bluuebunny/crossref_metadata_2025 huggingface dataset:
Sentinel node biopsy following neoadjuvant chemotherapy in biopsy proven node positive breast cancer: The SN FNAC study.
Authors: Boileau Jean-Francois , Poirier Brigitte , Basik Mark , Holloway Claire , Gaboury Louis , Sideris Lucas , Meterissian Sarkis H. , Arnaout Angel , Brackstone Muriel , McCready David R. , Karp Stephen Eric , Wright Frances Catriona , Younan Rami , Provencher Louise , Patocskai Erika , Omeroglu Atilla , Robidoux Andre
Published: March 2020

1018

Background: A significant and increasing proportion of patients (>30%) with biopsy proven node positive breast cancer will obtain a pathological complete response (pCR) in the axilla after neoadjuvant chemotherapy (NAC). If sentinel node biopsy (SNB) can accurately identify these patients, they could potentially avoid the morbidity of an axillary node dissection. The primary aim of this study is to evaluate the identification rate (IR), false negative rate (FNR) and accuracy of SNB in this setting. The accuracy of post NAC axillary ultrasound and clinical examination are evaluated as secondary endpoints. Methods: Patients with biopsy proven node positive breast cancer (T0-3, N1-2, M0) treated with NAC were eligible to participate in this multi-centre prospective trial. Following NAC, axillary ultrasound and clinical examination results were obtained. At time of surgery, all participants underwent both a SNB and a completion node dissection. A SNB IR greater than 90% and a FNR of less than 10% were pre-determined as being optimal. Results: From September 2009 to December 2012, 153 patients were accrued to the study. 7 patients were not eligible and 5 patients had not yet undergone surgery at the time of analysis. Axillary pCR rate = 34.0% (48/141). SNB IR = 87.2% (123/141), 95% CI [81.7%-92.7%] and FNR = 9.9% (8/81), 95% CI [3.4%-16.4%]. If only one sentinel node was removed, FNR = 19.0%(4/21); if there were 2 or more sentinel nodes, FNR = 6.6% (4/61) (p < 0.0001). Accuracy of SNB, axillary ultrasound and clinical examination were 93.5%, 63.2%, and 45.5% respectively. Conclusions: SNB following NAC in biopsy proven node positive breast cancer is associated with a suboptimal IR. FNR (less than 10%) and accuracy of SNB in this study are comparable to that of patients that present with clinically negative nodes. The FNR decreases when more than one sentinel node is identified. However, in an era where regional nodal radiation is increasingly used, the relevance of leaving residual disease in the undissected axilla after NAC is unknown and remains to be investigated. Clinical trial information: NCT00909441.
Effect of margin width on local recurrence (LR) in triple-negative (TN) breast cancer treated with breast-conserving therapy (BCT).
Authors: Pilewskie Melissa Louise , Ho Alice Y. , Orell Emily , Stempel Michelle , Chen Yu , Eaton Anne , Patil Sujata , Morrow Monica
Published: March 2020

1021

Background: Positive lumpectomy margins are associated with increased rates of LR after BCT; however, the effect of increasing negative margin distance on LR is controversial. Rates of LR vary by breast cancer subtype, with the highest rates seen in TN cancers. The purpose of this study was to examine the rate of LR in relationship to margin width in TN breast cancers treated with BCT. Methods: All women with TN breast cancer who underwent BCT between 1999-2009 were identified from a prospectively maintained database. Margins were defined as positive (tumor on ink), close (≤2mm), or negative (>2mm) for either invasive or in situ cancer. Patients with positive margins (n=46) were excluded. Statistical comparisons were by t tests, Fisher’s exact test, and Wilcoxon rank sum test. Cumulative incidence of LR was compared using competing-risks methodology. Results: Characteristics of the 535 cancers (in 534 patients) with close (n=71) and negative (n=464) margins are compared in the Table. At median follow-up of 84 months (range, 8-165 months) there were 37 local, 18 regional, and 77 distant recurrences or deaths as first events. 10 patients had LR prior to planned radiation therapy (RT). The cumulative incidence of LR at 60 months for patients with close margins was 7.3% (95% CI, 1.1-13.6), and 5.1% (3.0-7.2) for negative margins. After controlling for use of chemotherapy, there was no significant difference in LR between the entire close and negative margin groups (p=.07) or after exclusion of recurrences prior to RT (p=.06). A difference in the risk of distant recurrence or death was not observed (p=.60). Conclusions: Margin width greater than 2mm was not associated with a clinically meaningful reduction in LR risk. This, coupled with reports of similar LR in TN cancers treated with BCT or mastectomy, suggests that larger surgical procedures do not improve outcomes in this high-risk patient subset. [Table: see text]
The prognostic implications of redox protein expression in stage I-III triple-negative breast cancer.
Authors: Lee Soohyeon , Kim Da Rae , Kim Min Whan
Published: March 2020

