bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical features, treatment, and outcome in 108 patients with localized, high-grade synovial sarcoma (SS)
Authors: Gupta A. A. , Al-Hussaini H. , Yu C. , Griffin A. , Tsung V. , Stephens D. , Blackstein M. , Hogg D. , Ferguson P. , Wunder J. 
Published: August 2020

10584 Background: There remains ongoing controversy in the treatment of localized SS, with no clear consensus on routine use of chemotherapy. Methods: Between 1986 and 2007, 93 adult (AP) and 15 pediatric (PP) patients were diagnosed with high grade, localized SS at 2 centres in Toronto. Clinical records and pathology reports were examined. Survival distribution functions were estimated by Kaplan-meier and compared using Log-rank test. Results: Median age for AP and PP was 36 (range 14–76) and 14 (range 0.4–18) years, respectively. Sixty-six (61%) patients had large tumours (> 5 cm), 7 (6.5%) had neuro-vascular invasion, and 10 (9.3%) had bone invasion. 76 (82%) AP and 8 (53%) PP received radiation (RT). 16 (17%) AP and 13 (87%) PP received chemotherapy. All patients underwent definitive surgery with gross total resection; 9 patients (8 PP) had positive margins. Some patients received neoadjuvant chemotherapy, and response was evaluable in 15 patients: 10 SD, 2 PR, 1 CR, 1 PD. Relapse occurred in 32 patients: 28 distant, 3 local only, 1 local + distant. With a median follow-up of 5.6 years, EFS and OS was 72 ± 4.6% and 82 ± 4.2%, respectively and was similar for AP and PP. Patients with tumours > 5 cm had significantly worse EFS (63 ± 6.5%) compared to patients with small tumours (88 ± 5.4%, p=0.02), as did those with bone invasion (47 ± 18 vs.75 ± 4.9, p=0.05). The effect of chemotherapy was assessed in the entire cohort. Of 29 who received chemotherapy, 9 (31%) relapsed, and of 79 who did not receive chemotherapy, 23 (29%) relapsed. In patients with tumours >5 cm, relapse occurred in 41% (7/17) of those who received chemotherapy compared to 37% (18/49) in those that received no chemotherapy. Conclusions: Patients with SS < 5 cm have an excellent chance of cure with surgery and RT. Large tumours and those with evidence of bone invasion have a poor outlook. It is unlikely that chemotherapy contributes to an improvement in survival in SS. No significant financial relationships to disclose.
Clinical outcomes of systemic therapy for patients with desmoids
Authors: Camargo V. P. , Maki R. G. 
Published: August 2020

10585 Background: Desmoids are rare, slow growing, histologically benign tumors without metastatic potential. Methods: We examined outcomes of patients with desmoid tumors receiving systemic therapy at a single institution, to provide a basis for examination of newer agents. Retrospective chart review of 682 patients with desmoid tumors (1982–2006) from a prospectively collected sarcoma database. The activity of NSAIDs was not addressed. Patients without measurable disease, those receiving therapy we could not document, and those receiving prophylactic therapy were excluded. Results: A total of 70 patients received 163 lines of well-documented systemic therapy starting before 1/1/2007. Nine patients died, 7 of progressive disease/surgical complications, and two with Gardner syndrome-related malignancies. Demographics: 45 females (65%), median age 30 (range 15–75), 21 with Gardner syndrome (30%), median follow-up 68 months, and median of 2 lines of therapy (1–7). Intra-abdominal primary location was most common (29/70=41%). Tamoxifen, doxorubicin (including Caelyx/Doxil), imatinib, and methotrexate combinations were most commonly used. Five partial responses were observed with anthracyclines (43 courses administered), 2 with hormonal therapy (32 courses), and 1 with imatinib (35 courses), for 8 PR s. Conclusions: Anthracycline-containing regimens, hormonal therapy, and tyrosine kinase inhibitors have modest activity against desmoid tumors. The choice of therapy for these morbid and potentially fatal tumors should balance the efficacy of treatments with their short- and long-term side effects. No significant financial relationships to disclose.
Clinicopathological characteristics of subsequent breast cancers in patients with benign breast disease
Authors: Santana-Davila R. , Visscher D. W. , Vachon C. M. , Frost M. , Vierkant R. A. , Anderson S. S. , Degnim A. C. , Hartmann L. C. 
Published: August 2020

