RAB5A expression is a predictive biomarker for trastuzumab emtansine in breast cancer
Olav Engebraaten, Christina Yau, Kristian Berg, Elin Borgen, Øystein Garred, Maria E B Berstad, Ane S V Fremstedal, Angela DeMichele, Laura van 't Veer, Laura Esserman, Anette Weyergang, Olav Engebraaten, Christina Yau, Kristian Berg, Elin Borgen, Øystein Garred, Maria E B Berstad, Ane S V Fremstedal, Angela DeMichele, Laura van 't Veer, Laura Esserman, Anette Weyergang
Abstract
HER2 is a predictive biomarker for HER2-targeted therapeutics. For antibody-drug conjugates (ADCs; e.g., trastuzumab emtansine (T-DM1)), HER2 is utilized as a transport gate for cytotoxic agents into the cell. ADC biomarkers may therefore be more complex, also reflecting the intracellular drug transport. Here we report on a positive correlation between the early endosome marker RAB5A and T-DM1 sensitivity in five HER2-positive cell lines. Correlation between RAB5A expression and T-DM1 sensitivity is confirmed in breast cancer patients treated with trastuzumab emtansine/pertuzumab in the I-SPY2 trial (NCT01042379), but not in the trastuzumab/paclitaxel control arm. The clinical correlation is further verified in patients from the KAMILLA trial (NCT01702571). In conclusion, our results suggest RAB5A as a predictive biomarker for T-DM1 response and outline proteins involved in endocytic trafficking as predictive biomarkers for ADCs.
Conflict of interest statement
A patent application entitled “Diagnosis and treatment of cancer” by Anette Weyergang, Kristian Berg, Olav Engebraaten, and Maria E.B. Berstad, application number: WO 2018/234872 A1 is currently in the national phase.
© 2021. The Author(s).
Figures
References
- de Gramont A, et al. Pragmatic issues in biomarker evaluation for targeted therapies in cancer. Nat. Rev. Clin. Oncol. 2015;12:197–212. doi: 10.1038/nrclinonc.2014.202.
- Slamon DJ, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244:707–712. doi: 10.1126/science.2470152.
- Hernandez-Blanquisett A, et al. Current and emerging therapies of HER2-positive metastatic breast cancer. Breast. 2016;29:170–177. doi: 10.1016/j.breast.2016.07.026.
- Rimawi MF, Schiff R, Osborne CK. Targeting HER2 for the treatment of breast cancer. Annu. Rev. Med. 2015;66:111–128. doi: 10.1146/annurev-med-042513-015127.
- Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat. Med. 2000;6:443–446. doi: 10.1038/74704.
- Harbeck N, et al. HER2 dimerization inhibitor pertuzumab—mode of action and clinical data in breast cancer. Breast Care. 2013;8:49–55. doi: 10.1159/000346837.
- Lewis Phillips GD, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68:9280–9290. doi: 10.1158/0008-5472.CAN-08-1776.
- Verma S, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 2012;367:1783–1791. doi: 10.1056/NEJMoa1209124.
- Baron JM, Boster BL, Barnett CM. Ado-trastuzumab emtansine (T-DM1): a novel antibody-drug conjugate for the treatment of HER2-positive metastatic breast cancer. J. Oncol. Pharm. Pract. 2015;21:132–142. doi: 10.1177/1078155214527144.
- Erickson HK, et al. Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res. 2006;66:4426–4433. doi: 10.1158/0008-5472.CAN-05-4489.
- Martinez MT, et al. Treatment of HER2 positive advanced breast cancer with T-DM1: a review of the literature. Crit. Rev. Oncol./Hematol. 2016;97:96–106. doi: 10.1016/j.critrevonc.2015.08.011.
- Ritchie M, Tchistiakova L, Scott N. Implications of receptor-mediated endocytosis and intracellular trafficking dynamics in the development of antibody drug conjugates. mAbs. 2013;5:13–21. doi: 10.4161/mabs.22854.
- Drago JZ, Modi S, Chandarlapaty S. Unlocking the potential of antibody-drug conjugates for cancer therapy. Nat. Rev. Clin. Oncol. 2021 doi: 10.1038/s41571-021-00470-8.
- Baselga J, et al. Relationship between tumor biomarkers and efficacy in EMILIA, a phase III study of trastuzumab emtansine in HER2-positive metastatic breast cancer. Clin. Cancer Res. 2016;22:3755–3763. doi: 10.1158/1078-0432.CCR-15-2499.
- Kim SB, et al. Relationship between tumor biomarkers and efficacy in TH3RESA, a phase III study of trastuzumab emtansine (T-DM1) vs. treatment of physician’s choice in previously treated HER2-positive advanced breast cancer. Int J. Cancer. 2016;139:2336–2342. doi: 10.1002/ijc.30276.
