bluuebunny/crossref_metadata_2025_split huggingface dataset:
A gene expression signature of eventual brain metastases in patients with breast cancer
Authors: Tham Y. , Creighton C. , Gutierrez C. , Osborne C. K. , Brown P. , Chang J. C. 
Published: March 2020

1019 Background: The incidence of brain metastases (BM) from breast cancer may be increasing, in part due to more effective systemic therapy. A metastatic signature of bone or lung metastases has been identified in mice but not for BM in human. We hypothesized that gene expression patterns of primary breast cancers may provide a specific metastatic signature for eventual BM. Methods: Core biopsies from primary breast cancers of 11 patients with BM and 12 patients who have other non-brain metastases were identified. Double- stranded cDNA was synthesized using an oligo-dT primer containing a T7 RNA polymerase promoter, followed by in vitro transcription with biotinylated ribonucleotides. The labeled cRNA was hybridized to Affymetrix U133-A chips. Results: Of the patients with BM, 55% were ER negative/HER-2 positive while 36% were ER positive/HER-2 negative. Of the patients with non brain metastases, 42% were ER negative/HER-2 positive and 50% were ER positive/HER-2 negative, with. A differential pattern of gene expression was seen in primary tumors of patients with BM when compared with those who had non-brain metastases. Many more genes were found elevated in patients with BM over what would be expected by chance (after correcting for multiple testing). Tumors that developed BM had expression of genes related to the neurological development pathways such as fetal Alzheimer antigen, MAD, neuropilin 1, and others. Several kinase pathways were involved such as protein kinase C and casein kinase substrate in neurons 2, and A kinase (PRKA) anchor protein 13. These genes will be validated in an independent set of patients with BM and non-brain metastases using real time PCR. Conclusions: The identification of genes that may predict for future development of brain metastases has many implications in terms of screening or prophylactic treatment. This would also help identify potential targets for the treatment of brain metastases. No significant financial relationships to disclose.
A quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis comparing lapatinib plus capecitabine compared to capecitabine for metastatic breast cancer (MBC)
Authors: Sherrill B. , Allshouse A. , Amonkar M. , Stein S. 
Published: March 2020

1026 Background: Data for this analysis is from a Phase III randomized study that was stopped early by the IDMC since a planned interim analysis demonstrated the primary endpoint had been achieved i.e. longer time to disease progression for patients taking lapatinib plus capecitabine (L+C) versus capecitabine (C) alone. The study included women with refractory advanced or ErbB2+ MBC who had received prior therapy which included anthracyclines, taxanes and trastumuzab. The Q-TWiST method was used to compare the trade-off between toxicities and delayed progression. Methods: The area under overall survival curves for each treatment group was partitioned into three health states: toxicity (TOX), time without toxicity or disease progression (TWiST), and the period until death or end of follow-up following disease progression (REL). TOX is time spent with grade ¾ adverse events (AEs) during progression-free survival (PFS) time. TWiST is the remaining time prior to progression in which no serious AEs were experienced. The utility-weighted sum of the mean health state durations was derived and treatment comparisons of Q-TWiST were made at varying combinations of the utility weights using a threshold utility analysis. Results: The ITT population included 399 subjects ages 26–83 [L+C group N=198, C group N=201]. Overall median survival was 67 weeks based on data through 3APR2006. There was not a significant difference between groups in mean duration of serious AEs prior to progression. (L+C 1.7 weeks, C 1.5 weeks). Using utility weights of 0.5 for both TOX and REL, i.e. counting 2 days of TOX or REL as 1 day of TWiST, resulted in a 7-week difference in quality-adjusted survival favoring L+C (p = 0.0013). The Q-TWiST difference was significant across an entire matrix of possible utility weights. Results were robust in sensitivity analyses including all AEs. An observed-utility analysis based on EQ-5D scores is in progress. Conclusions: The longer time to disease progression with L+C versus C was achieved without increased time with serious AEs, resulting in more quality-adjusted survival for patients. No significant financial relationships to disclose.
A report of cardiac events in a phase II clinical study using trastuzumab combined with pertuzumab in HER2-positive metastatic breast cancer (MBC)
Authors: Portera C. C. , Walshe J. M. , Denduluri N. , Berman A. W. , Vatas U. , Rosing D. R. , Chow C. K. , Swain S. M. 
Published: March 2020

