Extracranial Metastases Research Articles

Nonsurgical Management of Melanoma Brain Metastasis: Current Therapeutics, Challenges, and Strategies for Progress.

This review aims to provide an overview of nonsurgical treatment strategies for central nervous system metastases in melanoma as well as discuss treatment challenges and future directions. Recent strategies for melanoma brain metastases have involved proving the intracranial activity of approved therapies as well as identifying novel drug targets. BRAF/MEK combination therapy has intracranial activity in those with BRAF V600 mutations, though disease control is shorter for intracranial than extracranial metastases. Immunotherapy and combination immunotherapies have emerged as providing durable responses in melanoma, and newer studies combining immunotherapy with targeted therapies are emerging. Continued challenges include penetration through the blood-brain barrier and development of resistance mechanisms. Novel therapeutic targets and methods to improve central nervous system penetrance are being identified through the application of deep DNA- and RNA-sequencing analyses. Radiation therapy approaches, especially stereotactic radiosurgery in combination or in sequence with systemic therapies, are also being investigated. Both targeted therapies and immunotherapies have revolutionized the field of melanoma treatment. Multimodality approaches with multidisciplinary teams will pave the way for the future of central nervous system disease treatment in melanoma.

Is there any opportunity for immune checkpoint inhibitor therapy in non-small cell lung cancer patients with brain metastases?

Although brain metastases occur in almost one-third of non-small cell lung cancer (NSCLC) patients, and immune checkpoint inhibitors (ICI) either as monotherapy or combined with chemotherapy are the new standard of care in the first line setting, most trials excluded patients with asymptomatic and/or untreated brain metastases. Brain metastases have a major clinical impact due to the worsening of the patient’s prognosis and quality of life. Furthermore, the incidence of brain metastases is increasing in NSCLC patients, due to a longer survival and better imaging techniques. Therefore, brain metastases are increasingly becoming a research topic. Recent clinical data endorses ICI as a therapeutic strategy in this subpopulation of NSCLC patients, although the immune environment in brain metastases is more immune ignorant compared with the microenvironment in the primary tumour or in the extracranial metastases. In this review we summarize the current evidence of ICI strategy in NSCLC patients with brain metastases, including trial and real-life data. We also state that the different tumor microenvironment between brain metastases and primary tumor may explain the discordance on the response rate during treatment with ICI. Last, we focus on future directions, including the role and optimal sequence of cranial irradiation and ICI, prognostic scores, the best response assessment and new imaging techniques.

EPEN-12. MULTIPLE RECURRENCES OF ANAPLASTIC EPENDYMOMA WITH EXTRA AXIAL AND EXTRA NEURAL METASTASIS IN A PEDIATRIC PATIENT

BackgroundEpendymomas are the third most common CNS tumor in the pediatric population, accounting for 10% of all CNS tumors. Co-occurring extraneural and extracranial metastasis of ependymomas are extremely rare, with only 1 reported adult case in current literature. Case DescriptionWe describe the case of a patient with multiple reoccurrences of anaplastic ependymoma. Initial imaging showed a 5 x 8 x 8 cm complex cystic mass with nodular enhancing components within the left occipital lobe. The 4th ventricle was intact and imaging was negative for metastasis. Pathology following resection demonstrated perivascular pseudorosettes, areas of calcification, and increased mitotic activity. Biopsy revealed GFAP, EMA, neurofilament, INI-1, and was negative for CAM5.2, confirming anaplastic ependymoma. Methylation studies for PFA or PFB subgroup differentiation were not available. The patient had recurrences at 4-, 5-, and 6-years after his initial diagnosis. Seven years from his initial diagnosis, the patient underwent resection of four nodular lesions from the occipital lobe and surrounding soft tissue. Pathology of these lesions and the lymph nodes/soft tissue confirmed anaplastic ependymoma. A PET scan showed increase uptake in the supraclavicular lymph nodes and had multiple bilateral pulmonary nodules. Scans at 3 months post-surgery were negative for leptomeningeal metastases but showed further lymph node involvement with progression of pulmonary disease. ConclusionCo-occurring extraneural and extracranial metastasis of ependymoma is a rare occurrence across all populations. To our knowledge, this would be the first published pediatric case of anaplastic ependymoma with lymph node, soft tissue, and pulmonary involvement. Treatment of ependymoma itypically local and the utility of chemotherapy remains unclear. Treatment options for extraneural mets is very limited, illustrating the need for new therapies and further studies directed at understanding the biology of these tumors and the factors that could influence their ability to metastasize to extraneural and extracranial sites.

Real-world utilization of EGFR TKIs and prognostic factors for survival in EGFR-mutated non-small cell lung cancer patients with brain metastases.

