bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical outcomes and survival of patients (pts) with sarcomatoid metastatic renal cell carcinoma (smRCC).
Authors: Tantravahi Srinivas Kiran , Stenehjem David D. , Agarwal Archana , Kollepara Sri Lakshmi S. , Batten Julia Anne , Ward Michael , Albertson Dan , Wang Junfeng , Liu Ting , Agarwal Neeraj
Published: February 2017

535

Background: SmRCC is a rare variant of RCC associated with poor outcome. No definitive therapeutic recommendations exist. We present survival outcomes in pts with smRCC treated with systemic therapy. Methods: From a single institutional database (years 2000-2012), we identified 21 pts with documented sarcomatoid features who received systemic therapy. Survival was assessed in the overall cohort and in subgroups divided by clinicopathologic characteristics, including the extent of sarcomatoid features, and Memorial Sloan-Kettering Cancer Center (MSKCC) risk criteria. Sarcomatoid component of the tumor was classified by predominant (≥20%) and non-predominant (<20%). Immunohistochemistry (IHC) analysis was performed for mammalian target of rapamycin (mTOR) signaling, phosphorylated ribosomal protein S6, proviral integration site proteins (PIM 1,2,3), Beta-catenin, E-cadherin, phosphatase and tensin homolog (PTEN), U3 small nucleolar ribonucleoprotein (IMP-3), p53, and epithelial membrane antigen (EMA) on tumor samples, where available. Results: 21 pts were included with a median age of 62 years (range 39-74) and 13 pts were male (62%). One pt received first line cytotoxic chemotherapy, 3 pts received first line immunotherapy, and 17 pts received targeted therapy. Pts belonged to the following MSKCC risk categories: 1 (5%) favorable, 13 (62%) intermediate and 7 (33%) poor risk. Median overall survival (OS) of the entire cohort was 249 days (95% CI 161-519 days). Median OS in pts stratified as MSKCC poor, intermediate, and good risk was 2556, 430, and 137 days respectively (Poor vs Intermediate HR 4.38, p = 0.0159, CI 1.30-19.90). There was no significant difference in OS in pts with sarcomatoid predominant disease vs. non-predominant disease (234 vs 286 days, p = 0.744, HR 0.85, CI 0.31-2.39). Conclusions: Overall OS in pts with smRCC is inferior compared to that reported in clear cell variant mRCC. Although MSKCC risk scores may be useful in determining prognosis, further studies are needed to identify relevant biomarkers and define the optimal therapeutic strategy for this disease. Correlation of survival outcomes with the IHC profile of tumors will be presented.
Population pharmacokinetic analysis of abiraterone acetate in healthy volunteers and chemotherapy-naive and chemotherapy-pretreated metastatic castration-resistant prostate cancer patients.
Authors: Stuyckens Kim , Saad Fred , Xu Steven , Ryan Charles J. , Smith Matthew R. , Griffin Thomas W. , Yu Margaret K. , Vermeulen An , Nandy Partha , Poggesi Italo
Published: February 2017

58

Background: Abiraterone acetate (AA) is an effective therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). AA is metabolized to abiraterone, an androgen biosynthesis inhibitor. We performed population pharmacokinetic (PK) analyses to estimate PK parameters after a 1,000 mg/d oral dose of AA in patients with mCRPC with and without prior chemotherapy and after a one-time 1,000 mg dose in healthy volunteers, to determine consistency between groups. Methods: Studies included in analysis: COU-AA-302 (pre-chemotherapy mCRPC); COU-AA-301 and COU-AA-006 (post-docetaxel mCRPC); and COU-AA-008, COU-AA-009, and COU-AA-014 (healthy subjects). A total of 4,627 plasma concentrations from 360 subjects were analyzed using nonlinear mixed-effects modeling. Results: A two-compartment model with three-transit compartments following sequential zero-first order kinetics was used to characterize the systemic absorption of abiraterone. Absorption-related parameters were affected by food intake. Abiraterone PK was characterized by an extensive apparent clearance, which was lower in patients with mCRPC (1505 L/h) compared with healthy subjects (2240 L/h), and by large apparent central (5630 L) and peripheral volumes of distribution (17,400 L). PK of abiraterone was similar in chemotherapy-naïve and chemotherapy-pretreated patients and was characterized by a relatively high between- and within-subject variability (eg, between-subject coefficient of variation [CV%] for relative bioavailability in the clinical studies was 61.1% and the CV% for within-subject variability was 71.3%). No factors other than food intake and patient-healthy volunteer status impacted PK. Conclusions: Based on this population PK model, the recommended 1,000 mg/d dose of AA results in similar abiraterone exposure for patients with mCRPC regardless of prior chemotherapy status. The food effect on absorption-related parameters in this analysis confirms current dosing instructions for AA. Clinical trial information: NCT00638690, NCT00887198.
Rectal toxicity after permanent iodine-125 seed implantation: Nationwide cohort study in Japan (J-POPS).
Authors: Katayama Norihisa , Yorozu Atsunori , Maruo Shinichiro , Kojima Shinsuke , Ohashi Toshio , Tanaka Nobumichi , Saito Shiro , Dokiya Takushi , Fukushima Masanori , Yamanaka Hidetoshi
Published: February 2017

