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Subtype switching in breast cancer brain metastases: a multicenter analysis.

ABSTRACT: BACKGROUND:Breast cancer (BC) brain metastases (BM) can have discordant hormonal or human epidermal growth factor receptor 2 (HER2) expression compared with corresponding primary tumors. This study aimed to describe incidence, predictors, and survival outcomes of discordant receptors and associated subtype switching in BM. METHODS:BCBM patients seen at 4 tertiary institutions who had undergone BM resection or biopsy were included. Surgical pathology reports were retrospectively assessed to determine discordance between the primary tumor and the BCBM. In discordant cases, expression in extracranial metastases was also assessed. RESULTS:In BM from 219 patients, prevalence of any discordance was 36.3%; receptor-specific discordance was 16.7% for estrogen, 25.2% for progesterone, and 10.4% for HER2. Because estrogen and progesterone were considered together for hormonal status, 50 (22.8%) patients switched subtype as a result; 20 of these switches were HER2 based. Baseline subtype predicted switching, which occurred in up to 37.5% of primary HR+?patients. Moreover, 14.8% of initially HER2-negative patients gained HER2 in the BM. Most (63.6%) discordant patients with extracranial metastases also had discordance between BM and extracranial subtype. Loss of receptor expression was generally associated with worse survival, which appeared to be driven by estrogen loss (hazard ratio?=?1.80, P?=?0.03). Patients gaining HER2 status (n =?8) showed a nonsignificant tendency toward improved survival (hazard ratio?=?0.64, P?=?0.17). CONCLUSIONS:In this multicenter study, we report incidence and predictors of subtype switching, the risk of which varies considerably by baseline subtype. Switches can have clinical implications for prognosis and treatment choice.

SUBMITTER: Hulsbergen AFC

PROVIDER: S-EPMC7471502 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Subtype switching in breast cancer brain metastases: a multicenter analysis.

Hulsbergen Alexander F C AFC Claes An A Kavouridis Vasileios K VK Ansaripour Ali A Nogarede Claudine C Hughes Melissa E ME Smith Timothy R TR Brastianos Priscilla K PK Verhoeff Joost J C JJC Lin Nancy U NU Broekman Marike L D MLD

Neuro-oncology 20200801 8

<h4>Background</h4>Breast cancer (BC) brain metastases (BM) can have discordant hormonal or human epidermal growth factor receptor 2 (HER2) expression compared with corresponding primary tumors. This study aimed to describe incidence, predictors, and survival outcomes of discordant receptors and associated subtype switching in BM.<h4>Methods</h4>BCBM patients seen at 4 tertiary institutions who had undergone BM resection or biopsy were included. Surgical pathology reports were retrospectively as ...[more]

PMID: 31970416

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Project description:Importance:Patients with breast cancer (BrCa) brain metastases (BrM) have limited therapeutic options. A better understanding of molecular alterations acquired in BrM could identify clinically actionable metastatic dependencies. Objective:To determine whether there are intrinsic subtype differences between primary tumors and matched BrM and to uncover BrM-acquired alterations that are clinically actionable. Design, Setting, and Participants:In total, 20 cases of primary breast cancer tissue and resected BrM (10 estrogen receptor [ER]-negative and 10 ER-positive) from 2 academic institutions were included. Eligible cases in the discovery cohort harbored patient-matched primary breast cancer tissue and resected BrM. Given the rarity of patient-matched samples, no exclusion criteria were enacted. Two validation sequencing cohorts were used-a published data set of 17 patient-matched cases of BrM and a cohort of 7884 BrCa tumors enriched for metastatic samples. Main Outcomes and Measures:Brain metastases expression changes in 127 genes within BrCa signatures, PAM50 assignments, and ERBB2/HER2 DNA-level gains. Results:Overall, 17 of 20 BrM retained the PAM50 subtype of the primary BrCa. Despite this concordance, 17 of 20 BrM harbored expression changes (<2-fold or >2-fold) in clinically actionable genes including gains of FGFR4 (n?=?6 [30%]), FLT1 (n?=?4 [20%]), AURKA (n?=?2 [10%]) and loss of ESR1 expression (n?=?9 [45%]). The most recurrent expression gain was ERBB2/HER2, which showed a greater than 2-fold expression increase in 7 of 20 BrM (35%). Three of these 7 cases were ERBB2/HER2-negative out of 13 ERBB2/HER2-negative in the primary BrCa cohort and became immunohistochemical positive (3+) in the paired BrM with metastasis-specific amplification of the ERBB2/HER2 locus. In an independent data set, 2 of 9 (22.2%) ERBB2/HER2-negative BrCa switched to ERBB2/HER2-positive with 1 BrM acquiring ERBB2/HER2 amplification and the other showing metastatic enrichment of the activating V777L ERBB2/HER2 mutation. An expanded cohort revealed that ERBB2/HER2 amplification and/or mutation frequency was unchanged between local disease and metastases across all sites; however, a significant enrichment was appreciated for BrM (13% local vs 24% BrM; P?<?.001). Conclusions and Relevance:Breast cancer BrM commonly acquire alterations in clinically actionable genes, with metastasis-acquired ERBB2/HER2 alterations in approximately 20% of ERBB2/HER2-negative cases. These observations have immediate clinical implications for patients with ERBB2/HER2-negative breast cancer and support comprehensive profiling of metastases to inform clinical care.

Dataset Information

Subtype switching in breast cancer brain metastases: a multicenter analysis.

Publications

Subtype switching in breast cancer brain metastases: a multicenter analysis.

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