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ABSTRACT: BACKGROUND:: Genomic testing to identify driver mutations that enable targeted therapy is emerging for patients with non-small-cell lung cancer (NSCLC). We report the implementation of systematic prospective genotyping for somatic alterations in BRAF, PIK3CA, HER2, and ALK, in addition to EGFR and KRAS, in NSCLC patients at the Dana-Farber Cancer Institute. METHODS:: Patients with NSCLC were prospectively referred by their providers for clinical genotyping. Formalin-fixed, paraffin embedded tumor samples were analyzed by Sanger sequencing for mutations in selected exons of EGFR, KRAS, BRAF, PIK3CA, and HER2. ALK rearrangements were detected by fluorescence in situ hybridization or immunohistochemistry. RESULTS:: Between July 1, 2009 and August 1, 2010, 427 specimens from 419 patients were referred for genomic characterization; 344 (81%) specimens were successfully genotyped with a median turnaround time of 31 days (range, 9-155). Of the 344 specimens, 185 (54%) had at least one identifiable somatic alteration (KRAS: 24%, EGFR: 17%, ALK: 5%, BRAF: 5%, HER2: 4%, PIK3CA: 2%). As of August 1, 2011, 63 of 288 advanced NSCLC patients (22%) had received molecularly targeted therapy based on their genotypic results, including 34 of 42 patients (81%) with EGFR mutations, 12 of 15 (80%) with ALK rearrangements, and 17 of 95 (18%) with KRAS, BRAF, or HER2 mutations. CONCLUSIONS:: Large-scale testing for somatic alterations in EGFR, KRAS, BRAF, PIK3CA, HER2, and ALK is feasible and impacts therapeutic decisions. As the repertoire for personalized therapies expands in lung cancer and other malignancies, there is a need to develop new genomics technologies that can generate a comprehensive genetic profile of tumor specimens in a time- and cost-effective manner.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 12/2012; 7(12):1767-1774. · 4.55 Impact Factor
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ABSTRACT: This retrospective study was undertaken to investigate the impact of initial gefitinib or erlotinib (EGFR tyrosine kinase inhibitor, EGFR-TKI) versus chemotherapy on the risk of central nervous system (CNS) progression in advanced non-small cell lung cancer (NSCLC) with EGFR mutations.
Patients with stage IV or relapsed NSCLC with a sensitizing EGFR mutation initially treated with gefitinib, erlotinib, or chemotherapy were identified. The cumulative risk of CNS progression was calculated using death as a competing risk.
One hundred and fifty-five patients were eligible (EGFR-TKI: 101, chemotherapy: 54). Twenty-four patients (24%) in the EGFR-TKI group and 12 patients (22%) in the chemotherapy group had brain metastases at the time of diagnosis of advanced NSCLC (P = 1.000); 32 of the 36 received CNS therapy before initiating systemic treatment. Thirty-three patients (33%) in the EGFR-TKI group and 26 patients (48%) in the chemotherapy group developed CNS progression after a median follow-up of 25 months. The 6-, 12-, and 24-month cumulative risk of CNS progression was 1%, 6%, and 21% in the EGFR-TKI group compared with corresponding rates of 7%, 19%, and 32% in the chemotherapy group (P = 0.026). The HR of CNS progression for upfront EGFR-TKI versus chemotherapy was 0.56 [95% confidence interval (CI), 0.34-0.94].
Our data show lower rates of CNS progression in EGFR-mutant advanced NSCLC patients initially treated with an EGFR-TKI compared with upfront chemotherapy. If validated, our results suggest that gefitinib and erlotinib may have a role in the chemoprevention of CNS metastases from NSCLC.