73

Background: The purpose of this report is to describe acute and late rectal toxicities and to evaluate factors associated with rectal toxicity in permanent seed implantation (PI) patients enrolled in a nationwide cohort study in Japan. Methods: A total of 2,339 patients in 46 institutes were evaluated. They were treated in the nationwide cohort study entitled Japanese Prostate Cancer Outcome Study of Permanent I-125 Seed Implantation (J-POPS) during the first two years, until June 2007. Rectal toxicities were evaluated using the National Cancer Institute - Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, which were obtained at 3, 12, 24, and 36 months after completion of radiotherapy. The odds ratios (OR) of factors associated with greater than or equal to grade 2 rectal toxicity were calculated using a logistic regression model, and the 95% confidence intervals (CI) were estimated. Results: Greater than or equal to grade 2 rectal toxicities were seen in 2.8% of all patients (1.7% in the PI monotherapy group and 6.4% in the external beam radiation therapy [EBRT] combination therapy group). On multivariate analysis, among all patients, greater than or equal to grade 2 rectal toxicity was associated with rectal volumes receiving 100% of the prescribed dose (R100) (OR, 1.93; 95% CI, 1.39–2.68) and EBRT addition (OR, 3.00; 95% CI, 1.39–6.32). R100 in the PI monotherapy group (OR, 1.67; 95% CI, 1.06–2.64), and R100 (OR, 2.07; 95% CI, 1.30–3.30) and interactive planning (OR, 0.46; 95% CI, 0.23–0.92) in the EBRT combination therapy group were also associated with greater than or equal to grade 2 toxicity. Greater than or equal to grade 2 toxicity was seen in 3.7% and 1.4% of patients with R100 greater than or equal to 1 ml and R100 less than 1 ml, respectively, in the PI monotherapy group (OR, 2.78; 95% CI, 1.28–6.05) and in 14.1% and 5.4% of patients with R100 greater than or equal to 1 ml and R100 less than 1 ml, respectively, in the EBRT combination therapy group (OR, 2.88; 95% CI, 1.28–6.45). Conclusions: Rectal toxicity was relatively limited compared to other reports. For Japanese PI patients, R100 should be less than 1 ml, both in PI monotherapy and in EBRT combination therapy, and interactive planning should be performed for EBRT combination therapy.
Comparing magnetic resonance imaging/ultrasound-fusion biopsy and systemic 12-core transrectal ultrasound biopsy for whole gland pathology.
Authors: Su Daniel , George Arvin , Siddiqui Minhaj , Rais-Bahrami Soroush , Stamatakis Lambros , Hong Cheng William , Rothwax Jason , Okoro Chinonyerem , Raskolnikov Dima , Shakir Nabeel , Walton-Diaz Annerleim , Simon Richard , Turkbey Baris , Wood Bradford J. , Choyke Peter L. , Pinto Peter A.
Published: February 2017

84

Background: Historically, pathologic findings from standard 12-core prostate biopsies are upgraded in 25 to 33% of patients after radical prostatectomy (RP). MRI/US fusion prostate biopsy has been shown to upgrade prostate cancer compared to standard 12-core biopsy in 32% of patients. MRI/US fusion biopsy may offer a more accurate representation of whole gland pathology. We evaluate the rate of pathologic upgrade in standard 12-core biopsy and MRI/US fusion biopsy when compared with whole gland pathology from RP. Methods: Patients who underwent random prostate biopsy, fusion biopsy and subsequently RP for prostate cancer from 2012 to 2013 were included. Pathology was reviewed by a single pathologist. The cohort was divided into clinically significant high-grade (Gleason score 4+3 or higher) and clinically insignificant low-grade (Gleason score 3+4 or lower) sub cohorts. Pathological upgrade was defined as any increase in Gleason sum or primary Gleason score. McNemar’s test was used to compare the proportion of patients who were upgraded from random biopsy to RP versus the proportion that were upgraded from fusion biopsy to RP. Results: Sixty eight patients underwent 12-core and fusion prostate biopsy then subsequently RP. Mean prostate-specific antigen was 9.2ng/ml. There are total of 43 patients with clinically insignificant low-grade and 25 patients with clinically significant high-grade. Fusion biopsy upgraded 19 patients (28%) compared to 12-core biopsy, eight of these patients had negative 12-core biopsy. Pathology on the RP specimen upgraded 18 of the 12-core results (26%) compare to only eight fusion biopsy results (11%). (p =0.0095) 14 patients (20%) who had clinically insignificant low-grade disease on 12-core biopsy were upgraded to clinically significant high-grade on RP. Only two patients (3%) with clinically insignificant low-grade from fusion biopsy were upgraded on RP. (p< 0.0005) Conclusions: Prostate cancer detected on MRI/US fusion prostate biopsy has significantly lower rates of pathologic upgrade than standard 12-core biopsy when both were compared to prostatectomy specimens. MRI/US fusion biopsy may represent whole gland pathology more accurately compared to 12-core biopsy.
Elective versus therapeutic neck dissection in the clinically node negative early oral cancer: A randomised control trial (RCT).
Authors: D'Cruz Anil , Dandekar Mitali , Vaish Richa , Arya Supreeta , Pantvaidya Gouri , Chaturvedi Pankaj , Chaukar Devendra , Pai P. S. , Deshmukh Anuja , Kane Shubhada , Nair Deepa , Nair Sudhir Vasudevan , Patil Asawari , Hawaldar Rohini W , Dhopeshwarkar Manasi , Agarwal Jaiprakash
Published: February 2017

LBA3

Background: Management of the neck in early oral cancers has been a matter of debate with clinical equipoise between elective (END) or therapeutic neck dissection (TND). Methods: This is a prospective phase III RCT (NCT00193765) to test the superiority of END at the time of primary surgery over TND (neck dissection at the time of nodal relapse) in patients with lateralized T1 or T2 squamous carcinoma of oral cavity, amenable to peroral excision. Patients were stratified based on size, site, sex and preoperative neck ultrasound. The primary end point was overall survival (OS) and secondary end point was disease-free survival (DFS). The trial was planned to demonstrate a 10% superiority (1-sided α = 0.05 and β = 0.2) in OS for END vs. TND, assuming 60% 5-year OS in TND arm, with a planned sample size of 710. Results: This trial was terminated after 596 patients were randomized between January 2004 and June 2014. An interim intent-to-treat analysis of initial 500 patients (255 in TND, 245 END) with a minimum follow-up of 9 months was performed as mandated by Data and Safety Monitoring Committee based on the number of observed deaths in each arm. Both arms were balanced for site and stage. There were 427 tongue, 68 buccal mucosa and 5 floor of mouth tumors; 221 were TI and 279 T2. At a median follow-up of 39 months there were 146 recurrences in TND and 81 in END arms respectively. The 3-year OS was significantly higher in END compared to TND arm (80.0% vs. 67.5%, HR = 0.63, 95%CI 0.44-0.89, p = 0.01) as was 3-year DFS (69.5% vs. 45.9%, HR = 0.44, 95%CI 0.34-0.58, p < 0.001). After adjusting for stratification factors in Cox regression, END continued to be significantly superior to TND for both OS and DFS. Conclusions: There were 8 excess deaths for every 15 excess recurrences in the TND arm. Elective neck dissection in patients with early oral SCC results in 37% reduction in mortality and should be considered the standard of care. Clinical trial information: NCT00193765.
PALOMA3: A double-blind, phase III trial of fulvestrant with or without palbociclib in pre- and post-menopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy.
Authors: Turner Nicholas C. , Ro Jungsil , Andre Fabrice , Loi Sherene , Verma Sunil , Iwata Hiroji , Harbeck Nadia , Loibl Sibylle , Bartlett Cynthia Huang , Zhang Ke , Giorgetti Carla , Randolph Sophia , Koehler Maria , Cristofanilli Massimo
Published: February 2017

