bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial heterogeneity of MRI response to first-line hormonal therapy to predict progression-free survival in metastatic breast cancer.
Authors: Kosmin Michael , Makris Andreas , Sokhi Heminder , Thijssen Toon , Padhani Anwar R.
Published: September 2018

e12544

Background: Whole-body magnetic resonance imaging (WB-MRI) can positively identify response to systemic therapy in metastatic breast cancer (MBC) by the analysis of water diffusivity, cellularity and cell variability. We adapted a novel methodology that captures patient-level, spatial response heterogeneity using the METastasis Response Assessment Diagnostic System (MET-RADS) using WB-MRI. This study evaluated whether spatial heterogeneity seen at the first response assessment is predictive of duration of treatment (i.e. progression-free survival, PFS) in patients on first line hormonal therapy for MBC. Methods: Patients on first line hormonal therapy for MBC had baseline and on-treatment response assessment WB-MRI scans. All patients had a primary breast mass in situ. Patients showing unequivocal disease progression at their first response assessment scans were excluded from further analysis. Criteria for response assessment utilised the methodology described by MET-RADS. A Likert five-point response assessment category (RAC) score (1 = response highly likely, 5 = progression highly likely) was applied to 14 anatomic regions (7 bone & 7 soft tissue). Two scores reflecting the dominant and next most common response per region were recorded, capturing inter- and intra-region response heterogeneity. A novel Response Heterogeneity Index (RHI) summarised the response heterogeneity at the patient level. RHI and depth of response (mean RAC score for all involved regions) and therapy duration were analysed. Results: Twenty-one patients with primary breast mass in situ were analysed. Patients with higher levels of response heterogeneity (defined as RHI > 5; n = 11) had significantly shorter PFS than those with RHI ≤5 (n = 10; median PFS: 11 vs 27 months; log rank test p = 0.011). The depth of response and PFS were unrelated (mean RAC ≤2.5 vs mean RAC > 2.5; median PFS: 21 vs 18 months; log rank test p = 0.46). There were no correlations between RHI score and mean RAC (r2= 0.007). Conclusions: A low spatial heterogeneity of response is predictive of improved PFS in patients receiving first line hormonal therapy for MBC.
A network meta-analysis of fulvestrant vs alternative first-line endocrine therapies for endocrine therapy-naive postmenopausal hormone receptor-positive advanced or metastatic breast cancer.
Authors: Telford Claire , Takyar Shweta , Joshi Parth , Ekman Mattias , Jones Nick
Published: September 2018

e12545

Background: Fulvestrant (F) is a selective estrogen degrader for hormone receptor-positive (HR+) locally advanced or metastatic breast cancer (LA/MBC). This network meta-analysis examined the efficacy of F (500 mg) vs alternative endocrine therapies (ETs) for first-line treatment of ET-naïve HR+ LA/MBC. Methods: Randomized controlled trials of first-line F, tamoxifen (Tam), anastrozole (A), exemestane (E), letrozole (L), and toremifene (T) for women (≥18 years) with HR+ LA/MBC and no prior ET were identified in a systematic review of MEDLINE, EMBASE, and Cochrane databases from inception to October 2016. Conference proceedings of the American Society of Clinical Oncology, European Society of Medical Oncology, and San Antonio Breast Cancer Symposium from 2013-2016 were hand searched. Trials of targeted combination therapies were excluded. Studies were checked for heterogeneity. A standard fixed-effect Bayesian network meta-analysis was conducted based on hazard ratios (HRs) and assuming proportional hazards for progression-free and overall survival (PFS/OS). Results: Seven eligible studies (1 Phase [Ph] 2, 5 Ph 3, 1 Ph 2/3) were identified. All had PFS data; five had OS data. Two trials compared F vs A; PFS data were available for both trials; sufficiently mature OS data for F were available from Ph 2 only. The proportional hazards assumption was met for PFS only.F had significantly improved PFS vs Tam (HR 0.57, 95% credibility interval [Crl] 0.44-0.73), A (HR 0.75, 95% Crl 0.62-0.91), E (HR 0.65, 95% Crl 0.47-0.91), and T (HR 0.53, 95% Crl 0.37-0.78). Numerically improved PFS was observed for F vs L (HR 0.81, 95% Crl 0.59-1.11). F had significantly improved OS vs Tam (HR 0.63, 95% Crl 0.40-0.98), A (HR 0.63, 95% Crl 0.42-0.94), and E (HR 0.56, 95% Crl 0.33-0.95). OS was numerically improved with F vs L (HR 0.66, 95% Crl 0.41-1.04). Conclusions: This analysis suggests improved PFS and OS for fulvestrant vs tamoxifen, anastrozole, exemestane, and letrozole, and PFS for fulvestrant vs toremifene. Further analysis should be conducted, using non-proportional hazard methods and more mature OS data, to confirm the OS results.
Analysis of real world patient compliance to everolimus-based therapy among post-menopausal women with hormone receptor positive and human epidermal growth factor receptor 2 negative (HR+/HER2-) metastatic breast cancer (mBC).
Authors: Princic Nicole , Brouillette Matthew , Tang Derek , Lin Chinjune , Lanoue Brad , Barghout Victoria E.
Published: September 2018

