Development Of CNS Metastases Research Articles

Longitudinal Monitoring of Circulating Tumor DNA to Assess the Efficacy of Immune Checkpoint Inhibitors in Patients With Advanced Genitourinary Malignancies.

Circulating tumor DNA (ctDNA) detection in blood has emerged as a prognostic and predictive biomarker demonstrating improved assessment of treatment response in patients receiving immune checkpoint inhibitors (ICIs). Here, we performed a pilot study to support the role of ctDNA for longitudinal treatment response monitoring in patients with advanced genitourinary (GU) malignancies receiving ICIs. Patients with histologically confirmed advanced GU malignancies were prospectively enrolled. All eligible patients received ICI treatment for at least 12 weeks, followed by serial collection of blood samples every 6-8 weeks and conventional scans approximately every 12 weeks until disease progression. ctDNA analysis was performed using Signatera, a tumor-informed multiplex-polymerase chain reaction next-generation sequencing assay. Overall, the objective response rate (ORR) was reported and its association with ctDNA status was evaluated. Concordance rate between ctDNA dynamics and conventional imaging was also assessed. ctDNA analysis was performed on 98 banked plasma samples from 20 patients (15 renal, four urothelial, and one prostate). The median follow-up from the time of initiation of ICI to progressive disease (PD) or data cutoff was 67.7 weeks (range, 19.6-169.6). The ORR was 70% (14/20). Eight patients ultimately developed PD. The overall concordance between ctDNA dynamics and radiographic response was observed in 83% (15/18) of patients. Among the three patients with discordant results, two developed CNS metastases and one progressed with extracranial systemic disease while ctDNA remained undetectable. In this pilot study, longitudinal ctDNA analysis for monitoring response to ICI in patients with advanced GU tumors was feasible. Larger prospective studies are warranted to validate the utility of ctDNA as an ICI response monitoring tool in patients with advanced GU malignancies.

TIPS-10 FEASIBILITY OF A MULTI-MODALITY CENTRAL NERVOUS SYSTEM SCREENING EVALUATION IN HER2+ BREASTCANCER PATIENTS

Abstract BACKGROUND Breast cancer is the most common cancer in the world and the second most common to metastasize to the central nervous system (CNS). CNS-metastases are the most common type of brain tumor and have a rising incidence. They are associated with neurologic morbidity and mortality and remain a major clinical challenge. Survival withCNS-metastases is short with a median survival in the order of months. The incidence of CNS-metastases is 5.1% in breast cancer however true prevalence is not known; at autopsy this incidence ranges between 20-40%. One contributing factor towards the development of CNS-metastases in breast cancer is HER2-positivity. Between 25%-48% of patients with HER2-positive metastatic breast cancer develop CNS-metastases. Currently, routine CNS surveillance imaging is not recommended, however guidelines suggest having a low threshold for evaluation with imaging and/or cerebrospinal fluid (CSF) analysis because of the high rate of CNS-metastases. The clinical relevance of occult CNS-metastases, survival after identification of occult CNS-metastases and the importance of earlier initiation of CNS therapy are unknown. Existing treatment strategies for CNS-metastases rely on a combinatorial approach of chemotherapy, radiotherapy and/or surgery which typically affords limited disease control. This trial seeks to study if surveillance imaging and CSF analysis are feasible as early disease detection mechanisms. METHODS This is a two-cohort study to establish feasibility of multi-modality CNS surveillance. Patients with HER2+ metastatic breast cancer patients (with no known CNS-metastases) who are either Stage IV (Cohort A) or Stage II/III are eligible (Cohort B). On study, patients will undergo MRI Brain and CSF analysis at 6 monthly intervals. CSF analysis includes cytology, circulating tumor cells and cell-free DNA analysis. We plan to enroll 20 patients (10 onto each cohort). 1 of 20 patients have enrolled. This is the first multi-modality screening feasibility study for patients HER2-positive breast cancer.

A disease registry study to prospectively observe treatment patterns and outcomes in patients with HER2+ unresectable locally advanced or metastatic breast cancer (aBC): Interim results of the ESTHER study (NCT02393924).

