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Case Report Open Access

Unmasking intratumoral heterogeneity: Postoperative revelation of subclonal divergence in de novo metastatic HR‑positive/HER2‑negative breast cancer: A case report

  • Authors:
    • Zeliha Birsin
    • Emir Çerme
    • Ceyda Sönmez Wetherilt
    • Zeynep Hande Turna
  • View Affiliations / Copyright

    Affiliations: Department of Internal Medicine, Faculty of Medicine, Division of Medical Oncology, Istanbul University‑Cerrahpaşa, 34098 Istanbul, Turkey, Department of Pathology, Faculty of Medicine, Istanbul University‑Cerrahpaşa, 34098 Istanbul, Turkey
    Copyright: © Birsin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 27
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    Published online on: February 24, 2026
       https://doi.org/10.3892/mco.2026.2936
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Abstract

Intratumoral heterogeneity poses a significant challenge in the management of metastatic hormone receptor‑positive (HR+), human epidermal growth factor receptor 2 (HER2)‑negative (HER2‑) breast cancer (BC), as it may contribute to treatment resistance and disease progression. Two cases of de novo metastatic HR+/HER2‑ BC with bone‑only metastases were reported. Both patients responded well to first‑line systemic therapy with CDK4/6 inhibitors and endocrine agents. Locoregional surgery was subsequently performed and revealed HER2‑positive subclones in the primary tumors that were not detected in the initial core biopsies. In one patient, HER2‑targeted therapy was initiated with sustained clinical benefit. In the second patient, CDK4/6 inhibitor therapy was initially continued, but the disease later progressed. Post‑treatment pathology can uncover distinct subclones, reflecting the dynamic nature of tumor biology. These cases highlight the potential value of surgical reassessment in selected patients with metastatic BC to guide individualized treatment strategies.
View Figures

Figure 1

HER2 evaluation in the initial core
needle biopsy and postoperative surgical specimen in Case 1.
Representative HER2 IHC and SISH images from the initial core
needle biopsy and the postoperative surgical specimen. (A) HER2 IHC
showing negative staining in the initial core needle biopsy
(original magnification, x400). (B) HER2 IHC demonstrating strong
membranous positivity (score 3+) in the postoperative surgical
specimen (original magnification, x400). (C) SISH analysis showing
no HER2 amplification in the initial core needle biopsy (original
magnification, x1,000, oil immersion). (D) SISH analysis
demonstrating HER2 amplification in the postoperative surgical
specimen (original magnification, 1,000, oil immersion). HER2,
human epidermal growth factor receptor 2; IHC,
immunohistochemistry; SISH, silver in situ
hybridization.

Figure 2

Histopathological evaluation of liver
metastasis in Case 2. Representative HER2 IHC and SISH images from
the liver metastasis biopsy. (A) HER2 IHC demonstrating a HER2-low
profile in the liver metastasis biopsy (original magnification,
x400). (B) SISH analysis showing no HER2 amplification in the liver
metastasis biopsy (original magnification, x1,000; oil immersion).
HER2, human epidermal growth factor receptor 2; IHC,
immunohistochemistry; SISH, silver in situ
hybridization.
View References

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Copy and paste a formatted citation
Spandidos Publications style
Birsin Z, Çerme E, Sönmez Wetherilt C and Turna ZH: Unmasking intratumoral heterogeneity: Postoperative revelation of subclonal divergence in <em>de novo</em> metastatic HR‑positive/HER2‑negative breast cancer: A case report. Mol Clin Oncol 24: 27, 2026.
APA
Birsin, Z., Çerme, E., Sönmez Wetherilt, C., & Turna, Z.H. (2026). Unmasking intratumoral heterogeneity: Postoperative revelation of subclonal divergence in <em>de novo</em> metastatic HR‑positive/HER2‑negative breast cancer: A case report. Molecular and Clinical Oncology, 24, 27. https://doi.org/10.3892/mco.2026.2936
MLA
Birsin, Z., Çerme, E., Sönmez Wetherilt, C., Turna, Z. H."Unmasking intratumoral heterogeneity: Postoperative revelation of subclonal divergence in <em>de novo</em> metastatic HR‑positive/HER2‑negative breast cancer: A case report". Molecular and Clinical Oncology 24.4 (2026): 27.
Chicago
Birsin, Z., Çerme, E., Sönmez Wetherilt, C., Turna, Z. H."Unmasking intratumoral heterogeneity: Postoperative revelation of subclonal divergence in <em>de novo</em> metastatic HR‑positive/HER2‑negative breast cancer: A case report". Molecular and Clinical Oncology 24, no. 4 (2026): 27. https://doi.org/10.3892/mco.2026.2936
Copy and paste a formatted citation
x
Spandidos Publications style
Birsin Z, Çerme E, Sönmez Wetherilt C and Turna ZH: Unmasking intratumoral heterogeneity: Postoperative revelation of subclonal divergence in <em>de novo</em> metastatic HR‑positive/HER2‑negative breast cancer: A case report. Mol Clin Oncol 24: 27, 2026.
APA
Birsin, Z., Çerme, E., Sönmez Wetherilt, C., & Turna, Z.H. (2026). Unmasking intratumoral heterogeneity: Postoperative revelation of subclonal divergence in <em>de novo</em> metastatic HR‑positive/HER2‑negative breast cancer: A case report. Molecular and Clinical Oncology, 24, 27. https://doi.org/10.3892/mco.2026.2936
MLA
Birsin, Z., Çerme, E., Sönmez Wetherilt, C., Turna, Z. H."Unmasking intratumoral heterogeneity: Postoperative revelation of subclonal divergence in <em>de novo</em> metastatic HR‑positive/HER2‑negative breast cancer: A case report". Molecular and Clinical Oncology 24.4 (2026): 27.
Chicago
Birsin, Z., Çerme, E., Sönmez Wetherilt, C., Turna, Z. H."Unmasking intratumoral heterogeneity: Postoperative revelation of subclonal divergence in <em>de novo</em> metastatic HR‑positive/HER2‑negative breast cancer: A case report". Molecular and Clinical Oncology 24, no. 4 (2026): 27. https://doi.org/10.3892/mco.2026.2936
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