bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical results of a phase II study of sorafenib in patients (pts) with non-GIST sarcomas (CTEP study #7060)
Authors: D'Adamo D. R. , Keohan M. , Schuetze S. , Undevia S. , Livingston M. , Cooney M. , Kraft A. , Saulle M. , Schwartz G. K. , Maki R. G. ,   CTEP Sorafenib for Sarcoma Group
Published: March 2020

10001

Background: Sorafenib, an oral multi-targeted tyrosine kinase inhibitor, approved for the treatment of renal carcinoma, inhibits tumor cell proliferation and angiogenesis. We performed a multi-institutional phase II trial of sorafenib in sarcoma. Methods: Six different histological categories were examined, each as a separate Simon two-stage trial. The starting dose of sorafenib was 400 mg PO BID. If â‰¥1 RECIST partial response (PR) was observed in the first 12 pts, 25 more were accrued to that arm. Results: 120 pts (40 M, 80 F) received 553 28-day cycles of therapy as of 1/07. Two RECIST PR were observed in 37 (6%) leiomyosarcoma (LMS) pts and at least 3 PR in 23 (13%) angiosarcomas (AS) pts. No PR were seen in pts with MFH, synovial sarcoma, malignant peripheral nerve sheath tumor (MPNST) or other sarcomas. Median time to progression (mTTP) is 10 (Â ± 2), 15 (Â ± 3), and 23 (Â ± 4) weeks for non-AS, LMS and AS pts, respectively (Kaplan-Meier estimate, Â ± SE). mTTP for AS is >2 fold longer than for other histologies (p=0.039, log rank), and compares favorably with single institution mTTP data for angiosarcoma (paclitaxel 17.3 wk, doxorubicin 16 wk, Fury et al. Cancer J. 2005; 11:241). 64/120 (53%) pts required dose reductions, mostly for dermatological toxicity (see abstract by Keohan, this meeting). Other grade 3, 4 and 5 toxicities included asthenia, hypertension, cardiomyopathy and hemorrhage. Two fatalities, from hemorrhage and intestinal perforation, were deemed possibly related to treatment. Correlative sorafenib pharmacokinetics, MAPK pathway activation and soluble markers of angiogenesis will be presented. Conclusions: Sorafenib has significant activity against angiosarcoma, although the RECIST response rate is low. Sorafenib is associated with disease control in other sarcoma subtypes (e.g. LMS). Accrual continues in AS and MPNST. Further study of sorafenib in sarcomas appears warranted, either in combination with cytotoxic chemotherapy or in a randomized setting. Supported in part by P01-CA47179 Sarcoma Program Project grant and N01 phase II grant.

[Table: see text]
Identification of biologically active cancer cells in blood and bone marrow of cancer patients
Authors: Panabières C. , Vendrell J. , Pellé O. , Rebillard X. , Riethdorf S. , Müller V. , Fabbro M. , Pantel K.
Published: March 2020

1001

Background: Metastasis is the main cause of cancer-related death. Single disseminated tumor cells (DTC) can be detected by sensitive immunocytochemical and molecular technologies, but it is still unclear whether these cells are viable and biologically active. Methods: We applied a novel enzyme-linked immunospot assay (‘EPISPOT‘) that reveals a fingerprint of specific proteins secreted from single viable epithelial tumor cells. The membrane of ELISPOT plates were coated with monoclonal antibodies against the tumor-associated marker proteins mucin-1 (MUC1) for breast cancer and prostate-specific antigen (PSA) for prostate cancer. In addition, dual fluorescent EPISPOT assays were developed to characterize MUC1+ and PSA+ cells (i.e. CK19, FGF2 secretion). Results: Even in the absence of overt metastases (stage M0), the EPISPOT assay revealed viable tumor cells in the peripheral blood of 65% of prostate cancer patients (n=31) and the bone marrow of 54% of breast cancer patients (n=37). Respective samples from non-carcinoma controls were EPISPOT- negative, whereas 80 to 100% of samples from metastatic patients (stage M1, n=40) were positive. The number of EPISPOT-positive cells in M0-patients ranged from 2 to 197 in the blood of prostate cancer patients and 1 to 262 in the bone marrow of breast cancer patients, while M1- patients showed significantly higher counts (prostate cancer, 1–684; breast cancer, 4–813). Interestingly, subsets of MUC1- or PSA-secreting cells expressed a breast stem cell-like phenotype (MUC1-/CK19+) or secreted FGF-2 as factor relevant for the growth of DTC, respectively. Conclusions: A significant fraction of cancer patients harbor viable and biologically active tumor cells in their blood and bone marrow, even in the absence of overt metastases. The multiparameter EPISPOT assay helps to identify these putative metastatic precursor cells.

No significant financial relationships to disclose.
Evaluation of local control in patients with non-metastatic Ewing sarcoma of the bone: A report from the Children's Oncology Group
Authors: DuBois S. G. , Krailo M. D. , Cook E. F. , Tarbell N. J. , Fryer C. J. , Gebhardt M. C. , Brown K. , Miser J. S. , Marina N. M. , Grier H. E.
Published: March 2020

