System Metastases In Patients Research Articles

A phase II study of atezolizumab, pertuzumab, and high-dose trastuzumab for central nervous system metastases in patients with HER2-positive breast cancer.

Patients with HER2-positive breast cancer brain metastases have few effective systemic therapy options. In a prior study, pertuzumab with high-dose trastuzumab demonstrated a high clinical benefit rate (CBR) in the central nervous system (CNS) in patients with brain metastases. The current trial evaluated whether the addition of atezolizumab to this regimen would produce further improvements in CNS response. This was a single-arm, multi-center, phase II trial of atezolizumab, pertuzumab, and high-dose trastuzumab for patients with HER2-positive breast cancer brain metastases. Participants received atezolizumab 1200 mg IV every 3 weeks (q3w), pertuzumab (loading dose 840 mg IV, then 420 mg IV q3w), and high-dose trastuzumab (6 mg/kg IV weekly for 24 weeks, then 6 mg/kg IV q3w). The primary endpoint was CNS overall response rate (ORR) per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Key secondary endpoints included CBR, overall survival (OS), and safety and tolerability of the combination. Among 19 enrolled participants, two had a confirmed intracranial partial response for a CNS-ORR of 10.5% (90% CI: 1.9%-29.6%). The study did not meet the prespecified efficacy threshold and was terminated early. The CBR was 42.1% at 18 weeks and 31.6% at 24 weeks. Seven patients (36.8%) required a dose delay or hold, and the most frequent any-grade adverse events were diarrhea (26.3%) and fatigue (26.3%). The addition of atezolizumab to pertuzumab plus high-dose trastuzumab does not result in improved CNS responses in patients with HER2-positive breast cancer brain metastases.

Incidence, characteristics, and management of central nervous system metastases in patients with inflammatory breast cancer.

Patients with inflammatory breast cancer (IBC) have a high risk of central nervous system metastasis (mCNS). The purpose of this study was to quantify the incidence of and identify risk factors for mCNS in patients with IBC. The authors retrospectively reviewed patients diagnosed with IBC between 1997 and 2019. mCNS-free survival time was defined as the date from the diagnosis of IBC to the date of diagnosis of mCNS or the date of death, whichever occurred first. A competing risks hazard model was used to evaluate risk factors for mCNS. A total of 531 patients were identified; 372 patients with stage III and 159 patients with de novo stage IV disease. During the study, there were a total of 124 patients who had mCNS. The 1-, 2-, and 5-year incidence of mCNS was 5%, 9%, and 18% in stage III patients (median follow-up: 5.6 years) and 17%, 30%, and 42% in stage IV patients (1.8 years). Multivariate analysis identified triple-negative tumor subtype as a significant risk factor for mCNS for stage III patients. For patients diagnosed with metastatic disease, visceral metastasis as first metastatic site, triple-negative subtype, and younger age at diagnosis of metastases were risk factors for mCNS. Patients with IBC, particularly those with triple-negative IBC, visceral metastasis, and those at a younger age at diagnosis of metastatic disease, are at significant risk of developing mCNS. Further investigation into prevention of mCNS and whether early detection of mCNS is associated with improved IBC patient outcomes is warranted.

Multimodal approach to the treatment of patients with radioiodine refractory differentiated thyroid cancer and metastases to the central nervous system.

The diagnosis of central nervous system metastases in patients with radioiodine refractory differentiated thyroid cancer is a late and rare event that occurs in less than 1% of patients. Definitive conclusions on the overall clinical management cannot be drawn due to the limited number of patients included in retrospective series or post hoc analysis from clinical trials. However, most data show a trend to an increased benefit from a multimodal approach. Local treatment based on surgical and/or radiation techniques is highly encouraged for symptom control and to reduce tumor burden in this location despite a high risk of clinical complications. In addition, systemic treatment with novel tyrosine kinase inhibitors has demonstrated activity in this subgroup of patients, improving an otherwise unfavorable prognosis.

Economic and health care resource utilization burden of central nervous system metastases in patients with metastatic melanoma.

