Annals of Oncology Advance Access originally published online on October 23, 2006
Annals of Oncology 2007 18(1):99-103; doi:10.1093/annonc/mdl323
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© 2006 European Society for Medical Oncology
lung cancer |
EGFR and KRAS mutations as criteria for treatment with tyrosine kinase inhibitors: retro- and prospective observations in non-small-cell lung cancer
1 Department of Thoracic Oncology
2 Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
* Correspondence to: Dr N. van Zandwijk, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Tel: +31-20-512-2958; Fax: +31-20-512-2572; E-mail: n.v.zandwijk{at}nki.nl
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionReferences |
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Results of individualized therapy guided by mutational tumor profile of patients with non-small-cell lung cancer are presented. After confirming the importance of epidermal growth factor receptor (EGFR) and KRAS mutations for (non)response on gefitinib in a retrospective series of patients, EGFR mutations were looked for before—and were a condition for—treatment with gefitinib or erlotinib. To increase the chance to find such a mutation, we selected patients on the basis of smoking status, gender and histopathology. Out of 41 patients selected, 13 (32%) were found to harbor an EGFR mutation. In nine of them it concerned deletions in exon 19 and in none of them KRAS mutations were detected. All nine patients with an exon 19 deletion had a favorable and continuing response to tyrosine kinase inhibitors (TKIs), while four other patients with point mutations responded less favorably: stable disease or a response of short duration. These observations confirm the potential role of EGFR and KRAS mutations in predicting (non)response to TKIs. Exon 19 deletions that are associated with the best responses might be used for first-line treatment selection, while KRAS mutations could play a role in excluding patients from treatment with TKIs.
Key words: EGFR mutation, erlotinib, gefitinib, KRAS mutation, NSCLC
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Two years have elapsed since mutations of the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) have been discovered in patients with non-small-cell lung cancer (NSCLC), who had dramatic clinical responses to treatment with gefitinib [1–3]. Additional clinical observations have revealed that EGFR mutations were more frequently detected in NSCLC patients with specific characteristics such as a non-smoking status, adenocarcinoma and in particular bronchioloalveolar carcinoma (BAC), female gender and Asiatic origin and have retrospectively confirmed that the presence of EGFR mutations is closely associated with a favorable response to treatment with tyrosine kinase inhibitors (TKIs) [4–12]. On the other hand, there is increasing evidence that the presence of KRAS mutations is associated with unresponsiveness to EGFR inhibitors [13, 14]. The fact that KRAS mutations and EGFR mutations were mutually exclusive in larger series of patients fits well with this concept [9].
We report our retro- and prospective experiences with EGFR and KRAS mutation status and response on EGFR TKIs. In a first exploratory series of patients, we focused on the relationship between post-treatment determination of EGFR and KRAS mutations and (absence of) response on TKIs. In the second series, patients received EGFR-inhibiting treatment only if they were found to harbor an EGFR mutation. Since female gender, a non-smoking status and adenocarcinoma or BAC are associated with a higher frequency of EGFR mutations, we have used these selection criteria to ‘enrich’ our patient population.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Two series of patients were analyzed. We determined EGFR and KRAS mutations retrospectively (i.e. after response assessment) in a series of patients included in the gefitinib Expanded Access Program (EAP) and presented elsewhere [5]. The selection of patients was directed by the availability of sufficient archival biopsy material. Molecular analyses of tumor biopsy specimens were done according to the Code of Proper Use of Human Tissues (Dutch Federation of Medical Scientific Societies).
A second series of patients participated in a prospective program. Between June 2004 and December 2005, patients with locally advanced or metastatic NSCLC were informed about the potential impact of EGFR mutation status on responsiveness to EGFR TKI therapy and were asked for their consent to analyze diagnostic specimens for EGFR mutations, if they had two out of three of the following characteristics: female gender, non-smoking status and BAC or adenocarcinoma. Patients who were shown to harbor a mutation in the EGFR TK domain were offered treatment with gefitinib or erlotinib within the framework of the compassionate use programs for these agents. Both studies had been approved by the Institutional Review Board of The Netherlands Cancer Institute. KRAS mutations were determined retrospectively. All patients provided written informed consent and the study was carried out in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines.
In both series of patients, the baseline assessment included medical history (including prior anticancer therapy), smoking history, physical examination and vital signs, performance status, complete blood cell count and blood biochemistry, chest X-ray and tumor assessment (X-rays or computed tomography scans). At follow-up (every 4–6 weeks), interval history, chest X-ray, tumor assessment, complete blood count and biochemistry were collected. Responses were determined using the Response Evaluation Criteria in Solid Tumors (RECIST) [15] criteria. Progression-free survival (PFS) curves were calculated by means of the Kaplan–Meier technique.
