Annals of Oncology Advance Access published January 24, 2016 1
Transformation of ALK rearrangement–positive adenocarcinoma to small cell lung cancer in association with acquired resistance to alectinib
Takeda1, K. Nakagawa1 1
Department of Medical Oncology, Kinki University Faculty of Medicine,
Osaka-Sayama, Japan 2
Department of Pathology, Kishiwada City Hospital, Kishiwada, Japan
*
Correspondence: (E-mail: [email protected])
Keywords: ALK inhibitor, alectinib, acquired resistance, transformation, small cell lung cancer
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at Orta Dogu Teknik University Library (ODTU) on January 28, 2016
N. Takegawa1, H. Hayashi1,*, N. Iizuka2, T. Takahama1, H. Ueda1, K. Tanaka1, M.
2
A 43-year-old woman was diagnosed with lung cancer accompanied by multiple lung and brain metastases. Thoracoscopic lung biopsy and pathological analysis revealed an
combination of cisplatin and pemetrexed, but she experienced disease progression after six cycles. Fluorescence in situ hybridization (FISH) analysis of the biopsied tumor tissue revealed rearrangement of the anaplastic lymphoma kinase gene (ALK), and treatment with crizotinib was therefore initiated. The patient achieved a partial response, but computed tomography (CT) revealed disease progression of pulmonary metastases after 6 months. Crizotinib was discontinued, and sequential chemotherapies including S-1, docetaxel, erlotinib, gemcitabine, and rechallenge with crizotinib were administered. Eighteen months after progression during the initial crizotinib treatment, CT again revealed progression of lung and brain metastases. Alectinib was then administered, and CT revealed a partial response (Fig. 1B, C). The patient was well managed with this drug for 13 months, after which she experienced disease progression (Fig. 1D). Transbronchial lung biopsy and pathological analysis performed to determine subsequent chemotherapy revealed a small cell lung cancer (SCLC) histology (Fig. 1E). FISH analysis of the new biopsy specimens showed
Downloaded from http://annonc.oxfordjournals.org/ at Orta Dogu Teknik University Library (ODTU) on January 28, 2016
adenocarcinoma histology (Fig. 1A). The patient underwent salvage therapy with the
3
ALK rearrangement (Fig. 1F), and immunohistochemical analysis detected both synaptophysin (Fig. 1G) and CD56 (Fig. 1H) immunoreactivity. The patient died soon thereafter as a result of rapid disease progression.
highly effective for treatment of non–small cell lung cancer (NSCLC) positive for ALK rearrangement. However, patients so treated eventually develop resistance to these agents. Mechanisms underlying the development of acquired resistance to ALK inhibitors include ALK amplification, ALK secondary mutation, and activation of bypass pathways [1]. Similar resistance mechanisms are operative in NSCLC patients positive for epidermal growth factor receptor gene (EGFR) mutations who are treated with EGFR-TKIs. In addition, a subset of EGFR-TKI–resistant tumors has been found to undergo histological transformation to SCLC [2]. However, despite the performance of repeat biopsies after disease progression in studies of NSCLC patients treated with crizotinib, as far as we are aware no case of SCLC transformation has been described. The present case now suggests that transformation to SCLC is a mechanism of acquired drug resistance in ALK rearrangement–positive patients treated with alectinib. It is possible that our patient originally harbored a combination of NSCLC and SCLC. However, histological evidence of SCLC was not apparent in the adequate tumor
Downloaded from http://annonc.oxfordjournals.org/ at Orta Dogu Teknik University Library (ODTU) on January 28, 2016
ALK tyrosine kinase inhibitors (TKIs) such as crizotinib and alectinib are
4
specimens obtained at the initial thoracoscopic lung biopsy. Alternatively, the transformation to SCLC might have resulted from molecular changes in tumor stem cells induced by alectinib treatment, as has been described for the transformation of
treatment [3]. In addition, loss of retinoblastoma protein (RB) expression has been associated with transformation to SCLC in EGFR-TKI–treated patients [4], and we detected loss of RB expression in the tumor specimens obtained after alectinib treatment (Fig. 1I, J). Our findings thus suggest that loss of RB is also associated with the development of acquired resistance to alectinib in ALK rearrangement–positive NSCLC. In summary, as far as we are aware, this is the first case of adenocarcinoma transformation to SCLC after ALK-TKI treatment confirmed by robust histological examination. Our case suggests that SCLC transformation is a mechanism of acquired resistance to such treatment, in particular for alectinib.
Disclosure KN. has received honoraria from Astellas Pharma Inc. and AstraZeneca K.K., grants from AstraZeneca K.K. and Taiho Pharmaceutical Co. Ltd., and research funding from
Downloaded from http://annonc.oxfordjournals.org/ at Orta Dogu Teknik University Library (ODTU) on January 28, 2016
EGFR mutation–positive adenocarcinoma to SCLC associated with EGFR-TKI
5
Taiho Pharmaceutical Co. Ltd. HH. has received lecture fees from AstraZeneca K.K., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., and Taiho Pharmaceutical Co. Ltd., as well as advisory fees from
All remaining authors have declared no conflicts of interest.