1035

Background: It is well known that increased reactive oxidative stress (ROS) in cancer cells correlates with poor prognosis and aggressiveness of tumor cells. The aim of this study is to investigate the expression of redox proteins in triple-negative, early breast cancer (TNBC) which shows aggressive phenotype among breast cancer and to demonstrate relationships between expression of ROS markers and clinical outcomes. Methods: Tissues from 135 cases of TNBC from curative surgery at Severance Hospital, Seoul, Korea, from December 2005 to January 2008 were analyzed. Immnunochemical (IHC) staining for redox proteins including thioredoxin reductase, glutathione S-transferase (GST) α, catalase, vitamin D-up-regulated protein 1 (VUDP), and manganese superoxide dismutase (MnSOD) was performed to evaluate the difference between clinicopathological parameters. The mono-carboxylate transporter 4 (MCT4) in stroma was done by IHC staining, too. Results: The median age of 135 TNBC patients was 48 (range 27-76). TNM staging were as follows; T1 (n=52, 38.5%), T2 (n=81, 60%), T3 (n=2, 1.5%), N0 (n=88, 65.2%), N1 (n=35, 25.9%), N2 (n=8, 5.9%), N3(n=4, 3.0%). Median follow up was 59 months (range 12-99). Samples were divided into high or low ROS expression level semi-quantitatively. The catalase high expressed group was tend to have lower N stage (p=0.016), lower tumor recurrence (p=0.02) as well as longer overall survival rates (p=0.05). Higher expression of MTC4 in stroma was strongly associated with higher MnSOD expression group analysis (p=0.015) and had significantly longer overall survival (p=0.032). Conclusions: This study shows the expression of ROS proteins could contribute defining aggressiveness of TNBC as well as the prognosis. Considering the lack of targeted molecules as well as molecular heterogeneity of TNBC, ROS markers may provide clues to clinical outcomes in TNBC.
Activity and duration of chemotherapy (CT) in different biologic subtype (BS) in metastatic breast cancer (MBC) patients (P).
Authors: Bighin Claudia , Del Mastro Lucia , Dozin Beatrice , Giraudi Sara , Levaggi Alessia , D'Alonzo Alessia , Lambertini Matteo , Poggio Francesca , Iacono Giuseppina , Miglietta Loredana , Pronzato Paolo
Published: March 2020

1036

Background: In MBC P the benefit of CT after the 1st line (L) is poorly defined. We evaluated activity of subsequent L of CT in different BS of MBC. Methods: MBC P treated in our center from 2007 to 2012 with ER, PgR and HER2 on primary tumor and at least 1 L of CT for MBC were evaluated. P were classified as Luminal A (ER and/or PgR +, HER2 -, Ki67≤14%), Luminal B (ER and/or PgR +, HER2 -, Ki67>14%), HER2+ (HER2+, any ER/PgR) and Triple-Negative ( ER-, PgR- and HER2-). Time on CT was calculated from the start of the 1st L to the end of the last L. Statistical analyses included Chi-square and Kruskal-Wallis tests, Kaplan-Meier curves and log-rank tests, and multivariate logistic regressions. Results: 207 P were identified, 52 were excluded because HER2 was unknown (19) or they did not receive any CT (33). Median follow-up was 31.4 months (m). The median number (N) of CT L was 2 (range 1-10). N of CT L and clinical benefit (CB) for every BS were reported in table. CB was inferior in TN P as compared with the other ones in 1st and in 2nd L ( p=.068 and p=.084 respectively in 1st and 2nd L). From 3rd L onward all P showed the same CB independently from BS. Time on CT related to median survival (S) for every BS was the same. At multivariate analysis the characteristics independently associated with a greater probability of receiving more than 4 CT L were age < 50 years (p=.021), HER2+ or TN disease (p=.027) and site of metastasis other than lung (p=.047). Conclusions: Our analysis showed that, despite the same time spent on CT, TN P received less benefit from 1st and 2nd L CT than other BS. On the other hand, young HER2+ P were more likely to receive multiple L of CT with a significant impact on median S (p=.044). [Table: see text]
RAD001-carboplatin combination in triple-negative metastatic breast cancer (TNMBC): A phase II trial.
Authors: Singh Jasmeet Chadha , Stein Stacy , Volm Matthew , Smith Julia Anne , Adams Sylvia , Meyers Marlene , Speyer James L. , Novik Yelena , Schneider Robert , Formenti Sylvia , Muggia Franco , Jhaveri Komal L. , Goldberg Judith D. , Heese Scott , Li Xiaochun , Davis Samantha , Tiersten Amy
Published: March 2020

1042

Background: Triple negative breast cancer cells often show genetic instability and inability to repair DNA damage rendering them sensitive to platinum agents. Rapamycin enhances platinum- induced apoptosis in breast cancer cell lines. We sought to explore the activity/toxicity of the of carboplatin with RAD001 in TNMBC. Methods: The primary objective of this study was to estimate clinical benefit rate/CBR (complete remission (CR) + partial remission (PR) + stable disease (SD) lasting >6 months) and the toxicity of this combination in women with TNMBC who have had 0-3 prior chemoregimens for MBC. 25 subjects were recruited. This design had > 80% power to test the null hypothesis that the CBR is ≤10% vs. alternative hypothesis that CBR is ≥ 30% (≥6 would need to achieve a clinical benefit). Prior Carboplatin was allowed. Women with treated brain metastasis were eligible. Originally, Carboplatin AUC 6 was administered q3 weeks with daily 5mg of RAD001 with a 3 patient run-in, then 10 mg daily. Due to excessive thrombocytopenia, the dose of Carboplatin was first amended to AUC 5 and then to AUC 4 with 5 mg of RAD001 (no escalation to 10 mg). Results: All 25 patients have been recruited. Median age is 58.There have been 1 CR, 6 PR’s, 2 SD's lasting >6 months and 6 PD’s. 3 patients were not evaluable. One SD achieved in a patient progressing on single agent Carboplatin. The estimated CBR is 36% (95% C.I.: 17%-55%). Median PFS is 3.3 months (95% C.I.: 2.4-7.7 months) from start of treatment. 7 patients (28%) had grade 3 or 4 thrombocytopenia and 3 (12%) had grade 3 neutropenia (no bleeding/ febrile neutropenia). Since amendment of Carboplatin to AUC 4 the regimen has been very well tolerated with only 11% grade 3 hemetoxicity. The grade 3 non-heme toxicities included nausea/ vomiting (n=1), mucositis (n=1) and dehydration (n=1). Grade 3 insomnia (n=1) and dyspnea (n=1) were thought to be unrelated to the treatment (no grade 3 fatigue/ interstitial lung disease). Conclusions: The study has achieved the primary end point of demonstrating clinical benefit in TNMBC. Dose limiting thrombocytopenia was an unexpected side effect requiring protocol amendment. Clinical trial information: NCT01127763.
A phase I study of neoadjuvant chemotherapy (NCT) with the gamma secretase (GS) inhibitor RO4929097 in combination with paclitaxel (P) and carboplatin (C) in women with triple-negative breast cancer (TNBC).
Authors: Mrozek Ewa , Wesolowski Robert , Lustberg Maryam B. , Layman Rachel M. , Ling Yonghua , Schaaf Larry J. , Phelps Mitch A. , Ivy S. Percy , Grever Michael R. , Shapiro Charles L.
Published: March 2020