1028 Background: T and P are humanized recombinant monoclonal antibodies (MoAB) that target different epitopes of HER2 extracellular domain. P blocks HER2’s ability to heterodimerize with other HER/ErbB receptors. Methods: This Ph II trial evaluates the efficacy and safety of T with P in patients (pts) with HER2+ (FISH +) MBC who had progressive disease (PD) on T-based therapy. Eligible pts must have had = 3 T-based regimens, normal (nl) left ventricular ejection fraction (EF=55%) and without significant cardiac history. Pts received IV T (6mg/kg) and P (420 mg) every 3 weeks (wks). EKG plus echocardiogram (ECHO) or cardiac MRI and tumor response were assessed every 3 and 6 wks, respectively. Results: Eleven pts received 39 (1 to 13) cycles, 1 pt achieved a partial response (PR) and 3 pts had stable disease. A total of 68 ECHOs and 8 cardiac MRIs were performed. Left ventricular systolic dysfunction (LVSD) with nl EKG was seen in 5 pts; Grade (Gr) 1 (n = 2) (EF 50–55%), Gr 2 (n = 2) (EF 40–50%) and Gr 3 (n = 1) (EF20–40%). Gr 2–3 events were associated with global hypokinesis. Gr 3 event was associated with symptomatic CHF. All 5 pts had received 240mg/m2 cumulative dose of doxorubicin, 2 pts (Gr 2–3) received chest wall radiation, and 1 pt (Gr 1) had HTN. Two pts with Gr 1–2 LVSD had a history of reduced EF during prior T-based treatment, which reversed to nl upon stopping T. Reduced EF appeared within 1–2 cycles, which returned to nl in 3 pts within 1wk to 3 months (mo) post discontinuing T/P. One pt had persistent Gr 2 LVSD 3 mo after the initial event. The pt with Gr 3 LVSD had extensive chest wall disease and died of PD and possibly CHF 2 mo after treatment termination. Conclusions: We observed Gr 1–3 LVSD in patients with HER2+ MBC who received dual MoAB treatment directed at HER2, in which very strict cardiac surveillance guidelines were required. One of 11 pts achieved PR and 1 pt had symptomatic CHF thus far. It is unknown whether the other events would have become symptomatic if treatment had continued. Further evaluation of the efficacy of combination T with P is required to define the overall risk and benefit. No significant financial relationships to disclose.
Breast cancer liver metastases (BCLM): What may be the role of surgery combined with chemotherapy?
Authors: Adam R. , Salmon R. , Elias D. , Rivoire M. , Cherqui D. , Jaeck D. , Gigot J. , Le Treut P. , Mantion G. , Belghiti J. 
Published: March 2020

1039 Background: Despite recent treatment improvements, the prognosis of BCLM is still poor. Hepatic resection (HR) has been associated with better outcome in selected patients, but its place in multimodality treatment of BCLM remains controversial. This study aimed to examine the outcome of a large cohort of patients selected for HR of BCLM and to define prognostic factors of survival, in a way to better define the place of surgery. Methods: A standardized questionnaire reviewing the main diagnostic and treatment modalities of primary tumor, liver metastases, response to medical therapies, type of surgical procedures, postoperative outcome, and survival following surgery, was sent to all contributing centers. Results: 460 patients treated with liver resection for BCLM from 1980 to 2000, were collected from 31 hepatobiliary surgery centers. Mean age was 51.8 years. Primary tumor, mainly adenocarcinoma, was treated by resection combined with chemotherapy and/or radiotherapy in most cases. Diagnosis of BCLM was made after an average of 54 months from the treatment of the primary tumor. BCLM were unique in 56% and associated to limited extrahepatic disease in 18.5% of patients. After initial treatment by systemic therapy (70% of patients), HR achieved a R0 resection in 82% of patients and was combined to extrahepatic resection for distant metastases in 9% of patients. Postoperative mortality (= 2 months) was 0.2%. Median survival was 45.4 months after HR, with an overall survival of 41% and 22% at 5 and 10 years, respectively. Disease-free survival rates were 14% and 10%, respectively. Four predictive factors were independently associated to an unfavourable outcome: tumor progression on chemotherapy before surgery (p = 0.0006, RR = 2.9), disease-free interval < 12 months after treatment of the primary tumor (p = 0.0003, RR = 2.1), extrahepatic metastases (p = 0.0002, RR = 1.9) and R2 liver resection (p < 0.0001, RR = 3.0). Conclusions: Inclusion of HR in the multimodality treatment of BCLM is safe and associated with a hope of long term survival (22% at 10 years). Surgery should be discussed on a multidisciplinary basis, particularly when potentially radical, in patients well controlled by chemotherapy with a long disease-free interval, and in the absence of extrahepatic disease. No significant financial relationships to disclose.
Identification of proteins promoting development of metastatic breast tumors
Authors: Seeley E. , Ellsworth R. E. , Ellsworth D. , Sanders M. , Hooke J. A. , Caprioli R. , Shriver C. D. 
Published: March 2020