e13039 Background: Over the last decade the standard-of-care treatment for patients with HER2+ aBC has included anti-HER2 therapies often combined with chemotherapy. These approaches have shown efficacy in clinical trials which have recruited patients in restricted populations defined by lines of therapy and previous treatments. There are few data regarding the long-term outcomes of patients treated with these regimens, including those with brain metastases. We conducted a prospective, multicentre non-interventional study to observe anti-cancer treatment regimens and clinical outcomes in patients with HER2 positive aBC. Methods: Adult patients diagnosed with HER2-positive aBC within the last 6 months were included. No specific treatment approach or course was mandated by the protocol. Source data was taken from the patient’s chart and other medical records, then reported by means of an electronic data collection system. Data regarding treatment received, efficacy (progression-free and overall survival (PFS), response rates (RR) and development of CNS metastases) and safety (including cardiac toxicity) were captured. Results: Between February 2015 and April 2018, 311 eligible patients were recruited with median age 57 years (24-96). At diagnosis of aBC the most common distant metastatic sites were bone (n = 145;47%), liver (n=117;38%), lung (n=100;32%) and brain (n=21;7%). First line treatment was with pertuzumab (P)/trastuzumab(T)/chemotherapy (n=212;68%), T/chemotherapy (n=45;14%), other T combinations without P (n=19;6%), Trastuzumab Emtansine regimens without T or P (n=16;5%) (19; 5% other combinations). Patients’ status as of cut-off date for this analysis (28th Feb 2022, median follow-up 44.1 months) is shown. The median PFS of patients treated in the 1st, 2nd and 3rd lines was 26.7 months, 10.7 months and 8.6 months. At the time of this analysis an additional 60 patients (19%) had developed brain metastases during first line. The number of patients starting 2nd, 3rd and 4th line treatment with brain metastases were 28 (22%), 17 (40%), 7 (37%) respectively. Conclusions: In routine clinical practice, as reflected by this registry, at least 40% of patients who initiate first line therapy for advanced breast cancer do not proceed to 3rd line therapy, and brain metastases become increasingly common. These findings have implications for selection of optimal 2nd and 3rd line treatment. Clinical trial information: ISRCTN02393924 . [Table: see text]

Development of CNS metastases in breast cancer patients treated with curative intent: a case-control study.

Background:The aim of this study was to identify risk factors that may predispose breast cancer patients to the development of CNS metastases.Materials & methods:We conducted a matched case–control study of breast cancer patients treated with surgery with curative intent. A total of 71 cases and 71 controls were analyzed, matched by year of surgery.Results:In our multivariable model, positive lymph node status (odds ratio [OR]: 5.08; CI: 2.04–12.65), the use of neoadjuvant chemotherapy (OR: 6.02; CI: 2.06–17.57) and triple-negative breast cancer (OR: 5.44; CI: 1.99–14.90) were statistically significant predictors of the development of CNS metastases.Conclusion:Women with certain risk factors have an increased odds of developing CNS metastases and evaluation of utility in brain metastases screening should be considered.

Abstract 1316: Preclinical evaluation of TUL-001, an EGFR inhibitor for the treatment of NSCLC with brain metastasis (BM)

Abstract Objective: Non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor-activating mutations (EGFRm+) have a much higher risk of developing CNS metastases. The cumulative incidence of BM and LM in these patients is more than 50%. These patients have poor prognosis as there are no approved drugs for these indications. Currently approved drugs can neither effectively treat brain metastases nor prevent development of the brain metastases due to their limited blood-brain-barrier (BBB) penetration. TUL-001 is a potent oral EGFR inhibitor, which has excellent potency and BBB (blood brain barrier) penetration ability, it can potently induces tumor regression both in the brain metastases and subcutaneous animal models. Methods: The anti-proliferative activity of TUL-001 was evaluated in PC-9 (EGFRExon19 Del), and A431 (EGFRWT) NSCLC cell lines. The anti-tumor activity was evaluated in PC-9-luc Lung cancer brain metastases model, which was monitored by an IVIS Xenogen imaging system. The in vivo anti-tumor activity also evaluated in PC-9 subcutaneous transplantation tumor model. Effects on EGFR signaling pathway were assessed by western blot analysis of the downstream effector proteins p-EGFR (Y1068), p-AKT (Ser473) and p-ERK (Thr202/Tyr204). Results: TUL-001 displayed potent anti-proliferative activity in the EGFR mutant cell line PC-9 (IC50 =3.74 nM), and less potent activity in the A431 (EGFRWT) cell line (IC50 = 54.1 nM), it has about 14 fold selectivity for EGFRExon19 Del over EGFRWT. TUL-001 significantly inhibited tumor growth at all doses tested in the PC-9-luc brain metastases model, and significantly prolong the overall survival for the test animals. In the PC-9 subcutaneous transplantation tumor model, TUL-001 can also shrinkage the tumors, and the TGI for the lower dose group (2.5mpk) was more than 120%. Western blot analysis of the tumor samples in the brain metastases model study showed that TUL-001 inhibited p-EGFR (Y1068), p-AKT (Ser473), and p-ERK (Thr202/Tyr204), indicating that the tumor growth inhibition was through inhibition of the resistant mutant EGFR. Conclusion: TUL-001 is a potent brain penetrant EGFR inhibitor, and showed excellent antitumor activity in preclinical tumor models. These results warrant TUL-001 going to the clinic study for exploration of its potential for treating EGFRm+ NSCLC cancer with and without brain metastasis. Citation Format: Xile Liu, Liwei Mu, Bin Liu, Shouting Wu, Degang Wang, Lu Zhang, Charles Z Ding, Lihong Hu, Weifeng Mao, Zhenzhen Zhu, Chen Chen, Yuanfeng Xia, Chichung Chan, Shuhui Chen. Preclinical evaluation of TUL-001, an EGFR inhibitor for the treatment of NSCLC with brain metastasis (BM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1316.

