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Transformation to small-cell carcinoma as an acquired resistance mechanism to AZD9291: A case report

View Article: PubMed Central - PubMed

ABSTRACT

AZD9291, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), benefits patients with T790M mutant non-small-cell lung cancer who fail treatment with first-generation EGFR TKIs. Acquisition of resistance to AZD9291 occurs inevitable and mechanisms need to be explored. We reported an advanced lung adenocarcinoma female with EGFR exon19 deletion treated on AZD9291 after failure of erlotinib and chemotherapy. Disease progressed again after 6 months treatment of AZD9291 with hepatic metastasis. Re-biopsy of the hepatic lesion showed histopathology transformation to small cell lung cancer, which harbored EGFR exon19 deletion. Therefore, small cell carcinoma transformation is one of potential resistance mechanisms to AZD9291 and regimen for small cell carcinoma may be one of the treatment options.

No MeSH data available.


Computed tomography scan images showed new hepatic lesions appeared after 6 months of AZD9291 treatment
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Figure 3: Computed tomography scan images showed new hepatic lesions appeared after 6 months of AZD9291 treatment

Mentions: A 52-year-old non-smoker female was first detected a 2 cm mass in right upper lobe of lung with computed tomography (CT) scan in May, 2014. She then underwent right upper lobectomy with regional lymph node dissection. The pathology diagnosis was adenocarcinoma with multiple metastasized lymph nodes in group 2 (9/9), group 4 (4/4), group 7 (7/7), group 9 (0/1) and group 10 (6/6) (Figure 1). EGFR exon19 deletion was detected by amplification refractory mutation system (ARMS). The patient was diagnosed as adenocarcinoma in right upper lobe, staged T2N2M0 (IIIA). She received adjuvant chemotherapy with gemcitabine plus cisplatin. However, multiple micronodules were found in bilateral lung after finishing two cycles of chemotherapy. Then she started treatment on erlotinib from Sep, 2014 and achieved partial response in one month. Regular CT examination was underwent every two months, and new bilateral lung lesions were found in Aug, 2015, after 11 months treatment of erlotinib. Because of the difficulty of re-biopsy, plasma circulating tumor DNA (ctDNA) was collected for EGFR mutation detection by ARMs. However, neither exon19 deletion nor T790M mutation was detected. The patient was given chemotherapy with pemetrexed plus nedaplatin. But disease progressed after two cycles. Then docetaxol plus bevacizumab was given but disease progressed again. Meanwhile, she had symptoms of cough and shortness of breath. Then she was on AZD9291 in Dec, 2015 after chemotherapy failure. The patient's symptoms improved dramatically in one month and CT scan showed disease improved obviously (Figure 2). She continued on treatment of AZD9291 until multiple hepatic lesions appeared in May, 2016 (Figure 3), while the lesions of lung were still stable. Liver biopsy was performed and histologic analysis showed as small cell lung cancer. Immunohistochemistry staining confirmed as strong positive for synaptophysin (Figure 4). ARMs analysis showed EGFR exon19 deletion, without T790M mutation. Because there were not sufficient tissue left for next generation sequencing assay (NGS) test, peripheral ctDNA was tested and detected mutations of EGFR exon19 deletion, P53 exon6 V203L-pTEN exon4 NC82 and PIK3CA exon10 E545Q. The level of the patient's neuronspecificenolase (NSE) was 113.8 ng/ml, which was 13 ng/ml in Dec, 2015 before treatment of AZD9291. Then the patient was treated on etopside and carboplatin in addition to AZD9291. Her NSE level decreased from 113.8 ng/ml to 28 ng/ml after one cycle of chemotherapy and then to 10 ng/ml after the second cycle. The CT examination after two cycles of chemotherapy showed smaller hepatic lesions but did not reach partial response. Now the patient was on further treatment and followed up.


Transformation to small-cell carcinoma as an acquired resistance mechanism to AZD9291: A case report
Computed tomography scan images showed new hepatic lesions appeared after 6 months of AZD9291 treatment
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5392352&req=5

Figure 3: Computed tomography scan images showed new hepatic lesions appeared after 6 months of AZD9291 treatment
Mentions: A 52-year-old non-smoker female was first detected a 2 cm mass in right upper lobe of lung with computed tomography (CT) scan in May, 2014. She then underwent right upper lobectomy with regional lymph node dissection. The pathology diagnosis was adenocarcinoma with multiple metastasized lymph nodes in group 2 (9/9), group 4 (4/4), group 7 (7/7), group 9 (0/1) and group 10 (6/6) (Figure 1). EGFR exon19 deletion was detected by amplification refractory mutation system (ARMS). The patient was diagnosed as adenocarcinoma in right upper lobe, staged T2N2M0 (IIIA). She received adjuvant chemotherapy with gemcitabine plus cisplatin. However, multiple micronodules were found in bilateral lung after finishing two cycles of chemotherapy. Then she started treatment on erlotinib from Sep, 2014 and achieved partial response in one month. Regular CT examination was underwent every two months, and new bilateral lung lesions were found in Aug, 2015, after 11 months treatment of erlotinib. Because of the difficulty of re-biopsy, plasma circulating tumor DNA (ctDNA) was collected for EGFR mutation detection by ARMs. However, neither exon19 deletion nor T790M mutation was detected. The patient was given chemotherapy with pemetrexed plus nedaplatin. But disease progressed after two cycles. Then docetaxol plus bevacizumab was given but disease progressed again. Meanwhile, she had symptoms of cough and shortness of breath. Then she was on AZD9291 in Dec, 2015 after chemotherapy failure. The patient's symptoms improved dramatically in one month and CT scan showed disease improved obviously (Figure 2). She continued on treatment of AZD9291 until multiple hepatic lesions appeared in May, 2016 (Figure 3), while the lesions of lung were still stable. Liver biopsy was performed and histologic analysis showed as small cell lung cancer. Immunohistochemistry staining confirmed as strong positive for synaptophysin (Figure 4). ARMs analysis showed EGFR exon19 deletion, without T790M mutation. Because there were not sufficient tissue left for next generation sequencing assay (NGS) test, peripheral ctDNA was tested and detected mutations of EGFR exon19 deletion, P53 exon6 V203L-pTEN exon4 NC82 and PIK3CA exon10 E545Q. The level of the patient's neuronspecificenolase (NSE) was 113.8 ng/ml, which was 13 ng/ml in Dec, 2015 before treatment of AZD9291. Then the patient was treated on etopside and carboplatin in addition to AZD9291. Her NSE level decreased from 113.8 ng/ml to 28 ng/ml after one cycle of chemotherapy and then to 10 ng/ml after the second cycle. The CT examination after two cycles of chemotherapy showed smaller hepatic lesions but did not reach partial response. Now the patient was on further treatment and followed up.

View Article: PubMed Central - PubMed

ABSTRACT

AZD9291, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), benefits patients with T790M mutant non-small-cell lung cancer who fail treatment with first-generation EGFR TKIs. Acquisition of resistance to AZD9291 occurs inevitable and mechanisms need to be explored. We reported an advanced lung adenocarcinoma female with EGFR exon19 deletion treated on AZD9291 after failure of erlotinib and chemotherapy. Disease progressed again after 6 months treatment of AZD9291 with hepatic metastasis. Re-biopsy of the hepatic lesion showed histopathology transformation to small cell lung cancer, which harbored EGFR exon19 deletion. Therefore, small cell carcinoma transformation is one of potential resistance mechanisms to AZD9291 and regimen for small cell carcinoma may be one of the treatment options.

No MeSH data available.