bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient-reported outcomes (PROs) in patients (pts) with PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC) from SOLAR-1.
Authors: Mayer Ingrid A. , Rugo Hope S. , Loibl Sibylle , Safra Tamar , Park Yeon Hee , Krivorotko Petr , Iwata Hiroji , Andre Fabrice , Conte Pier Franco , Ciruelos Eva , Juric Dejan , Park Jinhee , Wilke Celine , Mills David , Lteif Agnes , Campone Mario 
Published: May 2019

1039 Background: Approximately 40% of pts with HR+, HER2– ABC have tumors with a PIK3CA mutation, resulting in phosphatidylinositol 3-kinase (PI3K) pathway hyperactivation. Use of the oral α-specific PI3K inhibitor alpelisib (ALP) + fulvestrant (FUL) in SOLAR-1 significantly improved (vs placebo [PBO] + FUL) both progression-free survival (PFS) (median 11.0 vs 5.7 mo, respectively; HR 0.65; 95% CI, 0.50-0.85; P< 0.001) and objective response rate (ORR) (measurable disease: 36% vs 16%; P< 0.001) in the PIK3CA mutant cohort. In addition to primary efficacy and safety measures, PROs offer valuable insight into therapeutic benefit by measuring whether quality of life (QoL) is maintained during treatment. Methods: Postmenopausal women or men with HR+, HER2– ABC whose disease progressed on/after an aromatase inhibitor were randomized to receive ALP 300 mg once daily or PBO, + FUL 500 mg every 28 days + Cycle 1, Day 15. Secondary objectives included PROs using the EORTC QLQ-C30, EQ-5D-5L, and BPI-SF scales. PROs were collected at screening, every 8 wk for 18 mo then every 12 wk thereafter, at end of treatment, and during follow-up for efficacy. Linear mixed effects models were used to assess score changes from baseline. Time to 10% deterioration (TTD), an established measure of clinically meaningful change in QoL, was compared between the treatment arms’ survival distribution using Kaplan-Meier methodology. Results: At baseline, 93% of pts in the PIK3CA mutant cohort (n = 341) completed questionnaires; ≥75% completed them post-baseline. Adjusted mean changes from baseline in EORTC global health status/QoL scores were < 10% for all visits through wk 96 for both arms, with a mean difference between arms of < 3% for all visits. There was no difference between arms in TTD in global health/QoL status (HR 1.03; 95% CI, 0.72-1.48). Analysis of TTD in EORTC physical, social, and emotional functioning scores revealed no meaningful differences between arms. Conclusions: In addition to significantly improving PFS and ORR, overall QoL was maintained in pts treated with ALP + FUL. Clinical trial information: NCT02437318.
Next-generation sequencing (NGS) results among hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) patients treated with a CDK4 & 6 inhibitor: A retrospective observational study based on real-world data.
Authors: Hamilton Erika Paige , Jansen Valerie Malyvanh , Nash Smyth Emily Nash , Schlauch Daniel , Cuyun Carter Gebra , Willard Melinda D , Misch Amanda , Bowman Lee , Zhu Yajun Emily , McNeely Samuel , Lin Aimee Bence , Picard Shaita , Blackwell Kimberly , Burris Howard A. , Spigel David R. 