Abstract P1-19-06: The prognostic value of HER2, YKL-40 and IL-6 in cerebrospinal fluid in trastuzumab naïve breast cancer patients diagnosed with meningeal carcinomatosis

Abstract Background With the improvements in treatment of patients with metastatic HER2-positive breast cancer (BC) the development of CNS metastases has become a major limitation of life expectancy and quality of life for many patients. Meningeal carcinomatosis represents approximately 10-20% of CNS metastases. The prognosis of meningeal carcinomatosis remains extremely poor. In the present study, we analysed the prognostic value of HER2, YKL-40 and IL-6 in cerebrospinal fluid (CSF) of meningeal carcinomatosis. Methods Between June 1985 and August 1992 sixty-nine CSF samples were collected at Herlev Hospital from trastuzumab naïve BC patients suspected of meningeal carcinomatosis. The cohort was composed of BC patients from two previous studies. Meningeal carcinomatosis was confirmed by tumour cells in CSF (or autopsy/scans). The samples were centrifuged, frozen and kept at -80oC. The concentrations of YKL-40, IL-6 and HER2 in CSF were measured by commercial ELISA (Quidel and R&D) or Luminez (HER2 in second study). Overall survival in meningeal carcinomatosis was analysed with Kaplan-Meier curves and log rank tests using the median CSF value of HER2, YKL40 and IL-6 as cut off. Results 20 patients (29%) had meningeal carcinomatosis (18 patients had tumour cells in CFS, one was diagnosed by autopsy and one by CT scan; 13 of these patients participated in the first study and 7 in the second).10 patients had concomitant brain metastasis. The median survival was 35 days (4-305 days). The median [IQR] CSF concentration of YKL-40 was 284 ng/ml (187-597), IL-6 was15.9 pg/ml (6.5-51.0) and HER2 was 1.5 (0.36-8.70) in the patients with meningeal carcinomatosis. The survival was significantly shorter in patients with high levels of YKL-40 (p=0.03) and IL-6 (p=<0.01). The CSF HER2 level (p=0.51) or presence of brain metastasis (p=0.77) were not associated with survival. Conclusion In this cohort high levels of YKL-40 and IL-6 in CSF were associated with short survival in patients with BC and meningeal carcinomatosis. This was not found for HER2 in CSF or concomitant brain metastasis. Citation Format: Ryberg M, Johansen JS, Grantzau TL, Dehlendorff C, Nielsen DL. The prognostic value of HER2, YKL-40 and IL-6 in cerebrospinal fluid in trastuzumab naïve breast cancer patients diagnosed with meningeal carcinomatosis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-19-06.

Abstract P6-15-11: Weekly paclitaxel, pertuzumab and trastuzumab (TPH) neoadjuvant therapy for HER2 positive inflammatory breast cancer

Abstract Background: Inflammatory breast cancer (IBC) is inoperable at presentation, thus neoadjuvant systemic therapy (NAS) is the primary treatment for this aggressive disease. Due to its rarity, patients (pts) with IBC are incorporated into NAS clinical trials for locally advanced breast cancer, making it difficult to extrapolate efficacy specifically for pts with IBC. A commonly used regimen for the treatment of HER2+ IBC includes docetaxel, carboplatin, pertuzumab (P) and trastuzumab (H), yet only 6% of pts enrolled in the clinical trial for this regimen had IBC. We sought to examine the efficacy of maximizing anti-HER2 therapy combined with minimal chemotherapy using the THP regimen specifically for pts with HER2+ IBC. Methods: Pts with newly diagnosed HER2+ IBC received NAS with 16 weeks (wks) of paclitaxel (T) 80mg/m2/wk, H (2mg/kg/wk) and P(420mg/kg/3wk) followed by modified radical mastectomy (MRM) on a phase II prospective study. All pts had 2 research breast biopsies (rbx) for correlative assays prior to and 1 wk after the P (840mg/kg) and H (4 mg/kg) loading dose. Pts who achieved a pCR (pathologic complete response) could opt out of adjuvant doxorubicin (A) 60 mg/m2 + cyclophosphamide (C) 600mg/m2 x 4; pts with residual disease received AC. All pts received post-mastectomy radiation and maintenance P (420mg) + H (6mg/kg) every 3 wks x 12. Adjuvant endocrine therapy was given per standard of care. Primary objective was pCR rate in the breast and axillary lymph nodes. Residual Cancer Burden (RCB) was assessed. Based upon a Simon two-stage design, this regimen would be declared worthy of further study if >7/27 pCR were observed (15% vs 40%; target α=0.039 power=0.90). The study was closed after 23/27 pts were enrolled due to slow accrual. Results: 20 pts were enrolled as of 12/2016, 18 completed NAS and MRM. All but 1 had stage III disease at presentation. 1 pt was lost to follow-up; 1 developed CNS metastasis during NAS and did not undergo MRM. The mean age was 49 years, 10 pts had ER/PR negative disease. 15 pts completed 16 wks of T, 4 had 15 wks and 1 had 13 wks. During NAS, there was no grade (gd) 4 toxicity; 6 episodes of gd 3 toxicity (2 related to treatment-diarrhea); and no gd 3 cardiac events. In the intent to treat analysis, 10/20 pts achieved pCR (50%; 90% CI 30-70%) and 6 had RCB-1 (30%). 5 pts with RCB-1 response had <5 mm residual disease; 1 had lymph node involvement. Of those proceeding to MRM, pCR rate was 56% (10/18). 6/10 opted out of AC. Treatment and follow-up for clinical outcomes continue. Biologic correlatives investigating genomic profiling and patterns of HER2 resistance are being performed on rbx, residual disease and cfDNA. Conclusion: THP x 16wks is tolerable and effective NAS for HER2+ IBC, resulting in a high pCR rate with minimal toxicity. This study of NAS explored the benefit of maximizing HER2-directed therapy and minimizing chemotherapy and its associated toxicity. It has achieved its primary endpoint and will be used as the backbone NAS for HER2+ IBC, with future studies building upon this regimen. The result of this trial supports the benefit of clinical trials designed specifically for pts with IBC. Clinical trial information: NCT01796197. Citation Format: Overmoyer B, Regan M, Hu J, Nakhlis F, Dominici L, Lin NU, Freedman R, Morganstern DE, Partridge AH, Schlosnagle EJ, Hirshfield-Bartek J, Bellon J, Morikawa A, Harrison BT, Winer E. Weekly paclitaxel, pertuzumab and trastuzumab (TPH) neoadjuvant therapy for HER2 positive inflammatory breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-15-11.

