bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II trial of metronomic capecitabine and cyclophosphamide with lapatinib and trastuzumab in patients with HER2-positive metastatic breast cancer.
Authors: Kang Irene , Spicer Darcy V. , Lu Janice M. , Groshen Susan G. , Tsao-Wei Denice , Garcia Agustin A. 
Published: May 2019

e12508 Background: Metronomic chemotherapy is an emerging paradigm of cancer therapy in which low doses of chemotherapy are delivered at frequent intervals. Activity in patients with metastatic breast cancer (MBC) has been demonstrated in several phase II clinical trials. Methods: We proposed a regimen with metronomic chemotherapy and dual HER2 inhibition in HER2 positive patients with MBC. We hypothesized that this regimen will be highly active in MBC and have a favorable toxicity profile. Patients were treated on a 21-day cycle with capecitabine 1500mg PO daily, cyclophosphamide 50mg daily, lapatinib 1000mg PO daily and trastuzumab 6mg/kg IV once per 21-day cycle. This regimen was continued until disease progression or unacceptable toxicity. Primary endpoint was progression free survival (PFS). Secondary endpoints were overall response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and safety and tolerability of this regimen. Eligibility criteria were patients 18 years of age and older who had histologically confirmed HER2-positive metastatic breast cancer with prior trastuzumab use in the adjuvant or metastatic setting with no more than two prior regimens for MBC. Results: Ten patients were accrued from Jan 2014-Oct 2016. Median age was 52 (range 38 - 79) years. Median number of chemotherapy regimens for metastatic disease was 0.5 (range 0-2). Median PFS was 13.7 (95% CI: 2.6, 16.6) months. Median OS was 29.6 (95% CI: 11.8, 60.5+) months. ORR was 30%, and CBR was 70%. Grade 3 or 4 toxicities were identified in 6 patients. The most common toxicities of any grade were fatigue (100%), diarrhea (80%), anemia, neutropenia, ALT increase, nausea and hand-foot syndrome 50% each. One patient achieved CR for over 3 years and continues on treatment at time of this report. 8 patients progressed and 1 patient withdrew from study without response evaluation. The trial was closed due to lack of accrual. Conclusions: The proposed regimen of metronomic capecitabine and cyclophosphamide with lapatinib and trastuzumab appears to be active in patients with HER2 positive MBC but with significant toxicity. Clinical trial information: NCT01873833.
Drug-related pneumonitis during everolimus therapy in patients with metastatic breast cancer: Incidence, radiographic findings, and correlation with clinical outcome.
Authors: Gong Chengcheng , Xiao Qin , Hu Xi-Chun , Gu Yajia , Wang Biyun 
Published: May 2019

e12519 Background: Everolimus (EVE) in combination with endocrine therapy are approved for the treatment of HR+/HER2- metastatic breast cancers (MBC) patients. mTOR inhibitor-associated pneumonitis is one of the most worrying and common adverse drug events leading to treatment discontinuation. We investigated the incidence of drug-related pneumonitis (DRP) during EVE therapy in MBC patients and characterize radiographic patterns and clinical impact of pneumonitis. Methods: We retrospectively reviewed the data of MBC patients treated with EVE in Fudan University Shanghai Cancer Center from June 2013 to June 2017, who had baseline and at least one follow-up chest CT available for review (NCT 03730428). Serial chest CT scans were reviewed for abnormalities suspicious for DRP by an independent review of two radiologists. Log rank and Cox proportional hazards regression analysis were used for the time-to-event analysis. Results: DRP was radiographically detected in 45/86 patients (52.3%). Over 80% of DRP occurred in the first 4 months of treatment (cumulative risk 52.3%). Most patients with DRP were asymptomatic (n = 31, 68.9%). Among 14 patients with clinical manifestation, common symptoms included cough, fever and shortness of breath. DRP mostly distributed in bilateral lower lobes. Ground glass opacities and reticular opacities were seen in most of the cases. Elderly patients (OR 1.09, p = 0.002) and patients with baseline pneumonitis (OR 3.96, p = 0.023) are more likely to develop DRP. Patients who developed DRP had significantly longer progression free survival (median 6.8 vs 4.1 months, p = 0.024) and overall survival (OS, median 42.8 vs 21.3 months, p = 0.016). DRP was a predictor of improved OS by multivariate Cox analysis (HR 0.49, 95%CI 0.25-0.97, p = 0.040). Conclusions: DRP was noted in half of the MBC patients treated with EVE. Our preliminary data suggested that DRP would be a predictor for better outcome, which should be further investigated. Given the incidence and outcomes of patients with DRP, close monitoring, prompt diagnoses and appropriate treatment for DRP are critical for the preservation of patients’ quality of life and achievement of maximal treatment outcomes.
17-β estradiol promotes autophagy and induces cellular senescence in breast cancer cells.
Authors: Bajbouj Khuloud , Shafarin Jasmin , Hamad Mawieh 
Published: May 2019

