OC), oropharynx (OP), larynx (LAR), and hypopharynx (HP) HNSCC. A multivariate Cox proportional hazards model was used to evaluate whether the level of LNM was an independent prognostic factor. Site-specific recursive-partitioning analysis was performed to classify patients into different risk groups.

Results: In all, 14,499 patients, including OC (n = 2463), OP (n = 8567), LAR (n = 2332), and HP patients (n = 1137), were analyzed. Both the American Joint Committee on Cancer (AJCC) N classification and the level of LNM showed significant effects on overall survival (OS) in patients with OC, OP, or LAR HNSCC but not in patients with HP HNSCC. In patients with N2 disease, the AJCC subclassification (N2a, N2b, or N2c) was significantly associated with the OS of patients with OP and LAR HNSCC but not with the OS of patients with OC or HP HNSCC, whereas the level of LNM (primary, secondary, or tertiary) was significantly associated with the OS of patients with OC, OP, and LAR HNSCC but not HP HNSCC. With recursive-partitioning analysis, a simple, primary site-specific prognostic tool integrating the AJCC T and N classifications and the level of LNM was designed, and it could be easily used by health care providers in clinic.

Conclusions: The level of LNM is an independent prognostic factor for patients with locally advanced HNSCC and could add to the prognostic value of AJCC T and N classifications in patients with locally advanced HNSCC.
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http://dx.doi.org/10.1002/cncr.29780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742373PMC
February 2016

Prognostic value of pretherapy platelet elevation in oropharyngeal cancer patients treated with chemoradiation.

Int J Cancer 2016 Mar 9;138(5):1290-7. Epub 2015 Oct 9.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.

The purpose of this study is to evaluate potential associations between increased platelets and oncologic outcomes in oropharyngeal cancer patients receiving concurrent chemoradiation. A total of 433 oropharyngeal cancer patients (OPC) treated with intensity-modulated radiation therapy (IMRT) with concurrent chemotherapy between 2002 and 2012 were included under an approved IRB protocol. Complete blood count (CBC) data were extracted. Platelet and hemoglobin from the last phlebotomy (PLTpre-chemoRT, Hgbpre-chemoRT ) before start of treatment were identified. Patients were risk-stratified using Dahlstrom-Sturgis criteria and were tested for association with survival and disease-control outcomes. Locoregional control (LRC), freedom from distant metastasis (FDM) and overall survival (OS) were decreased (p < 0.03, p < 0.04 and p < 0.0001, respectively) for patients with PLTpre-chemoRT value of ≥350 × 10(9) /L. Actuarial 5-year locoregional control (LRC) and FDM were 83 and 85% for non-thrombocythemic patients while patient with high platelets had 5-year LRC and FDM of 73 and 74%, respectively. Likewise, 5-year OS was better for patients with normal platelet counts by comparison (76 vs. 57%; p < 0.0001). Comparison of univariate parametric models demonstrated that PLTpre-chemoRT was better among tested models. Multivariate assessment demonstrated improved performance of models which included pretherapy platelet indices. On Bayesian information criteria analysis, the optimal prognostic model was then used to develop nomograms predicting 3-, 5- and 10-year OS. In conclusion, pretreatment platelet elevation is a promising predictor of prognosis, and further work should be done to elucidate the utility of antiplatelets in modifying risk in OPC patients.
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http://dx.doi.org/10.1002/ijc.29870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779600PMC
March 2016

FDG-PET/CT as a Predictor of Outcome in EGFR-Mutant Non-Small-Cell Lung Cancer.

J Thorac Oncol 2015 Aug;10(8):1131-2

The University of Texas MD Anderson Cancer Center, Houston, Texas.

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http://dx.doi.org/10.1097/JTO.0000000000000599DOI Listing
August 2015

The Myb-p300 Interaction Is a Novel Molecular Pharmacologic Target.

Mol Cancer Ther 2015 Jun 20;14(6):1273-5. Epub 2015 May 20.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

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http://dx.doi.org/10.1158/1535-7163.MCT-15-0271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599702PMC
June 2015

Disease control and toxicity outcomes for T4 carcinoma of the nasopharynx treated with intensity-modulated radiotherapy.

Head Neck 2016 04 18;38 Suppl 1:E925-33. Epub 2015 Jul 18.

Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Treatment of T4 nasopharyngeal carcinoma (NPC) is challenging because of the proximity of the tumor to the central nervous system. The purpose of this study was to present our evaluation of disease control and toxicity outcomes for patients with T4 NPC treated with intensity-modulated radiation therapy (IMRT) and chemotherapy.

Methods: The medical records of 66 patients with T4 NPC treated from 2002 to 2012 with IMRT were reviewed. Endpoints included tumor control and toxicity outcomes (Common Terminology Criteria for Adverse Events [CTCAE v4.0]).

Results: Median follow-up was 38 months. Five-year rates of locoregional control, distant metastasis-free survival, progression-free survival (PFS), and overall survival (OS) were 80%, 62%, 57%, and 69%, respectively. Nodal involvement was associated with worse PFS (p = .015). Gross target volume (GTV) volume >100 cm and planning target volume (PTV) volume >400 cm were associated with worse OS (p = .038 and p = .004, respectively). Four patients had significant cognitive impairment, and 9 had MRI evidence of brain necrosis.

Conclusion: For patients with T4 NPC treated with IMRT and chemotherapy, survival and locoregional disease control rates have improved; however, late treatment toxicity remains a concern. © 2015 Wiley Periodicals, Inc. Head Neck 38: E925-E933, 2016.
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http://dx.doi.org/10.1002/hed.24128DOI Listing
April 2016

Relationship between tumor size and survival in non-small-cell lung cancer (NSCLC): an analysis of the surveillance, epidemiology, and end results (SEER) registry.

J Thorac Oncol 2015 Apr;10(4):682-90

*Department of Thoracic/Head & Neck Medical Oncology, †Department of Genomic Medicine, ‡Department of Biostatistics, §Department of Thoracic and Cardiovascular Surgery, MD Anderson Cancer Center, The University of Texas, Houston TX; ‖Department of Medicine, Harvard Medical School, Mount Auburn Hospital, Cambridge, MA; and ¶Levine Cancer Institute, Carolina HealthCare System, Charlotte, NC.

Introduction: Tumor size is a known prognostic factor for early stage non-small-cell lung cancer (NSCLC), but its significance in node-positive and locally invasive NSCLC has not been extensively characterized. We queried the Surveillance, Epidemiology, and End Results database to evaluate the prognostic value of tumor size for early stage and node-positive and locally invasive NSCLC.

Methods: Patients in Surveillance, Epidemiology, and End Results registry with NSCLC diagnosed between 1998 and 2003 were analyzed. Tumor size was analyzed as a continuous variable. Other demographic variables included age, gender, race, histology, primary tumor extension, node status, and primary treatment modality (surgery vs. radiation). The Kaplan-Meier method was used to estimate overall survival (OS). Cox proportional hazard model was used to evaluate whether tumor size was an independent prognostic factor.

Results: In all, 52,287 eligible patients were subgrouped based on tumor extension and node status. Tumor size had a significant effect on OS in all subgroups defined by tumor extension or node status. In addition, tumor size also had statistically significant effect on OS in 15 of 16 subgroups defined by tumor extension and nodal status after adjustment for other clinical variables. Our model incorporating tumor size had significantly better predictive accuracy than our alternative model without tumor size.

Conclusions: Tumor size is an independent prognostic factor, for early stage and node-positive and locally invasive disease. Prediction tools, such as nomograms, incorporating more detailed information not captured in detail by the routine tumor, node, metastasis classification, may improve prediction accuracy of OS in NSCLC.
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http://dx.doi.org/10.1097/JTO.0000000000000456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368494PMC
April 2015

ROS1--targeting the one percent in lung cancer.

Authors:
Kathryn A Gold

N Engl J Med 2014 Nov;371(21):2030-1

From the Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston.

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http://dx.doi.org/10.1056/NEJMe1411319DOI Listing
November 2014

Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing.

Science 2014 Oct;346(6206):256-9

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Honorary Faculty, Wellcome Trust Sanger Institute, Hinxton, UK CB10 1SA.

