Skip to main content

Advertisement

SpringerLink
Log in

Trophoblast Cell Surface Antigen 2 gene (TACSTD2) expression in primary breast cancer

  • Clinical trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

Trophoblast Cell Surface Antigen 2 (TROP2) is a glycoprotein expressed in many cancers. A TROP2 antibody–drug conjugate (ADC) was effective in metastatic triple-negative breast cancer (TNBC). We studied TROP2 gene (TACSTD2) expression and associations with tumor and clinical characteristics, as well as selected external genes in primary breast cancer.

Methods

TACSTD2 gene expression was evaluated using microarray data from I-SPY 1 (n = 149), METABRIC (n = 1992), and TCGA (n = 817). Associations with clinical features (Kruskal–Wallis test, all datasets), chemotherapy response (Wilcoxon rank sum test, I-SPY 1), recurrence free survival (Cox proportional hazard model, I-SPY 1 and METABRIC), and selected genes (Pearson correlations, all datasets) were determined.

Results

TACSTD2 gene expression was detectable in all breast cancer subtypes, with a wide range of expression (all datasets). TACSTD2 gene expression was lower in HER2 + than HR + /HER2- and TNBC (METABRIC: p = 0.03, TCGA p = 0.007), and in HER2 + enriched and luminal B breast cancer (METABRIC: p < 0.001, TCGA: p < 0.001). TACSTD2 expression was higher in grade I vs. II/III tumors (METABRIC: p < 0.001). No association with chemotherapy response (I-SPY 1) or recurrence free survival (I-SPY 1 and METABRIC) was seen. TACSTD2 has significant positive correlations with the expression of epithelial/adhesion genes and proliferative genes, but was inversely correlated with immune genes.

Conclusion

TACSTD2 gene expression was seen in all breast cancer subtypes particularly luminal A and TNBC, and correlated with the expression of genes involved in cell epithelial transformation, adhesion, and proliferation, which contribute to tumor growth. These results support the investigation of TROP2 ADC in all subtypes of breast cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

All of the datasets used for this study (I-SPY 1, METABRIC, and TCGA) are publically available. I-SPY 1 datasets were accessed through NCBI Gene Expression Omnibus (GEO) (https://identifiers.org/geo:GSE22226), METABRIC data through European Genome-phenome Archive (EGA) (https://identifiers.org/ega.dataset:EGAD00010000210 and https://identifiers.org/ega.dataset:EGAD00010000211), and TCGA data via cBioPortal for CancerGenomics (https://identifiers.org/cbioportal:brca_tcga_pub2015).

References

  1. Shvartsur A, Bonavida B (2015) Trop2 and its overexpression in cancers: regulation and clinical/therapeutic implications. Genes Cancer 6(3–4):84–105. https://doi.org/10.18632/genesandcancer.40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Zhao W, Kuai X, Zhou X, Jia L, Wang J, Yang X, Tian Z, Wang X, Lv Q, Wang B, Zhao Y, Huang W (2018) Trop2 is a potential biomarker for the promotion of EMT in human breast cancer. Oncol Rep 40(2):759–766. https://doi.org/10.3892/or.2018.6496

    Article  CAS  PubMed  Google Scholar 

  3. Goldenberg DM, Cardillo TM, Govindan SV, Rossi EA, Sharkey RM (2015) Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC). Oncotarget 6(26):22496–22512. https://doi.org/10.18632/oncotarget.4318

    Article  PubMed  PubMed Central  Google Scholar 

  4. Lin H, Zhang H, Wang J, Lu M, Zheng F, Wang C, Tang X, Xu N, Chen R, Zhang D, Zhao P, Zhu J, Mao Y, Feng Z (2014) A novel human Fab antibody for Trop2 inhibits breast cancer growth in vitro and in vivo. Int J Cancer 134(5):1239–1249. https://doi.org/10.1002/ijc.28451

    Article  CAS  PubMed  Google Scholar 

  5. Bardia A, Mayer IA, Diamond JR, Moroose RL, Isakoff SJ, Starodub AN, Shah NC, O’Shaughnessy J, Kalinsky K, Guarino M, Abramson V, Juric D, Tolaney SM, Berlin J, Messersmith WA, Ocean AJ, Wegener WA, Maliakal P, Sharkey RM, Govindan SV, Goldenberg DM, Vahdat LT (2017) Efficacy and safety of anti-trop-2 antibody drug conjugate sacituzumab govitecan (IMMU-132) in heavily pretreated patients with metastatic triple-negative breast cancer. J Clin Oncol 35(19):2141–2148. https://doi.org/10.1200/jco.2016.70.8297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ocean AJ, Starodub AN, Bardia A, Vahdat LT, Isakoff SJ, Guarino M, Messersmith WA, Picozzi VJ, Mayer IA, Wegener WA, Maliakal P, Govindan SV, Sharkey RM, Goldenberg DM (2017) Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate for the treatment of diverse epithelial cancers: safety and pharmacokinetics. Cancer 123(19):3843–3854. https://doi.org/10.1002/cncr.30789

