Alliance A071701: Genomically guided treatment trial in brain metastases.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS2573-TPS2573
Author(s):  
Priscilla Kaliopi Brastianos ◽  
Erin Twohy ◽  
Carey K. Anders ◽  
A. John Iafrate ◽  
Peter A. Kaufman ◽  
...  
Keyword(s):  
Brain Metastases ◽  
The United States ◽  
Pi3k Pathway ◽  
Clinical Test ◽  
Tumor Type ◽  
Breast Cancers ◽  
Primary Tumors ◽  
The Central Nervous System ◽  
Extracranial Metastases ◽  
Preclinical Work

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 .

Tumors of the Central Nervous System

2013 ◽  
pp. 20-58
Author(s):  
Keith L. Ligon ◽  
Karima Mokhtari ◽  
Thomas W. Smith
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Molecular Biology ◽  
Tumor Type ◽  
Primary Tumors ◽  
System P ◽  
Precise Diagnosis ◽  
The Central Nervous System ◽  
Classification Of Tumors

This chapter presents the most up-to-date classification of tumors of the nervous system, based on the histological appearance of the neoplasm and also on information derived from cytogenetics and molecular biology, now recognized worldwide as increasingly important for more precise diagnosis, prognosis, and therapeutic guidance. The chapter provides a detailed morphologic description of each major tumor type, with numerous illustrations of macroscopic and microscopic lesions. First we consider primary tumors of the nervous system, including those derived from neuroepithelial tissue (astrocytic, oligodendroglial, ependymal, neuronal, and glioneuronal), pineal tissue, peripheral nerve sheath, and meninges. Next lymphomas, hematopoietic neoplasms, and secondary (metastatic) neoplasms are described.

Brain metastases in patients diagnosed with a solid primary cancer during childhood: experience from a single referral cancer center

2014 ◽  
Vol 14 (4) ◽  
pp. 372-385 ◽  
Author(s):  
Dima Suki ◽  
Rami Khoury Abdulla ◽  
Minming Ding ◽  
Soumen Khatua ◽  
Raymond Sawaya
Keyword(s):  
Brain Metastasis ◽  
Brain Metastases ◽  
Primary Tumor ◽  
Lung Metastases ◽  
Cancer Center ◽  
Leptomeningeal Disease ◽  
Tumor Type ◽  
Primary Cancer ◽  
Extracranial Metastases ◽  
The Brain

Object Metastasis to the brain is frequent in adult cancer patients but rare among children. Advances in primary tumor treatment and the associated prolonged survival are said to have increased the frequency of brain metastasis in children. The authors present a series of cases of brain metastases in children diagnosed with a solid primary cancer, evaluate brain metastasis trends, and describe tumor type, patterns of occurrence, and prognosis. Methods Patients with brain metastases whose primary cancer was diagnosed during childhood were identified in the 1990–2012 Tumor Registry at The University of Texas M.D. Anderson Cancer Center. A review of their hospital records provided demographic data, history, and clinical data, including primary cancer sites, number and location of brain metastases, sites of extracranial metastases, treatments, and outcomes. Results Fifty-four pediatric patients (1.4%) had a brain metastasis from a solid primary tumor. Sarcomas were the most common (54%), followed by melanoma (15%). The patients' median ages at diagnosis of the primary cancer and the brain metastasis were 11.37 years and 15.03 years, respectively. The primary cancer was localized at diagnosis in 48% of patients and disseminated regionally in only 14%. The primary tumor and brain metastasis presented synchronously in 15% of patients, and other extracranial metastases were present when the primary cancer was diagnosed. The remaining patients were diagnosed with brain metastasis after initiation of primary cancer treatment, with a median presentation interval of 17 months after primary cancer diagnosis (range 2–77 months). At the time of diagnosis, the brain metastasis was the first site of systemic metastasis in only 4 (8%) of the 51 patients for whom data were available. Up to 70% of patients had lung metastases when brain metastases were found. Symptoms led to the brain metastasis diagnosis in 65% of cases. Brain metastases were single in 60% of cases and multiple in 35%; 6% had only leptomeningeal disease. The median Kaplan-Meier estimates of survival after diagnoses of primary cancer and brain metastasis were 29 months (95% CI 24–34 months) and 9 months (95% CI 6–11 months), respectively. Untreated patients survived for a median of 0.9 months after brain metastasis diagnosis (95% CI 0.3–1.5 months). Those receiving treatment survived for a median of 8 months after initiation of therapy (95% CI 6–11 months). Conclusions The results of this study challenge the current notion of an increased incidence of brain metastases among children with a solid primary cancer. The earlier diagnosis of the primary cancer, prior to its dissemination to distant sites (especially the brain), and initiation of presumably more effective treatments may support such an observation. However, although the actual number of cases may not be increasing, the prognosis after the diagnosis of a brain metastasis remains poor regardless of the management strategy.