Clinical Cancer Research 06/2012; 18(16):4406-14. · 7.74 Impact Factor
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Samuel J Aronson,
Eugene H Clark,
Lawrence J Babb,
Samantha Baxter,
Lisa M Farwell,
Birgit H Funke,
Amy Lovelette Hernandez, Victoria A Joshi,
Elaine Lyon,
Andrew R Parthum,
Franklin J Russell,
Matthew Varugheese,
Thomas C Venman,
Heidi L Rehm
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ABSTRACT: The future of personalized medicine will hinge on effective management of patient genetic profiles. Molecular diagnostic testing laboratories need to track knowledge surrounding an increasingly large number of genetic variants, incorporate this knowledge into interpretative reports, and keep ordering clinicians up to date as this knowledge evolves. Treating clinicians need to track which variants have been identified in each of their patients along with the significance of these variants. The GeneInsight(SM) Suite assists in these areas. The suite also provides a basis for interconnecting laboratories and clinicians in a manner that increases the scalability of personalized medicine processes.
Human Mutation 02/2011; 32(5):532-6. · 5.69 Impact Factor
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ABSTRACT: A small subset of patients with nonsmall cell lung cancer (NSCLC) harbors mutations in the epidermal growth factor receptor (EGFR) that predict unique sensitivity to EGFR tyrosine kinase inhibitors (TKIs). The characteristics and behavior of brain metastases (BMs) in these patients have not been well described. The longitudinal records of all NSCLC patients who underwent EGFR mutation screening at our center from August 2004 to November 2008 were reviewed for eligibility, and 93 patients were identified who developed BM during the course of their disease. Survival was estimated using the Kaplan-Meier method and the log-rank test. Multivariable predictors were assessed via the Cox proportional hazards model. Among the 93 patients with BM, 41 (44%) had mutations in EGFR, including 13 exon 19 deletions and 12 L858R mutations. Eighty-three percent of patients with BM were treated initially with whole brain radiation, either alone (53%) or in combination with craniotomy for neurosurgical resection (22%) or stereotactic radiosurgery (8%). Median survival from the time of BM was 11.7 months and was longer for patients with an EGFR mutation (14.5 vs 7.6 months, P = .09). On multivariable analysis, EGFR mutation (HR: 0.50, 95% CI: 0.30-0.82), age (HR: 1.03, 95% CI: 1.00-1.05), and active extracranial disease (HR: 3.30, 95% CI: 1.70-6.41) were independently associated with survival. In NSCLC patients with BM, EGFR mutation status is associated with improved survival, independent of age, functional status, extracranial disease status, and number of BMs.
Neuro-Oncology 11/2010; 12(11):1193-9. · 5.72 Impact Factor
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Serena Masciari, Victoria A. Joshi,
Rowena Mercado,
Jennifer L. Walsh,
Noralane M. Lindor,
Steven Gallinger,
John Hopper,
John D. Potter,
Robert W. Haile,
Raju Kucherlapati,
Sapna Syngal
Gastroenterology 01/2010; 138(5). · 11.68 Impact Factor
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Ion C Cirstea,
Kerstin Kutsche,
Radovan Dvorsky,
Lothar Gremer,
Claudio Carta,
Denise Horn,
Amy E Roberts,
Francesca Lepri,
Torsten Merbitz-Zahradnik,
Rainer König, [......],
Cristina Digilio,
Liborio Stuppia,
Eva Seemanova,
Len A Pennacchio,
Bruce D Gelb,
Bruno Dallapiccola,
Alfred Wittinghofer,
Mohammad R Ahmadian,
Marco Tartaglia,
Martin Zenker
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ABSTRACT: Noonan syndrome, a developmental disorder characterized by congenital heart defects, reduced growth, facial dysmorphism and variable cognitive deficits, is caused by constitutional dysregulation of the RAS-MAPK signaling pathway. Here we report that germline NRAS mutations conferring enhanced stimulus-dependent MAPK activation account for some cases of this disorder. These findings provide evidence for an obligate dependency on proper NRAS function in human development and growth.
