bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of improved survival (OS) and tumor control (TC) with interleukin-2 (IL2) with development of immune-related events (IREs): Data from the PROCLAIMSM registry.
Authors: Curti Brendan D. , Daniels Gregory A. , McDermott David F. , Clark Joseph , Kaufman Howard , Singh Jatinder , Kaur Meenu , Luna Theresa L. , Gregory Nancy C. , Hua Hong , Morse Michael , Wong Michael K.K. , Dutcher Janice P.
Published: September 2018

9528

Background: IREs are associated with immunotherapy (IT) for cancer and while reports suggest improvement in TC and OS with induced IREs, the long-term impact is unclear. IL2 has been the major IT for patients (pts) with renal cell carcinoma (RCC) and melanoma (MM) since 1992. We evaluated IREs reports in the PROCLAIMSM data base (2008-2016) of IL2-treated pts. Methods: Reports on 614 (MM) and 843 (RCC) pts were queried for IREs. IREs were categorized as occurring before, during, or after IL-2 and related to any checkpoint inhibitor (CPI). TC (CR+PR+SD) was compared between no IRE and IRE, using Fisher’s exact test. OS curves were estimated by Kaplan-Meier method, and comparison of no IRE/before IL2 with during/after IL2, was analyzed by log-rank test. Results: With a median (med) follow-up of 3.5+ years (range 1-8+ year), 140 IREs were reported in 118 pts (9.6% of all PROCLAIMSM pts): 93 (15%) in MM; 47 (5.6%) in RCC. 25 IREs were prior to IL2; 13 IREs were during IL2; 102 were after IL2. Of the latter 102, 31 were after IL2 and after subsequent CPI; 71 were attributed to IL2 only; and in 13, IREs were due to either IL2 or CPI. TC was 73% for IRE group vs 56% for no IRE group (p = 0.0054). OS was significantly greater for IRE group during/after IL2 compared to no IRE/before IL2 in MM, med 46 months (mo) vs 18 mo (p = 0.0001) and in RCC, med 61 mo vs 43 mo (p = 0.0196), independent of CPI IREs. Med # of IL2 doses was 19 in no IRE group, 39 in IRE during IL2 group, and 25 in IRE after IL2 group. IL2-related IREs were primarily vitiligo and thyroid dysfunction (70% of IL2 IREs), with limited further impact, while CPI-related IREs were often serious, requiring intervention (hypophysitis, colitis, hepatitis, uveitis) (52% of CPI IREs) and possibly chronic management. Conclusions: IREs following IL2 are associated with improved TC and OS. IREs resulting from IL2 and from CPIs are qualitatively different and likely reflect different mechanisms of action of immune activation and response.
Outcomes following progression on BRAF/MEK inhibition in metastatic melanoma.
Authors: Mason Robert , Heng Sharon , Atkinson Victoria
Published: September 2018

9537

Background: Restrictions in Australia dictate the prescription of BRAF/MEK inhibitors prior to immunotherapy in BRAF mutant metastatic melanoma (BRMM). We analysed patients (pts) with advanced BRMM after treatment with a BRAF/MEK inhibitor and use of second line immunotherapy (PD-1 inhibitor or CTLA4 inhibitor). Methods: Patients (pts) with BRMM from Princess Alexandra Hospital treated between June 2013 to June 2016 were identified retrospectively. Demographics, treatment pattern and survival were analysed. Results: 92 pts were identified. 50% had an elevated LDH at diagnosis. 30 pts had brain metastasis at diagnosis, of these pts 11 had cerebral progression on BRAF/MEK. 41 pts had radiotherapy, 50% had stereotactic/gamma knife and 50% WBRT. 68 pts progressed giving a median progression free survival (PFS) of 9 months (95% CI 6.4 – 11.6 m). The median PFS for pts with normal LDH was 14 months, opposed to 9 months if elevated. On progression 31 pts (36.5%) were not offered second line immunotherapy due to rapid deterioration or declining performance status. 26 (30.6%) were treated with PD-1 inhibitor; 7 (8.2%) had Ipilimumab, of these, 4 then had PD-1; 1 had combination therapy; 23.5% of pts continued on BRAF/MEK at analysis. Of the patients exposed to immunotherapy, 27 pts experienced disease progression, giving a median PFS survival of 2.5 months (95% CI 1.2 –3.6m). Conclusions: After BRAF/MEK inhibition, due to rapid disease progression and poor performance status a significant proportion of patients do not receive immunotherapy and received best supportive care. Disease control with single agent PD-1 is short after BRAF/MEK inhibitors. These patients may have benefited from first line immunotherapy. This cohort, while small, suggests further data is needed about optimal sequencing of targeted and immunotherapy.
Analysis of circulating tumor DNA (ctDNA) in pseudoprogression in anti-PD1 treated metastatic melanoma (MM).
Authors: Lee Jenny HJ , Long Georgina V. , Menzies Alexander M. , Guminski Alexander David , Kefford Richard , Rizos Helen , Carlino Matteo S.
Published: September 2018

