bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurocognitive functions and psychological distress in young adults with cancer (YAC): A prospective, longitudinal study.
Authors: Edelstein Kim , D'Agostino Norma Mammone , Pond Gregory Russell , Kavan Petr , Gupta Abha A. , Aubin Sylvie , Matthew Andrew , Wahl Kate , Crump Michael , Hodgson David C. , Bedard Philippe L. , Muanza Thierry , Batist Gerald , Bernstein Lori J.
Published: September 2018

10064

Background: Non-CNS cancer and treatments are associated with neurocognitive sequelae in older adults; whether YAC (age 18-39 yrs) are protected from these effects is unknown. In YAC, cancer interferes with education and occupational attainment and is associated with psychological distress. This prospective, inception-cohort study characterizes neurocognitive functions and psychological distress in YAC. Methods: YAC completed a 2-hr battery of standardized neurocognitive tests and questionnaires 1.7 ± 1 months after diagnosis prior to chemotherapy (mean ± SD, T1) and 8.2 ± 1.2 (T2) and 14.2 ± 1.6 (T3) months later. Healthy YA with no cancer history (HYA) were tested at similar time points. Tests were scored using published norms, transformed to T-scores, and grouped into neurocognitive domains. Results: YAC (n = 108; lymphoma, breast, gyne, GI, GU, sarcoma) were grouped according to whether they required chemotherapy (n = 70) or not (n = 38), and compared to 63 HYA. At baseline, there were no group differences in neurocognitive performance, number of impaired tests, or neurocognitive complaints (Kruskal Wallis, all p-values > .4). About 70% of each group completed assessments at T2 and T3. Mean performance improved over time (random effects models, all p-values < .01), but there were no group differences or interactions between group and time. There were also no differences in proportions of participants in each group whose test scores improved ( > 10 points) or declined ( < 10 points) from T1 to T2 or T3. Adjusting for psychological distress, fatigue, or neurocognitive complaints did not change these results, despite higher symptoms of somatic distress, anxiety and fatigue in YAC compared to healthy YA over time (all p-values < .03). Conclusions: Before chemotherapy and up to about 14 months later, YAC have elevated distress and fatigue, but do not demonstrate the cognitive decline reported in older cancer patients. Our findings are consistent with research suggesting that aging brains are more vulnerable to neurotoxic insult. Whether the effects of cancer treatment emerge later in YAC, placing them at risk for accelerated aging as reported in older patients, remains to be examined.
Survivorship care plans: Recommended vs delivered care.
Authors: Smith Karen L. , Sobel Talia , McGurk Kathy , Magnant Colette , Croog Victoria , Vaclavik Ida , Stearns Vered , Wolff Antonio C. , Wright Jean
Published: September 2018

10076

Background: The Committee on Cancer set a benchmark for the provision of survivorship care plans (SCP) to ≥50% of early cancer patients by the end of 2017 despite limited data indicating benefit. One hypothesis is that SCP will reduce overuse of medical care in survivors. Methods: We performed a retrospective review of all patients with early breast cancer (BC) who were seen by a single nurse practitioner (NP) for provision of SCP after completion of primary therapy (surgery, radiation +/- chemotherapy). We evaluated adherence to recommendations for follow-up (FU) care and testing in accordance with established guidelines. Results: Between August 2013 and December 2014, 152 patients received SCP after completion of primary therapy (median 2 months, range 0-27). 98% of SCP were given to patients, but only 38% were sent to primary care providers (PCP). Median FU was 23 months. Among 130 patients who did not undergo bilateral mastectomy for whom surveillance breast imaging (SBI) was recommended, 10 (8%) had 1st SBI ≥3 months earlier than time recommended (TR), 102 (78%) within 2 months of TR, 12 (9%) ≥3 months after TR, and 6 (5%) lacked confirmation of 1st SBI. Among 113 in whom 2nd SBI dates were specified, 25 (23%) had SBI ≥3 months earlier than TR, 62 (55%) within 2 months of TR, 7 (6%) ≥3 months after TR, and 18 (16%) lacked confirmation of 2nd SBI. Among 71 patients for whom first medical oncology (MO) FU visit dates are known, 64 (90%) occurred within 3 months of TR and among 81 patients for whom first radiation oncology (RO) FU visit dates are known, 67 (83%) occurred within 3 months of TR. However, among 47 patients for whom first FU visit dates with at least 2 types of providers (MO, RO and/or surgery) are known, 15 (32%) visited 2 providers within 2 months of one other. During the 1styear after completion of primary therapy, 22% underwent body imaging (CT, PET-CT, or bone scan) and 21% had liver function tests. Conclusions: Despite provision of a SCP to patients, PCP were often not notified and healthcare utilization exceeded recommendations. Nearly a third of patients had redundant visits, a fourth had SBI earlier than recommended, and a fifth had body imaging and lab testing. Ongoing efforts are needed to coordinate care and minimize unnecessary testing in BC survivors.
Association of nutritional parameters and survival in parenteral nutrition-supported (PN) gastrointestinal cancer patients.
Authors: Liu Wenli , Qdaisat Aiham , Lee Eric , Yeung Jason , Vu Khanh , Lin Junzhong , Canada Todd , Song Juhee , Cohen Lorenzo , Bruera Eduardo , Yeung Sai-ching J.
Published: September 2018

