bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vitro abrogation of acquired tamoxifen resistance using histone deacetylase inhibitors
Authors: Beeram M. , Russell D. , DeGraffenreid L. , Freeman J. 
Published: March 2020

10607 Tamoxifen (TAM) is a highly effective therapy for breast cancer. However, only 60% of estrogen receptor expressing (ER+) breast cancers respond to TAM (40% de-novo resistance). Continuous TAM treatment causes emergence of acquired resistance in these initially- responsive cancers. Strategies that abrogate TAM-resistance are therefore of significant clinical importance. One approach being studied is the use of histone deacetylase (HDAC) inhibitors. These compounds impact tumor biology both at the level of gene transcription and protein stability. In our study, we developed an in vitro model of tamoxifen resistance to test the efficacy of a hydroxamic acid derivative, Trichostatin A (TSA) at modulating breast cancer cell growth both in TAM responsive as well as TAM resistant cells. Forty-eight MCF-7 breast cancer single-cell colonies were isolated from a heterogeneous population, with 16 of the 48 (33%) surviving 4 months of continual growth in charcoal-stripped media with 10-7 M tamoxifen. ER expression was lost in 9 (56%) and HER-2 expression was acquired in 7 (44%) of the 16 resistant clones. The ER-negative cells demonstrated a concomitant increase in p-Rb, p21 and p27 levels, as well as significant increase in activation of both the PI3K and MAP kinase pathways. These results suggest that alteration of parent cell phenotype is an adaptive event at the transcriptional level, and is a significant mechanism for mediating TAM resistance. Inhibition of growth, by TSA, was studied in both the ER+ and ER- cells, with and without cotreatment with TAM. Cotreatment with TSA effectively blocked the emergence of resistance and prolonged the duration of response to TAM. The molecular mechanisms mediating this enhanced response were studied and focused on the effects of TSA on ER and HER-2 activity and expression. Our results indicate that short term exposure to TSA induces suppression of ER gene transcription, as well as targets ER for protein degradation where as long term exposure shows paradoxical effects at the genomic level. The effects of TSA on acquired HER-2 expression are being studied. These data have important clinical ramifications for the clinical development of HDAC inhibitors for the treatment of breast cancer patients. No significant financial relationships to disclose.
The TLR4 polymorphism predicts the response of breast cancer patients to anthracyclins
Authors: Ghiringhelli F. , Apetoh L. , Tesniere A. , Andre F. , Lidereau R. , Delaloge S. , Chompret A. , Kroemer G. , Zitvogel L. 
Published: March 2020

10612 Background: Conventional anticancer therapy mainly relies upon chemotherapy which supposedly directly eliminates tumor cells. However, we showed in mice that chemotherapy-induced tumor cell death markedly enhanced T-cell mediated tumor rejection, suggesting a role of innate immune receptors in the response to anthracyclins. Moreover, anthracyclins are less effective in athymic nude or Toll like receptor-4 (TLR4) deficient mice (Obeid et al. Nat. Med. 2006). A single nucleotide polymorphism (SNP) in TLR4 (896A/G, Asp299Gly) affecting the extracellular domain of TLR4 is associated with reduced endotoxin responses in humans. We addressed whether the TLR4 SNP could affect the response to anthracyclins in breast cancer patients. Methods: We included 280 patients from three cancer centers bearing non-metastatic breast cancer presenting with lymph node involvement and treated with anthracyclin-based regimen after local surgery. TLR4 genotyping performed on leukocytes (PCR based on exonuclease degradation of dual labelled allele-specific oligos) and statistical analyses were performed in a blinded fashion. Results: The frequency of Asp299Gly (heterozygote) and Gly299Gly (homozygote) TLR4 germline polymorphisms was 17.1 and 0.7 % respectively. Patients that exhibited a mutated TLR4 allele did not differ from patients displaying the normal TLR4 allele for all classical prognostic factors (age, pathological tumor size, lymph node involvement, tumor grade, hormone receptors, and median follow up, p>0.05). However, the frequency of metastases was statistically higher in the mutated TLR4 group five years after surgery (40% versus 26.5% in non mutated patients, p <0.05, RR: 1.7, 95% CI [1.2–3.6]). Moreover, the Kaplan Meier estimate of metastasis-free survival indicated an overall significantly lower percentage of metastases-free patients in the mutated TLR4 group (Log rank test, p = 0.03). Conclusions: It is the first demonstration of the role of innate immunity and TLR4 in the response to anthracyclins in localized breast cancer. No significant financial relationships to disclose.
A genomic signature of chemotherapeutic multidrug resistance provides a rational approach to identify patients for targeted therapy in advanced solid tumors
Authors: Anguiano A. , Mori S. , Chang J. , Vlahovic V. , Kelley M. J. , Ginsburg G. , Dressman H. , Nevins J. R. , Potti A. 
Published: March 2020