BACKGROUND: In patients with metastatic melanoma, central nervous system (CNS) involvement is associated with poor prognosis, increased costs, and higher health care resource utilization (HCRU); however, previous cost-estimate studies were conducted before widespread use of targeted therapies and immunotherapies. OBJECTIVE: To estimate costs and HCRU in patients with metastatic melanoma with and without CNS metastases in the current treatment era following introduction of targeted therapies and immunotherapies. METHODS: This real-world retrospective cohort study used data from the IQVIA PharMetrics Plus claims database to estimate and compare costs and HCRU in patients with metastatic melanoma by presence or absence of CNS metastases between January 2011 and June 2019. Patients with at least 2 melanoma claims, at least 2 metastatic claims, and continuous enrollment at least 6 months before and at least 1 month after first metastatic diagnosis were included. Mean per-patient-per-month (PPPM) costs are reported in 2019 US dollars. Analyses were also conducted by time period of first metastatic diagnosis: 2011-2014 (reflecting BRAF inhibitor monotherapy and anti-CTLA-4 therapy) and 2015-2019 (reflecting availability of BRAF and MEK inhibitor combinations and anti-PD-1/PD-L1 therapies). RESULTS: Of 4,078 patients, 1,253 (30.7%) had CNS metastases. Patients with CNS metastases were more likely to receive any treatment (89.1% vs 58.9%; P < 0.001), including systemic treatment (73.3% vs 55.4%; P < 0.001) and radiation (65.8% vs 11.8%; P < 0.001), and to have brain imaging any time after metastatic diagnosis (98.3% vs 67.2%; P < 0.001). In patients with CNS metastases, 40.0% had dexamethasone 4 mg within 30 days of CNS metastatic diagnosis. Patients with CNS metastases incurred higher total mean PPPM costs ($29,953 vs $14,996; P < 0.001). The largest contributors were total radiology ($2,351 vs $1,110), targeted therapies ($2,499 vs $638), and immunotherapies ($7,398 vs $5,036). HCRU and costs were higher in patients with vs without CNS metastases regardless of time period of first metastatic diagnosis. In patients with CNS metastases, use of any systemic treatment was increased in 2015-2019 vs 2011-2014 (81.2% vs 64.5%; P < 0.001), including chemotherapy (68.1% vs 50.0%; P < 0.001), immunotherapy (60.9% vs 30.1%; P < 0.001), and/or targeted therapies (32.7% vs 27.4%; P = 0.05). Mean total PPPM costs for patients with CNS metastases increased from $28,183 in 2011-2014 to $31,569 in 2015-2019 (P < 0.001); main drivers were immunotherapies and targeted therapies. CONCLUSIONS: CNS metastases occur frequently in patients with metastatic melanoma and are associated with significantly increased economic burden compared with patients without CNS metastases; the largest contributors to total costs in the current treatment era are radiology, targeted therapies, and immunotherapies. Brain imaging remains underused, and there is an opportunity to improve outcomes through early detection of CNS metastases, potentially reducing the high HCRU and costs associated with CNS metastases. DISCLOSURES: This study was funded by F. Hoffmann-La Roche Ltd. The sponsor was involved in the study design, data collection, data analysis, manuscript preparation, and publication decisions. Seetasith and Lee are employed by and report stock ownership in Genentech, Inc. Bartley and McKenna were employed by Genentech, Inc., at the time of this study and report stock ownership. Tawbi reports grants and personal fees from Genentech/Roche, Novartis, BMS, and Merck; grants from GSK and Celgene; and personal fees from Eisai, outside the submitted work. Kent, Burton, and Haydu have nothing to disclose. The results of this study were presented in part at the AMCP Nexus 2020 Virtual Meeting, October 19-23, 2020.

Abstract PD13-06: Incidence and management of central nervous system metastases in patients with inflammatory breast cancer

