bluuebunny/crossref_metadata_2025 huggingface dataset:
MicroRNA profiling analysis in a series of high-risk intestinal GISTs.
Authors: Calabuig Silvia , Martin Broto Javier , Sanchez-Izquierdo Dolors , Obrador Antonia , Ortega Luis , Casado Herraez Antonio , Valverde Claudia María , de Torres Ines , Poveda Andres , Ugalde Aitziber , Sala Angeles , Ramos Rafael , Gonzalez de Sande Luis Miguel , Losa Ferran , Lainez Nuria , Luna Fra Pablo , Cruz Josefina , Cubedo Ricardo , Lopez-Guerrero Jose Antonio ,   Spanish Group for Research on Sarcomas (GEIS)
Published: March 2020

10532

Background: Resected localized GISTs exhibit a wide range of biological behavior from low to high risk of recurrence. Risk categories (low, intermediate and high) are built from mitotic count, size and location. However, the molecular mechanism related to GIST relapse has not yet been fully clarified. The purpose of this study is to characterize miRNA expression profile in high risk GIST patients for both, recurred and not recurred, and detect those differentially expressed in these two subsets. Methods: Twelve cases of high risk intestinal GIST, 6 with relapse and 6 without relapse, were selected for this analysis. Sections were obtained for RNA extraction using the miRNeasy FFPE kit (Qiagen) and miRNA was hybridized to the GeneChip miRNA 3.0 Array (Affymetrix) including more than 1800 human miRNA. Normalization and statistical analysis were performed with Partek Genomic Suite 6.6 software by means of ANOVA test. Fold-change (FC) and p-values were applied to generate miRNA differentially expressed lists. Results: A subset of 85 miRNA were significantly deregulated (p<0.05; FC=1.5) when comparing both groups. Among them, the highest p-values and associated FC were: mir-4776 (FC= 1,95, p= 0,011;), mir-1973 (FC= 1,59, p= 0,014) mir-4649 (FC 1,74, p= 0,028) and mir-3605 (GC= 1,58, p=0,045). All of these were up-regulated in recurred patients. Interestingly, the two samples that correspond to the biggest tumors with relapse showed a significantly different expression profile that separated them from the rest of the samples. We have identified 44 miRNAs that discriminate these two samples from the rest and show a very high statistical significance. The most significantly up regulated miRNAs were miR-100 (FC= 90,87, p<0.0001), miR-30a (FC= 156,086, p<0.0001) and down regulated miR-1184 (FC= -24,94, p<0.0001) and miR-4529 (FC= -16,61, p<0.0001). These miRNAs are involved in cell cycle and cell proliferation. Conclusions: This is the first wide characterization of miRNA profile in high risk GIST. The highest differences in expression are related to not previously described miRNAs in GIST tumors. All of them are involved in cell cycle and cell proliferation, thus expecting to regulate many GISTs associated genes, related to the relapse event.
MAPK7 gene: A target for multimodal therapies.
Authors: Tesser-Gamba Francine , Petrilli Antonio Sergio , Paniago Mario Del Giudice , Alves Maria Teresa Seixas , Garcia-Filho Reynaldo Jesus , Toledo Silvia R. C.
Published: March 2020

10533

Background: Osteosarcoma (OS) is a class of cancer originating from the bone, affecting mainly children and young adults. In a previous work we observed that the overexpression of MAPK7 gene was significantly associated to tumor progression, a poor response to treatment, and worse overall survival, suggesting that MAPK7 could play an important role in osteosarcoma tumorigenesis. This present study investigated if any genomic structural alteration could be related to MAPK7 overexpression in OS samples. Methods: The MAPK7 gene was fully sequenced in 33 OS samples (15 prechemotherapy,15 post-chemotherapy and 3 OS cell lines) using the 3500 Genetic Analyser (Applied Biosystem) and 15 custom primers pairs that amplified overlapping genomic fragments. Results: From the 30 patient samples analyzed, 16 could not be completely sequenced. Samples containing these deleted regions were significantly correlated to clinical and pathologic features of patients with OS. No deletions were observed in patients with the favorable outcome (non-metastatic at diagnosis, >90% degree of necrosis in the surgical specimen and with complete remission at end of treatment). There was no correlation found between deletions and overexpression in pre-chemotherapy, even in patients that after chemotherapy still overexpressed MAPK7. Conclusions: Progress related to improved survival of patients with OS is at a plateau, and the intensification of therapy or incorporation of new therapeutic agents has not been successful, especially in patients metastatic at diagnosis. To our knowledge, no molecular marker for OS that could be related to its development, evolution or progression has been described yet. Based on our findings, we observed that patients who have no genomic deletion of MAPK7 gene respond better to treatment and have a favorable outcome. Studies available to date suggest that a single targeted therapy may not provide clinically significant anti-tumor effects, therefore we believe that specific inhibitors of the MAPK/ERK pathway are emerging as a relevant addition to multimodal therapies.
Does a diagnosis of GIST predict a second primary cancer?
Authors: Smith Myles JF , Mahar Alyson L. , Law Calvin , Ko Yoo-Joung
Published: March 2020