10078

Background: PN is a major tool in managing nutritional challenges in cancer patients. However, a clear set of clinical and biochemical indices to determine PN application in cancer patients has not been developed. We assessed the association between PN related nutritional parameters and survival in a large group of gastrointestinal (GI) cancer patients. Methods: 1197 consecutive GI cancer patients who received PN support between 08/01/08 – 08/01/13 were reviewed. Height, weight, plasma glucose (baseline and within 48 hours after PN initiation), surgical history, and pharmacy data including PN contents (dextrose, amino acids, and fat) and non-PN dextrose or fat in drug administration were recorded. Body mass index (BMI), Ideal body weight (IBW), PN and non-PN Calorie, and nitrogen were calculated for analysis. Data were entered into a multivariate analysis controlling for age, gender, cancer site, and medical comorbidities. Results: Median BMI was 25.4. 70% of the patients had unsteady weight ( > 2.5% change) before PN initiation. The magnitude of weight change was inversely related to survival (HR 1.02), P < 0.001). Patients with BMI > 25 and < 7.5% weight change prior to PN initiation had the most favorable survival. Glycemic instability (maximum plasma glucose variation > 100mg/dL) was independently related to shorter survival (HR 1.53, P < 0.001). Total calorie by IBW (kcal/kg/day) (HR 0.97, P < 0.001), non-PN calorie % (HR 1.04, P < 0.001), and calorie to nitrogen ratio (kcal:g) (HR 1.02, P < 0.001) were all independently associated with overall survival. Conclusions: Lower BMI, weight instability, and glycemic instability were adversely associated with survival. Higher total PN calorie and amino acid support were associated with better survival. Higher non-PN calorie % was adversely related to survival. Future studies must focus on developing a set of indices incorporating independent prognostic clinical and biochemical factors in determining PN application and monitoring in cancer patients. Optimum calorie and amino acids in PN support for cancer patients also require further investigation.
Secondary solid tumors in patients younger than 55 with chronic lymphocytic leukemia (CLL).
Authors: Carter Jordan Spencer , Lee William May , Nathan Rachel , Rivas Doris Maria , Liang Ya Yu , Jain Maneesh Rajiv , Ward Kristine Marie , Styler Michael
Published: September 2018

10083

Background: Patients with CLL are at an increased risk of secondary solid tumors. Few studies have looked at this risk in patients < 55, despite research suggesting that this is a distinct cohort with a longer overall survival. What data does exist has yielded variable results in limited populations. In light of this, our study utilized the SEER registry to look at secondary solid tumors in patients < 55 with CLL. Methods: 4559 patients 15-54 years old with CLL were identified in the SEER registry between 1973 and 2013. Cancer risk was assessed using standardized incidence ratios (SIR) of observed (O) and expected (E) cancers. 95% confidence intervals (CI) were calculated assuming a Poisson distribution. Results where the CI = 1 were excluded. Results: 498 patients (O/E = 1.4) developed a secondary solid tumor after CLL with a mean age at diagnosis of 48.8 and 59.9 years for CLL and a second tumor, respectively. Higher than expected risk was seen in lip (O/E = 7.5), non-epithelial skin (O/E = 5.4), salivary (O/E = 4.8), mesothelioma (O/E = 4.4), melanoma (O/E = 3.1), lung (O/E = 2.4), and kidney (O/E = 1.7) cancers. Uterine cancer had a lower risk (O/E = 0.4). Stratifying the cohort by gender and race found that lip cancer in whites (O/E = 7.6) and men (O/E = 7.3), descending colon cancer (O/E = 13.3) in blacks and ureter cancer (O/E = 19.8) in women posed the highest risks. Lung cancer was the most prevalent among all groups. Secondary tumor risk was elevated in the < 1, 1-5, 5-10, and 10-15 years after diagnosis with CLL (O/E = 2.3, 1.4, 1.5, and 1.4, respectively). The cancers with the highest SIR in each period were thyroid ( < 1 year, O/E = 9.2), lung (1-5 years, O/E = 3.1), nose/ear (5-10 years, O/E = 11.8), and lip (10-15 years, O/E = 15.6). In 4459 patients > 55 (O/E = 1.1), Kaposi sarcoma (O/E = 4.9), non-epithelial skin (O/E = 3.6), salivary (O/E = 2.8), melanoma (O/E = 2.1), nose/ear (O/E = 2.0), lip (O/E = 1.7), soft tissue (O/E = 1.6), lung (O/E = 1.4), kidney (O/E = 1.3), and colon cancers (O/E = 1.2) were significant. Conclusions: Patients < 55 have a unique tumor profile and greater risk of secondary solid tumors compared to patients > 55. This risk differs on the basis of gender, race, and survival time. Further research may help influence screening guidelines.
Chemotherapy-induced neutropenia risk models to guide the use of myeloid stimulating factors in intermediate risk chemotherapy: A cost and practicality analysis.
Authors: Jeurkar Chetan , Pompa Tiffany , Yeung Ho-man , Crilley Pamela A. , Topolsky David Lane , Styler Michael
Published: September 2018

10086

Background: The National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO) have published guidelines for use of prophylactic colony stimulating factors (CSF) for patients at risk for chemotherapy induced neutropenia (CIN). Both recommend CSF if the chemotherapy regimen has a >20% febrile neutropenia (FN) risk. If the regimen is of intermediate CIN risk, the guidelines are less definitive. In this study, we looked at lung cancer patients receiving intermediate CIN risk chemotherapy and applied two risk models developed by Hosmer et al and Bozcuk et al to see if they have adjunct value to the NCCN and ASCO guidelines to more accurately predict CIN. Methods: This was a retrospective study of 43 patients with a diagnosis of lung cancer who were treated with chemotherapy at Drexel University from 2005-2016. Risk models developed by Hosmer et al and Bozcuk et al along with the NCCN and ASCO guidelines were applied to the cohort of patients. Results: The Hosmer calculator recommended giving CSF to 26 patients, the Bozuk calculator for 22 patients, the NCCN guidelines for 25 patients and the ASCO guidelines for 38 patients. Sensitivities, specificities, and pricing information for one course of filgrastim are listed for each risk model in the Table. Conclusions: In lung cancer patients receiving intermediate CIN risk chemotherapy, the Hosmer calculator had the best combination of sensitivity, specificity, and ease of use. The Bozcuk calculator, while accurate, was more difficult to use. The NCCN guidelines missed more patients with severe CIN while the ASCO guidelines gave CSF to the greatest number of patients. The cost for using CSF would have been highest using the ASCO guidelines. Therefore, we recommend the Hosmer calculator for lung cancer patients receiving intermediate risk CIN chemotherapy as it lends to accurate but judicious use of CSF. [Table: see text]
Factors influencing the analgesic response over time of the oxycodone-naloxone association in painful cancer patients: GREAT study.
Authors: Corli Oscar , Legramandi Lorenzo , Marabese Mirko , Roberto Anna
Published: September 2018

