bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aromatase inhibition in male breast cancer patients: Biological and clinical implications
Authors: Doyen J. , Italiano A. , Largillier R. , Ferrero J. , Fontana X. , Thyss A. 
Published: August 2020

1130 Background: Because male breast cancer (MBC) is rare, treatment recommendations are derived from results of trials in female patients (pts). Although, several studies have shown the superiority of third-generation aromatase inhibitors (AI) over tamoxifen in menopausal women with advanced breast cancer, the role of such molecules remains unknown in male pts. We report here the largest experience about the efficacy of AI in MBC pts with advanced disease and their impact on estradiol (E) levels. Methods: MBC pts were selected from the breast cancer database of the Centre Antoine-Lacassagne (Nice, France) as follows: Metastatic disease with at least one measurable or assessable non-measurable lesion, estrogen receptor (ER) and/or or progesterone receptor (PR) positive, availability of complete clinical and histological data, evidence of progressive disease at initiation of AI, receipt of at least one month of treatment with non steroidal (anastrozole, letrozole) or steroidal (exemestane) AI. Sex hormone levels were retrospectively assessed on serum samples from our institutional serum bank. Results: 15 pts entered the study. Median age was 68 (range 39–85). 7 pts received previous lines of hormonal therapy (median = 1) and 3 pts a previous line of chemotherapy before the introduction of AI. The best response was complete response in 2 pts (13%), partial response in 4 pts (27%), stable disease (SD) in 2 pts (13%) and progressive disease (PD) in 7 pts (47%). The median duration of objective response (OR) was 11.6 months (95% confidence interval [CI] 7.6–15.5). At the time of analysis, 8 pts (53%) had died and 7 (47%) were still alive. The median PFS and OS were 4.4 months (95% CI 0.1–8.6) and 33 months (95% CI 18.4–47.6) respectively. The 1-year PFS and OS rates were 20% (95% CI 9.7–30.3) and 84.6% (95% CI 74.6–94.6), respectively. 9 out of 11 pts with available samples had E levels less than the lower limit of the assay during AI treatment. Among the 9 pts with E level decrease, four had OR, one had SD, and four had PD. 1 pt had E levels higher than the upper limit of the assay during AI treatment. This pt showed disease progression. Further data on FSH and testosterone levels will be presented at the meeting. Conclusions: AI are active in MBC pts. This activity is correlated with a significant reduction in E levels. No significant financial relationships to disclose.
Detection of locally advanced breast cancer in the I-SPY TRIAL (CALGB 150007/150012, ACRIN 6657) in the interval between routine screening
Authors: Lin C. , Moore D. , DeMichele A. , Ollila D. , Montgomery L. , Liu M. , Krontiras H. , Gomez R. , Esserman L. 
Published: August 2020

1503 Background: It is assumed that most locally advanced breast cancers (LABC) could be detected at an earlier stage with routine screening. However, LABCs may present between screens as interval cancers (IC). ICs present at an earlier age, with higher grade, larger size, and are associated with lower survival, compared to screen-detected cancers (SDC), and comprise 17% of cancers from population-based screening programs. We evaluated the screening history in patients with LABCs from the I SPY TRIAL, to determine the frequency of screening and ICs. Methods: Of 221 pts enrolled in the I-SPY TRIAL, a multisite neoadjuvant study for women with LABCs > 3cm in size, screening history and presentation were retrospectively collected for 154. Two groups, screened (S), defined as a mammogram within 2 years, or non screened (NS), previous mammogram more than 2 years prior, were evaluated (Table). The frequency of ICs at 1 and 2 years was determined in S pts. Frequency of mammographically occult (MO) tumors was determined for all. Results: Of the total, 99 (64%) and 55 (36%) were NS and S, respectively. Mean tumor size for all pts was 6.7cm. Only 11 (20%) of S pts were SDCs and 44 (80%) were ICs, with 24 (63%) diagnosed within 1 year and 14 (37%) between 1 and 2 yrs of their last normal mammogram. 24 (24%) NS patients were younger than the recommended screening age of 40; in the remaining 75 pts, 9 (12%) were MO. Only 20% of IC tumors were MO. ICs were of higher grade (44% vs 11% grade III), and tumor size (7.0cm vs 4.4cm) than their SDC counterparts. 80% of cancers detected in I SPY were NKI70 gene test poor prognosis. Relationship to breast density and subtype is currently being assessed. Conclusions: Women presenting with LABCs have a high likelihood (80%) of an IC. This suggests that the growth rate of LABCs precludes early detection by conventional screening. Understanding the biology of ICs will be important to develop better strategies for prevention and early detection. [Table: see text] No significant financial relationships to disclose.
Magnetic Resonance Imaging quantification of breast density in BRCA carriers following gonadotropin releasing hormone agonist (GnRHA)-based hormonal chemoprevention
Authors: Klifa C. , Sand S. , Vora L. , Press M. , Orisamolu A. , Pike M. , Spicer D. , Daniels A. , Blazer K. , Weitzel J. 
Published: August 2020

