bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized, double-blind phase II study of the oral tyrosine kinase inhibitor (TKI) axitinib (AG-013736) in combination with docetaxel (DOC) compared to DOC plus placebo (PL) in metastatic breast cancer (MBC)
Authors: Rugo H. S. , Stopeck A. , Joy A. A. , Chan S. , Verma S. , Lluch A. , Liau K. F. , Kim S. , Bycott P. , Soulieres D.
Published: March 2020

1003

Background: Single-agent DOC is commonly used to treat MBC. Axitinib (AG) is a potent TKI of VEGFRs. A phase I lead-in study identified 80 mg/m2 q3wks of DOC in combination with 5 mg BID of AG as the recommended phase 2 dose. The primary objective was to determine whether the time to progression (TTP) of AG+DOC arm is superior to DOC+PL. Methods: Pts with no prior chemotherapy for MBC and =12 mos from adjuvant chemotherapy (aCT), measurable disease, ECOG performance status (PS) of 0–2, and no uncontrolled brain metastases were randomly assigned (2:1) to receive treatment with either DOC+AG or DOC+PL without prophylactic growth factor in cycle 1. Tumor measurements were performed q9wks. Pts were stratified according to estrogen receptor (ER) status, prior aCT and PS (0–1 or 2). Results: A total of 168 pts were randomized. 92 pts had received prior aCT, 27 of whom received a prior taxane. Treatment arms were well balanced for prior adjuvant and taxane therapy. A median of 7 cycles of AG+DOC (range: 1–18) and 7 cycles of DOC+PL (range: 1–23) were administered. The most common non-hematologic adverse events observed in the AG+DOC arm included diarrhea (60%), nausea (53%), alopecia (51%), fatigue (49%), stomatitis (44%) and vomiting (40%). Grade 3/4 adverse events that were increased with AG+DOC vs DOC included febrile neutropenia (16 vs 7%), fatigue (13 vs 5%), stomatitis (13 vs 2%), diarrhea (11 vs 0%) and hypertension (5 vs 2%). Other grade 3/4 hematologic toxicities were similar in both arms. The median TTP (by RECIST) was 8.2 mo with AG+DOC arm and 7 mo with DOC+PL arm with a hazard ratio of 0.73 (prespecified, one-sided p=0.052). The overall response rate (ORR) was 40% for AG+DOC arm and 23% for DOC+PL arm (p=0.038). In a hypothesis-generating subgroup analysis, the median TTP in patients receiving prior aCT was 9.0 mo with AG+DOC arm and 6.3 mo with DOC+PL arm with a hazard ratio of 0.54 (p=0.012). Within this stratum, ORR was 45% for AG+DOC arm and 13% for DOC+PL arm (p=0.003). Conclusions: The anti-angiogenic TKI AG combined with DOC (80 mg/m2 q3wks) as first line therapy for MBC has an acceptable safety profile and promising anti-tumor activity.

No significant financial relationships to disclose.
Paclitaxel in patients (pts) with advanced angiosarcomas
Authors: Schlemmer M. , Reichardt P. , Verweij J. , Hartmann J. T. , Judson I. , Thyss A. , Blay J. Y.
Published: March 2020

10033

Background: Angiosarcomas represent a heterogenous group of rare sarcomas with specific clinical behaviour and risk factors. Paclitaxel has been suggested to induce tumor control in a proportion of pts with angiosarcoma while being inactive in other soft tissue sarcomas subtypes. The objective of this retrospective study was to investigate the antitumor activity of this compound in a larger series and a multicenter setting. Patients and Methods: Data from pts with angiosarcoma treated with paclitaxel in centers of the EORTC Soft Tissue and Bone Sarcoma Group were collected using a standardized data collection form. Results: Data from 32 pts were collected from 10 centers. There were 17 males and 15 females with a median age of 60.4 years (range 24–91). Eight pts (25%) had angiosarcomas of the face and scalp, 24 pts (75%) at other primary sites. Ten (31 %) pts had a previous cancer history, 7 of whom had been irradiated for breast cancer. Ten (31 %) pts had received 1st line chemotherapy (ctx) and 3 pts 2nd line ctx prior to treatment with paclitaxel. All 13 (40%) pretreated pts had doxorubicin, 5 pts in combination with ifosfamide as 1st line and 3 pts ifosfamide as 2nd line ctx. 21 (66 %) pts received paclitaxel 175 mg/m2 every 3 weeks, and 11 (34 %) received 75–100 mg/m2weekly. The overall response rate (RR) was 62.5 % [including 1 CR (3%) and 19 PR (59%)]; in pts with face and scalp primary sites the RR was 75% (1CR, 5 PR), whereas pts with angiosarcoma at other sites achieved a response in 58% (14 PR). PFS was 7.6 months for all 32 pts. Conclusion: Paclitaxel was an active agent in angiosarcoma in this retrospective multicenter study, also in angiosarcoma originating at other sites than scalp and face. These results need to be confirmed in a controlled, prospective phase II study.

No significant financial relationships to disclose.
Retrospective review of treatment for angiosarcoma at Fox Chase Cancer Center over the past 15 years
Authors: Saroha S. , Litwin S. , von Mehren M.
Published: March 2020