Published: May 2019

1042 Background: Few real-world studies have characterized the frequency of genomic alterations of MBC tumors. Data characterizing alterations before and after treatment containing a CDK4 & 6 inhibitor (CDK4 & 6i) are similarly limited. We explore the genomic landscape of HR+/HER2- MBC tumors from patients (pts) treated with a CDK4 & 6i in order to characterize potential mechanisms underlying sensitivity and resistance. Methods: NGS results of tumor and liquid biopsies obtained from 130 pts with estrogen receptor (ER+)/progesterone receptor (PR+)/HER2- MBC between Jan 2008 to Sept 2016 were analyzed. All pts received therapy containing a CDK4 & 6i for MBC at a community cancer network and had NGS results available before and/or after exposure to CDK4 & 6i. Samples were classified as sensitive (n = 69; duration of therapy ≥6 mo) or resistant (n = 61; duration of therapy < 6 mo). The frequency of genomic alterations with likely or known significance including short variants, indels, copy number variants, and fusions were characterized. Results: Alterations in 215 unique genes were identified from the NGS results; PIK3CA, TP53, ESR1, CCND1, and FGFR1 were the most frequently altered genes. Select alterations in ESR1 (n = 21 vs 9) and RAD21 (n = 5 vs 0) were more frequent after exposure to CDK4 & 6i. In NGS obtained before exposure to CDK4 & 6i, alterations in select genes including RB1, MDM2, AURKA, and MYC were more frequent in the resistant samples, whereas ARID1A alterations were more frequent in sensitive samples. Of the 6 pts with paired NGS samples pre- and post-CDK4 & 6i treatment, alterations in MYC, CDKN2A, PIK3CA, BRCA1, or RB1 were acquired in 3 pts. Conclusions: Based on real-world data, this study describes the genomic landscape of ER+/PR+/HER2- MBC tumors from pts treated with CDK4 & 6i and identifies potential mechanisms underlying sensitivity and resistance to this new class of drugs. Further evaluation in larger datasets is warranted. Data inclusive of other ER/PR subtypes will be presented.
Endocrine-based targeted combination versus endocrine therapy alone as first-line treatment in elderly patients with hormone receptor-positive advanced breast cancer: Meta-analysis of phase II and III randomized clinical trials.
Authors: Omarini Claudia , Piacentini Federico , Sperduti Isabella , Barbolini Monica , Isca Chrystel , Nasso Cecilia , Toss Angela , D'Onofrio Raffaella , Cortesi Laura , Barbieri Elena , Cascinu Stefano , Moscetti Luca 
Published: May 2019

1046 Background: Combined endocrine approaches have been widely investigated as first-line treatment in hormone receptors positive metastatic breast cancer. In particular, multiple randomized trials showed that the addiction of CDK (cyclin-dependent kinase) 4/6 inhibitors to endocrine therapy (ET) increase progression free survival (PFS). Elderly patients (aged ≥65 years) are under represented in most of the clinical studies. Moreover, due to the multi-morbidity and the major toxicity associated with the targeted agents, the combination strategy in that subgroup is widely discussed. The present meta-analysis aimed to understand the role of the new endocrine approaches in women aged ≥65 years. Methods: This meta-analysis included first line phase II/III randomized published trials comparing (ET) to the experimental strategy. Trials with no data about hazard ratios (HR) for PFS in the subgroup of patients aged ≥65 years were excluded. The heterogeneity of the data was evaluated by Chi-square Q test and I2 statistic. Results: 8 studies were included in the analysis. 4 trials (Paloma1/TRIO-18, Paloma2, Monaleesa2, Monarch3) investigated the role of CDK 4/6 inhibitors, 2 trials (SWOG and FACT) analysed the combination of Fulvestrant plus Aromatase Inhibitors, while other two trials explored the association of ET with Bevacizumab (LEA) and Temsirolimus (HORIZON), respectively. Overall, the meta-analysis showed a PFS advantage for the experimental arms [HR 0.77, p 0.016] with a significant high/moderate heterogeneity [I2 65.46%, p 0.005]. The 4 studies adding CDK4/6 inhibitors to ET showed a significant improvement in PFS compared to ET alone. No significant advantages for the addition of anti-angiogenic agents or Fulvestrant to ET have been found in elderly population subgroup. Conclusions: The novel experimental combo-strategies in the first line setting showed an improvement in PFS in the subgroup of elderly patients. Adding CDK4/6 inhibitors to ET significantly prolongs PFS as compared to ET alone. The magnitude of PFS benefit due to addition of CDK4/6 inhibitors to ET is age-independent.
Exploratory analysis of the effect of taselisib on downstream pathway modulation and correlation with tumor response in ER-positive/HER2-negative early-stage breast cancer from the LORELEI trial.