LBA502

Background: The growth of hormone receptor (HR) positive breast cancer (BC) is dependent on the cyclin dependent kinases CDK4/6, that promote G1-S phase cell cycle progression. Resistance to endocrine treatment remains a major clinical problem for patients with hormone receptor positive breast cancer. The PALOMA3 study assessed the efficacy of palbociclib and fulvestrant in endocrine-resistant advanced breast cancer. Methods: In this double-blind phase 3 study women with HR positive/HER2 negative advanced metastatic BC whose cancer had relapsed or progressed on prior endocrine therapy, were randomized 2:1 to palbociclib (Palbo, 125 mg/d orally for 3 wk followed by 1 wk off) and fulvestrant (F, 500 mg per standard of care) or placebo (PLB) and F. Pre- and peri-menopausal women also received goserelin. One previous line of chemotherapy for metastatic disease was permitted. The primary endpoint was investigator assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), response assessment, patient-reported outcomes, and safety and tolerability. A pre-planned interim analysis was performed after 195 PFS events by an independent data monitoring committee. Results: 521 pts were randomized, 347 to receive Palbo+F and 174 to PLB+F. Baseline characteristics were well balanced. The median age was 57 and 56 years, 79% were post-menopausal, 60% had visceral disease, and 79% were sensitive to prior endocrine therapy. Prior therapy included chemotherapy for advanced disease in 33% of pts. At the time of the interim analysis the study met the primary endpoint, median PFS was 9.2 months for Palbo+F and 3.8 months for PLB+F (HR 0.422, 95% CI 0.318 to 0.560, P<0.000001). Consistent benefit from Palbo was seen in pre- and post-menopausal women. The most common adverse effects Palbo+F versus PLB+F were neutropenia (78.8% vs. 3.5%), leucopenia (45.5% vs. 4.1%), and fatigue (38.0% vs. 26.7%). Febrile neutropenia was reported in 0.6% pts on Palbo+F and 0.6% pts on PLB+F. The discontinuation rate due to adverse events was 2.0% on Palbo and 1.7% on PLB. Conclusions: Palbociclib combined with fulvestrant improved progression free survival in hormone receptor positive advanced breast cancer that had progressed on prior endocrine therapy, and can be considered as a treatment option for these patients. Clinical trial information: NCT01942135.
Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell carcinoma of the head and neck (SCCHN): Preliminary results from KEYNOTE-012 expansion cohort.
Authors: Seiwert Tanguy Y. , Haddad Robert I. , Gupta Shilpa , Mehra Ranee , Tahara Makoto , Berger Raanan , Lee Se-Hoon , Burtness Barbara , Le Dung T. , Heath Karl , Blum Amy , Dolled-Filhart Marisa , Emancipator Kenneth , Pathiraja Kumudu , Cheng Jonathan D. , Chow Laura Q.
Published: February 2017

LBA6008

Background: Pembrolizumab (MK-3475) is a humanized monoclonal antibody that blocks interaction of PD-1 with its ligands, PD-L1 and PD-L2, thereby promoting activity of tumor-specific effector T cells. KEYNOTE 012 (NCT01848834) had previously demonstrated clinical activity of pembrolizumab 10 mg/kg every 2 weeks in patients (pts) with recurrent/metastatic SCCHN enriched for PD-L1–positive tumors with a response rate of 20%. We now report on the larger SCCHN expansion cohort of KEYNOTE 012, irrespective of biomarker status using a 3-weekly fixed dose. Methods: Pts with advanced SCCHN irrespective of PD-L1 expression or HPV status received a fixed dose of 200 mg pembrolizumab, intravenously, every 3 weeks. Pts were evaluated every 8 weeks with radiographic imaging. The primary end point was overall response rate (ORR) per investigator assessment (RECIST 1.1). Secondary objectives included progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) were assessed according to CTCAE v4. PD-L1 was assessed retrospectively by immunohistochemistry. Results: 132 pts with recurrent/metastatic SCCHN were enrolled. Mean (SD) age was 58.9 (9.7) years; 83.3% were male; 56.8% had ≥ 2 lines of therapy for recurrent disease. 73/132 pts (55.3%) remain on treatment. Out of 132 treated pts, 99 pts were available for this preliminary efficacy analysis with a post-baseline scan or discontinued therapy prior to the scan due to clinical progression or AE. ORR (confirmed and unconfirmed) per RECIST 1.1 was 18.2% (95% CI, 11.1-27.2) with 18 partial responses and 31.3% with stable disease. Biomarker analysis is ongoing and results will be presented. Drug-related AEs of any grade occurred in 47% of all enrolled pts, and drug-related grade ≥ 3 AEs occurred in 7.6%. The most common drug-related AEs ( ≥ 5%) of any grade were fatigue (12.1%), decreased appetite (6.8%), pyrexia (6.1%), and rash (5.3%). Conclusions: Pembrolizumab given at a fixed dose of 200 mg every 3 weeks was well tolerated and demonstrated a clinically meaningful ORR of 18.2% in pts with recurrent/metastatic SCCHN. Clinical trial information: NCT01848834.
Results of the PERSIST-1 phase III study of pacritinib (PAC) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia-myelofibrosis (PET-MF).
Authors: Mesa Ruben A. , Egyed Miklos , Szoke Anita , Suvorov Aleksandr , Perkins Andrew , Mayer Jiri , Ganly Peter , Jourdan Eric , Schouten Harry C. , Tosi Patrizia , Farber Charles Michael , Zachee Pierre , Scheid Christof , Dean James P. , Cernohous Paul , Nangalia Jyoti , Kiladjian Jean-Jacques , Vannucchi Alessandro M. , Mead Adam , Harrison Claire N.
Published: February 2017

