Showing papers by "Nan Lin published in 2015"

Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets

Abstract: Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing of 86 matched brain metastases, primary tumors, and normal tissue. In all clonally related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found potentially clinically informative alterations in the brain metastases not detected in the matched primary-tumor sample. In contrast, spatially and temporally separated brain metastasis sites were genetically homogenous. Distal extracranial and regional lymph node metastases were highly divergent from brain metastases. We detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases. Significance: Decisions for individualized therapies in patients with brain metastasis are often made from primary-tumor biopsies. We demonstrate that clinically actionable alterations present in brain metastases are frequently not detected in primary biopsies, suggesting that sequencing of primary biopsies alone may miss a substantial number of opportunities for targeted therapy. Cancer Discov; 5(11); 1164–77. ©2015 AACR . See related commentary by Stricker and Arteaga, [p. 1124][1] . This article is highlighted in the In This Issue feature, [p. 1111][2] [1]: /lookup/volpage/5/1124?iss=11 [2]: /lookup/volpage/5/1111?iss=11

Response assessment criteria for brain metastases: proposal from the RANO group

Abstract: CNS metastases are the most common cause of malignant brain tumours in adults. Historically, patients with brain metastases have been excluded from most clinical trials, but their inclusion is now becoming more common. The medical literature is difficult to interpret because of substantial variation in the response and progression criteria used across clinical trials. The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group is an international, multidisciplinary effort to develop standard response and progression criteria for use in clinical trials of treatment for brain metastases. Previous efforts have focused on aspects of trial design, such as patient population, variations in existing response and progression criteria, and challenges when incorporating neurological, neuro-cognitive, and quality-of-life endpoints into trials of patients with brain metastases. Here, we present our recommendations for standard response and progression criteria for the assessment of brain metastases in clinical trials. The proposed criteria will hopefully facilitate the development of novel approaches to this difficult problem by providing more uniformity in the assessment of CNS metastases across trials.

Global lung cancer risk from PAH exposure highly depends on emission sources and individual susceptibility

Abstract: The health impacts of polycyclic aromatic hydrocarbons (PAHs), the most concerning organic pollutants, depend not only on the locations and strengths of emission sources, but also on individual susceptibility. Moreover, trans-boundary transport makes them a global concern. In this study, a comprehensive analysis of the global health impacts of polycyclic aromatic hydrocarbons (PAHs) in ambient air is presented. Model resolution is critical in exposure modelling. Globally, incremental lifetime lung cancer risk (ILCR) induced by ambient PAH exposure is 3.1 × 10(-5). If the individual susceptibility was not taken into consideration, the overall risk would be underestimated by 55% and the proportion of highly vulnerable population would be underestimated by more than 90%. Emphasizing on individual susceptibility, our study provides an instrumental revision of current risk assessment methodology. In terms of lung cancer risk, the most important sources are combustion of biomass fuels (40%) and fossil fuels (14%) in the residential/commercial sector, coke (13%) and aluminium (12%) production, and motor vehicles (9%). PAHs can travel long distance globally especially within the Eurasian continent. Still, the risk is dominantly contributed by local.

Pollutant emissions from improved coal- and wood-fuelled cookstoves in rural households.

Abstract: Residential solid fuel combustion is a major source of many pollutants, resulting in significant impacts on air quality and human health. Improved stoves, especially some modern gasifier biomass models, are being deployed to alleviate household and ambient air pollution. Pollutant emissions from coal burning in improved metal stoves (n = 11) and wood combustion in modern gasifier stoves (n = 8) were measured in field in Hubei, China. The emissions of CO, TSP, OC, EC, and PAHs from coal burning in the improved iron stoves were generally lower than previously reported results for coal in traditional stoves. For pollutants from wood combustion in the gasifier stoves, the emissions were less than literature-reported values for wood burned in traditional stoves, comparable to those in improved stoves, but appeared to be higher than those for pellets in gasifier stoves in laboratory tests. The limitations of scarce data and large variances result in statistical insignificance. Daily emissions of targeted pollutants per household were found to be higher for wood burners, compared with households relying on coal. The gasifier stove had relatively high thermal efficiencies, but emissions of most air pollutants per delivered energy were not significantly different from those from the coal burning in improved iron stoves. Moreover, higher emissions of OC, EC, and PAHs were observed, indicating that caution and additional testing will be needed while designing future clean cookstove intervention programs.

