Messaggi chiave
- TRAIN-3 è uno studio di fase 2, a braccio singolo, teso a valutare i tassi di risposta radiologica e patologica (endpoint secondari) e la sopravvivenza libera da eventi a 3 anni (endpoint primario) in pazienti con carcinoma mammario HER2+ in stadio II-III avviate a terapia neoadiuvante (NA) sistemica e successiva chirurgia al raggiungimento di una risposta radiologica completa (rCR) secondo l’imaging con risonanza magnetica (RM) o dopo massimo 9 cicli di terapia NA.
- Negli anni 2019-2021, lo studio ha arruolato un totale di 467 pazienti. Il tasso di rCR dopo 1-3 cicli di terapia NA è stato del 36% nel sottogruppo con malattia HR- e del 29% nelle pazienti con tumore HR+. In presenza di rCR dopo ≤9 cicli di terapia NA, l’87 e 53% delle pazienti rispettivamente HR- e HR+ ha mostrato una risposta patologica completa (pCR). Il follow-up per l’endpoint primario è in corso.
- Circa un terzo delle pazienti con malattia HR-/HER2+ ha raggiunto la pCR dopo soli 3 cicli di terapia NA. Una strategia basata sull’imaging RM potrebbe consentire di limitare la durata della chemioterapia, ridurre gli effetti collaterali e preservare la qualità della vita in queste pazienti se confermata dall’analisi dell’endpoint primario. Esiste invece la necessità di individuare strumenti di monitoraggio più efficaci per la malattia HR+/HER2+.
Abstract
Bckground
- Patients with stage II-III HER2-positive breast cancer have good outcomes with the combination of neoadjuvant chemotherapy and HER2-targeted agents.
- Although increasing the number of chemotherapy cycles improves pathological complete response rates, early complete responses are common.
- We investigated whether the duration of chemotherapy could be tailored on the basis of radiological response.
Methods
- TRAIN-3 is a single-arm, phase 2 study in 43 hospitals in the Netherlands. Patients with stage II-III HER2-positive breast cancer aged 18 years or older and a WHO performance status of 0 or 1 were enrolled.
- Patients received neoadjuvant chemotherapy consisting of paclitaxel (80 mg/m2 of body surface area on day 1 and 8 of each 21 day cycle), trastuzumab (loading dose on day 1 of cycle 1 of 8 mg/kg bodyweight, and then 6 mg/kg on day 1 on all subsequent cycles), and carboplatin (area under the concentration time curve 6 mg/mL per min on day 1 of each 3 week cycle) and pertuzumab (loading dose on day 1 of cycle 1 of 840 mg, and then 420 mg on day 1 of each subsequent cycle), all given intravenously.
- The response was monitored by breast MRI every three cycles and lymph node biopsy.
- Patients underwent surgery when a complete radiological response was observed or after a maximum of nine cycles of treatment.
- The primary endpoint was event-free survival at 3 years; however, follow-up for the primary endpoint is ongoing.
- Here, we present the radiological and pathological response rates (secondary endpoints) of all patients who underwent surgery and the toxicity data for all patients who received at least one cycle of treatment.
- Analyses were done in hormone receptor-positive and hormone receptor-negative patients separately.
- This trial is registered with ClinicalTrials.gov, number NCT03820063, recruitment is closed, and the follow-up for the primary endpoint is ongoing.
Results
- Between April 1, 2019, and May 12, 2021, 235 patients with hormone receptor-negative cancer and 232 with hormone receptor-positive cancer were enrolled.
- Median follow-up was 26·4 months (IQR 22·9-32·9) for patients who were hormone receptor-negative and 31·6 months (25·6-35·7) for patients who were hormone receptor-positive.
- Overall, the median age was 51 years (IQR 43-59).
- In 233 patients with hormone receptor-negative tumours, radiological complete response was seen in 84 (36%; 95% CI 30-43) patients after one to three cycles, 140 (60%; 53-66) patients after one to six cycles, and 169 (73%; 66-78) patients after one to nine cycles.
- In 232 patients with hormone receptor-positive tumours, radiological complete response was seen in 68 (29%; 24-36) patients after one to three cycles, 118 (51%; 44-57) patients after one to six cycles, and 138 (59%; 53-66) patients after one to nine cycles.
- Among patients with a radiological complete response after one to nine cycles, a pathological complete response was seen in 147 (87%; 95% CI 81-92) of 169 patients with hormone receptor-negative tumours and was seen in 73 (53%; 44-61) of 138 patients with hormone receptor-positive tumours.
- The most common grade 3-4 adverse events were neutropenia (175 [37%] of 467), anaemia (75 [16%]), and diarrhoea (57 [12%]).
- No treatment-related deaths were reported.
Interpretation
- In our study, a third of patients with stage II-III hormone receptor-negative and HER2-positive breast cancer had a complete pathological response after only three cycles of neoadjuvant systemic therapy.
- A complete response on breast MRI could help identify early complete responders in patients who had hormone receptor negative tumours.
- An imaging-based strategy might limit the duration of chemotherapy in these patients, reduce side-effects, and maintain quality of life if confirmed by the analysis of the 3-year event-free survival primary endpoint.
- Better monitoring tools are needed for patients with hormone receptor-positive and HER2-positive breast cancer.