Citations

Background: Traumatic amputation of the digit requiring revision amputation at the level of the proximal phalanx provides the opportunity to improve flexor function via tenodesis of the remaining flexor digitorum superficialis (FDS) tendon. Salvage of the remaining FDS and performing flexor tenodesis to the proximal phalanx allows increased flexion at the metacarpophalangeal (MCP) joint. Methods: This series reviews FDS tenodesis, outlining its surgical technique with clinical and functional outcomes. Institutional review board–approved retrospective study was performed. Twelve digits in 8 patients were included. Results: Average flexion-extension arc of affected MCP joint was 82°, and average grip strength was 70% of unaffected extremity. No patients required revision surgery or revision amputation. One patient had a minor wound infection treated successfully with oral antibiotics. Conclusions: FDS tenodesis is a reliable motion-preserving procedure for patients with amputations at the level of the proximal phalanx to maintain flexion at the MCP joint.

Abstract Background: The need remains for novel agents that prolong survival and/or improve QOL in women with aBC. EP is a long-acting topoisomerase 1 inhibitor engineered to produce sustained exposure to irinotecan and its active metabolite SN38. Given previous efficacy seen in an earlier phase II trial in MBC, EP 145 mg/m2 every 3 weeks was compared to TPC (one of 7 single-agent regimens) in the randomized phase 3 BEACON study (NCT01492101). As reported at ASCO 2015 (abstract 1001), EP prolonged median overall survival by 2.1 months, although this did not reach statistical significance (12.4 vs 10.3 months; HR 0.87, p=0.08). Grade ≥ 3 adverse events were significantly less common with EP (48% vs 63% with TPC, p<0.001). We now present results of the QOL analyses. Methods: Patients completed validated health-related QoL (HRQoL) questionnaires, EORTC QLQ-C30 (version 3.0) and breast cancer-specific QLQ-BR23, pretreatment and every 8 weeks until progression, death or withdrawal of consent. Questionnaires were scored according to the EORTC manual. For each scale, raw scores were standardized via a linear transformation to a range from 0 to 100. Absolute scores and changes from baseline were analyzed longitudinally and categorically using a 5-point difference calculated by treatment group. Comparisons between treatment groups were conducted to evaluate the differences in global health status, functional scores and symptoms over time. Results: The majority of patients who were randomized (total: 733/852 [86%], EP: 378/429 [88%], TPC: 355/423 [84%]) completed at least one post-baseline HRQoL questionnaire. In the EORTC QLQ-C30, grade ≥ 3 AEs significantly impacted HRQoL measured by global health status and 5 additional functional domains. Of the six domains, compared to TPC in a longitudinal analysis, EP was statistically superior in the mean treatment effect through Week 32 in global health status p=0.02 and physical functioning scale p=0.01. EP was also numerically superior in all other scales. In EORTC QLQ-C30 and BR-23, a total of 13 symptoms were measured and categorically analyzed. There were no treatment differences in 7 of 13 symptom scales. EP was associated with worsening of 3 symptom scales: appetite loss, nausea/vomiting, and diarrhea. TPC was associated with worsening of 2 symptom scales: dyspnea and systemic side effects. Conclusions: In the phase 3 BEACON trial comparing EP to TPC, the more favorable toxicity profile of EP resulted in an improvement in global health status and physical function (results of the symptom scales confirmed the different toxicities of the two arms). EP remains a promising investigational therapy for aBC. Citation Format: Cortes J, Awada A, Perez EA, Rugo HS, Twelves C, Im S-A, Zhao C, Hoch U, Ney J, Hannah AL, O'Shaughnessy J. Impact of treatment on quality of life (QOL) in the BEACON study, a randomized phase III trial of etirinotecan pegol (EP) versus treatment of physician's choice (TPC) in patients (pts) with advanced breast cancer (aBC) whose disease has progressed following anthracycline (A), taxane (T) and capecitabine (C). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-11-08.

