bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized phase II study of dacarbazine plus gemcitabine versus DTIC alone in patients with advanced soft tissue sarcoma: A Spanish Group for Research on Sarcomas (GEIS) study
Authors: Garcia Del Muro X. , Fra J. , Lopez Pousa A. , Maurel J. , Martín J. , Martínez Trufero J. , Casado A. , Cruz J. , Gómez España M. A. , Lavernia J.
Published: August 2020

10529

Background: Dacarbazine (D) and gemcitabine (G) are active as single agents in the treatment of patients (pts) with advanced soft tissue sarcoma (STS) resistant to standard chemotherapy. The purpose of this study was to assess if the combination of D and G (Buesa et al. Cancer. 2004;101:2261) improved clinical outcome compared with standard D. Methods: Pts with advanced STS progressing after doxorubicin and ifosfamide, PS 0–2, no prior G or D, measurable disease and adequate organ function, were randomized to receive G 1,800 mg/m2 as a fixed dose infusion rate (10 mg/m2/min) and D 500 mg/m2 every 2 weeks, or D 1,200 mg/m2 alone every 3 weeks. Pts were stratified by PS and interval since the initial diagnosis. The primary endpoint was progression-free rate (PFR) at 3 months, based on EORTC reference values. A one-sample binomial design was used. To detect an increase in PFR at 3 months from 40% to 60% with a power of 80% and a two-sided alpha of 0.05, 49 pts had to be accrued per arm (an additional 10% was permitted, to allow for pts who could not be evaluated). Results: From November 2005 to September 2008, 113 pts from 18 centers were randomized. 3 pts were ineligible. Baseline characteristics were well-balanced between both arms. The median number of cycles administered of D+G and D were 6 (2–13) and 2 (1–10), respectively. PR and SD >12 weeks rates were 9% and 38% (D+G) vs. 4% and 19% (D) respectively (p=.01). PFR at 3 months was 59% (D+G) vs. 35% (D) (p=.001). 29 pts were free of progression at 3 months among the first 49 pts in the D+G arm (26 required to be the study positive). Median progression-free survival was 4.4 (D+G) vs. 1.9 (D) months (p=.002). Median overall survival was 17.1 (D+G) vs. 9.9 (D) months (p=.007). Asthenia, emesis and stomatitis were the most common nonhematologic effects. Severe anemia and thrombocytopenia were more frequent with D and granulocytopenia with D+G. Conclusions: The combination of D plus G is active and well-tolerated in pts with pretreated STS, yielding significant improvement in survival.

No significant financial relationships to disclose.
A dose-escalating study of XRP6258 in combination with capecitabine, in patients (pts) with metastatic breast cancer (MBC) progressing after anthracycline and taxane therapy: Preliminary results
Authors: Besse-Hammer T. , Villanueva C. , Campone M. , Machiels J. , Awada A. , Magherini E. , Dubin F. , Semiond D. , Pivot X. B.
Published: August 2020

1053

Background: Cabazitaxel (X), a new taxoid showed activity in taxane resistant MBC. Capecitabine (C) is approved in MBC pts pretreated with anthracycline and taxane. Methods: A standard 3+3 escalation scheme explored doses of combined intravenous X (Day (D)1) with oral C twice daily (D1to14), every 3 weeks (q3w). The study objectives were the identification of dose limiting toxicities (DLTs), recommended dose (RD) of the combination, assessment of safety, pharmacokinetics (PK) and activity at the RD in an expanded cohort. Results: 32 MBC pts pretreated with taxane and anthracycline were enrolled and treated (15 in the dose escalation part and 17 at the RD). Data for the first 25 pts, are available so far: median age 52 [34–74], ECOG-PS 0/1: 15/10, in first or second line chemotherapy, median of 3 (1–7) organs involved (mainly: bone, liver, lymph nodes). In the escalation part, X+C were administered at 3 dose levels (DL) (Table). DL2 was defined as the RD and the expansion cohort was initiated. PK analysis did not show any drug-drug interaction with this schedule of administration. Overall, out of the 25 pts (125cy), the main Gr3–4 toxicities (N pts) were asthenia (4), hand-foot syndrome (4), neutropenia (15), febrile neutropenia (1), neutropenic infection (1), no toxic death. Efficacy was observed at each DL with a total of 1 complete response, 4 partial responses (PR) and 16 stabilizations (including 3 unconfirmed PR). Conclusions: X was safely combined to C. X at 20 mg/m2 D1 + C at 1000 mg/m2 twice a D (D1–14), q3w is the RD. Updated results for efficacy and safety will be presented.

[Table: see text]

[Table: see text]
Type of progression in patients treated with imatinib for advanced gastrointestinal stromal tumor (GIST): A study based on the EORTC-ISG-AGITG trial 62005
Authors: Van Glabbeke M. M. , Verweij J. , Casali P. , Zalcberg J. , Le Cesne A. , Reichardt P. , Issels R. , Judson I. , Debiec-Rychter M. , Blay J.
Published: August 2020

