bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I pharmacokinetic (PK), and pharmacodynamic (PD) trial of the novel oral Notch inhibitor MK-0752 in patients (pts) with advanced breast cancer (BC) and other solid tumors
Authors: Krop I. E. , Kosh M. , Fearen I. , Savoie J. , Dallob A. , Matthews C. , Stone J. , Winer E. , Freedman S. J. , Lorusso P. 
Published: March 2020

10574 Introduction: Activation of Notch signaling occurs in ∼40% of human BCs and high Notch expression is associated with poor outcome. Inhibition of Notch inhibits BC cell proliferation in vitro. Notch signaling requires gamma secretase (GS), which cleaves Notch, releasing the Notch intracellular domain (NICD) to activate transcription of target genes. MK-0752 is a potent GS inhibitor. Methods: In Part 1 of the study, pts with advanced solid tumors were enrolled using an accelerated dose escalation with 1 pt/dose level until the occurrence of ≥Grade 2 toxicity, then 3–6 pts/dose level. MK-0752 was administered by once-daily oral dosing in 28-day cycles. Once a maximum tolerated dose (MTD) was established, an additional 22 pts with advanced BC were to be enrolled in Part 2. Six-point PK plasma profiles were collected over 24 hours on Days 1 and 28 and assayed by LC/MS/MS. PD measurement of plasma Abeta40 peptide (another gamma secretase substrate) was performed pre/post dose on Days 1 and 28. Tumor biopsies on Days 1 and 28 were obtained from a subset of pts to assess changes in Notch activity by immunohistochemical analysis of NICD. Results: In Part 1, two pts were enrolled at 450mg daily, and five pts at 600mg daily. Dose-limiting toxicities (DLTs) were Grade 3 diarrhea, constipation, nausea, and abdominal cramping at 600 mg. In Part 2, an additional 14 pts with BC were enrolled at 450mg daily. In this cohort, Grade 2/3 fatigue requiring dose reduction occurred in 6 pts. Grade 3 diarrhea (1pt), nausea (1 pt) and elevated liver transaminases (2 pt) were also observed. Mean PK parameters (at 450mg, 600 mg) on Day 1 were AUC0–24hr = 1036, 1065μM·hr, Cmax = 72, 61μM, C24hr = 25, 32μM, and tmax = 3, 7 hr. PD measurements of GS inhibition showed a 12–78% (mean 46%) decrease in plasma Abeta40 at 4 hours on Day 1 compared to predose. Conclusion: Continuous dosing of MK-0752 at 450mg daily in pts with BC was associated with significant toxicity, predominantly fatigue, and cannot be considered a MTD. An intermittent dosing schedule is being explored. MK-0752 at all doses inhibited GS, as demonstrated by decreases in plasma Abeta40. Analysis of efficacy and intratumoral Notch inhibition will be reported at the meeting. [Table: see text]
Cost-effectiveness of letrozole and anastrozole as adjuvant therapy for hormone receptor positive early breast cancer in postmenopausal women
Authors: Delea T. E. , Karnon J. , Barghout V. , Thomas S. K. , Papo N. L. 
Published: March 2020

10577 Background: The BIG 1–98 and ATAC studies demonstrated that, in postmenopausal women with hormone receptor positive (HR+) early breast cancer, 5 years of initial adjuvant therapy with the aromatase inhibitors (AIs) letrozole (LET) or anastrozole (ANA) is superior to tamoxifen (TAM). The cost-effectiveness TAM, LET, and ANA have not been previously evaluated using a consistent methodology. Methods: A Markov model was used to estimate the incremental cost per quality-adjusted life year (QALY) gained with initial adjuvant therapy with LET vs TAM, ANA vs TAM, and LET vs ANA in postmenopausal women with HR+ early stage breast cancer from the US healthcare system perspective. Probabilities of recurrence (including contralateral tumor) and adverse events (endometrial cancer, thromboembolism, fractures, hypercholesterolemia, MI, and stroke) for TAM were based primarily on published US population-based studies and trials of prophylactic TAM vs placebo. Corresponding probabilities for LET and ANA were calculated by multiplying probabilities for TAM by estimated relative risks of LET vs TAM and ANA vs TAM from the BIG 1–98 and ATAC trials respectively. Other probabilities, costs, and health-state utilities were obtained from published studies. Expected lifetime costs and QALYs were estimated for a cohort of HR+ postmenopausal women with early breast cancer, aged 61 years at therapy initiation and discounted at 3% annually. Probabilistic sensitivity analyses were conducted to assess precision of results. Results: Incremental cost per QALY gained for LET vs TAM is $33,536 (95% CI $20,409 to $70,566) and for ANA vs TAM is $38,967 (95% CI $23,826 to $81,904). Compared with ANA, LET is less costly ($9,647 vs $10,190) and gains more QALYs (0.29 vs 0.26), although differences in costs (95% CI -$1,669 to $671) and QALYs (95% CI -0.16 to 0.22) are not statistically significant. Conclusions: In postmenopausal women with HR+ early breast cancer, adjuvant therapy with either LET or ANA is cost-effective from a US healthcare system perspective. Although LET dominates ANA in our base-case analysis, definitive conclusions regarding the cost-effectiveness of LET vs ANA must await results of comparative clinical studies. [Table: see text]
Long-term follow-up after intraoperative radiotherapy (IORT) for breast cancer
Authors: Kraus-Tiefenbacher U. S. , Herskind C. , Bauer L. , Melchert F. , Wenz F. 
Published: March 2020

