bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase III, randomized, double-blind, placebo (Pla)-controlled study of pertuzumab (P) + trastuzumab (H) + docetaxel (D) versus Pla + H+ D in previously untreated HER2-positive locally recurrent/metastatic breast cancer (LR/MBC) (PUFFIN).
Authors: Xu Binghe , Li Wei , Zhang Qingyuan , Zhimin Shao , Jia Wang Xiao , Li Huiping , Sun Tao , Yin Yongmei , Zheng Hong , Zhang Hong , Chan Tiffanie , Lei Guiyuan , Restuccia Eleonora
Published: May 2019

1026

Background: In CLEOPATRA (NCT00567190), adding P to H + D significantly improved progression-free and overall survival (PFS/OS) v Pla + H + D in patients (pts) with previously untreated HER2-positive LR/MBC. PUFFIN (NCT02896855) is a China bridging study; the objective being to assess consistency of efficacy with CLEOPATRA. Methods: Pts with previously untreated HER2-positive LR/MBC were randomized 1:1 to P + H + D or Pla + H + D, stratified by visceral v non-visceral disease and hormone receptor status. The primary endpoint was investigator-assessed PFS. Secondary endpoints included objective response rate (ORR in pts with measurable baseline disease), OS, and safety. The target sample size (240) was determined based on the consistency threshold for PFS, defined as hazard ratio (HR) < 0.81, which maintains ≥ 50% of the risk reduction determined in CLEOPATRA (HR 0.62). Results: Two hundred forty-three pts were randomized. Baseline/disease characteristics and prior therapies were generally balanced between arms. For PFS, the HR was 0.69 (95% CI 0.49, 0.99) in the ITT population. No cases of heart failure or symptomatic left ventricular ejection fraction decline were reported. Efficacy/safety are shown in the table. Conclusions: PUFFIN met its primary endpoint. Overall, efficacy data were consistent with CLEOPATRA (ITT population and Asian subgroup). Safety was also consistent and in line with the known P safety profile, with no new or unexpected signals reported. PUFFIN adds to the totality of data with P in previously untreated HER2-positive LR/MBC, and supports the favorable benefit–risk profile of P in Chinese pts. Clinical trial information: NCT02896855. [Table: see text]
Association of polybromo-associated BAF (PBAF) complex mutations with overall survival (OS) in cancer patients (pts) treated with checkpoint inhibitors (ICIs).
Authors: Abou Alaiwi Sarah , Nassar Amin , El Bakouny Ziad , Berchuck Jacob E , Nuzzo Pier , Flippot Ronan , Flaifel Abdallah , Steinharter John A. , Baca Sylvan , Margolis Claire , Vokes Natalie , Du Heng , Shukla Sachet A , Braun David A. , Signoretti Sabina , Sonpavde Guru , Kwiatkowski David J. , Van Allen Eliezer Mendel , Choueiri Toni K.
Published: May 2019

