Biomarkers guiding breast cancer care

By Agata Buczak

​​Biomarker assessment using immune, genomic, and ctDNA approaches is increasingly informing prognostic stratification and recurrence risk across breast cancer subtypes​

Biomarker assessment is increasingly shaping prognostic stratification and recurrence risk across breast cancer subtypes. Data presented at the San Antonio Breast Cancer Symposium (SABCS) 2025 and shared through the licensed Best of SABCS^® 2025 meeting in Bulgaria highlight how immune markers, genomic profiling, and circulating tumor DNA (ctDNA) can refine post‑neoadjuvant and metastatic decision‑making, particularly in settings where residual disease and treatment resistance remain major clinical challenges.

Which biomarker profiles identify high‑risk subgroups in residual triple‑negative breast cancer?

In patients with residual triple‑negative breast cancer following neoadjuvant systemic treatment, integrated biomarker assessment can identify clinically distinct risk groups.^1,2 

Across neoadjuvant GBG/AGO‑B trials, Johannes Holdtschmidt et al. showed that evaluating Ki‑67 and tumor‑infiltrating lymphocytes (TILs) provides prognostic value and supports more precise post‑neoadjuvant risk stratification.¹ 

Consistently, in ECOG‑ACRIN EA1131, Sunil Badve et al. demonstrated that combined assessment of TIL levels and molecular subtype identifies a particularly high‑risk subgroup characterized by low TILs and a basaloid phenotype.² This biologic profile was associated with poorer outcomes, supporting its use to inform selection and intensification of adjuvant strategies.²

What is the clinical utility of ctDNA monitoring during neoadjuvant therapy in early HER2‑positive breast cancer?

In stage 1–3A human epidermal growth factor receptor 2 (HER2)‑positive breast cancer, emerging data suggest that ctDNA monitoring during neoadjuvant therapy may provide clinically relevant information.³ 

In the PHERGain trial, Antonio Llombart‑Cussac et al. showed that both baseline ctDNA detection and on‑treatment ctDNA dynamics correlated with pathologic complete response (pCR) and invasive disease‑free survival.³

How can genomic profiling inform prognosis in de novo metastatic HER2‑positive breast cancer?

Genomic profiling also informs prognosis in advanced disease. In patients with de novo metastatic HER2‑positive breast cancer, the presence of a pathogenic PIK3CA mutation was associated with poorer survival outcomes.⁴ 

In addition, tumor‑wide sequencing revealed a shift in mutational signatures from homologous recombination deficiency toward an APOBEC‑driven profile, suggesting a potential biological mechanism underlying treatment resistance.⁴

Which patients with ER‑positive breast cancer may benefit from extended endocrine therapy based on genomic signatures?

In postmenopausal women with non‑metastatic luminal estrogen receptor (ER)‑positive breast cancer who have completed 5 years of adjuvant endocrine therapy, genomic signatures may help guide decisions on treatment extension.⁵ 

In NSABP B-42, Eleftherios Mamounas et al. showed that a SET ER/PR signature >1.50 identified patients more likely to benefit from extended endocrine therapy, particularly those with lymph‑node involvement, prior aromatase inhibitor exposure, or preserved bone mineral density.⁵

How can tumor‑informed ctDNA testing guide recurrence risk assessment in early breast cancer?

In non‑metastatic luminal ER‑positive/HER2‑negative breast cancer, personalized tumor‑informed ctDNA testing is emerging as a tool for molecular residual disease assessment.⁶ 

In the PALLAS trial, Heather Parsons et al. demonstrated that ctDNA detection at predefined time points during and after treatment provided prognostic information for distant recurrence‑free survival, supporting its use in longitudinal risk assessment.⁶

Key takeaways

• Integrated assessment of TILs, Ki‑67, and molecular subtype refines risk stratification in residual triple-negative breast cancer 
• ctDNA monitoring during neoadjuvant therapy in early HER2‑positive disease shows predictive and prognostic value 
• Genomic profiling identifies adverse prognostic features in de novo metastatic HER2‑positive breast cancer 
• Genomic signatures such as SET ER/PR may help guide decisions on extended endocrine therapy 
• Tumor‑informed ctDNA testing offers prognostic insight into recurrence risk in early ER‑positive/HER2‑negative disease 

Read more about consensus and new recommendations from Best of 2025 SABCS® Bulgaria. 

References

1. Conforti, 2025. Distant disease-free survival as a surrogate endpoint for overall survival in randomised trials of neoadjuvant therapy for early breast cancer: a pooled analysis of GBG and AGO-B study group trials. https://www.doi.org/10.1016/s1470-2045(25)00546-7
2. Badve, 2026. Abstract RF3-06: Tumor infiltrating lymphocytes in post-NACT residual tumors in ECOG-ACRIN EA1131 - impact of intrinsic subtypes. https://www.doi.org/10.1158/1557-3265.Sabcs25-rf3-06
3. Bidard, 2026. Abstract PD5-08: Circulating tumour DNA (ctDNA) dynamics from patients with ER+, HER2- advanced breast cancer in the phase 3 EMBER-3 trial. https://www.doi.org/10.1158/1557-3265.Sabcs25-pd5-08
4. Turner, 2025. INAVO120: Phase III trial final overall survival (OS) analysis of first-line inavolisib (INAVO)/placebo (PBO) + palbociclib (PALBO) + fulvestrant (FULV) in patients (pts) with PIK3CA-mutated, hormone receptor-positive (HR+), HER2-negative (HER2-), endocrine-resistant advanced breast cancer (aBC). https://www.doi.org/10.1200/JCO.2025.43.16_suppl.1003
5. Mamounas, 2024. Breast cancer index and prediction of extended aromatase inhibitor therapy benefit in hormone receptor-positive breast cancer from the NRG oncology/NSABP B-42 trial. https://www.doi.org/10.1158/1078-0432.Ccr-23-1977
6. Parsons, 2026. Abstract RF3-04: Tumor-informed circulating tumor DNA analysis to assess molecular residual disease for prognosis and prediction of benefit from palbociclib in the PALLAS trial. https://www.doi.org/10.1158/1557-3265.Sabcs25-rf3-04

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