10613 Background: Multidrug resistance (MDR), the process by which cells resist many structurally and functionally unrelated drugs, remains a major challenge for cancer treatment. Strategies to reliably predict MDR will revolutionize cancer therapy. Methods: We made use of in vitro drug sensitivity data on 47 FDA approved chemotherapeutic agents from the NCI-60 database coupled with Affymetrix microarray data, to develop a gene expression signature of chemotherapeutic MDR, using a 'metagene’ approach to gene expression analysis (Potti et al, Nature Medicine, 2006). The capacity of the MDR signature to predict in vitro and in vivo resistance was evaluated in multiple independent cell line and patient cohorts. Results: A gene expression signature of chemotherapeutic MDR developed from cancer cell lines using a novel ‘metagene’ approach can accurately predict patients resistant to standard chemotherapeutic agents, including multi-drug regimens. This includes cohorts of patients with early stage breast cancer (n = 171; accuracy: 75.5%, sensitivity: 49.3%, specificity: 92%), patients who received neoadjuvant chemotherapy (n = 51; accuracy: 78.5%, sensitivity: 73.7%, specificity: 92.3%), and ovarian cancer (n = 105; accuracy: 83.8%, sensitivity: 71.8%, specificity: 93.7%). We further show that MDR signature expression is an independent prognostic factor in early stage breast cancer (p = 0.02, odds ratio: 3.49) and a large cohort of non-small cell lung cancer (p = 0.03, odds ratio: 5.70), in a multivariate analysis. Finally, to identify a rational therapeutic strategy in patients with the MDR phenotype, we have integrated the prediction of MDR with profiles of oncogenic pathway deregulation (Bild A, Nature, 2006) and show that targeting the Src pathway using a Src specific inhibitor (SU6656) circumvents MDR in the in vitro setting. Conclusions: The development of a gene expression signature of MDR, that can predict resistance to commonly used cytotoxic chemotherapies, provides a rational approach to developmental therapeutics, by identifying novel 'customized’ candidate drugs (e.g. targeting Src) for further clinical development. No significant financial relationships to disclose.
Phase I/II trial combining the HDAC inhibitor, valproic acid (VPA) and FEC100 (5-fluorouracil, epirubicin and cyclophosphamide) in locally advanced/metastatic breast cancer
Authors: Munster P. N. , Marchion D. C. , Schmitt M. , Bicaku E. , Lacevic M. , Minton S. , Carter W. , Daud A. 
Published: March 2020

1065 Background: Cell culture and xenograft studies suggest a synergistic interaction between histone deacetylase inhibitors (HDACi) and topoisomerase (topo) inhibitors, as well as other DNA targeting agents. Methods: In this phase I/II study, we determined the effects of escalating doses of VPA on the clinical efficacy and tolerability of epirubicin. The phase I part was open to patients will all solid tumors. A limited phase II part at the maximum tolerated dose (MTD) of VPA enrolled 10 breast cancer patients and incorporated the breast cancer regimen FEC100 (5-fluorouracil, epirubicin, cyclophosphamide (600/100/600 mg/m2)). VPA was given on days 1–3 prior to epirubicin/FEC100 in 3-week cycles. HDAC expression, histone acetylation and topo II expression were evaluated in pre-and post-VPA peripheral blood mononuclear cells and tumor samples. Results: Fifty-four (44 in phase I and 10 in phase II) patients [median age 55 (39–78)] received VPA (mg/kg/day): 15, 30, 45, 60, 75, 90, 100, 120, 140 and 160. Tumor types included: breast (10+10), melanoma (11), lung (6), sarcoma (2), GYN (2), GI (5) and others (8). Dose-limiting toxicities included somnolence, confusion and febrile neutropenia. No exacerbation of FEC100/epirubicin-related toxicities was observed. Objective responses in the phase I part 9/41 (22%) were seen across different tumor types despite a median number of 3 (0–6) prior regimens with stable disease/minor response in 16/41 (39%). In the breast-specific phase II part, partial responses to date were seen in 4/8 (50%) and stable disease in 2/8 (25%), progression in 1/8 (12.5%), 1/8 (12.5%) patients withdrew consent. All breast cancer patients with a response/stable disease received the maximal number of seven cycles. VPA plasma concentrations correlated with VPA dose. There was a positive correlation between histone acetylation and VPA dose as well as plasma levels in PBMC and further correlated with those in tumors. Conclusion: A sequence-specific combination of VPA and FEC100 in breast cancer is highly active without exacerbation of chemotherapy-induced toxicities. A neoadjuvant phase II trial using VPA (120 mg/kg) -> FEC100 in patients with early stage breast cancer is ongoing. [Table: see text]
Retrospective analysis of data from a phase I trial with a new adaptive method
Authors: Meille C. , Favier L. , Coudert B. , Barbolosi D. , Iliadis A. , Biville F. , Garnier J. , Ferri-Dessens R. 
Published: March 2020

