bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictors of complete response following disease recurrence in gastrointestinal stromal tumor (GIST) patient: A retrospective patient chart review analysis.
Authors: Conley Anthony Paul , Guérin Annie , Sasane Medha , Gauthier Geneviève , Schwiep Frances Annelies , Keir Christopher Hunt , Magestro Matt , Wu Eric Q.
Published: March 2020

10545

Background: Adjuvant imatinib (IM) treatment reduces the risk of GIST recurrence and improves survival particularly when IM is used for a longer duration among moderate to high risk patients. However, among patients who recur, little is known about the factors impacting the probability of achieving complete treatment response (CR). This study identifies factors associated with the probability of achieving CR among patients who had a recurrence following cessation of initial adjuvant IM treatment for a KIT + GIST. Methods: An online tool was used to retrieve clinical data on 410 patients who were treated with adjuvant IM for ≥6 months for primary resectable KIT+GIST, discontinued, had a recurrence after discontinuation, and then restarted IM or initiated sunitinib. Tumor and treatment characteristics were collected at primary diagnosis and disease recurrence. Patient response status was assessed by physicians based on different measures (e.g., RECIST, Choi, other subjective measures). Predictors of CR were identified using logistic regression models. Results: Among the 410 (IM = 314, sunitinib = 96) patients treated for GIST recurrence, 22.4% achieved CR (25.2% of pts on IM and 13.5% of patients on sunitinib). On average, CR was achieved after 11 weeks of treatment and only 2% of patients had a subsequent disease progression/recurrence. RECIST criteria were most widely used for CR evaluation in 68% of patients followed by subjective measures (29%) and Choi criteria (17%), respectively. Patients with a unifocal tumor (Odds Ratio[OR]=2.61; p<.001 ), small tumor size (≤2cm) (OR=2.16; p=.023), lower mitotic rate ≤5/50 HPF (OR=1.87; p=.017) at recurrence, or tumor recurrence inside gastrointestinal system (OR=2.27; p=.036) were more likely to achieve CR. Conclusions: Among study patients, 22.4% achieved CR following disease recurrence. The main predictors of CR were tumor focality, size, location, and the mitotic rate at recurrence. This suggests that detecting recurrence at an early stage and managing disease with re-initiation of KIT inhibitor therapy may improve the probability of achieving CR following recurrence.
Clinical experience with sunitinib (SU) in patients over age 65 with metastatic gastrointestinal stromal tumors (GIST): A retrospective study from the French Sarcoma Group (FSG).
Authors: Duffaud Florence , Ray-Coquard Isabelle , Marchal Frederic , Chaigneau Loic , Bouche Olivier , Huynh Thanh Khoa , Mancini Julien , Isambert Nicolas , Bompas Emmanuelle , Ryckewaert Thomas , Bertucci François , Le Cesne Axel , Landi Bruno , Rios Maria , Adenis Antoine , Blay Jean-Yves ,   French Sarcoma Group
Published: March 2020

10546

Background: Elderly GIST patients (pts) represent a consistent portion of all GIST pts, but are under-represented in clinical trials. Data on benefits, tolerance of SU in elderly GIST pts and their specific outcome are very limited. Methods: Charts of elderly pts (≥ 65 yrs)treated with SU in routine clinical practice from 11 Centres of the FSG were reviewed to evaluate the efficacy and safety of SU. Results: 71 elderly GIST pts were reviewed, with a median age of 74, [distributed as 65-74, n=36; 75-84, n=30; ≥ 85, n=5], 41 (57%) men, with median ECOG-PS= 1 (0-2), and median active comorbities of 1 (0-4). SU was administered after progression on first-line Imatinib (400 mg/d for 21 pts, 400 then 800 mg/d for 45 pts) or masitinib (5 pts). SU was started at 50 mg/d 4-wks-on/2 wks-off in 37 pts (52%), at 37.5 mg daily in 32 pts (45%), and at 25 mg daily in 2 pts. All but 2 pts experienced at least one adverse event (AE). Drug related AE were mainly of grade 1 or 2 (298/388, 76%), and medically manageable. Most frequent AE were fatigue (20%), diarrhea (11%), mucositis (7%), abdominal pain (7%), hand-foot syndrome (6%), neutropenia (6%), and hypertension (5%). Permanent dose reduction was reported in 33 pts (46%). In 17 pts (24%) SU was permanently stopped due to grade 3 or 4 AE. ; this occurred within 3 months after starting SU in 10 pts. At a median 36 months follow-up, 53 pts progressed, and 28 pts were alive. The median PFS and OS were 10.2 (0.2-54) and 21 (0.5-77) months, respectively. Univariate analysis showed that age (≤ 80), PS (<1), WBC (≤ 4 Giga/l), Hb and Albumin have a positive impact on OS (all p < 0.04) and PFS (all p < 0.05). In multivariate analysis, Albumin and Hb had an impact on OS and PFS, PS had an impact only on OS, and WBC only on PFS. A correlation was found between comorbidities and Grade 3/4 toxicities, but no correlation between any toxicities and outcome. Conclusions: Compared to data from clinical trials, SU yields similar rates of GIST control and OS in elderly pts despite frequent dose reductions or interruptions. Since comorbidities may increase the risks of AEs, careful follow-up to assess tolerance is particularly indicated in elderly GIST pts.
Impact of mutational status and other prognostic factors on survival in patients with advanced GIST treated with standard-dose imatinib (IM): Results from the BFR14 phase III trial of the French Sarcoma Group.
Authors: Domont Julien , Chabaud Sylvie , Ray Coquard Isabelle , Bui Binh , Adenis Antoine , Rios Maria , Bertucci François , Duffaud Florence , Cupissol Didier , Chevreau Christine , Bompas Emmanuelle , Emile Jean-François , Coindre Jean-Michel , Blay Jean-Yves , Le Cesne Axel
Published: March 2020