Tumors of the Central Nervous System

2018 ◽  
pp. 21-64
Author(s):  
Keith L. Ligon ◽  
Sandro Santagata ◽  
Franck Bielle
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Morphological Description ◽  
Tumor Type ◽  
Primary Tumors ◽  
System P ◽  
Precise Diagnosis ◽  
The Central Nervous System ◽  
Classification Of Tumors

This chapter presents the most up-to-date classification of tumors of the nervous system, based on the histological appearance of the neoplasm and on information derived from cytogenetics and molecular biology, which are now recognized worldwide as increasingly important for more precise diagnosis, prognosis, and therapeutic guidance. The chapter provides a detailed morphological description of each major tumor type, with numerous illustrations of macroscopic and microscopic lesions. First considered are primary tumors of the nervous system, including those derived from neuroepithelial tissue (astrocytic, oligodendroglial, ependymal, neuronal, and glioneuronal); pineal tissue; peripheral nerve sheath; and meninges. Next, lymphomas, hematopoietic neoplasms, and secondary (metastatic) neoplasms are described.

scholarly journals Differential and decreased expression of Fibulin 1, Fibulin 2, and Fibulin 5 in metastases to disparate organ sites in breast cancer.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Soft Tissues ◽  
The United States ◽  
Breast Cancers ◽  
Primary Tumors ◽  
Over Expression ◽  
Distant Organ ◽  
Organ Site ◽  
Public Datasets ◽  
The Brain

Breast cancer is a leading killer of women in the United States (1) and the main reason women diagnosed with breast cancer die is metastasis, or spread of the cancer from the breast to a distant organ site (2, 3). We mined public datasets (4, 5) to perform systems-level analyses of the most significant differences in gene expression (6) between breast cancers in humans and the metastases they generate. We found that fibulin-1, fibulin-2 and fibulin-5 were among the genes whose expression was most different between primary tumors of the breast and metastases to both the brain and the soft tissues. Moreover, we found uniform and significantly decreased expression of each differentially expressed fibulin gene in both tissue types. Fibulins-1, -2 and -5 should be targeted to assess whether over-expression of these genes can halt, delay or reverse metastasis in women with breast cancer.

scholarly journals Subtype switching in breast cancer brain metastases: a multicenter analysis

2020 ◽  
Vol 22 (8) ◽  
pp. 1173-1181 ◽  
Author(s):  
Alexander F C Hulsbergen ◽  
An Claes ◽  
Vasileios K Kavouridis ◽  
Ali Ansaripour ◽  
Claudine Nogarede ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Growth Factor Receptor ◽  
Hazard Ratio ◽  
Receptor Expression ◽  
Her2 Status ◽  
Primary Tumors ◽  
Pathology Reports ◽  
Breast Cancer Brain Metastases ◽  
Extracranial Metastases

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.

scholarly journals CMET-33. PHASE II STUDY OF PALBOCICLIB IN BRAIN METASTASES HARBORING CDK PATHWAY ALTERATIONS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi58-vi59
Author(s):  
Priscilla Brastianos ◽  
Justine Cohen ◽  
Nancy Wang ◽  
Eudocia Lee ◽  
Jennifer Ligibel ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Phase Ii Study ◽  
Cyclin Dependent Kinase ◽  
Stage Design ◽  
Primary Tumors ◽  
Grade 3 ◽  
Cycle Regulation ◽  
Preclinical Work