10537

Background: There have been reports of a high frequency of metachronous cancers in patients diagnosed with GIST. The purpose of this study was to identify and describe patients with GIST who develop second primary cancers, and to calculate standardized incidence ratios (SIRs) to quantify the risk of additional malignancy. Methods: This was a retrospective, population-based cohort study using SEER data. Individuals diagnosed with GIST from 2001-2009 were identified as having a malignant primary tumor in the digestive tract, and included the following sites: C15.0-C26.9; C48.0-48.8; C49.4-49.5; C80.9 and a recorded histology code of 8935 and 8936. This restricted timeframe was imposed to account for changes in the recording of GIST incidence. Individuals with a previous cancer diagnosis or diagnosed post mortem only were excluded. Multiple primary SIRs and 95% confidence intervals (CI) were calculated using SEER*Stat software (V.7.1.0) and compared to general population rates. The SIR was interpreted as an estimate of relative risk (RR). Comparison of characteristics between single and multiple cancer GIST patients was performed using chi-square tests, p-values of <0.05 were considered significant. Results: We identified n=1397 cases of GIST, of which 1291 analyzed. We observed a statistically significant increased incidence of second tumours in patients with a primary GIST (n=78, RR 1.36, 95% CI:1.1-1.7). Older age (p<0.001) and tumor grade (p=0.014) were associated with second primaries, with grade being the only significant variable remaining after logistic regression. In both sexes we observed a significantly increased incidence of kidney cancer (RR 4.3, 95% CI: 1.7-8.9). In females there was a 3 fold higher incidence of colon cancer (RR 2.96 95% CI: 1.2-6.1). Conclusions: Patients with a diagnosis of GIST have a higher incidence of second cancers when compared with standardized incidence in the general population. High grade GISTs were associated with an additional malignancy. Both sexes were observed to have increased incidence of kidney cancer, with females at an increased risk of developing colon cancer. As part of GIST surveillance, screening for colon cancer in females and kidney cancer in both sexes may be considered.
The role of surgical resection following imatinib treatment in patients with metastatic or recurrent GIST.
Authors: Ryoo Baek-Yeol , Park Seong Joon , Ryu Min-Hee , Sohn Byeong Seok , Kim Hwa Jung , Kim Ki-Hun , Oh Sung Tae , Yu Chang Sik , Yook Jeong Hwan , Kim Byung Sik , Kang Yoon-Koo
Published: March 2020

10550

Background: Several retrospective studies have suggested that surgical resection of residual lesions could be beneficial if resection was done after disease control (partial response or stable disease) with imatinib in patients with metastatic or recurrent GIST. However, the benefit of surgical resection has not been proven yet compared to imatinib alone. Therefore, we compared the outcomes of surgical resection of residual lesions after imatinib (SI group) with those of imatinib alone (IM group) in patients with metastatic or recurrent GIST controlled with imatinib treatment. Methods: A total of 134 patients with metastatic or recurrent GIST who showed at least 6 months of disease stabilization or response to imatinib were included in this retrospective analysis. Patients were categorized into SI (n=42) or IM (n=92) group. To reduce the selection bias, propensity scores and inverse-probability-weighting (IPTW) adjustment were used in the outcome analysis. Results: Patient and tumor characteristics were statistically similar between SI and IM groups, except median age (51 in SI, 58 in IM, p=0.002), and metastases to peritoneum (12 in SI, 56 in IM, p=0.001). The patients in SI group underwent surgery of residual disease after a median 19.1 months of imatinib treatment (range, 7.2-87.0). With a median follow-up of 58.9 months (range, 15.4-129.1), progression-free survival (PFS) and overall survival (OS) were significantly longer in SI group than in IM group (PFS, 87.7 vs 42.8 months, p=0,001; OS, not reached vs 88.8 months, p=0.001). Multivariate analysis revealed SI group as well as female sex, KIT exon 11 mutation, and low initial tumor burden were associated with longer PFS, and SI group and low initial tumor burden were associated with longer OS. Even after applying IPTW adjustment, SI group showed significantly better outcome in terms of PFS (hazard ratio [HR], 2.326; 95% CI, 1.034-5.236; p=0.0412) and OS (HR, 5.464; 95% CI, 1.460-20.408; p=0.0117). Conclusions: This study strongly suggests that surgical resection of the residual lesions after disease control with imatinib may be beneficial in patients with metastatic or recurrent GIST.
Sirolimus in advanced hemangioendothelioma.
Authors: Stacchiotti Silvia , Palassini Elena , Libertini Michela , Marrari Andrea , Bertulli Rossella , Morosi Carlo , Messina Antonella , Crippa Flavio , Dagrada Gianpaolo , Dei Tos Angelo Paolo , Gronchi Alessandro , Pilotti Silvana , Casali Paolo Giovanni
Published: March 2020

10565

Background: Haemangioendothelioma (HE) is a very rare vascular tumor. The epithelioid variant is characterized by a specific t(1;3)(p36.3;q25) translocation, resulting in the WWTR1-CAMTA1 fusion product. We retrospectively reviewed patients with HE treated with sirolimus, an mTOR inhibitor, at our institution. Methods: We identified 12 patients (M/F: 4/8 – mean age: 46 years – epithelioid HE/ retiform HE: 10/2 – locally advanced/multifocal: 1/11 – pretreated: 6) with advanced HE who were treated with sirolimus, as a single agent, 5 mg/day, from 2005 on. They had evidence of progression in the 3 months before starting treatment. The daily dose of sirolimus was adjusted according to drug blood levels (range 10-20 ng/dl). Response was evaluated with CT/MRI/PET scans after 4-6 weeks of treatment, then every 3 months, by RECIST and Choi criteria. WWTR1 gene rearrangement was evaluated by FISH, and the histochemical expression of mTOR effectors, S6 and 4BP1, is ongoing. Results: 10 patients are evaluable for response (2 pts are too early). Sirolimus daily dose ranged from 3 to 6 mg/day. Best response by RECIST was PR = 1, SD = 6 (all >6 months, range 6-48+), PD = 3 cases. In 3 cases, a Choi response could be detected. PET response was observed in 6/6 evaluated case. Median PFS (range) was 24 (3-48) months. Two patients with evidence of tumor stabilization while under sirolimus stopped their treatment after 12 and 24 months of therapy, respectively, with evidence of interval progression in both. A new disease stabilization was obtained after restoring sirolimus. Conclusions: HE is known for its potentially long-lasting course, even in typical cases with multicentric/multifocal disease. Progressive HE may require a medical therapy, but is insensitive to cytotoxic chemotherapy, while mainly andecdotal responses were reported to interferon, bevacizumab and thalidomide. In this retrospective series, sirolimus resulted in a high proportion of mainly non-dimensional, possibly long-lasting, tumor responses.
Impact of adjuvant treatments on local and metastatic relapse of soft-tissue sarcoma patients in the setting of competing risks.
Authors: Italiano Antoine , Le Cesne Axel , Mendiboure Jean , Blay Jean-Yves , Piperno-Neumann Sophie , Chevreau Christine , Delcambre Corinne , Penel Nicolas , Terrier Philippe , Ranchere-Vince Dominique , Lae Marick , Le Guellec Sophie , Michels Jean-Jacques , Robin Yves Marie , Bonvalot Sylvie
Published: March 2020

