bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential gene expression in liposarcoma: Insight into pathways for dedifferentiation?
Authors: Han Dale , Bloom Gregory C , Bui Marilyn M , Enkemann Steven , Yamauchi Hideko , Han Gang , Conley Anthony Paul , Zager Jonathan S. , Cheong David , Reed Damon R. , Lavey Robert S , Sondak Vernon K. , Letson Douglas D , Gonzalez Ricardo Jorge
Published: March 2020

10048

Background: Liposarcoma (LPS) dedifferentiation signifies conversion to a clinically aggressive phenotype, but the biologic processes required for this change have not been determined. We describe differential gene expression patterns between well-differentiated (WD) and dedifferentiated (DD) tumors to determine pathways involved in LPS dedifferentiation. Methods: From 1999 to 2006, 121 fatty tumors were resected at a single institution. Twenty tumors, consisting of atypical lipomatous tumors (ALT), WD LPS or DD LPS, were randomly selected and clinicopathologic characteristics were retrospectively reviewed. Gene expression profiling was performed on extracted RNA using the Affymetrix GeneChip platform. Differentially expressed genes were obtained and gene network analysis was done using GeneGO by MetaCore. Results: Median age was 59 years and 70% of cases were male. WD tumors, consisting of 3 ALT and 6 WD LPS, were compared with 11 DD LPS. After a median follow-up of 64 months, 7 patients had died of whom 6 had DD LPS. DD histology was associated with lower overall survival (p<0.05). Significance Analysis of Microarrays for WD tumors vs. DD LPS using a 0% false discovery rate showed differential expression of 188 genes. Network analysis of genes from WD tumors vs. DD LPS showed significant (p<0.001) differential regulation of glucose-activated transcription factor ChREBP (carbohydrate response element binding protein), a key element involved in lipogenesis, gluconeogenesis and glycolysis. There was also significant differential regulation of insulin signaling, PI3K-dependent and PKA signal transduction pathways and of amino acid, fatty acid and glucose metabolism pathways (p<0.05). These pathways, based on Gene Ontology cellular processes, mapped to gene networks primarily involved in lipid metabolism (p<0.05). Conclusions: Differential expression of genes involved in lipid metabolism networks is seen in DD LPS and changes in lipid metabolism may be associated with dedifferentiation. These differential gene expression patterns may help identify fatty tumors potentially at risk for progressing to a malignant or DD state and provide prognostic factors and therapeutic targets for patients with LPS.
Phase II study of neoadjuvant high-dose ifosfamide with concurrent radiotherapy followed by surgical resection in high-risk soft tissue sarcoma: A Spanish Group for Research on Sarcomas (GEIS) study.
Authors: Garcia del Muro Xavier , Lopez-Pousa Antonio , Flor Maria Jose , Redondo Andrés , Jurado Josefina Cruz , Andres Raquel , Casado Antonio , Fra Joaquin , Lopez-Martin Jose A. , Maurel Juan , Valverde Claudia María , Gallego Oscar , Narvaez Jose Antonio , Bague Silvia , Sanjuan Xavier , Vinyals Juan M
Published: March 2020

10052

Background: High-dose ifosfamide (HDI) has shown promising activity as single agent in first-line chemotherapy for advanced soft tissue sarcoma (STS). The purpose of this study was to assess the activity and toxicity of a preoperative doxorubicin-free regimen of HDI given concurrently with radiotherapy (RT) and followed by surgery in patients (pts) with localized high-risk STS. Methods: Pts with localized > 5 cm grade 2-3 and deep STS of the extremities and trunk wall, ≤65 years, no prior chemotherapy and ECOG PS 0-1 were enrolled in this multicenter phase II study. Pts received 3 cycles of preoperative HDI at a dose of 12 gr/m2 by continuous infusion over 5 days every 3 weeks, with mesna and prophylactic GCSF support, and concomitant external beam RT to a total dose of 50 Gy, followed by surgical resection. Postoperatively, pts with pathological response received 2 cycles of HDI and those with positive surgical margins 16 Gy of RT. The primary study endpoint was pathologic response (≥ 95% pathologic necrosis). A Simon 2-stage design (response rate P0=15%, P1=35%, α=0.10, β=0.10) required at least 2 responses in the first 17 pts to expand to a second cohort, and 7/32 responses to be considered of positive. Results: From March 08 to December 10, 34 pts were included. Two pts were ineligible. Median age was 54 (18-65). Tumor location was extremity (28 pts) and trunk wall (4). Preoperative planned treatment was completed in 87.5% pts. HDI was completed in 87.5% pts while RT in 94% pts. Grade 3-4 toxicities included neutropenic fever (3 pts), anemia (4), asthenia (2), infection (2) and radiation dermatitis (2). 31 pts underwent surgery: 27 were R0 resections, of which 2 were amputations, and 4 were R1 resections. Pathologic response was ≥ 95% necrosis in 9 pts (28%) and 50%-94% necrosis in 12 pts. After a median follow-up of 21 months, estimated 2-year rates for disease-free survival and overall survival were 58% (95%CI, 40%-77%) and 77% (95%CI, 61%-93%), respectively. Conclusions: Preoperative treatment with HDI given concurrently with RT in pts with high-risk STS is feasible and safe, yielding promising pathologic response rates.
The Italian Rare Cancer Network.
Authors: Sanfilippo Roberta , Tricomi Marco , Grosso Federica , Baldi Giacomo , De Troia Beatrice , Fumagalli Elena , Palassini Elena , Stacchiotti Silvia , Bertulli Rossella , Fiore Marco , Dei Tos Angelo Paolo , Casali Paolo Giovanni
Published: March 2020

