bluuebunny/crossref_metadata_2025_split huggingface dataset:
A pilot study of adjuvant bevacizumab after neoadjuvant chemotherapy for high-risk breast cancer
Authors: Mayer E. L. , Miller K. D. , Rugo H. S. , Peppercorn J. M. , Carey L. A. , Ryabin N. , Winer E. P. , Burstein H. J. 
Published: March 2020

561 Background: Patients with residual breast cancer after neoadjuvant chemotherapy are at increased risk of recurrence and may have chemotherapy-resistant disease. We sought to explore the role of novel antiangiogenic therapy in this patient population. Methods: This phase II trial evaluated the feasibility and toxicity of adjuvant antiangiogenic therapy. Eligible patients had stage II-III breast cancer with residual invasive carcinoma at surgery following anthracycline-containing neoadjuvant chemotherapy. Treatment consisted of bevacizumab 15 mg/kg given every three weeks for one year, starting no less than 1 month after surgery or 2 weeks after radiation. Concurrent endocrine and/or trastuzumab therapy was allowed. The primary endpoint was feasibility and tolerability of single agent bevacizumab. Results: 40 patients were treated with bevacizumab monotherapy. Median age was 50 years, 45% were stage III, 58% were hormone receptor positive, and 8% were HER2+. There were 11 delays in treatment administration (average delay = 7.2 days). To date, patients are on average through 10.4 of 17 planned cycles of therapy, with 3 patients completing treatment and 3 patients with tumor recurrence on study. Treatment-related toxicities include mild arthralgias (50%), headache (50%), epistaxis (20%), and hypertension (23%). One patient experienced reversible posterior leukencephalopathy related to hypertension, one patient had GI bleeding, and 4 subjects voluntarily removed themselves from the protocol. No cardiac dysfunction has been observed. Definitive feasibility/safety data and preliminary correlative studies will be available by June 2007. Conclusions: Adjuvant bevacizumab after neoadjuvant chemotherapy appears tolerable and feasible with side effects including hypertension, arthralgias, epistaxis, and headache. Three recurrences within a median follow-up of 7.5 months underscore the need for novel treatments among such patients. Ongoing trials are evaluating bevacizumab with oral chemotherapy. [Table: see text]
Detection of minimal residual disease (MRD) in peripheral blood of primary breast cancer patients: Translational research in the SUCCESS study
Authors: Jueckstock J. K. , Rack B. , Thurner-Hermanns E. , Forstbauer H. , Pantel K. , Ulmer H. , Beckmann M. , Lichtenegger W. , Janni W. J. , Friese K. 
Published: March 2020

565 Background: Patients with detection of MRD in bone marrow are known to have an increased risk for recurrence and a poorer clinical outcome. However, peripheral blood would be the preferable compartment to monitor treatment efficacy due to increased feasibility. The translational research program of the German SUCCESS-trial was established to evaluate MRD in peripheral blood at 4 different time points during adjuvant systemic treatment of breast cancer patients. Here first results of the detection of MRD at primary diagnosis and after adjuvant chemotherapy will be presented. Patients and Methods: Cells were separated by Ficoll-Hypaque density- gradient centrifugation followed by labelling of epithelial cells with the anti-cytokeratine-antibody A45-B/B3 (directed against cytokeratines 8, 18 and 19) and immunohistochemically staining with neu-fuchsin. All preparations were screened by two independent persons. Results: 328 breast cancer patients were analyzed at primary diagnosis. Among those, 133 patients returned for a 2nd blood sampling after completion of adjuvant chemotherapy. Most of the tumors were small (43% pT1, 51% pT2, 4% pT3, 1% pT4) but of intermdediate or unfavourable grade, (G1 7%, G2 48%, G3 45%). 66% of the patients were node-positive (34% pN0, 38% pN1, 20% pN2, 8% pN3) and a positive hormone receptor status was seen in 71%. In 22% the Her2-status was positive. MRD in peripheral blood was found in 31% of all patients before and in 9% after chemotherapy. The mean number of detected cells was 2 (range 1- 9). In 87,2 % of the patients who showed MRD at the first measurement no MRD was detected after chemotherapy. 16% of patients without detection of MRD at primary diagnosis showed MRD after chemotherapy. Neither tumor size (p= 0.624), lymph node metastases (p= 0.450), histopathological grading (p= 0.168), hormone receptor status (p= 0.270) or Her2/neu status of the primary tumor (p= 0.893) correlated with the presence of MRD. Conclusions: The detection of MRD in peripheral blood can be widely used and is suitable for repeated measurements. Further follow-up will show, if this method can be used for risk stratification and monitoring of treatment efficacy in adjuvant breast cancer. No significant financial relationships to disclose.
Prognostic (Px) significance of Ki67 before and after neoadjuvant chemotherapy (CT) in early breast cancer
Authors: Jones R. L. , Salter J. , Nerurkar A. , Parton M. , A’Hern R. , Smith I. E. , Dowsett M. 
Published: March 2020

