Association of BIM Deletion Polymorphism With Intrinsic Resistance to EGFR Tyrosine Kinase Inhibitors in Patients With Lung Adenocarcinoma | Genetics and Genomics | JAMA Oncology | JAMA Network
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Figure.  Kaplan-Meier Curve of Progression-Free Survival (PFS) Following EGFR-TKI Use in Patients With Lung Adenocarcinoma With Positive EGFR Mutations, Including Primary Resistance and Sensitive to EGFR-TKIs
Kaplan-Meier Curve of Progression-Free Survival (PFS) Following EGFR-TKI Use in Patients With Lung Adenocarcinoma With Positive EGFR Mutations, Including Primary Resistance and Sensitive to EGFR-TKIs

A, The difference in PFS between patients with BIM deletion and those with wild-type BIM was not statistically significant (P = .34). B, The difference in PFS between patients with heterozygous and homozygous BIM deletion was not statistically significant (P = .84). TKI indicates tyrosine kinase inhibitors.

Table.  Comparison of Clinical Characteristics of EGFR Mutation-Positive Patients With BIM Deletion Polymorphism and Wild-Type BIM
Comparison of Clinical Characteristics of EGFR Mutation-Positive Patients With BIM Deletion Polymorphism and Wild-Type BIM
1.
Mok  TS, Wu  YL, Thongprasert  S,  et al.  Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.  N Engl J Med. 2009;361(10):947-957.PubMedGoogle ScholarCrossref
2.
Ng  KP, Hillmer  AM, Chuah  CT,  et al.  A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer.  Nat Med. 2012;18(4):521-528.PubMedGoogle ScholarCrossref
3.
Lee  JK, Shin  JY, Kim  S,  et al.  Primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer harboring TKI-sensitive EGFR mutations: an exploratory study.  Ann Oncol. 2013;24(8):2080-2087.PubMedGoogle ScholarCrossref
4.
Isobe  K, Hata  Y, Tochigi  N,  et al.  Clinical significance of BIM deletion polymorphism in non-small-cell lung cancer with epidermal growth factor receptor mutation.  J Thorac Oncol. 2014;9(4):483-487.PubMedGoogle ScholarCrossref
5.
Costa  DB, Halmos  B, Kumar  A,  et al.  BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations.  PLoS Med. 2007;4(10):1669-1679.PubMedGoogle ScholarCrossref
6.
Kuroda  J, Puthalakath  H, Cragg  MS,  et al.  Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic.  Proc Natl Acad Sci U S A. 2006;103(40):14907-14912.PubMedGoogle ScholarCrossref
Research Letter
June 2016

Association of BIM Deletion Polymorphism With Intrinsic Resistance to EGFR Tyrosine Kinase Inhibitors in Patients With Lung Adenocarcinoma

Author Affiliations
  • 1Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan
  • 2Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei City, Taiwan
  • 3Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
JAMA Oncol. 2016;2(6):826-828. doi:10.1001/jamaoncol.2016.0016

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have dramatic treatment effects in patients with lung cancer who have EGFR mutations. However, 20% to 30% of EGFR-mutant patients do not respond to EGFR-TKI treatment.1BIM deletion polymorphism has been reported to confer intrinsic resistance to EGFR-TKIs in cell lines.2 We explored the impact of BIM polymorphism on treatment outcome of patients with advanced adenocarcinoma, comparing patients who experienced primary resistance with those who had partial response following EGFR-TKI treatment.

Methods

During June 2005 to December 2012, malignant pleural effusions (MPEs) of patients with lung adenocarcinoma were collected. Informed consent about the use of these specimens for future molecular studies was obtained before thoracentesis after approval by the institutional review board of National Taiwan University Hospital. Tumor cells from MPEs were analyzed for EGFR mutation by reverse transcriptase–polymerase chain reaction (RT-PCR) and BIM polymorphism analysis by PCR and fragment length analysis.2 Primary resistance was defined as clinical disease progression within 3 months without any evidence of objective response to EGFR-TKI.3 Patients with partial response and disease control for more than 3 months to EGFR-TKI were classified as the TKI-sensitive group. Patients harboring tumor with de novo T790M mutation were excluded. Because there was no discordance of BIM polymorphism (a germline alteration) between peripheral blood and cancer specimens,4 we could use the cancer cells of MPEs to detect BIM polymorphism. Patients’ clinical characteristics and progression-free survival (PFS) were analyzed. Statistical analysis was performed using χ2 test and Kaplan-Meier method.

Results

There were 56 patients in the primary resistance group and 271 patients in the TKI-sensitive group. Fifty-two patients (15.9%) had tumors with BIM deletion polymorphism. The BIM deletion frequency was not different between the 2 groups (95% CI, 0.45-2.16; P = .97) (Table). BIM deletion was unrelated to EGFR mutation types (P = .45). The subtypes (homozygous/heterozygous) showed no significant difference between the primary resistance (2 of 7 patients) and TKI-sensitive groups (4 of 39 patients; 95% CI, 0.06-2.35; P = .27, by Fisher exact test).

