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ARTICLE IN PRESS Lung Cancer xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Case report
Emergence of RET rearrangement co-existing with activated EGFR mutation in EGFR-mutated NSCLC patients who had progressed on first- or second-generation EGFR TKI Samuel J. Klempner a , Lyudmila A. Bazhenova b , Fadi S. Braiteh c , Petros G. Nikolinakos d , Kyle Gowen e , Claudia M. Cervantes a , Juliann Chmielecki e , Joel R Greenbowe e , Jeffrey S. Ross e,f , Philip J. Stephens e , Vincent A. Miller e , Siraj M. Ali e , Sai-Hong Ignatius Ou a,∗ a Division of Hematology-Oncology, Department of Medicine, Chao Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA 92868, USA b Divsion of Hematology-Oncology, Department of Medicine, University of California San Diego School of Medicine, La Jolla, CA 92307, USA c Comprehensive Cancer Centers of Nevada, Las Vegas, NV 89169, USA d University Cancer and Blood Center, Athens, GA 30607, USA e Foundation Medicine Inc., Cambridge, MA 02141, USA f Department of Pathology and Laboratory Medicine, Albany Medical Center, Albany, NY 12208, USA
a r t i c l e
i n f o
Article history: Received 8 June 2015 Accepted 24 June 2015 Keywords: RET rearrangement Non-small cell lung cancer EGFR mutations Post-progression Acquired resistance
a b s t r a c t Objectives: The gatekeeper mutation T790M mutation is the responsible for the majority of the resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with EGFRmutated non-small cell lung cancer (NSCLC). Other previously described resistance mechanisms include HER2 amplification, MET amplification, PIK3CA mutation, epithelial–mesenchymal transition (EMT), small cell transformation have also been identified. However other resistance mechanisms remains to be discovered. Materials and methods: Hybrid-capture based comprehensive genomic profiling (CGP) was performed on pre- and post-EGFR TKI progression EGFR-mutated NSCLC tumor samples during routine clinical care. We identify two paired pre- and post-EGFR TKI progression EGFR-mutated NSCLC patient tumor samples where both post EGFR TKI samples harbored in-frame CCDC6-RET rearrangements but not in the pre-EGFR TKI tumor samples. Furthermore analysis of the clinical database revealed one additional NCOA4-RET rearrangement co-existing with activated EGFR mutation in an EGFR-mutated NSCLC patient who had progressed on afatinib. None of the known resistance mechanisms to EGFR TKI including EGFR T790M, EGFR amplification, HER2 amplification, MET amplification, PIK3CA mutation, BRAF mutation, EMT or small cell transformation was identified in the three post progression samples that now harbored RET rearrangements. Results and conclusions: This is the first report of RET rearrangement co-existing with activated EGFR mutations in EGFR-mutated patients who had progressed on either first- or second generation EGFR TKI. As such, RET rearrangement may serve as a potential resistance mechanism to EGFR TKI in EGFR-mutated NSCLC. © 2015 Elsevier Ireland Ltd. All rights reserved.
∗ Corresponding author at: Chao Family Comprehensive Cancer Center Division of Hematology–Oncology,Department of Medicine University of California Irvine School of Medicine 101 The City Drive South, Bldg 56, RT 81, Rm241 Orange, CA 92868, USA. Fax: +1 1 714 456 2242. E-mail address: [email protected] (S.-H.I. Ou).
The gatekeeper EGFR T790M mutation accounts for approximately 60% of the acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in EGFR-mutated non-small cell lung cancer (NSCLC). Other mechanisms of acquired resistance identified include HER2 amplification, EGFR amplification, MET amplification, PIK3CA mutations, BRAF mutations, epithelial-mesenchymal transition (EMT), and small cell transformation [1–3]. However in as much as 15–20% of the cases the
http://dx.doi.org/10.1016/j.lungcan.2015.06.021 0169-5002/© 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: S.J. Klempner, et al., Emergence of RET rearrangement co-existing with activated EGFR mutation in EGFR-mutated NSCLC patients who had progressed on first- or second-generation EGFR TKI, Lung Cancer (2015), http://dx.doi.org/10.1016/j.lungcan.2015.06.021
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2
Fig. 1. (A) Integrative genomics viewer (IGV) of the EGFR exon 19 deletion and CCDC6-RET fusion from patient one. (B) Integrative genomics viewer (IGV) of the EGFR exon 19 deletion and CCDC6-RET fusion from patient two. (C) Integrative genomics viewer (IGV) of the EGFR L858R and NCOA4-RET fusion from patient three.
mechanism of acquired resistance to EGFR TKI is unknown and remains to be discovered [3]. Here we report the emergence of RET rearrangement in post EGFR TKI progression EGFR-mutated NSCLC patients while retaining the original activating EGFR mutation.