10034

Background: Angiosarcoma is a rare vascular neoplasm that may arise in a variety of anatomic locations. There is limited published data on chemotherapy treatment in angiosarcoma and data on taxane therapy does not utilize contemporary schedules. We present a retrospective analysis of our institution's experience with angiosarcoma over the past 15 years. We reviewed patient characteristics, overall survival and response to various chemotherapeutic agents. We specifically compared the response to weekly paclitaxel with all other chemotherapeutic agents used over the study period. Methods: Medical records of all the patients treated with the diagnosis of angiosarcoma at Fox Chase Cancer Center between January 1990 and June 2005 were reviewed. Overall survival was determined by the Kaplan-Meier method. Response to chemotherapy was determined at two-month follow-up after starting treatment. Clinician judgment was used to define response for superficial lesions. We compared the response to weekly paclitaxel with all other chemotherapy regimens using Fisher's exact test. p <0.10 was considered significant. Results: A total of 39 patients were identified. Most common sites for angiosarcoma were head and neck (including scalp) and breast. Median overall survival was 21 months. Since many patients received several lines of chemotherapy, 40 chemotherapy administrations were identified for analysis. 10 of 13 patients showed response to weekly paclitaxel versus 14 of 27 for non-paclitaxel regimens, which was not statistically significant by Fisher's exact test (2-tail, p=0.18). We also analyzed the response with respect to different anatomic locations of angiosarcoma and individual chemotherapy regimens used, however the numbers were too small for statistical comparisons. Conclusions: Angiosarcoma is an aggressive malignancy with poor survival rates. Our study demonstrated that paclitaxel has efficacy in angiosarcoma, although not statistically superior to non-taxane containing regimens.

No significant financial relationships to disclose.
Treosulfan high dose therapy with autologous stem cell rescue in high-risk Ewing tumors
Authors: Dirksen U. , Lanvers-Kaminski C. , Ranft A. , Bremer A. , Boos J. , Jürgens H.
Published: March 2020

10039

Background: High dose (HD) chemotherapy using a busulfan-containing regimen has been proven advantageous for some high risk Ewing tumor (ET) patients. HD busulfan is not compatible with radiotherapy to central axis sites. Treosulfan is a bifunctional alkylating agent, structurally related to busulfan, that has shown to be safe even in heavily pretreated patients and patients at risk to treatment related toxicity. Methods: In vitro: In order to compare the cytotoxicity of busulfan and treosulfan, growth inhibition was tested by a modified (4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium-bromide (MTT) assay. In vivo: 11 patients with primary disseminated ET and contraindication for busulfan HD treatment and 11 patients with relapsed ET were referred to HD treosulfan (36 g/m2) and melphalan (140 mg/m2) followed by autologous stem cell rescue. Results: In vitro: Busulfan and treosulfan were cytotoxic in a time and dose dependent manner. Treosulfan was 15-fold more cytotoxic compared to busulfan. In vivo: The median age in patients with disseminated ET was 14.3 years, in relapsed ET 22.7 years. Sex distribution was equal. Response status prior to HD treosulfan was: stable disease in 4, partial response in 6, complete remission in 8, progressive disease in 1, not documented in 3 patients. Median follow up time in patients with disseminated ET was 0.91 years. All patients are alive. Four patients have relapsed within 2 years after HD treatment. Median follow up time in relapsed ET was 1.35 years. Seven patients are in remission, one patient is under treatment and two patients have died after relapse. HD was well tolerated with mucositis °3 in seven, °4 in three, stomatitis °3 in four, °4 in three , neutropenic infection °3 in three and reversible myelitis in one patient. Conclusions: Treosulfan HD treatment is a feasible therapeutic option without overt acute toxicity for patients with advanced ET. Efficacy and late effects remain to be evaluated.

No significant financial relationships to disclose.
Tumor immunotherapy targeting WT1 (Wilms’ tumor gene) peptide for bone and soft-tissue sarcomas: A preliminary report
Authors: Ueda T. , Kakunaga S. , Oka Y. , Oji Y. , Tsuboi A. , Hashimoto N. , Myoui A. , Aozasa K. , Sugiyama H. , Yoshikawa H.
Published: March 2020

10042

Background: WT1 (Wilms’ tumor gene) is originally isolated as a tumor-suppressor gene in a subset of Wilms’ tumors, however, recent studies have indicated its oncogenic activity in various types of cancers, and demonstrated that WT1-specific cytotoxic T lymphocytes specifically kill WT1-expressing cancer cells, thus WT1 protein can be a molecular target for cancer immunotherapy as an attractive tumor rejection antigen. However, WT1 expression in human bone and soft-tissue sarcomas has been poorly understood. Methods: 1) The expression levels of WT1 gene were examined in 36 cases of various types of human bone and soft-tissue sarcomas using quantitative RT-PCR method. They included 12 MFH (11 soft-tissue, 1 bone), 9 osteosarcomas, 6 synovial sarcomas, 4 myxoid liposarcomas, 3 MPNST, one each case of angiosarcoma and clear cell sarcoma. 2) Then, we conducted a phase I/II clinical trial of tumor-specific immunotherapy targeting WT1 peptide for various kinds of cancers including 12 patients with locally advanced and/or metastatic sarcoma (bone 2, soft-tissue 10) which showed WT1 expression and HLA -A*2402. Patients were intracutaneously injected with 3.0mg of HLA- A*2402-restricted natural/or modified 9-mer WT1 peptide emulsified with Montanide ISA51 adjuvant weekly. After 12-times injection, clinical response was evaluated by RECIST. Results: 1) 28 (78%) out of 36 cases of various types of bone and soft-tissue sarcomas overexpressed the WT1 gene, and its expression at the protein level was confirmed by immunohistochemical analysis, suggesting a possibility of immunotherapy using WT1 peptide vaccine for sarcomas. 2) The clinical responses included 4 SD and 7 PD with a case of long-standing SD over 1.5 years. One patient discontinued treatment with patient's decision. There were no patients with objective response (PR/CR). Conclusion: The present preliminary study suggested that tumor immunotherapy using WT1 peptide vaccine can be a new treatment strategy for patients with bone and soft-tissue sarcomas.