Abstract Background: Patients (pts) with inflammatory breast cancer (IBC) have a high risk of central nervous system (CNS) metastasis (mets) with their associated impact on longevity and quality of life. Given evolving CNS-directed treatments, including focal radiation (RT), we compared the proportion of pts diagnosed with asymptomatic CNS mets before and after 2012 as data from Phase III trials in the preceding years (yr) increasingly supported the use of stereotactic radiosurgery (SRS). Specific attention was paid to pts treated with tri-modality therapy (TMT), defined as preoperative systemic therapy, surgery, and RT to determine whether screening for asymptomatic CNS mets would be beneficial. Methods: We retrospectively reviewed the records of pts diagnosed with IBC 1997-2019 and enrolled in an IRB-approved registry at a dedicated IBC center. CNS met-free survival time was defined as the time from IBC diagnosis to date of CNS mets. Alive CNS met-free pts were censored at their latest survival date and death was treated as a competing risk. Cumulative CNS mets incidence was computed. Analyses were stratified based on stage at diagnosis (III vs. de novo IV) and receipt of TMT. For pts completing TMT, the completion date was the starting point for cumulative incidence calculations. Overall survival (OS) was estimated as the time from CNS mets diagnosis to death, with censoring for pts who were still alive. Results: A total of 531 pts were identified; 372 (70%) with stage III; 159 (30%) with de novo Stage IV disease. The median follow-up for pts presenting with stage III and stage IV disease at diagnosis was 5.6 yr and 1.8 yr, respectively. 124 pts had CNS mets; 5 of them at diagnosis. CNS was the first site of mets or progression in 50 pts (9.4%). The cumulative incidence of CNS mets stratified by stage at diagnosis and receipt of TMT is seen in Table 1. Among the 50 de novo Stage IV pts who completed TMT, 4 developed CNS mets prior to surgery. The median overall survival (mOS) after CNS mets was 0.6 yr (IQR: 0.2 - 1.4). Results stratified by tumor subtype were: HER2+ disease (n=51) 1.4 yr (IQR: 0.6 - 3.7); hormone receptor+/HER2- (n=27) 0.6 yr (IQR: 0.2 - 1.2); triple negative (n=40) 0.2 yr (IQR: 0.1 - 0.5). Most pts with CNS mets (87/124, 70%) had neurologic symptoms prompting imaging. There was no difference in the proportion of asymptomatic pts diagnosed with CNS mets prior to or after 2012. Management of CNS mets was as follows: 47 pts (38%) received whole brain RT (WBRT) alone, 22 (18%) SRS alone, 15 WBRT + SRS (12%), 6 resection + WBRT (5%), and 5 resection + SRS (4%). The remaining pts received several of these modalities with or without intrathecal chemotherapy (13, 11%) or CNS treatment was not documented (16, 13%). A total of 258/531 pts have died (49%). Of these pts, 103 (40%) had CNS mets. 67/103 (65%) died due to CNS mets. Conclusions: Among pts with IBC completing TMT, the incidence of CNS mets is as high as 20% both in de novo Stage IV pts at 1 yr and in Stage III pts within 5 yrs, supporting routine surveillance brain MRI among pt with Stage IV disease. The majority of pts continue to receive WBRT with its resultant toxicities. Efforts should be made to identify CNS mets early to facilitate more focal therapy. Future research on systemic therapy with CNS penetrance for IBC patients should be pursued. These data support an ongoing prospective study of screening brain MRI in pts with Stage III IBC to quantify the incidence of CNS mets, utilization of WBRT and impact on neurologic quality of life (NCT04030507). Cumulative Incidence of CNS MetsNo.1 year (95% CI)2 year (95% CI)3 year (95% CI)Stage III (All)3725% (3-7)9% (6-12)18% (14-23)Stage IV (All)15417% (12-24)30% (22-37)42% (32-51)Stage III (TMT)3045% (3-8)11% (8-16)19% (14-24)Stage IV (TMT)4621% (10-34)28% (16-43)35% (20-50) Citation Format: Laura Warren, Samuel M Niman, Marie Claire Remolano, Jean Landry, Faina Nakhlis, Jennifer R Bellon, Meredith M Regan, Beth A Overmoyer. Incidence and management of central nervous system metastases in patients with inflammatory breast cancer [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 PD13-06.

Abstract PD13-04: Impact of tucatinib on health-related quality of life in patients with HER2+ metastatic breast cancer with stable and active brain metastases