10013

Background: Options for local control in patients (pts) with Ewing sarcoma (EWS) include surgery (S), radiation (R), or surgery plus radiation (S+R). The choice of local control depends on factors that also impact outcome in EWS, including tumor site, tumor size, and age. Our objective was to determine if risk of disease progression differs between local control methods, after controlling for potential confounders. Methods: We analyzed the cohort of pts with non-metastatic EWS of the bone treated on Intergroup Study-0091 (Grier et al, NEJM, 2003). Local control decisions were made on an individual basis. We excluded pts with tumors of the skull/face, progression prior to end of local control, or incomplete local control data. Disease progression was recorded from end of local control. Cumulative incidence of disease progression was determined using a competing risks approach. We constructed a Cox proportional hazards model of progression free survival incorporating local control mode and potential confounders into the model. Secondary analyses evaluated overall survival, local failure, and distant failure. Results: 329 pts met eligibility criteria for analysis. 122 pts received S, 142 received R, and 65 received S+R. The cumulative incidence of disease progression at 5 years was 22.1% (95% CI 15.1–29.9%) for S, 36.9% (29.0–44.9%) for R, and 48.1% (35.5- 59.7%) for S+R. Using R as the reference group and controlling for age, tumor size, tumor location, and chemotherapy regimen, the hazard ratio for progression was 0.66 (95% CI 0.38–1.13) for S and 1.55 (0.96–2.49) for S+R. The hazard ratio for death was 0.77 (95% CI 0.44–1.34) for S and 1.46 (0.88–2.42) for S+R. The hazard ratio for local failure was 0.38 (95% CI 0.15–0.98; p=0.04) for S and 0.77 (0.34–1.75) for S+R. The hazard ratio for distant failure was 0.78 (0.42–1.46) for S and 1.60 (0.91–2.82) for S+R. Conclusions: Observed differences in outcome between local control groups are largely due to confounding factors that affect outcome and local control choice. Risk of disease progression, distant failure, or death does not differ between pts who receive S or R. Pts who receive S have a decreased risk of local failure compared to pts who receive R.

No significant financial relationships to disclose.
Interruption of imatinib (IM) in GIST patients with advanced disease after one year of treatment: Updated results of the prospective French Sarcoma Group randomized phase III trial on long term survival
Authors: Rios M. , Lecesne A. , Bui B. , Adenis A. , Bertucci F. , Duffaud F. , Emile J. , Chabaud S. , Perol D. , Blay J. ,   French Sarcoma Group
Published: March 2020

10016

Background: IM the first-line treatment for advanced GIST, must be given continuously until disease progression (PD) or intolerance (Blay et al, ASCO 2004). The impact on long term overall survival (OS) of IM discontinuation in responding patients (pts) and its re-introduction at progression is unknown. Methods: This prospective multicenter BFR14 study was initiated in June 2002. After 1 year of IM 400mg/day, 58 pts free from progression were randomly offered to continue or interrupt IM until PD. Pts allocated to the interruption (I) arm could restart IM (same dose) in case of PD. Primary endpoint was progression-free survival (PFS); secondary endpoints were OS, secondary response after IM re-introduction, identification of molecular determinants of response. Survival data were compared using the log-rank test. Results: Pt characteristics were well balanced between the two arms. Current median follow- up after randomization is 37 months (range 0–42): 29/32 pts (91%) in arm I vs. 16/26 pts (62%) in continuous (C) arm experienced PD. IM interruption was significantly associated with reduced PFS (p<10-4) with a median of 6 months (95% CI, 3.5–9.5) for arm I. Among the 26 pts of I arm who restarted IM after first progression, 24 (92%) achieved tumor control (OR or SD), one progressed, one died from an unrelated cause. The 2-yr OS rates were 87% and 92% for arms I and C, respectively (P = 0.78). Conclusions: Despite a significant increase of PD in the experimental arm, IM re-introduction is safe and allows a tumor control in the majority of pts. No unfavourable impact of IM interruption on OS was reported. Treatment interruption could be a therapeutic option in advanced GIST pts exhibiting intolerance to IM. Updated results including mutational analysis will be presented at the meeting.

No significant financial relationships to disclose.
Preliminary efficacy and safety results of masitinib administered, front line in patients with advanced GIST. A phase II study
Authors: Bui B. N. , Blay J. , Duffaud F. , Hermine O. , Hermine O. , Le Cesne A.
Published: March 2020

10025

Background: Masitinib mesylate (MM; AB1010) is a protein tyrosine kinase inhibitor (tki) which, in vitro, has greater activity and selectivity than imatinib mesylate (IM) against the wild-type c-Kit receptor and the mutated form in the juxtamembrane region. MM also inhibits the PDGF and FGFR3 receptors. A phase I trial has shown MM safety and tolerability in patients (pts) with different tumor types. One pathological complete response was observed in a pt intolerant to IM. This evidence led to a multicenter phase II trial in non pretreated GIST pts. Methods: Twenty-six pts with advanced or metastatic GIST tumors naive to IM treatment were recruited by the end of October 2006. MM was given orally at the dose of 7.5 mg/Kg/d. Results: Preliminary results are available from 21/26 pts enrolled so far. There were 13 male, 8 female) with a median age of 61 years (range 33–81). The mean tumor size was 104 mm (29- 254), primary tumor origin was in the stomach in 8 cases and small intestine in 9 cases. At pathological review one patient was found to have a low grade stromal uterine sarcoma. After a median follow up of 9 months (4–15), 11/21 (52.4%) patients achieved a partial response, 8(38.1%) are in stable disease; 2 (9.5%) were considered in progression. Three PR were observed in patients with a primary in the lower GI tract and 7 in patients with gastric primary GIST. The low grade uterine sarcoma also showed PR. The progression occurred after 8 weeks in a pt with primary gastric origin, who failed also IM treatment afterwards. The most frequent AEs related to the study drug were Asthenia (observed in 15% of patients), Periorbital oedema, Muscle spasm, Nausea (40% each), Abdominal pain (35%), Rash, Abdominal pain upper, Diarrhea (30 % each) and Vomiting (25 %). Two patients stopped treatment at 87 and 189 days due to skin toxicity G3. Conclusions: These preliminary results, obtained in a small homogeneous population of patients with GIST naïve to IM treatment, show high efficacy of MM and warrant further trials to confirm the efficacy and complete the safety evaluation of this promising TKI. Definitive results and analysis of KIT/PRGFR mutational status will be presented during meeting.