Authors: Nuciforo Paolo , Hlauschek Dominik , Saura Cristina , de Azambuja Evandro , Fasani Roberta , Villagrasa Patricia , Muehlbacher Karoline , Sotiriou Christos , Prat Aleix , Pfeiler Georg , Hilbers Florentine , Wilson Timothy R. , Aimi Junko , Stout Thomas , Valero Vicente , Fesl Christian , Baselga Jose , Gnant Michael , Piccart Martine , Andre Fabrice 
Published: May 2019

1050 Background: Taselisib (T) is an oral, potent, selective inhibitor of Class I PI3-kinase with enhanced activity against PIK3CA mutant cancer cells. Results from the LORELEI trial have demonstrated a significant improvement in ORR (objective response rate) by centrally assessed magnetic resonance imaging in all randomized patients as well as in the PIK3CA mutant (MT) cohort treated with neoadjuvant T plus letrozole (L) compared to placebo (P) plus L. Here we present the results of exploratory analyses of selected pathway-related phosphoproteins. Methods: Baseline (BL) and week3 (W3) tumor biopsies were obtained from 334 patients enrolled in the trial. Phosphoproteins (pAKT, pPRAS40 and pS6) were analyzed by IHC. BL levels as well as changes from BL to W3 were correlated with response assessed either by ORR or cell cycle arrest (Ki67 at W3 < 2.7%). Results: In the overall population, BL phosphoproteins levels were similar between the T and P arms. Higher pAKT (p < 0.001) and pPRAS40 (p = 0.004) levels were observed in MT vs wild-type (WT), whereas the opposite result was found for pS6 (p = 0.03). Treatment-induced absolute changes of phosphoproteins adjusted for BL levels were not significantly different between the T and P arms in the overall population, except for pPRAS40 with higher decrease in the T arm (p = 0.014). After stratification for PIK3CA genotype, a significantly greater decrease in expression levels was observed for pPRAS40 (p < 0.001) and pS6 (p = 0.020) in MT tumors treated with T. The treatment effects were not significantly different in the WT population. A trend for an association between decrease in pS6 levels at W3 and improved ORR was observed in the MT (p = 0.08) and T (p = 0.09) subgroups. The magnitude of pS6 suppression at W3 was higher in tumors achieving a cell cycle arrest in the MT/T subgroup (biserial correlation = -0.473). Conclusions: Exploratory analyses of phosphoproteins showed bioactivity of taselisib as indicated by downstream pathway suppression. Translational research aiming to integrate these results with additional exploratory biomarkers data is currently ongoing. Clinical trial information: NCT02273973.
Lasofoxifene as a potential treatment for ER+ metastatic breast cancer.
Authors: Laine Muriel , Fanning Sean William , Greene Marianne , Chang Ya-fang , Phung Linda , Tan Tina T , Hiipakka Richard , Komm Barry , Greene Geoffrey 
Published: May 2019

1056 Background: Estrogen receptor positive (ER+) metastatic breast cancers (MBC) that express constitutively active somatic ESR1 mutations at Y537S and D538G allow tumors to progress in the presence of approved endocrine therapies. For patients with ER+ MBC, fulvestrant is the first line of treatment. Palbociclib or other CDK4/6 inhibitors are now being included. Preliminary studies show that lasofoxifene, a selective ERα modulator (SERM), was effective in reducing tumor growth in an endocrine resistant xenograph model expressing ERα mutations Y537S or D538G. Additionally, lasofoxifene more effectively inhibited the development of liver and lung metastases than fulvestrant. Lasofoxifene is currently under evaluation in a phase 2 study. Because certain combinations of a hormonal agents like fulvestrant improved efficacy, we investigated the combination of palbociclib and lasofoxifene as a potential therapeutic for mutant ESR1 MBC. We hypothesized that this combination should improve outcome and compared it to a combination with fulvestrant. Methods: We first determined the optimal dose of lasofoxifene in an intraductal (MIND) xenograph model of MCF-7 cells that express active ERα Y537S and D538G. Subsequently, we performed combination studies with lasofoxifene (10mg/kg 5/week SQ) +/- palbociclib (100mg/kg gavage, 5/week) or fulvestrant (5mg/mouse/week, SQ) +/- palbociclib. Results: Lasofoxifene alone was significantly more effective than fulvestrant at inhibiting the metastasis of both MCF7 Y537S and D538G tumors to the lungs and liver. Lasofoxifene + palbociclib was more effective than fulvestrant + palbociclib at reducing primary tumor growth; both combinations demonstrated an increased response. Lasofoxifene + palbociclib was more effective at inhibiting liver metastasis than either drug alone and was more effective than fulvestrant + palbociclib at reducing metastasis to the liver and lung. Structural studies showed that lasofoxifene effectively disrupts the active conformation of the ERα Y537S ligand-binding domain. Conclusions: These results demonstrate that lasofoxifene, in combination with CDK4/6 inhibitors like palbociclib, has promise for treating endocrine therapy resistant ER+ MBC patients whose tumors express activating ESR1 mutations, more effectively than either drug alone.
