bluuebunny/crossref_metadata_2025_split huggingface dataset:
Marrow cell genetic phenotype change induced by human lung cancer cells
Authors: Quesenberry P. J. , Del Tatto M. , Berz D. , Miner T. , Ng T. , Winer E. S. , Aliotta J. , Colvin G. , Dooner M. , Dooner G. , Fontaine J. P. 
Published: August 2020

11108 Background: Murine lung-derived microvesicles are capable of inducing lung-specific mRNA in marrow cells, when co-cultured across from these cells, but separated from them by a cell-impermeable (0.4 micron) membrane. These converted murine marrow cells showed mRNA elevations, lung-specific protein production and enhanced capacity to convert to lung epithelial cells after in vivo transplantation into irradiated mice. We examine here whether fresh tissue from lung cancer patients would have the same capacity to genetically alter co-cultured human marrow cells. Methods: Lung cancer samples were collected from 5 patients undergoing surgery. Minced tumor tissue at 50–100 mg was co-cultured in a semi-permeable culture plate insert opposite 3.0 ×106 human marrow cells. The marrow cells were harvested after 2–7 days of co-culture. Marrow cell RNA was analyzed for lung specific mRNA using real time RT-PCR. Relative levels of gene expression was expressed a fold increase compared to level in controls. Results: Lung cancers studied were adenocarcinoma, endobronchial alveolar carcinoma, bronchioloalveolar carcinoma, non-small cell carcinoma and squamous cell carcinoma. mRNAs for aquaporin 1–5, specific for type I pneumocytes and surfactant A-D, specific for type II pneumocytes, were measured. Aquaporin I was elevated in marrow cells from co culture with all lung cancers; elevations ranging from 2.15 to 56.7 fold (mean 23 fold). Similarly surfactant B mRNA was induced in marrow cells by all lung cancers with fold elevations ranging from 7.9 to 2164 (mean fold elevation 668). More variable elevations were also seen with aquaporin 3, 4, and 5, surfactant A, surfactant C, and surfactant D. Ultracentrifugation (28,000 g) of conditioned media from these cancers revealed the presence of microvesicles with diameters of 100–180 nm. Conclusions: These observations indicate that the genetic phenotype of cells in the vicinity of lung cancer cells can be altered and that these alterations might be mediated by microvesicle transfer of genetic information. No significant financial relationships to disclose.
Trastuzumab plus capecitabine and docetaxel as first-line therapy for metastatic breast cancer: Phase II results
Authors: Gennatas C. G. , Michalaki V. , Gennatas S. 
Published: August 2020

1111 Background: In human epidermal growth factor 2 (HER-2)-positive advanced breast cancer, taxanes plus trastuzumab are among the most widely applied options in the first-line setting. The addition of capecitabine to docetaxel significantly improves overall survival in anthracycline-pretreated metastatic breast cancer. We evaluated the efficacy and tolerability of trastuzumab plus capecitabine and docetaxel regimen as first-line therapy. Methods: Patients who had received adjuvant anthracyclines received docetaxel 75 mg/m2 day 1 and capecitabine 950 mg/m2 twice daily, days 1–14, every 3 weeks until disease progression or unacceptable toxicity. Trastuzumab was administered at a dose of 6 mg/kg every 3 weeks. Time to progression (TTP) was defined as primary end point. Results: Twenty eight patients were evaluable (median age 52 years, range 34–70). The regimen achieved objective responses in 11 patients (39%), including complete response in three patients (11%) and partial response in eight patients (28.5%). The median overall survival time was 25.5 months, and the median progression-free survival time was 7.8 months. The safety profile of the combination was favorable and predictable, with a low incidence of grade 3/4 adverse events. The most common adverse events were hand-foot syndrome, and GI toxicities. Severe myelosuppression was rare and cardiac toxicity did not occur. Conclusions: These data confirm that the combination of trastuzumab plus capecitabine and docetaxel is highly active in patients with HER-2-overexpressing anthracycline-pretreated breast cancer, and is well tolerated. No significant financial relationships to disclose.
