Development Of Central Nervous System Metastases Research Articles

The 31-GEP to identify patients with localized cutaneous melanoma at the highest risk of metastasis to the central nervous system.

9530 Background: Cutaneous melanoma (CM) metastasis to the central nervous system (CNS) has a poor prognosis; however, treatment of CNS metastasis while asymptomatic is associated with better outcomes. CNS imaging is not routinely recommended for patients with early-stage CM (i.e., AJCC stage I–II), yet ˜14% of patients with stage II melanoma will develop CNS metastases. The 31-gene expression profile test (31-GEP) identifies patients at a low (Class 1A), intermediate (Class 1B/2A), or high risk (Class 2B) of tumor recurrence and metastasis. We evaluated the association of CNS metastasis with the 31-GEP test result for the purpose of directing CNS-directed imaging to detect metastasis earlier and, thus, improve outcomes. Methods: A retrospective analysis of patients clinically tested with the 31-GEP from 2013-2017. Patients were included in the study if they had clinical or pathological AJCC stage I-II CM (n=1,662). Kaplan-Meier analysis was used to estimate 5-year recurrence-free survival (RFS), and the log-rank test was used to compare survival between groups. Patients with non-CNS metastasis were censored at the time of recurrence. Univariate analysis to identify predictors of CNS metastasis was performed for tumor location, mitotic rate, Breslow thickness, ulceration status, tumor-infiltrating lymphocytes, age, sex, regression, lymphovascular invasion, tumor subtype, and 31-GEP results. Only significant (p<0.01) factors in univariate analysis were included in Cox multivariable analysis. Results: Median follow-up time was 4.6 years (range: 0.02-14.5 years). Patients with a CNS metastasis tended to have thicker tumors (median 1.1 vs. 0.8, p=0.003), higher mitotic rate/mm2 (median 2.5 vs. 1.0, p<0.001) and a higher proportion of males (73% vs. 55%, p=0.03) than patients that did not develop CNS metastasis. Patients with a Class 2B result were significantly more likely to develop CNS metastasis (7.4% [15/202]) relative to patients with a Class 1B/2A (1.7% [5/291]) or Class 1A (0.9% [10/1,169], p<0.001) 31-GEP result. Patients with a Class 2B result had significantly lower 5-year RFS than patients with a Class 1B/2A or Class 1A result (91.6% vs. 98.2% vs. 99.1%, p<0.001) and had shorter times to CNS metastases (1.5 yrs. vs. 4.2 yrs. vs. 3.4 yrs. p<0.001). In multivariable analysis, only the 31-GEP Class 2B (HR=9.42, p<0.001) result was a significant predictor of CNS metastasis; mitotic rate, Breslow thickness, and ulceration were not significantly predictive. Conclusions: Under multivariable analysis, the 31-GEP was the only significant predictor of CNS metastasis, and CNS metastasis occurred early (1.5 yrs). Patients with early-stage I-II CM and a Class 2B result should be considered for CNS imaging to enable asymptomatic detection of CNS metastasis and, thus, improve survival relative to symptomatic CNS metastasis.

HER2 status in recurrent/metastatic androgen receptor overexpressing salivary gland carcinoma patients.

Overexpression of human epidermal growth factor receptor type 2 (HER2) occurs in almost 25-30% of androgen receptor (AR)-positive salivary gland carcinomas (SGCs), notably salivary duct carcinoma (SDC) and adenocarcinoma not otherwise specified (NOS). In the last years, several studies have reported the clinical benefit of HER2 directed therapies in this setting. This work aims at describing the natural history of AR-positive recurrent/metastatic (R/M) SGC patients, based on HER2 amplification status. Consecutive R/M AR-positive SGC patients accessing our Institution from 2010 to 2021 were analyzed. Descriptive statistics and survival analyses were performed to present the clinical characteristics of the selected patients and the outcomes, based on HER2 status. A specific focus was dedicated to patients developing metastases to the central nervous system (CNS). Seventy-four R/M AR-positive SGC patients (72 men) were analyzed. Median follow-up was 36.18 months (95% CI 30.19-42.66). HER2 status was available in 62 cases (84%) and in 42% the protein was overexpressed (HER2+). Compared with patients with HER2- SGCs, in patients with HER2+ disease, HR for disease recurrence was 2.97 (95% CI 1.44-6.1, p=0.003), and HR for death from R/M disease was 3.22 (95% CI 1.39-7.49, p=0.007). Moreover, the HER2+ group showed a non-significant trend towards a higher prevalence of CNS metastases (40% vs. 24%, p=0.263). Patients developing CNS metastases had shorter survival than those who did not; at bivariate analysis (covariates: CNS disease and HER2 status), HER2 status demonstrated its independent prognostic significance. In our patient population, HER2 amplification was a negative prognostic factor, and it was associated with a non-statistically significant higher risk of developing CNS metastasis. Further studies are needed to explore the potential clinical benefit of tackling the two biological pathways (AR and HER2) in patients affected by this rare and aggressive malignancy.

Risk and tropism of central nervous system (CNS) metastases in patients with stage II and III cutaneous melanoma.