1061 Background: Benign breast disease (BBD) is a significant risk factor for breast cancer (BC); however little is known about the aggressiveness of the BCs these patients develop. Shared features between select atypias and low-grade DCIS have led some to speculate that a history of BBD portends the development of well-differentiated BCs. Methods: The Mayo BBD cohort includes 9,376 women who had benign breast biopsies from 1967–1991. Data on BC events were obtained from medical records and questionnaires. Tissue from the BCs was reviewed by a single breast pathologist (DWV). Results: Our cohort included 6,244 patients with nonproliferative disease (NP), 2,801 women with proliferative disease without atypia (PDWA), and 331 with atypical hyperplasias (AH). With a median of 18 years of follow-up, 799 patients with BBD have developed breast cancer, 416 initially had NP, 313 had PDWA, and 70 AH. BC tissue was available for 703 of the women. The cancers were invasive ductal in 76.1% (n = 535), invasive lobular in 9.4% (n = 66), and DCIS alone in 14.5% (n = 102) patients. Grade is currently available for 500 women, and is well differentiated in 29.4% (n = 150), moderately differentiated in 42.7% (n = 218) and poorly differentiated in 27.8% (n = 142). In 537 cases the malignant tissue had a concurrent benign component consisting of NP in 24% (n = 129), PDWA in 25.1% (n = 135), and AH in 50.8% (n = 273). In regards to tumor size, 69.6% had T1 tumors, 24.9% T2 tumors, and 5.5% T3 disease. Metastasis to lymph nodes occurred in 25% of patients. Median time to BC was 12.3 years and did not differ across the different benign entities. Breast cancer developed within 5 years from the initial BBD in 163 women (20%). In this group, tumor size was greater (p = 0.02), and there were more poorly differentiated tumors (p = 0.006) than in those who later developed BC. Conclusions: In the BCs that have developed in our BBD cohort, we do not see a preponderance of well-differentiated, good-risk BCs. Patients diagnosed within 5 years of BBD appear to have BCs with more aggressive features. No significant financial relationships to disclose.
First-line lapatinib combined with letrozole versus letrozole alone for hormone receptor positive (HR+) metastatic breast cancer (MBC): Subgroup analyses of borderline FISH+, IHC 2+, HER2 unknown (UNK), and treatment-naive (TN) populations from EGF30008
Authors: O'Rourke L. , Pegram M. , Press M. , Pippen J. , Pivot X. , Gomez H. , Florance A. , Maltzman J. , Johnston S. , Johnston S. 
Published: August 2020

1062 Background: This double-blind, placebo-controlled, phase III trial assessed the benefit of adding lapatinib, an oral EGFR/HER2 tyrosine-kinase inhibitor, to letrozole alone in patients (pts) with HR+ MBC. The previously reported primary endpoint, investigator (INV) assessed PFS in HER2+ tumors, showed a significant benefit from dual therapy. Median PFS in the HR+ HER2+ population increased from 3 months (mo) in the letrozole/placebo group to 8.2 mo in the letrozole/lapatinib group [Hazard Ratio (95% CI)=0.71 (0.53,0.96), stratified log rank p = 0.019]. The HER-2-ve population did not derive benefit from the combination. Benefit from combined treatment was evaluated in a number of pre-planned exploratory subsets, including a noted trend in the HER2-ve population who progressed within 6 mo of receiving prior tamoxifen. Methods: 1286 pts were randomized to letrozole/lapatinib or letrozole/placebo. HER2 positivity was defined by a positive FISH ratio or by immunohistochemistry (IHC) 3+ in a central laboratory. INV assessed PFS in the sub-populations were analyzed using Kaplan-Meier with stratified log rank to compare treatment arms. These included tumor samples that were FISH borderline1.8–2.2 (n = 52), IHC 2+ (n = 215), HER2 status UNK (n = 115), and neo/adjuvant TN (n = 656). Results: INV assessed PFS demonstrated no significant prolongation for dual therapy for any of the exploratory populations [Hazard Ratio: (95%CI), p-value]; FISH 1.8–2.2 [1.03 (0.55, 1.95), p = 0.918]; IHC 2+ [1.13 (0.82, 1.57), p = 0.441]; HER2 UNK [0.71 (0.45,1.11), p = 0.126]; TN [0.88 (0.73, 1.07), [p = 0.199]. Conclusions: The combination of letrozole and lapatinib did not significantly improve PFS in any of the pts with lower levels of HER2 expression (borderline FISH, IHC 2+, or HER2 UNK) or in TN pts. These data confirm the HER2-ve result previously reported and substantiate that only tumors with the target benefit from the addition of a targeted therapy. [Table: see text]
A phase I/II study of CR011-vcMMAE, an antibody-drug conjugate, in patients (pts) with locally advanced or metastatic breast cancer (MBC)
Authors: Peacock N. , Saleh M. , Bendell J. , Rose A. A. , Dong Z. , Siegel P. M. , Crowley E. , Simantov R. , Vahdat L. 
Published: August 2020

