bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survival results with AP23573, a novel mTOR inhibitor, in patients (pts) with advanced soft tissue or bone sarcomas: Update of phase II trial
Authors: Chawla S. P. , Tolcher A. W. , Staddon A. P. , Schuetze S. , D'Amato G. Z. , Blay J. Y. , Loewy J. , Kan R. , Demetri G. D. 
Published: March 2020

10076 Background: AP23573 is an mTOR inhibitor that has demonstrated single-agent activity in a broad range of sarcoma tumor types in phase I phase II trials. Overall survival (OS) was monitored to characterize OS in the treated population and in the subset of patients who achieved a clinical benefit response (CBR). Methods: Pts with advanced sarcomas, with no restrictions on prior therapies, were enrolled into 4 cohorts based on histologic subtype, in a phase 2, Simon's 2-stage trial. AP23573 (12.5 mg, i.v.) was administered daily × 5 every 2 wks. Efficacy was assessed using RECIST, with CBR defined as a complete or partial response or stable disease for at least 16 wks duration. OS was defined as the time from the first dose of AP23573 to the date of death from any cause. Kaplan-Meier estimates of the survival times of the population were calculated with OS time censored at the last date the pt was known to be alive when the confirmation of death is absent or unknown. Patients are continuing to be followed for OS in this ongoing trial. Results: 212 pts (105 M/107 F; median age, 50.6 yrs ([17–79 yrs]) were treated. Most pts (79%) had received =2 prior treatments, and over 90% of pts had disease progression at time of enrollment. The overall CBR rate was 29%, including 5 PRs (4 bone sarcoma, 1 MFH). The median OS was 40.1 wks for the entire study population. In the subset of patients achieving CBRs the median time to OS was 67.6 wks, suggesting that achievement of CBR, which is a measure of tumor control, correlates with extending OS. Conclusions: AP23573 exhibits single-agent activity in pts with advanced sarcomas as demonstrated by the CBR rate as a primary efficacy endpoint. The results of the OS analysis suggest that achieving a CBR in this pt population can result in prolonged survival. The consistency of this finding should be further examined with other pt factors that are also hypothesized to correlate for survival in this pt population. [Table: see text] [Table: see text]
Serum proteomic prediction of progression-free survival in HER2-negative metastatic breast cancer patients receiving docetaxel as first-line treatment
Authors: Goncalves A. , Deblock M. , Esterni B. , Toiron Y. , Tarpin C. , Charaffe-Jauffret E. , Chabannon C. , Extra J. M. , Viens P. , Borg J. P. 
Published: March 2020

1010 Background: Docetaxel has become a standard in management of metastatic breast cancer (MBC) patients (pts). However, there is no validated clinical or biological marker allowing to predict which pts are most likely to benefit from it. We evaluated the ability of Surface enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF MS) to identify serum proteins that could predict for docetaxel activity. Methods: We prospectively collected pretreatment serum of 81 HER2- MBC pts receiving docetaxel as first-line treatment. Serum samples were denatured, and then incubated in triplicates with three different ProteinChip arrays (Ciphergen): H50, IMAC30-Cu and CM10. Arrays were analysed using a PBSIIc ProteinChip reader (Ciphergen). Results: Pt characteristics were the following: median age, 53 ys (34 -71); Hormonal Receptivity (HR) (yes/no/na, %) 76/15/9; Disease-free interval (DFI) (≤24 months/>24 months, %) 42/58; visceral disease (yes/no, %) 35/65; metastatic sites (<3/≥3,%) 85/15; Median follow-up, 19.8 months (95%CI, 16.1–21.9); Median Progression-free survival (PFS), 12.9 months (95%CI, 8.8–18). Overall, 521 protein peaks were resolved. Univariate Cox proportional hazards regression identified 20 proteins significantly associated to PFS (P < 0.01). A stepwise procedure using the Akaike information criterion was applied to build a Cox model with 7 protein peaks allowing to calculate a risk index for each pt. Using the risk index median value as cut-off, high-risk and low-risk populations with dramatic differences in PFS were identified (2-year PFS of 0% and 54.6%, p = 1.45 10–8). Validation methods included leave-one-out cross validation and iterative resampling. In a multivariate Cox regression including conventional prognostic factors (HR, DFI, visceral metastasis) and serum protein risk index, the latter retained the strongest independent prognostic significance for PFS. Identification of proteins with differential expression according to clinical outcome is ongoing. Conclusions: Serum proteomic profiling may help select MBC Pts who will benefit from treatment with docetaxel. Validation on an independent dataset is planned. No significant financial relationships to disclose.
Central nervous system (CNS) metastases (mets) in HER2+ metastatic breast cancer (MBC) patients (pts): Patterns of relapse and impact on survival
Authors: Verma S. , Azzi J. S. , Vandermeer L. A. , Spaans J. N. 
Published: March 2020