1043

Background: Notch receptors are overexpressed in TNBC. Notch activation involves the cleavage of Notch ligand/receptor complex by GS. RO4929097 (RO) is an oral inhibitor of GS. We are conducting a phase I NCT trial of intermittent RO in combination with P and C in TNBC to determine the dose limiting toxicity (DLT) and the maximum-tolerated dose (MTD) of RO. Because RO induces CYP3A4/5, plasma P and RO are quantified in real time to ensure P AUC exposure is not decreased. Methods: Women ≥ 18 years with clinical stage II/III TNBC received C AUC=6 on day 1 and weekly P 80 mg/m2 in combination with RO on days 1-3, 8-10 and 15-17 for six 21-day cycles. The starting dose of RO was 10 mg and escalated according to the 3+3 rule. DLT was defined as grade ≥3 (G3) non-hematologic toxicity (n-HT), grade 4 (G4) thrombocytopenia (TCP) or G4 neutropenia (NP) during cycle#1 (c1). Plasma specimens were analyzed for PK by a validated LC-MS/MS assay. Results: 13 pts were enrolled. Two pts enrolled at 10 mg RO with C AUC 6 developed G3,4 TCP during c1. The study was amended; the dose of C was decreased to AUC 5. No DLTs were observed with 10 mg RO and C AUC 5. Only 1 DLT ( G3 HTN) occured with 20 mg RO, but all 4 pts enrolled on this cohort required dose reductions of RO during subsequent cycles. The RO dose was de-escalated to 10 mg, additional 3 pts were treated with 10 mg RO. G≥3 HT included: G4 NP in 2 pts, G4 TCP in 1 pt, G3 NP in 6 pts, G3 anemia in 4 pts and G3 TCP in 5 pts. G≥3 n-HT included: G3 sensory neuropathy in 3 pts. G3 HTN, G3 fatigue and G3 depression occured in 1 pt each. There were no hospitalizations for treatment-related toxicities. PK studies indicate that P AUC ranged from 80% to 134% on week 3 compared to week 1. Ten pts completed 6 cycles of NCT, 3 are still receiving NCT. Five of 10 (50%) pts had complete pathologic response (pCR) in breast and axilla and 3 (30%) pts had minimal residual cancer in breast. Conclusions: The MTD of intermittent RO administered in combination with P and C is 10 mg. This MTD does not result in decreased P exposures. The pCR (50%) and minimal residual disease (30%) suggests this regimen is active in TNBC. Supported by the NCI/NIH Award Number U01CA076576. Clinical trial information: NCT01238133.
Next-generation sequencing (NGS) in patients with advanced metastatic breast cancer: Identification of molecular alterations and analysis of associations with treatment on phase I studies at MD Anderson Cancer Center.
Authors: Wheler Jennifer J. , Yelensky Roman , Moulder Stacy L. , Tsimberidou Apostolia Maria , Falchook Gerald Steven , Janku Filip , Atkins Johnique T. , Zinner Ralph , Karp Daniel D. , Hong David S. , Stephens Phil , Wolff Robert A. , Kurzrock Razelle
Published: March 2020

1051

Background: Matching molecular alterations in patients with breast cancer to targeted therapy may increase response rates. Methods: We analyzed 22 sequential breast cancer patients with next generation sequencing (NGS) profiling of their tumors profiling (FoundationOne) treated on Phase I trials at the Clinical Center for Targeted Therapy at MD Anderson Cancer Center. Objectives included: (1) characterize molecular alterations including mutations, amplifications and deletions, (2) evaluate associations between molecular alterations and response to therapy. Results: Twenty-two breast cancer patients, all female with median age 56 years were included. Twenty-one of 22 of patients (95%) analyzed demonstrated at least one molecular alteration. Twenty-one of 22 patients were evaluable for response to therapy (1 patient had not yet reached restaging). Sixteen patients were treated on Phase I trials with targeted therapy that was either directly or indirectly associated with a molecular alteration. Seven of these 16 patients (44%) achieved stable disease (SD) ≥6 months/partial response (PR)/complete response (CR) including 3 patients with PR and 1 patient with CR. Examples of molecular alterations include: mutations in PIK3CA (8 patients), PIK3R1 (2 patients), PTEN (1 patient), cMET (1 patient), NF1 (one patient); amplifications in CCND1 (8 patients), FGFR1 (4 patients), MYC (3 patients), MCL1 (3 patients), IRS2 (2 patients) and CCNE1(1 patient). Conclusions: A majority of patients with advanced or metastatic breast cancer whose tumors underwent NGS profiling demonstrated molecular alterations. Of the 9 patients who had either SD≥6 months/PR/CR on Phase I treatment, 7 (78%) had molecular alterations, either directly or indirectly associated with therapy. Further investigation of larger cohorts of patients with NGS is ongoing.
In vitro and in vivo activity of regorafenib (REGO) in drug-resistant gastrointestinal stromal tumors (GIST).
Authors: Serrano-Garcia Cesar , Heinrich Michael C. , Zhu Meijun , Raut Chandrajit P. , Eilers Grant , Ravegnini Gloria , Demetri George D. , Bauer Sebastian , Fletcher Jonathan A. , George Suzanne
Published: March 2020