103

Background: ICIs have shown benefit across several metastatic carcinomas, yet predictive biomarkers are still lacking. 20% of malignancies harbor alterations in ≥1gene that is part of PBAF complex. With recent data suggesting an association between PBRM1 mutations (mts) and outcomes in renal cell carcinoma (RCC) pts treated with ICIs (Miao, Science, 2018), we examined the association between PBAF mts and OS in ICI-treated patients across several solid cancer (ca) types. Methods: Of 6007 pts with different ca histologies and targeted exome sequencing (Oncopanel) at Dana Farber Cancer institute (DFCI), 138 pts had truncating mts in any PBAF gene (SMARCA4, PBRM1, and ARID2) or oncogenic missense mts in SMARCA4 and were treated with ICIs. 138 histology-matched DFCI pts had none. A publicly-available cohort (2:1 histology matched) from Memorial Sloan Kettering (MSKCC) (Samstein et al., Nature Genetics, 2019) of 621 ca pts (PBAF mutant [MT] = 207, PBAF wild type [WT] = 414) treated with ICIs was analyzed for association between PBAF mts and OS. OS was defined from time from ICI initiation. OS was compared by Cox regression between PBAF MT and PBAF WT. Hazard ratio (HR) was derived using univariable and multivariable analysis (MVA) adjusted for ICI regimen (single vs combination) and age. Results: Median (Md) follow-up for the combined cohort (n = 897) was 27 months (m). Major histologies were non-small cell lung ca (268; 29.9%), melanoma (220; 24.5%), RCC (181; 20.2%), and bladder ca (65; 7.2%). Results on univariable and MVA analyses from individual and combined cohorts are presented below. Conclusions: PBAF mts are associated with survival in ICI-treated ca pts. Work in progress with non-ICI treated pts will determine if this is prognostic or predictive of response. [Table: see text]
Clinical characteristics of patients with no evidence of disease (NED) versus residual disease (RES) to anti-HER2 therapy in metastatic breast cancer (MBC): A multi-institutional analysis.
Authors: Veitch Zachary William Neil , Bedard Philippe L. , Tang Patricia A. , Conway Jessica L. , Ribnikar Domen , Albaba Hamzeh , King Karen M. , Lupichuk Sasha M. , Cescon David W.
Published: May 2019

1034

Background: Anti-HER2 therapy has improved survival in HER2+ MBC. Yet, large patient cohorts with no evidence of disease (NED) with long-term follow up are incompletely described in the literature. We evaluated the clinical characteristics of patients with HER2+ MBC and prolonged response to anti-HER2 therapy, exhibiting NED vs Residual disease (RES). Methods: Patients treated with chemotherapy plus trastuzumab (CT) from 2005-2013, or taxane plus trastuzumab-pertuzumab (TTP), or trastuzumab-emtansine (TDM1) from 2012-2016 for HER2+ MBC at Princess Margaret Cancer Centre in Toronto, Ontario or in Alberta, Canada were included. Duration on anti-HER2 therapy (without switch) was collected. Patients with median duration of response (MDR; months) 2x higher than phase II/III trials for each regimen (CT = 18.2; TTP = 40.4; TDM1 = 25.2) were included to select for prolonged response. Clinical features (ie: stage at diagnosis, survival, etc) and oncologist/radiologist reported best response were collected. Responses were grouped as NED (including sclerotic bone metastases) or RES. Clinical variables were evaluated by Chi-square and survival by Kaplan-Meier (log-rank). Results: 2403 patients (CT = 1830; TTP = 394; TDM1 = 179) were evaluated. After cut-off, 119 patients (5%) were included, with NED in 41% (49/119) and RES in 59% (70/119). More women aged < 50 vs ≥50 (p = 0.015) had NED (61%) than RES (39%). No breast surgery (curative or metastatic) showed higher (p = 0.015) rates of NED (49%) relative to RES (27%). More women having NED (92%) than RES (37%) were still alive (p < 0.0001) at data cut-off, with improved mPFS (years; p < 0.0001) for NED (11.2, 95%CI: 11.2-NR) vs RES (3.0, 2.7-3.6), and mOS (years; p < 0.0001) for NED (NR) vs RES (3.4, 95%CI: 2.8-4.2). Significance persisted with TDM1 patients excluded. Treatment type (p = 0.053) and number of organs with metastases (p = 0.067) were of borderline significance. Conclusions: Patients with NED have improved survival compared to RES. Younger age and avoiding breast surgery correlates with NED. Evaluation of genomic factors influencing NED are planned.
Safety, efficacy, and biomarker analysis of pyrotinib in combination with capecitabine in HER2-positive metastatic breast cancer patients: A phase I clinical trial.
Authors: Ma Fei , Li Qiao , Guan Xiuwen , Chen Shanshan , Yi Zongbi , Lan Bo , Xing Puyuan , Fan Ying , Wang Jiayu , Luo Yang , Yuan Peng , Cai Ruigang , Zhang Pin , Li Qing , Xu Binghe
Published: May 2019