10536

Background: Development of resistance in GIST patients responding to targeted agents is heterogeneous, and different types of mutations may be observed in different lesions of the same patient. Progressive disease (PD) is defined as increase in size of initial lesions, occurrence of new lesions, or both (RECIST): mixed progression (MXPD), were new lesions develop when old lesions are still responding could represent a different type of biological event. We evaluated the impact of progression type and time to first PD (TTP) on survival after progression (SAP) in a randomized phase III trial comparing two doses of imatinib as first line treatment of GIST in 946 patients. Methods: PD was classified into 5 categories: PD in old lesion without new lesions (PD-), and new lesions associated with CR (CR+), PR (PR+), NC (NC+) and finally PD (PD+); MXPD was defined as CR+ or PR+. We investigated the correlations between type of PD, baseline patients’ characteristics, imatinib dose, TTP and SAP with univariate (UVA) and multivariate (MVA) analysis. Results: Currently, 516 patients with PD have been radiologically documented. PD-, CR+, PR+, NC+, and PD+ were observed respectively in 47%, 2%, 10%, 8%, and 33% of the cases. MXPD was more frequent in patients without prior chemotherapy (15% vs 8%), or with a long TTP (0–6 m: 1%; 6–12 m: 8%; 12–24 m: 12%; 24–60 m: 19%; 60+ m: 25%). MXPD was less frequent in KIT exon 9 mutants (7%) and wild types (4%) than in KIT exon 11 mutants (17%) (UVA), but this is entirely explained by their shorter TTP (MVA). No other correlation was found with imatinib dose or baseline factors. SAP was shown to increases with TTP (P<0.0001), and was independently (and adversely) affected by PD of old lesions and development of new lesions: when compared to PD- patients, TTP adjusted SAP hazard ratio for patients with new lesions were 0.28 (CR+), 1.07 (PR+), 1.32 (NC+) and 1.61 (PD+). SAP was longer after MXPD (UVA), but this is explained by their longer TTP (MVA). Conclusions: In GIST patients treated with imatinib, survival after first progression increases with time to progression and decreases with “severity” of progression. Mixed progressions occur later than other types of progression, and therefore lead to a longer further survival.

[Table: see text]
Age as prognostic factor in osteosarcoma
Authors: Hagleitner M. , Hoogerbrugge P. , Flucke U. , Schreuder H. , van de Luijtgaarden A. , van der Graaf W. , te Loo M.
Published: August 2020

10537

Background: Osteosarcoma may occur at all ages but has a distinct age distribution from 10 to 20 years old. Several retrospective studies of osteosarcoma suggest a favourable outcome for children compared to adults. To evaluate whether age is indeed related to outcome, we retrospectively analyzed patients with osteosarcoma under the age of forty. Furthermore, we retrospectively analyzed whether outcome of osteosarcoma in young adult patients is different when treatment took place in a pediatric or an adult oncology department. Methods: Patients with primary osteosarcoma treated in our hospital between 1978 and 2008 were included in this study. To evaluate the role of age, patients were divided in two groups: less than 20 and 20 - 40 years of age. Prognostic factors including histological response after neoadjuvant chemotherapy, were analyzed using Cox regression multivariate analysis. Results: In total, 102 patients with primary osteosarcoma were included. Overall survival (OS) of the whole population was 50.7% with a 5-years event-free survival of 47.1%. Age markedly affected survival with an OS of 61.1% in patients below 20 years of age and 38.6% in the patient group between twenty and forty years (p=0.014). There was no significant difference in prognostic factors, such as presence of metastasis at diagnosis. Pediatric patients under the age of 10 had a superior OS of 71.4% (p =0.02) compared to patients older than 10 years. Overall survival of patients aged 14–20 years was not significant different when treated in a pediatric oncology department as compared to treatment in an adult department (57.9% vs. 47.4%, p= 0.705) . Osteosarcoma patients older than 20 years, showed a worse histologic response to pre-operative chemotherapy and experienced more toxicity. Dose reduction due to toxicity was applied in 20.8% of adults vs. in 1.9% (p=0.002) of the children. Conclusions: Based on the results found in this study, we conclude that age is an independent prognostic factor for outcome of patients with primary osteosarcoma.

No significant financial relationships to disclose.
Clinical outcomes of patients with breast cancer in a phase I clinic: The M. D. Anderson Cancer Center experience
Authors: Wheler J. J. , Tsimberidou A. , Moulder S. , Cristofanill M. , Hong D. , Naing A. , Pathak R. , Liu S. , Feng L. , Kurzrock R.
Published: August 2020

1054

Background: Patients with metastatic breast cancer refractory to standard therapy are eligible for phase I trials. We assessed prognostic factors and clinical outcomes for patients with breast cancer in a phase I clinic focused on targeted agents. Methods: We reviewed the medical records of sequential patients with metastatic breast cancer who presented to our phase I clinic from September 2004 to May 2008. We assessed the relationship between overall survival and patients’ demographic and clinical characteristics using both univariate and multivariate (Cox proportional hazard model) analyses. Results: Ninety-two patients were identified with median age of 53 years (range 28 to 83 years). The median number of prior therapies was 5 (range 1 to 16). The median follow-up of surviving patients is 7.4 months. The median overall survival is 6.7 (95% CI: 5.2, 9.7) months. In univariate analysis, factors predicting shorter survival were elevated Ca-125 (p = 0.001) (Ca27.29 was not significant), albumin < 3.5 g/dL (p = 0.002), worsening ECOG performance status (p = 0.004), absolute neutrophil count < 7.3 x 109/L (p = 0.004), ≥ 10 prior treatment regimens (p = 0.008), ≥ 5 prior chemotherapy-only regimens (p = 0.008), body mass index (BMI) < 25 (p = 0.018), and elevated platelet counts (p = 0.007). In multivariate analysis, independent factors predicting shorter survival were ≥10 prior treatments (vs. <10 prior treatments) (HR = 3.27; 95% CI 1.37, 7.81; p = 0.0077), ECOG performance status 2–3 (vs. 0–1) (HR = 2.92; 95% CI 1.28, 6.66; p = 0.01), and albumin < 3.5 g/dL (vs. > 3.5g/dL) (hazard ratio [HR] = 2.88; 95% CI; 1.41, 5.89; p = 0.004). Of 78 patients treated on a first phase I trial, 14 (18%) demonstrated stable disease (SD), with a median duration of 18 weeks (range 10–25). Of those 19 patients treated on a second phase I trial, 6 (32%) had SD with a median duration of 12 weeks (range 8–17). Two of 4 (50%) patients treated on a third phase I trial had SD with a median duration of 20 weeks (range 16–24). Conclusions: Patients with metastatic breast cancer referred for our phase I studies had a median survival of 6.6 months. In this preliminary analysis, independent factors predicting shorter survival were ≥ 10 prior treatments, worsening ECOG performance status and low albumin levels.