10575

Background: Competing risk is the risk of an event that interferes with the probability of experiencing the disease-specific outcome of interest. Indeed, the occurrence of a competing risk (for instance death by local relapse or another cause) may preclude the onset of the event of interest (for instance metastatic relapse) or at least modify its probability. Competing risk is ignored by Kaplan Meier method and standard Cox survival model. Methods: 3369 adult patients with localized STS were included prospectively in the French Sarcoma Group (GSF) database from January 1990 to December 2009. The outcomes of interest were the cumulative probabilities of local (LR) and of metastatic (MR) relapse with death as a competing event. Estimations and 95% confidence intervals (CIs) were computed with the cumulative incidence function. Results: Median follow-up was 4.5 years. 1-year and 5-year cumulative incidence of LR were 6.4% (95% CI 5.6-7.3) and 25.9% (95% CI 24.2-27.6), respectively. Age, histological subtype, anatomic site and grade were independently associated with the cumulative probability of LR. After adjustment to these prognostic factors, adjuvant radiotherapy was associated with a significant impact on LR (HR=0.5 95% CI 0.4; 0.6, p <0.001). The magnitude of this effect was similar whatever the grade or the anatomic site. Because of the competing effect of death, adjuvant chemotherapy had no significant impact on the cumulative probability of LR. 1-year and 5-year cumulative incidence of MR were 7.4% (95% CI 6.5-8.3) and 26.9% (95% CI 25.2-28.7), respectively. Tumor depth, histological subtype, tumor size and grade were independently associated with the cumulative incidence of MR. After adjustment to these prognostic factors, adjuvant chemotherapy was associated with a significant impact on MR (HR=0.5 95% CI 0.4-0.7, p < 0.001) in grade 3 but not in grade 2 patients (HR=1.3 95% CI 0.9-1.9, p= 0.1). Conclusions: Adjuvant radiotherapy was associated with improved LR outcome even in patients with high risk of competing death from metastatic disease or other causes. Adjuvant chemotherapy was associated with improved MR outcome in patients with grade 3 but not grade 2 disease.
Prognostic significance of radiologic and histologic response to neoadjuvant chemotherapy in localized synovial sarcoma.
Authors: Chakiba Camille , Terrier Philippe , Ranchere-Vince Dominique , Neuville Agnes , Aarab Terrisse Safae , Blay Jean-Yves , Perrin Christophe , Bompas Emmanuelle , Italiano Antoine
Published: March 2020

10578

Background: The role of neoadjuvant and adjuvant chemotherapy in localized synovial sarcoma (SS) is still controversial. Histologic response to neoadjuvant chemotherapy is an independent prognostic variable in bone sarcomas. Data regarding the prognostic value of response to noeadjuvant chemotherapy in STS are limited. Methods: 68 patients with localized STS, treated with neoadjuvant anthracycline/ifosfamide-based chemotherapy and assessable for response to chemotherapy were included prospectively in the French Sarcoma Group (GSF) database from 1985 to 2011. All the cases were reviewed by the pathology subcommittee of the GSF. Radiological response to chemotherapy was assessed according to RECIST criteria. Good response was defined as partial response or stable disease according to RECIST and ≤10% recognizable tumor cells in the surgical specimen. Poor response was defined as stable or progressive disease according to RECIST and ≥ 50% recognizable tumors cells in the surgical specimen. All the other cases were defined as intermediate response. Results: Median age was 38 years. Median tumor size was 8 cm (range 2-20). 56% of tumors were located in the limbs and 52% were grade 3. Response to chemotherapy was considered as good in 9 cases (13%), intermediate in 20 cases (29.5%) and poor in 39 cases (57.5%). Median metastasis-free (MFS) and overall (OS) survivals were 45 (95% CI 11-79) and 84 months (95%CI 88-120), respectively. On univariate analysis, grade, tumor size and response to chemotherapy were significantly associated with metastasis-free survival (MFS). Radiological response according to RECIST has no prognostic value. On multivariate analysis, grade was the sole variable independently associated with MFS (HR=3.4, 95% CI 1.5-7.5, p=0.003). On univariate analysis, grade, and response to chemotherapy were significantly associated with overall survival (OS). On multivariate analysis, grade was the sole factor independently associated with OS (HR=2.5, 95% CI 1.2-5.7, p=0.03). Conclusions: Response to neoadjuvant chemotherapy may not have prognostic value in patients with SS. Grade represents the most significant predictive factor of outcome in this setting.
Poor prognostic features in angiosarcoma: A single institution retrospective study of 324 patients.
Authors: D'Angelo Sandra P. , Moraco Nicole H. , Qin Li-Xuan , Kuk Deborah , Carvajal Richard D. , Dickson Mark Andrew , Gounder Mrinal M. , Keohan Mary Louise , Antonescu Cristina R. , Singer Samuel , Schwartz Gary K. , Tap William D.
Published: March 2020