Recent data suggest that patients with stage III melanoma are at high risk for developing central nervous system (CNS) metastases. Because a subset of patients with stage II melanoma experiences worse survival outcomes than some patients with stage III disease, the authors investigated the risk of CNS metastasis in stage II melanoma to inform surveillance guidelines for this population. The authors examined clinicopathologic data prospectively collected from 1054 patients who had cutaneous melanoma. The χ2 test, the cumulative incidence, and Cox multivariable regression analyses were performed to evaluate the association between baseline characteristics and the development of CNS metastases. Patients with stage III melanoma had a higher rate of developing brain metastases than those with stage II melanoma (100 of 468 patients [21.4%] vs. 82 of 586 patients [14.0%], respectively; p =.002). However, patients who had stage IIC melanoma had a significantly higher rate of isolated first recurrences in the CNS compared with those who had stage III disease (12.1% vs. 3.6%; p=.002). The risk of ever developing brain metastases was similarly elevated for patients who had stage IIC disease (hazard ratio [HR], 3.16; 95% CI, 1.77-5.66), stage IIIB disease (HR, 2.83; 95% CI, 1.63-4.91), and stage IIIC disease (HR, 2.93; 95% CI, 1.81-4.74), and the risk was highest in patients who had stage IIID disease (HR, 8.59; 95% CI: 4.11-17.97). Patients with stage IIC melanoma are at elevated risk for first recurrence in the CNS. Surveillance strategies that incorporate serial neuroimaging should be considered for these individuals until more accurate predictive markers can be identified.

Integrated genomic and DNA methylation analysis of patients with advanced non-small cell lung cancer with brain metastases

BackgroundBrain metastasis is a common and lethal complication of non-small cell lung cancer (NSCLC). It is mostly diagnosed only after symptoms develop, at which point very few treatment options are available. Therefore, patients who have an increased risk of developing brain metastasis need to be identified early. Our study aimed to identify genomic and epigenomic biomarkers for predicting brain metastasis risk in NSCLC patients.MethodsPaired primary lung tumor tissues and either brain metastatic tissues or cerebrospinal fluid (CSF) samples were collected from 29 patients with treatment-naïve advanced NSCLC with central nervous system (CNS) metastases. A control group comprising 31 patients with advanced NSCLC who died without ever developing CNS metastasis was also included. Somatic mutations and DNA methylation levels were examined through capture-based targeted sequencing with a 520-gene panel and targeted bisulfite sequencing with an 80,672 CpG panel.ResultsCompared to primary lung lesions, brain metastatic tissues harbored numerous unique copy number variations. The tumor mutational burden was comparable between brain metastatic tissue (P = 0.168)/CSF (P = 0.445) and their paired primary lung tumor samples. Kelch-like ECH-associated protein (KEAP1) mutations were detected in primary lung tumor and brain metastatic tissue samples of patients with brain metastasis. KEAP1 mutation rate was significantly higher in patients with brain metastasis than those without (P = 0.031). DNA methylation analysis revealed 15 differentially methylated blocks between primary lung tumors of patients with and without CNS metastasis. A brain metastasis risk prediction model based on these 15 differentially methylated blocks had an area under the curve of 0.94, with 87.1% sensitivity and 82.8% specificity.ConclusionsOur analyses revealed 15 differentially methylated blocks in primary lung tumor tissues, which can differentiate patients with and without CNS metastasis. These differentially methylated blocks may serve as predictive biomarkers for the risk of developing CNS metastasis in NSCLC. Additional larger studies are needed to validate the predictive value of these markers.

Treatment and Prevention of Brain Metastases in Small Cell Lung Cancer.

Central nervous system (CNS) metastasis will develop in 50% of small cell lung cancer (SCLC) patients throughout disease course. Development of CNS metastasis poses a particular treatment dilemma due to the accompanied cognitive changes, poor permeability of the blood-brain barrier to systemic therapy and relatively advanced state of disease. Survival of patients with untreated SCLC brain metastases is generally <3 months with whole brain radiotherapy used as first-line management in most SCLC patients. To prevent development of CNS metastasis prophylactic cranial irradiation (PCI) is recommended in limited stage disease, after response to chemotherapy and radiation, while PCI may be considered in extensive stage disease after favorable response to upfront treatment. Neurocognitive toxicity with whole brain radiotherapy and PCI is a concern and remains difficult to predict. The mechanism of toxicity is likely multifactorial, but a potential mechanism of injury to the hippocampus has led to hippocampal sparing radiation techniques. Treatment of established non-small cell lung cancer CNS metastases has increasingly focused on using stereotactic radiotherapy (SRS) and it is tempting to extrapolate these results to SCLC. In this review, we explore the evidence surrounding the prediction, prevention, detection, and treatment of CNS metastases in SCLC. We further review whether existing evidence supports extrapolating less toxic treatments to SCLC patients with CNS metastases and discuss trials that may shed more light on this question.

European and US Real-World Treatment Patterns in Patients with Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer: A Retrospective Medical Record Review.

BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the preferred first-line (1L) therapy for EGFR mutation-positive (EGFRm) advanced/metastatic non-small cell lung cancer (NSCLC).ObjectiveOur objective was to describe real-world treatment patterns and T790M testing practices in patients with 1L disease progression (Europe/USA) following treatment with first- or second-generation EGFR-TKIs.MethodsThis was a retrospective, non-interventional medical record review of patients with EGFRm locally advanced/metastatic NSCLC from routine clinical practice (EGFR-TKI initiation: 1 January 2015 to 31 December 2017; follow-up: last available medical record). Endpoints were demographic/clinical characteristics, incidence of central nervous system (CNS) metastases/leptomeningeal disease, second-line (2L) treatment, T790M mutation testing, and osimertinib treatment prevalence.ResultsAmong 469 patients, 73% (n = 341/469) progressed on 1L EGFR-TKI treatment. Of those who progressed, 74% (n = 252/341) were tested for T790M, with 50% (n = 126/252) testing positive; 75% (n = 94/126) of T790M-positive patients received osimertinib (mostly 2L). Of the patients with progression, 24% (n = 83/341) did not receive 2L treatment, and 88% (n = 73/83) of these patients died. At diagnosis of advanced disease, 9% of patients (n = 41) had CNS metastases; at EGFR-TKI initiation, 14% of patients (n = 68) had CNS metastases. Over the study period, 11% of patients (n = 42) developed CNS metastases not detected at NSCLC diagnosis.ConclusionsRates of resistance mutation testing and subsequent utilization of recommended 2L therapies could be improved. As more targeted therapies are developed, it will be crucial to improve the molecular testing rates to ensure patients receive appropriate, effective, and timely treatment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40801-021-00261-8.

Impact of extracranial disease status on survival after initial central nervous system (CNS) involvement and radiation therapy in HER2+ breast cancer brain metastases (BCBM).

1041 Background: BCBMs are very common in metastatic HER2+ breast cancer. CNS-directed local therapy is the gold standard for treatment, followed by systemic HER2-targeted therapies. In patients with HER2+ BCBM and stable extracranial disease (ECD), consensus guidelines recommend continuing current systemic therapy after local therapy. Our goal was to determine the implications of ECD status at time of HER2+ BCBM first CNS involvement on outcomes including intracranial progression-free survival (PFS1) and overall survival (OS). Methods: Retrospective analysis was performed on data extracted from 77 patients with HER2+ BCBM who received CNS radiation at Duke between 2006 and 2020 following initial documentation of CNS involvement. Demographics, dates of metastatic and intracranial diagnosis, ECD status at first CNS involvement, systemic therapy, and outcomes were collected. The primary endpoint was PFS1 defined as the time from first CNS radiation to the subsequent documentation of intracranial progression (RANO-BM). OS was defined as time from first CNS radiation and first metastatic disease to date of death or last known alive. ECD status was defined by RECIST1.1 from systemic staging scans within 30 days of first CNS involvement. Results: In this patient cohort of HER2+ BCBMs undergoing CNS radiation at first CNS involvement, &gt;50% of patients had extracranial disease control: no ECD (25%) or stable/responding disease (31%). 52% of patients’ tumors were ER+. Median age was 50 years (range 27 – 75). Most patients (58%) developed first CNS involvement during adjuvant or first/second line metastatic therapy. For first CNS radiation, 49% received SRS and 48% WBRT. All patients with no ECD presented with isolated CNS disease as first metastatic presentation. Median OS in this cohort from initial metastatic disease to death was markedly worse for patients with no ECD (25.3m, 95% CI: 16.8 to 35.3) compared to those with progressive or stable/responding ECD (48.8m, 95% CI: 28.1 to 65; and 52.9 months, 95% CI: 43.7 to 73.3, respectively; p=0.03). Median OS from first CNS involvement to death was not statistically different amongst groups. This analysis did not detect median PFS1 differences based on ECD after first CNS radiation: progressive ECD (6.3m), no ECD (8.7m), or stable/responding ECD (10.6m) (p=0.13), though clinically meaningful differences were observed. Conclusions: Patients with isolated HER2+ BCBM with no ECD at the time of their initial CNS involvement (25% of population) have substantially worse OS compared to patients who present with ECD and develop CNS metastases later in their disease course. This population with isolated CNS disease at metastatic presentation deserves investigation of novel treatment algorithms, including earlier introduction of brain penetrable HER2-targeted agents.

Treatment patterns, testing practices, and outcomes in the pre-FLAURA era for patients with EGFR mutation-positive advanced NSCLC: a retrospective chart review (REFLECT).

Introduction:For epidermal growth factor receptor mutation-positive (EGFRm) non-small-cell lung cancer (NSCLC), EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are the preferred first-line (1 L) treatment in the advanced setting. Osimertinib, a third-generation EGFR-TKI, received full approval in 2017 for second-line (2 L) treatment of EGFR T790M-positive NSCLC. The REFLECT study characterizes real-world treatment/testing patterns, attrition rates, and outcomes in patients with EGFRm advanced NSCLC treated with 1 L first-/second-generation (1G/2G) EGFR-TKIs before 1 L osimertinib approval.Methods:Retrospective chart review (NCT04031898) of European/Israeli adults with EGFRm unresectable locally advanced/metastatic NSCLC, initiating 1 L 1G/2G EGFR-TKIs 01/01/15–30/06/18 (index date).Results:In 896 patients (median follow-up of 21.5 months), the most frequently initiated 1 L EGFR-TKI was afatinib (45%). Disease progression was reported in 81%, including 10% (86/896) who died at 1 L. By the end of study, most patients discontinued 1 L (85%), of whom 33% did not receive 2 L therapy. From index, median 1 L real-world progression-free survival was 13.0 (95% confidence interval (CI): 12.3–14.1) months; median overall survival (OS) was 26.2 (95% CI: 23.6–28.4) months. 71% of patients with 1 L progression were tested for T790M; 58% were positive. Of those with T790M, 95% received osimertinib in 2 L or later. Central nervous system (CNS) metastases were recorded in 22% at index, and 15% developed CNS metastases during treatment (median time from index 13.5 months). Median OS was 19.4 months (95% CI: 17.1–22.1) in patients with CNS metastases at index, 24.8 months (95% CIs not available) with CNS metastases diagnosed during treatment, and 30.3 months (95% CI: 27.1, 33.8) with no CNS metastases recorded.Conclusion:REFLECT is a large real-world study describing treatment patterns prior to 1 L osimertinib availability for EGFRm advanced NSCLC. Given the attrition rates highlighted in the study and the impact of CNS progression on outcomes, offering a 1 L EGFR-TKI with CNS penetration may improve patient outcomes in this treatment setting.