Brain metastases (BMs) cause morbidity and mortality in patients with non-small cell lung cancer (NSCLC). The optimal management of epidermal growth factor receptor (EGFR)-mutated NSCLC with BM is debatable. We aimed to investigate the impact of different treatments among patients with EGFR-mutated NSCLC. A cohort of 2058 lung cancer patients with BM between 2013 and 2018 was retrospectively studied. A total of 571 patients with EGFR-mutated NSCLC and BM were enrolled. All patients had received EGFR tyrosine kinase inhibitors (TKIs). Overall survival (OS) was measured from the diagnosis of BM to death or last follow-up. With a median follow-up of 35.2months (95% confidence interval [CI], 31.8-38.6), the median survival after BM was 21.3months (95% CI, 19.0-23.6). Osimertinib resulted in significantly superior survival after resistance to front-line TKIs (P < 0.0035); the median OS reached 28.0months (95% CI, 23.0-32.9), and the T790M status showed no difference in clinical effectiveness (P=0.386). The combination of TKIs and chemotherapy/vascular endothelial growth factor (VEGF) inhibitors (anti-VEGF) tended to have longer OS (P=0.271). Intracranial local radiotherapy significantly improved survival (P=0.0008). In multivariable analysis, we noted that age, Karnofsky performance score, EGFR mutation type, number of BMs and the presence of extracranial metastasis were independent pretreatment prognostic factors. In conclusion, EGFR TKIs have a significant effect on patients with EGFR-mutant BM, and the application of osimertinib further improves survival outcomes regardless of T790M status. Patients who undergo intracranial local therapy can achieve a survival benefit.

An immunogenomic analysis of melanoma brain metastases (MBM) compared to extracranial metastases (ECM).

9521 Background: Previous work has shown that MBM have a unique molecular profile compared to ECM. Description of the biology of MBM will facilitate the design of rational therapies for patients (pts) with MBM. Methods: We analyzed a previously published dataset from MD Anderson Cancer Center, which includes RNA-seq on surgically resected FFPE MBM (88 tumors from 74 pts) and surgically resected ECM from the same pts (50 from 34 pts). WES on 18 matched pairs of MBM and ECM was available. The STAR pipeline was used to estimate mRNA abundance. The DESeq2 package was used to perform differential gene expression (DGE) analyses. Pathway analysis was performed using Gene Set Enrichment Analysis (GSEA). Paired DGE and GSEA analyses comparing MBM vs. lymph node metastases (LN mets, n = 16) and MBM vs. skin mets (n = 10) were performed. CIBERSORT estimated relative abundance of immune cell types in MBM and ECM. The GATK Mutect2 pipeline was used to call somatic mutations using paired normal tumor samples. Mutations were annotated using the Ensembl Variant Effect Predictor and visualized using the Maftools package in R. RNA-seq was available on 54 primary cutaneous melanoma (CM) pt samples, including 19 CM which did not recur, 19 CM which recurred as MBM, and 16 CM which recurred as ECM. Gene Ontology or KEGG Pathway analysis was performed using goana function of limma package in R. Results: Comparing MBM vs. LN and MBM vs. skin mets, paired DGE identified 136 and 89 up-regulated genes with a fold change &gt; 2 and false-discovery rate (FDR) q-value &lt; 0.05. Moreover, 308 and 659 down-regulated genes with a fold change &lt; 0.5 were identified in MBM vs. LN and MBM vs. skin mets, respectively (q &lt; 0.05). Paired GSEA found that autophagy signaling pathways may be up-regulated in MBM vs. LN and MBM vs. skin mets. On a single-gene level, comparing both MBM vs. LN and skin mets, the most strongly up-regulated genes in autophagy pathways were GFAP and HBB, whereas fold changes in the majority of other autophagy-related genes were low and did not reach significance. Comparison between CM which recurred in brain vs. CM which did not recur identified up-regulation of autophagy pathways. No difference in autophagy pathway expression was observed comparing between CM with any recurrence vs. without recurrence. CIBERSORT identified an increased proportion of immune suppressive M2 macrophages compared to tumor suppressive M1 macrophages in both MBMs and ECMs. Conclusions: Up-regulation of autophagy pathways was observed in pt-matched MBM vs. LN and skin mets. This finding seemed to be driven by up-regulation of GFAP and HBB, which could reflect changes in the tumor microenvironment (TME). Future studies using single-cell RNA-seq or spatial transcriptomic technology will dissect the TME. A higher M2:M1 ratio may contribute to an immune suppressive tumor microenvironment in MBM and ECM and is targetable. Validation of our findings in an independent Duke dataset is ongoing.