Differential response of primary cultures of breast carcinomas to lapatinib in an in vitro chemoresponse assay
Authors: Hancher L. M. , Ervin P. R. , Brower S. L. 
Published: August 2020

1115 Background: Lapatinib (Tykerb) is a small molecule tyrosine kinase inhibitor that targets the intracellular domain of the epidermal growth factor receptor and HER-2, thereby inhibiting both growth and survival signaling pathways. Lapatinib is currently FDA-approved to treat HER-2-positive breast cancer previously treated with anthracycline and taxane therapies and trastuzumab. Due to the low population response rate of lapatinib, an integrated biomarker that can identify patients with an increased likelihood for response would be of great clinical utility. The current study describes an in vitro chemoresponse assay developed to predict sensitivity and resistance of primary cultures of human breast tumor specimens to lapatinib. Methods: The chemoresponse assay (ChemoFx) for lapatinib was developed using four different immortalized carcinoma cell lines (SK-OV3, BT474, MDA-MB-231, MCF7). In addition to cell lines, the chemoresponse assay was also performed on 55 first passage primary cultures of human breast carcinomas. All cultures were confirmed to contain keratin-positive epithelial cells using fluorescence immunocytochemistry. Cell lines and specimens were treated with a 10 dose concentration range of lapatinib for 72 hours and stained with DAPI; remaining live cells were counted on an inverted fluorescent imaging system. Resulting dose-response curves were analyzed and categorized as responsive, intermediate responsive, or non-responsive using a proprietary scoring algorithm. Results: All four cell lines (BT474, MDA-MB-231, MCF7, SK-OV3) were responsive to lapatinib treatment, with EC50 values of approximately 10 uM. Dose-response curves of the 55 primary breast cultures revealed that 9% of the specimens tested were responsive to lapatinib, 15% had an intermediate response, and 76% were non-responsive. These results are consistent with a reported clinical response rate of 10% for lapatinib. Conclusions: Initial results with the described integrated cell-based assay demonstrate that in vitro chemoresponse testing may be useful in predicting patient response to lapatinib. This type of in vitro biomarker is likely to increase the efficacy of the current chemotherapy decision-making process for oncologists and their patients. No significant financial relationships to disclose.
Trastuzumab use and CNS metastasis in Medicare patients diagnosed with metastatic breast cancer (MBC)
Authors: Griffiths R. , Lalla D. , Brammer M. , Herbert R. , Doan J. , Danese M. 
Published: August 2020

1123 Background: While trastuzumab was approved in 1998 for treating patients with HER-2-positive MBC, there is little information on its use in the Medicare setting. Methods: We used SEER-Medicare data to examine patterns of trastuzumab use in women diagnosed with MBC . An index date was defined as either the date of diagnosis (stage IV) or of first distant recurrence (stage 0-III). Included patients were diagnosed in 2000–2002, and had their first claim for trastuzumab between their index date and December 31, 2005, the end of the observation period. Patients were divided into those who received trastuzumab as part of their first treatment following their index date (Group A), and those who began trastuzumab after at least one course of chemotherapy (Group B). Chemotherapy agents were grouped into antimicrotubule (vinorelbine, docetaxel, paclitaxel, vincristine), anthracycline (doxorubicin, epirubicin), cyclophosphamide, other, and unknown. Results: 281 patients met the inclusion criteria. Overall, the median (mean) time from the index date to initial chemotherapy and/or trastuzumab treatment was 35 (94) days (range 1–1,587 days). The average duration of trastuzumab use (first to last administration) was 371 days (median 239), during which patients averaged 2.3 trastuzumab claims per month. There were 192 (68%) patients in Group A. The median (mean) time from diagnosis to initial treatment in Group A was 34 (94) days. 64 (33%) received trastuzumab alone, and 121 (63%) received trastuzumab with an antimicrotubule. In Group B (89 patients), the median (mean) time to initial chemotherapy was 41 (92) days. 36 (40%) received anthracycline and/or cyclophosphamide based therapy, 22 (25%) received an antimicrotubule without either an anthracycline or cyclophosphamide. The median (mean) time from initial chemotherapy to initial trastuzumab therapy was 233 (368) days. At that time, 29 (33%) received trastuzumab alone, and 54 (61%) received trastuzumab plus an antimicrotubule. Conclusions: To our knowledge, this is the first study to describe patterns of trastuzumab use in Medicare. When used for metastatic breast cancer, trastuzumab was most often provided soon after diagnosis as part of initial treatment, and usually with an antimicrotubule agent. [Table: see text]
Relationship and prognosis of hospho-Akt and CD44v6 in breast cancer
Authors: Yu P. , Zhou L. , Song K. , Li K. 