Survival outcomes and symptomatic central nervous system (CNS) metastasis in EGFR-mutant advanced non-small cell lung cancer without baseline CNS metastasis: Osimertinib vs. first-generation EGFR tyrosine kinase inhibitors

ObjectivesCentral nervous system (CNS) metastases are common complications in epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer (NSCLC) treated with EGFR-tyrosine kinase inhibitors (TKIs). However, for patients without baseline CNS metastasis, data regarding the incidence of symptomatic CNS metastasis with EGFR-TKI treatment and its risk factors are still rare. Materials and MethodsPatients with EGFR-mutant advanced NSCLC without baseline CNS metastasis who are receiving first- and/or third-generation EGFR-TKIs were included. Overall survival (OS), cumulative incidence of symptomatic CNS metastasis upon treatment failure, and their risk factors were evaluated. ResultsThere were 813 patients enrolled, with 562, 106, and 32 received first-line gefitinib, erlotinib, and osimertinib, respectively, while 113 received second-line osimertinib. At a median follow-up of 18.1 months, the median OS was 45.5 months. There were 38 patients developed symptomatic CNS metastases. Osimertinib-treated patients tended to have a lower risk of CNS metastases compared with those treated with first-generation EGFR-TKIs (p = 0.059). However, the cumulative incidence curves of symptomatic CNS metastasis tended to reach a plateau after approximately 3 years regardless of which generation was used, and incidences beyond that period were similar in the two groups. Patients with L858R mutation exhibited a higher risk of developing CNS metastasis than patients with 19del mutation (p = 0.001). Interestingly, the presence of baseline neuroimaging was not associated with the risk of developing CNS metastasis or OS. ConclusionCompared with first-generation EGFR-TKIs, osimertinib can delay but not prevent the development of symptomatic CNS metastasis. L858R mutation is an independent risk factor for CNS metastasis.

Preventing Symptomatic Central Nervous System Metastasis in EGFR-Mutant Advanced Non-Small Cell Lung Cancer: Comparison of First- and Third-Generation EGFR Tyrosine Kinase Inhibitors

Epidermal growth factor receptor (EGFR)-Tyrosine kinase inhibitors (TKIs) are standard treatment for EGFR-mutant advanced non-small cell lung cancer (NSCLC). Central nervous system (CNS) metastases, including brain parenchymal metastasis (BM) and leptomeningeal metastasis (LM), are common in the EGFR-TKI treatment failure. The different generation EGFR-TKIs have variant potencies of penetrating into the blood-brain-barrier. This study aims to compare the efficacy of first- and third-generation EGFR-TKIs in preventing symptomatic CNS metastases and to identify their risk factors. Patients with EGFR-mutant advanced NSCLC without baseline CNS metastasis and receiving EGFR-TKI treatment were selected. The cumulative incidence of symptomatic CNS metastasis upon treatment failure, and overall survival (OS) of patients who developed CNS metastasis, were measured from the initiation of EGFR-TKIs, using the Kaplan-Meier method. The risk factors for CNS metastasis, and predictors of OS were identified using Cox proportional hazard regression. 935 patients from two academic medical centers were enrolled, with 633, 143 and 35 receiving first-line gefitinib, erlotinib and osimertinib, respectively, the remain 124 patients received osimertinib for acquired T790M mutation. On baseline, 19del, L858R and uncommon mutations were detected in 427, 386 and 122 patients, respectively. At the median follow-up of 10 months, treatment failure was observed in 517 patients, of whom 45 developed symptomatic CNS metastasis, with 37 developing BM, 4 LM, and 4 with both BM and LM. The 1-year, 2-year and 3-year cumulative rate of symptomatic CNS metastasis, were 4.2%, 7.9% and 14.4%, respectively. There was no significant difference in symptomatic CNS metastasis among patients receiving gefitinib or erlotinib, while osimertinib treatment was found to have a lower rate compared to first-generation TKIs (HR 0.45; 95%CI 0.20-0.99, p = 0.049). However, cumulative rate of symptomatic CNS metastasis at 3-year in osimertinib group reached the similar level as the first-generation TKIs. Of interest, the curves of CNS metastasis tend to reached a plateau after three years no matter which generation was used. Patients harboring L858R mutation were at a higher risk of developing CNS metastasis, than other mutations (p = 0.003). Among the 45 patients with CNS metastasis, median OS was 22 months, and patients with single cranial lesion had a significant longer OS (p = 0.011). Compared with first-generation EGFR TKIs, osimertinib significantly delays the development of symptomatic CNS metastasis in the EGFR-mutant advanced NSCLC without baseline CNS metastasis. L858R mutation is a risk factor for CNS failure during EGFR-TKIs treatment.