No significant financial relationships to disclose.
Efficacy and safety of adjuvant post-surgical therapy with imatinib in patients with high risk of relapsing GIST
Authors: Zhan W. H. ,   China Gastrointestinal Cooperative Group
Published: March 2020

10045

Background: GIST has a high recurrenc e rate and disease-related mortality even after completed resection of primary tumor. Imatinib(IM) has shown tremendous efficacy in treating patients with metastatic and unresectable GISTs. The primary objective of the study was to evaluate the efficacy and safety of adjuvant post-surgical therapy with IM in GIST patients who had high risk to relapse. Methods: This prospective, open-label, multi-center trial was conducted in 16 hospitals in China. Patient eligibility criteria included patients >18 years old, diagnosed with CD117+ GIST of either =5cm macroscopic tumor size or = 5/50 HPF in mitosis count pathologically. Patients were started on IM 400mg/d for at least 12 months within 4 weeks after completed resection. Primary endpoint was relapse or metastasis rates. Secondary endpoints were disease free survival (DFS), overall survival rate (OSR) and quality of life. From Aug 16 2004 to Sep 13 2005, 57 patients (34 men) enrolled in the trial and average age of patients was 50.6. The primary tumor location was stomach in 50.9%, small intestine in 38.6%. Tumors size was >5cm in 92.9% of patients, and 73.7% of patients had a mitosis count over 5/50 HPF. The majority of patients tested positive for CD34 (82.5%) and negative SMA, S-100 and Desmin results. Results: Of 57 patients, as of date of data cut-off (Dec 31, 2006) 51 patients were included in the ITT analysis and 43 patients (75.4%) finished at least 12 months of IM treatment, and Tumor relapses or metastasis were identified in 2 patients (3.92%) 350 and 680 days post-operation. No death was reported. Median DFS was 385 days. 57.89% of the safety population had adverse events. No serious adverse event reported. 50.88% of the safety population had adverse events related to the treatment of IM based on the determination of investigators. The score in quality of life showed no statistically significant difference between the baseline and the follow-up visits. Conclusions: IM is a promising adjuvant post-surgical therapy in patients with high risk of relapsing GIST. But the optimal doses and duration of adjuvant treatment are still unknown. On the basis of this study, a multi-institutional randomized controlled trial will be necessary.

No significant financial relationships to disclose.
Verification of imatiNib cost-effectiveness in advanced gastrointestinal stromal tumor in British Columbia (VINCE)
Authors: Mabasa V. , Taylor S. C. , Chu C. C. , Moravan V. , Peacock S. , Knowling M.
Published: March 2020

10049

Background: To evaluate the cost-effectiveness of imatinib in British Columbia Cancer Agency (BCCA) patients with advanced gastrointestinal stromal tumors (GIST) in terms of median overall survival (OS) and median progression-free survival (PFS). Results were also compared to imatinib literature reports. Methods: A pragmatic, retrospective medical record review identified BCCA patients with advanced GIST who received imatinib or historical treatment during successive, pre-specified time periods. Data was collected on survival, duration of therapy, progression free status, and cost of drug, labour and supplies. Primary outcome was the cost-effectiveness of imatinib based on median-OS (Kaplan Meier method). Secondary outcomes were cost-effectiveness based on median overall-PFS, cost of therapy per patient, 1-year OS, and 1-year PFS. This study was conducted from the perspective of the BCCA. Sensitivity analyses varying effectiveness over the 95% CI, cost over the range of treatment duration, discounting level at 0, 3 and 5%, and comparing effectiveness to literature controls were performed. Life expectancy (mean survival), was also calculated and used in the CE sensitivity analysis. Results: Forty-six and 47 patients in the imatinib and historical groups respectively were analyzed. Median-OS in the imatinib group was 66.7 months (95% CI 61.7, infinity) compared to 7.7 months (95% CI 6.0, 12.6) in the historical group. Median-PFS was 45.3 months (95% CI 24.4, infinity) and 5.6 months (95% CI 3.5, 8.5) respectively. The 1-year OS and 1-year PFS for the imatinib group was 95.4% (95% CI 82.9, 99.2) and 81.4% (95% CI 66.1, 91.1) compared to 32.6% (95% CI 20.0, 48.1) and 17.4% (95% CI 8.3 - 32.0) in the historical group. No difference was seen between the imatinib study results and literature reports. The annual incremental cost-effectiveness ratio was $15,882 per median life year gained and $23,603 per median year of PFS for imatinib. Conclusions: Imatinib for advanced GIST is a cost- effective treatment in BC. Results were robust across the range of sensitivity analyses performed.

No significant financial relationships to disclose.
Evaluation of imatinib mesylate (IM) in patients with large volume gastrointestinal stromal tumors (GISTs)
Authors: Byrd D. M. , Demetri G. D. , Joensuu H. , von Mehren M. , Heinrich M. , Eisenberg B. , Fletcher J. , Corless C. , Fletcher C. , Heintz D. , Blanke C. D.
Published: March 2020

10054

Background: GIST size is one of the most important prognostic markers for recurrence and poor survival. However, little information exists regarding the relationship between tumor volume and clinical outcome after treatment with IM. A phase II randomized clinical trial of two dose levels of IM (400 vs. 600 mg daily) in pts with incurable GIST was previously presented (Proc ASCO 2001; Combined GI Symp 2004 and 2007). With median follow-up of 64 months, we report additional analyses of the relationship between tumor volume and IM efficacy. Methods: Data on initial tumor bulk were prospectively collected, and 146 pts were separated into quartiles according to total tumor volume: < 39.1 cm2 (n=36), 39.1 = 102.16 cm2 (n=37), 102.16 = 262.6 cm2 (n=36), = 262.6 cm2 (n=37). Tumor bulk was correlated with standard efficacy outcomes. Results: The overall response rate (CR + PR) for all pts was 68.1% (95% CI 59.8% - 75.5%). Median time-to-progression (TTP) was 24 months, and overall survival (OS) was 57 months. The overall response rates for the four quartiles according to tumor burden (lowest to highest) were: 64%, 70%, 75%, and 65% respectively. Median TTP by quartile was: 57, 25, 18, and 17 months. Median OS for these same groups: not reached, 57, 47, and 35 months. The Kaplan-Meier estimates of patients alive at 64 months based on tumor bulk were 62%, 40%, 44%, and 31% respectively. Disease bulk was an independent prognostic factor for overall survival using a Cox regression model including sex, performance status, IM dose, gender, age, prior chemotherapy, and tumor volume, but not when baseline hemoglobin was included. Conclusions: Pts with bulky GISTs progress sooner and die more quickly than those with lesser tumor volumes, though other factors may contribute as well. Even pts with the bulkiest tumors frequently respond to treatment with IM, however. TTP for this population approaches 1.5 yrs, and median survival for these pts approximates 3 yrs. One-third of pts with extraordinarily bulky GISTs are long-term survivors. The potential relationship between baseline hemoglobin and tumor bulk requires further investigation.

