Brain Metastases In Colorectal Cancer Research Articles

Identification of a gene expression signature associated with brain metastasis in colorectal cancer.

Brain metastasis (BM) in colorectal cancer (CRC) is a rare event with poor prognosis. Apart from (K)RAS status and lung and bone metastasis no biomarkers exist to identify patients at risk. This study aimed to identify a gene expression signature associated with colorectal BM. Three patient groups were formed: 1. CRC with brain metastasis (BRA), 2. exclusive liver metastasis (HEP) and, 3. non-metastatic disease (M0). RNA was extracted from primary tumors and mRNA expression was measured using a NanoString Panel (770 genes). Expression was confirmed by qPCR in a validation cohort. Statistical analyses including multivariate logistic regression followed by receiver operating characteristic (ROC) analysis were performed. EMILIN3, MTA1, SV2B, TMPRSS6, ACVR1C, NFAT5 and SMC3 were differentially expressed in BRA and HEP/M0 groups. In the validation cohort, differential NFAT5, ACVR1C and SMC3 expressions were confirmed. BRA patients showed highest NFAT5 levels compared to HEP/M0 groups (global p = 0.02). High ACVR1C expression was observed more frequently in the BRA group (42.9%) than in HEP (0%) and M0 (7.1%) groups (global p = 0.01). High SMC3 expressions were only detectable in the BRA group (global p = 0.003). Only patients with BM showed a combined high expression of NFAT5, ACVR1C or SMC3 as well as of all three genes. ROC analysis revealed a good prediction of brain metastasis by the three genes (area under the curve (AUC) = 0.78). The NFAT5, ACVR1C and SMC3 gene expression signature is associated with colorectal BM. Future studies should further investigate the importance of this biomarker signature.

Immunotherapy as a promising treatment strategy for dmmr colorectal cancer with brain metastasis: a case report

Brain metastasis in colorectal cancer is a rare occurrence with poor prognosis and limited treatment options. This case report presents a unique and previously unreported case of brain metastasis in a patient with dMMR (DNA mismatch repair-deficient) colorectal cancer. The patient, a 70-year-old male, initially presented with abdominal pain and was diagnosed with moderately differentiated adenocarcinoma of the right colon. Following surgical resection and adjuvant chemotherapy, the patient developed cognitive decline and was found to have a metastatic lesion in the left temporal lobe. Immunohistochemical analysis revealed MSH2 positivity and MSH6, MLH1, and PMS2 negativity, indicating dMMR status. Further genetic testing showed wild-type Kras, Nras, and Braf, and high tumor mutational burden (TMB). The patient was subsequently treated with pembrolizumab immunotherapy, resulting in a significant improvement of symptoms and a reduction in the size of brain metastasis. This case highlights the rarity and challenging management of brain metastasis in colorectal cancer, particularly in the context of dMMR tumors. The successful use of immunotherapy in this case provides valuable insights into the potential efficacy of immune-based treatments for dMMR colorectal cancer with brain metastasis, underscoring the need for further research in this field.

Survival and clinical characteristics of patients with colorectal cancer and brain metastases.