10580

Background: Angiosarcoma (AS) is a rare, malignant endothelial cell tumor of vascular origin with a five year overall survival (OS) of approximately 35%. It is a heterogenous disease whose natural history is poorly defined. We sought to identify clinical and treatment outcomes to better define this disease. Methods: In a retrospective study using an institutional sarcoma database, we identified all patients(pts) with AS treated at Memorial Sloan-Kettering Cancer Center between 1992-2011 and collected their correlative clinical information.Kaplan-Meier method and Cox’s proportional-hazard models were used to determine OS and prognostic factors. Hazard ratios (HR) are listed with their 95%confidence intervals (CI). Results: We identified 324 pts, median age was 63 (range 15-94), 127(39%) were men. At presentation, 188 (58%), 19 (6%) and 117(36%) had localized disease (L), local recurrences (LR) or distant metastases (M), respectively. L sites included: RT breast 43 (23%,) head&neck 33 (18%,) scalp 30 (16%,) breast 26 (14%,) extremity 23 (12%,) abdomen/pelvis 14 (7%,) thorax 10 (5%) and trunk 9 (5%). The median OS is 3.3 years (2.44-4.33) for pts w L disease and 0.89 years (0.74-1.11) for pts with M disease. Among pts that presented with L disease, 29% had a LR and the median local relapse free survival (RFS) time was not reached (8.71-NA); 31% had distant recurrences with a median distant RFS of 12.8 yrs (4.13-NA.) Among L disease patients, older age (HR 1.04, 1.03-1.06, p <0.0001) and site were independent predictors of decreased OS. Visceral tumors arising in the abdominal/pelvis (AP) (HR 2.89, 1.27-6.61, p = 0.012) had worse OS compared to those arising the breast. Conclusions: AS remains an aggressive, heterogenous malignancy with poor OS and high rates of local and distant recurrences. Patients with M disease do poorly. Adverse prognostic factors include AP visceral tumors and older age. These factors could be helpful for stratification in future clinical trials. The identification of genomic differences is necessary to define therapeutic targets in AS.
Preoperative Tru-Cut biopsy (POB) for the diagnosis of retroperitoneal soft tissue sarcomas (RPS) and risk of local recurrence (LR) compared to primary surgery of the tumor.
Authors: Boccone Paola , D'Ambrosio Lorenzo , Galizia Danilo , Palesandro Erica , Aliberti Sandra , Manca Antonio , Bertotto Ilaria , Russo Filippo , Racca Manuela , Gatti Marco , Pignochino Ymera , Aglietta Massimo , Grignani Giovanni
Published: March 2020

10583

Background: Regardless optimal surgery LR is still a major challenge in RPS affecting 60% of the patients (pts). To improve these results pre-operative radiotherapy +/- chemotherapy are under investigation. This strategy requires to perform a POB. The surgical removal of the whole needle track is mandatory for limb sarcomas, but it can hardly ever be achieved in RPS. We explored whether POB did increase the risk of LR in terms of tumor cell seeding (along the needle track) or in the tumor mass area. Methods: We scanned our prospectively (01/2000 to 12/2010) collected RPS database including 176 pts. Complete information (records, CT scans, biopsy-track, follow up data) were available and retrospectively examined in 100 pts. Pts were divided into: group A (POB), group B (direct surgery). The 7 year probability of disease free survival (DFS) was estimated for each pt (ASCO 2012 abs 10000). T student test and Fisher's exact test were used to compare the estimated DFS and the incidence of LR in the 2 groups, respectively. Kaplan-Meier method was used to estimate DFS and overall survival (OS). Results: In 51 male, 49 female, median age 58 years (22-81) RPS histotype distribution was: lipo 43, leio 28, pleomorphic 9 and other 20. RPS grades were: G1 29%, G2 32%, G3 39%. POB was performed in 25 pts (25%) without major complications. The baseline probability of 7 year DFS was 0.43 and 0.51 (p= .24) for group A and B, respectively. After a median follow up of 71 mos, LR was 8% and 23% (p> .05) for group A and B, respectively. No relapse along the needle track was detected. As expected, liposarcoma was associated with a higher rate of LR (Odds Ratio 5.6 CI 95% 2-13). Median DFS, local DFS and OS were 24, 88 and 71 months, respectively. Conclusions: With the limit of the retrospective nature of our data, we didn’t find any increased risk of LR for POB in RPS. Although surgery is still the standard therapy in RPS, knowledge of histotype and differential diagnosis might encourage to consider inclusion of pts into pre-operative clinical trials and to avoid surgery for other retroperitoneal tumors (e.g. lymphomas, germinal cell tumors, IgG4-related sclerosing disease).
The impact of patient-related factors on the occurrence of febrile neutropenia in breast cancer patients receiving (neo-)adjuvant chemotherapy with 5-fluorouracil, epirubicin, and cyclofosfamide (FEC) x6 or FEC x3 followed by docetaxel (D) x3.
Authors: Vulsteke Christof , Pfeil Alena , Brouwers Barbara , Schwenkglenks Matthias , Paridaens Robert , Pettengell Ruth , Dieudonné Anne-Sophie , Hatse Sigrid , Neven Patrick , Lambrechts Diether , Wildiers Hans
Published: March 2020

