bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized phase II study of perifosine (P) plus imatinib for patients with imatinib-resistant gastrointestinal stromal tumor (GIST)
Authors: Conley A. P. , Araujo D. , Ludwig J. , Ravi V. , Samuels B. L. , Choi H. , Thall P. F. , Patel S. , Benjamin R. , Trent J.
Published: August 2020

10563

Background: P inhibits activation of the Akt pathway which results in apoptosis and block cancer cell proliferation. Since AKT is a molecule downstream of Kit, its inhibition may overcome Kit-dependent imatinib resistance. We performed a phase II trial to assess antitumor activity of perifosine in patients with advanced GIST who were refractory to imatinib mesylate. Methods: Pts with Kit(+) advanced GIST who have PD on IM were eligible. Pts continued their current dose of IM and were randomized to one of two dosing schedules of P (Arm A: 100 mg p.o. qd x 28 + IM or Arm B: 900 mg [300 mg p.o tid] qweekly + qd IM). A Bayesian approach was utilized to assess a target response rate or 20% with an unacceptable toxicity rate of 15% or less. Response was measured at q8 wk intervals by RECIST and Choi criteria. The primary endpoint was to determine the efficacy of P with IM in pts with advanced GIST with PD while receiving IM. Results: From 8/2005 to 7/2008, 41 pts were accrued. After 1 pt exclusion and 2 cross-overs, 22 pts were in Arm A and 18 pts in Arm B. Median age was 58 (range, 32–82), 51% were male, and median ECOG PS was 1. The most common primary site of disease and metastasis was the stomach (29%) and liver (66%), respectively. KIT genotype was available for 22 pts(54%); 5(12%) WT, 13(32%) exon 11 mutations, and 4(10%) exon 9 mutations. The median number of cycles was 2 (range, 1–24). By Choi and RECIST, 30 pts(73%) and 36 pts(87%) were available for response, respectively. No CR was identified but the PR rate was 4/36 (11%) by Choi (4 PR, 9 SD) and 0/36 (0%) by RECIST (16 SD). 4/5 (80%) of pts with WT KIT appeared to benefit (Choi: 1 PR, 3 SD; RECIST: 4 SD). Median PFS and OS for 40 pts were 2.2 months and 18.3 months. No difference in PFS was noted for the 2 schedules. Toxicity was assessed in 39 pts; 46 grade 3 events and 4 grade 4 events (ALT elevation, blurred vision, fatigue, and mood alteration) were noted. The most common grade 3 event was fatigue (20%). Three pts (7%) were removed from the study for toxicity (Arm A:1 pt, Arm B:2 pts). Conclusions: The addition of P to IM has minimal activity in IM-refractory GIST although its activity in GIST with WT KIT may be further investigated.

No significant financial relationships to disclose.
Rechallenge with trabectedin in patients with responding myxoid liposarcoma
Authors: Sanfilippo R. , Grosso F. , Virdis E. , Morosi C. , Tercero J. C. , Gronchi A. , Pilotti S. , D'Incalci M. , Casali P. G.
Published: August 2020

10575

Background: To determine the efficacy of rechallenge with trabectedin (T) in patients with myxoid liposarcoma who were responding to T at the time of discontinuation but subsequently developed progressive disease. Methods: Since September 2002, 32 patients with recurrent or advanced myxoid liposarcoma received T at our institution within an expanded access program. We report herein 8 patients who received T for a median of 10 cycles (range 5–15) prior to discontinuation. We used RECIST criteria to classify patient response to therapy. During the initial administration of T, a CR had been observed in 2 patients, a PR in 3 patients, SD in 2 patients, and one had had tumor shrinkage but did not meet RECIST definition of PR. The median PFS was 24 months from treatment start, and 14 months (range 9–27) from treatment-end. In 6 of the 8 patients, the treatment had been discontinued in the absence of any evidence of disease: 4 patients had undergone complete surgical resection (R0) of residual disease and 2 patients had achieved a radiological complete response (CR). The other two patients stopped treatment voluntarily, one with a partial response (PR) and one with stable disease (SD). All these patients resumed treatment at the time of progression. Results: Following rechallenge with T, no PD was seen at first assessment, and no patients had to discontinue or reduce the dose due to toxicity. Response rate according to RECIST was 50%. At a median follow up of 7 months (range 2.7–12), the median TTP has not yet been reached. Treatment is still ongoing in 5 patients. Conclusions: Rechallenge with T can be beneficial in some patients with myxoid liposarcoma. If further data confirm this, treatment of progressing patients previously responding to T may include this option. Furthermore, studies on optimization of treatment duration upfront may be worthwhile.

[Table: see text]
Effect of metastasectomy and doxorubicin dose on the outcome of patients with metastastic leiomyosarcoma: A multicenter study
Authors: Penel N. , Italiano A. , Isambert N. , Bompas E. , Bousquet G. , Bousquet G. , Duffaud F.
Published: August 2020

10580

Background: The role of metastasectomy and front-line chemotherapy modalities remain debated in the metastastatic soft tissue sarcoma setting. Methods: Data from 147 M-LMS patients (1988–2008) reviewed in 6 French centers were retrospectively analyzed. Prognostic factors for progression-free and overall survivals (PFS and OS) were identified using log-rank tests and Cox multivariate analysis. The respective impact of treatment modalities on PFS and OS were assessed after adjustment to prognostic factors. Results: This database included 46 (31%) uterus and 101 soft-tissues (69%) M-LMS. All patients received doxorubicin as front-line regimen associated with ifosfamide in 78 cases (53%) or dacarbazine in 56 cases (38%). The planned dose of doxorubicin was > 60 mg/m2/3 weeks in 24 patients (16%). After front-line chemotherapy, 36 patients with lung metastasis (24%) underwent subsequent complete metastasectomy. The median PFS was 6 months. The univariate analysis identified the following prognostic factors for PFS: performance status (PS), grade, presence of liver or lung metastases. But, the multivariate analysis did not retain independent prognostic factor for PFS. Only one treatment parameter was associated with better PFS: planned doxorubicin dose superior to 60 mg/m2/3 weeks (HR=7.57 [1.32–10.40], p=0.023). The median OS was 14 months (1–115). The univariate analysis identified the following prognostic factors: PS, time interval between diagnosis and metastatic relapse, local relapse and grade. Under multivariate analysis, there was only one good prognostic factor for PFS: interval time between initial diagnosis and metastasis > 12 months (p=0.006). After adjustment to this factor, multivariate analysis shown that complete metastasectomy improved the PFS (HR=0.52, [0.38–0.87], p=0.012) and addition of ifosfamide was associated with worst outcome (HR=1.42 [1.05–2.10], p=0.028). Other chemotherapy parameters did not significantly modify OS. Conclusions: Doxorubicin dose and metastasectomy remain the cornerstone of the optimal treatment of M-LMS. Addition of Ifosfamide seemed to be associated with worst outcome. Dacarbazine seemed to have no significant impact.