1506 Background: Breast tissue density limits the usefulness of mammography as a surveillance tool in young women. Breast Magnetic Resonance Imaging (MRI) provides high tissue contrast and three-dimensional structural information not impaired by high breast density. We developed a volumetric “MR density” measure of breast structural composition that may be complementary to mammographic breast density. We tested this MR density measure in unaffected women with known high risk of breast cancer due to a BRCA gene mutation (or empiric risk > 30% lifetime), who were recruited in a phase II trial to study the effects of a hormonal chemoprevention regimen. Methods: Nine premenopausal high-risk women age 21 to 48 were treated with intranasal GnRHA (deslorelin), low-dose estradiol, and testosterone daily for 10 months. All patients underwent one contrast-enhanced breast MRI exam before and after treatment. We measured MR density as the ratio of fibroglandular tissue volume to total volume of the breast, at both time points. Our technique involved the semi-automated delineation of the breast and the automated segmentation of fibroglandular from adipose tissue. An “MR index” was also defined to quantify partial voluming effects due to the presence of adipose/fibroglandular edges in the MR data. Results: Eight out of nine patients showed a reduction in MR density (p = 0.026) with treatment. Three patients had less than 5% MR density at baseline, making it difficult to quantitate a change with treatment. All of the remaining six patients had reduced MR density after treatment (mean reduction 35.5%; p = 0.035). Conclusions: We have demonstrated the use of breast MR density as a robust volumetric quantitative measure of breast tissue composition. Our findings suggest that MR could be used to measure hormonal chemoprevention effects in BRCA carriers. [Table: see text]
Ethnic minority participation in Community Clinical Oncology Program (CCOP) research studies
Authors: Figueroa-Moseley C. D. , Morrow G. R. , Jean-Pierre P. , Purnell J. 
Published: August 2020

1550 Background: Low minority participation in clinical research is concerning for both research and for the public health. Objective: The aim of this project was to investigate barriers and successes in minority participation in cancer medical research and cancer clinical trials. More specifically to: (1) determine major environmental, cultural, and economic barriers confronted by minority patients with cancer; and (2) determine the components of an environment that supports greater recruitment and retention of minorities to Clinical Community Oncology Practice (CCOP) cancer studies. Methods: Six focus groups consisting of 8 to 12 current or former minority cancer patients and 18 health care practitioners, from geographically diverse areas, were recruited to participate in this qualitative study. Focus group participants were asked questions about their attitudes and beliefs concerning their cancer and medical research. Health care practitioners were questioned on site recruitment and retention practices. Results: Two major thematic areas emerged for providers: barriers minority recommendation to trials and reasons for why minorities are underrepresented in trials. The three thematic areas for focus group participants were perceptions of medical research, reasons for participation or nonparticipation, and effects of Tuskegee Syphilis Study on participation. Conclusions: The Tuskegee Syphilis Study may have been a major impetus for why many Blacks and other minorities in this sample do not participate in medical research. Providers seem to state what was obviously important in connecting with the community, however, their actions in the community varied. This qualitative study gives voice to communities which mistrust the medical community in general and medical research in particular, and highlights the need for interventions bridging the community and research. No significant financial relationships to disclose.
Phase II trial of oral gimatecan in adults with recurrent glioblastoma
Authors: Hu J. , Wen P. Y. , Abrey L. E. , Fadul C. , Drappatz J. , Salem N. , Amato A. , Carminati P. , Supko J. , Hochberg F. 
Published: August 2020