Nature Genetics 12/2009; 42(1):27-9. · 35.53 Impact Factor
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ABSTRACT: Dideoxy DNA sequencing is routinely used in research and, increasingly, in clinical care for the detection of DNA sequence
variants, single nucleotide changes, or small insertions or deletions, when the spectrum of DNA variation is unknown. DNA
sequence variation can be present in tumor tissue that is not present in the normal tissue from the same individual. This
somatic DNA sequence variation is often the cause of abnormal cell growth and/or regulation and, ultimately, tumorigenesis.
Identification of these oncogenic DNA sequence variants has successfully led to the development of cancer therapies, since
the abnormal protein products created from genomic DNA containing mutations can serve as targets for pharmacologic inhibition.
Somatic DNA sequence analysis will continue to be a valuable technique for biomarker discovery until the complete spectrum
of DNA variation observed in tumor tissue is understood.
KeywordsTumor–Sequencing–Cancer–Biomarker discovery–Sanger
04/2009: pages 205-220;
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ABSTRACT: Somatic mutations in the epidermal growth factor receptor (EGFR) are present in approximately 10% of nonsmall cell lung cancers, and higher in never-smokers, women, and Asians. Small in-frame deletions in exon 19 ( approximately 45%) and L858R mutation in exon 21 ( approximately 40%) predict response to treatment with tyrosine kinase inhibitors, whereas some others herald resistance. Direct sequencing of tumor DNA detects all EGFR mutations, but is limited by interference from nonmalignant cells within the samples. Concern over such interference has discouraged testing cytologic samples, but the adequacy of cytologic specimens for EGFR sequencing has not been studied.
EGFR sequencing of surgical and cytologic specimens at Brigham and Women's Hospital over the past 2 years was reviewed. Of 239 specimens, 227 (95%) were surgical, and 12 (5%) were cytologic (fine needle aspirations, pleural fluids, bronchial washings, and bronchoalveolar lavages).
Sixty-three (28%) surgical specimens showed EGFR mutations, whereas 143 (63%) were negative, 8 (3.5%) failed, and 14 (6.2%) were inconclusive (negative result in a heterogeneous sample). Seven (58%) cytologic specimens showed EGFR mutations, whereas 4 (33%) were negative, and 1 (8.3%) was inconclusive. Cytologic specimens were more likely to have a mutation than surgical specimens (P = .02). There was no significant difference in the frequency of inconclusive results.
Cytologic specimens are suitable for EGFR sequencing and show comparable sensitivity for mutation detection as compared with surgical specimens. The suitability of a sample should be determined on a case-by-case basis, and cytologic samples should not be dismissed as inadequate without a thorough review.
Cancer 03/2009; 117(1):67-72. · 4.77 Impact Factor
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ABSTRACT: Dideoxy DNA sequencing is routinely used in research and, increasingly, in clinical care for the detection of DNA sequence variants, single nucleotide changes, or small insertions or deletions, when the spectrum of DNA variation is unknown. DNA sequence variation can be present in tumor tissue that is not present in the normal tissue from the same individual. This somatic DNA sequence variation is often the cause of abnormal cell growth and/or regulation and, ultimately, tumorigenesis. Identification of these oncogenic DNA sequence variants has successfully led to the development of cancer therapies, since the abnormal protein products created from genomic DNA containing mutations can serve as targets for pharmacologic inhibition. Somatic DNA sequence analysis will continue to be a valuable technique for biomarker discovery until the complete spectrum of DNA variation observed in tumor tissue is understood.
Methods in molecular biology (Clifton, N.J.) 02/2009; 520:205-20.
