Breast Cancer

TACSTD2

  • Tumor-associated calcium signal transducer 2 (TACSTD2); encodes trophoblast cell-surface antigen 2 (Trop-2), a 40-kDa transmembrane glycoprotein of the EpCAM family
  • Gene Location: Chromosome 1 (1p32.1); TACSTD2 is intronless

Biology

  • Trop-2 is a calcium signal transducer involved in epithelial proliferation, adhesion, and migration. It is expressed at low levels in normal epithelium and upregulated across essentially all epithelial carcinomas, including every breast cancer subtype.1
  • Upregulation has been linked to accelerated tumor growth and less favorable prognosis, with signaling crosstalk through the PI3K/AKT/mTOR, MAPK/ERK, JAK/STAT, and Wnt/beta-catenin pathways.1
  • Unlike ESR1 or BRCA1/2, Trop-2 is not a therapeutic driver. It functions as a cell-surface delivery target: an antibody-drug conjugate binds surface Trop-2, internalizes, and releases a topoisomerase I inhibitor payload (SN-38 for sacituzumab govitecan, DXd for datopotamab deruxtecan). Both payloads are membrane-permeable enough to produce bystander killing of adjacent tumor cells.2,3

Etiology and Epidemiology

  • Trop-2 expression is near-universal in breast cancer and present at diagnosis rather than acquired under treatment pressure. In one 77-patient surgical series, 96.1% of breast tumors were Trop-2-positive, including 97.1% of triple-negative and 93.5% of HR-positive/HER2-negative tumors.1
  • Because expression is close to universal, no cut point has been clinically validated that separates responders from non-responders to the approved TROP2-directed agents. Expression level is not used to select patients.
  • Marked intratumoral heterogeneity and discordance between primary and metastatic sites further complicate any threshold-based approach, and membranous versus cytoplasmic localization appears to matter more than total staining intensity.1,4,9

Testing

When to Test:

  • TROP2 testing is not required before either approved TROP2-directed antibody-drug conjugate. Neither sacituzumab govitecan nor datopotamab deruxtecan carries an FDA-required companion diagnostic for TROP2 in breast cancer.2,3
  • The tests that actually gate these agents define the clinical setting: HR and HER2 status, including the IHC 0, IHC 1+, and IHC 2+/ISH-negative categories used in the HR-positive indications; PD-L1 CPS by 22C3 to establish PD-1/PD-L1 candidacy in first-line TNBC; and germline BRCA1/2 status where a PARP inhibitor is the competing option.2,3,5

Testing Methodologies:

  • Immunohistochemistry on formalin-fixed, paraffin-embedded tissue remains the primary method of assessing Trop-2 protein. In investigational settings, moderate-to-strong membranous staining in at least 10% of tumor cells has commonly been used to designate TROP2-high; by that convention 82% of triple-negative tumors qualified in one 807-patient cohort.9
  • Quantitative continuous scoring (QCS) applies a deep-learning digital-pathology algorithm to whole-slide images to derive a normalized membrane ratio (NMR), quantifying membrane-bound Trop-2 relative to total Trop-2. In the TROPION-Lung01 exploratory analysis, tumors were called QCS-NMR positive when at least 75% of tumor cells had an NMR at or below 0.56, indicating a greater cytoplasmic proportion; 63% of biomarker-evaluable patients were positive. QCS-NMR-positive patients treated with datopotamab deruxtecan had an objective response rate of 32.7% versus 10.3% with docetaxel and median progression-free survival of 6.9 versus 4.1 months (HR 0.57), with no separation in the QCS-NMR-negative group.4
  • Scope caution: QCS-NMR was developed and tested in non-small cell lung cancer, not breast cancer. It remains investigational, is not standardized across laboratories, and has no role in breast cancer treatment selection today. Note also that the positivity direction is counterintuitive: a lower membrane ratio defines the favorable group.4
  • There is no companion diagnostic for TROP2 and no validated plasma or circulating tumor DNA assay for TROP2 expression. For the sacituzumab govitecan plus pembrolizumab indication, patient selection is by PD-L1 IHC 22C3 pharmDx rather than by any TROP2 assay.5
  • UGT1A1 status is relevant to sacituzumab govitecan safety, since reduced UGT1A1 activity raises the risk of neutropenia, but the label does not mandate testing before treatment.2

Guideline Recommendations

  • No major guideline body currently recommends routine TROP2 testing in breast cancer, and ASCO biomarker guidance does not list TROP2 among biomarkers required to direct systemic therapy.
  • NCCN positions the TROP2-directed agents by clinical setting, subtype, and prior therapy rather than by a TROP2 result. Sacituzumab govitecan is listed as a preferred category 1 first-line option for metastatic TNBC with PD-L1 CPS below 10 and no germline BRCA1/2 pathogenic variant.6