1. Case Presentations Patient 1 is a 55 year-old Asian male never-smoker who presented with de-novo metastatic NSCLC in September 2011. He was treated with carboplatin/paclitaxel/bevacizumab followed by sequentially regimens of pemetrexed, carboplatin/gemcitabine, erlotinib, cislatin/navelbine/cetuximab, and docetaxel. Although he achieved a partial response to erlotinib lasting 9 months, EGFR mutation testing did not demonstrate the presence of any activating EGFR mutation. He eventually underwent biopsy of a progressing liver metastasis in October 2014. At that time both the original lung and the progressive liver metastasis biopsies were subjected to a hybrid-capture based comprehensive genomic profiling assay as previously described; [4] which identified an EGFR exon 19 deletion in both the original diagnosis sample and the liver metastasis at a mean allelic frequency (MAF) of 53% and 54% respectively. Additionally CCDC6-RET (C1; R12) fusion was detected from the liver biopsy obtained after progression on erlotinib therapy but not from the sample at the time of diagnosis. However he developed rapid hepatic progression and was not treated with any anti-RET targeted treatment. Patient 2 is a 73 year-old Asian female never-smoker who presented in 2012 with a metastatic recurrence twelve months after neoadjuvant chemoradiation and lobectomy for NSCLC adenocarcinoma. Her tumor at the time of diagnosis was EGFR wild type by
EGFR testing using reverse transcriptase-polymerase chain reaction. She was treated with three lines of cytotoxic chemotherapy over 12 months but developed disease progression in the left neck and lung parenchyma. A mediastinal lymph node biopsy was obtained and CGP revealed an EGFR exon 19 deletion mutation at a MAF of 75%. She received fourth line erlotinib for 10 months prior to developing progressive disease. A post erlotinib progression biopsy from a left cervical LN was found to harbor the original exon 19 EGFR deletion at a MAF of 62% and a novel acquired CCDC6-RET (C1; R12) fusion as demonstrated by CGP (Fig. 1B). Given these 2 cases of secondary acquired RET fusion in EGFR-mutated NSCLC patients who progressed on EGFR TKI, we retrospectively analyzed the Foundation Medicine Inc database and identified an addition case of NCOA4-RET (N6; R12) co-existing with EGFR L858R mutation (MAF 18%) in an EGFR-mutated NSCLC patient who had progressed on afatinib. The pre-afatinib sample was not subjected to CGP and hence we were not able to confirm NCOA4RET was an acquired mutation arising in the context of resistance to erlotinib.