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Gastroenterology 06/2008; 134(5):1284-8. · 11.68 Impact Factor
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Lecia V Sequist,
Renato G Martins,
David Spigel,
Steven M Grunberg,
Alexander Spira,
Pasi A Jänne, Victoria A Joshi,
David McCollum,
Tracey L Evans,
Alona Muzikansky,
Georgiana L Kuhlmann,
Moon Han,
Jonathan S Goldberg,
Jeffrey Settleman,
A John Iafrate,
Jeffrey A Engelman,
Daniel A Haber,
Bruce E Johnson,
Thomas J Lynch
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ABSTRACT: Somatic mutations in the epidermal growth factor receptor (EGFR) correlate with increased response in patients with non-small-cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs). The multicenter iTARGET trial prospectively examined first-line gefitinib in advanced NSCLC patients harboring EGFR mutations and explored the significance of EGFR mutation subtypes and TKI resistance mechanisms.
Chemotherapy-naïve patients with advanced NSCLC with >or= 1 clinical characteristic associated with EGFR mutations underwent direct DNA sequencing of tumor tissue EGFR exons 18 to 21. Patients found to harbor any EGFR mutation were treated with gefitinib 250 mg/d until progression or unacceptable toxicity. The primary outcome was response rate.
Ninety-eight patients underwent EGFR screening and mutations were detected in 34 (35%). EGFR mutations were primarily exon 19 deletions (53%) and L858R (26%) though 21% of mutation-positive cases had less common subtypes including exon 20 insertions, T790M/L858R, G719A, and L861Q. Thirty-one patients received gefitinib. The response rate was 55% (95% CI, 33 to 70) and median progression-free survival was 9.2 months (95% CI, 6.2 to 11.8). Therapy was well tolerated; 13% of patients had grade 3 toxicities including one grade 3 pneumonitis. Two patients with classic activating mutations exhibited de novo gefitinib resistance and had concurrent genetic anomalies usually associated with acquired TKI resistance, specifically the T790M EGFR mutation and MET amplification.
First-line therapy with gefitinib administered in a genotype-directed fashion to patients with advanced NSCLC harboring EGFR mutations results in very favorable clinical outcomes with good tolerance. This strategy should be compared with combination chemotherapy, the current standard of care.
Journal of Clinical Oncology 05/2008; 26(15):2442-9. · 18.37 Impact Factor
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ABSTRACT: New mutation detection technologies must keep pace by becoming more cost-effective while offering improved technical sensitivity and higher throughput capacity. In recent years, the number of mutation detection platforms available to the clinical researcher has grown to a point where it is difficult to keep track of all available options as well as their benefits and pitfalls. This unit provides an entry point for a variety of researchers who wish to analyze samples for known or novel mutations and need to determine which platform is most suited for their particular needs. A practical guide is provided in this unit, including a brief overview, information on assay parameters, design and cost considerations, as well as platform flexibility and scalability of the assay. Although the focus here is on applications involving human disease, many of these platforms can be easily adapted to the study of other organisms.
Current protocols in human genetics / editorial board, Jonathan L. Haines ... [et al.] 02/2008; Chapter 7:Unit 7.15.
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ABSTRACT: Epidermal growth factor receptor (EGFR)-targeted therapies have demonstrated variable success in treating individuals with non-small-cell lung cancer. Understanding the molecular mechanisms of response and resistance to this class of treatment has led to patient selection strategies that may improve outcomes. The second generation of EGFR-targeted therapies is now under clinical evaluation and may prove to be successful at circumventing a portion of primary or acquired resistance to first-generation tyrosine kinase inhibitors. These principles are generally applicable to the field of targeted therapy and predictive pharmacogenomics.
