Patients harboring ALK rearrangement adenocarcinoma after acquired resistance to crizotinib and transformation to small-cell lung cancer: a case report

Figures & data

Figure 1 Hematoxylin–eosin staining and immunohistochemistry in adenocarcinoma before crizotinib treatment.

Notes: (A) Hematoxylin–eosin staining revealed that tumor cells were lung adenocarcinoma (×200). (B) Immunohistochemical examination revealed that tumor cells were positive for monoclonal anti-TTF-1 antibody (×200). (C) Immunohistochemical examination revealed that tumor cells were positive for monoclonal anti-Napsin A antibody (×200).

Figure 2 Amplification plot of EML4-ALK-positive by amplification refractory mutation system method.

Figure 3 Hematoxylin–eosin staining and immunohistochemistry in small-cell cancer after crizotinib treatment.

Notes: (A) Hematoxylin–eosin staining revealed that tumor cells were lung small-cell cancer (×100). (B) Immunohistochemical examination revealed that tumor cells were positive for monoclonal anti-CD56 antibody (×100). (C) Immunohistochemical examination revealed that tumor cells were positive for monoclonal anti-Syn antibody (×200). (D) Immunohistochemical examination revealed that the tumor cell proliferation index was 98% for monoclonal anti-Ki-67 antibody (×100). (E) Immunohistochemical examination revealed that tumor cells were negative for monoclonal anti-CgA antibody (×100). (F) Immunohistochemical examination revealed that tumor cells were negative for monoclonal anti-PD-L1 antibody (×100).

Table 1 Primary antibodies used for immunhistochemical staining

Antibody	Clone	Dilution	Purchased from
TTF-1	SPT24	1:100	Zymed Laboratories, Inc.
NapsinA	OTI3E5	1:100	Zymed Laboratories, Inc.
P63	UMAB4	1:100	Zymed Laboratories, Inc.
CK5/6	D5/16B4	1:100	Zymed Laboratories, Inc.
CK8/18	Zym5.2	1:100	Zymed Laboratories, Inc.
SP-A	32E12	1:100	Zymed Laboratories, Inc.
CK	AE1/AE3	1:100	Zymed Laboratories, Inc.
Syn	EP158	1:100	Zymed Laboratories, Inc.
CgA	EP38	1:100	Zymed Laboratories, Inc.
CD56	UMAB83	1:100	Zymed Laboratories, Inc.
Ki-67	EP5	1:100	Zymed Laboratories, Inc.
PD-L1	SP142	1:100	Ventana Medical Systems, Inc.

Table 2 Details of the treatment process

Treatment	Time	Curative effect
Albumin paclitaxel + cisplatin, 2 cycles; albumin paclitaxel, 3 cycles	October 2014 to February 2015	SD
Anlotinib (clinical trial)	September 2015 to June 2016	SD
Gemcitabine + Nedaplatin	June 2016 to August 2016	PD
Docetaxel + bevacizumab, 4 cycles; bevacizumab, 2 cycles	August 2016 to November 2016	SD
Rechallenge with crizotinib	November 2016 to December 2016	PD

Abbreviations: SD, stable disease; PD, progressive disease.

Table 3 List of reported small-cell transformations resistant to crizotinib/alectinib/ceritinib/lorlatinib

Study	Cha et al^Citation6	Takegawa et al^Citation7	Fujita et al^Citation8	Miyamoto et al^Citation9	Caumont et al^Citation10	Levacq et al^Citation11
Ethnicity	Korean	Japanese	Japanese	Japanese	French	Belgian
Age (years)	72	43	67	58	63	53
Gender	Male	Female	Female	Female	Female	Female
Smoking history	40 pack-years	NA	Never smoker	Never smoker	Never smoker	Never smoker
CNS metastasis present	No	Yes	Yes	No	Yes	No
Resistance to most immediate prior crizotinib/alectinib/ceritinib/lorlatinib	Crizotinib	Alectinib (also crizotinib prior to alectinib)	Alectinib (also crizotinib prior to alectinib)	Alectinib (also crizotinib prior to alectinib)	Crizotinib	Ceritinib (also crizotinib prior to certinib)
Subsequent SCLC therapy	NA	None	Alectinib + irinotecan (with PR)	Cisplatin/irinotecan	NA	Cisplatin/etoposide followed by CAV
Study			Ou et al^Citation12			8 (present case)
Ethnicity			American			Chinese
Age (years)			35			49
Gender			Male			Male
Smoking history			Never smoker			Never smoker
CNS metastasis present			Yes			Yes
Resistance to most immediate prior crizotinib/alectinib/ceritinib/lorlatinib			Lorlatinib (also prior ceritinib to alectinib)			Crizotinib
First-line treatment assessment			Carboplatin/etoposide + alectinib			Etoposide

Abbreviations: CAV, chemotherapy regimen (cyclophosphamide + doxorubicin + vincristine); CNS, central nervous system; PR, partial response; SCLC, small-cell lung cancer; NA, not available.

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