Abstract
Breast cancer receptor status plays a critical role in treatment selection, yet receptor evolution throughout disease progression remains a significant challenge. This case describes a 58-year-old female initially diagnosed with estrogen receptor (ER)-positive (95%), progesterone receptor (PR)-negative (<5%), human epidermal growth factor receptor 2 (HER2)-negative (immunohistochemistry [IHC] 0, fluorescence in situ hybridization-negative) invasive ductal carcinoma. Over 6 years, her tumor transitioned to triple-negative breast cancer at recurrence, then reacquired ER expression (80%) in metastatic mediastinal lymph nodes. HER2 status evolved from IHC 0 → HER2-low (IHC 1+ → IHC 2+), directly influencing therapy selection. These receptor changes led to major systemic treatment modifications, including endocrine therapy, immunotherapy, CDK4/6 inhibitors, and antibody–drug conjugates. Given the extended response duration and improved tolerability of targeted therapies, accurate receptor assessment is essential to ensure that patients receive the most effective treatment. Literature reports receptor discordance rates of ER loss (19%), PR loss (34%), and HER2 fluctuations (15%), reinforcing the necessity of biopsy-driven treatment adaptation. While serial biopsies remain invasive, they provide essential molecular insights that optimize systemic therapy choices, allowing patients to remain on the most appropriate, well-tolerated regimen for as long as possible. This case highlights the clinical significance of receptor evolution and advocates for biopsy-guided precision oncology in metastatic breast cancer management. Ensuring accurate receptor reassessment through periodic molecular profiling can maximize therapeutic efficacy, improving response rates, treatment tolerability, and overall patient outcomes.
Keywords
Introduction
Breast cancer treatment is guided by the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). However, receptor status is dynamic, with 20% to 30% of patients exhibiting discordance between primary and metastatic disease, leading to significant therapeutic implications.1,2 Receptor expression changes due to tumor adaptation, therapeutic selection pressure, and genetic alterations,3,4 directly influencing systemic treatment choices.
HER2 status, in particular, has undergone major therapeutic evolution. Historically, HER2 positivity (immunohistochemistry [IHC] 3+, fluorescence in situ hybridization [FISH]-amplified) dictated eligibility for trastuzumab-based regimens, revolutionizing outcomes for HER2-overexpressing tumors. However, the emergence of HER2-low classification (IHC 1+ or IHC 2+, FISH-negative) has expanded targeted therapy options, particularly with trastuzumab deruxtecan, bridging the gap for tumors previously deemed HER2-negative. 5 Similarly, ER-positive breast cancer now demonstrates longer survival rates exceeding 5 years, a milestone rarely seen with chemotherapy alone, largely due to CDK4/6 inhibitors and endocrine-based strategies. 6
Given the profound influence of receptor status on treatment choices and survival outcomes, repeat biopsy remains indispensable in metastatic disease management, ensuring precise therapeutic adaptation and optimized treatment selection.7-9 This case underscores the clinical importance of receptor reassessment, particularly in the targeted therapy era, where sustained responses and improved tolerability necessitate precise molecular profiling. Incorporating serial biopsies into routine practice is critical for aligning evolving tumor biology with the most effective systemic therapy, ultimately enhancing treatment durability and patient outcomes.
Case Presentation
The patient, a 52-year-old female, presented with a self-palpated, tender left breast mass accompanied by skin changes. Initial imaging revealed a large, irregular tumor with nipple retraction and extensive skin thickening, prompting further evaluation. A core biopsy confirmed high-grade invasive ductal carcinoma, with ER positivity (>90%), PR negativity (<5%), and HER2 IHC 0, FISH-negative with programmed death-ligand 1 combined positive score (PD-L1 CPS 1), indicating low PD-L1 expression. The Ki-67 proliferation index was high (>20%), indicating aggressive tumor behavior. Concurrent axillary lymph node biopsy revealed metastatic adenocarcinoma, consistent with breast origin, suggesting nodal involvement. Based on imaging, biopsy findings, and clinical presentation, the patient was classified as cT4N1M0, consistent with locally advanced breast cancer. According to the AJCC eighth edition staging system, this corresponds to Stage IIIA disease, characterized by tumor extension to the skin and/or chest wall (T4) and metastasis to ipsilateral axillary lymph nodes (N1), without distant spread (M0). Given this classification, a multimodal approach incorporating systemic therapy, surgery, and radiation was pursued to optimize disease control and improve long-term outcomes.