9546

Background: We have previously shown that undetectable ctDNA either at baseline or during therapy predicted response in mm patients (pts) treated with anti-PD1 antibodies (aPD1). Pseudoprogression, defined as radiological progression prior to response, occurs in 8% of pts treated with aPD1. We sought to determine if ctDNA could differentiate pseudoprogression from true progression, defined as continued clinical or radiological disease progression. Methods: Between July 2014 and May 2016, pts receiving aPD1 had serial bloods for ctDNA. Included pts either had RECIST PD at first restaging or early clinical progression. Those with untreated brain metastases were excluded from the analysis. ctDNA was quantified using digital droplet PCR for mutations (BRAF/NRAS) at baseline and during the first 12 wks of treatment. Based on our prior studies, ctDNA results were grouped in to ‘favorable’ and ‘unfavorable’ ctDNA profiles (see Table), and these were compared in pts with true and pseudoprogression. Results: 29 pts were included, 28 with RECIST PD at first restaging and one with early clinical progression. 9 (31%) pts had a subsequent RECIST PR or SD and were considered pseudoprogression and 20 (69%) had true progression. Of the pseudoprogressors, 7/9 pts remained in response with a median follow-up of 20 months (mths). 2/9 pts had disease progression at 7 and 18 mths, with ctDNA that remained detectable with a > 10-fold decrease during treatment in both patients. Of those with true progression and a favourable profile, 1 had a > 10-fold decrease in ctDNA by wk 12 and was switched to MAPK therapy prior to further imaging, and the other had an undetectable ctDNA at wk 6 which increased again at wk 12. The latter pt had a new lesion on first restaging CT scan despite PR in all existing lesions with true PD on second restaging at wk 24. Conclusions: ctDNA in patients with mm at baseline and early on aPD1 treatment differentiates pseudo from true progression. [Table: see text]
Patterns of histologic response to neoadjuvant targeted therapy in patients with BRAF mutant melanoma.
Authors: Eroglu Zeynep , Khushalani Nikhil I. , Rich Jeani , Sarnaik Amod , Zager Jonathan S. , Markowitz Joseph , Brohl Andrew Scott , Sondak Vernon K. , Messina Jane
Published: September 2018

9584

Background: While BRAF and MEK inhibitors are approved for patients with BRAF V600 + unresectable/metastatic melanoma, their role in the neoadjuvant setting is less well defined. Results from small trials have noted robust response rates, but less is known about histological patterns of response in resected tumor specimens and relation to outcome in these patients (pts). Methods: In a retrospective study, we analyzed the clinical and pathologic patterns of response to neoadjuvant BRAF ± MEK inhibitor therapy in pts with locally advanced melanoma subsequently rendered disease free with surgery. Results: Twenty pts were identified, nine with stage IIIC and 11 with stage IV melanoma. Seven patients received neoadjuvant vemurafenib (VEM), 12 received dabrafenib + trametinib (D+T), and one encorafenib + binimetinib. The median duration of treatment was 7.8 months. Seven patients (35%) had a pathologic complete response (pCR); six of them had received combination therapy, 5 with D+T, 1 VEM with an HSP90 inhibitor. Four distinct histologic patterns were observed in the resected tumor specimens: necrotic, fibrotic/melanotic (tumoral melanosis), hyalinized, or mixed. With median follow-up of 25 months (range 1-60), six pts (30%) had experienced recurrence; three developed CNS metastases. Four of the six patients had received neoadjuvant D+T; three were restarted on their prior targeted therapy at recurrence and all responded. All 6 pts with recurrence had residual disease in the surgical specimen; three had no necrosis identified. In contrast to the 13 pts with persistent tumor, none of the 7 pCR pts has relapsed (p = 0.05). There was a trend towards improved relapse-free-survival (RFS) with a pCR, with a 1 yr of RFS-rate of 50.4% vs 100% in pCR.(p = 0.08) Of the 14 patients without subsequent recurrence, 9 had either a pure necrotic histology, or a mixed histological pattern that included necrosis. Conclusions: In locally advanced or M1a BRAF mutant melanoma, attaining a pCR to neoadjuvant targeted therapy may correlate with improved patient outcomes and be more likely achieved with combination therapy. Presence of necrosis in the surgical specimen appears be a favorable prognostic factor.
Long term follow up (LTFU) of adjuvant zoledronic acid (ZOL) in high risk early stage breast cancer (ESBC) defined by bone marrow (BM) disseminated tumor cells (DTC).
Authors: Vidula Neelima , Hwang Jimmy , Greenberg Sally , Melisko Michelle E. , Goga Andrei , Moasser Mark , Cudos Ariadna Gasol , Angelidakis Austin Nicholas , DeLuca Amy , Petrillo Laura A , Magbanua Mark Jesus Mendoza , Park John , Rugo Hope S.
Published: September 2018

e12001

Background: BM DTC & peripheral blood CTC indicate metastatic potential. Adjuvant bisphosphonates in postmenopausal patients (pts) result in less bone metastases and better survival. We studied ZOL’s impact on DTC, CTC, and outcomes in ESBC (ASCO, 2010) and now report updated LTFU. Methods: Forty-five pts with ESBC and DTC > 4/mL BM were given ZOL every 4 weeks for 24 months (mo). DTC were quantified at baseline (BL), 12 and 24 mo of ZOL with immunomagnetic enrichment and flow cytometry (Clin Cancer Res, 2015). Serial CTC, survival, recurrence and toxicity were studied. Results: Forty-five pts received ZOL (56% HR+, 18% HER2+, 40% TN, 96% prior chemo). BL median DTC was 13.3/mL (range 4-333). Median DTC decreased from BL to 12 mo (median reduction 6.5/mL, range -57.2 to 23.6) and from BL to 24 mo (median reduction 4.6/mL, range -43.1 to 160.1). For 33 pts with BM at all 3 times, DTC decreased: BL median 11.5/mL (range 4-59.3), 12 mo median 6.8/mL (range 0-28.5), 24 mo median 6.5/mL (range 0.3-168.6). At 12 & 24 mo, 32% & 26% had undetectable DTC respectively. Median CTC was 0.2/mL at BL (n = 45), 0.25/mL at 6 mo (n = 30), 0/mL at 12 mo (n = 22) & 0.2/mL at 24 mo (n = 23). At 123 mo median FU (range 5-154), 9 (20%) pts recurred. Median time to recurrence was 21 mo (range 6-105); 67 % (6/9) TN, 22% (2/9) ER+/HER2+. The first sites of recurrence were CNS in 33% (3), bone & viscera in 22% (2), viscera in 22% (2) and local in 22% (2). BL DTC > 30/mL was associated with higher recurrence (50% > 30 vs. 14% < 30, p = 0.039). All 3 pts with CNS disease had BL DTC > 30/mL. Of the pts who recurred, 4 had ≥ 1 serial BMA; 2/4 had increasing DTC before recurrence. Of 32 disease free pts with BMA at all 3 times, 72% (23) had decreased DTC from BL to 24 mo. Of the 13.3% (6) pts who died, 67% (4) had BL DTC > 30/mL, which was associated with a greater risk of death (50% > 30 vs. 5% < 30, p = 0.006). BL CTC > 0.8/mL was associated with higher recurrence (60% > 0.8 vs. 15% < 0.8, p = 0.047) & death (60% > 0.8 vs. 8% < 0.8, p = 0.013). ZOL was well tolerated. Conclusions: At 123 mo FU, BL DTC > 30/mL and CTC > 0.8/mL correlated with recurrence & death. In this single arm phase II study, adjuvant ZOL decreased DTC over time, supporting the anti-tumor effect of bisphosphonates. Clinical trial information: NCT00295867.
Chemotherapy induced-hair loss: A digni-life with DigniCap— Our experience and patient’s satisfaction.
Authors: Loparco Dario , Lutrino Stefania Eufemia , Orlando Laura , Schiavone Paola , Caliolo Chiara , Quaranta Annamaria , Fedele Palma , Marino Antonella , Calvani Nicola , D'amico Maria , Chetrì Maria Concetta , Caloro Manuela , Rizzo Pietro , Nacci Angelo , Sponziello Francesco , Mazzoni Enrica , Cinefra Margherita , Ferrara Pasqualinda , Cinieri Saverio
Published: September 2018

