bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of pemetrexed (P) plus gemcitabine (G) in relapsed ovarian cancer (OC): Dosing results and evidence of activity
Authors: Hensley M. L. , Derosa F. , Gerst S. R. , Sabbatini P. , Dupont J. , Konner J. , Goss T. , Orlando M. , Wang Y. , Aghajanian C. 
Published: March 2020

5083 Background: High expression of folate receptors on ovarian cancer cells may provide excellent targets for P. Preclinical data support synergism with G. Optimal doses of q 14 day P+G with vitamin support in pre-treated OC pts are not known. We sought to determine the maximally tolerated doses (MTD) and to assess for toxicity and activity in relapsed OC. Methods: Pts with relapsed OC, no prior P or G, KPS ≥ 70, and adequate organ function were eligible. Pts were enrolled in cohorts of 3, expanding to 6 if dose-limiting toxicity (DLT) was observed during the first 4 cycles. Pts received P at 300 (cohort 1) or 400 (cohort 2) or 500 (cohort 3) or 600 (cohort 4) mg/m2 followed by G 1500 mg/m2 q 14 d without GCSF. B12 and folic acid were given 1 week prior and continued throughout. DLT was defined as grade (gr) 4 neutropenia (ANC) lasting >7d or neutropenic fever (NF); gr 4 thrombocytopenia or gr 3 with bleeding; ≥gr 3 nonhematologic toxicity, except ALT, AST, alopecia, fatigue; treatment delay ≥1 week due to any unresolved toxicity. Response assessed by RECIST. Results: 16 pts (median age 55, range 43–75; median number prior cytotoxic regimens 2, range 1–4) have enrolled in 4 cohorts. 15 are evaluable for response (1 treated after resection of recurrence); 13 of these15 had a platinum-free interval <6 months. 1 pt in cohort 1 had global deterioration during cycle 1 and was replaced, with best response counted as progressive disease (PD). 1 pt in cohort 3 had dose delay ≥1 week, meeting DLT criteria. Cohort 3 was expanded to 6 pts with no further DLT. 3 pts enrolled in cohort 4 with no DLTs observed. Toxicities per cycle (n = 108): gr 3 ANC 31%; gr 4 ANC 27%; gr 3 dehydration 0.9%; gr 3 platelets 0.9%; 0 pts had NF. Median # cycles/pt was 6, range 1–16, median cycle length 14 d. Objective response was observed in 27% (4/15 pts: 4 PR; 7 SD; 4 PD). All 4 responses were among pts with platinum resistant disease. >50% decrease in CA125 for more than two measurements was observed in 9/15 (60%) pts with evaluable CA125s. Median time to progression is 15 wks (95% confidence interval 10–32 wks). Conclusions: MTD is not yet reached. P 500 mg/m2 + G 1500 mg/m2 with vitamin supplementation is safe in pts with previously treated OC. 27% of patients with platinum-resistant disease had objective responses. [Table: see text]
Combination therapy with pegylated liposomal doxorubicin and carboplatin in malignant gynecologic tumors. A prospective multicenter phase II trial of the AGO-OVAR and the AGO Kommission Uterus (AGO-K-Ut)
Authors: Hilpert F. , Loibl S. , Huober J. , Wimberger P. , Staehle A. , Jackisch C. , Wollschlaeger K. , Koelbl H. , Beckmann M. , Du Bois A. 
Published: March 2020