    Article  CAS  PubMed  Google Scholar 

  7. Starodub AN, Ocean AJ, Shah MA, Guarino MJ, Picozzi VJ Jr, Vahdat LT, Thomas SS, Govindan SV, Maliakal PP, Wegener WA, Hamburger SA, Sharkey RM, Goldenberg DM (2015) First-in-human trial of a novel anti-trop-2 antibody-SN-38 conjugate, sacituzumab govitecan, for the treatment of diverse metastatic solid tumors. Clin Cancer Res 21(17):3870–3878. https://doi.org/10.1158/1078-0432.ccr-14-3321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bardia A, Mayer IA, Vahdat LT, Tolaney SM, Isakoff SJ, Diamond JR, O’Shaughnessy J, Moroose RL, Santin AD, Abramson VG, Shah NC, Rugo HS, Goldenberg DM, Sweidan AM, Iannone R, Washkowitz S, Sharkey RM, Wegener WA, Kalinsky K (2019) Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med 380(8):741–751. https://doi.org/10.1056/NEJMoa1814213

    Article  CAS  PubMed  Google Scholar 

  9. Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, Brufsky A, Sardesai SD, Kalinsky K, Zelnak AB, Weaver R, Traina T, Dalenc F, Aftimos P, Lynce F, Diab S, Cortés J, O’Shaughnessy J, Diéras V, Ferrario C, Schmid P, Carey LA, Gianni L, Piccart MJ, Loibl S, Goldenberg DM, Hong Q, Olivo MS, Itri LM, Rugo HS (2021) Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med 384(16):1529–1541. https://doi.org/10.1056/NEJMoa2028485

    Article  CAS  PubMed  Google Scholar 

  10. Kalinsky K, Diamond JR, Vahdat LT, Tolaney SM, Juric D, O’Shaughnessy J, Moroose RL, Mayer IA, Abramson VG, Goldenberg DM, Sharkey RM, Maliakal P, Hong Q, Goswami T, Wegener WA, Bardia A (2020) Sacituzumab govitecan in previously treated hormone receptor-positive/HER2-negative metastatic breast cancer: final results from a phase I/II, single-arm, basket trial. Ann Oncol 31(12):1709–1718. https://doi.org/10.1016/j.annonc.2020.09.004

    Article  CAS  PubMed  Google Scholar 

  11. Krop I, Juric D, Shimizu T, Tolcher A, Spira A, Mukohara T, Lisberg AE, Kogawa T, Papadopoulos K, Hamilton E, Damodaran S, Greenberg J, Gu W, Kobayashi F, Guevara F, Jikoh T, Kawasaki Y, Meric-Bernstam F, Bardia A (2022) Datopotamab deruxtecan in advanced/metastatic HER2- breast cancer: Results from the phase 1 TROPION-PanTumor01 study. Cancer Res 82(4):GS1-05

    Google Scholar 

  12. Bardia A, Tolaney SM, Punie K, Loirat D, Oliveira M, Kalinsky K, Zelnak A, Aftimos P, Dalenc F, Sardesai S, Hamilton E, Sharma P, Recalde S, Gil EC, Traina T, O’Shaughnessy J, Cortes J, Tsai M, Vahdat L, Diéras V, Carey LA, Rugo HS, Goldenberg DM, Hong Q, Olivo M, Itri LM, Hurvitz SA (2021) Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer. Ann Oncology 32(9):1148–1156. https://doi.org/10.1016/j.annonc.2021.06.002

    Article  CAS  Google Scholar 

  13. Esserman LJ, Berry DA, Cheang MC, Yau C, Perou CM, Carey L, DeMichele A, Gray JW, Conway-Dorsey K, Lenburg ME, Buxton MB, Davis SE, van’t Veer LJ, Hudis C, Chin K, Wolf D, Krontiras H, Montgomery L, Tripathy D, Lehman C, Liu MC, Olopade OI, Rugo HS, Carpenter JT, Livasy C, Dressler L, Chhieng D, Singh B, Mies C, Rabban J, Chen YY, Giri D, Au A, Hylton N, (2012) Chemotherapy response and recurrence-free survival in neoadjuvant breast cancer depends on biomarker profiles: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657). Breast Cancer Res Treat 132(3):1049–1062. https://doi.org/10.1007/s10549-011-1895-2