e12546

Background: Patient compliance, typically not captured in clinical trials, may have profound effects on treatment effectiveness. As there has been limited real-world data, the objective of this analysis was to examine compliance among HR+/HER2- mBC patients treated with everolimus as a second or later line of therapy in the US across age groups. Methods: In this retrospective cohort study, the MarketScan Commercial and Medicare Supplemental claims databases were used to select post-menopausal HR+/HER2- mBC women who initiated an everolimus-based line of therapy during 1/1/2013- 7/31/2016 study period. The first secondary malignancy diagnosis was the index date. Patients had 6 months of continuous enrollment in their health plans pre- and post- index, and were followed until the earliest of disenrollment, inpatient death, or end of study. Compliance was measured using medication possession ratio (MPR) during a second (2L), third (3L) and fourth (4L) line of therapy. MPR was defined as total days of supply of everolimus during the line of therapy divided by total duration of the line. Results: Of 645 eligible mBC patients treated with everolimus during follow-up, there were 239, 142, and 80 with a 2L, 3L, and 4L of therapy respectively. Mean age overall was 61.1 + 11.7 years and average duration of follow-up was 718.3 + 304.1 days. Across all patients the median MPR ranged during each line from 0.90-0.92 and the majority (93.8%-97.5%) were highly compliant to therapy (defined as MPR>80%). These results were consistent for patients aged <65 and 65+ years across a 2L, 3L, and 4L of therapy (Table). Conclusions: This study shows high compliance for everolimus-based therapy within a 2L, 3L, and 4L of therapy and this is consistent across ages. This real world data suggests good drug manageability and may provide valuable information for clinicians in selecting treatment for mBC. [Table: see text]
Metronomic chemotherapy (mCHT) in HER2-ve advanced breast cancer (ABC) patients (pts): What has changed over the time? Preliminary results of the VICTOR-6 study.
Authors: Cazzaniga Marina Elena , Casadei Virginia , Cagossi Katia , Cavanna Luigi , Cursano Maria Concetta , De Conciliis Enrico Maria Romano , Gebbia Vittorio , Melegari Elisabetta , Pellegrino Benedetta , Pinotti Graziella , Rossello Rosalba , Russo Salvatore , Ortu Salvatore , Saracchini Silvana , Stocchi Lucia , Toniolo Davide , Scognamiglio Giovanni , Valerio Maria Rosaria , Vandone Anna Maria , Clivio Luca ,   On Behalf of The VICTOR-6 Study Group
Published: September 2018

e12552

Background: mCHT is the minimum biologically effective dose of a chemotherapeutic agent, given at regular dosing regimen with no prolonged drug free interval, that leads to anti-tumor activity. Old regimens included Cyclophosphamide-Methotrexate (CM), whereas in the last years new regimens, such as Vinorelbine (VRL) and Capecitabine (CAPE)-based have been developed. Aim of this observational retrospective ongoing study is to describe the use of mCHT in ABC pts across 5 years and the clinical characteristics of the pts together with efficacy of old (CM-like) vs new (VRL/CAPE-based) metronomic regimens in terms of response and disease control. Methods: We retrospectively identified from clinical records those HER2-ve ABC pts who have received any kind of mCHT in the years 2011-2015, alone, or in combination with a non-metronomic drug. Standard statistical approaches were used for describing the sample characteristics. Logistic and non proportional hazard analysis were used to identify factors associated with response, and time to treatment failure and survival, respectively. This preliminary analysis focuses on Response Rate (RR) and Disease Control Rate (DCR). Results: From June 2011 to December 2015, 267 pts have been identified till now and 233 are fully evaluable. Median age at mCHT start was 67 years. 81% was HR+ and 33% had non-visceral metastatic disease. 22% of the pts received CM, 55% VRL-based and 23% mCAPE-based regimens. mCHT use increased over the time from 15.0% (2011) to 30% (2015). As 1st-line treatment, CM was administered in 27% of compared with more than 48% of patients receiving CAPE/VRL-based regimens. Overall Response Rate (ORR) was 28% and Disease Control Rate (DCR) was 79%. Median duration of mCHT was 6.2 months. New generation metronomic regimens produced higher ORR in comparison to old ones (32% vs 13.5%), with similar duration of treatment (6.4 vs 5.4 months, respectively). Conclusions: The use of mCHT in the treatment of HER2-ve ABC pts has deeply changed across the last 5 years, being new generation regimens used in earlier lines of treatment, producing interesting results in terms of objective response and disease control.
Correlation between vitamin D deficiency and metastatic breast carcinoma in a predominantly Hispanic population: A retrospective study.
Authors: Chitnis Saurabh Deepak , Popescu-Martinez Andrea M.
Published: September 2018

e12553

Background: There have been numerous studies conducted linking Vitamin D deficiency to various cancers, including cancers of the breast. Studies associating Vitamin D deficiency and Breast cancer have shown mixed results in patients with no clear consensus. Recently published in vitro studies have shown that the active form of Vitamin D can inhibit the metastatic capability of breast cancer cell lines to bone. Based on this we aimed to elucidate whether there exists any correlation between Vitamin D deficiency at diagnosis and Metastatic breast cancer. Methods: Retrospective analysis of the EMR for women diagnosed with breast cancer and enrolled in Oncology database seen at NYMC-Metropolitan Hospital Center from 2010-2016 was done. Patients were grouped into either breast cancer with metastases or without metastases and their Vitamin D levels at diagnosis were reviewed. Patients with 25- Hydroxy Vitamin D levels measured within one year of diagnosis of breast cancer were included for the study. Study was planned from 2010-2016 specifically as Vitamin D levels for patients were not monitored as frequently prior to 2010. Results: From total of 102 patients who started follow up with Oncology clinic during the study time period, 2 were referred to our center for further management with diagnosis made prior to 2010 and were not included in the study. Out of the 100 patients considered, 58 patients had Vitamin D levels measured within a year of diagnosis of breast cancer and were included in the study. 70% of the population was Latino/Hispanic. The table represents the results of the study. Odds ratio for a patient with Vit D deficiency to develop metastatic breast cancer was 0.92 and relative risk was calculated to be 0.93. Conclusions: Based on above results, the outcome was similar in both groups. The odd’s ratio and the relative risk imply that there was no difference evidenced between both groups. These findings signify that there was no direct correlation between Metastatic breast cancer and Vitamin D deficiency at time of diagnosis in the population seen at our center. [Table: see text]
Routine clinical use of nab-paclitaxel for advanced / metastatic breast cancer in Germany: Final results of the prospective observational study NABUCCO.
Authors: Schroeder Jan , Potthoff Karin , Salat Christoph , Soeling Ulrike , Hansen Richard , Grebhardt Sina , Harde Johanna , Nusch Arnd , Marschner Norbert
Published: September 2018