1078

Background: Recently we described the impact of genetic variability on severe toxicity in breast cancer patients receiving (neo-) adjuvant FEC chemotherapy (Annals of Oncology 2013, In Press). We now further assessed the impact of a wide range of patient-related factors on FEC toxicity in routine clinical setting. Methods: Patients with early breast cancer receiving (neo-)adjuvant 6 cycles FEC or sequential 3 cycles of FEC and 3 cycles D were retrospectively evaluated through electronic chart review for febrile neutropenia (primary endpoint; CTC 3.0). Age at diagnosis, body mass index, body surface area, number of cycles received, germline genetic polymorphisms, and baseline biochemical variables (white blood cell count, absolute neutrophil count, platelets, aspartate aminotransferase, alanine aminotransferase, total bilirubin and creatinine) were available for most patients (missing data <10%). All patients had follow up for progression free survival (PFS) and overall survival (OS). Multivariate logistic regression analysis was performed including univariate associates of outcome with a p-value <0.25. Results: We identified 1,031 patients treated between 2000-2010 with 6x FEC (n=488) or 3x FEC followed by 3x D (n=543). 174 (16.9%) patients developed febrile neutropenia during FEC. After logistic regression analysis febrile neutropenia was found to be significantly associated with carriers of the rs45511401 variant T-allele in the MRP1 gene found in 12% of patients (p= 0.03, OR1.99, CI 1.07-3.71) and with increasing serum creatinine values (p=0.05 OR 4.58/CI 0.99-20.98); all other investigated patient-related parameters were not retained by the model. At a mean follow up of 5.2 years, the occurrence of febrile neutropenia was not correlated with PFS and OS. Conclusions: In this study, only the baseline level of serum creatinine and germline genetic polymorphisms in the MRP-1 gene were predictive for the occurrence of febrile neutropenia in patients receiving FEC chemotherapy. The occurrence of febrile neutropenia did not seem to impact on outcome.
A multicenter audit of the incidence of febrile neutropenia and neutropenia associated with docetaxel and cyclophosphamide (TC) chemotherapy for early breast cancer.
Authors: Lakhanpal Roopa , Stuart-Harris Robin , Chan Arlene , Kotasek Dusan , Beith Jane McNeil , Cuff Katharine , Bastick Patricia A. , Lee Clara Inkyung
Published: March 2020

1079

Background: A 2006 US Oncology trial reported that four cycles of docetaxel and cyclophosphamide (TC) resulted in better disease free and overall survival than four cycles of doxorubicin and cyclophosphamide (AC) in women with early breast cancer (EBC) and TC is now a frequently used adjuvant chemotherapy regimen for EBC. The 2006 trial reported that TC was associated with a 5% incidence of febrile neutropenia (FN), but others have noted a higher incidence of FN. Methods: We have conducted a multicentre retrospective audit of women with EBC treated with TC between January 2010 and July 2011, recruited from seven Australian centres. The primary endpoints of the study were the incidence of FN associated with the use of TC and also the incidence of grade 3 or 4 neutropenia during cycle one of TC. Patients receiving prophylactic granulocyte colony stimulating factor (G–CSF) or prophylactic antibiotics were excluded. Results: Of a total of 368 previously untreated women with EBC who received TC, 300 were evaluable for FN. The median age of the patients was 57 years. Overall, 73 (24.3%) patients developed FN. The highest incidence of FN was seen after cycle one (91.8%) of TC and the incidence of FN appeared higher in women under the age of 65 years. Of 304 patients evaluable for neutropenia during cycle one, eight (2.6%) developed grade 3 neutropenia and 191 (62.8%) developed grade 4 neutropenia. Conclusions: This is the largest study to date which reveals that TC is associated with a high incidence of grade 4 neutropenia and a high incidence of FN. The incidence of FN is above the 20% threshold for the use of G-CSF as primary prophylaxis as recommended by The EORTC and The National Comprehensive Cancer Network. Therefore, we recommend that G-CSF be considered as primary prophylaxis when TC is used as adjuvant chemotherapy for EBC.
Quantitative Ki-67 score as predictive of response to neoadjuvant chemotherapy in breast cancer.
Authors: Brown Jason R. , Lannin Donald R. , Killelea Brigid K. , DiGiovanna Michael , Rimm David
Published: March 2020

1085

Background: Neoadjuvant chemotherapy is administered prior to surgery for locally advanced tumors but does not confer any additional survival benefit. Measurement of Ki-67, a marker of cell proliferation, has been associated with response to therapy, but methods of measurement are controversial. There is no universal cut-point for association due to subjectivity in threshold for positivity and selection of the field of view. Here we propose that quantitative objective measurement for Ki-67 will provide a reproducible assay for likelihood of response to chemotherapy. Methods: A cohort of 115 consecutive (between 2002 and 2010) invasive breast cancer patients that received neoadjuvant therapy were included if pre-surgical biopsies were obtainable. Ki-67 expression was measured using quantitative immunofluorescence (AQUA) technology using the MIB-1 antibody. Images for each specimen were collected in 5 to 100 fields of view (FOV), and summary scores were obtained corresponding to the average and maximum of all the FOVs. Results: AQUA scoring was comparable to automated calculation of percent positive nuclei for prediction of response to chemotherapy (OR: 2.832 vs. 2.712). Both average and maximum AQUA scores showed Ki-67 expression was directly correlated to pathological complete response (pCR) (Ave p = 0.0002; Max p = 0.0011). Although examining the maximum field of view was more predictive of response to therapy (OR: 3.546 vs. 2.832), averaging all fields provided more sensitivity and specificity (AUC 0.769 vs. 0.732). Ki-67 average (p = 0.0025) and maximum (p = 0.0239) AQUA scores were also significant predictors of pCR in multivariable analysis with tumor size, nuclear grade, nodal status, ER status, and HER2 status considered. Conclusions: Measurement of Ki-67 expression by objective quantitative methods shows increased Ki-67 levels are an independent predictor of response to neoadjuvant chemotherapy. This assay is most sensitive and specific when the average Ki-67 expression from all fields of view is used.
A phase II study evaluating the safety and efficacy of sunitinib with weekly paclitaxel followed by doxorubicin and daily oral cyclophosphamide plus G-CSF as neoadjuvant chemotherapy (NC) for locally advanced (LABC) or inflammatory breast cancer (IBC).
Authors: Specht Jennifer M. , Kurland Brenda F. , Linden Hannah M. , Gralow Julie , Gadi Vijayakrishna K. , Ellis Georgiana Kehr , Rodler Eve T. , Chai Xiaoyu , Eun Jinny , Brown-Glaberman Ursa Abigail , Livingston Robert B. ,   Seattle Cancer Care Alliance Network Investigators
Published: March 2020

