Review Case Report For reprint orders, please contact: [email protected]
2014
Combined point mutation in KRAS or EGFR genes and EML4–ALK translocation in lung cancer patients Review
Jessica Jürgens1, Walburga Engel-Riedel1, Alexander Prickartz1, Corinna Ludwig1, Oliver Schildgen2, Ramona-Liza Tillmann2, Erich Stoelben1, Michael Brockmann1 & Verena Schildgen*,2
al.
9
2
2 1 7 /
Abstract: A total of three cases with novel constellations regarding mutation patterns in non-small-cell lung cancer (NSCLC) are reported. The mutation patterns that are observed are novel and unexpected. First, a combined simultaneous KRAS mutation and EML4–ALK translocation, both in the main tumor and a bone metastasis, were observed, these mutations are assumed to mutually exclude each other. A further two cases include a father and a daughter, both of whom are suffering from NSCLC with different EGFR mutation patterns. A common cause was assumed; however, could not be deduced to mutations in the KRAS, BRAF and EGFR genes. The aforementioned cases are important, as it must be taken into account that mutations previously assumed to be exclusive can occur in combination, may influence the clinical outcome and may require different therapy compared with single mutated tumors. It has to be discussed whether diagnostic algorithms need to be adapted. The cases of father and daughter show that further unknown factors can influence development of NSCLC.
uture
n KRAS or ocation
ture , UK
Lung cancer is the leading cause of cancer-related death. Histologically, the adenocarcinoma is known as one of the most frequent forms of lung cancer [1] . The currently practiced molecular genetic diagnostics and treatment follows a procedure, in which a BRAF, EGFR and an EML4–ALK analysis would not usually be considered in the case of a mutated KRAS gene [1] . Having previously described that the epidemiology of EML4–ALK translocations in Caucasian patients differs from previous studies, we have further investigated clinical cases with FISH-positive ALK translocations [2] . The following reports describe a case of the simultaneous occurrence of mutated KRAS gene and an ALK translocation. Moreover, two further cases are described of a father and his daughter both of whom suffered from non-small-cell lung cancer (NSCLC) with different mutation patterns, supporting the hypothesis that, so far, unknown inherited factors are involved in the onset of NSCLC.
Keywords
• case series • lung cancer • mutation • novel combination • NSCLC
Cases A 48-year-old female smoker (25 years of age) with a pathological fracture of the left humerus. The histological diagnosis suggested an osteolytic metastasis as part of a primary lung adenocarcinoma confirmed by biopsies. The metastasis was treated with compound osteosynthesis and postsurgical radiation. The subsequent chemotherapy cycle included bevacizumab, carboplatin and paclitaxel. Owing to an ongoing deterioration of the patient’s general condition, she received the best possible supportive care and died only 5.5 months following the initial diagnosis. Lungenklinik, Kliniken der Stadt Köln gGmbH, Klinikum der Privaten Universität Witten Herdecke mit Sitz in Köln, Köln, Germany Institut für Pathologie, Kliniken der Stadt Köln gGmbH, Krankenhaus Merheim, Klinikum der Privaten Universität Witten Herdecke mit Sitz in Köln, Institut für Pathologie, Ostmerheimer Str. 200, D-51109 Köln, Germany * Author for correspondence: Tel.: +49 221 8907 18887; Fax: +49 221 8907 3542; [email protected] 1 2
10.2217/FON.13.194 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(4), 529–532
part of
ISSN 1479-6694
529
Case Report Jürgens, Engel-Riedel, Prickartz et al. On molecular pathological investigation using the Therascreen® pyrosequencing assays (QIAGEN, Hilden, Germany) and the EML4– ALK probe system by Zytovision® (Berlin, Germany), as previously described [2,3] , both the major lung tumor and the metastasis carried a mutation in the KRAS gene (codon 12 GGT≥GTT, i.e., G12V; 47% limit of detection = 1%) and EML4–ALK fusion (Figure 1) . In the main tumor, the percentage of EML4– ALK translocation signal was 69%, and in the metastasis it was 85%. The second and third cases are of a 69-year-old man and his 43-year-old daughter. Both of whom were not frequent smokers. The male patient was diagnosed with a pulmonary adenocarcinoma of the right upper lobe with distant metastases in
several ribs and in an abdominal lymph node, and a TTF1-positive adenocarcinoma. Further investigations revealed an activating mutation in EGFR-codon 861 of exon 21 (38.4%, limit of detection 4.2%) and a wild-type sequence in the KRAS gene. At that time, no further molecular investigations were performed. The patient had a former smoking history of 15 packs/year. He was suffering from coronary heart disease and chronic lymphatic leukemia for several years without the need of any special therapy. We started first-line treatment with gefitinib 250 mg daily. A CT scan performed 2 months later showed disease progression of the main tumor as well as of the mediastinal lymph nodes and a new lymphangiosis carcinomatosa of the left lung. We stopped the gefitinib treatment
Figure 1. FISH of ALK and EML4 using the break apart TriCheck system by Zytovision®, Berlin, Germany. Diverted red and green signal indicate translocation of the ALK gene, cyan/turkish signals indicate EML4; in any case, more than 50% of cells in the tumor region had break-apart red and green signals that were divided by ≥2 signals distance. The image shows the original lung tumor.