5095 Background: To determine the toxicity and efficacy of combination therapy with pegylated liposomal doxorubicin (PLD) and carboplatin in patients with malignant gynecologic tumors. Methods: Patients with recurrent or advanced uterine sarcomas, endometrial, cervical or vaginal cancer or with recurrent platinum-sensitive ovarian cancer were treated with PLD 40mg/m2 and carboplatin AUC 6, q28 over 6 cycles (up to 10 cycles allowed). Primary and secondary endpoints were tolerability and efficacy. Efficacy was measured according to RECIST and/or CA-125 GCIG criteria. Results: 67 pts with recurrent ovarian cancer, 11 pts with uterine sarcomas, 31 pts with endometrial cancer and 31 pts with cervical or vaginal cancer have been recruited (total 140 pts, 87 pts evaluable for response). Grade 3/4 hematologic toxicities occured in 8% for anemia, 14% for thrombocytopenia, 23% for leukopenia, and 25% for neutropenia of whom 2% developed febrile neutropenia. Non-hematologic Grade 3/4 toxicities have been observed in more than 5% of all patients for the following items: asthenia (14%), pain (10%), dyspnea (9%), palmo-plantar-erythema (7%), nausea and vomiting (7%), diarrhea (5%). The median dose intensity was 94% for PLD and 97% for carboplatin. 76% of all non-progressing patients received at least 5 cycles. The overall response rate was 56% in ovarian cancer, 43% in uterine sarcomas, 44% in endometrial cancer, and 14% in cervical and vaginal cancer. Conclusions: PLD/carboplatin was well tolerated, even in pretreated patients. The combination showed remarkable efficacy in patients with uterine sarcomas, endometrial cancer, and ovarian cancer which merits further evaluation. CA 125 response criteria in ovarian cancer are under evaluation and will be presented on ASCO. However, the regimen had limited efficacy in cervical and vaginal cancer. A prospective randomized trial in recurrent ovarian cancer patients comparing carboplatin/PLD with paclitaxel/carboplatin has already been started within the international study group network (AGO-OVAR 2.9; CALYPSO-trial). [Table: see text]
Randomized, active-controlled study of denosumab (AMG 162) in breast cancer patients with bone metastases not previously treated with intravenous (IV) bisphosphonates (BP)
Authors: Lipton A. , Alvarado C. , De Boer R. , Steger G. G. , Tonkin K. S. , Kinsey A. , Fan M. , Jun S. 
Published: March 2020

512 Background: Receptor activator of NF-κB ligand (RANKL) is a key mediator of osteoclast formation, function, and survival. Denosumab, a fully human monoclonal antibody, binds and inhibits RANKL, thus suppressing excess osteoclastic activity associated with bone metastases. We report interim efficacy and safety results of an ongoing, phase 2 study of denosumab in IV BP treatment-naïve women with advanced breast cancer and bone metastases (BM). Methods: Eligible patients (pts; age ≥ 18 yrs with breast cancer; confirmed BM; naive to IV BP therapy) were stratified by chemo- or hormonal therapy and randomized to 1 of 6 cohorts (5 denosumab [double blind]; 1 IV BP [open label]; see table ). The primary endpoint was the % change from baseline (BL) to week 13 in the resorption marker, urinary N-telopeptide (uNTx), corrected for creatinine. Also evaluated were % of pts with ≥ 65% decrease in uNTX from BL, time to a 65% reduction in uNTx, % of pts with ≥ 1 skeletal-related event (SRE), and safety. Results: In total, 255 pts (∼40/cohort) were enrolled. Mean age was 57 to 59 yrs (denosumab cohorts) vs 52 yrs (BP). Most pts had > 2 sites of BM (denosumab, 74%; BP, 81%); 51% and 49% received concurrent chemo- or hormonal therapy, respectively. As shown in the efficacy table , the 120 mg Q4W dose resulted in the greatest % decrease from BL in uNTx. At data cutoff, the % of all denosumab pts with ≥ 1 SRE was 9% (20/212) vs 16% (7/43) of BP pts. Commonly reported adverse events (AE) among all pts included nausea, vomiting, asthenia, diarrhea, and bone pain. Of 198 denosumab pts tested, none developed anti-denosumab antibodies. Conclusion: In this interim analysis, denosumab resulted in rapid and sustained suppression of bone turnover and was at least as effective as IV BP at reducing the risk of SREs, with a safety profile similar to that seen in advanced breast cancer pts receiving cancer treatment. [Table: see text] [Table: see text]
EGFR expression in breast cancer: Association with biologic phenotype, prognosis, and resistance to adjuvant therapy
Authors: Rimawi M. F. , Weiss H. L. , Bhatia P. , Chamness G. , Elledge R. M. 
Published: March 2020