29 Background: Brain metastases (BM) are rare in colorectal cancer (CRC) with 1-3% of patients developing BM over their lifetime. There are no screening recommendations for BM in patients with CRC and most are diagnosed after a patient develops symptoms. Identifying the clinical characteristics for patients with CRC and BM may aid clinicians to consider BM early in symptom onset and potentially screen appropriate patients. Methods: We performed a retrospective chart review of patients >18 years diagnosed with CRC and BM at Yale New Haven Hospital from 1/2012-9/2021. Clinical characteristics were analyzed by descriptive statistics, time intervals were compared using the Mann-Whitney test, and survival analysis was done using the Kaplan-Meier method. Results: We identified 93 patients with CRC and BM. Median age at diagnosis was 56 years, 55% were male, 75% of patients had a left sided primary tumor and 47% were rectal primary. At initial diagnosis, 38% and 39% were stage III and IV respectively. RAS/RAF mutations were present in 45% of patients and all were mismatch repair proficient. The median time from CRC diagnosis to BM was 3.81 years (95% CI 3.09, 4.41) and median time from metastatic CRC to BM was 2.21 years (95% CI 1.48, 2.75). Median overall survival after developing BM was 0.49 years (95% CI 0.24, 0.70). Patients with RAS/RAF mutations had a decreased median time from CRC diagnosis to BM of 3.33 years (95% CI 2.69, 4.37) compared to RAS/RAF wildtype at 5.09 years (95% CI 4.44, 7.97) (p 0.0028). Median time to BM from CRC diagnosis was also decreased in females (p 0.01). The location of primary tumor did not significantly decrease time to BM. Prior to BM diagnosis, 76% of patients had lung metastasis. 84% of patients received treatment for BM while 14% had no BM treatment and 2% were unknown. For treatment 50% had Gamma Knife Radiosurgery, 22% underwent surgical excision +/- adjuvant radiation, and 12% underwent whole brain radiotherapy. After BM treatment, 43% of patients received additional chemotherapy. Conclusions: Although BM in CRC is uncommon, early diagnosis in those at risk is critical given the urgent nature of BM. Patients with CRC that develop BM frequently have tumors that originate in the left side of the colon and preexisting lung metastasis. In patients with CRC and BM, the majority develop BM > 3 years after initial CRC diagnosis, and BM onset is significantly shorter in females and patients with tumors harboring a RAS/RAF mutation. After BM diagnosis and treatment, less than half of patients are able to receive subsequent therapy, and median survival is < 6 months. [Table: see text]

A clinical prediction model for the presence of brain metastases from colorectal cancer.

We conducted this study to explore clinicopathological profiles of brain metastases (BM) and establish a clinical prediction model that predicts the presence of BM in colorectal cancer (CRC) patients. Patients with initially diagnosed CRC were reviewed between the year 2010 and 2015. Multiple imputations are used for handling missing values. Prognostic factors were identified by the univariate and multivariate Cox regression model. Univariate and multivariate logistic regression was used to identify the predictive factors for the presence of BM. A nomogram was constructed based on statistically significant risk factors of the presence of BM. The decision curve analysis (DCA) was used to assess the clinical usefulness and net benefits of the nomogram for the presence of BM. Four hundred ninety-five patients with brain metastasis at the initial diagnosis were identified, representing 0.24% of the whole cohort and 0.91% of the metastatic cohort. Multivariable logistic regression demonstrated that young age, positive CEA, adenocarcinoma, lower differentiated grade, presence of liver metastases, presence of lung metastases, and presence of bone metastases were significantly associated with higher risk of developing BM. The decision curve analysis inform clinical decisions were better than a scenario in which all patients or no patients are screened across a wide range of threshold at ≥ 0.027%. The risk estimates provided by the nomogram can be extremely useful for earlier diagnosis, especially when discussing screening strategy among high-risk patients.

The impact of neurological performance and volumetrics on overall survival in brain metastasis in colorectal cancer: a retrospective single-center case series

BackgroundBrain metastasis (BM) of colorectal cancer is a disease with a poor prognosis of only a few months survival. However, it is difficult to estimate the individual prognosis of each patient due to the lack of definitive prognosis parameters. The number of metastases and the Karnofsky performance score are known predictors for survival. We investigated whether or not the neurological performance score and the tumor volumetrics are equally suitable predictors for survival.DesignAll patients with histologically diagnosed BM linked to colorectal cancer between 2012 and March 2020 were reviewed. The Medical Research Council Neurological Performance Score was used to quantify neurological performance. Univariate analysis with Kaplan-Meier estimate and log-rank test was performed. Survival prediction and multivariate analysis were performed employing Cox proportional hazard regression.ResultsTwenty-five patients were included in our analysis with an overall survival of 4.9 months after surgery of the BM. Survival decreased in the univariate analysis with increasing postoperative neurological performance score, low Karnofsky performance score, absence of radiation therapy and radiation therapy modality. The neurological performance score is a reliable scoring parameter for estimating the prognostic course analogous to the Karnofsky performance score. Neither preoperative nor post resection residual tumor volume had any impact on overall survival in our small cohort.ConclusionOur data suggest that the postoperative neurological performance is a valuable prognostic factor for colorectal cancer patients with BM. Tumor volumetrics show no correlation to survival. Further investigations with a larger number of cases are mandatory.

The pattern of brain metastasis in colorectal cancer: Efficacy of metastasectomy, chemotherapy.