e12555

Background: nab-Paclitaxel ( nab-P) is approved for treatment of metastatic breast cancer (MBC) on a 3-week schedule based on results from the pivotal trial in which nab-P 260 mg/m2 showed a significant increase of progression-free survival compared with solvent-based paclitaxel. However, numerous studies suggest a weekly schedule might be a more effective and less toxic option (Gradishar 2011). Data beyond clinical trials is limited. Here we report on prospective non-interventional real-world effectiveness and safety data. Methods: The NABUCCO study was designed to collect data on routine treatment of 700 patients (pts) with MBC in Germany. Primary objective was time to progression (TTP), secondary objectives were overall response rate (ORR), overall survival (OS), dosage scheme of nab-P and safety parameters. Descriptive statistics were used to analyze the data. TTP and OS were calculated using the Kaplan-Meier method. Results: Between 4/2012 and 4/2015 697 evaluable pts at 128 sites had been enrolled. Baseline characteristics: Median age 62.3 years (range 29.2-89.3), age ≥ 70 years n = 200 (28.7%), ECOG PS ≥ 2 n = 49 (7.0%), visceral metastases n = 511 (73.3%). The majority of pts received nab-P as 1st-line (n = 280, 40.2%) or 2nd-line (n = 169, 24.2%) chemotherapy. 194 pts (27.8%) received a 3-week schedule, 491 pts (70.4%) a weekly schedule, 12 pts (1.7%) other. In the overall population, median TTP was 5.9 months (95% CI 5.6-6.4), median OS 15.5 months (95 % CI 14.2-17.3). For pts ≥ 70 years median TTP was 6.9 months (95 % CI 5.7-8.5), median OS 14.8 months (95 % CI 12.6-18.8). In the 3-week group median TTP was 5.7 months (95 % CI 5.2-6.9), median OS 15.1 months (95 % CI 12.3-17.5). In the weekly group median TTP was 6.0 months (95 % CI 5.6-6.5), median OS 16.3 months (95 % CI 14.4-18.5). 34.3% of pts developed adverse events grade 3/4 including leukopenia (7.9%), peripheral sensory neuropathy (4.3%) and infections (4.2%). Further subgroup analyses will be presented. Conclusions: nab-P is an effective and safe therapy for pts with MBC in a real world setting. It is as effective in older women as it is in their younger counterparts. A weekly schedule could be a reasonable option.
Metastases from lobular breast cancer as an unusual source of GI bleeding.
Authors: Clarke Emily , George James , Dean Andrew Peter
Published: September 2018

e12557

Background: With the exception of malignant melanoma, metastases to the GI tract are rare, especially as a first presentation of malignancy. We report a series of patients with GI metastases from lobular breast carcinoma as an unusual source of symptomatic GI bleeding. Methods: We conducted an electronic database search to identify solid tumour patients (excluding melanoma) with metastases to the GI tract. We then analysed the database by tumour type. Results: 3 cases of proven metastasis to the GI tract were identified. All had lobular breast cancer metastases. The database contained 240 patients with breast cancer, identifying 63 with infiltrating lobular carcinoma, 2 with micropapillary and 175 with invasive ductal carcinoma The 1st case had had invasive ductal breast carcinoma 6 years previously and presented with fatigue and shortness of breath from anaemia. Colonoscopy revealed a polyp which was removed. Histopathology showed metastatic lobular breast carcinoma. Further investigation then confirmed an occult breast mass with identical pathology. The 2nd case presented with 18 months of abdominal pain, previous colonoscopy was normal. After onset of anaemia and 25kg weight loss, upper GI endoscopy showed a markedly thickened stomach with evidence of recent bleeding and biopsies confirmed metastatic lobular breast carcinoma. The 3rd case presented with abdominal pain, subsequent blood tests showing a raised CA125 with omental and ovarian masses. Surgical debulking showed metastatic lobular breast carcinoma, though no primary breast lesion was detectable with mammography, ultrasound and MRI. 3 years later, investigation of anaemia with colonoscopy showed a caecal polyp with histology confirming lobular breast carcinoma. Conclusions: Despite all common tumour types being represented in the database it is notable that all 3 cases with mucosal GI metastases had lobular breast cancer. Previous evidence suggests a long latent period from initial diagnosis of breast cancer to development of GI metastases however our report suggests it can occur earlier in the illness. Clinicians should consider this as a rare cause of GI bleeding and further research to understand the mechanism of mucosal metastasis in lobular breast cancer is needed.
Circulating miR-200c-3p as a marker of metastatic disease at diagnosis in breast cancer patients.
Authors: Navarro Manzano Esther , Luengo-Gil Gines , Garcia-Garre Elisa , Fernandez Perez Maria Piedad , Fernandez Sanchez Ana , Ivars Rubio Alejandra , de la Morena Pilar , Zafra Gema Marin , Garcia Martinez Elena , Martínez Alberto , Gonzalez-Billalabeitia Enrique , Ayala Francisco
Published: September 2018

