Early On-treatment Transcriptional Profiling as Predictor of Response in Early-stage HER2-positive Breast Cancer

Non-randomized, open label, translational research study in women with early HER2-positive invasive breast carcinoma eligible for neoadjuvant treatment.

The aim of BIONHER is to assess the impact of short-term neoadjuvant dual HER2-blockade on HER2-positive breast cancer transcriptomic profile and to evaluate whether early on treatment tumor biopsy can improve the accuracy of predicting response over the pre-treatment alone.

This is a prospective study of paired tumor samples from patients with newly diagnosed HER2-positive breast cancer eligible for neoadjuvant treatment to evaluate whether early on-treatment biomarkers can improve the accuracy of predicting response over pre-treatment samples alone.

Sequential tumor biopsies will be obtained at two time points: before initiation of neoadjuvant dual HER2-blockade (pre-treatment, day 1) and 1 week later (day 8), before introduction of paclitaxel to the neoadjuvant treatment.

Following the completion of neoadjuvant paclitaxel, trastuzumab and pertuzumab (THP) for 16 weeks, patients will proceed to surgery. After surgery, adjuvant treatment (including need for Anthracyclines) will be followed as per clinical practice.

The study will comprise two phases: a discovery phase (n=60) where sequential paired tumor biopsies will be used for RNA-Seq analysis and assessment of tumor infiltrating lymphocytes (TILs) and CelTIL score. Radiomic characteristics of MRI, HER2Dx® and spatial transcriptomics (using GeoMx®) will be also evaluated.

This phase will be followed by a validation phase (n=20) in which prediction accuracy observed in the discovery phase will be validated by Nanostring gene expression analysis using a new cohort of patients with HER2-positive breast cancer eligible for neoadjuvant therapy.

Eligibility Criteria:
Inclusion Criteria:

* Written informed consent prior to beginning specific protocol procedures
* Untreated invasive breast carcinoma eligible for neoadjuvant treatment
* Histologically or cytologically confirmed human epidermal growth factor receptor 2 positive (HER2) Breast Cancer defined by ASCO/CAP guidelines based on the most recent analyzed biopsy or other pathology specimen; independently for estrogen receptor (ER) and progesterone receptor (PR)
* Female and male patients
* Age ≥18 years
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Adequate organ function defined as: Absolute neutrophil count (ANC) ≥1.5 × 109/L, Hemoglobin (Hgb) ≥10 g/dL, Platelets \>100 000/mm3, Creatinine ≤1.6 mg/dL, ALT and AST ≤2.5 × ULN, Alkaline phosphatase ≤5 ULN, Total bilirubin ≤1.5 mg/dL
* Baseline LVEF ≥50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan
* Negative β-HCG pregnancy test (serum) for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after the menopause. All subjects who are biologically capable of having children must agree and commit to the use of a reliable method of birth control from 2 weeks before administration of the first dose of investigational product until 28 days after last dose of investigational product
* Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule

Exclusion Criteria:

* Known metastatic disease
* Known or suspected hypersensitivity reaction to any investigational or therapeutic compound or their incorporated substances
* Concurrent congestive heart failure or LVEF \<50%
* History of significant comorbidities that, in the judgment of the investigator, may interfere with the conduction of the study, the evaluation of response, or with informed consent
* Use of any investigational agent or participation in another therapeutic clinical trial concurrently or in the previous 30 days before the enrollment
* Patients who are pregnant or breast-feeding
* Women of child-bearing potential who are unable or unwilling to use contraceptive measures
* Inability or unwillingness to abide by the study protocol or cooperate fully with the investigator
* Concurrent neoadjuvant cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy other than the trial therapies)