Patterns of histologic response to neoadjuvant targeted therapy in patients with BRAF mutant melanoma.

9584 Background: While BRAF and MEK inhibitors are approved for patients with BRAF V600 + unresectable/metastatic melanoma, their role in the neoadjuvant setting is less well defined. Results from small trials have noted robust response rates, but less is known about histological patterns of response in resected tumor specimens and relation to outcome in these patients (pts). Methods: In a retrospective study, we analyzed the clinical and pathologic patterns of response to neoadjuvant BRAF ± MEK inhibitor therapy in pts with locally advanced melanoma subsequently rendered disease free with surgery. Results: Twenty pts were identified, nine with stage IIIC and 11 with stage IV melanoma. Seven patients received neoadjuvant vemurafenib (VEM), 12 received dabrafenib + trametinib (D+T), and one encorafenib + binimetinib. The median duration of treatment was 7.8 months. Seven patients (35%) had a pathologic complete response (pCR); six of them had received combination therapy, 5 with D+T, 1 VEM with an HSP90 inhibitor. Four distinct histologic patterns were observed in the resected tumor specimens: necrotic, fibrotic/melanotic (tumoral melanosis), hyalinized, or mixed. With median follow-up of 25 months (range 1-60), six pts (30%) had experienced recurrence; three developed CNS metastases. Four of the six patients had received neoadjuvant D+T; three were restarted on their prior targeted therapy at recurrence and all responded. All 6 pts with recurrence had residual disease in the surgical specimen; three had no necrosis identified. In contrast to the 13 pts with persistent tumor, none of the 7 pCR pts has relapsed (p = 0.05). There was a trend towards improved relapse-free-survival (RFS) with a pCR, with a 1 yr of RFS-rate of 50.4% vs 100% in pCR.(p = 0.08) Of the 14 patients without subsequent recurrence, 9 had either a pure necrotic histology, or a mixed histological pattern that included necrosis. Conclusions: In locally advanced or M1a BRAF mutant melanoma, attaining a pCR to neoadjuvant targeted therapy may correlate with improved patient outcomes and be more likely achieved with combination therapy. Presence of necrosis in the surgical specimen appears be a favorable prognostic factor.

Retrospective Review for Prevalence and Survival in Metastatic Breast Cancer with Brain Metastasis in Two Patient Cohorts: One Collected 2000-2005 and the Second Collected 2006-2011

Purpose: To determine whether the new treatments for breast cancer CNS metastases improve survival by comparing the survival between two cohorts: 2000-2005 and 2006-2011. Patients and Methods: A retrospective, comparative, correlational chart review was performed. Data from 172 women diagnosed with CNS metastases between 2000 and 2011, was evaluated. Results: Approximately 10% of patients diagnosed with invasive breast cancer between 2000 and 2011 developed CNS metastases. The cohort was separated into four groups: luminal A (ER+ and/or PR+, HER2-), luminal B (ER+ and/or PR+, HER2+), HER2+ (ER -, PR-, HER2+) and TN (ER-, PR-, HER2-). There was a statistically significant difference in the overall survival between luminal A and luminal B (5.55 months vs. 15.3 months, respectively, p = 0.048). There was also a statistically significant difference in the overall survival between luminal B and TN (15.3 months vs. 7.49 months, respectively, p = 0.0181). There was no significant difference in overall survival between luminal B and HER2+ (15.3 months vs. and 10.98 months, respectively, p = 0.105), TN and HER2+ (7.49 months vs. 10.98 months, respectively, p = 0.514), and between luminal A and TN or HER2+ (5.55 months vs. 7.49 months, respectively, p = 0.428, or 5.55 months vs. 10.98 months, respectively, p = 0.491). Overall median survival of the patients in 2000-2005 and 2006-2011 were 6.64 months vs. 10.58 months, respectively (p = 0.0592). Conclusion: The results of our study showed that despite the new therapies there is little improvement in survival for brain metastasis in breast cancer.