1067 Background: Glycoprotein NMB (GPNMB), also known as osteoactivin, has been shown to regulate metastasis of breast cancer in vivo. CR011-vcMMAE, a fully-human monoclonal anti-GPNMB antibody conjugated to the tubulin inhibitor monomethylauristatin E, is safe and active in pts with advanced melanoma. This is the first study of CR011-vcMMAE in breast cancer. Methods: Eligible pts with MBC had ≥ 2 prior chemotherapy regimens, including a taxane, an anthracycline, and capecitabine; and ECOG PS ≤ 2. Doses were escalated to 1.88 mg/kg IV q3w (the maximum tolerated dose [MTD] in melanoma) using a standard 3+3 design. Immunohistochemistry (IHC) with goat polyclonal antibody to GPNMB was performed on pt biopsy specimens and on tissue microarrays containing normal breast, DCIS, breast tumor and lymph node metastases. Results: 10 pts with MBC (median age 57, range 36 - 69) had a median of 7 prior regimens and were treated with CR011-vcMMAE for a median of 2 cycles (range 1–4). In the first 2 pts at 1.34 mg/kg, dose limiting toxicity of worsening peripheral sensory neuropathy was observed. Pts with baseline neuropathy worse than grade 1 were subsequently excluded. Pts were treated at 1.0 mg/kg (n = 3), 1.34 mg/kg (n = 5), and 1.88 mg/kg (n = 2); enrollment at 1.88 mg/kg is continuing. Other adverse events (AEs) were grade 1/2 anorexia and pain in 4 pts; diarrhea, rash, fatigue, and neuropathy in 3 pts; and grade 3 rash in 1 pt. Evidence of antitumor activity has been observed. A response of 37% tumor shrinkage was seen in a pt after only 2 cycles and is ongoing. A second pt had a 51% reduction after 2 cycles, but had PD after 12 weeks. Breast tumor samples were more likely to stain positive for GPNMB than normal breast tissues. Conclusions: CR011-vcMMAE 1.34 mg/kg IV q3w is well-tolerated in heavily pretreated pts with MBC. The 1.88 mg/kg q3w dose is being assessed and phase II expansion is planned at the MTD. IHC of pt tumor specimens is being evaluated. [Table: see text]
Effect of race on the safety and efficacy outcomes of gemcitabine plus paclitaxel treated patients with metastatic breast cancer (MBC): Analyses from a phase III trial
Authors: Wang Y. , Tai D. , Zhao L. , Gill J. , Obasaju C. K. 
Published: August 2020

1070 Background: Population-based studies often attribute racial disparities in breast cancer outcomes to differences in access to treatment, quality of care, or other socioeconomic factors. In a controlled clinical trial setting, these systemic differences between races should be minimal. To evaluate the potential impact of race on outcomes in a controlled clinical setting, we retrospectively analyzed data from a phase III trial (B9E-MC-JHQG; NCT00006459 ) of patients (pts) with MBC. Methods: Analyses were performed on the JHQG trial database after 440 total pt deaths for both study arms. Demographics, safety, and efficacy were analyzed using safety population data from 3 racial groups: Caucasian (CA), Asian (AS), and Hispanic (HP). CA was the reference for all pair-wise comparisons. The logistic model was used to calculate odds ratios for tumor response and the Cox model was used to calculate hazard ratios for time-to-event parameters, adjusting for significant prognostic factors. Results: We report analyses of the gemcitabine (G) + paclitaxel (T) treatment arm. Demographics were balanced across the 3 groups with the exception that ER+/PR+ status was lower for AS compared to CA and HP; unknown ER/PR status was higher for AS. AS had significantly less neutropenia, fatigue, and nausea, but more anemia compared to CA and HP. Median number of treatment cycles completed was lower, but mean dose intensities for G and T were slightly higher, for AS. Response rate and progression-free survival were similar in the 3 groups. Overall survival (OS) and post-study chemotherapy (PSC) were significantly reduced for AS. Conclusions: Our analysis suggests that AS pts were better able to tolerate GT therapy compared to CA and HP pts. However, AS pts had the poorest OS outcome of the 3 racial groups, potentially due to reduced participation in PSC. [Table: see text] [Table: see text]
Imatinib-induced changes in gene expression and the metastatic potential of human breast carcinoma cells
Authors: Lorico A. , Anzanello F. , Rappa G. 
Published: August 2020