The median PFS of EGFR-TKI was 10.5 months among patients with BIM deletion and 8.5 months among those without BIM deletion (95% CI, 0.63-1.18; P = .34) (Figure, A). The difference in PFS between patients with heterozygous BIM deletion and those with homozygous BIM deletion was not significant (95% CI, 0.43-2.79; P = .84) (Figure, B). Furthermore, the differences in PFS between patients with and without BIM deletion were not significant among the primary resistance group (95% CI, 0.35-1.51; P = .37) or the TKI-sensitive group (95% CI, 0.58-1.18; P = .29).

Of the 286 patients with classic EGFR mutations, the BIM deletion frequency was not significantly different between the primary resistance group (17.1%) and the TKI-sensitive group (15.1%; 95% CI, 0.34-2.22; P = .76). The difference in PFS between patients with and without BIM deletion was not significant among patients with deletion in exon-19 (95% CI, 0.53-1.37; P = .51) or those with L858R mutation (95% CI, 0.51-1.42; P = .54).

Discussion

BIM mediates EGFR-TKI–induced apoptosis.5 If the BIM deletion conferred an intrinsic resistance to EGFR-TKI,2 the BIM deletion frequency in the primary resistance group should theoretically be higher than in the TKI-sensitive group. However, the present study did not reveal such phenomenon, and the frequencies remained similar after selection of EGFR classical mutations. Prior studies3,4 also showed that BIM polymorphism was not associated with clinical characteristics and the treatment response of EGFR-TKI. A possible reason is that the development of lung cancer did not completely dependent on the BIM pathway. Other possible survival mechanisms may play an important role after EGFR-TKI treatment.4 Furthermore, BIM protein concentrations have variable effects on apoptosis, and there is a dose-dependent effect of BIM on apoptosis and the degree of TKI resistance.6 In addition, BIM deletion polymorphism is found only in East Asians, but not in the white population.2

In conclusion, BIM deletion polymorphism does not account for intrinsic resistance to EGFR-TKI.

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Article Information

Corresponding Author: Jin-Yuan Shih, MD, PhD, Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan (jyshih@ntu.edu.tw).

Published Online: April 14, 2016. doi:10.1001/jamaoncol.2016.0016.

Author Contributions: Drs Wu and Shih had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Wu, Yang, Shih.

Acquisition, analysis, or interpretation of data: Wu, Liu, Yu, Shih.

Drafting of the manuscript: Wu, Yu, Shih.

Critical revision of the manuscript for important intellectual content: Wu, Liu, Yang, Shih.

Statistical analysis: Wu, Shih.

Obtained funding: Wu, Yang, Shih.

Administrative, technical, or material support: All authors.

Study supervision: Yu, Yang, Shih.

Conflict of Interest Disclosures: Dr Shih has received speaking honoraria from AstraZeneca, Roche, Pfizer, Boehringer Ingelheim, Merck Sharp & Dohme (MSD), Novartis, and Eli Lilly. No other disclosures are reported.

Funding/Support: This study was supported by grants 100-2314-B-002-132, 101-2314-B-002-167-MY3 (National Science Council, Taiwan), 102-S2158 (National Taiwan University Hospital, Taiwan), MOHW103-TDU-PB-211-144002 (Ministry of Health and Welfare), and NTUHYL102-M002 (National Taiwan University Hospital, Yun-Lin Branch, Yun-Lin, Taiwan). The Department of Medical Research at the National Taiwan University Hospital (Taipei/Taiwan) for providing laboratory facilities.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Mok  TS, Wu  YL, Thongprasert  S,  et al.  Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.  N Engl J Med. 2009;361(10):947-957.PubMedGoogle ScholarCrossref
2.
Ng  KP, Hillmer  AM, Chuah  CT,  et al.  A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer.  Nat Med. 2012;18(4):521-528.PubMedGoogle ScholarCrossref
3.
Lee  JK, Shin  JY, Kim  S,  et al.  Primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer harboring TKI-sensitive EGFR mutations: an exploratory study.  Ann Oncol. 2013;24(8):2080-2087.PubMedGoogle ScholarCrossref
4.
Isobe  K, Hata  Y, Tochigi  N,  et al.  Clinical significance of BIM deletion polymorphism in non-small-cell lung cancer with epidermal growth factor receptor mutation.  J Thorac Oncol. 2014;9(4):483-487.PubMedGoogle ScholarCrossref
5.
Costa  DB, Halmos  B, Kumar  A,  et al.  BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations.  PLoS Med. 2007;4(10):1669-1679.PubMedGoogle ScholarCrossref
6.
Kuroda  J, Puthalakath  H, Cragg  MS,  et al.  Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic.  Proc Natl Acad Sci U S A. 2006;103(40):14907-14912.PubMedGoogle ScholarCrossref
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