Poor prognostic factors of post-CNS recurrence survival in breast cancer patients.

2097 Background: Survival after the onset of metastases in the central nervous system is very short. However, some variables could indicate subsets of worse prognosis. Our aim was to determine the value of clinicopathological characteristics and prognostic scores in the post-SNC recurrence survival. Methods: We evaluated a retrospective cohort of 2597 breast cancer patients treated at the Instituto Nacional de Enfermedades Neoplasicas (Lima-Peru) between 2000-2005. Clinicopathological data was retrieved, RPA and GPA brain metastases prognostic scores were constructed and phenotypes were categorized according to the IHC expression in [HR+,HER2-], [Any HR, HER2+] and Triple Negative. Survival was calculated according to the Kaplan Meier methodology and cases were stratified by variables evaluated. The log-rank or Breslow tests were used when appropriate and multivariate analysis was done by the cox regression. A P<0.05 was considered statistically significant. Results: One hundred and fifty seven cases developed CNS metastasis, from which 23 developed leptomeningeal metastases. The post recurrence CNS survival was 0.405 years. There were not differences according to phenotype (P=0.102), histological grade (P=0.647), number of brain metastases (P=0.695) and metastases volume (P=0.155). We found statistic differences in regard to leptomeningeal carcinomatosis (present, 0.249ys vs absent 0.436ys; P=0.033); CSF infiltration (present, 0.115ys vs absent, 1.044ys; P=0.022); status of primary tumor (controlled, 0.501ys vs uncontrolled, 0.263ys; P<0.001); ECOG performance status (<2, 0.504ys vs ≥2, 0.288ys; P=0.030); and time from BC diagnosis to SNC metastases (<8 moths, 0.115 vs ≥8 months, 0.425ys; P=0.023). Cox regression identifies to CSF infiltration as statistically significant (HR=9.77; P=0.025). In regard to Prognostic scores, we found differences when cases were stratified according to RPA score (Class I, 0.564ys vs Class II, 0.455ys vs Class III, 0.288ys; P=0.049) and GPA score (0-1, 0.26ys vs 1.5-3, 0.455ys vs 3.5-5, 0,564; 0.048). Conclusions: RPA and GPA scores are more accurate to identify poor survival subsets in this group of patients than other tumor features (phenotype or histology).

Abstract P1-14-02: Different Outcomes in Breast Cancer (BC) Patients with CNS Metastases According to IHC Phenotype

Abstract Background: Phenotype plays an important role in BC biology and outcome. We evaluated the characteristics and outcomes of clinical stages I-III BC patients with recurrence according to the IHC phenotype: ER or PR+/HER2-; HER2+ (regardless the ER and PR status) and triple negative (ER-/PR-/HER2-), to determine the influence of phenotype in the SNC recurrence. Methods: We reviewed 1,232 clinical stage I-III BC treated at INEN (2000-2002). Phenotypes were categorized by IHC into [ER+ and/or PR+, HER2-], [ER-, PR-, HER2-] and [HER2+ (regardless ER/PR status)]. Patients were classified in 3 risk groups (recursive partitioning analysis [RPA]; Gaspar et al. Int J Radiat Oncol Biol Phys 1997;37:745) according to 4 criteria: those with Karnofsky Performance Status (KPS) less than 70 (Class III), those with a KPS of or more, aged less than 65, with a controlled primary, no other systemic metastases (Class I), all other patients (Class II). We used Kaplan-Meier estimates for comparing CNS-free metastases survival and survival after CNS recurrence according to IHC phenotype or classes. Results: A median follow-up of 7.6 years; 416 (33.8%) patients had local, regional or distant disease dissemination, and 454 (36.9%) deaths were registered. In total, 62 (5.0%) patients developed CNS metastases (60 cases of cerebral and 2 of meningeal metastases), 36 (2.9%) of whom had developed CNS metastases as the site of first recurrence. 12 (2.1%), 31 (7.7%) and 19 (7.5%) were ER or PR+/HER2-, HER2+ and triple negative, respectively. CNS metastases free survival shown significant differences between ER or PR+/HER2-, HER2+ and Triple negative (97.3%, 89.6% y 90.5%, respectively; P<0.001). Main multivariate predictive factor was IHC phenotype (P<0.001), using [ER or PR+/HER2-] as reference, other phenotypes were expressed by hazard ratios (HR); [HER2+] (HR=3.8, 95%CI; 1.9 - 7.4), triple-negative (HR=4.0, 95%CI; 1.9-8.4). In regard to the RPA groups, 3 (4.9%) were class I, 28 (45.9%) class II and 30 (49.2%) class III. Median survival after CNS recurrence was 12.9, 6.1 and 2.8 for RPA Class I,II and III, respectively]; however there was not significant differences (p=0.085). In the multivariate analysis for OS after SNC metastases, only phenotype was significant and Triple Negative have the higher risk (HR=2.064; IC95% 0.94 — 4.531; P=0.023), Risk groups have not significant effect (P=0.088). Phenotype and outcome Conclusion: IHC phenotype is a strong risk factor for outcome; triple negative, and Class III breast cancer patients present a shorter time to CNS recurrence and survival after CNS recurrence than other IHC phenotypes and other risk groups. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-14-02.

