Endocrine-sensitive disease rate in postmenopausal patients with estrogen receptor-rich/ERBB2-negative breast cancer receiving neoadjuvant anastrozole, fulvestrant, or their combination: a phase 3 randomized clinical trial

Messaggi chiave

ALTERNATE è uno studio di fase 3, randomizzato, in aperto, che ha testato l’ipotesi di un aumento del tasso di malattia endocrino-sensibile (ESD) con fulvestrant (F) in monoterapia o in combinazione con anastrozolo (A) rispetto ad A da solo in donne in post-menopausa con carcinoma mammario HR+/HER2- avviate a terapia neoadiuvante (NA). L’ESD era definita come risposta patologica completa o indice PEPI modificato pari a 0 (ypT1-2N0/N1mic/Ki67 ≤2,7%).
Nelle 1298 partecipanti valutabili, nessuno dei regimi contenenti F ha prodotto un miglioramento significativo del tasso di ESD (ESDR) o del grado di soppressione di Ki67 alla settimana 4. In particolare, la differenza in ESDR è stata del 4,1% con F rispetto ad A e dell’1,8% con A + F rispetto ad A. A + F si è associato a una soppressione significativamente superiore di Ki67 rispetto ad A nel sottogruppo con malattia luminal B.
A differenza di quanto osservato nel setting metastatico, fulvestrant, da solo o in aggiunta ad anastrozolo, non è risultato superiore ad anastrozolo in monoterapia quando somministrato come terapia NA. L’osservazione di un aumento dell’effetto antiproliferativo con la combinazione A + F nella popolazione luminal B merita ulteriori approfondimenti, soprattutto alla luce dell’attuale disponibilità di SERD somministrabili per via orale.

Importance

Adding fulvestrant to anastrozole (A+F) improved survival in postmenopausal women with advanced estrogen receptor (ER)-positive/ERBB2 (formerly HER2)-negative breast cancer. However, the combination has not been tested in early-stage disease.

Objective

To determine whether neoadjuvant fulvestrant or A+F increases the rate of pathologic complete response or ypT1-2N0/N1mic/Ki67 2.7% or less residual disease (referred to as endocrine-sensitive disease) over anastrozole alone.

Design, setting, and participants

A phase 3 randomized clinical trial assessing differences in clinical and correlative outcomes between each of the fulvestrant-containing arms and the anastrozole arm.
Postmenopausal women with clinical stage II to III, ER-rich (Allred score 6-8 or >66%)/ERBB2-negative breast cancer were included.
All analyses were based on data frozen on March 2, 2023.

Interventions

Patients received anastrozole, fulvestrant, or a combination for 6 months preoperatively.
Tumor Ki67 was assessed at week 4 and optionally at week 12, and if greater than 10% at either time point, the patient switched to neoadjuvant chemotherapy or immediate surgery.

Main outcomes and measures

The primary outcome was the endocrine-sensitive disease rate (ESDR).
A secondary outcome was the percentage change in Ki67 after 4 weeks of neoadjuvant endocrine therapy (NET) (week 4 Ki67 suppression).

Results

Between February 2014 and November 2018, 1362 female patients (mean [SD] age, 65.0 [8.2] years) were enrolled.
Among the 1298 evaluable patients, ESDRs were 18.7% (95% CI, 15.1%-22.7%), 22.8% (95% CI, 18.9%-27.1%), and 20.5% (95% CI, 16.8%-24.6%) with anastrozole, fulvestrant, and A+F, respectively.
Compared to anastrozole, neither fulvestrant-containing regimen significantly improved ESDR or week 4 Ki67 suppression.
The rate of week 4 or week 12 Ki67 greater than 10% was 25.1%, 24.2%, and 15.7% with anastrozole, fulvestrant, and A+F, respectively.
Pathologic complete response/residual cancer burden class I occurred in 8 of 167 patients and 17 of 167 patients, respectively (15.0%; 95% CI, 9.9%-21.3%), after switching to neoadjuvant chemotherapy due to week 4 or week 12 Ki67 greater than 10%.
PAM50 subtyping derived from RNA sequencing of baseline biopsies available for 753 patients (58%) identified 394 luminal A, 304 luminal B, and 55 nonluminal tumors.
A+F led to a greater week 4 Ki67 suppression than anastrozole alone in luminal B tumors (median [IQR], -90.4% [-95.2 to -81.9%] vs -76.7% [-89.0 to -55.6%]; P < .001), but not luminal A tumors.
Thirty-six nonluminal tumors (65.5%) had a week 4 or week 12 Ki67 greater than 10%.

Conclusions and relevance

In this randomized clinical trial, neither fulvestrant nor A+F significantly improved the 6-month ESDR over anastrozole in ER-rich/ERBB2-negative breast cancer.
Aromatase inhibition remains the standard-of-care NET.
Differential NET response by PAM50 subtype in exploratory analyses warrants further investigation.

Note: Funded by Alliance for Clinical Trials in Oncology; ALTERNATE ClinicalTrials.gov number, NCT01953588