Central nervous system metastases in breast cancer: the impact of age on patterns of development and outcome.

The purpose of this study is to explore differences in the pattern and outcome of central nervous system (CNS) involvement in breast cancer by age at diagnosis. A retrospective database of a tertiary cancer center yielded 174 consecutive patients with breast cancer who were diagnosed with CNS metastases in 2006-2019. Data on histopathology, characteristics of CNS involvement, treatments, and survival (at three time points during the disease course) were compared between patients aged ≤ 45 and > 45years. Pearson Chi-square or Fisher exact test and Kaplan-Meier survival curves with log-rank test were used for statistical analyses. Study population was divided according to age at diagnosis of breast cancer. 65 patients were ≤ 45years old and 109 patients > 45years old. The younger group was characterized by longer median overall survival (117.1months vs 88months, p = 0.017) and longer interval between breast cancer diagnosis to development of CNS metastases (97.4months vs 75.9months, p = 0.026). Median survival after development of CNS disease was not significantly different (18.7months vs 11.1months, p = 0.341), although it was significantly longer in younger patients within the subgroup of patients with triple-negative disease (22.5 vs 7.9months, p = 0.033). There were no between-group differences in number, location, and clinical presentation of CNS metastases or in systemic and CNS-directed treatment approaches. While the presentation of CNS involvement was similar between the different age groups, younger patients had significantly longer CNS-free interval and longer overall survival, and for the subgroups of triple-negative patients, younger age at breast cancer diagnosis was associated with longer survival after diagnosis of CNS disease.

Survival outcomes in an older US population with advanced melanoma and central nervous system metastases: SEER-Medicare analysis.

BackgroundCentral nervous system (CNS) metastasis is common in advanced melanoma patients. New treatment options have improved overall prognosis, but information is lacking for patients with CNS metastases. We investigated treatment patterns and survival outcomes in older melanoma patients with and without CNS metastases.MethodsA retrospective analysis of SEER‐Medicare, a population‐based linked database, was undertaken in patients aged > 65 years with advanced melanoma diagnosed from 2004 to 2011 and followed until 2013.ResultsA total of 2522 patients were included. CNS metastases were present in 24.8% of patients at initial metastatic diagnosis; 16.5% developed CNS metastases during follow‐up. Chemotherapy was the most common treatment regardless of CNS metastases. Overall survival (OS) was better for patients without CNS metastases (median, 9.5 months; 95% confidence interval [CI], 8.8‐10.2) vs patients with CNS metastases (3.63 months; 95% CI, 3.4‐3.9). Among patients with CNS metastases, median OS for targeted therapy, immunotherapy, and chemotherapy was 6 (95% CI, 2.5‐9.6), 5.5 (95% CI, 3.8‐7.5), and 4.5 (95% CI, 3.8‐5.4) months, respectively, vs 2.4 (95% CI, 2.1‐2.7) and 2.1 (95% CI, 1.8‐2.7) months for local radiotherapy and no treatment, respectively. Stereotactic radiosurgery demonstrated higher OS vs whole‐brain radiation therapy (median, 4.98 [95% CI, 3.5‐7.5] vs 2.4 [95% CI, 2.1‐2.7] months).ConclusionPatients with CNS metastases from melanoma remain a population with high unmet medical need despite recent advances in treatment. Systemic treatments (eg, BRAF‐targeted therapy and immunotherapy) and stereotactic radiosurgery demonstrated meaningful but modest improvements in OS. Further explorations of combinations of radiotherapy, BRAF‐targeted therapies, and immunotherapies are needed.

Abstract P3-08-41: Central nervous system metastases in breast cancer: The impact of age on patterns of development and outcome