No significant financial relationships to disclose.
Phase II study of pazopanib (GW786034) in patients (pts) with relapsed or refractory soft tissue sarcoma (STS): EORTC 62043
Authors: Sleijfer S. , Papai Z. , Le Cesne A. , Scurr M. , Ray-Coquard I. , Collin F. , Pandite L. , Marreaud S. , De Brauwer A. , Blay J.
Published: March 2020

10031

Background: Currently, there is no standard treatment for pts with advanced STS who relapse after or during standard chemotherapy. Since VEGF is involved in the pathogenesis of STS subtypes, pazopanib, a multi-targeted tyrosine kinase inhibitor of VEGF- receptors 1–3, PDGFR-a and β, and c-kit was explored. Methods: Pts had intermediate or high grade advanced or metastatic STS, were ineligible for chemotherapy or had received no more than one combination or 2 single cytotoxic agents for advanced disease. Pts had WHO performance 0–1 and adequate organ function. Progressive disease had to be documented within the last 6 months. Treatment was oral pazopanib at 800 mg daily. Primary end point was progression-free survival at 12 weeks. Secondary end points included response, safety, and overall survival. 4 different strata were studied: leiomyosarcomas, adipocytic STS, synovial sarcomas, and other types of STS. Simon 2-stage design was applied (P1: 40%; P0: 20%; a=β=0.1). Results: As of 11 October, 2006, 111 pts were enrolled. 98.2% had received prior chemotherapy. In 44 pts with validated data no grade 3–4 hematological toxicities were seen, grade 3–4 bilirubin and creatinine elevations in 2 and 1 pts, respectively. Other toxicities (all grades; grade 3–4) were fatigue (53.6%; 9.7%), hypertension (31.7%; 9.7%), and diarrhea (29.3%; 4.8%). Of 80 pts included in the 1st stages of all 4 strata together, 27 were alive and progression-free at 12 weeks. The 2nd stage was opened for further accrual in 3 strata. Complete accrual is anticipated in February 2007. Conclusions: In relapsed or refractory advanced STS, pazopanib has acceptable toxicity. These preliminary results justify further investigation of pazopanib in STS.

No significant financial relationships to disclose.
Osteosarcoma in patients over 65 years old
Authors: Longhi A. , Errani C. , Ferrari C. , Bertoni F. , Bacchini P. , Mercuri M. , Bacci G. , Picci P. , Ferrari S.
Published: March 2020

10037

Background: Few data are available in literature about osteosarcoma in patients older than 65.We reviewed the incidence and outcome of osteosarcoma in elderly over 65 in our casistic. Materials and Methods: Patients with high grade osteosarcoma treated in our Institute from 1961 to 2006 aged >65. End point was overall survival (OS). Results: 43 patients aged more than 65 treated for high grade osteosarcoma at our Institute were found: 22 male and 21 females, median age was 69 (range 65–80), 29 had localized disease and 13 were metastatic, 33 had extremity localization and 10 axial, 29 patients had a primitive osteosarcoma and 13 (30%) had a sarcoma in Paget's disease, 1 pt ha post-RT osteosarcoma. Median interval from symptoms to diagnosis was 4 months (0–73) 32 out of 43 received surgery for primitive tumour: 18 had a resection with endoprosthesis, 13 had amputation, 1 pt had palliative surgery, the others received palliative RT, 14 patients received chemotherapy (anthracycline, cisplatin, ifosfamide).2 major complication related to chemotherapy were observed: one toxic death and one septic shock. Twenty-one patients reached a disease free status after surgery. Median OS for all 43 pts was 19 months (SE 3),mean 35 mos (range 3–229), 3 years OS for the all group was 25%. Three years OS (Kaplan-Meyer) for pts with localized disease was 41,5% vs 0% for metastatic pts, 3 yrs OS for pts who had surgery was 30% compared to 0% for those without surgical treatment.Significant prognostic factors (Breslow statistic) were: localized vs metastatic (P<0,004) and surgery vs no surgery (P<0.00005,) The other variables (sex, type of surgery, chemotherapy) were not statistically significant.In another study on patients aged 40–60 with localized osteosarcoma of the extremity we found an OS at 8 years of 62%. Conclusions: Osteosarcoma in this subgroup of elderly is frequently associated to Paget disease and their OS is worse compared to adult of younger age. We need to improve our strategy of treatment to increase the cure rate of these elderly patients.

No significant financial relationships to disclose.
Adding cisplatin (CDDP) to imatinib (IM) re-establishes tumor response following secondary resistance to IM in advanced chordoma
Authors: Casali P. G. , Stacchiotti S. , Grosso F. , Messina A. , Crippa F. , Tamborini E. , Bertieri R. , Collini P. , Pilotti S. , Gronchi A.
Published: March 2020

10038

Background: IM is active in advanced chordoma, possibly by targeting PDGFRB. Secondary progressions following response have been observed. The case of a pt with sacral chordoma and lung adenocarcinoma responding to CDDP soon after stopping IM prompted us to combine the two drugs in IM-resistant advanced chordoma. Methods: Since February 2006, 6 advanced chordoma pts (F=4, M=2; mean age 56 yrs; PS 0–2) with a secondary resistance to IM following previous response, have started IM 400 mg/day + low-dose CDDP (25 mg/sqm/wk) on an individual use basis. Results: One pt completed her treatment (after 7 mos, reaching a total dose of CDDP = 525 mg/sqm), and, following ablation of the residual lesion, is now continuing on IM alone. The remaining pts are on combination therapy (4 for <2 mos). After 4–6 weeks, 4 pts had a PET response (SUV max decrease ≥25%), with subjective improvement and stable disease on CT/MRI, while 2 were metabolically stable. In the 2 pts treated for >12 weeks, a minor dimensional response was observed after 3 mos. The single pt who completed combination therapy had a continuous PET scan improvement throughout treatment, and pre-ablation biopsy of residual tumor showed histological signs of tumor response (marked cellular depletion and sclerohyalinosis in most of the sample, with residual tumor cells intermingled with inflammatory ones). Conclusions: In 4 out of 6 advanced chordoma pts progressing on IM, a tumor response was re-established by adding CDDP, and 2 pts treated for a relatively longer interval showed dimensional tumor shrinkage. Four more pts are starting therapy, and results will be updated. An independent cytotoxic effect of CDDP cannot be ruled out, but sensitivity of chordoma to CDDP is at best occasional. The combination of IM and CDDP may have synergic activity in chordoma.