Efficacy and safety of anti-PD-1 antibody SHR-1210 combined with apatinib in patients with advanced triple-negative breast cancer.
Authors: Liu Jieqiong , Jiang Zefei , Li Qian , Li Ying , Liu Qiang , Song Erwei 
Published: May 2019

1066 Background: PD-1/PD-L1 blockade monotherapy delivered positive outcomes in early-phase trials in advanced triple-negative breast cancer (TNBC). However, t he highest objective response rate (ORR) is 18.5%. IMPassion130 trial has demonstrated that only PD-L1+ TNBC had overall survival benefit from anti-PD-L1 antibody combined with chemotherapy. Preclinical studies found that antiangiogenic therapy could sensitize anti-PD-1 treatment via inducing PD-L1 expression and increasing CTLs infiltration in tumor microenvironment. Thus, we designed a phase II, open-label trial (NCT03394287) of SHR-1210 (anti-PD-1 antibody) in combination with apatinib (VEGFR2 inhibitor) in patients with advanced TNBC. Methods: 20-58 advanced TNBC patients whose systemic therapy lines in the metastatic setting was less than 3, will be randomly (1:1) enrolled from Sun Yat-sen Memorial Hospital to receive either SHR-1210 200mg Q2W plus apatinib 250mg, continuous dosing (d1-d14), or SHR-1210 200mg Q2W plus apatinib 250mg, intermittent dosing (d1-d7), until progression or unacceptable toxicities. Primary endpoint was ORR. Secondary end points included PFS, DCR, TTR, DoR, CBR, one year-OS and toxicity. Results: Until Jan 30, 2019, 34 patients were enrolled, 10 in the intermittent dosing arm, and 24 in the continuous dosing arm. 26 (76.5%) patients had prior systemic therapy in the metastatic setting. At the cutoff date (Jan 30, 2019), 28 patients were evaluable for ORR as per RECIST. The ORR was 47.4% (9 of 19) in the continuous dosing cohort, and no confirmed objective response was found in the intermittent dosing arm. The DCR was 68.4% in the continuous dosing arm, whereas it was 44.4% in the other arm. The median PFS was 2 months in the intermittent dosing cohort, while it was not reached in the continuous dosing cohort. The most common adverse events (AEs) was fatigue (65.0%), hand-foot syndrome (63.3%), and elevated aspartate aminotransferase and/or alanine aminotransferase (73.3%). There were no treatment-related deaths. Another 5 patients will be enrolled into the continuous dosing arm because of its favorable response. Conclusions: Anti-PD-1 antibody SHR-1210 combined with apatinib demonstrates favorable clinical activity and a manageable safety profile in patients with advanced TNBC. Clinical trial information: NCT03394287.
Patient-reported outcomes (PROs) from the phase III IMpassion130 trial of atezolizumab (atezo) plus nabpaclitaxel (nP) in metastatic triple-negative breast cancer (mTNBC).