Published: August 2020

1126 Background: The purpose of this study was to investigate the relationship between pAkt and CD44v6 expression of breast cancer after surgery. We also evaluated the expression patterns and predictive value of pAKT and CD44v6 in breast cancer tissues. Methods: Expression of pAkt and CD44v6 protein was detected using immunohistochemistry in 98 patients. The correlation between the expression of pAkt, CD44v6, and other disease-related characteristics with treatment outcome was investigated. Kaplan-Meier survival analysis and Cox regression were used to observe the correlation between variables and the prognostic value. Results: Of all these 98 cases, 37 cases (37.8%) were observed as positive for pAkt expression, and there were 25 cases (51.0%) pAKT positive expression in the lymph node (+) and 15 (30.6%) in lymph node (-) of 49 cases. pAkt expression had no significant difference in node-positive group and node-negative group. We examined the relationship between pAKT and HER2 expression, pAkt expression was positively correlated with HER-2 expression (p = 0.009). A statistically significant difference in positive staining for pAkt was observed between CD44V6-positive and CD44V6-negative tumors (p = 0.016). CD44v6 positive tumors showed a statistically very highly significant association between node-positive and node-negative (p = 0.013). For prognosis value, a week relationship was observed between pAkt and OS, but DFS was inversely associated with pAkt staining intensity (p = 0.061, p = 0.004). There had a statistical correlation between CD44v6 overexpression and OS and DFS (p = 0.026 and 0.006 respectively). Univariate analysis revealed that lymph node status and CD44V6 were significantly associated with decreased OS and DFS, but there had no significant difference between variables and OS and DFS by multivariate analysis. Conclusions: Our data suggested that there had a intensive relationship between pAKT and CD44v6 expression in breast cancer tissues. We demonstrated that both pAkt and CD44v6 were significantly assiociated with a decreased OS and DFS in breast cancer patients. pAKT and CD44v6 overexpressed in cancer cells may be sensitive markers for predicting the treatment outcome in breast cancer patients. No significant financial relationships to disclose.
Dose-escalating study of continuative low dose of oral vinorelbine in patients with advanced breast cancer
Authors: Felici A. , Russillo M. , Di Segni S. , Fabi A. , Ferretti G. , Carlini P. , Contestabile M. , Nuvoli B. , Sperduti I. , Cognetti F. , Papaldo P. 