e12016

Background: Alopecia (A) is one of the most emotionally distressing side effects of chemotherapy (CT). CT-induced A may lead to a negative body image, contributing to worsen the quality of life (QoL). The cancer treatments, especially in breast cancer (BC) patients (pts), often bring with it body image challenges, causing low self-esteem and having a detrimental effect on intimate relationships. DigniCap System (DCS), using the scalp cooling system, has been shown to reduce CT-induced A. The aim of this observational prospective study was to describe our experience. Methods: From February to December 2016, 31 consecutive pts with early stage BC who received anthracycline and/or taxane-based neoadjuvant or adjuvant treatment were enrolled. A nurse and a psychologist were dedicated. All pts received a psychological evaluation (EORTC QLQ-BR23; EORTC QLQ-C30; TAM; VAS). A has been graduated according to the Dean’s scale: G0 = no A; G1 < 25% A; G2 = 25–50% A; G3 = 50–75% A; G4 > 75% A. Results: A total of 31 pts were enrolled; 2 pts were not included because too early. Median age was 48 years (range 33-66). The majority of pts (96.5%) received adjuvant CT; only one patients received preoperative CT. Fifteen pts (51.7%) received 4 courses of EC (epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 iv on day 1, every 21 days) followed by 12 courses of paclitaxel (P) (80 mg/m2 iv weekly); the remaining pts received 4 courses of EC (n = 13; 44.8%) or P and concurrent trastuzumab (2 mg/Kg iv; loading dose 4 mg/kg) for 12 consecutive doses (n = 1; 3.4%). All grade of A was observed in 96.5% (n = 28): G1 in 15 pts (51.7%), G2 in 5 pts (17%), G3 in 7 pts (24.1%) and G4 in 1 pt (3.4%). Among G1/2 DCS-related side effects, sore scalp and coldness were the main toxicity (52%). The other adverse events (AEs) were: headache G1/2 (44.8%); neck pain (34.5%) and heavy head (41.4%). No serious AEs were reported. Overall, 7% (n = 2) of pts discontinued DCS because of unsatisfactory hair preservation (n = 1) and headache (n = 1). Conclusions: Our results confirm previous evidences, showing that DCS is a good chance to keep hair during CT. In particular, it is interesting that 26 pts (89.6%) did not use wig or head cover.
Adjuvant treatment decision in patients with node-negative, ER+/Her2-, early stage breast cancer with Oncotype DX (ODX) recurrence score (RS) of 11-30: Impact of clinicopathologic features.
Authors: Garcia Gwenalyn , Kedia Shiksha , Thumallapally Nishitha , Moussaly Elias , Abbasi Saqib , Murukutla Srujitha , Dai Qun
Published: September 2018

e12022

Background: The ODX RS predicts the risk of distant recurrence and the benefit of adjuvant chemotherapy (CT) in patients with ER+/Her2- breast cancer. High RS predicts a large benefit whereas low RS predicts minimal benefit from CT. A prospective trial showed that patients with low RS of 0-10 may be safely spared adjuvant CT. Recommendations in patients with intermediate RS are less clear. We performed a retrospective study of adjuvant therapy decision in patients with RS 11-30. Methods: We identified patients with ER+/Her2-, node-negative breast cancer with ODX RS 11-30 treated at our center from 2010-2016. Data on patient age, type of surgery, tumor size, grade, lymphovascular invasion (LVI), RS and treatment were collected. Statistical associations were tested using Chi square/Fisher's exact test and t test. Logistic regression analysis was used to determine odds ratios (OR). Results: 76 patients were identified. 86% (65/76) of them received adjuvant endocrine therapy alone and 14% (11/76) received adjuvant CT plus endocrine therapy. Patient characteristics are shown in the table. Using univariate analysis, significant predictors of receiving CT included RS, LVI, and ER positivity. In the patients who received CT, RSs were all ≥ 18 whereas in the group who did not receive CT, 42% (27/65) patients had RS 11-17. Increase in RS was associated with increase in the likelihood of receiving CT (OR 1.40, 95% CI 1.14-1.74, p=0.00017). Decrease in ER positivity was correlated with increased likelihood of receiving CT (OR 0.922, 95% CI 0.856-0.992, p=0.03). The presence of LVI increased the likelihood of receiving CT (OR 26.24, 95% CI 4.16-165.43, p=0.0005). Conclusions: In patients with ER+/Her2-, node-negative breast cancer with RS 11-30, the majority received endocrine therapy alone. RS and some clinicopathologic features (LVI, ER) impacted the decision to receive CT. [Table: see text]
Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (SEVI), a selective CYP17 lyase and AR inhibitor.
Authors: Speers Corey Wayne , Chandler Benjamin , Zhao Shuang , Liu Meilan , Wilder-Romans Kari , Olsen Eric , Nyati Shyam , Rae James M. , Hayes Daniel F. , Spratt Daniel Eidelberg , Wahl Daniel Richard , Feng Felix Yi-Chung , Pierce Lori J.
Published: September 2018

