Chemotherapy-free Trastuzumab and Pertuzumab in HER2-positive Breast Cancer: FDG-PET Response-adapted Strategy.

Investigational Medicinal Products (IMPs) will be trastuzumab and pertuzumab, carboplatin, and docetaxel, as well as all endocrine therapy drugs to be administered according to HR status (hormone receptor). For cohort C, trastuzumab SC (subcutaneous) and pertuzumab IV will be IMPs until a maximum of 18 cycles. Patients will be randomly assigned in a 1:4 ratio, with a randomization stratified by HR status to receive trastuzumab and pertuzumab with docetaxel and carboplatin (cohort A) or trastuzumab and pertuzumab ± endocrine therapy according to HR status (cohort B). A F-FDG PET/CT will be performed at baseline (total body) and after 2 cycles of neoadjuvant therapy. Central review of F-FDG PET/CT will be mandatory. Patients allocated into cohort A will continue with the same treatment for a total of six cycles regardless of 18F-FDG PET/CT results. Patients enrolled into cohort B showing at least 40% reduction of the SUVmax of F-FDG PET/CT respect to baseline (PET responders) will continue with the same treatment for a total of 8 cycles. PET-non responders patients will also receive neoadjuvant chemotherapy based on six cycles of docetaxel and carboplatin concurrently with trastuzumab and pertuzumab for all cycles. Following surgery, cohort B/PET responders patients who do not achieve a pCR will additionally receive six cycles of docetaxel and carboplatin concurrently with trastuzumab and pertuzumab for all cycles. Moreover, all patients from cohorts A/B must complete 18 cycles of trastuzumab and pertuzumab, along with adjuvant endocrine therapy and radiotherapy according to HR status (hormone receptor) and institutional practices, respectively. An additional exploratory cohort (cohort C) will include patients with evidence of subclinic M1 at baseline 18F-FDG PET/CT, but not previously detected by routine clinical assessment. These patients will receive trastuzumab and pertuzumab with docetaxel and carboplatin for a total of six cycles. After first six cycles, these patients will receive trastuzumab and pertuzumab ± endocrine.therapy according to HR status for at least 12 additional cycles after surgery (only if surgery is performed). According to institutional practices, it will be allowed to continue treatment with trastuzumab and pertuzumab, along endocrine therapy on the basis of HR status, as maintenance therapy until disease progression or unacceptable toxicity. A sub-set of 42 patients (35 patients from cohort A and 7 patients from cohort B) from 5 sites in Spain are participating in the LINGain sub-study "Prospective evaluation of predictive/prognostic immunogenicity biomarkers for target therapy in HER2-positive early breast cancer within the PHERGain study" : Hospital General de Valencia, Hospital Clínico Universitario de Valencia, IVO, Hospital La Fe and Hospital Arnau de Vilanova.