Publications by authors named "Erin M Bertino"

23 Publications

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Advances in epigenetic therapeutics with focus on solid tumors.

Clin Epigenetics 2021 Apr 20;13(1):83. Epub 2021 Apr 20.

The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA.

Epigenetic ("above genetics") modifications can alter the gene expression without altering the DNA sequence. Aberrant epigenetic regulations in cancer include DNA methylation, histone methylation, histone acetylation, non-coding RNA, and mRNA methylation. Epigenetic-targeted agents have demonstrated clinical activities in hematological malignancies and therapeutic potential in solid tumors. In this review, we describe mechanisms of various epigenetic modifications, discuss the Food and Drug Administration-approved epigenetic agents, and focus on the current clinical investigations of novel epigenetic monotherapies and combination therapies in solid tumors.
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http://dx.doi.org/10.1186/s13148-021-01069-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056722PMC
April 2021

Bone Metastases, Skeletal-Related Events, and Survival in Patients With Metastatic Non-Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitors.

J Natl Compr Canc Netw 2021 Apr 20:1-7. Epub 2021 Apr 20.

3Division of Medical Oncology, and.

Background: Bone metastases and skeletal-related events (SREs) are a frequent cause of morbidity in patients with metastatic non-small cell lung cancer (mNSCLC). Data are limited on bone metastases and SREs in patients with mNSCLC treated using immune checkpoint inhibitors (ICIs), and on the efficacy of bone-modifying agents (BMAs) in this setting. Here we report the incidence, impact on survival, risk factors for bone metastases and SREs, and impact of BMAs in patients with mNSCLC treated with ICIs in a multi-institutional cohort.

Patients And Methods: We conducted a retrospective study of patients with mNSCLC treated with ICIs at 2 tertiary care centers from 2014 through 2017. Overall survival (OS) was compared between patients with and without baseline bone metastases using a log-rank test. A Cox regression model was used to evaluate the association between OS and the presence of bone metastases at ICI initiation, controlling for other confounding factors.

Results: We identified a cohort of 330 patients who had received ICIs for metastatic disease. Median patient age was 63 years, most patients were treated in the second line or beyond (n=259; 78%), and nivolumab was the most common ICI (n=211; 64%). Median OS was 10 months (95% CI, 8.4-12.0). In our cohort, 124 patients (38%) had baseline bone metastases, and 43 (13%) developed SREs during or after ICI treatment. Patients with bone metastases had a higher hazard of death after controlling for performance status, histology, line of therapy, and disease burden (hazard ratio, 1.57; 95% CI, 1.19-2.08; P=.001). Use of BMAs was not associated with OS or a decreased risk of SREs.

Conclusions: Presence of bone metastases at baseline was associated with a worse prognosis for patients with mNSCLC treated with ICI after controlling for multiple clinical characteristics. Use of BMAs was not associated with reduced SREs or a difference in survival.
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http://dx.doi.org/10.6004/jnccn.2020.7668DOI Listing
April 2021

Treatment of Non-Small-Cell Lung Cancer Based on Circulating Cell-Free DNA and Impact of Variation Allele Frequency.

Clin Lung Cancer 2020 Dec 2. Epub 2020 Dec 2.

Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Comprehensive Cancer Center, Columbus, OH.

Background: Next-generation sequencing of circulating cell-free DNA (cfDNA) can identify sensitizing and resistance mutations in non-small-cell lung cancer (NSCLC). cfDNA is helpful when tissue is insufficient for genomic testing or repeat biopsy is not feasible or poses unacceptable risk. Here we report the experience of cfDNA testing at the time of diagnosis and how this intervention can help avoid further invasive interventions, how it can be used to determine initiation of therapy, and how variation allele frequency of the somatic alteration affects response to subsequent treatment.

Patients And Methods: This is a single-institution retrospective study of patients with advanced NSCLC who had cfDNA from plasma tested using the Guardant360 panel, which identifies somatic genomic alterations by massive parallel sequencing of target genes. An institutional Clinical Laboratory Improvement Amendments tissue panel using fluorescence in situ hybridization (for MET, RET, ROS1, and ALK) and next-generation sequencing for selected genes was used for tissue analysis. Actionable mutations are those with US Food and Drug Administration-approved targeted therapies (EGFR, ALK, ROS, BRAF, NTRK fusions) or therapies soon to be approved (RET fusions and MET amplifications, or MET exon 14 skipping mutation).

Results: A total of 163 blood samples from 143 patients were evaluated, 82 at diagnosis and 81 at disease progression. A total of 94 cases had tissue and cfDNA testing performed within 12 weeks of each other. Seventy-six (81%) of 94 cases were concordant, of which 22 cases were concordantly positive and 54 concordantly negative. Eighteen (19%) of 94 cases were discordant, of which 11 had negative blood and positive tissue results, and 7 had positive blood and negative tissue results. cfDNA testing had a sensitivity of 67% (95% confidence interval [CI], 51%, 83%), specificity of 89% (95% CI, 81%, 97%), negative predictive value of 83% (95% CI, 74%, 92%), and positive predictive value of 76% (95% CI, 60%, 91%). Nineteen (21%) of 82 cfDNA samples analyzed at diagnosis had actionable mutations identified (4 EGFR exon 19 deletion, 2 EGFR exon 21 L858R, 2 EGFR L861Q, 1 L861R, 4 EML4-ALK fusion, 2 CD74-ROS1 fusion, 2 MET exon 14 skipping mutation, 2 KIF5B-RET fusion). Of the 82 patients with cfDNA testing performed at the time of diagnosis, 8 patients (10%) initiated targeted therapy on the basis of cfDNA results only, with 6 patients experiencing partial response, 1 patient complete response, and 1 patient stable disease. The response rate for patients who initiated targeted therapies on the basis of cfDNA only at diagnosis was 88%. Variant allele frequency had no impact on response.

