285 POSTER Expression of the growth factor receptors HER2 and EGFR in primary tumors and in brain metastases of breast cancers

TPS2573 Background: Brain metastases, most commonly derived from melanoma, lung and breast cancers, are the most common brain tumor, with approximately 200,000 cases diagnosed annually in the United States. Median survival is on the order of months. For patients with clinically symptomatic brain metastases, approximately half succumb due to intracranial progression. In preclinical work, we demonstrated that brain metastases and primary tumors are often genetically distinct with frequent alterations in the CDK and PI3K pathway (Brastianos, Carter et al. Cancer Discovery 2015). Methods: We are currently accruing to a prospective multi-arm phase II study of CDK, PI3K/mTOR, and NTRK/ROS1 inhibitors in patients with brain metastases harboring alterations associated with sensitivity to these inhibitors (abemaciclib, paxalisib and entrectinib), respectively. Patients with new, recurrent or progressive brain metastases are eligible for this trial. Previously obtained tissue from brain metastases and extracranial sites (primary or extracranial metastases) are screened for the presence of these alterations, and if present in both tumor sites, patients will receive the appropriate corresponding targeted treatment. Screening is carried out with the SNaPshot NGS assay, which is a fully validated clinical test designed and developed at the MGH Center for Integrated Diagnostics. The primary endpoint of response rate (RR) in the central nervous system as per RANO criteria will be evaluated separately for each inhibitor, stratified by histology within each arm. There will be 21 evaluable patients assigned to each of the CDK and PI3K inhibitor and tumor type cohorts (breast, lung and other) and 10 patients assigned to the NTRK/ROS1 inhibitor cohort (lung) for a total of 136 evaluable patients. Although current systemic therapy for brain metastases is often ineffective, we hypothesize that targeted therapies will demonstrate efficacy in patients harboring the appropriate mutations. This study represents a novel individualized therapeutic approach in brain metastases, a disease with a critical need for effective therapy. Support: U10CA180821, U10CA180882, https://acknowledgments.alliancefound.org ; Genentech, Kazia Therapeutics Limited, Eli Lilly; Clinical trial information: NCT03994796 .

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A gene expression signature of eventual brain metastases in patients with breast cancer

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.1019 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 1019-1019

Author(s):

Y. Tham ◽

C. Creighton ◽

C. Gutierrez ◽

C. K. Osborne ◽

P. Brown ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Brain Metastases ◽

Lung Metastases ◽

Expression Patterns ◽

Gene Expression Signature ◽

Breast Cancers ◽

Primary Tumors ◽

Er Positive ◽

Her 2

1019 Background: The incidence of brain metastases (BM) from breast cancer may be increasing, in part due to more effective systemic therapy. A metastatic signature of bone or lung metastases has been identified in mice but not for BM in human. We hypothesized that gene expression patterns of primary breast cancers may provide a specific metastatic signature for eventual BM. Methods: Core biopsies from primary breast cancers of 11 patients with BM and 12 patients who have other non-brain metastases were identified. Double- stranded cDNA was synthesized using an oligo-dT primer containing a T7 RNA polymerase promoter, followed by in vitro transcription with biotinylated ribonucleotides. The labeled cRNA was hybridized to Affymetrix U133-A chips. Results: Of the patients with BM, 55% were ER negative/HER-2 positive while 36% were ER positive/HER-2 negative. Of the patients with non brain metastases, 42% were ER negative/HER-2 positive and 50% were ER positive/HER-2 negative, with. A differential pattern of gene expression was seen in primary tumors of patients with BM when compared with those who had non-brain metastases. Many more genes were found elevated in patients with BM over what would be expected by chance (after correcting for multiple testing). Tumors that developed BM had expression of genes related to the neurological development pathways such as fetal Alzheimer antigen, MAD, neuropilin 1, and others. Several kinase pathways were involved such as protein kinase C and casein kinase substrate in neurons 2, and A kinase (PRKA) anchor protein 13. These genes will be validated in an independent set of patients with BM and non-brain metastases using real time PCR. Conclusions: The identification of genes that may predict for future development of brain metastases has many implications in terms of screening or prophylactic treatment. This would also help identify potential targets for the treatment of brain metastases. No significant financial relationships to disclose.

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Quantitative HER2 levels and steroid receptor expression in primary breast cancers and in matched brain metastases.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.603 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 603-603 ◽

Cited By ~ 1

Author(s):

Wojciech Biernat ◽

Renata Duchnowska ◽

Tomasz Trojanowski ◽

Tomasz Mandat ◽

Anna Kowalczyk ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Breast Tumors ◽

Steroid Receptor ◽

Receptor Expression ◽

Nuclear Staining ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Her2 Positive ◽

Primary Tumors

603 Background: Breast cancer patients with HER2-positive tumors are at high risk for brain metastases. In the current study we examined expression of ER, PR and HER2 in primary breast tumors and in matched brain metastases, as changes of their levels might reflect modes of escape from therapy. Methods: Fifty-three pairs of matched formalin-fixed paraffin-embedded samples from primary breast cancers and brain metastases were assayed for ER and PR status by immuno-histochemistry, whereas HER2 expression was quantified using the novel HERmark assay. Nuclear staining of ER and PR >10%, and relative fluorescence of HER2 >17.8/mm2 were considered as positive results. Results: HER2 levels in brain metastases were generally higher than in the primary tumors (p = 3e-6), with a median increase of 1.9-fold (range 0.08 to 199-fold). There were also substantial differences in ER and PR status between primary tumors and brain metastases. Loss of steroid receptor positivity in brain metastases was more frequent than its gain (ER: 46% vs. 26%; p = 0.16; PR: 57% vs. 23%; p = 0.044). These changes resulted in a net increase in the number of HER2-positive/ER-negative brain metastases, which more than doubled the proportion of primary breast tumors with this phenotype (26% vs. 11%, respectively; p = 0.08). Additionally, HER2 levels in the primary tumors significantly correlated with overall survival when stratified by ER status (p = 0.011). Conclusions: Brain metastases of breast cancer show significant changes in steroid receptor status and in quantitative HER2 levels compared to matched primary tumors. These data provide a rationale for future studies and may help in designing treatment strategies that target the most likely escape pathways of breast cancer.

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JARID1A and IGF2R are concomitantly up-regulated in trastuzumab-treated human breast cancers.

10.31219/osf.io/734ux ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Growth Factor ◽

Expression Profiles ◽

Regulation Of Gene Expression ◽

Metastatic Breast ◽

Growth Factor Signaling ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Primary Tumors

Epigenetic regulation of gene expression is a mechanism by which signals transduced at the plasma membrane be can translated into differences in mRNA quantity and gene product at the protein level (1, 2). Trastuzumab is widely utilized for the treatment of adjuvant and metastatic breast cancer (3). We found, using analysis of public microarray and published multiplexed gene expression data (4, 5), that the histone lysine H3K4 demethylase JARID1A was among the genes whose expression was most significantly different when comparing the global gene expression profiles of trastuzumab-treated breast cancers and breast cancers not treated with trastuzumab. Expression of JARID1A in cancer cells has been associated with a drug-tolerant state with reduced drug sensitivity, dependent on insulin-like growth factor (IGF) signaling (6). Interestingly, we found that IGF2R was also among the genes whose expression was most significantly different transcriptome-wide when comparing the primary tumors of breast cancer patients treated with trastuzumab or not. These data clearly demonstrate up-regulation of a receptor for key growth factor signaling and together suggest that trastuzumab could be hard-wiring tumor cells for drug resistance.

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