573 Background: High levels of the proliferation marker Ki67 are associated with a higher response rate to CT but poorer long-term outcome. The Px significance of Ki67 before CT and at surgical excision was compared. Methods: 103 patients treated with CT with pre- and post- (excision) CT tissue and a further 181 with only excision tissue available were identified, 37 and 76 of these respectively were ER+ and also received tamoxifen. The following factors were considered pre-CT and at excision (where relevant) for their relationship with relapse-free (RFS) and overall (OS) survival: ER, PR, HER2, grade, Ki67, histological type, vascular invasion, age/menses, T and N stage, pre-therapy operability, clinical response, CT regimen, type of surgery, adjuvant therapy, pathological tumour size and nodal involvement. Results: In the paired cohort univariate analysis of RFS the following factors were associated with poorer Px (a) pre-CT: ER- (p=0.003); increasing T stage (p<0.001), N stage (p=0.002) and Ki67 (p<0.001); (b) at excision: increasing grade (p=0.01), tumour size (p=0.02), nodal status (p<0.001) and Ki67 (p<0.001); no adjuvant endocrine therapy (p<0.001). On multivariate analysis only excision Ki67 (p<0.001) was significant although there was a suggestion pre-therapy Ki67 was important (p<0.10). On univariate analysis of OS the following factors associated with poorer Px (a) pre-CT: ER- (p=0.006); increasing T stage (p<0.001) and Ki67 (p<0.001); (b) at excision: increasing grade (p=0.04), tumour size (p=0.005), nodal status (p<0.03) and Ki67 (p<0.001); no adjuvant endocrine therapy (p=0.001). On multivariate analysis both pre-CT and excision Ki67 were significant independent predictors but the latter was more highly significant. (p<0.02 + p<0.0001, respectively) Assessing the combined group of 284 patients, after 5 years the highest and lowest tertiles of excision Ki67 had strikingly different Px: RFS 36% and 73%; OS 50% and 85%, respectively. Conclusions: Ki67 after CT is a strong predictor of long-term outcome. The greater significance of Ki67 in the excision sample may be due to this identifying patients in whom residual highly proliferative disease remains after CT. No significant financial relationships to disclose.
A correlative study of cardiac biomarkers and left ventricular ejection fraction (LVEF) from N9831, a phase III randomized trial of chemotherapy and trastuzumab as adjuvant therapy for HER2-positive breast cancer
Authors: Kutteh L. A. , Hobday T. , Jaffe A. , LaPlant B. , Hillman D. , Kaufman P. , Davidson N. , Martino S. , Moreno A. , Perez E. 
Published: March 2020