1074 Background: Imatinib mesylate (imatinib) is a potent and selective inhibitor of the tyrosine kinases, Bcr-Abl, c-Kit and platelet-derived growth factor receptors (PDGFRs). Since its advent for the successful treatment of chronic myelogenous leukemia in 2001, the clinical efficacy of imatinib has been investigated in many other human malignancies, including breast cancer. Based on recent reports that chemotherapy selects more invasive and metastasizing cells, we have hypothesized that exposure of breast cancer cells to imatinib could enhance their malignant behavior. Methods: MA-11 breast carcinoma cells, originating from bone marrow micrometastases, were exposed to imatinib in vitro for seven days. After four days of recovery in drug-free medium, biological properties and gene expression pattern were compared with those of the parental cell line. In a separate set of experiments, the effects of in vivo administration of imatinib to athymic nude (nu/nu) mice carrying MA-11 tumors were investigated. Results: In vitro, imatinib treatment increased the motility and invasiveness of the breast cancer cells, and induced over-expression of drug transporters and of a set of genes associated with aggressive and metastatic behavior (Table). In vivo, nu/nu mice subcutaneously implanted with MA-11 cells and treated with nine daily intraperitoneal doses of 60 mg/Kg imatinib developed with greater frequency distant organ metastases vs. control mice implanted with MA-11 and treated with the vehicle alone. Conclusions: Our data caution against the clinical use of imatinib in breast cancer; imatinib-selected breast cancer cells represent an important tool to investigate the pro-metastatic role of differentially expressed genes. [Table: see text] No significant financial relationships to disclose.
Phase II trial of the histone deacetylase inhibitor, vorinostat, to restore hormone sensitivity to the antiestrogen tamoxifen in patients with advanced breast cancer who progressed on prior hormone therapy
Authors: Munster P. N. , Lacevic M. , Thomas S. , Christian C. , Ismail-Khan R. , Melisko M. , Rugo H. , Minton S. E. 
Published: August 2020

1075 Background: Modulation of estrogen receptor signaling is one of the most successful modalities in the treatment of estrogen receptor (ER) positive breast cancers. However, hormone therapy resistance remains a challenging problem. Histone deacetylases (HDAC) have emerged as a recent strategy to interfere with hormone receptor signaling by modulating the estrogen and progesterone receptor. Here we report the findings from a phase II trial evaluating the HDAC inhibitor, vorinostat and the anti-estrogen, tamoxifen, placed in context with correlative studies. Methods: Patients with ER-positive metastatic breast cancer who progressed on prior hormonal therapy and up to three chemotherapy regimens were treated with 400 mg vorinostat daily for three of four weeks and 20 mg tamoxifen daily, continuously. Histone acetylation was evaluated in peripheral blood mononuclear cells. Results: To date, 29 patients [median age 53 years (34–71)] have been treated with the combination. Pulmonary emboli were observed in 2/29 (7%) patients. Other grade 3/4 toxicities included fatigue (5/29, 17%), anorexia (2/29, 7%), diarrhea (1/29, 3%), nausea/vomiting (3/29, 10%), hypokalemia (1/29, 3%), liver enzyme elevation (1/29, 3%), lymphopenia (5/29, 17%) and leukopenia (4/29, 13%). Predominant grade 2 toxicities included fatigue, nausea/vomiting/diarrhea, hyperglycemia, anorexia, and myelosuppression. Six (21%) patients had an objective response, and 3/29 (10%) additional patients had disease stabilization for >6 months; 13/29 (45%) patients had at least one prior chemotherapy regimen for metastatic disease, 28/29 (92%) patients had progressed after exposure to at least one and 16/29 (55%) patients after two aromatase inhibitors, and 18/29 (62%) patients had received prior adjuvant tamoxifen. H3 and H4 histone acetylation was seen at day 8 suggesting adequate vorinostat plasma levels. Histone acetylation and baseline HDAC expression will be presented. Conclusions: These findings suggest that the addition of an HDAC inhibitor to tamoxifen in patients who have progressed on prior hormonal therapy and/or adjuvant tamoxifen may restore hormone sensitivity. No significant financial relationships to disclose.
Evaluation of Mena isoforms as a surrogate for epithelial mesenchymal transformation and erlotinib resistance in breast carcinoma
Authors: Ghiuzeli C. M. , Roussos E. T. , Wyckoff J. B. , Sun D. , Wang Y. , Patsialou T. , Goswami S. , Gertler F. B. , Condeelis J. S. 
Published: August 2020