10089

Background: The prolonged use of opioids is usually associated with the appearance of adverse events as drowsiness, constipation, nausea/vomiting, and dizziness. Some effects are self-limiting over time for the onset of tolerance while others, as constipation, persist. Clinical studies demonstrated that the association oxycodone-naloxone (OXN), reduced the constipation in the presence of unchanged analgesic efficacy. Though, the variability of the analgesic response to OXN is not explained yet. The aim of this study was to evaluate the association between the clinical and genetics factors and analgesics response at OXN. Methods: In this study the cancer patients with moderate to severe pain received OXN and followed for 28 days. At each visit pain intensity modifications of therapy and adverse drug reactions (ADRs) were recorded. The primary efficacy endpoint was the proportion of responders, defined as patients with a decrease of the average pain intensity from baseline to last visit ≥30% and a final average pain score≤4, measured on 0-10 numerical rating scale. Genetic tests to identify SNPs related to opioid response were performed in each patient. Results: 14 centers participated in the study and recruited 206 patients. Among 176 patients analyzed for a primary endpoint the mean age was 68 (SD 10); 56% were male. Average and worst pain intensity decreased from baseline to last visit from 6.2 to 2.9 and from 8.3 to 4.6 respectively. 81% of patients were responders. Digestive system tumors (p = 0.05), concomitant thyroid endocrinopathy (p = 0.023), psychological irritability (p = 0.0029) and breakthrough pain at baseline were found to decrease the risk of positive response. None of the investigated polymorphisms influenced the analgesic response. Moderate to severe intensity ADRs were mainly constipation (26%), drowsiness (19%) and dry mouth (12%). Conclusions: In patients with moderate to severe cancer pain, OXN showed a strong analgesic effect (about 50% pain reduction). In comparison with other studies the induced constipation appears substantially lower. Some clinical factors influence the analgesic response while none genetic polymorphisms modulate the response. Clinical trial information: NCT02293785.
LOTUS (NCT02162719): A double-blind placebo (PBO)-controlled randomized phase II trial of first-line ipatasertib (IPAT) + paclitaxel (P) for metastatic triple-negative breast cancer (TNBC).
Authors: Dent Rebecca Alexandra , Kim Sung-Bae , Im Seock-Ah , Espie Marc , Blau Sibel , Tan Antoinette R. , Isakoff Steven , Oliveira Mafalda , Saura Cristina , Wongchenko Matthew , Kapp Amy V. , Chan Wai Y. , Singel Stina M. , Maslyar Daniel J. , Baselga Jose
Published: September 2018

1009

Background: The oral Akt inhibitor IPAT is being evaluated in cancers with a high prevalence of PI3K/Akt pathway activation, including TNBC. Methods: Eligible patients (pts) had measurable inoperable locally advanced/metastatic TNBC previously untreated with systemic therapy. Pts were stratified by prior (neo)adjuvant therapy, chemotherapy-free interval and tumor PTEN status, and randomized 1:1 to P 80 mg/m2 (d1, 8 & 15) with either IPAT 400 mg or PBO (d1–21) q28d until progression or unacceptable toxicity. Co-primary endpoints were progression-free survival (PFS) in the ITT population and pts with PTEN-low tumors by IHC. Secondary endpoints included objective response rate (ORR), duration of response (DoR) and overall survival in the ITT and IHC PTEN-low populations, efficacy in pts with PIK3CA/AKT1/PTEN-altered tumors by next-generation sequencing (NGS), and safety. Results: Baseline characteristics were generally balanced between arms. Efficacy is shown below. The most common grade ≥3 AEs (grouped terms) were diarrhea (23% IPAT+P vs 0% PBO+P; no grade 4 or colitis in either arm), neutropenia (18% vs 8%), asthenia (5% vs 6%), peripheral neuropathy (5% vs 5%) and pneumonia (5% vs 0%). More pts receiving IPAT+P than PBO+P had an AE leading to dose reduction of IPAT/PBO (21% vs 6%) or P (38% vs 11%) but median cumulative dose intensity was similar (IPAT/PBO: 99% vs 100%; P: 100% vs 100%). AEs led to IPAT/PBO discontinuation in 13% vs 11% of pts, respectively; 2 pts (3%) discontinued IPAT for grade 3 diarrhea. Conclusions: Adding IPAT to P for TNBC modestly improved PFS in the ITT pts. The effect was more pronounced in the prespecified subgroup with PIK3CA/AKT1/PTEN alterations, warranting further evaluation of IPAT in these pts. AEs were manageable. Clinical trial information: NCT02162719. [Table: see text]
Two-year trends of taxane-induced neuropathy in women enrolled in a randomized trial of acetyl-l-carnitine (SWOG S0715).
Authors: Hershman Dawn L. , Unger Joseph M. , Crew Katherine D. , Ebnesajjad Cyrus , Greenlee Heather , Fehrenbacher Louis , Moinpour Carol , Minasian Lori M. , Lew Danika L , Wong Siu-Fun , Wade James Lloyd , Fisch Michael , Albain Kathy S. , Henry Norah Lynn
Published: September 2018