[Table: see text]
Ifosfamide, carboplatin, and etoposide (ICE) in combination with regional hyperthermia (RHT) in chemotherapy-pretreated nonresponders with locally advanced high-risk soft tissue sarcoma (HR-STS)
Authors: Nickenig C. , Buecklein V. , Lindner L. H. , Abdel-Rahman S. , Kuhlencordt M. , Hiddemann W. , Issels R. D.
Published: August 2020

10581

Background: Regional hyperthermia (RHT) improves outcome in combination with neoadjuvant chemotherapy as first-line therapy in locally advanced HR-STS (Issels et al., Abstract 10009, ASCO 2007). Efficacy of ICE combined with RHT as second-line treatment strategy in pts with locally advanced HR-STS pretreated with anthracycline-based chemotherapy ± RHT was evaluated. Methods: Between 9/97 and 6/08, 49 pts were treated with ICE + RHT (median age: 51 years, range: 21–74 years), with high-grade (G2 24 pts; G3 25 pts) STS histology (20 Lipo-Sa; 6 Leiomyo-Sa, 6 MPNST, 5 NOS, 2 DSRCT, 10 others). As first-line therapy 35 pts had received chemotherapy combined with RHT and 14 pts without RHT. Second-line ICE consisted of 1.5 g/m2 ifosfamide, 100 mg/m2 carboplatin, and 150 mg/m2 etoposide on days 1–4 combined with RHT on two days and was repeated on day 28 (4–6 cycles). Besides toxicity, primary and secondary endpoints were objective response (OR) (RECIST), progression free rate (PFR) at 3 and 6 months, and overall survival (OS). Results: Pts received a median of 4 ICE cycles (range 1–8) in combination with RHT. Hematological toxicity grade III (11 pts)/ IV (23 pts) occurred in 34 pts (69 %), 3 pts (6 %) suffered from therapy-related deaths due to infection during cytopenia (2 pts) or postsurgery-related complications (1 pt). In 35 of 49 pts evaluable for OR, 26% achieved objective remission (1 CR + 8 PR), 51% showed stable disease (18 SD) and 23% progressive disease (8 PD). OR rates after initial chemotherapy with or without RHT were 17 % (4 PR of 24 pts) and 45% (1 CR + 4 PR of 11 pts), respectively (p=0.13). Irrespective of pretreatment, for all pts the PFR after 3 and 6 months was 87% (CI95=96%-77%) and 76% (CI95=88%-63%) and median OS was 22 months (CI95=29–16 months). Conclusions: Second-line ICE combined with RHT is feasible and effective in pts with locally advanced HR-STS non-responding to first-line anthracycline-based chemotherapy with or without RHT. (Supported by Deutsche Krebshilfe and HelmholtzZentrum münchen - German Research Center for Environmental Health)

No significant financial relationships to disclose.
Clinical features and course of brain metastases in triple-negative breast cancer: Comparison with HER2+ and other type
Authors: Jang G. , Lee S. , Ahn J. , Jung K. , Lee H. , Gong G. , Kim H. , Ahn S. , Ahn S. , Kim S.
Published: August 2020

1064

Background: Incidences and clinical aggressiveness of intracranial metastasis in triple negative (TN) breast cancer have not been well delineated compared to HER2+ subtype. Methods: Patients (pts) who were diagnosed with primary breast cancer at Asan Medical Center from January 1990 to July 2006 were screened (Lee SS, Breast Cancer Res Treat. 2008). All pts with brain metastases, identified by CT or MRI, were included and classified into three subtypes (TN, HER2+ and other). The clinical features and course of brain metastases with TN breast cancer, defined according to immunohistochemical staining and HER2 FISH analysis, were reanalyzed and compared among three groups. Results: Of 7,872 breast cancer pts, 198 pts developed brain metastases and 61 pts with unknown ER, PR, or HER2 status were excluded. Of 137 pts, incidences of TN, HER2+ and other group were 32% (44), 50% (69), and 18% (24), respectively. The median age at the time of brain metastases was 46 years (yr) (range 29–70 yr) in TN group, 48 yr (range 27–78 yr) in HER2 group, and 37 yr (range 25–62 yr) in other group with no significant difference. Clinical parameters such as performance status, previous adjuvant chemotherapy or radiotherapy, was similarly distributed among groups except that pts with earlier stages (I, II) were more prevalent in TN group compared to other two groups (59% vs 36% vs 38%, p = 0.01). With a median follow-up duration of 99 months (m), the median time from initial diagnosis of primary breast cancer to brain metastases was significantly shorter in TN group, compared with other two groups (TN, HER2, other; 20 m vs 32 m vs 45 m, p = 0.01) and the one from diagnosis of primary cancer to the first distant metastases at any sites was also shorter (16 m vs 23 m vs 23 m, p = 0.005). The median overall survival from diagnosis of primary cancer was significantly shorter in TN group (31 m vs 39 m vs 57 m, p = 0.02) and however, the one after brain metastases was not different among 3 groups (5.9 m vs 5.2 m vs 8.8 m, p = 0.31). Conclusions: TN breast cancer showed earlier brain metastases, earlier distant metastases at any sites and shorter overall survival in spite of high proportion of early stages, compared with other phenotypes. Preventive and therapeutic strategies of brain metastases in TN breast cancer are urgently needed.