10548

Background: Factors predicting progression free survival (PFS) and overall survival (OS) of patients (pts) with advanced GIST treated with 400 mg daily dose IM were investigated. As mutational status was a secondary objective of the BFR14 study, we wanted to evaluate the added value of these genomic profiles to conventional clinical prognostic factors. Methods: 434 pts were included in this prospective multicenter trial from June 2002 to July 2009. Prognostic factors for survival were investigated in the cohort where the mutational status was available. A multivariate Cox model including baseline characteristics statistically significant in univariate were included in a backward procedure to identify independent prognostic factors for PFS then OS. Results: Mutational analysis were available in 322 pts. Material was insufficient in 55 cases (12.5%), incomplete results were obtained in 39 pts (9%). There were 196 KIT genetic alterations (exon 11: 173 pts, exon 9: 22 pts, exon 17: 1 pt), 6 GIST with a PDGFRA mutations and 26 GIST WT. The analysis of prognostic factors was performed in all mutated and non-mutated GIST (221 pts) except for pts with a KIT exon 17 and PDGFRa mutation. As of January 2013, median follow-up was 73 months (m) (CI95%:63; 86), 147 progressions (67%) were notified and 84 deaths (38%) occurred. The median PFS and OS were 12.3 m (CI95%: 2.1;32.7) and 54.9 m (CI95%:16.5;83.8) for WT GIST, 12.6m (CI95%: 6.1;30.8) and 55m (CI95%:33.5;83.0) for KIT exon 9 and 39.4m (CI95%: 31.4;54.4) and not reached for KIT exon 11, respectively. An initial low tumour volume, gender (female), and CD34 positivity were the three independent prognostic factors of a higher PFS. A higher OS was independently predicted by PS, low neutrophil counts, KIT exon 11 alterations, normal lymphocyte count, lower tumor size and female’s gender. Conclusions: GIST pts harboring a KIT exon 11 mutations have the better outcome but the mutational status is not the only prognostic factor influencing the outcome of pts. The clinical (gender, PS, tumor size) and biological characteristics (lymphocytes and neutrophil counts) remain critical for OS.
Correlation of PTEN loss and PI3K/AKT/mTOR pathway upregulation with malignant peripheral nerve sheath tumor (MPNST) development and outcome.
Authors: Shurell Elizabeth , Vergara-Lluri Maria Espera , Li Yunfeng , Tran Linh M , Nakashima Jonathan , Barzan Kathleen , Tam Brenna , Bernthal Nicholas , Tap William D. , Eckardt Jeffrey , Eilber Frederick R. , Dry Sarah M , Wu Hong , Eilber Frederick C.
Published: March 2020

10555

Background: MPNST is an aggressive soft tissue sarcoma often arising from preexisting neurofibromas (NF). Our previous study using murine models demonstrated that PTEN loss and PI3K/AKT/mTOR pathway upregulation is a potential mechanism of malignant transformation. The goal of this study is to determine whether a similar mechanism also drives human MPNST development. Methods: A tissue microarray was created from 144 surgical specimens (MPNST n=58, NF n=51, schwannoma n=11, and normal nerve n=24). Cores were stained in triplicate for PTEN and PI3K pathway-associated markers (PTEN, P-AKT, P-S6, GLUT1, SKP-2), other previously identified alterations (p53, p16, P-ERK and c-Myc) as well as tumor grade biomarkers Ki-67 and cleaved caspase 3. Density, intensity and subcellular localization of each marker were quantified and compared using linear regression and survival analysis was performed using Cox proportional hazards modeling. Results: Consistent with our mouse model study, P-S6, GLUT1 and SKP-2, downstream surrogate markers for PI3K pathway, are upregulated in MPNST compared to benign NF (p=0.002, p=0.000, p=0.016, respectively). Upregulated GLUT1 is notable as we have shown that FDG imaging can be used to stratify MPNST lesions from benign. In the 34 primary MPNST patients, PTEN protein expression correlated with improved disease specific survival (DSS) and disease free survival (DFS) (p=0.066 and p=0.014, respectively). In this cohort, large size (p=0.085), low PTEN (p=0.066), and low c-MYC (p=0.001) were associated with poor DSS. Large size (p=0.074), low PTEN (p=0.023), skp2 (p=0.097), p-AKT (p=0.086), and c-MYC (p=0.001) all correlated with poor DFS. NF-1 patients and spontaneous patients had different expression patterns associated with survival. NF-1 patients had improved DSS with high p53 (p=0.044) and smaller size (p=0.013), whereas spontaneous patients showed improved DSS only with increased c-MYC (p=0.008). Conclusions: PTEN loss and PI3K/AKT/mTOR pathway activation are important in MPNST development/prognosis and serves as a potential therapeutic target.
A phase Ib/II study of imatinab and everolimus in patients with PDGFRA+ synovial sarcoma.
Authors: Keohan Mary Louise , Tap William D. , Dickson Mark Andrew , D'Angelo Sandra P. , Carvajal Richard D. , Gounder Mrinal M. , Morales Rita Elena , Condy Mercedes M. , Hameed M , Ho Alan Loh , Vasuveda S , Qin Li-Xuan , Luke Jason J. , Takebe Naoko , Schwartz Gary K.
Published: March 2020