e12559

Background: MicroRNAs are involved in cancer biology through their role in regulation of protein expression. The miR-200 family plays a dual role in breast cancer (BC), both regulating epithelial to mesenchymal transition and promoting metastatic colonization. Plasma levels of miR-200 have been previously evaluated as prognostic factors in early and metastatic BC (MBC) but its role as a potential diagnostic marker is less well established. The aim of this study was to determine the potential diagnostic value of miR-200c-3p plasmatic levels in women with locally advanced and metastatic BC. Methods: We included 73 BC patients and 14 controls. Plasma samples were obtained at diagnosis, before treatment. RNA from plasma samples was extracted with NucleoSpin miRNA plasma (Macherey-Nagel). We analyzed expression levels of miR-200c-3p, which were relativized (2-ΔΔCT method) to miR-16. Non-parametric statistical tests were used to determine the association of miR-200c levels with clinical variables. Receiver-operating curves (ROC) were constructed and diagnostic ability evaluated. Kaplan-Meier curves and Cox models were used for survival analyses. Results: 73 BC patients were included: 36 locally advanced BC (LABC) and 37 MBC (7 recurrences and 30 MBC at initial diagnosis [MBCID]). Plasma miR-200c levels were significantly higher in MBC than in controls (p = 0.001) and in LABC (p = 0.001). We found differences neither for age nor for estrogen receptors, HER2, tumor subtype or histology. Overall and disease free survival did not differ by miR-200c levels in any of the groups. Among MBC patients, higher levels were observed in MBCID (p = 0.023). In the group of women with an initial diagnosis of BC (n = 65), high miR-200c levels (over 1st tertile) identified metastatic disease with a sensitivity of 90.0% (95%CI: 72.3-97.4%) and a specificity of 51.4% (95%CI: 34.3-68.3%); negative predictive value: 85.7%; positive predictive value: 61.4%; ROC AUC: 0.79. Conclusions: MiR-200c plasma levels are higher in BC patients with metastatic disease at diagnosis, and might be clinically useful to identify them. Further research on miR200c biological role in MBC and validation in larger populations with sequential samples are warranted.
Long-term responders to first-line bevacizumab-based therapy in metastatic breast cancer (MBC) patients: Results of the observational study LORENA.
Authors: Ramos Vazquez Manuel , Redondo Andres , Manso Luis , Gil Miquel , Garau Isabel , Perez-Carrion Ramon , Garcia-Garre Elisa , Rodriguez Cesar Augusto , Chacon Jose Ignacio , Lopez-Vivanco Guillermo
Published: September 2018

e12563

Background: Randomized controlled trials in MBC patients evaluating bevacizumab as first-line treatment showed improvements in tumor response and progression-free survival (PFS) when added to chemotherapy. The aim of the LORENA study was to describe the clinical features, prognosis factors and safety of bevacizumab and chemotherapy treatment for MBC in routine practice. Methods: Observational, multicentre, ambispective study conducted in Spain. The study had a retrospective and a prospective phase. Data were obtained from March 2012 to October 2013. In the retrospective phase, eligible patients were women with metastatic or locally-advanced breast cancer, treated with bevacizumab as a first-line therapy, and progression-free survival for ≥ 12 months. In the prospective phase, patients were followed-up and assessed as per routine clinical practice. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Univariate and multivariate analyses of prognostic factors were performed. Results: 148 women from 38 centers were included. The mean age was 52 (±11) years. Bone, lung and liver were the most frequent metastasis sites. 138 patients were HER2-neg. on diagnosis (data unknown in 10 patients). The mean exposure to bevacizumab was 18 (±11) months. Most patients had objective response, 23% complete response, and 57% partial response. Median OS was 58.2 months and median PFS was 22.7 months. In multivariate analyses, OS was higher in patients with hormonal maintenance therapy (HMT) (p = 0.009; HR = 2.0) and in patients not treated with taxanes before the metastatic diagnosis (p < 0.0001; HR = 3.3); also, PFS was higher in patients with HMT (p = 0.002; HR = 1.8). No adverse events were observed other than those reported previously. Conclusions: Outcomes of OS and PFS suggest a benefit from bevacizumab maintained therapy. HMT was a PFS prognosis factor. HMT and not having been treated with taxanes before the metastatic diagnosis were two independent OS prognosis factors. Our results could provide further evidence supporting the use of bevacizumab as maintenance therapy for MBC patients.
A pilot phase II trial of cabergoline in the treatment of metastatic breast cancer.
Authors: Costa Ricardo Lima Barros , Santa-Maria Cesar Augusto , Scholtens Denise M. , Jain Sarika , Gradishar William John , Clevenger Charles V , Kaklamani Virginia G.
Published: September 2018

