tbuckley/cabot-search huggingface dataset:
Clinical course of 771 patients with bilateral breast cancer (BBC): Characteristics associated with overall and recurrence-free survival
Authors: G. A. Beinart, A. M. Gonzalez-Angulo, K. Broglio, J. Mejia, A. Ruggeri, E. Mininberg, G. N. Hortobagyi, V. Valero
Journal: Journal of Clinical Oncology (2007)

546 Background: Women with a personal history of breast cancer have an annual incidence of 0.5–1% and a cumulative incidence from 3–20% of subsequently developing contralateral breast cancer. Despite numerous retrospective and case-control studies, risk factors related to overall (OS) and recurrence-free survival (RFS) in BBC are still being defined. The purpose of our study was to describe tumor properties, patient characteristics, and method of cancer detection for a large cohort of BBC patients, and to assess the associations of these factors with OS and RFS. Methods: A retrospective chart review was conducted of the BCMS (Breast Cancer Management System) database at MD Anderson Cancer Center. Among BBC patients, we compared primary versus contralateral tumors and synchronous versus metachronous cancers. Patient and second tumor characteristics were evaluated for an association with OS and RFS, as measured from diagnosis of the second tumor. Results: Of 11,234 primary breast cancer patients seen for an initial visit between 7/1/1997 to 12/31/2004, 771 patients (6.9%) were diagnosed with BBC. One hundred forty nine (19.3%) patients have died, and one hundred forty eight (19%) have relapsed. Stage 0 was present in 39.4% of synchronous second tumors disease versus 20.6% of metachronous second tumors (p&lt;0.001). The 5-year OS rates based on stage of the second tumor were 87.7%, 87.7%, 69.6%, 45.1%, and 23.8% for Stages 0, I, II, III, and IV, respectively (p&lt;0.0001). The 5-year OS rates for second tumor detection via mammogram/prophylactic mastectomy, physical exam, and self-exam were 81.6%, 70.9%, and 65.3%, respectively (p=0.01). In addition, lymphovascular invasion (LVI), nuclear grade, hormonal receptor status, and histology were significantly associated with OS and RFS (p&lt;0.05). In a multivariable analysis, clinical stage and LVI remained significantly associated with OS (p&lt;0.05). Conclusions: This study represents the largest single institution review of BBC. Numerous second tumor characteristics were associated with survival. The results emphasize the importance of earlier detection and improved staging for contralateral breast cancer. No significant financial relationships to disclose.
Nail changes induced by weekly paclitaxel as a surrogate marker for response assessment in patients with metastatic breast cancer
Authors: A. Jain, P. P. Bapsy, L. Dasappa, G. Babu, U. Batra, K. V. Sajeevan, K. Saini, T. Singh, S. Attili
Journal: Journal of Clinical Oncology (2008)

12019 Background: Weekly paclitaxel dosing schedule has superior response rate and increases time to tumor progression in comparison to three weekly dosing schedule. The toxicity profile of weekly schedule is totally different from three weekly paclitaxel with neuropathy and nail changes more common than hypersensitivity reactions and neutropenia. We analysed the response assessment of weekly paclitaxel in combination with transtuzumab in relation to nail changes as a primary surrogate marker. Methods: Kidwai memorial institute of oncology is a regional cancer center in southern India with annually out patient input of approximately 17,000 patients. A total of 20 patients of metastatic breast cancer who progressed on any first line adjuvant chemotherapy not including taxanes as one of the drug were treated over a period of 6 months from January 2006 to August 2006. All patients were treated with Perez schedule of 80mg/m2 of weekly paclitaxel over a period of one hour and transtuzumab therapy with loading dose of 4mg/kg followed by 2mg/kg weekly. Primary objectives of study was to study time to tumor progression and over all survival in relation to nail changes induced by weekly paclitaxel. The response assessment was done using RECIST Criteria and toxicity assessment with CTC version 3.0. Results: Out of twenty patients fifteen (75%) developed nail changes. Grade one nail changes (discoloration, ridging, pitting) were present in 10 patients (50%) and grade two nail changes(partial or complete loss of nail, pain in nail bed) were present in 5 patient(25%).None of the patients developed grade three nail changes(interfering in the activities of daily living). All patients had partial responses irrespective of nail changes and their severity. Conclusions: Nail changes cannot be used as a surrogate marker for response assessment in patients of metastatic breast cancer treated with weekly paclitaxel based schedule. No significant financial relationships to disclose.
