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Osimertinib for Epidermal Growth Factor Receptor Mutation–Positive Lung Adenocarcinoma That Transformed to T790M-Positive Squamous Cell Carcinoma
October 2017
References 1. Shah SU, Mashayekhi A, Shields CL, et al. Uveal metastasis from lung cancer: clinical features, treatment, and outcome in 194 patients. Ophthalmology. 2014;121:352–357. 2. Mok TS, Wu Y-L, Ahn M-J, et al. Osimertinib or platinum– pemetrexed in EGFR T790M–positive lung cancer. N Engl J Med. 2017;376:629–640. 3. Jardel P, Sauerwein W, Olivier T, et al. Management of choroidal metastases. Cancer Treat Rev. 2014;40:1119–1128.
Osimertinib for Epidermal Growth Factor Receptor Mutation–Positive Lung Adenocarcinoma That Transformed to T790M-Positive Squamous Cell Carcinoma To the Editor: We report a case of EGFR mutation–positive lung cancer transformed into squamous cell carcinoma after treatment with an EGFR tyrosine kinase inhibitor (TKI). In addition, because T790M was also
Disclosure: The authors declare no conflict of interest. Address for correspondence: Hiroyuki Suzuki, MD, PhD, Department of Chest Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan. E-mail: [email protected] ª 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. ISSN: 1556-0864 http://dx.doi.org/10.1016/j.jtho.2017.06.071
Letters to the Editor
e167
4. Maskell D, Geropantas K, Kouroupis M, Glenn A, Ajithkumar T. Treatment of choice for patients with EGFR mutation-positive non-small cell lung carcinoma presenting with choroidal metastases: radiotherapy or TKIs? Can J Ophthalmol. 2017;52:e22–e25. 5. Nair AG, Asnani HT, Mehta VC, et al. Tyrosine kinase inhibitors in the treatment of choroidal metastases from non-small-cell lung cancer: a case report and review of literature. Ocul Oncol Pathol. 2017;3:28–33.
expressed, administration of osimertinib had a therapeutic effect. A 69-year-old man presented with dyspnea. He was a former smoker. Chest radiography and whole-body positron emission tomography (PET) and computed tomography (CT) (PET-CT) revealed a right lower lobe mass, enlarged mediastinal lymph nodes, and multiple bone metastases (Fig. 1A). Bronchial biopsy showed a lung adenocarcinoma (Fig. 2A). Molecular analysis revealed an EGFR exon 19 deletion (del19). Erlotinib was prescribed, and the patient’s symptoms improved rapidly. Follow-up CT revealed a partial response (Fig. 1B). However, CT and PET-CT performed the following year showed multiple lung metastases, liver metastasis, and exacerbation of bone metastasis (Fig. 1C and F). A CT-guided needle biopsy of a metastatic lung tumor (Fig. 1D) demonstrated squamous cell carcinoma (SCC) (P40 positive and thyroid transcription factor 1–negative) (Fig. 2B–D) with the original EGFR del19 and an EGFR exon 20 T790M mutation. Osimertinib was started as secondline treatment, and a partial response was observed on CT and PET-CT images about 3 months later (Fig. 1E–G). Transformation to lung SCC together with EGFR T790M expression is thought to create resistance to
Figure 1. Clinical course and treatments, chest computed tomography (CT) and positron emission tomography (PET)-CT. (A) CT image before erlotinib administration. (B) Chest CT image 3 months after initiation of erlotinib. (C) Chest CT image 12 months after initiation of erlotinib. (D) CT-guided biopsy of the lung tumor at time of progression. (E) Chest CT image 3 months after initiation of osimertnib. (F) PET-CT image 12 months after initiation of erlotinib. (G) PET-CT image 3 months after initiation of osimertnib.
e168
Letters to the Editor
Journal of Thoracic Oncology
Vol. 12 No. 10
Figure 2. Lung biopsy specimens. (A) Pre–erlotinib treatment first biopsy specimen stained with Papanicolaou stain. (B) Second biopsy specimen stained with hematoxylin and eosin. (C) Second biopsy specimen stained with P40 stain. (D) Second biopsy specimen stained with thyroid transcription factor 1.