Abstract Background Patients (pts) with human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer (MBC) who have brain metastases (BM) have limited treatment options and lower health-related quality of life (HRQoL) compared with pts without BM (Hurvitz 2019). HER2CLIMB is a randomized trial (2:1) of tucatinib vs. placebo in combination with trastuzumab and capecitabine in pts with HER2+ MBC that included pts with stable and active brain metastases (NCT02614794). In HER2CLIMB, the addition of tucatinib to trastuzumab + capecitabine demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) in pts with HER2+ MBC and in those with stable and active BM, with importantly, a tolerable and manageable safety profile (Murthy 2020). An evaluation of the impact of tucatinib on HRQoL in pts with stable and active BM is presented here. Methods HRQoL data were available from 330 of 612 pts, including 163 pts with BMs. HRQoL was assessed using the EQ-5D-5L tool which includes a visual analog scale (EQ-VAS) and a descriptive system (EQ-5D) comprising 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. Data were collected at Cycle 1 Day 1, Cycles 3-9 (every 2 cycles; 21-day cycles), Cycle 12 and beyond (every 3 cycles), and at the 30-day follow-up. The EQ-5D-5L scores were summarized by cycle for each treatment arm. Time to deterioration, defined as a &amp;gt;7-point change from baseline on the EQ-VAS, was estimated by the Kaplan-Meier approach. The median time to deterioration (and 95% CIs) were computed for each arm. Results In total, 163 pts with stable and active BM were included in this HRQoL analysis, 107 pts on the tucatinib arm and 56 pts on the placebo arm. Compared to the placebo arm, pts on the tucatinib arm had an approximately 49% reduction in the risk of deterioration (hazard ratio: 0.51; 95% CI: 0.28, 0.93); the median time to deterioration has not been reached in the tucatinib arm with available follow-up and was 5.5 months (95% CI; 4.2, -) in the placebo arm. Decline in all domains of the EQ-5D-5L and the EQ-VAS scores were seen once pts discontinued therapy, particularly on the ‘usual activities’ domain. Additional available QoL data will be presented. Conclusions Pts with MBC and BM treated with tucatinib in combination with trastuzumab + capecitabine demonstrated significantly longer and clinically meaningful time to deterioration of HRQoL. HRQoL was maintained throughout the treatment course, allowing them to receive full benefit of the therapeutic approach and resulting in statistically significant and clinically meaningful improvement in OS. References Hurvitz SA, O’Shaugnessy J, Mason G, et al. Central Nervous System Metastasis in Patients with HER2-Positive Metastatic Breast Cancer: Patient Characteristics, Treatment, and Survival from SystHERs. Clin Cancer Res. 2019;25(8):2433-2441.Murthy RK, Loi S, Okines A, et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2020;382(7):597-609. Citation Format: Andrew Wardley, Volkmar Mueller, Elisavet Paplomata, Laurence Crouzet, Nayyer Iqbal, Sramila Aithal, Margaret Block, Søren Cold, Marie-Agnes By, Olwen Hahn, Teja Poosarla, Erica Stringer-Reasor, Marco Colleoni, David Cameron, Giuseppe Curigliano, Kendra DeBusk, Muriel Siadak, Jorge Ramos, Xuebei An, Karen Gelmon. Impact of tucatinib on health-related quality of life in patients with HER2+ metastatic breast cancer with stable and active 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 PD13-04.

Identification of risk factors for central nervous system metastasis in patients with breast cancer with neurologic symptoms.

The current study was performed to identify factors that are present at the time of breast cancer (BC) diagnosis that are associated with a higher rate of central nervous system metastasis (CNSm). The authors analyzed a database of patients with a confirmed diagnosis of BC who were referred for a neuro-oncology consultation at the National Cancer Institute in Mexico City, Mexico, from June 2009 to June 2017. Information was collected prospectively and included demographic, pathologic, and clinical data at the time of diagnosis of BC. Bivariate and multivariate logistic regression models were built to estimate the associations between the development of CNSm and the time after BC diagnosis. Among 970 patients with BC, 263 (27%) were diagnosed with CNSm. The median time from BC diagnosis to the development of CNSm was 33months (interquartile range, 15-76months). After multivariate analysis, age <50years at the time of BC diagnosis (odds ratio [OR], 2.5; 95% confidence interval [95% CI], 1.8-3.5 [P<.0001]), human epidermal growth factor receptor 2 (HER2)-positive status (HER2+) (OR, 3.6; 95% CI, 2.1-6.1 [P<.0001]), luminal B/HER2+ subtype (OR, 3.1; 95% CI, 1.9-5.3 [P<.001]), triple-negative subtype(OR, 2.4; 95% CI, 1.5-4 [P=.001]), and Karnofsky performance status ≤70 (OR, 6.6; 95% CI, 4.5-9.6 [P<.0001]) were associated with a higher frequency of CNSm. Brain parenchyma was the most common site of CNSm. The median overall survival after a diagnosis of CNSm was 12.2months (95% CI, 9.3-15.1months). CNSm is not uncommon among patients with BC, particularly in those with neurologic symptoms who require neuro-oncology evaluation and are aged <50years at the time of diagnosis, have HER2+ or triple-negative subtypes, have a poor Karnofsky performance status, and/or have ≥2 non-CNS metastases.

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.