e12568

Background: The prolactin receptor can be overexpressed in breast cancer, and pre-clinical data indicate that it contributes to the pathobiology of breast cancer. Cabergoline is a potent dopamine receptor agonist of D2 receptors and has a direct inhibitory effect on pituitary prolactin secretion resulting in reduced serum prolactin levels. Methods: A pilot phase II study of cabergoline in patients with metastatic breast cancer was conducted with primary end point of best overall response rate (ORR) among patients with measurable disease. Eligible patients had metastatic breast cancer, any receptors status was allowed, and there was no limit of prior lines of therapy. Both measurable and unmeasurable diseases (RECIST 1.1) were allowed. Cabergoline 1mg orally, twice weekly (1 cycle = 4 weeks) was given until disease progression or unacceptable toxicity. Immunohistochemistry prolactin receptor staining was performed on available baseline tumor tissue, and serum prolactin levels were serially assessed. Results: A total of 20 women were enrolled, 19 of whom were evaluable for response (one patient died on C1D7 of unrelated causes). Mean age was 62 (range 42-83); 15 (75%) were Caucasian; mean number of prior lines of therapy 5 (range 0-14). Tumor receptor statuses were distributed as follows: HR+/HER2+ 1(5%), HR+/HER2- 18 (80%), HR-/HER2+ 1 (5%). Analysis was performed after a median follow-up of 6.8 months (0.2-26.2). Best ORR was 8.3% among 12 patients with measurable disease. Results for secondary endpoints were as follows: 4-month CBR = 26% (including patients with measurable and non-measurable disease), median PFS = 1.9 months, and median OS = 10.4 months. Most common treatment related AEs were nausea (30%), fatigue (25%), and elevation in alkaline phosphatase (15%). The highest-grade AE was a single grade 3 treatment-related pain in extremity. Nine patients had sufficient baseline tissue for analysis, there was no correlation between baseline tumor prolactin receptor expression and clinical benefit ( p= 0.24). Additional correlative work is ongoing. Conclusions: Cabergoline was well tolerated and associated with modest anti-tumor activity. Clinical trial information: NCT01730729.
Immunohistochemical (IHC) sub-classification of 105 triple negative breast cancers (TNBC).
Authors: Stacoffe Marion , Vinceneux Armelle , Arbion Flavie , Vegas Helene , Fromont Gaelle , Linassier Claude
Published: September 2018

e12577

Background: Molecular data have shown that TNBC was a heterogeneous group of tumors. The objective was to evaluate prognosis of IHC sub-classification adapted from molecular model. Methods: We used IHC sub-classification based on positivity for androgen receptor (AR) (Roche, SP 107), cytokeratine 5/6 (CK) (Dako, D5/16B4) and Epidermal growth factor receptor (EGFR) (Biosd, 31G7). Samples with more than 10% AR nuclear immunostaining were considered positive. Threshold for CK and EGFR was 1%. We distinguished 4 groups of tumors: AR phenotype (AR+, EGFR-, CK5/6-), basal-like phenotype (AR-, EGFR+/-, CK5/6 +/-), triple-negative phenotype (AR-, EGFR-, CK5/6-) and mixed group (AR+, EGFR+/-, CK5/6 +/-). Tissue micro-array blocks were constructed with samples from a retrospective cohort treated in adjuvant setting for non metastatic TNBC in a single institution from 2003 to 2013. Survival data were estimated by the Kaplan-Meier method and compared by the log-rank test in univariate analysis. Multivariate analysis including tumor size (T), lymph nodes status (N) and lymphovascular invasion (LVI) was performed using Cox model. Results: 105 patients were followed-up for a median period of 56.3 months [6-155]. Median age was 54 years [29-80]. 57.1% were stage pT1, 41.9% were pN+ and 37,1% presented LVI. 11 patients were classified as AR phenotype, 35 as basal-like, 46 as triple-negative phenotype and 13 as mixed group. 18 patients developed metastases: 3/11 AR, 5/35 basal-like, 6/46 triple-negative and 4/13 mixed group. No difference was observed between TNBC subgroups in terms of disease free survival DFS (p = .98) and overall survival OS (p = .86). T, N and LVI were the only prognostic factors (p = .05, p = .05 and p = .046 respectively). Conclusions: We found no impact of IHC sub-classification of TNBC. Correlation between IHC and molecular biology is in progress.
Efficacy and safety of eribulin in patients with triple negative metastatic breast cancer: Real life experience.
Authors: Manikhas Alexey , Kovalenko Elena , Manzyuk Valentina , Bolotina Larisa V , Zhilyaeva Larisa , Karabina Elena , Ponomarenko Dmitry
Published: September 2018

e12580

Background: Eribulin demonstrates improved overall survival compared to standard treatments, Her2-negative and TNBC patients have the most survival benefit. We sought to describe treatment patterns of eribulin and clinical outcomes among TNBC patients with advanced breast cancer treated in community oncology practices across the Russian Federation. Methods: Patients treated with eribulin anytime between January 1, 2014 and January 1, 2017 with a diagnosis of MBC were identified by providers within the Russia Oncology Research Center. Providers reviewed the health records (electronic or paper-based) and abstracted selected data points into an electronic case report form for each eligible patient. Results: A total 52 TNBC patients were considered by 10 providers. A median of age at start of eribulin was 47,5 (39-55) yrs and ECOG status 0-1 were assessed. Most of the pts (92,3%) had visceral mts, a median number metastatic disease regions was 2 (1-3). Eribulin was administered as the 1st and 2nd line of BC treatment to 14 (26,9%) pts, 3rd line – to 9 (17,3%), the 4thand later lines – to 29 (55,8%) pts. Objective response occurred in 5 (9,6%) pts. Stable disease registered in 24 (46,1%) pts. Median PFS was 3,0 months (95% CI 1,9-8,55). Overall the drug was well tolerated. The most common type of toxicity was hematologic. Neutropenia gr II was observed in 8 (15,4) pts and III-IV gr in 6 (11,5%), two cases of febrile neutropenia were registered. 4 (7,7%) pts experienced fatigue gr II. Peripheral neuropathy gr II was observed in 4 (7,7%) pts. Dose reduction due to toxicity was performed in 8 (15,4%) pts. Treatment was never withdrawn due to toxicity. Conclusions: This is the first real-life study of clinical outcomes, for patients initiating eribulin therapy for TNBC in community oncology practices throughout the Russian Federation. . Our experience with Eribulin in TNBC patients confirms it efficacy and safety in all lines of treatment, including intensively pretreated patients in this hard-to-treat population.
Association of family history and location of BRCA1 and BRCA2 mutations in triple-negative breast cancer patients.
Authors: Tan Yen Yen , Muhr Daniela , Rappaport-Fuerhauser Christine , Gschwantler-Kaulich Daphne , Grimm Christoph , Polterauer Stephan , Pfeiler Georg , Berger Andreas , Tea Muy-Kheng Maria , Singer Christian F.
Published: September 2018