EGFR TKI therapy. In the present case, because T790M was expressed after transformation to SCC, we started osimertinib and confirmed a therapeutic effect. Several mechanisms for acquisition of tolerance to EGFR TKIs are known, including T790M.1 For cases that show EGFR TKI resistance, repeat biopsy is required. Histologic change of EGFR-mutant lung adenocarcinoma to SCC was recently reported in four cases2–4 (Table 1), and such transformation may be a resistance mechanism. In this case, erlotinib was administered for 12 months to treat EGFR-mutant (del19) stage IV adenocarcinoma. Follow-up CT
confirmed multiple lung metastases. The regenerated metastatic lesions were histologically confirmed to be poorly differentiated SCC, and genetic analysis showed T790M expression together with del19, which was also observed in the primary nucleus. In EGFR-mutated adenocarcinoma, the so-called transformation could be secondary to metaplastic plasticity of the tumor cells; however, the possibility of a mixed tumor (i.e., adenosquamous tumor selecting a different tumor component under the pressure of an EGFR TKI) cannot be excluded. Double cancer is also possible. In this case, maintenance of the original EGFR
Table 1. Summary of the Main Clinicopathologic and Molecular Characteristics of Change/Transformation of EGFR-Mutated Adenocarcinoma into Squamous Cell Carcinoma Sex/Age (y)
Smoker
Stage
EGFR Mutation
EGRF TKI (mo)a
F/63
Never
IV
L858R
Erlotinib (5)
F/66 F/79 F/74 M/69
Never Never Former Former
IV IV IV IV
ex19 delE746-A750 L858R ex19
Erlotinib (8) Gefitinib (15) Gefitinib (10) Erlotinib (12)
a
Acquired Gene Alterations
Second-/Third-Line Therapy
PIK3CA ex20 (H1047R) None T790M T790M T790M
Cis/pem, gefitinib Carbo/gem None RT, gefitinib RT Osimertinib
Reference Levin et al.2 Kuiper et al.3 Jukna et al.4 Jukna et al.4 Current article
Months to progression to EGFR TKI. TKI, tyrosine kinase inhibitor; F, female; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene; ex20, exon 20; Cis, cisplatin; pem, pemetrexed; Carbo, carboplatin; gem, gemcitabine; ex19, exon 19; delE746, deletion E746; RT, radiotherapy; M, male.
October 2017
Letters to the Editor
mutation after histologic transformation made the possibility of a second primary tumor unlikely. Because the primary tumor specimen was cytodiagnostic, we cannot deny the possibility that the primary lesion was adenosquamous or that the SCC component was mixed within the primary lesion.3 Recent clinical trials have reported efficacy of osimertinib for treatment of T790M-positive NSCLC.5 Osimertinib has also been administered to a small number of patients with T790M-positive SCC, but details on the therapeutic effect have not been reported. In this case, we could control T790M-positive SCC progression by osimertinib administration. Therefore, the establishment of a post–EGFR TKI treatment strategy will need to be based on the results of a repeat biopsy and detailed genetic testing of biopsy specimens. Naoyuki Okabe, MD, PhD, Hironori Takagi, MD Respiratory Surgery Takeda General Hospital Aizuwakamatsu, Japan Hayato Mine, MD, Satoshi Fukai, MD Initial Training Physicians Takeda General Hospital Aizuwakamatsu, Japan
Novel Mutation Pair L858M/L861Q Caused Resistance to Both Firstand Third-Generation EGFR Inhibitors, but Was Found to Be Sensitive to the Combination of Lapatinib and Erbitux To the Editor: We have read the recent brief report titled “EGFR L858M/L861Q cis Mutations Confer Selective Sensitivity
Disclosure: The authors declare no conflict of interest. Address for correspondence: David Reisman, MD, PhD, University of Florida, 2033 Mowry Road, Gainesville, FL 32611. E-mail: David. [email protected]fl.edu ª 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. ISSN: 1556-0864 http://dx.doi.org/10.1016/j.jtho.2017.06.069
e169
Hiroyuki Minemura, MD, PhD Department of Pulmonary Medicine Fukushima Medical University School of Medicine Fukushima, Japan Hiroyuki Suzuki, MD, PhD Department of Chest Surgery Fukushima Medical University School of Medicine Fukushima, Japan
References 1. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3:75ra26. 2. Levin PA, Mayer M, Hoskin S, Sailors J, Oliver DN, Gerber DE. Histologic transformation from adenocarcinoma to squamous cell carcinoma as a mechanism of resistance to EGFR inhibition. J Thorac Oncol. 2015;10:e86–e88. 3. Kuiper JL, Ronden MI, Becker A, et al. Transformation to a squamous cell carcinoma phenotype of an EGFR-mutated NSCLC patient after treatment with an EGFR-tyrosine kinase inhibitor. J Clin Pathol. 2015;68:320–321. 4. Jukna A, Montanari G, Mengoli MC, et al. Squamous cell carcinoma “transformation” concurrent with secondary T790M mutation in resistant EGFR-mutated adenocarcinomas. J Thorac Oncol. 2016;11:e49–e51. 5. Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinumpemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376:629–640.