e12102

Background: Increased rates of locoregional recurrence have been observed in TNBC despite chemotherapy and radiation (RT). A novel radiosensitizer screen nominated the AR as a promising target for treatment of radioresistant breast cancer, including TNBC. We assessed in vitro activity of SEVI (VT-464), a selective CYP17 lyase and AR inhibitor, as a potential radiosensitizer in AR+ TNBC model. Methods: Clonogenic survival assays were used to determine the intrinsic RT sensitivity of 21 breast cancer cell (BCC) lines. IC50 values were determined for 130 clinically available compounds and correlation coefficients were calculated using IC50 values and SF-2Gy. Gene expression was measured using RNA Seq or qRT-PCR and protein expression was measured using RPPA arrays. AR function was assessed using functional inhibition with SEVI in MDA-MB-453, ACC-460, SUM-185 (all three AR+ TNBC), MDA-MB-231 (AR- TNBC), and T47D (AR- ER+) BCC lines. Double-stranded DNA (dsDNA) break repair was assessed with γH2AX foci counting. Results: Our novel radiosensitizer screen identified the activity of bicalutamide, an AR antagonist, in RT-resistant BCC lines (R2 = 0.46, p-value < 0.01). Heterogeneity in AR expression was identified in human BCC lines. There was a strong correlation between AR RNA expression and protein expression across all BC intrinsic subtypes. AR inhibition using SEVI induced radiation sensitivity in vitro with an enhancement ratio (ER) of 1.24-1.62 in three different AR+ TNBC lines. No such radiosensitization was seen in AR(-) TNBC or ER+, AR(-) BCC lines. Radiosensitization was at least partially dependent on impaired dsDNA break repair with significant delays in dsDNA break repair at 16 and 24 hours in all AR+ TNBC lines examined (p-value < 0.01). Conclusions: Our results implicate the AR as a mediator of radioresistance in breast cancer and support the rationale for developing seviteronel as a novel radiosensitizing agent in AR+ TNBC.
Evaluation of antiangiogenic therapy with bevacizumab in addition to neoadjuvant chemotherapy in the treatment of locally advanced breast cancer.
Authors: McCammack Erin , Birhiray Reumu
Published: September 2018

e12115

Background: Anti-angiogenic therapy improves outcomes in cancer therapy; we hypothesized an improved outcome with the addition of bevacizumab to dose dense neoadjuvant chemotherapy (ddNAC) in the treatment of locally advanced breast cancer (LABC). Methods: We added bevacizumab to ddNAC in the pre-operative management of LABC. Eligible subjects signed an informed consent, had biopsy and radiographically confirmed stage II-III LABC and absence of major organ malfunction. ddNAC was comprised of docetaxel 35mg/M2 intravenous (IV) on days 1 and 8, capecitabine 800mg/M2 by mouth two times a day on days 1-14 and bevacizumab 15mg/kg IV repeated every 21 days for 4 cycles, followed with doxorubicin 60 mg/M2 and cyclophosphamide 600mg/M2IV with peg-filgrastim 6mg given subcutaneously on day 1, every 14 days for 4 cycles (TX/ddAC). Subsequently, subjects underwent surgery and adjuvant radiation and/or hormonal therapy as clinically indicated. The primary objective was the pathologic complete response rate (pCR). As a secondary end point, we compared the rates of pCR with our prior study of the same chemotherapy regimen without bevacizumab (n = 52). Lastly, we evaluated the safety and tolerability of the regimen. Results: 34 subjects were enrolled and 31 completed the study. Using a modified intent to treat analysis, pCR with residual in-situ carcinoma (pCRinv) was 3/31 (9.7%), total pCR 8/31 (25.8%), and residual invasive carcinoma 20/31 (64.5%). In comparison, our prior study results, presented at the 2006 San Antonio Breast Cancer Symposium, showed a pCRinv7/52 (13.5%), total pCR 27/52 (52%), and rate of residual invasive carcinoma of 25/52 (48%). Observed toxicities included hand/foot syndrome, alopecia, nausea/vomiting, mucositis, neutropenia, febrile neutropenia, nail changes and hyperlacrimation. There was one treatment related death. Conclusions: The addition of bevacizumab to chemotherapy (TX/ddAC) did not improve the observed rates of pCR. However, the role of capecitabine in the neoadjuvant setting needs to be explored further. Moreover a post hoc analysis of the efficacy of the regimen in LABC subtypes is ongoing, with biologic correlates.
Pathological complete response in HER2 positive breast cancer treated with trastuzumab and chemotherapy: Predictive factors report.
Authors: Gasol Cudós Ariadna , Morales Serafin , Novell Alvarez Anna , Serrate Lopez Anna , Velasco Sanchez Ana , Salud Salvia Antonieta
Published: September 2018

