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Breast Cancer Awareness Month 2025
Jason Armstrong
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Introduction
Breast cancer remains the most commonly diagnosed cancer in women worldwide, and one of the leading causes of cancer-related death. Despite major advances in screening and treatment, more than 2.3 million people are diagnosed each year, resulting in 670,000 deaths from the disease. Outcomes vary by subtype. Hormone receptor-positive, HER2-positive, and triple-negative breast cancers differ in prevalence, prognosis, and treatment options. Triple-negative disease, for example, accounts for about 15% of cases but carries a higher risk of recurrence and limited targeted therapies.
Genomic research continues to reshape our understanding of breast cancer biology. From tumor-informed liquid biopsy to subtype-specific mutational profiles, insights from large-scale sequencing and integrative studies are translating into new opportunities for early detection, risk prediction, and personalized therapy. Yet, progress brings new challenges, such as ensuring breakthroughs are applied equitably across populations, recognising sex- and age-related differences, and adapting treatment strategies to diverse clinical contexts.
This article looks at five recent papers that together illustrate these themes, showing how genomics is helping to advance breast cancer care, and highlighting the importance of inclusivity, diversity, and clinical nuance in applying new knowledge.
Whole-genome Sequencing ctDNA for early Breast Cancer - Garcia-Murillas et al., 2025
Circulating tumor DNA (ctDNA) refers to fragments of tumor-derived DNA that are released into the bloodstream. Analysing ctDNA provides a non-invasive way to monitor cancer. In breast cancer, ctDNA has potential for detecting molecular residual disease (MRD), tracking treatment response, and predicting relapse before clinical symptoms appear.
This study tested whether a whole-genome sequencing (WGS)-based, tumor-informed ctDNA assay could improve the sensitivity of ctDNA detection, MRD detection, and relapse prediction, compared with existing approaches. The team analysed 617 plasma samples from 78 patients across hormone receptor-positive, HER2-positive, and triple-negative subtypes. Each patient had a personalized panel built from WGS of tumor and germline DNA, covering a median of 1451 variants.
Detection rates were high: ctDNA was found at diagnosis in 98% of patients, including all HER2-positive and triple-negative cases. The WGS method outperformed exome-based assays and digital PCR, particularly for low-level ctDNA. Notably, 39% of positive samples fell within the ultra-low range (<100 parts per million), which is often missed by less-sensitive methods.
After treatment, ctDNA detection strongly predicted outcomes. In all 11 patients who relapsed, ctDNA was detected before clinical recurrence, with a median lead time of 15 months. None of the 60 patients who remained ctDNA-negative after surgery relapsed during more than six years of follow-up.
These findings suggest that ultrasensitive WGS-based assays can identify relapse risk earlier and with greater accuracy than current methods. The results indicate that ctDNA could be used to adjust adjuvant treatment, intensifying therapy for patients with persistent ctDNA while sparing those with no detectable signal from unnecessary treatment.
ctNDA and Equity in Breast Cancer - Aronson et al., 2025
ctDNA has shown promise as a non-invasive tool for tumor profiling, MRD detection, and treatment monitoring in breast cancer. Assays based on next-generation sequencing (NGS), digital PCR, and tumor-informed approaches can identify mutations, such as those in ESR1, PIK3CA, and PTEN, that inform prognosis and guide therapy selection.
This review highlights that the performance and adoption of ctDNA are not equal across populations. Black women, who are almost twice as likely as White women to be diagnosed with triple-negative breast cancer, also face poorer survival for all breast cancer subtypes. Despite higher ctDNA positivity rates in some studies, Black patients remain underrepresented in clinical trials and are less likely to receive genotype-matched therapies. For example, none of the Black patients with PIK3CA mutations in one analysis were enrolled in a relevant clinical trial, compared with 11.5% of White patients.
Similar findings have been reported elsewhere. In Ghana, ctDNA was detectable in all patients tested using whole-genome sequencing, even with low-depth coverage, suggesting feasibility in low-resource settings. Yet, access remains limited due to infrastructure and cost constraints. Studies in China and India also report distinct mutation patterns compared with Western cohorts, underlining the need for diverse datasets.
The authors conclude that ctDNA could widen disparities if validation and implementation do not account for biological and systemic differences. Inclusive research, equitable insurance coverage, and broader access to testing in community and global settings are essential to ensure ctDNA supports all patients, not only those overrepresented in trials.
RBness: Proteogenomic Insights into RB1 Pathway Dysregulation - Iacovacci et al., 2025
The retinoblastoma tumor suppressor gene (RB1) is often mutated or deleted in cancers, including breast, lung, and prostate cancer, leading to dysregulation of the RB pathway. For example, RB1 mutations and deletions are implicated in around 13% of triple-negative breast cancers.
This study introduced a proteogenomic approach to identify tumors that share the transcriptional profile of RB1-defective cancers, without RB1 mutations or deletions; a phenomenon the authors deemed as “RBness”. Analysis of over 1000 breast tumors revealed that nearly 30% of cases exhibited RBness, characterised by upregulation of RB/E2F target genes and aggressive molecular subtypes (basal-like, HER-enriched). Importantly, patients with RBness had similarly poor outcomes as those with true RB1 defects.