Abstract Background: Etirinotecan pegol (EP) is a long-acting Top1 inhibitor providing sustained levels of active metabolite throughout the entire chemotherapy cycle. The phase 3 BEACON trial compared EP to treatment of physician's choice (TPC) in patients with advanced breast cancer, demonstrating a non-statistically significant 2.1 month difference in survival favoring EP in the intent to treat population. A novel aspect of the BEACON trial is to explore the utility of biomarkers measured in CTCs for predicting efficacy with EP. Pre- and post-treatment CTCs were isolated from blood of 77% of the 852 BEACON patients. Target-specific pharmacodynamic biomarkers for EP measured in CTCs were analyzed to identify patients most responsive to treatment with EP. Methods: Donation of blood samples for CTC analysis was voluntary. Participating BEACON patients had serial (baseline, Cycle 2 Day 1 [C2D1], Cycle 4 Day 1 [C4D1], End of Treatment) 7.5-mL whole blood samples drawn in EDTA tubes and shipped within 96 hours ambient to ApoCell (Houston, TX) for processing. PBMCs were separated by Ficoll® gradient, and CTCs were isolated using ApoStream® technology. Isolated cells were deposited on three slides and stained for DAPI, CD45, cytokeratin markers, as well as Top1, Top2, Ki67, γH2AX, Rad51, ABCG2, and TUNEL. Biomarkers were quantified by iCys® laser scanning cytometer equipped with image analysis software, and correlated with OS using Cox multiple regression and Kaplan-Meier analyses. Results: The CTC substudy yielded 611 pre-treatment, 519 C2D1, 268 C4D1, and 431 End of Treatment samples. Among the successfully processed blood samples, 98% had detectable CTCs, with a median of 63, 46, 51, and 57 CTCs/mL at baseline, C2D1, C4D1, and End of Treatment, respectively. Cox regression analyses of CTC number and percentage of Top1, Top2, Ki67, or TUNEL positive CTCs identified a correlation for post-treatment number of Top1-positive CTCs with OS in patients receiving EP. To assess the impact of Top1-positive CTCs, patients were classified as Top1-High (> median) or Top1-Low (≤ median) based on the percent of Top1-positive CTCs at baseline. Among the Top1-High patients at baseline, significantly improved OS (HR 0.54, p=0.007) was observed for those who converted to Top1-Low after their first treatment with EP (C2D1), but not TPC (HR 1.12, p=0.613). These results suggest that decreased number of Top1-positive CTCs may reflect EP target engagement with Top1, as these patients derived the most benefit from treatment. Conclusions: CTC collection and analysis was successfully incorporated into the phase 3 BEACON study, with 77% patient participation. CTC detection rate using ApoStream® was high, permitting evaluation of biomarkers at baseline and post-treatment. Significantly improved OS was observed in patients who had a decreased number of Top1-positive CTCs following cycle 1 of EP. Citation Format: Rugo HS, Cortes J, Awada A, O'Shaughnessy J, Twelves C, Im S-A, Hannah AL, Lu L, Sy S, Caygill K, Zajchowski D, Davis DW, Hoch U, Perez EA. Early change in topoisomerase 1 (Top1) positive circulating tumor cells (CTCs) is associated with overall survival (OS) in patients with advanced breast cancer after treatment with etirinotecan pegol. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-13-02.

Abstract Background: Etirinotecan pegol (EP) is the first long-acting topoisomerase 1-inhibitor providing sustained level of active metabolite that concentrate in the tumor for an entire chemotherapy cycle. In a Phase 2 study (Lancet Oncology 2013), EP demonstrated a 29% overall response rate in patients with metastatic breast cancer, leading to the Phase 3 global BEACON study in this population. Detection of circulating tumor cells (CTCs) using immunomagnetic EpCAM-based methods have been conceptually accepted as a "liquid tumor biopsy". To circumvent the limited recovery of CTCs these methods provide for molecular profiling applications, we isolated CTCs based on an antibody-independent, continuous flow dielectrophoresis (DEP) technology (ApoStream®). We developed quantitative multiplex immunofluorescent assays for target-specific pharmacodynamics (PD) biomarkers for EP in CTCs isolated pre- and post-treatment. Here we present the distribution of the PD biomarkers in CTC samples collected from BEACON patients. Methods: Donation of blood samples for CTC analysis was voluntary. BEACON patients participating in the substudy had serial (pre-dose, Cycle 2 Day 1, Cycle 4 Day 1, End of Treatment) 7.5-mL whole blood samples drawn in EDTA tubes and shipped ambient to ApoCell (Houston, TX) within 96 hrs for processing. PBMCs were separated by Ficoll® gradient, and CTCs were isolated using ApoStream® technology. Isolated cells were deposited on three slides and stained for DAPI, CD45, and cytokeratin markers, as well as 2-3 of the seven PD markers, and analyzed by iCys® laser scanning cytometer equipped with image analysis software. CTC count, mean fluorescence intensity (MFI) of PD biomarkers, and % marker-positive cells were analyzed for their distribution. Results: 75% of the 852 BEACON patients participated in the CTC substudy, yielding 649 pre-treatment CTC samples. As of Mar14, 538 Cycle 2 Day 1, 281 Cycle 4 Day 1, and 394 End of Treatment samples were collected. 98% of pre-treatment blood samples were successfully processed. 97% had detectable CTCs, with a median of 504 CTCs (interquartile range: 128-1432). PD markers could be analyzed in 83-92% of samples after implementing a minimum requirement of 10 CTCs analyzed. Staining was positive for Top1, Top2, μH2Ax, Rad51, ABCG2, Ki67, and TUNEL in 82%, 71%, 14%, 30%, 20%, 56%, and 94% of samples, respectively. Percent of marker-positive cells varied from 0.2-69%, with 6- to 37-fold interquartile ranges. Median MFI in these cells varied between 25x103 and 100x103, with 1.2- to 1.6-fold interquartile ranges. Conclusions: CTC collection was successfully incorporated into the BEACON study, with 75% patient participation. CTC detection rate using ApoStream® was high, permitting evaluation of biomarkers at baseline and over time. EP target-specific PD biomarkers can be measured in CTCs isolated from patients participating in BEACON and will be assessed for their potential to predict clinical response. Final BEACON efficacy and safety results are expected in early 2015, which will allow further analysis of CTCs with patient outcome (response, PFS, OS) and change in CTCs at time of progression. Citation Format: Edith A Perez, Katie Caygill, Alison L Hannah, Javier Cortes, Ahmad Awada, Joyce O'Shaughnessy, Christopher Twelves, Hope Rugo, Seock-Ah Im, Kenna Anderes, Darren W Davis, Ute Hoch. Etirinotecan pegol target-specific pharmacodynamic biomarkers in circulating tumor cells from patients with metastatic breast cancer in the phase 3 BEACON study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-10-03.