2009 Background: Gimatecan is a highly lipophilic oral camptothecin analogue with impressive preclinical activity in glioma models. Methods: We conducted a multicenter two-stage phase II trial to evaluate the efficacy of gimatecan in adults with recurrent glioblastoma. Eligibility criteria included ≤1 prior treatment for recurrent disease, age ≥18, ECOG performance status 0 or 1, and normal organ function. Patients taking enzyme-inducing anti-seizure medications were excluded. Gimatecan 1.22 mg/m2 was given orally once daily for 5 consecutive days during each 28-day cycle. Radiographic response was evaluated by MRI after every second cycle. The primary endpoint of the study was 6 months PFS. A Simon's 2-stage design was used in which 19 patients were evaluated in the first stage, with an additional 36 patients accrued if > 4 patients in stage 1 achieved 6 month PFS. Results: A total of 29 patients were enrolled in the study, with median age of 58 years (range, 25–77 years); 58.6% female; all of whom had received prior surgery, radiation therapy, and at least one regimen of chemotherapy. The daily dose was reduced to 1.0 mg/m2 after four of the first 10 patients experienced grade 4 hematologic toxicity. One patient was removed from trial due to toxicity (grade 3 leukopenia and thrombocytopenia). Treatment delay occurred in 11 patients (38%) and dose reduction was necessary in eight patients (28%). Treatment-related grade 3/4 toxicities included thrombocytopenia (17.2%), leukopenia (17.2%), and neutropenia (10.3%). Only 1/19 patients treated with 1.0 mg/m2/day experienced grade 3/4 hematologic toxicity. The 18% reduction in the daily dose resulted in a 19% decrease in the concentration of total gimatecan in plasma prior to administration of the fifth daily dose (56 ± 23 vs. 45 ± 20 ng/mL) and a 33% decrease in the AUC for dose 5 (8.0±4.8 vs. 5.3±4.2 ng*h/mL). Only one patient had a partial radiographic response by the modified Macdonald criteria and stable disease was the best response in 13 patients. All other patients had progressive disease after two cycles of therapy. Only three patients (12%) were progression-free at 6 months. Median time to progression was 12.0 weeks (95% CI: 7.0, 17.0). Conclusions: Treatment with single-agent gimatecan 1.0 mg/m2/day for 5 days, repeated every 28-days showed minimal efficacy. [Table: see text]
Bevacizumab in combination with radiotherapy plus concomitant and adjuvant temozolomide for newly diagnosed glioblastoma: Update progression-free survival, overall survival, and toxicity
Authors: Gruber M. L. , Raza S. , Gruber D. , Narayana A. 
Published: August 2020

2017 Background: Prognosis of glioblastoma (GBM) is very poor. Standard treatment includes surgical resection (SR), radiation (RT), concomitant and adjuvant chemotherapy with temozolomide (TMZ). Our objective is to assess the treatment efficacy, safety and survival in patients with newly-diagnosed GBM treated with RT, TMZ, and bevacizumab in the upfront management. Methods: From 2006–2008, 51 eligible patients (age >18, KPS >70) with newly-diagnosed GBM divided into two groups. Group A (n = 20) was treated with RT (60Gy) and concomitant TMZ (75mg/m2 daily for 42 days) with bevacizumab (10mg/kg every 2 weeks), 29 days following surgery, followed by up to six cycles of adjuvant TMZ (150mg/m2,daily x 7d, q28 with bevacizumab at 10mg/kg days 8 and 22 of each 28 day cycle. Group B (n = 31) received similar treatment without bevacizumab. Both groups were followed up until tumor progression (PFS). Recurrence was defined according to MacDonald Criteria. The end points were PFS, overall survival (OS) and toxicity. Results: Median bevacizumab infusions were 12 (4–32). Median follow-up was14 months for both groups. 6 months PFS survival in Group A was 77.5% and in Group B was 51.6%. Median PFS in Group A was 17 months compared to 7 months in Group B (p < 0.0001, HR = 0.26). Median OS has not been reached in Group A and was 17 months in Group B. One and 2 year OS were 83% and 57% in Group A compared to 72% and 6.5% in Group B (p = 0.02) ). Post-RT and temodar toxicities include thrombocytopenia (1 patient; Gr 3 and fatigue (3 patient;1 Gr 3), bevacizumab related toxicities with RT include leg ulcer with cellulites (1 patient; Gr 3) and pulmonary embolism with thrombocytopenia (1 patient; Gr 4), hypertension (2 patients; Gr 1), and asymptomatic blood products on MRI (2 patients). Conclusions: Bevacizumab has demonstrated efficacy, acceptable toxicity, improved PFS and OS in the upfront management of GBM. No significant financial relationships to disclose.
Phase II trial of radiation therapy/temozolomide followed by temozolomide/sorafenib in the first-line treatment of glioblastoma multiforme (GBM)
Authors: Lamar R. E. , Spigel D. R. , Burris H. A. , Markus T. M. , Kuzur M. , Ervin T. , Fichtel L. , Greco F. A. , Hainsworth J. D. 
Published: August 2020