10558

Background: Our group previously reported that PDGFRA is the most highly overexpressed kinase gene in synovial sarcoma. Our preclinical studies also demonstrated synergistic anti-tumor activity by inhibiting both PDGFRA and mTOR signaling with imatinib and rapamycin respectively in PDGFRA + synovial sarcoma cell lines. Based on these data, a phase Ib/II study to evaluate the toxicity and efficacy of imatinib and everolimus was undertaken. Methods: The primary endpoint of the phase 1b portion of the study was to determine the maximum tolerated dose (MTD) of everolimus administered with imatinib. Starting dose of everolimus and imatinib was 5 mg/day and 400 mg/day respectively. Response rate (RR) by RECIST was the primary end-point of the Phase II study. The phase II study used a Simon two stage design. 9 patients (pts) were to be accrued initially. If there were no responses, further accrual would be stopped and treatment declared ineffective. If there was at least 1 response, an additional 15 pts would be accrued for a total of 24. Key eligibility: metastatic disease, any number of priors. Pre and post treatment tumor biopsies were mandated. Results: 12 pts were treated.5 M and 7 F, median age 44 (range: 22-71), median priors 4 (range: 0 - 6). Two DLTs were observed at dose level 2 (10 mg everolimus /400 mg imatinib) with grade 3 transaminases and hypophosphatemia. Everolimus 5 mg/ imatinib 400 mg was the MTD in the phase II study. 10 pts evaluable for response, included 4 pts treated at the MTD in the Phase 1b study. There were no RECIST responses. Stable disease was observed in 3 pts (7, 7, 19 mos.). Western blot and IHC analysis of matched pair tumor biopsies indicate inhibition of p-AKT, p-S6 and decreases in Ki 67. Conclusions: Imatinib and everolimus failed to achieve its primary response endpoint. However, prolonged stable disease in 3 pts in association with inhibition of PDGFRA and mTOR suggest clinical benefit and biological effect for this drug combination. Clinical trial information: CTEP 8603.
A large retrospective analysis of trabectedin in 885 patients with advanced soft tissue sarcoma.
Authors: Le Cesne Axel , Ray-Coquard Isabelle , Duffaud Florence , Chevreau Christine , Penel Nicolas , Bui Binh , Piperno-Neumann Sophie , Delcambre Corinne , Rios Maria , Chaigneau Loic , Le Maignan Christine , Guillemet Cecile , Bertucci François , Bompas Emmanuelle , Linassier Claude , Collard Olivier , Even Caroline , Ducimetiere Francoise , Cousin Philippe , Blay Jean-Yves
Published: March 2020

10563

Background: Trabectedin (Yondelis) is the first marine-derived antineoplastic drug approved in Europe for the treatment of patients with recurrent ASTS or for patients unsuited to receive anthracyclines and ifosfamide. We retrospectively analyzed the RetrospectYon database with patients’ data treated with trabectedin between Jan 2008 - Dec 2011. Methods: Trabectedin was given at the approved dose of 1.5 mg/m2 as a 24-h infusion every 3 weeks. Patients who achieved partial response (PR) or stable disease (SD) after 6 cycles could receive maintaining trabectedin treatment. Uni- and multivariate analyses of prognostic factors were performed. Results: 885 patients (486 women) from 26 centers in France with ASTS with a median age of 54 years (range 12-84) were included. Most had leiomyosarcoma (36%), liposarcoma (18%) or synovial STS (11%). At baseline, performance status (PS) was 0 in 26%, 1 in 47% and >1 in 27% of patients. A median of 4 trabectedin cycles (range 1-28) was given as a 2nd (41%), 3rd (39%) or ≥4th (20% of patients) treatment line. Toxic death and unscheduled re-hospitalization occurred in 0.5% and 8% of patients, respectively.The objective response rate was 15% (6 complete and 127 PR), and SD rate was 45.5% (n=403). After a median follow-up of 22.6 months (range 0.03-51.2), the patients who received trabectedin as 2nd, 3rd or ≥4th line had the median PFS of 4.3, 4.2 and 3.4 months, respectively, and the median OS of 12.9, 12.3 and 9.5 months. Multivariate analysis identified liposarcoma, leiomyosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma (UPS) and trabectedin line as independent prognostic factors for PFS, and UPS, angiosarcoma, rhabdomyosarcoma, gender, PS and trabectedin line for OS. After 6 cycles, 205 of the 273 patients with non-progressive disease received trabectedin as maintenance treatment and obtained a superior PFS (median 11 vs. 7.2 months, p=0.0001) and OS (median 25.1 vs. 16.9 months, p<0.0001) that those who stopped trabectedin after 6 cycles. Conclusions: Patients with ASTS treated with trabectedin had PFS and OS comparable or better to those observed in phase II/III trials. Trabectedin maintenance beyond 6 cycles is associated with improved OS and warrants further exploration.
Efficacy and safety of hypofractionated preoperative radiotherapy in treatment of localized extremity/trunk wall soft tissue sarcoma (STS): Final results of the study.
Authors: Rutkowski Piotr , Kosela Hanna Melania , Kolodziejczyk Milena , Dziewirski Wirginiusz , Zdzienicki Marcin , Morysinski Tadeusz
Published: March 2020

10564

Background: The primary treatment of STS is surgical resection combined with pre- or postoperative radiotherapy. Conventional fractionation in neoadjuvant radiotherapy is 50Gy (fractions: 2Gy/day). Radiobiological studies shown that alpha/beta ratios of some sarcoma cells are below 10Gy, what is rationale for hypofractionation. Aim of the study was to assess the efficacy and safety of hypofractionated radiotherapy in preoperative setting in patients with STS treated in one institution. Methods: 220 patients (median age 54years) participated in this prospective study (2006-2010). Median follow up is 34 months. 140 patients (64%) had high grade (G3) tumors, median size -9cm (45% ≥10cm), 68% on lower limb. 137 patients (62.2%) had primary tumors. Preoperative radiotherapy 5x5 Gy per 5 consecutive days was applied, with immediate tumor resection. Results: R0 resection was possible in 79%. 61 patients died (3-year overall survival OS 72%), 91 (41%) had disease relapse. Local recurrence (LR) was found in 20% of the patients (3-year LR-free survival 80%). Negative prognostic factors for LR were: tumor size ≥10cm (p=0.037), grade 3 (p=0.0041) and primary vs. recurrent tumor with borderline significance. LRs had significant impact on OS (p=0.0001). 101 patients (46%) had any kind of complications, majority on lower limb (early: 17.2% prolonged healing of the wound >1month, 12.7% -wound dehiscence, 4% -prolonged punctures of lymph fluid, 2.7% -acute skin toxicity; late: 0.9% -severe fibrosis with contracture, 11% -prolonged edema. 2.7% -bone fracture), but only 6.3% required additional surgery. Conclusions: In this non-selected group of advanced STS use of hypofractionated preoperative radiotherapy was associated with similar local control (80%) when compared to previously published studies. The early toxicity is tolerable, with small rate of late complications. Presented results warrants evaluation in randomized trial.
Targeted next generation sequencing of sarcomas for identification of therapeutic targets.
Authors: Ravi Vinod , Ali Siraj M. , Ramesh Naveen , Meric-Bernstam Funda , Palmer Gary A. , Hwu Patrick , Patel Shreyaskumar , Futreal Andrew
Published: March 2020