[Table: see text]
Phase III trial of ixabepilone plus capecitabine compared to capecitabine alone in patients with metastatic breast cancer (MBC) previously treated or resistant to an anthracycline and resistant to taxanes
Authors: Vahdat L. T. , Thomas E. , Li R. , Jassem J. , Gomez H. , Chung H. , Peck R. , Mukhopadhyay P. , Klimovsky J. , Roché H.
Published: March 2020

1006

Background: Patients with MBC who have progressed after anthracyclines and taxanes have limited treatment options. Ixabepilone, a novel epothilone B analog, is active in resistant breast cancer. Methods: In this large multinational phase III trial, patients with MBC who were anthracycline pretreated and met predefined resistance criteria to taxanes were randomized to ixabepilone (40mg/m2 IV over 3h Q3w) + capecitabine (1,000mg/m2 PO BID Q14d) or capecitabine (1,250mg/m2 PO BID Q14d). The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR), safety, and overall survival (available after 2007). Response and progression were assessed by an independent review committee (IRC) and the investigators (INV). Results: 752 patients were randomized. Median age was 53; 84% had visceral disease, 48% and 43% had 1 and =2 prior metastatic regimens. Median of 5 and 4 cycles of ixabepilone + capecitabine and capecitabine were administered. Ixabepilone + capecitabine was superior to capecitabine. Significant benefit was consistently maintained across predefined subgroups, including HER2-/ER- /PR- and HER2+. *Primary analysis of PFS; hazard ratio= 0.75. Grade (G) 3/4 adverse events included neuropathy (ixabepilone + capecitabine 23% vs capecitabine 0%), hand-foot syndrome (18% vs 17%), and fatigue (9% vs 3%). Neuropathy was cumulative and reversible (median time to resolution of G3/4 to baseline/G1 was 6 weeks). G3 and 4 neutropenia were reported in 32% and 36% vs 9% and 2%, respectively; febrile neutropenia was 5% with ixabepilone + capecitabine. Toxic death rate was 3% vs 1%. Patients with liver dysfunction were at greater risk. Conclusions: Ixabepilone + capecitabine has superior efficacy to capecitabine across endpoints and has a manageable safety profile in this heavily pretreated population. It offers a new potential option for patients with MBC.

[Table: see text]

No significant financial relationships to disclose.
Analysis of toxicity in a phase II study of sorafenib in soft tissue sarcoma (STS)
Authors: Keohan M. , D'Adamo D. , Qin L. , Saulle M. , Caltieri L. , Schuetze S. , Wright J. J. , Schwartz G. , Maki R.
Published: March 2020

10061

Background: Sorafenib (BAY 43–9006) is an oral multi-targeted kinase inhibitor. Sorafenib causes dermatologic toxicity and hypertension, although the mechanisms are poorly understood. We observed significant toxicity requiring dose reductions in our phase II study of sorafenib in STS. Methods: 120 patients (40 M, 80 F; median age, 55 years) were treated between 10/05 and 12/06; accrual continues. All patients initially received sorafenib 400 mg BID. 118/120 registered patients were evaluable for toxicity. Clinical and laboratory variables were analyzed for association with dose reduction, using Kruskal-Wallis rank sum test for continuous variables and Fisher exact test for categorical variables. Variables significant at the p=0.05 level were further analyzed with a multivariate logistic regression model for their effects on dose reduction. Results: 53% of patients (63/118) required dose reductions, 53/63 for grade 2 or greater skin toxicity. Most common grade 3–4 drug-related toxicities included lymphopenia (14%), rash (12%), and hand-foot skin reaction (10%). Sex, height, weight, BSA and serum creatinine (Cr) were significantly associated with dose reduction by univariate analysis. Adjusting for sex and/or low serum Cr, BSA was not significantly associated with dose reduction. Sex and low serum Cr were borderline statistically significant predictors of dose reductions when both variables were included in a multivariate model. Only female sex remained a significant predictor when eliminating one outlier with BSA 2.83 (p=0.04). Conclusions: Female gender appears associated with skin toxicity, requiring dose reductions. Based on this multivariate analysis, a starting dose of 400 mg oral daily in women may limit side effects. Correlation with trough serum sorafenib levels is pending. This study is funded in part by NCI Grant P01-CA47179.

No significant financial relationships to disclose.
Imatinib for the treatment of aggressive fibromatosis/desmoid tumors (AF/DT) failing local treatment: updated outcome and predictive factors for progression free survival. A FNCLCC French Sarcoma Group-GETO study
Authors: Fayette J. , Dufresne A. , Penel N. , Le Cesne A. , Bui Nguyen B. , Tubiana-Hulin M. , Guillemet C. , Chabaud S. , Jimenez M. , Blay J. Y.
Published: March 2020