579 Background: N9831 and other clinical trials have demonstrated the additive survival benefit of trastuzumab (H) therapy with chemotherapy for patients with resected HER-2 positive breast cancer. Cardiac toxicity (CTox) is increased by this strategy. Prediction of or early detection of CTox is important. Methods: 95 patients provided informed consent. Brain natriuretic peptide (BNP), C-reactive protein (CRP), troponin T (TnT) and I (TnI), TNF-alpha, IL-1b, and IL-6 were to be drawn at baseline, after initiation of doxorubicin/cyclophosphamide (AC), after initiation of paclitaxel (T), and after the initiation of H (may have been given concurrently with T). 67 patients with at least a baseline sample, a post-treatment sample, and a baseline and subsequent evaluation of LVEF were studied. No patient in this group had a grade 3 decline in LVEF. Only 3 of these patients did not receive H. Values above the 99th percentile were considered abnormal for troponin. 40 ng/ml was considered elevated for BNP. Results: Values of CRP, TNF-alpha, IL- 6 and IL1b changed in very few patients and without a discernible pattern. For further evaluation of BNP, TnI, and TnT, 2 definitions of CTox were tested: 1. a >10% drop in LVEF from baseline (n=27) and 2. a drop in LVEF of 10–15% to less than the institutional lower limit of normal (LLN) OR a >15% decline in LVEF (n=14). No pre-treatment marker appeared to predict a > 10% decline in LVEF (definition 1). For patients fulfilling definition 2, pre-treatment BNP > 40 was seen in 21% of patients vs 8% of normals (nls) (p= 0.18) and an abnormal TnI (>0.04) was seen in 21% vs 6% of nls (p=0.10). Only doubling of BNP appeared promising as a serial marker of CTox using definition 2 (27% vs 7% for nls (p = 0.09). Conclusions: Baseline BNP and TnI and serial measures of BNP may be promising for further investigation for the prediction and detection of treatment-related CTox. Due to limitations of the study including the small numbers of patients analyzed, the difficulty in defining CTox, and the variation in the timing of sample procurement and assessment, these data are considered exploratory. Supported by CA-25224, CA-2115, CA 38926, CA31946. No significant financial relationships to disclose.
Comparison of vascularity measures from PET and MRI for improved breast tumor characterization and therapeutic response evaluation
Authors: Partridge S. C. , Eby P. R. , Doot R. K. , White S. W. , Kurland B. F. , Schubert E. K. , Dunnwald L. K. , Lehman C. D. , Mankoff D. A. 
Published: March 2020

589 Background: Dynamic contrast-enhanced MRI (DCE-MRI) and positron emission tomography (PET) are two imaging modalities previously shown to be predictive of response to neoadjuvant therapy in breast cancer. As the two techniques are functionally very different, the extent of their agreement or discordance for tumor characterization is not well understood. The purpose of this study was therefore to investigate the association between quantitative DCE-MRI enhancement kinetics and 15O-water PET/18F-FDG PET blood flow and metabolic measures of breast tumors. Methods: We retrospectively evaluated exams for 20 patients with locally advanced breast cancer (LABC) who underwent both 15O-water/18F-FDG PET and DCE-MRI. PET measures included 15O-water blood flow, 18F-FDG transport rate constant from blood to tissue (K1), and FDG metabolic rate. DCE-MRI measures included functional tumor volume, initial peak enhancement (PE), and a delayed signal enhancement ratio (SER) assessing washout. Pearson’s correlations and multivariate stepwise regression analyses were performed; p<0.05 was considered significant. Results: PET 15O-water blood flow correlated significantly with DCE-MRI peak SER (r=0.8) and tumor volume (r=0.7). PET K1 measures correlated significantly with DCE-MRI peak PE (r=0.7), peak SER (r=0.6) and tumor volume (r=0.6). By multivariate analysis, SER was the strongest independent MRI correlate of PET blood flow, and PE the strongest MRI correlate for K1. No significant correlations were observed between 18F-FDG PET metabolic rate and the DCE-MRI kinetic parameters. Also, while blood flow and K1 were strongly correlated (r=0.9, p=0.0001), blood flow and metabolic rate were not (r=0.4, p=0.12). Conclusions: The associations between PET and MRI measures may lead to a better understanding of angiogenesis, vascular permeability, and glucose transport in LABC. A lack of correlation of metabolic rate with blood flow and DCE MRI kinetics suggests that 18F-FDG PET provides complimentary metabolic information independent of vascular factors. The combination of MRI and PET may be helpful in understanding tumor pharmacodynamics in response to novel therapy. No significant financial relationships to disclose.
Pathologic complete response (pCR) following weekly (wkly) paclitaxel (cremophor or albumin-bound) and carboplatin (TC) ± trastuzumab (H), ± bevacizumab (B) in patients (pts) with doxorubicin/cyclophosphamide-resistant (AC-Res) and AC-sensitive (AC-S) large and inflammatory breast cancer
Authors: Mehta R. S. , Schubbert T. , Kong K. , Hsiang D. , Butler J. , Baick C. 
Published: March 2020