10594 Background: IORT for breast cancer with new treatment modalities is becoming increasingly important. In our department IORT is delivered by a mobile x-ray source (Intrabeam) producing isotropic 50 kV x-ray fields. Because this treatment modality includes single high doses to the normal breast tissue, careful evaluation of early and late toxicity is mandatory. Methods: Between 2/02 and 12/05 161 patients received IORT either as a tumour-bed boost (103) before 46 Gy external beam radiotherapy (EBRT) or as partial breast irradiation (58). Median age was 64.6 years (35–95), median tumour size was 15 mm (1–45). Spherical applicators (2.0 -5.0 cm diameter) were inserted into the tumourbed, giving a single dose of 20 Gy. Follow-up (f/u) included physical examination and ultrasound 1 week, 2 months, then every 6 months after therapy and mammography at yearly intervals. Radiobiological modelling of the expected spatial distribution of late reaction was done for typical cases using the linear-quadratic model with special consideration of relative biologic effectiveness, spatial dose distribution and dose rate. Results: Mean (f/u) time was 22 months. Minor postoperative side effects included erythema (5%), delayed wound healing (4%), mastitis (1%) and hematoseroma (4%). A fibrotic induration of the tumour bed was observed in 9, 18, 22, 23 and 26% of the patients at 2, 6 12, 24 and 36 month (f/u). Reoperation was required in 2 patients after 10 and 12 months, one mastectomy due to a fibrotic change of the whole breast and one local drainage of a fat necrosis. Conclusions: Although 2/3 of the patients were treated with a combination of IORT and EBRT, acute reactions in all patients were mild. Predominant late effect was an induration of the tumour bed which slowly began to resolve 1–3 years after therapy. The low level of clinically late reactions observed so far is in agreement with radiobiologic predictions from radiobiological modelling. No significant financial relationships to disclose.
Anastrazole treatment in breast cancer does not cause androgenic effect
Authors: Mundia M. , Ali M. F. 
Published: March 2020

10614 Background: Aromatse Inhibitors are a class of drugs that inhibit tumor growth in hormone receptor positive breast cancers in postmenopausal women. They exert their action by inhibiting the enzyme aromatse involved in the last step in conversion of Androgens to estrogens. They are currently used extensively in both advanced and adjuvant treatments. Methods: Clinical Charts of postmenopausal women, with estrogen receptor positive breast cancer, receiving the non-steroidal aromatse inhibitor, Anastrazole 1 mg daily at a community oncology practice were evaluated for androgenic effect of the drug. Review included presence of clinical Hirsutism and serum testosterone levels. Results: There were 33 women, receiving Anastrazole, 29 for adjuvant therapy, and 4 for metastatic disease. Age 51–77years (median: 63 years), Duration of Anastrazole therapy 6 months to 42 months (median: 18 months), There was no Clinical evidence of hirsutism noted. Serum testosterone levels varied from 9 ng/ml to 58 ng/ml. (Normal range: 14–76 ng/ml) in 32 women. 1 woman had a serum testosterone level of 86 ng/ml with no clinical hirsutism. The most common side effect of Anastrazole was arthralgias, seen in three women. Conclusions: Anastrozole 1 mg daily does not appear to cause any clinical androgenic effect, or elevation of serum testosterone levels. No significant financial relationships to disclose.
Trastuzumab associated with successive cytotoxic therapies beyond disease progression in metastatic breast cancer
Authors: Garcia-Saenz J. , Martin M. , Bueno C. , Sampedro T. , Lopez-Tarruella S. , Puente J. , Villalobos L. , Rodriguez L. , Garcia B. , Casado A. , Diaz-Rubio E. 
Published: March 2020

