In a groundbreaking study published in Nature, researchers have unveiled comprehensive insights into the genomic and transcriptomic landscapes of HER2-positive breast cancers, challenging and refining existing diagnostic and therapeutic paradigms. Traditionally, immunohistochemistry (IHC) targeting the HER2 protein, encoded by the ERBB2 gene, has served as the clinical gold standard for detecting HER2-positive breast tumors. However, the latest data reveal that this method, while highly sensitive, does not always perfectly coincide with genomic alterations such as PAM50 molecular subtypes or ERBB2 gene copy number amplifications. This uncovers a nuanced molecular heterogeneity that could impact both diagnosis and treatment strategies in breast oncology.
The researchers observed intriguing exceptions within their cohort, where intense ERBB2 focal amplifications stemming from extrachromosomal DNA (ecDNA) could be present even in cases labeled as HER2 IHC 0. Conversely, certain tumors with robust HER2 IHC 3+ staining lacked conspicuous ERBB2 gene amplification. This disconnect highlights the complexity of gene expression regulation and amplification mechanisms. For example, a luminal B subtype tumor with HER2 IHC 3+ exhibited much lower ERBB2 transcription levels than typical HER2-enriched cases, resembling the transcriptional profile of HER2 IHC 0 tumors. These findings underscore the importance of integrating multi-omic layers to accurately classify and treat breast cancers.
Moving beyond diagnostic characterization, the study rigorously evaluated the predictive power of integrated genomic and transcriptomic data for therapeutic response among HER2-positive breast cancer patients undergoing neoadjuvant treatment with the TCHP regimen—a potent combination of docetaxel, carboplatin, trastuzumab, and pertuzumab. Among 75 patients, nearly half achieved a pathological complete response (pCR), a critical marker for favorable prognosis. However, the molecular profiles of responders and non-responders diverged significantly: non-pCR cases more frequently belonged to luminal subtypes and exhibited hormone receptor positivity and PIK3CA mutations, all markers known to influence resistance to HER2-targeted therapies.
Crucially, those who achieved pCR displayed markedly higher ERBB2 expression levels and a greater incidence of ERBB2 focal amplifications, suggesting that quantitative genomic features surpass IHC alone in predictive utility. While HER2 IHC 3+ status showed exceptional sensitivity for predicting response, ERBB2 copy number offered superior precision, specificity, and likelihood ratios. This stronger predictive capacity, validated in external cohorts such as the TransNEO study, advocates for incorporating ERBB2 copy number assessment into clinical decision algorithms to optimize patient stratification for anti-HER2 therapy.
One revelation that challenges the prevailing notion associating extrachromosomal DNA with poor cancer prognosis was the observation that despite ecDNA presence correlating with high ERBB2 copy numbers, its presence did not significantly influence pCR rates. This implies that absolute ERBB2 copy number, rather than the DNA amplification mechanism, may be the principal determinant of therapeutic response in HER2-positive breast cancer. It also illuminates the potential of ecDNA-derived ERBB2 amplifications as actionable targets, opening avenues for next-generation therapies tailored to these unique genomic contexts.
Delving deeper into the genomic instability landscape, the study identified a notable enrichment of chromothripsis—catastrophic chromosomal shattering and haphazard reassembly events—in patients who responded completely to TCHP therapy. This counterintuitive correlation suggests that chromothripsis-associated tumor genomic disruptions might sensitize cancers to aggressive combinational therapies. Incorporating chromothripsis status into predictive models further enhanced the precision and specificity in identifying patients likely to respond favorably, underscoring the clinical relevance of complex structural variations in treatment outcome predictions.
The implications of this work are broad and profound. By transcending traditional diagnostic frameworks centered around IHC and single-gene metrics, the research advocates for a layered genomic approach that embraces focal gene amplifications, transcriptomic expression patterns, and structural chromosomal aberrations. Such an integrated perspective could revolutionize the personalization of HER2-targeted therapies—ensuring that patients receive treatments most likely to yield durable responses while sparing non-responders from unnecessary toxicity.
Moreover, the findings prompt critical reconsideration of the role of ERBB2 amplification mechanisms. The dissociation between ecDNA presence and treatment efficacy hints at nuanced biological processes influencing cancer cell survival under therapeutic pressure. This insight could fuel the development of novel therapeutics aimed at ecDNA-specific vulnerabilities, potentially overcoming resistance mechanisms rooted in extrachromosomal gene amplifications.
This research also sheds light on the heterogeneity within clinically defined HER2-positive tumors, suggesting that molecular subtyping and assessment of mutational landscapes, including PIK3CA mutations, are indispensable for fully understanding treatment response variability. As the molecular underpinnings of resistance and sensitivity become clearer, clinicians can tailor neoadjuvant regimens more effectively, perhaps integrating PI3K inhibitors or hormone therapies where warranted.
Importantly, the study underscores the power of whole-genome sequencing in elucidating the complex architecture of cancer genomes in unprecedented detail. By deploying this technology at scale across 1,364 breast cancer cases, the researchers have created a comprehensive resource that paves the way for precision oncology approaches that dynamically incorporate genomic instability patterns, gene dosage effects, and transcriptomic activity into clinical workflows.
This paradigm shift towards multi-dimensional cancer profiling holds the promise of elevating clinical trial design, biomarker discovery, and ultimately, patient outcomes. As the landscape of breast cancer therapy evolves, incorporating genome-wide insights may become the standard of care, optimizing therapeutic index and guiding drug development.
In summary, this pioneering research redefines the molecular characterization of HER2-positive breast cancer by illustrating the complexity and clinical relevance of ERBB2 amplification beyond IHC. It highlights the predictive superiority of genomic copy number and chromothripsis status in forecasting responses to TCHP neoadjuvant therapy, offering a more textured understanding of tumor biology and therapeutic vulnerabilities. This work marks a critical step forward in the genomics-driven personalization of breast cancer treatment, setting a new benchmark for integrating whole-genome data into clinical oncology.
Subject of Research: Genomic and transcriptomic characterization of HER2-positive breast cancers with respect to treatment response prediction.
Article Title: Whole-genome landscapes of 1,364 breast cancers.
Article References:
Kim, R., Yu, J., Lim, J. et al. Whole-genome landscapes of 1,364 breast cancers. Nature (2025). https://doi.org/10.1038/s41586-025-09812-3
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41586-025-09812-3
Keywords: HER2-positive breast cancer, ERBB2 amplification, extrachromosomal DNA, chromothripsis, neoadjuvant therapy, TCHP regimen, whole-genome sequencing, genomic instability, predictive biomarkers, transcriptomics, precision oncology