e12523 Background: The fact that estrogen (17-β estradiol or E2) is a known carcinogen notwithstanding, mounting evidence suggest that E2 has the potential to exert anti-cancer effects against various forms of cancer. Using in vitro models we, and others, have previously demonstrated that E2 disrupts intracellular iron metabolism in such a way that arrests cell cycling in breast and ovarian cancer cells. However, the cellular and molecular correlates underlying this cytostatic effect of E2 in cancer cells remain elusive. Methods: In this study, metastatic (MDA-MB-231) and non-metastatic (MCF-7) breast cancer cells treated with 20 nM E2 were assessed for mitochondrial function, cell proliferation, apoptosis and senescence at different time points post treatment. Results: E2 treatment resulted in a significant mitochondrial membrane depolarization; an outcome that associated with a significant loss of mitochondrial function and the accumulation of auto-phagosomes. It also significantly upregulated the expression of the cell cycle regulating cyclin-dependent kinase inhibitor, p21 protein and enhanced the activation (de-phosphorylation) of the tumour suppressor retinoblastoma (Rb) protein. Although, as previously shown, E2 did not induced classis apoptosis; it resulted in a significant elevation in senescence-associated β- galactosidase levels. Conclusions: In summary, these findings suggest that E2 treatment mediates its anti-cancer potential by disrupting mitochondrial function and precipitating autophagy and cell senescence.
Tumor mutational burden and spectrum in hormone receptor-positive breast cancer patients from India.
Authors: Minhas Sachin , Bhalla Sunita , Veldore Vidya , Ganvir Madhusudan , Ramprasad VL , Aggarwal Shyam 
Published: May 2019

e12524 Background: Breast cancer is the most common type of cancer found in females in India. Moreover, more than 50% of the breast cancers in India are found to be hormone receptor positive (HR+). In this research we calculated the Tumor Mutational Burden (TMB) and studied the spectrum of mutations in HR+ breast cancer patients from India. Methods: Thirty five patients of HR+ breast cancer were enrolled in this study. Their FFPE tumor DNA was subjected to hybrid capture-based NGS assay which provided a comprehensive coverage of 170 key cancer-related genes. TMB was measured as the total number of non-synonymous coding mutations per megabase (mutations/MB). Results: Almost 50 percent (seventeen out of thirty five) of samples were found to be having either high or very high mutational burden with TMB values ranging between 148.84/MB to 734.65/MB. Nine out of thirty five samples had medium mutational burden with TMB values ranging between 59.15/MB to 137.39/MB and an equal number of samples were found to be having low mutational burden with TMB values ranging between 15.26/MB to 53.43/MB. Furthermore, we also made some interesting observations with respect to the mutational spectrum of these tumors. The most frequently mutated genes were PIK3CA and TP53. We also discovered BRCA1 and BRCA2 mutations in our study population which was a notable observation as BRCA mutations occur rarely in HR+ breast cancer in other populations of the world. The complete list of genes found to be mutated in our population is given in table. Conclusions: These preliminary results show that a substantial number of HR+ breast cancer patients could have high mutational burden. Recent clinical trials like KEYNOTE-028 suggest that such patients may get benefit from immune checkpoint inhibitor drugs. These results indicate that the Indian population has a higher TMB and a slightly different mutation spectrum compared to the other populations of the world. The study also indicates that generalizations regarding the use immunotherapy in different populations should not be made as the genetic make-up of every global population is slightly different and unique. Thus, there is a need to conduct studies like this in a much larger and different populations of the world. [Table: see text]
REACHAUT: First-line (1L) ribociclib (RIB) + endocrine therapy (ET) in HR+, HER2- metastatic breast cancer (MBC) in the real-world setting.
Authors: Singer Christian F. , Öhler Leopold , Egle Daniel , Greil Richard , Petru Edgar , Balic Marija , Marhold Maximilian , Pfeiler Georg , Brunner Christine , Kwasny Werner , Galid Arik Armon , Tinchon Christoph , Eisterer Wolfgang , Haslbauer Ferdinand , Hubalek Michael , Redl Andreas , Hock Karin , Hennebelle Mathias , Mraz Bernhard , Steger Guenther G. 
Published: May 2019