10617 Background: Whether trastuzumab should be continued after tumor progression remains unknown.We describe the activity of successive trastuzumab-containing regimens in patients with HER2-overexpressing metastatic breast cancer, as well as the response rate, time to progression and predictive factors for response. Methods: Descriptive retrospective study of trastuzumab activity in patients with HER2-overexpressing metastatic breast cancer treated at our hospital from 10/1999 to 07/2005. Results: 93 consecutive patients were evaluated obtaining an objective response rate (OR) for first-time administration of trastuzumab of 46.2%; stable disease (SD) 24.7%; clinical benefit (CB) 71%. Median time-to-progression (TTP) was 5 months (range: 1–39+). A total of 47 pts (50.5%) received a second trastuzumab-containing regimen with an OR of 29.8%; SD 21.3%; CB 51.1%; TTP 4 months (range: 1–31). A total of 21 pts (22.6%) received a third trastuzumab-containing regimen; OR 38.1%; SD 23.8%; CB 61.9%; TTP 4 months (range: 1–30+). A total of 10 pts (10.8%) received a fourth trastuzumab-containing regimen; OR 20%; SD 20%; CB 40%; TTP 4 months (range: 1–37). 5 pts (5.4%) received a fifth trastuzumab-containing regimen; OR 0%; SD 60%. Age < 45 years is a significant prognostic factor (p: 0.005, 95% CI, OR 5.6 (1.5–20.6)). A better response rate in the successive trastuzumab-containing regimens was observed, when there was a response in the first regimen: p = 0.04; 95% CI; OR 3.84 (1.07–14.65). With a follow-up of 16,5 months 45 pts (48,4%) are alive. Conclusions: Trastuzumab-containing therapies beyond disease progression in metastatic breast cancer show activity. There were more responses in younger pts. Those pts who had a previous response to trastuzumab therapy were more likely to respond to successive trastuzumab-containing regimens. Additional controlled studies are needed to test this approach. No significant financial relationships to disclose.
Impact of pre-operative three different regimens on breast-conservation surgery (BCS) and pathological complete response rates (pCR) in locally advanced breast cancer (LABC) in Pakistani patients
Authors: Alidina A. G. , Lal A. , Khan S. 
Published: March 2020

10628 Background: Locally advanced breast cancer accounts for 28% (n 350) of all breast cancer cases (1370 patients) treated at our Aga Khan University Hospital over the last 15 years. This is sharp comparison to the US data (only 3–6% of all cases). Methods: Patients with LABC who received surgery upfront were excluded. One hundred and seventy cases receiving PC were evaluated. Patients receiving TAC (taxotere, Adriamycin and cyclophosphamide)chemotherapy (n 60) were evaluated in a prospective Phase II study (2003- ongoing). These were then compared with FAC/AC or CMF regimens given from1998–2005, the data of which were extracted for Breast Cancer Tumor registry. Women were eligible if they were; histological confirmed invasive infiltrating carcinoma, clinical TNM: T3, T4, N2, N3, M0, as per AJCC (6th edition), PS 0–1, with adequate renal, liver and hematological functions. Patients were treated with regimens TAC containing T (75 mg/m2), A (50 mg/m2) and C (500 mg/m2) or FAC: F (500 mg/m2), A (50 mg/m2) and C (500 mg/m2) or A (60 mg/m2) C (600 mg/m2) and CMF: C (600 mg/m2), M (40 mg/m2) and F (600 mg/m2) q3wk 2 to 4 cycles. Type of surgery depended upon the response rates and the patients’ desire. Balance to complete a total of 4–6 cycles of chemotherapy was given in the adjuvant setting. Adjuvant hormone therapy was given for receptor positive cases. Results: Demographics, response rates, BCS and toxicities are reported in table. Conclusions: Locally advanced breast cancer is common in this region, owing to lack of screening. Preoperative TAC chemotherapy leads to impressively higher response rates, pathological complete response rates and probability of BCS, than when compared with FAC/AC chemotherapy or CMF chemotherapy, given in the same setting. Where as survival data of patients with TAC is not available, we feel that this will be superior to AC/FAC or CMF, given higher pathological complete response rates. [Table: see text] No significant financial relationships to disclose.
HER-2 status of the primary breast cancer in patients with relapse at least five years after the initial diagnose
Authors: Tomasevic Z. I. , Jovanovic D. , Radosevic-Jelic L. , Tomasevic Z. , Vasovic S. , Stamatovic L. , Jelic S. , Spasic J. 
Published: March 2020