No significant financial relationships to disclose.
A retrospective study of parameters influencing survival after surgical resection of lung metastases of bone and soft tissue sarcomas
Authors: Piperno-Neumann S. , Homicsko K. , Mussot S. , Anract P. , Laurence V. , Pierga J. , Mignot L. , Chapelier A.
Published: August 2020

10541

Background: Due to the high rate of isolated lung metastases of sarcomas, a multidisciplinary approach combining chemotherapy with pulmonary metastasectomy (PM) is helpful to achieve R0 resection and try to increase progression free survival (PFS) and overall survival (OS). The aim of this retrospective study is to describe the clinical and tumor features of 70 consecutive operated patients and to identify the factors influencing survival. Methods: 70 patients undergoing PM at Foch Hospital or CCML between 1995 and 2006 were identified, with follow-up (FU) for a minimum of 3 years after last PM. Statview program has been used to create survival curves, Cox proportional hazard model for multivariate analysis. Results: 64 patients had grade II/III sarcomas of mainly lower limb origin.15 patients had synchronous lung metastases, 35 showed bilateral lesions (mean number of 4, mean size of 12 mm). No patient had extrapulmonary disease at the time of PM. 51% were primary bone sarcomas (24 osteo, 9 Ewing, 3 chondro) and 49 % were soft tissue sarcomas (including 12 synovial, 9 leio). The primary tumor treatment consisted in conservative surgery in 58 patients (83%). 49 patients received neo and/or adjuvant chemotherapy, 22 patients had postoperative radiotherapy. All patients underwent PM: 1 pneumonectomy, 15 lobectomy and 54 wedge resection. 21 patients required bilateral PM. The resection margins were classified R0/R1/R2 in 54/16/0 patients, R0 was confirmed in 44 by CT scan in a month after PM. With a median FU from diagnosis of 7.7 years, the median OS for all patients reached 59 months, and the median survival after metastasectomy (OSPM) 31 months. The 5-year OS and OSPM rates were 77% and 59% respectively. The mean PFS was 20 months. 25 patients underwent subsequent PM for recurrent lung metastases, 30 are still alive. On univariate analysis, primary high grade, DFI>24 months, number of metastases>3 and largest diameter>25 mm were significant negative factors for OS. Multivariate analysis confirmed the importance of high grade, DFI, and size of metastases for OS. R0 was associated with prolonged PFS after PM. Conclusions: Accurate patient selection and technical aspects of PM are related to optimal R0 rate. DFI may be a surrogate marker for tumor biology.

No significant financial relationships to disclose.
ACRIN 6665/RTOG 0132 phase II trial of neoadjuvant imatinib mesylate (IM) for primary and recurrent operable malignant GIST: Imaging findings and correlation with genotype and GLUT4 expression
Authors: Van den Abbeele A. D. , Gatsonis C. , de Vries D. J. , Melenevsky Y. , Szot Barnes A. , Yap J. T. , Godwin A. K. , Blevins M. , Eisenberg B. , Siegel B. A.
Published: August 2020

10552

Background: IM has improved the treatment of GIST patients (pts), but few achieve objective response despite significant clinical benefit. Imaging of tumor metabolism may provide earlier assessment of therapeutic response. In this study, FDG-PET metabolic response (MR) was compared with RECIST, GLUT4 expression, and KIT/PDGFRA mutation status. Methods: FDG-PET was done at baseline, 1–7 days, and 4 or 8 weeks (wk) after IM initiation. Best objective response was defined by RECIST. Immunohistochemical (IHC) tumor GLUT4 expression and mutation analyses were done at baseline and/or surgery. Background-subtracted SUVmax was measured in all lesions and summed; MR based on EORTC criteria was compared to RECIST, GLUT4 expression, and KIT/PDGFRA mutation status. Results: FDG-PET showed high tumor glycolytic activity at baseline (mean SUVmax = 14.2, range: 1.3–53.2), decreasing after 1 wk of IM (5.5, range: 0.5–47.7, p < 0.001, n = 44), and again prior to surgery (3.0, range: 0.5–36.1, p < 0.001, n = 40). FDG-PET response at wk 1 was 3 complete MR (CMR), 33 partial MR (PMR), 6 stable metabolic disease (SMD), and 2 progressive metabolic disease (PMD). Prior to surgery, FDG-PET response was 3 CMR, 33 PMR, 4 SMD, and no PMD. For 39 pts, RECIST best response was 2 PR, 36 SD, and 1 PD. GLUT4 expression decreased in 19 pts with PMR, and 3 with SMD. Among 12 pts with exon 11 mutation, 11 had PMR, 1 SMD; among 5 pts with wild-type genotype, 4 had PMR, and 1 SMD. Conclusions: After IM initiation, MR by FDG-PET was documented earlier (1–7 days), and was of much greater magnitude (36/40) than that documented by RECIST (2/39). IHC data suggest that: (1) GLUT4 plays a role in FDG uptake in GIST; (2) GLUT4 decreases in most pts with PMR; and, (3) the biologic action of IM interacts with glycolysis and GLUT4 expression. No difference in PMR was seen in pts with exon 11 vs. wild type mutations.