530
Future Oncol. (2014) 10(4)
future science group
Combined point mutation in KRAS or EGFR genes & EML4–ALK translocation in lung cancer patients and started therapy with pemetrexed, carboplatin and bevacizumab. After four cycles, a CT scan showed partial remission of all tumor manifestations and – beside this – a pulmonary embolism and a thrombus in the left ventricle, being probably a side effect of bevacizumab. The patient underwent maintenance therapy with pemetrexed. He died 3 months later from respiratory failure due to lung metastases. His 43-year-old daughter came to our hospital 1 year later, with extensive lymphangiosis carcinomatosa of the lung and numerous brain metastases. The transbronchial biopsy showed a TTF1-positive adenocarcinoma with an ALK-rearrangement (73% of tumor cells rearranged as determined by FISH) and wild-type sequences for EGFR, KRAS and BRAF. Following consideration of a somehow hereditary disease, we performed a subsequent analysis of the father’s tissue, where we found an ALK rearrangement concurrent with the already known EGFR mutation, the percentage of EML4–ALK translocation signal was 85% as determined by FISH analyses. The daughter underwent palliative radiotherapy of the brain and then changed to another hospital to receive first-line treatment with crizotinib. Unfortunately, we could not get any information regarding further progression as the patient was admitted to another hospital. Discussion In the reported case, the patient was diagnosed with a combined KRAS mutation and EML4– ALK translocation. According to recent publications, mutated KRAS should exclude the simultaneous occurrence of an EML4–ALK translocation [4–10] . Although we cannot exclude the fact that despite the mutations appearing in different cells, they still occur in the same tumors; thereby the most likely explanation is that the mutations occur in the same cells as the bone metastasis and therefore have the same pattern as the main tumor, thus the well known fact that tumors can consist of mixed populations
Case Report
appears more unlikely. Microdissection of different parts of the tumors could have helped to analyze these options in more detail, but unfortunately is not available in our institute. Moreover, immunohistochemistry for the detection of EML4–ALK fusion proteins would have been of interest but was not available for these cases. Unfortunately, it was impossible to follow the daughter who changed to another hospital or physician any further; although, we are connected with virtually all hospitals and oncologists treating lung cancer in the area of Cologne. Nevertheless, although multiple driver mutations occurring simultaneously in a single patient are rare, such cases are described in the literature with a frequency of 2% of double mutations [11] . In concurrence with our observation, this raises the question as to whether the described case should be considered as a rare exception or whether the currently practiced molecular–pathological diagnostic and treatment procedure should be challenged and potentially extended by additional molecular– pathological investigations. We recommend testing all of the mentioned parameters in the respective patients, as long as there is no contradicting information that patients with combined mutations do not profit from oral ALK inhibitor therapy [12–14] . This proposal is supported by the fact that dual EGFR and ALK mutated tumor cells can be treated with a combination of drugs that target both the EGFR pathway and the kinase domain of ALK [15] . Furthermore, it needs to be taken into account that to date unknown inherited factors may influence or trigger the onset of NSCLC. The two cases of a father and daughter, both suffering from NSCLC with different mutation patterns, clearly indicated the involvement of an unknown, and, maybe, inherited factor that was not detected by standard routine diagnostics. Unfortunately, due to limited amounts of tumor material available for further diagnostics and loss of the patients it was impossible to analyze if the EML4–ALK
Executive summary ●●
Combined mutation in non-small-cell lung cancer may occur more often than previously assumed.