    Article  CAS  PubMed  Google Scholar 

  14. Esserman LJ, Berry DA, DeMichele A, Carey L, Davis SE, Buxton M, Hudis C, Gray JW, Perou C, Yau C, Livasy C, Krontiras H, Montgomery L, Tripathy D, Lehman C, Liu MC, Olopade OI, Rugo HS, Carpenter JT, Dressler L, Chhieng D, Singh B, Mies C, Rabban J, Chen YY, Giri D, van ’t Veer L, Hylton N, (2012) Pathologic complete response predicts recurrence-free survival more effectively by cancer subset: results from the I-SPY 1 TRIAL–CALGB 150007/150012, ACRIN 6657. J Clin Oncol 30(26):3242–3249. https://doi.org/10.1200/jco.2011.39.2779

    Article  PubMed  PubMed Central  Google Scholar 

  15. Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Graf S, Ha G, Haffari G, Bashashati A, Russell R, McKinney S, Langerod A, Green A, Provenzano E, Wishart G, Pinder S, Watson P, Markowetz F, Murphy L, Ellis I, Purushotham A, Borresen-Dale AL, Brenton JD, Tavare S, Caldas C, Aparicio S (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486(7403):346–352. https://doi.org/10.1038/nature10983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Johnson WE, Li C, Rabinovic A (2007) Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics (Oxford, England) 8(1):118–127. https://doi.org/10.1093/biostatistics/kxj037

    Article  Google Scholar 

  17. Ciriello G, Gatza ML, Beck AH, Wilkerson MD, Rhie SK, Pastore A, Zhang H, McLellan M, Yau C, Kandoth C, Bowlby R, Shen H, Hayat S, Fieldhouse R, Lester SC, Tse GM, Factor RE, Collins LC, Allison KH, Chen YY, Jensen K, Johnson NB, Oesterreich S, Mills GB, Cherniack AD, Robertson G, Benz C, Sander C, Laird PW, Hoadley KA, King TA, Perou CM (2015) Comprehensive molecular portraits of invasive lobular breast cancer. Cell 163(2):506–519. https://doi.org/10.1016/j.cell.2015.09.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. GeneCards—the human gene database. www.genecards.org (accessed April 29, 2022).

  19. Pereira B, Chin SF, Rueda OM, Vollan HK, Provenzano E, Bardwell HA, Pugh M, Jones L, Russell R, Sammut SJ, Tsui DW, Liu B, Dawson SJ, Abraham J, Northen H, Peden JF, Mukherjee A, Turashvili G, Green AR, McKinney S, Oloumi A, Shah S, Rosenfeld N, Murphy L, Bentley DR, Ellis IO, Purushotham A, Pinder SE, Børresen-Dale AL, Earl HM, Pharoah PD, Ross MT, Aparicio S, Caldas C (2016) The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nat Commun 7:11479. https://doi.org/10.1038/ncomms11479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. NCI Clinical Trials Using Sacituzumab Govitecan. https://www.cancer.gov/about-cancer/treatment/clinical-trials/intervention/sacituzumab-govitecan. Accessed 29 Apr 2022

  21. NCT03901339. Study of Sacituzumab Govitecan-hziy versus treatment of physician’s choice in participants with HR+/HER2- metastatic breast cancer. https://clinicaltrials.gov/ct2/show/NCT03901339 (accessed April 29, 2022)

  22. Ambrogi F, Fornili M, Boracchi P, Trerotola M, Relli V, Simeone P, La Sorda R, Lattanzio R, Querzoli P, Pedriali M, Piantelli M, Biganzoli E, Alberti S (2014) Trop-2 is a determinant of breast cancer survival. PLoS ONE 9(5):e96993. https://doi.org/10.1371/journal.pone.0096993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Guerra E, Trerotola M, Tripaldi R, Aloisi AL, Simeone P, Sacchetti A, Relli V, D’Amore A, La Sorda R, Lattanzio R, Piantelli M, Alberti S (2016) Trop-2 induces tumor growth through AKT and determines sensitivity to AKT inhibitors. Clin Cancer Res 22(16):4197–4205. https://doi.org/10.1158/1078-0432.ccr-15-1701