Conclusions: Initiation of targeted therapy for advanced NSCLC was feasible based only on identification of actionable mutations by cfDNA testing in 9% of the cases for which tissue diagnosis could not be obtained. Actionable targets were identified by cfDNA in 20% of the samples sent at diagnosis. A substantial number of patients benefited from cfDNA testing at initial diagnosis because it identified actionable mutations that led to appropriate targeted treatments.
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http://dx.doi.org/10.1016/j.cllc.2020.11.007DOI Listing
December 2020

Phase IB Study of Osimertinib in Combination with Navitoclax in -mutant NSCLC Following Resistance to Initial Therapy (ETCTN 9903).

Clin Cancer Res 2021 Mar 29;27(6):1604-1611. Epub 2020 Dec 29.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Osimertinib is an effective therapy in -mutant non-small cell lung cancer (NSCLC), but resistance invariably develops. Navitoclax is an oral inhibitor of BCL-2/BCL-xL that has exhibited synergy with osimertinib in preclinical models of -mutant NSCLC. In hematologic malignancies, BCL-2 family inhibitors in combination therapy effectively increase cellular apoptosis and decrease drug resistance.

Patients And Methods: This single-arm phase Ib study evaluated safety, tolerability, and feasibility of osimertinib and navitoclax, including dose expansion in T790M-positive patients at the recommended phase II dose (RP2D). Eligible patients had advanced -mutant NSCLC with prior tyrosine kinase inhibitor exposure. Five dose levels were planned with osimertinib from 40 to 80 mg orally daily and navitoclax from 150 to 325 mg orally daily.

Results: A total of 27 patients were enrolled (18 in the dose-escalation cohort and nine in the dose-expansion cohort): median age 65, 67% female, 48% exon 19 del, and 37% L858R, median one prior line of therapy. The most common adverse events were lymphopenia (37%), fatigue (22%), nausea (22%), and thrombocytopenia (37%). No dose-limiting toxicities were seen in dose-escalation cohort; osimertinib 80 mg, navitoclax 150 mg was chosen as the RP2D. Most patients (78%) received >95% of planned doses through three cycles. In expansion cohort, objective response rate was 100% and median progression-free survival was 16.8 months. A proapoptotic effect from navitoclax was demonstrated by early-onset thrombocytopenia.

Conclusions: Oral combination therapy with navitoclax and osimertinib was safe and feasible at RP2D with clinical efficacy. Early thrombocytopenia was common, supporting an target engagement by navitoclax. Further study of BCL-2/BCL-xL inhibition to enhance osimertinib activity is warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976451PMC
March 2021

Brief report: inhaled corticosteroid use and the risk of checkpoint inhibitor pneumonitis in patients with advanced cancer.

Cancer Immunol Immunother 2020 Nov 29;69(11):2403-2408. Epub 2020 Jul 29.

Division of Medical Oncology, The Ohio State University, 320 W 10th Ave, Columbus, OH, USA.

Background: Checkpoint inhibitor pneumonitis (CIP) is an immune-related adverse event that may complicate treatment with immune checkpoint inhibitors (ICI) and can cause significant morbidity. We sought to identify predictors for the development of CIP, and whether the use of inhaled corticosteroids (ICS) at time of ICI may be protective.

Methods: Patients with advanced cancer treated with ICI from 2011 and 2018 were included in this study. CIP attribution to ICI was determined by treating physician at time of diagnosis. Predictors were assessed by univariate and multivariable Cox proportional hazard models.

Results: We identified 837 pts treated with ICI, of whom 30 (3.6%) developed grade 2 or higher CIP. 82 patients (9.8%) were receiving ICS at time of ICI and had increased risk of developing CIP with hazard ration (HR) of 4.22 (95% CI 1.93-9.21, p < 0.001) compared to those patients not receiving ICS. Patients with age ≥ 65 years had increased risk of developing CIP (HR 2.12, 95% CI 1.02-4.40, p = 0.044), as did 209 patients with lung cancer (198 NSCLC and 11 SCLC) compared to other types of cancers (HR 3.15, 95% CI 1.54-6.46, p = 0.002). In multivariable analysis, age ≥ 65 years, lung cancer diagnosis, and ICS use remained statistically associated with the development of CIP, with adjusted HR for ICS 3.09 (95% CI 1.32-7.24, p = 0.009).

Conclusions: Patients treated with ICS at time of ICI initiation had an increased risk of developing CIP. We further identified older adults with age ≥ 65 years and lung cancers as independent risk factors for CIP.
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http://dx.doi.org/10.1007/s00262-020-02674-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572636PMC
November 2020

Second cancer incidence in CLL patients receiving BTK inhibitors.