10510

Background: KIT and PDGFRA mutations (mut) are the crucial transforming events in most GISTs, and tyrosine kinase inhibitors (TKIs) with activity against KIT and PDGFRA, such as imatinib (IM) (front-line therapy) and sunitinib (SU) (second-line therapy), are effective treatments in GIST patients (pts). Resistance to IM and SU is commonly associated with evolution of secondary kinase mut. REGO is a multi-targeted TKI that inhibits KIT, PDGFR, and other oncologic targets and has recently shown benefit in pts with metastatic GIST after progression on standard treatments. We evaluated the in vitro and in vivo activity of REGO compared with IM, SU, and sorafenib (SOR) (a multi-TKI structurally related to REGO). Methods: REGO, IM, SU, and SOR inhibition of viability and KIT phosphorylation was assessed in human GIST cell lines and in Ba/F3 cells transformed by KIT oncoproteins with IM-resistant ATP binding pocket or activation-loop mut. KIT/PDGFRA genotyping was performed in GISTs responding or progressing on REGO in the academic phase II clinical trial. Results: In GISTs with KIT exon 11 mutant oncoproteins, REGO potently inhibited viability, KIT phosphorylation, and downstream effector phosphorylation (AKT, MAPK, S6). IM-resistant activation loop mut were more potently inhibited by REGO than SU, whereas the gatekeeper IM-resistant mut T670I was inhibited by both REGO and SU, and the common ATP-binding pocket mutant V654A was more potently inhibited by SU than REGO. Two GIST metastases progressing in one pt after initial response to REGO contained KIT V654A mut. SOR and REGO demonstrated comparable in vitro overall activity. Representative GIST cell line viability IC50s are shown in the Table (values in bold indicate expected clinical relevance). Conclusions: In vitro studies confirm REGO is a potent inhibitor of KIT exon 11 mut in GIST and appears to have stronger activity than SU against the most common KIT activation-loop mut observed in GIST. Ongoing clinical correlative analyses from REGO-treated study patients will be presented. [Table: see text]
Can postoperative radiotherapy be omitted in localized standard-risk Ewing sarcoma? An observational study of the Euro-EWING Group.
Authors: Gaspar Nathalie , Brennan Bernadette , Jeys Lee , Dirksen Uta , Foulon Stephanie , Cassoni Anna , Seddon Beatrice M. , Claude Line , Marec-Berard Perrine , Streitbuerger Anne , Whelan Jeremy , Paulussen Michael , Grimer Robert , Le Deley Marie-Cécile , Jurgens Heribert
Published: March 2020

10518

Background: Uncertainty exists on the most appropriate use of surgery, radiotherapy (RT) or both for treatment of primary Ewing sarcoma (ES). The objective of this study was to assess the impact of postoperative RT on local control in pts with localized ES and good (<10% residual cells) histologic response to chemotherapy (CT). Methods: We analyzed data of all pts included in the EE99-R1 trial (comparing 2 consolidation CT regimens) undergoing surgery after induction CT. Local recurrence (LR) cumulative incidence (CI) was estimated using a competing risk approach. As local therapy was not randomized but tailored to the individual patient and tumor characteristics, impact of RT was assessed in multivariable models, adjusted for possible confounders: country, age, tumor type, site and volume, quality of resection and histologic response. We also evaluated the heterogeneity of RT effect by patient and tumor characteristics (interaction). Results: Among the 599 pts included from 1999 to 2009, 142 (24%) had received postoperative RT. With median follow-up of 6.2 yrs, disease failure was reported in 156 pts, including a LR in 67 (with concomitant metastases in 28), leading to an 8-yr LR-CI = 12% (se 1.4%). Overall survival = 21% (se 5%) 3 yrs after LR (31% in isolated LR). Controlling for possible confounders, the risk of LR was halved in pts treated by surgery + RT (HR=0.43, 95%CI, 0.21-0.88, p=0.02) compared to surgery alone. Postoperative RT had a rather homogeneous positive effect in all studied subgroups. The benefit of RT was very significant in pts with a tumor volume of >200mL at diagnosis and 100% necrosis. Although not significant, we observed a trend for benefit associated with RT in terms of disease-free, event-free and overall survival. Conclusions: LR contributes significantly to disease failures in this standard risk group who experience few systemic failures. Outcome after LR is very poor. Postoperative RT appears to improve local control for all pts. Good histologic response and complete resection of residual mass may not be sufficient criteria to omit RT. Further study of RT in ES is required to assess the balance between benefit and risk (secondary malignancies, functional sequelae). Clinical trial information: NCT00020566.
TBCRC 019: An open label, randomized, phase II trial of nanoparticle albumin-bound paclitaxel (nab-PAC) with or without the anti-death receptor 5 (DR5) monoclonal antibody tigatuzumab (TIG) in patients with metastatic triple negative breast cancer (TNBC).
Authors: Vaklavas Christos , Abramson Vandana Gupta , Lin Nancy U. , Liu Minetta C. , Rugo Hope S. , Nanda Rita , Storniolo Anna Maria , Traina Tiffany A. , Li Yufeng , Patil Sujata , Hayes Daniel F. , Van Poznak Catherine H. , Nangia Julie R. , Irvin William Johnson , Krontiras Helen , De Los Santos Jennifer F. , Haluska Paul , Wolff Antonio C. , Forero-Torres Andres ,   on behalf of the Translational Breast Cancer Research Consortium (TBCRC)
Published: March 2020