Multicenter study for brain metastasis from breast cancer in Korea: The significance of molecular subtype (Korean Radiation Oncology Group 1612).

e14008 Background: We analyzed the treatment outcome of breast cancer patients with brain metastases (BM) in Korea to identify the prognostic factors and the role of whole brain radiation therapy (WBRT). Methods: Seven hundred thirty patients of breast cancer with BM treated at 17 institutions in Korea from 2000 to 2014 were analyzed. The median follow-up duration was 12 months. The analysis consisted of three cohorts: in cohort A, a total of 730 patients were included; in cohort B, 538 patients with available follow-up imaging after initial brain-directed treatment; and in cohort C, 54 patients receiving salvage WBRT due to recurrent BM after initial Stereotactic radiosurgery or WBRT. Overall survival (OS) was calculated from BM diagnosis in cohort A or from the last day of salvage WBRT in cohort C. Results: Median OS of cohort A was 15 months. In multivariate analysis, histologic grade 3, extracranial metastasis, number of BM &gt; 4, hormone receptor (HR) or HER2 negativity, and shorter time interval to diagnosis of BM were associated with inferior OS. Among 538 patients in cohort B, 201 showed subsequent development of new BM at a median of 11 months after stereotactic radiosurgery or WBRT for the management of initial BM (at 1 year, HR+/HER2- 51.9%, HER2+ 44.0%, and TNBC 69.6%, respectively; p = 0.008). Upfront WBRT reduced subsequent development of new BM, which showed the significant difference among molecular subtypes (HR+/HER2-, 42% reduction at 1 year, p &lt; 0.001; HER2+, 18.5%, p = 0.004; TNBC, 16.9%, p = 0.071). Multivariate analysis showed that shorter time interval to BM, TNBC subtype, extracranial systemic disease, number of BM &gt; 4, and involvement of both tentoria increased subsequent development of new BM. Anti-HER2 therapy for HER2+ patients and upfront WBRT significantly reduced risk of new BM. In cohort C, upfront WBRT prolonged the salvage WBRT-free duration (median 6.9 vs. 8.7 months, p = 0.058). Median OS was 6.8 months after salvage WBRT. Longer interval to salvage WBRT, controlled primary tumor, high dose of salvage WBRT (BED10 &gt; 37.5 Gy), and systemic treatment after salvage WBRT showed better OS. Uncontrolled extracranial systemic disease and salvage WBRT due to local progression without distant intracranial failure showed worse OS. Conclusions: The rates of new BM showed the significant differences among molecular subtypes. Upfront WBRT decreased subsequent development of new BM and this effect was dependent on the molecular subtype as well. Anti-HER2 therapy for HER2+ patients significantly decreased the subsequent development of new BM. On salvage WBRT setting, the patients having high dose of salvage WBRT, stable extracranial systemic disease and subsequent systemic therapy showed better OS.

Outcomes of immunotherapy (ICI) alone vs tyrosine kinase inhibitors (TKI) alone versus ICI and TKI combined in renal cell carcinoma brain metastasis.

2030 Background: Renal cancer is the fourth most common cause of metastatic tumors to the brain. Tyrosine kinase inhibitors (TKIs) targeting VEGFR and other receptors, such as sunitinib, pazopanib, etc., have been used as first line for renal cell carcinoma brain metastasis (RCCBM). Immune Checkpoint Inhibitors (ICIs) targeting PD-L1 and CTLA-4 interactions, such as nivolumab and ipilimumab respectively, have also been used as first line treatment for RCCBM. However, the efficacy of TKIs alone, ICIs alone, or TKIs and ICIs combined as first line treatment has emerged as a topic of interest. Methods: Patients with RCCBM treated with either TKIs, ICIs, or both at our tertiary care center from 2010-2019 were evaluated. Overall Survival (OS) was measured from initiation of either TKI or ICI therapy to date of death or last follow up. The Cox proportional hazard model was used to determine differences in OS. Results: 218 patients with RCCBM were included. Of these, 32 were treated with ICIs alone, 112 were treated with TKIs alone, and 76 were treated with a combination of ICIs and TKIs. For ICI treatment alone the median age at diagnosis was 61 years (Interquartile range (IQR) 38-82), 72% of the patients were male, and 97% were white. For TKI treatment alone the median age at diagnosis was 58 years (IQR 37-82), 70% of the patients were male, and 92% were white. For the combination cohort the median age at diagnosis was 63 years (IQR 45-79), 69% of the patients were male, and 97% were white. OS for patients receiving ICI, TKI, and combination treatment had a median of 69.1, 42.7, and 126.0 months and a 2-year rate of 77%, 69%, and 93%, respectively. With ICI treatment as a reference, TKI treated patients had an OS hazard ratio of 1.32 (95% CI = 0.78 - 2.21, p = 0.30) and ICI/TKI combination had an OS hazard ratio of 0.52 (95% CI = 0.30 - 0.92, p = 0.024). Conclusions: A combination treatment of ICIs and TKIs was associated with an increase in OS when compared to treatment with either TKIs or ICIs alone in patients with RCCBM. These results should be interpreted cautiously due to treatment selection bias. Further studies need to be done to control for other patient variables such as performance status, number of intracranial lesions, and extra-cranial metastasis.[Table: see text]

Clinical and pathological characteristics of breast cancer with resected brain metastasis.