We determined EGFR and KRAS mutations by isolating DNA from formalin-fixed paraffin-embedded tumor biopsies. Serial 10-µm paraffin sections were deparaffinized by standard procedures and incubated for 16 hours in 1 M sodium thiocyanate at 37°C, followed by 2 x 5 min wash in phosphate-buffered saline (Dulbecco). Subsequently, the region containing the highest percentage of tumor cells (at least 50%) was microdissected. The tissue was then transferred to a tube containing digestion buffer: 2 mg/ml proteinase-K (Roche Diagnostics, Pleasanton, California, USA) in 10 mM Tris–HCl (pH 8.0), 50 mM KCl, 2.5 mM MgCl2, 0.5% Tween-80 and 0.1 mg/ml gelatin. Tubes were incubated for 24 hours at 55°C, proteinase-K was then heat inactivated at 95°C for 10 minutes, and after centrifugation the supernatant was transferred to a clean tube and stored at 4°C until used.
For EGFR mutation analysis, exons 18–21 were PCR amplified using exon-specific primers: exon 18 forward primer (18-F): 5'-GCTGAGGTGACCCTTGTCTC-3'; exon 18 reverse primer (18-R): 5'-CTCCCCACCAGACCATGA-3'; 19-F: 5'-CATGTGGCACCATCTCACA-3'; 19-R: 5'-CAGCTGCCAGACATGAGAA-3'; 20-F: 5'-CATGCGTCTTCACCTGGAA-3'; 20-R: 5'-AGCAGGTACTGGGAGCCAAT-3'; 21-F: 5'-CCTCACAGCAGGGTCTTCTC-3' and 21-R: 5'-TGCCTCCTTCTGCATGGTA-3'. After an initial round of PCR amplification, PCR products were visualized by agarose gel electrophoresis to check the quality of the PCR products. The (in frame) deletions in exon 19 were in general visible at this stage as a double band. Subsequently, PCR fragments were purified and subjected to cycle sequence reactions using BigDye Terminators (DNA sequencing kit, Applied Biosystems, Foster City, California, USA) The sequence fragments were precipitated and analyzed using an automated sequencer (ABI3700).
In addition, we have carried out PCR fragment analysis using a fluorescently labeled (FAM) primer on the automated sequencer for sensitive detection of the exon 19 deletion. Alternative 19-F primer: 5'-FAM-CATGTGGCACCATCTCACA-3'.
For KRAS mutation, analysis of codon 12 was carried out as above with forward primer 5'-AGGCCTGCTGAAAATGACTG-3' and reverse primer 5'-TCAAAGAATGGTCCTGCACC-3'.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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In the retrospective series, mutation status was determined in 15 out of 92 patients included in the Iressa EAP of whom archival biopsies could be retrieved. This group comprised three patients with an objective response, two patients with stable disease (SD) and 10 patients with progressive disease, while on gefitinib. EGFR mutations were exclusively seen in responding patients. In all three responders, an in-frame deletion (exon 19) was detected. KRAS mutations were not seen in those responders, while they were detected in 30% of patients progressive on gefitinib (Table 1).
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In the prospective series, 41 patients were selected for the assessment of EGFR and KRAS mutation status. Thirteen (out of 41 = 32%) biopsies were found to contain an EGFR mutation. In none of them a KRAS mutation was detected. The median age of the mutation-positive patients was 55; three of them were ex-smokers and 10 were never smokers. Seven of them were females. In nine (out of 13) patients, gefitinib or erlotinib was the first anti-tumor treatment that was prescribed. Table 2 displays the list of patients ordered by response.
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Nine out of the 13 patients with mutations in the EGFR gene had an in-frame deletion in exon 19. In seven cases this was a 15-base-pair deletion. Four patients presented with point mutations, in three cases located in exon 21 and in the remaining cases in exon 18 (two mutations).
All patients with an exon 19 deletion had a swift response on erlotinib or gefitinib. So did three out of four remaining patients with another type of mutation. One patient with a point mutation (exon 21) showed a less favorable course on therapy (erlotinib): after a short stabilization of disease, symptomatic and radiological progression was noticed.
The very first patient in the prospective series, who had attained a complete response on gefitinib, was offered to switch to erlotinib when the results of the BR.21 study had become public [16]. A severe pleuritic reaction (grade III) was noted after a few weeks of erlotinib treatment, causing interruption of therapy. At that time, a pulmonary nodule was noted and surgery with a complete surgical resection of the node with BAC could be carried out. After surgery, gefitinib was reinstituted and this patient remains in remission, >20 months after the initial start of TKI therapy.