[Table: see text]
Combination chemotherapy with consecutive low-dose cisplatin with ifosfamide and epirubicin (CLD-IEP) in uterine sarcoma
Authors: Murakami F. , Ogawa N. , Yamada M. , Sakurai S. , Ishiya T. , Katase K. , Hasumi K. , Shimizu Y.
Published: March 2020

10057

Background: To evaluate the efficacy and toxicity of CLD-IEP for patients (pts) with sarcoma uteri. Methods: Eligible criteria were: a histologic proof of advanced or recurrent sarcoma uteri; measurable lesions; age between 18 and 80 yrs; WHO PS 0–3; WBC = 3,000/μL; platelet count = 100,000/μL; hemoglobin level = 9 g/dL; adequate liver function; C-Cr = 40 mL/min; no lung, heart, or brain disease; no previous neoplastic disease; no prior chemotherapy; and informed consent. The CLD-IEP regimen was ifosfamide 700 mg/m2 infused over 2 hrs days 1 through 3; epirubicin 50 mg/m2 bolus day 5; and cisplatin 15 mg/m2 infused over 4 hrs days 1 through 5. The treatment was repeated at 4-week intervals. Results: To date, forty eligible pts (16 leiomyosarcoma [LMS], 4 endometrial stromal sarcoma, and 20 carcinosarcoma) were enrolled in this study and all pts were assessable for response, toxicity, and survival. The median age was 52 yrs (range, 28–77). Thirteen pts received CLD-IEP in the neoadjuvant setting. Nine pts had prior radiotherapy. After a median of 4 cycles (range, 2–13), we observed objective responses in 24 pts (60%), with 5 (13%) CRs and 19 (48%) PRs (95% CI, 42% to 78%, 4% to 22%, 30% to 66%, respectively). Of 16 pts with LMS, 1 CR and 7 PRs (1 pt with good PR surviving more than 48 months after the start of CLD-IEP) were observed. Median overall survival time (MOS) after the start of CLD-IEP for all 40 pts was 17 months (range, 3 to 62). MOS was 20.5 months in the responders versus 9 months in the non-responders (Log-rank, p=0.023). The median progression-free survival time of the responders was 10.5 months. NCI-CTC grade 3 or 4 leucopoenia, neutropenia, thrombocytopenia, and anemia occurred in 63%, 75%, 12%, and 18%, respectively. There was no significant nausea/vomiting, nephrotoxicity, or CNS toxicity. Conclusions: CLD-IEP regimen has significant to moderate anti-tumor activity with acceptable toxicity in pts with sarcoma uteri including LMS.

No significant financial relationships to disclose.
Randomized phase II study of trabectedin in patients with liposarcoma and leiomyosarcoma (L-sarcomas) after failure of prior anthracylines (A) and ifosfamide (I)
Authors: Morgan J. A. , Le Cesne A. , Chawla S. , von Mehren M. , Schuetze S. , Casali P. G. , Nieto A. , Elsayed Y. , Izquierdo M. A. , Demetri G. D. ,   Yondelis Sarcoma Study Group
Published: March 2020

10060

Background: Trabectedin, a marine-derived antineoplastic agent, binds to the minor groove of DNA and has previously shown activity in L-sarcomas in single-arm trials. This multicenter, randomized study aimed to characterize the anticancer efficacy with two dosing regimens of trabectedin in pts with treatment-refractory L-sarcomas. Methods: Eligible pts had measurable advanced L-sarcoma, progression despite at least prior A and I, PS 0–1 and adequate organ function. Pts were randomized to IV trabectedin, 1.5 mg/m2, 24h every 3 weeks (q3wk-24h) or 0.58 mg/m2, 3h weekly × 3 on a 28-day cycle (qwk-3h). Primary endpoint is time-to-progression (TTP) and secondary endpoints PFS, overall survival, response, and safety. With 217 events, study provided 90% power to detect a 37% risk reduction in TTP (2-sided 5% significance). Results: 270 pts were randomized as of 5/31/06. Baseline characteristics were comparable: median (range) 2 (1–7) metastatic sites and 2 (1–6) prior regimens; 62% had additional prior agents; 67% had bulky (≥5cm) disease. In the q3wk-24h vs qwk-3h arms median n. cycles were 5 (1–37) vs 2 (1–21); 38% vs 19% received ≥7 cycles. In protocol-specified primary analysis, median (95% CI) TTP was 3.7 (2.1–5.4) vs 2.3 (2.0–3.5) mo [HR: 0.734; p=0.0302] favoring the q3wk-24h arm. Median PFS was 3.3 (2.1–4.6) vs 2.3 (2.0–3.4) mo [HR: 0.755; p=0.0418] and median survival (n=175 events) was 13.8 (12.5–17.9) vs. 11.8 (9.9–13.9) mo [HR: 0.823; p=0.1984]. Benefit from the q3wk-24h arm was more pronounced in pts with central pathology confirmed diagnosis of L-sarcomas. More neutropenia, ↑AST/ALT, emesis and fatigue occurred in the q3wk 24-h. Febrile neutropenia was rare (0.8–1.6%). No cumulative toxicities were noted. Conclusions: Trabectedin can provide clinical benefit to pts with L-sarcoma following failure of all conventional treatment options. Significantly better TTP was noted with the q3wk-24h regimen, although this resulted in somewhat more neutropenia and transaminitis without clinical consequences. No cumulative toxicities were apparent in either arm. Although both dosing regimens are efficacious, there appears to superior disease control with the q3wk-24h arm in this population.