1089 Background: Breast cancer brain metastasis (BCBM) has poor prognosis and limited therapeutic options. Studies have shown that BCBM may differ from their matched primary tumors in receptor subtypes and genomic characteristics. However, studies have been limited by the tissue availability of BCBM. Taking advantage of our institutional database of resected BCBM with matched primary breast samples, this study aimed to investigate the clinical and pathological characteristics of patients with resected BCBM. Methods: We performed retrospective chart review for all breast cancer patients who had resected BCBM samples at our institution over the last 20 years. Hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status of the primary breast and BCBM samples, location of BCBM, and extracranial metastases at time of BCBM diagnosis were categorized. Overall survival (OS) from time of BCBM diagnosis was calculated using the Kaplan-Meier method. Progression interval and receptor subtype switching from primary diagnosis to brain metastasis were computed and compared using Wilcoxon rank sum test and Fisher’s exact test, respectively. Results: Eighty-six patients were included in this study (median age at time of BCBM diagnosis 54.3 [range 28.3-84.0] years, median follow up 26.0 months). These included 47 HR+, 15 HER2+, 20 triple negative (TN), 4 unknown subtype breast samples, and 42 HR+, 18 HER2+, 17 TN and 9 unknown subtype brain samples. OS was significantly shorter in patients with TN compared to HR+ or HER2+ subtype, whether the TN status was in the primary breast tumor (median 20.5 vs 34.0 months, p = 0.04, thresholded at year 2) or in the brain metastasis (median 16.0 vs 34.0 months, p = 0.02, thresholded at year 2). No significant difference in OS was observed between HR+ and HER2+ groups. There was no significant difference in the progression interval from primary diagnosis to brain metastasis among receptor subtypes. From primary tumor to brain metastasis, receptor subtype switching occurred in 10 out of 73 patients (13.7%) for estrogen, 20 out of 70 (28.6%) for progesterone (PR), and 6 out of 72 (8.3%) for HER2. Receptor subtype switching did not significantly correlate with OS. Presence of extracranial metastases at time of BCBM diagnosis corresponded to significantly lower OS compared to no extracranial metastasis (16.5 vs 36.0 months, p = 0.01). No significant difference in OS was observed between patients with cerebral vs cerebellar brain metastases. Conclusions: These data indicate that patients with TN BCBM disease have the worst overall survival among all receptor subtypes. Metastases in extracranial sites at time of BCBM diagnosis significantly decreased survival. Location of the brain metastasis and receptor subtype switching from primary diagnosis to BCBM, which was relatively infrequent outside of the PR group, did not significantly correlate with OS in this limited data set.

Prognostic Factors and Current Treatment Strategies for Renal Cell Carcinoma Metastatic to the Brain: An Overview.

Simple SummaryBrain metastases are a commonly recognized poor prognostic factor in patients with cancer. Due to their poor prognosis, these patients were commonly excluded from the most important clinical trials that have revolutionized the oncological clinical practice. Renal cell carcinoma represents one of the most frequent neoplasia that metastasize to the brain. Due to the therapeutical advances the overall survival of brain metastatic renal cell carcinoma is improved even in the absence of tailored studies that are need to plan an adequate therapeutic strategy for these patients.Renal cell carcinoma (RCC) is one of primary cancers that frequently metastasize to the brain. Brain metastasis derived from RCC has the propensity of intratumoral hemorrhage and relatively massive surrounding edema. Moreover, it confers a grim prognosis in a great percentage of cases with a median overall survical (mOS) around 10 months. The well-recognized prognostic factors for brain metastatic renal cell carcinoma (BMRCC) are Karnofsky Performance Status (KPS), the number of brain metastasis (BM), the presence of a sarcomatoid component and the presence of extracranial metastasis. Therapeutic strategies are multimodal and include surgical resection, radiotherapy, such as stereotactic radiosurgery due to the radioresistance of RCC and systemic strategies with tyrosin kinase inhibitors (TKI) or Immune checkpoint inhibitors (ICI) whose efficacy is not well-established in this setting of patients due to their exclusion from most clinical trials. To date, in case of positive prognostic factors and after performing local radical therapies, such as complete resection of BM or stereotactic radiosurgery (SRS), the outcome of these patients significantly improves, up to 33 months in some patients. As a consequence, tailored clinical trials designed for BMRCC are needed to define the correct treatment strategy even in this poor prognostic subgroup of patients.

Clinical Oncology Research and Reports (E-ISSN: 2693-4787) Dear Dr. Wilma D. Heemsbergen, Greetings! I am writing this email to introduce our Journal “Clinical Oncology Research and Reports” due for release our upcoming issue in the End of May. We have just gone through your published manuscript which was quite interesting “Breast-shape changes during radiation therapy after breast-conserving surgery” so we

Extracranial metastases from glioblastoma multiforme (GBM) are rare, especially cutaneous metastasis. However, the metastatic mechanism of GBM remains unknown with no current consensus regarding the best therapeutic regimen. We report the clinical, imaging and pathological features of a case of a 47 years old man with primary glioblastoma; who 12 months after receiving a macroscopically total resection and adjacent radiotherapy, developed scalp metastasis and subsequent multiple skin metastasis. We also discuss the details of this case in comparison with the previously reported cases in literature in terms of clinical presentation, lesions’ site, management and survival.

High expression of cell adhesion molecule 2 unfavorably impacts survival in non-small cell lung cancer patients with brain metastases.