Published: August 2020

1128 Background: Low and continuative dose of antineoplastic drugs has been shown to have an antiangiogenic activity. The rapid absorption and relatively short half-life of the oral formulation of vinorelbine are favorable pharmacokinetic characteristics to test a continuative low-dose schedule. Methods: Patients with measurable metastatic breast cancer were treated with escalating dose of oral vinorelbine from 50 mg/m2 per week to 90 mg/m2 per week until progressive disease or unacceptable toxicity. These patients were administered one third of the total weekly dose 3 times per week, every other day. A pharmacokinetic analysis was planned at the first 3 weeks of drug assumption. Results: Of twenty-two patients included in the study, 3 were treated at 50 mg/m2/w (level 1), 5 at 60 mg/m2/w (level 2), 3 at 70 mg/m2/w (level 3), 8 at 80 mg/m2/w (level 4), and 3 at 90 mg/m2/w (level 5); we are still enrolling patients at this level. The median age was 59 years (range 23–75). The median number of prior lines of chemotherapy and hormonal therapy was 2 (range 0–4 for CT and 0–5 for OT). Fifteen of 22 patients had visceral metastasis. No dose-limiting toxicities have been observed until now. The main toxicities were: asymptomatic neutropenia grade 4 in two patients (1 in level 4 and 1 in level 5), asthenia grade 3 in 7 patients (1 at level 1, 2 at level 2, 1 at level 3, 3 at level 4), neurotoxicity grade 3 in two patients (one at level 2 and one at level 4). One patient experienced an intestinal sub-occlusion and hospitalization was required with no permanent side effects. One patient had a partial response, five a stable disease, fourteen progressed and two are not evaluated yet. At 1 year, five of the twenty evaluable patients are died by disease. Samples of twenty patients were collected for pharmacokinetic analysis that will be presented at the meeting. Conclusions: The continuative split 3 times per week oral vinorelbine is feasible, and at 90 mg/m2/w we have not reached yet the maximum tolerated dose. No significant financial relationships to disclose.
In situ protein expression of RRM1, ERCC1, and BRCA1 in metastatic breast cancer patients treated with gemcitabine-including chemotherapy
Authors: Metro G. , Zheng Z. , Fabi A. , Mottolese M. , Monteiro A. N. , Vici P. , Boulware D. , Lara Rivera S. , Cognetti F. , Bepler G. 
Published: August 2020

1129 Background: Ribonucleotide reductase 1 (RRM1) is a determinant of gemcitabine efficacy in non-small cell lung cancer (NSCLC) and pancreatic cancer. We investigated the tumoral levels of RRM1 in a population of metastatic breast cancer (MBC) patients treated with gemcitabine-based regimens. The protein levels of the excision repair cross-complementation group 1 (ERCC1) and breast and ovarian cancer susceptibility gene 1 (BRCA1) were also measured. Methods: Fifty-five patients were treated and followed prospectively from September 2004 to December 2007. Treatment consisted of gemcitabine plus a taxane in 46 patients and gemcitabine plus pegylated liposomal doxorubicin in 9 patients. RRM1, ERCC1, and BRCA1 were determined by automated in situ protein quantification (AQUA v1.6) on a tissue microarray containing triplicate tumor specimens. Results: The average scores for RRM1, ERCC1, and BRCA1 ranged from 245.6–2, 774.1, 74.0–410.3, and 54.4–1, 833.1, respectively. A statistically significant correlation between the levels of expression of all three markers (Spearman's rho > .36; P < 0.007) was observed. There was no significant association between RRM1, ERCC1, or BRCA1 levels and disease response, progression free survival, or overall survival. Conclusions: In tumor specimens from patients with MBC, RRM1, and BRCA1 had a range of expression and pattern of distribution that makes these markers potentially suitable for clinical decision making. In contrast, the relatively narrow range of ERCC1 expression might signify that ERCC1 protein levels are not useful predictors of platinum efficacy in MBC. Consistent with what has been shown in NSCLC, RRM1, ERCC1, and BRCA1 levels were significantly correlated, suggesting that the coexpression of such DNA repair proteins may be universal to epithelial malignancies. The lack of correlation between marker levels and clinical outcome may be explained by the specific chemotherapy combinations used. No significant financial relationships to disclose.
Safety of a novel capecitabine dosing schedule when combined with lapatinib in patients with HER2-positive metastatic breast cancer refractory to trastuzumab
Authors: Traina T. A. , Theodoulou M. , Feigin K. , Patil S. , Geneus S. , Modi S. , Fornier M. , Lake D. , Norton L. , Hudis C. 