Targeted Therapy

Approved Agents

  • Two TROP2-directed antibody-drug conjugates are FDA-approved in breast cancer: sacituzumab govitecan (2020) and datopotamab deruxtecan (2025). Neither is selected by a TROP2 assay.2,3
  • Sacituzumab govitecan was first approved in April 2020 for pretreated metastatic TNBC, with regular approval in April 2021 based on ASCENT, expansion to HR-positive/HER2-negative disease in February 2023 based on TROPiCS-02, and two first-line TNBC indications on June 24, 2026 based on ASCENT-03 and ASCENT-04/KEYNOTE-D19.2,5
  • Datopotamab deruxtecan was approved January 17, 2025 for pretreated HR-positive/HER2-negative disease based on TROPION-Breast01, with a first-line TNBC indication added May 22, 2026 based on TROPION-Breast02.3,7,8
  • The two agents now overlap in first-line PD-1/PD-L1-ineligible TNBC. Sacituzumab govitecan is additionally available with pembrolizumab for PD-L1 CPS of 10 or higher and in later lines; datopotamab deruxtecan carries no combination indication in breast cancer.2,3

Sacituzumab Govitecan-hziy (Trodelvy)

  • FDA-Approved Indication:
    • As a single agent for the first-line treatment of adults with unresectable locally advanced or metastatic triple-negative breast cancer who are not candidates for PD-1 or PD-L1 inhibitor-based therapy.2
    • In combination with pembrolizumab, or pembrolizumab and berahyaluronidase alfa-pmph, for the first-line treatment of adults with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1 (CPS greater than or equal to 10) as determined by an FDA-authorized test.2
    • For adults with unresectable locally advanced or metastatic TNBC who have received two or more prior systemic therapies, at least one for metastatic disease.2
    • For adults with unresectable locally advanced or metastatic HR-positive, HER2-negative (IHC 0, IHC 1+, or IHC 2+/ISH-negative) breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting.2
  • Mechanism of Action:
    • Trop-2-directed antibody-drug conjugate comprising a humanized anti-Trop-2 antibody linked by a hydrolyzable linker to SN-38, the active metabolite of irinotecan and a topoisomerase I inhibitor.2
    • Carries a boxed warning for severe or life-threatening neutropenia and severe diarrhea.2

Drug Information:

Learn more about Sacituzumab Govitecan ›

Patient Resources:

https://www.trodelvy.com/

Datopotamab Deruxtecan-dlnk (Datroway)

  • FDA-Approved Indication:
    • For adults with unresectable or metastatic triple-negative breast cancer who are not candidates for PD-1/PD-L1 inhibitor therapy.3
    • For adults with unresectable or metastatic HR-positive, HER2-negative (IHC 0, IHC 1+, or IHC 2+/ISH-negative) breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease.3
  • Mechanism of Action:
    • Trop-2-directed antibody-drug conjugate pairing a humanized anti-Trop-2 IgG1 antibody with the exatecan derivative DXd, a topoisomerase I inhibitor, through a tetrapeptide-based cleavable linker.3
    • No boxed warning. Interstitial lung disease, ocular surface toxicity, and stomatitis are the notable labeled risks.3

Drug Information:

Learn more about Datopotamab Deruxtecan ›

Patient Resources:

https://www.datroway.com/

References

1. Lai J, Deng S, Cao J, et al. Identification of biomarker associated with Trop2 in breast cancer: implication for targeted therapy. Discov Oncol. 2024;15:413. doi:10.1007/s12672-024-01261-0

2. TRODELVY (sacituzumab govitecan-hziy) for injection. Prescribing information. Gilead Sciences, Inc; revised 06/2026. Accessed July 2026.

3. DATROWAY (datopotamab deruxtecan-dlnk) for injection. Prescribing information. Daiichi Sankyo, Inc; revised 05/2026. Accessed July 2026.

4. Garassino MC, Sands J, Paz-Ares L, et al. Normalized membrane ratio of TROP2 by quantitative continuous scoring is predictive of clinical outcomes in TROPION-Lung01. Presented at: IASLC 2024 World Conference on Lung Cancer; September 8, 2024; San Diego, CA.

5. US Food and Drug Administration. FDA approves sacituzumab govitecan-hziy as monotherapy and in combination with pembrolizumab for first-line treatment of triple-negative breast cancer. June 24, 2026. Accessed July 2026.

6. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.5.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed July 2026. To view the most recent and complete version of the guideline, go online to NCCN.org.

7. US Food and Drug Administration. FDA approves datopotamab deruxtecan-dlnk for unresectable or metastatic, HR-positive, HER2-negative breast cancer. January 17, 2025. Accessed July 2026.

8. US Food and Drug Administration. FDA approves datopotamab deruxtecan-dlnk for unresectable or metastatic triple-negative breast cancer. May 22, 2026. Accessed July 2026.

9. Trophoblast cell-surface antigen 2 (TROP2) expression in triple-negative breast cancer. BMC Cancer. 2022;22(1):1014. doi:10.1186/s12885-022-10076-7