2. Discussion We are the first to report the co-existence of functional RET rearrangement and activated EGFR mutation in NSCLC. RET rearrangements have been shown to actionable driver mutations on their own in NSCLC [5–7] analogous to ALK- and ROS1-rearrangement in NSCLC. Although the co-existence of dual actionable driver mutations in NSCLC is rare, [8] it has been reported in literature especially receptor tyrosine kinase (RTK) fusions involving the anaplastic lymphoma kinase (ALK) and acti-
Please cite this article in press as: S.J. Klempner, et al., Emergence of RET rearrangement co-existing with activated EGFR mutation in EGFR-mutated NSCLC patients who had progressed on first- or second-generation EGFR TKI, Lung Cancer (2015), http://dx.doi.org/10.1016/j.lungcan.2015.06.021
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vated EGFR mutations [9]. However most of these dual actionable driver mutations are identified from tumor samples that were treatment-naïve. As such it remains unknown which one of the two actionable driver mutations is the dominant driver mutation and the treatment strategy be it sequential or combination targeted therapy. Alternatively the RET rearrangement may exist as a minor clone in the our three EGFR-mutated NSCLC samples and could have expanded clonally while the activated EGFR mutated tumor clone was inhibited by EGFR TKI, a clinical scenario analogous to the appearance of the gatekeeper T790M mutation during EGFR TKI [10] However, we did not detect the existence of RET rearrangement in the pre-EGFR TKI tumor sample at >500x coverage. Intron 11 of RET is a known site of fragile DNA secondary structures and is thought to be more susceptible to topoisomerase I and topoisomerase II mediated DNA breakage and increased recombination in response to radiation-induced DNA damage [11–12]. Recent RET breakpoint analysis suggests small, 2.0 kilobase, nonspecific regions spanning RET exon 11 to intron 11 are involved in nearly all RET-rearranged NSCLC [13]. Currently there is insufficient data to suggest that the traditional chemotherapy and/or targeted therapy would predispose to chromosomal rearrangement. We did not detect other well-established resistance mechanisms to first- or second generation EGFR TKIs in EGFR-mutated NSCLC EGFR such as T790M mutation, amplification of HER2 or MET, mutations in PIK3CA or BRAF, histologic changes such as epithelialmesenchymal transition or small cell transformation. Hence this report indicated RTK kinase fusions might function as a potential acquired resistance mechanism to EGFR TKI in EGFR-mutated NSCLC analogous to the situation where activating of the EGFR pathway can confer resistance to crizotinib in the treatment of ALK-rearranged NSCLC [14]. Therefore combination therapy with anti-EGFR and anti-RET therapy will likely be required to overcome this resistance. Definitive proof that RET rearrangement is an acquired resistance mechanism to EGFR TKI will require clinical response to combination anti-EGFR and anti-RET therapy. None of the patients reported in this reported received combination antiEGFR and anti-RET therapy. This report provide the basis for the hypothesis that an actionable driver mutation can also serve as a mechanism for acquired resistance mechanism for another actionable driver mutation and that acquired RET rearrangement can potential serve an additional resistance mechanism to EGFR TKI in EGFR-mutated NSCLC. Conflict of interest
3
Kyle Gowen, Juliann Chmielecki, Joel R Greenbowe, Siraj Ali, Jeffrey S. Ross, Philip J. Stephens, and Vicent A. Miller are employees of Foundation Medicine, Inc and hold stocks and stock options in Foundation Medicine, Inc. Sai-Hong Ignatius Ou has received honorarium as a member of the Speaker bureau and Advisory Board for Pfizer and Roche. Lyudmila A. Bazhenova, Fadi S. Braiteh, Petros G. Nikolinakos, and Claudia M. Cervantes have nothing to declare. References [1] L.V. Sequist, B.A. Waltman, D. Dias-Santagata, S. Digumarthy, A.B. Turke, P. Fidias, et al., Sci. Transl. Med. 3 (March (23)) (2011) (75) 75ra26. [2] H.A. Yu, M.E. Arcila, N. Rekhtman, C.S. Sima, M.F. Zakowski, W. Pao, et al., Clin. Cancer Res. 19 (2013) 2240–2247. [3] D.R. Camidge, W. Pao, L.V. Sequist, Acquired resistance to TKIs in solid tumours: learning from lung cancer, Nat. Rev. Clin. Oncol. 11 (2014) 473–481. [4] A. Drilon, L. Wang, M.E. Arcila, S. Balasubramanian, J.R. Greenbowe, J.S. Ross, et al., 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. (January (7)) (2015) [Epub ahead of print]. [5] A. Drilon, L. Wang, A. Hasanovic, Y. Suehara, D. Lipson, P. Stephens, et al., Response to cabozantinib in patients with RET fusion-positive lung adenocarcinomas, Cancer Discov. 3 (2013) 630–635. ˜ [6] G.S. Falchook, N.G. Ordónez, C.C. Bastida, P.J. Stephens, V.A. Miller, L. Gaido, et al., Effect of the RET Inhibitor vandetanib in a patient With RET fusion-positive metastatic non-small-cell lung cancer, J. Clin. Oncol. (November (3)) (2014) [Epub ahead of print]. [7] A.E. Drilon, C.S. Sima, R. Somwar, R. Smith, M.S. Ginsberg, G.J. Riely, et al., Phase II. study of cabozantinib for patients with advanced RET-rearranged lung cancers, Clin. Oncol. 