●●
Diagnostic algorithms may need to be adopted for combined mutations and should not stop once a single mutation is identified.
●●
Therapy outcomes of patients with combined mutation require special documentation in order to optimize therapies accordingly.
future science group
www.futuremedicine.com
531
Case Report Jürgens, Engel-Riedel, Prickartz et al. breakpoints of both patients were identical and whether a germ-line mutation was present. Thus, future studies should also focus in more detail on the discovery of such unknown host factors or other common factors from the patients’ environment which are not routinely analyzed or screened for during the patients’ anamnesis.
in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Informed consent disclosure Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest 5
References 1
2
3
4
532
Felip E, Gridelli C, Baas P, Rosell R, Stahel R. Metastatic non-small-cell lung cancer. consensus on pathology and molecular tests, first-line, second-line, and third-line therapy. 1st ESMO Consensus Conference in Lung Cancer; Lugano 2010. Ann. Oncol. 22(7), 1507–1519 (2011). Schildgen V, Lochi V, Lüsebrink J, Brockmann M, Schildgen O. Epidemiology of EML4–ALK translocations in a small, German non-small-cell lung cancer patient cohort. Pers. Med. 9(8), 801–803 (2012). Schildgen V, Schulz C, Lüsebrink J et al. Combination of Pyrosequencing ® and Sanger sequencing reveals alleged novel mutation in exon 18 of EGFR. Pers. Med. 10(2), 201–209 (2013). Butrynski JE, D’Adamo DR, Hornick JL et al. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N. Engl. J. Med. 363(18), 1727–1733 (2010).
6
The authors state that they have obtained verbal and written informed consent from the patients for the inclusion of their medical and treatment history within this case report.
Camidge DR, Doebele RC. Treating ALK-positive lung cancer – early successes and future challenges. Nat. Rev. Clin. Oncol. 9(5), 268–277 (2012). Chabner BA. Early accelerated approval for highly targeted cancer drugs. N. Engl. J. Med. 364(12), 1087–1089 (2011).
7
Cheng H, Xu X, Costa DB, Powell CA, Halmos B. Molecular testing in lung cancer. The time is now. Curr. Oncol. Rep. 12(5), 335–348 (2010).
8
Choi YL, Soda M, Yamashita Y et al. EML4–ALK mutations in lung cancer that confer resistance to ALK inhibitors. N. Engl. J. Med. 363(18), 1734–1739 (2010).
9
Kwak EL, Bang YJ, Camidge DR et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363(18), 1693–1703 (2010).
10 Mano H. Non-solid oncogenes in solid
tumors. EML4–ALK fusion genes in lung cancer. Cancer Sci. 99(12), 2349–2355 (2008).
Future Oncol. (2014) 10(4)
11 Kim S, Kim TM, Kim DW et al.
Heterogeneity of genetic changes associated with acquired crizotinib resistance in ALK-rearranged lung cancer. J. Thorac. Oncol. 8(4), 415–422 (2013). 12 Quest Diagnostics® – Mutation testing cascade
for patients who are candidates for EGFR antagonist therapy. http://questdiagnostics.com/hcp/intguide/ HematOnc/Gastrointestinal/TS_EGFR_ Pathway.pdf 13 Aisner DL, Marshall CB. Molecular pathology
of non-small cell lung cancer. A practical guide. Am. J. Clin. Pathol. 138(3), 332–346 (2012). 14 Li T, Kung HJ, Mack PC, Gandara DR.