Abstract Background: Breast cancer is the second most common cause of central nervous system (CNS) metastasis, leading to a significant decrease in survival rate. High risk groups for CNS involvement include younger age, human epidermal growth factor 2 (HER2) over-expression, estrogen receptor (ER) and progesterone receptor (PR) negativity, high histologic grade, and presence of systemic metastases. Young age at diagnosis of breast cancer is associated with more aggressive biological behavior and worse prognosis than in the elderly. However, data are limited regarding CNS involvement in this group of patients. Although it could be expected that younger patients would also have a poor prognosis after the diagnosis of CNS metastases, earlier studies have demonstrated conflicting results, some with favorable outcomes for this unique group. In this study we aimed to explore the differences in the patterns and outcome of CNS involvement according to age at diagnosis of breast cancer (≤45 years vs. &amp;gt;45 years). Methods: A retrospective database of consecutive breast cancer patients who were treated in our institute and were diagnosed with CNS metastases during 2006-2019 was generated. Data analyzed included age at diagnosis of breast cancer, age at diagnosis of CNS involvement, histopathological factors (histology, grade, hormone receptor and HER2 status), treatments given before and after CNS involvement, characteristics of CNS involvement (location, number of brain deposits, clinical manifestations), overall survival, time to CNS progression, and survival after diagnosis of CNS disease. Results: Study cohort was comprised of 174 patients: 65 patients were age≤45 and 109 patients were older than 45 at breast cancer diagnosis. The percentage of patients with triple-negative breast cancer was higher among the younger age group (24.6% vs. 14.7%). Median overall survival from breast cancer diagnosis was significantly longer for younger patients [117.1 months (95% CI 67.2-167) vs. 88 months (95% CI 65.6-110.4), p=0.017]. Median time from breast cancer diagnosis to development of CNS metastases was also significantly longer in the younger age group [58.1 months (95% CI 46.5-69.6) vs. 37.5 months (95% CI 22.9-52.2), p=0.021]. Median survival as measured from time of CNS involvement was 18.7 months (95% CI 10.8-26.6) in the younger group vs. 11.1 months (95% CI 7.8-14.5) in the older patients (p=0.341). Survival of patients with triple-negative breast cancer from time of CNS metastases diagnosis was significantly longer for the younger age group [22.5 months (95% CI 1.2-43.8) vs. 7.9 months (95% CI .77-15.1), p=0.033]. The number, location and clinical presentation of CNS metastases were not statistically different between the two groups. Systemic and CNS-directed treatment approaches were also similar. Conclusion: While the presentation of CNS metastasis was similar between the different age groups, younger patients had significantly longer CNS-free interval and longer overall survival. Numerically, after diagnosis of CNS involvement younger patients had longer survival, but the difference was statistically significant only for patients with triple-negative disease. Citation Format: Matan Ben-Zion Berliner, Shlomit Yust-Katz, Inbar Lavie, Alexandra Amiel, Dalia Zoref, Daniel Hendler, Hadar Goldvaser, Michal Sarfaty, Ofer Rotem, Olga Ulitsky, Tali Siegal, Victoria Neiman, Rinat Yerushalmi. Central nervous system metastases in breast cancer: The impact of age on patterns of development and outcome [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-41.

Central Nervous System Metastasis in Patients With Urothelial Carcinoma: Institutional Experience and a Comprehensive Review of the Literature.

Central nervous system (CNS) metastasis in patients with urothelial carcinoma (UC) is uncommon and poorly understood. We aimed to explore the clinical behavior and outcomes of this unique patient population. We performed a retrospective analysis of patients with UC and CNS metastasis, treated in our institution (2006-2018), along with an exploratory patient-point meta-analysis of a similar patient population derived from a comprehensive literature review. Data regarding diagnosis, management, and outcomes were extracted. Overall survival, time to CNS metastasis (TTCM), and residual survival (RS) from CNS involvement to death were calculated (Kaplan-Meier method). Cox regression was used for testing key clinicopathologic associations. We identified 20 "institutional" and 154 "literature" patients with adequate data granularity for analysis. Median TTCM was 17.7 (institutional cohort) and 10 (literature cohort) months. Most patients who developed CNS metastases had previous non-CNS metastasis (15/20 [75%] and 103/154 [67%], respectively). CNS lesions without previous history of metastasis were identified in 5/20 (25%) and 33/154 (21%) cases and those patients had a shorter TTCM. CNS lesions in the absence of known UC history were also documented in 18/154 (12%) literature cases. Multifocal CNS disease was associated with shorter RS in both cohorts in univariate, but not multivariate, analysis. We observed a variability in disease presentation and course, with a subset of patients showing an early predilection for CNS insult, potentially reflecting a diverse underlying biology. Genomic profiling studies, elucidating the molecular landscape, and driving future treatments should be considered in this setting.

Impact of breast cancer molecular subtypes on the incidence, kinetics and prognosis of central nervous system metastases in a large multicentre real-life cohort

BackgroundMetastatic breast cancer (MBC) behaviour differs depending on hormone receptors (HR) and human epidermal growth factor receptor (HER2) statuses.MethodsThe kinetics of central nervous system (CNS) metastases (CNS metastasis-free survival, CNSM-FS) and subsequent patient’s prognosis (overall survival, OS) according to the molecular subtype were retrospectively assessed in 16703 MBC patients of the ESME nationwide multicentre MBC database (Kaplan–Meier method).ResultsCNS metastases occurred in 4118 patients (24.6%) (7.2% at MBC diagnosis and 17.5% later during follow-up). Tumours were HER2−/HR+ (45.3%), HER2+/HR+ (14.5%), HER2+/HR− (14.9%) and triple negative (25.4%). Median age at CNS metastasis diagnosis was 58.1 years (range: 22.8–92.0). The median CNSM-FS was 10.8 months (95% CI: 16.5–17.9) among patients who developed CNS metastases. Molecular subtype was independently associated with CNSM-FS (HR = 3.45, 95% CI: 3.18–3.75, triple-negative and HER2−/HR+ tumours). After a 30-month follow-up, median OS after CNS metastasis diagnosis was 7.9 months (95% CI: 7.2–8.4). OS was independently associated with subtypes: median OS was 18.9 months (HR = 0.57, 95% CI: 0.50–0.64) for HER2+/HR+ , 13.1 months (HR = 0.72, 95% CI: 0.65–0.81) for HER2+/HR−, 4.4 months (HR = 1.55, 95% CI: 1.42–1.69) for triple-negative and 7.1 months for HER2−/HR+ patients (p <0.0001).ConclusionsTumour molecular subtypes strongly impact incidence, kinetics and prognosis of CNS metastases in MBC patients.Clinical trial registrationNCT03275311.