e12133

Background: Achieving a pathological complete response (pCR) in HER2 positive disease is a surrogate of survival. Several factors were studied in order to predict pCR, but only negative estrogen receptor is correlated to pCR. Methods: 168 patients (March 2002-December 2016) with neoadjuvant trastuzumab-based treatment were retrospectively analyzed in order to find if common clinicopathological factors, HER2 expression and immune infiltrates could correlate with pCR. Results: Median age was 55 years (29-86), median tumor size of 39mm and 53% of tumors had initial nodal involvement. 45% of patients were estrogen and 71% progesterone receptor negative and median ki67 expression was of 43%. Otherwise HER2 expression was analyzed by immunohistochemistry, FISH amplification and mRNA expression; we also determined the presence of immune infiltrates stromal and intratumoral L45 lymphocytes, PD1 and PD-L1. A 38% pCR rate was found in whole population. In the univariate model we found and association with pCR and: estrogen receptor negative (p = 0.003; OR 2.5), high HER2 expression by mRNA in tissue > 3.9 (p = 0.012; OR 8.4), stromal L45 expression > 35% (p = 0.001; OR 5.3), stromal PD1 expression > 10 (p = 0.004; OR 4.5). The most powerful factor associated with pCR is HER2 mRNA expression > 3.9, with 82% of pCR rate in those tumors; followed of L45 stromal expression > 35%, with 76% of pCR rate. Conclusions: Factors related to pCR are mostly estrogen receptor negative and high HER2 expression by mRNA and high L45 stromal infiltrates. With those variables, we could design a predictive model in order to perform the best neoadjuvant treatment to increase the pCR rate.
Real-world effectiveness of fulvestrant monotherapy as first hormonal therapy in metastatic breast cancer patients.
Authors: Olufade Temitope O , Skinner Karen E , Di Santo Nicola , Shenolikar Rahul A. , Walker Mark Stephen , Schwartzberg Lee Steven
Published: September 2018

e12537

Background: Fulvestrant is a selective estrogen receptor degrader approved as monotherapy for postmenopausal women with estrogen-receptor-positive metastatic breast cancer (MBC) who progress following anti-estrogen therapy. The recent Phase 3 FALCON study for hormone therapy (HT) naïve women showed increased median progression-free survival (PFS) (16.6 months) in fulvestrant treated patients (pts) compared with anastrozole (13.8 months), but real-world data are lacking. This study examined the real-world effectiveness of fulvestrant monotherapy as first (L1) or second line (L2) treatment after MBC diagnosis. Methods: This was a retrospective medical record review from 10 US community oncology practices. Female pts initiated fulvestrant monotherapy as the first HT after MBC diagnosis, administered as L1 or as L2 treatment following L1 chemotherapy. Fulvestrant was initiated between 1/1/2011 and 12/31/2015. Pts were classified as HT naïve; and HT relapse status: early relapse (≤12 months of adjuvant HT completion), late relapse (>12 months). Time to first chemotherapy (TTC), PFS, and overall survival (OS) were evaluated using Kaplan-Meier analyses. Results: The study included 121 pts: mean (SD) age 65.7 (11.4) years, 81.8% Caucasian, 94.2% postmenopausal/undocumented, and 92.0% HER2-/undocumented. Overall, 15.7% were de novo metastatic and 86.0% initiated fulvestrant in L1. At the start of fulvestrant, 40.5% had visceral metastasis. The study results (Table 1) suggest better outcomes (TTC, PFS, OS) in HT naïve and late relapse pts, than early relapse pts. Conclusions: First line fulvestrant in the real-world setting demonstrates comparable PFS benefit to clinical trial results and appeared successful in delaying chemotherapy initiation in HT naïve and late relapse pts. This finding supports the use of fulvestrant monotherapy as the first hormonal therapy in a metastatic setting. [Table: see text]
Can 8 week 18F-FDG PET/CT predict clinical response in evaluation of bone metastases in breast cancer?
Authors: Azad Gurdip Kaur , Cousin Francois , Swampillai Angela , Taylor Benjamin P , Sandri Ines , Harries Mark , Mansi Janine , Cook Gary J. R.
Published: September 2018

e12539

Background: 18F-FDG (fluorodeoxyglucose) PET/CT scan is widely used for staging and response assessment of metastatic breast cancer. However, the role of early treatment response assessment of bone metastases remains undefined and the optimal method not yet determined. Our hypothesis was that early 18F-FDG PET/CT can predict subsequent clinical response and our aim was to compare early 8 week 18F-FDG PET/CT with clinical response assessment up to 12 weeks in bone metastases following endocrine treatment. Methods: Eighteen patients starting endocrine treatment for de novo or progressive bone metastases were prospectively recruited. 18F-FDG PET/CT scans were performed before and 8 weeks after treatment. Percentage change in maximum SUV (SUVmax) from the same ≤ 5 index lesions was measured. Clinical response up to 12 weeks, (combination of CT/bone scintigraphy, patient symptoms, Ca-15.3), assessed by an oncologist blinded to PET imaging findings was used as a reference standard. Results: In the 4 patients with progressive disease (PD); SUVmax increased ( > 25%) in 2/20 (10%) and was stable in 15/20 (75%) lesions. Clinically, 2/4 (50%) patients had stable symptoms and 2/4 (50%) worsening bone pain at 8 and 12 weeks. Ca-153 increased ( > 40%) in 3/4 (75%) patients. Conventional imaging at 12 weeks showed PD in all 4 patients. In the 7 patients with clinical partial response (PR); SUVmax decreased ( < 25%) in 23/35 (66%) and remained stable in 10/35 (29%) lesions. Ca-153 decreased ( > 80%) in 4/7 (57%) patients. Clinically, symptoms remained stable or improved in 6/7 (86%) patients at 8 and 12 weeks. Conventional scanning at 3 months showed either PR (n = 3) or SD (n = 4). In the 7 patients with stable disease (SD); SUVmax remained unchanged in 15/27 (56%) and decreased in 12/27 (44%) lesions. Ca-153 showed minimal changes in 6/7 (86%) patients. Conventional scans showed SD in all 7 patients. Conclusions: Our data show that although 18F-FDG PET/CT is reliable at predicting PR or SD, it has poorer predictive ability for clinical PD in bone metastases at 8 weeks. Intra-patient heterogeneity of response between lesions is a common observation. Clinical trial information: 12/LO/1801.
Treatment patterns in metastatic triple-negative breast cancer (mTNBC).
Authors: Jiang Shan , Hill Kala , Varghese Della , Waldeck Adrian Reg , Botteman Marc
Published: September 2018

