bluuebunny/crossref_metadata_2025_split huggingface dataset:
New potential therapeutic-sequence strategies of TDM1 in the revolutionary era of metastatic HER2-positive breast cancer treatment: A monocentric retrospective experience.
Authors: Sanò Maria Vita , Castellana Luisa , Caffarelli Silvia , Fallica Giuseppa , Chiarenza Maurizio , Ali Marco , Dimarco Rosanna , Vita Maria Grazia Di Leo , Picone Antonio , Aiello Rosa Anna , Caponnetto Domenica , Casella Tiziana , Caruso Michele 
Published: May 2020

e13014 Background: EMILIA study showed benefits in terms of both progression free survival (PFS) and overall survival (OS) administering Ado-trastuzumab emtansine (T-DM1) vs lapatinib-capecitabine in HER2+ mBC patients (pts) treated at least with a previous trastuzumab-taxane-based therapy. However a paucity of data is available on TDM1 efficacy after dual anti HER2 blockade with pertuzumab and trastuzumab (PT). Instead TH3RESA trial revealed the positive impact on OS of T-DM1 also in heavily pre-treated (at least 2 lines of T, lapatinib and taxanes regimens) pts. We conducted a retrospective analysis reporting innovative findings on the sequence of anti-HER2 treatments and how it could be potentially optimized. Methods: Between June 15, 2014 and January 31, 2020 we identified HER2+ (IHC: 3+ or 2+/FISH amplified) mBC pts treated with T-DM1, either as second-line after progression on dual blockade PT (Cohort PT) or after ≤ 3 anti her2-combined regimens (trastuzumab o lapatinib plus chemotherapy) (Cohort T). 74 pts received T-DM1: Cohort T n = 34 (all females, median age = 52,7), Cohort PT n = 40 (39 females, 1 male, median age = 52,2). Within Cohort T: 64,7 % of pts (n = 22) received T-DM1 after 1 previous anti her2-combined regimen, 20,6 % (n = 7) and 14,7 % (n = 5) in third and fourth lines, respectively. Instead, the whole Cohort PT received second line T-DM1 after pertuzumab/trastuzumab. Results: Median progression- free survival was 10,2 in Cohort T and 3,7 months in Cohort PT. As regards the best response rate, 8,8 % (n = 3/34) and 52,5 % (n = 21/40) of pts reported a progressive disease (PD) into the Cohorts T and PT, respectively: stable disease (SD) 38,2 % (n = 13/34) versus 15 % (n = 6/40); partial response (PR) 23,5 % (n = 8/34) vs 15 % (n = 6/40); complete response (CR) 23,5 % (n = 8/34) vs 12,5 % (n = 5/40). Almost 2/3 (n = 21/34) of Cohort T and half (n = 20/40) of Cohort PT pts had a 3+ IHC status. Conclusions: Our data suggest a lower efficacy of T-DM1 after progression on dual HER2-blockade PT. After all, EMILIA trial did not robustly evaluate the role of T-DM1 in this specific subset of pts. Obviously, larger prospective studies are necessary in order to optimize the best sequence strategy in the treatment of metastatic HER2+ BC, in light of the increasingly innovative anti-HER2 agents.
Real-world effectiveness of post-T-DM1 treatments in HER2-positive metastatic breast cancer: KBCSG-TR1917 observational study.