Leukemia 2020 12 23;34(12):3197-3205. Epub 2020 Jul 23.

Department of Internal Medicine, Division of Hematology, Arthur G James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

Chronic lymphocytic leukemia (CLL) is associated with perturbed immune function and increased risk for second primary malignancies (SPM). Ibrutinib and acalabrutinib (BTKi) are effective therapies for CLL resulting in partial restoration of immune function. The incidence of and risk factors for SPM in CLL patients receiving BTKi are not yet characterized. We retrospectively determined the incidence of SPM in CLL patients treated with ibrutinib or acalabrutinib at our institution between 2009 and 2017, assessed for association between baseline characteristics and SPM incidence, and compared the observed to expected cancer incidence among age, sex, and year matched controls without CLL. After a median of 44 months follow-up, 64/691 patients (9%) were diagnosed with SPM (excluding non-melanoma skin cancer [NMSC]). The 3-year cumulative incidence rate was 16% for NMSC and 7% for other SPM. On multivariable analysis, smoking was associated with increased SPM risk (HR 2.8 [95% CI: 1.6-4.8]) and higher baseline CD8 count was associated with lower SPM risk (HR 0.9 for 2-fold increase [95% CI: 0.8-0.9]). The observed over expected rate of SPM was 2.2 [95% CI: 1.7-2.9]. CLL patients treated with BTKi remain at increased risk for SPM, and secondary cancer detection is an important consideration in this population.
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http://dx.doi.org/10.1038/s41375-020-0987-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688551PMC
December 2020

Effect of Erlotinib Plus Bevacizumab vs Erlotinib Alone on Progression-Free Survival in Patients With Advanced EGFR-Mutant Non-Small Cell Lung Cancer: A Phase 2 Randomized Clinical Trial.

JAMA Oncol 2019 Oct;5(10):1448-1455

Biological Sciences Division, University of Chicago Medicine, Chicago, Illinois.

Importance: Erlotinib is a standard first-line therapy for patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Median progression-free survival (PFS) with erlotinib is approximately 10 months.

Objective: To determine whether adding bevacizumab to erlotinib treatment results in superior progression-free survival compared with erlotinib alone.

Design, Setting, And Participants: This phase 2 randomized clinical trial compared erlotinib plus bevacizumab with erlotinib alone in EGFR-mutant NSCLC. The trial was conducted in 17 US academic and community medical centers among 88 patients with EGFR exon 19 deletion or exon 21 L858R mutation based on local testing and stage 4 NSCLC who were eligible for bevacizumab. Patients were enrolled between November 2, 2012, and August 22, 2016, and followed up for a median (range) of 33 (0.7-62.5) months. Data were analyzed on August 28, 2018, and included data from November 2, 2012, to August 20, 2018.

Interventions: Patients were randomized with equal allocation to 150 mg of oral erlotinib daily alone or with 15 mg/kg of intravenous bevacizumab every 3 weeks. Study therapy continued until disease progression, unacceptable adverse event, or withdrawal of consent.

Main Outcomes And Measures: The primary outcome was PFS as assessed by the investigator; secondary outcomes were objective response rate (ORR), adverse events, and overall survival (OS). Analysis was designed to detect a hazard ratio (HR) of 0.667 for PFS (an improvement from a median PFS of 10 to 15 months).

Results: Among 88 patients enrolled, the median (range) age was 63 (31-84) years; 62 patients (70%) were female; 75 (85%) were white, 8 (9%) were African American, 3 (3%) were Asian, and for 2 (2%), data on race were not available. Forty-eight patients (55%) were never smokers, 45 patients (51%) were of Eastern Cooperative Oncology Group performance status 1, and 59 patients (67%) had EGFR exon 19 deletion. Compared with erlotinib, the combination did not result in a significant difference in PFS (HR, 0.81; 95% CI, 0.50-1.31; P = .39; median PFS 17.9 [combination] and 13.5 months [erlotinib]), ORR (81% vs 83%; P = .81), and OS (HR, 1.41; 95% CI, 0.71-2.81; P = .33; median OS, 32.4 months [combination] and 50.6 months [erlotinib]). Adverse events of grade 3 or higher observed in 5 or more patients in the combination and erlotinib arms were skin eruption in 11 (26%) vs 7 (16%) patients, diarrhea in 4 (9%) vs 6 (13%) patients, hypertension in 17 (40%) vs 9 (20%) patients, and proteinuria in 5 (12%) vs 0 (0%) patients.

Conclusions And Relevance: Erlotinib plus bevacizumab compared with erlotinib did not result in a significant improvement in PFS in EGFR-mutant NSCLC.

Trial Registration: ClinicalTrials.gov identifier: NCT01532089.
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http://dx.doi.org/10.1001/jamaoncol.2019.1847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692685PMC
October 2019

Change in neutrophil to lymphocyte ratio during immunotherapy treatment is a non-linear predictor of patient outcomes in advanced cancers.

J Cancer Res Clin Oncol 2019 Oct 31;145(10):2541-2546. Epub 2019 Jul 31.

Division of Medical Oncology, Department of Internal Medicine, Ohio State University Wexner Medical Center, 320 W 10th Ave, A450B Starling Loving Hall, Columbus, OH, 43210, USA.