No significant financial relationships to disclose.
Evaluating the impact of relative total dose intensity (RTDI) on patient's short- and long-term outcome in taxane- and anthracycline-based chemotherapy of metastatic breast cancer: A pooled analysis
Authors: Loibl S. , Nekljudova V. , Skacel T. , Schwenkglenks M. , Lück H. , Brodowicz T. , Zielinski C. , von Minckwitz G.
Published: August 2020

1065

Background: The consequences of reducing chemotherapy dose intensity might be extensive, potentially affecting short- and long-term outcomes as well as patient quality of life, the dose and schedule are of central concern in the delivery of chemotherapy. Methods: This statistical analysis was based on individual subject data of 934 patients (pts) obtained from the following prospective, open-label, randomised phase III trials in metastatic breast cancer that recruited between 1996 and 2005 investigating an anthracycline/taxane based first-line chemotherapy: CECOG trial, AGO-Mamma-1 and AGO-Mamma-3 trial. The primary objective of the analysis was to evaluate the influence of RTDI on progression free survival (PFS) in different predefined binary RTDI cuts from 75% to 95% with an interval at every 5%. Relative total dose intensity (RTDI) is the ratio of actual total dose intensity and planned total dose intensity, expressed as a percentage. RTDI quantifies dose reductions and delays, as well as premature discontinuations in treatment. Results: Overall cuts pts with higher RTDI had a shorter PFS compared to those with lower RTDI. A time dependent term for low RTDI was included in the analysis and showed the opposite effect after approximately 60 weeks. The overall median PFS was 39 weeks. Analysis of the Kaplan-Meier curve identified many early events in patients with high RTDI. We hypothesized that patients with a primary progression (PP) who have by definition a high RTDI were responsible for this effect. The PFS excluding 114 patients with PP showed no difference for patients with high compared to those with low RTDI. The median overall survival (OS) for the whole study population was 98 weeks. Excluding patients with PP, the median OS was 118 weeks (95% CI [103–136]) for those with RTDI ≥ 85% versus 96 weeks (95% CI [83–119]) if RTDI was < 85% (log-rank p = 0.0086). The results were comparable across other cut levels. Conclusions: Maintaining RTDI in patients not experiencing PP might have significant impact on overall survival.

No significant financial relationships to disclose.
Phase I trial of escalating doses of weekly everolimus (RAD001) in combination with docetaxel for the treatment of metastatic breast cancer (MBC)
Authors: Moulder S. L. , Rivera E. , Ensor J. , Gonzalez-Angulo A. , Christofanilli M. , Booser D. , Giordano S. , Brewster A. , Hortobagyi G. , Tran H.
Published: August 2020

1066

Background: Inhibition of mTOR with everolimus (E) may improve efficacy in combination with docetaxel (D), but both drugs are metabolized by CYP3A4, thus a pharmacokinetic (PK) interaction may also exist. Methods: 15 patients (pts) with MBC were treated with docetaxel and everolimus using the continuous reassessment method (CRM) to determine maximum tolerated dose (MTD). Docetaxel doses were 40–75 mg/m2 IV on day 1 of a 21 day cycle. Everolimus doses were 20–50 mg PO on days 1 and 8 of a 21 day cycle (except cycle 2, where only day 8 was given to allow single agent PK analyses of both drugs). Response was measured every 2 cycles using RECIST. Results: Median age= 58 years and 77% of pts had >2 prior chemotherapies for MBC. Initially 2 of 2 pts treated (D= 75 mg/m2, E= 30 mg) developed DLT (neutropenic fever/infection), prompting a mandatory PK evaluation for all pts enrolled in subsequent cohorts. A second cohort of 3 patients (D=60 mg/m2, E=20mg) had no DLT, but no pts received day 8 of E due to grade 3–4 neutropenia. PK analyses demonstrated a 42% lowered (-42%) D clearance at the 60 mg/m2 in the presence of E (n=1). Subsequent cohorts were accrued at D=40 mg/m2 with escalating doses of E (Table). For the entire group, an 18% decrease (-18%) in D clearance was observed when D was administered concomitantly with E. High interpatient variability of D clearance was observed (range +16% to -135%). No pts had CR/PR, but 6 had SD>4 cycles and 2 had SD=8 cycles. Conclusions: Weekly everolimus appears to cause widely variable and unpredictable changes in docetaxel clearance making this combination unfeasible.

[Table: see text]

No significant financial relationships to disclose.
Preliminary results of a phase II study of liposomal cisplatin-vinorelbine combination as first-line treatment in HER2/neu negative metastatic breast cancer (MBC)
Authors: Farhat F. S. , Ibrahim K. , Kattan J. , Bitar N. , Jalloul R. , Nsouly G. , Ghosn M. , Haddad N. , Bou Karroum M. , Tamraz S. , Shamseddine A.
Published: August 2020