10053

Background: Rare cancers (RC) are a challenge in terms of quality of care, access to health resources and clinical research. The Italian Rare Cancer Network (RTR: “Rete Tumori Rari”) is a clinical collaborative effort to improve quality of care in adult rare solid cancers in Italy. RTR enables institutions to share clinical cases and to rationalize access to distant reference centers minimizing patient migration. It indirectly promotes collaborative clinical research by encouraging accrual into clinical trials and supporting observational studies. Methods: RTR includes 150 oncology institutions across Italy. Clinical cases are shared asynchronously over a secure Web resource. Data, images and transactions are stored in an online clinical record. Patients are shared: 1. "logically”, when they are dealt with following common clinical practice guidelines; 2. "virtually”, when they are discussed over the network between two or more centers; 3: "physically", when they are referred to an excellence center for a specific treatment modality. Pathology review is arranged through transferal of paraffin-embedded specimens and upload of consultations. While it was chosen not to implement telepathology facilities, a teleradiology resource is now available. Results: From 2003 to 2011, more than 5,000 rare cancers cases (mostly sarcomas) have been uploaded. More than 1,300 teleconsultations have been delivered, while more than 1,000 patients moved across the network during their experience of disease. 700 cases were reviewed pathologically: amongst 365 cases originally diagnosed as soft tissues sarcomas up to 2010, treatment-relevant discordances were recorded in more than one third. An observational prospective study on gastrointestinal stromal tumors was done, enrolling 800 patients. An original paper documenting the activity of a drug in a highly specific sarcoma subgroup was published. Conclusions: Clinical asynchronous online collaboration on RC is feasible through a Web-based secure environment and proved the most practical way of clinical distant sharing. Pathologic review was a crucial network service, with a special added value in RC. Retrospective and prospective observational studies, and unplanned observations in very rare cases, were an interesting by-product.
Advanced soft-tissue sarcoma in patients over age 75: Patterns of care and survival.
Authors: Garbay Decoopman Delphine , Keohan Mary Louise , Cioffi Angela , Maki Robert G. , Bui Nguyen Binh , Italiano Antoine
Published: March 2020

10057

Background: There are no data regarding the management and the outcome of elderly patients (pts) diagnosed with advanced soft-tissue sarcoma (STS). Methods: The charts of pts aged ≥ 75 years and diagnosed with metastatic and/or unresectable STS between 1990 and 2011 at Memorial Sloan Kettering (New York) and Institut Bergonié (Bordeaux, France) were reviewed. Results: 189pts were included.Median age was 79 years (range 75-93).160 pts (84.5%) had metastatic disease. The most frequent histological subtype was leiomyosarcoma (n=57, 30%). The median age-adjusted Charlson comorbidity score was 10 (range 5-17). 120 pts (63.5%) received systemic therapy whereas 69 pts (36.5%) were managed with best supportive care (BSC) only. Pts who received BSC only were more likely ≥ 80 years old (58% versus 38%, p=0.01) and with performance status (PS) ≥ 2 (35% versus 14%, p=0.01). Single agent and combination therapy were delivered in 87 (72.5%) and 33 (27.5%) cases respectively. 67 pts (56%) received a 1st-line anthracycline-containing regimen. The median progression-free survival of pts treated with systemic therapy was 4 months (95% CI: 2.5-5.5). 21 pts (17.5%) had to stop 1st line treatment because of toxicity. On multivariate analysis, age ≥ 80 years, PS ≥ 2, and single-agent therapy were significantly associated with poor PFS. 51 pts received one or more further lines of therapies. At the time of analysis, 170 pts (90%) had died. 96% of deaths were related to the disease. The median OS for the entire cohort of pts was 9.6 months (95% CI: 7.3-12). The 1-year and 2-year OS rates were 43% (95% CI: 36–50), and 22% (95% CI: 16–28), respectively. The median OS of pts managed with systemic therapy and BSC were 12.5 months (95% CI: 8.4-16.6) and 5.1 months (95% CI: 3.7-6.5), respectively (p=0.02). However, on multivariate analysis, PS ≥ 2 and age-adjusted Charlson score ≥ 10 were the sole independent factors significantly associated with OS. Conclusions: A high proportion of elderly pts with advanced STS were considered unfit for chemotherapy. The OS of STS pts ≥ 75 years who were managed with systemic therapy seems similar to that of younger pts. Further efforts are needed to better define the optimal care for fit and unfit elderly pts with advanced STS.
Drug treatment (tx) patterns and survival among patients (pts) with metastatic or recurrent soft tissue sarcoma (m/rSTS) refractory to at least one prior therapy.
Authors: Wagner Michael , Amodu Leo , Duh Mei Sheng , Korves Caroline , Solleza Franco , Mykletun Andrew , Manson Stephanie , Diaz Jose , Neery Maureen P. , Demetri George D.
Published: March 2020