10093

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and disabling side effect of taxanes that leads to suboptimal treatment and adversely affects quality of life. Acetyl-L-Carnitine (ALC) was unexpectedly found to increase CIPN in a randomized trial. We investigated the long-term patterns of CIPN among patients enrolled in this trial. Methods: S0715 was a randomized, double-blind, multi-center trial comparing ALC (1000 mg TID) versus placebo for 24 weeks in women with stage I-III breast cancer undergoing taxane-based chemotherapy. The primary objective was to determine if ALC prevents CIPN as measured by the 11-item neurotoxicity (NTX) component of the FACT-Taxane scale at 12 weeks. Additional assessments were conducted at weeks 24, 36, 52 and 104. We examined the reduction of NTX score over 2 years using linear mixed models for longitudinal data, adjusting for stratification factors and the baseline NTX score. Individual assessment time-points were examined using linear regression. Results: SWOG S0715 registered 437 patients, of whom 409 were eligible and evaluable, including 208 assigned to receive ALC and 201 to placebo. Patterns of evaluability were similar over time by arm. The results for the primary outcome of interest, NTX, show a statistically significant (p = 0.01) average difference of -1.39 (95% CI: -2.47 to -0.31) between treatment groups, with the ALC group having lower scores (worse CIPN) on average than the placebo group. These differences were particularly evident at Weeks 24 (p = 0.02), 36 (p = 0.04), and 52 (p = 0.02). A clinically meaningful (≥5 points) reduction in NTX score over baseline was observed more frequently for the ALC vs. control arm (week 24, 41% vs. 34%; week 36, 41% vs. 28%; 1 year, 41% vs. 32%; 2 years, 40% vs. 34%). For both treatment groups 2 year NTX scores were significantly different compared to baseline (p < 0.001). Conclusions: For both groups NTX scores were reduced with taxane-therapy and remained persistently low 2-years following treatment. Twenty-four weeks of ALC therapy resulted in significantly worse CIPN at weeks 24 36 and 52. Understanding the mechanism of this persistent effect may inform prevention and treatment strategies. Clinical trial information: NCT00775645.
RCT of brief behavioral therapy (BBT-CI) for cancer-related insomnia and circadian rhythm during chemotherapy in a community oncology setting (NCORP).
Authors: Palesh Oxana , Scheiber Caroline , Tong Bingjie , Packer Melissa , Kesler Shelli , Janelsins Michelle Christine , Guido Joseph John , Heckler Charles E. , Schmidt Karen , Mustian Karen Michelle
Published: September 2018

10094

Background: Insomnia is experienced by up to 80% of cancer patients, and it frequently co-occurs with circadian rhythm disruption. The relationship is reciprocal in that disruption in circadian rhythm can cause or result from insomnia and vice versa. There are no effective brief behavioral interventions that can be delivered directly in infusion centers. We aimed to evaluate the efficacy of a novel intervention, BBT-CI, for improving sleep and circadian rhythm disruption in BC patients undergoing chemotherapy. Methods: In our phase II, two-arm, randomized clinical trial, 71 BC patients (mean age = 52.5) who reported moderate insomnia were randomized to: 1) BBT-CI or 2) a healthy eating behavioral control (HEAL). BBT-CI and HEAL were delivered over 6 weeks (2 face-to-face sessions + 4 phone calls) at 5 NCI-funded NCORP clinics by trained assistants. Sleep disruption was measured with the Insomnia Severity Index (ISI) and circadian rhythm with the Actiwatch-64 (Mesor, Amplitude, and Acrophase for 12- and 24-hour cycles). Participants completed the ISI at baseline and post-intervention and wore the Actiwatch for 7 days prior to each visit. Results: The study showed excellent feasibility and acceptability of BBT-CI as reflected by a recruitment rate of over 75% and an intervention adherence of 74%, with 75% of intervention components successfully delivered by trained community staff. ANCOVA results indicate that patients who received BBT-CI exhibited improvements in insomnia compared to HEAL at post-intervention (p = .049) and at 1-month follow-up (p = .002). Furthermore, results reveal a significant treatment effect in circadian rhythm at post-intervention for 24-hour amplitude (p = .009) and 12-hour Acrophase (p = .012) as well as a trend for Mesor in favor of BBT-CI (p = .10). Conclusions: BBT-CI demonstrated greater improvements in insomnia and circadian rhythm than HEAL. In addition, this novel intervention has shown efficacy in community oncology clinics. BBT-CI has the potential of changing clinical practice as it reduces patients’ psychophysiological symptoms and burden due to its behavioral design and capacity to be delivered directly in infusion centers. Clinical trial information: NCT02002533.
A genome-wide association study (GWAS) meta-analysis of chemotherapy-associated cognitive impairment (CACI) in Asian early-stage breast cancer patients (ESBC).
Authors: NG Terence , Yeo Hui Ling Angie , Shwe Maung , Gan Yan Xiang , Foo Koon Mian , Loh Wei-Jen Kiley , Koo Si-Lin , Chay Wen Yee , Tan Tira Jing Ying , Beh Sok Yuen , Lim Hsuen Elaine , Lee Guek Eng , Dent Rebecca Alexandra , Yap Yoon Sim , Ng Raymond C.H. , Chu Pak Yan Pat , Khor Chiea Chuen , Ho Han Kiat , Chan Alexandre
Published: September 2018

10096

Background: Genetic variations among genes regulating neuronal function, neurotransmission and plasticity may contribute to varying risk of CACI. In order to fully elucidate the complex genetic structure underlying CACI, a GWAS meta-analysis was performed to identify genetic variants associated with CACI among ESBC patients. Methods: A GWAS meta-analysis of two independent cohorts totaling 266 chemotherapy-receiving ESBC patients (mean age: 51.0 ± 9.2 years; 80.8% Chinese) was performed. Patients’ self-perceived cognitive function was assessed using the validated FACT-Cog (v.3). Genome-wide genotyping was performed using the Illumina HumanOmniExpress-24 version 1.1 BeadChips kits. Each beadchip contains over 700,000 genetic markers. Covariates included in the meta-analysis were the first two dimensions of the multi-dimensional scaling. Results: After applying stringent quality control measures and removing four population outliers, data from 546,399 SNPs were available for 84 cases and 170 controls. In the meta-analysis, two SNPs (rs6443264 and rs4686371) exceeded the suggestive threshold of P < 1×10-5 (Table). Following adjustment for the first two MDS dimensions in the meta-analysis, both SNPs remained as top two SNPs with P < 1×10-4. Both rs6443264 and rs4686371 are located in chromosome 3p25 and lie in the intronic regions encoding OGG1 and ARPC4 genes, respectively. Alteration of the OGG1 gene could compromise the functions of downstream neuronal genes, and modification of the ARPC4 gene could affect the formation of the actin-related protein 2/3 complex and impair memory formation. Conclusions: To the best of our knowledge, this is the first GWAS meta-analysis to identify two loci, namely rs6443264 and rs4686371 that are suggestive of genome-wide association with CACI among Asian ESBC patients. [Table: see text]
Genomic risk prediction of aromatase inhibitor-related arthralgias (AIA) in breast cancer (BC) patients using a novel analytical algorithm (NAA).
Authors: Reinbolt Raquel E. , Sonis Stephen T. , Timmers Cynthia Dawn , Fernández-Martínez Juan Luis , deAndrés-Galiana Enrique J. , Hashemi Sepehr , Miller Karin , Ramaswamy Bhuvaneswari , Wesolowski Robert , Noonan Anne M. , Dewani Shabana Jaynul , Williams Nicole Olivia , Sardesai Sagar D. , Pilarski Robert , Lustberg Maryam B.
Published: September 2018