33 (2015) (suppl; abstr 8007). [8] J.F. Gainor, A.M. Varghese, S.H. Ou, S. Kabraji, M.M. Awad, R. Katayama, et al., ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1683 patients with non-small cell lung cancer, Clin. Cancer Res. 19 (2013) 4273–4281. [9] S.H. Ou, C.H. Bartlett, M. Mino-Kenudson, J. Cui, A.J. Iafrate, Crizotinib for the treatment of ALK-rearranged non-small cell lung cancer: a success story to usher in the second decade of molecular targeted therapy in oncology, Oncologist 17 (2012) 1351–1375. [10] N. Karachaliou, C. Mayo-de las Casas, C. Queralt, I. de Aguirre, B. Melloni, F. Cardenal, et al., Association of EGFR L858R mutation in circulating free DNA with survival in the EURTAC trial, JAMA Oncol. 1 (2015) 149–157. [11] L.M. Mulligan, RET revisited: expanding the oncogenic portfolio, Nat. Rev. Cancer 14 (2014) 173–186. [12] L.W. Dillon, L.C. Pierce, C.E. Lehman, Y.E. Nikiforov, Y.H. Wang, DNA topoisomerases participate in fragility of the oncogene RET, PLoS One 8 (9) (2013) e75741. [13] T. Mizukami, K. Shiraishi, Y. Shimada, H. Ogiwara, K. Tsuta, H. Ichikawa, et al., Molecular mechanisms underlying oncogenic RET fusion in lung adenocarcinoma, J. Thorac. Oncol. 9 (2014) 622–630. [14] T. Sasaki, J. Koivunen, A. Ogino, M. Yanagita, S. Nikiforow, W. Zheng, et al., A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors, Cancer Res. 71 (2011) 6051–6060.
Samuel J. Klempner has received honorarium as a member of the Speaker bureau for Foundation Medicine Inc.
Please cite this article in press as: S.J. Klempner, et al., Emergence of RET rearrangement co-existing with activated EGFR mutation in EGFR-mutated NSCLC patients who had progressed on first- or second-generation EGFR TKI, Lung Cancer (2015), http://dx.doi.org/10.1016/j.lungcan.2015.06.021
ARTICLE IN PRESS Lung Cancer xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Case report
Emergence of RET rearrangement co-existing with activated EGFR mutation in EGFR-mutated NSCLC patients who had progressed on first- or second-generation EGFR TKI Samuel J. Klempner a , Lyudmila A. Bazhenova b , Fadi S. Braiteh c , Petros G. Nikolinakos d , Kyle Gowen e , Claudia M. Cervantes a , Juliann Chmielecki e , Joel R Greenbowe e , Jeffrey S. Ross e,f , Philip J. Stephens e , Vincent A. Miller e , Siraj M. Ali e , Sai-Hong Ignatius Ou a,∗ a Division of Hematology-Oncology, Department of Medicine, Chao Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA 92868, USA b Divsion of Hematology-Oncology, Department of Medicine, University of California San Diego School of Medicine, La Jolla, CA 92307, USA c Comprehensive Cancer Centers of Nevada, Las Vegas, NV 89169, USA d University Cancer and Blood Center, Athens, GA 30607, USA e Foundation Medicine Inc., Cambridge, MA 02141, USA f Department of Pathology and Laboratory Medicine, Albany Medical Center, Albany, NY 12208, USA
a r t i c l e
i n f o
Article history: Received 8 June 2015 Accepted 24 June 2015 Keywords: RET rearrangement Non-small cell lung cancer EGFR mutations Post-progression Acquired resistance
a b s t r a c t Objectives: The gatekeeper mutation T790M mutation is the responsible for the majority of the resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with EGFRmutated non-small cell lung cancer (NSCLC). Other previously described resistance mechanisms include HER2 amplification, MET amplification, PIK3CA mutation, epithelial–mesenchymal transition (EMT), small cell transformation have also been identified. However other resistance mechanisms remains to be discovered. Materials and methods: Hybrid-capture based comprehensive genomic profiling (CGP) was performed on pre- and post-EGFR TKI progression EGFR-mutated NSCLC tumor samples during routine clinical care. We identify two paired pre- and post-EGFR TKI progression EGFR-mutated NSCLC patient tumor samples where both post EGFR TKI samples harbored in-frame CCDC6-RET rearrangements but not in the pre-EGFR TKI tumor samples. Furthermore analysis of the clinical database revealed one additional NCOA4-RET rearrangement co-existing with activated EGFR mutation in an EGFR-mutated NSCLC patient who had progressed on afatinib. None of the known resistance mechanisms to EGFR TKI including EGFR T790M, EGFR amplification, HER2 amplification, MET amplification, PIK3CA mutation, BRAF mutation, EMT or small cell transformation was identified in the three post progression samples that now harbored RET rearrangements. Results and conclusions: This is the first report of RET rearrangement co-existing with activated EGFR mutations in EGFR-mutated patients who had progressed on either first- or second generation EGFR TKI. As such, RET rearrangement may serve as a potential resistance mechanism to EGFR TKI in EGFR-mutated NSCLC. © 2015 Elsevier Ireland Ltd. All rights reserved.