1052

Background: TIG, an agonistic anti-DR5 monoclonal antibody, triggers apoptosis in DR5+ human tumor cells without the aid of crosslinking. TIG has shown strong in vitro and in vivo activity against basal-like breast cancer cells that is enhanced by chemotherapy like paclitaxel. Methods: Randomized 2:1 phase II trial of nab-PAC with/without TIG in TNBC patients. Patients stratified by prior exposure to chemotherapy in the metastatic setting. Patients received nab-PAC weekly x 3 and TIG every other week, every 28 days. Primary endpoint was overall response rate (ORR). Secondary objectives were safety, progression free survival (PFS), TIG immunogenicity, and PK. Biopsies and circulating tumor cells were collected. The trial was not powered to compare arms but allowed early stopping for futility and was sized to estimate ORR with 95% CI. Results: 64 patients enrolled, 60 treated; 39 in the combination arm and 21 in the nab-PAC arm. Of the 39 in the combination arm, there were 2 CR, 9 PR (1 near CR, 96% tumor reduction), 11 SD and 17 PD; ORR 28% (95% CI 14%-42%). Of the 21 in the single agent arm, there were no CR, 8 PR, 4 SD and 9 PD; ORR 38% (95% CI 17%-59%). Higher ORRs were seen in the chemotherapy naïve patients (58% vs. 15% combination and 42% vs. 35% single agent). 2 patients with CR, 1 near CR, and 1 PR in the combination arm are still on therapy (602+, 531+, 466+, 460+ days). PFS was similar in both groups (3.6 months); higher in chemotherapy naïve patients. Combination was well tolerated (most toxicities grade 1/2); the most common AEs were fatigue, alopecia, peripheral sensory neuropathy, anemia, neutropenia, nausea, thrombocytopenia, anorexia, diarrhea, and vomiting. No grade 4 or 5 toxicity. No apparent added toxicity with TIG was seen. Conclusions: Combination therapy with nab-PAC + TIG was well tolerated, without apparent improvement in ORR relative to nab-PAC alone; however, 4 subjects treated as first-line had prolonged clinical benefit with the combination, and correlative studies will investigate markers that might predict clinical outcome (Next-Gen genomic analysis). Clinical trial information: F101004001.
Association of perioperative radiation therapy with outcome in 204 patients with primary retroperitoneal sarcoma: A two-institution study.
Authors: Kelly Kaitlyn Jane , Yoon Sam S. , Kuk Deborah , Qin Li-Xuan , Dukleska Katerina , Chang Kevin , DeLaney Thomas F. , Brennan Murray F. , Singer Samuel
Published: March 2020

10520

Background: Radiation therapy (RT) for retroperitoneal and pelvic sarcomas (RPS) is controversial. We examined the association of perioperative, advanced modality RT on outcomes in primary RPS. Methods: Prospectively maintained databases were reviewed to compare primary RPS patients (pts) treated at two institutions between 2003 and 2011. Clinicopathologic variables were analyzed with endpoints of local recurrence-free survival (LRFS) and disease-specific survival (DSS). Results: At one institution 172 pts were treated with surgery alone while at the other 32 pts were treated with surgery and perioperative proton beam or intensity-modulated RT ± intraoperative RT. The groups were similar in age, gender, tumor grade, tumor size, and margin status (p = NS). The RT group had a lower percentage of retroperitoneal versus pelvic tumors and leiomyo/liposarcoma versus other histologies (p < 0.05). Median follow-up was 38.7 months (36.9 for RT group, 38.8 for surgery alone). Five-year predicted LRFS was 91% (95% CI, 79-100%) in the RT group and 65% (57-74%) in the surgery only group (p = 0.06). RT was marginally significant in univariate analysis of LRFS. Upon adjusting for univariate predictors, RT was significantly associated with better LRFS (p = 0.046; Table). Five-year predicted DSS was 93% (95% CI, 82-100%) in the RT group and 84% (78-91%) in the surgery-only group (p = 0.25). The only independent predictor of DSS was age. Morbidity was higher in the RT group (41% vs 17%; p= 0.004). Conclusions: In this retrospective study, the addition of advanced modality RT to surgery for primary RPS was associated with a reduced risk of local recurrence, although this did not translate into a statistically significant improvement in DSS. This treatment strategy warrants further investigation in a randomized trial. [Table: see text]
Role of glutathione S-transferase and cytochrome P-450 polymorphisms in the clinical outcome of osteosarcoma patients.
Authors: Trujillo-Paolillo Alini , Salinas-Souza Carolina , Dias-Oliveira Indhira , Petrilli Antonio Sergio , Toledo Silvia R. C.
Published: March 2020

10535

Background: Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. Glutathione S-transferase (GST) and Cytochrome P-450 (CYP) family genes are involved in almost all anticancer drugs metabolism. The polymorphisms in these genes are associated with anticancer drugs resistance and toxicity events. This study aims to investigate the genotype frequencies of GSTM1, GSTT1, GSTM3, CYP1A2, CYP2C9 and CYP3A5 genes in OS patients and the influence of these polymorphisms in their clinical outcome. Methods: We investigated the peripheral blood DNA of 70 OS patients (25 metastatic and 45 nonmetastatic at diagnosis), following the GLATO - Latin American Group of Osteosarcoma Treatment - 2006. GSTM1 and GSTT1 deletion polymorphisms were examined through a multiplex-PCR and the GSTM3 polymorphism of three base pair-deletion using PCR-RFLP method. CYP1A2, CYP2C9 and CYP3A5 single nucleotide polymorphisms (SNPs) were investigated through real time PCR using TaqMan probe. Results: We found that GSTM1 null genotype was correlated with relapse occurrence (p=0,031) in patients that received high doses of chemotherapy. The CYP1A2*F allele was associated with lung metastasis (p=0,032), lung relapse (p=0,018) and high grade of ototoxicity (p=0,039). The CYP3A5*3 allele was associated with high grade of hepatotoxicity (p=0,010). The presence of at least one GSTM3*B allele was associated with better overall survival (p=0,045). The presence of CYP3A5*3 homozygous genotype was associated with better overall survival (p=0,043) in metastatic patients at diagnosis. The genotype GSTM3*B/ GSTM1 present, GSTM3*B/ GSTT1 present and GSTM3*B/CYP3A5*3 in metastatic patients at diagnosis were associated with better survival (p=0,048; p=0,004; p=0,012, respectively). Conclusions: The findings of this study suggest that GST and CYP polymorphisms may have a role in treatment response and may be an important marker in the future to personalized therapy in OS. Furthermore, CYP1A2*F allele is correlated with risk of lung metastasis and GSTM3*B homozygous genotype in combination with GSTM1 present, GSTT1 present and CYP3A5*3 were associated with better survival.
The influence of gastrointestinal resection on sunitinib exposure in GIST patients.
Authors: de Wit Djoeke , van Erp Nielka P , Khosravan Reza , Wiltshire Robin , Allred Randy U. , Demetri George D. , Guchelaar Henk-jan , Gelderblom Hans
Published: March 2020