10102

Background: Many BC patients treated with aromatase inhibitors (AIs) develop AIA; 20% have symptoms severe enough to effect treatment compliance. Results of candidate gene studies to identify AIA risk are limited in scope. In this case-controlled study, we evaluated the potential of a NAA to predict AIA using germline single nucleotide polymorphism (SNP) data obtained prior to treatment initiation. Methods: Systematic chart review of 700 AI-treated patients with stage I-III BC between 2003-2012 identified asymptomatic patients (n = 39) and those with clinically significant AIA resulting in AI termination or therapy switch (n = 123). Germline DNA was obtained from peripheral blood cells and SNP genotyping performed using the Affymetrix UK BioBank Axiom Array to yield 695,277 SNPs. The identity of the cluster of SNPs that most closely defined AIA risk was discovered using an NAA that sequentially combined statistical filtering and a machine learning algorithm. NCBI PhenGenI and Ensemble databases were used to define gene attribution of the 200 most discriminating SNPs. Phenotype, pathway, and ontologic analyses assessed functional and mechanistic validity. Results: Cases and controls were similar in demographic characteristics. A cluster of 70 SNPs, correlated to 57 genes (accounting for linkage disequilibrium), was identified. This SNP group predicted AIA occurrence with a maximum accuracy of 75.93%. Strong associations with arthralgia, breast cancer, and estrogen phenotypes were seen in 19/57 genes (33%) and were functionally and ontologically consistent. Conclusions: Using a NAA, we identified a 70 SNP cluster that predicted AIA risk with fair accuracy. Phenotype, functional, and pathway analysis of attributed genes was consistent with clinical phenotypes. This study is the first to link a specific SNP/gene cluster to AIA risk independent of candidate gene bias. An ongoing prospective companion study will be used to validate and to expand upon results.
A prospective randomized controlled trial of hydrating nail solution for prevention or treatment of onycholysis in breast cancer patients who received neoadjuvant/adjuvant docetaxel chemotherapy.
Authors: Kim Ji-Yeon , Ok Oh-Nam , Seo Jeong Ju , Lee Soo-Hyeon , Ahn Jin Seok , Park Yeon Hee
Published: September 2018

10108

Background: Onycholysis and other nail toxicities occur in approximately 20-30% of breast cancer(BC) patients receiving docetaxel(D) chemotherapy. Onycholysis, the separation of the nail plate from nail bed, is also often associated with painful paronychia decreasing patients’ the efficacy of a hydrating nail solution (EVONAIL solution, Evaux Laboratories, France) for the prevention and treatment of D-induced onycholysis and nail toxicities. Methods: This study is a prospective randomized controlled study of hydrating nail solution for prevention or treatment of onycholysis in patients with BC receiving neo/adjuvant 3-weekly D after doxorubicin plus cyclophosphamide. In experimental arm, each patient painted hydrating nail solution on nails and periungual areas once a day till developing onycholysis grade 2 or more. After Gr 2 onycholysis development, patients painted EVONAIL twice a day regardless of treatment arms. The primary endpoint is the incidence of onycholysis Gr 2 or more and recovery rate from Gr2 onycholysis. The secondary endpoints include: the incidence of all grade onycholysis; duration from first docetaxel treatment until onycholysis symptom appearance; degree of pain from nail toxicities; the incidence of other nail toxicities. Results: Since Aug 2015 to May 2016, 103 patients were enrolled and completed this study (Experimental arm(E) : 51, control arm(C): 52). Of 103 patients, 25 cases of Gr1 and 22 of Gr2 onycholysis were observed (Gr1 and 2(n,(%)) : 8(15.7%) and 7(13.7%) in E, 17(32.7%) and 15(21.4%)in C, respectively). Hydrating nail solution resulted in statistically significant reduction of Gr2 onycholysis compared to C (HR = 0.39, 95% CI 0.16, 0.96; P = 0.041) and all grade onycholysis decreased in experimental arm with statistical significance (HR = 0.37, 95% CI 0.20-0.69, P = 0.002). However, the effect of onycholysis treatment was not observed. Conclusions: Hydrating nail solution significantly reduced the incidence of D induced onycholysis in BC patients (NCT02670603). Clinical trial information: NCT02670603.
Chemotherapy induced nausea and vomiting in breast cancer treated with antiemetic prophylaxis as recommended by the ASCO antiemesis guidelines.
Authors: Copher Ronda , Knoth Russell L. , Magee Glenn , Misir Soamnauth , McBride Ali
Published: September 2018