to Afatinib” that was recently published in the Journal of Thoracic Oncology.1 The brief report suggested that afatinib may be a beneficial therapeutic option for a subset of patients with lung cancer with rare EGFR mutations in their tumors. EGFR mutation analysis of an NSCLCadenocarcinoma in a 35-year-old woman treated at our institution showed the same two relatively infrequent mutations: positivity for exon 21 L861Q c.2582T>A and exon 21 L858M c.2572C>A. Interestingly, review of the published data shows that these two mutations do not occur separately but rather only in combination. Our patient showed resistance to the first-generation and third-generation tyrosine kinase inhibitors (TKIs) erlotinib and rociletinib, respectively. However, we used a combination of the secondgeneration TKIs afatinib and cetuximab with partial response. We selected this combination on the basis of published case reports showing that this combination can overcome EGFR resistance. Hence, our patient was treated with cetuximab and afatinib for 10 weeks, after which a follow-up positron emission tomography– computed tomography scan showed stable disease. The patient was continued on this regimen for another 15 weeks, and follow-up scans showed no evidence of
References 1. Shah SU, Mashayekhi A, Shields CL, et al. Uveal metastasis from lung cancer: clinical features, treatment, and outcome in 194 patients. Ophthalmology. 2014;121:352–357. 2. Mok TS, Wu Y-L, Ahn M-J, et al. Osimertinib or platinum– pemetrexed in EGFR T790M–positive lung cancer. N Engl J Med. 2017;376:629–640. 3. Jardel P, Sauerwein W, Olivier T, et al. Management of choroidal metastases. Cancer Treat Rev. 2014;40:1119–1128.
Osimertinib for Epidermal Growth Factor Receptor Mutation–Positive Lung Adenocarcinoma That Transformed to T790M-Positive Squamous Cell Carcinoma To the Editor: We report a case of EGFR mutation–positive lung cancer transformed into squamous cell carcinoma after treatment with an EGFR tyrosine kinase inhibitor (TKI). In addition, because T790M was also
Disclosure: The authors declare no conflict of interest. Address for correspondence: Hiroyuki Suzuki, MD, PhD, Department of Chest Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan. E-mail: [email protected] ª 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. ISSN: 1556-0864 http://dx.doi.org/10.1016/j.jtho.2017.06.071
Letters to the Editor
e167
4. Maskell D, Geropantas K, Kouroupis M, Glenn A, Ajithkumar T. Treatment of choice for patients with EGFR mutation-positive non-small cell lung carcinoma presenting with choroidal metastases: radiotherapy or TKIs? Can J Ophthalmol. 2017;52:e22–e25. 5. Nair AG, Asnani HT, Mehta VC, et al. Tyrosine kinase inhibitors in the treatment of choroidal metastases from non-small-cell lung cancer: a case report and review of literature. Ocul Oncol Pathol. 2017;3:28–33.