LBA7006

Background: PAC is a potent JAK2 inhibitor without significant JAK1 inhibition with minimal myelosuppression in early-phase studies in MF. Methods: The efficacy and safety of daily oral PAC was compared to BAT (2:1 randomization stratified for risk and platelet count). The 10 endpoint was the proportion of ITT patients (pts) achieving ≥ 35% spleen volume reduction (SVR) at week (wk) 24 by centrally reviewed MRI or CT. Secondary endpoints included the proportion achieving ≥ 50% reduction in total symptom score (TSS) at wk 24 using the MPN Symptom Assessment Form. Results: Patients:327 were enrolled (PAC:220, BAT:107), 62% with 10 MF. Median time from diagnosis was 1.12 years (PAC 0.99, BAT 1.60): 32% and 15% had a platelet counts < 100,000/µL or <50,000/ µL; 75% were JAK2V617F positive. Efficacy: The median duration of treatment was 16.2 months PAC and 5.9 months BAT. Sixty-two percent of BAT patients received active disease directed therapy. The SVR rates at week 24 were 19.1% for PAC vs. 4.7% for BAT (p=0.0003) in ITT and 25% vs. 5.9% (p=0.0001) in the evaluable population. 79% of BAT patients crossed over to PAC; 21% had achieved a >35% reduction in spleen volume at data cutoff. TSS composite V1 + V2 response rates were 24.5%for PAC vs. 6.5% for BAT (p<0.0001) by ITT, and were 40.9% vs. 9.9% in evaluable pts (p<0.0001). Efficacy with baseline cytopenias: In pts with <100,000 and <50,000 platelets/μ/L, the SVR rates were 16.7% for PAC vs. 0% for BAT (p=0.009), and 22.9% vs. 0% (p=0.045) by ITT and 23.5% vs. 0% (p=0.007) and 33.3% vs. 0% (p=0.037) in evaluable pts. In RBC transfusion dependent pts, 25.7% of PAC pts became RBC independent vs. 0% of BAT pts (p=0.043). Safety: The most common adverse events (AE) for PAC were diarrhea, nausea, and vomiting; (grade 3 were <5%, <1%, <1% respectively). Hematologic AEs were similar between PAC and BAT. Conclusions: This study demonstrated PAC was well tolerated and induced significant and sustained SVR and symptom control even in patients with severe thrombocytopenia. PAC therapy resulted in RBC transfusion independence in a significant proportion of pts. Clinical trial information: NCT01773187.
Biological indicators of response and resistance to PARP inhibition in BRCA wild-type breast cancer.
Authors: Hassan Saima Noor , Esch Amanda , Heiser Laura , Gray Joe W.
Published: February 2017

125

Background: Although PARP inhibitors are currently being tested in clinical trials in breast cancer patients, it is not well understood which subgroup of patients will best respond to such therapy or how to combine anti-PARP therapy to improve therapeutic response. Methods: We assessed the response of a panel of 8 HER2-negative breast cancer cell lines against three PARP inhibitors: veliparib, olaparib, and BMN 673. Efficacy of carboplatin as a single agent and in combination with PARP inhibitors was determined. Therapeutic response and cellular phenotype were elucidated using live-cell imaging, high-content imaging and immunofluorescence. We computed IC50 as the measure of sensitivity to each PARP inhibitor across the panel of cell lines. Cellular phenotype was ascertained by quantifying endpoints for apoptosis and DNA damage. Results: BMN 673 demonstrated the highest potency, with IC50 values in the nanomolar range, while the IC50 values of olaparib and veliparib were in the micromolar range. Drug sensitivity was independent of BRCA mutational status. Biomarkers of apoptosis and DNA damage varied with the PARP inhibitor and across different cell lines. The resistant cell lines could be classified into two groups that varied in DNA damage response and cell death due to DNA damage. A combined DNA damage – cell death (DDD) Response Score was developed and correlated strongly with IC50 values in BRCA wild-type breast cancer cell lines. The DDD Response Score identified cell lines that were highly sensitive to single-agent PARP inhibitors or carboplatin. A Response Score that identified intermediate sensitivity may predict which cell lines may benefit from the combination of anti-PARP therapy and carboplatin. Conclusions: Overall, a spectrum of response to three different PARP inhibitors was identified in a panel of eight breast cancer lines. Cellular phenotype can help classify resistant cancer cell lines. We have developed an experimental approach that may help to inform which breast cancer subtypes may benefit from PARP inhibitors and carboplatin, both as single agents, and in combination.
Delta 32 mutation in CCR5 gene and its association with breast cancer.
Authors: Azhar Abid , Fatima Faria , Hameed Abdul , Saleem Saima
Published: February 2017