Genotyping and genomic profiling of non-small-cell lung cancer. implications for current and future therapies. J. Clin. Oncol. 31(8), 1039–1049 (2013). 15 Sasaki T, Koivunen J, Ogino A et al. A novel
ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res. 71(18), 6051–6060 (2011).
future science group
2014
Combined point mutation in KRAS or EGFR genes and EML4–ALK translocation in lung cancer patients Review
Jessica Jürgens1, Walburga Engel-Riedel1, Alexander Prickartz1, Corinna Ludwig1, Oliver Schildgen2, Ramona-Liza Tillmann2, Erich Stoelben1, Michael Brockmann1 & Verena Schildgen*,2
al.
9
2
2 1 7 /
Abstract: A total of three cases with novel constellations regarding mutation patterns in non-small-cell lung cancer (NSCLC) are reported. The mutation patterns that are observed are novel and unexpected. First, a combined simultaneous KRAS mutation and EML4–ALK translocation, both in the main tumor and a bone metastasis, were observed, these mutations are assumed to mutually exclude each other. A further two cases include a father and a daughter, both of whom are suffering from NSCLC with different EGFR mutation patterns. A common cause was assumed; however, could not be deduced to mutations in the KRAS, BRAF and EGFR genes. The aforementioned cases are important, as it must be taken into account that mutations previously assumed to be exclusive can occur in combination, may influence the clinical outcome and may require different therapy compared with single mutated tumors. It has to be discussed whether diagnostic algorithms need to be adapted. The cases of father and daughter show that further unknown factors can influence development of NSCLC.
uture
n KRAS or ocation
ture , UK
Lung cancer is the leading cause of cancer-related death. Histologically, the adenocarcinoma is known as one of the most frequent forms of lung cancer [1] . The currently practiced molecular genetic diagnostics and treatment follows a procedure, in which a BRAF, EGFR and an EML4–ALK analysis would not usually be considered in the case of a mutated KRAS gene [1] . Having previously described that the epidemiology of EML4–ALK translocations in Caucasian patients differs from previous studies, we have further investigated clinical cases with FISH-positive ALK translocations [2] . The following reports describe a case of the simultaneous occurrence of mutated KRAS gene and an ALK translocation. Moreover, two further cases are described of a father and his daughter both of whom suffered from non-small-cell lung cancer (NSCLC) with different mutation patterns, supporting the hypothesis that, so far, unknown inherited factors are involved in the onset of NSCLC.
Keywords
• case series • lung cancer • mutation • novel combination • NSCLC
Cases A 48-year-old female smoker (25 years of age) with a pathological fracture of the left humerus. The histological diagnosis suggested an osteolytic metastasis as part of a primary lung adenocarcinoma confirmed by biopsies. The metastasis was treated with compound osteosynthesis and postsurgical radiation. The subsequent chemotherapy cycle included bevacizumab, carboplatin and paclitaxel. Owing to an ongoing deterioration of the patient’s general condition, she received the best possible supportive care and died only 5.5 months following the initial diagnosis. Lungenklinik, Kliniken der Stadt Köln gGmbH, Klinikum der Privaten Universität Witten Herdecke mit Sitz in Köln, Köln, Germany Institut für Pathologie, Kliniken der Stadt Köln gGmbH, Krankenhaus Merheim, Klinikum der Privaten Universität Witten Herdecke mit Sitz in Köln, Institut für Pathologie, Ostmerheimer Str. 200, D-51109 Köln, Germany * Author for correspondence: Tel.: +49 221 8907 18887; Fax: +49 221 8907 3542; [email protected] 1 2
10.2217/FON.13.194 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(4), 529–532
part of
ISSN 1479-6694
529
Case Report Jürgens, Engel-Riedel, Prickartz et al. On molecular pathological investigation using the Therascreen® pyrosequencing assays (QIAGEN, Hilden, Germany) and the EML4– ALK probe system by Zytovision® (Berlin, Germany), as previously described [2,3] , both the major lung tumor and the metastasis carried a mutation in the KRAS gene (codon 12 GGT≥GTT, i.e., G12V; 47% limit of detection = 1%) and EML4–ALK fusion (Figure 1) . In the main tumor, the percentage of EML4– ALK translocation signal was 69%, and in the metastasis it was 85%. The second and third cases are of a 69-year-old man and his 43-year-old daughter. Both of whom were not frequent smokers. The male patient was diagnosed with a pulmonary adenocarcinoma of the right upper lobe with distant metastases in
several ribs and in an abdominal lymph node, and a TTF1-positive adenocarcinoma. Further investigations revealed an activating mutation in EGFR-codon 861 of exon 21 (38.4%, limit of detection 4.2%) and a wild-type sequence in the KRAS gene. At that time, no further molecular investigations were performed. The patient had a former smoking history of 15 packs/year. He was suffering from coronary heart disease and chronic lymphatic leukemia for several years without the need of any special therapy. We started first-line treatment with gefitinib 250 mg daily. A CT scan performed 2 months later showed disease progression of the main tumor as well as of the mediastinal lymph nodes and a new lymphangiosis carcinomatosa of the left lung. We stopped the gefitinib treatment
Figure 1. FISH of ALK and EML4 using the break apart TriCheck system by Zytovision®, Berlin, Germany. Diverted red and green signal indicate translocation of the ALK gene, cyan/turkish signals indicate EML4; in any case, more than 50% of cells in the tumor region had break-apart red and green signals that were divided by ≥2 signals distance. The image shows the original lung tumor.