1041 Background: Primary breast tumors are constantly shedding tumor cells into the circulatory and lymphatic systems. Although detection of occult tumor cells is a risk factor for recurrence and progression, tumor cells remain detectable years after initial diagnosis in patients without clinical or histological detection of metastasis. Thus the question remains as to why some women with circulating tumor cells develop metastatic breast cancer while others do not. Methods: Negative lymph nodes from women with node negative (n=22) and node positive disease (n=36) were obtained from patients enrolled in the Clinical Breast Care Project. Negative lymph node status was confirmed by IHC analysis. Frozen tissues were sectioned and mounted on gold coated MALDI target plates for protein expression profiling. Hematoxylin and eosin (H&E) stained slides were prepared from serial sections for histological characterization. MALDI matrix was deposited as individual spots on the tissue sections in a histology directed manner to assay specific areas and tissue types of interest. Mass spectral data were then acquired from multiple sites across each tissue section. Results: 131 features were observed in negative nodes from patients without metastatic disease and 129 in negative nodes from patients with lymph node metastases. While the majority of features detected were similar between the two groups, 8.5% were differentially expressed. Two of the features which were expressed at significantly higher levels in nodes from patients with metastatic disease have been putatively identified as thymosin β4 and thymosin β10. Conclusions: Thymosin β4 and 10 have been associated with disease progression and metastatic capacity in a number of tumor types. The overexpression of these proteins in tumor-negative nodes from patients with metastatic disease in other regional nodes suggests lymph nodes do not play a passive role in metastasis, rather, expression of a specific subset of proteins creates an hospitable environment to facilitate colonization. These markers of metastasis may permit molecular discrimination of those patients with indolent disease from those at risk for metastasis and will thus allow for the design of customized treatment regimens to more effectively treat, or prevent, metastatic spread. No significant financial relationships to disclose.
Alterations in calcium metabolism in patients on long-term bisphosphonate therapy for metastatic breast cancer (MBC): A potential therapeutic target?
Authors: Simmons C. , Dranitsaris G. , Clemons M. , Wong B. Y. , Veith R. , Cole D. E. 
Published: March 2020

1044 Background: The effect of long-term potent BP use on calcium homeostasis in MBC pts is poorly understood. These effects and the need for calcium and Vitamin D supplementation may have significant implications for pt management in both the metastatic and adjuvant settings. Methods: We evaluated serum calcium (sCa), PTH, and 25(OH)D levels and their inter-relationships in 30 MBC pts after prolonged BP use for bone metastases (BM), compared with a control group (CG) of 1484 normal women without bone or mineral disease (JCEM 2003;88:185). The MBC pts were prescribed oral calcium (1g/d) and vitamin D (400IU/d) for 1 month prior to analysis. To determine whether MBC pts differed from CG with respect to the sCa-PTH correlation, logistic regression was performed with sCa, log-transformed PTH and an interaction term (Ca × lnPTH). Results: Mean age of the two groups did not differ [MBC group (58.5 ± 2.0 yr) vs. CG (55.2 ± 0.4 yr, p >.05)]. VitD-deficiency (25vitD < 40 nM) was equally prevalent in the two groups [MBC (23%) vs. CG (25%)]. sCa was significantly higher in MBC pts (2.473 ± 0.019 mM) compared to CG (2.377 ± 0.003, p <0.001). However, PTH was not decreased in MBC pts (4.60 ± 0.36 pM), compared to CG (4.56 ± 0.06, t-test, p=0.91). Logistic regression was highly significant (p<0.0001), as were coefficients for both explanatory variables (sCa, p <0.0001 and lnPTH, p = 0.009) and their interaction (p=0.011). Conclusion: In pts with BM and prolonged BP use there appears to be a shift in the calcium set-point such that PTH release is activated by higher levels of sCa than in controls. We are currently studying whether prophylaxis for relative vit D deficiency in this population can not only correct this shift but also improve pt symptoms No significant financial relationships to disclose.
NCCTG phase II trial N0531of weekly nab-paclitaxel (nab-p) in combination with gemcitabine (gem) in patients with metastatic breast cancer (MBC)
Authors: Roy V. , LaPlant B. R. , Gross G. G. , Bane C. L. , Palmieri F. M. , Perez E. A. 
Published: March 2020