1017 Background: Several studies have documented an increase in the incidence of CNS mets in HER2+ MBC pts (Bendell, 2003; Heinrich, 2003). Of interest is whether there are any specific patterns of CNS metastasis and if they have an impact on survival. Methods: This retrospective study included 100 HER2+ MBC pts who received trastuzumab with or without chemotherapy for their disease between Jan 1/00 and Jan 1/05. Pts were selected for the presence (n=50) or absence (n=50) of CNS mets. Demographics, location of mets and timeline-related variables (survival) were compared. Results: In 50 MBC pts with CNS mets, the most common site was the cerebellum (82%); and symptoms were related to increased intracranial pressure, primarily as a result of disease-related cerebral edema (73%). Compared to 50 pts without CNS mets, there was no statistically significant difference in overall survival from the time of initial diagnosis of breast cancer. Of interest, pts with CNS mets lived longer (61.3 months) than pts without CNS mets (47.1 months). However, survival after disease progression or recurrence significantly favoured patients with CNS mets (36.8 months v. 22.0 months respectively; p=0.02). Causes of death in both cohorts were also examined. Conclusions: In our observation, CNS mets did not have an adverse effect on overall survival. In fact, pts who developed CNS mets lived longer than those pts without CNS mets. This may in part be due to more aggressive management of CNS mets, or lack of extracranial progression. No significant financial relationships to disclose.
Trastuzumab treatment and the risk of central nervous system (CNS) metastases
Authors: Pinder M. C. , Chang H. , Broglio K. R. , Michaud L. B. , Theriault R. L. , Sahin A. , Buchholz T. , Hortobagyi G. N. , Esteva F. J. 
Published: March 2020

1018 Background: In the era of trastuzumab, HER2-positive breast cancer confers an increased risk of central nervous system (CNS) metastases. While several studies have examined CNS metastases in trastuzumab-treated patients, data are sparse regarding CNS metastases in trastuzumab-naïve HER2-positive patients. We evaluated time to CNS metastasis, death, and death subsequent to brain metastasis in relation to trastuzumab treatment. Methods: The study population included 750 patients diagnosed with HER2-positive metastatic breast cancer (HER2+ MBC) between June 1977 and January 2006. The association between trastuzumab treatment and the outcomes of time to CNS metastasis and time to death following CNS metastasis were determined using Cox proportional hazards models that included trastuzumab treatment as a time-dependent covariate. Multivariable Cox proportional hazards models were fit to determine the association between trastuzumab treatment and outcomes after adjustment for known prognostic factors. Patients with HER2+ MBC treated at our institution before trastuzumab was available served as our control group. Results: Of the 750 patients included, 689 patients received trastuzumab during the follow-up period while 61 patients were not treated with trastuzumab. Median follow-up was 32 months. A total of 251 patients developed CNS metastases. After adjusting for other prognostic variables including age, ER status, PR status, pathological stage, and site of initial metastasis, patients who received trastuzumab had 2.84 times the risk of CNS metastases (95 % CI = 1.87, 4.30, p < 0.0001) compared to patients who did not receive trastuzumab. Time to death following brain metastasis did not differ significantly between trastuzumab- treated and -untreated patients. Conclusions: In our large series, patients with HER2+ MBC treated with trastuzumab were at significantly increased risk of developing CNS metastases compared to patients who did not receive trastuzumab. This finding warrants further investigation into biological mechanisms that may account for this difference. No significant financial relationships to disclose.
BCIRG 007: Serum HER2 levels in women with metastatic HER2-amplified breast cancer
Authors: Valero V. , Roche H. , Pienkowski T. , Canon J. , Zhao Y. , Carney W. , Mackey J. , Taupin H. , Buyse M. , Slamon D. 
Published: March 2020