530
Future Oncol. (2014) 10(4)
future science group
Combined point mutation in KRAS or EGFR genes & EML4–ALK translocation in lung cancer patients and started therapy with pemetrexed, carboplatin and bevacizumab. After four cycles, a CT scan showed partial remission of all tumor manifestations and – beside this – a pulmonary embolism and a thrombus in the left ventricle, being probably a side effect of bevacizumab. The patient underwent maintenance therapy with pemetrexed. He died 3 months later from respiratory failure due to lung metastases. His 43-year-old daughter came to our hospital 1 year later, with extensive lymphangiosis carcinomatosa of the lung and numerous brain metastases. The transbronchial biopsy showed a TTF1-positive adenocarcinoma with an ALK-rearrangement (73% of tumor cells rearranged as determined by FISH) and wild-type sequences for EGFR, KRAS and BRAF. Following consideration of a somehow hereditary disease, we performed a subsequent analysis of the father’s tissue, where we found an ALK rearrangement concurrent with the already known EGFR mutation, the percentage of EML4–ALK translocation signal was 85% as determined by FISH analyses. The daughter underwent palliative radiotherapy of the brain and then changed to another hospital to receive first-line treatment with crizotinib. Unfortunately, we could not get any information regarding further progression as the patient was admitted to another hospital. Discussion In the reported case, the patient was diagnosed with a combined KRAS mutation and EML4– ALK translocation. According to recent publications, mutated KRAS should exclude the simultaneous occurrence of an EML4–ALK translocation [4–10] . Although we cannot exclude the fact that despite the mutations appearing in different cells, they still occur in the same tumors; thereby the most likely explanation is that the mutations occur in the same cells as the bone metastasis and therefore have the same pattern as the main tumor, thus the well known fact that tumors can consist of mixed populations
Case Report
appears more unlikely. Microdissection of different parts of the tumors could have helped to analyze these options in more detail, but unfortunately is not available in our institute. Moreover, immunohistochemistry for the detection of EML4–ALK fusion proteins would have been of interest but was not available for these cases. Unfortunately, it was impossible to follow the daughter who changed to another hospital or physician any further; although, we are connected with virtually all hospitals and oncologists treating lung cancer in the area of Cologne. Nevertheless, although multiple driver mutations occurring simultaneously in a single patient are rare, such cases are described in the literature with a frequency of 2% of double mutations [11] . In concurrence with our observation, this raises the question as to whether the described case should be considered as a rare exception or whether the currently practiced molecular–pathological diagnostic and treatment procedure should be challenged and potentially extended by additional molecular– pathological investigations. We recommend testing all of the mentioned parameters in the respective patients, as long as there is no contradicting information that patients with combined mutations do not profit from oral ALK inhibitor therapy [12–14] . This proposal is supported by the fact that dual EGFR and ALK mutated tumor cells can be treated with a combination of drugs that target both the EGFR pathway and the kinase domain of ALK [15] . Furthermore, it needs to be taken into account that to date unknown inherited factors may influence or trigger the onset of NSCLC. The two cases of a father and daughter, both suffering from NSCLC with different mutation patterns, clearly indicated the involvement of an unknown, and, maybe, inherited factor that was not detected by standard routine diagnostics. Unfortunately, due to limited amounts of tumor material available for further diagnostics and loss of the patients it was impossible to analyze if the EML4–ALK
Executive summary ●●
Combined mutation in non-small-cell lung cancer may occur more often than previously assumed.