10062

Background: The optimal treatment of AF/DT failing local treatments is not defined. We report long term results and predictive factors for response to imatinib in AF/DT. Methods: Pts =18 years with advanced AF/DT from all sites in whom neither curative surgery nor radiotherapy (RT) was possible were eligible. Imatinib was given at the dose of 400mg/d (and increased to 800 mg/d if progression) during 1 year then stopped. Primary endpoint was the progression free at 3 months. A two stages Simon‘s optimal design was used with p0=10%, p1=30%, a=0.05 and 90% power (18 pts first stage, total of 35 evaluable pts). Predictive factors were investigated using tissue-microarrays (TMA) and KIT mutation analysis. Results: Between 09/2004 and 10/2005, 40 pts were included in 15 centers. Median age was 40 (range 20–72) with 30% males. Primary sites were extra abdominal, mesenteric, and abdominal wall in 69, 18, and 13% of pts respectively. 23% had received RT. Prior systemic treatments were: NSAID, hormonotherapy or chemotherapy (CT) in 33%, 45% and 20% of pts respectively. Median treatment duration of imatinib is 9 months (range 0.8–13.8). G4 and G3 toxicities were notified in 0 and 17 patients (42.5%) respectively: rash (4 pts), abdominal pain (3 pts), and vomiting (3 pts). 38 pts (95%) are evaluable at 3 months, with 1 (3%) CR, 3 (8%) RP, 31 (82%) SD and 3 (8%) PD. With a median follow-up of 13.8 months, 13 of the 40 pts had progressed. PFS at one year is 71% and 1 patient died (PD). 8 patients received an increased dose of imatinib upon progression under a 400mg/d dose: 3 reprogressed and 5 achieved tumor stabilization during 5+, 6+, 8+ months. PFS was correlated to weight or to previous CT, but not to gender, Gardner, age, PS, size, site. Using TMA, the expression of PDGFR β and a β catenin, E-cadherine, cyclinD1, M-CSFR, estrogen receptor β, ERK, phospho-Akt-Ser473, phospho-MEK1–2 were investigated. None of the CycD1+ tumors have progressed so far. 3 mutations of KIT exon 10 were detected in 10 patients tested. All achieved tumor control. Conclusions: Imatinib induces prolonged disease stabilization in the majority of evaluable patients with AF/DT. Prognostic factors were identified.

[Table: see text]
A multivariate analysis of a series of 382 primary retroperitoneal sarcomas (RPS)
Authors: Rivoire M. , Bonvalot S. , Castaing M. , Stoeckle E. , Laplanche A. , Le Cesne A. ,   French Association of Surgery
Published: March 2020

10065

Background: A national retrospective study was conducted by the French Association of Surgery on primary RPS in order to define the best type of surgery and determine prognostic factors for abdominal recurrence and patient survival. There is still no consensus concerning the precise value of the extent of surgery and additional treatment modalities. Methods: Types of surgery were classified as: “systematic complete resection”, which is a systematic or partial resection of non-involved contiguous organs to achieve wide margins, “contiguously involved organ resection” and “simple complete resection”, a resection of the tumor with grossly negative margins. Survival was determined with the Kaplan-Meier method. Univariate and multivariate prognostic analyses were performed using logrank test and Cox model. Results: Data of 382 pts operated between 1985 and 2005 were retrospectively reviewed. Median age was 57 years (range 14–87). Median tumor size was 18 cm. Systematic complete resection, contiguously involved organ resection and simple complete resection were performed for 134 (35%), 153 (40%) and 87 (23%) pts, respectively. Eight pts (2%) had a biopsy without resection and 45 pts (12%) had macroscopic residual disease. Tumor was spilled during surgery for 76 pts (20%). Systematic complete resection and no spilling of the tumor were highly correlated with the number of pts operated by center (p-values <10-4). Histologic negative margins (136 pts, 36%) were highly correlated with systematic complete resection (p-value <10-4). Chemotherapy and radiotherapy were given to 135 (35%) and 122 pts (32%). Median survival was 6 years whereas median time to abdominal recurrence and metastasis were 4 and 15 years, respectively. On multivariate analysis, pre op biopsy, low grade, no spilling of the tumor, negative margins and number of pts operated by center were the significant factors predicting abdominal recurrence control whereas low grade, no spilling of the tumor and no macroscopic residual disease significantly predicted better overall survival. Conclusions: Tumor grade and quality of surgery were the two main prognostic factors for abdominal recurrence and overall survival. Surgical experience of these rare tumors and systematic complete resection decreased abdominal recurrence rate.

No significant financial relationships to disclose.
The actin-bundling motility protein fascin and vascular endothelial growth factor (VEGF) are universally over-expressed in human angiosarcoma
Authors: Dim D. , Ravi V. , Tan J. , Hicks D. , Wong M.
Published: March 2020

10068

Background: Angiosarcoma is a highly aggressive soft tissue malignancy with a dismal progression-free survival (PFS). Treatment options for disseminated disease are limited and present systemic therapies have not shown evidence of prolonging overall survival. In this regard, a greater understanding of the molecular and cellular basis of the tumor phenotype of this uncommon malignancy and how these features correlate to clinical behavior would be an important step towards identifying potential new molecular targets for therapy. Our previous work show that acquisition of the chemotherapy-resistant phenotype by angiosarcoma cells occurs concomitantly with a marked increase in cell motility and VEGF expression. Increased expression of the angiogenic factor VEGF and the motility protein fascin have been associated with more aggressive clinical course in a number of other tumor types and may play a direct role in the biologic behavior of these malignancies. Therefore, in the current study, we sought to characterize angiosarcoma by immunohistochemistry for the expression of VEGF and fascin, and compared the staining pattern to benign vascular tumors. Methods: 20 cases of angiosarcoma, and 5 cases of hemangioma were stained for tumor cell expression of VEGF and fascin using anti-VEGF polyclonal antibody (clone A-20, 1:50, Santa Cruz Biotechnology, Santa Cruz, CA) and antibody to fascin (clone 55K-2, 1:500, DakoCytomation, Carpinteria, CA). Results: Surprisingly, every case of angiosarcoma showed high expression for both VEGF and fascin with moderate to strong staining intensity in 75 to 100% of the tumor cells for each case. By comparison, both proteins were either absent or only weakly positive in hemangiomas. Conclusions: In the current study we found high levels of VEGF and fascin universally expressed in angiosarcomas, which was not the case for benign vascular tumors. These factors maybe part of the malignant phenotype for these tumors and contribute to an aggressive clinical course through enhanced cell motility and autocrine/paracrine signaling. Additional study will be needed to better define a role for these proteins in angiosarcoma and to determine if they might represent potential new molecular targets for therapy.