∗ Corresponding author at: Chao Family Comprehensive Cancer Center Division of Hematology–Oncology,Department of Medicine University of California Irvine School of Medicine 101 The City Drive South, Bldg 56, RT 81, Rm241 Orange, CA 92868, USA. Fax: +1 1 714 456 2242. E-mail address: [email protected] (S.-H.I. Ou).
The gatekeeper EGFR T790M mutation accounts for approximately 60% of the acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in EGFR-mutated non-small cell lung cancer (NSCLC). Other mechanisms of acquired resistance identified include HER2 amplification, EGFR amplification, MET amplification, PIK3CA mutations, BRAF mutations, epithelial-mesenchymal transition (EMT), and small cell transformation [1–3]. However in as much as 15–20% of the cases the
http://dx.doi.org/10.1016/j.lungcan.2015.06.021 0169-5002/© 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: S.J. Klempner, et al., Emergence of RET rearrangement co-existing with activated EGFR mutation in EGFR-mutated NSCLC patients who had progressed on first- or second-generation EGFR TKI, Lung Cancer (2015), http://dx.doi.org/10.1016/j.lungcan.2015.06.021
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Fig. 1. (A) Integrative genomics viewer (IGV) of the EGFR exon 19 deletion and CCDC6-RET fusion from patient one. (B) Integrative genomics viewer (IGV) of the EGFR exon 19 deletion and CCDC6-RET fusion from patient two. (C) Integrative genomics viewer (IGV) of the EGFR L858R and NCOA4-RET fusion from patient three.
mechanism of acquired resistance to EGFR TKI is unknown and remains to be discovered [3]. Here we report the emergence of RET rearrangement in post EGFR TKI progression EGFR-mutated NSCLC patients while retaining the original activating EGFR mutation.
1. Case Presentations Patient 1 is a 55 year-old Asian male never-smoker who presented with de-novo metastatic NSCLC in September 2011. He was treated with carboplatin/paclitaxel/bevacizumab followed by sequentially regimens of pemetrexed, carboplatin/gemcitabine, erlotinib, cislatin/navelbine/cetuximab, and docetaxel. Although he achieved a partial response to erlotinib lasting 9 months, EGFR mutation testing did not demonstrate the presence of any activating EGFR mutation. He eventually underwent biopsy of a progressing liver metastasis in October 2014. At that time both the original lung and the progressive liver metastasis biopsies were subjected to a hybrid-capture based comprehensive genomic profiling assay as previously described; [4] which identified an EGFR exon 19 deletion in both the original diagnosis sample and the liver metastasis at a mean allelic frequency (MAF) of 53% and 54% respectively. Additionally CCDC6-RET (C1; R12) fusion was detected from the liver biopsy obtained after progression on erlotinib therapy but not from the sample at the time of diagnosis. However he developed rapid hepatic progression and was not treated with any anti-RET targeted treatment. Patient 2 is a 73 year-old Asian female never-smoker who presented in 2012 with a metastatic recurrence twelve months after neoadjuvant chemoradiation and lobectomy for NSCLC adenocarcinoma. Her tumor at the time of diagnosis was EGFR wild type by
EGFR testing using reverse transcriptase-polymerase chain reaction. She was treated with three lines of cytotoxic chemotherapy over 12 months but developed disease progression in the left neck and lung parenchyma. A mediastinal lymph node biopsy was obtained and CGP revealed an EGFR exon 19 deletion mutation at a MAF of 75%. She received fourth line erlotinib for 10 months prior to developing progressive disease. A post erlotinib progression biopsy from a left cervical LN was found to harbor the original exon 19 EGFR deletion at a MAF of 62% and a novel acquired CCDC6-RET (C1; R12) fusion as demonstrated by CGP (Fig. 1B). Given these 2 cases of secondary acquired RET fusion in EGFR-mutated NSCLC patients who progressed on EGFR TKI, we retrospectively analyzed the Foundation Medicine Inc database and identified an addition case of NCOA4-RET (N6; R12) co-existing with EGFR L858R mutation (MAF 18%) in an EGFR-mutated NSCLC patient who had progressed on afatinib. The pre-afatinib sample was not subjected to CGP and hence we were not able to confirm NCOA4RET was an acquired mutation arising in the context of resistance to erlotinib.