e12588

Background: We assessed the prevalence of family history and its association with germline BRCA1/2mutation status/location and age at onset in triple-negative breast cancer (TNBC) patients. Methods: 266 patients with TNBC < 60 years unselected for family history of cancer were enrolled and germline DNA was sequenced to identify mutations. Family pedigrees were prospectively collected from these patients. Logistic regression was used to investigate family history and its association with mutation type/location and age at onset. ROC curves were constructed to determine good predictors of BRCAmutations. Results: BRCA mutations were identified in 18.0% of all patients (15.0% BRCA1, 3.0% BRCA2). BRCA1 carriers have a significantly earlier age at onset than non-mutation carriers (40 vs 49 years; p < .001). While 39/124 (31.4%) patients with family history of cancer carried a BRCA1/2 mutation, 9/142 (6.3%) BRCA carriers had no family history of cancer. BRCA1 carriers with ≥1BC in the family are commonly identified in the breast cancer cluster regions (53.1%). BRCA2 carriers more commonly cluster within the ovarian cancer regions. Of note, this difference was not statistically significant. Women with mutations in BRCA1 OCCR are diagnosed at a younger age. TNBC diagnosed ≤45 years with ≥1BC and ≥1OC in the family are good predictors of BRCA1 mutation (AUC 0.867). Conclusions: Young women with TNBC and a family history of BC and OC are likely to have a BRCA mutation. Specific BRCA mutation locations may add to the identification of a subgroup of TNBC patients with a relatively higher risk of subsequent ovarian cancer. Identification of high-risk TNBC patients with BRCA1 mutation will enable clinicians to optimize cancer management for this phenotype, but will require further validation in larger studies.
Parallel mutation screening and methylation quantification improves the molecular diagnostic yield for colorectal cancer.
Authors: Min Jun , Lan Xiaoliang , Qin Zi , Liu Xiaojie , Zhang Sufen , Nguyen John , Gore Athurva , Liu Rui , Liang Li
Published: September 2018

e13003

Background: Recurrent somatic mutations and methylation patterns have previously been identified as biomarkers for non-invasive screening of colorectal cancer (CRC). However, most clinical screening assays have focused on a limited number of genomic loci, potentially reducing sensitivity and specificity. Here, we examined the potential utility of using an expanded set of mutation and methylation markers to improve screening accuracy of CRC. Methods: Pairs of colorectal tumor and tumor-adjacent tissues were resected from 41 CRC patients in Nanfang Hospital (NFH), China. The DNA was extracted, processed, and sequenced with Singlera Genomics’ OncoAim assay, which detects mutations across 59 genes implicated in cancer and quantifies the methylation level for key CRC genes. Matched pre- or post-surgery plasma samples were also collected and processed in parallel. Results: Thirty-eight tumor samples (93%) contained somatic mutations with greater than 5% allele frequency, while twenty-nine tumor samples (71%) contained aberrant methylation patterns. Among the tumor-adjacent samples, six contained somatic mutations and eight contained epigenetic abnormalities. Out of three tumor samples without any detectable somatic mutations, one showed an aberrant methylation pattern. Importantly, aberrant methylation patterns in tumor samples were also detected in matched plasma samples. Conclusions: Parallel mutation screening and methylation analysis not only improves the diagnostic yield, but also paves the way for non-invasive monitoring on patients with no common mutations.
Pcarrier: Individual and family distributions of a susceptibility gene for breast and ovarian cancer based on family history.
Authors: Lefebvre Alexandra , de Pauw Antoine , Stoppa-Lyonnet Dominique , Nuel Gregory
Published: September 2018

e13005

Background: Most of the BRCA1/2 and PALB2 analyses performed in patients with a personal and familial history (FH) of breast/ovarian cancer are negative. In this context, there is no targeted analysis available to identify relatives at high risk (carrier of the causal hypothetical mutated gene). Thus, the recommendations of surveillance to all relatives are based only on the FH of cancer. At the Institut Curie we assess the degree of severity of the FH by calculating the probability of carrying a single autosomal dominant susceptibility gene without taking into account genotyping results but using the LINKAGE software with the parameters of the Claus-Easton model (1993). This reliable but old tool has a slow console interactive interface (roughly 15 min of clinicians time for each assessed family). Methods: We rewrite the model as a Bayesian network combining Mendelian genetics with classical survival analysis. All probabilistic computations are performed through belief propagation (sum-product algorithm) over real numbers or polynomials. The programming language is C++. Results: pCarrier is a modern and efficient implementation of the Claus-Easton model for clinicians with the following features: 1) fast non-interactive command line ( < 1s to process a previously registered family) combined with a graphical user-friendly interface; 2) computations dealing with monozygotic twins or loops without any human intervention (ex: loop breaking); 3) choice between the original discretized model (individual FH into 14 classes) and its continuous version (piecewise constant hazard); 4) marginal individual carrier distribution for all individuals in the pedigree; 5) joint distribution of the number of carriers among any group of individuals (ex: in the entire family, among the living only). Conclusions: pCarrier is experimented since January 2017 in the Institut Curie as a replacement of the existing tool and appears so far to be dramatically faster and easier to use for the clinicians, highly reliable (consistence with the existing tool), and able to provide new useful decision-making probabilities using the distribution of the number of carriers.
Oncologists’ use of tumor sequencing findings and patient derived benefit.
Authors: Gornick Michele Caroline , Cobain Erin Frances , Le Lan Q. , Stoffel Elena Martinez , Chinnaiyan Arul M. , Roberts J. Scott
Published: September 2018