e12527 Background: RIB + aromatase inhibitor (AI) is approved as 1L treatment (tx) for HR+, HER2− MBC. Real-world data on efficacy and safety of RIB+AI are limited. REACHAUT, a prospective, noninterventional trial assessed the safety of RIB+AI in 1L setting in postmenopausal patients (pts) with HR+, HER2− MBC in a real-world setting. First interim analysis results about safety are presented. Methods: 75 postmenopausal pts with HR+, HER2− MBC, QTc < 450 msec, and no prior ET for advanced disease were enrolled at 13 sites. 1L chemotherapy (CT) was allowed. Results: At data cutoff (25-Jan-2019), 61 pts were evaluable for safety (ongoing, n = 44; discontinued, n = 17). Median duration of follow-up was 29 d. Median age at baseline was 65 y ( < 65 y, n = 28; ≥65 y, n = 33); ECOG performance status was 0 (n = 39) and 1 (n = 12). 42.6% had visceral (lung, liver) metastases (mets), while 34.4% had bone only mets. Most common prior tx included CT (29.5% in neoadjuvant/adjuvant/metastatic setting) and ET (41%). Pts received RIB in 1L (93.4%) and second-line (6.6%) setting. In 80.3% pts receiving RIB, the ET partner included letrozole (57.4%), exemestane (11.5%), anastrozole (9.8%). Median duration of RIB exposure was 100 d. Median time to first AE was 14 d. 83.6% pts experienced AEs with mild (63.9%) to moderate (50.8%) severity. Serious AEs were noted in 6.6% pts. Most common AEs were neutropenia (42.6%) and QTc prolongation (24.6%). 4.9% pts had hepatobiliary AEs. Due to AEs, dose adjustments (4.9%) and dose interruptions (19.8%) were needed. No deaths were reported; median PFS was not reached. Subgroup analysis by age ( < 65 y vs ≥65 y) showed that the incidence of AEs was 55.9% vs 44.1%. Neutropenia was reported in 46.4% pts aged < 65 y vs 39.3% pts aged ≥65 y; QT prolongation events were noted in 21.4% pts aged < 65 y vs 27.2% pts aged ≥65 y. Dose adjustments and dose interruptions were needed in 14.3% and 46.4% pts aged < 65 y vs 15.2% and 45.5% pts aged ≥65 y. Conclusions: Overall safety of RIB+AI in routine clinical practice in REACHAUT was consistent with that reported in the MONALEESA-2 study. In real-world setting, pt age ( < 65 y vs ≥65 y) had minimal impact on AEs. Clinical trial information: NIS006622.
Different maintenance strategies versus observation in patients with hormone receptor-positive metastatic breast cancer after first-line chemotherapy: A real-world study and meta-analysis.
Authors: Hong Huangming , Wang Ying , Yu Yunfang , Li Chenchen , Ren Wei , Tang Jun , Ye Guolin , Yao Herui 
Published: May 2019

e12529 Background: Current guidelines lack definitive evidence regarding the clinical outcomes associated with different maintenance strategies for hormone-receptor (HR) positive metastatic breast cancer (MBC). We aimed to evaluate different maintenance modalities after first-line chemotherapy in this setting. Methods: We conducted a multicenter real world study to compare maintenance chemotherapy, endocrine therapy and observation in patients with HR positive MBC who achieved disease control after first-line chemotherapy. The primary endpoint was overall survival (OS), secondary endpoint was progression-free survival (PFS). We further examined the results from fourteen multicenter prospective studies in a meta-analysis. Results: A total of 928 patients were enrolled in the real world study. The median age was 48 years (range, 18 to 76 years). Of these patients, 269 received chemotherapy, 330 received endocrine therapy and 329 received observation as their maintenance treatment. OS was significantly longer in the chemotherapy group and endocrine therapy group than in the observation group (median 33.0 vs 36.0 vs 19.0 months, respectively, P < 0.001), as was PFS (median 12.0 vs 14.0 vs 8.0 months, respectively, P < 0.001). However, there was no significant difference of OS between chemotherapy group and endocrine therapy group (HR, 0.947, 95% CI: 0.743-1.207, P = 0.656), so did PFS (HR, 0.969, 95% CI: 0.787-1.194, P = 0.765). In the meta-analysis of all cohorts (2706 participants), maintenance endocrine therapy provide similar PFS and OS compare with chemotherapy, but with lower odds of G1-G2 adverse events. Conclusions: Our study provided strong evidence for OS and PFS benefits of maintenance therapy over observation after first-line chemotherapy in HR positive MBC patients. Maintenance endocrine therapy was noninferior to chemotherapy with less treatment-related toxicity, which was worthy of a clinical recommendation.
Mixed invasive ductal-lobular carcinoma: Clinicopathological characterization and clinical outcomes.
Authors: Nasrazadani Azadeh , Li Yujia , Tseng George , Xavier Jennifer , Hugar Sarah , Lee Adrian V. , Lucas Peter C. , Jankowitz Rachel Catherine , Oesterreich Steffi , McAuliffe Priscilla F. 
Published: May 2019