Authors: Adams Sylvia , Dieras Veronique , Barrios Carlos H. , Winer Eric P. , Schneeweiss Andreas , Iwata Hiroji , Loi Sherene , Patel Sheetal , Henschel Volkmar , Chui Stephen Y. , Rugo Hope S. , Emens Leisha A. , Schmid Peter 
Published: May 2019

1067 Background: In the IMpassion130 study in 1L mTNBC (N = 902), PFS with atezo + nP was significantly better than with placebo (P) + nP in ITT (HR, 0.80) and PD-L1 IC+ (HR, 0.62) patients (pts). Clinically meaningful OS improvement (HR, 0.62) was also seen in PD-L1+ pts. PROs were used to document pt perspectives on overall clinical benefit of atezo + nP. Methods: Pts received either atezo 840 mg or P q2w + nP 100 mg/m2 on days 1, 8 and 15 of each 28-day cycle until disease progression or intolerance. Pts completed the EORTC QLC-C30 and breast cancer module (QLQ-BR23) on day 1 of each cycle, at end of treatment (Tx) and q4w during follow-up for 1 y. Time to deterioration (TTD; first ≥ 10-point decrease from baseline [BL] held for 2 cycles) in HRQoL was a pre-defined secondary endpoint. Exploratory endpoints included TTD in function, and mean and mean change from BL scores (changes ≥ 10 considered clinically meaningful) in HRQoL, function and disease/Tx-related symptoms. Results: BL completion was 92% (QLQ-C30) and 89% (QLQ-BR23) and remained > 80% through Cycle 20 in both ITT and PD-L1 IC+ pts. No differences in median TTD in HRQoL (ITT: HR, 0.97 [95% CI: 0.80, 1.18]; PD-L1 IC+: HR, 0.94 [95% CI: 0.69, 1.28]), physical function (ITT: HR, 1.04 [95% CI: 0.86, 1.26]; PD-L1 IC+: HR, 1.02 [95% CI: 0.76, 1.37]) or role function (ITT: HR, 1.01 [95% CI: 0.83, 1.22]; PD-L1 IC+: HR, 0.77 [95% CI: 0.57, 1.04]) were observed between arms in either population. Mean scores at BL for HRQoL (ITT: 66.0 [atezo + nP] vs 64.3 [P + nP]; PD-L1 IC+: 67.5 vs 65.0), physical function (ITT: 80.4 vs 79.2; PD-L1 IC+: 82.8 vs 79.4) and role function (ITT: 72.7 vs 71.0; PD-L1 IC+: 73.7 vs 71.7) were similar between arms and throughout the course of Tx. In both arms, HRQoL, physical and role function, and Tx symptoms (fatigue, diarrhea, nausea, vomiting) were stable during Tx, with no clinically meaningful changes seen until pts discontinued Tx. Conclusions: PRO data suggest that atezo + nP was tolerable and similar to nP alone in maintaining HRQoL and day-to-day function relative to BL. This confirms atezo + nP had clinical benefit without compromising HRQoL, physical and role function, or worsening Tx symptoms vs P + nP in 1L mTNBC. Clinical trial information: NCT02425891.
Determinants of concordance in clinically relevant genes (CRG) from synchronously acquired tumor biopsies (tBx) and ctDNA in metastatic breast cancer (MBC).
Authors: Oliveira Mafalda , Ruiz-Pace Fiorella , Matito Judit , Perez-Lopez Raquel , Suñol Anna , Bellet Meritxell , Escriva-de-Romani Santiago , Zamora Esther , Gomez Patricia , Garrigós Laia , Capelán Marta , Arumí Miriam , Ortiz Carolina , Amair-Pinedo Fabiola , Mancuso Francesco M , Espinosa-Bravo Martin , Nuciforo Paolo , Dienstmann Rodrigo , Vivancos Ana , Saura Cristina 
Published: May 2019

1075 Background: NGS in ctDNA from MBC is feasible and results may be informative for patients’ management, especially in non-luminal tumors (Oliveira et al, ASCO 2018). We aimed to study the determinants of concordance in CRG in a cohort of 60 MBC patients undergoing tBx and ctDNA collection. Methods: MiSeq Amplicon-based NGS (59 cancer-related genes) was performed in one single metastatic lesion per patient and compared with liquid biopsies taken at the same time point at disease progression to prior treatment. The concordance in CRG ( PIK3CA, AKT1, ERBB2, ESR1, PTEN, BRAF, FGFR1, HRAS, KRAS, and PIK3R1) in tBx vs ctDNA was determined at patient and at mutation (mut) level and correlated with mutant allele fraction (MAF), total disease volume (TDV), and clinical characteristics. True positive in plasma (TPP): patient with a mut detected both in ctDNA and tBx. TDV was defined as all metastasis volume assessed by CT scan (excluding sclerotic bone metastasis), and