18FDG-PET was successful in identifying patients with HER2-positive early-stage breast cancer who were more likely to benefit from chemotherapy-free treatment with trastuzumab and pertuzumab.
Fluorodeoxyglucose (18FDG-PET) in HER2-positive early-stage breast cancer may be useful for identifying patients who can benefit from chemotherapy-free treatment with trastuzumab (Herceptin) and pertuzumab (Perjeta) by a pathological response–adapted strategy, according to results of the phase 2 PHERGain trial (NCT03161353) publishing in The Lancet Oncology.
Results for the 3-year invasive disease-free survival end point are pending, with successful readout possibly indicating viability of the approach for selecting patients who do not require chemotherapy.
“To our knowledge, this is the first strategy-based, de-escalation study in the neoadjuvant or adjuvant setting using an [18FDG-PET]-based, pathological response–adapted design in patients with HER2-positive, early-stage breast cancer. PHERGain met its first co-primary endpoint by showing that 37.9% of patients who received dual HER2 blockade with trastuzumab and pertuzumab, with or without endocrine therapy, and who were [18FDG-PET] responders achieved a pathological complete response in the breast and axilla and, accordingly, might avoid chemotherapy as part of their treatment,” wrote the investigators of the study.
This study was a randomized, open-label trial of 356 participants across 45 hospitals in Europe and the United Kingdom. Patients were women 18 years or older with centrally confirmed, HER2-positive stage I to III invasive operable breast cancer with at least 1 breast lesion evaluable by 18FDG-PET. Patients were required to have an MRI after 2 cycles of neoadjuvant therapy and before surgery, an ECOG performance status of 0 or 1, and left ventricular friction of 55% or more. Patients were excluded if they were diagnosed with stage IV cancer, bilateral breast cancer, or previous systemic therapy for invasive breast cancer.
Patients were randomly assigned in a 4:1 fashion to group A (n = 71; 19%) who received docextaxel, carboplatin, trastuzumab, and pertuzumab, or to group B (n = 285; 76%) with therapy including trastuzumab and pertuzumab alone. Patients with subclinical metastases (5%) were assigned to the exploratory cohort. Randomization was stratified by hormone receptor status. All the drugs were administered intravenously except for trastuzumab which was given subcutaneously.
Imaging was done prior to randomization and again after 2 cycles of prescribed therapy. Patients with hormone receptor–positive status treated in group B initially received 2 cycles of letrozole if they were postmenopausal or tamoxifen if they were premenopausal or perimenopausal.
18FDG-PET responders in group B continued on the same treatment for 6 more cycles with or without endocrine therapy. 18FDG-PET nonresponders were switched to neoadjuvant therapy consisting of 6 cycles of docextaxel and carboplatin plus concurrent trastuzumab and pertuzumab. In group A, patients received 6 cycles of therapy regardless of imaging results. Surgery was performed 2 to 6 weeks after the last therapy dose, but adjuvant trastuzumab and pertuzumab were continued for 1 year in responders and nonresponders along with adjuvant endocrine thearpy and radiation. Patients from both groups continued adjuvant treatment if there was an absence of disease progression or unacceptable toxicity.
The coprimary end points were the proportion of 18FDG-PET responders in group B who achieved a pathological complete response (pCR) and the 3-year invasive disease-free survival rate. Some key secondary end points were breast and axillary pathological response rates in both group A and B and in 18FDG-PET nonresponders in group B.
After 2 cycles of the treatment, 81% of patients were 18FDG-PET responders. No patient who received the neoadjuvant therapy during study treatment had tumor progression.
A pCR was achieved in 86 out of 227 responding patients in group B (37.9%; 95% CI 31.6–44.5; P < .0001), whereas pCR for nonresponders occurred in 15 out of 58 patients (25.9%; 95% CI, 15.3–39.0; P = .068).
In group A, pCR occurred in 40 out of 61 responders (65.6%; 95% CI, 52.3-77.3) and in 1 out of 10 nonresponders (10%; 95% CI, 0.2-44.5; P =0.013). Overall, the pCR rate was 57.7% (95% CI, 47.4-69.4) in group A and 35.4% (95% CI, 29.9-41.3) in group B (P < .0001).
Treatment-related adverse events occurred more frequently in group A (28%) versus group B (4%). The most serious events related to chemotherapy were febrile neutropenia (18% in group A vs 13 in 18FDG-PET nonresponders in group B) and neutropenia (7% versus 4%, respectively).
“The activity and disease-free survival results with adding trastuzumab and pertuzumab to chemotherapy in HER2-positive, early-stage breast cancer has initiated a debate regarding the necessity, duration, and intensity of neoadjuvant or adjuvant chemotherapy in these patients,” wrote the investigators.
Pérez-García JM, Gebhart G, Ruiz Borrego M, et al. Chemotherapy de-escalation using an 18F-FDG-PET-based pathological response-adapted strategy in patients with HER2-positive early breast cancer (PHERGain): a multicentre, randomised, open-label, non-comparative, phase 2 trial. Lancet Oncol. 2021;22(6):858-871. doi:10.1016/S1470-2045(21)00122-4