1090

Background: Sunitinib (S) is an oral tyrosine kinase inhibitor with anti-tumor and anti-angiogenic activity. The primary objective of this trial was to assess the pathologic complete response rate (pCR) in patients (pts) treated with NC consisting of S with weekly paclitaxel (T) followed by doxorubicin and daily oral cyclophosphamide plus G-CSF (AC+G-CSF). Correlative studies including circulating biomarkers are reported separately. Methods: Pts with HER2 negative LABC or IBC were eligible for this multicenter, phase II trial. Pts received S 25 mg po daily with T 80 mg/m2 IV Qweek (wk) x 12 wks, then AC+G-CSF (doxorubicin 24 mg/m2 IV Qwk + oral cyclophosphamide 60 mg/m2po daily + G-CSF 5 mcg/kg SC days 2-7) x 15 wks. pCR in the breast and axilla was assessed at surgery, and the MDACC CPS+EG score (validated score combining clinical and pathologic results for predicting survival in the neoadjuvant setting) was calculated. Results: 70 pts (ages 33-79) were enrolled; 68 received protocol therapy. 37 (53%) had ER and/or PR positive tumors. 2 patients were unevaluable (hypersensitivity to T, toxicity possibly related to S) and 3 withdrew consent prior to surgery. 61 pts reported any grade AE in S+P period. Among grade 3 or 4 AEs, neutropenia was most common in S+P period occurring in 31/68 (46%). pCR in the breast was observed in 27% (17/63, 95% CI 17%-40%) and breast and axilla in 15/63 (24%). In pts with ER positive tumors, pCR rate in breast was 8/34 (24%) and 9/29 (31%) for pts with ER negative tumors. 18 evaluable pts (29%) had CPS+EG scores ≤2, 40 (63%) had CPS+EG scores of ≥3, and 5 had insufficient information to calculate the CPS+EG score. When response was defined as pCR and/or CPS+EG score ≤ 2, 28 pts (44%) were responders. Conclusions: NC with T+S followed by AC+G-CSF was well tolerated. Using a combined definition of response of pCR and/or CPS+EG score ≤2, 28/63 (44%) pts had response; 19/34 (56%) for ER positive and 9/29 (31%) for ER negative disease. The addition of S to NC may result in promising incremental benefit for pts with ER positive breast cancer. Clinical trial information: NCT00513695.
Randomized phase II trial of gemcitabine versus gemcitabine and imatinib mesylate in patients with previously treated metastatic breast cancer.
Authors: Munshi Pashna Neville , Toppmeyer Deborah , Wong Serena Tsan-Lai , Ganesan Shridar , Tkaczuk Katherine Hanna , Cianfrocca Mary E. , Kaklamani Virginia G. , Gradishar William John , Somer Robert A. , Sharan Kanu , Grana Generosa , Lerma Pauline Marie O. , Pliner Lillian F. , Wieder Robert , Kane Michael P. , Kim Sinae , Tan Antoinette R.
Published: March 2020

1091

Background: Gemcitabine (GEM) as a standard 30-min infusion has activity as a single-agent in metastatic breast cancer (mbc). Prolonged infusion of GEM at a fixed dose rate (FDR) of 10 mg/m2/min is associated with greater formation of active metabolite and may result in improved antitumor activity. Imatinib mesylate (IM)-mediated inhibition of PDGFR reduces tumor interstitial fluid pressure allowing for improved chemotherapy penetration into tumors. We evaluated the addition of IM to FDR GEM in patients (pts) with previously treated mbc. Methods: This was a randomized phase II trial in mbc pts who progressed after 1 but no more than 2 prior cytotoxic regimens. Eligibility included measurable disease; no prior GEM or IM exposure. Group 1 received FDR GEM IV 1250 mg/m2 at 10 mg/m2/min (over 120 min) on days 3 and 10 every 21 days; Group 2 received the same FDR GEM dose and schedule plus IM 400 mg orally daily on days 1-5 and 8-12 every 21 days. Primary endpoint was time to progression (TTP). Sample size of 40 pts per group was needed to detect an 8 mo increase in TTP with the combination (80% power, α = .05, 2-sided). Secondary endpoints included ORR and safety. Results: Between 5/2006-4/2011, 44 pts were randomized (22 per group). Study closed early due to slow accrual. Median age 54 (31-75); median ECOG PS 1 (0-2); 52% were hormone receptor-positive and HER2-negative; 27% triple-negative, and 20% HER2-positive. Median number of cycles was 2 in Group 1 (range 1-12) and 3.5 in Group 2 (range 1-13). Most common adverse events (%) of any grade, Group 1 vs Group 2 were neutropenia (68 vs. 78), anemia (48 vs. 65), thrombocytopenia (24 vs. 47), nausea (40 vs. 52) and vomiting (24 vs. 21). One gr 4 thrombotic thrombocytopenic purpura occurred in Group 2. Median TTP were 2 mo (95% CI: 1-5 mo) in Group 1 and 2.5 mo (95% CI: 1-5 mo) in Group 2 (p = 0.3 log rank test). ORR was 9.1% in each group (95% CI: 1.6-30.6%), with 2 PRs in each group. Stable disease (≥ 3 mo) was 32% in Group 1 and 41% in Group 2. Conclusions: This study was underpowered to draw any conclusion regarding a difference in TTP between the two groups at the time it was prematurely closed. Combination of IM and FDR GEM showed a trend to increased toxicity compared to FDR GEM alone. Clinical trial information: NCT00323063.
The prognostic and predictive impact of genomic grade index (GGI) versus central grade or molecular class in intermediate-risk breast cancer (BC): Results from the EC-Doc trial.
Authors: Gluz Oleg , Liedtke Cornelia , Peyro Saint Paul Helene P. , Nitz Ulrike , Kates Ronald E. , Huober Jens Bodo , Hartmann Arndt , Kreipe Hans Heinrich , Pelz Enrico , Erber Ramona , Kuhn Walther , Harbeck Nadia
Published: March 2020