Safety and efficacy of first-line bevacizumab (B) plus chemotherapy (CT) for locally recurrent or metastatic breast cancer (LR/mBC): Analysis of MO19391 according to CT

1033 Background: Combination of B with first-line paclitaxel (TP) or docetaxel (TD) significantly improves PFS vs taxane alone in pts with LR/mBC. The open-label, multicenter MO19391 trial further assessed safety and efficacy of first-line B plus a taxane in >2,000 pts in routine clinical practice. Methods: Eligible pts had HER2- negative LR/mBC (or HER2-positive LR/mBC progressing after trastuzumab-containing therapy), ECOG PS 0–2, no prior CT for LR/mBC and no evidence of CNS metastases. Pts received B 10mg/kg q2w or 15mg/kg q3w plus the physician's choice of taxane (TP or TD alone or with another CT) or other non-anthracycline CT according to physician's standard of care. Treatment was continued until disease progression, unacceptable toxicity, or refusal. The primary endpoint was safety (NCI CTCAE v3.0); secondary endpoints included TTP, OS, and safety in pts developing CNS metastases. Results: From Sept 2006 to June 2008, 2,027 pts from 37 countries were enrolled. Median follow-up is 7.4 months. CT included a taxane (alone or with CT) in ∼75% of pts. Non-taxane agents included capecitabine (X) and vinorelbine (V). In the overall population, median age was 54 years (range 21–93), 70% were ER and/or PgR positive, and 32% had disease-free interval (DFI) ≤24 months. Baseline characteristics were broadly similar across subgroups. However, the X monotherapy subgroup included fewer pts with >3 metastatic lesions and more with a DFI ≤24 months and/or triple-negative disease compared with other subgroups. Safety and efficacy results grouped by CT are shown below. OS data are still immature (85% of pts alive at this analysis). Conclusions: In this large phase IV study, safety and efficacy of B plus TP or TD was similar to results of E2100 and AVADO. Variations in toxicities were consistent with the known profiles of each CT and no new safety signals for B were observed. The lowest incidences of serious Aes were seen with B plus TP or X. TTP was shorter with X and non-taxane combinations. Such findings are potentially attributable to small pt numbers and differences in baseline characteristics. These results show that B can be safely and effectively combined with a wide range of commonly used CT regimens as first-line therapy for mBC. [Table: see text] [Table: see text]

Meningeosis carcinomatosa beim Mammakarzinom

Breast cancer is the solid tumour with the highest incidence rate of meningitis carcinomatosa. The HER2-positive and triple-negative phenotypes are possible high risk constellations for the development of CNS metastases in these subgroups. It is expected that improved efficacy of new treatment options will lead to a further increase of CNS metastases in breast cancer patients, especially in case of tumours with HER2-overexpression and pre-treatment with the monoclonal antibody trastuzumab. Based on the total population, the prognosis of meningitis carcinomatosa is generally unfavourable. However, occasional reports of long-term survivors continue to arise, especially among breast cancer patients. The development of new cytostatic drugs aims to improve the current standard treatment, which includes intrathecal chemotherapy with cytostatics. Liposomal cytarabine is characterized by a more favourable pharmacokinetic profile in comparison with the former reference substance methotrexate, allowing significantly prolonged application intervals. In the light of current clinical data, it is reasonable to assume that this drug has increased significance in patients with meningeal metastatatized breast cancer. Especially subgroups with additional favourable criterions, which require further definition in future studies, may profit from the intrathecal treatment with liposomal cytarabine.

Treatment strategies in CNS metastases

Background: CNS metastases constitute the most common brain malignancy in adults and, therefore, represent a challenging issue in cancer treatment. Purpose: To review the role and indication of the various treatment options in the context of important prognostic factors that may guide the selection of patients who could benefit from each treatment modality. Methods: Therapeutic approaches in treating CNS metastases include surgery, radiotherapy and systemic chemotherapy, and are reviewed through a critical evaluation of published recent literature; however, in the majority of most common malignancies spreading to the CNS, treatment remains largely palliative and rarely curative, as is the case for other metastastic sites. Conclusions: It is anticipated that a multidisciplinary approach with rapid integration of new treatment strategies is required for the treatment of patients developing CNS metastases, ultimately aiming to prolong survival, preserve neurologic function and improve quality of life.