1068

Background: The frequent use of anthracyclines and taxanes in breast cancer's adjuvant setting has lead to drug resistance and cardiac toxicity. This has raised the need for new agents in the metastatic setting. Cisplatin-vinorelbine combination recently showed interesting results with an overall response rate of 64%. Nevertheless, the use of cisplatin was limited by the frequently induced nausea, vomiting, and nephrotoxicity. Liposomal cisplatin (Lipoplatin) is a nontoxic alternative agent to cisplatin. The aim of this study is to evaluate the efficacy and safety of liposomal cisplatin-vinorelbine combination in first line MBC patients (pts). Methods: From August 2007 to October 2008, 30 of 35 programmed pts with MBC and no prior treatment for their metastatic disease, PS 0–2, HER2/neu negative, and at least one measurable lesion, were enrolled. Of these 30 recruited pts, 26 with available data were analyzed. Treatment included I.V. vinorelbine 30 mg/m2 on days 1 and 8, and liposomal cisplatin 120 mg/m2 on days 1, 8, and 15. Cycles were repeated every 3 weeks for a total of 6 cycles. Primary objectives: objective response rate, time to treatment failure (TTF), and time to progression (TTP). Secondary objectives: overall survival and treatment-related toxicity. Results: The median age was 49 years (29–74). 69% of pts had visceral metastases. 35% had one metastatic site, 46% had 2, 19% had 3 or more. A total of 120 cycles were administered with a median number of 6 per patient. At the time of the analysis 22 pts were evaluable for response. An objective tumor response was observed in 11 pts (50%) and complete response in 1 patient (4.5%). Ten (45.5%) pts had stable disease. The median TTF and TTP were 5 and 8 months respectively. All pts (26) were evaluable for toxicity. The majority of adverse events were mild to moderate. No WHO grade 3–4 nephrotoxicity or neuropathy was noted. Grade 3–4 nausea/vomiting was observed in 3 pts (11.5%). Three pts (11.5%) had grade 3 anemia and 18 pts (69.2%) had grade 3–4 neutropenia. Three pts (11.5%) developed febrile neutropenia with no secondary mortality. Conclusions: The new combination of liposomal cisplatin and vinorelbine shows promising activity and good tolerance as first line treatment for HER2/neu negative MBC. Pts’ enrollment is ongoing. Updated results will be presented at the meeting.

[Table: see text]
What is the evidence for rechallenging with anthracyclines or taxanes in metastatic breast cancer? A review of the data
Authors: Krell J. , Harper-Wynne C. , Miles D. , Misra V. , Cleator S. , Krell D. , Palmieri C.
Published: August 2020

1072

Background: Anthracyclines and taxanes are widely used in the adjuvant setting for high risk, early stage breast cancer. This raises the issue of what is the optimal therapy for those patients who relapse, and what the potential role, if any, there is for rechallenge with these agents. The current evidence base for rechallenging with anthracyclines/anthracediones and taxanes in metastatic breast cancer (MBC) is examined in this study. Methods: Medline/Pubmed database searches were performed upto October 2008 to identify studies in which patients (pts) were rechallenged with anthracyclines/anthracediones or taxanes in MBC. Results: The efficacy data, as well as the safety data relating to neurotoxicity and cardiotoxicity from these studies, are summarized in the Table. Twenty-seven studies were identified (20=anthracycline/anthracedione, 7= taxane) of which only two were prospective studies. Both were small (n= 74 & 51) and related to anthracycline rechallenging. Conclusions: Evidence exists to support rechallenging with anthracyclines and taxanes. However, there are few prospective data on reexposure to taxanes and no data comparing anthracyclines versus taxanes following adjuvant exposure to both agents, supporting the need for clinical trials in this area. Such trials should ideally incorporate a cross-over design at treatment failure, which would shed light on the optimal sequence in which these agents should be administered.

[Table: see text]

No significant financial relationships to disclose.
A phase I/II trial of ispinesib, a kinesin spindle protein (KSP) inhibitor, dosed q14d in patients with advanced breast cancer previously untreated with chemotherapy for metastatic disease or recurrence
Authors: Gomez H. L. , Philco M. , Castaneda C. , Pimentel P. , Escandon R. , Seroogy J. , Saikali K. , Wolff A. , Conlan M.
Published: August 2020

1077

Background: KSP is a mitotic kinesin essential for cell cycle progression. Ispinesib, a selective KSP inhibitor, blocks mitotic spindle assembly with cell cycle arrest in mitosis and subsequent cell death. On a q21d schedule, the MTD was 18 mg/m2. In a phase II trial of ispinesib dosed at 18 mg/m2 q21d in patients (pts) with advanced breast cancer after anthracycline and taxane failure, the response rate was 4/45 (9%). This trial evaluates ispinesib given on d1 and d15 q28d, thus increasing dose density. Methods: In phase I of this phase I/II trial, DLT and MTD of ispinesib given d1 and d15 q28d will be determined. Eligibility criteria: advanced breast cancer; no prior chemotherapy (CT) except neoadjuvant or adjuvant and ≥ 1 yr elapsed since CT; no CNS metastases; ECOG 0–1. This is a standard 3+3 dose escalation trial design, starting at 10 mg/m2 and escalating based on tolerability in cycle (cy) 1. Pharmacokinetic data are collected in cy 1. Results: Phase I of the trial is ongoing. 16 pts were treated at 3 dose levels: 10 (n = 3), 12 (n = 6), and 14 mg/m2 (n = 7). 9 pts were stage IV; 11 were chemo-naïve; 5 had prior anthracycline and/or taxane; 4 were HER-2+ and 5 ER-, PR-, HER-2-. The most frequent toxicity was neutropenia. 88% of pts in cy 1 (grade 3/4 in 75%; no febrile neutropenia). Mild GI toxicity occurred in <37.5% of pts. There was no neuropathy or alopecia. At the 14 mg/m2 dose level, 2/7 pts had DLTs of transient grade 3 AST and ALT increases after cy 1 d15 dosing; both without increases upon retreatment; 1 in a pt with liver metastases; neither pt had significant increases in alkaline phosphatase or bilirubin. The 12 mg/m2 cohort was expanded to 6 pts without DLT. 3 pts had partial response (after 1 [n = 1] and 4 [n = 2] cy, respectively); 1 confirmed and ongoing after 8+ cy; 4 pts had stable disease ≥4 mo. Conclusions: Ispinesib appears to be well tolerated on a q14d dosing schedule at doses tested to date. A dose-density equal to that given in the prior phase II trial (0.86 mg/m2/d) was tolerated with the q14d schedule with preliminary evidence of efficacy. Further exploration of the 14 mg/m2 dose level is planned.