Significance of Circulating Tumor Cells in Metastatic Triple-Negative Breast Cancer Patients within a Randomized, Phase II Trial: TBCRC 019

Abstract: Purpose: Circulating Tumor cells (CTC) are prognostic in metastatic breast cancer (MBC). We tested whether EpCAM based capture system (CellSearch®) is effective in patients with triple negative (TN) MBC, and whether CTC-apoptosis and clustering enhances the prognostic role of CTC. Experimental Design: CTC enumeration and apoptosis was determined using the CXC CellSearch® kit at baseline and days 15 and 29 in blood drawn from TN MBC patients who participated in a prospective randomized phase II trial of nanoparticle albumin-bound paclitaxel (nab-PAC) with or without tigatuzumab (TIG). Association between levels of CTC and patient outcomes was assessed using logistic regression, Kaplan Meier curves, and Cox proportional hazards modeling. Results: Nineteen of 52 (36.5%), 14/52 (26.9%), and 13/49 (26.5%) patients who were evaluable had elevated CTC (≥5CTC/7.5 ml WB) at baseline, days 15 and 29, respectively. Patients with elevated vs. not elevated CTC at each time point had worse progression free survival (PFS) (p=0.005, 0.0003, 0.0002, respectively). The odds of clinical benefit response for those who had elevated vs. low CTC at baseline and days 15 and 29 were 0.25 (95% CI: 0.08-0.84, p=0.024), 0.19 (95% CI: 0.05-0.17, p=0.014), and 0.06 (95% CI: 0.01-0.33, p=0.001), respectively. There was no apparent prognostic effect comparing CTC-apoptosis vs. non-apoptosis. Presence of CTC-cluster at day 15, and day 29 was associated with shorter PFS. Conclusions: CTC were detected using CellSearch® assay in approximately one-third of TN MBC patients. Elevated CTC at baseline and days 15 and 29 were prognostic, and reductions in CTC levels reflected response.

TBCRC 019: A Phase II Trial of Nanoparticle Albumin-Bound Paclitaxel with or without the Anti-Death Receptor 5 Monoclonal Antibody Tigatuzumab in Patients with Triple-Negative Breast Cancer.

Abstract: Purpose: Tigatuzumab (TIG), an agonistic anti-DR5 antibody, triggers apoptosis in DR5+ human tumor cells without crosslinking. TIG has strong in vitro/in vivo activity against basal-like breast cancer cells enhanced by chemotherapy agents. This study evaluates activity of TIG and chemotherapy in patients with metastatic triple negative breast cancer (TNBC). Experimental Design: Randomized 2:1 phase II trial of albumin-bound paclitaxel (nab-PAC) + TIG in patients with TNBC stratified by prior chemotherapy. Patients received nab-PAC weekly x 3 + TIG every other week, every 28 days. Primary objective was within-arm objective response rate (ORR). Secondary objectives were safety, progression free survival (PFS), clinical benefit, and TIG immunogenicity. Metastatic research biopsies were required. Results: Among 64 patients (60 treated; TIG/nab-PAC n=39 and nab-PAC n=21), there were 3 complete remissions (CRs), 8 partial remissions (PRs; 1 almost CR), 11 stable diseases (SDs) and 17 progressive diseases (PDs) in the TIG/nab-PAC arm (ORR=28%), and no CRs, 8 PRs, 4 SDs and 9 PDs in nab-PAC arm (ORR=38%). There was a numerical increase in CRs and several patients had prolonged PFS (1025+, 781, 672, 460, 334) in the TIG/nab-PAC arm. Grade 3 toxicities were 28% and 29% respectively with no grade 4-5. Exploratory analysis suggests an association of ROCK1 gene pathway activation with efficacy in the TIG/nab-PAC arm. Conclusions: ORR and PFS were similar in both. Preclinical activity of TIG in basal-like breast cancer and prolonged PFS in few patients in the combination arm support further investigation of anti-DR-5 agents. ROCK pathway activation merits further evaluation.

Tripchlorolide improves cognitive deficits by reducing amyloid β and upregulating synapse-related proteins in a transgenic model of Alzheimer's Disease.