Lapatinib (L) plus capecitabine (C) in HER2+ advanced breast cancer (ABC): Genomic and updated efficacy data

1035 Background: EGF100151 demonstrated L+C improved TTP relative to C alone in women with HER2 positive, trastuzumab- exposed ABC (Geyer, NEJM;355(26):2006). We report updated efficacy data and results of correlative studies to determine if gene expression levels in the 5-FU and HER pathways are associated with clinical benefit in L+C. Methods: Tumor blocks are available on 217/399 patients, and so far sufficient mRNA has been extracted from 64/217 blocks using qRT-PCR. Tumors were evaluated for expression of HER1–4, TS, TP, PTEN, c-MYC. In addition to univariate and multivariate analyses, a SpotFire™ DecisionTree analysis was performed to determine the genes most significantly associated with RR; these genes were further analyzed for association with TTP. Results: Updated efficacy results through April 3, 2006 demonstrate: TTP L+C (27 wks)vs C (19 wks) HR 0.57 [0.43,0.77] p=0.00013; ORR L+C (24%)vs C (14%), Odds Ratio 1.9[1, 1.34] p=0.017; OS L+C vs C HR 0.78 [0.55,1.12] p=0.177; progression in CNS L+C (2%)vs C (11%) p=0.0445. Preliminary analysis of the first 64 samples indicates that elevated baseline mRNA expression of HER2 is associated with a higher RR and longer TTP (p<0.0001) with L+C. The opposite was seen in the C arm, where elevated HER2 mRNA expression seemed to predict for a poorer outcome. Analyses of ErbB3,4, PTEN and MYC as well as TS did not correlate with RR. Conclusion: The updated efficacy results confirm the prior demonstrated benefit of L+Cvs C and provide the first evidence for a systemic anti-HER2 therapy to have an effect on the development of CNS metastases. This preliminary analysis suggests a correlation between elevated HER2 mRNA levels and RR/TTP. Further investigation, including full genome microarray analysis of samples is ongoing. [Table: see text]

Updated results of a randomized phase II study comparing two schedules of temozolomide in combination with sorafenib in patients with advanced melanoma

8527 Background: The preliminary results for 90 patients (pt) on this 4-arm phase II trial testing sorafenib (SO), an oral Raf kinase/VEGFR2 inhibitor, and temozolomide (TEM) in pt with metastatic melanoma (MM) were presented in 2006. Since then 88% of target accrual is completed and the study is open at a second institution. The primary objective of this study is to estimate the duration of progression- free survival (PFS). Secondary objectives are to determine the optimal dosing of TEM, response, and toxicity rates. Correlative studies include BRAF genotyping and assessment of intratumoral Raf inhibition, and apoptosis. Methods: Pt with MM and ECOG PS<2 are eligible. Prior therapy is allowed. Target accrual is 167 pt in 1 stage. All pt receive SO 400 mg po bid continuously. After 1 week of SO alone, pt without brain metastasis or prior TEM (A+B) are randomized to receive either extended dosing (ED): TEM 75 mg/m2 po qd for 6/8 weeks (Arm A), or standard dosing (STD): TEM 150 mg/m2 po qd for days1–5/28 (Arm B). Pt with prior TEM are treated with ED (Arm C) and pt with brain metastasis without prior TEM are treated with STD (Arm D). Responses are assessed using RECIST. Results: Accrual is complete for arms A and B. Results for 147 pt were evaluated ( Table ). SO + TEM resulted in a 19% overall response rate (ORR) [95% CI 11–30%] for pt on arms A+B. In this group, 3/78 pt (4%) developed CNS metastases while on study. Pt on arm D had a 17 % ORR [95% CI 7–34%]. Common grade 3 toxicities were hand-foot syndrome (14%), rash (9%), nausea (9%), and diarrhea (5%). Grade 3 lymphopenia was more common in arm A v. B (43% v. 16%, p=0.01). No significant difference in PFS was found between pt with WT v. mutant BRAF (n=33). Therapy-induced apoptosis was found in 8/9 serial biopsies. Analysis of MAPK phosphorylation in serial biopsies is planned. Conclusions: Updated results confirm the encouraging antitumor activity and tolerability of SO + TEM in pt with MM without a prior history of TEM. No significant financial relationships to disclose. [Table: see text]

Infusional topotecan with concurrent radiation followed by consolidation etoposide platinum and docetaxel for patients with high risk unresectable stage III non-small cell lung cancer (NSCLC)

17042 Background: Good PS patients (pts) with locally advanced NSCLC treated with concurrent chemoradiotherapy have a 20–40% 3 year survival. Treatment is arduous and poor PS or high risk pts often cannot complete a full course of treatment. The optimal combination of chemotherapy and radiation and the role of consolidation chemotherapy are unknown. Despite response rates exceeding 50%, most pts eventually progress with brain as the first site of relapse in up to 30%. Continuous infusion chemotherapy is better tolerated than intermittent chemotherapy combined with radiation and may improve outcome in other locally advanced aerodigestive malignancies, however it has not been studied extensively in NSCLC. Topotecan is active in NSCLC, can safely be combined with radiation, can be given by continuous infusion and penetrates the CNS making it an attractive study agent in locally advanced NSCLC. Methods: In this pilot study, 20 pts were treated with infusional topotecan 0.4 mg/m2/d with 3D conformal radiation to 63 Gy both delivered M-F for 7 weeks. Pts without progressive disease underwent consolidation chemotherapy with etoposide and platinum for one cycle to take advantage of upregulation of topoisomerase II by topotecan. Two cycles of docetaxel consolidation followed. Study endpoints include response, time to progression, survival, toxicity and development of CNS metastases. Results: All pts have completed induction chemoradiotherapy. 12/20 have completed consolidation. 17/20 pts had a PR and 1/20 SD after induction chemoradiation. 1 pt developed CNS metastases 228 days after study entry and is alive with disease at 541 days. 3 pts had pulmonary emboli. Therapy has been well tolerated with 1/20 grade 4 lymphopenia. Grade 3 hematologic toxicity was seen in 17/20 pts. Other grade 3 toxicities include esophagitis (3/20), esophageal stricture (2/20), pneumonitis (6/20), fatigue (6/20), weight loss (1/20). Conclusion: Continuous infusion topotecan with radiation is well tolerated and shows evidence of activity in the management of poor risk patients with unresectable stage III NSCLC. Survival data will be presented at the meeting. No significant financial relationships to disclose.