[Table: see text]
Effect of early detection of occult brain metastases in HER2-positive breast cancer patients on survival
Authors: Niwinska A. , Tacikowska M. , Lemanska I. , Pienkowski T. , Murawska M.
Published: March 2020

1015

Aim: The aim of the study was to compare disease free survivals (DFS), survivals from the detection of brain metastases, overall survivals (OS) and the causes of death between two patient groups: group I with disseminated HER2-positive breast cancer and occult brain metastases and group II with symptomatic brain metastases. Material and Methods: MRI screening of the brain was performed in 80 HER2-positive breast cancer pts treated with trastuzumab and cytostatics for visceral metastases. In 29 pts (34%) in whom occult brain metastases were detected, whole brain radiotherapy (WBR) to the brain (30 Gy in 10 fractions) was performed (Group I). They were compared with 48 pts with symptomatic brain metastases treated at the same clinic during the same time period (Group II). Both groups were comparable regarding the site of distant metastases and the type of treatment. All pts in both groups had distant metastases to the lung and/or liver. Results: Median DFS in group I was 17 months and in Group II- 19.9 months (p=0.61). Median survival from dissemination of the disease (visceral metastases) to the detection of occult and symptomatic brain metastases was 9 and 15 months, respectively (p=0.21). Median survival calculated from the detection of brain metastases was 9 and 9.3 months, respectively (p=0.76). Median OS of pts with occult and symptomatic brain metastases was 53.8 and 52 months, respectively (p=0.79). In the group with occult brain metastases 15% of pts died because of progression in the brain and in the group of symptomatic brain metastases the rate of cerebral death was 48%. Conclusions: WBR performed during the asymptomatic period decreased the rate of cerebral deaths, but did not prolong overall survival. Screened MRI of the brain during the asymptomatic period did not improve the outcome of pts with HER2-positive breast cancer and with visceral metastases.

No significant financial relationships to disclose.
Quantitative multimarker analysis in circulating tumor cells of patients with breast cancer
Authors: Fersis N. , Koliogiannis D. , Sisic L. , Schlehe B. , Battista M. J. , Sohn C. , Kaul S.
Published: March 2020

1021

Background: The purpose of this study was clinical application of new methods for quantitative gene expression analysis of circulating tumor cells (CTC) in breast cancer patients. Methods: The high affinity antibodies BM7 (MUC-1) and VU1D9 (EpCAM) were used for immunomagnetic tumor cell enrichment in 10 mL of peripheral EDTA-blood of patients with primary breast cancer (n=167) and metastatic disease (n=131). Separated cells were lysed and used for mRNA isolation and c-DNA synthesis. The breast carcinoma- associated markers MUC1 and EpCAM were determined by conventional RT-PCR. The markers cytokeratin 19 (CK19), mammaglobin 1, survivin, HER-2, CXCR4 and prostate-specific ets factor (PSE) were amplified by real-time quantitative RT-PCR using primers and FAM-labeled TaqMan probes selected with the UniversalProbeLibrary system (Roche AG, Basel, CH). The β-actin transcript served as internal process quality control. Specificity of the RT-PCR was confirmed by examination of blood of healthy donors. Results: Sensitivity for every single transcript was adjusted to 2 tumor cells per 5 ml blood. Tumor-associated transcripts were detected in 31 of 167 (18.5%) patients with primary breast cancer. The marker with the highest incidence of 81% was MUC1. Patients with metastatic disease (n=131) had a positivity rate of 56% and were characterized by multiple marker expression. During a 12 (9–15) months follow-up of 81 patients with primary breast cancer, multimarker positivity was determined in 10 patients, and in three of these patients early metastasis was clinically confirmed. In patients with metastatic disease the CK19 positive CTCs co-expressed either survivin, PSE, CXCR4 or HER2 in more than 70% of the cases. Conclusion: Using a combination of preanalytical immunomagnetic tumor cell enrichment, followed by a multigene quantitative RT- PCR approach, we describe a sensitive detection system for rare circulating breast carcinoma cells. By quantitative expression analysis, survivin, PSE, CXCR4 and HER2 together with CK19 were identified as reliable markers for early detection of metastasis and for prediction of risk of recurrence. The marker panel can be extended further to match patients to best drugs and to predict treatment benefits.

No significant financial relationships to disclose.
Differential survival following trastuzumab treatment based on quantitative HER2 expression and HER2:HER2 dimerization in a clinic-based cohort of patients with metastatic breast cancer
Authors: Toi M. , Sperinde J. , Huang W. , Saji S. , Ohno S. , Nakamura S. , Iwata H. , Masuda N. , Aogi K. , Bates M.
Published: March 2020