40 Background: Colorectal cancer patients with brain metastases experience poor outcomes; however treatment strategies are understudied. In this study, we investigated the impact of different treatments for colorectal cancer patients with brain metastases. Methods: We identified stage 4 colorectal adenocarcinoma patients with brain metastasis using the National Cancer Database diagnosed between 2010 and 2015. Patients with unknown survival data, other histologies, and multiple primary sites were excluded. Patients with and without brain metastasis were compared using the Chi-square test. Kaplan-Meier method was performed to calculate univariable overall survival (OS). We used the Cox regression model for multivariable analysis after adjusting by age, race/ethnicity, comorbidity score, surgery, chemotherapy, and radiotherapy. Results: Among 75,901 patients with stage 4 colorectal adenocarcinoma, 1.6% had brain metastasis. Patients with brain metastasis were more likely to have bone (23% vs. 5%, p < 0.001) and lung metastasis (52% vs. 21%, p < 0.001), but less likely to have liver metastasis (56% vs. 72%, p < 0.001) compared to patients without brain metastasis. Patients with brain metastasis had higher KRAS mutation rate (54% vs. 43%, p < 0.001). Patients with brain metastasis were more likely to be age ≥ 50 years (85% vs. 83%, p = 0.01), white race (76% vs. 71%, p = 0.001), and receive radiotherapy (63% vs. 12%, p < 0.001). Total 26.4% of patients with brain metastasis underwent metastasectomy, and those patients had better OS compared to patients with non-metastasectomy (median OS 12 vs. 4 months, p < 0.001). Median OS in all patients with brain metastasis was 5.5 months. Patients with brain metastasis who received multiagent chemotherapy had improved OS compared with patients who received single-agent chemotherapy (mOS 13 vs. 6 months, p < 0.001). Patients with brain metastasis who received brain radiotherapy had better OS (mOS 6.3 vs. 3.7 months, p = 0.005) than those who did not. On multivariable analysis, metastasectomy (HR 0.65 95% CI [0.57-0.75]) and receipt of multiagent chemotherapy (HR 0.68 95% CI [0.54-0.86]) were associated with favorable prognosis, but brain radiotherapy was not (HR 1.04 95% CI [0.91-1.19]). Conclusions: Brain metastases are rare in colorectal cancer but portend poor survival. Lung and bone metastases are found more frequently in these patients. Treatment with metastasectomy or multiagent chemotherapy is associated with improved overall survival.

The Infratentorial Localization of Brain Metastases May Correlate with Specific Clinical Characteristics and Portend Worse Outcomes Based on Voxel-Wise Mapping.

Simple SummaryBrain metastases (BMs) are cancerous lesions that originated from cancers outside the brain. Specific types of BMs are found distributing in specific brain areas. The infratentorial regions are frequently affected, causing severe neurological symptoms. Thus, it is necessary to investigate what types of tumors tend to form infratentorial BMs and whether these lesions are more fatal. By analyzing substantial brain imaging data of BMs, we found the vulnerability of infratentorial regions to most types of BMs, and found the infratentorial localization of BMs was significantly associated with young age, male sex, lung neuroendocrine and squamous cell carcinomas, more active cell division of the tumors, and patients with poorer outcomes. Additionally, infratentorial involvement might predict worse outcomes for patients who received surgery. Our findings underlined the distinctive role of infratentorial localization of BMs and its potential relationship with specific clinical characteristics, which may assist diagnosis, treatment choice, and prognostic prediction of BMs.The infratentorial regions are vulnerable to develop brain metastases (BMs). However, the associations between the infratentorial localization of BMs and clinical characteristics remained unclear. We retrospectively studied 1102 patients with 4365 BM lesions. Voxel-wise mapping of MRI was applied to construct the tumor frequency heatmaps after normalization and segmentation. The analysis of differential involvement (ADIFFI) was further used to obtain statistically significant clusters. Kaplan-Meier method and Cox regression were used to analyze the prognosis. The parietal, insular and left occipital lobes, and cerebellum were vulnerable to BMs with high relative metastatic risks. Infratentorial areas were site-specifically affected by the lung, breast, and colorectal cancer BMs, but inversely avoided by melanoma BMs. Significant infratentorial clusters were associated with young age, male sex, lung neuroendocrine and squamous cell carcinomas, high expression of Ki-67 of primaries and BMs, and patients with poorer prognosis. Inferior OS was observed in patients with ≥3 BMs and those who received whole-brain radiotherapy alone. Infratentorial involvement of BMs was an independent risk factor of poor prognosis for patients who received surgery (p = 0.023, hazard ratio = 1.473, 95% confidence interval = 1.055–2.058). The current study may add valuable clinical recognition of BMs and provide references for BMs diagnosis, treatment evaluation, and prognostic prediction.