17

Background: Chemokine C-C motif receptor type 5 (CCR5) is a chemokine receptor protein, which is present on the cell surface. Its potential role in cancer progression and metastasis has been implicated. Deletion mutation of 32 base pairs (bp) in the open reading frame of the CCR5 gene (CCR5Δ32) may lead to the malformation of the protein. This study aimed to examine the role of CCR5Δ32 mutation and its association with breast cancer. Methods: Blood samples of 500 breast cancer patients were included in the study. The samples were compared with age and sex matched healthy controls. Mutation of CCR5Δ32 was analyzed by sequence specific primers by polymerase chain reaction (PCR). They were examined on agarose gel electrophoresis. Statistical analyses were performed using software SPSS 17.0 (Chicago, IL., USA). The genotypic frequencies of patients and controls were tested by applying the chi‐square test. Results: Two types of CCR5 allelic mutations were found in the breast cancer samples. The mutation was of a 32 (bp) DNA fragment. Homozygous insertion (I/I) and heterozygous deletion (I/D) was found in the open reading frame of the regulatory region of the gene. The chi square analyses showed significant positive association between I/I and I/D allele in breast can patients with CCR5 delta 32 mutation (χ2 15.07, p < 0.01). Conclusions: This deletion in the promoter region of the CCR5 gene produces a non-functional receptor which may increase inflammation, leading to the enhanced progression of tumor.
Aromatase inhibitors and the risk of contralateral breast cancer in BRCA mutation carriers.
Authors: Nemati Shafaee Maryam , Gutierrez-Barrera Angelica M. , Lin Heather Y. , Arun Banu
Published: February 2017

3

Background: Contralateral breast cancer (CBC) risk in BRCA1 & 2 mutations is up to 64%. Patients (pts) with estrogen receptor positive (ER+) breast cancer (BC) are offered tamoxifen (TAM) or Aromase inhibitors (AI) adjuvantly. Reports suggest that TAM may reduce the risk of CBC in BRCA mutation; however there is no such data on the effect of AIs. Here, we evaluate the effect of TAM and AI as potential CBC risk reducers in a cohort of women with known BRCA status. Methods: 1043 BC pts receiving genetic counseling and BRCA testing were included. 13 had metastasis, 168 had a variant BRCA, and 50 had synchronous BC, and were excluded. Of the 812 remaining pts, 153 had a deleterious BRCA 1 or 2 mutations. Pts were followed from the diagnosis of BC until CBC, death, or last follow-up. The study had IRB approval. Univariate analyses were performed to test the significance of each variable in relation to BRCA status using chi-square tests for categorical variables and t tests for continuous variables. Results: The median age at diagnosis of BC was 42.3 years (range: 21-84). Median follow up was 8.6 years. 86% (700) had ER+ tumors, 80% were diagnosed with T1-2, and 81% had N0-N1. 76% (622) received TAM, and 37% (304) received AI. A total of 68 (8.7%) CBCs occurred of which 14% (21/153) occurred in BRCA carriers vs 7% (47/659) in BRCA non-carriers. Multivariate analyses indicated that BRCA status and AI use were significantly associated with CBC. Specifically, compared with BRCA negative, pts with BRCA1+ or BRCA2+ had larger hazard of developing CBC, Hazard Ratio (HR) (95% confidence interval (CI)) = 2.49 (1.21, 5.10), p = 0.013 for BRCA1+ vs Negative. HR (95%CI) = 1.97 (1.05, 3.73), p = 0.036 for BRCA2+ vs Negative. Compared to pts who did not receive AI, those who received AI had smaller hazard of developing CBC, HR (95%CI) = 0.42 (0.22, 0.81), p = 0.01. The interaction between AI and BRCA status was not significant (p = 0.4), hence all pts benefited from AI use in terms of CBC risk reduction. TAM use did not show significant effect on the risk of CBC in univariate and multivariate analyses (p > 0.13). Conclusions: This is the first report showing that AIs can reduce risk of CBC in women with BC who have a BRCA mutation. This finding should be validated in larger independent cohorts.
Predictors of chemotherapy-induced peripheral neuropathy among breast cancer patients treated with taxanes.
Authors: Candelario Nellowe , Wongrakpanich Supakanya , Morginstin Mark S.
Published: February 2017

90

Background: Breast cancer is one of the most common types of cancer. Taxanes are used to treat both early and metastatic breast cancer. Chemotherapy-induced peripheral neuropathy (CIPN) is its most common dose-limiting side effect that is debilitating and that could alter the treatment outcomes. This study aims to assess the predictors in the development and severity of CIPN. Methods: A retrospective review of 229 breast cancer patients was done to identify if age, BMI, race, smoking history, alcohol use, diabetes, chronic kidney disease (CKD), estrogen (ER), progesterone receptor (PR) and HER2 status, type and dose of taxane were predictors in the development and severity of CIPN. Patients who had incomplete data and baseline neuropathy were excluded from the study. Severity of peripheral neuropathy was graded from 1 to 4. Pearson Chi-square and T-test were done to determine the presence of statistical difference in the development and severity of CIPN among the above predictors. Odds ratio was computed using logistic regression analysis. Results: Among the 229 patients in this study, 158 (69%) developed neuropathy, 90 (57%) of whom had grade 1 neuropathy. Majority of the subjects in this study were African American (75.1%). Age, BMI, race, smoking, alcohol use, CKD and diabetes did not show any statistical significance as predictors of development and severity of CIPN (p > 0.05). Patients with ER+/PR- and ER+/PR+ had lower odds of developing neuropathy with OR 0.36 (p = 0.006) and 0.44 (p = 0.026) respectively. HER2 positivity was associated with higher chances of neuropathy (OR 2.11, p = 0.028). Paclitaxel was associated with higher chances of neuropathy compared to docetaxel (OR 2.89, p = 0.02). Dose of paclitaxel did not show any difference in the occurrence of CIPN. Those treated with paclitaxel had more severe neuropathy (p = 0.04). Conclusions: Positive ER and PR receptors have lower chances of developing CIPN. HER2 positivity is a predictor in the development of neuropathy. Paclitaxel is more neurotoxic than docetaxel. Age, race, BMI, smoking, alcohol use, diabetes and CKD were not predictors in the development and severity of CIPN.
Results of a phase Ib study of Q-122 treatment of vasomotor symptoms in breast cancer patients.
Authors: Painter Wendy , Speed April L. , Phillips Kiwita , Pemu Priscilla , Robertson Alice , Sands Earl , Ofili Elizabeth
Published: February 2017