Management of Central Nervous System Metastases in Patients With Advanced Anaplastic Lymphoma Kinase-Rearranged Non–Small-Cell Lung Cancer During Crizotinib Treatment

BackgroundCentral nervous system (CNS) progression is a common manifestation of acquired resistance to crizotinib in anaplastic lymphoma kinase (ALK)-rearranged non–small-cell lung cancer (NSCLC). However, an optimal tailored treatment approach has not been established in patients with CNS failure during crizotinib treatment. Patients and MethodsPatients with ALK-rearranged NSCLC with CNS progression during crizotinib treatment between January 2013 and December 2016 were included for analysis. Clinical data for different treatments after CNS failure during crizotinib treatment were retrospectively collected. ResultsAmong the 44 patients who had CNS progression during crizotinib treatment, 19, 15, 8, and 2 patients received crizotinib treatment beyond progressive disease (CBPD), a second ALK tyrosine kinase inhibitor (TKI), chemotherapy, and best supportive care, respectively. Post progression survival offered by treatment with a second ALK TKI was significantly more favorable than that of chemotherapy (P < .001) or CBPD (P = .045). In addition, patients who received sequential treatment with a second ALK TKI had significantly longer intracranial time to progression (IC-TTP) compared with those treated with chemotherapy (P < .01) or CBPD after radiotherapy (P = .003). In the 7 patients who received brigatinib, the median IC-TTP was 21.8 months (95% confidence interval, 11.7-32.0). The additional use of CNS radiotherapy in patients treated with a second ALK TKI showed no significance in terms of IC-TTP (P = .54). ConclusionAlthough CBPD is an option in patients with isolated CNS progression during crizotinib treatment, sequential treatment with a second ALK TKI, particularly brigatinib, might be preferable. The newly approved TKI, brigatinib, showed promise in the control of brain metastases, even without radiotherapy.

Central Nervous System Metastasis in Patients with HER2-Positive Metastatic Breast Cancer: Patient Characteristics, Treatment, and Survival from SystHERs.

Patients with HER2-positive metastatic breast cancer (MBC) with central nervous system (CNS) metastasis have a poor prognosis. We report treatments and outcomes in patients with HER2-positive MBC and CNS metastasis from the Systemic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs). SystHERs (NCT01615068) was a prospective, U.S.-based, observational registry of patients with newly diagnosed HER2-positive MBC. Study endpoints included treatment patterns, clinical outcomes, and patient-reported outcomes (PRO). Among 977 eligible patients enrolled (2012-2016), CNS metastasis was observed in 87 (8.9%) at initial MBC diagnosis and 212 (21.7%) after diagnosis, and was not observed in 678 (69.4%) patients. White and younger patients, and those with recurrent MBC and hormone receptor-negative disease, had higher risk of CNS metastasis. Patients with CNS metastasis at diagnosis received first-line lapatinib more commonly (23.0% vs. 2.5%), and trastuzumab less commonly (70.1% vs. 92.8%), than patients without CNS metastasis at diagnosis. Risk of death was higher with CNS metastasis observed at or after diagnosis [median overall survival (OS) 30.2 and 38.3 months from MBC diagnosis, respectively] versus no CNS metastasis [median OS not estimable: HR 2.86; 95% confidence interval (CI), 2.05-4.00 and HR 1.94; 95% CI, 1.52-2.49]. Patients with versus without CNS metastasis at diagnosis had lower quality of life at enrollment. Despite advances in HER2-targeted treatments, patients with CNS metastasis continue to have a poor prognosis and impaired quality of life. Observation of CNS metastasis appears to influence HER2-targeted treatment choice.

Central Nervous System Metastases in Patients With Cervical Carcinoma

Cervical cancer (CC) is the most common malignancy throughout developing countries, although considered rare, central nervous system metastasis (CNSm) does occur. This study aimed to describe our experiences and compare them to other published cases. From May 2009 to August 2015, the files of all patients with CC treated at our referral center were reviewed. We found 27 patients with CC and CNSm. Mean age at the time of CNS diagnosis was 50 ± 11 years, mean interval between initial CC and CNSm was 46 months; the most frequent initial International Federation of Gynecology and Obstetrics stage was IIB with 17 patients followed by IB in 4. Fifty-nine percent of patients had lung metastases at the time CNSm were diagnosed. Headache was the most common symptom, followed by weakness, altered mental status, and ataxia/cerebellar. Mean survival was 8.2 months after CNSm was discovered; 3 patients are still alive. The present study describes the largest series of patients with CNSm from CC; this rare complication should be suspected in patients with CC who present with headache, ataxia, cranial nerve palsy, visual disturbance, altered mental status, focal weakness, or other neurological symptom, without other plausible explanation.