Abstract: Alzheimer's disease (AD) is characterized by early impairments in memory and progressive neurodegeneration. Disruption of synaptic plasticity processes that underlie learning and memory contribute partly to this pathophysiology. Tripchlorolide (T4 ), an extract from a traditional Chinese herbal Tripterygium wilfordii Hook F, has been shown to be neuroprotective in animal models of Parkinson's disease and to improve cognitive deficits in senescence-accelerated mouse P8. In this study, we investigated the effect of T4 on cognitive decline and synaptic plasticity in five times familial AD (5XFAD) mice co-expressing mutated amyloid precursor protein and presenilin-1. Five-month-old 5XFAD mice and wild type littermates were intraperitoneally injected with T4 , 5 μg/kg or 25 μg/kg, every other day for 60 days. T4 treatment significantly improved spatial learning and memory, alleviated synaptic ultrastructure degradation, up-regulated expression of synapse-related proteins, including synaptophysin, post-synaptic density-95, N-methyl-D-aspartate receptor subunit 1, phosphorylation of calcium/calmodulin dependent protein kinase II α, and phosphorylation of cyclic AMP-response element binding protein, and promoted activation of the phophoinositide-3-kinase-Akt-mammalian target of rapamycin signaling pathway in 5XFAD mice. Accumulation of amyloid β (Aβ) may contribute to synapse dysfunction and memory impairment in AD. We found that T4 treatment significantly reduced cerebral Aβ deposits and lowered Aβ levels in brain homogenates. These effects coincided with a reduction in cleavage of β-carboxyl-terminal amyloid precursor protein (APP) fragment, levels of soluble APPβ, and protein expression of β-site APP cleaving enzyme 1. Taken together, our findings identify T4 as a potent negative regulator of brain Aβ levels and show that it significantly ameliorates synaptic degeneration and cognitive deficits in a mouse model of AD.

Phase II Study of Lapatinib in Combination With Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer: Clinical Outcomes and Predictive Value of Early [18F]Fluorodeoxyglucose Positron Emission Tomography Imaging (TBCRC 003)

Abstract: Purpose Lapatinib plus trastuzumab improves outcomes relative to lapatinib alone in heavily pretreated, human epidermal growth factor receptor 2–positive metastatic breast cancer (MBC). We tested the combination in the earlier-line setting and explored the predictive value of [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) for clinical outcomes. Patients and Methods Two cohorts were enrolled (cohort 1: no prior trastuzumab for MBC and ≥ 1 year from adjuvant trastuzumab, if given; cohort 2: one to two lines of chemotherapy including trastuzumab for MBC and/or recurrence < 1 year from adjuvant trastuzumab). The primary end point was objective response rate by RECIST v1.0; secondary end points included clinical benefit rate (complete response plus partial response plus stable disease ≥ 24 weeks) and progression-free survival. [18F]FDG-PET scans were acquired at baseline, week 1, and week 8. Associations between metabolic response and clinical outcomes were explored. Results Eighty-seven p...

TBCRC 019: A phase II trial of nanoparticle albumin-bound paclitaxel with or without the anti-death receptor 5 monoclonal antibody tigatuzumab in patients with triple negative breast cancer

Abstract: Purpose: Tigatuzumab (TIG), an agonistic anti-DR5 antibody, triggers apoptosis in DR5+ human tumor cells without crosslinking. TIG has strong in vitro/in vivo activity against basal-like breast cancer cells enhanced by chemotherapy agents. This study evaluates activity of TIG and chemotherapy in patients with metastatic triple-negative breast cancer (TNBC). Experimental Design: Randomized 2:1 phase II trial of albumin-bound paclitaxel (nab-PAC) ± TIG in patients with TNBC stratified by prior chemotherapy. Patients received nab-PAC weekly × 3 ± TIG every other week, every 28 days. Primary objective was within-arm objective response rate (ORR). Secondary objectives were safety, progression-free survival (PFS), clinical benefit, and TIG immunogenicity. Metastatic research biopsies were required. Results: Among 64 patients (60 treated; TIG/nab-PAC n = 39 and nab-PAC n = 21), there were 3 complete remissions (CR), 8 partial remissions (PR; 1 almost CR), 11 stable diseases (SD), and 17 progressive diseases (PD) in the TIG/nab-PAC arm (ORR, 28%), and no CRs, 8 PRs, 4 SDs, and 9 PDs in the nab-PAC arm (ORR, 38%). There was a numerical increase in CRs and several patients had prolonged PFS (1,025+, 781, 672, 460, 334) in the TIG/nab-PAC arm. Grade 3 toxicities were 28% and 29%, respectively, with no grade 4–5. Exploratory analysis suggests an association of ROCK1 gene pathway activation with efficacy in the TIG/nab-PAC arm. Conclusions: ORR and PFS were similar in both. Preclinical activity of TIG in basal-like breast cancer and prolonged PFS in few patients in the combination arm support further investigation of anti-DR5 agents. ROCK pathway activation merits further evaluation. Clin Cancer Res; 21(12); 2722–9. ©2015 AACR. See related article by Paoletti et al., p. 2771

