Role of repeat biopsies of metastatic and recurrent lesions for the study of tumor heterogeneity in luminal breast cancer: Retrospective and prospective analyses

Introduction. Current guidelines (NCCN, ESMO, RUSSCO) for the treatment of breast cancer (BC) with the disease progression recommend performing a repeat biopsy with a reassessment of immunohistochemical (IHC) status. However, due to the weak evidence base, the indications and clinical significance of repeat biopsies are not clear, and repeated IHC examinations of histological specimens have not yet been introduced into routine practice. The dependence of the change in the tumor immunophenotype on its clinical and biological characteristics, and hence the potential markers for deciding to perform a repeat biopsy, remain poorly studied.

Aim. To evaluate phenotypic variability of luminal BC based on comparison of repeat biopsies of recurrent/metastatic lesions with biopsies of primary tumors before treatment, and to study the effect of this variability on the treatment of the disease.

Materials and methods. Between 2019 and 2024, 100 patients with early luminal A and B BC underwent a core biopsy of the primary tumor before treatment and a biopsy of a recurrent or metastatic lesion after the disease progression. In our study, the influence of the main clinical and morphological factors (patient's age, tumor differentiation degree, localization of metastases, presence of the driver mutations in the BRCA1/2 and PIK3CA genes, IHC subtype of the tumor, as well as administered chemotherapy, antihormonal, and radiation therapy) on the frequency of detection of discordance between paired biopsies was determined. The impact of discordance detection on further treatment approaches was also assessed.

Results. Discordance of the IHC study results between the primary tumor before treatment and recurrent/metastatic lesions was found in 57% of cases, of which 37 cases were associated with a change in the tumor subtype, 20 cases with the loss/acquisition of IHC parameters that do not lead to conversion. Tumor subtype conversion was observed in 37% of cases. The luminal A subtype was the most unstable; in 54% (20/37) of cases, it converted into the luminal B subtype. The IHC discordance detection led to a treatment change in 48% of cases (27/57). There was no statistically significant effect of the studied clinical and morphological factors (see materials and methods) on the probability of discordance detection. However, the probability of conversion by multivariate analysis was significantly less in the luminal B subtype (70% less than in luminal A subtype) [odds ratio (OR) lumА/lumВ = 0.30, 95% confidence interval 0.10-0.80; p = 0.018], and adjuvant antihormonal therapy with tamoxifen was associated with a 79% reduction in the probability of conversion when compared with adjuvant treatment with aromatase inhibitors [OR IA/TAM = 0.29 (95% confidence interval 0.10-0.82); p = 0.024].

Conclusion. Performing a repeat biopsy in patients with luminal BC can reveal the discordance of IHC characteristics in 57% (57/100) of patients and the therapy-induced tumor subtype conversion in 37% (37/100) of patients, which led to a change in treatment approaches in more than 1/3 of cases (48%, 27/57). Risk factors for conversion of the IHC subtype include the luminal A subtype of the primary tumor and adjuvant antihormonal therapy with aromatase inhibitors. For this category of patients, a repeat biopsy is necessary since it helps to individualize further anti-tumor treatment.