10631 Background: HER-2 status of the primary breast carcinoma in the subgroup of patients who relapsed after many years is not well known. The aim of this paper is to determine the HER-2 status of the primary breast cancer in patients with late relapse, defined as local recurrence, distant metastases or carcinoma in the contralateral breast, at least five years after the initial diagnosis Methods: During six month period (June-November 2005) 1256 patients were diagnosed with primary or relapsed breast cancer at the IORS. HER-2 (HercepTest, DAKO) status was determined on the archived pathological specimens of patients with late relapse. Results: One hundred eleven patients (111/1256; 8,8%) were diagnosed with late relapse. At the time of the initial diagnose, majority of patients have been treated for early breast carcinoma. Median age at the initial diagnose was 50 years (33–74). Initial tumor characteristic were: ductal carcinoma 49%; lobular carcinoma 41%;cancer mastitis 6,5%;not reported 3,5%; T1 34%; T2 52%; T3 4,5%; T4 6%;unknown 3,5%; Nodal status: positive 73,5%; negative 23%;not reported 3,5% Steroid receptor status: ER and/or PR positive 59%; both negative 14%; unknown 27%. Median time to relapse is 7 years, (range 5–29), the most frequent first relapse sites were: local recurrence (22%); carcinoma of the contralateral breast (18%); bone metastases (18%). Archived pathological specimens are identified for 63/111 (56,7%) patients and HER-2 status of the those primary breast carcinoma is: 0+ 36,5%; 1+ 34,9%; 2+ 9,5%; 3+ 14,2%; Thirty four patients (30,6%) had disease free interval 10 or more years, and HER-2 3+ in this subgroup is 17,6% (6/34). Conclusions: Long disease free interval in breast cancer patients is usually explained by initial more favorable cancer characteristics. Still, a significant percentage (14,2%) of our patients with median time to relapse of 7 years, initially had breast cancers with HER-2 3+. No significant financial relationships to disclose.
Primary endocrine therapy with anastrozole for early operable primary breast cancer in the elderly: Early clinical and biological data
Authors: Cheung K. L. , Ying M. W. , Green A. R. , Agrawal A. , Paish C. E. , Winterbottom L. , Ellis I. O. 
Published: March 2020

10647 Background: The initial treatment for early operable primary breast cancer (PBC) is surgery. Primary endocrine therapy with tamoxifen has been used in the elderly with estrogen receptor positive (ER+) PBC who refuse or are unfit for surgery. Current randomized data showed superiority of aromatase inhibitors (AIs) over tamoxifen in neoadjuvant, adjuvant and metastatic settings, it is possible that AIs may be a better therapeutic option in this context. We report the early clinical and biological data in using primary anastrozole for ER+ operable PBC in the elderly. Methods: Elderly (> 70) patients with ER+ early operable PBC (< 5cm), who refused or were unfit for surgery, and who had contraindications to tamoxifen, were treated with anastrozole 1mg daily as primary endocrine therapy. All had disease assessable by UICC criteria and received treatment for ≥ 6 months unless they progressed prior. Standard immunohistochemical staining was performed on tumor tissue, obtained by core biopsy, for ER, progesterone receptor (PgR) and HER2. Positivity for ER and PgR was defined by H-score ≥ 50, and HER2 positivity was defined as 3+. Results: Thirty-two patients received anastrozole as described during a two-year period. Thirty (93.8%) patients reached clinical benefit (CB = objective response (OR) + durable stable disease) at 6 months, with 11 (34.4%) ORs (complete response + partial response). Anastrozole was well tolerated with no patients withdrawn due to side effects. All patients had ER+ tumors. The response status at 6 months is stratified according to PgR and HER2 is shown in the table . Conclusions: Early clinical data has shown excellent efficacy and tolerability of anastrozole as primary endocrine therapy for early operable PBC in the elderly. The PgR and HER2 status did not appear to predict response within this group of ER+ tumors, but there was a trend towards a better quality of response (more ORs) for PgR positive/ HER2 negative tumors. Follow-up for longer-term efficacy assessment is continuing. [Table: see text] [Table: see text]
Neoadjuvant, biweekly, dose-dense chemotherapy with epirubicin (E) and cyclophosphamide (C) followed by docetaxel (T) in primary breast cancer (BC)
Authors: Cramer E. , Moers C. , Zarghooni V. , Bosse K. , Mallmann P. , Warm M. 
Published: March 2020