1035

Background: Cross-signaling in the ErbB family is an important mechanism in Trastuzumab resistance. Pyrotinib is an irreversible pan-ErbB inhibitor targeting EGFR/HER1, HER2 and HER4, which may offer the potential for improved efficacy to block HER2 signaling in trastuzumab-resistant breast cancer. This phase I study assessed the safety, tolerability, maximum-tolerated dose (MTD), pharmacokinetics, antitumor activity and predictive biomarkers of pyrotinib in combination with capecitabine in patients with HER2-positive metastatic breast cancer (MBC). Methods: Patients received oral pyrotinib 160 mg, 240 mg, 320 mg, or 400 mg once daily continually plus capecitabine 1000mg/m2 twice daily on days 1 to 14 of a 21-day cycle. Pharmacokinetic blood samples were collected predose on day 1 and day 14 of treatment. Next-generation sequencing (NGS) was performed on circulating tumor DNA (ctDNA) to probe for predictive biomarkers of this combination. Results: A total of 28 patients were enrolled. All 28 (100%) patients experienced at least one treatment-related Adverse Events (AE), which were predominantly grade 1 or 2. Grade 3 treatment-related AE occurred in 12 (42.9%) patients; anemia (14.3%) and diarrhea (10.7%) were the most common grade 3 AEs. Three (10.7%) patients discontinued capecitabine administration due to AEs. The overall response rate (ORR) was 78.6% (95% CI: 59.0% to 91.7%), and the disease control rate (complete response+ partial response+ stable disease) was 96.4% (95% CI: 81.7% to 99.9%). The median progression-free survival (PFS) was 22.1 months (95% CI: 9.0 to 26.2 months). ORR was 70.6% (12/17) in trastuzumab-pretreated patients and 90.9% (10/11) in trastuzumab-naive patients. NGS analysis of all genetic alterations of HER2 bypass signaling pathway, PI3K/Akt/mTOR pathway and TP53 in baseline blood samples suggested that concomitant (two or more) genetic alterations were significantly associated with poorer PFS compared to none or one genetic alteration (median, 15.8 vs. 26.2 months, p = 0.006). Conclusions: Pyrotinib in combination with capecitabine are well-tolerated and demonstrate promising antitumor activity in HER2-positive MBC patients. Clinical trial information: NCT02361112.
Association of HER2 alterations and ESR1 mutations in cell-free DNA (cfDNA) with circulating tumor cells (CTCs), multiple metastasis, and prognosis in stage III/IV breast cancer (BCa).
Authors: Zhang Qiang , Gerratana Lorenzo , Shah Ami N. , Davis Andrew A. , Flaum Lisa E. , Zhang Youbin , Qiang Wenan , Behdad Amir , Gradishar William John , Platanias Leonidas C. , Cristofanilli Massimo
Published: May 2019