expressed, administration of osimertinib had a therapeutic effect. A 69-year-old man presented with dyspnea. He was a former smoker. Chest radiography and whole-body positron emission tomography (PET) and computed tomography (CT) (PET-CT) revealed a right lower lobe mass, enlarged mediastinal lymph nodes, and multiple bone metastases (Fig. 1A). Bronchial biopsy showed a lung adenocarcinoma (Fig. 2A). Molecular analysis revealed an EGFR exon 19 deletion (del19). Erlotinib was prescribed, and the patient’s symptoms improved rapidly. Follow-up CT revealed a partial response (Fig. 1B). However, CT and PET-CT performed the following year showed multiple lung metastases, liver metastasis, and exacerbation of bone metastasis (Fig. 1C and F). A CT-guided needle biopsy of a metastatic lung tumor (Fig. 1D) demonstrated squamous cell carcinoma (SCC) (P40 positive and thyroid transcription factor 1–negative) (Fig. 2B–D) with the original EGFR del19 and an EGFR exon 20 T790M mutation. Osimertinib was started as secondline treatment, and a partial response was observed on CT and PET-CT images about 3 months later (Fig. 1E–G). Transformation to lung SCC together with EGFR T790M expression is thought to create resistance to
Figure 1. Clinical course and treatments, chest computed tomography (CT) and positron emission tomography (PET)-CT. (A) CT image before erlotinib administration. (B) Chest CT image 3 months after initiation of erlotinib. (C) Chest CT image 12 months after initiation of erlotinib. (D) CT-guided biopsy of the lung tumor at time of progression. (E) Chest CT image 3 months after initiation of osimertnib. (F) PET-CT image 12 months after initiation of erlotinib. (G) PET-CT image 3 months after initiation of osimertnib.
e168
Letters to the Editor
Journal of Thoracic Oncology
Vol. 12 No. 10
Figure 2. Lung biopsy specimens. (A) Pre–erlotinib treatment first biopsy specimen stained with Papanicolaou stain. (B) Second biopsy specimen stained with hematoxylin and eosin. (C) Second biopsy specimen stained with P40 stain. (D) Second biopsy specimen stained with thyroid transcription factor 1.
EGFR TKI therapy. In the present case, because T790M was expressed after transformation to SCC, we started osimertinib and confirmed a therapeutic effect. Several mechanisms for acquisition of tolerance to EGFR TKIs are known, including T790M.1 For cases that show EGFR TKI resistance, repeat biopsy is required. Histologic change of EGFR-mutant lung adenocarcinoma to SCC was recently reported in four cases2–4 (Table 1), and such transformation may be a resistance mechanism. In this case, erlotinib was administered for 12 months to treat EGFR-mutant (del19) stage IV adenocarcinoma. Follow-up CT
confirmed multiple lung metastases. The regenerated metastatic lesions were histologically confirmed to be poorly differentiated SCC, and genetic analysis showed T790M expression together with del19, which was also observed in the primary nucleus. In EGFR-mutated adenocarcinoma, the so-called transformation could be secondary to metaplastic plasticity of the tumor cells; however, the possibility of a mixed tumor (i.e., adenosquamous tumor selecting a different tumor component under the pressure of an EGFR TKI) cannot be excluded. Double cancer is also possible. In this case, maintenance of the original EGFR
Table 1. Summary of the Main Clinicopathologic and Molecular Characteristics of Change/Transformation of EGFR-Mutated Adenocarcinoma into Squamous Cell Carcinoma Sex/Age (y)
Smoker
Stage
EGFR Mutation
EGRF TKI (mo)a
F/63
Never
IV
L858R
Erlotinib (5)
F/66 F/79 F/74 M/69
Never Never Former Former
IV IV IV IV
ex19 delE746-A750 L858R ex19
Erlotinib (8) Gefitinib (15) Gefitinib (10) Erlotinib (12)
a
Acquired Gene Alterations
Second-/Third-Line Therapy
PIK3CA ex20 (H1047R) None T790M T790M T790M
Cis/pem, gefitinib Carbo/gem None RT, gefitinib RT Osimertinib
Reference Levin et al.2 Kuiper et al.3 Jukna et al.4 Jukna et al.4 Current article
Months to progression to EGFR TKI. TKI, tyrosine kinase inhibitor; F, female; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene; ex20, exon 20; Cis, cisplatin; pem, pemetrexed; Carbo, carboplatin; gem, gemcitabine; ex19, exon 19; delE746, deletion E746; RT, radiotherapy; M, male.