Authors: Masuda Norikazu , Yoshinami Tetsuhiro , Yasojima Hiroyuki , Kittaka Nobuyoshi , Takahashi Masato , Ohtani Shoichiro , Kim Seung Jin , Kurakami Hiroyuki , Yamamoto Naoko , Yamada Tomomi , Takata Takehiko , Nakayama Takahiro 
Published: May 2020

e13020 Background: For patients with HER2-positive, unresectable and/or metastatic breast cancer (HER2+ mBC), T-DM1 is now the standard of care after trastuzumab and/or pertuzumab-based therapy. On the other hand, there is limited evidence after T-DM1 treatment. To clarify the treatment options and the effectiveness of drug therapy just after T-DM1 (post–T-DM1 therapy), we performed a multicenter observational study in patients with HER2+ mBC. Methods: This study enrolled consecutive patients who met eligibility criteria; Japanese female patients with HER2+ mBC, 20 years of age or older, who received at least one subsequent drug treatment except for an investigational drug after discontinuing T-DM1 between Jan 2014 and Dec 2018. To investigate the effectiveness of post–T-DM1 therapy, the real-world progression-free survival (rwPFS), time to treatment failure (TTF), overall survival (OS), objective response rate (ORR) and clinical benefit rate (CBR) were evaluated. Tumor response was exactly assessed by investigators according to RECISTv1.1. Results: Of 205 patients who were treated with T-DM1 at five institutions, 138 patients were enrolled and 128 patients were included in the analysis (data-cut off: Jul 31 2019). The median age of the patients was 59 years (range 27–84), and the median duration of T-DM1 treatment was 5.1 months (range 0.0–41.4). Ninety-two patients (71.9%) had an ECOG PS score of 0 or 1. Of the 128 patients, 34 (26.6%) patients received lapatinib + capecitabine therapy, 35 (27.3%) trastuzumab-based therapy (excluding pertuzumab), 36 (28.1%) pertuzumab-containing therapy, and 23 (18.0%) other therapy except for anti-HER2 therapy. In the 111 patients with measurable lesions, ORR was 22.5% (95% CI: 15.1–31.4). The median rwPFS was 5.7 months (95% CI: 4.8–6.9), median TTF 5.6 months (95% CI: 4.6–6.4), median OS 22.8 months (95% CI: 18.2–32.4), and the CBR was 47.7% (95% CI: 38.8–56.7) in the 128 patients. Conclusions: We clarified that the effectiveness of post–T-DM1 therapy was limited among the current standard treatment options. Therefore, to improve the prognosis in the later settings of HER2+ mBC, novel treatment options are warranted in the future. Clinical trial information: UMIN000038296 .
Metastasis by semi-quantitative oestrogen receptor expression in stage I-III early diagnosed triple positive breast cancer patients.
Authors: Van de Kerkhof Jasmine , Floris Giuseppe , Desmedt Christine , Laenen Annouschka , Slembrouck Laurence , Punie Kevin , Smeets Ann , Nevelsteen Ines , Van Nieuwenhuysen Els , Weltens Caroline G , Janssen Hilde , Han Sileny N. , Van Gorp Toon , Berteloot Patrick , Vergote Ignace , Wildiers Hans , Neven Patrick 
Published: May 2020

e13031 Background: Some breast cancer subtype-specific demographics and histopathological characteristics can be associated with metastatic outcome. Semi-quantitative oestrogen receptor (sqER) is prognostic in ER-positive HER2-negative tumours. Here, we studied sqER for outcome in early diagnosed triple positive breast cancers (TPBC;ER+/PR+/HER2+). Methods: Retrospective monocentric study of all consecutive early diagnosed TPBC (July 2002 - Dec 2017). Immunohistochemistry (IHC) was used for ER, PR and HER2; IHC ≥1% ER/PR was pos; HER2 was FISH-confirmed. Low sqER was defined as Allred score < 7/8. Local therapy was surgery +/- radiotherapy; systemic treatment was (neo)-adjuvant chemotherapy and trastuzumab and endocrine treatment. The clinicopathological variables we studied apart from sqER were age, menopausal status, BMI, parity, tumor grade and clinical stage at diagnosis. Variables were analysed by a Fishers Exact or Mann-Whitney U test. All reported p-values are two-sided. Cox regression was used to investigate howqER is associated with distant metastasis. Results: We included 415 female patients. 18% had low sqER; these were younger and more likely premenopausal at diagnosis; p < 0.001. Other studied variables didn’t differ by sqER-expression. 7% developed metastasis after a mean follow up of 86 months. High sqER-TPBCs as compared to low sqER-TPBCs were less likely to metastasize (HR 0.42; 95 CI 0.19-0.91). Conclusions: Low sqER in TPBC, present in about a fifth of these tumours, is typically associated with younger age and premenopausal status at diagnosis. Low sqER TPBC are more likely to metastasize when compared to TPBC with high sqER levels. [Table: see text]
The neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios predict efficacy of CDK 4/6 inhibitors in women with hormone receptor-positive/HER2-negative advanced breast cancer.