[Table: see text]
Anastrozole and goserelin combination as first treatment for premenopausal receptor positive advanced or metastatic breast cancer: A phase II trial
Authors: Roche H. H. , Thierry D. , Chieze S. , Pierre K. , Veyret C. , Abadie S. , Campone M. , Florence D.
Published: August 2020

1079

Background: Aromatase inhibitors (AIs) have shown high activity in postmenopausal women. However, as AIs do not suppress ovarian oestrogen synthesis, they are not effective in premenopausal women. The aim of this trial was to assess the efficacy of the combination of anastrozole and goserelin (LHRH agonist) in premenopausal women with advanced or metastatic hormonal receptor positive breast cancer. Methods: Premenopausal women with advanced estrogen receptor (ER) and/or progesterone receptor (PR) positive breast cancer were enrolled in this open, multicentre, non-comparative phase II trial and received anastrozole 1mg/day p.o. and gosereline 3.6 mg subcutaneously monthly until progression. The primary endpoint was objective response rate (ORR) assessed according to RECIST criteria. Results: Thirty-three patients (33), with a mean age of 44 (+ 5.9) years, PS 0–2, were enrolled from December 2001 to May 2005. All patients were ER positive and 75.8% PR positive and 6 patients (18.2%) received adjuvant treatment with anti estrogens. There were 4 (12.1%) complete responses (CR), 14 (42.4%) partial responses (PR), and 11 (33.3%) stable diseases (SD), giving an ORR of 54.6% (IC 95% [36.4; 71.9]). Twenty-one (63.6%) patients showed a clinical benefit (CR+PR+SD≥24 weeks) for a median duration of 13.7 (IC 95% [8.74; 22.97]) months. Median time to progression was 13 (6;33) months. The most commun AEs were hot flush in 29 (87.9%), arthralgia in 13 (39.4%) and nausea in 12 (36.4%) patients. Conclusions: The combination of anastrozole and gosereline is well tolerated and appears to be an effective treatment of premenopausal women with advanced breast cancer in this exploratory phase II trial.

No significant financial relationships to disclose.
Impressive survival data with semimetronomic oral chemotherapy with old agents in heavily treated metastatic breast cancer patients
Authors: Mutlu H. , Bozcuk H. , Ozdogan M. , Artac M. , Coskun H. S. , Kargi A. , Uysal M. , Savas B.
Published: August 2020

1082

Background: To assess the efficacy of semi-metronomic regimen metronomic cyclophosphomide with oral etoposide in heavily treated patients with metastatic breast cancer. Methods: Consecutive metastatic breast cancer (MBC) patients predominantly refractory to antracyclines, taxanes, and antimetabolites receiving semi-metronomic regimen of metronomic cyclophosphomide with oral etoposide were evaluated for clinical efficacy and toxicity. This novel regimen comprised of continuous oral cyclophosphomide 50 mg/day, and oral etoposide given as 2 x 50 mg/day for 5 days. Results: A total of 42 MBC patients received this treatment in 2.5 years (May 2005-October 2008). The median age was 51.5 (29–81), ER and/or PR receptor status was positive in 67%, and c-erb-B2 overexpression existed in 50%. The biologically favorable group, hormone responsive and c-erb-B2 negative comprised of 36% of cases. The portions of patients with visceral metastases, cranial metastases, and 2 or more organ involvement were 82%, 24%, and 65%, respectively. Subjects had received this treatment in the fourth or more advanced setting in 50% of cases (after a median of 2.5 cycles). The median overall and progression free survival figures were 25 and 10.5 months, respectively. No toxic mortality occurred, and the treatment was well tolerated. Toxicity and response data are being updated currently. Conclusions: Semi-metronomic treatment with metronomic cyclophosphomide and oral etoposide is a novel and effective strategy in heavily pretreated MBC patients. Survival data and low cost may make this regimen a highly preferable option in this difficult patient group.

No significant financial relationships to disclose.
Phase II study of sagopilone (ZK-Epo) in patients with recurrent metastatic breast cancer (MBC)
Authors: Morrow P. H. , Divers S. G. , Provencher L. , Luoh S. , Petrella T. M. , Giurescu M. , Fielding L. , Wang Y. , Hortobagyi G. N. , Vahdat L. T.
Published: August 2020

1083

Background: Sagopilone is a novel, fully synthetic epothilone, which represents a new class of microtubule stabilizing agents. It has shown significant pre-clinical activity in taxane resistant breast cancer cell lines and in tumor models, as well as clinical activity in both taxane naïve and pretreated MBC. Methods: MBC patients who received ≤ 3 prior anthracycline and taxane containing chemotherapies were eligible. Sagopilone was given either at 16 mg/m2 (arm A) or at 22 mg/m2 (arm B, amended additional cohort) IV over 3 hours every 21 days for up to 6 cycles. The primary end point was tumor response by RECIST. The Simon 2-Stage design required 3 responders in the first 24 evaluable patients in stage 1 and 10 responders in 65 evaluable patients to declare success. Results: Between June 2006 and June 2008, 65 patients were enrolled and treated (39 in arm A, 26 in arm B). Majority of metastases were in lymph nodes (62%), liver (55%), bone (49%), lung (37%), and cutaneous sites (19%). Median number of cycles delivered was 2 (1–17). Neither arm met Stage 1 criteria for responders. Nevertheless, 2 patients in arm A and 1 in arm B had confirmed partial response, and lasted 4, 7, and 2 months, respectively. 26% patients in arm A, and 42% in arm B had stable disease. 42 patients discontinued study prior to cycle 6 due to progressive disease/death, 14 due to adverse events, and 1 due to other reasons. All 65 patients are evaluable for safety. Adverse events documented or reported in ≥ 20% patients are: sensory neuropathy 80% (23% grade 3), nausea 57% (no grade 3), fatigue 45% (12% grade 3), vomiting 29% (no grade 3), myalgia 28% (5% grade 3), diarrhea 25% (2% grade 3), insomnia 25% (no grade 3), pain in extremity 25% (2% grade 3), headache 23% (5% grade 3), arthralgia 22% (5% grade 3), constipation 22% (2% grade 3). Conclusions: Sagopilone had limited activity in these heavily pretreated MBC patients. It appeared tolerable at both dose levels.