10061

Background: Limited clinical data on real-world practice patterns are available for care of pts with m/rSTS. This study evaluated drug tx patterns and outcomes in m/rSTS pts following failure of prior chemotherapy based on data from a U.S. referral academic cancer center. Methods: Data from medical records consented for research use were retrospectively reviewed at Dana-Farber Cancer Institute for pts with m/rSTS who were ≥18 years, commenced 2nd-line systemic therapy between 1/1/2000 and 2/4/2011, had confirmed disease progression on or after 1st-line therapy and had ≥3 months of observation. Pts were excluded if they had been diagnosed with gastrointestinal stromal tumor, bone sarcoma or dermatofibrosarcoma protuberans, or had ever been treated with pazopanib. Histologic subtype, tx type and duration, tx modifications (e.g., discontinuation) and reasons for modifications were examined. Overall survival, time to progression and clinician-assessed tumor response were collected. Results: Study pts had leiomyosarcoma (n=50), synovial cell sarcoma (n=7), liposarcoma (n=5) and other histologic subtypes (n=39). These 101 pts received an average 4 lines of tx (maximum=10 lines). Wide variations were noted in each line of tx (Table) with no consistent nor dominant regimens. Median 2nd-line tx duration was 4.1 months (95%CI 2.9-5.0). Among 98 pts who discontinued 2nd-line tx, 72 (73%) did so due to progressive disease, 10 due to “completion” of planned tx, and 6 to adverse events. Median progression-free survival from initiation of 2nd-line tx varied across regimens from 2.0 to 6.5 months (overall median 5.5 months). Conclusions: The wide variation in ≥2nd-line tx confirms there is no single “standard” of care for m/rSTS. The majority of pts discontinued 2nd-line tx due to progressive disease and often received additional lines of tx, indicating frequent physician and pt switching of tx. [Table: see text]
Rechallenge with trabectedin in patients with locally advanced or metastatic soft tissue sarcoma following drug holiday: The experience of the French Sarcoma Group (FSG).
Authors: Saada Esma , Rahal Chahineze , Ray Coquard Isabelle , Italiano Antoine , Chevreau Christine , Isambert Nicolas , Bui Binh , Cassar Alexia , Desmoulins Isabelle , Le Cesne Axel , Blay Jean-Yves , Thyss Antoine
Published: March 2020

10062

Background: Trabectedin (T) is a marine-derived alkaloid used to treat advanced soft tissue sarcomas (STS) after ifosfamide and/or anthracyclins failure. Since then, the FSG evaluated the clinical benefit in re-administrating T after an initial hold, either medically indicated or upon patient’s request. Methods: Following an online request, clinical and histopathological data were collected from six centers of the FSG who declared to have rechallenged patients. Baseline data were collected and analyze will be used. Results: From 1999 to 2011, 49 pts with T drug holiday have been identified (26 male/ 23 female), with a median age of 50 y [23-75]. Most frequent histotypes were: myxoid liposarcoma (18, 36.7%), leiomyosarcomas (13, 26.5 %) and well-differentiated/dedifferentiated liposarcoma (9, 18%). WHO grade were 1 in 14 (29%), 2 in 19 (39%) and 3 in 5 (10%) pts respectively. Patients who had a maximum of 2, 3 or 4 therapeutic sequences (TS) with T (drug-holiday and rechallenge) were 41/49 ,7/49 and 1/49 respectively. Median number of cycles for 1, 2, 3 and 4 TS were 7 [3-21], 6 [2-30], 6 [2-9] and 6. Median total number of cycles was 15 [6-43]. Median duration of drug-holiday for 1, 2 and 3 TS were 11 [3-91], 7 [2-29] and 4 months [1-5]. Grade 3-4 toxicities incidence decreased with the number of TS (occurred in 36%, 29%, 14% and 0% of pts with 1, 2, 3 and 4 TS) as well as mean T dose per cycle (1.3 mg/m², 1.2 mg/m², 1.1 mg/m² and 1.1 mg/m² for TS 1, 2, 3, 4). Efficacy decreased with number of TS (Number of CR/PR/SD/PD were 1 (2%)/15 (31%)/33 (67%)/0 for TS1; 0/4 (8%)/29 (59%)/16 (3%) for TS2; 0/1 (14%)/2 (29%)/4 (57%) for TS3 and 0/0/0/1(100%) for TS4). Median overall survival was 5.0 y [2.7-7.3] since T introduction, and 1.5 y [0.1-4.8], 0.8 y [0.5-1.3] and 0.6 y following 2nd, 3rd and 4th T reintroduction respectively. Objective response after TS2 were seen in 4 cases of grade 1 sarcomas. Conclusions: Due to the lack of cumulative toxicities over time with T, its rechallenging in responding patients to T (no progression under T) have to be considered in advanced STS.
Whole-body PET/MR in soft tissue sarcoma (STS) patients.
Authors: Richter Stephan , Platzek Ivan , Beuthien-Baumann Bettina , van den Hoff Joerg , Laniado Michael , Kotzerke Joerg , Kroschinsky Frank , Ehninger Gerhard , Schuler Markus Kajo
Published: March 2020

10068

Background: PET/MR (positron emission tomography/magnetic resonance imaging) is a new whole-body hybrid imaging technique that combines metabolic and cross-sectional diagnostic imaging. To date the only available clinical data are drawn from feasibility studies in small series of head and neck cancers and intracranial tumors. Imaging by combined PET and computed tomography (PET/CT) has been investigated in STS for biopsy guidance, response assessment and grading. Methods: This exploratory analysis evaluated the outcomes of PET/MRI in 21 patients with STS in different treatment settings: (a) neoadjuvant setting, (b) metabolic-driven local therapy in metastatic sarcoma, and (c) palliative treatment. For examination we used an Ingenuity PET/MR system (Philips Healthcare). It combines a 3-Tesla MRI and a PET scanner with time-of-flight technology. Results: PET/MR shows a high contrast imaging without significant artifacts or distortions. (a) Four patients with high-risk sarcoma (3 rhabdo, 1 pleomorphic) completed the planned neoadjuvant therapy. Change in tumor size did not correlat with pathologic response, whereas surgical outcome was well predicted by metabolic changes. Due to this finding the preplanned course of chemotherapy for one patient was changed. (b) To prolong disease stabilization of 3 patients with a remnant metabolic activity in a single spot they underwent a surgical resection of a single metastatic lesion or had a local radiotherapeutic approach. (c) In 3 patients with stable disease after first-line treatment with combination of anthracyline and ifosfamide persisting metabolic activity indicated a switch to another alternative 2nd line regime. Trabectedin as 2nd line therapy decreased metabolic activity that finally resulted in a tumor regression. Conclusions: To our knowledge this is the first report on patients with STS examined with whole-body-PET/MR. PET/MR is feasible in STS and may provide valuable information in treatment, monitoring and prognosis of patients with STS. This technique may help to choose accurate and on-time treatment option without unnecessary time delay. Further prospective studies to evaluate PET/MR in STS are warranted.
Atypical vascular neoplasms and risk of development of angiosarcoma.
Authors: Ravi Vinod , Gupta Rohan , Demicco Elizabeth G , Araujo Dejka M. , Ludwig Joseph A. , Benjamin Robert S. , Wang Wei-Lien , Patel Shreyaskumar
Published: March 2020