1067 Background: The phase I trial CAPEV CGFL 01 [ESMO, Vienne, Austria: 2004.V 52–53] aimed to find the Maximum Tolerated Dose (MTD) of i.v. Vinorelbine when associated with oral Capecitabine for three cycles of 21 days in metastatic breast cancer (MBC). Method: Vinorelbine was administered at d1 and d15 and Capecitabine b.i.d. from d1 to d14 (fixed at 2,000 mg/m2/day). Trial design was based on “3+3” scheme with predetermined dose levels of Vinorelbine starting at 25 mg/m2/day. Ten patients (age 46–67 years) with MBC were enrolled in this trial. A new phase I adaptive method [Statistical Methods in Biopharmacy. Statistical Innovations in Clinical trials, Paris September 2005] under validation was used to analyze data available from the CAPEV trial. This method performs precise definition of Dose Limiting Toxicity (DLT) and modeling of all the grades of toxicity. The method allows sequential real time analysis of data by alternating estimation and design steps. Results: Most frequent toxicities were hematological (anemia and neutropenia) and cytolysis. Three DLTs occurred for the first 6 patients included at the starting level of Vinorelbine. De-escalation to 20 mg/m2 was done at the 7th patient but a new DLT occurred for the 7th patient and lead to trial ending at the 10th patient. Firstly, by analyzing all available data, Vinorelbine MTD was calculated at 20.2±4.04 mg/m2/day. Secondly, data was processed according to the inclusion time of patients; the adaptive method calculated a Vinorelbine MTD equal to 19.5±8.34 mg/m2/day as early as the 4th patient. Conclusion: The administration scheme of i.v. Vinorelbine and oral Capecitabine tried in this study cannot be retained for MBC treatment. However, early convergence of adaptive method clearly shows its high performance in the de-escalation scheme and Vinorelbine MTD determination. With this method Vinorelbine MTD could have been determined with the 4th patient data without needing the inclusion of 6 additional patients (4th and not 7th patient). This method should be used in prospective phase I trials and in parallel with classical and clinical method of MTD determination. No significant financial relationships to disclose.
Bortezomib and capecitabine in patients with metastatic breast cancer previously treated with taxanes and/or anthracyclines: Final results of a phase I/II study
Authors: Schmid P. , Regierer A. , Kiewe P. , Schippinger W. , Greil R. , Lehenbauer-Dehm S. , Niederle N. , Freier W. , Van de Velde H. , Possinger K. , Kuehnhardt D. 
Published: March 2020

1072 Background: Capecitabine has shown substantial activity in taxane and/or anthracycline pretreated breast cancer patients. Bortezomib, a 26S proteasome inhibitor, has been shown to increase sensitivity to chemotherapy. This phase I/II trial was initiated to evaluate the combination of capecitabine and bortezomib in heavily pretreated patients with metastatic breast cancer. Methods: Patients with metastatic breast cancer and prior taxane and/or anthracycline therapy were treated with bortezomib (1.0–1.3 mg/m2; days 1, 4, 8 & 11) and capecitabine (1,500–2,500 mg/m2, days 1–14) in 3-weeks intervals for up to 8 cycles. Primary endpoints were to determine the optimal doses for the combination (phase I) and the tumor response rate (RR) (phase II). Secondary endpoints included safety, time to progression (TTP), duration of response (DR), and overall survival (OS). Results: A total of 35 patients were enrolled and 29 patients were assessable for response. The majority of patients had received 2 or 3 lines of chemotherapy (69% and 14%, respectively) prior to the study. The maximum tolerated doses (MTD) were bortezomib 1.3 mg/m2 and capecitabine 2500 mg/m2. Dose limiting toxicities were Grade 3 stomatitis in 1 out of 6 patients at 1.0/2,000 and Grade 3 diarrhea in 1 out of 6 patients at 1.3/2,500. Myelosuppression was low. Non-hematological toxicities were generally mild to moderate with no G4 toxicity being observed. Most common side effects were thrombocytopenia (Grade 3/4 27% of patients), diarrhea (18%), hand-foot syndrome (12%), peripheral neuropathy (12%), leucopenia (9%) and asthenia (9%). The overall RR was 17.2% and an additional 31% of patients had stable disease (31%; 4 unconfirmed). In the 21 patients treated at the MTD, RR was 17.6% and 47% of patients had SD. Median TTP and OS were 3.5 months (95% CI 1.9–4.4) and 7.5 months (95% CI 5.6–14.6), respectively. Median DR was 4.4 months. Conclusions: The combination of bortezomib and capecitabine is well tolerated and has moderate antitumour activity in heavily pretreated breast cancer. [Table: see text]
Fulvestrant in advanced breast cancer following following failure of tamoxifen and a third generation aromatase inhibitor
Authors: Wang J. , Jain S. , Heller W. , Mackie D. , Watson V. , Dweck M. , Coombes R. C. , Palmieri C. 
Published: March 2020