Phase II trial of Pexa-Vec (pexastimogene devacirepvec; JX-594), an oncolytic and immunotherapeutic vaccinia virus, followed by sorafenib in patients with advanced hepatocellular carcinoma (HCC).
Authors: Jeong Heo, Caroline Breitbach, Mong Cho, Tae-Ho Hwang, Chang Won Kim, Ung Bae Jeon, Hyun Young Woo, Ki Tae Yoon, Jun Woo Lee, James Burke, Theresa Hickman, Lara Longpre, Richard H. Patt, David H. Kirn
Journal: Journal of Clinical Oncology (2013)

4122^ Background: Pexa-Vec is a vaccinia virus engineered to express granulocyte-macrophage colony stimulating factor (GM-CSF), thereby stimulating direct oncolysis, tumor vascular disruption and anti-tumor immunity (Nat Rev Cancer 2009). Pexa-Vec was shown to replicate in metastatic tumors following intratumoral (IT) or intravenous (IV) administration (Lancet Oncol 2008; Nature 2011). Preclinical and clinical data suggest that Pexa-Vec-induced acute vascular disruption sensitizes tumors to anti-angiogenic effects of sorafenib (Mol Ther 2011). Methods: Treatment-refractory HCC patients received Pexa-Vec for 3 weeks (Day 1 IV, Day 8 IT and Day 22 IT) followed by sorafenib at Day 25. The primary objective of the study was to determine the safety of Pexa-Vec followed by sorafenib. Secondary objectives include disease control rate based on mRECIST and Choi (hypodensity) response criteria after Pexa-Vec only (Day 25) and after sorafenib initiation (Week 6 and 12). Optional assessments included response by positron-emission tomography (PET). Data summarized prior to database lock. Results: Enrollment is completed: 25 patients of which 20 were refractory to sorafenib. The treatment regimen was well-tolerated. Transient flu-like symptoms, including fever (n=23; 92%), chills (n=19; 76%), headache and nausea (n=10; 40%), abdominal pain and lymphopenia (n=10; 40%) were the most common adverse events following Pexa-Vec. Sorafenib toxicities were consistent with the expected profile. After Pexa-Vec alone the Choi tumor response rate was 47%. Following subsequent sorafenib therapy, 75% had Choi responses, including 81% of sorafenib-failure patients. The mRECIST disease control rate was 62% with Pexa-Vec alone and 59% following initiation of sorafenib. Two of 4 patients evaluable for PET response exhibited decreased PET signal after Pexa-Vec. Conclusions: Pexa-Vec was well-tolerated and associated with Choi tumor responses and disease control in patients with advanced HCC. Subsequent sorafenib was well-tolerated and associated with Choi responses. Further trials of Pexa-Vec in HCC patients are warranted. Clinical trial information: NCT01171651.