Published: August 2020

1131 Background: Capecitabine (C) is active in breast cancer and is usually dosed for 14 days (d) followed by a 7d rest (14 - 7). We described a mathematical method which predicts the optimal schedule for C to be 7d followed by a 7d rest (7 - 7) (Norton et al, Amer Assn Can Res. 2005). The MTD of C(7 - 7) is 2,000mg BID (Traina et al, J Clin Oncol. April 2008). Lapatinib (L) improves time to progression when added to C(14 - 7) in patients (pts) with HER-2-positive (+) metastatic breast cancer (MBC) that progressed after trastuzumab (T). To optimize this effective combination, we are testing C(7 - 7) + L in a phase II trial. Methods: Eligible pts have measurable, HER-2(+) MBC that has progressed after T. HER-2(+)=IHC 3+ or FISH>2. Pts have normal LVEF by MUGA, ECOG performance status (PS) <2 and normal organ function. <3 prior chemotherapy (CRx) regimens are permitted. Prior fluoropyrimidine is excluded. Therapy (tx) consists of C (2,000 mg BID, 7 - 7) and L (1,250 mg, daily). Cycle length = 4 wk. Pts are evaluated for toxicity q4 weeks (wk), for response q12wk; LVEF by MUGA q12wk. Primary endpoint: response rate (RR). Secondary endpoints: toxicity, stable disease >6 months, PFS. Using a Simon optimal 2-stage design, with alpha = 10%, power = 90% to discriminate between RR 10% and 25%, 21 pts will be accrued to the first stage. If >2 pts respond, 29 additional pts will be enrolled. If >7/ 40 pts respond, then C(7 - 7) + L will be considered worthy of further study. Results: As of January 5, 2008, 6 pts are enrolled and evaluable. Median (med) age 64 yrs (42–71), med ECOG PS 1 (0–1), ER/PR(+) 3, HER-2(+) 6, sites of MBC: bone (2), viscera (4), soft tissue (5). Med baseline LVEF 62% (51–68%). Prior tx: Adjuvant: CRx (5), hormone tx (3), T (3); MBC: CRx (2), hormone tx (1), T (3). After a med of 3 cycles (1–4), there were no grade 3, 4, or 5 events. Tx-related toxicity is: Gr 2 fatigue (1); Gr 1 AST (4), diarrhea (3), ALT (2), vomiting (1), hand-foot (1), fatigue (1). No withdrawls due to reduced LVEF. Two pts evaluable for response: PR = 1, SD<6 mo = 1. Conclusions: Capecitabine (7 - 7) + lapatinib appears well tolerated compared to C(14 - 7)+L (Geyer et al). Additional safety and efficacy data is anticipated prior to this meeting. [Table: see text]
Combination of trastuzumab, oxaliplatin, and docetaxel as first-line treatment in HER2-positive metastatic breast cancer patients: First-step results of a phase II trial (HOT trial)
Authors: Amoroso D. , Donati S. , Valsuani C. , Puccetti C. , Rondini M. , Siclari O. , Tartarelli G. , Giannessi P. , Falcone A. , Camerini A. 