10071

Background: Atypical vascular neoplasms are rare cutaneous lesions that develop following radiation therapy to the breast that have evidence of atypia but do not meet all criteria for a diagnosis of angiosarcoma. They typically have a benign course and are managed by surgical resection. Histopathological changes consistent with atypical vascular neoplasm are commonly found adjacent to angiosarcoma and have lead some investigators to believe that these may be precursor lesions to development of angiosarcoma. Methods: We performed a retrospective review of all patients with a diagnosis of atypical vascular neoplasm from 2002 to 2012. Patient with a prior/concurrent history of angiosarcoma were excluded from the analysis. Primary objective of the study was to determine the percentage of patients with atypical vascular neoplasms that progressed to angiosarcoma on long-term follow-up. Results: 37 patients were identified in the tumor registry at MD Anderson cancer center with a diagnosis of atypical vascular neoplasm between 2002 and 2012 with a median follow-up of 24 months. The median age of the study population was 53. Females represented 89% of the study population. Atypical vascular neoplasms occurred most frequently in the breast/chest (70%) and 68% of patients had a prior history of breast cancer. 54% of patients had prior radiation therapy. The median time to development of atypical vascular neoplasms from radiation therapy was 52 months. Among patients who underwent surgical resection with negative margins, there were no recurrences. We failed to observe any progression to angiosarcoma in the study population. Conclusions: Patients with atypical vascular neoplasms may not progress to angiosarcoma and are best managed with surgical resection.
Navigation-assisted surgery for bone and soft tissue tumors with bony extension.
Authors: Ieguchi Makoto , Hoshi Manabu , Takada Jun , Hidaka Noriaki , Shigeoka Yasushi , Nakamura Hiroaki
Published: March 2020

10073

Background: In recent times,minimally invasive surgery, such as endoscopic surgery, has gained a lot of popularity.The navigation system was introduced to orthopedic surgery in the 1990s. These days, computed tomography (CT)-based navigation systems are commonly used in spine and joint replacement surgery because of their precision. The aim of our study was to evaluate the accuracy and efficacy of navigation-assisted excision of bone and soft tissue tumors. Methods: From January 2006 to December 2009, we performed navigation-assisted surgery in 16 patients (11 men and 5 women; mean age, 39 years; range, 13-70 years). We diagnosed 9 benign bone tumors and 7 malignant bone and soft tissue tumors. In 2 patients, the malignant soft tissue tumors infiltrated the adjacent bones. We performed excisional biopsies for the benign tumors and en bloc excisions for the malignant tumors. In all the cases, the point registration method was used with 10 skin markers that were placed around the tumor. Each excisional difference between the preoperative and postoperative plans was evaluated histologically or by postoperative CT. Results: The mean preoperative registration matching time was 12.8 min (range, 8-25 min). The total mean preparation time was 24 min (range, 16-35 min). The mean accuracy of this system, which was determined using the skin markers, was 0.93 mm (range, 0.6-1.5 mm). All biopsied and excised specimens were evaluated by pathologic examination and postoperative CT imaging. The mean difference between the planned margin and postoperative CT or the excised histological specimen was 0 to 4 mm. The mean follow-up period was 53.2 months (range, 10-70 months). There were no local recurrences, except for a case of chordoma that required excision of skip metastases and a case of extraskeletal osteosarcoma, in which the patient died from the disease. Conclusions: We report our experience with navigation-assisted surgery for bone and soft tissue tumors performed using skin markers. Navigation-assisted surgery was indicated in the case of sufficiently reliable, accurate, and minimally invasive resections.
Relationship of CUL4A gene underexpression and prognosis in localized high-risk soft tissue sarcoma (STS) patients of limbs or trunk wall.
Authors: Martin Broto Javier , Lopez-Pousa Antonio , Ramos Rafael , Gronchi Alessandro , Casali Paolo Giovanni , Gutierrez Antonio , Picci Piero , Ferrari Stefano , Cruz Josefina , Luna Fra Pablo , Casado Antonio , Cubedo Ricardo , Lasso Roberto , Poveda Andres , De Juan Ana , Balana Carmen , Calabuig Silvia , Obrador Antonia , Lopez-Guerrero Jose Antonio
Published: March 2020

