Intrinsic Subtype Switching and Acquired ERBB2/HER2 Amplifications and Mutations in Breast Cancer Brain Metastases

Abstract

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 PARTICPANTS 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.

Exome-capture RNA sequencing of decade-old breast cancers and matched decalcified bone metastases

“…Finally, considering that we have previously shown that brain metastases acquire highly recurrent gains in clinically actionable genes following colonization (13), particularly in HER2, we analyzed an expanded set of these genes in BoMs. All tumors harbored significant gains and losses, some of which were highly recurrent.…”

“…Collectively, these observations provide further evidence of acquired transcriptional remodeling in metastatic lesions and suggest that precision care in advanced cancers may benefit from defining longitudinal changes in tumor transcriptomes. Further research into these longitudinal transcriptional remodeling events is demanded -especially given their high recurrence rates -including identifying events that may be specific or more likely to occur in metastases from certain anatomic sites, such as HER2 gains in brain metastases (13).…”

“…Expression gains and losses in clinically actionable genes. Because of the observed acquisition of clinically actionable targets reported in other studies of paired primary and recurrent tumors (12,13), a paired expression analysis to define clinically actionable expression changes in ER-positive BoMs was performed (Supplemental Table 13). Using stringent, case-informed cutoffs for expression alterations (Supplemental Figure 5), the genes that most commonly exhibited a longitudinal loss of expression included PIK3C2G (8 of 11 cases, 73%), ESR1 (7 of 11 cases, 64%), and TUBB3 (6 of 11 cases, 55%) ( Figure 5A and Supplemental Figure 6).…”

“…Large-scale molecular characterizations of patient-matched samples -primary tumors and synchronous or asynchronous matched metastases -show that metastatic lesions acquire features distinct from primary tumors that are clinically actionable or confer therapy resistance (11)(12)(13). Indeed, current treatment guidelines in breast cancer recommend a metastatic biopsy to guide therapy in advanced disease if possible (14).…”

Breast Cancer: Multiple Subtypes within a Tumor?

“…Longitudinal studies that involve serial assessment of multiple tissue and liquid biopsies also reflect changes in sub-clonal populations that correspond to disease progression and differential responses to therapy [38]. Importantly, there is evidence that demonstrates intrinsic subtype switching in breast cancer brain metastases relative to primary tumors [39]. In this particular study, molecular changes in Her2 and intrinsic subtype switching to Her2-enriched subtypes can be associated with brain metastasis, indicating that the brain micro-environment may favor the progression of Her2 driven malignancies.…”