Authors: Zattarin Emma , Fabbroni Chiara , Ligorio Francesca , Nichetti Federico , Lobefaro Riccardo , Rivoltini Licia , Capri Giuseppe , Bianchi Giulia Valeria , De Braud Filippo G. , Vernieri Claudio 
Published: May 2020

e13032 Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors combined with endocrine therapies (ETs) are a mainstay of treatment for patients (pts) with hormone receptor-positive advanced breast cancer (HR+ aBC). Preclinical evidence indicates that their ability to stimulate antitumor immunity may crucially contribute to their anticancer activity. The neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) reflect systemic inflammation and immune system functional status and could be associated with CDK 4/6 inhibitor efficacy in pts with HR+ aBC. Methods: A retrospective, monocentric study was performed to investigate the association between NLR or PLR, as measured at baseline and after the first three treatment cycles, and progression free survival (PFS) in HR+ aBC pts treated with CDK 4/6 inhibitors. The thresholds for NLR and PLR were defined using the maximally selected rank statistics. Cox proportional hazard model was used to evaluate the impact of these parameters on PFS at univariate and multivariable analysis. Results: We evaluated a total number of 162 pts. Of them 142 were treated with palbociclib, 17 with ribociclib and 3 with abemaciclib plus ETs between January 2017 and December 2019 at our Institution. NLR and PLR at baseline were not associated with PFS. Conversely, high NLR ( > 3) and high PLR ( > 323.6) after three treatment cycles were associated with significantly lower PFS (p = 0.011 and p = 0.013, respectively). Multivariable analysis confirmed an independent association between high NLR or PLR and lower PFS (aHR 3.66, 95% CI 1.44-9.33, p = 0.007 and aHR 2.79, 95% CI 1.36-5.70, p = 0.005, respectively). Conclusions: To the best of our knowledge this is the first study to show a significant association between high NLR or PLR values and lower PFS in HR+ aBC pts treated with CDK 4/6 inhibitors. The association was not present with baseline values but only when NLR or PLR were measured after three treatment cycles, suggesting potential immunomodulatory activity of CDK 4/6 inhibitors.
CDK4/6 inhibitors and hormone therapy in hormone receptor-positive advanced breast cancer: Real-world data and intrinsic subtypes defined by PAM50.
Authors: Diaz Redondo Tamara , Lavado-Valenzuela Rocío , Dominguez-Recio Maria Emilia , Ruíz Sofía , González Flores Encarnación , Lopez-Lopez Jose Antonio , de Luque Vanessa , Morales-Estevez Cristina , Robles-Lasarte Marta , Perales-Adan Jesus , Saez Lara Enrique , Alvarez Martina , Sanchez-Muñoz Alfonso , Godoy Ana , Villar Ester , Carabantes Francisco , Baena-Cañada Jose Manuel , Jerez Jose Manuel , Ribelles Nuria , Alba Emilio 
Published: May 2020

e13035 Background: CDK 4/6 inhibitors plus hormone therapy(HT) has been approved by FDA and EMA for the treatment of hormone receptor positive HER2 negative advanced breast cancer (HR+/HER2-BC) with improvement in PFS consistently demonstrated in several clinical trials. Benefit in OS has also been demonstrated in Monaleesa3 and Monarch2 clinical trials. To date we don`t have real-world data and no single biomarker has been validated to identify subgroups that would benefit most from this new drugs. Methods: This is a multicenter, real life, observational study. From January 2015 to December 2019 we recruited 98 patients with immunohistochemical(IHC) HR+/HER2-BC treated with CDK4-6 inhibitor plus HT. All patients were classified into intrinsic molecular subtypes based on PAM50 signature done centrally in diagnostic/metastatic biopsies. Results: The clinical and treatment characteristic are in table. In IHC studies all population were classified as luminalA (40%) and LuminalB (60%) but we found HER2 enriched patients (6%) defined by PAM50. The median PFS for all population was 14 months and median PFS for Luminal A subtype was 12 months and 15 months for Luminal B with no statistically significant differences between them. Conclusions: Based on the results obtained, the intrinsic molecular subtype defined by PAM50 does not appear to be associated with differences in PFS in our study group. However, a study with a larger number of patients would be necessary. Inhibitors of CDK4/6, have established a central role in the management of HR+/HER2-BC. There is a clear benefit in PFS and OS but we still don’t know which patients will benefit from this therapy and who will not while the side effects such chronic neutropenia, QTC prolongation and diarrhea could have a negative impact on their quality of life. Its mandatory to explore a good biomarker to direct therapy. [Table: see text]
Monitoring of PIK3CA and ESR1 mutations in circulating tumor DNA as predictive and prognostic biomarkers in patients with endocrine-resistant ER+/HER2- advanced breast cancer.