99

Background: Breast cancer patients taking tamoxifen (TAM) or an aromatase inhibitor (AI) often develop severe vasomotor symptoms (VMS) yet the only FDA approved non-hormonal treatment for VMS, 7.5 mg paroxetine, has a warning against concomitant use with TAM. Q-122, an orally-available small molecule, is being developed to address this unmet medical need. Results from the Phase 1b study, Q-1001, are presented. Methods: Q-1001 was a Phase 1 open-label, two-dose, dose-escalation study of the safety and preliminary effectiveness of Q-122 in females with breast cancer currently taking TAM or an AI and experiencing an average of at least 7-8 moderate to severe hot flashes per day. Key exclusion criteria included significant renal or hepatic disease, untreated hyperthyroidism and clinically significant abnormal laboratory findings. The study period included a 2 week drug-free screening phase, 28 day treatment phase, and 2 week drug-free follow-up period. Subjects were initially enrolled into Group 1 (100 mg Q-122) followed by Group 2 (200 mg Q-122). Safety was assessed by review of adverse events (AEs), physical findings and laboratory values. The primary efficacy endpoints were mean changes in frequency and severity (hot flash severity score, HFSS) of moderate and severe hot flashes from baseline to Week 4. Menopausal symptoms were assessed using the Greene Climacteric Scale (GCS). Results: 10 and 11 subjects received 100 and 200 mg Q-122 respectively; 8 subjects in each group completed the study. At the end of treatment for groups 1 and 2 respectively, the daily average frequency of hot flashes was reduced from 9.9 to 4.1 and from 8.6 to 3.2, and the mean HFSS was reduced by 62% and 68% from baseline values. Menopausal symptoms assessed using the GCS were significantly reduced from baseline (psychological: -82%; somatic: -65%; vasomotor: -65%). All AEs (n = 29) were either mild (79%) or moderate (21%) in severity and only 3 (all in one subject) were considered possibly related to study drug. Conclusions: Treatment with Q-122 resulted in significant reduction in the frequency and severity of VMS and improvement in menopausal symptoms as assessed by the GCS. No safety issues associated with the use of Q-122 were identified in this study.
Anamorelin in patients with advanced non-small cell lung cancer and cachexia: Results from the phase III studies ROMANA 1 and 2.
Authors: Temel Jennifer S. , Currow David Christopher , Fearon Kenneth , Yan Ying , Friend John , Abernethy Amy Pickar
Published: February 2017

175

Background: Cancer anorexia-cachexia syndrome is common in patients with non-small cell lung cancer (NSCLC). It is characterized by loss of lean body mass (LBM) and negatively impacts quality of life. Anamorelin HCl (ANAM) is a novel investigational ghrelin receptor agonist with anabolic and appetite-enhancing activity. Methods: Two randomized, double-blind, Phase 3 ROMANA 1 (N = 484; NCT01387269) and ROMANA2, (N = 495; NCT01387282) trials assessed ANAM (100 mg) efficacy/safety versus placebo in patients with unresectable stage III/IV NSCLC and cachexia ( ≥ 5% weight loss within prior 6 months or BMI < 20 kg/m2) over 12 weeks. Co-primary endpoints were change from baseline over 12 weeks in LBM and hand grip strength (HGS). Secondary endpoints included changes in body weight and in the anorexia-cachexia subdomain of the Functional Assessment of Anorexia/Cachexia Therapy questionnaire, and pooled survival from ROMANA 1 and 2. Exploratory post-hoc analyses determined change in total body and fat mass from baseline to 12 weeks. Results: Over 12 weeks ANAM significantly increased LBM vs placebo in ROMANA 1 (1.10 vs -0.44 kg, p < 0.001) and ROMANA 2 (0.75 vs -0.96 kg, p < 0.001); HGS was similar in the two arms. In both studies ANAM vs placebo increased body weight (2.20 vs 0.14 kg, p < 0.001; and 0.95 vs -0.57 kg, p < 0.001) and improved anorexia/cachexia symptoms (4.12 vs 1.92, p < 0.001; and 3.48 vs 1.34, p = 0.002). Increases in total body mass (2.87 vs 0.07 kg, p < 0.001; and 2.04 vs -0.59 kg, p < 0.001) and in fat mass (1.21 vs -0.13 kg, p < 0.001; and 0.77 vs 0.09 kg, p = 0.012) were observed for ANAM vs placebo. ANAM was well tolerated; the most frequent drug-related adverse event in ROMANA 1 and 2 was hyperglycemia (5.3% and 4.2%). There was no difference between study arms in median 1-year survival. Conclusions: In two global, Phase 3 studies, ANAM treatment for 12 weeks was well tolerated, and increased LBM, body weight, total body mass and fat mass indicating anabolic activity and suggesting restoration of energy balance in advanced NSCLC patients with cachexia. ANAM also improved anorexia-cachexia symptoms/concerns. Similar pooled survival was observed between the study arms. Clinical trial information: NCT01387269, NCT01387282.
Development of a question prompt sheet for cancer patients receiving outpatient palliative care.
Authors: Arthur Joseph Anthony , Yennu Sriram , Williams Janet L. , Tanco Kimberson Cochien , Liu Diane D , Bruera Eduardo
Published: February 2017