She underwent neoadjuvant chemotherapy (AC i.e. Adria-mycin (doxorubicin) and Cytoxan (cyclophosphamide) followed by weekly paclitaxel), bilateral mastectomy with direct implants and radiation therapy. The final pathology confirmed a 9.2 cm high-grade invasive ductal carcinoma in the left breast, with positive lymphatic invasion but negative margins. Lymph node involvement was observed in 3 of 11 nodes, supporting a ypT3 pN1a classification. Receptor status remained ER-positive, PR-negative, and HER2-negative, guiding further endocrine therapy decisions. After 3 years of endocrine therapy, anastrozole was discontinued due to severe joint pain. The patient transitioned to letrozole, completing 4 years of endocrine therapy before presenting erythema, skin thickening, and hyperpigmentation near the surgical scar. Initial antibiotic therapy failed, prompting a punch biopsy. These biopsy findings confirm a triple-negative breast cancer (TNBC) transformation, with HER2-low classification (IHC 1+, FISH-negative) and PD-L1 CPS 10, indicating high PD-L1 expression.
Given this recurrence pattern, pembrolizumab was initiated alongside weekly carboplatin and paclitaxel for 3 months as neoadjuvant therapy, followed by surgical excision. The patient underwent removal of the left breast implant, along with excision of overlying skin and axillary lymph nodes. Pathology confirmed an 8 cm Grade 3 invasive ductal carcinoma with dermal and subcutaneous involvement, skin ulceration, intraepidermal spread, and dermal lymphatic invasion. Margins were positive at the superior border, with close medial and inferior margins, while the lateral margin was negative. A left axillary mass measuring 1.5 cm was identified as invasive ductal carcinoma, Grade 3, located <1 mm from the inked margin, though no definitive lymph node was present. Following surgical resection, the patient completed adjuvant radiation therapy to the left chest wall. Pembrolizumab was continued as adjuvant treatment, with capecitabine added as adjuvant therapy. The patient tolerated 7 of the planned 8 cycles of capecitabine, but treatment was discontinued due to toxicity (mucositis). Pembrolizumab was continued indefinitely.
Six years into the initial diagnosis, the patient remained stable on pembrolizumab for 2 years before developing mediastinal adenopathy concerning for metastatic progression. Imaging revealed small radiodense pulmonary nodules bilaterally and a stable hypodense hepatic lesion, prompting further evaluation. A bronchoscopy with endobronchial ultrasoud (EBUS) confirmed malignant cells in mediastinal lymph nodes (Station 7 and 4R), consistent with invasive ductal carcinoma, with ER expression returning (>80%), PR-negative (0%), and HER2 (IHC 0), leading to a shift in systemic treatment. Given this hormone receptor-positive recurrence, therapy was adjusted to fulvestrant and ribociclib, achieving disease stability for 1 year.
Seven years from the initial diagnosis and 1 year into hormone therapy, the patient presented with a 2-week history of nonproductive cough and shortness of breath, prompting evaluation with chest X-ray, which revealed bilateral pleural effusion, more prominent on the left. A left thoracentesis was performed, with cytology showing atypical cells suspicious for metastatic involvement from the known breast primary. Pleural fluid analysis demonstrated GATA3 positivity, consistent with the breast primary, while ER was negative. Other markers could not be obtained due to scant cellularity, limiting further characterization. A brain MRI showed no evidence of metastatic disease, supporting the absence of Central Nervous System (CNS) involvement, while computed tomography scan of chest, abdomen and pelvis (CT CAP) confirmed no progression elsewhere. Given the loss of ER expression in pleural fluid cytology and limited cellularity preventing comprehensive receptor profiling, treatment decisions were guided by a presumed triple-negative phenotype. Sacituzumab govitecan was chosen as an antibody–drug conjugate targeting Trop-2, aligning with TNBC-directed therapeutic strategies. Though initial treatment status remained uncertain, follow-up imaging and clinical assessment demonstrated at least a partial response 3 months later, suggesting therapeutic benefit (Table 1).