[Table: see text]
A novel metronomic schedule of oral vinorelbine for the treatment of metastatic breast cancer in elderly patients: A phase II trial
Authors: Addeo R. , Faiola V. , Cennamo G. , Guarrasi R. , Montella L. , Iodice P. , Sgambato A. , Capasso E. , Caraglia M. , Del Prete S.
Published: August 2020

1085

Background: Oral vinorelbine (VNR) is particularly useful in elderly patients due to its favorable toxicity profile. Several studies demonstrated that this drug seems to represent an active treatment for metastatic breast cancer (MCB). We evaluated the clinical efficacy and tolerance of metronomic chemotherapy with oral VNR. Methods: Women were eligible if they had a histologically proven untreated MBC and were > 70 years old. A two-staged Simon accrual design was adopted for this phase II trial. Patients were required to have negative estrogen receptor status, at least one bidimensionally measurable target lesion, Karnofsky performance status >70; life expectancy > 3 months. Each patient received oral vinorelbine 80 mg/m2 fractionated in days 1, 3, and 5, three week on-one week off, every 4 weeks, for a maximum of six cycles unless disease progression or unacceptable toxicity. Results: Thirty-two patients with MBC were eligible, assessable for response, and toxicity. The median age was 75 years (range 70–84), sixteen patients (50%) had a Karnofsky performance status of 90–100. The main comorbidities recorded were: hypertension in 9 (28%) patients and diabetes mellitus in 6 (19%). The overall response rate (on an intent-to-treat basis) was 41% (13 of 32; 95% CI, 20%-54%). Two complete response and 11 partial responses were noted. In addition, other 10 patients (31%) had stable disease of > 4 months duration, and 9 patients (28 %) had disease progression. Median time to disease progression was 7.1 months and median overall survival was 12.7 months. The schedule was well tolerated, grade 3 toxicity was observed only in two patients. Conclusions: Metronomic oral VNR can be safely administered to elderly patients with MBC and is active in this population. Final data analysis will be presented.

No significant financial relationships to disclose.
Fulvestrant in the treatment of advanced breast cancer: A systematic review and meta-analysis of randomized controlled trials
Authors: Mauri D. , Valachis A. , Polyzos N. P. , Mavroudis D. , Georgoulias V. , Casazza G.
Published: August 2020

1087

Background: The purpose of the study was to compare efficacy and tolerability of fulvestrant with aromatase inhibitors and tamoxifen that actually represent the standard of care in hormonesensitive breast cancer. Methods: Systematic review and meta-analysis of available trials. Primary outcomes were overall survival, time to progression, clinical outcome, and objective response. Secondary outcome was the tolerability profile of the drugs. Results: Four trials were identified with 2,125 eligible patients. There was no statistically significant difference between fulvestrant and other hormonal agents in terms of overall survival (pooled HR: 1.047, 95% CI: 0.688 to 1.592), time to progression (pooled HR: 0.994, 95% CI: 0.691 to 1.431), clinical benefit (pooled OR: 1.044, 95% CI: 0.828 to 1.315), or objective response rate (pooled OR: 0.949, 95% CI: 0.736 to 1.224). A higher incidence of joint disorders (pooled OR: 0.621, 95% CI: 0.424 to 0.909; p = 0.014) was noted in patients receiving hormonal agents other than fulvestrant. Conclusions: Fulvestrant was similar to other hormonal agents with respect to efficacy measures, with good tolerability profile.

No significant financial relationships to disclose.
Study on external Chinese herbal medicine LC07 treating capecitabine-induced hand-foot syndrome in metastatic breast cancer
Authors: Jia L. , Lou Y. , Tan H.
Published: August 2020

1088

Background: With the capecitabine being increasingly used in the treatment of metastatic breast cancer (MBC), the common side effect of capecitabine, hand-foot syndrome (HFS) has become a main problem which can distress both physicians and patients. Severe HFS such as severe pain can have a negative impact on quality of life (QOL) of these patients and cause reduced dosage or even stopping chemotherapy. No effective treatment for HFS can be available at present. Over the years we have used LC07, a kind of external agents from Chinese herbs (Herba Geranii, etc.), to treat capecitabine-induced HFS. In this study, the efficacy and safety of LC07 were evaluated in patients with MBC and HSF. Methods: Eligible patients includes patients with MBC, who had HFS (NCI-CTC grade ≥1) after receiving single capecitabine chemotherapy (1,250 mg/m2, PO, twice daily, cycled days 1–14, every 21 days). LC07 granules 10g was dissolved in 1,000mL of warm water (keep 34°C-37°C in a footbath), the patients soaked their feet and hands in this lotion for 20 minutes, twice daily for 7 days. An independent researcher assessed symptoms before and after treatment. Evaluation criteria, CR as symptom disappearing completely, PR as NCI-CTC grade for HFS decreasing by more than 1 level after treatment, the total response rate as CR+PR. The QOL of these patients were also evaluated before and after treatment using a FACT-B questionnaire (Version 4.0-Chinese). Results: 42 patients (pts) have been enrolled in this study. All of them are Asian and female. Media age 51.5 yrs (25–72). Grade 1 for HFS was seen in 8 pts, G2 in 19 pts, and G3 in 15 pts. The total response rate was 83.3% (35/42), CR 38.1% (16/42), PR 45.2% (19/42). The average time from therapy to pain relief was 1.8±0.8 days, the skin lesion of HFS including dermatitis, peeling, ulceration have been improved after treatment. The QOL scores before and after treatment were 77.24±25.69 and 109.17±20.53, respectively (p < 0.01). No side effects such as skin allergies related to LC07 was found in this study. Conclusions: In the treatment of capecitabine-induced HFS, the external Chinese medicine LC07 is fast effective for relieving pain, and it has the features of easy use and no skin allergies. Thus LC07 can improve the QOL of patients with MBC and HFS.