Platinum sensitivity and CD133 expression as risk and prognostic predictors of central nervous system metastases in patients with epithelial ovarian cancer.

BackgroundTo characterize prognostic and risk factors of central nervous system (CNS) metastases in patients with epithelial ovarian cancer (EOC).MethodsA retrospective analysis of Xijing Hospital electronic medical records was conducted to identify patients with pathologically confirmed EOC and CNS metastases. In addition to patient demographics, tumor pathology, treatment regimens, and clinical outcomes, we compared putative cancer stem cell marker CD133 expression patterns in primary and metastatic lesions as well as in recurrent EOC with and without CNS metastases.ResultsAmong 1366 patients with EOC, metastatic CNS lesions were present in 29 (2.1%) cases. CD133 expression in primary tumor was the only independent risk factor for CNS metastases; whilst the extent of surgical resection of primary EOC and platinum resistance were two independent factors significantly associated with time to CNS metastases. Absence of CD133 expression in primary tumors was significantly associated with high platinum sensitivity in both patient groups with and without CNS metastases. Platinum resistance and CD133 cluster formation in CNS metastases were associated with decreased survival, while multimodal therapy including stereotactic radiosurgery (SRS) for CNS metastases was associated with increased survival following the diagnosis of CNS metastases.ConclusionsThese data suggest that there exist a positive association between CD133 expression in primary EOC, platinum resistance and the increased risk of CNS metastases, as well as a less favorable prognosis of EOC. The absence of CD133 clusters and use of multimodal therapy including SRS could improve the outcome of metastatic lesions. Further investigation is warranted to elucidate the true nature of the association between platinum sensitivity, CD133 expression, and the risk and prognosis of CNS metastases from EOC.

Erlotinib in combination with pemetrexed/cisplatin for leptomeningeal metastases and cerebrospinal fluid drug concentrations in lung adenocarcinoma patients after gefitinib faliure.

Limited treatment options are available for lung cancer with brain metastases. Recent reports indicated that erlotinib and pemetrexed had synergistic effects in lung adenocarcinoma. Thus, we speculated that erlotinib plus pemetrexed/cisplatin may be more effective for the treatment of refractory central nervous system metastases in patients after gefitinib failure. Six lung adenocarcinoma patients with leptomeningeal metastasis (LM) who showed initial good response to gefitinib and subsequent gefitinib resistance were enrolled in this retrospective study. Five of the six patients had an epidermal growth factor receptor (EGFR) mutation in the primary tumor tissues or plasma. One patient showed complete remission, two patients showed a partial response, and two patients had stable disease. Performance and symptoms improved in the six patients. The survival time after the combination therapy was from 8 to 15months (median, 9months). There was no significant difference in cerebrospinal fluid (CSF) penetration rates of erlotinib between the erlotinib-only and the combination groups (P = 0.44). Erlotinib combined with pemetrexed/cisplatin may be effective in the treatment of LM in EGFR mutation patients after gefitinib failure. Small but measurable penetration of erlotinib and pemetrexed into the CSF was observed.

Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel: results from the randomized phase III study CLEOPATRA

Results from the phase III trial CLEOPATRA in human epidermal growth factor receptor 2-positive first-line metastatic breast cancer demonstrated significant improvements in progression-free and overall survival with pertuzumab, trastuzumab, and docetaxel over placebo, trastuzumab, and docetaxel. We carried out exploratory analyses of the incidence and time to development of central nervous system (CNS) metastases in patients from CLEOPATRA. Patients received pertuzumab/placebo: 840 mg in cycle 1, then 420 mg; trastuzumab: 8 mg/kg in cycle 1, then 6 mg/kg; docetaxel: initiated at 75 mg/m(2). Study drugs were administered i.v. every 3 weeks. The log-rank test was used for between-arm comparisons of time to CNS metastases as first site of disease progression and overall survival in patients with CNS metastases as first site of disease progression. The Kaplan-Meier approach was used to estimate median time to CNS metastases as first site of disease progression and median overall survival. The incidence of CNS metastases as first site of disease progression was similar between arms; placebo arm: 51 of 406 (12.6%), pertuzumab arm: 55 of 402 (13.7%). Median time to development of CNS metastases as first site of disease progression was 11.9 months in the placebo arm and 15.0 months in the pertuzumab arm; hazard ratio (HR) = 0.58, 95% confidence interval (CI) 0.39-0.85, P = 0.0049. Overall survival in patients who developed CNS metastases as first site of disease progression showed a trend in favor of pertuzumab, trastuzumab, and docetaxel; HR = 0.66, 95% CI 0.39-1.11. Median overall survival was 26.3 versus 34.4 months in the placebo and pertuzumab arms, respectively. Treatment comparison of the survival curves was not statistically significant for the log-rank test (P = 0.1139), but significant for the Wilcoxon test (P = 0.0449). While the incidence of CNS metastases was similar between arms, our results suggest that pertuzumab, trastuzumab, and docetaxel delays the onset of CNS disease compared with placebo, trastuzumab, and docetaxel. NCT00567190.

