MRI-based personalisation of neoadjuvant chemotherapy duration in HER2-positive early breast cancer (TRAIN-3): primary results from a multicentre, single-arm, phase 2 study.

BACKGROUND

Neoadjuvant treatment comprising six to nine cycles of anti-HER2 based chemotherapy yields high pathological complete response rates and excellent survival outcomes in patients with stage II-III HER2-positive breast cancer but comes with noteworthy side-effects. The TRAIN-3 study investigated if patients treated with this regimen who have a rapid complete radiological response on MRI are candidates for early surgery. The study showed that one-third of patients with hormone receptor-negative tumours and one-sixth of patients with hormone receptor-positive tumours had a pathological complete response after only three cycles of chemotherapy. Here, we report the results of the primary endpoint, 3-year event-free survival.

METHODS

TRAIN-3 is a multicentre, single-arm, phase 2 study conducted across 43 hospitals in the Netherlands. Patients with stage II-III HER2-positive breast cancer aged 18 years or older and with a WHO performance status of 0 or 1 were eligible for inclusion. Patients received neoadjuvant chemotherapy consisting of paclitaxel (80 mg/m2, day 1 and 8 of each 21-day cycle, intravenous), trastuzumab (6 mg/kg on day 1 of each cycle [loading dose 8 mg/kg on day 1 of cycle 1], intravenous), carboplatin (area under the curve 6 mg/mL per min on day 1 of each cycle, intravenous) and pertuzumab (420 mg on day 1 of each cycle [loading dose 840 mg on day 1 of cycle 1], intravenous) for up to nine cycles, and were referred for surgery once a complete radiological response was observed on MRI. Patients who had a pathological complete response post-surgery completed 1 year of adjuvant trastuzumab and pertuzumab. Patients with residual invasive disease in the resection specimen continued chemotherapy for a total of nine cycles, followed by 14 cycles of trastuzumab emtansine (3·6 kg/mg, day 1 of each 21-day cycle, intravenous). Adverse events of grade 3 or worse and grade 2 or worse left ventricular ejection fraction and neuropathy were registered until 30 days after the last adjuvant treatment cycle. The primary endpoint was 3-year event-free survival; analyses were done in hormone receptor-negative and hormone receptor-positive patients separately on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov (NCT03820063); recruitment is closed, and follow-up for secondary endpoints is ongoing.

FINDINGS: Between April 1, 2019, and May 12, 2021, 235 patients with hormone receptor-negative tumours and 232 with hormone receptor-positive tumours were enrolled. All participants, except one, were female. Median follow-up was 40·1 months (IQR 35·3-45·6). 3-year event-free survival was 92·2% (95% CI 88·7-95·9) in patients with hormone receptor-negative tumours and 92·0% (88·5-95·6) in patients with hormone receptor-positive tumours. In total, 40 (9%) patients had experienced an event (19 [8%] patients in the hormone receptor-negative group and 21 [9%] in the hormone receptor-positive group). 3-year event-free survival rates among patients treated with one to three cycles were 96·1% (95% CI 91·8-100) in the hormone receptor-negative group and 98·6% (95·8-100) in the hormone receptor-positive group. Event-free survival rates for patients receiving four to six cycles were 89·2% (82·4-96·6) and 94·2% (88·8-99·9), and for those receiving seven to nine cycles, 90·6% (83·8-98·1) and 85·4% (78·3-93·1%), respectively. The most common grade 3-4 adverse events were neutropenia (187 [40%] of 467), anaemia (82 [18%]), diarrhoea (60 [13%]), thrombocytopenia (46 [10%]), and hypokalaemia (35 [7%]), and treatment-related serious adverse events occurred in 56 (12%) patients. The frequency of grade 3-4 adverse events and grade 2 or worse neuropathy increased with the increasing number of neoadjuvant chemotherapy cycles. No treatment-related deaths were reported.

INTERPRETATION: MRI-guided optimisation of neoadjuvant chemotherapy duration was associated with favourable 3-year event-free survival outcomes in patients with stage II-III HER2-positive breast cancer. This approach represents a novel strategy that reduces treatment burden, minimises toxicity, and preserves quality of life in a subset of patients with early HER2-positive breast cancer.

FUNDING: Roche Netherlands.