513 Background: Expression of the epidermal growth factor receptor (EGFR) in preclinical models of breast cancer is associated with increased proliferation and resistance to apoptosis. In clinical studies, EGFR has been inconsistently linked to poor outcome. We hypothesized that EGFR expression, when objectively and uniformly assessed, is associated with an aggressive biologic phenotype and resistance to systemic adjuvant therapy. Methods: In a database of 54,865 patients with breast cancer, EGFR status was known on 2,567. EGFR levels were measured centrally by ligand binding assay performed on frozen tissue. Tumors with ≥10 fmol/mg of cytosol protein were prospectively deemed positive. Clinical and biological features of EGFR positive and negative tumors were compared. Disease-free survival (DFS) and overall survival (OS) were assessed in systemically untreated patients (untreated patients, n=1068) and those who received hormonal and/or chemotherapy (treated patients, n=1256). Results: 475 out of 2,567 tumors (18.5%) were EGFR positive. Compared to EGFR negative tumors, EGFR positive tumors were more common in younger (<50 years, 40% vs 24% p<0.0001), premenopausal (20% vs 10%, p<0.0001), and black women (10% vs 6% p=0.005). EGFR expression was associated with larger tumors (64% vs 46%, p<0.0001), aneuploidy (68% vs 46%, p<0.0001), high S-phase fraction (53% vs 22%, p<0.0001), and nodal involvement (43% vs 37%, p=0.009). Co-expression of other biomarkers was also studied. EGFR positive tumors were more likely to be HER2 positive (26% vs 16%, p<0.0001), but less likely to be ER positive (60% vs 88%, p<0.0001), and PR positive (26% vs 65%, p<0.0001). In a multivariate analysis, EGFR expression independently correlated with worse DFS (HR=1.6, 95%CI=1.2–2.2, p=0.001) and OS (HR=1.7, 95% CI=1.2–2.4, p=0.001) in treated patients, but not in untreated patients. Conclusions: EGFR expression is more common in breast tumors in young and black women. It is associated with lower hormone receptor levels, higher proliferation, genomic instability, nodal involvement, and HER2 over-expression. It is correlated with significant resistance to adjuvant hormonal and chemotherapy. Blocking EGFR activity may help overcome this resistance in selected patients. No significant financial relationships to disclose.
Biological and clinical outcomes from a phase II placebo-controlled neoadjuvant study of anastrozole alone or with gefitinib in postmenopausal women with ER/PgR+ breast cancer (Study 223)
Authors: Dowsett M. , Smith I. , Skene A. , Llombart A. , Mayordomo J. , Detre S. , Salter J. , Beresford E. , Magill P. 
Published: March 2020

515 Background: Gefitinib, an EGFR-tyrosine kinase inhibitor, reduces breast cancer cell growth and potentiates endocrine therapy in model systems. This double-blind multicentre study compared anastrozole 1 mg/day alone with anastrozole + gefitinib 250 mg/day as neoadjuvant therapy for breast cancer in a novel design aiming to assess additional benefit from gefitinib in individual patients. Methods: Postmenopausal women with stage I-IIIB breast cancer and ER and/or PgR+ tumours received anastrozole for 16 wks and were randomised (2:5:5 ratio) to: combination with gefitinib for 16 wks (AG); placebo for 2 wks then gefitinib for 14 wks (A:AG, to test for additional Ki67 suppression); placebo for 16 wks (A alone). Biopsies were taken at baseline, 2 and 16 wks. Primary comparison was change in Ki67 by 16 wks. Secondary comparison was objective tumour response rate (ORR) using UICC/WHO criteria at 16 wks. Results: 206 patients (pts) were randomised: (31 AG, 90 A:AG, 85 A alone); demography was well balanced between the groups. 109 pts were evaluable for Ki67: 59 AG + A:AG; 50 A alone. Change in Ki67 levels at 16 wks was not significantly different in those pts who received gefitinib + anastrozole versus anastrozole alone (p=0.257). The addition of gefitinib after 2 weeks of anastrozole did not further suppress Ki67 levels (p=0.164). 188 pts were evaluable for ORR (109 AG + A:AG; 79 A alone). The ORR was 48% in pts who received gefitinib + anastrozole and 61% in pts treated with anastrozole alone (p=0.067). Conclusions: Neither the biological nor the clinical activity of anastrozole was enhanced by the addition of gefitinib; although non-significant, both endpoints unexpectedly suggested a trend against the combination in this patient population. Molecular investigations of signal transduction pathways are underway to understand the significance of these findings. [Table: see text] [Table: see text]
Adjuvant radiotherapy (RT) and trastuzumab in stage I-IIA breast cancer: Toxicity data from North Central Cancer Treatment Group Phase III trial N9831
Authors: Halyard M. Y. , Pisansky T. M. , Solin L. J. , Marks L. B. , Pierce L. J. , Dueck A. , Perez E. A. 
Published: March 2020

