Receptor discordance in breast cancer brain metastases: when knowledge is power.
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ABSTRACT:
SUBMITTER: Sammons S
PROVIDER: S-EPMC7594573 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:There is limited knowledge of the biology of breast cancer (BC) brain metastasis (BM). We primarily aimed to determine the mutations in BCBM and to compare the mutational pattern with the matched primary breast cancer (BC). Secondary aims were to determine mutations in each subgroup (Luminal A-/B-like, HER2+ and TNBC) of BCBM, and to determine survival according to specific mutations. We investigated 57 BCBMs, including 46 cases with matched primary tumors (PT) by targeted Next Generation Sequencing (NGS) using the Cancer Hotspot Panel v2 (ThermoFisher Scientific) covering 207 targeted regions in 50 cancer related genes. Subtype according to immunohistochemistry was re-evaluated. NGS results fulfilling sequencing quality criteria were obtained from 52 BM and 41 PT, out of which 37 were matched pairs. Pathogenic mutations were detected in 66% of PTs (27/41), and 62% of BMs (32/52). TP53 mutations were most frequent; 49% (20/41) of PTs and 48% (25/52) in BMs, followed by PIK3CA mutations; 22% (9/42) in PTs and 25% (13/52) in BMs. Mutations in CDH1, EGFR, HRAS, RB1 CDKN2A and PTEN were detected in single pairs or single samples. Mutational pattern was discordant in 24% of matched pairs. We show a discordance of PIK3CA and TP53 mutations of roughly 25% indicating the need to develop methods to assess mutational status in brain metastasis where analysis of cell-free DNA from cerebrospinal fluid (CSF) has shown promising results.
| S-EPMC8651781 | biostudies-literature
Project description:BackgroundBreast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM).MethodsA retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM.ResultsThe overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors-nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17-28 mo, P = 0.12; HER2, 15-19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27-18 mo, P = 0.02; HER2, 30-18 mo, P = 0.08).ConclusionsReceptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly.Key points1. Receptor discordance alters subtype in 32% of BCBM patients.2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively.3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment.
| S-EPMC7523450 | biostudies-literature
Project description:BackgroundsA significant proportion of breast cancer patients showed receptor discordance between primary cancers and breast cancer brain metastases (BCBM), which significantly affected therapeutic decision-making. But it was not always feasible to obtain BCBM tissues. The aim of the present study was to analyze the receptor status of primary breast cancer and matched brain metastases and establish radiomic signatures to predict the receptor status of BCBM.MethodsThe receptor status of 80 matched primary breast cancers and resected brain metastases were retrospectively analyzed. Radiomic features were extracted using preoperative brain MRI (contrast-enhanced T1-weighted imaging, T2-weighted imaging, T2 fluid-attenuated inversion recovery, and combinations of these sequences) collected from 68 patients (45 and 23 for training and test sets, respectively) with BCBM excision. Using least absolute shrinkage selection operator and logistic regression model, the machine learning-based radiomic signatures were constructed to predict the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status of BCBM.ResultsDiscordance between the primary cancer and BCBM was found in 51.3% of patients, with 27.5%, 27.5%, and 5.0% discordance for ER, PR, and HER2, respectively. Loss of receptor expression was more common (33.8%) than gain (18.8%). The radiomic signatures built using combination sequences had the best performance in the training and test sets. The combination model yielded AUCs of 0.89, 0.88, and 0.87, classification sensitivities of 71.4%, 90%, and 87.5%, specificities of 81.2%, 76.9%, and 71.4%, and accuracies of 78.3%, 82.6%, and 82.6% for ER, PR, and HER2, respectively, in the test set.ConclusionsReceptor conversion in BCBM was common, and radiomic signatures show potential for noninvasively predicting BCBM receptor status.