10577

Background: Sarcomas are a diverse group of mesenchymal tumors with significant heterogeneity. Evolving personalized cancer care strategies require identification of recurrent genomic alterations that can be targeted therapeutically. Due to the rarity of these tumors and lack of fresh or frozen tissue in routine clinical practice, DNA sequencing has been a challenge. Objective: To demonstrate the feasibility of a next-generation sequencing (NGS) platform that utilizes archival formalin-fixed paraffin-embedded (FFPE) tissue to evaluate the spectrum of DNA alterations seen in sarcomas. Methods: Study population included 35 consecutive patients with advanced sarcoma presenting to the sarcoma center at MD Anderson Cancer Center beginning August 2012 with archival FFPE tissue available for NGS. DNA was extracted from FFPE samples and used for hybridization capture and NGS on the Illumina HiSeq 2000 platform. A total of 182 cancer-associated genes and 37 introns of 14 commonly rearranged genes were evaluated for genomic alterations. In the absence of an individual–matched normal control, germline variations were removed using dbSNP and the remaining variants were classified on the basis of current knowledge of specific variants from cancer databases such as COSMIC. Results: 35 patients (10 Angiosarcomas, 9 Leiomyosarcomas, 3 synovial sarcomas, 13 other subtypes) underwent DNA extraction with a median yield of 3376 ng tumor DNA. The average sequencing depth was >900X. 43% of patients had point mutations/indels previously described in COSMIC and/or in known mutation hotspots. 54% of patients showed structural variants such as amplifications, deletions or rearrangements. 68% of genomic alterations are in genes that are actionable. We identified an apparently novel variant in KDR T771R in 2/10 patients with angiosarcoma. KDR amplifications were identified in 20% of patients with angiosarcoma. Outcomes of matched targeted therapy of patients with actionable targets will be presented with more mature follow-up. Conclusions: Targeted NGS of DNA from archival FFPE tissue is feasible with the potential for identifying actionable targets and discovery of novel mutations.
Phase I and pharmacokinetic study of sorafenib in Kaposi sarcoma.
Authors: Uldrick Thomas S. , Wyvill Kathleen , Peer Cody , Polizzotto Mark Niccolo , O'Mahony Deirdre , Bernstein Wendy , Aleman Karen , Steinberg Seth M. , Venzon David J. , Pittaluga Stefania , Little Richard F. , Figg William Douglas , Yarchoan Robert
Published: March 2020

10588

Background: Kaposi sarcoma (KS) is a multifocal angioproliferative disorder. VEGFR2-3, PDGFR and c-kit are implicated in KS pathogenesis and inhibited by sorafenib (So). KS is commonly HIV-associated. The antiretroviral drug ritonavir (R) inhibits CYP3A4, and may affect So metabolism and tolerability. Methods: We performed a phase I study of So in KS. HIV+ patients (pts) were eligible if on combination antiretroviral therapy (cART) for >3 months with progressive KS or >4 months with no KS regression. Dose level 1 for pts on R-containing cART (R1) was So 200 mg daily, for pts not receiving R (NR1) So 200 mg every 12 hours. Treatment cycles were 21 days. So pharmacokinetic assessment performed cycle 1 day 8. Adverse event (AE) grade (Gr) by CTCAE v3.0 (2006-10) and v4.0 (2011-12). KS response graded by modified ACTG criteria. Results: 10 pts, R1 (8), NR1 (2). Baseline characteristics: median (med) (range) age 49 (35-72), CD4 in HIV+ 500 cells/uL (35, 747), time on cART 9 months (3.5, 27), previous KS therapies 2 (0-5). 9 HIV-infected, 8/9 HIV viral load <50 copies/mL. 6 had KS-associated edema. Med number cycles 4 (1, 13). Common AE at least possibly attributable to So: anemia, AST/ALT elevation, lipase elevation, hypertension, proteinuria, fatigue, infection, voice alteration. Dose-limiting toxicities (DLT): R1- Gr3 asymptomatic elevated lipase (1), Gr4 thrombocytopenia (1, likely due to multicentric Castleman disease); NR1- Gr3 hand-foot syndrome not resolved by week 6 (1). Other Gr 3-4 AE: R1- hand-foot syndrome (1), Gr3 thrombocytopenia (1), Gr3 transient cerebral ischemia (1), Gr3 hypertension (1); NR1- Gr3 hypertension (2). Best response: partial response (PR) (2), stable disease (SD)(5), progressive disease (1), not evaluable (2). Med duration SD 12 weeks (5, 33). 5/6 with KS-associated edema had objective decrease in edema. R was not associated with clear difference in So CMax or AUC at steady state. Conclusions: Preliminary estimate of PR or better is 20%. Even in some cases where KS did not respond, KS-associated edema improved. However, So was relatively poorly tolerated, with DLT observed at R1 and NR1, and these doses did not yield better responses than established therapies. Additional studies evaluating R’s effect on So metabolites are warranted. Clinical trial information: NCT00287495.
Insurance status as a strong predictor of outcome in triple-negative breast cancer (TNBC): A multi-institutional retrospective study.
Authors: Biswas Tithi , Prasad Shreya , Zagar Timothy , Efird Jimmy , James Sarah E. , Walker Paul R. , Raab Rachel Elizabeth , Carey Lisa A. , Marks Lawrence B.
Published: March 2020