10547

Background: GIST patients often have an altered anatomy of the GI tract due to either primary resection of the tumor or palliative surgery. It is unknown whether such GI resections affect the exposure to sunitinib and its active metabolite SU12662. Previous studies showed that the exposure to imatinib and nilotinib was decreased in GIST patients with prior major gastrectomy. Therefore, we postulated that GI resections might similarly affect sunitinib exposure. Methods: A retrospective analysis was performed to assess the effect of GI resections on sunitinib exposure. Pharmacokinetic data from 305 GIST patients included in 4 phase I-II trials were analyzed. Patients were subdivided into 6 groups according to prior GI surgery: 1)Major gastrectomy: 2)Partial gastrectomy: 3)Small bowel resection: 4)Combination of gastrectomy and small bowel resection: 5)Colon resection and 6)Controls with no prior GI surgery. Patients with uncertain GI resections were excluded. Dose normalized exposure (AUC0-24hr) of sunitinib and SU12662 was estimated with a population PK approach using NONMEM. Analysis of covariance was performed to test for significant differences in AUC between each of the subgroups and controls. Results: The geometric mean of total exposure to sunitinib and SU12662 was decreased by 21% and 28% in subgroup 4, (n=8; sunitinib: 931 ng*hr/mL (95%CI;676-1283) and SU12662: 354 ng*hr/mL (95%CI;174-720)) compared to controls (n=63; sunitinib: 1177 ng*hr/mL (95%CI;1097-1263) and SU12662: 491 ng*hr/mL (95%CI;435-555)), with the differences being significant (p<0.05) on the log scale. However, no significant differences in total exposures were observed between each of the other subgroups and control. Conclusions: In patients with a combined gastrectomy and small bowel resection, sunitinib and SU12662 exposure is significantly decreased as compared to subjects with no prior GI surgery. Contrary to previous results for imatinib, gastrectomy alone does not appear to influence sunitinib exposure. This should be taken into consideration for the treatment of GIST patients who had a gastrectomy. In theory, such patients might have better outcomes if treated with sunitinib, given the risk of subtherapeutic exposure to imatininb.
Patterns of toxicities and outcome in children versus adolescents/young adults (AYA) with metastatic rhabdomyosarcoma (RMS): A report from the Children’s Oncology Group (COG) Soft Tissue Sarcoma Committee.
Authors: Gupta Abha A. , Lyden Elizabeth , Anderson James Robert , Arndt Carola A. S. , Rodeberg David Anthony , Michalski Jeff M. , Parham David , Meyer William H. , Hawkins Douglas S. , Weigel Brenda
Published: March 2020

10554

Background: Age at diagnosis is a prognostic factor in patients with RMS. We sought to determine whether AYA with metastatic alveolar (ARMS) or embryonal (ERMS) RMS had a different failure-free survival (FFS) compared to younger patients, and to identify treatment related factors that may be associated with outcome. Methods: COG ARST0431 patients were reviewed. The incidence of toxicities (AE, grade3/4 using CTCAEv3) by age was determined in 4 reporting periods (RP: wks 1-6; RP2:7-19; RP3: 20-34; RP4: 35-54). The AEs in younger patients (<=13 years) were compared with those in AYA. Fisher’s exact test was used to compare differences between the groups. Results: Of 109 patients, 60 (55%) were AYA. In RP1, they were more likely to have nausea/vomiting (4.1 vs. 16.9%, p=0.06), pain (6.1 vs. 20.3%, p=0.05), and metabolic disturbances (4.1 vs. 20.3%, p=0.02) compared to younger patients. In RP4, older patients trended to have less infection (15.8 vs. 30.1, p=0.07). All other toxicities were similar between the two age cohorts in the other RPs. AYA were less likely to complete therapy (52 vs. 73%, p=0.03) and more likely (in RP 4) to have unplanned dose modifications (outside of protocol guidelines) (23 vs. 2.7%). Of patients that completed therapy, there was no age-related difference in the time to completion. As shown in the table, younger patients had better 3-yr FFS, driven by a lower FFS for AYA with ARMS. Conclusions: This evaluation suggests that AYA with RMS were less likely to complete therapy and experienced a higher prevalence of pain and nausea compared to younger patients; the role of reporting bias and reasons for treatment discontinuation need further study. Children were more likely than AYA to have infection. Inferior FFS was only seen in AYA with ARMS suggesting a clear need for novel therapies for these patients. This study may be underpowered to demonstrate significant differences in other toxicities or in FFS among ERMS patients. [Table: see text]
Assessment of multimodality therapy use for extremity sarcoma in the United States.
Authors: Sherman Karen L. , Wayne Jeffrey D. , Agulnik Mark , Bentrem David J. , Bilimoria Karl Y.
Published: March 2020