1025

Background: Women with metastatic breast cancer (MBC) that overexpress HER2 experience improved overall survival (OS) when treated with trastuzumab. Immunohistochemistry (IHC) for HER2 protein expression and fluorescence in situ hybridization (FISH) for HER2 gene amplification are the preferred methods of determining HER2 positivity. However, not all HER2 positive patients respond equally well to trastuzumab. We describe the identification of subgroups of HER2+ patients with distinct clinical outcomes based on their quantitative levels of HER2 expression and HER2:HER2 dimerization. Methods: 75 patients with MBC drawn from six oncology clinics in Japan were assayed for HER2 expression and HER2:HER2 dimerization using FFPE specimens by the eTag assay, a proximity-based assay designed to detect and quantify protein-protein dimers. All patients had MBC, were treated with at least one chemotherapy (CT) regimen prior to receiving trastuzumab, and had FFPE specimens available for testing. 33% had at least 3 metastatic sites. 88% were selected for treatment based on IHC and 12% based on FISH. 16% were treated with trastuzumab alone and 84% with trastuzumab plus CT. Median clinical follow-up was 26 months. Cox proportional hazards and Kaplan-Meier (KM) analyses were performed. Results: The most significant variables associated with OS were the presence of brain metastases and the total number of metastases. In the overall population, correcting for the confounding influence of number of metastases, KM analyses demonstrated that patients with higher HER2 expression survived significantly longer than patients with lower HER2 expression (HR for death = 0.36, p = 0.0036). This relationship was even more significant for HER2:HER2 dimers (HR = 0.29, p = 0.0003). Conclusions: In a clinic-based population of Japanese women with MBC treated with heterogeneous prior and concomitant (with trastuzumab) CT regimens, the quantitative levels of HER2 expression and HER2:HER2 dimerization identified subsets of patients within a population of pre-selected HER2+ patients with different probabilities of long-term survival following trastuzumab treatment.

No significant financial relationships to disclose.
Safety and tolerability of lapatinib in combination with taxanes (T) in patients with breast cancer (BC)
Authors: Crown J. P. , Burris H. A. , Jones S. , Koch K. M. , Fittipaldo A. , Parikh R. , Koehler M.
Published: March 2020

1027

Background: Lapatinib (L) is an oral, dual ErbB1/B2 tyrosine kinase inhibitor. T are mainstay of BC treatment. The side-effects seen with T in combination with gefitinib and erlotinib include neutropenia, diarrhea and rash. Based on preclinical synergy, early clinical studies with L and paclitaxel (P) or docetaxel (D) were studied. Methods: We summarize pharmacokinetics (PK) and preliminary safety data from 192 patients. Results: PK analysis for EGF10009 (q3w), show systemic exposure was increased for both L (21%) and P (23%) at doses of 1500mg daily and 175mg/m2/q3w, respectively. PK analysis in EGF10021 , (L 1250 mg & D 75 mg/m2 with prophylactic pegfilgrastim) indicated no significant effect on systemic exposure of either agent. Toxicities across all studies include i.e., for all patients = grade 3, neutropenia (7.3%), diarrhea (18.2%), rash (3.6%). The rate of adverse events for neutropenia and rash were similar to each agent alone, however diarrhea was more common. The frequency and severity of diarrhea was increased in studies EGF10009 and EGF102580 where no proactive treatment of diarrhea was introduced, whereas in EGF105764, with proactive treatment, currently no =grade 3 diarrhea has been reported. The data show that the combination of L and P has clinical activity (>70% RR reported in EGF102580). Conclusions: T plus L combinations have a predictable and manageable safety profile and clinical activity of P plus L combination was observed. Proactive diarrhea management is essential for these combinations. Based on the PK data, no dose adjustments are required, and any dose adjustments should be toxicity-based. Ongoing clinical studies investigating the combinations of L with T, and combinations of L with T plus trastuzumab will be reported in the future.

[Table: see text]

No significant financial relationships to disclose.
Epirubicin (E) cardiac toxicity: A retrospective analysis of 1,097 patients (pts) treated for metastatic breast cancer (MBC)
Authors: Ryberg M. , Nielsen D. L. , Cortese G. , Nielsen G. , Andersen P. K. , Skovsgaard T.
Published: March 2020

1029

Background: The object of the study was to conduct an analysis and assess a recommended cumulative dose of E corresponding to a 5 % risk for cardiotoxicity taking into account: dose administrations, concurrent risk of dying of MBC and possible predictors of cardiotoxicity. Methods: Data from 1097 consecutive anthracycline naïve pts was retrieved. Pts developing cardiac heart failure according to New York Heart Association (NYHA) Class =II were recorded as having E cardiotoxicity. Statistics: two extended Cox multivariate analysis (events: cardiotoxicity and mortality of MBC) followed by competing risk analysis. Results: 125 pts (11.4%) developed cardiotoxicity. Predictors for increasing the cardiotoxicity hazard ratio (HR) were: 1. cumulative dose of E: as the rate increased with 37% per every 100 mg/m2 E, when given as first line treatment for advanced disease, 2. increasing age as the rate increased with 28.7 % per additional 10 year, 3. x-ray including the heart (HR=2.08), 4. tamoxifen for relapse (HR=1.87), 5. pre-disposition to cardiac disease (HR=3.01). Mortality rate for MBC: the survival was significant lower in pts with increasing tumour burden, poorer performance status, previous adjuvant CMF, and with increasing age. The HR for mortality was significantly increased by increased duration of treatment with E and was highest in the first three months than later on. The risk of cardiotoxicity increased mostly during the first 8 months after cessation of E nearly becoming constant later on. The cumulative dose of E corresponding to a 5 % cardiotoxicity risk was found to be both significantly lower than previously assumed (900 mg/m2) and depend on predictors for mortality and cardiotoxicity. Thus, a pts with no predictors at age 40 the level of 5% risk was 806 mg/m2, at age 50 = 739 mg/m2, at age 60 = 673 mg/m2 and at age 70 = 609 mg/m2. Conclusion: The risk of cardiotoxicity of E was more pronounced than expected and occurred on a much lower cumulative dose of E. Increasing age, x-ray, tamoxifen and pre-disposition to cardiac disease contributed significantly to this.