Authors: Fuentes Antrás Jesús , García-Barberán Vanesa , Gonzalo Irene , Moreno Fernando , López-Cade Igor , Ramírez-Ruda Carmen , Bueno Oskia , Ascaso del Rio Ana , Pascual Alejandro , Ocana Alberto , Caldes Trinidad , Garcia-Saenz Jose Angel 
Published: May 2020

e13045 Background: Combination therapeutic strategies including CDK4/6 inhibitors and an endocrine backbone are the standard of care of treatment for patients with estrogen receptor positive (ER+)/HER2- advanced breast cancer (ABC). Endocrine agents mainly include aromatase inhibitors, which target ER-driven transcription, and fulvestrant, which functions as ER antagonist. PI3K-AKT-mTOR is a key point of resistance to endocrine therapy, activated in 40% of these patients by mutations concentrated in critical regions of PIK3CA, coding for the p110 catalytic subunit α of PI3K. Additionally, 30% of patients previously exposed to non-steroidal aromatase inhibitors develop mutations in the ligand binding domain of ESR1, causing endocrine resistance by constitutive activation of the ER. Furthermore, metastasis and primary tumors may show a highly heterogenous mutational landscape. Monitoring the dynamic changes of these mutations in ctDNA may provide a non-invasive, real-time and accessible tool to convey predictive/prognostic information and guide decisions on sequential endocrine therapies. Methods: Pre-planned interim analysis results of an observational, prospective cohort pilot study to assess the predictive and prognostic value of monitoring PIK3CA and ESR1 mutations in ctDNA of patients with endocrine-resistant ER+/HER2- ABC. We have studied longitudinal liquid biopsies from 30 patients using digital PCR to interrogate PIK3CA mutations (H1047R / E545K) and ESR1 mutations (D538G / Y537S). Blood samples were drawn at the time of progression to endocrine therapy, at 8 weeks of subsequent endocrine line and at new progression. This exploratory analysis will provide preliminary data on clinical homogeneity, treatment regimens, median follow-up and progression-free survival, mutation incidence and intraindividual variation of mutant allele frequency and copy number. The percentage of progressors at 24 weeks of follow-up according to the mutational status will be evaluated by using the Fisher’s exact test. The predictive potential of ctDNA biomarkers will be characterized by ROC curve analysis. Tracking ctDNA mutations to predict endocrine resistance in a real-world setting represents a critical step towards precision medicine in oncology.
Real-world incidence, duration, and severity of treatment-emergent (TE) neutropenia among patients (pts) with metastatic breast cancer (MBC) treated with ribociclib (RIB) or palbociclib (PAL).
