Dynamic clonal remodelling in breast cancer metastases is associated with subtype conversion

Background: Changes in the clinical subtype (CS) and intrinsic subtype (IS) between breast cancer (BC) metastases and corresponding primary tumours have been reported. However, their relationship with tumour genomic changes remains poorly characterised. Here, we analysed the association between genomic remodelling and subtype conversion in paired primary and metastatic BC samples. Methods: A total of 57 paired primary and metastatic tumours from GEICAM/2009-03 (ConvertHER, NCT01377363) study participants with centrally assessed CS (n = 57) and IS (n = 46) were analysed. Targeted capture and next-generation sequencing of 202 genes on formalin-fixed paraffin-embedded samples was performed. Th…

PI3K pathway mutations and PTEN levels in primary and metastatic breast cancer.

Abstract The purpose of this work was to determine whether there are differences in PIK3CA mutation status and PTEN protein expression between primary and matched metastatic breast tumors as this could influence patient management. Paraffin sections of 50 μm were used for DNA extraction and slides of 3 μm for immunohistochemistry (IHC) and FISH. Estrogen receptor, progesterone receptor, and HER2 IHC were repeated in a central laboratory for both primary tumors and metastases. PTEN levels were assessed by IHC and phosphoinositide 3-kinase (PI3K) pathway mutations were detected by a mass spectroscopy–based approach. Median age was 48 years (range: 30–83 years). Tumor subtype included 72% horm…

Concordance of Genomic Alterations between Primary and Recurrent Breast Cancer

Abstract There is growing interest in delivering genomically informed cancer therapy. Our aim was to determine the concordance of genomic alterations between primary and recurrent breast cancer. Targeted next-generation sequencing was performed on formalin-fixed paraffin-embedded (FFPE) samples, profiling 3,320 exons of 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer. Point mutations, indels, copy-number alterations (CNA), and select rearrangements were assessed in 74 tumors from 43 patients (36 primary and 38 recurrence/metastases). Alterations potentially targetable with established or investigational therapeutics were considered “actionable.” Alterations…

Abstract PD3-06: Neratinib + fulvestrant for HER2-mutant, HR-positive, metastatic breast cancer: Updated results from the phase 2 SUMMIT trial

Abstract Background: HER2 mutations define a rare subset of metastatic breast cancer (MBC) with a unique mechanism of oncogenic addiction to HER2 signaling. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated single-agent clinical activity in HER2-mutant MBC. In HER2-mutant, HR+ MBC, neratinib + fulvestrant (N+F) appears synergistic vs single-agent neratinib, possibly due to more complete inhibition of bi-directional signaling between HER2 and estrogen receptors. Here we describe interim efficacy results of the expanded HER2-mutant, HR+ MBC cohort treated with N+F from SUMMIT (NCT01953926). Methods: HR+ MBC patients (pts) with HER2 mutations documented by local te…

Abstract PD3-6: ConvertHER: Evolution of genomic alterations from primary to metastatic breast cancer

Abstract Background: Changes in breast cancer receptor status over disease progression and treatment have been described to a point that could alter response to therapy. There is growing interest in delivering biomarker/genomically-based targeted therapies. We aimed to determine the concordance of genomic alterations between primary (P) and metastatic (M) breast cancer in a prospective collection study. Methods: Targeted capture and next-generation sequencing was performed on formalin-fixed paraffin-embedded (FFPE) samples, profiling 202 cancer relevant genes in 61 pairs (primary and corresponding recurrence/metastasis). Tumors were classified at baseline as [hormone receptor (HR)+/HER2-, H…

Abstract P1-19-08: Neratinib + trastuzumab + fulvestrant for HER2-mutant, hormone receptor-positive, metastatic breast cancer: Updated results from the phase 2 SUMMIT ‘basket’ trial

Abstract Background: HER2 mutations define a subset of metastatic breast cancers (MBCs) with a unique mechanism of oncogenic addiction to HER2 signaling. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has been shown to have encouraging clinical activity when combined with fulvestrant in HER2-mutant, hormone receptor-positive (HR+) MBC [Smyth et al. SABCS 2018]. Genomic analyses suggest that acquired resistance to neratinib may occur by the acquisition of additional HER2 alterations, which may amplify HER2 pathway signaling [Won et al. AACR 2019]. We therefore explored whether dual HER2-targeted therapy may improve clinical benefit in this setting. Here we describe initial res…

51P Pooled analysis safety profile of futibatinib in patients with advanced solid tumors, including intrahepatic cholangiocarcinoma (iCCA)

Efficacy and Determinants of Response to HER Kinase Inhibition in HER2-Mutant Metastatic Breast Cancer

Abstract HER2 mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER+ patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of m…