10109

Background: Current ASCO Antiemesis Guidelines recommend triple antiemetic therapy (a 5HT3RA, an NK1, and dexamethasone) to prevent chemotherapy (CT) induced nausea and vomiting (CINV) in patients undergoing highly emetogenic chemotherapy (HEC). This study evaluated whether this regimen resulted in reduced rates of CINV in patients diagnosed with breast cancer (BC) and initiated on HEC. The primary outcomes of interest were rates of acute and delayed CINV in patients whose antiemesis prophylaxis was or was not in accordance with the ASCO guideline (i.e., Per-guideline vs. Non-Guideline). Costs of treating CINV were also calculated. Methods: Patients were identified in the Premier Healthcare database, a complete geographically diverse census of inpatients and hospital-based outpatients. Adults treated for BC with HEC during the years 2012-14 were identified and stratified based on their antiemesis prophylaxis. Rates of acute (day of CT) and delayed CINV (days 2-7 post CT) were calculated following initiation of HEC. CINV was defined by ICD9 codes for nausea and vomiting or volume depletion/dehydration or use of a rescue antiemetic. Rates of CINV and health care costs were then compared between the two cohorts. Results: A total of 8,388 patients were included in the analysis. Of these, 5,447 (65%) had treatment Per-Guideline and 2,941 (35%) were Non-Guideline. For acute CINV, Per-Guideline patients had a significantly lower rate of CINV when compared to Non-Guideline patients (1.7% vs. 3.2%, respectively, p < .001). Similarly, in delayed CINV Per-Guideline patients had significantly lower rates of CINV when compared to Non-Guideline patients (15.4% vs. 19.1%, p < .001). Patients who experienced CINV also had significantly greater total health care costs versus those without CINV ($32,199 vs. $20,163, respectively, p < .001). Conclusions: The results showed adherence to the ASCO Antiemesis Guidelines led to lower rates of CINV and lower costs. Although defining CINV by claims may tell an incomplete story, this study suggests that following the ASCO Antiemesis Guidelines may help both patients and payers of health care costs.
Trastuzumab-related subclinical cardiotoxicity in patients with early stage HER2-positive breast cancer: A retrospective single-center cohort study.
Authors: Aseyev Olexiy , Rushton-Marovac Moira , Crawley Freya L. , Johnson Christopher , Dent Susan Faye
Published: September 2018

10123

Background: Trastuzumab-based therapy (TT) is standard treatment for HER2-positive breast cancer (HBC). Subclinical cardiotoxicity (SCTx), defined as asymptomatic decline in left ventricular ejection fraction (LVEF) > 10% to < 50%, has been reported in up to 30 % of HBC patients (pts) receiving TT. Objectives included: determine prevalence of SCTx; associated risk factors (RF); and completion rates of TT in pts with HBC referred to a cardio-oncology clinic (COC). Methods: HBC patients receiving TT referred to the Ottawa Hospital COC were included. Demographics, TNM staging, performance status, stage, cardio-vascular (CV) RF (history of heart disease, hypertension, smoking, dyslipidemia, and diabetes), cardiac medications (CM) (ACE-inhibitors, beta-blockers), baseline LVEF, previous cancer therapy, baseline anthracycline exposure, previous radiation therapy (RT) (including mediastinal RT) were collected. LVEF was evaluated by ECHO or MUGA. Rate of successful completion of TT among pts with SCTx was determined. Risk ratio (RR) and logistic regression analysis was performed. Results: 240/408 BC pts referred to the COC (2008-2016) had HBC and 163/240 (68%) were referred with SCTx while on TT. 139/163 (85 %) pts with SCTx recovered after COC assessment: 77/163 (47%) pts were prescribed CMs. A significantly higher proportion of recovery was observed in pts who did not require CM (0.92 vs 0.78, p = 0.012; RR = 0.85, 95%CI:0.74-0.91). A total of 129/163 (79%) pts who experienced SCTx finished a full course of TT. Regression analysis found baseline LVEF, diabetes, and diastolic blood pressure as significant RFs for SCTx. There were no independent predictors for recovery after asymptomatic drop in LVEF while on TT. Diabetes (OR:2.97, 95%CI:1.3-6.8) and left chest wall RT (OR:2.4, 95%CI:1.1-5.6) significantly increased risk of permanent TT interruption in pts with asymptomatic drop in LVEF. Conclusions: The majority of HBC pts who experience SCTx can safely complete a full course of TT; many without use of CMs. While CV RFs were associated with increased risk of SCTx, this did not impact CV recovery after asymptomatic drops in LVEF.
Circulating PD-L1 (programmed death-ligand 1) and outcomes in a HER2-positive metastatic breast cancer cohort treated with first-line trastuzumab.
Authors: Ali Ayesha , Krecko Laura , Leitzel Kim , Ali Suhail M. , Drabick Joseph J. , Halstead E Scott , Nagabhairu Vinod , Marks Eric , Polimera Hyma Vani , Richardson Angelique Ellerbee , Evans Robert , Spiegel Howard , Köstler Wolfgang , Esteva Francisco J. , Lipton Allan
Published: September 2018

1024

Background: Recently the immune checkpoint inhibitors (ICIs) have demonstrated efficacy across a wide variety of cancers, but have been less effective in breast cancer. PD-L1 (B7-H1, CD274) is a ligand produced by many tumor cells and some immune cells, and suppresses the T cell immune response. This allows tumor cells to escape immune detection. PD-L1 is used as a companion tumor tissue IHC biomarker for patient selection for some of the FDA-approved ICIs (pembrolizumab), but not for others (nivolumab, atezolizumab). Circulating PD-L1 has been detected in multiple myeloma, renal, lung, and gastric cancer, but not in breast cancer. Here we correlated serum PD-L1 levels with outcome in a HER2-positive metastatic breast cancer cohort treated with trastuzumab. Methods: Pretreatment serum was obtained from 63 metastatic breast cancer patients before starting first-line trastuzumab-containing therapy. A novel ELLA microfluidic channel immunoassay platform (ProteinSimple, San Jose, CA) was employed to quantitate serum PD-L1. Serum PD-L1 levels were analyzed using continuous, quartile, and dichotomous (25%, median, and 75%) cutpoints. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Results: On a continuous basis, patients with higher serum PD-L1 had a significantly reduced PFS (p = 0.045) and overall survival OS (p = 0.004) compared to patients with lower serum PD-L1 levels. Patients with the higher quartiles of serum PD-L1 also trended to have reduced PFS (0.11) and significantly reduced OS (p = 0.015) compared to the lower quartiles of serum PD-L1. Finally, using either the 25th or 75th percentile of serum PD-L1 as dichotomous cutpoint, patients with higher serum PD-L1 had significantly reduced OS (p = 0.04). Conclusions: Higher circulating PD-L1 levels were prognostic for reduced PFS and OS in HER2-positive metastatic breast cancer patients treated with first-line trastuzumab. Circulating PD-L1 deserves further study for prognostic and predictive biomarker utility in larger trials of immune checkpoint inhibitors and other immunotherapies in breast and other cancers. AA, LK contributed equally.
TBCRC 036: Window of opportunity clinical trial reveals adaptive kinome reprogramming in single and combination HER2-targeting in breast cancer (BrCa).
Authors: Angus Steven P , Stuhlmiller Timothy , Sciaky Noah , Chen Xin , Naim Rashid , Tanioka Maki , Gallagher Kristalyn K. , Forero Andres , Krop Ian E. , Thompson Alastair Mark , Murthy Rashmi Krishna , He Xiaping , Perou Charles M. , Earp Shelton , Carey Lisa A. , Johnson Gary L.
Published: September 2018