10656 Background: Primary chemotherapy is established in the treatment of local advanced BC. Two important advances are the chance to detect the clinical responders during the chemotherapy and an increasing rate of breast conserving surgery (BCS). According to the promissing results of dose-dense chemotherapy schedules in the adjuvant setting we tested the benefit of this approach in a primary chemotherapy protocol. Methods: This clinical trial (01/2003–11/2005) enrolled 93 females with advanced (cT2-cT4), non metastatic BC. The pts received four courses of E (90 mg/m2) and C (600 mg/m2) q2w, followed by four courses of T (100/75 mg/m2) q2w. The severe hand-foot-skin reaction NCI-CTG grade 3 during the T courses of the first pts (G1: n = 19) lead to a dose reduction of T to 75 mg/m2 for the following pts (G2: n = 73). During the first four cycles Pegfilgrastim was applied to prevent neutropenic complications. After every two cycles the actual tumor size was measured by clinical and sonographical examination. The clinical and pathological response, the toxicity and the rate of BCS were evaluated. Results: Pathological complete remission (pCR) of the invasive tumors was observed in 7/19 pts (G1) and 17/73 (G2), pathological partial remission (pPR) in 7/19 pts (G1) and 28/73 (G2), minimal response (pMR) in 3/19 pts (G1) and 14/73 (G2), a stable disease in 2/19 pts (G1) and 11/73 (G2). Two pts in group two showed a progressive disease (pPD). Three pts developed neutropenic fever and stopped the chemotherapy after the 5th and 6th cycle, respectively. One patient died after the 8th cycle in neutropenic sepsis. During this trial the main side effect of T was a hand-foot-skin reaction. Conclusions: This neoadjuvant dose-dense chemotherapy is a potent schedule for the treatment of primary BC. Using T with 75 mg/m2 instead of 100 g/m2 is generally better tolerated. The first group of pts treated with T 100 mg/m2 exhibited a higher frequency of pCR (36.8%) compared to the pts treated with 75 mg/m2 (pCR 23.3%), (p = 0.23). But the increased rate of severe side effects lead to an early dose reduction to 75 mg/m2 in this clinical trial.These first promissing results will be improved in an enlarged number of pts. No significant financial relationships to disclose.
A phase II multicenter study of combination chemotherapy with capecitabine (C) and intravenous (iv) vinorelbine (V) in patients (pts) with pretreated metastatic breast cancer (MBC)
Authors: Davis A. J. , Lewis C. R. , Moylan E. J. , Parnis F. X. , Brew S. E. , Ackland S. P. 
Published: March 2020

10665 Background: MBC pts have often already received, or are inappropriate for, anthracyclines and taxanes. 5-Fluorouracil and vinorelbine is an active, well tolerated combination regimen. Capecitabine (C), a fluoropyrimidine carbamate derivative, has the advantage of oral administration. The aim of this study is to determine the efficacy and safety of C and iv vinorelbine (V) in pts with MBC. Methods: Between May 2003-June 2005 21pts with pretreated MBC, maximum of 1 prior metastatic regimen, received C 1000mg/m2 bd day 1–14 and V 25 mg/m2 iv d1+ d8 q21 days. All pts had measurable disease (RECIST), baseline KPS ≥ 80% and adequate baseline organ function. The primary endpoint was response; secondary endpoints were time to progression (TTP), duration of response, survival and safety. Results: Median age was 56 years (range 38–73); median KPS 90%. All pts had received anthracyclines and 62% taxanes. 20pts were evaluable for response and 21 for toxicity. Objective responses were seen in 7/20 (35%) (95% CI 18–57%), including 2 CR, and stable disease (SD) in 4/20 (20%) (95% CI 8–42%). Median duration of response was 6.9 mths (95% CI 4.7–13.1); TTP 5.8 mths (95% CI 2.8–6.8) and survival 12.2 mths (95% CI 8.7–15.7), with a median followup of 12.2 mths. The main toxicity was haematological with 15 episodes of G3 and one G4 neutropenia in 10 pts and 1 pt respectively and 2 episodes of G3 febrile neutropenia in 1 pt. Other G3 toxicities included diarrhoea, fatigue and hypokaleamia in 2 pts each and headache, anorexia, stomatitis, dehydration, and peripheral neuropathy in 1 pt each. There were no other G4 toxicities or treatment related deaths. The median dose intensity of C was 7941mg/m2/wk (85% of intended, range 51–102%) and for V 12.4 mg/m2/wk (75% of intended, range 48–100%). Conclusion: The combination of capecitabine and iv vinorelbine is active and generally well tolerated in pts with pretreated MBC. The recent availability of oral vinorelbine provides an opportunity to explore a fully oral combination chemotherapy regimen for pts with MBC. [Table: see text]