1048 Background: Previous trials with p plus gem show significant antitumor activity in MBC. Nab-p has lower toxicity compared to p with similar therapeutic effects. This study assessed proportion of confirmed tumor responses and toxicity profile of this combination. Methods: Single stage phase II study enrolled patients (pts) with measurable MBC eligible for 1st line chemotherapy (chemo). Pts treated (tx) with nab-p 125 mg/m2 followed by gem 1,000 mg/m2 days 1 and 8 of 21 day cycle. Dose modifications allowed for both drugs. Primary endpoint was proportion of confirmed responses; complete response (CR), partial response (PR) by RESIST criteria on two consecutive evaluations at least 6 weeks apart. 41 evaluable pts required to test the null hypothesis that the confirmed response rate was at most 40% against the alternative of at least 60%. Results: 50 pts enrolled 11/05 to 5/06. Median age 56 (29–86). 40 pts (80%) visceral disease, 34 (68%) ER positive, 28 (56%) PR positive, 1 (2%) HER2 positive, 1 (2%) prior trastuzumab treatment (tx). 25 (50%) had prior adjuvant chemo, including 15 (30%) prior taxane. Median follow-up 7 mos (3–12). Median of 6 cycles of tx completed (1–15). 41 pts discontinued tx, due to progression (41%), pt refusal (27%), adverse events (17%), alternate tx (7%). Confirmed response rate 48% (95% CI: 34–63%): 4 CR, 20 PR. Median duration of response 6.6 mos (95% CI: 5.7, not reached), median progression-free survival (PFS) 7.9 mos (95% CI: 5.3–9.3). Rate of overall survival (OS) at 6 mos 91% (95% CI: 84–100%), 6 month PFS 58% (95% CI: 45–74%). Median OS not reached. 30 pts required dose delays on total of 52 cycles, mostly due to hematologic AEs. 9 pts (19%) had grade (gr) 4 adverse event (AE), 32 (67%) had maximum gr 3 AE. Most common gr 3/4 AEs: neutropenia (52%), fatigue (26%), anemia (14%), dyspnea (14%), thrombocytopenia (12%). Four pts had gr 3 neuropathy. Conclusions: Nab-paclitaxel in combination with gem has clear activity in patients with MBC. Manageable hematologic, but no other significant toxicities. Study ongoing to correlate efficacy with caveolin-1 levels with results expected Spring 2007. Follow up study of this combination with an anti-angiogenesis agent is in development. No significant financial relationships to disclose.
Preclinical testing of a novel regimen of capecitabine (C) in combination with bevacizumab (B) and trastuzumab (T) in a breast cancer xenograft model
Authors: Traina T. A. , Higgins B. , Theodoulou M. , Dugan U. , Kolinsky K. , Zhang Y. , Heimbrook D. , Packman K. , Hudis C. , Norton L. 
Published: March 2020

1049 Background: Mathematical methods applied to xenograft breast cancer models have determined that the maximum impact of C therapy occurs after ∼7 days (7d) of treatment (Norton AACR 2005). The model predicts that doses of C beyond 7d will contribute to toxicity without additional antitumor benefit. The tolerability and anti-tumor activity of C 7d on/7d off (7/7) in female nude mice bearing KPL-4 breast cancer xenografts has been established (SABCS 2006). We now report preclinical models of C7/7 with targeted therapies. Methods: We evaluated the tumor growth inhibition (TGI%) and increase in life span (ILS%) of C7/7 and B with or without T in female nude mice bearing KPL-4, HER2+ breast cancer xenografts. C at maximum tolerated dose (MTD) and ½MTD were tested in combination with conventional doses of the antibodies. Results: C7/7 at MTD is well tolerated in combination with conventional dose B + T. No toxicity was observed at any dose level. The addition of B ± T to C7/7 monotherapy significantly improves TGI%. Survival is significantly prolonged for the combination of C7/7 MTD with B ± T. Comparative results for C7/7 at MTD and ½ MTD are shown in the Table . Additional comparative data will be shown at the meeting. Assessment of ILS% is ongoing for the triplet C7/7 + B + T but has exceeded 463% and >152 days. Conclusions: The improvement in response and survival shown here supports the study of combination C7/7 with B and T. Combinations with B and anti-HER2 therapy will be tested in the clinical, Phase II program at MSKCC. [Table: see text] [Table: see text]
Monitoring tumor response to ZD4190 therapy with an 18F labeled angiogenesis imaging agent
Authors: Morrison M. S. , Ricketts S. , Barnett J. , Constantinou M. , Tessier J. , Wedge S. R. 
Published: March 2020