Receptor for advanced glycation end-products (RAGE) - soluble form (sRAGE) and gene polymorphisms in patients with breast cancer
Authors: P. Tesarova, M. Kalousova, M. Jachymova, O. Mestek, L. Petruzelka, T. Zima
Journal: Journal of Clinical Oncology (2007)

21113 Background: Receptor for advanced glycation end products (RAGE) may be involved in the pathogenesis of the cancer progression and metastasis. Pathological effects mediated via RAGE are physiologically inhibited by soluble RAGE (sRAGE), so the higher sRAGE levels may confer the patients with cancer with better outcome.. Our aim was to study sRAGE and RAGE gene polymorphisms in patients with breast cancer. Methods: We studied sRAGE and RAGE polymorphisms in 120 patients with breast cancer (subdivided based on the clinical stage, histologic grading, expression of hormonal and C-erb B2 receptors) and in 92 healthy controls. Results: Despite higher serum concentrations of AGEs, serum concentrations of sRAGE were lower in patients with breast cancer compared to healthy controls (1581 ± 777 vs. 1803 ± 632 ng/ml, p &lt; 0.05). Serum levels of sRAGE were higher in patients with advanced breast cancer (stage III), lower grade and positive estrogen receptors and intermediate positivity of C-erb B2 (Her-neu) receptors and were also influenced genetically (G82S and 2184 AG polymorphisms of the RAGE gene). Conclusions: Decreased sRAGE levels in patients with breast cancer may contribute to the progression of the disease. Patients with better outcome (with low grade and positive estrogen receptors) have higher sRAGE levels. Progression of the disease, may, however, increase sRAGE levels, possibly as a compensatory mechanism to counteract further progression. No significant financial relationships to disclose.
Female patients with soft tissue sarcoma are at a higher risk for developing breast cancer
Authors: I. Jiveliouk, R. Geva, M. Inbar, O. Merimsky
Journal: Journal of Clinical Oncology (2007)

10071 Background: An increased incidence of MPM has been reported in association with STS. In a series of 1350 adults with STS almost 10% were diagnosed with additional primaries. The incidence of breast cancer (BC) in the general population is 97/10 5 ,(Israel-Cancer-Registry) and the incidence of STS is 1.5/10 5 (Enzinger&amp;Weiss). It is expected that approx. 1.5/10 5 × 97/10 5 of the general population will have both BC and STS. Methods: A retrospective search of the database of approx. 1,350 adult STS patients, who were referred, diagnosed, or treated at our center between 1995- 2005. Results: A group of 132 patients (F=62) with STS had at least one additional malignancy. Twenty-five (25/62=40%) had BC, before or after STS. A family history of malignancy was reported by 8/25 patients (32%), 3 with a specific breast cancer family history. STS types varied. Sixteen (16/25) patients had breast cancer as their first primary, 9 as their second or third. Of 17 patients with first primary BC, the sarcoma appeared in the RT field in 2, and in 1 it appeared in a lymphedematous ipsilateral arm. Of eight patients with first primary sarcoma, only one got chemotherapy prior to the diagnosis of BC. Median interval between 1 st to 2 nd malignancy was 6.9 years (0.7–31y) when the BC was diagnosed first, and 3.8y (0–47y) when the BC was the second. Exposure to carcinogens, or therapeutic radiation and cytotoxics, given for the 1 st tumor prior to the 2 nd tumor, was recorded in 58%. The incidence of BC among all patients (females + males) with STS-first (in our database) followed by a second malignancy is 8/58 (14%), or 7/23 (30%) female patients with STS-first, or 25/890 (3%) of all female patients with STS in the registry of STS. The incidence of STS among the BC patients is rather low, and most of the cases in this series are not therapy related (14/17). The median survival of patients with BC-first was 312 months, versus 383 months for STS-first (p=NS). Among patients with BC-first, the median survival of patients with RT related sarcoma was 265 months, versus 312 months for RT unrelated STS (p= 0.6). Conclusions: Second primary BC in patients with STS-first is higher than the expected incidence of BC for this population. Screening for BC should be incorporated into the regular follow-up of patients with STS. No significant financial relationships to disclose.