Racial differences in outcomes for patients with metastatic breast cancer by disease subtype

Abstract: Treatment advances have differed by breast cancer subtype. We examined the impact of race on survival of women with metastatic breast cancer by disease subgroup. Using surveillance, epidemiology, and end results -Medicare data, we included white and black patients aged ≥66 with de novo metastatic breast cancer diagnosed between 1998 and 2009. Using trastuzumab as a proxy for human epidermal growth factor receptor 2 (HER2)-positive status, we defined three disease subgroups: (1) HER2-positive (received trastuzumab), (2) HER2-negative/unknown (never received trastuzumab)/hormone receptor (HR)-positive, and (3) HER2-negative/unknown/HR-negative. Multivariate Cox proportional models assessed the impact of race on overall survival (OS) and breast cancer-specific survival by subgroup. We also examined trastuzumab treatment patterns. Among 4364 women (86 % white, 14 % black), 9 % had HER2-positive, 72 % had HER2-negative/unknown/HR-positive, and 18 % had HER2-negative/unknown/HR-negative tumors. Patients with HER2-positive disease experienced longer median OS compared with others: 2.4 versus 1.8 years for women with HER2-negative/unknown/HR-positive and 0.5 years for women with HER2-negative/unknown/HR-negative disease (P < 0.001). Racial differences in OS were only observed among patients with HER2-positive tumors: median OS: 1.4 versus 2.7 years for black and white women, adjusted hazard ratio 1.45; 95 % Confidence interval 1.01–2.08. Results for breast cancer-specific survival were similar. We also observed racial differences in trastuzumab utilization, with longer median time to trastuzumab initiation and lower likelihood of continuation over time for black (vs. white) patients. Among women with de novo metastatic breast cancer, racial differences in survival were only apparent for those with inferred HER2-positive tumors. Further study of how treatment patterns affect outcomes is warranted.

The Influence of Radiology Image Consultation in the Surgical Management of Breast Cancer Patients

Abstract: Patients referred to comprehensive cancer centers arrive with clinical data requiring review. Radiology consultation for second opinions often generates additional imaging requests; however, the impact of this service on breast cancer management remains unclear. We sought to identify the incidence of additional imaging requests and the effect additional imaging has on patients’ ultimate surgical management. Between November 2013 and March 2014, 153 consecutive patients with breast cancer received second opinion imaging reviews and definitive surgery at our cancer center. We identified the number of additional imaging requests, the number of fulfilled requests, the modality of additional imaging completed, the number of biopsies performed, and the number of patients whose management was altered due to additional imaging results. Of 153 patients, the mean age was 55 years; 98.9 % were female; 23.5 % (36) had in situ carcinoma (35 DCIS/1 LCIS), and 76.5 % (117) had invasive carcinoma. Additional imaging was suggested for 47.7 % (73/153) of patients. After multidisciplinary consultation, 65.8 % (48/73) of patients underwent additional imaging. Imaging review resulted in biopsy in 43.7 % (21/48) of patients and ultimately altered preliminary treatment plans in 37.5 % (18/48) of patients (Fig. 1). Changes in management included: conversion to mastectomy or breast conservation, neoadjuvant therapy, additional wire placement, and need for contralateral breast surgery. Our analysis of second opinion imaging consultation demonstrates the significant value that this service has on breast cancer management. Overall, 11.7 % (18/153) of patients who underwent breast surgery had management changes as a consequence of radiologic imaging review.

Distribution and fate of synthetic musks in the Songhua River, Northeastern China: influence of environmental variables.