BackgroundLung cancer is one kind of malignant tumor with a high risk for morbidity and mortality compared to other solid organ malignancies. Brain metastases occur in 30–55% of non-small cell lung cancer (NSCLC) patients. Prognosis of NSCLC patients with brain metastases is very poor. Our previous study showed that cell adhesion molecule 2 (CADM2) could regulate the development of brain metastasis in NSCLC cells. Therefore, the objective of the study is to evaluate the effect of CADM2 on the prognosis of NSCLC patients with brain metastases.MethodsThe expression of CADM2 was detected by quantitative real-time polymerase chain reaction (qRT-PCR) in the tissue of the primary tumor. Patients were followed up and overall survival (OS) was calculated. The relationships between CADM2 and clinicopathological features were analyzed using the chi-square test. Kaplan-Meier analysis was carried out to demonstrate the influence of CADM2 on the OS of patients. Univariate and multivariate Cox analyses were used to determine the prognosis of NSCLC patients with brain metastases.ResultsA total of 139 NSCLC patients with brain metastases from the Affiliated Cancer Hospital & Institute of Guangzhou Medical University, treated between January 2015 and December 2017 were evaluated retrospectively. The expression level of CADM2 in patients ranged from 1 to 17.2677, with a median of 6.0772. Chi-square analysis showed that CADM2 gene expression level was not significantly associated with gender, age, tumor location, histological subtype, tumor T stage, extracranial metastasis, or smoking status. However, CADM2 expression was notably associated with risk for lymph node metastasis. The results of the Kaplan-Meier analysis showed that high expression [CADM2 messenger RNA (mRNA) ≥6.0772] of CADM2 was markedly associated with poor prognosis. Univariate and multivariate Cox analyses demonstrated that CADM2 was an independent risk factor for survival in NSCLC patients with brain metastases (P<0.05).ConclusionsCADM2 expression is up-regulated and closely associated with disease progression and poor prognosis in NSCLC patients with brain metastases. CADM2 expression warrants special consideration given its potential prognostic significance that might help inform clinical decision making.

Outcomes of changing systemic therapy in patients with relapsed breast cancer and 1 to 3 brain metastases

The development of brain metastases (BMs) in breast cancer (BC) patients remains a challenging complication. Current clinical practice guidelines recommend local treatment of BMs without changing systemic therapy (CST) in patients with stable extracranial disease. We retrospectively investigated the impact of CST (when applicable as per treating physician’s discretion) following the diagnosis and management of oligometastatic (1–3) BMs in patients without extracranial metastases on the progression-free survival time (PFS), and overall survival (OS). Hazard ratios (HRs) were calculated using the Cox proportional hazard model. Among the 2645 patients with BC and BMs treated between 2002 and 2015, 74 were included for analysis. 40.5% of patients had HER2 + disease. Median time from diagnosis of BC to BMs was 17.6 months. 54%, 8%, and 38% of BMs were managed by radiation, craniotomy, or combination, respectively. Following the primary management of BMs, we observed that CST occurred in 26 (35.5%) patients, consisting of initiation of therapy in 13.5% and switching of ongoing adjuvant therapy in 22%. Median PFS was 6.6 months among patients who had CST compared to 7.1 months in those who did not (HR = 0.88 [0.52–1.47], p = 0.62). Median OS was 20.1 months among patients who had CST compared to 15.1 months in those who did not (HR = 0.68 [0.40–1.16], p = 0.16). Upon the successful local management of oligometastatic BMs in patients without extracranial disease, we did not find a significant difference in survival between patients who experienced a change in systemic therapy as compared to those who did not.

Real-world analysis of clinicopathological characteristics, survival rates, and prognostic factors in patients with melanoma brain metastases in China.

We aimed to establish the clinicopathological characteristics and prognostic factors of patients with melanoma brain metastases (MBM) in the East Asian population. Overall survival (OS) and intracranial progression-free survival (PFS) were evaluated by Kaplan-Meier analysis. Cox regression analyses were used to determine prognostic factors associated with intracranial PFS and OS. Between July 2007 and December 2019, 431 patients diagnosed with MBM were enrolled. Mucosal subtype (p = 0.013), LDH level (p = 0.014), the number of MBM ≥ 4 (p = 0.02), local treatment (p < 0.0001) and the use of PD-1 inhibitors (p < 0.0001) were independent prognostic factors for intracranial PFS. Mucosal subtype (p = 0.022), LDH level (p = 0.005), no extracranial metastasis (p = 0.01), concurrent liver metastasis (p = 0.004), local treatment (p = 0.001) and the use of PD-1 inhibitors (p < 0.0001) were independent prognostic factors for OS. Mucosal subtype brain metastases had a poor response to PD-1 inhibitors (p = 0.007), with a shorter intracranial PFS than other subtypes. In BRAF mutation patients with MBM, the first-line BRAF/MEK inhibitor therapy group had an advantage in OS compared to the first-line anti-PD-1 therapy group (p = 0.043). Our findings depict clinical characteristics and prognostic factors of MBM in the East Asian population, suggesting the mucosal subtype as an adverse prognostic and predictive factor for patients with MBM. For BRAF mutation patients with MBM, first-line BRAF/MEK inhibitor therapy may bring a potential survival benefit compared to first-line anti-PD-1 therapy.

