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Original Article

Free Access

Mutation Profiling of Lung Cancers with Long-Term Response to Gefitinib Therapy

Gautschi O.a · Stadelmann C.a · Aebersold-Keller F.a · König K.b · Büttner R.b · Heukamp L.C.c · Betticher D.d · Baumann C.e · Buser K.f · Calderoni A.g · Casty A.e · DʼAddario G.h · Irlé C.i · Mamot C.j · Morant R.k · Trojan A.l · Pellicioli E.m · Jehle-Schwertfeger S.m · Aebi S.a · Diebold J.a

Author affiliations

aTumorzentrum, Luzerner Kantonsspital, Lucerne, Switzerland; bInstitute of Pathology, University Hospital of Cologne, Germany; cNEO New Oncology AG, Cologne, Germany; dMedical Oncology, Hôpital Cantonal Fribourg, Switzerland; eLindenhofspital, Berne, Switzerland; fKlinik Engeried, Berne, Switzerland; gClinica SantʼAnna di Sorengo, Lugano, Switzerland; hOnkologie, Kantonsspital, Schaffhausen, Switzerland; iHôpital de la Tour, Meyrin, Switzerland; jOnkologie/Hämatologie, Kantonsspital Aarau, Switzerland; kTumorzentrum ZeTuP, Rapperswil, Switzerland; lOnkoZentrum, Zurich, Switzerland; mAstraZeneca AG, Zug, Switzerland

Corresponding Author

PD Dr. med. Oliver Gautschi

Medizinische Onkologie, Departement Medizin und Tumorzentrum

Luzerner Kantonsspital

Spitalstrasse 10, 6000 Luzern, Switzerland

oliver.gautschi@luks.ch

Related Articles for ""

Oncol Res Treat 2015;38:560-569

Abstract

Background: The role of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in the treatment of patients with advanced non-small cell lung cancer (NSCLC) and unknown EGFR mutation status has recently been questioned. Patients and Methods: We conducted a retrospective study of patients with unknown EGFR mutation status and long-term response (LTR) to gefitinib in the Swiss Iressa expanded access program (EAP). We assessed patient characteristics, and performed Sanger sequencing and next generation sequencing on archived tumor tissue. We hypothesized that EGFR mutations are prevalent in patients with LTR. Results: Of 430 patients in the EAP, 18 (4%) fulfilled our definition of LTR, and 16 of them had archived tumor tissue. Patient characteristics were as expected for age, sex, and smoking history. Median duration of therapy was 38 months (range 24-142 months). Sanger sequencing revealed EGFR exon 18-21 mutations in 6 (38%) of the tumors. Next generation sequencing revealed no further EGFR-mutated cases, but reported in 15 (94%) of the tumors mutations in other genes (ALK, BRAF, DDR2, KEAP1, MET, PTEN, STK11) previously associated with NSCLC. Conclusion: Larger studies are needed to define the prognostic values of different driver mutations in patients with NSCLC.

© 2015 S. Karger GmbH, Freiburg


Keywords

Lung cancer · Next generation sequencing · Targeted therapy · Epidermal growth factor receptor · Gefitinib ·


Introduction

Lung cancer is the most important cause of cancer-related death [1]. Approximately 70% of patients with lung cancer have metastatic disease at the time of diagnosis. Many of these patients receive palliative therapy, often including chemotherapy. In 2004, the predictive role of activating mutations in the epidermal growth factor receptor (EGFR) for response to EGFR tyrosine kinase inhibitor (TKI) therapy was first described [2,3,4]. In 2007, anaplastic lymphoma kinase (ALK) rearrangement was reported to be predictive for successful ALK inhibitor therapy [5]. Today, diagnostic EGFR and ALK testing is a standard of care in patients with advanced non-small cell lung cancer (NSCLC) and nonsquamous histology [6]. The proportion of patients with EGFR mutation or ALK rearrangement is approximately 15-20%, depending on the population. Further actionable driver mutations with lower incidence (< 3%) were identified recently, involving BRAF, DDR2, FGFR1, HER2, MET, RET, ROS1, and other genes [7,8,9,10,11,12]. Current guidelines support the use of drugs targeting those mutations in pretreated patients, preferentially within clinical trials [13].