[Table: see text]
Simultaneous gastrointestinal stromal tumor (GIST) and desmoid fibromatosis (DF)
Authors: Dumont A. G. , Lev D. , Lazar A. , Joensuu H. , Trent J.
Published: August 2020

10568

Background: Desmoid Fibromatosis (DF) is one of a group of rare fibrous tissue proliferations (2–4 cases per year per million) which tend to be locally aggressive but have no propensity for metastasis. Gastrointestinal Stromal Tumor (GIST) is the most common mesenchymal tumors of the gastrointestinal tract and also rare (15–20 cases per year per million). Anecdotal reports of individuals with both diseases led us to investigate the number of patients at our institute with both types of cancer and their clinical, and histopathologic features. Methods: We identified four cases of GIST associated with DF at the M. D. Anderson Cancer Center between 1995 and 2008 using an IRB-approved protocol. Two more cases were identified from the patient database at the University of Helsinki. Results: Our patients were three men and three women aged from 39 to 66. Two patients were African Americans and 3 were Caucasians. In 5 cases, the GIST was diagnosed prior to the DF while one case had both tumors synchronous at presentation. The primary site of the GIST was gastric in 4 cases and the others were jejunal and mesenteric. Three patients had their DF occur in the surgical incision site mimicking a recurrence of GIST. The 3 others were intra-abdominal DF. There were no cases of DF occurring outside of the GI tract. One GIST patient was metastatic at presentation and one developed metastasis before DF was diagnosed. In 5 cases, imatinib mesylate was administered to the patients with partial response. In all cases KIT expression was observed immunohistochemically for GIST and but not for DF. Additionally, all cases of DF but no cases of GIST were found to have beta-catenin expression by immunohistochemistry. Conclusions: Our findings suggest that concurrent DF may occur in patients with GIST. Additionally, DF may mimic the recurrence of GIST or imatinib resistance. The association of these two sarcomas should be further explored.

No significant financial relationships to disclose.
Solitary fibrous tumor: A retrospective analysis on 65 patients from a reference center
Authors: Palassini E. , Stacchiotti S. , Collini P. , Pilotti S. , Pastorino U. , Cantù G. , Fiore M. , Gronchi A. , Casali P. G.
Published: August 2020

10572

Background: Solitary fibrous tumors (SFT) are very rare mesenchymal tumors with an unpredictable malignant potential. We retrospectively reviewed the long-term outcome of patients operated on at the Istituto Nazionale Tumori (INT), Milan, in a 18-year time span. Methods: All patients who underwent surgery at INT from 1990 to 2008 for primary SFT or first local relapse were retrospectively reviewed. Clinical and pathologic data were recorded. Local recurrence, distant metastases and overall survival were analyzed both from time of diagnosis and from time of local recurrence/distant metastasis. Biomolecular studies are ongoing for those cases whose frozen material is available. Results: 65 patients were identified (M/F: 33/32 - age: mean 54 yrs, range 19–85 yrs - site: peritoneum 45%, pleura 21%, lower-limb 17%, other 18% - extension at diagnosis: localized 94%, locally-advanced/unresectable 3%, metastatic 3% - size: median 11 cm, range 2–40 cm). The median follow-up was 54 months (range 0–185 months). The overall 5/10-year survival (OS), local relapse-free survival (LRFS) and metastasis-free survival (DRFS) were, respectively, 92/91%, 89/86%, 94/89%. The 5-year OS, LRFS, DMRFS after the first local relapse were, respectively, 100%, 67%, 89%. The overall incidence of metastases was 17% (lung was the commonest site). The 5-year post-metastasis OS was 45%. Multivariate analysis on clinical and pathologic/molecular prognostic factors is ongoing. Conclusions: SFT arise from a variety of anatomic sites. Surgery is curative in most patients, and local relapse has a limited impact on prognosis. Pathologic prognostic factors are under investigation to help identify the minority of patients with a poor clinical outcome.

No significant financial relationships to disclose.
Trabectedin for advanced sarcomas failing doxorubicin: Analysis of 189 unreported patients in a compassionate use program
Authors: Blay J. , Penel N. , Italiano A. , Duffaud F. , Rios M. , Collard O. , Bertucci F. , Isambert N. , Chaigneau L. , Zintl P.
Published: August 2020

10574

Background: Between 2005 and 2008, 387 patients (pts) with advanced sarcoma failing doxorubicin were treated in a compassionate use program (ATU) of trabectedin in France using the standard 1.5mg/m2/CI 24h q21d regimen. The purpose of this study was to assess the outcome of pts treated in this program. Methods: From 2005 to 2008, 87 centers (ctrs) included at least 1 pt in the ATU program. Inclusion criteria were those of the EORTC trial (J Clin Oncol, 2005;23:5276), with no restriction on the previous number of lines. A simple CRF with 22 items was used to collect pts characteristics and outcome. One hundred eighty-nine pts files were collected as of December 20, 2008. Univariate and multivariate analyses of prognostic factors was performed. Results: Two hundred thirty-five pts were included in the 17 ctrs in which >4 pts were treated. Forty-four ctrs treated only 1 pt. Fifty-two percent were female; major histological subgroups were leiomyosarcoma (29%) and liposarcoma (20%). All pts had been treated with doxorubicin and ifosfamide, 3 (1.5%) in adjuvant setting only. Trabectedin was given in 1st, 2nd, 3rd, or 4th line in metastatic phase in n=8, 69, 66, 42 pts respectively (median: 3rd line). The median number of courses were 3 (range 1–24). Best response reported were PR, n=15 (8%), SD, n=68 (36%) and PD, n=94 (50%), NE, n=11 (6%). With a median follow-up of 805 days (d), median PFS and OS were 91 d and 309 d respectively. 27/127 (20%) evaluable pts had to be hospitalized for treatment related side effects. PFS was superior in myxoid liposarcoma (MyxLPS) (median 192 d vs 69 d, p=0.003), retroperitoneal sarcomas (median 104 d vs 69 d, p=0.006), and grade 1 tumors (median 141 d vs 70 d, p=0.01). In multivariate analysis (Cox model), tumor site, grade 1, histotype were the only independent prognostic factors for PFS. For OS, favorable prognostic factors in univariate analysis were histotypes (MyxLPS, MFH), grade 1 lesions, retroperitoneal site, no hospitalisation for toxicity (p<0.01 all) while Cox model identified female gender, tumor site, histotype as the only independent prognostic factors for OS. Conclusions: In this compassionate use program for heavily pretreated pts with advanced sarcomas, trabectedin yielded PFS and OS close to those observed in phase II and III trial. PFS and OS are superior in myxLPS, retroperitoneal sarcomas, and grade 1 tumors.