Downloaded from http://annonc.oxfordjournals.org/ at Orta Dogu Teknik University Library (ODTU) on January 28, 2016
AstraZeneca K.K., Boehringer Ingelheim Japan Inc., and Eli Lilly Japan K.K.
6
References 1.
Isozaki H, Takigawa N, Kiura K. Mechanisms of Acquired Resistance to ALK
2015; 7: 763-783. 2.
Stewart EL, Tan SZ, Liu G, Tsao MS. Known and putative mechanisms of
resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations-a review. Transl Lung Cancer Res 2015; 4: 67-81. 3.
Oser MG, Niederst MJ, Sequist LV, Engelman JA. Transformation from
non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol 2015; 16: e165-172. 4.
Niederst MJ, Sequist LV, Poirier JT et al. RB loss in resistant EGFR mutant
lung adenocarcinomas that transform to small-cell lung cancer. Nat Commun 2015; 6: 6377.
Downloaded from http://annonc.oxfordjournals.org/ at Orta Dogu Teknik University Library (ODTU) on January 28, 2016
Inhibitors and the Rationale for Treating ALK-positive Lung Cancer. Cancers (Basel)
7
Figure Legend Figure 1. Pathological, immunostaining, and CT findings for the present patient. (A)
tumor obtained at diagnosis revealing an adenocarcinoma histology. (B–D) Contrast-enhanced CT of the chest before (B) as well as 2 months (C) and 13 months (D) after initiation of alectinib therapy. The primary tumor (arrows) had decreased in size at 2 months and manifested disease progression at 13 months. (E) Hematoxylin-eosin staining of a specimen of the primary tumor obtained after alectinib treatment revealing an SCLC histology. (F) FISH analysis of the primary tumor at second biopsy with break-apart probes (red and green) showing ALK translocation. (G, H) Immunohistochemical analysis revealing diffuse staining for synaptophysin (G) and CD56 (H) in the primary tumor at second biopsy. (I, J) Immunohistochemical analysis showing substantial RB expression in the primary tumor before (I) but not after (J) alectinib treatment.
Downloaded from http://annonc.oxfordjournals.org/ at Orta Dogu Teknik University Library (ODTU) on January 28, 2016
Hematoxylin-eosin staining for a thoracoscopic lung biopsy specimen of the primary
8
Downloaded from http://annonc.oxfordjournals.org/ at Orta Dogu Teknik University Library (ODTU) on January 28, 2016
Transformation of ALK rearrangement–positive adenocarcinoma to small cell lung cancer in association with acquired resistance to alectinib
Takeda1, K. Nakagawa1 1
Department of Medical Oncology, Kinki University Faculty of Medicine,
Osaka-Sayama, Japan 2
Department of Pathology, Kishiwada City Hospital, Kishiwada, Japan
*
Correspondence: (E-mail: [email protected])
Keywords: ALK inhibitor, alectinib, acquired resistance, transformation, small cell lung cancer
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at Orta Dogu Teknik University Library (ODTU) on January 28, 2016
N. Takegawa1, H. Hayashi1,*, N. Iizuka2, T. Takahama1, H. Ueda1, K. Tanaka1, M.
2
A 43-year-old woman was diagnosed with lung cancer accompanied by multiple lung and brain metastases. Thoracoscopic lung biopsy and pathological analysis revealed an
combination of cisplatin and pemetrexed, but she experienced disease progression after six cycles. Fluorescence in situ hybridization (FISH) analysis of the biopsied tumor tissue revealed rearrangement of the anaplastic lymphoma kinase gene (ALK), and treatment with crizotinib was therefore initiated. The patient achieved a partial response, but computed tomography (CT) revealed disease progression of pulmonary metastases after 6 months. Crizotinib was discontinued, and sequential chemotherapies including S-1, docetaxel, erlotinib, gemcitabine, and rechallenge with crizotinib were administered. Eighteen months after progression during the initial crizotinib treatment, CT again revealed progression of lung and brain metastases. Alectinib was then administered, and CT revealed a partial response (Fig. 1B, C). The patient was well managed with this drug for 13 months, after which she experienced disease progression (Fig. 1D). Transbronchial lung biopsy and pathological analysis performed to determine subsequent chemotherapy revealed a small cell lung cancer (SCLC) histology (Fig. 1E). FISH analysis of the new biopsy specimens showed
Downloaded from http://annonc.oxfordjournals.org/ at Orta Dogu Teknik University Library (ODTU) on January 28, 2016
adenocarcinoma histology (Fig. 1A). The patient underwent salvage therapy with the
3
ALK rearrangement (Fig. 1F), and immunohistochemical analysis detected both synaptophysin (Fig. 1G) and CD56 (Fig. 1H) immunoreactivity. The patient died soon thereafter as a result of rapid disease progression.