Pharmacogenomics 10/2007; 8(9):1211-20. · 3.97 Impact Factor
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ABSTRACT: Somatic mutations in the epidermal growth factor receptor gene (EGFR) are detected in a subset of lung adenocarcinomas, particularly bronchioloalveolar carcinoma (BAC) and adenocarcinoma with bronchioloalveolar features (AWBF), and correlate with clinical response to tyrosine kinase inhibitors (TKIs). In contrast, lung adenocarcinomas refractory to TKIs often have activating mutations in KRAS but lack EGFR mutations. Some adenocarcinomas have mucinous histology, but the clinical and molecular significance of the mucinous pattern is less well studied. We analyzed 43 BAC and AWBF tumors submitted for EGFR mutation testing to identify histopathological features that predicted EGFR or KRAS mutations. EGFR mutations were detected in 14 of 30 (47%) nonmucinous tumors, whereas 0 of 13 mucinous tumors harbored an EGFR mutation (P = 0.003). Missense mutations in KRAS codon 12 were detected in six of seven (86%) mucinous adenocarcinomas but only 3 of 18 (17%) nonmucinous adenocarcinomas (P = 0.003). Thus, in BAC/AWBF mucinous differentiation was significantly correlated with the absence of EGFR mutation and presence of KRAS mutation, suggesting that mucinous BACs/AWBFs are unlikely to respond to TKIs. Therefore, our data suggest that EGFR sequence analysis could be avoided in BAC/AWBF when true mucinous morphology is identified, avoiding the associated testing costs.
Journal of Molecular Diagnostics 08/2007; 9(3):320-6. · 3.58 Impact Factor
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Amy E Roberts,
Toshiyuki Araki,
Kenneth D Swanson,
Kate T Montgomery,
Taryn A Schiripo, Victoria A Joshi,
Li Li,
Yosuf Yassin,
Alex M Tamburino,
Benjamin G Neel,
Raju S Kucherlapati
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ABSTRACT: Noonan syndrome, the most common single-gene cause of congenital heart disease, is characterized by short stature, characteristic facies, learning problems and leukemia predisposition. Gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase SHP2, cause approximately 50% of Noonan syndrome cases. SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and Noonan syndrome mutants enhance ERK activation ex vivo and in mice. KRAS mutations account for <5% of cases of Noonan syndrome, but the gene(s) responsible for the remainder are unknown. We identified missense mutations in SOS1, which encodes an essential RAS guanine nucleotide-exchange factor (RAS-GEF), in approximately 20% of cases of Noonan syndrome without PTPN11 mutation. The prevalence of specific cardiac defects differs in SOS1 mutation-associated Noonan syndrome. Noonan syndrome-associated SOS1 mutations are hypermorphs encoding products that enhance RAS and ERK activation. Our results identify SOS1 mutants as a major cause of Noonan syndrome, representing the first example of activating GEF mutations associated with human disease and providing new insights into RAS-GEF regulation.
Nature Genetics 02/2007; 39(1):70-4. · 35.53 Impact Factor
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ABSTRACT: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with clinical response and prolonged survival in patients with non-small cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs). We began screening patients for somatic EGFR mutations by DNA sequencing as part of clinical care in 2004. We performed a retrospective cohort study of 278 patients with NSCLC referred for EGFR testing over a 10-month period. Tumor samples underwent direct DNA sequence analyses of EGFR exons 18 through 24. We determined the clinical characteristics and EGFR mutation status of the patients and analyzed their response to therapy and survival. EGFR somatic mutations were identified in 68 (24%) of patients. A minimal smoking history was the strongest clinical predictor of harboring a mutation. In multivariable analyses, each pack-year of smoking corresponded to a 5% decreased likelihood of having an EGFR mutation. Among 92 patients with unresectable disease undergoing subsequent systemic therapy, EGFR mutations were associated with an increased response rate to EGFR TKIs (p < .0001) but not chemotherapy. Overall survival was significantly prolonged in EGFR mutation-positive patients (p = .001), with a median survival of 3.1 years compared with 1.6 years in mutation-negative patients, after adjusting for age, gender, and stage at diagnosis. Integrating molecular profiling into clinical care is feasible in NSCLC patients and provides useful clinical information.