[Table: see text]
The influence of bisphosphonates on bone turnover markers in patients (pts) with breast cancer (BC)
Authors: Keller A. , Heim K. , Welzel G. , Findeisen P. , Neumaier M. , Wenz F.
Published: August 2020

1058

Background: The relevance of the bone metabolism for the prognosis of BC pts is becoming widely accepted. Bisphosphonates are increasingly used in BC pts as prophylactic (antitumor benefits) or as therapeutic agents for the prevention of skeletal related events (SREs). The bone resorption marker peptide-bound collagen type I cross-links C-telopeptides (ICTP) and the bone formation marker N-terminal propeptide of type I collagen (PINP) may become important tools to monitor the bone metabolism and may be influenced by co-medication. Methods: ICTP and PINP were measured in serum samples (n = 252) under standardized conditions. We included BC pts without (n=118, 58±11 yrs) and with bone metastases (BM, n=23, 64 + 12 yrs). For comparison 111 prostate cancer (PC) pts without (n = 84, 70 ± 6 yrs) and with BM (n = 27, 67 ± 10 yrs) were investigated. Results: The median ICTP (5.41 vs 4.34 ug/l, p = 0.04 [Mann-Whitney test]) and PINP (44.9 vs 36.3 ug/l, p = 0.08) values were higher in BC pts with BM as compared to no BM. The presence of BM (< 3 vs 1–3 mets) increased ICTP and PINP values further, whereas bisphosphonates lead to a significant reduction in PINP to normal values in these pts (58.3 vs 32.8 ug/l, p = 0.01). Tamoxifen increased ICTP (4.85 ± 1.8 ug/l) and decreased PINP (36.7 ± 14.3 ug/l), whereas aromatase inhibitors (AIs) increased ICTP (4.93 ± 1.7 ug/l) and PINP (49.4 ± 24.7 ug/l). The same effects were seen in PC pts with and without BM, LHRH had a similar effect like AIs, whereas the impact of antiandrogens was like tamoxifen. Age and gender had no significant influence on ICTP or PINP in BC and PC pts. Conclusions: Markers of bone metabolism may be useful for the diagnosis and follow-up of pts with BC and PC with and without BM. Bone metastases and aromatase inhibitors increased serum ICTP and PINP, whereas bisphosphonates induced a significant decrease in serum PINP.

[Table: see text]
Phase I study of bavituximab, a novel anti-phosphatidylserine monoclonal antibody in patients with advanced refractory cancer: Preliminary results
Authors: Ibrahim N. K. , Wong L. , Rosen L. , Shan J.
Published: August 2020

1080

Background: Aminophospholipid are normally expressed on damaged or apoptotic cells, as well as on the intravascular surface of EC of vessels feeding the tumor as a result of the tumor microenvironment (e.g., hypoxia, reactive oxygen species). Bavituximab (B), a novel monoclonal antibody against PS, has demonstrated preclinical anti-tumor activity by eliciting both innate and adaptive immune responses specific to tumor vasculature. Here we report preliminary results of the phase I study in patients (pts) with advanced solid tumors. Methods: This is a phase I, dose escalation, safety, tolerability and pharmacokinetic (PK) study, as well as to define DLT, MTD and/or maximum effective dose (MED) in pts with advanced refractory cancers. Planned cohorts of 6 pts, each were to receive 0.1, 0.3, 1 or 3 mg/kg. Escalation was permitted if mean cohort Cmax ≤ 65 mcg/mL and dose limiting toxicities (DLT) was observed in ≤ 1 of 6 pts. No premedication was planned or needed. DLT was defined as ≥ grade 3 drug-related adverse events (AE), ≥ grade 2 PT, or ≥ grade 3 aPTT. B was given as a 90 minute IV infusion (on days 0, 28, 35, 42 for the first two dose cohorts and 0, 7, 14, 21 for the third- and fourth-dose cohorts. Although not a study endpoint, tumor response was collected at day 56. Results: Data are available for the first 20 pts enrolled (10 breast, 3 colorectal, 2 pancreatic, 1 each of hepatocellular carcinoma, head and neck, melanoma, mesothelioma, and prostate cancer). Cohorts by dose: 0.1 mg/kg (8 pts), 0.3 mg/kg (6pts), and 1 mg/kg (6pts). Median age was 59 years and 70% of pts were females. (Q: see attached Excel file). No DLTs or drug-related severe AEs were reported. Common drug-related AEs were fatigue (7pts), nausea (6 pts), dry skin (3 pts), constipation (2 pts) and dyspnea (2 pts). All AEs were grade 1 or 2 and no dose relationship was observed. PK was dose proportional with mean serum Cmax of 2.3, 5.2 and 16.6 mcg/mL for the 0.1, 0.3 and 1 mg/kg groups, respectively. No accumulation of B was seen after multiple weekly dosing. Conclusions: Single agent bavituximab is well tolerated to date, with a predictable PK profile. Accrual of the last planned cohort is underway. MTD has not been reached. Final results will be available for presentation at the time of the Meeting.