Abstract: Contamination levels and spatial and temporal distributions of six typical synthetic musks (SMs) in water and sediment of the Songhua River in Northeastern China were investigated. Experimental data for 72 water and 52 sediment samples collected at 29 sampling sites over 12 months spanning 2011–2012 showed that the Songhua River had been contaminated to different degrees at various sites separately from the river’s source. The polycyclic musks 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta-(g)-2-benzopyran (HHCB) (Galaxolide) and 7-acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (AHTN) (Tonalide) were found most frequently and at the highest levels. Concentrations of HHCB were <2–37 ng/L in water and <0.5–17.5 ng/g dry weight (dw) in sediment. AHTN was <1–8 ng/L in water and <0.5–5.7 ng/g dw in sediment. Statistical relationships between SM concentrations and four environmental variables (temperature, illumination, runoff, and population density) in the Songhua River Basin were formulated. Concentration levels varied proportionately with the size of the city along the river, while the distribution patterns showed clear seasonal variations. HHCB/AHTN ratios mirrored the transfer and transmitting process of SMs. Concentrations of target compounds were correlated with each other, suggesting similar exposure sources. Environmental risk assessment of SMs presented seasonal variations and provided baseline information on SM exposure in the Songhua River Basin.

Expression of microRNA-106b and its clinical significance in cutaneous melanoma.

Abstract: MicroRNA-106b (miR-106b) is overexpressed in various types of cancers and is associated with the regulation of carcinogenic processes. However, its clinical significance in cutaneous melanoma has not been reported. qRT-PCR was performed to examine the expression of miR-106b in 15 cases of dysplastic nevi, 17 cases of melanoma metastases, and 97 cases of primary cutaneous melanoma tissue samples. Survival rate was determined with Kaplan-Meier and statistically analyzed with the log-rank method between groups. Survival data were evaluated through multivariate Cox regression analysis. Significant differences in miR-106b expression were shown between dysplastic nevi and primary cutaneous melanomas (P < 0.01), between primary melanomas and metastatic cutaneous melanomas (P < 0.01), and between primary cutaneous melanomas and metastatic cutaneous melanomas (P < 0.001). We found that high miR-106b expression was correlated with Breslow thickness (P = 0.002), tumor ulceration (P = 0.002), and advanced clinical stage (P < 0.001). The patients with high miR-106b expression showed shorter 5-year overall survival than those with low miR-106b expression (P = 0.02; log-rank test). Multivariate regression analysis showed that the status of miR-106b expression was an independent prognostic factor for overall survival (HR = 2.09, 95%CI: 1.11-10.26, P = 0.02). This study showed that miR-106b may contribute to the progression of cutaneous melanoma and its up-regulation may be independently associated with poor prognosis of cutaneous melanoma. This suggests that miR-106b might serve as a promising biological marker for further risk stratification in the management of cutaneous melanoma.

Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets

Abstract: UNLABELLED Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing of 86 matched brain metastases, primary tumors, and normal tissue. In all clonally related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found potentially clinically informative alterations in the brain metastases not detected in the matched primary-tumor sample. In contrast, spatially and temporally separated brain metastasis sites were genetically homogenous. Distal extracranial and regional lymph node metastases were highly divergent from brain metastases. We detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases. SIGNIFICANCE Decisions for individualized therapies in patients with brain metastasis are often made from primary-tumor biopsies. We demonstrate that clinically actionable alterations present in brain metastases are frequently not detected in primary biopsies, suggesting that sequencing of primary biopsies alone may miss a substantial number of opportunities for targeted therapy.

Toward a Relational Account of Neighborhood Governance Territory-Based Networks and Residential Outcomes in Urban China

Abstract: Although changes in urban space often mean a restructuring of social relations, few studies elucidate why network-related frameworks are inherently related to residential outcomes in urban neighborhoods. By proposing a relational account of neighborhood governance, we investigate outcomes of neighborhood governance by incorporating a series of measures of network forms of organization, network-based social capital, and neighborly interactions. Based on a collaborative survey project conducted in Guangzhou, we find that neighborhood ties and neighborly interactions are positively associated with neighborhood attachment and cohesion, whereas uneven power relations between grassroots governments and civic homeowners associations are negatively associated with these two measures. These results not only reveal new social dynamics in urban space but also lend support to a relational account of neighborhood governance.