1069

Background: TNBC accounts for about 15-20% of all breast cancer. TNBC has particularly aggressive clinical course and accounts for a disproportionate number of breast cancer relapses and deaths in early stage disease. TNBC also have worse prognosis especially in African American (AA) women compared with white women. This retrospective study aims to investigate various clinical and demographic prognostic factors in TNBC. Methods: 476 TNBC patients who were treated at Eastern Carolina University and University of North Carolina, CH between 4/96 and 9/11 were included in this analysis. We collected data on age, race, grade, lymphovascular invasion (LVI), stage, treatments including surgery, chemotherapy, radiation, chemotherapy drugs, insurance type and year of treatment. Overall Survival (OS) was computed from the date of diagnosis to the date of death or last FU. For disease free survival (DFS), patients were scored if they failed either locally or distally. The Cox proportional-hazards regression model was used to compute hazard ratios. Results: The median age was 52 years (21-88 years) with median FU of 3.7 years. 49% women were white race followed by AA 223 (47%) and Hispanic or other race (5%). Stage (p<0.001), grade (p=0.02), surgery (p<0.0001), adjuvant chemotherapy (p=0.025), LVI (p=0.05) and type of insurance were significant predictor of OS. Similarly, stage (p<0.0001), surgery (p<0.0001), LVI (p=0.03) and insurance were significant predictors for DFS. On multivariate analysis, stage, surgery and adjuvant chemotherapy remained statistically significant predictors. Medicaid vs. Private Insurance also remained a significant detriment of survival (OS: HR=3.6, p<0.0001; DFS: HR=2.8, p<0.0001) as did having No Insurance for OS (HR=2.0, p=0.0074). Conclusions: To our knowledge, this is a largest retrospective study showing type of insurance to be a strong predictor of outcome in this very specific breast cancer subtype which remained significant after adjusting all other variables. Further insight is needed to determine the cause of this finding.
Plasma VEGF-a, angiopoietin-2 (ANG2) and soluble(s)TIE2 in patients (pts) with HER2-negative locally recurrent or metastatic breast cancer (LR/MBC) treated with first-line bevacizumab (A) and paclitaxel (T) without or with capecitabine (X).
Authors: Lam Siu W. , de Groot Steffen M. , Honkoop Aafke H. , Nota Nienke M. , Jager A. , van der Velden Ankie M.T. , Bos Monique M.E.M. , Linn Sabine C. , Van Den Bosch J. , Kroep Judith R. , Braun J. J. , de Haas Richard R. , Smorenburg Carolien H. , de Graaf Hiltje , Portielje Johanna Elisabeth A. , Los Maartje , de Gooyer Domingo , van Tinteren Harm , Boven Epie ,   Dutch Breast Cancer Trialists' Group (BOOG)
Published: March 2020

1072

Background: In the randomized phase II ATX trial, pts with HER2-negative LR/MBC were treated with first-line AT or ATX. We determined the prognostic value for outcome of VEGF-A, ANG2 and sTIE2 measured at baseline on cycle 1 day 1 (C1D1) and after cycle 1 (C2D1). Methods: 312 pts were randomized in 1:1 ratio to AT (T 90 mg/m2 on d1, 8, 15 and A 10 mg/kg on d1, 15 q4w x 6 cycles, followed by A 15 mg/kg on d1 q3w for next cycles) or ATX (T 90 mg/m2 on d1, 8, A 15 mg/kg on d1 and X 825 mg/m2bid on d1–14 q3w x 8 cycles, followed by the same dose of A and X q3w for next cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), response duration (RD), overall survival (OS) and safety. Plasma proteins on C1D1 (N = 173) and on C2D1 (N = 142) were measured by ELISA. The association of protein levels (continuous variable) with PFS and OS was evaluated by Cox proportional hazards model and Martingale residual plot. Results: At a median follow-up of 39 months (mo), there were 292 PFS events and 242 deaths. ATX significantly improved PFS as compared to AT (median 11 vs. 8.4 mo, stratified HR = 0.52; 95% CI, 0.41 – 0.67; P < .001). The confirmed ORR in measurable disease (N = 268) was 67% in ATX vs. 50% in AT. Median RD was 6.4 mo (95% CI, 6.1 – 8.3) in ATX v 5.4 mo (95% CI, 5.1 – 6.0) in AT. Median OS was 24.1 mo in ATX vs. 23.1 mo in AT (P= .44). The aselected ‘biomarker’ cohort (N = 173) and overall trial cohort had similar baseline characteristics. ANG2 on C1D1 moderately correlated with sTIE2 on C1D1 (Pearson’s r = .44, P < .001). High ANG2 on C1D1 was significantly associated with poor OS (HR = 1.6; 95% CI, 1.1 – 2.3; P = .01), but not with poor PFS (HR = 1.3; 95% CI, 1.0 – 1.3; P = .07). ANG2 on C2D1 was not significantly associated with OS (HR = 1.55; 95% CI, 0.99 – 2.4; P = .057) or with PFS (P= .6). sTIE2 and VEGF-A were not associated with outcome. All pts had very low levels of free VEGF-A on C2D1 (median 8 pg/ml). Conclusions: In HER2-negative LR/MBC, ATX is more effective (PFS, ORR and RD) than AT. A very high plasma level of ANG2 at baseline indicates a high risk for poor survival. Clinical trial information: NTR1348.
Assessing the impact of CMF/FEC/FEC-DOC/ETC (dose-dense) adjuvant chemotherapy in dependency of positive axillary lymph nodes on survival: A retrospective multicenter cohort study of 4,526 breast cancer patients receiving adjuvant chemotherapy.
Authors: Schwentner Lukas , Van Ewijk Reyn , Hoffmann Isabell , Kreienberg Rolf , Blettner Maria , Wöckel Achim ,   BRENDA Study Group
Published: March 2020