Background: The neutrophil to lymphocyte ratio (NLR) is known to be prognostic for patients with advanced cancers treated with immune checkpoint inhibitors (ICI), but has generally been evaluated as a single threshold value at baseline. We evaluated NLR at baseline and within first month during treatment in patients who received ICI for advanced cancer to evaluate the prognostic value of baseline and of changes from baseline to on-treatment NLR.

Methods: A retrospective review of patients with advanced cancer treated with ICI from 2011 to 2017 at the Ohio State University was performed. NLR was calculated at the initiation of ICI and repeated at median of 21 days. Overall survival (OS) was calculated from the initiation of ICI to date of death or censored at last follow-up. Significance of Cox proportional hazards models were evaluated by log-rank test. Calculations were performed using the survival and survminer packages in R, and SPSS.

Results: 509 patients were identified and included in the analysis. Patients with baseline and on-treatment NLR < 5 had significantly longer OS (P < 0.001). The change in NLR overtime was a predictor of OS and was observed to be non-linear in nature. This property remained statistically significant with P < 0.05 after adjusting for age, body mass index, sex, cancer type, performance status, and days to repeat NLR measurement. Patients with a moderate decrease in NLR from baseline had the longest OS of 27.8 months (95% CI 21.8-33.8). Patients with significant NLR decrease had OS of 11.4 months (95% CI 6.1-16.7). Patients with a significant increase in NLR had the shortest OS of 5.0 months (95% CI 0.9-9.1).

Conclusions: We confirmed the prognostic value of NLR in patients with advanced cancer treated with ICIs. We found that change in NLR over time is a non-linear predictor of patient outcomes. Patients who had moderate decrease in NLR during treatment with ICI were found to have the longest survival, whereas a significant decrease or increase in NLR was associated with shorter survival. To our knowledge, this is the first study to demonstrate a non-linear change in NLR over time that correlates with survival.
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http://dx.doi.org/10.1007/s00432-019-02982-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751277PMC
October 2019

Homologous recombination and DNA repair mutations in patients treated with carboplatin and nab-paclitaxel for metastatic non-small cell lung cancer.

Lung Cancer 2019 08 17;134:167-173. Epub 2019 Jun 17.

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States.

Objectives: Chemotherapy remains a cornerstone treatment in non-small cell lung cancer either in combination with checkpoint inhibitors or as subsequent therapy. Identifying molecular predictors of response allows for optimal treatment selection. We performed genomic analysis on tumor samples of patients treated with carboplatin and nab-paclitaxel as part of a phase II trial to evaluate the prognostic and predictive value of mutations in DNA repair pathway in patients treated with this regimen.

Materials And Methods: Next-generation sequencing libraries were produced using a capture-based targeted panel covering the coding exons of 278 genes on patients treated on clinical trial NCT00729612. Overall survival (OS) and progression-free survival (PFS) were assessed as part of the clinical outcomes and correlated with mutation analysis.

Results: Of 63 patients enrolled, 25 patients had sufficient and acceptable DNA isolated from archival tumor samples for targeted sequencing. The most commonly altered pathways included DNA repair (DR) including Fanconi anemia and homologous recombination, JAK-STAT signaling, IGF-1, mTOR, and MAPK-ERK. Four patients with mutations in homologous recombination mutations had a shorter PFS (hazard ratio [HR] = 4.54, 95% CI 1.2, 17.1, p = 0.026) and OS (HR = 6.3, 95% CI 1.8, 21.3, p = 0.003).

Conclusion: In this analysis of patients with predominantly squamous cell non-small cell lung cancer treated with carboplatin and nab-paclitaxel in a phase II trial, patients with mutations in homologous recombination pathways had shorter overall and progression-free survival. Validation on additional datasets of patients treated with platinum-based chemotherapy and immunotherapy combinations is warranted.
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http://dx.doi.org/10.1016/j.lungcan.2019.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194132PMC
August 2019

Identifying patterns of care for elderly patients with non-surgically treated stage III non-small cell lung cancer: an analysis of the national cancer database.

Radiat Oncol 2018 Oct 5;13(1):196. Epub 2018 Oct 5.

Department of Radiation Oncology, at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, 460 W. 10th Avenue, Columbus, OH, 43210, USA.

Background: To compare patterns of care for elderly patients versus non-elderly patients with non-surgically treated stage III non-small cell lung cancer (NSCLC) using the National Cancer Database (NCDB). We hypothesize that elderly patients are less likely to receive curative treatments, including concurrent chemoradiation (CCRT), compared to non-elderly patients.

Methods: We identified patients from the NCDB between 2003 and 2014 with non-surgically treated stage III NSCLC. We defined elderly as ≥70 years old and non-elderly <70 years old. Treatment categories included: no treatment, palliative treatment (chemotherapy alone, radiation (RT) alone <59.4 Gy or chemoradiation (CRT) <59.4 Gy), or definitive treatment (RT alone ≥59.4 Gy or CRT ≥59.4 Gy). Differences in treatment between elderly and non-elderly were tested using the χ test.

Results: We identified 57,602 elderly and 55,928 non-elderly patients. More elderly patients received no treatment (24.5% vs. 13.2%, P < 0.0001) and the elderly were less likely to receive definitive treatment (48.5% vs. 56.3%, P < 0.0001). CCRT was delivered in a significantly smaller proportion of elderly vs. non-elderly patients (66.0% vs. 78.9%, P < 0.0001 in patients treated with definitive intent; 32.0% vs. 44.5%, P < 0.0001 in patients receiving any treatment; and 24.2% vs. 38.6%, P < 0.0001 amongst all patients).