The Oncologist 01/2007; 12(1):90-8. · 3.91 Impact Factor
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Lecia V Sequist, Victoria A Joshi,
Pasi A Jänne,
Daphne W Bell,
Panos Fidias,
Neal I Lindeman,
David N Louis,
Jeffrey C Lee,
Eugene J Mark,
Janina Longtine,
Peter Verlander,
Raju Kucherlapati,
Matthew Meyerson,
Daniel A Haber,
Bruce E Johnson,
Thomas J Lynch
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ABSTRACT: As the literature about epidermal growth factor receptor (EGFR) mutations grows and screening for mutations becomes increasingly integrated into clinical care, it is important to examine how best to do somatic mutational analyses and how best to use the test results in clinical decision making. We began offering mutation screening by comprehensive direct sequence analysis of exons 18 to 24 of the tyrosine kinase domain of EGFR in August 2004 as part of clinical cancer care and protocol therapy at our institutions. All identified potential mutations are confirmed with three to five independent PCRs of the original genomic DNA sample and, if not previously noted in the literature, are compared with the patient's germ-line DNA to ensure the finding is somatic. We formally analyzed the first 100 patients to undergo EGFR sequence analysis and found that testing was feasible and significantly affected the treatment of patients with non-small cell lung cancer (NSCLC). Patients harboring EGFR mutations were significantly more likely to receive recommendations for therapy with EGFR tyrosine kinase inhibitors (i.e., gefitinib or erlotinib) than patients without mutations. However, negative EGFR test results did not prevent physicians from administering these agents to selected patients. Ideally, a standardized technique for mutation testing could be developed, with demonstrated reproducibility and validity. Clinical trials incorporating molecular diagnostics are ongoing to assess the efficacy of EGFR tyrosine kinase inhibitors as first-line therapy for metastatic NSCLC and as adjuvant therapy for early-stage resected NSCLC. It is likely that mutation testing and other molecular analyses will be most useful in these two clinical situations.
Clinical Cancer Research 08/2006; 12(14 Pt 2):4403s-4408s. · 7.74 Impact Factor
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David M Jackman,
Beow Y Yeap,
Lecia V Sequist,
Neal Lindeman,
Alison J Holmes, Victoria A Joshi,
Daphne W Bell,
Mark S Huberman,
Balazs Halmos,
Michael S Rabin,
Daniel A Haber,
Thomas J Lynch,
Matthew Meyerson,
Bruce E Johnson,
Pasi A Jänne
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ABSTRACT: Somatic mutations in the epidermal growth factor receptor (EGFR) have been detected in patients with non-small cell lung cancer (NSCLC) and are associated with sensitivity to treatment with gefitinib or erlotinib. Our study explored the relationship between the two most common types of somatic EGFR mutations, exon 19 deletions and the L858R point mutation, and outcomes of patients following treatment with gefitinib or erlotinib.
Tumor specimens obtained before treatment with gefitinib or erlotinib were analyzed for EGFR mutations. Patients with exon 19 deletion or L858R mutations were identified. The response rate, time to progression, and overall survival were determined for the two groups.
We identified 36 patients with NSCLC and an EGFR mutation who were treated with gefitinib or erlotinib. Patients with an exon 19 deletion had a significantly longer overall survival compared with patients with an L858R mutation (38 versus 17 months; P = 0.04). There were also trends toward higher response rate (73% versus 50%) and improved time to progression (24 versus 10 months) for the patients with an exon 19 deletion, although these were not independently significant in a multivariate analysis. A difference in response rate for patients treated with gefitinib compared with erlotinib was also noted [18 of 23 (78%) versus 3 of 9 (33%); P = 0.04]. No obvious difference in time to progression or overall survival was noted between gefitinib- and erlotinib-treated patients.
Patients with NSCLC and EGFR exon 19 deletions have a longer survival following treatment with gefitinib or erlotinib compared with those with the L858R mutation. Pooling of greater numbers of patients and completion of prospective trials are needed to further define the predictive and prognostic roles of different EGFR mutations with respect to treatment with gefitinib, erlotinib, and other EGFR inhibitors.