Predicting Prognosis of Breast Cancer Patients with Brain Metastases in the BMBC Registry-Comparison of Three Different GPA Prognostic Scores.

Simple SummaryThe incidence of brain metastases from breast cancer is increasing and the treatment is still a major challenge. Several scores have been developed in order to estimate the prognosis of patients with brain metastases by objective criteria. Here, we validated all three published graded-prognostic-assessment (GPA)-scores in a subcohort of 882 breast cancer patients with brain metastases in the Brain Metastases in the German Breast Cancer (BMBC) registry. Although all three available GPA-scores were associated with OS, they all show limitations mainly in predicting short-term (below 3 months) survival but also in long-term (above 12 months) survival. We discuss the test performances of all scores in our work and provide evidence how physicians should use them as a tool to select patients for different treatment options.Several scores have been developed in order to estimate the prognosis of patients with brain metastases (BM) by objective criteria. The aim of this analysis was to validate all three published graded-prognostic-assessment (GPA)-scores in a subcohort of 882 breast cancer (BC) patients with BM in the Brain Metastases in the German Breast Cancer (BMBC) registry. The median age at diagnosis of BM was 57 years. All in all, 22.3% of patients (n = 197) had triple-negative, 33.4% (n = 295) luminal A like, 25.1% (n = 221) luminal B/HER2-enriched like and 19.2% (n = 169) HER2 positive like BC. Age ≥60 years, evidence of extracranial metastases (ECM), higher number of BM, triple-negative subtype and low Karnofsky-Performance-Status (KPS) were all associated with worse overall survival (OS) in univariate analysis (p < 0.001 each). All three GPA-scores were associated with OS. The breast-GPA showed the highest probability of classifying patients with survival above 12 months in the best prognostic group (specificity 68.7% compared with 48.1% for the updated breast-GPA and 21.8% for the original GPA). Sensitivities for predicting 3 months survival were very low for all scores. In this analysis, all GPA-scores showed only moderate diagnostic accuracy in predicting the OS of BC patients with BM.

Poor performance status and brain metastases treatment: who may benefit from the stereotactic radiotherapy?

Poor Performance Status (PS) of cancer patients, defined as PS score 2-3, is an impediment for many drug- and irradiation-based treatments, supported by the trials that exclude subjects with PS < 1. Reports on the benefits of stereotactic radiotherapy (SRT) for brain metastases (BMs) in poor PS patients are scarce. We sought to review the characteristics and survival outcomes of this cohort, to assess who may benefit most from SRT. We retrospectively evaluated 73 patients with PS 2 or 3 (63 and 10 cases) treated with SRT for 150 BMs from 2012 to 2018. Patients' characteristics and post-SRT survival, stratified by concomitant systemic treatment (CST) were assessed using the Kaplan-Meier method (p-value < 0.05). Non-small cell lung cancer was the most frequent primary tumor. Extracranial metastases were present in 86.3% of patients. The median overall survival (mOS) after SRT was estimated as 6.0months (range 0.2-37.7), with 6- and 12-month survival rates of 51.0% and 21.0%, respectively. CST was administrated to 59.7% of patients (immunotherapy, target therapy or chemotherapy). Patients treated with CST presented larger mOS (6.7 vs. 4.4months for patients treated with SRT alone, p = 0.3), and better 6- and 12-month survival rates (59% and 24% vs. 37% and 18% in patients not treated with CST). Survival rate after SRT for BMs in poor performance patients, especially with PS 2, can justify SRT, in particular if an effective systemic treatment is available. Both SRT and CST should be more accessible for these patients in clinical practice.

Abstract PS15-10: Survival outcomes and prognosis for patients with triple negative breast cancer who received stereotactic radiosurgery for brain metastases