For the therapy of patients with activating EGFR mutations, gefitinib, erlotinib, and afatinib are approved in Switzerland. Gefitinib (Iressa®, AstraZeneca, Wedel, Germany) was the first EGFR TKI in clinical development. Early trials in unselected patients demonstrated moderate antitumor activity, and the ISEL trial failed to show a statistically significant survival difference between gefitinib and placebo [14,15,16]. The IPASS trial, initiated after the discovery of EGFR mutations, did select the patients, and was clearly positive [17]. Further trials confirmed that gefitinib, erlotinib, and afatinib have superior activity compared with chemotherapy in patients with EGFR exon 19 deletion or L858R [18,19,20,21]. In patients with wild type EGFR (or unknown EGFR mutation status), the role of EGFR TKIs is currently debated [22,23]. In Switzerland, erlotinib is the only EGFR TKI approved independently of EGFR mutation status, based on the results of the BR.21 and SATURN trials [24,25]. Other predictive biomarkers than EGFR mutations were not identified [26,27]. For afatinib, the LUX-Lung-8 trial showed superior (but modest) activity compared with erlotinib in patients with squamous NSCLC, who generally have EGFR wild type [28].

Between 2000 and 2004, hundreds of patients were registered in the global Iressa expanded access program (EAP). EAPs are also known as early access programs, named patient programs, or compassionate use programs. They are very common in oncology, and supported by many health authorities under the conditions that patients may benefit from the drug, the drug has a good tolerability profile, no alternative therapies exist, and the company agrees. Efficacy and safety data from the Iressa EAP were previously reported from the USA, Asia, and Europe [29,30,31]. A group in Germany reported on 20 patients with long-term response (LTR) in the EAP [32]. 11 (55%) had tumor samples available for molecular analysis, 10 had EGFR mutations, and some displayed stem cell-like gene expression patterns. To the best of our knowledge, attempts to identify multiple oncogenic driver mutations in the Iressa EAP were not made yet. We conducted the present study to address this topic.

Patients and Methods

Patient Selection

The Swiss part of the Iressa EAP was open for registration between November 2000 and April 2004 to provide access to gefitinib for patients with advanced NSCLC before marketing authorization of the drug. Eligible patients received 250 mg of gefitinib daily until disease progression or unacceptable toxicity. Patients were registered in an anonymized way, including the date of the first and the last drug order by the treating physician. The reporting of serious adverse events (SAE) was requested. For the current study, patients had to fulfill 2 criteria: LTR defined as minimal duration of 24 months of gefitinib therapy, and archived tumor material available for central sequencing. We retrospectively collected from the Swiss EAP database LTR, patient age, sex, smoking history, tumor histology (World Health Organization classification of 2000), tumor stage (Union for International Cancer Control (UICC) classification of 1997), metastatic sites, and previous therapies.

Tumor Sequencing

Archived tumor material obtained at the time of diagnosis was requested from local pathology institutes, and centralized in Luzern. Samples were microdissected, tumor DNA was extracted, and conventional Sanger sequencing of EGFR exons 18-21 was performed, using routine diagnostic protocols with external quality assessment [33]. Massive parallel sequencing was performed in Cologne on the Illumina® platform (Illumina, Inc., San Diego, CA, USA), using TrueSeq® Amplicon lung panels #3 and #4 (Illumina) [34]. These panels cover most somatic mutations presently known in NSCLC (table 1).

Table 1

Next generation sequencing panels used in this study

http://www.karger.com/WebMaterial/ShowPic/487038

Statistical Analysis

Patient characteristics and sequencing results were presented in a descriptive way. Quantitative variables were expressed by median and range values. We hypothesized that activating EGFR mutations will be prevalent in patients with LTR and informative sequencing results.

Ethical Considerations

The study was approved by the Ethical Committee Luzern (no. 11031), and conducted in agreement with the Declaration of Helsinki. Due to the long follow-up, individual patient consent was not feasible, because most patients were no longer alive.

Results

Iressa EAP

A total of 464 requests were made for the Swiss part of the EAP, and 430 patients received at least 1 order of gefitinib (fig. 1). Safety and tolerability in the overall population was acceptable, drug-related SAEs were reported in 21 (5%) patients. Median duration of treatment was 3 months. 36 (8%) patients received gefitinib for longer than 12 months. 18 (4%) patients received gefitinib for 24 months or longer, and thus met our definition of LTR.

Fig. 1

Flow diagram of the Swiss Iressa expanded access program (EAP).

http://www.karger.com/WebMaterial/ShowPic/487035

Study Population

Of the 18 patients with LTR, 16 (89%) had archived tumor material available for sequencing. Median duration of therapy was 38 months (range 24-142 months), 1 patient remained alive and on gefitinib therapy at the time of analysis. Representative tumor imaging was available from some patients (fig. 2). No pneumonitis or other drug-related SAEs were reported in the LTR patients. Clinical characteristics were available from all 16 patients with tumor tissue (table 2). Sex distribution was balanced. Median age at registration was 62 years (range 35-76 years). 9 patients had a positive smoking history. 12 patients had previous chemotherapy, 5 had previous radiotherapy. All patients had tumors with predominantly nonsquamous NSCLC histology, confirmed by central pathology.