1078 Background: Epithelial to mesenchymal transition (EMT) is an important step in invasiveness and has been shown to correlate with metastatic potential in several cancer cell lines, including breast carcinoma. However, given the heterogeneity of tumors in vivo, EMT has not been a reliable marker of metastatic potential in cancer patients. Mena, a member of the enabled (ena)/vasodilator-stimulated phophoprotein (VASP) family, which controls cell motility, is upregulated in the invasive subpopulation of breast cancer cells. Mena is alternatively spliced to include one of four exons: +, ++, invasive (INV), or 11a. In the presence of MenaINV, tumor cells are able to invade even at epidermal growth factor (EGF) concentrations that would otherwise be undetectable by the tumor cells. Currently, there are several clinical and genetic characteristics which can predict sensitivity to erlotinib, an EGF receptor inhibitor, but further studies are necessary. Methods: The animal models used were the polyoma middle T antigen (PyMT) transgenic mouse and severe combined immunodeficiency (SCID) xenografted tumors derived from injection with a human breast carcinoma line, MDA-MB-231, and a rat adenocarcinoma line, MTLn3, with forced expression of MenaINV and Mena11a. Invasive cells and average primary tumor cells were collected using the in vivo invasion assay and Fluorescence activated cell sorting (FACS), respectively, and imaged via immunofluorescence. Results: We show that in both the PyMT and MDA-MB-231 animal models, invasive cells are significantly more mesenchymal than average primary tumor cells, indicating they have undergone EMT. The MTLn3-MenaINV cells are more mesenchymal-like, whereas the Mena11a are more epithelial-like. We also expect that cells with a high Mena INV/11a ratio invade despite the presence of erlotinib. No significant financial relationships to disclose.
Effect of dasatinib on the activity of trastuzumab in HER2-overexpressing breast cancer cells
Authors: Seoane S. , Montero J. C. , Pandiella A. , Ocana A. 
Published: August 2020

1084 Background: Breast cancer is the most common neoplasia in women. Although important advances in its treatment have been made along the last years, in the metastatic setting this disease remains incurable. One group of molecules involved in breast cancer genesis/progression are tyrosine kinases. HER-2 is a receptor tyrosine kinase that is overexpressed in a subset of patients with breast cancer. Targeting of HER-2 with trastuzumab a monoclonal antibody that acts on HER-2 has demonstrated clinical benefit. However, as a single agent its antitumoral activity is limited. Methods: Here we have investigated whether the action of trastuzumab, can be potentiated by dasatinib, a small molecule inhibitor that acts on several receptor and non-receptor tyrosine kinases. To this end, we have used cancer cell lines and in vivo xenografted mouse models. MTT proliferation and other apoptosis assays, biochemical and microarray experiments were performed to investigate the molecular bases of the action of the combined trastuzumab plus dasatinib treatment. Results: Combination of trastuzumab and dasatinib was synergic on breast cancer cells overexpressing HER-2, but not on cells with a normal complement of its receptor. In vivo xenograft studies confirmed the antitumoral action of this drug combination. Studies on the mechanism of action showed that this drug combination triggered apoptosis in HER-2 overexpressing cells. Apoptosis was evidenced by increased Annexin V staining, and was found to occur in a caspase-independent manner. In addition, an action of the drug combination on cell cycle could be identified, and the drugs decreased cyclins E1/2, B, and Cdk2, in addition to increasing p27. Microarray as well as biochemical analyses showed that the drug combination provoked a decrease in HER receptor phosphorylation, followed by interruption of downstream signalling. These changes resulted in alterations in the levels of proteins involved in DNA repair. Moreover, treatment with the drug combination caused a DNA damage response as evidenced by increased γH2AX. Conclusions: The effective antitumoral action of the drug combination opens new avenues for the clinical exploration of this drug combination in breast cancer patients overexpressing HER-2. No significant financial relationships to disclose.