[Table: see text]
Multiple biomarker expression in circulating tumor cells (CTCs) from locally advanced/inflammatory (LA/IBC) and metastatic breast cancer (MBC) patients (pts)
Authors: Bruce R. H. , Hseih H. B. , Curry D. N. , Krivacic R. T. , Lazarus N. , Frankel P. , Lau S. , Somlo G.
Published: August 2020

1092

Background: Numeration of CTCs from MBC pts is predictive of outcome. Quantitative changes in CTC-s are currently tested for their potential to monitor therapy (Rx). Biomarker characterization of CTCs may be a useful adjunctive guide for Rx selection. Methods: At the COHCC between May 1, 2008 and December 31, 2008, consecutively treated pts with LABC/IBC, or with newly diagnosed/progressing MBC were accrued. Blood samples (20–30 mL) were procured prior to initiating neoadjuvant (neo)Rx (LABC and IBC patients) or systemic Rx (MBC), and were sent to PARC for analysis. A novel high-speed scanning instrument located CTCs from cytokeratin (CK) labeling enabling high resolution images to be selectively acquired using digital microscopy. From these images, CTCs were identified by CK, DAPI (nuclear marker) and CD45, and protein expression levels were determined for HER-2, estrogen receptor (ER), Excision repair cross-complementation group 1 (ERCC1), and EGFR. Cell lines with expression of each marker were used for normalization of the cell intensities, and a scoring system was used to account for relative number and expression levels of markers on the CTCs. Results: Twenty-seven pts with LABC, 4 pts with IBC, and 11 pts with MBC were enrolled. We have observed CTCs prior to initiating neoRx in all pts with IBC relative to 39% of all LABC/IBC cases, and in 57% of pts (n:14) with HER-2+ primary BC versus 24% (n = 17) with HER-2- BC . ER status, size, or grade did not predict for CTC detection. Numeration of CTCs was seen in 45% of pts with MBC. Expression of EGFR and ERCC1 was detected in 3 of 4, and 2 of 4 tested CTC samples from MBC cases. Expression of HER-2 and ER was observed on 1 of 3 and 3 of 4 CTC samples; there was discrepancy between the CTC expression profile and HER-2 and ER status of the primary BC in one case each. Conclusions: Detecting multiple markers in CTCs from pts with MBC is feasible, and similar testing in LABC/IBC patients is needed. Such multiplex testing may allow for more personalized Rx for pts with LABC/IBC and MBC.

No significant financial relationships to disclose.
Correlation of release of endothelial (progenitor) cells after chemotherapy: Kinetics with response and survival
Authors: Roodhart J. M. , Langenberg M. H. , Vermaat J. S. , Lolkema M. P. , Witteveen P. O. , Voest E. E.
Published: August 2020

11002

Background: Recently we have shown that in preclinical models and in cancer patients certain types of chemotherapy can induce an acute release of progenitor cells (Shaked et al, Cancer Cell 2008). In the preclinical models these cells diminished the efficacy of chemotherapy. Little is known of the kinetics of circulating endothelial (progenitor) cells (CE(P)C) release after chemotherapy in humans and their respective temporal functionality. Here we investigated the temporal changes in CE(P)C release after chemotherapy. Methods: Patients with mainly advanced cancer treated with various types of MTD chemotherapy were included. Blood sampling was performed at base line, 4 hours, 7 and 21 days after start chemotherapy. The mononuclear cell fraction was analyzed for CE(P)C as previously described (Duda et al, Nature Protocols 2007) Response to chemotherapy was assessed after 3 cycles of chemotherapy following the RECIST criteria. Progression free survival (PFS) was monitored. Wilcoxon matched pairs test, Spearman correlation and the Kaplan-Meyer method were used. Results: 69 patients were included, 49 were evaluable for the complete data set. In all patients treated with paclitaxel there was an immediate increase in EPC 4 hours after start of treatment (median 246% (p<0.05). Other combinations of chemotherapy induced a decrease in EPC (53%, p < 0.01). These immediate changes did not correlate with response or PFS. At day 7, both CEC and EPC levels correlated with change in tumor volume after 3 cycles of chemotherapy (r 0.4, p<0.05). At day 21 after start of chemotherapy, we found a consistent increase in EPC (315%, p 0.01) and CEC (291%, p 0.01) levels compared to baseline, independent of the chemotherapeutic used or of the presence of a tumor. CEC levels after 7 and 21 days correlated with PFS, regardless of the type of chemotherapy (day 7: HR 0.26 (95%CI 0.05–0.52, p <0.01) and day 21: HR 0.4 (95%CI 0.1–0.9, p<0.05). EPC levels did not correlate with PFS. Conclusions: These findings indicate that the longterm release of CE(P)C is a common phenomenon after treatment with chemotherapy. The correlation with a clinical response provides further support for the biological relevance of these cells.The extend of this release may influence the response to therapy and the prognosis.

No significant financial relationships to disclose.
Weekly versus 3-weekly docetaxel (D2) plus doxorubicin (D4) for first-line treatment of metastatic breast cancer (MBC)
Authors: Stemmler H. , Harbeck N. , Groell der Rivera I. , Vehling-Kaiser U. , Rauthe G. , Abenhardt W. , Sommer H. , Meerpohl H. , Kiechle M. , Heinemann V.
Published: August 2020

1101

Background: We investigated the toxicity and efficacy of weekly applied docetaxel compared to its standard 3-weekly application in pts previously untreated with chemotherapy for MBC. Methods: In the D2 trial (>60 yrs or KPS 60–80%), pts were randomized to receive docetaxel either on a 3-weekly (75 mg/m2 q3w) or on a weekly schedule (30 mg/m2 d1, 8, 15 q4w). In the D4 study (<65 yrs or KPS 70–100%), pts received doxorubicin (50 mg/m2, d 1) in addition to docetaxel given either at q3w dose of 75 mg/m2 or at as 35 mg/m2 (days 1, 8, 15, q4w). Results: The primary endpoint (toxicity) was achieved in D2 and failed in D4. Both studies were terminated prematurely (D2 n = 102/162 D4 n = 85/242 pts). In the D2 study, leucopenia ≥grade 3 was significantly less frequent in the weekly arm (4.2% q1w versus 51.9% q3w, p < 0.0001). In the weekly versus 3-weekly arm ORR was 26.8% versus 46.9% (p = 0.08), TTP was 5.4 versus 6.3 months (p = 0.91), and OS was 22.7 versus 15.8 months (p = 0.24). In the D4 study, an unexpectedly low rate of leucopenia ≥grade 3 was observed in the 3-weekly arm (29.7% q3w versus 35.7% q1w, p = 0.21). In the weekly versus 3-weekly arm, ORR was 50.0% versus 55.0% (p = 0.82), TTP was 6.2 versus 10.3 months (p = 0.36), and OS was 20.5 versus 28.9 months (p = 0.98). Non-hematological toxicity ≥grade 3 was generally mild and comparable within the two schedules. Conclusions: The present data support the feasibility of both, the weekly and the 3-weekly regimen of docetaxel application either as a single-agent or in combination with doxorubicin. As expected, leucopenia seems avoidable in the weekly scheduled of single-agent docetaxel (D2), whereas a combined weekly schedule of docetaxel/doxorubicin as given in the D4 study failed to confirm an expected lower rate of leucopenia.