e12531 Background: Mixed Invasive Ductal-Lobular Carcinoma (IDC-L) is a histological subtype of invasive breast carcinoma comprised of both ductal and lobular morphologies. There is limited information on the relative proportions of the individual components in IDC-L and on outcomes compared to invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC). Methods: Clinical information was abstracted from 16,308 patients with invasive breast cancer seen at UPMC Magee Women’s Hospital from 1990-2017 using the UPMC Network Cancer Registry. A systematic chart review was performed on a subset of patients annotated with IDC-L (n=806); however, a thorough review of pathology reports led to the exclusion of all but 408 patients for further analysis, due to the lack of a standardized definition of IDC-L. Of the 408 cases, 92% were estrogen receptor (ER)+. Survival of patients with ER+ IDC-L (n=376) was compared to ER+ IDC (n=9,716) and ER+ ILC (1,465). For a subset of IDC-L cases (n=54), distributions of individual subtype components were abstracted from pathology reports. Results: IDC-L made up 2.5% of the total cases (408/16,308). IDC-L tumors were on average 31% ductal and 69% lobular (p =0.001). Survival analysis showed worse disease free survival (DFS) (p=0.05) and overall survival (OS) (p=0.002) in patients with ER+ ILC compared to ER+ IDC, with ER+ IDC-L patients showing a median OS superior to ILC yet inferior to IDC counterparts (ns). Conclusions: Identification of patients with IDC-L through cancer registry protocols representative of standard practices by national cancer registries revealed a lack of a standardized definition of mixed IDC-L. Reliance on accuracy of these diagnoses calls in to question the reliability of prior clinico-pathologic analyses reported on this topic. DFS and OS of IDC-L patients falls between that of IDC and ILC patients while ILC patients showed significantly worse outcome. The predominant distribution of lobular morphology in IDC-L tumors suggests this subtype may have additional characteristics similar to lobular rather than ductal carcinomas. Comprehensive clinical and molecular characterization of a carefully identified IDC-L cohort is underway.
CDK 4/6 inhibitors (CDKi) + endocrine therapy (ET) in ER-positive metastatic breast cancer (mBC) patients according ET sensitivity: A systematic review and meta-analysis.
Authors: Piezzo Michela , Riemma Maria , Cianniello Daniela , Caputo Roberta , Fusco Giuseppina , Di Gioia Germira , Cerillo Ivana , Licenziato Marina , Buonfanti Gaetano , Cocco Stefania , Di Lauro Vincenzo , De Laurentiis Michelino 
Published: May 2019