Better treatments needed for breast cancer brain metastases

Abstract: Up to half of patients with advanced HER2-positive breast cancer will develop brain metastases. Radiation therapy (and surgery for patients who present with a single lesion) remains the standard of care on initial diagnosis; however, treatment of subsequent progression is based mainly on expert opinion rather than the results of well controlled trials. Although median survival after a diagnosis of brain metastasis now exceeds 2 years in patients with good performance status and HER2-positive disease, this outcome has resulted in patients who live long enough to have substantial morbidity from additional CNS progression and long-term eff ects of radiation. Better options for the prevention and treatment of brain metastases are clearly needed. In The Lancet Oncology, Javier Cortés and colleagues report the results of LUX-Breast 3, a randomised phase 2 trial comparing afatinib alone, or in combination with vinorelbine, versus investigator’s choice of treatment, in women with HER2-positive breast cancer and progressive brain metastases during or after treatment with trastuzumab, lapatinib, or both. The most popular regimens in the investigator’s choice arm were trastuzumab plus vinorelbine (11 [26%] of 43 patients) and lapatinib plus capecitabine (eight [19%] patients) Study accrual was completed in just over 1 year, underscoring the high unmet clinical need. The primary endpoint of patient benefi t (defi ned as the absence of CNS or extra-CNS disease progression, no tumour-related worsening of neurological signs or symptoms, and no increase in corticosteroid dose) at 12 weeks was achieved in 18 (41·9%) of 43 patients given investigator’s choice, 12 (30·0%) of 40 given afatinib alone, and 13 (34·2%) of 38 given afatinib plus vinorelbine, with no between-group diff erences in effi cacy. However, the afatinib-containing treatments seemed to be less well tolerated. Despite the negative result, this well designed study provides important lessons for drug development and clinical care. Designing randomised trials in this setting has been challenged by the absence of an obvious standard-of-care control group, because of the shortage of approved regimens for this indication. Single-group studies have often used the results of the lapatinib trials as a reference point; however, increasing exposure to lapatinib in the clinical setting has made results of contemporary uncontrolled studies diffi cult to interpret. Cortés and colleagues’ study is the fi rst to take a pragmatic approach by allowing investigators to choose the active control regimen, and thus provides the most robust benchmark we now have available against which to assess novel agents, particularly in the post-radiation setting. Notably, median overall survival in this group of heavily pretreated patients was about 1 year in the groups receiving afatinib alone and investigator’s choice of treatment. Six (14%) of 43 patients treated with investigator’s choice achieved a CNS objective response with a median duration of response of 192 days. Together with data from other studies, these results support the practice of treating patients with systemic agents as an alternative to repeated courses of radiation. Furthermore, they argue strongly against the still-prevalent practice of excluding patients with brain metastasis from early-phase clinical trials on the basis of their presumed short life expectancy. This trial draws attention to the growing importance of both CNS activity and tolerability as potential diff erentiators between investigational drugs in what has become a crowded space. The initial phase 2 study of afatinib in HER2-positive breast cancer, excluded patients with active brain metastases and showed similar activity of afatinib compared with lapatinib historical controls. Nevertheless, afatinib was taken to a phase 3 trial (LUX-Breast 1), which compared trastuzumab plus vinorelbine with afatinib plus vinorelbine in patients without active CNS disease pretreated with trastuzumab. Despite a similar tumour response and progression-free survival in both treatment groups, overall survival and safety were better in the trastuzumab plus vinorelbine group. In view of the results of LUX-Breast 1 and Cortés’ study, further development of afatinib for use in breast cancer has been halted. In retrospect, an earlier assessment of CNS activity might have altered the decision to bring the drug forward in breast cancer. Despite extracranial activity in the phase 2 (in which 10% of patients achieved an objective response) and phase 3 afatinib trials (LUX-Breast 1, in which 46% of patients achived an objective response), no CNS responses to afatinib alone Lancet Oncol 2015

Abstract P1-13-04: Enobosarm for the treatment of metastatic, estrogen and androgen receptor positive, breast cancer. Final results of the primary endpoint and current progression free survival