591 Introduction: Historically, pCR is rare in AC-Res in contrast to AC-S BC except following TCH in HER2+ BC in preliminary analysis (SABCS-2004, #1110). Moreover, robust predictors of pCR are needed. Methods: 106 consecutive BC pts on neoadjuvant studies were treated with GM/G-CSF supported dose-dense AC (except 7**- Table ), 2 cycles if AC-Res and 4 if AC-S. Pts then received 9–12 wkly TC (3 wks on, 1 off) ± 6–8 bi-wkly B if HER2- or +12–16 wkly H if HER2+, followed by surgery. Fisher’s exact test was performed to compare pCR percentages by various characteristics. Results: pCR in breast and lymph nodes in 38 of 84 assessable tumors in the first 82 pts were documented. 67% (56/84) tumors were reduced to ≤5 mm. Overall, no difference in pCR rates were found between AC-S and AC-Res BC, but pCR rates were 2- to 4-fold higher in HER2+, AC-S (79%) and AC-Res (65%) subsets compared to HER2-, AC-S (32%) and AC-Res (16%) subsets. Higher pCR rates were associated with HER2+/hormone receptor- (HR-) > HER2+/HR+, HER2-/HR- (triple-) > HER2-/HR+, and within the HER2+ subset-IHC 3+/FISH+ or unknown > IHC 3+/FISH- or IHC 1–2+/FISH+, and ductal > other histology. No patient had clinical cardiac dysfunction or EF <50, except 1 on AC/TC. 13/106 (12%) progression or death at a median follow-up of 22 months (range 2–46) is mostly due to stage IV and CNS progression. Conclusion: Short course of TCH achieves a high rate of pCR in AC-Res and AC-S, HER2+ BC in contrast to TC ± B in AC-Res and AC-S, HER2- BC. This is the first demonstration of high rate of complete AC resistance reversal across stage II-IV, inflammatory and recurrent HER2+ BC. In vivo response adjusted 2–4 cycles of dose-dense AC limited clinical cardiac toxicity. HER2+ (IHC 3+/FISH+ or unknown), HR- and ductal histology are significant predictors of high pCR. HER2 and HR confer 4 predictive subtypes of BC. [Table: see text] No significant financial relationships to disclose.
Association of polymorphic drug metabolizing enzymes (DME) with outcomes in breast cancer patients treated on the ECOG 2190/Intergroup 0121 (E2190/Int0121) study
Authors: Gor P. P. , Gray R. J. , Horn M. , Rebbeck T. R. , Gimotty P. A. , Aplenc R. , Pins M. , Tallman M. S. , DeMichele A. 
Published: March 2020

596 Background: Disparate outcomes of breast cancer patients after adjuvant chemotherapy may be influenced by variation in drug metabolism due to genetic polymorphisms in DME. Cyclophosphamide and thiotepa require activation by cytochrome P450 (CYP) and detoxification by glutathione-S-transferase, two highly polymorphic enzymes. We hypothesized that variants in CYP3A4(*1B), GSTM1 and GSTT1 would impact survival outcomes after adjuvant chemotherapy, with effects potentially modulated by chemotherapy dose. Methods: We performed a retrospective cohort study of patients enrolled on E2190/Int0121, a randomized trial of cyclophosphamide (C), doxorubicin (A), and fluorouracil (F) versus CAF + high dose chemotherapy (HDC) using cyclophosphamide and thiotepa followed by stem cell rescue; disease-free survival (DFS) and overall survival (OS) were equivalent in the clinical trial. PCR-based methods were used to genotype hematologic stem cells. Hazard ratios for genotypes were obtained using Cox regression. Results: Stem cell samples and clinical data from August 1, 1991 through August 1, 2005 were available for 347/540 of patients enrolled; 151 patients on CAF and 196 on CAF + HDC arms, respectively. Median follow-up was 9.8 years. See table . CYP3A4*1B allele carriers had significantly poorer DFS (HR 1.84) in the combined cohort and CAF arm (HR 1.87), but not in the HDC arm; OS was not significant by CYP3A4 genotype. GSTM1 null homozygotes in the combined cohort and HDC arm had significantly better DFS (HR 0.70 and 0.66, respectively) and OS (HR 0.67 and 0.57, respectively), but not in the CAF arm. GSTT1 null homozygotes had significantly worse DFS (HR 2.3) and OS (2.02) in the CAF arm, but not in the HDC arm or combined cohort. Conclusions: In the overall E2190/Int0121 cohort, polymorphisms in activating (CYP3A4*1B) and inactivating (GSTM1) DME significantly impact DFS and OS. The detrimental effect of GSTT1 in the CAF arm appears to be ameliorated by HDC. [Table: see text] No significant financial relationships to disclose.
Impact on overall survival of primary tumor extirpation in breast cancer patients who present with stage IV disease
Authors: Lang J. E. , Rao R. , Feng L. , Meric-Bernstam F. , Bedrosian I. , Kuerer H. M. , Singletary S. E. , Hunt K. K. , Hortobagyi G. N. , Babiera G. V. 
Published: March 2020