1073 Background: Endocrine therapy is a key modality in the management of estrogen receptor positive metastatic breast cancer. Fulvestrant (ICI 182,780) is an estrogen receptor downregulator. It has previously been shown to be as effective as anastrozole in patients who had previously progressed on tamoxifen. Methods: A retrospective study was carried out of metastatic breast cancer patients treated at Charing Cross Hospital between 2002–2005 who had received fulvestrant following treatment failure with tamoxifen and a third generation aromatase inhibitor. All patients were postmenopausal and received fulvestrant 250mg IM every 28 days. Measurable disease was assessed by response evaluation criteria in solid tumors (RECIST). Results: A total of 45 patients were identified with a median age of 60 (range 36 to 90). The ER status was known in 95% (n=43) of patients and was positive in all cases, it was unknown in 2% (n=2). At the time of commencing fulvestrant, 96% (n=43) had metastatic disease and 4% (n=2) locally advanced disease. All patients had received at least 2 lines of prior endocrine therapy (including adjuvant therapy), at time of starting fulvestrant the median number of prior regimens was 3 (range 3–5). Fulvestrant was administered for a median of 4 months (range 1 to 20 months), with 4 patients currently still receiving therapy as of 1 November 2006. Of the 45 patients, 2.2% (n=1) achieved a partial response, while 31% (n=14) achieved stable disease for at least 6 months. Thus, 33.3% (n=15) obtained clinical benefit (defined as PR or SD for at least 6 months). The response rates based on line of therapy will be presented. Of the 45 patients, 41 were evaluable for survival data. The median survival of the remaining patients from the start of fulvestrant therapy was 9 months (range 1 to 48 months). Of the 44 patients, 14% (n=6) remain alive. The treatment was well tolerated and toxicity data will be presented. Conclusions: Fulvestrant is well tolerated and is efficacious as treatment for advanced breast cancer that has failed tamoxifen and a third generation aromatase inhibitors. No significant financial relationships to disclose.
Prognosis value of hormonal and HER2 receptors on overall survival (OS) and disease-free interval (DFI) in metastatic breast cancer (MBC)
Authors: Francis L. , Olivier T. , Frédérique P. , Catherine A. , Marie-Ange M. , Ines R. , Xavier D. , Pierre G. , Hervé C. , Philippe C. 
Published: March 2020

1077 Background: In MBC, positive HR constitute a favourable prognostic factor and predict response to an hormonal therapy. Conversely HER-2 overexpression is an adverse prognostic factor associated with a more aggressive tumor. In this retrospective study we analysed overall survival (OS) and disease-free interval (DFI) of three phenotypes: HR-/HER-2- (triple negative); HR+/HER-2- (luminal) and HER-2 overexpression (HER-2+). Methods: We evaluated 511 patients with a MBC treated at Centre Jean Perrin from 1973 to 2006. A comparative lecture of oestrogenic, progestative and HER-2 receptors was performed by IHC. At present, HR and HER-2 status were re-evaluated on 166 initial tumor sample of this data base by two pathologists (study currently ongoing). Median age of patients was 54.8 years. 120 (23.6%) patients were directly metastatic (M1), 391 (76.4%) relapsed distantly (M0). Metastatic patients received a median number of 2 lines of chemotherapy (range, 0–14) and/or a median number of 1 line (range, 0–8) of hormonotherapy. 92 (55.4%) patients had a luminal phenotype, 48 patients (28.9%) were HER-2+ and 26 patients (15.7%) were triple negative. Results: Among these 166 tumors, OS was significantly different between these three populations (p=0.00056). DFI variation was not signicant (p=0.083). These data showed that: - Luminal phenotype had the better OS (median survival of 36.5 months) and DFI (51.09 months) - HER-2+ phenotype (33 of 48 patients were treated with trastuzumab from 1999) had an intermediate prognostic on OS (median survival of 31.1 months) and DFI (42.2 months) - Triple negative phenotype had a poor prognostic on OS (median survival of 12.8 months) and the worse DFI (32.64 months) Conclusions: In metastatic breast cancer, luminal phenotype patients had the best OS; HER-2+ phenotype (treated by herceptin) had an intermediate OS, and triple negative phenotype had the worse OS. No significant financial relationships to disclose.
Influence of letrozole on plasma estrogen levels in postmenopausal patients with metastatic breast cancer and the effect of estrogen levels on response rates
Authors: Zidan J. , Abzah A. , Chetver L. , Basher W. , Shneider J. , Tamam S. 
Published: March 2020

