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Purpose: Therapeutic options for breast cancer (BC) treatment are constantly evolving. The Human Epidermal Growth Factor 2 (HER2)-low BC entity is a new subgroup, representing about 55% of all BC patients. New antibody–drug conjugates demonstrated promising results for this BC subgroup. Currently, there is limited information about the conversion of HER2 subtypes between primary tumor and recurrent disease. Methods: This retrospective study included women with BC at the University Medical Centre Wuerzburg from 1998 to 2021. Data were retrieved from patients' records. HER2 evolution from primary diagnosis to the first relapse and the development of secondary metastases was investigated. Results: In the HR-positive subgroup without HER2 overexpression, HER2-low expression in primary BC was 56.7 vs. 14.6% in the triple-negative subgroup (p < 0.000). In the cohort of the first relapse, HER2-low represented 64.1% of HR-positive vs. 48.2% of the triple-negative cohort (p = 0.03). In patients with secondary metastases, HER2-low was 75.6% vs. 50% in the triple negative subgroup (p = 0.10). The subgroup of HER2-positive breast cancer patients numerically increased in the course of disease; the HER2-negative overall cohort decreased. A loss of HER2 expression from primary BC to the first relapse correlated with a better OS (p = 0.018). No clinicopathological or therapeutic features could be identified as potential risk factors for HER2 conversion. Conclusion: HER2 expression is rising during the progression of BC disease. In view of upcoming therapeutical options, the re-analysis of newly developed metastasis will become increasingly important. [ABSTRACT FROM AUTHOR]

Purpose. This case report highlights the complexities of managing metastatic breast cancer with dynamic HER2 status in a 56-year-old female with multiple comorbidities, including cardiovascular, endocrinological and renal conditions. Materials and method. The patient was diagnosed in January 2023 with ductal carcinoma in her left breast (ER 60%, PR 10%, HER2 negative, Ki67 70%). She began neoadjuvant chemotherapy in February 2023 with epirubicin and cyclophosphamide, followed by paclitaxel. In April 2023, a new pulmonary lesion was found and removed, revealing a typical pulmonary carcinoid. In July 2023, she also underwent excision of a basal cell carcinoma from her nose. After completing chemotherapy, in September 2023 the patient had a radical left mastectomy and axillary lymphadenectomy. Pathology showed invasive ductal carcinoma (G3, Nottingham 8, ypT3 N3a), with residual disease, ER 90%, PR 15%, HER2 negative (1+). She received radiotherapy in December 2023 and started letrozole with abemaciclib in January 2024. Results. Despite the initial treatment, new hepatic lesions were discovered in July 2024. The biopsy revealed the presence of liver metastasis of moderately differentiated NST breast carcinoma, with a significant change in HER2 status, from negative to positive (HER2 3+). The patient also experienced renal complications, requiring multiple nephrology interventions. Conclusions. This case highlights the importance of reassessing HER2 status during metastatic progression, as receptor conversion can alter treatment options. The shift from HER2 negative to HER2 positive in liver metastasis shows the need for a tailored therapeutic approach and emphasizes the role of the dynamic tumor biology in guiding patients’ treatment. [ABSTRACT FROM AUTHOR]

Abstract Background The clinical benefits associated with targeted oncology agents are generally limited to subsets of patients. Even with favorable biomarker profiles, many patients do not respond or acquire resistance. Existing technologies are ineffective for treatment monitoring as they provide only static and limited information and require substantial amounts of tissue. Therefore, there is an urgent need to develop methods that can profile potential therapeutic targets with limited clinical specimens during the course of treatment. Methods We have developed a novel proteomics-based assay, Collaborative Enzyme Enhanced Reactive-immunoassay (CEER) that can be used for analyzing clinical samples. CEER utilizes the formation of unique immuno-complex between capture-antibodies and two additional detector-Abs on a microarray surface. One of the detector-Abs is conjugated to glucose oxidase (GO), and the other is conjugated to Horse Radish Peroxidase (HRP). Target detection requires the presence of both detector-Abs because the enzyme channeling event between GO and HRP will not occur unless both Abs are in close proximity. Results CEER was able to detect single-cell level expression and phosphorylation of human epidermal growth factor receptor 2 (HER2) and human epidermal growth factor receptor 1 (HER1) in breast cancer (BCa) systems. The shift in phosphorylation profiles of receptor tyrosine kinases (RTKs) and other signal transduction proteins upon differential ligand stimulation further demonstrated extreme assay specificity in a multiplexed array format. HER2 analysis by CEER in 227 BCa tissues showed superior accuracy when compared to the outcome from immunohistochemistry (IHC) (83% vs. 96%). A significant incidence of HER2 status alteration with recurrent disease was observed via circulating tumor cell (CTC) analysis, suggesting an evolving and dynamic disease progression. HER2-positive CTCs were found in 41% (7/17) while CTCs with significant HER2-activation without apparent over-expression were found in 18% (3/17) of relapsed BCa patients with HER2-negative primary tumors. The apparent 'HER2 status conversion' observed in recurrent BCa may have significant implications on understanding breast cancer metastasis and associated therapeutic development. Conclusion CEER can be multiplexed to analyze pathway proteins in a comprehensive manner with extreme specificity and sensitivity. This format is ideal for analyzing clinical samples with limited availability.