1036

Background: The monitoring of CTCs and cfDNA in metastatic BCa showed ability to predict treatment resistance and survival. Here we report a highly significant correlation between HER2 alterations and ESR1 mutations of cfDNA with CTCs and prognosis of BCa, which may help to predict disease recurrence and treatment benefit. Methods: A total of 85 blood samples (7.5ml/each) were collected from 85 patients with stage III/IV BCa who received treatments at Northwestern RHLCCC. CTC enumeration was performed in FDA approved CELLTRACKS ANALYZERII System (Menarini). Plasma cfDNA was analyzed using Guardant360 NGS-based assay including a 73-gene panel for genomic alterations or mutations. We previously reported cut-off of 5.7% (2018 ASCO) was used to dichotomize the prognostic value of cfDNA percentage. Kruskal-Wallis test was used for statistics. Results: Of the 85 whole samples analyzed, there were 72 samples and 67 samples without ESR1 mutations (ESR1-) and HER2 alterations ( HER2-) respectively, and there are 13 samples and 18 samples that had ESR1 mutations ( ESR1+) and HER2 alterations ( HER2+, 10 amplified, 7 mutated, 1 for both) respectively. CTC positive (≥5) were detected in 13/57 ESR1-HER2- samples (Group 1) and 5/15 ESR1- HER2+ samples (Group 2), 7 /10 ESR1+ HER2- samples (Group 3), 3/3 ESR1+ HER2+ samples (Group 4). The median CTCs number/sample in Group 3 (15 CTCs) and Group 4 (12 CTCs) were significantly higher than Group 1 (0 CTC) and Group 2 (2 CTCs) (P = 0.0020). There were a significant higher average metastasis sites in Group 3 (3 sites) and Group 4 (3 sites) in compared to Group 1 (2 sites) and Group 2 (1 site) (P = 0.0035). Furthermore, patients in Group 4 ( ESR1+ HER2+) has the worst prognosis in compared to other groups (P = 0.0151) on overall survival. Conclusions: Both ESR1 mutations and HER2 alterations in cfDNA contribute to CTCs detection and disease metastasis sites independently, when ESR1 mutations plays a major role. The synergy of ESR1 mutation and HER2 alteration expands the predictive role of liquid biopsy tests monitoring the metastatic prognosis and endocrine resistance for clinical decision-making.
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]
Phase II clinical trial using anti-CD3 x anti-HER2 bispecific antibody armed activated T cells (HER2 BATs) for HER2-negative (0-2+) metastatic breast cancer.
Authors: Lum Lawrence G. , Thakur Archana , Al-Kadhimi Zaid S. , Deol Abhinav , Simon Michael S. , Schalk Dana , Liu Qin , Flaherty Lawrence E.
Published: May 2019

1080

Background: This study presents a phase II cell therapy trial in 32 women with metastatic or locally advanced HER2- breast cancer (BrCa) who received infusions of anti-CD3 x anti-HER2 bispecific antibody armed activated T cells (BATs). This phase II study (NCT 01022138) was conducted to determine if BATs infusions could improve time to progression (TTP) and overall survival (OS), as well as to confirm the toxicity profile of BATs. Methods: The phase II included 32 patients with a median of 4 lines of therapy (7 TNBC and 25 HR/PR+ HER2- patients) with an average age of 52.5 years (range 28-75 years). Twenty-one patients had ≥3 lines of prior therapy and 11 patients had 1-2 lines. Peripheral blood mononuclear cells (PBMC) were stimulated with anti-CD3 antibody and expanded in IL-2, armed with HER2Bi, and aliquoted for the clinical trial. Patients received oncologist’s choice of chemotherapy (4 cycles/4 months) followed by 3 infusions of BATs given once per week for 3 weeks and a boost given 12 weeks after the 3rd infusion. Results: Fifteen of 32 (ORR of 46.8%) who had received any cells had stable disease (SD) at 1 month after the last infusion, and 8 of 15 (25%) had SD > 4 months. For patients who completed 3 or 4 infusions (17-83 x 109 BATs), 8 of 31 patients had TTP > 4 months. One patient completed 2 infusions (17 x 109 BATs). There were no dose limiting toxicities (DLTs). Tumor markers decreased in 13 of 23 (56.5%) patients with evaluable markers. The median OS was 13.8, 16.5, and 12.4 months for all, ER/PR+, and TNBC, respectively. OS for all patients with chemosensitive (chemoS) and chemoresistant (chemoR) disease was 14.6 and 8.6 months (NS), respectively. OS for chemoS and chemoR disease in HER2- ER/PR+ patients was 16.5 and 8.6 months (NS), respectively. OS for chemoS and chemoR disease in TNBC patients was 12.4 and 22.6 months, respectively (NS). The median TTP for all, HER2- ER/PR+, and TNBC patients was 2.7, 2.9, and 1.4 months, respectively. Increases in serum IL-2 and IL-12 were associated with BATs infusions. Conclusions: Targeting HER2- tumors was safe. There were trends toward improved survival in patients who were HER2-/ER/PR+ TNBC, patients who were chemoS, was associated with increased TTP and OS in all groups, and was associated with decreased tumor markers in those who received 4 infusions. Immune studies showed evidence for induction of adaptive immunity directed at breast cancer antigens. Targeting metastatic HER2- BrCa with BATs shows promise. Clinical trial information: NCT 01022138.
ARID1a as a marker of prognosis and increased sensitivity to CDK4/6, mTOR 1/2 and Src homology region 2 phosphatase (SHP 1/2) inhibitors in breast cancer (BC).
Authors: Mariotti Veronica , McLeod Howard L. , Soliman Hatem Hussein
Published: May 2019