e12589

Background: Real-world treatment patterns have not been extensively described in mTNBC. There is no generally accepted standard of care (SoC) in mTNBC or consensus regarding the use of multidrug regimens. We assessed drug-utilization patterns in commercially-insured US patients (pts) with mTNBC. Methods: Adult females with ≥1 breast cancer and ≥1 distant secondary malignant neoplasm diagnosis codes (2011-2015) were identified from the IMS LifeLink claims database. mTNBC status was approximated via receipt of any chemotherapy (chemo) post-metastatic diagnosis (mDx) in absence of pre-/post-mDx hormone replacement therapy/contraceptives or trastuzumab usage. First regimen (FR) was defined as the first chemo agent used post-mDx; chemo agents started ≤30 days of this first agent were counted as combination (combo) FR. Second regimen (SR) was defined as the chemo agent following FR by >30 days, or the same agent if there was a ≥90-day gap after FR. Kaplan-Meier survival curves were used to estimate time to SR initiation. Predictors of FR combo therapy and SR initiation were identified via logistic and Cox proportional hazard (CPH) regressions, respectively. Results: 2,949 pts received FR (median age: 53 years). Progression to SR occurred in 54% and 68% of pts at 12 and 36 months post-FR initiation, respectively. Median (95% CI) time between FR and SR was 81 (75-87) days. 39% and 27% of pts in FR and SR received combo therapy. Patients with age <55, surgery, no radiation, or more comorbidities during the pre-metastatic period were more likely to receive combo FR (Table). Pts with no surgery, more comorbidities, or combo FR, were more likely to start SR. Conclusions: There is no generally accepted SOC in mTNBC.Over half of mTNBC pts do not receive combo therapy and a majority progress to a SR within 1 year. [Table: see text]
Modified Glasgow prognostic score in a North American population of metastatic lung cancer patients: Baseline characteristics from the SNAP trial.
Authors: Stroud Chipman Robert Geoffrey , Walker Paul R. , Cherukuri Sulochana Devi , Sharma Nitika , Cherry Cindy , Parent Teresa , Hardin Jessica
Published: September 2018

e13072

Background: There is a growing body of evidence that implicates inflammation as a mechanism of disease progression and reduced survival in patients with advanced cancer (Laird B et al. Oncologist 2013;18:1050-5.). Specifically, elevated c-reactive protein (CRP) levels have been associated with a severe symptom burden including pain, dyspnea, fatigue, nausea/vomiting, impaired quality of life, and inferior overall survival (Laird B et al. Oncologist 2013;18:1050-5.). The Modified Glasgow Prognostic Score (mGPS) is a composite inflammatory score based on CRP and serum albumin with proven prognostic value in patients with advanced lung cancer (Simmons CP et al. Lung Cancer 2015;88:304-309.). There is a significant body of evidence supporting the use of the mGPS in both Europe and Asia but the significance of the mGPS in a North American population has not been completely elucidated. We present preliminary data from a group of patients from Eastern North Carolina. Methods: Serum albumin and CRP were drawn at baseline and patients were followed for clinical course and overall survival. Patients with a dx of cancer were included regardless of stage. Clinicopathological features were abstracted from the chart and compared to a similar population from Europe (Simmons CP et al. Lung Cancer 2015;88:304-309.). Statistical comparisons were done by chi-squared test. Results: Two-hundred and twenty seven patients were eligible. Of these, 110 had either stage IV NSCLC (N= 97) or extensive stage small cell lung cancer (n=13). Median CRP was 21.9 mg/L (0.01 - 329.5). Median serum albumin was 3.4 g/dl (2.3-4.6). The number of patients with mGPS of 0, 1, and 2 were 27 (24.5%), 37 (33.6%) and 46 (41.8%), respectively. As compared to the population from Europe, the chi squared statistic was 10.1229 (p = 0.0063). There was no significant association between mGPS and race (p = 0.2277) or gender (p=0.0607). Conclusions: Lung cancer patients in Eastern North Carolina possess a strikingly poor inflammatory signature with significant implications for quality of life and survival. [Table: see text]
Patterns of head and neck cancer incidence, mortality, and survival in the U.S. Hispanic population.
Authors: Oh Melissa S. , Jiang Renjian , Liu Yuan , Zhu Xiting , Saba Nabil F. , Henriquez Oswaldo A.
Published: September 2018

e13084

Background: To compare the incidence, mortality, and survival of head and neck cancer (HNCA) in the U.S. Hispanic population to other racial/ethnic groups. Methods: Using the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program, we compared the incidence and mortality of cancer of the oral cavity, pharynx, and larynx between the U.S. Hispanic population versus other racial and ethnic subgroups, as well as the annual percent change between 2000-2013. A comparative analysis for different groups stratified by age and sex was performed. Survival analysis was performed using Kaplan-Meier estimate and logistic regression analysis. Results: The incidence of oral cavity, pharyngeal, and laryngeal cancers were significantly lower in Hispanics compared to Non-Hispanics (p < 0.05). The incidence of laryngeal cancer decreased significantly at a rate of 2.5% annually (p < 0.05), while incidence of oral cavity and pharyngeal cancers remained unchanged in U.S. Hispanics. The mortality rate for oral cavity, pharyngeal, and laryngeal cancers in the U.S. Hispanic population were 1.4 per 100,000, 1.1 per 100,000, and 1.2 per 100,000 respectively. Mortality rates in Hispanics were significantly lower compared to Non-Hispanics (p < 0.05). Non-Hispanics Blacks had the highest HNCA-related mortality among all the compared groups. The mortality of HNCA was significantly declining annually in the U.S. Hispanic population (p < 0.05). Conclusions: The incidence and mortality of HNCA in the U.S. Hispanic population appears to be declining and is significantly lower compared to Non-Hispanics.
A multicenter, 3-arm, open-label, phase IIa clinical trial to evaluate the safety and efficacy of tanibirumab (VEGFR2 mAb), in patients with recurrent glioblastoma (GBM).
Authors: Cher Lawrence , Nowak Anna K. , Iatropoulos George , Lee Weon Sup , Lee Seon Young , Shim Sang Ryeol , Yoo Jin San
Published: September 2018

