Chemotherapy-free Trastuzumab and Pertuzumab in HER2-positive Breast Cancer: FDG-PET Response-adapted Strategy.
Chemotherapy-free Trastuzumab and Pertuzumab in HER2-positive Breast Cancer: FDG-PET Response-adapted Strategy.
The study assess the early metabolic effects of neoadjuvant treatment with trastuzumab and
 pertuzumab (± endocrine therapy) on the primary tumor and axillary lymph nodes and their
 predictive value for pathologic complete response (pCR) in the breast and axilla.

 And also assess 3-year invasive disease-free survival (iDFS) in patients with HER2-positive
 (HER: human epidermal receptor) breast cancer treated with neoadjuvant trastuzumab and
 pertuzumab (± endocrine therapy) using a 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.
Inclusion Criteria:

 1. Written informed consent prior to beginning specific protocol procedures.

 2. Female or male patients ≥ 18 years of age.

 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

 4. Histologically proven invasive breast cancer.

 5. Operable breast cancer (cT1-3 and/or cN0-2 tumors) (breast cancer TNM classification)

 6. Tumor size larger than or equal to 1.5 centimeter (cm) in diameter by magnetic
 resonance imaging (MRI) or ultrasound with a significant 18F-FDG uptake defined as
 maximum standarized uptake value (SUVmax: maximum standarized uptake value) ≥1.5 x
 SUVmean (mean standarized uptake value) liver + 2 SD (standard deviation.

 Multicentric/multifocal tumors will be allowed only if:

 1. Histological confirmation of at least two lesions.

 2. All tumors must be HER2-positive.

 3. Largest lesion must be larger than or equal to 1.5 cm in diameter by MRI or
 ultrasound.

 7)Centrally confirmed HER2-positive disease according to the 2018 American Society of
 Clinical Oncology/College of American Pathologists (ASCO/CAP) criteria.

 8)Patient must have known estrogen receptor (ER) and progesterone receptor (PR) status
 locally determined prior to study entry.

 Patient has adequate bone marrow, liver, and renal function:

 9)Hematological: White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophil count
 (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x109/L, and hemoglobin ≥ 10.0 g/dL (≥ 6.2
 mmol/L).

 10)Hepatic: total bilirubin ≤ institutional upper limit of normal (ULN) (except for
 Gilbert's syndrome); alkaline phosphatase (ALP) ≤ 2.5 times ULN; aspartate transaminase
 (AST) and alanine transaminase (ALT) ≤ 1.5 times ULN.

 11)Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min/1.73 m2 for
 patients with creatinine levels above institutional normal.

 12)Patient must be accessible for treatment and follow-up.

 Exclusion Criteria:

 1. Previous treatment with chemotherapy, anti-HER2 therapy, radiation therapy, or
 endocrine therapy for invasive breast cancer.

 2. cT4 and/or cN3 tumors (TNM breast cancer classification)

 3. Bilateral breast cancer.

 4. Evidence of metastatic disease by routine clinical assessment chest x-ray, liver
 ultrasound, and bone scan; or computed tomography (CT) scan of thorax and abdomen and
 bone scan, except patients with subclinic M1 (metastases) at baseline only according
 to 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography
 (PET/CT) that will be allowed to be included into cohort C.

 5. Known hypersensitivity reaction to any investigational or therapeutic compound or
 their incorporated substances.

 6. History of other malignancy within the last five years prior to first dose of study
 drug administration, except for curatively treated basal and squamous cell carcinoma
 of the skin and/or in situ cervical carcinoma.

 7. Left ventricular ejection fraction (LVEF) below 55% as determined by multiple-gated
 acquisition (MUGA) scan or echocardiography (ECHO).

 8. Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) despite
 adequate antihypertensive treatment.

 9. Clinically significant cardiovascular disease [stroke, unstable angina pectoris, or
 documented myocardial infarction within six months prior to study entry; history of
 documented congestive heart failure (CHF) (New York Heart Association II-III-IV);
 symptomatic pericarditis; documented cardiomyopathy; ventricular arrythmias with the
 exception of benign premature ventricular contractions; conduction abnormality
 requiring a pacemaker; other arrhythmias not controlled with medication].

 10. Active uncontrolled infection at the time of enrollment.

 11. Current known infection with HIV, hepatitis B virus, or hepatitis C virus.

 12. Patients with pulmonary disease requiring continuous oxygen therapy.

 13. Previous history of bleeding diathesis.

 14. Patient is currently receiving anti-coagulant therapy, chronic treatment with
 corticosteroids, or another immunosuppressive agent (standard premedication for
 chemotherapy and local applications are allowed).

 15. Major surgical procedure or significant traumatic injury within 14 days prior to
 randomization or anticipation of need for major surgery within the course of the study
 treatment.

 16. Patient has other concurrent severe and/or uncontrolled medical conditions that would,
 in the investigator´s judgment, contraindicate her participation in the clinical
 study.

 17. Concurrent participation in other clinical trial, except other translational studies.

 18. History of receiving any investigational treatment within 28 days prior to
 randomization.

 19. Pregnant or breast-feeding women or patients not willing to apply highly effective
 contraception as defined in the protocol.

 LINGain sub-study: The LINGAIN project intends to include a total of 126 blood samples from
 PHERGain trial, as follows:

 105 from patients treated with trastuzumab and pertuzumab ± endocrine therapy (according to
 HR status); 21 from patients treated with trastuzumab and pertuzumab + carboplatin and
 docetaxel.