Conclusions: In this large study of patients with non-surgically treated stage III NSCLC, elderly patients were less likely to receive any treatment or treatment with definitive intent compared to the non-elderly. The lack of use of concurrent or sequential chemotherapy in the elderly with stage III NSCLC suggests that the optimal treatment approach for this vulnerable population remains undefined.
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http://dx.doi.org/10.1186/s13014-018-1142-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173899PMC
October 2018

Incidence, Risk Factors, and Effect on Survival of Immune-related Adverse Events in Patients With Non-Small-cell Lung Cancer.

Clin Lung Cancer 2018 11 22;19(6):e893-e900. Epub 2018 Aug 22.

Division of Medical Oncology, Ohio State University Wexner Medical Center, James Cancer Hospital and Solove Research Institute, Columbus, OH.

Background: The risk factors for immune-related adverse events (irAEs) remain undefined. Recently, a correlation between irAEs and clinical benefit was suggested. We examined the risk factors for irAEs and their effect on survival in patients with non-small-cell lung cancer (NSCLC) who had received immunotherapy.

Patients And Methods: We performed a retrospective review of patients with NSCLC treated with single-agent immunotherapy at our institution. irAEs were determined by treating physician diagnosis. A landmark analysis was performed at 3 months using log-rank tests and the Bonferroni method.

Results: irAEs occurred in 27 of 91 patients (30%). The median overall survival (OS) for patients with irAEs was longer than that for patients without (24.3 vs. 5.3 months; hazard ratio, 2.75; 95% confidence interval, 1.54-4.92; P < .001). However, a landmark analysis of patients after 3 months of treatment revealed no difference in OS between patients with and without irAEs. No increased risk of pneumonitis was seen in patients with previous thoracic radiotherapy, although these patients had shorter survival (4.2 vs. 9.7 months; P = .004). Radiotherapy after the initiation of immunotherapy (n = 15) did not increase the risk of irAEs or pneumonitis; however, these patients had improved OS (17.3 vs. 6.0 months; P = .016).

Conclusion: The development of irAEs did not significantly correlate with survival when controlling for the duration of therapy in a landmark analysis. We found no increased risk of pneumonitis or irAEs in patients who had received radiotherapy. Radiotherapy before immunotherapy was associated with shorter survival, and radiotherapy after immunotherapy was associated with improved survival.
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http://dx.doi.org/10.1016/j.cllc.2018.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193681PMC
November 2018

The Addition of Chemotherapy to Radiation Therapy Improves Survival in Elderly Patients with Stage III Non-Small Cell Lung Cancer.

J Thorac Oncol 2018 03 8;13(3):426-435. Epub 2018 Jan 8.

Department of Radiation Oncology, The Ohio State University, Columbus, Ohio. Electronic address:

Introduction: Elderly patients account for the majority of lung cancer diagnoses but are poorly represented in clinical trials. We evaluated the overall survival (OS) of elderly patients with stage III NSCLC treated with definitive radiation compared with that of patients treated with definitive chemoradiation.

Methods: We conducted a comparative effectiveness study of radiation therapy versus chemoradiation in elderly (≥70 years old) patients with stage III NSCLC not treated surgically diagnosed from 2003 to 2014; the patients were identified by using the National Cancer Database. Two cohorts were evaluated: patients (n = 5023) treated with definitive radiation (≥59.4 Gy) and patients (n = 18,206) treated with definitive chemoradiation. Chemoradiation was further defined as concurrent (radiation and chemotherapy started within 30 days of each other) or sequential (radiation started >30 days after chemotherapy). We compared OS between the treatment groups by using the Kaplan-Meier method and Cox proportional hazards regression before and after propensity score matching (PSM).

Results: Treatment with chemoradiation was associated with improved OS versus that with radiation both before PSM (hazard ratio [HR] = 0.66, 95% confidence interval [CI]: 0.64-0.68, p < 0.001) and after PSM (HR = 0.67, 95% CI: 0.64-0.70, p < 0.001). Relative to concurrent chemoradiation, sequential chemoradiation was associated with a 9% reduction in the risk for death (HR = 0.91, 95% CI: 0.85-0.96, p = 0.002).

Conclusions: We found that definitive chemoradiation resulted in a survival advantage compared with definitive radiation in elderly patients. Sequential chemotherapy and radiation was superior to concurrent chemoradiation. Although prospective trials are needed, this analysis suggests that chemoradiation should be strongly considered for elderly patients and the optimal sequencing of chemotherapy and radiation remains an unanswered question for this patient population.
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http://dx.doi.org/10.1016/j.jtho.2017.11.135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910031PMC
March 2018

Lung Cancer Patients with Germline Mutations Detected by Next-Generation Sequencing and/or Liquid Biopsy.

J Thorac Oncol 2018 02 5;13(2):e17-e19. Epub 2017 Oct 5.

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2017.09.1962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910030PMC
February 2018

Tumor spread through air space (STAS) is an important predictor of clinical outcome in stage IA lung adenocarcinoma.