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Background: An effective communication strategy is the fundamental backbone in the delivery of an impeccable palliative care intervention. Different communication tools are sometimes utilized to enhance discussions between patients and their physicians. An example is a question prompt sheet (QPS) which is a structured list of potential questions available for the patient to ask their doctor during a clinical encounter. Although it has been shown to improve physician-patient interaction during clinical consultations, there is paucity of data on its use in the palliative care setting. The objective of this study was to develop a QPS that is feasible and applicable in palliative care clinical practice. Methods: An expert group of experienced physicians and mid-level providers were invited to participate in the study. The process was conducted in 3 Delphi rounds. In the last round, the top 25 questions with the highest level of endorsement were chosen and used towards the development of the QPS. Results: One hundred percent of the 22 experts invited to participate in the study accepted the invitation and completed all the 3 Delphi rounds. They consisted of 82% physicians and 18% mid-level providers. Participants were mostly males (59%), had a median age of 42 years, and a median of 8 years’ experience in palliative care. 98% of the top 25 questions for the QPS were endorsed by at least 50% of the expert panel in round 3. Twenty-eight percent of the questions were about symptoms, treatment and lifestyle, 24% were about commonly asked questions by caregivers, 20% were regarding end-of-life issues, 16% were regarding the nature of palliative care service, and 12% were regarding the type of available support. The question which had the highest number of endorsements among the panel members was “Is there someone I can talk to about my fears, concerns, spiritual or religious needs?” Conclusions: A 25-item, single page QPS containing some of the most relevant questions in diverse aspects of advanced cancer care and feasible for use in clinical practice was developed in this study. Further studies are needed to determine the clinical effectiveness of the QPS in assisting patient physician communication.
RAINBOW: A global, phase 3, double-blind study of ramucirumab (RAM) plus paclitaxel (PTX) versus placebo (PL) plus PTX in the treatment of advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy—An age-group analysis.
Authors: Muro Kei , Bodoky Gyorgy , Cesas Alvydas , Chao Yee , Clingan Philip , Hironaka Shuichi , Komatsu Yoshito , Kurteva Galina Petrova , Lipatov Oleg N. , Nishina Tomohiro , Oh Sang Cheul , Ohtsu Atsushi , Shimada Yasuhiro , Sugimoto Naotoshi , Van Cutsem Eric , Carlesi Roberto , Chandrawansa Kumari , Wilke Hansjochen
Published: February 2017

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Background: RAM is a human IgG1 monoclonal antibody VEGF-R2 antagonist. The RAINBOW trial demonstrated that RAM added to PTX significantly improved overall survival (OS), progression free survival (PFS), and objective response rates (ORR) in 2nd-line gastric and GEJ adenocarcinoma patients (pts). Outcomes are reported by pts aged <65 and ≥65 yrs. Methods: Pts with advanced gastric and GEJ adenocarcinoma after disease progression on platinum- and fluoropyrimidine-based chemotherapy were randomized 1:1 to receive RAM (8 mg/kg) or placebo (PL) on days 1 and 15 plus PTX 80 mg/m2IV on days 1, 8, and 15 of a 28-day cycle. Eligible pts had ECOG PS ≤ 1 and adequate organ function. OS was the primary endpoint. Secondary endpoints included PFS, ORR, and safety. Results: Baseline characteristics were generally well balanced. Outcomes are summarized in the Table. The incidence of Grade ≥3 adverse events (AEs) was higher in the RAM+PTX arms for both age groups and similar across age groups. Grade ≥3 AEs occurring in ≥10% of pts and at higher rate in the RAM+PTX arm, and febrile neutropenia are shown in the Table. Conclusions: RAM+PTX conferred similar improvements over PL+PTX for OS, PFS, and ORR in both age groups. Toxicity profiles were similar in both groups, although a relatively higher incidence of Grade ≥3 neutropenia and leukopenia in pts ≥65 years was noted. [Table: see text]
False-negative rate for HER2 testing in 738 gastric and gastroesophageal junction cancers (GEC) from two global randomized clinical trials.
Authors: Cunningham David , Shah Manish A. , Smith Dustin , Zoudilova Maria , Hack Stephen Paul , Kang Alice , Phan See-Chun , Jubb Adrian M. , Ruschoff Josef
Published: February 2017

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Background: False-negative HER2 testing in GEC may deny patients the benefit of HER2-targeted therapy. The aim of this study is to estimate the false-negative rate for HER2 testing in GEC and to evaluate predictive factors that might be used to select patients for re-testing. Methods: Two clinical trials conducted in patients with HER2-negative GEC were conducted by Genentech (NCT01662869 and NCT01590719). Information on local HER2 results was collected and testing was repeated centrally by immunohistochemistry (IHC; Ventana, 4B5 antibody) and FISH. HER2 positivity was determined using published criteria (Mod Pathol 2012;25:637). Results: Of 1,189 patients screened, 738 GECs were HER2 negative by local testing and had central results available. Twenty-nine patients (3.9%, 95% confidence interval [CI] 2.5–5.3) were locally HER2 negative, but centrally HER2 positive. The cases showed a wide geographic distribution, a mixture of biopsies (n=19) and resections (n=10), and a mixture of gastric cancer (n=20) and GEC (n=9). All false-negative cases were centrally confirmed to be Lauren’s intestinal (n=25) or mixed (n=4) morphology; amongst intestinal/mixed GEC, the false-negative rate was 6.4% (95% CI 4.1–8.6). Detailed local testing results were available for 25 cases, of which 21 cases showed local IHC scores of 0 or 1+ but were centrally IHC 2+/FISH positive (n=17) or IHC 3+ (n=4). The remaining 4 cases were locally HER2 IHC 2+, FISH negative, but centrally IHC 2+, FISH positive. Conclusions: A clinically significant false-negative rate of 6.4% was observed for HER2 testing in GEC (intestinal/mixed type). Several measures might improve the accuracy of HER2 testing, including running FISH and IHC on all cases, carefully evaluating internal positive controls, improving the education of pathologists, and retesting cases with mixed or intestinal morphology. Clinical trial information: NCT01590719 and NCT01662869.
Real-world treatment patterns of previously treated advanced gastric and gastroesophageal junction adenocarcinoma (GC) in the United Kingdom (UK).
Authors: Liepa Astra M. , Brown Jacqueline , Bapat Bela , Kaye James A.
Published: February 2017

