Individualized treatment

In the clinic, we mainly use anticancer drugs based on outcomes of clinical trials that have identified the best treatment for the average breast cancer patient, not considering differential patient and tumor characteristics that define the case mixes studied. Hence, this approach serves only those patients whose outcome improves substantially with ‘the best treatment’ identified, while harming patients that do not derive benefit, or even develop metastasis or progress due to the same treatment. The focus of our research line is to unravel underlying tumor and host mechanisms that ultimately define treatment efficacy and develop tests that will guide individualized treatment decisions in the clinic and eventually improve survival. For this purpose, we use several genome-wide approaches and molecular techniques, in order to dissect the mechanisms that divide clinically well-defined cohorts of breast cancer patients into resistant and sensitive to a particular treatment. We have a close collaboration with the groups of Jos Jonkers and Jacco van Rheenen, who use genetically engineered mouse models for breast cancer, to study differential drug sensitivity in a controlled fashion. In addition, we collaborate with the group of Wilbert Zwart, focusing on molecular mechanisms underlying endocrine therapy resistance.

A second research line focuses on prognostic molecular classifiers for adjuvant systemic treatment advice in breast cancer in collaboration with the groups of Lodewyk Wessels and Rene Bernards.

Molecular mechanisms underlying sensitivity to alkylating agents

Our institute previously described characteristic DNA copy number aberrations of BRCA1- and BRCA2-mutated breast cancers. We called these profiles BRCA-like profiles. In posthoc analyses of several randomized controlled trials we have demonstrated that BRCA1-like breast cancer patients derive significant benefit from alkylating agents and PARP inhibition in the (neo)adjuvant setting. These findings are now investigated in a prospective, randomized trial (NCT02810743). Recently, we demonstrated that EZH2 is overexpressed in human BRCA1-deficient breast cancers and might predict sensitivity to high-dose, alkylating chemotherapy in HER2-negative, non-BRCA1-like, EZH2 overexpressing stage III breast cancers. Furthermore, EZH2 inhibition potentiated cisplatin efficacy in Brca1-deficient murine mammary tumors.

Endocrine therapy resistance in the adjuvant and metastatic setting

We showed that IGF-1R pathway activation contributes to adjuvant tamoxifen resistance in early breast cancer patients. Next, we showed that treating breast cancer cells with linsitinib can thwart IGF-1R signaling and restore tamoxifen’s efficacy. Patients with activated IGF-1R pathways may therefore do better with tamoxifen combined with linsitinib than tamoxifen alone.

Combining endocrine therapy with PI3K/mTOR inhibition has shown promise in metastatic, estrogen receptor (ER)–positive breast cancer. In a phase 1b trial we investigated the combination of tamoxifen with taselisib, a potent, selective, PI3kinase inhibitor. Twelve of 30 patients (40%) had disease control for 6 months or more. Circulating tumor DNA studies using next-generation tagged amplicon

sequencing identified early indications of treatment response and mechanistically  relevant correlates of clinical drug resistance (e.g., mutations in KRAS, ERBB2) in some patients

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