Breast cancer index in premenopausal women with early-stage hormone receptor-positive breast cancer

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2 Settembre 2024
O’Regan RM, Zhang Y, Fleming GF, et al.

Breast cancer index in premenopausal women with early-stage hormone receptor-positive breast cancer

JAMA Oncol 2024 Aug 15:e243044. Epub ahead of print
Simonpietro Marrocco Settembre 2024

Messaggi chiave

  • A partire dalla popolazione di SOFT, è stato condotto uno studio traslazionale prospettico-retrospettivo volto a valutare la performance del Breast Cancer Index (BCI) come marcatore prognostico e predittivo del beneficio della soppressione ovarica (OFS) in aggiunta all’endocrinoterapia adiuvante standard in pazienti in premenopausa con carcinoma mammario (BC) HR+.
  • Delle 3047 pazienti di SOFT, 1687 disponevano di campioni di tessuto tumorale idonei all’esecuzione del test genomico. Le pazienti che presentavano tumori con basso rapporto BCI HOXB13/IL17BR (H/I) (57,6%) hanno ottenuto un beneficio assoluto a 12 anni in intervallo libero da BC pari all’11,6% con exemestane + OFS (hazard ratio [HR], 0,48; IC 95%, 0,33-0,71) e al 7,3% con tamoxifen + OFS (HR, 0,69; IC 95%, 0,48-0,97) rispetto a tamoxifen da solo. Di contro, non è stato osservato alcun beneficio nelle pazienti con tumori BCI(H/I)-high. Il valore continuo del BCI è risultato prognostico in termini di intervallo libero da recidiva a distanza (DRFI) nel sottogruppo N0, con DRFI a 12 anni del 95,9, 90,8 e 86,3% nei tumori N0 a rischio BCI rispettivamente basso, intermedio e alto.
  • Poiché l’integrazione dell’OFS nel trattamento adiuvante del BC HR+ può comportare l’insorgenza di tossicità aggiuntive, la disponibilità di un biomarcatore genomico dotato di valore prognostico e predittivo potrebbe risultare estremamente utile per la selezione delle pazienti con maggiori probabilità di trarre beneficio da tale approccio intensivo.

Abstract

Importance

  • Adjuvant ovarian function suppression (OFS) with oral endocrine therapy improves outcomes for premenopausal patients with hormone receptor-positive (HR+) breast cancer but adds adverse effects.
  • A genomic biomarker for selecting patients most likely to benefit from OFS-based treatment is lacking.

Objective

  • To assess the predictive and prognostic performance of the Breast Cancer Index (BCI) for OFS benefit in premenopausal women with HR+ breast cancer.

Design, setting, and participants

  • This prospective-retrospective translational study used all available tumor tissue samples from female patients from the Suppression of Ovarian Function Trial (SOFT).
  • These individuals were randomized to receive 5 years of adjuvant tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS.
  • BCI testing was performed blinded to clinical data and outcome.
  • The a priori hypothesis was that BCI HOXB13/IL17BR ratio (BCI[H/I])-high tumors would benefit more from OFS and high BCI portended poorer prognosis in this population.
  • Settings spanned multiple centers internationally.
  • Participants included premenopausal female patients with HR+ early breast cancer with specimens in the International Breast Cancer Study Group tumor repository available for RNA extraction.
  • Data were collected from December 2003 to April 2021 and were analyzed from May 2022 to October 2022.

Main outcomes and measures

  • Primary end points were breast cancer-free interval (BCFI) for the predictive analysis and distant recurrence-free interval (DRFI) for the prognostic analyses.

Results

  • Tumor specimens were available for 1718 of the 3047 female patients in the SOFT intention-to-treat population.
  • The 1687 patients (98.2%) who had specimens that yielded sufficient RNA for BCI testing represented the parent trial population.
  • The median (IQR) follow-up time was 12 (10.5-13.4) years, and 512 patients (30.3%) were younger than 40 years.
  • Tumors were BCI(H/I)-low for 972 patients (57.6%) and BCI(H/I)-high for 715 patients (42.4%).
  • Patients with tumors classified as BCI(H/I)-low exhibited a 12-year absolute benefit in BCFI of 11.6% from exemestane plus OFS (hazard ratio [HR], 0.48 [95% CI, 0.33-0.71]) and an absolute benefit of 7.3% from tamoxifen plus OFS (HR, 0.69 [95% CI, 0.48-0.97]) relative to tamoxifen alone.
  • In contrast, patients with BCI(H/I)-high tumors did not benefit from either exemestane plus OFS (absolute benefit, -0.4%; HR, 1.03 [95% CI, 0.70-1.53]; p for interaction = 0.006) or tamoxifen plus OFS (absolute benefit, -1.2%; HR, 1.05 [95% CI, 0.72-1.54]; p for interaction = 0.11) compared with tamoxifen alone.
  • BCI continuous index was significantly prognostic in the N0 subgroup for DRFI (n = 1110; p = 0.004), with 12-year DRFI of 95.9%, 90.8%, and 86.3% in BCI low-risk, intermediate-risk, and high-risk N0 cancers, respectively.

Conclusions and relevance

  • In this prospective-retrospective translational study of patients enrolled in SOFT, BCI was confirmed as prognostic in premenopausal women with HR+ breast cancer.
  • The benefit from OFS-containing adjuvant endocrine therapy was greater for patients with BCI(H/I)-low tumors than BCI(H/I)-high tumors.
  • BCI(H/I)-low status may identify premenopausal patients who are likely to benefit from this more intensive endocrine therapy.
  • receptor expression is a known positive prognostic and predictive factor in breast cancer; however, limited evidence exists on its impact on prognosis of young patients harboring BRCA pathogenic variant (PV).
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