J Thorac Dis 2017 Aug;9(8):2283-2285

The James Cancer Hospital and Solove Research Institute, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.

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http://dx.doi.org/10.21037/jtd.2017.07.69DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594112PMC
August 2017

Relationship between Overall Survival and Response or Progression-Free Survival in Advanced Non-Small Cell Lung Cancer Patients Treated with Anti-PD-1/PD-L1 Antibodies.

J Thorac Oncol 2016 11 3;11(11):1927-1939. Epub 2016 Aug 3.

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio. Electronic address:

Introduction: Alternative predictive end points for overall survival (OS), such as tumor response and progression-free survival (PFS), are useful in the early detection of drug efficacy; however, they have not been fully investigated in patients with advanced NSCLC treated with anti-programmed death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) antibodies.

Methods: In a systematic review of the reported prospective clinical trials, data for response rate, median PFS, and median OS were extracted from 12 arms in 10 reported clinical trials using anti-PD-1/PD-L1 antibody, and their correlation was investigated. In a retrospective analysis at our institution, OS was compared according to tumor response on 5- to 9-week computed tomography scans and status of being progression-free at 8, 16, and 24 weeks by landmark analysis in 71 patients with advanced NSCLC treated with anti-PD-1/PD-L1 antibodies between 2013 and 2015.

Results: In a systematic review, moderate correlations between median OS and median PFS (p = 0.120, r = 0.473) and between median OS and response rate (p = 0.141, r = 0.452) were identified using the Spearman correlation coefficient, although these correlations were not statistically significant. In a retrospective analysis of patients treated at our institution, disease control (partial response [PR]/stable disease versus progressive disease/not evaluable), and progression-free status at 8, 16, and 24 weeks significantly predicted OS (Cox proportional hazards model, PR/stable disease versus progressive disease/not evaluable, p = 0.0104, HR = 3.041; 8-week progression-free yes versus no, p = 0.0183, HR = 2.684; 16-week progression-free yes versus no, p = 0.0036, HR = 4.009; and 24-week progression-free yes versus no, p = 0.0002, HR = 12.726).

Conclusions: Both disease control (PR plus stable disease status) and landmark progression-free survival were correlated with OS, with the longer interval landmark PFS being the best predictor of survival in patients with NSCLC treated with anti-PD-1/PD-L1 antibodies.
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http://dx.doi.org/10.1016/j.jtho.2016.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086375PMC
November 2016

A Phase I Trial to Evaluate Antibody-Dependent Cellular Cytotoxicity of Cetuximab and Lenalidomide in Advanced Colorectal and Head and Neck Cancer.

Mol Cancer Ther 2016 09 25;15(9):2244-50. Epub 2016 Jul 25.

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.

mAbs can induce antibody-dependent cellular cytotoxicity (ADCC) via the innate immune system's ability to recognize mAb-coated cancer cells and activate immune effector cells. Lenalidomide is an immunomodulatory agent with the capacity to stimulate immune cell cytokine production and ADCC activity. This phase I trial evaluated the combination of cetuximab with lenalidomide for the treatment of advanced colorectal and head and neck squamous cell cancers (HNSCC). This trial included patients with advanced colorectal cancer or HNSCC. Treatment consisted of cetuximab 500 mg/m(2) i.v. every two weeks with lenalidomide given orally days 1-21 on a 28-day cycle. Three dose levels of lenalidomide were evaluated (15, 20, 25 mg). Correlative studies included measurement of ADCC, FcγRIIIA polymorphism genotyping, measurement of serum cytokine levels, and flow cytometric analysis of immune cell subtypes. Twenty-two patients were enrolled (19 colorectal cancer, 3 HNSCC). Fatigue was the only dose-limiting toxicity. One partial response was observed and 8 patients had stable disease at least 12 weeks. The recommended phase II dose is cetuximab 500 mg/m(2) with lenalidomide 25 mg daily, days 1-21. Correlative studies demonstrated a dose-dependent increase in natural killer cytotoxic activity with increasing doses of lenalidomide. Cetuximab and lenalidomide were well tolerated. There was a lenalidomide dose-dependent increase in ADCC with higher activity in patients enrolled in cohort 3 than those enrolled in cohorts 1/2. Although response was not a primary endpoint, there was evidence of antitumor activity for the combination therapy. Further investigation of lenalidomide as an immunomodulator in solid tumors is warranted. Mol Cancer Ther; 15(9); 2244-50. ©2016 AACR.
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http://dx.doi.org/10.1158/1535-7163.MCT-15-0879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805142PMC
September 2016

Stromal Caveolin-1 Is Associated With Response and Survival in a Phase II Trial of nab-Paclitaxel With Carboplatin for Advanced NSCLC Patients.

Clin Lung Cancer 2015 Nov 13;16(6):466-74. Epub 2015 May 13.

Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Columbus, OH. Electronic address:

Unlabelled: In this phase II trial, carboplatin with nanoparticle albumin-bound (nab)-paclitaxel as first-line therapy for advanced non-small-cell lung cancer (NSCLC) was evaluated. Most patients had squamous cell histology. Tumor-associated stromal caveolin-1 (Cav-1) expression was correlated with improved response rate and survival in NSCLC patients who received nab-paclitaxel in this phase II trial. These results suggest Cav-1 might serve as a potential biomarker in this patient population.