An open-label multicenter phase II study of bevacizumab for the treatment of angiosarcoma
Authors: M. Agulnik, S. H. Okuno, M. Von Mehren, B. Jovanovic, B. Brockstein, R. S. Benjamin, A. M. Evens
Journal: Journal of Clinical Oncology (2009)

10522 Background: The limited therapeutic options and dismal prognosis for patients (pts) with angiosarcomas (AS) provide a strong rationale for the evaluation of new therapies. Preclinical studies in AS tumor models have shown antitumor effects of antiangiogenic agents. We conducted a phase II study to determine the antitumor effect of bevacizumab in AS. Methods: The study was a two-stage design in which patients with newly diagnosed or relapsed/refractory AS and epithelioid hemangioendotheliomas were treated with bevacizumab 15 mg/kg IV every 3 weeks. Treatment was continued until progression or unacceptable toxicity. Response was assessed by RECIST criteria. Results: To date, of 29 pts enrolled, 28 received treatment. Baseline data on 29 pts are: M:F= 12:17 and median age 62 (range 18–94). Three pts are not evaluable (1 too early, 2 full treatment not given). Among 26 pts evaluable for response so far: 3 have PR (range 3–16 cycles), 13 have SD (3–32 cycles) and 10 have PD. ORR 3/26 (12%). After 141 cycles of therapy, only 1 grade 4 adverse event occurred (thrombocytopenia) and 5 patients experienced a grade 3 adverse event (anemia, pleural effusion, congestive heart failure, pain, headache, and nausea). Conclusions: Bevacizumab monotherapy for AS resulted in a response rate of 12% and tumor stabilization achieved by 62% of pts. Further studies with bevacizumab in combination with chemotherapy should be explored in this disease. No significant financial relationships to disclose.
Nonmetastatic osteosarcoma of the extremity: Neoadjuvant chemotherapy with methotrexate (MTX), cisplatin (CDP), doxorubicin (ADM) with or without ifosfamide (IFO)—A randomized trial of the Italian Sarcoma Group (ISG/OS-1).
Authors: S. Ferrari, G. Cefalo, A. Tamburini, A. Comandone, F. Fagioli, P. G. Casali, G. Bisogno, M. Mercuri, P. Picci, G. Bacci
Journal: Journal of Clinical Oncology (2010)

9506 Background: To compare two chemotherapy protocols with MTX, CDP, ADM and IFO, given according to different schedule, but same cumulative dose in patients with non-metastatic osteosarcoma of the extremity. Methods: Patients aged ≤ 40 years, were randomized to receive two regimens with same cumulative dose (ADM 420mg/m2, MTX 120g/m2, CDP 600 mg/m2, IFO 30g/m2), but different duration (ArmA 44, ArmB 34 weeks). Preoperative treatment. ArmA: Two blocks of MTX (12g/m2), CDP (120mg/m2) and ADM (75mg/m2). Arm B: Two cycles of MTX (12g/m2) and alternating cycles with CDP (120mg/m2)/ADM (70mg/m2), IFO(6g/m2) /CDP(120mg/m2) and IFO(6g/m2)/ ADM (70mg/m2). Postoperative treatment.ArmA: MTX-CDP-ADM were used in good histologic responders [GR (tumor necrosis≥90%)], three cycles of ifosfamide (10/m2) were added in PR. ArmB: CDP/ADM (weeks 12-25), IFO/CDP (week 17), IFO/ADM (weeks 20-30) and MTX (weeks 15-16-23-24-28-29-33-34) were given. Results: From April 2001 to December 2006, 246 patients were enrolled [median age 14 (4-39)] 228 (93%) underwent limb-salvage surgery [ArmA 92%, ArmB 96%, p=0.5]. 109/243 (45%) patients were GR [ArmA 48%, ArmB 42%, p=0.4]. Three (1.2%) patients died as a result of treatment-related toxicity (ArmA 1, ArmB 2) The mean received dose-intensity was 0.82 [ArmA 0.91, ArmB 0.74, p=0.02]. 2,398 cycles were evaluated. Incidence of grade 4 neutropenia was 30% [ArmA 18%, ArmB 43%, p<0.001]. and G4 thrombocytopenia was 21% [ArmA 11%, ArmB 31%, p<0.001].With a median follow-up of 53 months (1-104) 5-year overall (OS) and event-free survival (EFS) were 74 % and 61%. Arm A 5-year OS and EFS: 75% (95%CI 66-83%) and 65% (95%CI 56-74%), Arm B 5-year OS and EFS: 74% (95%CI 65-82%) and 56.5% (95%CI 47-66%). Conclusions: The addition of ifosfamide to MTX, CDP and ADM since the preoperative phase does not improve the GR rate and increases the haematological toxicity. A similar probability of survival can be expected when ifosfamide is added to MTX CDP ADM in all patients or only in a selected population of poor responders to MTX CDP ADM. No significant financial relationships to disclose.