A modified recursive partitioning analysis for predicting overall survival in patients with non-small cell lung cancer and central nervous system metastases.

e20604 Background: Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancers. Most patients with NSCLC have metastases at diagnosis and 30-50% of them will present brain lesions during follow-up. Nonetheless, patients with central nervous system (CNS) spread are poorly represented in clinical trials and the management of this clinical scenario is not standardized. Prognostic tolls are needed to help to guide the best approach for these patients. Methods: Descriptive, analytical, retrospective, single center study. Patients &gt; 18 years of age diagnosed with NSCLC who developed CNS metastases treated at AC Camargo Cancer Center from January 2007 to December 2017 were included. The primary endpoint was overall survival (OS). The secondary endpoint was intracranial progression-free survival (IC-PFS). An exploratory analysis of prognostic factors associated with OS was undertaken. The Kaplan-Meier method was used to calculate OS and IC-PFS. We used the Cox Proportional Hazard model to assess the prognostic role of clinical and pathological characteristics on IC-PFS and OS. Variables with p &lt; 0.20 at univariate analysis were used to generate a multivariate model. A survival tree was generated based on the two most statistically significant variables in the multivariate model. A p &lt; 0.05 was considered statistically significant. Results: 311 patients were included. Median age was 60 years-old (IQR 54-68), 72.6% had an ECOG performance status 0 or 1 and 18.3% had a driver mutation detected ( EGFR, ALK or ROS1). IC-PFS was 7.1 months (95%CI 6.1-8.6) and OS was 10.3 months (95%CI 8.7-13.1). At multivariate analysis, the two most statistically significant prognostic factors associated with poor OS were ECOG performance status 2-4 (HR 2.12; 95%CI 1.40-3.20; p &lt; 0.01) and the absence of a known driver mutation (HR 3.30; 95%CI 1.50-3.87; p &lt; 0.01). Based on the curves generated by the survival tree, a prognostic model was developed - the Modified Recursive Partitioning Analysis (mRPA). This model stratified our cohort in four subgroups with significantly different OS (3.1 to 43 months). mRPA was better than RPA and GPA to predict prognosis in our population. Conclusions: OS and IC-PFS in patients with NSCLC and CNS metastases were better than previously reported. However, prognosis is widely variable and is directed mainly by performance status and the presence of a driver mutation. We propose a new prognostic model that my help to guide the treatment of these patients in the future. This model needs external validation.

Development of central nervous system metastases as a first site of metastatic disease in breast cancer patients treated in the neoadjuvant trials GeparQuinto and GeparSixto

BackgroundThe incidence of central nervous system (CNS) metastases in breast cancer patients is rising and has become a major clinical challenge. Only few data are published concerning risk factors for the development of CNS metastases as a first site of metastatic disease in breast cancer patients. Moreover, the incidence of CNS metastases after modern neoadjuvant treatment is not clear.MethodsWe analyzed clinical factors associated with the occurrence of CNS metastases as the first site of metastatic disease in breast cancer patients after neoadjuvant treatment in the trials GeparQuinto and GeparSixto (n = 3160) where patients received targeted treatment in addition to taxane and anthracycline-based chemotherapy.ResultsAfter a median follow-up of 61 months, 108 (3%) of a total of 3160 patients developed CNS metastases as the first site of recurrence and 411 (13%) patients had metastatic disease outside the CNS. Thirty-six patients (1%) developed both CNS metastases and other distant metastases as the first site of metastatic disease. Regarding subtypes of the primary tumor, 1% of luminal A-like (11/954), 2% of luminal B-like (7/381), 4% of HER2-positive (34/809), and 6% of triple-negative patients (56/1008) developed CNS metastases as the first site of metastatic disease.In multivariate analysis, risk factors for the development of CNS metastases were larger tumor size (cT3–4; HR 1.63, 95% CI 1.08–2.46, p = 0.021), node-positive disease (HR 2.57, 95% CI 1.64–4.04, p < 0.001), no pCR after neoadjuvant chemotherapy (HR 2.29, 95% CI 1.32–3.97, p = 0.003), and HER2-positive (HR 3.80, 95% CI 1.89–7.64, p < 0.001) or triple-negative subtype (HR 6.38, 95% CI 3.28–12.44, p < 0.001).ConclusionsEspecially patients with HER2-positive and triple-negative tumors are at risk of developing CNS metastases despite effective systemic treatment. A better understanding of the underlying mechanisms is required in order to develop potential preventive strategies.