Authors: Schwartzberg Lee S. , Zarate Juan Pablo , Chandiwana David , Yu Chu-Ling , Balu Sanjeev , Kanakamedala Hemanth , Turner Stuart J 
Published: May 2020

e13048 Background: Neutropenia is the most common adverse event following administration of CDK4/6 inhibitors RIB and PAL for hormone receptor–positive (HR+) MBC. There are limited comparative real-world data on TE neutropenia in pts receiving these agents. Here we report incidence, duration, and severity data on TE neutropenia in such pts from an electronic health record dataset and administrative claims. Methods: This retrospective study comprised 2 mutually exclusive cohorts of pts with MBC receiving RIB or PAL. Pts were matched 1:1 based on age and year of treatment start. Prior baseline activity of ≥6 mo was required. The MarketScan claims databases was used to evaluate incidence rates of TE neutropenia from Jan 1, 2015, to Dec 31, 2018, in pts receiving RIB or PAL. Rate ratio was calculated using a Poisson model. Data on neutropenia severity and duration were obtained from Optum de-identified Electronic Health Record dataset. Neutropenia severity was defined by neutrophil counts from lab tests (grade 1/2, 1000- < 1500/μL; grade 3, 500- < 1000/μL; grade 4 < 500/μL) within the first 180 days of treatment. Neutropenia duration was estimated using Kaplan-Meier analysis and defined as the time between first abnormal neutrophil result and a lab result demonstrating neutropenia resolution. Results: After 1:1 matching, 152 pts from the MarketScan database were included in both the PAL and RIB cohorts; 168 matched pts were included from the Optum dataset. Neutropenia was reported in 38 pts (25%) in the PAL group and 25 pts (17%) in the RIB group. The rate of neutropenia per person–treatment year was 0.5 (95% CI, 0.4-0.7) in PAL pts vs 0.4 (95% CI, 0.3-0.6) in RIB pts. The rate ratio of neutropenia between treatments (PAL vs RIB) was 1.4 (95% CI, 0.8-2.3), which was not statistically significant, likely due to small sample size. Rates of neutropenia by severity with PAL vs RIB were 32% vs 32% for grade 1/2, 35% vs 26% for grade 3, and 4% vs 4% for grade 4, respectively. The rate ratio for grade 3 or grade 4 neutropenia (PAL vs RIB) was 1.3 (95% CI, 0.9-1.8). Median neutropenia duration was 29 vs 20 days ( P< .01) with PAL vs RIB. Conclusions: Treatment of HR+ MBC with RIB and PAL requires optimal management of TE neutropenia. Real-world data showed that pts with MBC receiving PAL had a numerically higher rate of neutropenia than pts receiving RIB. Rates of grade 3 neutropenia were higher with PAL vs RIB, and duration of neutropenia was longer with PAL vs RIB. Economic burden analyses of neutropenia will be presented.
Resensitization of palbociclib-resistant MCF-7 cells by inhibiting TGF-β-induced epithelial-mesenchymal transition.
Authors: Chang Minsun , Park Sujeong , An Byung Ha 
Published: May 2020

e13061 Background: Inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) is the most recent therapeutic method to treat estrogen receptor (ER)-positive breast cancer. Three CDK4/6 inhibitors have been approved by the FDA. The acquired resistance to CDK4/6 inhibitors are expected to have a negative impact on success of breast cancer therapy. It is critical to understand the molecular mechanisms underlying drug resistances to devise a better regimen or overcome drug resistance. Methods: The derivative MCF-7 (MCF-7:PR) cells which exert acquired resistance to palbociclib (PCB), one of the FDA-approved CDK4/6 inhibitors, are recently established. The EMT characteristics, major mechanisms for the EMT, and inhibition of TGF-β signaling pathways are studied in MCF-7:PR cells. Results: The mesenchymal markers are increased and the epithelial ones are decreased at both mRNA and protein levels in our cell line model. Transwell migration and would healing assays also demonstrated that MCF-7:PR cells exert EMT properties. Hyperactivation of TGF-β/Smad signaling was observed in MCF-7:PR cells. Chemical inhibition of TGF-β signaling lead to diminished cell migration and resistance to PCB. Conclusions: Resistance to PCB in MCF-7 cells resulted in significant changes in cell motility and molecular markers associated with EMT. In particular, TGF-β signaling is closely related to EMT and its inhibition reversed the EMT and cellular response to PCT. Our findings suggest that the modulation of EMT via inhibition of TGF-β signaling can be one of strategies to bypass PCB resistance in ER-positive breast cancer.