1082

Background: ARID1a (AT Rich Interactive Domain 1A) is part of the SWI/SNF complex, which regulates gene transcription, and is believed to be a tumor suppressor gene. Low ARID1a expression has been associated with poor prognosis in BC. The aim of this study was to explore the clinical significance of ARID1a mutation and expression loss, and its potential as a therapeutic target in BC. Methods: We analyzed publicly available genomic databases to study the clinical implication of ARID1a mutations and gene expression in BC. Results: ARID1a was mutated in ~5-7 % of BCs within TCGA/METABRIC/MSK (5511 samples), but did not show differences in frequency between histology, grade, or estrogen receptor (ER)/HER2 receptor status. MSK metastatic tissue samples had higher incidence of ARID1a mutation compared to primary tumor samples (7.6% vs 4.4%, χ2 P = 0.0073). Analysis of ARID1a in KMPLOT showed that lower gene expression was associated with worse relapse-free survival and overall survival across all BCs, but the difference was primarily in molecularly classified luminal A tumors. Mutations in ARID1a did not show an association with outcomes in TCGA/METABRIC/MSK datasets. Pathway analysis of ARID1a showed it is involved in regulating ER ligand driven signaling and interacts with targets regulated by CDK4 and mTOR activity. CancerRxgene drug sensitivity analyses on BC cell lines revealed that ARID1a mutated BC cell lines were significantly more sensitive to palbociclib, SHP1/2, and mTOR1/2 inhibitors compared to ARID1a wildtype cell lines. Conclusions: Reduced activity of ARID1a in luminal BC cells may negatively affect prognosis by altering ER signaling leading to activation of druggable resistance mechanisms, particularly in metastatic tissue. Loss of function ARID1a mutations may sensitize cancer cells to CDK4/6, mTOR1/2, and SHP1/2 inhibitors in vitro. Further research in ARID1a mutated ER+ BCs using combinations of these inhibitors is warranted.
Evaluation of oral S-1 as a first-line chemotherapy for metastatic HER2-negative breast cancer: An analysis of two randomized phase III studies (SELECT BC-CONFIRM and SELECT BC).
Authors: Nishimura Reiki , Mukai Hirofumi , Uemura Yukari , Akabane Hiromitsu , Park Youngjin , Takahashi Masato , Sagara Yoshiaki , Takashima Tsutomu , Fujisawa Tomomi , Hozumi Yasuo , Kawahara Takuya , Watanabe Takanori
Published: May 2019