No significant financial relationships to disclose.
Extra-abdominal fibromatosis: Can aggressive management be avoided in a subgroup of patients?
Authors: Bonvalot S. , Eldweny H. , Haddad V. , Missenard G. , Vanel D. , Terrier P. , Oberlin O. , Le Cesne A. , Le Péchoux C.
Published: March 2020

10077

Background: The objective was to evaluate the impact of surgery as first-line treatment on event -free survival (EFS) of primary aggressive fibromatosis. Methods: Treatments were categorized into: surgery with or without radiotherapy and non surgical strategies with systemic treatment alone or wait and see policy. Event-free survival curves were estimated using the Kaplan-Meier method. Results: The sex ratio was 39 males/73 females. The median age at the time of the first diagnosis was 30 years. The median size of the primary was 60 mm. Eighty-nine patients (79.5%) had initial resection of their primary tumor followed by postoperative radiotherapy in 13 cases. Twenty-three patients (20.5%) did not undergo surgery but received systemic treatment or watch and wait policy. Median follow-up was 76 months. Three years EFS was 49%. In the univariate analysis, patients with microscopically complete surgery had a similar outcome to that of patients in the non-surgery group (65% vs 68% for 3-yr EFS respectively). Gender, age, tumor size, treatment period and strategy (surgery versus no surgery) were not statistically significant. Quality of resection according to margins and the tumor site were the only prognostic factors. There was a significant correlation between the tumor site and the quality of surgery (p= 0.0002). Tumor site was the only prognostic factor that remained in the multivariate analysis. Conclusions: Surgical removal as initial treatment was not found to influence the outcome. A subset of patients could be managed with a non aggressive policy. When surgery is finally necessary, it should be performed with the aim of achieving negative margins. Predictive biological factors influencing tumor evolution have to be defined

No significant financial relationships to disclose.
CALGB 150002: Correlation of HER2 and chromosome 17 (ch17) copy number with trastuzumab (T) efficacy in CALGB 9840, paclitaxel (P) with or without T in HER2+ and HER2- metastatic breast cancer (MBC)
Authors: Kaufman P. A. , Broadwater G. , Lezon-Geyda K. , Dressler L. G. , Berry D. , Friedman P. , Winer E. P. , Hudis C. , Ellis M. J. , Seidman A. D. , Harris L. N.
Published: March 2020

1009

Background: Accurate assessment of HER-2 is critical in MBC and predicts benefit from T. We have previously shown low level amplification of HER-2 associated with ch17 polysomy is common in IHC 2+ cases that are FISH(-). However, the clinical relevance of this is unknown. Methods: CALGB 150002, a correlative companion to 9840, was designed to assess the predictive role of HER-2 in MBC pts treated with weekly vs q 3W P ± T. Pts HER-2(-) locally were randomized to ±T. 585 pts were enrolled in 9840; 304 blocks were available for central analysis with DAKO HercepTest (IHC) and Pathvysion (FISH). Logistic regression was used to test HER-2:ch17 ratio and HER-2 copy # as predictor of response rate (RR) to T in HER-2(+) pts. 1-sided Fisher’s Exact Test was used to compare RR of P vs P+T in pts with ch17 polysomy on central testing (>2.2 copies ch17/cell), but defined as HER-2(-) locally and randomized to T. Results: In pts HER-2(+) locally, FISH is a significant predictor of RR to P+T. A higher HER-2:ch17 ratio is associated with a higher RR by logistic regression (p=0.033, n=95). No interaction is seen between HER-2 and P schedule, p=0.71. On central testing of cases IHC(-) locally, 16/140 (11%) were IHC 3+ and 5/133 (4%) HER-2 amplified. In 21 HER-2(-) cases reclassified as HER-2 3+ or FISH (+) centrally, we do not find a difference in RR to P vs P+T. However among 133 cases HER-2(-) locally and central FISH(-) we find 32 with ch17 polysomy (copy # ch17 = 2.2); 12 treated with P alone, and 19 with P+T (see table for RR). Conclusions: These data suggest a higher RR to P+T in HER-2(+) pts with a higher HER-2:ch17 ratio, consistent with a relationship between RR to T and HER-2 copy #. In FISH(-) cases we note an increased RR to P+T vs P in cases with ch17 polysomy, typically reported clinically as HER-2(-). This analysis suggests that T might be effective in a subpopulation of breast cancer conventionally defined as HER-2(-), but in fact displaying low level HER-2 amplification.

[Table: see text]

[Table: see text]
Goserelin plus anastrozole in the treatment of premenopausal hormone receptor positive, recurrent or metastatic breast cancer
Authors: Carlson R. W. , Schurman C. M. , Rivera E. , Chung C. T. , Phan S. C. , Dice E. K. , Thomas E. , Valero V.
Published: March 2020