289. Adenoviral-Mediated p53 Gene Therapy (Advexin) in a Patient with Li-Fraumeni Syndrome with a Mixed Germ Cell Tumor: Tolerability and Response

Li-Fraumeni syndrome is an autosomal dominant disorder characterized by familial clustering of malignancies, predominantly sarcomas, breast cancer, brain tumors and adrenocortical carcinoma; an inordinate pattern of multiple primaries; and occurrence at a young age. Approximately 70% of the cases can be attributed to TP53 germ-line mutation 73% of which are located in the coding regions of exons 5 to 8. The index patient is a 25 year old woman presenting in 2002 with abdominal pain, anorexia and vomiting leading to the diagnosis of granulosa cell tumor confirmed by IHC-the second such case reported with the syndrome. TP53 sequencing showed 151delG, a frameshift mutation in exon 4. The mutation results in a stop codon downstream. Results of IHC for gene expression are pending. She was initially treated with bleomycin, cisplatin and velban. Following recurrence in 2004, the patient was received Ifosfamide, cisplatin and etoposide followed by the substitution of paclitaxel for Ifosfamide after development of encephalopathy. Disease progression eventuated in pelvic radiation and, with the development of CNS metastases, whole brain radiation.

Low-Dose Outpatient Chemobiotherapy With Temozolomide, Granulocyte-Macrophage Colony Stimulating Factor, Interferon-α2b, and Recombinant Interleukin-2 for the Treatment of Metastatic Melanoma

The objective of this study was to further investigate the efficacy and safety of low-dose outpatient chemobiotherapy in patients with unresectable metastatic melanoma. Thirty-one patients with histologically confirmed unresectable measurable metastatic melanoma were enrolled onto an open-label, multicenter phase II study. The treatment regimen consisted of oral temozolomide followed by subcutaneous biotherapy with granulocyte macrophage colony-stimulating factor, interferon-alfa, and recombinant interleukin-2 (rIL-2). Twenty-eight patients (90%) had M1c disease, and 58% had three or more sites of metastasis. Four patients (13%), all with M1c disease, had a complete response, and four patients had a partial response. The median progression-free survival was 4.9 months and the median overall survival was 13.1 months. Two patients (6%) developed CNS metastasis as the first site of disease progression, and 7 (23%) of 30 experienced CNS progression after receiving chemobiotherapy. A total of 112 cycles of therapy were administered. Toxicity occurred in 78% of the cycles and was grade 1 or 2 in the majority of cases and easily managed. Grade 4 toxicity occurred in 3% of the cycles. This low-dose chemobiotherapy combination produces clinical responses in patients with metastatic melanoma, even in those with M1c disease, is well tolerated, and allows home dosing. It offers a reasonable alternative to high-dose regimens, such as high-dose biochemotherapy or rIL-2 requiring prolonged periods of hospitalization, or single agent outpatient regimens, such as dacarbazine, which is usually not effective in patients with M1c disease. Furthermore, it may protect against the development of brain metastases.

High incidence of brain metastases at the time of death in women with metastatic breast cancer treated with trastuzumab

765 Introduction: Since Trastuzumab was introduced for the treatment of over-expressing HER 2 metastatic breast cancer a high incidence of patients (P) who developed CNS metastases have been reported. Methods: We retrospectively studied all the P with metastatic breast cancer treated at our hospital with T in order to assess the incidence of CNS metastases at the time of death. From January/99 to April/02, 42 P, all of them HER 2+++ (Dako's Herceptest or FISH +) were treated. Results: Median follow-up from starting T was 12 months (3–48). Response rate: Complete responses 7P (16,6%), Partial 13P (31%), Stable 9P (21,4%) and Progressive disease 13P (31%). By the time of analysis, 21P had died, all of them from progressive disease. 12P of them had CNS metastases diagnosed before death (57%): 4P were diagnosed prior to T and 8P during T treatment. In 6 of these cases CNS was the only site of progressive disease. Median time from beginning T and SNC metastases diagnosis was 7 months and median time from SNC involvement and death was 2 months. Conclusions: Incidence of SNC metastasis detected in women with metastatic breast cancer treated with T is very high by the time of death and this involvement is a dismal prognosis indicator. Prophylactic strategies should be investigated to avoid SNC progression, especially if a patient achieve an objective response with trastuzumab. No significant financial relationships to disclose.