Changing molecular profile of brain metastases compared with matched breast primary cancers and impact on clinical outcomes

Thomson, Alastair; McGrane, John; Mathew, Joseph; Palmer, Joanne; Hilton, DA; Purvis, Grace; Jenkins, Richard C.

doi:10.1038/bjc.2016.34

Cited by 43 publications

(24 citation statements)

References 65 publications

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“…Compared to published data, ER loss was more common in our series (NCR 80% vs. 36%), especially as only one of the ER negative patients gained ER expression ( Table V). The data on PgR conversion in the literature are varying widely from 1 conversion in 41 matched pairs (19) to a 25% conversion rate (8) that is very similar to our study. Former studies have shown Her2/neu expression to be more stable than the ER or PgR (22,23).…”

Section: Discussionsupporting

confidence: 85%

Discordance and Conversion Rates of Progesterone-, Estrogen-, and HER2/neu-Receptor Status in Primary Breast Cancer and Brain Metastasis Mainly Triggered by Hormone Therapy

Timmer

Werner

Röhn

et al. 2017

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In summary, receptor conversion is frequent during disease progression. Therefore, the receptor status of the primary tumor is invalid for planning a therapy targeted against brain metastases, especially after hormone-therapy. In these cases, new tissue collection by biopsy or resection is mandatory for the selection of adequate therapeutic targets and accurate decision-making for systemic therapies.

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Section: Discussionsupporting

confidence: 85%

Discordance and Conversion Rates of Progesterone-, Estrogen-, and HER2/neu-Receptor Status in Primary Breast Cancer and Brain Metastasis Mainly Triggered by Hormone Therapy

Timmer

Werner

Röhn

et al. 2017

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“…In our series of six HER2-positive breast cancers with brain metastasis, four cases harbored TP53 likely pathogenic mutations private to or enriched in the brain metastases. Indeed, our results here, as well as those from previous studies [ 33 – 36 ], suggest that breast cancers may undergo clonal shifts and acquire additional somatic genetic alterations in the progression from primary to metachronous brain metastasis after systemic therapy. HER2 amplification as a truncal alteration is likely to be true for the majority of HER2-positive breast cancers.…”

Section: Discussionsupporting

confidence: 83%

Genetic heterogeneity and actionable mutations in HER2-positive primary breast cancers and their brain metastases

Mattos-Arruda

Piscuoglio

et al. 2018

Oncotarget

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Brain metastases constitute a challenge in the management of patients with HER2-positive breast cancer treated with anti-HER2 systemic therapies. Here we sought to define the repertoire of mutations private to or enriched for in HER2-positive brain metastases. Massively parallel sequencing targeting all exons of 254 genes frequently mutated in breast cancers and/or related to DNA repair was used to characterize the spatial and temporal heterogeneity of HER2-positive breast cancers and their brain metastases in six patients. Data were analyzed with state-of-the-art bioinformatics algorithms and selected mutations were validated with orthogonal methods. Spatial and temporal inter-lesion genetic heterogeneity was observed in the HER2-positive brain metastases from an index patient subjected to a rapid autopsy. Genetic alterations restricted to the brain metastases included mutations in cancer genes FGFR2, PIK3CA and ATR, homozygous deletion in CDKN2A and amplification in KRAS. Shifts in clonal composition and the acquisition of additional mutations in the progression from primary HER2-positive breast cancer to brain metastases following anti-HER2 therapy were investigated in additional five patients. Likely pathogenic mutations private to or enriched in the brain lesions affected cancer and clinically actionable genes, including ATR, BRAF, FGFR2, MAP2K4, PIK3CA, RAF1 and TP53. Changes in clonal composition and the acquisition of additional mutations in brain metastases may affect potentially actionable genes in HER2-positive breast cancers. Our observations have potential clinical implications, given that treatment decisions for patients with brain metastatic disease are still mainly based on biomarkers assessed in the primary tumor.

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“…Duchnowska et al 10 and Thomson et al 11 reported ERBB2/HER2-negative to ERBB2/HER2-positive switching frequencies of 16% and 18% respectively in BrM via IHC. Gutierrez et al 12 reported an ERBB2/HER2-switching frequency of 11% in tamoxifen-resistant tumors, and notably, 6 of 7 cases with ERBB2 / HER2 expression gains were ER-positive.…”

Section: Discussionmentioning

confidence: 99%

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

Hartmaier²,

et al. 2017

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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.

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Changing molecular profile of brain metastases compared with matched breast primary cancers and impact on clinical outcomes

Cited by 43 publications

References 65 publications

Discordance and Conversion Rates of Progesterone-, Estrogen-, and HER2/neu-Receptor Status in Primary Breast Cancer and Brain Metastasis Mainly Triggered by Hormone Therapy

Discordance and Conversion Rates of Progesterone-, Estrogen-, and HER2/neu-Receptor Status in Primary Breast Cancer and Brain Metastasis Mainly Triggered by Hormone Therapy

Genetic heterogeneity and actionable mutations in HER2-positive primary breast cancers and their brain metastases

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

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