1030

Background: Aromatase inhibitors (AIs) are highly active in postmenopausal women with hormone receptor positive breast cancer. However, the AIs do not suppress ovarian estrogen synthesis and are not effective in premenopausal women. This phase II study was initiated to estimate the activity of anastrozole when given with ovarian suppression by goserelin in premenopausal women with ER and/or PgR positive metastatic breast cancer. Methods: Premenopausal women with measurable recurrent or metastatic, ER and/or PgR positive breast cancer; no prior AI or LH-RH agonist/antagonist; no adjuvant chemotherapy within 6 months; ECOG performance status of 0–2; adequate organ function; and who provided signed, informed consent were eligible. A 2 stage phase II design was utilized. Treatment was with goserelin 3.6 mg SQ q4wk and anastrozole 1 mg/day begun on day 22 of protocol treatment. Treatment was continued to disease progression. Results: 35 patients (pts) were enrolled. Three were excluded from analysis for the following: 1 postmenopausal, 1 consent withdrawal, 1 early oophorectomy. Of the remaining 32 pts, median age was 43 yrs (range 26–51 yrs), 18 (56%) had prior chemotherapy, and 9 (28%) had prior SERM. Pts were Asian/Middle Eastern 22%, Caucasian 62%, Black 13%, Hispanic 3%. Disease sites were lymph node 50%, breast 44%, bone 81%, lung 41%, liver 22%, pleural effusion 6% and soft tissue 6%. Receptor status was ER+/PgR+ 75%, ER+/PgR- 22% and ER-/PgR+ 3%. Response: Treatment resulted in complete response (CR) in 1(3%), partial response (PR) in 11(34%), stable disease 6+ mos (SD) in 11(34%), and clinical benefit (CR+PR+SD) 23 (72%). Median TTP was 8 mos (range 2 - 63+ mos); median OS was 26 mos (range 11 - 63+ mos). Estradiol levels were detectable in 30/31 pts at baseline (median 56 pg/ml, range <10 - 273 pg/ml). Mean estradiol levels (pg/ml) were 75 at baseline, 21 at 1 mos, 19 at 3 mos, and 15 at 6 mos. TOXICITY: One grade 3 weight loss. All other toxicities were grade 1–2. Conclusions: Ovarian suppression with goserelin in combination with anastrozole is well tolerated and highly active in the treatment of premenopausal, hormone receptor-positive metastatic breast cancer. Support provided by AstraZeneca Pharmaceuticals

No significant financial relationships to disclose.
A phase I study of trastuzumab-MCC-DM1 (T-DM1), a first-in-class HER2 antibody-drug conjugate (ADC), in patients (pts) with HER2+ metastatic breast cancer (BC)
Authors: Beeram M. , Krop I. , Modi S. , Tolcher A. , Rabbee N. , Girish S. , Tibbitts J. , Holden S. , Lutzker S. , Burris H.
Published: March 2020

1042

Background: ADCs utilize tumor-specific and/or over-expressed surface antigens that undergo internalization to deliver highly potent anti-tumor agents via linkage to antigen-specific monoclonal antibodies (MoAbs). T-DM1 contains the humanized anti-HER2 MoAb trastuzumab (T) previously demonstrated to prolong survival in HER2+ BC to which a highly potent antimicrotubule drug (DM1) derived from maytansine has been chemically linked. Maytansine has been studied as a free drug with responses noted in breast and lung cancer pts; principal adverse events (AEs) were nausea, vomiting, diarrhea, and neuropathy. The MCC linker employed in T-DM1 provides a stable bond between T and DM1 that is designed to prolong exposure and reduce the toxicity of T-DM1 while maintaining activity; T-DM1 is the first ADC with an MCC linker in clinical trials. T-DM1 has activity in T-resistant HER2+ BC xenografts; its principal preclinical toxicities were reversible transaminase elevations, reversible decreases in platelets, and neuropathy. Methods: This ongoing first-in-human phase I study is evaluating the safety and pharmacokinetics (PK) of T-DM1 given IV q3 weeks to pts with HER2+ metastatic BC who have progressed on a T-containing regimen. Results: Seven pts (median age 58 (range 47–70); all PS 0–1; median number prior chemo regimens 6 (range 5–11)) have received 24 doses of T-DM1 at 5 dose levels (0.3–4.8 mg/kg). Related grade (gr) 1–2 AEs include elevations in hepatic transaminases (2 pts), fatigue (2 pts), anemia (1 pt), and thrombocytopenia (TCP, 1 pt). Related gr 3–4 AEs have been limited to rapidly reversible gr 4 TCP at 4.8 mg/kg (1 pt). There has been no cardiac toxicity. Consistent with preclinical modeling, dose dependent decrease in clearance was observed for T-DM1 across dose levels. One pt at 2.4 mg/kg has maintained an ongoing partial response for 6 cycles. Conclusions: At these initial doses, gr =2 AEs related to T-DM1 have been infrequent and manageable; gr 4 (dose-limiting) rapidly reversible TCP was seen at 4.8 mg/kg. T-DM1 PK is consistent with q3-week dosing. Objective tumor response has been observed. Enrollment is ongoing to determine the maximum tolerated dose of q3-week T-DM1.

No significant financial relationships to disclose.
A phase II study of pemetrexed and doxorubicin in patients with advanced or metastatic breast cancer (MBC)
Authors: Blasinska-Morawiec M. , Martin M. , Salas F. , Falcon S. , Rolski J. , Ferrari B. L. , Guedez N. , Simms L. , Gulyas S. , Melemed A.
Published: March 2020

1047

Background: Pemetrexed has a single-agent activity in MBC while doxorubicin is an established agent in breast cancer chemotherapy. This phase II study investigated the combination in patients with advanced or MBC who had not been previously treated with anthracyclines. Primary objective was to evaluate the overall response rate. Methods: Patients received pemetrexed 500 mg/m2 (10-min intravenous infusion) followed by doxorubicin 50 mg/m2 on day 1 of six 21-day cycles. Additional cycles were permitted based upon: absence of progressive disease, adequate cardiac function, and a maximum cumulative limit of doxorubicin 450 mg/m2. Routine folic acid and vitamin B12 supplementation was given to all patients. Results: A total of 79 women with advanced or MBC were enrolled at 15 centers in 7 countries. Major racial groups were Caucasians (50.6%) and Hispanics (24.1%). Median age was 55 years (range, 26–79) and most (91.1%) had performance status of 0 or 1. Patients had either metastatic (72.2 %) or locally advanced disease (27.9%). Sixteen (20.3%) patients had received prior adjuvant chemotherapy. A median of 6 cycles (range, 1–9) was delivered. During the 438 cycles, no doses were omitted, and 7 doses were reduced (3 for pemetrexed, 4 for doxorubicin). A total of 129 doses (29.5%) were delayed, primarily due to scheduling conflicts (84 doses) and neutropenia (19 doses). The relative dose intensity for both drugs was 93%. Overall response rate was 60.8% (95% CI, 49.1–71.6) with complete response in 8 patients (10.1%), partial response in 40 patients (50.6%), and stable disease in 20 patients (25.3%). Maximum CTC grade 3 and 4 toxicities observed in >5% patients were neutropenia (19 patients, 24.1%), leukopenia (8 patients, 10.1%), and vomiting (5 patients, 6.3%). Five deaths occurred during study treatment, 2 of which had causes (diarrhea, pneumonia) possibly related to the study drugs. One patient had resting left ventricular ejection fraction decreased to <50% after 6 cycles and did not receive further treatment. Conclusions: The combination of pemetrexed and doxorubicin was well tolerated and had promising response in patients with advanced or MBC. Survival and time-to-event results are forthcoming.