1092

Background: Potential markers for adjuvant taxane-based chemotherapy (CTx) in early, intermediate-risk BC include histologic grade (HG), Ki-67, Genomic Grade (GG) or molecular classification. The randomized EC-Doc trial demonstrated improvements in DFS and OS for EC-Doc vs. FEC in patients with 1-3 positive LN. Methods: Centrally assessed protein expression data by IHC, histology/HG (n=772) and GG (n=476) were obtained. Luminal A/B classes were defined as: ER/PR+/KI-67<20/>20% and/or HER2+. Correlations/concordance of these factors were estimated; impact on DFS and value for predicting taxane-based CTx benefit was assessed. Results: Low, equivocal and high GG (GG-1/-EQ/-3) categories were observed among 54 (11%); 60 (13%); 358 patients (76%) and associated with decreasing 5-yr-DFS rates of 100%, 92% and 82% (p < 0.001).There is only 60% concordance between local (L)/central(C) HG assessments and 63% between GG and C-HG. 37.7% of GG-3 tumors were L- HG3 vs. 72% C-HG3; 79% of C-HG2 and 83% of L-HG2 tumors were re-classified (56-71% to GGI3). Only 5.6-6% of GG1 were HG1 by L/C-HG respectively.GG was prognostic only in L-HG subgroups.In univariate subgroup analyses, EC-Doc was significantly superior to FEC: C-G3 (HR=0.58, 0.39-0.93), high Ki-67 (HR=0.55, 0.32E0.92) and GG-3 (HR=0.58, 0.34-0.99) subgroups. In multivariate analyses of HR+ disease (including age, therapy, GGI category, tumor size, LN status, central/local HG, Ki-67, HER2), either C-HG3 / high Ki-67 (as dichotomous variables) or C-HG3 / GGI (as continuous variable) were identified as independent prognostic factors.In interaction analysis, only C-HG, luminal A subtype and interaction of luminal-B/therapy were significant. If local HG was included instead of C-HG, only GG was as independent prognostic factor. Conclusions: These data support GGI as independent prognostic factor in early HR+ BC and as predictive marker regarding taxane benefit by univariate analysis. There is heterogeneity between L/C-HG and GGI. C-HG and Ki-67 assessment appear similarly informative. A predictive effect regarding benefit of taxane-containing CTx was seen in the IHC-luminal B subtype.
Guidelines for the definitions of time-to-event endpoints in randomized clinical trials: Results of the DATECAN Project for Breast Group.
Authors: Gourgou Sophie , Dabakuyo Tienhan Sandrine , Asselain Bernard , Azria David , Cameron David A. , Cardoso Fatima , Poortmans Philip M. ,   DATECAN Group
Published: March 2020

1094

Background: With the necessity of reducing randomized clinical trial (RCT) duration, cost and number of patients, surrogate endpoints of overall survival (OS) are increasingly being used in cancer RCTs. However, most of these endpoints currently lack of standardized definition enabling a comparison of RCT results. Some recommendations have been proposed for specific cancer sites but they do not rely on a formal consensus methodology. The objective of the Definition for the Assessment of Time-to-event Endpoints in CANcer trials (DATECAN) project is to provide guidelines to standardize definitions of time-to-event endpoints in RCTs for different cancer sites. Here, we present results for BREAST cancer. Methods: We relied on the modified Delphi consensus method, a validated formalized consensus process for the development of practice guidelines. International experts with various backgrounds and expertises were involved. First, the coordinating committee, a group of statisticians and epidemiologists involved in the design and conduct of RCTs, led a comprehensive literature review to identify time-to-event endpoints, events of interest and the existence of guidelines in adjuvant and metastatic settings. The steering committee, which included additional medical experts, validated the list and prepared the questionnaire sent for rating to an independent expert committee. Results: The consensus process involved 2 rounds of scoring (31 experts) and 1 in-person meeting (in parallel to ASCO'12). Each expert had to rate on a 1-9 scale if s/he agreed or not for including events (e.g. death from breast cancer) in the definition of time-to-event endpoints (e.g. progression-free survival). 150 events had to be scored for the 11 selected endpoints. Consensus was reached for 57% of the events after the 2 rounds of scoring. After the in-person meeting, consensus was reached for all the remaining events except one. Conclusions: The DATECAN guidelines should help standardizing definitions of commonly used endpoints. This process should (i) facilitate the comparison of RCTs and (ii) improve the quality of future RCTs by providing better estimation of sample size and treatment effect.
Improved outcome and selection bias in primary breast surgery for patients with metastatic breast cancer.
Authors: Hadzikadic Gusic Lejla , Falcone John , McGuire Kandace P. , Soran Atilla , Diego Emilia , Thomas Christine R. , McAuliffe Priscilla F. , Bonaventura Marguerite , Johnson Ronald , Ahrendt Gretchen M.
Published: March 2020