523 Background: Adjuvant trastuzumab (Herceptin [H]) with chemotherapy improves outcome in HER2+ breast cancer (BC). Preclinical studies suggest H may enhance RT. We herein assess if H given with adjuvant RT increases adverse events (AE) after breast conserving surgery or mastectomy. Methods: N9831 randomized 3505 women with pT1–3N1–2M0, pT2–3N0M0, or pT1cN0M0 (ER/PR negative) HER2+ BC to doxorubicin (A) and cyclophosphamide (C) followed by weekly paclitaxel (T), AC→T→H, or AC→TH→H. Post-lumpectomy breast ± nodal RT was recommended, as was post-mastectomy chest wall + nodal RT (>3 nodes +); internal mammary RT was prohibited. RT started within 5 weeks of completion of T and allowed concurrently with H. 2324 eligible patients were enrolled on study prior to April 25, 2004: 1460 patients receiving RT are available for analysis of RT-associated AEs. Also, 1286 patients on +H arms who completed T (908 +RT and 378 -RT) are available for analysis of clinical cardiac events (CE). Rates of RT-associated AEs were compared across treatment arms, and rates of CE were compared for +RT vs -RT patients within +H arms. All reported p-values are for chi-squared statistics. Results: With a median follow-up of 1.5 years, significant differences among arms in RT-associated AEs were not identified. No significant differences across arms in +RT patients existed in the incidence of skin reaction (p=0.78), pneumonitis (p=0.78), dyspnea (p=0.87), cough (p=0.54), esophageal dysphagia (p=0.26), or neutropenia (p=0.16). There was a significant difference in +RT patients in the incidence of leukopenia (p=0.02) with higher incidence rates in the arms receiving H. RT did not increase the frequency of CE. In the AC→T→H arm, the incidence of CE was 2.2% in +RT patients versus 2.9% in -RT patients. In the AC→TH→H arm, the incidence of CE was 1.5% in +RT patients versus 6.3% in -RT patients. No difference in CE was seen between left- and right-sided RT fields in +RT patients in either +H arm. Conclusion: Concurrent administration of adjuvant RT with H in early stage breast cancer patients is not associated with an increased incidence of acute RT AEs. Further follow-up is required to assess late AEs. No significant financial relationships to disclose.
Phase III randomized trial to evaluate the use of gabapentin alone vs with continuing an antidepressant in women failing an antidepressant for the treatment of hot flashes: North Central Cancer Treatment Group Study N00C3
Authors: Loprinzi C. L. , Kugler J. W. , Barton D. L. , Dueck A. C. , Tschetter L. K. , Nelimark R. A. , Balcueva E. P. , Carlson M. D. , Duane S. F. , Corso S. W. 
Published: March 2020

526 Background: Antidepressants do not adequately alleviate all HFs. Based on placebo-controlled data demonstrating that GABA is an alternative therapy for HFs, this trial was initiated to test whether the combination of an antidepressant and GABA was better than GABA alone in PTS with inadequate HF control on an antidepressant alone. Methods: Eligible PTS on antidepressants with bothersome HFs were randomized to two groups. PTS kept a daily HF diary during a baseline wk (while continuing their antidepressant). Following the baseline wk, all PTS were given GABA 300 mg at hs for 3 days, then BID for 3 days, and then TID for 22 days. One group continued their antidepressant while the other group was weaned off it over several days. PTS continued a daily HF diary during this 4-wk period. Efficacy was measured using the mean daily HF number and score; the latter measured by assigning points (1–4, for mild to very severe) to each HF and then adding the points for a given time. The study design provided 80% power to detect a difference in the changes from baseline at 4 wks between the two groups of 1.2 HFs/day, or 3 points/day in HF scores. Results: 115 PTS were randomized and given GABA. PTS continuing their antidepressant reported a 48% mean reduction in HF score after 4 wks, vs 49% for PTS stopping it (p=0.97). Mean HF numbers were reduced 50% and 47%, respectively (p=0.54). 16 other symptoms and quality of life items were measured by PT-completed weekly questionnaires, with the only suggestive changes from baseline between the two arms being more mood troubles after 2 wks of treatment (p=0.06) and more nervousness after 4 wks of treatment (p=0.01) in PTS stopping their antidepressant. Also, a mild temporary increase in dizziness after 1 wk of treatment was observed in the same group (p=0.08) suggestive of an antidepressant withdrawal reaction. Conclusion: This trial failed to provide any evidence that the combination of GABA and an antidepressant decreased HFs any more than did GABA alone in PTS who had inadequate HF control with an antidepressant alone. The 50% reduction in HFs in both arms is commensurate with the efficacy of GABA delineated in other published reports. No significant financial relationships to disclose.
The impact of FDG PET in the staging of breast cancer
Authors: Carr C. E. , Conant E. F. , Rosen M. A. , Schnall M. D. , Davidson R. 
Published: March 2020