1020 Background: BCIRG 007 is a multicenter, phase 3 randomized trial comparing docetaxel and trastuzumab (TH) with docetaxel, platinum salt (cisplatin or carboplatin) and trastuzumab (TCH) as first line chemotherapy in women with metastatic breast cancer (MBC). Women enrolled in the study had to have primary breast tumors with HER2 amplification as determined by centralized FISH analysis. Methods: We determined the percentage of subjects with HER2 amplification who had elevated (>15ng/mL) baseline levels of serum HER2 prior to the initiation of trastuzumab-based therapies. Baseline was considered to be the last available determination within 21 days prior to first treatment. Results: The median baseline serum HER2 levels was 75.8 ng/mL (range=8–3,280 ng/mL) for all subjects (n=123), with no statistical difference between subjects randomized to receive TH (median=65.9 ng/mL, n=64) and those randomized to receive TCH (median=89.9 ng/mL, n=59). Overall, 89% of the 123 subjects with HER2-amplified primary tumors had serum HER2 levels >15 ng/mL at the time of metastatic disease (86% in TH vs 92% in TCH). Conclusions: There was no statistical impact of baseline serum HER2 levels on any important clinical event: response to treatment, clinical benefit (response or stable disease for more than 24 weeks), disease progression or death. Conversely, when serum HER2 was measured over time, subjects with higher levels had an elevated risk of experiencing progressive disease (p=.003), even after adjustment for extent of disease (1 or 2 vs 3 or more organs involved) and presence of visceral disease. These analyses suggest that monitoring serum HER2 levels over the course of disease may be a means for detecting progressive disease in women with HER2 amplified breast cancer. Given the long intervals between the serum HER2 measurement and progression (up to 9 months), caution is required in interpreting these results. No significant financial relationships to disclose.
Changes in estrogen receptor (ER), progesterone receptor (PR) and HER2/neu status with time: Discordance rates between primary and metastatic breast pathology samples
Authors: Broom R. J. , Tang P. , Simmons C. , Bordeleau L. , O’Malley F. P. , Miller N. , Andrulis I. L. , Brenner D. M. , Clemons M. 
Published: March 2020

1024 Background: The occurrence of changes in tumor receptor profile (ER, PR and HER-2/neu) between primary and metastatic tissue has been recognised and may have significant treatment implications. Previous reports on receptor discordance rates have tended to be from sub-studies of clinical trials. We sought to evaluate the degree of ER, PR and HER-2/neu receptor discordance in patients treated at two Canadian cancer centres. Methods: Archival data was collected on patients for whom tissue from both primary and metastatic sites was available. Patients with recurrences in the breast or axilla were excluded. ER, PR and HER-2/neu status in the primary and metastasis were compared. Additional information including adjuvant therapy and time to metastasis biopsy was gathered. Results: To date, data is available on 80 patients. Hormone receptor (HR) status was available for 96% of primaries and 56% of metastases. HR status on both the primary and the metastasis was performed in 51% of cases. The discordance rate for ER was 21% (2-sided p=0.0096). 12% of patients changed from ER+ to ER- and 9% changed from ER- to ER+. The discordance rate for PR was 37% (2-sided p=0.0001), with all of these patients changing from PR+ to PR-. No significant HR discordance was found among different adjuvant hormone therapy subgroups. There was no correlation between HR discordance and time to rebiopsy. No discordance for HER-2/neu was found. Conclusions: Significant discordance for HR status was observed, 21% for ER and 37% for PR. HER-2/neu discordance was not observed. We are currently exploring the practical implications of these discordance rates on the management of advanced breast cancer patients in a prospective trial. No significant financial relationships to disclose.
Final Results of ECOG1100: A phase I/II study of combined blockade of the ErbB receptor network in patients with HER2- overexpressing metastatic breast cancer (MBC)
Authors: Moulder S. L. , O’Neill A. , Arteaga C. , Pins M. , Sparano J. , Sledge G. , Davidson N. 
Published: March 2020