| S-EPMC9207517 | biostudies-literature
Project description:BackgroundUp to 40% of patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer develop brain metastases (BMs). Understanding of clinical features of these patients with HER2-positive breast cancer and BMs is vital.Patients and methodsA total of 2948 patients from the Brain Metastases in Breast Cancer registry were available for this analysis, of whom 1311 had primary tumors with the HER2-positive subtype.ResultsPatients with HER2-positive breast cancer and BMs were-when compared with HER2-negative patients-slightly younger at the time of breast cancer and BM diagnosis, had a higher pathologic complete response rate after neoadjuvant chemotherapy and a higher tumor grade. Furthermore, extracranial metastases at the time of BM diagnosis were less common in HER2-positive patients, when compared with HER2-negative patients. HER2-positive patients had more often BMs in the posterior fossa, but less commonly leptomeningeal metastases. The median overall survival (OS) in all HER2-positive patients was 13.2 months (95% confidence interval 11.4-14.4). The following factors were associated with shorter OS (multivariate analysis): older age at BM diagnosis [≥60 versus <60 years: hazard ratio (HR) 1.63, P < 0.001], lower Eastern Cooperative Oncology Group status (2-4 versus 0-1: HR 1.59, P < 0.001), higher number of BMs (2-3 versus 1: HR 1.30, P = 0.082; ≥4 versus 1: HR 1.51, P = 0.004; global P = 0.015), BMs in the fossa anterior (HR 1.71, P < 0.001), leptomeningeal metastases (HR 1.63, P = 0.012), symptomatic BMs at diagnosis (HR 1.35, P = 0.033) and extracranial metastases at diagnosis of BMs (HR 1.43, P = 0.020). The application of targeted therapy after the BM diagnosis (HR 0.62, P < 0.001) was associated with longer OS. HER2-positive/hormone receptor-positive patients showed longer OS than HER2-positive/hormone receptor-negative patients (median 14.3 versus 10.9 months; HR 0.86, P = 0.03), but no differences in progression-free survival were seen between both groups.ConclusionsWe identified factors associated with the prognosis of HER2-positive patients with BMs. Further research is needed to understand the factors determining the longer survival of HER2-positive/hormone receptor-positive patients.
| S-EPMC9271494 | biostudies-literature
Project description:Approximately 10% to 15% of women with metastatic breast cancer will develop brain metastases. Treatment options for these women remain limited, particularly at the time of central nervous system (CNS) relapse following completion of initial CNS-directed therapy. Historically, prior studies have broadly examined systemic treatments for breast cancer brain metastases with mixed, but overall disappointing, results. More recently, studies have increasingly selected patients based on breast cancer subtype and have examined novel, targeted agents that have preclinical suggestion of blood-brain barrier penetration. Correlative science objectives, with both tissue-based and novel imaging endpoints, are more frequently incorporated into trials of this nature, with the goal of enhancing our understanding of possible predictors of response. This review summarizes the current and emerging data on systemic therapy for breast cancer brain metastases and provides a framework for future directions in treating this clinically-challenging entity.
| S-EPMC3383009 | biostudies-literature
Project description:BackgroundChange in hormone receptor (estrogen [ER] and progesterone [PR]) and/or human epidermal growth factor receptor type 2 (HER2) status during the evolutionary course of metastatic breast cancer and the effect of tumor classification subtype switching remain understudied and underappreciated in brain metastasis patients.MethodsUsing preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, a systematic review of series published prior to April 2020 obtained from the Medline database of biopsied or resected breast cancer brain metastasis (BCBM) was performed. Weighted random effects models were used to calculate pooled estimates.Results15 full-text articles were included with receptor expression analyses on 1373 patients who underwent biopsy or resection of at least one intracranial lesion to compare to the primary tumor. Primary tumor receptor expression immunophenotypes were 45.0% ER+, 41.0% ER-, 31.0% PR+, 51.0% PR-, 35% HER2+, and 47.0% HER2-. Corresponding BCBM immunophenotypes were 19.0% ER+, 31.0% ER-, 13.0% PR+, 40.0% PR-, 21.0% HER2+, and 26.0% HER2-. On primary/BCBM comparison, 540 patients (42.6%) exhibited discordance in any receptor with 17.0% (95% CI: 13.0%-23.0%) discordant on ER, 23.0% (95% CI: 18.0%-30.0%) discordant on PR, and 12.0% (95% CI: 8.0%-16.0%) discordant on HER2 status. The most common receptor conversions found in BCBM were ER loss 11.0% (95% CI: 8.0%-16.0%), PR loss 15.0% (95% CI: 11.0%-21.0%), and HER2 gain 9.0% (95% CI: 7.0%-11.0%).ConclusionsBCBM exhibits significant receptor expression discordance in comparison to primary tumors in approximately 40% of patients. Classification patterns need to be analyzed to determine factors predictive of BCBM/primary tumor discordance. Overall, tumor subtype switching and its effect on clinical management remains underappreciated.