1027

Background: HER2 targeting is challenging due to heterogeneity in response and resistance. Adaptive kinome reprogramming (AKRP) is a resistance mechanism to kinase-targeted therapy (Rx) in TNBC ( Cancer Discovery2017). We studied AKRP in HER2+ BrCa by comparing transcriptome and kinome profiles before and after Rx with FDA-approved anti-HER2 drugs and combinations: trastuzumab (T), pertuzumab (P), T+P, or T+ lapatinib (T+L). Profiling was by RNA sequencing (RNAseq) and multiplexed inhibitor beads coupled with mass spectrometry (MIB/MS). MIB affinity-purification selectively enriches the functional kinome ( > 250 kinases per sample) for identification/quantification by MS. Methods: Eligible patients (pts) had biopsy then randomization to: T (8 mg/kg iv), P (840 mg iv), T+P (same doses), or T+L (8mg/kg iv x1, 1000 mg po/d) 7 days before breast surgery. RNAseq and MIB/MS on paired pre- and post-Rx samples were analyzed using DESeq2 (comparison of mean difference in log2fold change (post/pre)) and MaxQuant (kinome response profiling) software. Results: Of 23 evaluable pts, we obtained informative paired RNAseq data in 13 (5 T, 3 P, 3 T+P, 2 T+L), and identified distinct expression responses (padj≤0.05) between Rx arms, such as FGFR4 increase in P vs T or T+P. All samples had HER2 enrichment by RNAseq. Kinome response profiling from 11 pts (3 T, 3 P, 4 T+P, 2 T+L) revealed consistent increases in MIB binding (abundance a/o activity) of several tyrosine kinases regardless of Rx, including immune-related kinases SYK, IRAK4, FGR, and FES. Other kinases, such as p90Rsk and GSK3B, exhibited increased binding in response to T and T+P, but not P alone. While not quantifiable in every sample due to detection limits, HER2 inhibition was observed by loss of MIB binding in select post-Rx versus pre-Rx comparisons. Conclusions: HER2 inhibition upregulates and activates specific receptor tyrosine kinases in tumor cells as well as alterations that may reflect changes in the immune compartment. HER2+ BrCa exhibit plasticity, characterized by distinct expression and kinome profile changes within 1 week of initiating Rx, and reprogramming in both immune responses and BrCa cells. Clinical trial information: NCT01875666.
Survival by HER2 receptor status in stage IV breast cancer: SEER 2010-2012.
Authors: Thomas Alexandra , Khan Seema Ahsan , Lynch Charles , Schroeder Mary Chen
Published: September 2018

1032

Background: Therapeutic advances have altered the course of once highly lethal HER2+ breast cancer (BC). We report survival in a recent population-based cohort by HER2 status, overall, and within hormone receptor(HR)+ BC. Methods: Surveillance, Epidemiology, and End Results Program data were queried to identify women diagnosed 2010-2012 with Stage IV BC as first cancer. Patients were grouped by HER2 and HR status. Kaplan Meier estimates of 3-yr observed survival (OS) were compared with log-rank tests. A multivariate cox model was fitted for the HER2+ cohort. Results: 3-yr OS for HER2+(any HR), HR+/HER- and triple-negative (TN) BC was 52.3%, 48.4% and 16.0% respectively (p<0.01 HER2+(any HR) vs TNBC; p=0.20 HER2+(any HR) vs HR+/HER2-). Across registries, OS for HER2+(any HR) BC ranged from 29.2% to 61.7% (p=0.05). On Cox model, survival in HER2+(any HR) BC was associated with age 50+ (Hazard ratio (HR) 1.84, 95% CI 1.45-2.34), HR+ status (HR 0.70, 0.58-0.84), high histologic grade (HR 1.30, 0.58-0.84), surgery (HR 0.40, 0.33-0.49), separated marital status (HR 1.72, 1.4-2.13), year 2012 (HR 0.81, 0.64-1.04), and registry (varies by reference group). For HR+ BC, OS also differed by HER2 status: 55.3% for HR+/HER+ and 48.4% for HR+/HER2- (p<0.01). 3-yr OS by HER2 status for women presenting with HR+ BC is shown (Table). Conclusions: Survival in de novo Stage IV HER2+ BC in the United States exceeds that in HER2- BC, with median survival >3 yrs. Survival was significantly better for HR+/HER+ BC than HR+/HER- BC. Disparate OS in HER2+ BC suggest opportunities may remain to fully realize advances in HER2-directed therapy. Given recent therapeutic advances, the trend of HER2+ survival gains from 2010 to 2012 will likely continue. [Table: see text]
Assessment of ESR1 and ERBB2 mutations in estrogen receptor positive (ER+) metastatic breast cancers (MBC).
Authors: Basu Gargi D. , White Tracey , LoBello Janine R , Kurdoglu Ahmet , Trent Jeffrey M. , Halbert Matthew J , Royce Thomas , O'Shaughnessy Joyce
Published: September 2018