2018 Background: Anti-angiogenesis agents have recently shown activity in the treatment of patients (pts) with GBM. We added sorafenib, a multi-targeted TKI, to the standard first-line treatment of patients with GBM. Methods: Pts with histologically documented GBM were eligible at diagnosis or after resection. Additional entry criteria: ECOG PS 0 or 1; adequate organ function; ability to swallow pills; standard exclusions for antiangiogenesis agents. All pts initially received radiation therapy (total 60 Gy, 2 Gy by single daily fractions) plus temozolomide (75mg/m2 po daily). Four weeks after completion of radiation therapy, pts received temozolomide (150mg/m2 po days 1–5, repeated every 21 days for 6 cycles) plus sorafenib (400mg po bid daily x 24 weeks). Pts were evaluated every 8 weeks during temozolomide/sorafenib therapy, and every 3 months after therapy ended, until tumor progression. Median PFS was the primary endpoint. Results: Between April 2007 and July 2008, 45 pts were enrolled. The median age was 54 years; 30 pts (67%) had previous partial or complete surgical resection. 39 pts (87%) completed concurrent RT/temozolomide therapy, while 6 pts were removed from treatment (PD 4, toxicity 1, intercurrent event 1). 39 pts began treatment with temozolomide/sorafenib; 3 have completed all planned treatment, 8 remain on treatment, and 28 stopped treatment early (PD 22, toxicity 2, intercurrent event 1, pt decision 3). Best responses are as follows: CR, 1 pt (2%); PR, 5 pts (11%); stable disease, 22 pts (49%); progressive disease, 14 pts (31%). After a median follow-up of 9 months, median PFS for all pts was 6 months (95% confidence intervals, 2.7–7.8 months). Median PFS for pts who received at least 1 dose of sorafenib is also 6 months. The median overall survival is 16 months (95% CI, 7.2-NR months). Grade 3/4 toxicity during temozolomide/sorafenib was uncommon; 7 pts (16%) required dose reductions of sorafenib during their treatment course. Conclusions: The addition of sorafenib to standard treatment with RT/temozolomide is feasible and well tolerated by most pts. Preliminary efficacy is similar to standard therapy; updated results will be presented. [Table: see text]
KAAD-cyclopamine sensitize malignant glioma cells to TRAIL-mediated apoptosis
Authors: Siegelin M. 
Published: August 2020

2025 Background: Malignant gliomas are the most aggressive human brain tumors without any curative treatment. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic because TRAIL induces almost selectively apoptosis in cancer cells. The main obstacle in TRAIL-based therapy is that many glioblastoma cells are resistant. In the present study we found that the Hedgehog inhibitor, KAAD-cyclopamine, potently sensitized primary glioma cells to TRAIL-mediated apoptosis. Methods: Established cell lines and isolated primary tumor glioblastoma cells were treated with achievable plasma concentrations of TRAIL, KAAD-cyclopamine, or the combination of both. Apoptosis was assessed by Annexin V/Propidiumiodide staining and subsequent flow cytometric analysis. Activation of caspases and expression of apoptosis related proteins were determined by immunoblotting. For transfection experiments primary glioma cells were electroporated with plasmids encoding the cDNA of c-FLIP and bcl-2. Results: We established a stable culture model for isolated primary human glioma cells. In contrast to cell lines, isolated primary tumor cells from all investigated glioma patients were highly TRAIL resistant. Single treatment with KAAD-cyclopamine or TRAIL does not induce cytotoxicity in malignant glioma cells. However, treatment with KAAD-cyclopamine in combination with TRAIL induces rapid apoptosis in TRAIL-resistant glioma cells. Notably, normal human astrocytes were not affected by the combination treatment consisting of KAAD-cyclopamine and TRAIL. KAAD-cyclopamine led to an upregulation of death receptor 4 and 5 and down-regulation of bcl-2 and c-FLIP. Furthermore, over-expression of both bcl-2 and c-FLIP attenuated KAAD-cyclopamine facilitated TRAIL-mediated apoptosis. Conclusion: The widespread TRAIL resistance in primary glioma cells described here questions the therapeutic clinical benefit of TRAIL as a monotherapeutic agent. Overcoming TRAIL resistance by KAAD-cyclopamine cotreatment might, however, provide a powerful therapeutic option for glioma patients. No significant financial relationships to disclose.
Effect of daclizumab on TReg counts and EGFRvIII-specific immune responses in GBM
Authors: Sampson J. H. , Archer G. E. , Bigner D. D. , Schmittling R. J. , Herndon J. E. , Davis T. , Friedman H. S. , Keler T. , Reardon D. A. , Mitchell D. A. 
Published: August 2020