No significant financial relationships to disclose.
Phase II study of irinotecan plus capecitabine in patients with anthracycline and taxane pretreated metastatic breast cancer
Authors: Lee K. S. , Ro J. , Park I. H. , Kim E. A. , Nam B.
Published: August 2020

1093

Background: Irinotecan (I) and capecitabine (X) have demonstrated single agent activity against breast cancer by different antitumor mechanism without cross-resistance. To assess the objective response rate (RR) of IX combination in metastatic breast cancer (MBC) patients (pts) was the primary end point. Methods: Anthracycline- and taxane-pretreated pts with measurable disease, age ≥ 18 years, adequate organ functions, and ECOG performance score (PS) 0–2 were eligible. Sample size of 36 was calculated with Simon's two stage minimax design. Pts received I 80 mg/m2 intravenously on days 1 and 8 and X 1,000 mg/m2 orally twice daily on days 1–14 of every 21-day cycle. Results: Between September 2006 and April 2008, 36 pts with median age of 50 years (range, 28–71) were enrolled. Median follow-up was 17 months (range, 8.3+ - 27.7+). Among 35 evaluable pts excluding 1-consent withdrawal, 86% received at least one prior chemotherapy for MBC; 20% had stage IV disease with 66% lung/37% liver metastases; 80% had PS 0–1; 77% had hormone receptor (HR) positive tumors, 20% triple negative disease and 3% HER-2 positive tumors. Overall RR was 60% (95% CI, 43.5–74.5) with median response duration of 6.3 months (range, 1.0+-17.1+); 2 CR (6%), 19 PR (54%), 8 SD (23%), and 6 PD (17%) with similar RR between HR+ (63%) versus triple negative disease (57%). Median survival was not reached with 76% estimated survival at 1-year, and median progression free survival (PFS) was 7.3 months (range, 0.7–21.1+). Pts received a median of 8 cycles of treatment (range, 1–26+). G1, G2, and G3 hand-foot syndrome were observed in 34%, 17%, and 0%, respectively. NCI grade ≥ 3 adverse events were: neutropenia (60%); asthenia, diarrhea, and vomiting (9%, each); transaminase elevation and febrile neutropenia (6%, each); abdominal pain, anorexia, fatigue, myalgia, and nausea (3%, each). Conclusions: I and X combination by this schedule and doses is highly efficacious in anthracyline- and taxane-pretreated MBC pts with manageable toxicities. Further investigation of this combination in phase III trials is warranted.

No significant financial relationships to disclose.
Correlation of FcγR IIa-H131R and IIIa-V158F polymorphisms and clinical outcome of trastuzumab in both neoadjuvant and metastatic setting in patients with HER-2 positive breast cancer
Authors: Tamura K. , Shimizu C. , Koizumi F. , Kouno T. , Katsumata N. , Kinoshita T. , Aogi K. , Nishio K. , Ando M. , Fujiwara Y.
Published: August 2020

1100

Background: The antibody dependent cell mediated cytotoxicity (ADCC) affects an efficacy of Immunoglobulin G1 antibody, including trastuzumab which is a humanized anti-HER-2 monoclonal antibody, through fragment C receptor (FcγR) polymorphisms. One report suggested that allotype of two kinds of FcγR single nucleotide polymorphisms (SNPs) are associated with clinical outcome of patients (pts) with metastatic breast cancer (BC) who received combination trastuzumab with taxane. Ethnic difference was reported in frequency of these SNPs between Western and Asian pts. The objective of this prospective study was to evaluate whether these SNPs are associated with pathological complete response (pCR) in neoadjuvant (N) setting with pts who received trastuzumab based chemotherapy, and objective response (OR) in metastatic (M) setting in pts who received single trastuzumab. Methods: Eligible criteria include HER-2 positive BC, chemotherapy-naïve, measurable disease, PS 0–2 and adequate organ functions. Pts in N setting received standard FEC (5-fluorouracil/epirubicin/cyclophosphamide q3w for 4cycles followed by weekly paclitaxel/trastuzumab for 12 weeks. Pts in M setting received single trastuzumab q1w until progression. 384 SNPs of different FcγR loci were assessed from genomic DNA extracted from peripheral blood by GOLDEGATE beads array (illumina Co.). Results: Nineteen operable and 36 metastatic HER-2 positive BC pts have been enrolled in each N and M setting, respectively. pCR in N setting was 26.3%, and OR in M setting was 22.2%. The frequencies of FcγRIIa131 genotypes were H/H 43%, H/R 49%, R/R 8%, and that of FcγRIIIa158 were V/V 43%, V/F 47%, F/F 10%, respectively. 131H/H genotype was significantly correlated with pCR (p = 0.0034) and OR (p = 0.037). 158V/V genotype had a tendency to be correlated with pCR (p = 0.067) and was significantly correlated with OR (p = 0.037). The median PFS was 8.9 months for pts with 131H/H and 3.8 months for R carriers (H/R or R/R). Conclusions: Our data for the first time suggest that these two SNPs predict pCR to trastuzumab based chemotherapy in N setting, and OR to single trastuzumab in M setting.

No significant financial relationships to disclose.
Detection of MSC-like cells in soft tissue sarcoma cell lines and primary tumors
Authors: Wirths S. , Malenke E. , Wiesner T. , Buehring H. , Hartmann J. , Kopp H. G.
Published: August 2020