Background: The combination of bevacizumab with platinum-based chemotherapy results in greater response rate (RR) and overall survival (OS) in advanced non-small-cell lung cancer (NSCLC). Bevacizumab is contraindicated in patients with squamous histology or hemoptysis. Nanoparticle albumin-bound (nab)-paclitaxel is a novel formulation of paclitaxel with greater dose tolerance and improved efficacy. We hypothesized that nab-paclitaxel and carboplatin would be superior to alternative doublets in advanced NSCLC patients ineligible for bevacizumab.

Patients And Methods: We conducted a single-arm phase II trial (NCT00729612) with carboplatin and nab-paclitaxel on day 1 of a 21-day cycle to evaluate RR (primary end point), safety, toxicity, and OS. Eligibility included: squamous histology, hemoptysis, or ongoing anticoagulation. Correlative studies included immunohistochemistry for secreted protein acid rich in cysteine (SPARC) and caveolin-1 (Cav-1).

Results: Sixty-three patients were enrolled. Most patients had squamous cell carcinoma (n = 48); other reasons for eligibility included hemoptysis (n = 11) and anticoagulation (n = 2). Toxicity Grade ≥ 3/4 included neuropathy, cytopenias, and fatigue. RR was 38% (24 partial response/0 complete response); 20 patients had stable disease (32%). Median progression-free survival was 5 months and median OS was 9.7 months. Immunohistochemistry for SPARC and Cav-1 was performed in 38 and 37 patients respectively. Although no association was found for SPARC expression in tumor or stroma with RR or OS, we found that higher Cav-1 levels in tumor-associated stroma was associated with improved RR and OS.

Conclusion: Carboplatin and nab-paclitaxel every 21 days demonstrated promising efficacy with tolerable toxicity in NSCLC patients ineligible for bevacizumab therapy. Further analysis and validation of Cav-1 and SPARC expression in tumor and stromal compartments as prognostic and/or predictive biomarkers of NSCLC or nab-paclitaxel treatment is warranted.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5076571PMC
http://dx.doi.org/10.1016/j.cllc.2015.05.004DOI Listing
November 2015

Consensus guidelines for the management and treatment of neuroendocrine tumors.

Pancreas 2013 May;42(4):557-77

Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305-5826, USA

Neuroendocrine tumors are a heterogeneous group of tumors originating in various anatomic locations. The management of this disease poses a significant challenge because of the heterogeneous clinical presentations and varying degrees of aggressiveness. The recent completion of several phase 3 trials, including those evaluating octreotide, sunitinib, and everolimus, demonstrate that rigorous evaluation of novel agents in this disease is possible and can lead to practice-changing outcomes. Nevertheless, there are many aspects to the treatment of neuroendocrine tumors that remain unclear and controversial. The North American Neuroendocrine Tumor Society published a set of consensus guidelines in 2010, which provided an overview for the treatment of patients with these malignancies. Here, we present a set of consensus tables intended to complement these guidelines and serve as a quick, accessible reference for the practicing physician.
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http://dx.doi.org/10.1097/MPA.0b013e31828e34a4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304762PMC
May 2013

A phase II study of modulated-capecitabine and docetaxel in chemonaive patients with advanced non-small cell lung cancer (NSCLC).

Lung Cancer 2013 Jan 16;79(1):27-32. Epub 2012 Oct 16.

The Ohio State University Wexner Medical Center, Department of Internal Medicine, Division of Medical Oncology, Columbus, OH, USA.

Introduction: This phase II single-arm trial of docetaxel and capecitabine in previously untreated non-small cell lung cancer (NSCLC) patients was designed to evaluate response rate of this regimen based on promising efficacy data from phase II testing in pre-treated NSCLC patients. The trial also evaluated the correlation between peripheral blood dihydropyrimidine dehydrogenase (DPD) expression and efficacy/toxicity.

Methods: Patients with advanced NSCLC (metastatic, including malignant pleural effusion) without prior chemotherapy were enrolled. Baseline DPD screening was performed; patients with baseline DPD level < 0.07 nmol/min/mg protein were considered ineligible for the study. Treatment included a 28-day cycle of docetaxel 36 mg/m(2) on days 1, 8, 15 and capecitabine 1250 mg/m(2)/day in divided doses on days 5-18. Overall response rate (RR) was the primary endpoint with a target RR of 50%. Correlative studies included evaluation of DPD activity levels in peripheral blood and correlation with clinical responses.

Results: Twenty-eight patients received 86 cycles of treatment (median 3 cycles) and were evaluable for response. The RR was 18% (5 patients); RR did not meet the pre-specified efficacy endpoint and the trial was stopped. 14 patients had stable disease (SD - 50%) and 4 patients had SD >12 weeks. Median time to progression was 3.3 months (95% CI 1.5-4.6 months). Median overall survival was 10.5 months (95% CI: 3.2-15 months). Main toxicities included fatigue, stomatitis and leukopenia. DPD levels ranged from 0.06 to 0.26 nmol/min/mg. The majority of responders (4/5) had DPD levels ≤0.1 nmol/min/mg. Most of the responders (4/5) experienced grade 3 toxicities including leukopenia, dehydration, fatigue, and diarrhea. None of the patients (0/4) with higher DPD levels (> 0.2 nmol/min/mg) had a response.