Genomic signatures reveal DNA damage response deficiency in colorectal cancer brain metastases

Brain metastases (BM) of colorectal cancer (CRC) are rare but lethal, and an understanding of their genomic landscape is lacking. We conduct an analysis of whole-exome sequencing (WES) and whole-genome sequencing (WGS) data on 19 trios of patient-matched BMs, primary CRC tumors, and adjacent normal tissue. Compared with primary CRC, BM exhibits elevated mutational signatures of homologous recombination deficiency (HRD) and mismatch repair deficiency (MMRD). Further analysis reveals two DNA damage response (DDR) signatures could emerge early and are enhanced in BM tissues but are eliminated eventually in matched primary CRC tissues. BM-specific mutations in DDR genes and elevated microsatellite instability (MSI) levels support the importance of DDR in the brain metastasis of CRC. We also identify BM-related genes (e.g., SCN7A, SCN5A, SCN2A, IKZF1, and PDZRN4) that carry frequent BM-specific mutations. These results provide a better understanding of the BM mutational landscape and insights into treatment.

EP-1655 Cost-effectiveness analysis of stereotactic radiotherapy in colorectal cancer brain metastases

EP-1655 Cost-effectiveness analysis of stereotactic radiotherapy in colorectal cancer brain metastases

Brain metastases in colorectal cancer: prognostic factors and survival analysis.

Colorectal cancer (CRC) brain metastases (BM) are an uncommon and late event. We aim to investigate the impact of clinical factors, treatment modalities and RAS/BRAF status on the outcomes of CRC patients with BM. We retrospectively analysed CRC patients who developed BM in our centre between January 1997 and June 2017. Clinical factors, treatment modalities, RAS/BRAF status and survival were evaluated. Twenty-eight patients were recorded; 82% had left-sided (LS) CRC and 71% had lung metastases. Median time to BM diagnosis was 36months (m) and 93% of patients received local treatment of BM (43% whole brain radiotherapy, 50% surgery). Right-sided (RS) CRC showed shorter time to BM, not previously described (9.3 vs 46.6m for RS and LS CRC, respectively; HR = 4.7, p = 0.006). Median overall survival (mOS) from BM treatment was 9.5m, better in patients who underwent surgery than those treated with radiotherapy alone (12.1 vs 4.6m, respectively; HR = 0.3, p = 0.019) and in those without progressive metastatic extracranial disease (7.2 vs 20.9m, for progressive and non-progressive, respectively; HR = 0.3, p = 0.056). Patients with two or more metastatic extracranial locations showed worse prognosis (5.9 vs 16.3m, for > 2 vs 0-1, respectively; HR = 3.7, p = 0.015). RAS/BRAF status did not showed prognostic value. Time to BM diagnosis is shorter in RS CRC. The presence of two or more metastatic extracranial locations and progressive metastatic extracranial disease at the time of BM diagnosis could be bad prognosis factors for CRC BM patients.

HER2 positive rates are enriched amongst colorectal cancer brain metastases: A study amongst 1,920 consecutive patients.

3612Background: Brain metastases (BM) from colorectal cancer (CRC) are a rare but increasing event as patients survive longer. While human epidermal growth factor receptor 2 (HER2) gene amplificati...

Brain Metastasis from Colorectal Cancer: Predictors and Treatment Outcomes

Objective: Difficulties are associated with the management of brain metastasis (BM), which portends a poor prognosis in the treatment of colorectal cancer (CRC). The aim of the present study was to identify risk factors for BM in CRC and evaluate the outcomes of various treatment modalities. Methods: We retrospectively reviewed data on a total of 2,238 patients with primary CRC who underwent surgical resection at our hospital between 1999 and 2014. Predictive factors for BM and prognostic factors after the diagnosis of BM were examined by univariate and multivariate analyses using Cox proportional hazards models. Results: Three patients (0.1%) had BM at the initial diagnosis, and 23 patients (1.2%) developed metachronous BM during the median follow-up period of 44.6 months. Lung and bone metastases were identified as independent predictive factors for BM. Median survival after the diagnosis of BM was 7.4 months. Stereotactic radiosurgery, administered to 41% of the patients with BM, was associated with a better postdiagnostic survival. Conclusion: CRC patients with metastasis to the lung or bone were at a higher risk of BM. Because the survival is still limited, it is crucial to determine the treatment strategy in consideration of the characteristics of each therapy and quality of life in CRC patients with BM.