e13522

Background: Treatment of recurrent GBM remains a challenge. The VEGF signal transduction pathway is upregulated in GBM. We evaluated Tanibirumab, a mAb to VEGFR2, in an open-label, dose-escalation, 3-arm, Phase 2a clinical trial. Primary and secondary endpoints were determining safety and efficacy (6-month PFS, ORR, DCR and OS). Methods: Eligibility criteria included age ≥19 yrs at 1st or 2nd recurrence of GBM, measurable disease, KPS≥80, and no prior bevacizumab. Patients were enrolled in 3 arms: Arm 1 (8mg/kg d1,8,15/q28 days); Arm 2 (12mg/kg d1,8,15/q28 days) and Arm 3 (12mg/kg weekly). Response evaluation with MRI (RANO criteria) including DCE, was performed every 2 cycles. Results: 12 patients were enrolled over 10 months from 2 sites: 3 patients each in Arms 1 & 2; 6 in Arm 3. The median age was 50 years and 8 were male. 6 patients had second recurrence. At 1st infusion, 8 out of 12 were on baseline corticosteroids. 10 patients have progressed. No dose limiting toxicities (DLT) were observed. Cutaneous hemangiomas (CH) were frequent (83% of patients) and all G2 or less. No drug-related G3 or 4 AEs were observed. All SAEs were unrelated to the study drug apart from G2 bleeding haemangioma and G2 cerebral haemorrhage. Expected AEs with anti-angiogenic drugs (hypertension; impaired wound healing) were not observed. Among 12 patients allocated to Arm 1, 2 and 3, no objective radiological responses were observed. 3 patients demonstrated stable disease (SD); 2 patients had SD beyond 4 cycles and are still receiving treatment at weeks 45 (Arm 1) & 20 (3). This was correlated with the highest expression of VEGFR2 using immunohistochemistry on archival tumour and blood vessels. Only 2 patients needed to initiate or increase corticosteroids for control of tumor edema while on treatment. Current data are immature to determine time to event efficacy endpoints (PFS,OS). Conclusions: Tanibirumab can be safely administered to patients with recurrent GBM, with CH being common. SD was seen in 2 patients up to 10+ months, with some indication that VEGFR2 expression may be a response biomarker. Clinical trial information: NCT03033524.
Nivolumab for patients with recurrent glioblastoma progressing on bevacizumab: A retrospective case series.
Authors: Chamberlain Marc C. , Kim Bryan T.
Published: September 2018

e13538

Objective: A single institution retrospective evaluation of nivolumab following disease progression on bevacizumab in adults with recurrent glioblastoma (GBM) with an objective of determining progression free survival (PFS). Background: There is no accepted therapy for recurrent GBM after failure of bevacizumab. Methods: 16 adults, ages 52-72 years (median 62), with recurrent GBM were treated. All patients had previously been treated with surgery, concurrent radiotherapy and temozolomide, and post-radiotherapy temozolomide. Bevacizumab (with or without lomustine) was administered to all patients at first recurrence. Patients were treated with nivolumab only (3mg/kg) once every 2 weeks at second recurrence. One cycle of nivolumab was defined as 2 treatments. Neurological evaluation was performed bi-weekly and neuroradiographic assessment every 4 weeks. Results: A total of 37 treatment cycles (median 2) were administered of nivolumab in which there were 14 Grade 2 adverse events (AEs) and Grade 3 AEs in 2 patients. No Grade 4 or 5 AEs were seen. Following 1 month of nivolumab, 7 patients’ demonstrated progressive disease and discontinued therapy. No patient demonstrated a response though 9 patients demonstrated neuroradiographic stable response. Survival in the entire cohort ranged from 2 - 6 months with a median of 3.5 months (CI: 2.8, 4.2). Median and 6-month PFS at 6 months was 2.0 months (range 1-5 months; CI: 1.3, 2.7) and 0% respectively. Conclusions: Nivolumab salvage therapy demonstrated no survival advantage in patients with recurrent bevacizumab refractory GBM emphasizing a continued unmet need in neuro-oncology.
CD205, a target antigen for a novel antibody drug conjugate (ADC): Evaluation of antigen expression on non-Hodgkin lymphoma (NHL).
Authors: Canzonieri Vincenzo , Gattei Valter , Spina Michele , Polizzi-Anselmo Annalisa , Attanasio Nickolas , Kaplan Angelo , Bigioni Mario , Merlino Giuseppe , Matera Mariagiuseppa , Manunta Silvia , Dusek Rachel , Rohlff Christian , Fedi Valentina , Binaschi Monica , Pellacani Andrea Ugo Enrico , Simonelli Cecilia
Published: September 2018