Luminal Subtypes Predict Improved Survival Following Central Nervous System Metastasis in Patients With Surgically Managed Metastatic Breast Carcinoma

Metastatic breast cancer to the central nervous system (CNS) is second only to lung cancer metastasis to the CNS in frequency. Patients with triple-negative primary breast cancer and those with human epidermal growth factor receptor 2 (HER2)-positive primary breast cancer are at an increased risk for metastasis. Very little is known about predictive or prognostic variables once patients develop CNS metastases. Currently, therapeutic options are limited, with surgery generally offered primarily to those with solitary lesions. To determine the influence of molecular subtypes of metastatic breast cancer on survival from the time of CNS metastasis and to aid in the prognostic stratification of these patients. We identified 59 cases of metastatic breast cancer to the CNS and analyzed them for various demographic and clinicopathologic parameters. Tumors were categorized into molecular subtypes using immunohistochemical methods: luminal A [estrogen receptor (ER⁺)/Ki67low], luminal B (ER⁺/Ki67 high), intrinsic HER2 (ER⁻/HER2⁺), and triple-negative. Survival after CNS metastasis for each group was plotted using a Kaplan-Meier curve, and multivariate analysis was performed. Patients with metastases from luminal tumors had a statistically significant survival advantage when compared with those of the triple-negative phenotype. Importantly, survival among patients with luminal A and luminal B tumors was not significantly different. Similarly, patient's age, histologic grade, and number of lesions did not contribute to determining outcomes. Estrogen receptor positivity (ie, luminal phenotype) of tumors appears to determine outcomes after development of metastases. In contrast, proliferation rate had little or no effect on the long-term survival. Understanding the biology of metastases can help stratify patients into prognostically meaningful categories and tailor treatment regimens for individual patients.

Central Nervous System Metastases in Patients with HER2-Positive Metastatic Breast Cancer: Incidence, Treatment, and Survival in Patients from registHER

registHER is a prospective, observational study of 1,023 newly diagnosed HER2-positive metastatic breast cancer (MBC) patients. Baseline characteristics of patients with and without central nervous system (CNS) metastases were compared; incidence, time to development, treatment, and survival after CNS metastases were assessed. Associations between treatment after CNS metastases and survival were evaluated. Of the 1,012 patients who had confirmed HER2-positive tumors, 377 (37.3%) had CNS metastases. Compared with patients with no CNS metastases, those with CNS metastases were younger and more likely to have hormone receptor-negative disease and higher disease burden. Median time to CNS progression among patients without CNS disease at initial MBC diagnosis (n = 302) was 13.3 months. Treatment with trastuzumab, chemotherapy, or surgery after CNS diagnosis was each associated with a statistically significant improvement in median overall survival (OS) following diagnosis of CNS disease (unadjusted analysis: trastuzumab vs. no trastuzumab, 17.5 vs. 3.8 months; chemotherapy vs. no chemotherapy, 16.4 vs. 3.7 months; and surgery vs. no surgery, 20.3 vs. 11.3 months). Although treatment with radiotherapy seemed to prolong median OS (13.9 vs. 8.4 months), the difference was not significant (P = 0.134). Results of multivariable proportional hazards analyses confirmed the independent significant effects of trastuzumab and chemotherapy (HR = 0.33, P < 0.001; HR = 0.64, P = 0.002, respectively). The effects of surgery and radiotherapy did not reach statistical significance (P = 0.062 and P = 0.898, respectively). For patients with HER2-positive MBC evaluated in registHER, the use of trastuzumab, chemotherapy, and surgery following CNS metastases were each associated with longer survival.