e13016

Background: Despite increasing use of tumor genomic sequencing in clinical oncology, there is currently limited understanding of how oncologists interpret and apply this information to a patient’s clinical management. Methods: We surveyed oncologists who referred patients with refractory cancers to the Michigan Oncology Sequencing (MI-ONCOSEQ) program which uses integrative clinical sequencing to detect multiple classes of somatic and germline molecular aberrations including point mutations, amplifications, insertions/deletions, gene fusions, and outlier gene expression from June 2014-February 2015. Patients were also surveyed approximately 2 weeks after notification of completion of sequencing. In addition, we conducted chart reviews to ascertain how many patients’ clinical management was changed or derived clinical benefit as a result of sequencing. Results: Forty-three oncologists (37% female, 98% academic medical center practice), referring 112 patients ( M = 2, range: 1-9) completed the survey (response rate = 93%). Oncologists reported an intention to change 22% of patients’ treatment plans on the basis of sequencing results, with referral to a clinical trial (N = 12; 50%) as the most frequently endorsed intended change. However, few patients (N = 9, 38%) had an actual change in clinical management. Barriers identified included patient factors, ineligibility for identified treatment, and loss to follow-up/deceased. Of the 57 patients who completed post-sequencing surveys, 34 (60%) reported that results of sequencing had not been disclosed. However, patient records had documentation that results disclosure had indeed taken place in 41% of cases. Conclusions: Although expectation of enrollment in clinical trials is frequently proposed as the indication for genomic sequencing, practice barriers remain. These include lack of access to studies, severity of patient illness and challenges to effective communication of results.
A closer look at next generation sequencing (NGS) in breast cancer: A retrospective analysis.
Authors: Laderian Bahar , Sandoval Leon ANA CRISTINA , Alsharhan Loulwa , El Ashry Dorraya , Lippman Marc E.
Published: September 2018

e13023

Background: Targeted cancer therapy has been posited to revolutionize treatment paradigms in oncology. There are, a paucity of data regarding the use of NGS in breast cancer (BC). Herein we report our experience with NGS in a consecutive series of BC patients. Methods: Using an IRB approved protocol, we retrospectively identified patients with BC treated at the Sylvester Comprehensive Cancer Center (UMMSOM) who underwent NGS. Data were collected on demographics, tumor characteristics, genomic mutation profiles, and subsequent response to targeted therapy after 3 months. Results: Between January 2013 and April 2016, 101 BC patients underwent NGS. The mean age at diagnosis was 49. Ninety-one percent were stage IV, 6% were stage III, 2% were stage II, and 1% were stage I. Fifty percent had estrogen receptor (ER)+, HER2- tumors, 31% had triple-negative tumors, 13% had HER2+, ER+ tumors, and 6% had HER2+, ER- tumors. Ninety-six percent had at least one mutation, of which 78% had a targetable mutation. Sixteen patients received targeted therapy (TT). The average time between NGS and TT was 5 months ranging 0-22 months, during which seven patients received other systemic therapy. The most common reasons for not receiving TT were no actionable mutations (24%), not meeting criteria for an available clinical trial (14%), stable disease (SD) (13% ), lost to follow up (11%), physician decision (11%). Of the 16 patients who received TT, 7 patients had progression of disease, 3 died before response could be evaluated and presumably had no benefit, 2 discontinued TT due to side effects, 1 had SD, 1 had a partial response, and 2 were too early to be assessed. Conclusions: The majority of BC patients in our series had actionable mutations. However, TT was not offered to a significant number of patients for a multiplicity of reasons and the clinical benefit in those patients treated according to NGS findings was dismal. While NGS is surely a promising technology that should be utilized in combination with molecular tumor board, a host of reasons limit its usefulness at this time and its expense may well not justify its use outside of clinical trials.
A prospective study of stress, anxiety and depression response to undergoing genetic assessment at the time of ovarian cancer diagnosis.
Authors: Frey Melissa Kristen , Lee Sarah S. , Schwartz Zachary , Gerber Deanna , Martineau Jessica , Lutz Kathleen , Reese Erin , Dalton Emily , Pothuri Bhavana , Curtin John P , Blank Stephanie V.
Published: September 2018

e13024

Background: Genetic assessment (GA) is recommended for all women with ovarian cancer however little is known about the psychological implications of this intervention. We sought to evaluate the psychological response to GA in newly diagnosed ovarian cancer patients as part of our facilitated genetics referral pathway. Methods: English-speaking patients with ovarian cancer undergoing GA at the time of cancer diagnosis completed three validated anxiety, stress and depression survey instruments immediately prior to and following GA and again 6-9 months after GA. Results: Forty-eight English-speaking patients underwent GA; 43 (90%) completed the pre-GA survey, 32 (67%) post-GA survey and 11 (23%) 6-9 months follow-up survey. Eight patients (17%) had documented psychiatric diagnoses (5 anxiety, 2 depression, 1 anxiety+depression) prior to cancer diagnosis. Overall, patients demonstrated mild to moderate stress, clinically significant anxiety and borderline depression (Table 1). There was no change in depression, anxiety or stress scores when comparing pre- to post-GA surveys. Age, stage, method of treatment, performance status at enrollment and history of psychiatric disorders were not associated with anxiety, stress or depression. Conclusions: A genetic testing pathway whereby GA is encouraged and facilitated at the time of diagnosis has not increased patient depression, anxiety or stress in our cohort. Concern about causing additional emotional distress should not deter clinicians from early genetics referral. [Table: see text]
Molecular profiling of cancer outliers.
Authors: Jung Kyungsuk , Bilusic Marijo , Pei Jianming , Slifker Michael , Zhou Yan , Flieder Douglas B , Gray Phillip , Plimack Elizabeth R.
Published: September 2018