Table 2

Characteristics of patients with long-term response (LTR)

http://www.karger.com/WebMaterial/ShowPic/487037

Fig. 2

Tumor imaging from patient no. 2. A 18FDG-PET/CT at baseline, and computed tomography scans B, D at baseline, and after C 3 years and E 4 years of gefitinib therapy.

http://www.karger.com/WebMaterial/ShowPic/487034

Tumor Sequencing

Sanger sequencing and next generation sequencing (NGS) were run in parallel, using DNA from the 16 available tumor samples (table 3). Sanger revealed 6 EGFR-mutated tumors: 1 mutation in exon 18 (G719A), 3 in exon 19 (deletion), and 2 in exon 21 (L858R and L861Q). These EGFR mutations occurred in 3 (30%) of 10 patients with positive smoking history, and in 3 (43%) patients with negative smoking history. NGS confirmed 5 EGFR-mutated tumors, and could not confirm 1 EGFR-mutated tumor because of limited DNA. Further mutated genes by NGS included TP53 (n = 7), KEAP1 (n = 4), MET (n = 3), BRAF (n = 2), CTNNB1 (n = 2), DDR2 (n = 2), KRAS (n = 2), STK11 (n = 2), ALK (n = 1), and PTEN (n = 1). All TP53 mutations occurred in patients with positive smoking history. 11 tumors had more than 1 driver mutation, 2 tumors had 4 coexisting mutations, and only 1 had no detectable mutations at all.

Table 3

Sequencing results

http://www.karger.com/WebMaterial/ShowPic/487036

Discussion

EGFR TKIs are well established in the treatment of patients with advanced NSCLC and EGFR mutations, but their role in patients with EGFR wild type has recently been questioned [22,23]. In vitro, many cell lines with EGFR wild type were resistant to a TKI [35]. Further complicating the issue, diagnostic tests can be false-negative, and NGS may have superior sensitivity over Sanger sequencing [36].

We retrospectively analyzed tumors from patients with LTR in the Swiss Iressa EAP which was open for registration between 2000 and 2004 before the discovery of EGFR mutations. Because radiological tumor assessment was not mandatory in the EAP, we used a clinical definition of LTR, and a threshold corresponding to a doubling of the median progression-free survival of patients with EGFR mutations treated with a TKI, and to a doubling of the median overall survival of patients with EGFR wild type and chemotherapy [17,18,19,20,21,37]. There is no generally accepted definition of LTR, and other groups used a higher cutoff [32]. In the Swiss EAP, 18 (4%) patients met our definition of LTR, and we were capable of retrieving and sequencing tumors from 16 of them. Their clinical characteristics (age, sex, smoking) were consistent with the characteristics of patients with EGFR mutations in a recent German cohort [38]. Contrary to our expectation, many (63%) of our LTR patients had EGFR wild type, including the 3 patients with the longest duration of therapy (99, 100, and 142 months). NGS did not reveal more EGFR mutant cases than Sanger, suggesting that false-negative Sanger sequencing was not a problem. Whether tumor heterogeneity was responsible for the low EGFR mutation rate, and whether additional EGFR mutant patients would have been identified by using circulating DNA, remains elusive [39,40]. Future EAPs with targeted therapies should include prospective biobanking of tissue and blood, if possible.

The rate of driver mutations identified by NGS in our study was higher than in a recent study by the US Lung Cancer Mutation Consortium [41]. Although we cannot rule out a chance effect, our LTR patients appeared to have an accumulation of rare mutations, including BRAF, KEAP1, and DDR2. Many of these mutations are at the same time prognostic markers, and targets for molecular therapy [7,9,42,43,44,45]. Despite earlier assumptions, EGFR mutations themselves were not prognostic in a recent meta-analysis [46]. Gefitinib is selective for EGFR, and it is unlikely that off-target effects, or other targeted agents, biased the results of our study. Consistent with a prior publication, coexistence of different mutations in the same tumor was frequent, supporting parallel rather than sequential testing [36]. Implementation of NGS is currently ongoing in many diagnostic laboratories. Results of yet unknown clinical relevance will be generated, and local datasets will have limited scientific value. Large organizations have initiated programs to gather genomic and clinical data, and to conduct new trials in patients with specific cancer subtypes. One example is the SPECTA program coordinated by the European Organisation for Research and Treatment of Cancer (EORTC). Such collaborative efforts are important, and will lead to further progress in the field.

