In the European phase II PHERGain study reported in The Lancet Oncology, Pérez-García et al found that an F-18 fluorodeoxyglucose positron-emission tomography (F-18 FDG-PET) response–based strategy may be able to identify patients with HER2-positive early breast cancer who may benefit from chemotherapy-free neoadjuvant treatment with dual HER2 blockade.

Study Details

The open-label trial included 356 patients from sites in Spain, France, Belgium, Germany, the United Kingdom, Italy, and Portugal. They were randomly assigned 1:4 between June 2017 and April 2019 to receive neoadjuvant therapy in group A (n = 71) or group B (n = 285). Group A received docetaxel at 75 mg/m², carboplatin at area under the curve = 6, subcutaneous fixed-dose trastuzumab at 600 mg, and pertuzumab at a loading dose of 840 mg followed by maintenance dosing at 420 mg. Patients in group B initially received two cycles of trastuzumab and pertuzumab.

F-18 FDG-PET scans were performed prior to random assignment and after two treatment cycles. Group A patients completed six 3-week cycles of treatment regardless of F-18 FDG-PET results. In group B, F-18 FDG-PET responders continued trastuzumab and pertuzumab for an additional six cycles, whereas F-18 FDG-PET nonresponders were switched to six cycles of docetaxel, carboplatin, trastuzumab, and pertuzumab. Surgery was performed at 2 to 6 weeks after the last dose of study treatment.

The co-primary endpoints were the proportion of F-18 FDG-PET responders in group B with a pathologic complete response (pCR) in the breast and axilla (ypT0/is ypN0) after eight cycles of treatment (compared with the historical response rate of 20%) and 3-year invasive disease–free survival of patients in group B. Follow-up to assess invasive disease–free survival is ongoing.

Pathologic Complete Response

Median follow-up was 5.7 months (interquartile range = 5.3–6.0 months). A total of 227 (80%) of 285 patients in group B were F-18 FDG-PET responders; of these, 86 (37.9%, 95% confidence interval [CI] = 31.6%–44.5%, P < .0001, compared with the historical rate of 20%) had pCR.

Among 58 F-18 FDG-PET nonresponders in group B, pCR was achieved in 15 (25.9%, 95% CI = 15.3–39.0%, P = .068 vs group B F-18 FDG-PET responders). Overall, pCR was achieved in 41 (57.7%, 95% CI = 47.4%–69.4%) of 71 patients in group A and in 101 (35.4%, 95% CI = 29.9%–41.3%) of 285 in group B (P < .0001). In group A, pCR occurred in 40 (65.6%, 95% CI = 52.3%–77.3%) of 61 F-18 FDG-PET responders and 1 (10.0%, 95% CI = 0.2%-44.5%) of 10 F-18 FDG-PET nonresponders (P = .013).

Adverse Events  

Grade 3 and 4 adverse events occurred in 59% of patients in group A vs 12% of group B, with the most common hematologic events being anemia (9% vs 1%), neutropenia (24% vs 4%), and febrile neutropenia (21% vs 4%). Serious adverse events occurred in 29% vs 5% of patients. In group A, 40% of patients required carboplatin dose reduction and 40% required docetaxel dose reduction. Among the 56 F-18 FDG-PET nonresponders in group B, 38% required carboplatin dose reduction and 34% required docetaxel dose reduction. Interruption of both trastuzumab and pertuzumab occurred in 10% of patients in group A and 10% of patients in group B, including 10% of F-18 FDG-PET responders and 13% of F-18 FDG-PET nonresponders. No deaths occurred during neoadjuvant treatment.

Global health status on the EORTC Quality of Life Questionnaire QLQ-C30 declined by ≥ 10% in 65.0% (95% CI = 46.5%–72.4%) of group A patients and in 35.5% (95% CI =29.7%–41.7%) of group B patients, including 30.2% (95% CI = 24.0%–37.0%) of group B F-18 FDG-PET responders.

The investigators concluded, “F-18 FDG-PET identified patients with HER2-positive, early-stage breast cancer who were likely to benefit from chemotherapy-free dual HER2 blockade with trastuzumab and pertuzumab, and a reduced impact on global health status. Depending on the forthcoming results for the 3-year invasive disease–free survival endpoint, this strategy might be a valid approach to select patients not requiring chemotherapy.”

Javier Cortés, MD, of the International Breast Cancer Center, Quiron Group, Barcelona, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by F. Hoffmann-La Roche. For full disclosures of the study authors, visit thelancet.com.