highly effective for treatment of non–small cell lung cancer (NSCLC) positive for ALK rearrangement. However, patients so treated eventually develop resistance to these agents. Mechanisms underlying the development of acquired resistance to ALK inhibitors include ALK amplification, ALK secondary mutation, and activation of bypass pathways [1]. Similar resistance mechanisms are operative in NSCLC patients positive for epidermal growth factor receptor gene (EGFR) mutations who are treated with EGFR-TKIs. In addition, a subset of EGFR-TKI–resistant tumors has been found to undergo histological transformation to SCLC [2]. However, despite the performance of repeat biopsies after disease progression in studies of NSCLC patients treated with crizotinib, as far as we are aware no case of SCLC transformation has been described. The present case now suggests that transformation to SCLC is a mechanism of acquired drug resistance in ALK rearrangement–positive patients treated with alectinib. It is possible that our patient originally harbored a combination of NSCLC and SCLC. However, histological evidence of SCLC was not apparent in the adequate tumor
Downloaded from http://annonc.oxfordjournals.org/ at Orta Dogu Teknik University Library (ODTU) on January 28, 2016
ALK tyrosine kinase inhibitors (TKIs) such as crizotinib and alectinib are
4
specimens obtained at the initial thoracoscopic lung biopsy. Alternatively, the transformation to SCLC might have resulted from molecular changes in tumor stem cells induced by alectinib treatment, as has been described for the transformation of
treatment [3]. In addition, loss of retinoblastoma protein (RB) expression has been associated with transformation to SCLC in EGFR-TKI–treated patients [4], and we detected loss of RB expression in the tumor specimens obtained after alectinib treatment (Fig. 1I, J). Our findings thus suggest that loss of RB is also associated with the development of acquired resistance to alectinib in ALK rearrangement–positive NSCLC. In summary, as far as we are aware, this is the first case of adenocarcinoma transformation to SCLC after ALK-TKI treatment confirmed by robust histological examination. Our case suggests that SCLC transformation is a mechanism of acquired resistance to such treatment, in particular for alectinib.
Disclosure KN. has received honoraria from Astellas Pharma Inc. and AstraZeneca K.K., grants from AstraZeneca K.K. and Taiho Pharmaceutical Co. Ltd., and research funding from
Downloaded from http://annonc.oxfordjournals.org/ at Orta Dogu Teknik University Library (ODTU) on January 28, 2016
EGFR mutation–positive adenocarcinoma to SCLC associated with EGFR-TKI
5
Taiho Pharmaceutical Co. Ltd. HH. has received lecture fees from AstraZeneca K.K., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., and Taiho Pharmaceutical Co. Ltd., as well as advisory fees from
All remaining authors have declared no conflicts of interest.
Downloaded from http://annonc.oxfordjournals.org/ at Orta Dogu Teknik University Library (ODTU) on January 28, 2016
AstraZeneca K.K., Boehringer Ingelheim Japan Inc., and Eli Lilly Japan K.K.
6
References 1.
Isozaki H, Takigawa N, Kiura K. Mechanisms of Acquired Resistance to ALK
2015; 7: 763-783. 2.
Stewart EL, Tan SZ, Liu G, Tsao MS. Known and putative mechanisms of
resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations-a review. Transl Lung Cancer Res 2015; 4: 67-81. 3.
Oser MG, Niederst MJ, Sequist LV, Engelman JA. Transformation from
non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol 2015; 16: e165-172. 4.
Niederst MJ, Sequist LV, Poirier JT et al. RB loss in resistant EGFR mutant
lung adenocarcinomas that transform to small-cell lung cancer. Nat Commun 2015; 6: 6377.
Downloaded from http://annonc.oxfordjournals.org/ at Orta Dogu Teknik University Library (ODTU) on January 28, 2016
Inhibitors and the Rationale for Treating ALK-positive Lung Cancer. Cancers (Basel)
7
Figure Legend Figure 1. Pathological, immunostaining, and CT findings for the present patient. (A)
tumor obtained at diagnosis revealing an adenocarcinoma histology. (B–D) Contrast-enhanced CT of the chest before (B) as well as 2 months (C) and 13 months (D) after initiation of alectinib therapy. The primary tumor (arrows) had decreased in size at 2 months and manifested disease progression at 13 months. (E) Hematoxylin-eosin staining of a specimen of the primary tumor obtained after alectinib treatment revealing an SCLC histology. (F) FISH analysis of the primary tumor at second biopsy with break-apart probes (red and green) showing ALK translocation. (G, H) Immunohistochemical analysis revealing diffuse staining for synaptophysin (G) and CD56 (H) in the primary tumor at second biopsy. (I, J) Immunohistochemical analysis showing substantial RB expression in the primary tumor before (I) but not after (J) alectinib treatment.
Downloaded from http://annonc.oxfordjournals.org/ at Orta Dogu Teknik University Library (ODTU) on January 28, 2016
Hematoxylin-eosin staining for a thoracoscopic lung biopsy specimen of the primary
8
Downloaded from http://annonc.oxfordjournals.org/ at Orta Dogu Teknik University Library (ODTU) on January 28, 2016