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Background: With no licensed therapies for previously treated advanced GC, little is known on how patients (pts) are managed after 1st-line chemotherapy (CTx) has failed. We present real-world data on characteristics, treatments, and resource utilization (RU) for such pts in the UK. Methods: Physicians who treat pts with advanced GC completed a web-based chart review detailing clinical and RU data for 3-4 de-identified pts each. Eligible pts were ≥18 years old, diagnosed Jan 2007-Mar 2012 with advanced GC, received 1st-line fluoropyrimidine+platinum, and had ≥3 months of follow-up after 1st-line discontinuation (DC). Data were summarized descriptively. Results: From Jun to Jul 2013, 58 physicians provided data for 200 pts. Pts’ mean age was 61 years; 69.5% were male. At advanced stage diagnosis, ECOG performance status (PS) was 21% 0, 72.5% 1, and 6.5% 2. The most common 1st-line regimens were capecitabine (cape)+oxaliplatin+epirubicin (epi) (34%), cape+cisplatin+epi (20.5%) and 5-FU+cisplatin+epi (13%). The most common reasons for 1st-line DC were completion of planned regimen (63%) and disease progression (24%). ECOG PS at 1st-line DC was 5% 0, 57.5% 1, 32% 2, 5.5% 3. 28.5% received 2nd-line, and 79% of these had PS 0/1 at start of 2nd-line. 21 unique 2nd-line regimens were reported; most common were docetaxel (28%), paclitaxel (11%), trastuzumab (9%), cape (7%) and irinotecan (7%). Among pts who received 2nd-line, 5% received 3rd-line. (See table.) The most common contributing reasons for hospitalization were palliative care and disease progression. Conclusions: In our study sample of advanced GC, the minority of pts received subsequent CTx after 1st-line CTx. There was considerable variation in 2nd-line regimens, although primarily monotherapy. Pts who received 2nd-line CTx had numerically similar or lower rates of supportive care. [Table: see text]
Comprehensive genomic profiling of biliary tract cancers to reveal tumor-specific differences and genomic alterations.
Authors: Ross Jeffrey S. , Wang Kai , Catenacci Daniel Virgil Thomas , Chmielecki Juliann , Ali Siraj M. , Elvin Julia Andrea , Yelensky Roman , Lipson Doron , Hawryluk Matthew J. , Miller Vincent A. , Stephens Philip J. , Javle Milind M.
Published: February 2017

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Background: Intrahepatic cholangiocarcinoma (IHCCA), extrahepatic cholangiocarcinoma (EHCCA) and gallbladder carcinomas (GBCA) typically present at an advanced stage and systemic chemotherapy provides only modest benefit in most cases. We queried whether comprehensive genomic profiling (GCP) of IHCCA, EHCCA and GBCA would reveal clinically relevant genomic alterations (CRGA) that could lead to targeted therapies. Methods: DNA was extracted from 40µ of FFPE sections from 412 IHCCA, 57 EHCCA and 85 GBCA. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of >600X for 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. The CGP assay included base substitutions, INDELs, copy number alterations and fusions/rearrangements. CRGA were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: Patient characteristics were similar for all three tumor types. IHCCA and GBCa were more common in females and EHCCA were more common males. CGP revealed the results in the Table. Multiple antitumor responses to targeted therapies in each of the 3 tumor types will be presented. Conclusions: IHCCA, EHCCA and GBCA share GA in cell cycle regulation (CDKN2B) and chromatin remodeling (ARID1A). IHCCA features FGFR fusions, IDH1/2 substitutions, BRAF substitutions and MET amplification with a low KRAS mutation frequency. EHCCA and GBCA feature ERBB2 amplifications (GBCA > EHCCA) and PIK3CA/MTOR pathway alterations. EHCCA has a high KRAS mutation frequency whereas the KRAS GA in GBCA is low. The diverse landscape of CRGA in biliary tract cancers can serve as targets for therapies for patients with CCA, BDCA and GBCA and have the potential to improve outcomes for these aggressive forms of malignancy. [Table: see text]
Effect of coadministered beta blocker and COX-2 inhibitor to patients with pancreatic cancer prior to receiving albumin-bound (Nab) paclitaxel.
Authors: Bhattacharyya Gouri Shankar , Babu K Govind , Bondarde Shailesh Arjun , Biswas Ghanashyam , Ranade Anantbhushan , Parikh Purvish M. , Bascomb Newell F. , Malhotra Hemant
Published: February 2017

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Background: Paclitaxel protein-bound particles nab-paclitaxel plus gemcitabine is rapidly becoming the standard of care for patients with metastatic adenocarcinoma of the pancreas (mPCa). Preclinical and clinical studies of beta-blockers and NSAIDs show a benefit of these drugs in pancreatic cancer. The aim of this study was to evaluate the impact of the co-administration of the beta blocker propranolol (P) and the selective COX-2 inhibitor etodolac (E) on survival of patients with mPCa receiving GemNab as standard of care. PE is presumed to target the adrenergic and prostaglandin stress systems activated in cancer that induce changes in tumor microenvironment, immune system, and HPA axis leading to tumor promotion and immune tolerance. Data on the use of nab-paclitaxel plus gemcitabine (GemNab) with a beta blocker and NSAID in the clinical setting is lacking. Methods: Patients with mPCa were eligible for this randomized investigator initiated trial. Patients received PE daily for one week prior to starting GemNab. PE was administered in a chronodosed regimen to maximize the therapeutic benefit and minimize side effects. The primary endpoint was survival. Twenty-three patients were randomized to either GemNab or GemNab after one week of propranolol and etodolac (PEGemNab). The median age was 62.8 years; 68.2% male. Pain at time of diagnosis as reported in 80% of the patients in the GemNab arm and in 76.9% of the PEGemNab arm and jaundice was observed in 40% and 23% of the GemNab and PEGemNab arms, respectively. Results: Progression free survival was 7.2 and 11.8 months in the GemNab and PEGemNab arms, respectively. Overall survival was 10.5 months for the GemNab arm and 15.9 months for the PEGemNab arm. The treatment was well-tolerated with no unexpected adverse events. Conclusions: Administration of PE one week prior to Paclitaxel protein-bound particles with gemcitabine significantly increased progression free and overall survival. No unexpected adverse reactions were seen. Additional data on cytokine and cancer markers will be presented.