Hyperhomocysteinemia in cancer patients with thrombosis is not associated with methylene tetrahydrofolate reductase (MTHFR) gene mutations is down regulated by low molecular weight heparin (LMWHs) treatment
Authors: D. Hoppensteadt, M. Tobu, O. Iqbal, J. Cunanan, J. Fareed, S. Deitcher
Journal: Journal of Clinical Oncology (2005)

2056 Background: MTHFR gene mutations, nutritional factors (folic acid/ B12) and anticancer drugs are primarily responsible for the observed hyper-homocysteinemia in cancer patients. In addition, it is well known that cancer patients exhibit increased prevalence of thrombotic events which may be due to the effects of homocysteine on endothelial function. The aim of this study was to demonstrate that an upregulation of homocysteine is multifactorial in cancer associated thrombosis. Methods: In three groups of 210 patients who were diagnosed with cancer and thrombosis and in a group of medical patients (cancer free) with thrombosis who were enrolled in a treatment study with LMWH, (Reviparin, n=90), blood levels of homocysteine were measured using an ELISA method (Diazyme Laboratories, San Diego, CA). In addition, molecular methods utilizing PCR were used to measure the MTHFR (677 and 1298) variants. Results: On a cumulative basis the cancer patients with thrombosis exhibited a relatively higher level of homocysteine (12.8± 4.9; range 2.2–39.4 uM/L) in comparison to normal (n=140, 4.8± 3.9; range 2.8=6.9 uM/L) and medical patients with thrombosis (5.3± 3.1; range 2.1–9.8 uM/L). Of the 210 cancer patients profiled for the molecular analysis 42/210 (20%) were positive for the 677 variant and 24/210 (11%) were positive for the 1298 variant. Similar results were obtained in the medical patients and normal volunteers. In one group of cancer patients (n=72) who were treated with a LMWH for 4–6 weeks, a down-regulation of homocysteine levels (4.8±2.5 uM/L) was noted. Conclusions: These results clearly suggest that, cancer patients with thrombosis exhibited a relatively higher homocysteine levels independent of MTHFR mutations. Medical (cancer free) patients with thrombosis do not exhibit this increase in circulating homocysteine levels. Thus, other relevant factors such as the chemotherapeutic agents contribute to this acquired upregulation of homocysteine. These observations also suggest that LMWHs are capable of reducing the homocysteine levels which may contribute to the observed effects of these agents. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis
Effects of skeletal complications on total medical care costs in patients with bone metastases of solid tumors
Authors: T. E. Delea, J. M. McKiernan, J. Brandman, J. Sung, M. Raut, G. Oster
Journal: Journal of Clinical Oncology (2005)

8094 Background: Patients with bone metastases of breast, lung, and prostate cancer often experience skeletal-related complications including pathological fracture, spinal cord compression, hypercalcemia, or pain requiring surgery, radiotherapy, or opioid analgesics (collectively, skeletal-related events [SREs]). Effects of SREs on total medical-care costs have not been compared across patients with different tumor types. Methods: We used a US health insurance claims database (7/94–6/02) to quantify the impact of SREs on total medical-care costs in patients with bone metastases of various solid tumors. Subjects included in this analysis had ≥2 encounters with a diagnosis of primary breast, lung, or prostate cancer and ≥2 encounters with a diagnosis of metastases to bone. For each tumor type, Kaplan-Meier estimated medical-care costs were compared for propensity-matched samples of patients with SREs versus without SREs. Results: We identified 1702 patients with bone metastases of breast (n=617), lung (n=543), and prostate cancer (n=542), of whom 