Biopsy Site-Specific Receptor Discordance and Therapeutic Modification.
Abbreviations: ER, estrogen receptor; FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; LN, lymph node; N/A, not applicable; PD-L1 CPS, programmed death-ligand 1 combined positive score; PR, progesterone receptor.
Discussion
Breast cancer receptor discordance is a critical yet often overlooked phenomenon that has direct implications for treatment sequencing. By highlighting the dynamic shifts in receptor expression, this case reinforces the necessity of biopsy-driven precision oncology and underscores its relevance beyond oncology specialists. Improved awareness of receptor evolution can enhance clinical decision-making across disciplines, ensuring optimal treatment strategies for metastatic disease. Over 7 years post-diagnosis, the patient has remained on continuous systemic therapy, demonstrating how biopsy-guided treatment modifications can support extended survival despite the aggressive nature of the disease. Receptor evolution, particularly ER loss transitioning to TNBC, required a shift to immune checkpoint therapy (pembrolizumab), while subsequent ER reexpression in metastatic lesions enabled CDK4/6 inhibition therapy (ribociclib + Faslodex).10,11
HER2 fluctuations (IHC 0 → IHC 2+) influenced eligibility for HER2-low therapies, reinforcing the role of repeat biopsies in guiding individualized treatment.9,12 Additionally, PD-L1 CPS changes affected the duration and continuity of immunotherapy, further demonstrating how molecular adaptation drives therapeutic decisions. 11 Studies indicate that receptor discordance is observed in up to 40% of cases, with real-world data supporting biopsy-driven therapy refinement to improve survival rates.10-12
Receptor evolution in metastatic breast cancer is not a linear or predictable process. While dedifferentiation can occur, receptor status changes are influenced by multiple factors, including therapeutic selection pressure, genomic alterations, and epigenetic modifications. This complexity underscores the necessity of repeat biopsies, allowing clinicians to track molecular adaptation and ensure that systemic therapy remains aligned with tumor biology. Correct sequencing of therapies plays a pivotal role in prolonging disease control and overall survival. The strategic transitions between endocrine therapy, immunotherapy, targeted agents, and antibody–drug conjugates ensure optimized responses at various disease stages. 10 For example, early integration of immune checkpoint inhibitors during a period of PD-L1 CPS positivity, followed by chemotherapy, helped delay progression.11,12 Similarly, reintroducing endocrine therapy after ER reexpression extended disease control, supporting personalized sequencing strategies.
Ultimately, the ability to adapt treatments based on molecular reexpression and receptor shifts reinforces the necessity of serial biopsies in metastatic breast cancer management. This case highlights how precise therapeutic adjustments—driven by receptor discordance—can maximize response rates, optimize treatment selection, and improve long-term outcomes in advanced disease. Sequencing of targeted therapies has significantly increased survival across multiple cancers, including melanoma, lung, and breast cancer.13-15 Additionally, toxicity management remains a critical factor—while targeted therapies reduce systemic toxicity compared to traditional chemotherapy, they introduce unique adverse effects (eg, immune-related toxicities, cardiotoxicity), requiring careful monitoring.
Ultimately, this case reinforces the necessity of biopsy-driven precision oncology, ensuring that evolving tumor biology aligns with the most effective systemic therapy, optimizing survival outcomes and improving long-term disease control.
Conclusion
Breast cancer receptor status is dynamic, necessitating periodic biopsy to align treatment strategies with evolving tumor biology. This case highlights the clinical relevance of receptor discordance, emphasizing how serial biopsies refine personalized treatment approaches in metastatic disease. Continuous molecular profiling enables optimal therapy selection, ultimately improving survival outcomes.
Footnotes
Acknowledgements
None.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval
Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent
Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.