2. Discussion We are the first to report the co-existence of functional RET rearrangement and activated EGFR mutation in NSCLC. RET rearrangements have been shown to actionable driver mutations on their own in NSCLC [5–7] analogous to ALK- and ROS1-rearrangement in NSCLC. Although the co-existence of dual actionable driver mutations in NSCLC is rare, [8] it has been reported in literature especially receptor tyrosine kinase (RTK) fusions involving the anaplastic lymphoma kinase (ALK) and acti-
Please cite this article in press as: S.J. Klempner, et al., Emergence of RET rearrangement co-existing with activated EGFR mutation in EGFR-mutated NSCLC patients who had progressed on first- or second-generation EGFR TKI, Lung Cancer (2015), http://dx.doi.org/10.1016/j.lungcan.2015.06.021
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vated EGFR mutations [9]. However most of these dual actionable driver mutations are identified from tumor samples that were treatment-naïve. As such it remains unknown which one of the two actionable driver mutations is the dominant driver mutation and the treatment strategy be it sequential or combination targeted therapy. Alternatively the RET rearrangement may exist as a minor clone in the our three EGFR-mutated NSCLC samples and could have expanded clonally while the activated EGFR mutated tumor clone was inhibited by EGFR TKI, a clinical scenario analogous to the appearance of the gatekeeper T790M mutation during EGFR TKI [10] However, we did not detect the existence of RET rearrangement in the pre-EGFR TKI tumor sample at >500x coverage. Intron 11 of RET is a known site of fragile DNA secondary structures and is thought to be more susceptible to topoisomerase I and topoisomerase II mediated DNA breakage and increased recombination in response to radiation-induced DNA damage [11–12]. Recent RET breakpoint analysis suggests small, 2.0 kilobase, nonspecific regions spanning RET exon 11 to intron 11 are involved in nearly all RET-rearranged NSCLC [13]. Currently there is insufficient data to suggest that the traditional chemotherapy and/or targeted therapy would predispose to chromosomal rearrangement. We did not detect other well-established resistance mechanisms to first- or second generation EGFR TKIs in EGFR-mutated NSCLC EGFR such as T790M mutation, amplification of HER2 or MET, mutations in PIK3CA or BRAF, histologic changes such as epithelialmesenchymal transition or small cell transformation. Hence this report indicated RTK kinase fusions might function as a potential acquired resistance mechanism to EGFR TKI in EGFR-mutated NSCLC analogous to the situation where activating of the EGFR pathway can confer resistance to crizotinib in the treatment of ALK-rearranged NSCLC [14]. Therefore combination therapy with anti-EGFR and anti-RET therapy will likely be required to overcome this resistance. Definitive proof that RET rearrangement is an acquired resistance mechanism to EGFR TKI will require clinical response to combination anti-EGFR and anti-RET therapy. None of the patients reported in this reported received combination antiEGFR and anti-RET therapy. This report provide the basis for the hypothesis that an actionable driver mutation can also serve as a mechanism for acquired resistance mechanism for another actionable driver mutation and that acquired RET rearrangement can potential serve an additional resistance mechanism to EGFR TKI in EGFR-mutated NSCLC. Conflict of interest
3