52% (breast and prostate) to 55% (lung) experienced at least one SRE during the observation period (mean 6.0 mos [lung] to 15 mos [breast]). After matching for age, gender, and comorbidities using propensity score, there were 201, 162 and 181 pairs of SRE/no SRE patients with breast, lung, and prostate cancer, respectively. In SRE patients, costs of SRE treatment ranged from $9,480 (95%CI $7,625-$11,374) in lung to $13,940 ($11,240-$16,856) in breast cancer. Differences (SRE vs no SRE) in total costs (SRE treatment and other care) ranged from $20,792 ($4,829-$36,475) in prostate to $48,173 ($19,068-$77,684) in breast cancer. Median survival was greater in SRE vs no SRE patients in lung cancer (p=.048); there was a similar trend in breast and prostate cancers. After adjusting for differences (SRE vs no SRE) in survival, differences (SRE vs no SRE) in total costs ranged from $18,051 in prostate to $43,548 in breast cancer. Conclusions: Costs of SREs in patients with solid tumors and bone metastases are substantial across tumor types and may be greatest in breast cancer. Treatments which prevent SREs, such as intravenous bisphosphonates, may reduce these costs. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Aventis
Phase 1 trial of SNS-314, a novel selective inhibitor of aurora kinases A, B, and C, in advanced solid tumor patients
Authors: F. Robert, H. Hurwitz, C. F. Verschraegen, R. Advani, C. Berman, P. Taverna, M. Evanchik
Journal: Journal of Clinical Oncology (2008)

14642 Background: The Aurora Kinases are a family of serine/threonine kinases (Aurora kinases (AK) A, B, and C) that play a key role in orderly progression through mitosis and have been implicated in a wide range of human tumors. Elevated expression levels of AKs have been detected in a high percentage of melanoma, colon, breast, ovarian, gastric, and pancreatic tumors, and in a subset of these tumors the AURKA locus (20q13) is amplified. SNS-314, a novel aminothiazole-derived urea, is a selective inhibitor of AKs A, B, and C with IC50 values in the low nanomolar range. Methods: The trial is a standard 3+3 phase 1 dose escalation study design. Patients (pts) with advanced solid tumors were treated with SNS-314 given as a three hour IV infusion once weekly X 3 (28 day cycle). Primary endpoints of the study are: safety, tolerability, and DLT assessment. Secondary endpoints of the study include: pharmacokinetic (PK) evaluation on Days 1 and 15 and pharmacodynamic (PD) evaluation. PD evaluation assesses ploidy and histone H3 phosphorylation (pHH3) in cells obtained by buccal mucosal swabs and punch skin biopsies. Results: A total of 9 pts (5M/4F) have been enrolled into 3 cohorts: median age=56 (range 37–66). The initial dose was 30 mg/m2 with subsequent dose escalation according to a modified Fibonacci schema. No dose limiting toxicity (DLT) or grade 3 or higher related adverse events have been observed to date. PK analysis revealed SNS-314 has a moderate to low clearance, and the plasma exposure increase was dose proportional. Plasma exposure was not significantly affected by repeat administration of SNS-314. Based on average in vitro cellular pHH3 EC90 estimates, the target serum concentration is 1μM which was achieved at all dose levels for a minimum duration of 4 hours. PD assessment of polyploidy and pHH3 is ongoing. Conclusions: SNS-314 is a novel inhibitor of AKs A, B, and C. At the 120 mg/m2 dose level, serum concentrations have exceeded preclinical target threshold levels. PD assessment of drug-mediated target modulation is ongoing. The compound has been well tolerated with no observed DLTs. Enrollment and dose escalation continues. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Sunesis Pharmaceuticals Sunesis Pharmaceuticals Sunesis Pharmaceuticals Sunesis Pharmaceuticals