e14039

Background: CD205 is a type I C-type lectin receptor normally expressed on various APC and some leukocyte sub-populations, characterized by a cytoplasmic domain containing protein motifs crucial for endocytosis and internalization. These features make CD205 ideal to be exploited as target of a novel ADC. MEN1309/OBT076 is a humanized IgG1 antibody against CD205, conjugated through a cleavable linker to a potent maytansinoid microtubule disruptor, DM4. Indeed, impressive results were obtained in high and low CD205 expressing xenografts for solid tumours and NHL. In vitro experimental model describing the by-stander effect of MEN1309 was implemented. Methods:A retrospective analysis to evaluate the CD205 expression on archival NHL biopsies was performed in the CRO-National Cancer Institute, Aviano IT. An immunohistochemistry (IHC) was performed on 1 slide per case, using a commercial antibody NCL-L-DEC205 (clone 11A10, Leica Biosystems). All slides were visually evaluated and a validated staining scoring system was applied, ranging from negative score 0 to strong immunostaining score 3+. Percentages (from 0 to 100%) of negative and positive tumor cells (scored as follows: 1-25% = score 1; 26-50% = score 2; 51-75% = score 3; 76-100% = score 4) were reported for each individual slide.Evaluation of correlations between CD205 expression and clinical characteristics is ongoing. Results: 100 cases of Diffuse Large B Cells Lymphomas (DLBCL) and 33 of Follicular Lymphomas (FL) were analysed. 60% of DLBCL cases were positive for CD205 and 39% had more than 25% of positive cells (score ≥2), while the 16% showed 2+/3+ staining intensity. 79% of FL cases were CD205 positive and 66% had more than 25% of positive cells, while the 27% showed 2+/3+ staining intensity. Conclusions: CD205 is heterogeneously expressed in the majority of DLBCL and FL cases. Data on the correlation between CD205 expression and clinical features will be discussed.MEN1309 has shown anti-tumour activity in vitro and in vivo even in low antigen expressing tumours. Hence CD205 expression among NHL, even if heterogeneous, makes, both DLBCL and FL, promising settings in which to explore MEN1309 activity in an upcoming FIH trial.
Some characteristics of invasive candidiasis pathogens.
Authors: Kutsevalova Olga Yu. , Kit Oleg Ivanovich , Panova Natalia I. , Lysenko Irina B. , Dmitrieva Viktoria V. , Rozenko Dmitry , Gevorkyan Yuri , Legostaev Vladislav , Shatokhina Olga N. , Pak Elena E. , Nikolaeva Nadezhda V. , Kozel Yuliya Yu. , Kuznetsov Sergei A. , Kozyuk Olga V. , Kapuza Elena A. , Mkrtchyan Gulnara A. , Bespalova Aleksandra I. , Starzhetskaya Maria V. , Kovalenko Vera A. , Shashkina Larisa Yu.
Published: September 2018

e14084

Background: The purpose of the study was to determine the etiology of invasive candidiasis (IC) and investigate in vitro activity of caspofungin and azoles for blood isolates of Candida fungi. Methods: We performed a multidisciplinary prospective study of isolates of patients with clinical signs of IC obtained in intensive care units (ICU), oncohematology and oncology departments of hospitals in Rostov-on-Don and Rostov region in 2012-2015. Candida fungi were identified using MALDI-TOF MS; interpretation was performed according to CLSI 2012, M27-S4 criteria. Sensitivity testing was performed using the Sensititre system (Trek Diagnostic Systems, England). Results: 92 Candida isolates were obtained from blood culture: C.albicans - 31.5% (29) and non-albicans - 68.5% (63), including C.tropicalis 30.2% (19), C.parapsilosis 28.6% (18), C.glabrata 19.0% (12), C.krusei 15.9% (10) and C.guilliermondii 6.3% (4). C. albicans were found mostly in oncological departments (44%) compared with ICU – 30% (р=0.003) and departments of oncohematology – 26%. The table demonstrates comparative activities of caspofungin, fluconasole and voriconasole (susceptible – S, intermediate – I, resistant – R) in % to Candida spp. Conclusions: Candida non albicans prevailed among IC pathogens (68.5%), which could be associated with the use of azole antifungal agents for prophylaxis and empirical therapy. Dominating isolates showed decreased activity to caspofungin and azoles. Acquired resistance to azoles was noted for C. parapsilosis and C. albicans. All cases of invasive candidiasis require susceptibility testing for caspofungin and azoles before starting therapy with these agents. [Table: see text]
Pharmacodynamic phase I study using FLT PET/CT in advanced solid malignancies treated with a sequential combination of X-82 and docetaxel.
Authors: Harmon Gil Edward , Rampurwala Murtuza M. , Scarpelli Matt , Eickhoff Jens C. , Carmichael Lakeesha , Kolesar Jill , Binger Kimberly , Heideman Jennifer , Perlman Scott , Liang Chris , Dukart Gary , Jeraj Robert , Liu Glenn , Bruce Justine Yang
Published: September 2018

e14088

Background: Increased tumor proliferation has been observed during withdrawal of anti-angiogenic therapy, known as withdrawal flare, which has been demonstrated using [18-F] fluorothymidine [FLT] PET/CT . Sequencing chemotherapy may increase therapeutic window by better synchronizing treatment with tumor proliferation during the flare. This study utilizes FLT PET/CT to assess X-82, a novel VEGFR TKI, used in sequence with docetaxel. Methods: Pts with at least 1 lesion evaluable with FLT PET/CT underwent 21-day treatment cycles with X-82 daily on days 2-15. Starting in cycle 2 (C2), docetaxel was given on day 1 of each cycle. FLT PET/CTs were obtained on days 1 and 15 in cycles 1 and 2. Tumors were identified by a nuclear medicine physician and manually segmented. The maximum tumor FLT uptake SUVmax and the total tumor FLT uptake SUVtotal were extracted for each tumor. To quantify changes in tumor FLT uptake, SUVs were log transformed and included in mixed effects models with random effects accounting for intrapatient correlation of tumor responses. Results: 14 pts were treated with median 3.5 cycles (range 0-12). 4 pts with 13 metastatic tumors completed all PET scans and were included in the pharmacodynamic assessment. 1 pt had an unconfirmed PR and 7 pts had stable disease per RECIST 1.1. The mean percent (%) change in tumor SUV during C1 (X-82 monotherapy) was -13% for SUVmax (P = 0.04) and -17% for SUVtotal (P = 0.14). The mean % change in tumor SUV during C2 (X-82 + docetaxel) was -44% for SUVmax (P = 0.03) and -59% for SUVtotal (P < 0.01). There was a significantly greater decrease in SUV in C2 than in C1 for both SUVmax (P = 0.03) and SUVtotal(P = 0.02). Ten grade 3 AEs possibly related to X-82 were noted in 6 pts, including infections, cytopenias, and vascular complications. Conclusions: Diminished tumor proliferation was observed during X-82 treatment, indicating successful targeting of VEGFRs. Sequential combination of X-82 plus docetaxel showed greater decreases in tumor proliferation compared to X-82 monotherapy indicating value in sequencing chemotherapy during VEGFR TKI treatment breaks. There is evidence that combination therapy is both safe and effective. Clinical trial information: NCT 02146222.