October 2017
Letters to the Editor
mutation after histologic transformation made the possibility of a second primary tumor unlikely. Because the primary tumor specimen was cytodiagnostic, we cannot deny the possibility that the primary lesion was adenosquamous or that the SCC component was mixed within the primary lesion.3 Recent clinical trials have reported efficacy of osimertinib for treatment of T790M-positive NSCLC.5 Osimertinib has also been administered to a small number of patients with T790M-positive SCC, but details on the therapeutic effect have not been reported. In this case, we could control T790M-positive SCC progression by osimertinib administration. Therefore, the establishment of a post–EGFR TKI treatment strategy will need to be based on the results of a repeat biopsy and detailed genetic testing of biopsy specimens. Naoyuki Okabe, MD, PhD, Hironori Takagi, MD Respiratory Surgery Takeda General Hospital Aizuwakamatsu, Japan Hayato Mine, MD, Satoshi Fukai, MD Initial Training Physicians Takeda General Hospital Aizuwakamatsu, Japan
Novel Mutation Pair L858M/L861Q Caused Resistance to Both Firstand Third-Generation EGFR Inhibitors, but Was Found to Be Sensitive to the Combination of Lapatinib and Erbitux To the Editor: We have read the recent brief report titled “EGFR L858M/L861Q cis Mutations Confer Selective Sensitivity
Disclosure: The authors declare no conflict of interest. Address for correspondence: David Reisman, MD, PhD, University of Florida, 2033 Mowry Road, Gainesville, FL 32611. E-mail: David. [email protected]fl.edu ª 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. ISSN: 1556-0864 http://dx.doi.org/10.1016/j.jtho.2017.06.069
e169
Hiroyuki Minemura, MD, PhD Department of Pulmonary Medicine Fukushima Medical University School of Medicine Fukushima, Japan Hiroyuki Suzuki, MD, PhD Department of Chest Surgery Fukushima Medical University School of Medicine Fukushima, Japan
References 1. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3:75ra26. 2. Levin PA, Mayer M, Hoskin S, Sailors J, Oliver DN, Gerber DE. Histologic transformation from adenocarcinoma to squamous cell carcinoma as a mechanism of resistance to EGFR inhibition. J Thorac Oncol. 2015;10:e86–e88. 3. Kuiper JL, Ronden MI, Becker A, et al. Transformation to a squamous cell carcinoma phenotype of an EGFR-mutated NSCLC patient after treatment with an EGFR-tyrosine kinase inhibitor. J Clin Pathol. 2015;68:320–321. 4. Jukna A, Montanari G, Mengoli MC, et al. Squamous cell carcinoma “transformation” concurrent with secondary T790M mutation in resistant EGFR-mutated adenocarcinomas. J Thorac Oncol. 2016;11:e49–e51. 5. Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinumpemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376:629–640.
to Afatinib” that was recently published in the Journal of Thoracic Oncology.1 The brief report suggested that afatinib may be a beneficial therapeutic option for a subset of patients with lung cancer with rare EGFR mutations in their tumors. EGFR mutation analysis of an NSCLCadenocarcinoma in a 35-year-old woman treated at our institution showed the same two relatively infrequent mutations: positivity for exon 21 L861Q c.2582T>A and exon 21 L858M c.2572C>A. Interestingly, review of the published data shows that these two mutations do not occur separately but rather only in combination. Our patient showed resistance to the first-generation and third-generation tyrosine kinase inhibitors (TKIs) erlotinib and rociletinib, respectively. However, we used a combination of the secondgeneration TKIs afatinib and cetuximab with partial response. We selected this combination on the basis of published case reports showing that this combination can overcome EGFR resistance. Hence, our patient was treated with cetuximab and afatinib for 10 weeks, after which a follow-up positron emission tomography– computed tomography scan showed stable disease. The patient was continued on this regimen for another 15 weeks, and follow-up scans showed no evidence of