    Article  CAS  PubMed  Google Scholar 

  24. Li X, Teng S, Zhang Y, Zhang W, Zhang X, Xu K, Yao H, Yao J, Wang H, Liang X, Hu Z (2017) TROP2 promotes proliferation, migration and metastasis of gallbladder cancer cells by regulating PI3K/AKT pathway and inducing EMT. Oncotarget 8(29):47052–47063. https://doi.org/10.18632/oncotarget.16789

    Article  PubMed  PubMed Central  Google Scholar 

  25. Tang G, Tang Q, Jia L, Chen Y, Lin L, Kuai X, Gong A, Feng Z (2019) TROP2 increases growth and metastasis of human oral squamous cell carcinoma through activation of the PI3K/Akt signaling pathway. Int J Mol Med 44(6):2161–2170. https://doi.org/10.3892/ijmm.2019.4378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gu QZ, Nijiati A, Gao X, Tao KL, Li CD, Fan XP, Tian Z (2018) TROP2 promotes cell proliferation and migration in osteosarcoma through PI3K/AKT signaling. Mol Med Rep 18(2):1782–1788. https://doi.org/10.3892/mmr.2018.9083

    Article  CAS  PubMed  Google Scholar 

  27. Sawanyawisuth K, Tantapotinan N, Wongkham C, Riggins GJ, Kraiklang R, Wongkham S, Puapairoj A (2016) Suppression of trophoblast cell surface antigen 2 enhances proliferation and migration in liver fluke-associated cholangiocarcinoma. Ann Hepatol 15(1):71–81. https://doi.org/10.5604/16652681.1184223

    Article  CAS  PubMed  Google Scholar 

  28. Rugo HS, Bardia A, Tolaney SM, Arteaga C, Cortes J, Sohn J, Marmé F, Hong Q, Delaney RJ, Hafeez A, André F, Schmid P (2020) TROPiCS-02: A Phase III study investigating sacituzumab govitecan in the treatment of HR+/HER2- metastatic breast cancer. Future Oncol (London, England) 16(12):705–715. https://doi.org/10.2217/fon-2020-0163

    Article  CAS  Google Scholar 

  29. NCT03901339. Study of IMMU-132 in HR+/HER2- MBC (TROPICS-02). https://www.cancergov/about-cancer/treatment/clinical-trials/search/v?id=NCI-2019-03005&loc=0&q=sacituzumab&rl=2&t=C4872 (accessed July 13, 2020)

Download references

Acknowledgements

The authors would like to acknowledge the I-SPY 1 study participants and staff. While this study was not funded, the I-SPY 1 clinical trial (CALGB 150007/150012; ACRIN 6657) was funded through the Alliance grant U10CA180821.

Funding

No funding was provided for this work.

Author information

Author notes

  1. Christina Yau and Hope Rugo have contributed equally to this work.

Authors and Affiliations

  1. Massachusetts General Hospital Cancer Center, 55 Fruit Street, Bartlett Hall Extension 1-213, Boston, MA, USA

    Neelima Vidula

  2. University of California San Francisco, San Francisco, CA, USA

    Christina Yau & Hope Rugo

Authors
  1. Neelima Vidula
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christina Yau
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hope Rugo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to this study’s design, data analysis, and manuscript preparation. The authors have read and approved the final manuscript.

Corresponding author

Correspondence to Neelima Vidula.

Ethics declarations

Conflict of interests

NV: Research support (not related to this work) for clinical trials to the institution (MGH): Pfizer, Daehwa, Radius, Merck, Novartis. Advisory Board participation (single session, not related to this work): OncoSec, AbbVie, and Gilead. CY: Research funding (not related to this work) to the institution (UCSF): NCI and Quantum Leap Healthcare Collaborative.HSR: Research support (not related to this work) for clinical trials through the University of California: Pfizer, Merck, Novartis, Lilly, Roche, Odonate, Daiichi, Seattle Genetics, Macrogenics, Sermonix, Astra Zeneca, OBI, Gilead, Ayala. Honoraria (not related to this work): Puma, Samsung, Napo.

Ethical approval

Institutional Review Board review and consent of patients was not required for this study as it involved analysis of publically available de-identified datasets.

Consent to participate

N/A.

Consent to publish

N/A.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 47 KB)

Supplementary file2 (PDF 59 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vidula, N., Yau, C. & Rugo, H. Trophoblast Cell Surface Antigen 2 gene (TACSTD2) expression in primary breast cancer. Breast Cancer Res Treat 194, 569–575 (2022). https://doi.org/10.1007/s10549-022-06660-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-022-06660-x

Keywords

Search

Navigation