Abstract P6-03-05: Dual HER2 blockade of an activating driver HER3 mutation: A proof of principle study in a metastatic breast cancer patient
Authors: Bidard Francois-Clement , Ng Ck , Tulukcuoglu Ezgi , Piscuoglio S , Descroix Stephanie , Mignot Laurent , Viovy Jean-Louis , Cottu Paul , Sigal Brigitte , Vincent-Salomon Anne , Weigelt Britta , Pierga Jean-Yves , Reis-Filho Jorge 
Published: May 2015

Abstract
Background: HER3 is the only member of the EGFR family with an impaired kinase domain. Pre-clinical work has suggested that activating hotspot point mutations in HER3/ERBB3 may constitute drivers of tumor progression. Mutant HER3 oncogenic activity was shown to be dependent on HER2 signaling. In vitro and in vivo experiments have suggested that HER2-targeting therapies could be effective to block mutant HER3 oncogenic signaling. Through high-depth whole exome sequencing analysis of the primary breast cancer and liver metastasis of a patient with stage IV disease, we identified a clonal, activating HER3 mutation in both the primary tumor and metastasis, and sought to define whether this mutation would constitute a driver of the disease and be a therapeutic target.
Patient and method: A 46 yo women was diagnosed in 2012 with de novo synchronous metastatic breast cancer. Biopsies of the primary breast cancer and of the liver metastasis were performed before any treatment within the ESOPE prospective study (NCT01956552). Pathologic examination revealed a high-grade invasive ductal carcinoma with low expression of estrogen and progesterone receptors (both 20%) and intermediate HER2 (++) expression by immunohistochemical analysis without HER2 gene amplification by fluorescence in situ hybridization. While high-depth (250x) whole exome massively parallel sequencing (HiSeq) of the primary tumor and liver metastasis was ongoing, the patient received two lines of chemotherapy (anthracycline- and taxane-based). Data analysis revealed that both the primary tumor and the liver metastasis displayed a clonal G284R HER3 mutation at a high allelic frequency compatible with the distribution of a driver genetic alteration. Single nucleotide polymorphism (SNP6) arrays and sequencing confirmed the lack of HER2 gene amplification. At time of progression, after two lines of chemotherapy (05/2014), the patient had a baseline blood draw and PET-CT and was administered trastuzumab (6 mg/kg q3w) in combination with lapatinib (1250mg qd), with no chemotherapy.
Results: Treatment was well tolerated with no dose reduction. Protein-ligation assay (PLA) by rolling-circle amplification performed at baseline showed HER2-HER3 heterodimers in circulating tumor cells. After only 15 days of treatment, PET-CT displayed a complete metabolic response and a slight decrease of the diameter of liver metastasis (-20%). At day 21, no CTCs were detected in 7.5ml of peripheral blood and CA15.3 dropped from 45 (baseline) to 32 (upper limit = 30). ctDNA was also collected and is currently being analyzed. Dual blockade has been pursued; updated follow-up will be presented at the meeting.
Conclusion: HER3 mutations are particularly rare in breast cancer (&lt;1% of breast cancers) and no trial is currently assessing the relevance of HER2-blockade in this subgroup. On the basis of an extreme response to dual HER2 blockade with no chemotherapy, we confirm the published preclinical data and suggest that these patients may benefit from anti-HER2 therapies. A prospective global registry for HER3 mutated breast cancers cases and their response to specific systemic therapies may facilitate the accrual of data to support the use of anti-HER2 agents in this patient population.
Citation Format: Francois-Clement Bidard, Ck Ng, Ezgi Tulukcuoglu, S Piscuoglio, Stephanie Descroix, Laurent Mignot, Jean-Louis Viovy, Paul Cottu, Brigitte Sigal, Anne Vincent-Salomon, Britta Weigelt, Jean-Yves Pierga, Jorge Reis-Filho. Dual HER2 blockade of an activating driver HER3 mutation: A proof of principle study in a metastatic breast cancer patient [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-03-05.