11000

Background: Soft tissue sarcomas (STS) are a heterogeneous group of mesodermal tumors hypothetically originating from mesenchymal stem cells (MSC). While the expression profile of bone marrow derived MSCs and their in vitro differentiation potential have been examined extensively, knowledge regarding the in vivo counterparts of MSC is still evolving. We hypothesized that MSC-like cells within STS could represent sarcoma initiating cells. Methods: To target rare human cell populations including MSCs, an exclusive antibody panel was developed. The target antigens include platelet-derived growth factor receptor-β (CD140b), HER-2/erbB2 (CD340), TNFRSF16 (CD217), frizzled-4 (CD344), the recently described W8B2 antigen, as well as several surface antigens identified by novel antibodies. To define the expression pattern of MSC-markers in STS, both cell lines and primary tumor samples in suspension and in snap frozen sections were investigated. To reveal functional differences between identified rare tumor populations single cell proliferation kinetics were investigated after FACS-sorting. Results: All cell lines und primary tumor samples revealed expression of selected markers. Antigens identifying subpopulations within all sarcoma samples investigated, were selected for functional studies. These included frizzled-4, TNFRSF16, W5C5 and W8B2. Liposarcoma (SW872), leiomyosarcoma (SK-LMS) and fibrosarcoma (HT1080) cell lines enclosed subpopulations with differential expression of above markers and by FACS based limiting dilution it was demonstrated that only fractions of viable cells contained proliferative capacity. Cells lacking expression of CD271 had lower proliferative capacity compared to mock sorted HT1080 or SK-LMS, while CD271+ SW872 had significantly higher proliferation. The antigen defined by W5C5 identified cells with high proliferative capacity compared to control in SW872 and SK-LMS and its lack in HT1080 identified a subpopulation with largely reduced proliferation. Conclusions: Subpopulations within STS cell lines and primary sarcoma tissue express novel MSC-markers and display increased proliferative capacity, potentially reflecting the existence of sarcoma initiating cells.

No significant financial relationships to disclose.
Construction of a five-marker protein-based model for stage-independent assessment of prognosis in breast cancer
Authors: Giltnane J. M. , Rapp J. , Moeder C. , Camp R. L. , Kluger H. , Molinaro A. , Rimm D.
Published: August 2020

11013

Background: While the TNM method for assessment of stage in breast cancer is simple and robust, molecular methods for limited patient subsets are gaining popularity (i.e Oncotype Dx or Mammaprint). We hypothesized that multiplexed quantitative measurement of proteins known to be involved in breast cancer signaling pathways of growth, proliferation, survival, and metastasis can enhance clinical methods of predicting prognosis in all patients. Methods: We assessed the expression of twenty-three proteins (ER, PR, EGFR, HER2, HER3, HER4, ERK, PTEN, PI3Kp85α, PI3Kp110α, p27/Kip1,EIF4E, FOXO3,AKT1, AKT2, AKT3, MYC, cyclinD1, FOXO1, mTOR, p70S6Kb, NFkB and BCL2) in four subcellular compartments by automated quantitative analysis of protein expression (AQUA) on tissue microarrays of the archival Yale breast cancer cohort (n=676). To project future performance of these markers including clinicopathological parameters, we constructed univariate and multivariate logistic regression models using leave-one-out cross-validation and calculated prediction error (PE) estimates of each model's value to predict a binary endpoint of 10 year survival. In addition, we constructed univariate and multivariate Cox models of ten year disease specific survival (DSS). Results: By Cox univariate analysis, ER, PR, PTEN, and BCL2 were directly correlated with DSS, while FOXO1, HER2, HER3, and PI3Kp110α were inversely correlated with DSS. A five-variable logistic regression model of 10 year survival including nuclear AKT1, BCL2, nuclear FOXO1, cytoplasmic mTOR, and nuclear p70S6Kb (prediction error= .274) surpasses performance of TNM staging (PE=.367) and the Nottingham Prognostic Index (PE=.326). The same model is associated with 10-year DSS by Cox proportional hazard (p=<.00001) independent of TNM stage and NPI. Conclusions: Our protein-based, multiplexed approach to prognostic classification was superior to traditional methods (TNM or NPI) and single biomarkers in this retrospective cohort. Current outcomes are influenced by modern therapies, limiting the direct impact of this analysis. However, molecular profiling of primary tumor linked to outcome paves the way for the incorporation of new prognostic models into prospective studies.

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Use of microarray analysis of differentially expressed genes in luminal B subtype of breast cancers to evaluate NHERF1 as a marker of endocrine resistance
Authors: Rody A. , Karn T. , Solbach C. , Ruckhaeberle E. , Hanker L. , Ahr A. , Gaetje R. , Holtrich U. , Kaufmann M.
Published: August 2020

11015

Background: In vitro and in vivo data demonstrate that the expression of estrogen receptor (ER) in breast cancer is mainly associated with low proliferation. Gene expression profiling has recently been used to identify a group of high proliferating estrogen receptor positive breast cancers (the luminal B subtype), which are associated with a prognosis that is even worse than that of high proliferating estrogen receptor negative tumors. The analysis of those tumors might provide valuable information about breast cancer biology and could be helpful for adjuvant or neoadjuvant treatment decisions.Methods and Results: We analyzed microarray data from breast cancer specimens to gain insight into genes which play a role in estrogen receptor signalling. Genes were identified showing strong expression in high proliferating ER-positive tumors but no expression in either Ki67-/ER+ or Ki67+/ER- samples. Among these genes the Na+/H+ exchanger regulatory factor NHERF1 was found. We assessed the clinical relevance of NHERF1 transcript levels using a total of 2469 breast cancers. Analysis indicates that enhanced NHERF1 expression is associated with metastatic progression and poor prognosis of breast cancer patients. We found no correlation between NHERF1 and the nodal status as well as age, but positive correlations for tumor size (P<0.001), grade (P<0.001) and erbb2 (P=0.033). Weak NHERF1 expression correlated with longer disease free survival (DFS) in grade 1 and 2 tumors, but not in grade 3 breast cancers. Since NHERF1 expression is strongly linked to the presence of ER, the predictive value for endocrine treatment was analyzed. For samples with weak or none NHERF1 expression a treatment benefit was observed (P=0.007). While untreated patients display a 10 yr DFS rate of 67.2 ± 3.8%, endocrine treatment resulted in 80.1 ± 4.0%. In contrast no differences in disease free survival were found for corresponding NHERF1 expressing breast cancers. Conclusions: Our data indicate that expression of NHERF1 defines a state of differentiation, where breast cancer cells are refractory to endocrine treatment.

No significant financial relationships to disclose.