10559

Background: National guidelines for extremity sarcoma recommend multidisciplinary consultation, but treatment approaches are not standardized. Our objectives were to (1) examine trends in the multimodality treatment of extremity sarcoma in the US, (2) examine adjuvant therapy practice patterns, and (3) identify factors associated with the use and sequencing of adjuvant treatment. Methods: Using the National Cancer Data Base (2000-2009), use of multimodality treatment for non-metastatic extremity sarcoma was examined. Regression models were developed to identify factors associated with adjuvant therapy receipt and treatment sequence. Results: A total of 22,051 patients underwent resection (Stage I: 45%, stage II: 28%, Stage III: 27%). Trend analysis demonstrated relatively constant rates of radiation therapy (RT) (58% to 65%), chemotherapy (21% to 23%), and any adjuvant therapy (65% to 72%), however the proportion receiving neoadjuvant therapy increased (RT: 14% to 28%; chemotherapy: 9% to 13%; any: 18% to 27%; all p <0.001). Stage-specific treatment use is shown in the table below. Though RT rates were similar for all histologies, chemotherapy rates for synovial sarcoma were higher for all stages (I: 24.3%; II: 24.9%; III: 53.2%, p < 0.001). After adjusting for differences in tumor factors, patients were more likely to receive neoadjuvant therapy (chemotherapy and/or RT) if treated at high-volume academic center (p<0.001). After adjusting for histology, patients were more likely to receive adjuvant radiation therapy if younger, healthier, privately insured, or tumor size >5cm. Patients were more likely to receive adjuvant chemotherapy if were younger, healthier (fewer comorbidities), underinsured, treated at a high-volume academic center, or tumor size >5cm. Conclusions: Use of a multimodality approach for extremity sarcoma management has increased over time, particularly for neoadjuvant therapy. However, practice patterns are related to hospital type and socioeconomic factors. There may remain opportunities to increase multidisciplinary care and multimodality treatment for extremity sarcoma in the United States. [Table: see text]
Desmoid tumor (DT): Clinical and treatment characteristics and quality of life (QoL) in a large cohort from a referral center.
Authors: Ronellenfitsch Ulrich , Wiedemann Bea , Menge Franka , Jakob Jens , Hohenberger Ralph , Kasper Bernd , Hohenberger Peter
Published: March 2020

10566

Background: Due to its low incidence, evidence regarding DT is scarce, and consensus on recommended treatment is difficult to achieve. This study systematically assesses clinical presentation, treatment characteristics and QoL in a large cohort of DT patients (pts). Methods: Demographic and clinical variables were retrieved from a database of 224 pts with histologically confirmed DT presenting to our referral center from 10/04-7/12. For a subset of 46 pts, QoL was assessed with the SF-12 questionnaire. The distribution of variables in the entire pt population and clinically relevant subgroups was calculated and compared with appropriate statistics (t-test, nonparametric tests). Denominators varied due to non-availability of variables for some pts. Results: 153 (68.3%) pts were female. Mean age at first diagnosis was 36.9 (3-73) yrs. Primary tumor site was limb/intraabdominal/rectus abdominis/trunk in 40/43/43/66 (21/22/22/35%) of 192 pts. 65/108 (60%) pts recalled a trauma or medical intervention at the DT site. 38/43 (88%) pts with rectus abdominis DT were female, and 31/38 (82%) had previous pregnancies, median time to DT diagnosis after end of pregnancy was 17 months. Primary therapy was resection/imatinib/tamoxifen/watchful waiting in 136/9/8/7 (83/6/5/4%) pts. Resection was R0/R1/R2 in 47/66/22 (35/49/16%) pts. After R0/R1 resection, DT recurred in 46% and 62% resp. after a median of 356/334 days. Physical/mental SF-12 summary scores were 39.2/40.8, 41.5/45.4, and 48.0/44.5 in pts with limb, intraabdominal, and trunk DT and 38.6/42.6 and 43.3/42.5 in pts with and without recurrence (reference population score 50; all p>0.05 for subgroup comparisons). Five women delivered a healthy child in parallel to clinically existent DT. 56% of our patients are alive with disease, whereas 44% have no evidence of disease. Conclusions: In 83% of DT pts, resection is the first treatment step and is R0 only in one third. 60% of the pts recall trauma/medical intervention at the DT site. Rectus abdominis DT occur after a median of 1.5 yrs after pregnancy. Despite the fact that 56% of our pts live with disease, their QoL is only slightly decreased, with lowest values for physical QoL in pts with recurrence.
Cetuximab in combination with docetaxel (T) in patients with operable, triple-negative breast cancer (TNBC): Preliminary results of a multicentre neoadjuvant pilot phase II study.
Authors: Nabholtz Jean Marc , Mouret-Reynier Marie-Ange , Van-Praagh Isabelle , Servent Véronique , Jacquin Jean-Philippe , Bourcier Anne-Véronique , Del Piano Francesco , Dubray-Longeras Pascale , Nayl Beatrice , Abrial Catherine , Kwiatkowski Fabrice , Dauplat Marie-Mélanie , Radosevic-Robin Nina , Cayre Anne , Uhrhammer Nancy , Bidet Yannick , Chalabi Nassera , Bignon Yves-Jean , Penault-Llorca Frederique , Chollet Philippe
Published: March 2020