No significant financial relationships to disclose.
Different prognostic value of cytokeratin-19 mRNA-positive circulating tumor cells according to estrogen receptor status in early breast cancer
Authors: Ignatiadis M. , Xenidis N. , Perraki M. , Apostolaki S. , Politaki E. , Kafousi M. , Stathopoulos E. , Sotiriou C. , Georgoulias V. , Mavroudis D.
Published: March 2020

10500

Background: We have previously shown that the detection of cytokeratin-19 (CK-19) mRNA-positive circulating tumor cells (CTCs) predicts poor clinical outcome in node-negative breast cancer patients. Here, we examined the prognostic value of CK-19 mRNA-positive CTCs in early breast cancer patients focusing on clinically relevant subgroups based on estrogen receptor (ER) status. Methods: We analysed peripheral blood from 448 consecutive patients with stage I-III breast cancer after surgery and before the initiation of any adjuvant treatment for the presence of CK-19 mRNA-positive CTCs using a real-time RT-PCR assay. The effect of CK-19 mRNA-positive CTCs on clinical outcome of patients with ER-positive, ER-negative, and triple-negative (ER/PR/HER2-negative) tumors was investigated. Results: CK-19 mRNA-positive CTCs were detected in 181 (40.4%) of the 448 patients; 109 (41.5%) of 263 patients with ER-positive, 71 (40.6%) of 175 patients with ER-negative and 27 (35%) of 77 patients with triple-negative tumors. There was no significant difference in the proportion of patients with detectable CK-19 mRNA-positive CTCs in the ER-negative and ER-positive subgroups (p=0.856). After a median follow-up of 53 months, patients with CK-19 mRNA-positive CTCs experienced reduced disease-free survival (DFS) (p<0.0005) and overall survival (OS) (p<0.0005); this was mainly observed in patients with ER-negative (p<0.0005 and p<0.0005, respectively) and triple-negative (p=0.008 and p=0.001, respectively) but not with ER-positive (p=0.174 and p=0.364, respectively) tumors. In multivariate analyses, detection of CK-19 mRNA-positive CTCs was the strongest independent prognostic factor associated with reduced DFS and OS in the entire cohort (p<0.0005 and p=0.009, respectively), in ER-negative (p<0.0005 and p=0.003, respectively) and triple-negative (p=0.020 and p=0.022, respectively) but not in ER-positive tumors (p=0.350 and p=0.621, respectively). Conclusions: Detection of CK-19 mRNA-positive CTCs predicts poor clinical outcome at five years follow-up, only in patients with ER-negative and triple-negative, but not with ER-positive, early breast cancer.

No significant financial relationships to disclose.
KRAS mutation is highly predictive of cetuximab resistance in metastatic colorectal cancer
Authors: Di Fiore F. , Le Pessot F. , Lamy A. , Charbonnier F. , Sabourin J. , Paillot B. , Frebourg T. , Michel P.
Published: March 2020

10502

Background: In metastatic colorectal cancer (MCRC), no molecular predictive markers to cetuximab response have been yet established. The aim was to evaluate whether KRAS gene mutations, EGFR immunochemistery (IHC) and EGFR gene copy number correlate with response to cetuximab. Methods: 59 patients with MCRC treated by cetuximab between July 2004 and December 2005 were retrospectively included. Clinical data were collected and tumour response was evaluated according to RECIST criteria. EGFR IHC was performed using the Dako kit. The EGFR gene copy number was determined by FISH (Fluorescence in-Situ Hybridization). Detection of KRAS gene mutations on exon 2 was performed by sequencing of extracted paraffin-embedded DNA and then by 2 methods, SNaPshot and PCR-LCR, specifically developed to detect small fractions of mutated tumor cells. Response to cetuximab was studied according to clinical data, IHC, FISH and KRAS mutation analysis using the Fischer exact test. Predictive factors of response were determined by logistic regression. Skin reactions were collected but not considered for this analysis as regards the lack of accurate grading in a retrospective study. Times to progression (TTP) were calculated using the Kaplan-Meier method and compared with log-rank test. Results: 12 patients (20.3%) responded to cetuximab (2 patients with complete response and 10 patients with partial response), 19 (32.2%) had stable disease and 28 (47.5%) were in disease progression. A KRAS mutation was detected in 22/59 tumours and, in 6 cases, was missed by sequencing analysis but detected using the SNaPshot and PCR-LCR assays. No KRAS mutation was found in responders patients. KRAS mutation was associated with disease progression (p = 0.0005) and TTP was significantly decreased in mutated KRAS patients (3 vs 5.5 months, p = 0.015). There was no correlation between EGFR IHC and cetuximab response. No EGFR gene copy number increase was detected in responders patients. Predictive factors of cetuximab resistance were KRAS mutation (p=0.003; OR:0.10; 95IC:0.22–0.40) and age<60 (p=0.024; OR:0.13; 95IC:0.02–0.77). Conclusions: KRAS mutation is highly predictive of cetuximab resistance in MCRC. Our study also highlights the need of sensitive methods to ensure an efficient mutation detection.

No significant financial relationships to disclose.