Abstract Background A Phase III trial (Study 301; NCT00337103) in MBC comparing eribulin (E) with capecitabine (C) showed a trend for improved overall survival (OS) (hazard ratio [HR] 0.88; 95% CI 0.77, 1.00; P = 0.056) but not progression-free survival (PFS) (HR 1.08; 95% CI 0.93, 1.25; P = 0.30) with E. In order to investigate this apparent discordance, post-hoc analyses assessed the effect of PPT and events defining disease progression on OS. Methods Pts with locally advanced or MBC who had received an anthracycline and a taxane (≤2 prior chemotherapy regimens for advanced disease), were randomized to E (554) or C (548). Co-primary endpoints were OS and PFS. The impact of PPT on OS was assessed by analysis of exploratory PPT subgroups. Analyses of OS sensitivity censoring at time of PPT, and OS adjusted by PPT as a time-dependent covariate in a Cox regression model, were performed. The relationship between OS and progression events (appearance of a “new” lesion or metastasis [NM]; increase in size of pre-existing lesions [IPEL]; or other [death, clinical progression, or censored]) was investigated using Cox regression. Results PPT was received by 70% and 62% of E and C pts, respectively. For E pts, there were no significant OS differences by PPT (Table 1). Excluding 56 pts (22 E, 34 C) who received anti-HER2 therapy as PPT from the intent-to-treat OS analysis, OS was longer with E (HR 0.86; 95% CI 0.76, 0.99; nominal P = 0.03). OS sensitivity analysis censoring at time of PPT was consistent with the overall study results (HR 0.82; 95% CI 0.65, 1.03). Assessment of the overall effect of PPT, adjusting by PPT as a time-dependent covariate in a Cox regression model, showed that OS was longer with E (HR 0.85; 95% CI 0.75, 0.97; nominal P = 0.02). Progression due to NM or IPEL occurred in 271 and 147 of E pts, and 285 and 129 of C pts, respectively. Median OS was similar between arms in pts with IPEL and longer with E vs C in pts with NM (Table 2). Pts who progressed due to NM were at higher risk of death (HR 2.12; 95% CI 1.84, 2.43; nominal P<0.01). Conclusions Treatment with C or any other PPT after progression on E did not account for the trend in OS benefit with E observed in the primary analysis. Pts who progressed with NM had a worse prognosis than those with IPEL. The appearance of NM was highly correlated with OS, and the apparent discordance between PFS and OS seems to be related to these different progression events. Tab 1: OS by PPT after EPPTAll ptsC as 1stOther than C as 1stC at any timeOther than C at any timeNoneN554221169275115164Median OS, months (95% CI)15.9 (15.2, 17.6)18.3 (15.8, 20.9)19.9 (17.6, 24.0)19.6 (17.6, 21.5)18.0 (15.4, 22.7)7.4 (6.2, 9.1) Tab 2: OS by progression event Progression event NMIPELOther ECECECN271285147129136134Median OS, months (95% CI)15.5 (14.2, 17.5)12.9 (11.3, 14.5)17.4 (14.4, 19.7)17.4 (15.3, 20.9)16.7 (14.8, 24.2)15.5 (11.7, 18.3)HR (95% CI)0.81 (0.68, 0.97)1.13 (0.87, 1.46)0.78 (0.59, 1.03)Nominal P -value0.020.350.08Time to NM or death, months (95% CI)5.8 (5.2, 6.5)5.2 (4.3, 5.9)NANAHR (95% CI)0.90 (0.77, 1.05)NANANominal P-value0.17NANA Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-13-03.