Development of Central Nervous System Metastases in Patients with Advanced Non–Small Cell Lung Cancer and Somatic EGFR Mutations Treated with Gefitinib or Erlotinib

Gefitinib and erlotinib can penetrate into the central nervous system (CNS) and elicit responses in patients with brain metastases (BM) from non-small cell lung cancer (NSCLC). However, there are incomplete data about their impact on the development and control of CNS metastases. Patients with stage IIIB/IV NSCLC with somatic EGFR mutations initially treated with gefitinib or erlotinib were identified. The cumulative risk of CNS progression was calculated using death as a competing risk. Of the 100 patients, 19 had BM at the time of diagnosis of advanced NSCLC; 17 of them received CNS therapy before initiating gefitinib or erlotinib. Eighty-four patients progressed after a median potential follow-up of 42.2 months. The median time to progression was 13.1 months. Twenty-eight patients developed CNS progression, 8 of whom had previously treated BM. The 1- and 2-year actuarial risk of CNS progression was 7% and 19%, respectively. Patient age and EGFR mutation genotype were significant predictors of the development of CNS progression. The median overall survival for the entire cohort was 33.1 months. Our data suggest a lower risk of CNS progression in patients with advanced NSCLC and somatic EGFR mutations initially treated with gefitinib or erlotinib than published rates of 40% in historical series of advanced NSCLC patients. Further research is needed to distinguish between the underlying rates of developing CNS metastases between NSCLC with and without EGFR mutations and the impact of gefitinib and erlotinib versus chemotherapy on CNS failure patterns in these patients.

Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Central Nervous System Metastases

To determine the incidence, outcomes, and current strategies for management of brain metastases in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. A literature review was performed to obtain data on central nervous system metastases in patients with breast cancer. HER2 amplification/overexpression is a prognostic and predictive factor for the development of CNS metastases. Autopsy data show that the incidence rate for CNS metastases in patients with breast cancer is approximately 30%; this may be higher (ie, 30% to 50%) in patients with HER2-positive disease. Treatment with trastuzumab is not associated with an increased incidence of CNS metastases. Data from three phase III adjuvant trials showed the incidence was similar between patients who received trastuzumab and those who did not. Furthermore, trastuzumab can significantly improve overall survival in HER2-positive patients who already have CNS metastases compared with patients who do not receive trastuzumab or those who have HER2-negative brain metastases. This survival advantage is conferred via systemic control of the disease. The current standard of care for patients with CNS metastases is whole-brain radiotherapy (WBRT), with or without surgery, or stereotactic radiosurgery. In the future, novel therapies or combinations of therapies may additionally improve survival in these patients. The incidence of CNS metastases in trastuzumab-treated patients is similar to that in all patients with HER2-positive disease. Trastuzumab can improve survival in patients with HER2-positive disease with CNS metastases.

Risk factors for central nervous system metastasis in patients with metastatic breast cancer

Patients with metastatic breast cancer (MBC) and central nervous system (CNS) involvement have an impaired survival and quality of life. In this study, we investigated the risk factors for CNS metastasis among patients with MBC. The risk factors for development of CNS metastasis were analyzed in 154 patients with MBC. Expression of c-erbB-2, Ki-67, p53, and hormone receptors was examined by immunohistochemistry (IHC) in breast cancer tissue samples from the 154 patients. Kaplan-Meier and log-rank tests were used for the analysis of overall survival (OS). Chi-square test was used for univariate analysis. Median OS was significantly poorer for patients with CNS metastasis as compared with patients with no CNS metastasis (OS, 23 mo vs 30 mo, respectively;p = 0.03). Ki-67 and p53 overexpressions by IHC, and lung metastasis as the first site of relapse, were associated with a higher risk of developing CNS metastasis in the univariate analysis (p <or= 0.05). The presence of lung metastasis (odds ratio [OR]= 2.82, 95% confidence interval [CI]: 1.13-7.00,p = 0.02) and p53 overexpression (OR = 2.44, 95% CI: 0.99-6.00,p = 0.05) were the two predictive factors associated with occurrence of CNS metastasis in the multivariate analysis. In this study, the presences of lung metastasis as the first site of relapse and p53 overexpression were predictive for the occurrence of CNS metastasis in patients with MBC. Life expectancy of patients with CNS metastasis is significantly shorter than those without CNS metastasis. These results may have clinical significance in counseling MBC patients with regard to their prognosis.

Does trastuzumab increase the risk of isolated central nervous system metastases in patients with breast cancer?

Does trastuzumab increase the risk of isolated central nervous system metastases in patients with breast cancer?