Metastatic breast cancer represents an incurable condition associated with an average survival time of 18 to 24 months.

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1 TACT-2C Trial A phase II randomized, open-label study evaluating the addiction of trastuzumabto (nabtm)-paclitaxel as first line treatment in primary HER2 negative metastatic breast cancer patients with HER2 positive Circulating Tumor Cells (CTCs) Daniele Generali Dipartimento Universitario Clinico di Scienze Mediche, Chirurgiche e della Salute Università degli Studi di Trieste convenzionato con U.O. Multidisciplinare di Patologia Mammaria U.S. Terapia Molecolare e Farmacogenomica AZ. Istituti Ospitalieri di Cremona

2 Background: Recent metanalysis demonstrated that the detection of CTCs using CellSearch system, prior to initiation of a new therapy represent the strongest predictor of progression free survival (PFS) and overall survival(os) CTCs may represent a real time biopsy especially in the metastatic setting, and may better represent tumor genetics than primary tumors(nolé F et al. Ann Oncol 2008) HER2 status of tumor cells detected in metastatic sites, bone marrow, or peripheral blood of patients with advanced disease may differ from original primary tumor in the range of 0%-33.2% (Lorincz T etalpnas2004;guarnerivetal.theoncologist2008 ) Trastuzumab/Pertuzumab-based therapy in patients with HER-2 negative primary tumor, who acquired subsequently HER2 gene amplification on CTCs are anecdotal and not confirmed in randomized trials (Guarneri V et al. The Oncologist 2008) HER2 overexpression in CTCs is acquired in 8 out of 45 patients (18%) and lost in 3 out of 16 patients(19%) during a treatment containing trastuzumab. Patients with HER2 overexpression in CTCs had poorer progression-free survival compared with those without CTCs or with HER2-ve CTCs(log-rank P =.036) nab-paclitaxel is not just another taxane but is a targeted chemotherapy that represents a new treatment advance for women with MBC

3 Rationale Metastatic breast cancer represents an incurable condition associated with an average survival time of 18 to 24 months. Improvements in diagnostic technologies have failed to provide tests that help in demonstrating treatment efficacy and facilitate selection of appropriate treatment. Recent clinical trials demonstrated that the detection of CTCs using CellSearch system, prior to initiation of a new therapy represent the strongest predictor of PFS and OS

4 PRIMARY ENDPOINT The primary end-point will be the valuation of the overall CB (defined as CR+PR+SD) among evaluable patients at 24 weeks after treatment initiation. SECONDARY ENDPOINTS To evaluate the early response based on CTCs variations as a predictor of patients outcome; To validate the prognostic significance of HER2+ve CTCs in patients with primary HER2-ve MBC; To obtain RNA from EpCAM+ CTC isolated from MBC patients using the Veridex Profile kit or RosetteSepfor the gene profiling by RT-PCR; gene transcripts to be measured will include HER2-neu, PI3K, PTEN, pakt, mtor. To evaluate the prognostic and predictive significance of circulating HER2 and EGFR in serum samples To determine HER2 expression, proliferation index in fine needle aspirate (FNA) biopsies (optional). To evaluate the Progression-Free Survival (PFS) To determine patient s tolerability and safety of the treatment. To evaluate the Quality of Life.

5 All patients giving informed consent can be screened and registered in the study. All inclusion/exclusion criteria will be checked during the screening procedure. As soon as the eligibility is verified, including HER2 overexpression on CTCs (at least 1 CTC positive), the patient will be randomized via a web based application made available to the centres by NMS-MIO or designee. Patients will be assigned to treatment accordingtoa1:1ratio

6 TACT-2c Trial: Trastuzumaband Pertuzumabcombined (nabtm)-paclitaxel in the 1st-line HER2-ve MBC/ HER2+ve CTC n=45 Pertuzumab + Trastuzumab P D Patients with HER2ve- MBC/HER2+ve CTC (N = 90) 1:1 n=45 nab-tm-paclitaxel 6 cycles recommended nab-tm-paclitaxel 6 cycles recommended P D Trastuzumab: 8mg\kg followed by 6 mg\kg every 3 weeks Pertuzumab: 840 mg followed by 420 mg every 3 weeks *In ARM B (nab-tm-p) in case of disease progression (within 6 cycles) trastuzumab will be added MBC, metastatic breast cancer; PD, progressive disease

7 NUMBER OF SUBJECTS AND CENTERS The number of patients was calculated according to a Simon two-stage phase II study design. In the first stage, 15 patients will be accrued in each arm. If in one arm 7 or less patients with CB out of the 15 patients are observed, accrual to that arm will be terminated, and the conclusion will be that that regimen is not worth developing. On the contrary, if at least 8 patients with CB are observed with a regimen, and its tolerability is judged adequate by the Investigators, 30 additional patients will be treated with that schedule, leading to 45 patients per arm. It is expected that 90 subjects will be overall enrolled over a planned recruitment period of 30 months. Note: in order to achieve the complete sample size 430 patients will be screened. Itisexpectedthatapproximately3centresinItalywilltakepartinthisstudy. Enrolment will be competitive among the participating investigational sites.

8 Up to Now: Start 9 Nov2015 Numberof PatientsScreenedfor CTC/HER2+= 0 out of 3 evaluations Improvement with new CTC device