Kyle Gowen, Juliann Chmielecki, Joel R Greenbowe, Siraj Ali, Jeffrey S. Ross, Philip J. Stephens, and Vicent A. Miller are employees of Foundation Medicine, Inc and hold stocks and stock options in Foundation Medicine, Inc. Sai-Hong Ignatius Ou has received honorarium as a member of the Speaker bureau and Advisory Board for Pfizer and Roche. Lyudmila A. Bazhenova, Fadi S. Braiteh, Petros G. Nikolinakos, and Claudia M. Cervantes have nothing to declare. References [1] L.V. Sequist, B.A. Waltman, D. Dias-Santagata, S. Digumarthy, A.B. Turke, P. Fidias, et al., Sci. Transl. Med. 3 (March (23)) (2011) (75) 75ra26. [2] H.A. Yu, M.E. Arcila, N. Rekhtman, C.S. Sima, M.F. Zakowski, W. Pao, et al., Clin. Cancer Res. 19 (2013) 2240–2247. [3] D.R. Camidge, W. Pao, L.V. Sequist, Acquired resistance to TKIs in solid tumours: learning from lung cancer, Nat. Rev. Clin. Oncol. 11 (2014) 473–481. [4] A. Drilon, L. Wang, M.E. Arcila, S. Balasubramanian, J.R. Greenbowe, J.S. Ross, et al., 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. (January (7)) (2015) [Epub ahead of print]. [5] A. Drilon, L. Wang, A. Hasanovic, Y. Suehara, D. Lipson, P. Stephens, et al., Response to cabozantinib in patients with RET fusion-positive lung adenocarcinomas, Cancer Discov. 3 (2013) 630–635. ˜ [6] G.S. Falchook, N.G. Ordónez, C.C. Bastida, P.J. Stephens, V.A. Miller, L. Gaido, et al., Effect of the RET Inhibitor vandetanib in a patient With RET fusion-positive metastatic non-small-cell lung cancer, J. Clin. Oncol. (November (3)) (2014) [Epub ahead of print]. [7] A.E. Drilon, C.S. Sima, R. Somwar, R. Smith, M.S. Ginsberg, G.J. Riely, et al., Phase II. study of cabozantinib for patients with advanced RET-rearranged lung cancers, Clin. Oncol. 33 (2015) (suppl; abstr 8007). [8] J.F. Gainor, A.M. Varghese, S.H. Ou, S. Kabraji, M.M. Awad, R. Katayama, et al., ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1683 patients with non-small cell lung cancer, Clin. Cancer Res. 19 (2013) 4273–4281. [9] S.H. Ou, C.H. Bartlett, M. Mino-Kenudson, J. Cui, A.J. Iafrate, Crizotinib for the treatment of ALK-rearranged non-small cell lung cancer: a success story to usher in the second decade of molecular targeted therapy in oncology, Oncologist 17 (2012) 1351–1375. [10] N. Karachaliou, C. Mayo-de las Casas, C. Queralt, I. de Aguirre, B. Melloni, F. Cardenal, et al., Association of EGFR L858R mutation in circulating free DNA with survival in the EURTAC trial, JAMA Oncol. 1 (2015) 149–157. [11] L.M. Mulligan, RET revisited: expanding the oncogenic portfolio, Nat. Rev. Cancer 14 (2014) 173–186. [12] L.W. Dillon, L.C. Pierce, C.E. Lehman, Y.E. Nikiforov, Y.H. Wang, DNA topoisomerases participate in fragility of the oncogene RET, PLoS One 8 (9) (2013) e75741. [13] T. Mizukami, K. Shiraishi, Y. Shimada, H. Ogiwara, K. Tsuta, H. Ichikawa, et al., Molecular mechanisms underlying oncogenic RET fusion in lung adenocarcinoma, J. Thorac. Oncol. 9 (2014) 622–630. [14] T. Sasaki, J. Koivunen, A. Ogino, M. Yanagita, S. Nikiforow, W. Zheng, et al., A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors, Cancer Res. 71 (2011) 6051–6060.
Samuel J. Klempner has received honorarium as a member of the Speaker bureau for Foundation Medicine Inc.
Please cite this article in press as: S.J. Klempner, et al., Emergence of RET rearrangement co-existing with activated EGFR mutation in EGFR-mutated NSCLC patients who had progressed on first- or second-generation EGFR TKI, Lung Cancer (2015), http://dx.doi.org/10.1016/j.lungcan.2015.06.021