●●
Diagnostic algorithms may need to be adopted for combined mutations and should not stop once a single mutation is identified.
●●
Therapy outcomes of patients with combined mutation require special documentation in order to optimize therapies accordingly.
future science group
www.futuremedicine.com
531
Case Report Jürgens, Engel-Riedel, Prickartz et al. breakpoints of both patients were identical and whether a germ-line mutation was present. Thus, future studies should also focus in more detail on the discovery of such unknown host factors or other common factors from the patients’ environment which are not routinely analyzed or screened for during the patients’ anamnesis.
in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Informed consent disclosure Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest 5
References 1
2
3
4
532
Felip E, Gridelli C, Baas P, Rosell R, Stahel R. Metastatic non-small-cell lung cancer. consensus on pathology and molecular tests, first-line, second-line, and third-line therapy. 1st ESMO Consensus Conference in Lung Cancer; Lugano 2010. Ann. Oncol. 22(7), 1507–1519 (2011). Schildgen V, Lochi V, Lüsebrink J, Brockmann M, Schildgen O. Epidemiology of EML4–ALK translocations in a small, German non-small-cell lung cancer patient cohort. Pers. Med. 9(8), 801–803 (2012). Schildgen V, Schulz C, Lüsebrink J et al. Combination of Pyrosequencing ® and Sanger sequencing reveals alleged novel mutation in exon 18 of EGFR. Pers. Med. 10(2), 201–209 (2013). Butrynski JE, D’Adamo DR, Hornick JL et al. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N. Engl. J. Med. 363(18), 1727–1733 (2010).
6
The authors state that they have obtained verbal and written informed consent from the patients for the inclusion of their medical and treatment history within this case report.
Camidge DR, Doebele RC. Treating ALK-positive lung cancer – early successes and future challenges. Nat. Rev. Clin. Oncol. 9(5), 268–277 (2012). Chabner BA. Early accelerated approval for highly targeted cancer drugs. N. Engl. J. Med. 364(12), 1087–1089 (2011).
7
Cheng H, Xu X, Costa DB, Powell CA, Halmos B. Molecular testing in lung cancer. The time is now. Curr. Oncol. Rep. 12(5), 335–348 (2010).
8
Choi YL, Soda M, Yamashita Y et al. EML4–ALK mutations in lung cancer that confer resistance to ALK inhibitors. N. Engl. J. Med. 363(18), 1734–1739 (2010).
9
Kwak EL, Bang YJ, Camidge DR et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363(18), 1693–1703 (2010).
10 Mano H. Non-solid oncogenes in solid
tumors. EML4–ALK fusion genes in lung cancer. Cancer Sci. 99(12), 2349–2355 (2008).
Future Oncol. (2014) 10(4)
11 Kim S, Kim TM, Kim DW et al.
Heterogeneity of genetic changes associated with acquired crizotinib resistance in ALK-rearranged lung cancer. J. Thorac. Oncol. 8(4), 415–422 (2013). 12 Quest Diagnostics® – Mutation testing cascade
for patients who are candidates for EGFR antagonist therapy. http://questdiagnostics.com/hcp/intguide/ HematOnc/Gastrointestinal/TS_EGFR_ Pathway.pdf 13 Aisner DL, Marshall CB. Molecular pathology
of non-small cell lung cancer. A practical guide. Am. J. Clin. Pathol. 138(3), 332–346 (2012). 14 Li T, Kung HJ, Mack PC, Gandara DR.
Genotyping and genomic profiling of non-small-cell lung cancer. implications for current and future therapies. J. Clin. Oncol. 31(8), 1039–1049 (2013). 15 Sasaki T, Koivunen J, Ogino A et al. A novel
ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res. 71(18), 6051–6060 (2011).
future science group