Clinically, RBness predicted response to chemotherapy and neoadjuvant treatment, with higher rates of pathological complete responses in trials such as BrighTNess and I-SPY2. In ER-positive disease, RBness was also linked to resistance to CDK4/6 inhibitors, suggesting a role in treatment stratification. CRISPR screens also showed that cancers with RBness share synthetic lethal vulnerabilities with RB1-deficient tumors, highlighting potential therapeutic targets.
These findings establish RBness as a biologically and clinically meaningful phenotype. By extending the impact of RB1 pathway dysregulation beyond RB1 mutations, the work shows the value of integrative proteogenomics in refining risk prediction and guiding therapy in breast cancer.
Male versus Female Breast Cancer: Genomic Profiling Across Subtypes - Kadamkulam Syriac et al., 2024
Male breast cancer (MaBC) is rare, accounting for less than 1% of all breast cancer cases. As a result, its genomic features are less well studied. This large-scale comparison analysed 252 males and 2708 female metastatic breast cancers, stratified by subtype, using comprehensive genomic profiling (CGP).
The results revealed both shared biology and distinct differences. In ER-positive/HER2-negative tumors (the most common male subtype), MaBC showed more frequent alterations versus female disease in GATA3 (26.2% vs 15.9%), BRCA2 (13.8% vs. 5.3%), MDM2 (13.3% vs. 6.1%), and CDK4 (7.1% vs. 1.8%). By contrast, TP53 (11.0% vs. 42.6%) and ESR1 (5.7% vs. 14.6%) were less common in men.
For triple-negative disease, which was rare in men, TP53 mutations were again far less frequent (25.0% vs 84.4%). Across all subtypes, men had higher rates of breast cancer susceptibility gene alterations, particularly BRCA2 (14.6% vs 9.1%).
These findings suggest that while MaBC and female breast cancer share broad features, their mutational landscapes diverge in important ways. The enrichment of BRCA2 alterations in men highlights potential for PARP inhibitor therapy, while the lower prevalence of TP53 mutations and higher rates of MDM2 alterations suggest alternative mechanisms of p53 pathway disruption. Differences in ERBB2 and PIK3CA alterations may also contribute to poorer outcomes observed in men with HER2-positive disease.
Overall, this study demonstrates that sex-specific genomic differences exist and should be considered when designing treatment strategies and clinical trials.
Genomic Landscape of Breast Cancer in Elderly Patients - Selenica et al., 2025
Breast cancer biology is influenced by age, yet the genomic features of tumors in elderly patients have remained poorly defined. Selenica et al. (2025) re-analysed sequencing data from 1918 breast cancers profiled with the MSK-IMPACT assay, comparing elderly patients (≥65 years) with younger groups. Their findings reveal both broad similarities and age-related differences.
In primary ER-positive, HER2-negative cancers, tumors from elderly patients displayed higher rates of PIK3CA and CDH1 mutations, but fewer TP53 mutations, than those from younger individuals. These differences reflect a higher rate of lobular tumors, linked to CDH1 mutations, and lower genomic instability in older patients. In metastatic disease, resistance-associated alterations emerged more frequently. Tumors from elderly patients showed increased rates of FAT1 and RB1 mutations, which are linked to resistance against CDK4/6 inhibitors, while invasive lobular carcinomas in this group carried more activating ERBB2 mutations, compared with younger patients. By contrast, ESR1 mutations, often implicated in endocrine resistance, were less common in older patients, suggesting a shift towards alternative resistance mechanisms.
The study also examined homologous recombination deficiency (HRD) and DNA damage response genes. Germline mutations in these genes were less frequent in elderly patients, yet somatic alterations were somewhat more common. Many of these were mono-allelic events, raising the possibility that they represent age-associated mutagenesis rather than functionally significant HRD.
Taken together, these results indicate that breast cancer in elderly patients harbours distinctive patterns of genomic change with direct clinical relevance. The prevalence of PIK3CA and ERBB2 alterations highlights opportunities for targeted therapies, while the emergence of different resistance mechanisms suggests the need for age-aware strategies when managing endocrine and CDK4/6 inhibitor therapies in this population.
Conclusions
These studies highlight the pace and breadth of discovery in breast cancer genomics. Advances in ctDNA analysis demonstrate how liquid biopsy could transform early detection and relapse prediction, while parallel work warns that such tools must be implemented equitably to avoid deepening disparities. Integrative approaches such as RBness broaden our view of pathway disruption beyond single-gene mutations. Comparative profiling of male versus female disease underscores the need to recognise sex-specific genomic features when tailoring cancer treatment, and the analysis of elderly patients reveals distinct mutational patterns that call for age-aware therapeutic strategies.
Together, these studies demonstrate that breast cancer is not a single disease, but a spectrum shaped by subtype, ancestry, sex, and age. Genomics is providing new levels of resolution of these differences, opening the way to more personalized and effective care. However, researchers, clinicians, and health services face challenges to ensure innovations are broadly accessible and clinically meaningful for all patients. Breast Cancer Awareness Month reminds us that awareness must go hand in hand with action. To harness new insights effectively, equity and inclusivity must be central to their application.
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