Abstract Background: Triple-negative breast cancer (TNBC) has a high propensity for brain metastasis (BM) with poor prognosis. Stereotactic radiosurgery (SRS) has emerged as an effective treatment option for BM. However, clinical outcomes after SRS for BM from TNBC have not been well defined. We evaluated survival outcomes and prognostic factors among TNBC patients who received SRS for BMs.Methods: We retrospectively reviewed 99 patients with TNBC and BM who had received SRS at a single large-volume cancer center from May 2008 through April 2018. For the initial treatment of BM, 73 patients received SRS, 25 received whole-brain radiotherapy (WBRT), and 1 patient received surgery. Endpoints were overall survival (OS) from BM diagnosis, BM progression-free survival (BMPFS) from start of BM treatment, and times to intracranial local and distant failure from start of BM treatment. Both intracranial local and distant failure were considered BM progression. Local failure was defined as an increase in size of any treated lesions on imaging or assessment of treating physicians; enlargement attributable to radiation necrosis or post-radiation change was not counted as local failure. Kaplan-Meier analysis and Cox proportional hazard regression models were used to estimate survival curves and identify prognostic factors.Results: The median follow-up time from BM diagnosis was 12.7 months (95% confidence interval [CI] 1.3–52.1). The median age at BM diagnosis was 52 (range 24-82). The median interval between the diagnosis of primary breast cancer and BM was 25.8 months (95% CI 8.7–120.3). Of the 99 patients, 81 (81.8%) had 1-3 BMs and 18 (18.2%) had &amp;gt;3 BMs at diagnosis. The median OS time for all patients was 13.3 months (95% CI 10.3–16.4), and the cumulative survival rates were 55.1% at 1 year and 29.2% at 2 years. Factors independently associated with increased risk of death in multivariate analysis were Karnofsky performance score (KPS) ≤70 (p=0.01) and uncontrolled extracranial metastasis at BM diagnosis (p=0.05). No difference was found in OS according to type of initial treatment for BMs. Of the initial 99 patients, 12 were excluded from the evaluation of BMPFS, local and distant failure for missing follow-up imaging after initial treatment. The median BMPFS time was 7.2 months (95% CI 5.1–9.3). Of the 87 evaluable patients, 23 (26.4%) developed local recurrence after initial treatment, and among these 10 of 61 patients (16.4%) had received SRS and 13 of 25 patients (52%) had received WBRT. Patients initially treated with SRS had longer time to local failure than WBRT (50th percentile not reached vs. median 14.0 months, p=0.001). Multivariate analysis showed higher risk of local failure for patients who initially received WBRT versus SRS (hazard ratio [HR] 3.4, p=0.005). Forty-nine of 87 patients (56.3%) developed distant brain recurrence after initial treatment, and among these 35 of 61 patients (57.4%) had received SRS and 14 of 25 patients (56%) had received WBRT. No difference in risk of distant brain failure was found for patients initially treated with SRS versus WBRT (p=0.24). No difference was found in time to develop distant failure after initial treatment with SRS (median 18.4 months) versus WBRT (median 12.8 months, p=0.24).Conclusion: Patients with BM from TNBC had a median OS time of 13.3 months and a BMPFS time of 7.2 months. KPS≤70 and uncontrolled extracranial disease at the time of BM diagnosis were independent prognostic factors that increase risk of death. Patients initially treated with SRS had a longer time to develop intracranial local failure than those initially given WBRT, and this may be related to patient selection. Further prospective studies of larger numbers of patients with BM from TNBC are needed for a more accurate comparison of treatment modalities. Citation Format: Ran An, Yan Wang, Fuchenchu Wang, Chao Gao, Akshara Singareeka Raghavendra, Diana Amaya, Nuhad K Ibrahim, Jing Li. Survival outcomes and prognosis for patients with triple negative breast cancer who received stereotactic radiosurgery for brain metastases [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS15-10.

Abstract PS7-87: Incidence, treatment and survival of patients with brain metastases at initial metastatic breast cancer diagnosis: A real-world experience in national cancer center, China

Abstract Background: To characterize the incidence, treatment and survival of patients with brain metastases at initial diagnosis of metastatic breast cancer (MBC) in China. Methods: The China National Cancer Center database was used to identify 2087 MBC patients diagnosed between 2003 to 2015. Clinicopathological features, treatment and survival information were extracted. Multivariable logistic and Cox regression were performed to determine factors predictive of brain metastases at MBC diagnosis and survival, respectively. Results: Brain metastases occurred in ninety patients (4.3%) at MBC diagnosis, and in 27 patients (2.5%), 42 patients (7.2%) and 21 patients (5.2%) with hormone receptor positive, human epidermal growth factor receptor 2 negative (HR+HER2-), HER2-positive and triple negative breast cancer (TNBC), respectively. HER2-positive subtype (OR = 2.38; 95% CI 1.40 -4.04; p &amp;lt;0.0001), TNBC subtype (OR = 1.89; 95% CI 1.02-3.51; p =0.005), and metastases to all three sites of bone, liver and lungs (OR = 3.23; 95% CI 1.52-6.87; p =0.002) were shown to increase the risk of BM at MBC diagnosis. Median survival after BM was 23.7 months. First-line tyrosine kinase inhibitors (TKI) improved survival compared to trastuzumab-based regimen (44.9 vs 35.4 months, p=0.09). Factors that independently decreased BM death risk were ECOG&amp;lt;2, brain metastases only and multidisciplinary treatment. Conclusion: HER2-positive and TNBC subtypes have a higher incidence of BM at initial MBC diagnosis. Brain screening might be considered in patients with HER2-positive or triple-negative diseases or with extensive extracranial metastases. First-line TKI and multidisciplinary treatment helped to extend survival. Citation Format: Yiqun Li, Qiao Li, Hongnan Mo, Xiuwen Guan, Shaoyan Lin, Zijing Wang, Yimeng Chen, Ye Zhang, Dainan Zhang, Shanshan Chen, Ruigang Cai, Jiayu Wang, Yang Luo, Ying Fan, Peng Yuan, Pin Zhang, Qing Li, Fei Ma, Binghe Xu. Incidence, treatment and survival of patients with brain metastases at initial metastatic breast cancer diagnosis: A real-world experience in national cancer center, China [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-87.