e13025

Background: A few patients with metastatic cancer survive exceptionally longer than others under the same treatment. We hypothesized that there is a specific biologic signature in genetic profiles of long-term survivors that plays a key role in sensitivity to systemic treatment. Methods: Twenty-six patients with metastatic cancer treated at Fox Chase cancer center with exceptional response were included in the study. Exceptional response was defined as complete response > 1 year or stable disease/partial response > 2 years at any time during the disease course. Archived tumor specimens of 16 patients were sequenced and analyzed using Ambry Genetics 142 gene panel. In addition, genes expressions in tumor tissues from 23 exceptional responders and 23 matched controls (age, sex and tumor type) were analyzed using two NanoString nCounter PanCancer panels (Pathway and Immune Profiling). Results: See Table. Conclusions: Multiple common mutations of NOTCH2, NF1, FANCD2, PIK3CB and EPHA5 were found in tumors that responded exceptionally well to treatments. Additionally, certain genes were significantly over-expressed or under-expressed in these tumors compared to matched controls. Underlying mechanisms that these genetic alterations foster, leading to susceptibility to treatment and prolonged patient survival, should be further studied. [Table: see text]
Differences in the immune microenvironment and genomic characteristics of TNBC in African American women compared to other races.
Authors: Szekely Borbala , Safonov Anton Mikhailovich , Karn Thomas , Bhagwagar Sanaea , Killelea Brigid K. , Silber Andrea , Hatzis Christos , Pusztai Lajos
Published: September 2018

e13028

Background: African American (AA) women are more likely to be diagnosed with triple negative breast cancer (TNBC) compared to other races and have lower pathologic complete response rate to neoadjuvant therapy. Our goal was to assess differences in the immune microenvironment and genomic characteristics of TNBC by race using the TCGA data set. Methods: We compared the expression levels of 13 previously reported immune metagenes (CTL, Mphages, MHC1, Tregs, IF1, NK, STAT1, MHC2, Giam, Tfh, Tinh, Tstim, LCK), histologic tumor infiltrating lymphocyte (TIL) count and overall mutational load, neoantigen load, clonal heterogeneity assessed using the MATH score, amplification and deletion loads of between AA (n = 58) and non-AA TNBC (n = 114). Data was downloaded from the TCGA website, immune metagene expression and MATH scores were calculated as previously reported. Distributions between cohorts were compared using the Mann-Whitney U-test. Results: Among the immune metagenes only the cytotoxic T cell (CTL) metagene showed lower expression in AA patients (3.64 versus 4.08, unadjusted p = 0.046). TIL count was available in 51 of 58 AA and 91 of 114 of non-AA cases, and no significant difference was observed between the racial groups (p = 0.55). We also did not observe statistically significant differences in the mutational load (p = 0.36), neoantigen load (p = 0.38), clonal heterogeneity represented by the MATH score (p = 0.54), and amplification and deletion loads (p = 0.23 and 0.83 respectively) between the two TNBC race groups. We also assess the expression distribution of the immune signatures in an independent Affymetrix gene expression dataset including 40 AA and 323 non-AA patients with TNBC. Similar to the TCGA, there were no significant race differences in the immune signatures, including in the CTL metagene. Conclusions: These results suggest that the differences in prevalence and treatment response seen between TNBC in AA and non-AA patients are unlikely to be due to differences in the immune microenvironment and the genomic landscape of TNBC. However, more subtle comparison in the immune biology of these cancers can only be studies with more focused methods.
Screening for antineoplastic ionic liquids by targeting RLIP76.
Authors: Khan Muhammad Saad , Hardwicke Fred L. , Igid Henry Palangdao , Kaleem Hassan , Awasthi Sanjay , Armstrong Daniel
Published: September 2018

e13033

Background: RLIP76 is a stress-responsive multispecific transporter which functions as an anti-apoptotic protein in cancer cells. The targeting of RLIP76 by antibodies, antisense, or siRNA modalities causes complete regression of cancers such as melanoma, colon cancer and lung cancer. We carried out studies to determine whether the ATPase activity of purified recombinant human RLIP76 protein (encoded by RALBP1, chromosome 18p11.22) can be used to screen for novel ionic liquid compounds with antineoplastic activity. Methods: A series of ionic liquid compounds were tested for their ability to inhibit or activate the ATPase activity and doxorubicin transport activity of purified recombinant human RLIP76. The growth inhibitory effects of these compounds were monitored in human non-small cell lung cancer cell line NCI H358, with human aorta vascular smooth muscle cells serving as non-malignant controls. Results: ATPase activation correlated with doxorubicin transport inhibition. More importantly, the antineoplastic activity towards lung cancer cells was also correlated with degree of ATPase activation or transport inhibition. Cytotoxicity towards the non-neoplastic cell line was 1-2 orders of magnitude less than observed for the lung cancer cells, a characteristic of other agents that target RLIP76. The predicted antineoplastic effect was confirmed in H358 xenografts in nude mice. Conclusions: These studies indicate the potential utility of screening for antineoplastic agents using recombinant RLIP76 and also demonstrate antineoplastic activity of a novel ionic liquid compound.