Published: August 2020

1132 Background: The addiction of trastuzumab to standard chemotherapy has improved the outcome of HER-2-positive metastatic breast cancer (MBC) pts. Oxaliplatin and docetaxxel are among the most active agents in MBC pts pretreated with anthracyclines. In vitro studies showed synergistic effect of the combination. We investigated the feasibility and the safety of the 3-drug combination given as first line chemotherapy (CT) in HER-2-positive MBC. Methods: HER-2-positive MBC pts were prospectively enrolled to receive a first-line treatment consisting of trastuzumab 8 mg/kg loading dose iv (followed by 6 mg/kg) on day 1, docetaxel 75 mg/sqm iv on day 1, and oxaliplatin 70 mg/sqm on day 2 every 21 days. All pts received peg-filgrastim 6 mg on day 3 to prevent bone marrow toxicity. Pts received up to 9 cycles of CT. Primary end points were overall response rate (ORR) (according to RECIST criteria), clinical benefit (CB), and tolerability. Cardiac function was evaluated by echocardiography at baseline, each 3 courses and at the end of treatment. Results: To date, 13 pts have been enrolled (median age 59 yrs [range 34–70]; ECOG PS 0) representing the first-step accrual according to Minimax design. Ten pts had previously received anthracyclines as adjuvant treatment and 11 pts presented with visceral metastasis. All pts received at least 6 cycles of treatment with 7 pts continuing up to 9 cycles. Response and toxicity data are available for all pts. Two pts experienced CR, 7 pts PR, and 4 pts showed SD (lasting more than 6 months in 3 cases) with an ORR of 70% and a CB of 100%. No pts progressed during treatment. No grade 4 toxicity was observed. Most common grade 3 toxicities were diarrhea (18%), nausea/vomiting (22%), mucositis (11%). In particular, 2 episodes of febrile neutropenia were reported and no grade 4 haematologycal toxicity was observed. No significative reduction of LVEF were reported. Conclusions: The combination of trastuzumab, oxaliplatin, and docetaxel (HOT combination) showed promising activity and was well tolerated as first-line treatment in pts with HER-2-positive MBC. Peg-filgrastim profilaxis improved safety profile. No significant financial relationships to disclose.
A phase II study of GW786034 (pazopanib) in patients with recurrent or metastatic invasive breast carcinoma: Results after completion of stage I: A trial of the Princess Margaret Hospital Phase II Consortium
Authors: Taylor S. K. , Chia S. , Dent S. , Clemons M. , Grenci P. , Wang L. , Oza A. M. , Ivy P. , Pritchard K. , Leighl N. 
Published: August 2020

1133 Background: Pazopanib, an oral small molecule inhibitor of VEGFR, PDGFR, and KIT, has demonstrated activity in phase I, with a recommended phase II dose of 800 mg/d (Hurwitz H et al, J Clin Oncol. 2005;23[16 suppl]:3012.1). We evaluated the activity of single agent pazopanib in recurrent or metastatic breast cancer (MBC). Methods: In this 2-stage design, patients with recurrent or MBC received pazopanib 800 mg/d. The primary endpoint was objective response rate (ORR) of 20%. Response in 3 out of 18 patients was required to go to stage 2. Treatment was continued until progression. Results: 21 patients entered stage 1; 67% were ER positive and all were HER-2-negative. Prior lines of chemotherapy were 1 in 76% and 2 in 14%. Of the 19 evaluable patients, 2 patients remain on treatment. 14 (74%) stopped due to progressive disease, 2 (10%) due to adverse events, and 1 (5%) due to patient request. Best response was partial response (PR) in 1 (5%), stable disease (SD) in 11 (58%), and progressive disease in 7 (37%). Clinical benefit rate (CR, PR, or SD for ≥ 6 months) was 26%. Median time to progression (TTP) was 3.7 months (95% C.I. 1.7 months - not reached). 9 out of 18 patients (50%) with measurable target lesions had some decrease in target lesion size. Estimated progression-free survival at 3 months was 55%, and 28% at 6 months. Adverse events were grade 3/4 elevations in AST (14%) and ALT (10%), and grade 3 hypertension and neutropenia (14% each). Other common events were grade 1/2 lymphopenia, neutropenia, diarrhea, fatigue, skin hypopigmentation, hypertension, nausea, vomiting, anorexia, and headache. Conclusions: Pazopanib is well tolerated and demonstrates activity in pretreated breast cancer. While the target ORR of 20% has not been met, rates of SD and TTP are comparable to other active agents in this setting, and therefore pazopanib may be an interesting agent for future studies in breast cancer. [Table: see text]