10079

Background: Genes involved in cell cycle checkpoints and chromosome stability seem to be relevant in distant metastases appearance in STS. CUL4A is an E3 ubiquitin ligase that has been related to both p16 activation and maintenance of genomic stability. Expression of CUL4A has been scarcely described in some tumors with divergent outcome and there are no publications regarding its expression in STS patients. We previously showed that protein underexpression of CUL4A in metastatic STS was related to poor survival. Methods: The expression level of CUL4A was determined by quantitative qPCR and was retrospectively performed in a subset of 39 high-risk (grade 3, deep tumours and > than 5 cm) localized STS of limbs or trunk wall patients for which histological material and clinical data were available. Patients of this series were enrolled prospectively into a randomized clinical trial conducted by the Italian and Spanish sarcoma groups (ISG-GEIS 0101) comparing 3 vs 5 cycles of epirrubicin and ifosfamide. Differences in PFS, RFS, and OS were calculated using log-rank test Results: The median age was 51 years with a median follow-up of 52 months. The pathologic subtypes were undifferentiated pleomorphic sarcoma (35.3%), synovial sarcoma (23.5%) and mixed subtypes (41.2%). Location was distributed as inferior limbs (66.6%), upper limbs (25.5%) and trunk wall (7.9%). No relationship was seen between CUL4A expression and clinical variables (histologic types, location, size or response to neoadjuvant treatment). The expression level of CUL4A was significantly associated with events of progression, 65% vs 32%, p =0.037, for expression values under and over the median respectively. Regarding 4 y actuarial survival, there was a significant worse PFS and RFS for patients underexpressing CUL4A (p=0.041 and 0.009 respectively) and a trend towards worse OS (p=0.056). Conclusions: Expression of CUL4A gene shows a prognostic role in sarcomas within this high risk localized subset of STS patients. The outcome of this exploratory analysis is aligned with our hypothesis that genes implicated in cell cycle regulation and chromosome stability could play a relevant prognostic role in STS.
Phase I, open-label study of olaparib plus cisplatin in patients with advanced solid tumors.
Authors: Balmaña Judith , Tung Nadine M. , Isakoff Steven J. , Graña Begoña , Ryan Paula D. , Rafi Rezvan , Tracy Michael , Winer Eric , Baselga José , Garber Judy Ellen
Published: March 2020

1009

Background: Olaparib (AZD2281) is an oral PARP inhibitor active in advanced ovarian and breast cancers. We conducted a multicenter, dose-finding study assessing safety/ tolerability of olaparib capsules plus cisplatin in patients (pts) with advanced solid tumors (NCT00782574), for potential use in the neoadjuvant setting. Methods: Pts received 21-day(d) cycles of olaparib, continuously (Cont) or intermittently (Int), plus cisplatin on d1 of each cycle.Each cohort recruited ≥3 evaluable pts with expansion to ≥6 pts if ≥1 had a dose-limiting toxicity. The last cohort was expanded to ensure ≥6 pts completed 4 treatment cycles. Pts who completed 6 combined therapy cycles or who stopped cisplatin due to cisplatin-related toxicity could enter the monotherapy phase (up to 400 mg BID olaparib). Primary objective: safety/ tolerability of ≥4 combined cycles; secondary objectives: pharmacokinetics, antitumor activity. Results: 54 pts received treatment; pts had breast (n=42), ovarian (n=10), pancreatic (n=1) or peritoneal (n=1) cancer. Median number of prior regimens = 4 (1–13). C2, C4 and C6 enrolled >6 pts. Most common grade (G) 3/4 AEs: neutropenia (n=9; 16.7%), leukopenia (n=4; 7.4%), anemia (n=3; 5.6%), vomiting (n=3; 5.6%). In C1–C5, 3 pts had AEs leading to discontinuation: 1 in C2 (thrombocytopenia); 2 in C3 (fatigue; complex migraine, dyspnea). In C6, all pts have ended combination phase and no G3/4 hematologic AEs were seen. Overall, 46% of pts had a dose reduction; 32% due to hematologic AEs. There were no drug-related deaths. 35 pts (65%) completed ≥4 combined cycles (C6, n=8). 18/54 evaluable pts (33%) had an objective response (complete, n=1; partial, n=17); 23 (43%) achieved stable disease. 7 pts (13%) had durable responses on monotherapy for ≥1 year. PK and BRCA1/2 data will be presented. Conclusions: Hematologic AEs led to dose reductions + schedule changes of olaparib with cisplatin 75 mg/m2. Tolerability improved with cisplatin 60 mg/m2. Antitumor activity was seen during combination and olaparib monotherapy phases, with some long responders. [Table: see text]
DNA repair metagene signature as a prognostic and predictive factor in molecular breast cancer subtypes.
Authors: Santarpia Libero , Iwamoto Takayuki , Di Leo Angelo , Hayashi Naoki , Stampfer Martha , Guarducci Cristina , Symmans William Fraser , Hortobagyi Gabriel N. , Pusztai Lajos , Giampaolo Bianchini
Published: March 2020

1012

Background: We aimed to assess the prognostic and predictive role of DNA repair genes in breast cancer (bc) molecular subtypes. Methods: We evaluated Affymetrix gene expression profiling from untreated N- patients (N = 684), neoadjuvant treated tumors with taxanes- (N = 320), anthracyclines- (N = 211), and cisplatin- (N = 22) containing regimens. We assessed within 3 BC molecular subgroups (ER+/HER2-, HER2+, and ER-/HER2-) bimodality distribution, prognosis by association with distant relapse (N = 454, N = 105, and N = 125) and predictive value for likelihood of pathological complete response (pCR) (N = 208, N = 105, and N = 240). Moreover, we explored the function of relevant genes in BC cell lines. Results: Three genes (ERCC2, XRCC3, and RECQL4) showed bimodality in each bc subtype. Eight genes were associated with poor prognosis (including RECQL4) and 1 gene with good prognosis (ATM) [P < .0001] only in ER+/HER2- tumors. Our results suggest a subtype and treatment specific association with pCR although they did not satisfy stringent criteria for false discovery correction. In ER-/HER2- mismatch repair (MR) (MSH2 and MSH6) and MTMR15 genes were associated with response and resistance to taxane-containing regimens, respectively. TOP2A was the only gene associated with response to anthracycline but not taxanes in HER2+ tumors. RECQL4 had a positive trend with higher pCR in both ER+ and ER-/HER2- tumors. In in vitro studies we found that RECQL4 interacts with PARP1 and that the expression of these genes was correlated with sensitivity to chemotherapy and PARP inhibitors. Conclusions: We identified MR genes as potential predictive markers of response to taxanes-based regimens in ER-/HER2-. A novel gene RECQL4 showed bimodal distribution, prognostic value, and a trend for predictive association with response to taxanes-based chemotherapy, which was also confirmed by in vitro analysis. ATM deserves further evaluation as prognostic marker in ER+/HER2-.
Cancer gene profile of metastatic breast cancer.
Authors: Meric-Bernstam Funda , Frampton Garrett , Ferrer-Lozano Jaime , Yelensky Roman , Palmer Gary A. , Cronin Maureen T. , Stephens Philip J , Hale Katherine Stemke , Barrera Juan , Burgues Octavio , Lluch Ana , Mills Gordon B. , Gonzalez-Angulo Ana M.
Published: March 2020