1074

Background: Adjuvant chemotherapy has changed dramatically in the last decades. Anthracycline-/taxane-based and dose-dense chemotherapy regimens improved survival in node positive breast cancer. This study tries to answer the following questions: (1) Are there differences in survival dependent on chemotherapy regimens in 0/0-3/4-10/<10 positive lymph nodes? (2) Is it possible to define a cut-off of positive lymph nodes for the use of Taxane-based and dose dense chemotherapy? Methods: This German is a multi-center [17 participating hospitals all are certified as breast cancer centers] retrospective cohort study. We included CMF (1.385), FEC (1.170), FEC-DOC (1.723), and dose-dense ETC (248) into the analysis. Results: In case of 0 LN CMF/FEC/FEC-DOC did not show significant differences in DFS, but OAS was significantly impaired by the use of FEC-DOC in 0 LN [p=0.024; HR=2.02 (95% CI: 1.10-3.73)] (no ETC use in 0 LN). In case of 1-3 positive LN CMF/FEC/FEC-DOC/ETC did not differ significantly in survival parameters. But in 4-10 LN FEC-DOC [p=0.049; HR=0.67 (95% CI: 0.44-0.99)] and ETC [p=0.024; HR=0.56 (95% CI: 0.34-0.93)] demonstrated a significant benefit in DFS and a strong trend in OAS. Dose-dense ETC showed a significant improvement in DFS [p=0.003; HR=0.35 (95% CI: 0.17-0.69)] and OAS [p=0.009; HR=0.35 (95% CI: 0.16-0.77)] in patients with >10 positive LN. Conclusions: Our data confirms that Taxane-based chemotherapy does not improve DFS in LN negative breast cancer, but rather demonstrated an inferior OAS. But in LN positive breast cancer we can demonstrate a benefit by the use of Taxane-based chemotherapy regimens. Furthermore, dose-dense ETC demonstrated a significant benefit in survival in >10 positive LN.
Community use of anthracyclines in metastatic breast cancer (MBC).
Authors: Krook James Edward , Kumar Akhil , Fishman Marc L. , Shimp William S. , Bobolts Laura Rose , Fishman Val , Davis Sharon , Huff Dinah , Anthony Carol , Walton Robert , Hrushesky William J.
Published: March 2020

1080

Background: For decades, anthracyclines have been among the most useful treatments for women with MBC. Though recent publications have confirmed an overall decline in the use of anthracyclines in BC, most of that decline was felt to be due to its diminished utilization in the adjuvant management of BC. Current community anthracycline usage pattern in MBC is not known. We investigate and report, herein, how community oncologists in the southeast USA are currently utilizing anthracyclines for MBC. Methods: All chemotherapy treatment requests for HER2+ and HER2- Stage 4 BC were examined, from 2009 through 2012. Chi-Square test was performed for interaction between age and anthracycline utilization, with p-value less than 0.05 considered significant. The proportion of women who had been treated previously in the adjuvant setting with low cumulative doses of anthracyclines, which would have some effect upon subsequent use, was not retrievable. Results: During this span, 420 unique chemotherapy requests were initiated for 247 patients. These included 54 anthracycline requests for 50 MBC patients. The use of anthracyclines for metastatic HER2+ BC was virtually absent (one in 63 requests among 42 patients). The remaining 357 chemotherapy requests were for treatment of 205 HER2- MBC patients. Anthracyclines were employed in 22% of women under 65 years of age and in 25% of those older than 65 (p = 0.77). Approximately 83% (45/54) of anthracycline-requests were for conventional doxorubicin, either alone or in combination with other agents. The rest were for liposomal doxorubicin (6/54) or epirubicin (3/54). Conclusions: Data from the southeast USA identifies that anthracyclines are virtually never used in HER2+ MBC. Even in HER2- MBC, anthracyclines are used in only one out of 4 patients suffering from this disease. The effect of this unheralded alteration in oncology practice must be carefully considered when trends in metastatic breast cancer control are examined. [Table: see text]
Effect of capping chemotherapy dose on chemotherapy effect in morbidly obese women with breast cancer.
Authors: Porter David James , Wilson Michelle
Published: March 2020

1081

Background: Obesity adversely affects outcomes from adjuvant (adj) chemotherapy for breast cancer. Capping of chemotherapy dose has been implicated as one factor that may contribute to this. We postulated that if capping resulted in underdosing, this would be reflected in the incidence of dose dependent toxicities (DDT) such as mucositis and haematological toxicity. Methods: We retrospectively reviewed records of breast cancer patients (pts) commencing adj chemotherapy from 1 Jan 2010-31 Dec 2010 at the Auckland Regional Blood and Cancer Service identified using a prospective pharmacy database. Baseline characteristics, BSA, body mass index (BMI), neutrophil (ANC) nadir, relative dose intensity (RDI) and dose limiting complications (DLC) were recorded. Results: 174 pts were identified. Median age was 49 yrs (24-73). 17.8% had a BSA >2. 3.2% pts with BSA>2 had BMI <30. 42% had a BMI ≥30 (17.9-61.0), of whom 59% had a BSA ≤2. All patients with BSA >2 had dose capping. 71 pts had a DLC. Neutropenic fever/infection or treatment delays from neutropenia were more common if BSA ≤2 vs. >2 (p=0.08) but not with other DDT. Treatment deferrals (18.8 vs. 16.1%) dose reductions (25.2 vs. 32.3%) and mucositis were similar in both groups. Mean baseline ANC was 4.4 in pts with BSA ≤2 and >2. Mean ANC nadir was 0.8 and 1.3 respectively (p<0.01). r2BSA vs nadir ANC was 0.012. G3/4 neutropenia was seen 76.5% of pts with BSA ≤2 vs. 44.8% if BSA >2 (RR 1.3 p<0.01). No pt had > G1 thrombocytopenia. Mean RDI was 93.2 and 94.8 respectively (p=0.4) Conclusions: Previous studies show ANC nadirs correlate well with drug exposure (area under plasma concentration vs. time curve) but poorly with BSA. Therefore we used hematological and DDT as surrogate measures for drug exposure in pts with and without capped doses. There was more G3/4 neutropenia (p<0.01) in uncapped pts but rates of other DDT were similar. Since BSA based dosing has little impact on inter-pt variability in systemic drug exposure and trials where capping was not used still show a poorer outcome in obese pts, these results suggest dose capping is a minor contributor to the worse outcomes in morbidly obese breast cancer pts having adj chemotherapy. Addressing obesity itself may be more important.
Neoadjuvant versus adjuvant chemotherapy with taxanes and anthracycline-based regimen: Which leads to better outcome in patients with different subtype breast cancer?
Authors: Yang Houpu , Wang Shu , Zhou Lixin , Guo Jiajia , Cao Yingming , Zhou Bo , Cheng Lin , Xie Fei , Liu Hongjun , Tong Fuzhong , Liu Miao , Liu Peng , Wang Siyuan , Yang Deqi , Zhang Jiaqing
Published: March 2020