- Subik K, et al. The expression patterns of ER, PR, HER2, CK5/6, EGFR, Ki-67 and AR by immunohistochemical analysis in breast cancer cell lines. Breast Cancer. 2010;4:35–41.
- Dillon RL, et al. Trastuzumab-deBouganin conjugate overcomes multiple mechanisms of T-DM1 drug resistance. J. Immunother. 2016;39:117–126. doi: 10.1097/CJI.0000000000000115.
- Zerial M, McBride H. Rab proteins as membrane organizers. Nat. Rev. Mol. Cell Biol. 2001;2:107–117. doi: 10.1038/35052055.
- Austin CD, et al. Endocytosis and sorting of ErbB2 and the site of action of cancer therapeutics trastuzumab and geldanamycin. Mol. Biol. Cell. 2004;15:5268–5282. doi: 10.1091/mbc.e04-07-0591.
- Perez EA, et al. Relationship between HER2 expression and efficacy with first-line trastuzumab emtansine compared with trastuzumab plus docetaxel in TDM4450g: a randomized phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Breast Cancer Res. 2014;16:R50. doi: 10.1186/bcr3661.
- Fabi A, et al. Efficacy and safety of T-DM1 in the ‘common-practice’ of HER2+ advanced breast cancer setting: a multicenter study. Oncotarget. 2017;8:64481–64489. doi: 10.18632/oncotarget.16373.
- Hardy-Werbin M, et al. Real-world data on T-DM1 efficacy—results of a single-center retrospective study of HER2-positive breast cancer patients. Sci. Rep. 2019;9:12760. doi: 10.1038/s41598-019-49251-5.
- Thuss-Patience PC, et al. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 2017;18:640–653. doi: 10.1016/S1470-2045(17)30111-0.
- Stenmark H. Rab GTPases as coordinators of vesicle traffic. Nat. Rev. Mol. Cell Biol. 2009;10:513–525. doi: 10.1038/nrm2728.
- Bertelsen V, Stang E. The mysterious ways of ErbB2/HER2 trafficking. Membranes. 2014;4:424–446. doi: 10.3390/membranes4030424.
- Cortese K, et al. The HSP90 inhibitor geldanamycin perturbs endosomal structure and drives recycling ErbB2 and transferrin to modified MVBs/lysosomal compartments. Mol. Biol. Cell. 2013;24:129–144. doi: 10.1091/mbc.e12-04-0282.
- Grant BD, Donaldson JG. Pathways and mechanisms of endocytic recycling. Nat. Rev. Mol. Cell Biol. 2009;10:597–608. doi: 10.1038/nrm2755.
- Frittoli E, et al. A RAB5/RAB4 recycling circuitry induces a proteolytic invasive program and promotes tumor dissemination. J. Cell Biol. 2014;206:307–328. doi: 10.1083/jcb.201403127.
- Perez EA, et al. Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: Final results from MARIANNE. Cancer. 2019;125:3974–3984. doi: 10.1002/cncr.32392.
- Barker AD, et al. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin. Pharmacol. therapeutics. 2009;86:97–100. doi: 10.1038/clpt.2009.68.
- Clark, A. S. et al. Neoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2-positive breast cancer in the adaptively randomized I-SPY2 trial. Nat. Commun.21, 100 (2021).
- Wolf DM, et al. DNA repair deficiency biomarkers and the 70-gene ultra-high risk signature as predictors of veliparib/carboplatin response in the I-SPY 2 breast cancer trial. NPJ Breast Cancer. 2017;3:31. doi: 10.1038/s41523-017-0025-7.
- Wulfkuhle, J. D. et al. Evaluation of the HER/PI3K/AKT family signaling network as a predictive biomarker of pathologic complete response for patients with breast cancer treated with neratinib in the I-SPY 2 TRIAL. JCO Precis. Oncol.2, 10.1200/po.18.00024 (2018).
- Wolf DM, et al. Mechanism of action biomarkers predicting response to AKT inhibition in the I-SPY 2 breast cancer trial. NPJ Breast Cancer. 2020;6:48. doi: 10.1038/s41523-020-00189-2.
- Nanda R, et al. Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: an analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial. JAMA Oncol. 2020;6:676–684. doi: 10.1001/jamaoncol.2019.6650.
- Montemurro F, et al. Safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive advanced breast cancer: Primary results from the KAMILLA study cohort 1. Eur. J. Cancer. 2019;109:92–102. doi: 10.1016/j.ejca.2018.12.022.
- Allred DC, Harvey JM, Berardo M, Clark GM. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod. Pathol. 1998;11:155–168.
- Collins LC, Botero ML, Schnitt SJ. Bimodal frequency distribution of estrogen receptor immunohistochemical staining results in breast cancer: an analysis of 825 cases. Am. J. Clin. Pathol. 2005;123:16–20. doi: 10.1309/HCF035N9WK40ETJ0.
Source: PubMed