Acknowledgment

We thank AstraZeneca for supporting the study.

Disclosure Statement

LCH is an employee of NEO New Oncology AG; EP and SJS are employed by AstraZeneca. All other authors reported no potential conflicts of interest related to this study. AstraZeneca provided access to Swiss Iressa EAP data, and paid for tumor sequencing. The company did not provide writing assistance, or influence interpretation of results.


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    External Resources
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  39. Bai H, Wang Z, Chen K, Zhao J, Lee JJ, Wang S, Zhou Q, Zhuo M, Mao L, An T, Duan J, Yang L, Wu M, Liang Z, Wang Y, Kang X, Wang J: Influence of chemotherapy on EGFR mutation status among patients with non-small-cell lung cancer. J Clin Oncol 2012;30:3077-3083.
  40. Goto K, Ichinose Y, Ohe Y, Yamamoto N, Negoro S, Nishio K, Itoh Y, Jiang H, Duffield E, McCormack R, Saijo N, Mok T, Fukuoka M: Epidermal growth factor receptor mutation status in circulating free DNA in serum: from IPASS, a phase III study of gefitinib or carboplatin/paclitaxel in non-small cell lung cancer. J Thorac Oncol 2012;7:115-121.
  41. Kris MG, Johnson B, Berry LD, Kwiatkowski DJ, Iafrate AJ, Wistuba II, Varella-Garcia M, Franklin WA, Aronson SL, Su PF, Shyr Y, Camidge DR, Sequist LV, Glisson BS, Khuri FR, Garon EB, Pao W, Rudin C, Schiller J, Haura EB, Socinski M, Shirai K, Chen H, Giaccone G, Ladanyi M, Kugler K, Minna JD, Bunn PA: Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 2014;311:1998-2006.
  42. Blackhall FH, Peters S, Bubendorf L, Dafni U, Kerr KM, Hager H, Soltermann A, O'Byrne KJ, Dooms C, Sejda A, Hernández-Losa J, Marchetti A, Savic S, Tan Q, Thunnissen E, Speel EJ, Cheney R, Nonaka D, de Jong J, Martorell M, Letovanec I, Rosell R, Stahel RA: Prevalence and clinical outcomes for patients with ALK-positive resected stage I to III adenocarcinoma: results from the European Thoracic Oncology Platform Lungscape Project. J Clin Oncol 2014;32:2780-2787.
  43. Marchetti A, Felicioni L, Malatesta S, Grazia Sciarrotta M, Guetti L, Chella A, Viola P, Pullara C, Mucilli F, Buttitta F: Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol 2011;29:3574-3579.
  44. Takahashi T, Sonobe M, Menju T, Nakayama E, Mino N, Iwakiri S, Nagai S, Sato K, Miyahara R, Okubo K, Hirata T, Date H, Wada H: Mutations in Keap1 are a potential prognostic factor in resected non-small cell lung cancer. J Surg Oncol 2010;101:500-506.
  45. Xu C, Buczkowski KA, Zhang Y, Asahina H, Beauchamp EM, Terai H, Li YY, Meyerson M, Wong KK, Hammerman PS: NSCLC driven by DDR2 mutation is sensitive to dasatinib and JQ1 combination therapy. Mol Cancer Ther 2015;Epub ahead of print.
  46. Zhang Z, Wang T, Zhang J, Cai X, Pan C, Long Y, Chen J, Zhou C, Yin X: Prognostic value of epidermal growth factor receptor mutations in resected non-small cell lung cancer: a systematic review with meta-analysis. PLoS One 2014;9:e106053.

Author Contacts

PD Dr. med. Oliver Gautschi

Medizinische Onkologie, Departement Medizin und Tumorzentrum

Luzerner Kantonsspital

Spitalstrasse 10, 6000 Luzern, Switzerland

oliver.gautschi@luks.ch


Article / Publication Details

First-Page Preview
Abstract of Original Article

Received: September 22, 2015
Accepted: October 01, 2015
Published online: October 21, 2015
Issue release date: November 2015

Number of Print Pages: 10
Number of Figures: 2
Number of Tables: 3

ISSN: 2296-5270 (Print)
eISSN: 2296-5262 (Online)