1084

Background: Neoadjuvant chemotherapy was reported to lead to equal outcome with adjuvant therapy in operable breast cancer. However, different molecular subtypes show variant response to chemotherapy, which is associated with different long-term prognosis. This study was to clarify whether molecular subtypes lead to different outcome between neoadjuvant and adjuvant chemotherapy. Methods: We identified 406 patients with stage II-III breast cancer who were treated with neoadjuvant or adjuvant chemotherapy between 2000 and 2008. To minimize the confounding bias, only patients received taxanes and anthracycline based regimen (TA) were included. Cases were divided according to receipt of neoadjuvant and adjuvant therapy. Data were compared using χ2test and analysis of variance. Kaplan-Meier Curves were generated. Results: Of the 406 patients, 201(49.5%) received neoadjuvant chemotherapy and 205(50.5%) received adjuvant TA regimen. The pCR rate was 12.9%(26/201) in total, and 7%, 14%, 33.3%, 19.4% for Luminal A, Luminal B, HER2+ and Triple negative breast cancer(TNBC), respectively. The HER2+ and TNBC have significantly higher rates of pCR than Luminal type (p<0.05). In general the two groups showed little survival variance (p=0.073 for DFS and p=0. 601 for OS). In Luminal B, neoadjuvant settings led to worse disease free survival (DFS) and overall survival (OS) than adjuvant settings after controlling for the covariates associated with survival in unadjusted tests (HR=0.41, p=0.028 for DFS; HR=0.32, p=0.020 for OS). In HER2+ subtype, neoadjuvant group corresponded to better DFS and OS (HR=5.65, p=0.024 for DFS; HR=10.52, p=0.010 for OS). On the contrary, patients with TNBC and Luminal A undergoing neoadjuvant chemotherapy had equal DFS and OS compared with patients receiving adjuvant therapy (p>0.05). Conclusions: The results demonstrate survival difference between patients receiving neoadjuvant and adjuvant cytotoxic therapy in variant subtypes. Prospective studies are necessary to determine if the finding is durable and optimize the timing of chemotherapy for breast cancer with different molecular background.
Circulating biomarkers in patients receiving neoadjuvant chemotherapy combined with sunitinib for locally advanced breast cancer.
Authors: Brown-Glaberman Ursa Abigail , Specht Jennifer M. , Iannone Maria , Kurland Brenda F. , Livingston Robert B. , Stopeck Alison
Published: March 2020

1089

Background: Biomarkers to guide the use of antiangiogenic therapy are lacking. Circulating endothelial cells (CECs) and their progenitor cells (CEPs) are increased in cancer patients. VCAM is an endothelial protein increased in response to VEGF stimulation, while CAIX is elevated in states of hypoxia; both correlate with tumor aggressiveness. Methods: We examined these circulating biomarkers in a phase II neoadjuvant trial in 63 patients (pts) with locally advanced HER2 negative breast cancer treated with 12 weeks (wks) of paclitaxel (T) plus sunitinib (S) followed by 15 wks of daily oral cyclophosphamide and weekly doxorubicin plus daily G-CSF (AC+G-CSF). Toxicity and clinical outcomes are reported as a separate abstract. Blood was collected at baseline, wk 12 and pre-surgery. For this analysis, responders were defined as patients with a pathologic complete response (pCR) and/or MDACC CPS+EG score ≤ 2 (a validated score combining clinical and pathologic results for predicting survival in the neoadjuvant setting). Plasma VCAM and CAIX levels were measured by ELISA using commercially available validated kits and CEC/CEPs by flow cytometry in our laboratory as previously published. Results: 28 (44%) pts were responders. CECs decreased significantly in response to T+S (p = 0.04) but not further with AC+G-CSF. No significant changes were seen in CEPs. VCAM and CAIX levels increased in pts with baseline levels below the median in response to T+S (VCAM p = 0.0003, CAIX p = 0.009). ER negative tumors had higher levels of plasma VCAM and CAIX at baseline compared to ER positive tumors (VCAM p = 0.01, CAIX p = 0.1). Lower baseline levels of VCAM and CAIX were associated with both response and pCR. VCAM and CAIX levels were correlated at baseline (r = 0.4, p = 0.01). Conclusions: CEC, VCAM, and CAIX levels significantly changed after treatment with T + S. Higher baseline levels of VCAM and CAIX were associated with ER negative tumors and lower response rates. Our results suggest that elevated baseline VCAM and CAIX levels are associated with more aggressive biology, and may correspond to less (not more) favorable outcome with the addition of a targeted antiangiogenic agent. Clinical trial information: NCT00513695.
Phase Ib study of eribulin (ERB) and cyclophosphamide (CTX) in metastatic breast cancer (MBC).
Authors: Truong Thach-Giao , Pelayo Michael , Grabowsky Jennifer A. , Melisko Michelle E. , Magbanua Mark Jesus Mendoza , Moasser Mark M. , Reinert Anne , Hwang Jimmy , Park John W. , Munster Pamela N. , Rugo Hope S.
Published: March 2020