1015

Background: There is great interest in using genomic information to guide therapy selection in cancer patients. The aim of this study was to determine the spectrum of genomic alterations identified in MBC patients, and evaluate the concordance of alterations between primary and recurrent tumors. Methods: We performed comprehensive profiling on formalin-fixed paraffin embedded samples from 42 patients with MBC using a targeted next generation sequencing (NGS) assay in a CLIA laboratory (Foundation Medicine). Genomic libraries were captured for 3,230 exons in 182 cancer related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to an average depth of 390X with 99% of bases covered >100X. In total 30 primary and 37 recurrent tumors were profiled, including 3 separate recurrences in 1 patient and matched primary-recurrences in 22 patients. Point mutations, indels, copy number alterations and rearrangements were assessed. Alterations that are targetable with established or investigational therapeutics were considered “actionable”. Results: At least 1 genomic alteration was identified in all but 2 breast samples (both primary tumors). Point mutations were identified in several cancer-related genes including PIK3CA, TP53, PTEN, CDH1, ARID1A, AKT1, NF1, FBXW7 and FGFR3. Amplification was observed in HER2; 11 of 12 HER2 IHC positive samples were found to have HER2 gains by NGS; in addition, a HER2 gain was identified by NGS in a HER2- (1+ IHC) sample. Amplification of PIK3CA, IGF1R, FGFR2, AKT2, MDM2, and MCL1 plus a CDKN2A homozygous deletion were also identified. While the majority of known driver alterations (85%) were concordant in the matched pairs of primary and recurrent tumors, in 11 of 22 sets there was at least 1 discordant driver alteration, and these included both gains and losses of potential therapeutic targets. Overall 32 of 42 patients (76%) had an actionable genomic alteration. Conclusions: Genomic profiling of breast cancer samples reveals genomic alterations in most metastatic breast cancer patients. Over three quarters of patients have actionable findings, suggesting that genomic profiling may assist in individualized pathway-directed therapy.
A gene expression signature of MEK pathway activation to predict survival in triple-negative breast cancer.
Authors: Balko Justin M. , Sanders Melinda , Kuba Maria Gabriela , Pinto Joseph A. , Doimi Franco F. , Gomez Henry Leonidas , Arteaga Carlos L.
Published: March 2020

1024

Background: Tumor cell proliferation measured by Ki67 in the surgically removed tumor after neoadjuvant chemotherapy (NAC) has been shown to predict patient outcome in breast cancer. It is unclear from these studies if breast cancer subtype may account in part for the predictive ability of Ki67. Thus, we tested whether Ki67 score in the surgically-resected residual tumor (RT) after NAC predicted outcome in a cohort of triple negative breast cancer (TNBC). Gene expression profiling was performed to identify molecular subtype and test the association with gene modules indicative of signaling pathway activation. Methods: Ki67 was scored in the RT of 89 patients with stage II-III TNBC (ER/PR/HER2 negative by IHC at diagnosis) that had been treated with NAC. Expression levels for 450 genes were quantified by Nanostring. Ki67, node and menopause status, age, therapy type (± taxanes), molecular subtype, and gene expression scores were tested for association to RFS and OS using univariate and multivariate CoxPH models. Results: Ki67 score in the post-NAC RT demonstrated a wide range (1.5-77.7%; median: 36.2%). Twenty seven % of RTs were 3+ HER2 by IHC. Molecular subtype in the RT was as follows: 64% Basal-like; 20% HER2-enriched; 6% LumA; 6% LumB; 4% Normal-like. In univariate analyses to respectively predict RFS and OS, node status (p=0.005 and p=0.02), number of nodes (p=0.003 and p<0.001), and the score of a gene expression module of MEK pathway activation (p=0.04 and p=0.01,) were significant. Basal-like subtype approached significance for RFS (p=0.1) and OS (p=0.05). In multivariate analyses, node status (p=0.002 for RFS and p<0.001 for OS) and MEK pathway activation score (p=0.04 and p=0.01) were significant predictors. Conclusions: Ki67 in the RT after NAC was not predictive of outcome in a cohort of TNBC. However, a gene expression signature of activated MEK was negatively associated with outcome. These data are consistent with the reported preclinical activity of MEK inhibitors against basal-like breast cancer cells and a possible role of this signaling pathway in chemotherapy resistance. They also support deep sequencing studies to identify genetic alterations in the RAS/MEK/MAPK pathway in TNBC.
Impact of surgery and radiation of the primary among women with de novo stage IV breast cancer.
Authors: Dawood Shaheenah S. , Dent Rebecca Alexandra , Gupta Sudeep , Litton Jennifer Keating , Mustafa Rashid , Cortes Javier , Mittendorf Elizabeth Ann , Gonzalez-Angulo Ana M. , Buchholz Thomas A.
Published: March 2020

