» Apply now PDF Show all positions


Division of Clinical Oncology, Department of Internal Medicine, Medical University of Graz

Supervisor: Dr. Marija Balic
Availability: This position is available.
Offered by: Medical University of Graz
Application deadline:Applications are accepted between August 03, 2022 00:00 and September 20, 2022 23:59 (Europe/Zurich)




HER2-positive breast cancer (BC) is characterized by the overexpression of the HER2 protein as determined by immunohistochemistry or by the amplification of HER2/neu gene as determined by in-situ hybridization. HER2 overexpression was traditionally associated with poor prognosis. However, the treatment of HER2 positive disease has vastly improved over the last two decades, starting with the introduction of the monoclonal antibody trastuzumab as the first HER2-directed targeted treatment. Its implementation in the treatment of mBC patients with HER2 overexpression led to significant improvements in progression-free survival (PFS) and overall survival (OS). NerHer 1 is an investigator initiated clinical study in patients with metastastic breast cancer

In this study proposal, we suggest evaluating the efficacy of neratinib with two possible combination partners as 3rd-line or beyond 3rd-line therapy. Combination partners for neratinib will be at the discretion of treating physicians, enabling 2 possible treatment options: Neratinib + Trastuzumab + Vinorelbine or Neratinib + Trastuzumab

Hypothesis and Objectives:

We hypothesise that with implementation of biomarker analyses including ctDNA longitudinal trajectories, mutational profile and epigenomic changes we may establish correlation with response and resistance and translate this knowledge into the evaluation of resistance mechanisms with in vitro modelling.


Exploratory endpoints of the NerHer study will be focus of the thsis and involve  evaluation of biomarkers potentially predicting for response to neratinib + combination partners and/ or resistance:

We will perform assessment of HER2 gene copy numbers (primary tumor, if indicated; optionally cell-free tumor DNA (ctDNA)), HER2/neu mutation status, and PIK3Ca mutation status (ctDNA)

Mutational profile of ctDNA will be performed with Avenio kit. WGS will be performed for evaluation of novel resistance mechanisms and methylation profile of ctDNA will be evaluated in good responders vs. patients with very short progression free survival in order to evalute potential of methylation profiles for prediction of response and prognosis.

Assessment of baseline and longitudinal trajectories of circulating ctDNA fraction as assessed by mFAST-Seq (so-called Z-score).



Badache, A., and A. Goncalves

            2006   The ErbB2 signaling network as a target for breast cancer therapy. J Mammary Gland Biol Neoplasia 11(1):13-25.

Baselga, J., et al.

            2012   Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366(2):109-19.

Baweja, M., et al.

Blackwell, K. L., et al.

            2010   Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol 28(7):1124-30.

Blackwell, K. L., et al.

            2019   Neratinib in Combination With Trastuzumab for the Treatment of Patients With Advanced HER2-positive Breast Cancer: A Phase I/II Study. Clin Breast Cancer 19(2):97-104.e4.

Burstein, H. J., et al.

            2010   Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol 28(8):1301-7.

Cardoso, F., et al.

            2020   5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann Oncol 31(12):1623-1649.

Johnston, S., et al.

            2009   Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 27(33):5538-46.

Klastersky, J., et al.

            2016   Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Ann Oncol 27(suppl 5):v111-v118.

Marty, M., et al.

            2001   Oral vinorelbine pharmacokinetics and absolute bioavailability study in patients with solid tumors. Ann Oncol 12(11):1643-9.

Meyers, B. F., et al.

            1999   Bilateral sequential lung transplantation without sternal division eliminates posttransplantation sternal complications. J Thorac Cardiovasc Surg 117(2):358-64.

Owens, M. A., B. C. Horten, and M. M. Da Silva

            2004   HER2 amplification ratios by fluorescence in situ hybridization and correlation with immunohistochemistry in a cohort of 6556 breast cancer tissues. Clin Breast Cancer 5(1):63-9.

Rampaul, R. S., et al.

            2005   Clinical value of epidermal growth factor receptor expression in primary breast cancer. Adv Anat Pathol 12(5):271-3.

Rugo, H. S., et al.

            2021   Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol 7(4):573-584.

Slamon, D. J., et al.

            1987   Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785):177-82.

Slamon, D. J., et al.

            1989   Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244(4905):707-12.

Zaczek, A., B. Brandt, and K. P. Bielawski

            2005   The diverse signaling network of EGFR, HER2, HER3 and HER4 tyrosine kinase receptors and the consequences for therapeutic approaches. Histol Histopathol 20(3):1005-15.