Cancers are composed of populations of cells with distinct molecular and phenotypic features, a phenomenon termed intratumor heterogeneity (ITH). ITH in lung cancers has not been well studied. We applied multiregion whole-exome sequencing (WES) on 11 localized lung adenocarcinomas. All tumors showed clear evidence of ITH. On average, 76% of all mutations and 20 out of 21 known cancer gene mutations were identified in all regions of individual tumors, which suggested that single-region sequencing may be adequate to identify the majority of known cancer gene mutations in localized lung adenocarcinomas. With a median follow-up of 21 months after surgery, three patients have relapsed, and all three patients had significantly larger fractions of subclonal mutations in their primary tumors than patients without relapse. These data indicate that a larger subclonal mutation fraction may be associated with increased likelihood of postsurgical relapse in patients with localized lung adenocarcinomas.
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http://dx.doi.org/10.1126/science.1256930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354858PMC
October 2014

Selective antitumor activity of ibrutinib in EGFR-mutant non-small cell lung cancer cells.

J Natl Cancer Inst 2014 Sep 10;106(9). Epub 2014 Sep 10.

Department of Thoracic and Cardiovascular Surgery (WG, LW, HL, SW, BD, JAR, WLH, SGS, BF) and Department of Lymphoma and Myeloma (MW, ZO, LZ) and Department of Thoracic/Head and Neck Medical Oncology (JVH, KAD), The University of Texas MD Anderson Cancer Center, Houston, TX; Hamon Center for Therapeutic Oncology, The Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX (JM); Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China (WG).

Ibrutinib, which irreversibly inhibits Bruton tyrosine kinase, was evaluated for antitumor activity in a panel of non-small cell lung cancer (NSCLC) cell lines and found to selectively inhibit growth of NSCLC cells carrying mutations in the epidermal growth factor receptor (EGFR) gene, including T790M mutant and erlotinib-resistant H1975 cells. Ibrutinib induced dose-dependent inhibition of phosphor-EGFR at both Y1068 and Y1173 sites, suggesting ibrutinib functions as an EGFR inhibitor. Survival was analyzed by Kaplan-Meier estimation and log-rank test. All statistical tests were two-sided. In vivo study showed that ibrutinib statistically significantly suppressed H1975 tumor growth and prolonged survival of the tumor bearing mice (n = 5 per group). The mean survival times for solvent- and erlotinib-treated mice were both 17.8 days (95% confidence interval [CI] = 14.3 to 21.3 days), while the mean survival time for ibrutinib-treated mice was 29.8 days (95% CI = 26.0 to 33.6 days, P = .008). Our results indicate that ibrutinib could be a candidate drug for treatment of EGFR-mutant NSCLC, including erlotinib-resistant tumors.
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http://dx.doi.org/10.1093/jnci/dju204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200057PMC
September 2014

A phase I/II study combining erlotinib and dasatinib for non-small cell lung cancer.

Oncologist 2014 Oct 28;19(10):1040-1. Epub 2014 Aug 28.

University of Texas MD Anderson Cancer Center, Houston, Texas, USA;

Background: EGFR and Src are frequently activated in non-small cell lung cancer (NSCLC). In preclinical models, combining EGFR and Src inhibition has additive synergistic effects. We conducted a phase I/II trial of the combination of Src inhibitor dasatinib with EGFR inhibitor erlotinib to determine the maximum tolerated dose (MTD), pharmacokinetic drug interactions, biomarkers, and efficacy in NSCLC.

Methods: The phase I 3+3 dose-escalation study enrolled patients with solid tumors to determine the MTD. The phase II trial enrolled patients with advanced NSCLC who had undergone no previous treatments to determine progression-free survival (PFS) and response. Pharmacokinetic and tissue biomarker analyses were performed.

Results: MTD was 150 mg of erlotinib and 70 mg of dasatinib daily based on 12 patients treated in the phase I portion. No responses were observed in phase I. The 35 NSCLC patients treated in phase II had an overall disease control rate of 59% at 6 weeks. Five patients (15%) had partial responses; all had activating EGFR mutations. Median PFS was 3.3 months. Epithelial-mesenchymal transition markers did not correlate with outcomes.

Conclusion: The combination of erlotinib and dasatinib is safe and feasible in NSCLC. The results of this study do not support use of this combination in molecularly unselected NSCLC.
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http://dx.doi.org/10.1634/theoncologist.2014-0228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201000PMC
October 2014