2034 Background: TRegs are increased in patients with GBM and constitutively express the high affinity interleukin-2 receptor (IL-2Rα). Treatment with an antibody that blocks IL-2Rα signaling functionally inactivates and eliminates TRegs without inducing autoimmune toxicity in murine models. We hypothesized that daclizumab, a commercially-available, IL-2Rα-specific antibody would function identically.Methods: A randomized phase II clinical trial assessed the effects of daclizumab in the context of the cancer vaccine, CDX-110, which is comprised of an EGFRvIII-specific peptide sequence linked to KLH. EGFRvIII is a constitutively activated and immunogenic mutation not expressed in normal tissues, but widely expressed in GBMs and other neoplasms. In patients with newly-diagnosed, EGFRvIII+ GBM, after resection and radiation/TMZ, patients received CDX-110 vaccinations biweekly x 3, then monthly until tumor progression in combination with TMZ (200 mg/m2 x 5/28 days). Half the patients were randomized to receive daclizumab (1mg/Kg x1) at the first vaccine. The others received saline in a double-blinded fashion.Results: There were no drug related SAEs. EGFRvIII-specific immune responses were generated in all patients, and all immune responses were sustained or enhanced during subsequent TMZ cycles. Preliminary analysis (n = 4) suggests that daclizumab reduces Treg (CD4+CD25+CD45RO+FOXP3+) numbers [change 82.4 ± 7.1% from baseline (p = 0.011; t-test)] without reducing overall CD8+ or CD4+ T-cell counts. Tregs decreased only 3.7 + 11.0% after vaccination in the saline treated group during the same interval. Preliminary analysis (n = 4) also suggest that daclizumab enhanced EGFRvIII-specific immune responses (p = 0.01; t-test) and enhanced the titer of cytotoxic EGFRvIII-specific IgG1 isotype antibodies compared to the saline treated group (p = 0.003; t-test) and compared to previously vaccinated patients who did not receive daclizumab (p = 0.0015; t-test). TTP and OS survival in both arms has not been reached. Conclusions: Daclizumab may reduce Treg counts in patients with GBM. TMZ and daclizumab may enhance EGFRvIII-targeted immune responses despite lymphodepletion. These combinations are currently under further investigation. [Table: see text]
Phase II trial of intracerebral administration of CpG oligonucleotide for patients with recurrent glioblastoma
Authors: Ursu R. , Carpentier A. , Metellus P. , Barrie M. , Meng Y. , Laigle-Donadey F. , Tibi A. , Chinot O. , Carpentier A. F. 
Published: August 2020

2043 Background: CpG-ODN are immunostimulating oligodeoxynucleotides containing CpG motifs. When injected locally, they can induce tumor rejection in animal models. In a phase I clinical trial, intra-tumoral infusions of CpG-ODN in glioblastoma patients were well tolerated at doses up to 20 mg. This multicenter phase II trial was designed to study the efficacy and tolerance of a local treatment by CpG-ODN in patients with recurrent glioblastoma. Methods: Patients with recurrent GBM occurring at least three months after radiotherapy and previously treated with one at least regimen of chemotherapy received 20mg CpG- ODN (CpG-28) by convection-enhanced delivery. The percentage of patients without tumour progression at 6 months after inclusion was the primary endpoint. Secondary endpoints were tolerance, survival, and radiological response. Results: Thirty-four patients were enrolled in two centers and thirty-one patients received the treatment. The 6-months progression free survival (PFS) was 19%. One partial response and 3 minor responses were observed. Eight patients (24%) were alive after 1 year, and 5 patients (15%) were alive 2 years after inclusion. The median overall survival was 28 weeks.Treatment was usually well tolerated. Among 6 patients studied, the pharmacokinetic profile of CpG-28 in the blood was heterogeneous. CpG-28 reached up to 79 ng/mL at the end of infusion in one patient. Return to baseline concentration occurred at around 70 hours after the start of infusion. Half-life estimates were variable ranging from 3 to 24 hours. The mean area under the plasma concentration-time curve (AUC) ranged from 0.07 to 0.65 μg x hr/ml. Conclusions: CpG-28 induced a few cases of radiological reponses, but the impact on the 6-months PFS was minimal in this population. However, the presence of long-term survivors suggest that this treatment might have been beneficial in some patients, whose molecular or clinical characteristics remain to be defined. [Table: see text]