10507 Background: While a number of novel therapies are being developed to inhibit the growth or survival of tumor vasculature, there are limited methods available for measuring changes in tumor vascularity. In order to quantify tumour vascularity by PET imaging, we examined an 18F-radiolabeled small peptide (AH111585) containing an RGD (Arg-Gly-Asp) sequence. This peptide binds with high affinity (nM) to avβ3 integrin, a cell adhesion receptor that is highly expressed on tumor neovasculature, but expressed at low levels on mature endothelium and epithelial cells. 18F-AH111585 was used to examine the response of human lung tumor xenografts to treatment with ZD4190, a small molecule inhibitor of VEGF signaling. Methods: MicroPET (using 18F-AH111585) and microCT imaging data was acquired pre and post 3 doses of ZD4190 (100 mg/kg, p.o., over 3 days) or vehicle in CD-1 nude mice bearing Calu-6 tumor xenografts. 18F-AH111585 was administered 2 h prior to microPET imaging (10 min) to allow for tumor uptake and background tissue clearance. Tumor and background tissue uptake was determined from the images (expressed as %id/g). Results: Uptake of 18F-AH111585 in Calu-6 tumors was reduced following 3 doses of ZD4190, with an average reduction of 31.8 ± 4.6 % (calculated from imaging ROI data), whereas increased 18F-AH111585 uptake was observed in tumors of vehicle treated mice (average increase of 26.9 ± 9.4 %). The difference between treated and control group uptake was statistically significant (P<0.01; two- tailed t-test). Tumor size (assessed via caliper measurement) remained comparable over the duration of treatment. Skeletal muscle, used as a reference tissue for ROI analysis, demonstrated equivalent uptake pre and post therapy. Conclusions: The data demonstrate that 18F-AH111585 can detect changes in tumor uptake following acute treatment with a VEGF signaling inhibitor (ZD4190). The results suggest that this imaging agent may be useful for monitoring changes in tumor vascularity. No significant financial relationships to disclose.
BRCA1 breast cancer risk is modified by CYP19 polymorphisms in Ashkenazi Jews
Authors: Raskin L. , Lejbkowicz F. , Barnett-Griness O. , Reisfeld D. , Dishon S. , Almog R. , Rennert G. 
Published: March 2020

10511 Background: The lack of full penetrance of mutations in the BRCA genes suggests the possible existence of other modifying genes and/or environmental factors. Exposure to sex hormones is an established major risk factor for breast cancer. The polymorphisms ( rs700518 (Val80), [TTTA]n) in CYP19, a gene encoding the estrogen synthesizing enzyme P450 aromatase, may be associated with risk of breast cancer in BRCA carriers and/or non-carriers. Methods: An analysis of 922 breast cancer cases and 901 healthy controls, including 408 BRCA carriers and 1,415 non-carriers was carried out. Cases and controls of Ashkenazi origin came from a population-based case-control study of breast cancer in Northern Israel, enriched with BRCA carriers (with and without cancer) from a clinical familial cancer service. DNA samples were genotyped for Ashkenazi BRCA1,2 mutations (185delAG, 5382insC, 6174delT) and CYP19 polymorphisms by allelic discrimination using 7900HT ABI sequence detection system. Statistical analyses were performed using SPSS, SAS, and R language. Results: The Val80 G/G genotype was associated with a significantly increased risk of breast cancer as compared to the A/A genotype in BRCA1 carriers (OR=2.2; 95%CI=1.04–4.53; p=0.039) but not in BRCA2 carriers (OR=0.45, 95%CI=0.17–1.16; p=0.098). A similar magnitude association, though not statistically significant, was found between the Val80 and ER-negative status of breast tumors. A reconstructed common haplotype composed of four haplotype-tagging SNPs in Haplotype Block 4, covering the CYP19 coding region, was also significantly associated with breast cancer risk in 210 carriers of BRCA1 (OR=3.4; 95%CI=1.5–7.8; p=0.004). No significant association between CYP19 polymorphisms and breast cancer risk was found in non-carriers. Conclusions: Our data suggest that the CYP19 Val80 polymorphism and a haplotype including this polymorphism are associated with increased breast cancer risk in BRCA1 carriers. As a higher number of repeats in intron 4 ([TTTA]n polymorphism) is found in complete linkage disequilibrium with the Val80 G allele and is associated with higher estrogen levels, this mechanism could explain the phenotypic uniqueness of the carriers. No significant financial relationships to disclose.