e12532 Background: Addition of CDKi to ET in ER-positive mBC has proven effective in improving both progression-freesurvival (PFS) and Objective Response Rate (ORR). However, no randomized clinical trial (RCT) has so far shown a significant increase of Overall Survival (OS). We carried out a metanalysis of all RTCs to better characterize the efficacy of CDK4/6i in some relevant subgroups, with particular reference to OS. Methods: Literature search of main databases was carried out up to 08 Dec 2018. Hazard ratios (HRs) for PFS and OS and risk ratios (RRs) for ORR were extracted/calculated for each trial and then pooled by using both fixed and random effect model. Confidence intervals (CIs) at 95% were calculated for each statistics. Kaplan-Meier meta-curves were generated by pooling data of all trials, among ET sensitive and ET resistant pts. Results: Eight RCTs were included accounting for a total of 4580 pts, 2802 receiving a CDKi (palbociclib, ribociclib or abemaciclib) in association with ET (NSAI, tamoxifene or fulvestrant) and 1778 receiving ET alone or plus placebo. Pooled analysis of HRs showed a significant improvement in PFS, regardless ET sensitivity, disease site, number of metastatic sites and treatment free interval. Analysis of OS included 3 RCTs with a total of 1243 pts and showed a statistically significant improvement of OS (HR 0.769 [95% CI 0.638, 0.926], p-value 0.006). Pooled estimate for RR showed higher ORR in CDK 4/6 arm both in ET sensitive (RR 1.35 [95% CI 1.19, 1.52]) and ET resistant group (RR 2.19 [95% CI 1.66, 2.89]). Similarly, pts with measurable disease showed a RR of 1.34 (95% CI 1.20, 1.50) in ET sensitive group and 2.26 (95% CI 1.72, 2.96) in ET resistant group. Pooled survival curves showed an absolute benefit in PFS, both in ET sensitive (median PFS: NR vs 15 months) and ET resistant (median PFS: 19.2 vs 8.9 months). Conclusions: Our findings suggest that addition of CDKi to ET improve clinical outcome in terms of PFS, ORR and OS, irrespective of pts/tumor characteristics.
Prognostic values of cell free DNA, CA 15.3, and ESR1 circulating mutations variations in hormone receptor (HR)-positive metastatic breast cancer (MBC) patients under aromatase inhibitor (AI).
Authors: Augusto Laetitia , Beaussire Ludivine , Lequesne Justine , Perdrix Anne , Sefrioui David , Fontanilles Maxime , Leheurteur Marianne , Di Fiore Frédéric , Sarafan-Vasseur Nasrin , Clatot Florian 
Published: May 2019

e12534 Background: Circulating cell free DNA (cfDNA), CA 15.3 and circulating tumor DNA (ctDNA) have been associated with survival in MBC. These 3 biomarkers have never been compared. Methods: We retrospectively included all patients treated in our center between 2010 and 2012 for a HR+ MBC, who had clinical progression during the first line of aromatase inhibitor (AI) and available plasma samples. CfDNA level (ng/mL), CA 15.3 level (U/mL) and ESR1 circulating mutation level (Y537N, Y537S, Y537C and D538G, identified by ddPCR) were determined at time of clinical progression (Tp) and 3 months before (Tp-3). Biomarkers values at Tp and Tp-3 as well as their variations were analyzed according to clinical progression and overall survival (OS). Results: 91 patients were analyzed. CA 15.3 was elevated ( > 30 U/mL) in 71/91 (78%) at Tp and 62/91 (68%) at Tp-3. Higher CA 15.3 was associated with worse OS, especially at Tp (HR = 1.0006/unit at both times, p = 0.009 at Tp; p = 0.08 at Tp-3). Higher cfDNA was associated with worse OS, both at Tp and Tp-3 (HR = 1.006/unit, p < 0.0001 and HR = 1.007/unit, p = 0.02, respectively). An ESR1 mutation was detected in 14/91 at Tp-3 (15%) and 28/91 at Tp (31%). ESR1 mutation detection was strongly correlated with OS both at Tp and Tp-3 (HR = 2.4, p = 0.0005 and HR = 1.97, p = 0.03, respectively). Between Tp-3 and Tp, overall median CA 15.3 and ESR1 mutation level increased (p < 0.0001 and p = 0.007, respectively) and were related to poorer OS (HR = 1.007/unit, p = 0.0002 and HR = 3.1, p = 0.05). In contrast, CfDNA was not correlated at all with clinical progression (36/91 increase, 36/91 decrease, and 19/91 stable cfDNA). ROC curve analysis identified a 59% CA 15.3 increase as the best cut-off for predicting progression, but with poor performance (AUC = 0.64). Multivariate analysis showed that CA 15.3 at Tp (HR = 1.0006/unit, p = 0.006), cfDNA at Tp (HR = 1.005/unit, p = 0.01), ESR1 detection at Tp (HR = 2.7, p = 0.0002) and CA 15.3 increase between Tp-3 and Tp (HR = 1.006/unit, p = 0.003) were associated with poor OS. Conclusions: All 3 biomarkers are correlated with OS in MBC treated with AI. CfDNA variation is poorly related to clinical progression while CA 15.3 variation or ESR1 mutation detection are much more reliable. Overall the better performance is observed with ESR1 mutation detection.