1078 Background: The aromatase inhibitor (AI) letrozole and other members of this treatment group are very effective in the treatment of postmenopausal women with breast cancer. AIs markedly reduce estrogen levels in postmenopausal women by inhibiting aromatase. At menopause estradiol levels are about 25 pmol/l. Estradiol levels are higher in plasma of women with breast cancer as compared with women with no breast cancer. The purpose of this prospective study is to evaluate estradiol levels before and during letrozole treatment and the effect of primary estradiol levels and their decrease on response rate. Methods: Letrozole 2.5 mg/day orally was given to 50 patients (pts) with metastatic and locally advanced breast cancer (MBC). All pts had measurable disease. Overnight fasting clotted blood samples used for assessment of serum levels of estradiol at baseline and after 3, 6 and 12 months. Estradiol levels were compared to clinical response in this single stage study. Results: Mean age was 56 years (range 46–89 y). Mean years from menopause to starting letrozole was 9 years.12% of pts received previous hormonotherapy and and 30% received chemotherapy for their metastatic disease. Estradiol levels decreased from a mean of 40 pmol/l before letrozole to 40 pmol/l and <40 pmol/l in 19 pts (38%). No difference in estradiol depression rate was found between the 2 groups. In the first group (estradiol >40 pmol/l) objective response rate was 48%: 4 complete responses (CR) and 11 partial responses (PR) out of 31 pts, 12 pts had stabilization of the disease (SD). In the second group 3 pts had CR, 5 had PR: objective response rate of 42% (8/19), and 42% SD. There is a trend (not significant) for higher response rate in pts with higher estradiol levels at the beginning of treatment. Conclusions: Letrozole was found to cause very high estradiol suppression and high response rates in postmenopausal women with advanced breast cancer. A trend was found for higher response rates in pts with higher estradiol levels at baseline although difference was not significant. This is the first study to address this issue. No significant financial relationships to disclose.
Kinetics of CEA and CA15–3 correlate with response in patients undergoing chemotherapy for metastatic breast cancer
Authors: Stieber P. , Laessig D. , Heinemann V. , Untch M. , Kahlert S. , Nagel D. 
Published: March 2020

1087 Background: The aim of this retrospective analysis was to determine the correlation between tumor marker kinetic (TMK) like CEA and/ or CA 15–3 and imaging during of MBC pts. Methods: TMK (CEA, AxSYM, Abbott; CA 15–3, Elecsys, Roche) were evaluated in MBC pts at the beginning of palliative chemotherapy (pre-treatment value = A), after 20–30 days (1st intermediate value = B), after 40–60 days (2nd intermediate value = C) and at the time of staging with imaging techniques (D). Response to treatment was assessed by UICC criteria. Two criteria for progressive and two for non-progressive disease based on TMK were established. The 1st criterion for progression required that the increase from A to C had to be >25 %, and the increase per day from A to C had to be greater than the increase from A to B. The 2nd criterion for progression required that D should be >25% than A and an increase of C to D was required. The 1st criterion for non-progressive disease required that the decrease from A to C had to be > 25% and C < B. The 2nd criterion for non-progressive disease required D <25% than B and D < C. Results: 54 (70%) pts showed a correlation of TMK and imaging results. In 10 (13%) pts no correlation was obtained, and in 13 (17%) pts no biochemical statement was possible because of divergent TMK. Using our criteria a sensitivity of 70.2 % was reached. Conclusion: We could show a correlation between TMK and imaging results. After validation in a prospective trial using our criteria in clinical practice could improve therapeutic monitoring and reduce radiation exposure in pts with MBC. No significant financial relationships to disclose.