1033 Background: Activation of EGF receptor has been associated with resistance to trastuzumab in breast cancer cell lines. EGFR tyrosine kinase inhibitors inhibit HER2 phosphorylation and synergize with trastuzumab in HER2+ cell lines that co-express EGFR. Methods: Pts with MBC and HER2 overexpression by immunohistochemistry (3+) and/or HER2 gene-amplification by FISH, 0–2 prior chemotherapy regimens for met disease, LVEF 50%, and no prior trastuzumab were treated with trastuzumab 2 mg/kg/wk and gefitinib 250- 500 mg/day until disease progression, unacceptable toxicity or withdrawal of consent. The phase I portion of the trial used a 3+3 design to determine MTD. In the phase II portion of the trial, patients were stratified based upon prior chemotherapy exposure (Group 1= no prior exposure to chemotherapy, Group 2= prior exposure to 1–2 chemotherapy regimens). Response measured using RECIST criteria. The primary endpoint was to increase proportion progression free from 50 to 65% at 6 months in Group 1 and from 50 to 70% at 3 months in Group 2. Results: Phase I: DLT (Grade 3 diarrhea) occurred in 2/3 patients treated at the 500 mg/day dose level of gefitinib in combination with weekly trastuzumab. 0/3 patients treated at the 250 mg/day dose level experienced DLT. This was considered MTD and was the dose selected for the Phase II portion of the trial. Phase II: 36 eligible pts were enrolled. Most patients were ECOG PS of 0 and had visceral organ involvement. Of the patients enrolled in Group 1, one pt achieved a CR, one PR and 7 had SD (≥ 24 weeks). Median time to progression (TTP) was 2.9 months (95% CI, 2.5–4). In Group 2 no responses were observed with a median TTP of 2.5 months (95% CI, 1.5- 2.7). Most common severe toxicities were rash (grade 3, 14%) and diarrhea (grade 3, 30%). No grade 3 cardiac toxicity was encountered. Conclusions: Trastuzumab in combination with gefitinib at doses of 250 mg/day demonstrated an acceptable toxicity profile; however, during planned interim analysis, the TTP did not meet predetermined statistical endpoints required for study continuation. These results do not support the further use of this combination and have implications for other trials using trastuzumab and EGFR TK inhibitors simultaneously. [Table: see text]
Preliminary results of a multicenter phase II trial of vinflunine (with trastuzumab in HER2+ pts) as first-line treatment in metastatic breast cancer
Authors: Peacock N. W. , Spigel D. R. , Mainwaring M. G. , Thompson D. S. , Simons L. , Rubin M. S. , McCleod M. , Harwin W. N. , Schreiber F. J. , Yardley D. A. 
Published: March 2020

1043 Background: Vinflunine (VFL) is a new and innovative microtubule inhibitor of the vinca alkaloid class that achieves high intracellular concentrations. By inhibition of tubulin polymerization, cell proliferation is arrested leading to apoptotic death. Demonstrating anti- angiogenic and vascular disrupting activities, VFL has demonstrated significant efficacy as 2nd line chemotherapy in MBC (M. Campone, BJC 2006). This trial was designed to evaluate the response rate and safety of VFL as 1st line therapy in MBC as well as its activity in combination with trastuzumab in HER2+ MBC pts. Methods: Eligibility: 0 prior regimens for MBC, > 6 mo from adjuvant therapy, RECIST measurable disease, ECOG PS 0–2, adequate organ function, < G2 neuropathy. Treatment: 320 mg/m2 IV over 20 minutes q3 weeks; 280 mg/m2 with trastuzumab 6 mg/kg q3 weeks in HER2+ pts. Response evaluations q9 weeks; treatment continued until progression or toxicity. A total of 96 pts will be enrolled, 48 pts per each of 2 cohorts, HER2- and HER2+. Results: 18 pts are enrolled, 13 pts evaluable for toxicity and 12 pts for response. 3 pts received VFL monotherapy and 10 pts were treated with VFL + trastuzumab. Median age: 59 years (43–78). ECOG PS 0: 9 pts, 1: 3 pts, 2: 1 pt. Prior adjuvant chemo: 7 pts (54%), with 5 prior anthracyclines and 6 prior taxanes. 2 pts received adjuvant hormonal therapy only. 4 pts presented with de novo stage IV HER2+ MBC. Metastatic disease sites: liver: 6 pts, lung: 7 pts, bone: 5 pts, lymph nodes: 6 pts. 46% had 3 or more sites of organ involvement. Median of 3 cycles (range:1 - 11) was delivered. 7 pts (58%, all HER2+) had a PR and 4 pts (33%) achieved SD. Only 1 pt progressed. Heme toxicity: G3/4 neutropenia: 2 pts (16%); no febrile neutropenia was noted. G3 non-heme toxicity consisted of N/V: 2 pts and myalgia, 2 pts. There were no G4 events. 4 pts were hospitalized (vomiting: 2, cerebro-vascular accident: 1, back pain: 1 pt). 92% of pts remain free of progression at 6 months. Median TTP has not been reached. Conclusions: Vinflunine is a promising new drug with a high level of activity as first line MBC therapy, especially in combination with trastuzumab. VFL is well tolerated in this patient population with a manageable toxicity profile. Accrual to this trial continues. [Table: see text]
Phase I study of a novel capecitabine schedule based on Norton-Simon mathematical modeling
Authors: Theodoulou M. , Traina T. A. , Dugan U. , Lake D. , Fornier M. , Feigin K. , Patil S. , Edwards C. , Norton L. , Hudis C. A. 
Published: March 2020