Bone scintigraphy and PET-CT: A necessary alliance for bone metastasis detection in breast cancer?
Authors: Santos Joana Cristo , Abreu Miguel Henriques , Santos Miriam Seoane , Duarte Hugo , Alpoim Tiago , Sousa Susana , Abreu Pedro Henriques 
Published: May 2020

e13070 Background: Bone is one of the main sites of breast cancer metastasis. Staging of this kind of disease spread can be performed in locally advanced cases with PET-CT in conjunction with Bone Scintigraphy. The purpose of this work is to compare the efficiency of bone metastasis detection between PET-CT and bone scintigraphy. Methods: Prospective analysis of locally advanced breast cancer patients treated in a Comprehensive Cancer Center between 2014 and 2019 that performed PET-CT and Bone Scintigraphy in the staging. Interval between the two exams could not exceed 2 months. Clinical and pathological characteristics of the disease were collected from electronic files and independently clinical images reports were considered to evaluate the ability of each imaging modalities to identify bone disease. In discrepancy cases a re-analysis of the images by two independent nuclear physicians was performed to validate the findings. Results: We analyzed 204 cases. The majority of them had ductal carcinomas (72.5%), cT2/3 (70%), cN1/2(61.8%) and G2/3 (94.6%), luminal B- like, HER2 positive disease (49.2%). In this cohort, bone metastasis was documented in 52 (25.5%) patients. PET-CT presented 97.0% of accuracy, surpassing the 94.1% presented by Bone Scintigraphy. The latter failed to correctly detect bone metastasis in 11 (5.4%) patients and only outperformed PET-CT in 3 (1.5%) patients. The main difference between the two modalities was the non-detection of cranium lesions in PET-CT images. Conclusions: PET-CT showed higher efficiency in bone metastasis detection than Bone Scintigraphy, probably because it detects lytic lesions. The non-detection of cranium ones can be harmful and so modifications in the image acquisition are required to improve the quality of PET-CT, avoiding other exams in bone staging.
Macrocytosis as a predictor of response to capecitabine in solid cancers: A meta-analysis.
Authors: Almugbel Fahad , Al-Showbaki Laith , Nadler Michelle , Desnoyers Alexandra , Saleh Ramy , Amir Eitan 
Published: May 2020

e13080 Background: Capecitabine is an effective oral chemotherapy that is widely used in a number of solid cancers both as monotherapy or in combination with other anti-cancer drugs. It has been suggested that mean corpuscular volume (MCV) is associated with response to capecitabine. Methods: We searched PubMed for studies exploring the association between capecitabine and macrocytosis or MCV. We extracted the hazard ratios (HR) reporting progression-free (PFS) or overall survival (OS) data when comparing macrocytosis to normal/low MCV. If HR were not directly reported, we estimated them from survival plots using the Parmar method. HR were then pooled in a meta-analysis using generic inverse variance and random effects modeling. Results: Among the 13 identified studies, five were eligible for analysis, comprising a total of 446 patients. One study was a randomized trial and four were retrospective cohort studies. Mean patient age was 53 and cancer sites included breast (n = 226; 50%), colon (n = 131; 29 %) and stomach (n = 89; 19%). Capecitabine was used in combination with other drugs in 64% of patients. There was no association between macrocytosis and PFS (HR 0.91, 0.60-1.38, p = 0.65). Among the 3 studies reporting OS data, there was a significant negative association between macrocytosis and worse OS (HR 1.79, 1.38-2.34, p < 0.001). Conclusions: Macrocytosis in patients treated with Capecitabine was found to have no impact on PFS, but was associated with an inferior OS. This finding suggests that macrocytosis is more likely to be a prognostic factor rather than a predictive biomarker of response to capecitabine.