1095

Background: ERB is a non-taxane microtubule inhibitor approved for the treatment (Tx) of taxane (TAX) and anthracycline-treated MBC based on improved OS compared to treatment of physician choice. In the adjuvant setting, docetaxel/CTX (TC) was superior to doxorubicin/CTX for DFS and OS. ERB is active in TAX-resistant disease with a low rate of peripheral neuropathy (PN); its primary dose-limiting toxicity (DLT) is bone marrow suppression. We hypothesized that the combination of ERB and CTX would be well tolerated and active in patients with TAX-resistant disease, with potential applicability to the adjuvant setting. Methods: We designed a 3+3 phase Ib study of ERB, administered in 2 escalating doses on day 1 and 8, with CTX 600 mg/m2day 1 every 21 days. Eligibility included PN ≤ grade 1. Correlative studies to identify predictors of response and toxicity included whole blood for SNPs, GWAS, circulating tumor cells (CTC), and archived tumor RNA/protein expression analysis. Toxicity assessment included QoL and evaluation of PN. Results: 6 patients (pts) with MBC, median age 50 (47-63), were enrolled. All pts had prior TAX exposure and 4 pts had baseline grade 1 PN. Tumor characteristics included hormone receptor + (5 pts), HER2+ (2 pts), and triple-negative (1 pt). Median number of prior Tx for MBC was 5 (1-8). No DLTs were observed; the RP2D is eribulin 1.4 mg/m2 on D1 and D8 with CTX D1 600mg/m2. Neutropenia was the only G3/G4 non-DLT observed at this dose, requiring GCSF support in cycle1 in 2 of 3 pts. All grade toxicities included neutropenia (50%), thrombocytopenia, fatigue, nausea, PN, rash, mucositis, alopecia (33% each), and elevated liver enzymes (17%). Pts received a median of 5.5 cycles (range 3-13), with 3 pts still on Tx. Responses included 2PRs (33%) and 4 SD (67%). 2 pts stopped study Tx for QoL and continued ERB alone. Only 2 pts met threshold of >5CTC/7.5ml at baseline; these had a mean decrease of 90.5% at the start of cycle 2. Conclusions: ERB and CTX is a well-tolerated regimen with promising activity in MBC, with the primary toxicity being neutropenia requiring growth factor support. A phase II study in MBC is underway. Additional correlative studies are ongoing including molecular analyses of CTC. Clinical trial information: NCT01554371.
Effect of very small tumor size on recurrence-free survival and breast cancer-specific mortality stratified by guideline adherence: An analysis of the BRENDA Study Group.
Authors: Wöckel Achim , Schwentner Lukas , Wischnewsky Manfred , Kreienberg Rolf , Wolters Regine ,   BRENDA Study Group
Published: March 2020

1096

Background: Small tumor size (<5mm, T1a) carry an excellent prognosis, despite a variety of treatment approaches. Controversy exists over the extent of treatment, as to whether less than conventional treatment can be done. We therefore sought to explore the effect of very small tumor size on RFS and BCSM stratified by guideline adherence. Methods: The multicenter study population included 8935 early breast cancer patients diagnosed between 1992-2008, where 614 patients (6.9%) were T1a. T1a-patients were categorized according to guideline adherence and the influence on survival was calculated by Cox proportional hazard analyses (adjusted for age, grading, nodal status, hormonal status and co-existing morbidity). Results: The median age was 61 years and the median follow-up was 55 months. 449 [73.1%] patients were postmenopausal. 13.1% had G1, 61.9% G2 and 25% G3. 81.9% were HR positive and 18.4% HER2/neu-positive. 77.1% were N0, 11.9% had 1-3 and 11% more than 3 affected lymph nodes. Only 262 (42.7%) pts. were guideline adherent. Compared to guideline adherent patients RFS and BCSM were significantly (p< 0.001) worse for guideline-non-adherent patients (RFS: HR=3.88; 95% C.I.: 1.91-7.87) and (BCSM: HR= 4.28; 95% C.I.:2.04-9.00). After adjusting for age, grading, nodal status, hormone receptor status and comorbidity guideline adherence was still the most important variable for RFS and BCSM (RFS: p<0.001; HR=3.71; 95%C.I.: 1.80-7.67) and (BCSM: p<0.001; HR=3.82; 95% C.I.:1.80-8.11).The most important impact on RFS and BCSM had guideline violations of radiation (RFS: p=0.001; HR=3.19;95%C.I.:1.66-6.13) and (BCSM: p=0.009;HR=2.42;95%C.I.:124-4.72) respectively of chemotherapy (RFS: p=0.001;HR=1.43; 95%C.I.:1.43-4.39) and (BCSM: p<0.001;HR=3.17;95%C.I.:1.84-5.46). Conclusions: There is a strong association between guideline adherence and improved recurrence free survival and reduced breast cancer-specific mortality for breast cancer patients with very small tumor size. Violation of treatment guidelines for postoperative irradiation or chemotherapy is clearly associated with a deterioration of prognosis.
Axillary lymph node ratio (LNR) versus pathologic nodal stage (pN) as a prognostic factor in breast cancer: Validation of Vinh-Hung's model in an Indian population.
Authors: Batra Swati , Ganguly Manomoy , Kannan Narayanan , Talwar Rajnish , Takkar Puneet , Soneji Dharmesh , Kulshreshtha Pranjal , Sanchety Naveen , Kalaivani Mani
Published: March 2020

1099

Background: The axillary lymph node ratio (LNR), i.e., the ratio of positive over excised lymph nodes offers potentially improved prognostication, selection for adjuvant therapy and inter-institutional comparability compared to conventional pathological nodal staging (pN). A consensus on appropriate cut-offs however, remains to be achieved. Values of 0.20 and 0.65 to classify patients into low, intermediate and high-risk groups were proposed by Vinh-Hung et al, in the largest study on the subject till date. We perform a validation of the LNR concept for the first time in an independent patient population from the Indian subcontinent. Methods: 225 patients with a median follow-up of 42 months (range: 2 – 246 months) who underwent upfront surgery for breast cancer at a tertiary care hospital in Delhi, India, were retrospectively analysed, using Cox multivariate regression. Results: Using the above cut-off points, 10-year disease-free survival (DFS) rates of 83%, 74% and 28% and adjusted hazard ratios (HR) of 1.19 (95% CI 0.33 to 4.37), 2.21 (95% CI 0.75 to 6.51) and 6.88 (95% CI 1.58 – 29.92; P = 0.01) were obtained for the low-, intermediate- and high-risk groups respectively. The corresponding risks for the pN1, pN2 and pN3 categories were 1.74, 1.74, and 1.35, representing inadequate, even reversed prognostic separation. When both the LNR and pN were included as continuous variables, the nodal ratio remained prognostically significant with an adjusted HR of 12.33 (95% CI 1.1 – 142.5, P = 0.04) in contrast to the number of positive nodes which were not found to be significantly associated with DFS (HR = 0.97, 95% CI 0.9 – 1.1, P = 0.41). Conclusions: The LNR outperformed the pN staging in predicting DFS in our cohort of patients, irrespective of whether it was modeled as a categorical or a continuous variable. Simultaneous analysis with pN only increased its prognostic weight and resulted in exclusion of pN from the multivariate model. Our study thus provides independent external validation of Vinh-Hung’s proposed cut-offs and contributes to the growing body of literature supporting the incorporation of a ratio-based system into breast cancer staging.