Brain metastases from colorectal cancer: characteristics and management.

Brain metastases (BMs) are the most common intracranial neoplasms in adults, but they rarely arise from colorectal cancer (CRC). The objective of this study was to report an overview of the characteristics and current management of CRC BMs. A systematic review on CRC BMs was performed using Medline database from 1983 to 2015. The search was limited to studies published in English. Review articles, not relevant case report or studies or studies relating to animal and in vitro experiments were excluded. BMs occurred in 0.06-4% of patients with CRC. Most BMs were metachronous and were associated with lung (27-92%) and liver (12-80%) metastases. Treatment options depended on the number of BMs, the general conditions of the patient and the presence of other metastases. Most frequent treatment was whole-brain radiotherapy (WBRT) alone (36%), with median overall survival comprised between 2 and 9 months. Median overall survival was better after surgery alone (from 3 to 16.2 months), or combined with WBRT (from 7.6 to 14 months). After stereotactic radiosurgery alone, overall survival could reach 9.5 months. Many favourable prognostic factors were identified, such as high Karnofsky performance status, low recursive partitioning analysis classes, lack of extracranial disease, low number of BMs and possibility to perform surgical treatment. BMs from CRC are rare. In the presence of favourable prognostic factors, an aggressive management including surgical resection with or without WBRT or stereotactic radiosurgery can improve the overall survival.

RAS mutations affect pattern of metastatic spread and increase propensity for brain metastasis in colorectal cancer.

RAS and PIK3CA mutations in metastatic colorectal cancer (mCRC) have been associated with worse survival. We sought to evaluate the impact of RAS and PIK3CA mutations on cumulative incidence of metastasis to potentially curable sites of liver and lung and other sites such as bone and brain. We performed a computerized search of the electronic medical record of our institution for mCRC cases genotyped for RAS or PIK3CA mutations from 2008 to 2012. Cases were reviewed for patient characteristics, survival, and site-specific metastasis. Among the 918 patients identified, 477 cases were RAS wild type, and 441 cases had a RAS mutation (394 at KRAS exon 2, 29 at KRAS exon 3 or 4, and 18 in NRAS). RAS mutation was significantly associated with shorter median overall survival (OS) and on multivariate analysis independently predicted worse OS (HR, 1.6; P < .01). RAS mutant mCRC exhibited a significantly higher cumulative incidence of lung, bone, and brain metastasis and on multivariate analysis was an independent predictor of involvement of these sites (HR, 1.5, 1.6, and 3.7, respectively). PIK3CA mutations occurred in 10% of the 786 cases genotyped, did not predict for worse survival, and did not exhibit a site-specific pattern of metastatic spread. The metastatic potential of CRC varies with the presence of RAS mutation. RAS mutation is associated with worse OS and increased incidence of lung, bone, and brain metastasis. An understanding of this site-specific pattern of spread may help to inform physicians' assessment of symptoms in patients with mCRC.

The clinical and pathological features of 133 colorectal cancer patients with brain metastasis: a multicenter retrospective analysis of the Gastrointestinal Tumors Working Committee of the Turkish Oncology Group (TOG).