1040

Background: Mutations (mut) in ESR1 have been reported in ER+ breast cancers (BC) as an acquired resistance mut to aromatase inhibitor (AI) therapy. Acquired ERBB2 mut have also been reported in MBC patients (pts) that cause activated ERBB2 signaling. The emergence of acquired secondary mut presents challenges in effective treatment approaches. Methods: Comprehensive genomic profiling was performed on 83 BC samples with 48 metastatic; 34 primary samples. Targeted next-generation sequencing was performed on 562 cancer associated genes in paired tumor and blood DNA (germline) samples. Results: ESR1-mut were found in 23%(11/48) of ER+ MBC tissues with no mut detected in primary ER+ BCs. Mutations-D538G, Y537S and E380Q in the ligand binding domain of ER were the most common alterations, found in 54.5%, 18% and 18% of ESR1 mut samples, respectively. An ER+ HER2- liver biopsy obtained after 20 mos on AI + everolimus had ESR1-D538G and TSC2 structural event. Protein array showed high expression of androgen receptor (AR) and p-AR and activation of ERBB1/2/3, p-SRC and p-4EBP1 in this sample. Further, a functionally uncharacterized ESR1 mut was found in ER+, HER2+ and a triple negative MBC tissue (the primary BC had been ER+). Mut in PI3K pathway (PIK3CA, ARID1A, TSC1/2, PTEN) were present in 8/11 samples with ESR1 mut. Activating mut in ERBB2 were found in 3/83 samples; all 3 were in ER+ MBC samples with one case harboring mut in both ERBB2 and ESR1 (E380Q – uncertain degree of constitutive activity). Interestingly, a BC sample with ER+ HER2- liver met harbored both ERBB2 (V777L) and ERBB3 (E928G) mut; this pt responded well to trastuzumab/pertuzumab (HP) therapy. A pt with ER+ HER2-ERBB2- L755S mut met to gallbladder found after 7 mos on letrozole/palbociclib therapy responded well to HP and T-DM1 therapy. All 3 ERBB2-mut cancers had a CDH1 frameshift mut suggesting enrichment in pretreated lobular MBCs (Ross J. CCR, 2013). Conclusions: This study shows a 23% and 6% ESR1 and ERBB2 mut rate in MBC samples. No ESR1 and ERBB2 mut were present in primary BC samples. Our findings suggest that pts with lobular MBC should be monitored for acquired ERBB2 mut, and that ERBB2 mut may not arise in BCs which harbor known constitutively active ESR1 mut.
Efficacy and safety in elderly patient subsets across studies investigating endocrine monotherapy versus combination therapy in patients with HR+/HER2−advanced breast cancer.
Authors: Freedman Rachel A. , Tolaney Sara M.
Published: September 2018

1045

Background: Combination of endocrine therapy and targeted agents in 1st and 2nd-line therapy prolong progression-free survival (PFS) in patients with hormone receptor–positive (HR+), HER2 − advanced breast cancer (ABC). However, a greater risk of adverse events (AEs) and a greater possibility of drug-drug interaction, associated with combination therapy, present challenges in older patients. Methods: This study reviewed PFS and safety data in age-stratified subsets from Phase II or III clinical trials comparing endocrine monotherapy vs combinations of endocrine or targeted therapy in patients with HR+, HER2−ABC. Results: Among 9 identified studies, combination therapy that included ribociclib, palbociclib, and everolimus significantly reduced risk of disease progression vs monotherapy in older and younger patient subsets (Table). For combination therapy that included ribociclib or palbociclib, frequency of discontinuations due to AEs was similar between the subsets; more frequent discontinuations due to AEs were noted in the ≥70-year subset with everolimus. Conclusions: Combination endocrine therapies involving CDK4/6 or mTOR inhibitors have similar efficacy but vary in tolerability among older and younger patients with HR+, HER2− ABC. [Table: see text]
Characteristics of disease activity able to identify risk categories and probability to respond to first-line endocrine therapy (ET) in HR+ve/HER2-ve metastatic breast cancer (MBC) patients (pts): Dream or reality? Evaluation of a composite risk score in a subgroup population of the GIM 13-AMBRA study.
Authors: Mustacchi Giorgio , Cazzaniga Marina Elena , Giordano Monica , Garrone Ornella , Beano Alessandra , Del Mastro Lucia , Livi Lorenzo , Iezzi Laura , Michelotti Andrea , Turletti Anna , Riccardi Ferdinando , De Laurentiis Michele , Marchetti Paolo , Biganzoli Laura , Montemurro Filippo , Romagnoli Emanuela , De Placido Sabino , Pronzato Paolo ,   On Behalf of GIM 13-AMBRA Study Group
Published: September 2018

1049

Background: The appropriate choice of 1st-line therapy in HR+ve/HER2-ve MBC pts is becoming more complicated since the data of front-line Fulvestrant and CDK 4/6 Inhibitors have been released. In the absence of predictive biomarkers of tumor response, one possible option is the recently proposed “composite score” (Schmid, ESMO 2016), composed by visceral tumor burden (VTB) and Disease-Free-Interval (DFI) to identify risk categories and the probability of response to ET or chemotherapy (CHT). Aim of the present analysis is to describe the choices of 1st-line treatment and the response rate, according to the mentioned score in a population of HR+/HER2-ve MBC. Methods: We used data of the HR+ve pts of the AMBRA study, a longitudinal cohort study, describing the choice of first and subsequent lines of treatment in HER2-ve MBC pts (SABCS 2016 P5-15-07 & P5-14-09). Using median DFI and VTB three categories of risk have been identified: Low (DFI > 24 months & VTB-), Intermediate (DFI £ 24 months & VTB- or DFI > 24 months & VTB+) and High (DFI £ 24 months & VTB+). This analysis describes the choices of 1st-line therapy and relative response rate according to these risk categories. Results: So far, 791/1500 pts have been registered into the AMBRA study, 673 of them (85%) with HR+ MBC and 659 (83.3%) are evaluable for this analysis. Risk categories and response to therapy are detailed in the table below. Conclusions: No conclusion can be done regarding the “High Risk” group because of the low number of pts treated with ET alone. Regarding the “Low” and “Intermediate” risk categories, we can conclude that the proposed “composite risk score” doesn’t seem to discriminate MBC patients who could be treated with ET alone or with a more aggressive treatment, at least in terms of response rate. [Table: see text]