Abstract: Background: Historically, androgens have been utilized for the treatment of breast cancer (BC) as the androgen receptor (AR) is the most highly expressed steroid receptor in BC (75-95% of estrogen receptor positive (ER+) and 50% of ER negative). Reports of the use of androgens in metastatic BC (MBC) indicate that women progressing on tamoxifen have the ability to respond to synthetic androgens with overall response rates in the range of 20-60%; however, these steroidal androgens also exhibit virilizing side effects, thus limiting clinical use. A non-steroidal, tissue-selective, AR modulator (SARM), such as enobosarm, offers a targeted approach of AR activation without virilization or estrogenic effects. Methods: This is a phase II proof of concept study examining the efficacy and safety of once daily enobosarm 9 mg in post-menopausal women with ER+ MBC who had responded to adjuvant and/or salvage endocrine therapy. Therapy is continued until patients display evidence of disease progression. The proportion of AR+ patients with clinical benefit response (CBR) at 6 months is the primary endpoint; defined as patients with a complete response (CR), partial response (PR), or stable disease (SD) as detailed in modified RECIST 1.1. AR status of metastatic disease will be correlated with CBR. Serum prostate specific antigen (PSA) will be assessed as a biomarker of AR activation by drug. Secondary endpoint is progression free survival (PFS). Results: Patient demographics: mean age 63.7 years, mean time from diagnosis 11.0 years, 72.7% prior chemotherapy, 89% (17/19) AR+. After a median follow-up of 81 days (range 7-304 days), preliminary results of 22 patients: 9 SD as best response, median duration 212 days. Current disposition of patients: 15 PD after a median 80 days (range 15-304 days), 4 SD (1 on treatment for Conclusions: Enobosarm demonstrates promise as a novel endocrine agent for AR+ MBC. The primary endpoint has been achieved, with 6/17 AR+ patients meeting statistical threshold for success (35% CBR at 6 months). Serum PSA appears to be a surrogate marker for AR activity associated with enobosarm administration. Based upon these favorable preliminary findings, a larger phase II study is anticipated. Citation Format: Beth Overmoyer, Pedro Sanz-Altimira, Ann H Partridge, Martine Extermann, Jane Liu, Eric Winer, Nancy Lin, Michael Hassett, Leroy Parker, Ryan Taylor, Michael Hancock, Susan Small, Mary Ann Johnston. Enobosarm for the treatment of metastatic, estrogen and androgen receptor positive, breast cancer. Final results of the primary endpoint and current progression free survival [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-13-04.

Intraoperative awareness risk, anesthetic sensitivity, and anesthetic management for patients with natural red hair: a matched cohort study

Abstract: Purpose The red-hair phenotype, which is often produced by mutations in the melanocortin-1 receptor gene, has been associated with an increase in sedative, anesthetic, and analgesic requirements in both animal and human studies. Nevertheless, the clinical implications of this phenomenon in red-haired patients undergoing surgery are currently unknown.

Variation in type of adjuvant chemotherapy received among patients with stage I breast cancer: A multi-institutional study

Abstract: BACKGROUND Among patients with stage I breast cancer, there is significant uncertainty concerning the optimal threshold at which to consider chemotherapy, and when considered, there is controversy regarding whether to consider non-intensive versus intensive regimens. The authors examined the types and costs of adjuvant chemotherapy received among patients with stage I breast cancer. METHODS The current study was a prospective cohort study including patients with stage I breast cancer who were treated at a National Comprehensive Cancer Network center from 2000 through 2009. Stage was defined according to the version of the American Joint Committee on Cancer Staging Manual applicable at the time of diagnosis. Stratifying by human epidermal growth factor receptor 2 (HER2), the authors examined the percentage of patients receiving intensive versus non-intensive chemotherapy regimens and the factors associated with type of chemotherapy administered using multivariable logistic regression. Costs of the most common regimens were estimated. RESULTS Of 8907 patients, 33% received adjuvant chemotherapy. Among those individuals, there was an increase in the use of intensive chemotherapy within the last decade, from 31% in 2000 through 2005 to 63% in 2008 through 2009 (including an increase in the use of the combination of docetaxel, carboplatin, and trastuzumab) among patients with HER2-positive disease and from 15% in 2000 through 2005 to 41% in 2008 through 2009 among patients with HER2-negative disease (32% of patients with hormone receptor-positive and 59% of patients with triple-negative disease). Among patients treated with non-intensive regimens, there was an increase in the use of the combination of docetaxel and cyclophosphamide noted, with a decrease in the use of the doxorubicin and cyclophosphamide combination. The choice of regimen varied significantly by institution. The major drivers of cost variation were the incorporation of biologics (eg, trastuzumab) and growth factors, with significant variation even within non-intensive and intensive regimens. CONCLUSIONS Over time, there was an increase in use of intensive regimens among Stage I breast cancer, with striking institutional and cost variations. Cancer 2015;121:1937–1948. © 2015 American Cancer Society.