598 Background: Limited data exists regarding optimal local therapy for patients who present with stage IV breast cancer with an intact primary tumor. Two retrospective series, from the National Cancer Data Base and the Geneva Cancer Registry, showed that surgery may improve overall survival in these patients. Our institutional experience demonstrated improved metastatic progression-free survival after a median follow-up of 32.1 months but did not show a survival benefit at short term follow-up. We evaluated the impact of local control on overall (OS) and disease-specific survival (DSS) in this population after a longer follow-up interval to determine if a survival benefit could be demonstrated from local surgical treatment for selected patients with stage IV breast cancer. Methods: We reviewed the records of all patients at our institution who presented from 1997–2002 with stage IV disease with an intact primary tumor. OS and DSS were estimated by the Kaplan-Meier method. The log-rank test was used to compare the difference in survival between surgical and non-surgical patients. Multivariate statistical analysis was performed using the Cox proportional hazards model. Results: Of 220 patients identified with stage IV disease with an intact primary tumor, 80 (36%) underwent surgical resection of the primary tumor; 39 (49%) had segmental mastectomy and 41 (51%) had a total mastectomy. There were 140 (64%) patients who did not undergo surgery. The median follow-up duration from time of presentation to our institution was 58.6 months and the median OS time after presentation was 45.8 months. After adjustment for covariates, surgery was associated with improved OS (p=0.03) and DSS (p=0.04) compared to the non-surgical group. Conclusions: With a median follow-up time of 58.6 months, patients who presented with stage IV breast cancer with an intact primary tumor treated surgically had significantly improved OS and DSS compared to patients who did not undergo surgery. Our findings may be limited by a selection bias. Therefore, we feel that the issue of surgical intervention for the primary tumor in stage IV breast cancer patients deserves to be carefully studied in a well-designed, prospective, multi-center trial. No significant financial relationships to disclose.
No statistical impact of intra-tumoral overexpression of EGFR, VEGF and p53 on the overall survival in head and neck squamous cell cancer (HNSCC): Preliminary results of the GORTEC 99–02 randomized trial
Authors: Metges J. , Volant A. , Auperin A. , Gregoire V. , Maingon P. , Lesaunier J. , Calais G. , Bourhis J. 
Published: March 2020

6010 Background: Predictive and prognostic factors are warranted to improve the management of HNSCC patients. We designed a prospective study to analyze the p53 status, vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) tumoral overexpression of the patients included in the GORTEC 99–02 prospective phase III trial which compared conventional radiotherapy (RT) plus 5FU and carboplatin (FUP) vs RT with concomitant boost and FUP vs very accelerated RT Methods: This propective study has been designed to include 820 patients. We present here the results in a sub group of 219 patients for whom the immunohistochemical overexpression of EGFR, P53 and VEGF was analyzed. Association beetween these markers and TNM staging, age, sex,disease progression and survival was evaluated. Tumor overexpression was assessed by immunohistochemistry for EGFR (Dako EGFR pharmDx™ kit), VEGF (Santa Cruz Biotech), P53 (Dako). EGFR status was defined as positive or negative.If positive, we evaluated the percentage of cells presenting the same intensity of staining. Staining pattern was qualified as “diffuse” if more than 95% of cancer nests were stained with the same intensity, and as “mosaic” if the staining was heterogeneous Statistical analysis were performed using Spearman correlation coefficient, Kruskal-Wallis test for quantitative variables, chi2 and Fisher exact test for qualitative variables and Logrank test and cox model for survival analysis. Multivariate analysis of survival took into account T and N status, tumor localisation and the type of treatment. Results: Positive expression for P53, VEGF and EGFR were respectively found in 56.4%, 61.1% and 94%.Diffuse EGFR status was associated with higher T status (p=0.0141). VEGF(+) status was associated with increased EGFR staining (p=0.0017). Patients with p53+ status were younger than p53(-) (p=0.0362). P53,VEGF and EGFR expressions were not significatively related to survival Conclusions: These preliminary results don’t found any relationship between intra-tumoral markors and survival in HNSCC.Work supported by a french PHRC from the national Institute of Health No significant financial relationships to disclose.