1045 Background: We have previously described a mathematical method to optimize chemotherapy dose and schedule (Norton et al, AACR 2005). Capecitabine (C) has activity in breast cancer when conventionally dosed for 14 days (d) q3 weeks (14/7). However, the predicted optimal dosing schedule for C using our model is 7d followed by a 7d rest (biweekly, 7/7). We tested this hypothesis in a Phase I/II study described below. Methods: Eligible patients (pts) have measurable, metastatic breast cancer (MBC), ECOG performance status (PS) =2 and normal organ function. There is no limit to number of prior chemotherapy (CRx) regimens. Pts with prior fluoropyrimidine for MBC are excluded. HER2+ pts must not be candidates for trastuzumab. C is given in divided daily doses for 7d followed by a 7d rest. A standard “3+3” dose escalation scheme employs flat dosing which begins at 1,500mg BID and increases by 500mg/dose level. Primary endpoint is the maximum tolerated dose (MTD), defined as the highest dose for which the incidence of dose-limiting toxicity (DLT) is <33%. Results: 19 pts are now accrued; 17 pts have been treated, 2 withdrew prior to receiving C. Medians: age 47 y (range 34–62 y) and ECOG PS 0 (range 0–2). Sites of MBC: bone 8, viscera 16, soft tissue 11. ER/PR+ 11. HER2+ or unknown 2. Prior adjuvant tx: CRx 17, hormone tx 10. Six pts had adjuvant fluoropyrimidine-based tx. Three pts had 1 prior CRx for MBC; 12 pts received first-line hormone tx for MBC. Fifteen pts had prior anthracycline and taxane. Treatment-related toxicities after a median of 4 cycles (range 1–10) are shown in the table . The MTD has not been reached. Pts continue accrual to the 2500mg/2500mg dose level. Conclusions: Capecitabine 7/7 is well tolerated and allows for safe delivery of higher daily doses than routinely used in practice, as predicted by the mathematical model. Capecitabine 7/7 will be tested in a Phase II program at MSKCC in combination with targeted agents. [Table: see text] No significant financial relationships to disclose.
A phase II study of anastrazole and fulvestrant in combination with gefitinib in patients with newly diagnosed ER-positive breast cancer
Authors: Massarweh S. A. , Tham Y. L. , Weiss H. , Fuqua S. , Huang J. , Elledge R. 
Published: March 2020

1050 Background: Endocrine therapy for ER+ breast cancer is effective and relatively nontoxic, but is limited by de novo and acquired resistance. Preclinical studies suggest that complete ER blockade along with inhibition of co-expressed growth factor receptors enhances endocrine response and overcomes resistance. Methods: We conducted a phase II trial of combined anastrazole and fulvestrant with gefitinib, an EGFR tyrosine kinase inhibitor, as intial therapy in postmenopausal women with locoregional or metastatic ER+ breast cancer. A tumor core biopsy was done at baseline and after 3 weeks. Patients received treatment for 4 months. Surgery was then offered if the tumor was operable. Primary endpoint was clinical response as defined by RECIST criteria and secondary endpoints were safety/tolerability, complete pathologic response rate (pCR), and biomarker analysis. Planned sample size was 60 patients, but the study closed after 15 patients were enrolled because of poor accrual. Results: Median age at diagnosis was 67 years. Median clinical tumor size was 7 cm and 4 patients had metastases. 11 patients (73%) had ER+/PgR+ tumors and 4 (27%) had ER+/PgR- disease. 3 patients withdraw from the study before response was assessed. Of the12 remaining patients there were 2 complete responses (17%), 5 partial responses (42%), 5 with stable disease (42%), and 2 (17%) with progressive disease. Of the 7 patients who had surgery at 4 months, none had pCR. Most common adverse events were rash in 4 patients, Diarrhea in 4, joint symptoms in 3, and abnormal LFT’s in 3. All adverse events were reversible. Biomarkers, including arrays and Ki67, are pending and will be presented at the meeting. Conclusions: Complete ER blockade using anastrazole and fulvestrant with EGFR inhibition is well-tolerated and has activity in this cohort of patients with relatively advanced ER+ breast cancer. Despite its documented benefit and low toxicity, accrual to neoadjuvant endocrine therapy studies remains poor in the US, largely because of physician hesitance to refer patients for non-chemotherapy studies. More effort is needed to increase physician awareness about the value of endocrine therapy, and to increase accrual to trials that address the question of endocrine resistance. [Table: see text]