Clinical Outcomes and Prognostic Factors in HER-2 Positive Breast Cancer with Brain Metastasis: A Single-centre Experience.

To determine the characteristics and prognosis of brain metastasised HER-2 positive breast cancer (BC) patients. Descriptive study. Ankara Oncology Training and Research Hospital, Turkey between 2000 and 2019. HER-2 positive BC patients were analysed retrospectively and 105 patients were included in the study. Age 18 years and over, HER-2 positive BC, with BM (brain metastases) were the inclusion criteria. Patients with secondary malignancies, those with missing data, and irregular follow-up were excluded from the study. The age, type of treatment, Eastern Cooperative Oncology Group Performance Status (ECOG PS) score, BM date, and the last contact date of the patients were obtained from the hospital records. The Kaplan-Meier method was used to determine the time to BM and OS. Independent factors affecting OS and time to BM were determined using the Cox regression model. Patients with ECOG PS score of 0-1 at the time of the BM had 19 months median overall survival (OS), while patients with ECOG PS score of 2 had 8 months (p <0.01). Median OS after BM was 32 and 14 months for patients with one BM and patients with multiple BM, respectively (p <0.01). Multivariate cox regression analyses revealed that time to progression of BM was shorter in patients with high-grade tumors compared to patients with low-grade tumors (p= 0.048), and in patients with de-novo metastasis compared to patients without de-novo metastasis (p= 0.003). Conclusıon: Tumor grade and de-novo metastasis (extracranial metastasis at the time of diagnosis) are independent predictive factors that may cause the earlier occurrence of BM and affect mortality in BC patients. Key Words: Brain metastasis, Breast cancer, HER-2 positive, Metastasis.

Brain Metastases from Uterine Cervical and Endometrial Cancer.

Simple SummaryThis review investigated the prevalence, clinical characteristics, clinical presentation, diagnosis, treatment, and prognosis of patients with brain metastases from uterine cervical carcinoma (CC) and uterine endometrial carcinoma (EC). The findings of this review indicate the factors that can facilitate better treatment selection and, consequently, better outcomes in patients with CC and EC.Reports on brain metastases (BMs) from uterine cervical carcinoma (CC) and uterine endometrial carcinoma (EC) have recently increased due to the development of massive databases and improvements in diagnostic procedures. This review separately investigates the prevalence, clinical characteristics, clinical presentation, diagnosis, treatment, and prognosis of BMs from CC and uterine endometrial carcinoma EC. For patients with CC, early-stage disease and poorly differentiated carcinoma lead to BMs, and elderly age, poor performance status, and multiple BMs are listed as poor prognostic factors. Advanced-stage disease and high-grade carcinoma are high-risk factors for BMs from EC, and multiple metastases and extracranial metastases, or unimodal therapies, are possibly factors indicating poor prognosis. There is no “most effective” therapy that has gained consensus for the treatment of BMs. Treatment decisions are based on clinical status, number of the metastases, tumor size, and metastases at distant organs. Surgical resection followed by adjuvant radiotherapy appears to be the best treatment approach to date. Stereotactic ablative radiation therapy has been increasingly associated with good outcomes in preserving cognitive functions. Despite treatment, patients died within 1 year after the BM diagnosis. BMs from uterine cancer remain quite rare, and the current evidence is limited; thus, further studies are needed.

Recursive Partitioning Analysis of Systemic Therapy after Radiotherapy in Patients with Brain Metastases

Purpose: The purpose of this study was to identify factors associated with the initiation or continuation of systemic treatment after brain irradiation. The outcome of interest was a utilization rate of at least 75%, given that active extracranial disease is common in patients with brain metastases. If left untreated, extracranial disease limits survival, regardless of successful local treatment of the brain metastases. In this context, systemic therapy has been shown to improve survival, e.g., after whole-brain radiotherapy. Patients and Methods: The study included 185 patients with active extracranial disease, 60% of whom received systemic therapy. Results: Survival from the start of brain irradiation was longest in patients who received additional immune checkpoint inhibitors, endocrine treatment, or anti-HER-2 drugs. After uni- and multivariate analyses, Eastern Cooperative Oncology Group performance status (PS) was selected as the first prediction criterion in the recursive partitioning analysis (RPA) decision tree analysis. RPA was successful for patients with PS 0–1, but patients with PS 2 had lower treatment utilization rates (maximum 60–70%, with a disease-dependent impact of age and LabBM score [blood test results]). The highest utilization rates were observed in (1) patients with PS 0 and (2) those with breast cancer, small-cell lung cancer, or lung adenocarcinoma with PS 1. Conclusions: These results inform the multidisciplinary discussion and treatment planning for the common scenario of simultaneous intra- and extracranial metastases.