1098

Background: Retrospective studies showing improved survival in patients with metastatic breast cancer (MBC) who undergo surgical treatment of the primary tumor have been criticized for bias in favor of younger, healthier women with lower disease burden. We attempted to identify these biases in our population. Methods: Our institutional cancer registry was queried for patients with MBC from 1994-2010. Demographics, clinical, radiologic and pathologic staging, as well as treatments and outcomes were recorded. Surgical and non-surgical groups were compared for differences in overall survival (OS) and clinicopathologic variables, including comorbidities, using uni- and multivariate analysis. Results: Ninety-one patients with metastatic disease identified within 3 months of initial diagnosis were eligible. 53% (48 pts) had primary breast surgery and 47% (43 pts) did not undergo surgery. Patients in the surgery group were younger on univariate analysis (mean age 53 vs. 62, p<0.01). Neither BMI (mean 30 vs. 29 kg/m²) nor Charlson comorbidity score (mean 6 in both groups) were significantly different, p=NS. Bone metastases were more common in the surgery group (48 vs. 26%) and multiple metastases in the non-surgery group (35 vs. 17%), p<0.05. Patients in the non-surgery group had ≥ 1 visceral metastasis when compared to the surgery group (62 vs. 35%), p<0.05. Higher OS was demonstrated in the surgery group both with Kaplan Meier curves (p<0.05) and univariate analysis (mean 3 vs. 2 yrs, 95% CI 2.6, 3.7), p<0.05. Survival was higher in the surgery group (p<0.01), at 1 year, but this difference did not persist at 3 and 5 years. On multivariate analysis, only difference in age remained significant (p<0.01). Conclusions: Our study supports existing data that women with MBC who have surgical treatment of the primary tumor have an improved survivorship. However, it also suggests a bias towards increased use of surgery in patients who are younger with smaller burden of metastatic disease. We did not find a bias in favor of healthier patients. Further study to determine the mechanism and magnitude of benefit of primary tumor extirpation is still needed.
Neoadjuvant bevacizumab: Surgical complications of mastectomy with and without reconstruction.
Authors: Kansal Kari Joanne , Dominici Laura Stewart , Tolaney Sara M. , Isakoff Steven J. , Krop Ian E. , Smith Barbara L. , Jiang Wei , Potler Hannah , Brock Jane E. , Winer Eric P. , Golshan Mehra
Published: March 2020

1100

Background: Neoadjuvant therapy is commonly used in operable breast cancer. We prospectively evaluated the surgical complications in a cohort of patients who underwent mastectomy following neoadjuvant doxorubucin hydrochloride/cyclophosphamide/paclitaxel (AC/T) plus bevacizumab and compared the rate of complications to a matched cohort of neoadjuvant AC/T without bevacizumab. Methods: One hundred patients with HER2-negative breast cancer enrolled in a single-arm trial of neoadjuvant AC/T plus bevacizumab (cohort 1), 60 of these patients underwent mastectomy and were matched with 59 patients who received standard neoadjuvant AC/T (cohort 2) over a similar time period in the same healthcare system. All patients underwent mastectomy with or without reconstruction. Fisher’s exact tests were used to compare complication rates, with a p<0.05 was considered significant. Results: Patients were matched well in terms of demographics. The overall complication rate was 33% in cohort 1 and 31% in cohort 2 (P-value=0.84; Table). In cohort 1, 7 of 23 (30%) patients who underwent immediate expander/implant reconstruction had complications, including 2 patients who had explantation of their reconstructions. In cohort 2, 0 of 8 (0%) had complications (p value=0.15). Conclusions: Nearly a third of patients undergoing neoadjuvant therapy with AC/T with or without bevacizumab developed a postoperative complication after mastectomy. The use of bevacizumab was not associated with a significant increase in surgical complications, although this is a non-randomized data with a small sample size. As larger data sets become available with the use of neoadjuvant bevacizumab with mastectomy, further refinement may be necessary. [Table: see text]
Acute and late side effects after intraoperative electron radiotherapy during breast conserving surgery of breast cancer.
Authors: Matuschek Christiane , Boelke Edwin , Janni Wolfgang , Zwiefel Karin , Simiantonakis Ioannis , Njanang Freddy-Joel , Budach Wilfried , Alessandro Marina
Published: March 2020

1101

Background: Intraoperative boost irradiation as part of breast-conserving therapy is a perfect method to adequately capture the high risk tumor relapse area. The most homogeneous dose distribution is achieved with electrons. Intraoperative electron radiotherapy (IOERT) as a boost for breast cancer releases a high single dose of radiation to the breast tissue; therefore acute toxicity is of particular attention. To date there is only inadequate information available on breast cancer patients treated with IORT using electrons applied as a boost. We therefore analyzed the acute toxicity and late side effects after radiotherapy with 10 Gy as a boost with a minimum follow-up of 3 months. Methods: A total of 385 patients treated with IOERT (10 Gy with 5, 7 and 9 MeV electrons) with a dedicated robotic linac (NOVAC 7, New Radiant Technology, Aprilia, Italy) to the tumor bed during breast-conserving surgery as a boost followed by whole-breast radiotherapy (WBRT,50- 50.4 Gy; 1.8-2 Gy per fraction) were included in this study. All patients underwent a retrospective follow-up regarding acute and late side effects. Toxicities were documented using the common toxicity criteria (CTC 4.0 of the European Organization for Research and Treatment of Cancer) and normal tissues subjective, objective, management and analytic scales (LENT-SOMA). Results: The IOERT was well tolerated and the cosmetic results were good. As a side effect there were five patients with seroma. Two patients developed a secondary wound healing. Two patients developed chronic pain in the irradiated breast. Ten patients developed a grade 2 fibrosis. The remaining patients did not develop any grade 3 or 4 side effects. The observed toxicity rates were not influenced by age, tubus size, electron energy or systemic therapy. 80 patients had a follow up longer than 5 years. Three of them developed distant metastasis and one patient died. Conclusions: After IOERT of the breast using electrons we did not find any unexpected acute and late toxicity rates.