530 Background: To evaluate the impact of whole-body fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) in staging breast cancer beyond the breast and axilla. Methods: 200 women, mean age 51 yrs (range 28–81) with breast cancer were enrolled in an IRB approved multi-modality imaging trial from 3/02 to 5/05. After imaging with film screen mammography ± ultrasound (US), patients underwent digital mammography, whole breast US, magnetic resonance imaging (MRI), and whole body FDG PET. Imaging reports and patient charts were reviewed and distant lesions were classified: 1 = no uptake; 2 = physiologic uptake; 3 = non-suspicious uptake; 4 = suspicious uptake without work-up; 5 = suspicious uptake with work-up. Decisions to forego work-up in class 4 lesions were clinical. Class 5 PET lesions were evaluated by confirmatory studies, including computed tomography (CT), MRI, x-ray (XR), bone scan (BS), or pathology. Patients also underwent standard staging with chest XR and BS per clinical judgment. Results: 189/200 (95%) women received PET scans. PET identified 71 distant areas of increased uptake in 42/189 (22%) women. 59/71 (83%) lesions were considered suspicious in 33/42 (79%) women: 50/59 (85%) lesions were class 5 and 9/59 (15%) class 4. Of the 50 class 5 lesions, 19 (38%) were true positive (TP) for neoplastic disease, 2 (4%) were TP for non-neoplastic disease, and 29 (58%) were false positive (FP). The positive predictive value (PPV) for class 5 lesions was 40%. The 19 TP distant sites of malignancy occurred in 6/189 (3%) patients; 4 of these patients (67%) also had TP distant sites identified by standard staging procedures. PET alone identified TP distant disease in 2/189 (1%) women. PET identified 29 FP findings in 22/189 (12%) patients. FP findings prompted 17 CTs, 8 XRs, 2 MRIs, and 1 BS. MRI revealed 2 additional neoplasms that had been false negatives (FN) by PET in 2/189 (1%) women. Conclusions: Whole-body FDG-PET added little additional information in staging our patients with known primary breast cancer, based on low PPV and equivalent TP and FN rates. Additionally, the high FP rate of PET in these patients may prompt unnecessary, costly, and invasive follow-up studies. No significant financial relationships to disclose.
Predicting non-sentinel lymph node involvement in breast cancer patients
Authors: Kohrt H. E. , Olshen R. A. , Goodson W. H. , Rouse R. V. , Bailey L. , Philben V. , Dirbas F. M. , Stockdale F. E. , Carlson R. W. , Jeffrey S. S. 
Published: March 2020

531 Background: Current convention is to perform a completion axillary lymph node dissection (ALND) for invasive breast cancer (BC) patients (pts) with positive sentinel lymph node(s) (+SLN), even though <50% will have non-sentinel lymph node metastasis (+NSLN). Our goal was to develop and compare predictive models of NSLN status among +SLN pts to identify for whom completion ALND may be omitted. Methods: We constructed 3 models by recursive partitioning with receiver-operating-characteristic curves (RP-ROC), boosted classification and regression trees (CART), and a multivariate logistic regression (MLR) informed by CART. Models were developed using a multi-institutional database of 1,040 BC pts who underwent SLN biopsy and completion ALND at academic or community hospitals as part of a prospective, consented study. Accuracies were compared to the Memorial Sloan-Kettering Breast Cancer Nomogram (Nomogram). Results: 976 BC pts had evaluable SLNs and 285 had +SLNs; 101(35.4%) +SLN pts had +NSLNs. Tumor size, lymphovascular invasion (LVI), and SLN metastasis size were the best predictors of risk (multivariate P-values<0.001) of +NSLN. 39 of 156 +SLN pts (25%) with T1 tumors had +NSLNs vs. 62 of 129 (48%) with T2/T3 tumors. 73.7% with LVI vs 19.5% without LVI had +NSLNs. 4.7% of pts with isolated tumor cells, 42% with micrometastasis and 71% with macrometastasis in SLN had +NSLNs. MLR informed by CART identified 2 highly predictive variables, the LVI × size of SLN metastasis [OR 4.73(3.11–7.20, 95%CI), P<0.001] and tumor size × size of SLN metastasis [OR 1.18(1.10–1.26, 95%CI), P<0.001]. While RP-ROC and boosted CART stratified pts into low-risk (4.3%-9.9%), moderate-risk (33.3%-42.9%), and high-risk (62.2%-93%) groups, MLR predicted NSLN status with accuracy superior to RP-ROC, boosted CART, and the Nomogram: 83.3%, 76.7%, 67.7%, and 76.7%, respectively, after 10-fold cross validation. The Nomogram’s sensitivity was significantly inferior to those of RP-ROC, boosted CART, and MLR: 53.8%, 78.8%, 78.2%, and 78.0%, respectively. Conclusions: In pts with +SLNs, interactions between clinicopathologic characteristics are highly informative in predicting risk of +NSLN. However, neither our methods nor the Nomogram achieved sufficient accuracy to recommend a change in current clinical practice. No significant financial relationships to disclose.