1032

Background: The aim of this retrospective study was to determine the impact of surgery(S) and radiation(R) therapy to the primary tumor among patients (pts) with stage IV denovo breast cancer. Methods: The SEER registry was used to identify pts with denovo stageIV breast cancer diagnosed between 1988 and 2008. Pts were divided into 4 groups based on type of treatment to primary tumor: both S+R, S alone, R alone, or no treatment of primary (no S/R). Breast cancer specific survival (BCS) was calculated from the date of diagnosis of breast cancer to the date of death from breast cancer or last follow up. Survival outcomes were estimated by the Kaplan-Meier method, and Cox models were fit to determine the association between treatment of primary and survival after adjusting for potential confounders (e.g age, grade, hormone receptor and race). Results: 25903 pts were identified; 4640 (17.9%) S+R, 6556 (25.3%) S, 4467 (17.2%) R, and 10240 (39.5%) no S/R. 1183 (4.6%) had surgery to sites other than the primary. Median age was 63 years. Median follow-up was 14 months. Median BCS was 23 months. Median BCS among pts who underwent S+R, S, R and no S/R was 36 months, 31 months, 18 months and 15 months respectively (p<0.0001). Among pts who underwent S+R, median BCS among pts who did and did not have surgery to sites other than primary was 50 months and 41 months respectively (p=0.029). Of the pts treated with S+R 10-year BCS was 18%. In the multivariable model compared to women who were in the no S/R group those who underwent S (HR= 0.59, 95%CI 0.55- 0.62,p<0.0001) and S+R (HR=0.51, 95%CI 0.47-0.55,p<0.0001) had decreased risk of death from breast cancer and those who underwent R (HR=1.13, 95% CI 1.04-1.21, p=0.002) had an increased risk of death from breast cancer. Pts who had surgery to sites other than the primary tumor had decreased risk of death from breast cancer compared to those who did not (HR=0.80, 95%CI 0.72-0.89,p<0.0001). Conclusions: Our results indicate that S+R of the primary breast tumor among pts with denovo stage IV breast cancer maybe associated with a decreased risk of death from breast cancer. A select subgroup of pts who undergo S+R may also benefit from surgery to sites other than the primary which may afford them maximum survival advantage.
Comprehensive investigation of adverse event (AE)-related costs in patients with metastatic breast cancer (MBC) treated with first- and second-line chemotherapies.
Authors: Hurvitz Sara A. , Guerin Annie , Brammer Melissa G. , Guardino Ellie , Zhou Zheng-Yi , Kaminsky Michael S , Wu Eric Q. , Lalla Deepa
Published: March 2020

1037

Background: MBC is incurable and managed with ongoing therapy. This study examined the incremental costs of chemotherapy-associated AEs in MBC. Methods: The PharMetrics Integrated Database (2000-2010) was used to identify MBC pts treated either 1st or 2nd line with a taxane (T) (paclitaxel or docetaxel) or capecitabine (C)-based regimen for ≥30 days (defined as a treatment episode (TE)). Incremental costs attributable to AEs were assessed by comparing costs incurred during TEs with and without AEs. AEs were identified using medical claims with a diagnosis for ≥1 event of interest (e.g., infections, fatigue, anemia, neutropenia). Pt characteristics were balanced between comparison groups (with and w/o AEs) using inverse probability weighting method. Incremental monthly costs due to AEs were estimated during the TEs and included the following cost components: inpt (IP), outpt (OP), emergency room (ER), other medical service, pharmacy costs (chemotherapy and other drugs), and total healthcare costs. Statistical comparisons were conducted using Wilcoxon tests. Results: 3,222 women (mean age=57) received a T or C as 1st or 2nd-line therapy for MBC. Of the 2,678 1st-line pts, 69.7% received T and 30.3% with C; average monthly total costs ranged from $9,159 to $10,298. AEs were commonly seen in pts treated with 1st-line T and C (94.6% and 83.7%). On average, the total monthly incremental cost associated with AEs was 38% higher ($3,547) for T and 9% higher ($854) for C. IP and other drug costs accounted for a majority of these costs. Of 1,084 2nd-line pts, 66% received T and 34% C, with average monthly total costs ranging from $5,950 to $12,979. 94.4% of T pts and 84% of C pts in the 2nd-line had an AE. The average total monthly incremental cost associated with AEs for T was $5,320 and $4,933 for C (69.5% and 82.9% higher vs pts w/o AEs). Pharmacy costs accounted for a majority of increased costs seen in pts with AEs treated with T; IP and OP accounted for a majority of these costs in pts treated with C. Conclusions: This is the 1st study assessing costs associated with AEs for tx of mBC. AEs are associated with a substantial economic burden that is mainly explained by increased IP, OP, and pharmacy costs.
Association between vitamin D deficiency and breast cancer histology: A retrospective database review.
Authors: Bhargava Ranjana S. , Zhu Yue , Weinstock Chana , Hanna Nader , Tkaczuk Katherine Hanna , Bao Ting , Chumsri Saranya
Published: March 2020