Brain metastasis in colorectal cancer is highly rare. In the present study, we aimed to determine the frequency of brain metastasis in colorectal cancer patients and to establish prognostic characteristics of colorectal cancer patients with brain metastasis. In this cross-sectional study, the medical files of colorectal cancer patients with brain metastases who were definitely diagnosed by histopathologically were retrospectively reviewed. Brain metastasis was detected in 2.7 % (n = 133) of 4,864 colorectal cancer patients. The majority of cases were male (53 %), older than 65 years (59 %), with rectum cancer (56 %), a poorly differentiated tumor (70 %); had adenocarcinoma histology (97 %), and metachronous metastasis (86 %); received chemotherapy at least once for metastatic disease before brain metastasis developed (72 %), had progression with lung metastasis before (51 %), and 26 % (n = 31) of patients with extracranial disease at time the diagnosis of brain metastasis had both lung and bone metastases. The mean follow-up duration was 51 months (range 5-92), and the mean survival was 25.8 months (95 % CI 20.4-29.3). Overall survival rates were 81 % in the first year, 42.3 % in the third year, and 15.7 % in the fifth year. In multiple variable analysis, the most important independent risk factor for overall survival was determined as the presence of lung metastasis (HR 1.43, 95 % CI 1.27-4.14; P = 0.012). Brain metastasis develops late in the period of colorectal cancer and prognosis in these patients is poor. However, early screening of brain metastases in patients with lung metastasis may improve survival outcomes with new treatment modalities.

Curative Intent Treatment for Colorectal Cancer with Isolated Brain Metastases: A Case Report

Introduction: Brain metastases (BM) are a rare complication of colorectal cancer (CRC), typically presenting late in the course of the disease and are associated with other systemic metastases. Management of solitary brain metastases in colorectal cancer is still not well established. Case presentation: We describe the case of a 65 year-old man presenting with a solitary brain metastasis as the first sign of colon cancer. The treatment approach included surgical resection of the brain lesion followed by resection of the primary tumor, systemic chemotherapy and local radiation therapy to the BM. Conclusion: This curative intent approach has resulted in dramatically prolonged patient’s survival compared to the average reported in the literature, now nearly 2.5 years after presentation. Our case describes the feasibility of a multidisciplinary curative intent approach to solitary BM in CRC.

Clinical outcome with gamma-knife surgery or surgery for brain metastases from colorectal cancer

The aim of this study was to investigate the clinical outcomes after gamma knife surgery (GKS) or surgery as the first treatment for brain metastases in colorectal cancer (CRC). Of the 4350 patients diagnosed with CRC at our institution identified from 1987 to 2009, 27 patients who underwent GKS (GKS group) and 11 who underwent surgery (surgery group) were included. The oncologic outcomes were compared between the two groups. Local control was significantly better in the surgery group than in the GKS group (90% versus [vs.] 71.4%, respectively; p=0.006). The rate of symptom relief after 3months was significantly higher in the surgery group than in the GKS group (72.7 vs.18.5%, respectively; p=0.005). The median survival after GKS was 5.6months and surgery was 16.2months. In multivariate analysis, controlled primary tumor (p=0.038) and solitary metastasis (p=0.028) were correlated with prolonged overall survival, whereas surgery (p=0.034) was associated with longer local control. Surgery for brain metastasis from CRC is more advantageous in local control and neurologic symptom palliation than GSK. In multivariate analysis, overall survival was associated with controlled primary tumor and solitary metastasis.

Comment on “Clinical Features and Course of Brain Metastases in Colorectal Cancer: An Experience from a Single Institution”

Re: Damiens K, Ayoub JP, Lemieux B, et al. Clinical features and course of brain metastases in colorectal cancer: an experience from a single institution. Curr Oncol 2012;19:254–8. [...]

Response to Bernardi and Colleagues

Re: Bernardi D, Tomassi O, Stefani M, Di Giacobbe A. Comment on “Clinical features and course of brain metastases in colorectal cancer: an experience from a single institution.” Curr Oncol 2013;20:e278. [...]

Cerebral Venous Thrombosis: A Mimic of Brain Metastases in Colorectal Cancer Associated with a Better Prognosis

Malignancy is known to be one of the predisposing factors of cerebral venous thrombosis (CVT) due to its hypercoagulable state. CVT is a rare disorder which can lead to frequent misdiagnoses of brain metastases in such cases. We report here the case of a 35-year-old female with metastatic colon adenocarcinoma presenting with sudden neurological symptoms. Brain MRI and magnetic resonance venography confirmed the presence of CVT. She was treated with low molecular weight heparin followed by warfarin. She recovered and is doing well on warfarin after 5 months of diagnosis of CVT. CVT should be strongly suspected as a cause of neurological dysfunction in any case of disseminated malignancy including colon adenocarcinoma. Rapid diagnosis and initiation of therapy should be considered because of its favourable outcome.