| S-EPMC8055057 | biostudies-literature
Project description:After the introduction of trastuzumab, a monoclonal antibody that binds to human epidermal growth factor receptor 2 (HER2), the overall survival (OS) among patients with HER2-positive breast cancer has been substantially improved. However, among these patients, the incidence of brain metastases (BM) has been increasing and an increased proportion of them have died of intracranial progression, which makes HER2-positive breast cancer brain metastases (BCBM) a critical issue of concern. For local control of limited BM, stereotactic radiosurgery (SRS) and surgical resection are available modalities with different clinical indications. Postoperative or preoperative radiation is usually delivered in conjunction with surgical resection to boost local control. Adjuvant whole-brain radiotherapy (WBRT) should be deferred for limited BM because of its impairment of neurocognitive function while having no benefit for OS. Although WBRT is still the standard treatment for local control of diffuse BM, SRS is a promising treatment for diffuse BM as the technique continues to improve. Although large molecules have difficulty crossing the blood brain barrier, trastuzumab-containing regimens are critical for treating HER2-positive BCBM patients because they significantly prolong OS. Tyrosine kinase inhibitors are more capable of crossing into the brain and they have been shown to be beneficial for treating BM in HER2-positive patients, especially lapatinib combined with capecitabine. The antiangiogenic agent, bevacizumab, can be applied in the HER2-positive BCBM scenario as well. In this review, we also discuss several strategies for delivering drugs into the central nervous system and several microRNAs that have the potential to become biomarkers of BCBM.
| S-EPMC5627687 | biostudies-literature
Project description:Breast cancer is a common cause of brain metastases, with metastases occurring in at least 10-16 % of patients. Longer survival of patients with metastatic breast cancer and the use of better imaging techniques are associated with an increased incidence of brain metastases. Unfortunately, patients who develop brain metastases tend to have poor prognosis with short overall survival. In addition, brain metastases are a major cause of morbidity, associated with progressive neurologic deficits that result in a reduced quality of life. Tumor subtypes play a key role in prognosis and treatment selection. Current therapies include surgery, whole-brain radiation therapy, stereotactic radiosurgery, chemotherapy and targeted therapies. However, the timing and appropriate use of these therapies is controversial and careful patient selection by using available prognostic tools is extremely important. This review will focus on current treatment options, novel therapies, future approaches and ongoing clinical trials for patients with breast cancer brain metastases.
| S-EPMC4657380 | biostudies-literature
Project description:Brain metastases from breast cancer (BCBM) constitute the second most common cause of brain metastasis (BM), and the incidence of these frequently lethal lesions is currently increasing, following better systemic treatment. Patients with ER-negative and HER2-positive metastatic breast cancer (BC) are the most likely to develop BM, but if this diagnosis remains associated with a worse prognosis, long survival is now common for patients with HER2-positive BC. BCBM represents a therapeutic challenge that needs a coordinated treatment strategy along international guidelines. Surgery has always to be considered when feasible. It is now well established that stereotaxic radiosurgery allows for equivalent control and less-cognitive toxicities than whole-brain radiation therapy, which should be delayed as much as possible. Medical treatment for BCBM is currently a rapidly evolving field. It has been shown that the blood-brain barrier (BBB) is often impaired in macroscopic BM, and several chemotherapy regimens, antibody-drug conjugates and tyrosine-kinase inhibitors have been shown to be active on BCBM and can be part of the global treatment strategy. This paper provides an overview of the therapeutic option for BCBM that is currently available and outlines potential new approaches for tackling these deadly secondary tumours.
| S-EPMC7782834 | biostudies-literature
Project description:IntroductionBrain metastases are a common cause of morbidity and mortality in patients with breast cancer. Local central nervous system (CNS) directed therapies are usually the first line treatment for breast cancer brain metastases (BCBM), but those must be followed by systemic therapies to achieve long-term benefit. Systemic therapy for hormone receptor (HR+) breast cancer has evolved in the last 10 years, but their role when brain metastases occur is uncertain.MethodsWe performed a systematic review of the literature focused on management of HR+ BCBM by searching Medline/PubMed, EBSCO, and Cochrane databases. The PRISMA guidelines were used for systematic review.ResultsOut of 807 articles identified, 98 fulfilled the inclusion criteria in their relevance to the management of HR+ BCBM.ConclusionsSimilar to brain metastases from other neoplasms, local CNS directed therapies are the first line treatment for HR+ BCBM. Although the quality of evidence is low, after local therapies, our review supports the combination of targeted and endocrine therapies for both CNS and systemic management. Upon exhaustion of targeted/endocrine therapies, case series and retrospective reports suggest that certain chemotherapy agents are active against HR+ BCBM. Early phase clinical trials for HR+ BCBM are ongoing, but there is a need for prospective randomized trials to guide management and improve patients' outcome.
| S-EPMC10049940 | biostudies-literature