Conclusion: The response rate for the regimen did not demonstrate sufficient activity and further study of this regimen in this setting is not indicated. Interestingly, the results suggest that low DPD expression may be associated with response to capecitabine but also with increased toxicity.
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http://dx.doi.org/10.1016/j.lungcan.2012.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549571PMC
January 2013

Romidepsin: a novel histone deacetylase inhibitor for cancer.

Expert Opin Investig Drugs 2011 Aug 24;20(8):1151-8. Epub 2011 Jun 24.

The Ohio State University, Comprehensive Cancer Center, Department of Internal Medicine, Columbus, USA.

Introduction: Romidepsin is a novel histone deacetylase (HDAC) inhibitor, with a recent approval for treatment of cutaneous T-cell lymphoma (CTCL). HDAC inhibitors represent a novel approach to anti-tumor therapy. In contrast to traditional cytotoxic chemotherapy, HDAC inhibitors target underlying epigenetic changes leading to malignant transformation. Further study of romidepsin and similar agents in solid and hematologic malignancies is ongoing.

Areas Covered: This review discusses the development of romidepsin, its mechanism of action, pivotal clinical trials, drug toxicity and its recent approval for CTCL treatment. Key clinical trials covered include Phase I/II testing of romidepsin in solid and hematologic malignancies. In addition, the Phase II trial in CTCL leading to FDA approval of romidepsin is reviewed in detail. Literature search was performed using PubMed; keywords and concepts used included romidepsin, T-cell lymphoma and HDAC inhibitors.

Expert Opinion: Romidepsin is a potent HDAC inhibitor with demonstrable activity in T-cell lymphoma. In contrast to vorinostat, romidepsin is approved as second-line therapy. Current approval only includes CTCL; promising results have been demonstrated in Phase II testing of peripheral T-cell lymphoma subtypes. Future directions include expanded indications in T-cell lymphomas as well as novel combinations with other HDAC inhibitors and other therapeutic agents.
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http://dx.doi.org/10.1517/13543784.2011.594437DOI Listing
August 2011

Benefits and limitations of antiangiogenic agents in patients with non-small cell lung cancer.

Lung Cancer 2010 Dec;70(3):233-46

Department of Internal Medicine, Division of Hematology-Oncology, The Ohio State University Medical Center, 320 West 10th Avenue, Columbus 43210, OH, United States.

Lung cancer is one of the most common cancers and, unfortunately, the most deadly. Most patients present either with locally advanced or metastatic disease or develop disease recurrence after local therapies. For these patients, chemotherapy has been the primary treatment but often yields less than optimal results. Recent advances in targeted therapies have raised the promise of improved outcomes for patients. In particular, angiogenesis has been identified as a viable target. Several approaches have been developed, including monoclonal antibodies and tyrosine kinase inhibitors against angiogenic growth factors, particularly vascular endothelial growth factor, and novel vascular disrupting agents. In this review, the role of these antiangiogenic agents in patients with non-small cell lung cancer will be discussed, with an emphasis on bevacizumab and other agents under development and clinical testing (i.e., tyrosine kinase inhibitors and vascular disrupting agents).
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http://dx.doi.org/10.1016/j.lungcan.2010.08.018DOI Listing
December 2010

Ixabepilone as monotherapy or in combination for the treatment of advanced breast cancer.

Breast Cancer (Dove Med Press) 2010 May 24;2:13-23. Epub 2010 May 24.

Department of Internal Medicine, Division of Hematology-Oncology, The Ohio State University Medical Center, Columbus, Ohio, USA.

Advanced breast cancer represents a therapeutic challenge for oncologists. Chemotherapy with anthracyclines and taxanes has improved survival in this setting, but resistant and refractory disease is common. Ixabepilone, an epothilone, is a recently approved chemotherapeutic agent, both as a single agent and in combination with capecitabine, with efficacy in patients with resistant advanced disease. In this review, the distinctive properties of this drug are discussed, as well as the clinical evidence of efficacy. Ongoing clinical trials are exploring the role of ixabepilone in several clinical settings: neoadjuvant, adjuvant, and novel combinations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3846877PMC
http://dx.doi.org/10.2147/bctt.s5430DOI Listing
May 2010

Pulmonary neuroendocrine/carcinoid tumors: a review article.

Cancer 2009 Oct;115(19):4434-41

Department of Internal Medicine, Ohio State University College of Medicine, Columbus, Ohio, USA.

Neuroendocrine tumors are a unique malignant neoplasm that can arise from the respiratory tree. Although well-differentiated bronchial neuroendocrine tumors (also called carcinoid tumors) are reported to account for approximately 25% of all neuroendocrine tumors, they represent only 1% to 2% of all lung cancers. The epidemiology, clinical behavior, and treatment of neuroendocrine carcinoid tumors differ significantly from other lung malignancies. In this article, the recent data regarding these tumors were reviewed with attention to the treatment modalities used. Although conventional cytotoxic therapy has not been reported to demonstrate much promise in this entity over the past 4 decades, newer molecular targeted agents including those that targeted angiogenesis and the mammalian target of rapamycin (mTOR) pathway have shown encouraging results in early phase trials for advanced carcinoid tumors.
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http://dx.doi.org/10.1002/cncr.24498DOI Listing
October 2009