1039

Background: Vitamin D (Vit D) deficiency has been shown to be associated with a higher risk of developing breast cancer. Inverse association has also been shown between vit D level and tumor size. However, the association between vit D deficiency and breast cancer histology remains unclear. Preclinical data has suggested that vit D plays an essential role in the terminal differentiation of breast cells. Thus, we hypothesize that vit D deficiency would be associated with estrogen receptor-negative tumors, particularly triple-negative breast cancers (TNBC) which are associated with aggressive clinical course. Methods: We conducted a retrospective database review to obtain information including age, race, tumor histology, size, stage, and vit D levels in newly diagnosed breast cancer patients at University of Maryland Greenebaum Cancer Center. Results: 150 patients presented between July 2008 and August 2011 were included in this analysis. Average age at diagnosis was 57 (range 30-87), and 56% of patients were African American. Overall, 80% of the patients were vit D deficient at diagnosis, with levels < 30 ng/ml. African-American patients were more likely to be severely vit D deficient with levels < 10 ng/ml compared to Caucasians (33% vs. 7.5%, p= 0.0002). Patients with TNBC were more likely to be vit D deficient at diagnosis compared to hormone receptor-positive patients (93% vs. 76%, p =0.015). These patients also had the lowest mean (18) and median (16) of vit D levels compared to all other patients. This difference is also statistically significant in multivariate analysis when adjusted for age, race, and stage (OR 3.96; p=0.04). Regardless of the ER/PR status, Her 2 negative patients were more vit D deficient compared to Her 2 positive patients (86% vs. 61%, p=0.001). Unlike previous studies, no correlation was seen between tumor size and vit D levels. Furthermore, there is also no association between stage, nodal involvement, or Ki67 and vit D level. Conclusions: Vit D deficiency is common among patients with newly-diagnosed breast cancer, particularly African American patients. Patients with TNBC have a significantly higher likelihood of being vit D deficient than patients with other histological subtypes.
Gene expression profiles of circulating tumor cells in metastatic breast cancer patients.
Authors: Mostert Bianca , Sieuwerts Anieta M , Kraan Jaco , Bolt-de Vries Joan , Peeters Dieter , Dirix Luc , Seynaeve Caroline M. , Jager A. , de Jongh Felix E , Hamberg Paul , Stouthard Jacqueline , Kehrer Diederik F. S. , Look Maxime P , Smid Marcel , Jiang Yuqiu , Wang Yixin , Gratama Jan W , Foekens John A , Martens John W.M , Sleijfer Stefan
Published: March 2020

10504

Background: A circulating tumor cell (CTC) count is an established prognostic factor in metastatic breast cancer. Besides enumeration, CTC characterization promises to further improve outcome prediction and treatment guidance. We have previously shown the feasibility of measuring the expression of a panel of 96 clinically relevant genes in CTCs in a leukocyte background, and in the current study, we determined the prognostic value of CTC gene expression profiling in metastatic breast cancer. Methods: CTCs were isolated and enumerated from blood of 130 metastatic breast cancer patients prior to start of first-line systemic, endocrine or chemotherapeutic, therapy. Of these, 103 were evaluable for mRNA gene expression levels measured by quantitative RT-PCR in relation to time to treatment switch (TTS). Separate prognostic CTC gene profiles were generated by leave-one-out cross validation for all patients and for patients with ≥5 CTCs per 7.5 mL blood, and cut-offs were chosen to ensure optimal prediction of patients who might benefit from an early therapy switch. Results: In the total cohort, of whom 56% received chemotherapeutic and 44% endocrine therapy, baseline CTC count (≥5 versus <5 CTCs/7.5 mL blood) predicted for TTS (Hazard Ratio (HR) 2.92 [95% Confidence Interval (CI) 1.71 – 4.95] P <0.0001). A 16-gene CTC profile for all patients and a separate 9-gene CTC profile applicable for patients with ≥5 CTCs were identified, which distinguished those patients with TTS or death within 9 months from those with a more favorable outcome. Test performance for both profiles was favorable; the 16-gene profile had 90% sensitivity, 38% specificity, 50% positive predictive value (PPV) and 85% negative predictive value (NPV), and the 9-gene profile performed slightly better at 92% sensitivity, 52% specificity, 66% PPV and 87% NPV. In multivariate Cox regression analysis, the 16-gene profile was the only factor independently associated with TTS (HR 3.15 [95%CI 1.35 – 7.33] P 0.008). Conclusions: Two CTC gene expression profiles were discovered, which provide prognostic value in metastatic breast cancer patients. This study further underscores the potential of molecular characterization of CTCs.
Circulating DNA analysis and concordance with tumor section analysis in the detection of KRAS and BRAF point mutations from metastatic colorectal cancer.
Authors: Thierry Alain R. , Mouliere Florent , El Messaoudi Safia , Rolet Fanny , Lamy Pierre-Jean , Lopez-Crapez Evelyne , Mollevi Caroline , Bibeau Frederic , Loriot Virginie , Gongora Celine , Del rio Maguy , Molina Franck , Mathonnet Muriel , Pezet Denis , Ychou Marc
Published: March 2020

10505

Background: We developed a specific method for circulating cell-free DNA (ctDNA) enabling the detection of point mutations. CtDNA exists at high level in patients with different types of cancer, and presents great potential in regards, in particular, to its low invasiveness, rapid data turnaround and cost effectiveness. We described here the first blinded prospective study on the comparison of KRAS and BRAF mutational status data obtained from the analysis of ctDNA and tumor section. Methods: Intplex is a refined Q-PCR-based method specifically designed to analyze ctDNA. IntPlex allows not only the detection of point mutations, but also the determination of tumor-ctDNA concentration and fragmentation index simultaneously. Intplex sensitivity is 0.01% (mutant to WT ratio) and is unprecedented among Q-PCR-based methods. The study was conducted from a multicenter cohort of 79 metastatic CRC patients not having received chemo- or radio-therapy within the month prior to blood sample collection. Results: Mutational status could not be determined in 9 samples with one of the two methods. CtDNA analysis showed 100% specificity and 87% sensitivity for KRAS detection (only three samples are misclassified) as compared to tumor section analysis with 23/70 (33%) positive samples, the concordance value being 96%. For BRAF mutation, the method exhibited a specificity and a sensibility of 100% with 5/70 (7%) positive samples (concordance of 100%). When combining KRAS and BRAF mutations, 100% specificity, 89% sensibility and 98% concordance were determined. The three discordant samples may be explained by the malignant genotype of primary tumor versus metastasis, or by the sensitivity of our detection method. The mutation load (median, 12.4%) expressed as the proportion of mutant allele in ctDNA is highly variable (0.037% to 69%) among mutated samples showing a very high inter-individual heterogeneity. Conclusions: Our blinded prospective multicenter study clearly showed for the first time that tumor section analysis might be advantageously replaced by ctDNA analysis, enlarging personalized medicine power for cancer patients.