Abstract BACKGROUND Up to 25% of all cancer patients will develop brain metastases and prognosis remains poor. In preclinical work, we discovered that more than 50% brain metastases genomically diverge from primary tumors and harbor alterations in genes involved with cell cycle regulation. We thus initiated a phase II study to evaluate the efficacy and safety of the cyclin dependent kinase (CDK) 4/6 inhibitor, palbociclib, in patients with recurrent brain metastases with alterations in the CDK pathway (NCT02896335). METHODS The primary endpoint of the trial is the rate of intracranial benefit (defined as CR, PR, or SD, per RANO) at 8 weeks after the start of palbociclib. A Simon two-stage design was used to compare the rate of intracranial benefit for a null rate of 10% against an alternative of 30%. Fifteen patients were to be enrolled in the first stage. If fewer than 2 responders were observed, then the study would stop for insufficient evidence of efficacy. If 6 or more responders were observed among the total of 30, this treatment regimen would be considered worthy of further study. CSF, blood samples and tumor samples were collected to elucidate the genomic determinants of response to CDK inhibitors in the brain. RESULTS A total of 14 patients have been accrued (5 with breast cancer, 4 with melanoma, 3 esophageal and 2 with non-small cell lung cancer) thus far. One or more grade-3 or higher adverse events at least possibly related to treatment were seen in six (42%) patients, the majority being hematologic toxicities. At the time of the data analysis, eight (57%) patients had achieved intracranial benefit. Therefore, the study met primary endpoint. CONCLUSIONS In this unique, genomically-guided brain metastasis trial, we demonstrate that the CDK 4/6 inhibitor, palbociclib, is well-tolerated and has activity in patients with brain metastases.

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

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.

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

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 603-603 ◽  
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.

Gamma Knife surgery as sole treatment for multiple brain metastases: 2-center retrospective review of 1508 cases meeting the inclusion criteria of the JLGK0901 multi-institutional prospective study

2010 ◽  
Vol 113 (Special_Supplement) ◽  
pp. 48-52 ◽  
Author(s):  
Toru Serizawa ◽  
Masaaki Yamamoto ◽  
Yasunori Sato ◽  
Yoshinori Higuchi ◽  
Osamu Nagano ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Gamma Knife ◽  
Class Ii ◽  
Hazard Ratio ◽  
Gamma Knife Surgery ◽  
Inclusion Criteria ◽  
Primary Tumors ◽  
Poor Prognostic Factor ◽  
Group A ◽  
Group B

Object The authors retrospectively reviewed the results of Gamma Knife surgery (GKS) used as the sole treatment for brain metastases in patients who met the eligibility criteria for the ongoing JLGK0901 multi-institutional prospective trial. They also discuss the anticipated results of the JLGK0901 study. Methods Data from 1508 consecutive cases were analyzed. All of the patients were treated at the Gamma Knife House of Chiba Cardiovascular Center or the Mito Gamma House of Katsuta Hospital between 1998 and 2007 and met the following JLGK0901 inclusion criteria: 1) newly diagnosed brain metastases, 2) 1–10 brain lesions, 3) less than 10 cm3 volume of the largest tumor, 4) no more than 15 cm3 total tumor volume, 5) no findings of CSF dissemination, and 6) no impairment of activities of daily living (Karnofsky Performance Scale score < 70) due to extracranial disease. At the initial treatment, all visible lesions were irradiated with GKS without upfront whole-brain radiation therapy. Thereafter, gadolinium-enhanced MR imaging was performed every 2–3 months, and new distant lesions were appropriately retreated with GKS. Patients were divided into groups according to numbers of tumors: Group A, single lesions (565 cases); Group B, 2–4 tumors (577 cases); and Group C, 5–10 tumors (366 cases). The differences in overall survival (OS) were compared between groups. Results The median age of the patients was 66 years (range 19–96 years). There were 963 men and 545 women. The primary tumors were in the lung in 1114 patients, gastrointestinal tract in 179, breast in 105, urinary tract in 66, and other sites in 44. The overall mean survival time was 0.78 years (0.99 years for Group A, 0.68 years for Group B, and 0.62 years for Group C). The differences between Groups A and B (p < 0.0001) and between Groups B and C (p = 0.0312) were statistically significant. Multivariate analysis revealed significant prognostic factors for OS to be sex (poor prognostic factor: male, p < 0.0001), recursive partitioning analysis class (Class I vs Class II and Class II vs III, both p < 0.0001), primary site (lung vs breast, p = 0.0047), and number of tumors (Group A vs Group B, p < 0.0001). However, no statistically difference was detected between Groups B and C (p = 0.1027, hazard ratio 1.124, 95% CI 0.999–1.265). Conclusions The results of this retrospective analysis revealed an upper CI of 1.265 for the hazard ratio, which was lower than the 1.3 initially set by the JLGK0901 study. The JLGK0901 study is anticipated to show noninferiority of GKS as sole treatment for patients with 5–10 brain metastases compared with those with 2–4 in terms of OS.

Sign in / Sign up

Export Citation Format

Share Document