1083

Background: Anthracycline regimens and taxane have been first line chemotherapeutic options for HER2 negative metastatic breast cancer. In a previous phase III trial (SELECT BC), non-inferiority of S-1 was demonstrated in terms of overall survival (OS). The SELECT BC-CONFIRM study was designed to confirm the results of the SELECT BC study and to combine the two randomized studies. Methods: Patients (n = 618) in the first trial were randomly assigned (1:1) to the S-1 group or the taxane group. Patients (n = 230) in the second trial (SELECT BC-CONFIRM) were randomly assigned to the anthracycline group or the S-1 group. Treatment continued until tumor progression, unacceptable toxic effects, or completion of six courses in the standard regimen group and four courses in the S-1 group. The primary endpoint was OS and secondary endpoints were progression-free survival (PFS), time to treatment failure, adverse events, HRQOL and cost-effectiveness. A pooled analysis of the two studies was predefined to confirm the results of the SELECT BC study. Results: 1. The HR for the anthracycline group was 1.09 [95%CI 0.80-1.48] in SELECT BC-CONFIRM, and the estimated predictive posterior probability that the HR does not exceed the threshold 1.333 was 90.27%. 2. Median OS was 32.7 months (S-1 group) and 36.3 months (standard treatment group). S-1 was not inferior to standard treatment in terms of OS (p non-inferiority = 0.0062). Median PFS was 11.2 months (S-1 group) and 11.2 months (standard treatment group). 3. Treatment was discontinued due to adverse events (i.e., neutropenia, febrile neutropenia, fatigue and edema) in 5.7% in the S-1 group and 6.6% in the standard treatment group 4. The EORTC QLQ-C30 questionnaire (global health status) revealed that there was no difference between the S-1 and anthracycline groups (p = 0.257), but there was a significant difference between the S-1 and taxane groups (p = 0.0039). Conclusions: S-1 is not inferior to taxane or anthracycline with respect to OS as a first-line treatment for MBC. S-1 should be considered a new option as a first-line chemotherapy for HER2-negative metastatic breast cancer patients. Clinical trial information: UMIN000005449.
Oral paclitaxel in the treatment of metastatic breast cancer (MBC) patients.
Authors: Dai Ming-Shen , Chao Ta-Chong , Chiu Chang-Fan , Lu Yen-Shen , Shiah Her-Shyongi , Wu Yi-Yin , Cheng Wei-Hong , Chan Wing Kai , Hung Tak , Hung Noelyn , Cutler David , Kwan Rudolf , Kramer Douglas , Chao Tsu-Yi
Published: May 2019

1084

Background: Intravenous (IV) paclitaxel is an effective treatment for breast cancer. Oral administration paclitaxel is preferable to IV regarding minimizing IV injections, anaphylactic reactions to cremaphor, steroid pre-medications, hospital visits, and relevant costs. However, paclitaxel has poor oral absorption due to active excretion by P-glycoprotein (P-gp) in the intestinal cells. Oraxol (Athenex, USA) is an oral paclitaxel and HM30181, a novel oral inhibitor of intestinal P-gp which enables the oral administration of paclitaxel. We report the final results of a pharmacokinetics (PK) study, including clinical response and tolerability of Oraxol in treatment of metastatic breast cancer patients. Methods: Multicenter, single-arm, open-label, PK study of Oraxol (HM30181A at 15mg, plus oral paclitaxel 205mg/m2) administered orally for 3 consecutive days weekly for up to 16 weeks. Paclitaxel PK was assessed at week-1 and week-4. Tumor Response was measured at weeks 8 and 16 using RECIST criteria 1.1. Toxicity was assessed using CTCAE v4.03. Results: Twenty-eight MBC patient were studied with a mean age of 56.6 years (range: 38 - 79 yrs). 26 patients had failed mutiple previous chemotherapies. There were 11 (42.3%) partial response, 12 (46.2%) stable disease and 3 (11.5%) progressive disease in 26 evaluable patients. Three patients had treatment-related SAEs (grade ≥3 neutropenia) and all patients recovered completely. PK results showed that the AUC of oral paclitaxel at week-1 was reproducible at week-4 (3050 to 3594 ng-hr/mL). Conclusions: Oral paclitaxel showed very encouraging anti-cancer activity in MBC patients who failed previous chemotherapies with acceptable toxicity. Weekly oral paclitaxel can achieve paclitaxel exposure similar to that of weekly IV paclitaxel (80mg/m2) reported previously. PK of oral paclitaxel is reproducible. Clinical trial information: NCT03165955.