Figure 1 shows the PFS curve of those patients in the prospective series separated according to mutation type. In addition to the patient who shortly after attaining SD progressed on erlotinib, two other patients with mutations in exon 21 have experienced disease progression, while, as of writing, no progressions were seen in the patients with exon 19 deletions. The mean progression-free interval was 430 days [confidence interval 294–567] for the whole series.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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The discovery of EGFR and KRAS mutations associated with sensitivity and resistance to EGFR TKIs represents a major breakthrough in our understanding of which patients will benefit from this type of therapy. Since June 2004 several retrospective series have been published largely confirming the original reports and also our retrospective data fits very well in this concept. These reports also made it clear that important conclusions can be drawn from observations in a relatively little number of patients and this also pertains to the series presented here. The importance of EGFR mutation status in predicting a favorable clinical response (>90%) to TKIs is supported by data of 13 patients but especially meaningful are the results within specific groups of mutations. The fact that every exon 19 deletion-positive tumor patient attained a favorable response and the less positive results in patients with other mutations add support to the suggestion from retrospective observations that different groups of EGFR mutations confer different sensitivity to TKIs [17–19]. Very recently, the Spanish Lung Cancer Group has also disclosed the results of their phase II experience with erlotinib in first-line in patients with EGFR mutations. Almost identical outcomes with an overall response rate of 82% and the best results in patients with an exon 19 deletion have been observed [20]. Gefinitib induced comparable results in 16 Japanese chemotherapy-naive NSCLC patients, but survival differences according to mutation type were not reported [21]. All these observations taken together form a strong argument to consider EGFR mutation status and in particular exon 19 deletion as a selection criterion for first-line treatment with TKIs.
The fact that KRAS mutations were not encountered in patients with EGFR mutations and that they were associated exclusively with patients experiencing disease progression during therapy with gefitinib supports the idea to further develop KRAS mutations as an exclusion criterion for treatment with TKIs [13–14].
Should EGFR TKIs be selectively prescribed? The randomized, placebo-controlled, double-blind trial (BR.21) with erlotinib in the second and third lines showed that this molecule conferred a survival and quality of life benefit to the whole NSCLC population including male smokers with squamous cell carcinoma [16]. In an almost identical trial (Iressa Survival Evaluation in Lung Cancer) gefitinib was tested and a similar response rate was recorded as in BR.21. This response rate, however, did not translate into a significant survival benefit. Subgroup analyses showed that never smokers and patients of Asian origin in the gefitinib arm had best survival [22]. EGFR mutations, three or four times more frequent among Asian patients [9], form an explanation for this result and may also serve as an argument for selective prescription of TKIs. Also, the high response rates to TKIs in first line in Asian patients seem to support the idea of customizing therapy according to mutation status [23, 24]. Responses have, however, also been documented in patients without mutations. Undetected EGFR mutations are being used to explain these observations and this explanation seems especially reasonable if limited tumor material was available. We saw the accuracy of sequence analysis falling below the detection limit if the biopsy material available contained <60% tumor cells. Others have pointed to the difficulties in working with small, formalin-fixed, paraffin-embedded biopsy specimens and have suggested that some of the novel variant mutations reported might have been artificially induced by working with small amounts DNA [25, 26]. Full sequencing of the EGFR TK domain is laborious and requires ample biopsy material. To accurately check for exon 19 deletions, we have preformed fragment analysis in addition to sequence analysis. In our hands this technique was sensitive and reliable but is only applicable to deletions. Recently rapid PCR-based detection and sensitive enzymic screening methods have been described to determine EGFR mutations without sequencing and we look forward to additional studies with these techniques [27, 28].
How to further translate our findings into daily clinical practice? The simplest strategy would be the selection of patients according to those clinical characteristics associated with increased mutation frequency (female gender, Asian ethnicity, BAC or adenocarcinoma non-smokers). In the prospective series, we seemed to have tripled the chances to detect a mutation by such an ‘enrichment’ procedure. These clinical criteria, however, would bring us around 30% of patients with a mutation and leave us with 70% with almost no chance to favorably respond on TKIs. Mutation status accurately (>80%) predicted a favorable response and exon 19 deletions did that in 100%. Thus, when efficacy of chemotherapy in advanced NSCLC is taken into account, exon 19 mutations are in an excellent position to serve as a tool for first-line treatment selection. According to the Catalogue of Somatic Mutations in Cancer database, this type of mutation accounts for 30% of NSCLC mutations presented [29]. Other prospective studies using mutation status as a selection criterion are still underway (Target Trial, PI: T. Lynch). If the favorable current results will be confirmed, it seems reasonable to introduce this criterion for patient selection for TKIs in first line.
As mentioned earlier, KRAS mutations may be used in the reverse situation, i.e. the selection of ‘resistant’ patients thereby avoiding the prescription of unnecessary therapy. This is relevant for the selection of patients for second- or third-line therapy.
Received for publication July 7, 2006. Revision received August 2, 2006. Accepted for publication August 3, 2006.
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