For additional information: http://www.karger.com/ORT


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    External Resources
  36. Drilon A, Wang L, Arcila ME, Balasubramanian S, Greenbowe JR, Ross JS, Stephens P, Lipson D, Miller VA, Kris MG, Ladanyi M, Rizvi NA: Broad, hybrid capture-based next-generation sequencing identifies actionable genomic alterations in lung adenocarcinomas otherwise negative for such alterations by other genomic testing approaches. Clin Cancer Res 2015;21:3631-3639.
  37. Gautschi O, Mach N, Rothschild SI, Li Q, Stahel RA, Zippelius A, Cathomas R, Früh M, Betticher DC, Peters S, Rauch D, Feilchenfeldt J, Bubendorf L, Savic S, Jaggi R, Leibundgut EO, Largiadèr C, Brutsche M, Pilop C, Stalder L, Pless M, Ochsenbein AF; Swiss Group for Clinical Cancer Research: Bevacizumab, pemetrexed, and cisplatin, or bevacizumab and erlotinib for patients with advanced non-small-cell lung cancer stratified by epidermal growth factor receptor mutation: phase II trial SAKK19/09. Clin Lung Cancer 2015;16:358-65.
  38. Schuette W, Schirmacher P, Eberhardt WE, Fischer JR, von der Schulenburg JM, Mezger J, Schumann C, Serke M, Zaun S, Dietel M, Thomas M: EGFR mutation status and first-line treatment in patients with stage III/IV non-small cell lung cancer in Germany: an observational study. Cancer Epidemiol Biomarkers Prev 2015;24:1254-1261.
  39. Bai H, Wang Z, Chen K, Zhao J, Lee JJ, Wang S, Zhou Q, Zhuo M, Mao L, An T, Duan J, Yang L, Wu M, Liang Z, Wang Y, Kang X, Wang J: Influence of chemotherapy on EGFR mutation status among patients with non-small-cell lung cancer. J Clin Oncol 2012;30:3077-3083.
  40. Goto K, Ichinose Y, Ohe Y, Yamamoto N, Negoro S, Nishio K, Itoh Y, Jiang H, Duffield E, McCormack R, Saijo N, Mok T, Fukuoka M: Epidermal growth factor receptor mutation status in circulating free DNA in serum: from IPASS, a phase III study of gefitinib or carboplatin/paclitaxel in non-small cell lung cancer. J Thorac Oncol 2012;7:115-121.
  41. Kris MG, Johnson B, Berry LD, Kwiatkowski DJ, Iafrate AJ, Wistuba II, Varella-Garcia M, Franklin WA, Aronson SL, Su PF, Shyr Y, Camidge DR, Sequist LV, Glisson BS, Khuri FR, Garon EB, Pao W, Rudin C, Schiller J, Haura EB, Socinski M, Shirai K, Chen H, Giaccone G, Ladanyi M, Kugler K, Minna JD, Bunn PA: Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 2014;311:1998-2006.
  42. Blackhall FH, Peters S, Bubendorf L, Dafni U, Kerr KM, Hager H, Soltermann A, O'Byrne KJ, Dooms C, Sejda A, Hernández-Losa J, Marchetti A, Savic S, Tan Q, Thunnissen E, Speel EJ, Cheney R, Nonaka D, de Jong J, Martorell M, Letovanec I, Rosell R, Stahel RA: Prevalence and clinical outcomes for patients with ALK-positive resected stage I to III adenocarcinoma: results from the European Thoracic Oncology Platform Lungscape Project. J Clin Oncol 2014;32:2780-2787.
  43. Marchetti A, Felicioni L, Malatesta S, Grazia Sciarrotta M, Guetti L, Chella A, Viola P, Pullara C, Mucilli F, Buttitta F: Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol 2011;29:3574-3579.
  44. Takahashi T, Sonobe M, Menju T, Nakayama E, Mino N, Iwakiri S, Nagai S, Sato K, Miyahara R, Okubo K, Hirata T, Date H, Wada H: Mutations in Keap1 are a potential prognostic factor in resected non-small cell lung cancer. J Surg Oncol 2010;101:500-506.
  45. Xu C, Buczkowski KA, Zhang Y, Asahina H, Beauchamp EM, Terai H, Li YY, Meyerson M, Wong KK, Hammerman PS: NSCLC driven by DDR2 mutation is sensitive to dasatinib and JQ1 combination therapy. Mol Cancer Ther 2015;Epub ahead of print.
  46. Zhang Z, Wang T, Zhang J, Cai X, Pan C, Long Y, Chen J, Zhou C, Yin X: Prognostic value of epidermal growth factor receptor mutations in resected non-small cell lung cancer: a systematic review with meta-analysis. PLoS One 2014;9:e106053.
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