1057

Background: Cetuximab is an antiboby targeting the epidermal growth factor receptor (EGFR) to which a role has been suggested in TNBC. Therefore, we evaluated the combination of docetaxel with cetuximab as neoadjuvant therapy of operable TNBC. Methods: 35 patients with stage II-IIIA disease were prospectively included in this multicentre pilot study. Systemic therapy (ST) consisted of 6 cycles of T (100 mg/m2) q.3 weeks, in combination with weekly cetuximab (first dose : 400mg/m², then : 250 mg/m²/week) for 6 cycles. All patients underwent surgery at completion of ST. Complete pathologic response (pCR) was the primary endpoint (Sataloff : J Am Coll Surg 1995 ; Chevallier : Am J Clin Oncol 1993), with toxicity and biologic ancillary studies as secondary endpoints. Results: Patients characterisctics are as follows : mean age 48 [28-67] ; T1 : 3%, T2 : 73%, T3 : 24% (mean tumor size : 40 mm [15-100]) ; N0 : 61% and N1-N2 : 39%; invasive ductal carcinoma : 100%; Scarff-Bloom-Richardson Grade III : 73%, grade II : 27%. The median number of cycles was : T : 6 [1-6], cetuximab : 15 [1-18]. Pathological complete response was 24% according to Chevallier and Sataloff’s classifications and 28% if we consider response in breast. Preliminary results on 23 patients show an overall clinical response rate of 57% (22% CR). Conservative surgery was performed in 75% of cases. Skin toxicity was the main side-effect : grade II : 39%, grade III : 36%, grade IV : 3%. Neutropenia grade IV : 12.7%, febrile neutropenia : 1.3%, infection : 0%. Hand-foot syndrome grade III : 3%, grade II : 3%. Ungueal toxicity grade III : 3%, grade II : 33%. Conclusions: These preliminary results suggest that cetuximab in combination with Tappears to have a modest efficacy in operable TNBC. Clinical trial information: NCT00600249.
Synovial sarcoma: Is chemotaxis important to tumor progression?
Authors: Palmerini Emanuela , Benassi Maria Serena , Benini Stefania , Pazzaglia Laura , Staals Eric L. , Gamberi Gabriella , Gambarotti Marco , Picci Piero , Ferrari Stefano
Published: March 2020

10571

Background: Synovial sarcoma (SS) is a rare and aggressive soft tissue tumor. In a first study (Palmerini E, Cancer 2009) we analyzed clinical prognostic factors in a retrospective series of 250 patients (pts) who were treated at Rizzoli Institute between 1976 and 2006. Stage, age, size, histology and use of radiotherapy influenced survival, whereas the role of chemotherapy was unproven. In the present study on the same patient population, in order to identify new prognostic factors and potential therapeutic targets, a panel of markers involved in chemotaxis and tumor growth were assessed. Methods: The expression of the chemokine receptor CXCR4 (a marker for chemotaxis which plays a critical roles in cancer progression) and the insulin-like growth factor receptor-1 (IGFR1) (a marker of growth activation ) were evaluated by IHC staining. Results: Tissue samples were available for the analysis in 88 patients (45 female and 43 male); median age was 37 years (range 11-63); size of the lesion was > 5 cm in 60 patients (71%); histology was biphasic in 30 (34%) of patients. All pts underwent surgery, 56% of pts underwent adjuvant radiotherapy (RT) and 68% adjuvant chemotherapy. With a median follow-up of 6 years (1-30 years), the 5-year overall survival (OS) was 70% (60-81). A positive stain for IGFR1 was detected in 55 pts (62.5%), with expression in the nucleus in 21 pts. CXCR4 was expressed in 74 pts (84%), nuclear pattern in 31 pts. No relation between IGFR1 and CXCR4 expression and clinical variables was found. The 5-year OS was 63% (95%CI 41-85%) for pts with positive IGFR1/nuclear expression and 73% (95%CI 61-85%) p = 0.05, in pts with negative IGFR1/nuclear staining. Similarly, the 5-year OS was 47% (95%CI 27-66%) in patients with positive CXCR4/nuclear expression and 86% (95%CI 76-96%), p = 0.003, in negative cases. In a multivariate analysis including age, histology, size and use of RT, nuclear expression of IGFR1 and CXCR4 were confirmed statistically significant independent factor for OS. Conclusions: The nuclear expression of CXCR4 or IGFR1 negatively influences the survival in patients with SS. Further studies addressing the role of CXCR4 as a potential target in this high risk subgroup of SS patients are needed.
Isolated limb perfusion for soft-tissue sarcoma and regional melanoma.
Authors: Derbel Olfa , Neidhardt Eve-Marie , Stoltz Adeline , Meeus Pierre , Dupre Aurelien , Combemale Patrick , Ray-Coquard Isabelle , Cassier Philippe Alexandre , de la Fouchardière Arnaud , Ranchere-Vince Dominique , Blay Jean-Yves
Published: March 2020

10579

Background: Isolated limb perfusion (ILP) represents a treatment option for locally advanced melanoma and sarcoma confined to a limb. The advantage of this approach is to deliver high-dose regional chemotherapy without serious systemic effects. However, the ILP technique involves a complex and invasive operative procedure, requiring accurate monitoring to avoid major local toxicity. Methods: From November 2004 to December 2011, 58 patients underwent IPL for unresectable soft tissu sarcoma (STS= 34) and advanced in-transit melanoma (n=24). IPLs were performed at mild hyperthermic conditions with 1-2 mg of TNF and 40-80 mg of melphalan (M) for arm and leg perfusions, respectively. The response rate, disease free intervals, overall survival, toxicity and limb salvage rate were evaluated. Results: Median age was 68 years (range: 29-91 years), with 58% of women. For sarcoma patients, median tumor size was 60 mm, 16 patients (47%) had a high grade STS. Twenty-one patients (61%) received IPL before definitive surgery. Eight patients finally underwent amputation, giving a long-term limb salvage of 77%. The overall response rate was 73.5% (Complete response rate 14.7%, partial response rate 58.8 %). For melanoma patients, 9 (38%) had an AJCC stage III disease, the median thickness of the primary tumor was 3.5 mm. A complete response was obtained in 21% of patients while 54% exhibited a partial response. The local and metastatic recurrence rates were similar between sarcoma and melanoma patients (41% and 33% respectively). All but one of the patients with non-operated sarcoma presented a local or metastatic relapse.There was no mortality and no systemic toxicity. Regional toxicity (Wieberdink scale) was: grade I (no reaction) 53 %, II (erythema, oedema) 34%, III (blistering) 8% and IV 3%. The median local relapse-free survival was 40 months in sarcoma group (26.6 months for non operated patients) and 10 months in melanoma one. The overall 3-years survival rate was 44% for sarcoma and 25% for melanoma patients. Conclusions: ILP induces a high tumour response rate, leads to a high limb salvage rate but is associated with an important recurrence rate. It provides a limb salvage alternative to amputation when local control is necessary.