Diagnosis of brain metastases in breast cancer patients resulting from neurological symptoms

ObjectivesBreast cancer (BC) is the leading cause of morbidity and mortality. Neurological symptoms are highly feared because they are associated with central nervous system metastases (CNSm). So, we aimed to analyze the association of neurological symptoms with CNSm. Patients & MethodsPatients with BC referred for a neuro-oncological evaluation at a cancer referral center from June 2012 to December 2017 were included. Demographic, oncological history, comorbidities, clinical symptoms and signs, and their correlation with CNSm were prospectively acquired during consultation in a computerized database. Analyses included descriptive observations, bivariate, and logistic linear regression tests that compared associations. ResultsA total of 857 patients with BC were referred for assessment. The most frequently occurring symptoms included headache, focal motor weakness, focal-sensitive complaints, and visual complaints. Of the 1029 neuro-oncology diagnoses made, the most common were CNSm, primary headache, and chemotherapy-induced neuropathy. The risk factors associated with CNSm in patients with neurological symptoms were HER2+, younger age at cancer diagnosis, presence of extracranial metastases, and >1 neurological symptom (mainly headache: hazard ratio (HR), 2.1 [95% confidence interval (CI), 1.5–2.7]; visual complaints: HR, 2.3 (95%CI, 1.2–4.2); and ataxia: HR, 2.1 (95%CI,1.04–4.3). ConclusionsClinical symptoms and cancer characteristics were correlated with the development of CNSm. Specific risk and protective factors were identified.Among BC patients with neurological symptoms, CNSm should always be considered, especially in patients with certain oncological and clinical features.

Development of CNS metastases and survival in patients with inflammatory breast cancer.

Inflammatory breast cancer (IBC) is associated with a poor prognosis and high risk of central nervous system (CNS) metastases. We retrospectively reviewed stage III-IBC patients compared with noninflammatory invasive ductal carcinoma (NI-IDC) patients treated between January 1, 1984, and December 31, 2011, who began primary treatment within 1 year of diagnosis and had been followed up for at least 1 year before the development of CNS metastasis or death. Cumulative CNS metastasis incidence and post-CNS metastasis overall survival (OS) estimates were computed. Multivariable Cox proportional hazard models explored factors for post-CNS metastasis survival. A total of 2323 patients were identified (589-IBC/1734-NI-IDC). Eighty-one IBC patients developed CNS metastasis, versus 154 NI-IDC patients. The 2-, 5-, and 10-year cumulative CNS metastasis incidence rates in IBC and NI-IDC were 9.8%, 15.8%, 17.4% and 6.5%, 10.1%, and 12.7%, respectively. This was significantly different between IBC and NI-IDC patients (P = .0037). Multicovariate competing risk regression models in IBC and NI-IDC patients showed no statistically significant associations with the risk of developing CNS metastasis, except neoadjuvant taxane use in NI-IDC patients (hazard ratio, 0.45; 95% confidence interval, 0.24-0.83; P = .011). The median follow-up was 7.2 years, and the median post-CNS metastasis OS was not significantly different between IBC (7.6 months) and NI-IDC (5.6 months) patients. One hundred ninety patients with CNS metastasis died. HER2-positive patients had better OS, with a median 14.1 versus 4.3 months (P < .0001). Age >50 years (P = .012) but not IBC status was a significant predictor of post-CNS metastasis survival. IBC patients demonstrated higher CNS metastasis incidence rates but OS following CNS metastases is similar in both groups. HER2 status and age may play prognostic roles. Cancer 2018;124:2299-305. © 2018 American Cancer Society.

Relationship between human epidermal growth factor receptor 2 (HER2) status and central nervous system metastases in gastroesophageal cancer.

145 Background: Central nervous system (CNS) metastases (mets) in gastroesophageal (GE) cancers are rare. There have only been limited studies examining the role of HER2 status in CNS mets in GE cancers. Methods: A retrospective analysis was performed for patients (pts) treated for GE cancers at the Princess Margaret Cancer Centre from 2011-2016. Quantitative and qualitative data were collected for all pts with CNS mets. Kaplan-Meier method was used to calculate overall survival (OS) and CNS progression free survival (PFS) for CNS mets pts. Results: Of 34 GE cancer pts diagnosed with CNS mets, 11 were HER2+, 11 HER2- and 12 had unknown HER2 status. Median time from initial cancer diagnosis to CNS mets was 10.3 months (13.4 in HER2+, 5.8 in HER2-, 11.7 in HER2 unknown). Characteristics at CNS mets diagnosis included: median age 63; 85% male; 74% had extracranial systemic mets; performance status ECOG 0-1 (64%), 2 (12%), 3-4 (24%). Treatment for CNS mets is shown in Table 1. Median OS from diagnosis of CNS mets was 6.1 months (95%CI 3.2-16.4) for all pts, 17.1 (95%CI 9.9-NA) in HER2+, 1.8 (95%CI 0.6-NA) in HER2-, 6.0 (95%CI 1.9-NA) in HER2 unknown, p=0.01. Median OS from initial cancer diagnosis was 18.5 months (95%CI 13.6-33.7) for all pts, 28.9 (95%CI 21.32-NA) in HER2+, 10.8 (95%CI 6.37-NA) in HER2-, 18.6 (95%CI 10-NA) in HER2 unknown, p=0.015. The 1 year CNS PFS rate was 35% (95%CI 22.1 – 55.5%) for all pts, 53% (95%CI 29.9 – 94%) in HER2+, 18.2% (95%CI 5.3 – 63.7%) in HER2-, 33% (95%CI 15 – 74.2%) in HER2 unknown, p=0.053. Conclusions: HER2+ pts tended to develop CNS mets later than HER2-. HER2+ pts were more likely to receive CNS-directed interventions, with more HER2+ pts having surgery for CNS mets while more HER2- had supportive care. This analysis is the first to suggest that in pts with CNS mets, HER2+ pts had longer survival than HER2-, both from initial diagnosis and after developing CNS metastases.[Table: see text]