Abstract Interactions between the malignant plasma cells of multiple myeloma and stromal cells within the bone marrow microenvironment are essential for myeloma cell survival, mirroring the same dependence of normal bone marrow-resident long-lived plasma cells on specific marrow niches. These interactions directly transduce prosurvival signals to the myeloma cells and also induce niche production of supportive soluble factors. However, despite their central importance, the specific molecular and cellular components involved remain poorly characterized. We now report that the prototypic T cell costimulatory receptor CD28 is overexpressed on myeloma cells during disease progression and in the poor-prognosis subgroups and plays a previously unrecognized role as a two-way molecular bridge to support myeloid stromal cells in the microenvironment. Engagement by CD28 to its ligand CD80/CD86 on stromal dendritic cell directly transduces a prosurvival signal to myeloma cell, protecting it against chemotherapy and growth factor withdrawal-induced death. Simultaneously, CD28-mediated ligation of CD80/CD86 induces the stromal dendritic cell to produce the prosurvival cytokine IL-6 (involving novel cross-talk with the Notch pathway) and the immunosuppressive enzyme IDO. These findings identify CD28 and CD80/CD86 as important molecular components of the interaction between myeloma cells and the bone marrow microenvironment, point to similar interaction for normal plasma cells, and suggest novel therapeutic strategies to target malignant and pathogenic (e.g., in allergy and autoimmunity) plasma cells.

Purpose This phase III study compared the efficacy and safety of bevacizumab (BV) when combined with several standard chemotherapy regimens versus those regimens alone for first-line treatment of patients with human epidermal growth factor receptor 2–negative metastatic breast cancer. Patients and Methods Patients were randomly assigned in 2:1 ratio to chemotherapy plus BV or chemotherapy plus placebo. Before random assignment, investigators chose capecitabine (Cape; 2,000 mg/m 2 for 14 days), taxane (Tax) -based (nab-paclitaxel 260 mg/m 2 , docetaxel 75 or 100 mg/m 2 ), or anthracycline (Anthra) -based (doxorubicin or epirubicin combinations [doxorubicin/cyclophosphamide, epirubicin/cyclophosphamide, fluorouracil/epirubicin/cyclophosphamide, or fluorouracil/doxorubicin/cyclophosphamide]) chemotherapy administered every 3 weeks. BV or placebo was administered at 15 mg/kg every 3 weeks. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), 1-year survival rate, objective response rate, duration of objective response, and safety. Two independently powered cohorts defined by the choice of chemotherapy (Cape patients or pooled Tax/Anthra patients) were analyzed in parallel. Results RIBBON-1 (Regimens in Bevacizumab for Breast Oncology) enrolled 1,237 patients (Cape cohort, n = 615; Tax/Anthra cohort, n = 622). Median PFS was longer for each BV combination (Cape cohort: increased from 5.7 months to 8.6 months; hazard ratio [HR], 0.69; 95% CI, 0.56 to 0.84; log-rank P < .001; and Tax/Anthra cohort: increased from 8.0 months to 9.2 months; HR, 0.64; 95% CI, 0.52 to 0.80; log-rank P < .001). No statistically significant differences in OS between the placebo- and BV-containing arms were observed. Safety was consistent with results of prior BV trials. Conclusion The combination of BV with Cape, Tax, or Anthra improves clinical benefit in terms of increased PFS in first-line treatment of metastatic breast cancer, with a safety profile comparable to prior phase III studies.

AbstractA panel of members of the 2009 International Myeloma Workshop developed guidelines for risk stratification in multiple myeloma. The purpose of risk stratification is not to decide time of therapy but to prognosticate. There is general consensus that risk stratification is applicable to newly diagnosed patients; however, some genetic abnormalities characteristic of poor outcome at diagnosis may suggest poor outcome if only detected at the time of relapse. Thus, in good-risk patients, it is necessary to evaluate for high-risk features at relapse. Although detection of any cytogenetic abnormality is considered to suggest higher-risk disease, the specific abnormalities considered as poor risk are cytogenetically detected chromosomal 13 or 13q deletion, t(4;14) and del17p, and detection by fluorescence in situ hybridization of t(4;14), t(14;16), and del17p. Detection of 13q deletion by fluorescence in situ hybridization only, in absence of other abnormalities, is not considered a high-risk feature. High serum β2-microglobulin level and International Staging System stages II and III, incorporating high β2-microglobulin and low albumin, are considered to predict higher risk disease. There was a consensus that the high-risk features will change in the future, with introduction of other new agents or possibly new combinations.