[Table: see text]
Deletion of 9p21 in urine specimens collected from patients with a history of hematuria and bladder cancer
Authors: Crewell K. , Qian J. , Weber D. , Medina M. , Hossain D. , Bostwick D. G.
Published: August 2020

11038

Background: Fluorescence in situ hybridization (FISH) of voided urine sediment is a sensitive and specific test for the detection of urothelial carcinoma. Common bladder cancer FISH testing consists of 4 DNA probes to chromosomes 3, 7, and 17 and band 9p21. The pattern of enumeration anomalies for these 4 DNA probes are not well documented. We sought to determine the incidence of chromosomal anomalies detected by these 4 probes in urine specimens. Methods: Urine samples from a total of 13,284 patients with a history of hematuria and/or bladder cancer were included for study. FISH was performed in each case using fluorescence-labeled probes to the pericentromeric regions of chromosomes 3, 7, and 17 and band 9p21; cytology was also performed in all cases. Follow-up bladder biopsy information was collected from 280 cases. Results: In total, 91.6% (12163/13284) of urine samples were sufficient for FISH analysis. The overall FISH positive rate was 5.7% (691/12163), and the most frequent patterns of chromosomal anomalies were gains of chromosomes 3 and 7 (56.5%), 7 and 17 (51.6%), and 3 and 17 (36.9%). Deletion of 9p21 was observed in only 12% of cases, and was never observed as the only chromosomal anomaly. The mean number of positive cells in FISH-positive cases was 8.8 (range 4–22). Among 280 cases with matching bladder biopsies, 178 (63.6%) had urothelial carcinoma. FISH was more sensitive than cytology for the detection of urothelial carcinoma (77.4% vs. 53.5%, respectively) (p= 0.03), but there was no significant difference in specificity (68% vs. 71.6%, respectively) (p> 0.05). Conclusions: Gains of chromosomes 3 and 7 by FISH were the most common enumeration anomalies in urine specimens, while deletion of 9p21 only was rare and never seen isolation. FISH was significantly more sensitive than cytology for the detection of urothelial carcinoma with equivalent specificity.

No significant financial relationships to disclose.
Association of BRCA1 mutations with diminished ovarian reserve: A common genetic mechanism for breast/ovarian cancer, and infertility?
Authors: Oktay K. , Kim J. , Barad D. , Gleicher N. , Babayev S.
Published: August 2020

11039

Background: 25% of all breast cancers (BC) occur prior to menopause and preservation of fertility is an important quality of life issue for these women. We recently reported an ovarian stimulation (OS) protocol utilizing letrozole for women with BC who wish to preserve their fertility by embryo freezing. Because BRCA+ young women are highly represented among those undergoing fertility preservation, and because knock out models showed a relationship between DNA repair genes and germ cell development, we hypothesized that women with BRCA mutations have diminished oocyte reserve (DOR). Methods: We analyzed the letrozole-OS data to assess the association between BRCA mutations and number of oocytes retrieved, which is the most direct non-invasive method of assessing ovarian reserve. Women with infertility history and age>37 were excluded. Results: Of 125 BC patients who underwent OS between 5/03 and 11/08, 82 met the criteria, of which 47 (57%) had BRCA testing. Of those, 14 (30%) were BRCA+; 9 BRCA1+, 4 BRCA2+, and 1 + for both. Mean ages of those untested, BRCA-, and + women were similar (33.0±2.9 vs 32.8±2.9 vs 33.0±2.8; p=0.97)). Age-adjusted poor response (PR) rate (<4 oocytes retrieved) was significantly higher in BRCA+ (28.6%; 4/14) compared to BRCA- (3%;1/33, p=0.009) and untested (2.9%; 1/35, p=0.007). All poor responders were BRCA1+ with one also having a mutation in BRCA2. A BRCA mutation was associated with 17.7 times the relative risk (RR) of PR (95% CI 1.4–214; p=0.024). The mean number of oocytes was significantly lower in BRCA1+ but not BRCA2+ compared to BRCA- and untested (p=0.05). BRCA1 but not BRCA2 mutations were associated with PR with a RR of 24.0 (95% CI 1.9–298; p=0.013). When only mutations of known clinical significance were included, the RR for PR further increased (RR=36, 95% CI 2.5–503; p=0.008) suggesting a common mechanism between BRCA-induced cancer and premature diminishment of oocyte reserve. Conclusions: Because women with BRCA1 mutations may have DOR prematurely, they should be counseled for possible higher risk of ovarian failure and infertility after chemotherapy, and referred for fertility preservation. Diminished ovarian reserve may be a new component of the Hereditary Breast Ovarian Cancer Syndrome.