No significant financial relationships to disclose.
A phase II trial of capecitabine (C) in combination with the farnesyltransferase (FT) inhibitor (FTI), tipifarnib (T), in patients (pt) with metastatic breast cancer (MBC): ECOG trial 1103
Authors: Wang M. , Gradishar W. J. , Sparano J. A. , Perez E. A. , Sledge G.
Published: March 2020

1036

Background: Approximately 30% of human cancers have mutated Ras genes that produce proteins that remain in an active state causing uncontrolled proliferative signals. Post-translational modification of Ras include farneyslation catalyzed by FT. Tipifarnib (R115777) is an oral FTI active against human tumor cell lines and exhibiting modest single agent activity in pts with previously treated MBC. A previous phase I trial reported that CT inhibited farneyslation in peripheral blood mononuclear cells without affecting the pharmacokinetics of either agent. Objective: To evaluate objective response rate (ORR) of CT in taxane refractory MBC and to secondarily evaluate associated toxicity and progression-free survival (PFS). Methods: Pt with measurable MBC, previously treated (rx) with an anthracycline and relapse on a taxane or within 30 days (d). Study rx: T- 300 mg, po BID × 14 d plus C- 1,000 mg/m2, po BID × 14 d, followed by 7 d rest. Tumor reassessment was repeated q 3 cycles. The study was designed to detect improvement in ORR from 25% with C alone to 40% for the CT combination (90.5% power; type I error rate of 9.9%; 21 responses in 64 eligible pt needed to be promising. Results: 66/71 pt are available for primary analysis. Median age 50 yrs. Performance status: 0–1, 100%. ORR: PR-4.8% (3/62) [95% CI 0.01, 0.13], SD - 21% (13/62) [ 95% CI 0.12, 0.33]. Median survival - 10.6 months. Toxicity (%): anemia - 8(G3/4), neutropenia - 30 (G3/4), thrombocytopenia - 8 (G3/4), HFS-8 (G3), nausea/vomiting - 11(G3), diarrhea - 8 (G3), sensory neuropathy - 5 (G3). Conclusion: CT in taxane -refractory MBC has low antitumor activity without excessive toxicity. More mature data, including PFS, will be presented.

No significant financial relationships to disclose.
Ki-67 is a Luminal B marker that identifies a high-risk subgroup in hormone receptor positive and node negative breast cancer
Authors: Cheang M. , Voduc D. , Leung S. , Turbin D. , Bernard P. S. , Ellis M. , Mardis E. , Perou C. M. , Nielsen T. O.
Published: March 2020

10521

Background: Gene expression profiling studies have revealed prognostically significant intrinsic breast cancer subtypes, designated Luminal A, Luminal B, Basal and Her2. Expression of ER and associated genes characterizes the luminal breast cancers. The Lum B subgroup is associated with poor outcome, but we lack immunohistochemical (IHC) markers to distinguish Lum A and Lum B subgroups. MKI67 is one gene known to be highly expressed in Lum B tumors, encoding the Ki-67 protein, a robust marker of cell proliferation. In this study, we perform IHC analysis of Ki-67 in a large breast cancer tissue microarray. Methods: Our patient cohort consists of 2222 consecutive cases of invasive breast cancer referred to the BC Cancer Agency from 1986 to 1992. Archival paraffin tissue blocks were used to construct a tissue microarray that was then stained for Ki-67 using a commercially available mouse monoclonal antibody. Ki-67 staining was scored quantitatively by automated image analysis and a tumor was positive if the percent positive nuclei was >30%’ Results: Of the 2,222 patients, there are 1,437 Luminal tumors as defined by IHC (ER or PR positive). As Her2 positive status is an established marker of poor prognosis, we excluded these tumors from our analysis. Of the remaining tumors, 9% were Ki-67 positive when using a ki-67 cut off of 30% positive nuclei. In survival analysis of patients ER/PR positive and Her2 negative, we found that Ki-67 identifies a population with poor prognosis (10-yr BCSS 60% vs. 80%). In a multivariate Cox regression we found that Ki-67 is independently prognostic. We repeated Cox regression analysis including only node negative patients and again found that Ki-67 is an independent predictor of poor outcome. Conclusions: Ki-67 has prognostic significance on multivariate survival analysis. Hormone receptor positive and node negative status is typically associated with a favorable outcome for breast cancer. However, Ki-67 is able to identify a small, but clinically significant subgroup with a particularly poor outcome. Defining the Luminal B subtype as (ER or PR) positive and (HER2 or Ki-67) positive, results in a subgroup that contains 18% of hormone receptor positive breast cancers with 10-yr BCSS of 61%.

No significant financial relationships to disclose.
MC1R variants and melanoma risk: First study on Melan-Cohort
Authors: Soufir N. , Bagait Miss L. , Oudin Miss C. , Wolkenstein P. , Descamps V. , Dupin N. , Lebbé C. , Basset-Seguin N. , Saiag P. , Grandchamp B.
Published: March 2020