Variation in the Attitudes of Medical Oncologists Toward Research Biopsies in Patients With Metastatic Breast Cancer

Abstract: Background.Tissue fromresearch biopsies provides access to insights into tumor biology. We aimed to determine medical oncologists’ (MOs’) attitudes toward research biopsies in patients with metastatic breast cancer (MBC). Materials and Methods. A total of 309 breast MOs from NationalCancerInstitute(NCI)-designatedcancercenterswere invited to complete a self-administered survey about their attitudes toward approaching patients for research purposeonlybiopsies(RPOBs),performedasastandaloneprocedure,or additionalbiopsies,performedwithaclinicallyindicatedbiopsy. The MOs were asked to predict what proportion of their MBC patients would consider undergoing research biopsies. Results. Of the 309 MOs, 221 (72%) responded. Of these 221 MOs, 30 were ineligible, leaving 191 eligible responders. NearlyalltheMOsreportedtheywerecomfortableapproach

Abstract PD3-5: Whole exome sequencing (WES) of HER2+ metastatic breast cancer (MBC) from patients with or without prior trastuzumab (T): A correlative analysis of TBCRC003

Abstract: Background: Although the spectrum of genomic alterations in primary, treatment-naive breast tumors has been described, the genomic landscape of HER2+ MBC remains underexplored. Furthermore, tumor genomic alterations that arise after progression on anti-HER2 therapy are largely unknown. Methods: We prospectively collected metastatic tumor biopsies from patients (pts) enrolled on TBCRC003 (NCT00470704), a phase II study evaluating the combination of lapatinib (L) and T in pts with HER2+ MBC who had varying degrees of prior T exposure. We performed WES on baseline metastatic biopsies and normal DNA from 57 pts. In 36 pts, we also performed WES on pre-treatment primary tumors. Tumors were analyzed for point mutations, insertions/deletions, and copy number alterations. Results: Total accrual was 116 pts. 87 pts were registered in one of two efficacy cohorts: Cohort 1 included pts w no prior T for MBC. Pts with prior adjuvant T were included if the interval from last T to 1st recurrence > 12 months. Cohort 2 included pts with 1-2 prior lines of T for MBC or recurrence within 12 months of adjuvant T. An additional 29 pts were enrolled in a biomarker cohort (Cohort 3). Per-protocol efficacy analyses for 85 pts deemed evaluable are shown below: As we previously reported (Wagle et al, ASCO 2014), across 57 metastatic tumors, significant recurrently mutated genes were TP53 (n=30; 53%) and PIK3CA (n=19; 33%). The frequency of mutant TP53 and PIK3CA was not significantly different from 119 primary, treatment-naive HER2+ tumors sequenced in the TCGA study (50%, p=0.8 and 27%, p=0.5, respectively). Recurrent copy number alterations were also similar to TCGA data. Comparing the 38 pts who received any prior T with the 19 pts who did not, there was no significant difference in the incidence of mutant TP53 (53% vs 53%, p=1.0) and PIK3CA (37% vs 26%, p=0.6). We identified mutations in the HER2 kinase domain in 4/38 pts who received prior T (11%), as compared to 0/19 T-naive pts. HER2 kinase domain mutations have been identified in ∼2% of HER2-negative cancers but An analysis comparing paired archival primary tumors and baseline metastatic biopsies from 36 pts to identify genomic alterations acquired or enriched in the metastatic tumors will be presented. Conclusions: We present an analysis of the genomic landscape of HER2+ MBC, including comparisons between matched primary tumors and metastatic biopsies. Somatic HER2 kinase mutations in pts with HER2+ MBC treated with prior T suggests that these mutations may be involved in resistance to T, and may predict poor response to additional anti-HER2 therapy with combined L and T. Novel therapeutic approaches may be required for these pts. Citation Format: Nikhil Wagle, Nancy U Lin, Andrea L Richardson, Ignaty Leshchiner, Ingrid A Mayer, Andres Forero-Torres, Timothy J Hobday, Elizabeth C Dees, Rita Nanda, Mothaffar F Rimawi, Hao Guo, William T Barry, Ron Bose, Wei Shen, Antonio C Wolff, Stacey B Gabriel, Levi A Garraway, Eric P Winer, Ian E Krop. Whole exome sequencing (WES) of HER2+ metastatic breast cancer (MBC) from patients with or without prior trastuzumab (T): A correlative analysis of TBCRC003 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD3-5.