No significant financial relationships to disclose.
LKB1 mutations in mucinous bronchioloalveolar carcinoma occurring in Peutz-Jeghers syndrome patients
Authors: Osoegawa A. , Takeda Y. , Kometani T. , Ondo K. , Fukuyama S. , Hirai F. , Nosaki K. , Seto T. , Oda S. , Ichinose Y.
Published: August 2020

11047

Background: Mutations in the gene encoding Liver Kinase B1, LKB1, are common in patients with Peutz-Jeghers syndrome (PJS), which is characterized by mucocutaneous pigmentation, intestinal polyps and a high incidence of cancers at variable sites (colorectal, gynecological, breast, pancreas, and lung). Although tumors occurring in PJS patients are known to contain mucin-rich conmponents, mucinous bronchioloalveolar carcinomas (mBACs) arising from the PJS background have only rarely been reported. Here we report two mBAC patients with PJS. We further explored the LKB1 gene in these two patients and, in addition, eight sporadic mBAC patients. Methods: Frozen tissue specimens were collected from ten mBAC patients who underwent surgery in our department from 2002 to 2008, and high molecular weight genomic DNA was extracted from them and stocked in the bio-bank. Written informed consent was obtained from each patient, and ethical approval was obtained from the IRB. The nucleotide sequence of LKB1 (EX01–09) was determined by genomic PCR-direct sequencing. Loss of heterozygosity (LOH) was analyzed by high resolution fluorescent microsatellite analysis (HRFMA) using two microsatellite markers that encompass the LKB1 locus, D19S886 and D19S565. Results: Among 11 tumors derived from the 10 patients, 9 distinct LKB1 mutations were found in 7 tumors (4 G:C to A:T transitions; 3 G:C to C:G transversions; 2 single nucleotide insetion/deletion). All of three tumors obtained from the two PJS patients harbored a same sequence alteration. Although LOH was not observed in these tumors, independent sequence alterations were found in two of the three tumors, which may suggest biallelic inactivation of LKB1 in tumors occurred in the PJS patients. Conclusions: The relatively high frequency of LKB1 mutation in mBAC patients may suggest its implication in lung carcinogenesis, at least in mBAC, and its potential as a therapeutic target.

[Table: see text]

No significant financial relationships to disclose.
Diabetes in elderly patients with breast cancer in the United States: An analysis of data from the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked database
Authors: O'Malley C. D. , Danese M. , Lindquist K. , Griffiths R. , Gleeson M. , Einhorn T. , Wyszynski D.
Published: August 2020

11050

Background: Despite increases in both breast cancer and diabetes, little is known about their co-occurrence. With evidence that cancer and diabetes can reflect related processes such as obesity, understanding the prevalence of diabetes in patients with breast cancer is critical. Methods: Using the SEER-Medicare linked database, 52,977 women newly diagnosed with breast cancer at ages 66+ years during 1998–2002 were identified, and a random sample of Medicare beneficiaries without cancer, matched (1:1) on sex and residence county were selected as a comparison cohort. The occurrence of diabetes was defined as ≥1 hospital or ≥2 physician service claims, and the date of cancer diagnosis served as the index date for the breast cancer patient and her matched cancer-free individual. For both cohorts, diabetes prevalence was measured for the ≥12 months prior to the index date, and incidence was estimated for non-diabetic patients during three time periods after the index date (3 months, 12 months, and overall), with follow-up through 2005. Prevalence and incidence rates (per 1,000 person-years) and their 95% confidence intervals (CI) are standardized to the age and race distribution of the breast cancer group. Results: Rates were higher in breast cancer patients for all time periods, particularly shortly after diagnosis. This pattern of heightened risk immediately following cancer diagnosis held when rates were stratified by age, stage, and race/ethnicity.For both cohorts, diabetes incidence was typically two times greater in Blacks and Hispanics compared to Whites. Conclusions: Older women with breast cancer are at increased risk for diabetes, suggesting that there may be shared biologic pathways such as insulin, INSR, IGF-1, and IGF-1R. [Table: see text]

[Table: see text]
Implementation of genomic predictors of chemotherapy response for guiding preoperative therapy in a prospective breast cancer trial
Authors: Marcom P. K. , Datto M. B. , Barry W. T. , Geradts J. , Foster T. L. , Dressman H. K. , Olson J. , Potti A. , Ginsburg G. , Nevins J. R.
Published: August 2020

11057

Background: Personalized approaches to breast cancer therapy depend on genomic assays. While assays based on fixed tissues offer greater convenience, the spectrum of biology interrogated is limited. Full-transcriptome assays using microarrays are more challenging, but have the advantage of providing multiple prognostic and predictive signatures in one assay. We have created a clinical infrastructure with the objective of obtaining full genome expression data on breast cancer samples as a clinical assay for use in a prospective trial. Methods: “Performance of Genomic Expression Profiles to Direct the Use of Preoperative Chemotherapy for Early Stage Breast Cancer” is a prospective trial validating genomic signatures for predicting response to doxorubicin (A) or docetaxel (T) treatment in HER2 negative cancers. Fresh-frozen cores are reviewed by the study pathologist for tumor content. RNA is then extracted and probe generated to hybrize to an Affymetrix U133Plus2.0 microarray. Microarray data quality is determined using summary metrics for U133Plus2.0 arrays and principal component analysis (PCA) plots. The data is then used for predicting A or T sensitivity. Results: Thirteen cancers have been analyzed in the context of the above trial. Histologic type was lobular for 1, and predominantly ductal for 12 (10 ER positive, 3 ER negative). Median tumor size was 3.4 cm (range, 1.8–5.7). Microarray analysis was successful on 11 tumors (84%), providing data of sufficient quality to make predictions of A and T sensitivity. One sample hybridization failed QC as detected by PCA analysis, and one sample had insufficient RNA. The median “tissue to array data” time and “study consent to initiation of treatment” time were 5 days (range, 3–8) and 14 days (range, 11–36), respectively. Conclusions: Our initial experience shows that full-genome expression analysis on frozen tumor using an Affymetrix platform is feasible as a clinical assay for breast cancer. The resulting data is being used in a prospective marker validation protocol for predicting chemosensitivity. The data can also be analyzed for a variety of other potential prognostic and predictive signatures for guiding therapy.

No significant financial relationships to disclose.