10524

Background: The presence of functional variants of MC1R, has been shown to be associated with melanoma (MM) risk in different populations worldwide. We had previously shown in a first case - control pilot study that MC1R variants were associated the risk of melanoma (MM) in France. Methods: In order to confirm and precise these results on a larger sample, we performed a case-control study with patients from Melan-Cohort, a prospective cohort from the Paris’ region. After signature of informed consents and extraction of blood DNAs, MC1R variants were sought by automatic sequencing in 270 patients (95 familial MM, 54 multiple sporadic MM, and 121 ‘single‘ MM) and in 154 controls sex, age, and ethnic matched. Usual statistical calculations (Chi2, odd ratios, logistic regression) were carried out. Results: MC1R functional variants were present in 73% of the patients versus 43% of controls (p<0.0001). The presence of only one variant was significantly associated with melanoma risk (OR 2.9 [1.88–4.5]), and the presence of two variants doubled the risk (OR, 6.91 [3.33–14.3]). Furthermore, each of the seven variants, RHC (i.e associated with the Red Hair Phenotype; R142H, R151C, R160W, D294H) or non-RHC (V92M, V60L, R163Q) was individually associated with melanoma risk (OR ranging from 2.8 to 14). The frequency of variants was similar in each sub-group of MM examined (familial, multiple sporadic, or ‘single‘). However, RHC variants were significantly more frequent in the familial subgroup (p = 0.0045) and non RHC were significantly more frequent in the “single” MM subgroup (p = 0.0006). In addition, we confirm that the risk related to MC1R largely persisted after stratification on each clinical risk factor: hair and eyes color, skin type, and nevi count. On the other hand, there was no association between the presence of MC1R variant and the histological type of MM, the age at diagnosis, and the Breslow index. Conclusion: Our results confirm the important role of MC1R on melanoma risk in France and this independently of clinical risk factors. Surprisingly, both RHC and non-RHC variants were associated with melanoma risk, but RHC variants have possibly a higher penetrance. Finally, the presence of MC1R variants does not seem to be correlated with the speed of evolution (Breslow index) of melanoma.

No significant financial relationships to disclose.
Cluster mir-17–92 is differentially expressed in colon cancer patients and embryonic colon tissue and may contribute to carcinogenesis through E2F1 expression
Authors: Garcia-Foncillas J. , Navarro A. , Bandres E. , Artells R. , Moreno I. , Gel B. , Ibeas R. , Moreno J. , Miguel M. , Gurpide A. , Monzo-Planella M.
Published: March 2020

10525

Background: Mature microRNAs (miRNA) are small RNA molecules that act as negative regulators of gene expression, either inhibiting mRNA by blocking its translation into protein or destroying it by RNA interference. Many miRNAs participate in essential processes, including normal embryonic development and carcinogenesis. Methods: We have assessed 156 mature miRNAs in colon tissue from eleven 7–12-week human embryos and 44 colorectal human samples. Data were analyzed using TIGR Multiexperiment viewer. Two multivariate permutation test were performed. Potential target genes of differentially expressed miRNAs are evaluated by western blot. Results: 28 miRNAs were expressed in stage I tumor tissue but not in the corresponding normal tissue, and 13 of these 28 miRNAs (46%) were also expressed in embryonic tissue. Sixty-four miRNAs were differentially expressed in stage II tumor tissue, and 29 of these 64 miRNAs (45%) were also expressed in embryonic tissue. Some miRNAs that are active during embryogenesis, such as mir-17–92, miR-181a, miR-181b and miR-181c (linked to HOXA11), and miR-10a (linked to HOXB8)23, are also expressed during tumor growth. The analysis of 156 miRNAs by K-means support revealed two well-differentiated groups: the embryos of 7–8 weeks and those of 9–12 weeks. Lower miRNA expression was also observed in tumor tissue from stage I in comparison with stage II disease (P=0.014). Analysis of potential target genes revealed that cluster mir-17–92 is differentially expressed in colon cancer and embryonic tissue and may contribute to carcinogenesis through E2F1 expression. Conclusions: Our findings indicate that miRNAs expressed during the embryonic development of the human colon are also expressed in colon tumor tissue. During colon organogenesis, miRNA expression is at first high, while cells are still undifferentiated, but expression levels decrease as cells become more differentiated. In contrast, during the development of colorectal cancer, this process is reversed.

No significant financial relationships to disclose.
Gene copy numbers of HER family in breast cancer
Authors: Wełnicka-Jaskiewicz M. , żaczek A. , Bielawski K. P. , Jańkiewicz J. , Badzio A. , Olszewski W. , Konopa K. , Rhone P. , Senkus-Konefka E. , Jassem J.
Published: March 2020

10544

Background: Most clinicopathological analyses of HER alterations in breast cancer were limited to single HER family members. Since the activation of certain HER receptors is possible only as a result of their dimerization, determining the alterations of all four HER genes may be more relevant. The aim of the study was to estimate the frequency of disorders in all four HER genes, and to determine their correlation with the clinical and histological features in breast cancer patients. Methods: Gene copy number (GCN) of ERBB oncogenes was analyzed with double differential PCR (ddPCR) in a consecutive series of 225 breast cancer patients. Statistical analysis was performed with a set of nonparametric tests. Results: Amplifications of HER1, HER2, HER3 and HER4 were detected in 15%, 26%, 10% and 15% of cases respectively, and deletions in 31%, 2%, 2% and 7% cases respectively. Abnormal GCN of at least one, and at least two oncogenes was found in 65% and 31% of the tumors, respectively. Average GCNs of all HER oncogenes significantly correlated with each other. These correlations were particularly high for HER2/HER3, HER2/HER4 and HER3/HER4 (all p<10-8), and were much stronger in N(+) compared to N(-) tumors. HER1 deletions were associated with the lack of progesterone receptor (p=0.03), whereas HER3 and HER4 amplifications were more common in well differentiated tumors (p=0.03 and 0.047 respectively). At univariate analysis disease-free survival (DFS) and overall survival (OS) were related with T and N stage, and HER1 amplification. The multivariate analysis showed that DFS was influenced by T, N and HER1 amplification, whereas OS by T, N and tumor grade. Conclusions: Our results indicate a key role of HER heterodimers in tumor progression and confirm that HER2 is the preferred partner for other HER oncogenes in this process. Deletions of HER1 were associated with unfavourable characteristics, whereas HER3 and HER4 amplifications may be linked with less aggressive phenotypes.

No significant financial relationships to disclose.