analyzed by an experienced radiologist using the 3DSlicer semiautomatic segmentation tool (TDV = pixel size x number of pixels). Results: Concordance in CRG at patient and mut level was 72% and 55%, respectively. Concordance for ERBB2 (1/1; 100%) and PIK3CA (17/22; 77%) was higher than for ESR1 (8/20; 40%) and AKT1 (2/6; 33%). ctDNA failed to detect 14 mut present in tBx ( ESR1 n = 5, PIK3CA n = 5, AKT1 n = 3, BRAF n = 1). Concordance was 100% for non-luminal and 60% for luminal cases (P = 0.01). In univariate analysis, concordance was not associated with MAF in tBx (P = 0.15), TDV (p = 0.86), number of prior lines of therapy (P = 0.57), number of metastatic sites (P = 0.56) or presence of visceral metastasis (P = 1.0). In patients with PIK3CA mut (N = 22), those with TPP had a numerically higher TDV than those where a PIK3CA mut was not detected in ctDNA (20.9cm3 vs 5.1cm3, P = 0.28). Across all patients, in the multivariate logistic model adjusted for other factors, TDV was a determinant of TPP (OR 1.02, 95%CI 1.0-1.06; P = 0.059). For each increase of 1cm3 in TDV, there was a 2% increase in the probability of detecting a mut in ctDNA. Conclusions: Our results suggest that liquid biopsy testing for the detection of actionable CRG is clinically valid in MBC, although its yield depends on several factors – tumor subtype, analyzed gene, and possibly tumor volume – that reflect both tumor heterogeneity and tumor shedding rate. Due to the potential clinical implications, the observation that mutation detection in ctDNA may correlate with tumor volume merits further study in a larger dataset.
First-line (1L) ribociclib (RIB) plus letrozole (LET) for postmenopausal women with hormone receptor-positive (HR+), HER2- advanced breast cancer (ABC): MONALEESA-2 long-term safety results.
Authors: O'Shaughnessy Joyce , Campone Mario , Andre Fabrice , Nusch Arnd , Grischke Eva-Maria , Villanueva Cristian , Marschner Norbert , Winer Eric P. , Paluch-Shimon Shani , Rodriguez-Lorenc Karen , Hilliard Annie , Le Gac Fabienne , Ridolfi Antonia , Hortobagyi Gabriel N. 
Published: May 2019

1078 Background: In the phase III MONALEESA-2 study (NCT01958021), 1L treatment (Tx) with RIB (cyclin-dependent kinase 4/6 inhibitor) plus LET significantly prolonged PFS vs placebo (PBO) + LET in patients (pts) with HR+/HER2– ABC (HR 0.56; P<0.0001). In the primary publication (data cutoff, Jan 2016), the median duration of exposure was 13.0 mo (RIB + LET) and 12.4 mo (PBO + LET), and the most common all-grade adverse events (AEs) in the RIB + LET arm were neutropenia (74.3%), nausea (51.5%), infections (50.3%), fatigue (36.5%), and diarrhea (35.0%; Hortobagyi GN, et al. N Engl J Med. 2016;375:1738-48). Here we present long-term safety data from MONALEESA-2. Methods: Pts received either RIB + LET (n=334) or PBO + LET (n=330). AEs were graded per CTCAE v4.03. Results: As of data cutoff (Oct 2018), 79 (24%) pts (RIB + LET) and 39 (12%) pts (PBO + LET) remained on Tx. The median duration of exposure was 20.2 mo (range, 0-54) for RIB + LET and 14.1 mo for PBO + LET, and 30% and 17%, respectively, had ≥ 36 mo of exposure. Neutropenia was the most common exposure-adjusted any-grade AE of special interest (AESI) in the RIB + LET arm (Table). AEs were the most common reason for RIB dose reductions (56.6%) and interruptions (73.4%). Discontinuations due to AEs occurred in 19.2% and 4.2% of pts in the RIB + LET and PBO + LET arms, respectively, and the most common AEs leading to discontinuation in the RIB + LET arm were increased ALT (4.5%), GI disorders (3.3%), and increased AST (2.7%). Prolonged QT led to dose interruption in 0.9% of patients (no discontinuations), and the additional follow-up did not reveal any sudden deaths related to prolonged QT interval beyond the 1 identified in the primary analysis. Conclusions: AEs occurring with 1L RIB + LET in postmenopausal pts with HR+/HER2– ABC were manageable and the safety profile was comparable to that in the primary report. Clinical trial information: NCT01958021. [Table: see text]