Clinical Cancer Research 08/2006; 12(13):3908-14. · 7.74 Impact Factor
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Pasi A Jänne,
Ana M Borras,
Yanan Kuang,
Andrew M Rogers, Victoria A Joshi,
Hema Liyanage,
Neal Lindeman,
Jeffrey C Lee,
Balazs Halmos,
Elizabeth A Maher,
Robert J Distel,
Matthew Meyerson,
Bruce E Johnson
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ABSTRACT: Mutations in the epidermal growth factor receptor (EGFR) are associated with clinical and radiographic responses to EGFR tyrosine kinase inhibitors gefitinib and erlotinib. Currently available methods of EGFR mutation detection rely on direct DNA sequencing, which requires isolation of DNA from a relatively pure population of tumor cells, cannot be done on small diagnostic specimens, and lack sensitivity. Here we describe the use of a sensitive screening method that overcomes many of these limitations.
We screened 178 non-small cell lung cancer specimens for mutations in exons 18 to 21 of EGFR using a DNA endonuclease, SURVEYOR, which cleaves mismatched heteroduplexed DNA. Samples were analyzed by high-performance liquid chromatography on the Transgenomic WAVE HS system. Selected specimens that produced digestion products using SURVEYOR were subsequently reanalyzed by size separation or under partially denaturing conditions, followed by fractionation and sequencing. The specimens included DNA isolated from frozen tumor specimens, dissected formalin-fixed, paraffin-embedded tumor specimens undergoing clinical sequencing, and undissected formalin-fixed, paraffin-embedded specimens. One hundred sixty specimens were independently analyzed using direct DNA sequencing in a blinded fashion.
EGFR mutations were detected in 16 of 61 fresh frozen tumor specimens, 24 of 91 dissected formalin-fixed, paraffin-embedded tumor specimens, and 11 of 26 undissected formalin-fixed, paraffin-embedded tumor specimens. Compared with sequencing, the sensitivity and specificity of the present method were 100% and 87%. The positive and negative predictive values were 74% and 100%, respectively. SURVEYOR analysis detected 7 (4%) mutations that were not previously detected by direct sequencing.
SURVEYOR analysis provides a rapid method for EGFR mutation screening with 100% sensitivity and negative predictive value. This unbiased scanning technique is superior to direct sequencing when used with undissected formalin-fixed, paraffin-embedded specimens.
Clinical Cancer Research 03/2006; 12(3 Pt 1):751-8. · 7.74 Impact Factor
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ABSTRACT: Effective and tolerable palliative treatments are needed for patients with incurable squamous cell carcinoma of the head and neck (SCCHN). Single-agent targeted therapies have limited activity in this setting. The feasibility of adding celecoxib to gefitinib for the treatment of incurable SCCHN is unknown.
Nineteen patients with unresectable recurrent locoregional and/or distant metastatic SCCHN with progressive disease after at least one prior chemotherapy or chemoradiotherapy regimen were enrolled onto this single-institution phase I study. Three dose levels were explored: (1) celecoxib 200 mg twice daily plus gefitinib 250 mg daily; (2) celecoxib 400 mg twice daily plus gefitinib 250 mg daily; and (3) celecoxib 400 mg twice daily plus gefitinib 500 mg daily.
No dose-limiting toxicities were encountered at any dose level. The most common toxicities were acneiform rash, diarrhea, hand reaction, dyspepsia, and anemia. Four of 18 patients assessable for response (22%; 95% CI, 2% to 42%) achieved a confirmed partial response.
The combination of gefitinib 500 mg daily plus celecoxib 400 mg twice daily is well-tolerated. The encouraging responses seen in this early study suggest further evaluation of epidermal growth factor receptor and cyclooxygenase-2 inhibitors in SCCHN is warranted.
Journal of Clinical Oncology 11/2005; 23(28):6976-81. · 18.37 Impact Factor
