bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic impact of ESR1 mutations in ER+ HER2- MBC patients prior treated with first line AI and palbociclib: An exploratory analysis of the PADA-1 trial.
Authors: Bidard Francois Clement , Callens Celine , Dalenc Florence , Pistilli Barbara , De La Motte Rouge Thibault , Clatot Florian , D'hondt Veronique , Teixeira Luis , Vegas Helene , Everhard Sibille , Lemonnier Jerome , Bieche Ivan , Pradines Anne , Paitel Jean FranCois , Spaeth Dominique , Moullet Isabelle , Pierga Jean-Yves , Berger Frederique , Hardy-Bessard Anne-Claire , Bachelot Thomas 
Published: May 2020

1010 Background: The question of which is the best endocrine partner to CDK4/6 inhibitors in first line for ER+ HER2- metastatic breast cancer (MBC) remains open. ESR1 mutations might be of paramount importance, as they confer resistance to AI but not to SERD. In pts treated with first line palbociclib-AI combination (PADA-1 trial, NCT03079011), we investigated ESR1mut detection rate at inclusion, prior to any therapy, and their prognostic impact. Methods: The PADA-1 phase 3 trial (NCT03079011, UCBG-GINECO) evaluates the utility of monitoring the onset of ESR1mut in cell-free DNA (with a ddPCR assay [Jeannot et al, Oncogene 2020]) of pts receiving AI-palbociclib in first line. Included pts had no prior therapy for MBC and no overt resistance to AI. Results: N = 1017 ER+ HER2- MBC pts were included in 22 months from 04/2017 and had their cfDNA tested for ESR1mut at inclusion and during therapy. N = 33/1017 pts had a detectable circulating ESR1mut at inclusion (3.2%, 95%CI [2.2;4.5]), ESR1mut positivity being associated with a prior exposure to AI in the adjuvant setting (p < 0.01). N = 1 pt died after 1 month on treatment. In N = 25/32 evaluable pts (78%), ESR1mut became undetectable in cfDNA (AF < 0.1%) within the first 5 months on treatment, with a median time to ESR1mut ‘clearance’ of 34 days. Among these 25 pts, 14 pts (56%) had ESR1mut detected again during therapy; 2 pts (8%) experienced a progression with no ESR1mut detected; the remaining 9 patients (36%) were still both ESR1mut -free and progression-free at time of analysis. With a median FU time of 12.4 months (range: 0-25.3m) under AI-palbociclib, the 33 ESR1mut-positive pts had a shorter PFS (median: 17.5mo, 95%CI[10.5-NR]) than the 984 ESR1mut-negative pts (median not reached), with an estimated HR = 2.8 [1.6;5.0]. Updated data will be presented at the meeting. Conclusions: ESR1mut are rarely detected in the cfDNA of ER+ HER2- MBC patients with no overt resistance to AI. The quick ‘clearance’ of ESR1mut under treatment and the observed 17.5 months-long median PFS both suggest that the AI-palbociclib combination retain a clinical activity in this population. ESR1mut-positivity prior was however associated with a significantly shorter PFS, suggesting that ESR1mut positivity at baseline could accelerate the onset of resistance to AI-palbociclib. These findings may put into perspective the incoming results of the PARSIFAL trial. Clinical trial information: NCT03079011 .
Results of ENCORE 602 (TRIO025), a phase II, randomized, placebo-controlled, double-blinded, multicenter study of atezolizumab with or without entinostat in patients with advanced triple-negative breast cancer (aTNBC).
Authors: O'Shaughnessy Joyce , Moroose Rebecca L. , Babu Sunil , Baramidze Kakhaber , Chan David , Leitner Stuart P. , Nemsadze Gia , Ordentlich Peter , Quaranto Christine , Meyers Michael L. , González Graf Valeria , Smith Taunya J. , Bee-Munteanu Valerie , Fresco Rodrigo , Slamon Dennis J. 
Published: May 2020

1014 Background: Chemotherapy remains as the only standard treatment option for aTNBC in second and subsequent lines. Entinostat (ENT) is an oral, class I-selective histone deacetylase inhibitor, that has shown antitumor activity in preclinical models of TNBC when combined with immune checkpoint blockade. ENCORE 602 evaluated the efficacy and safety of atezolizumab (ATEZO) + ENT vs ATEZO + placebo (P) in patients (pts.) with pretreated aTNBC. Methods: Pts. with previously treated aTNBC (PD-1/PD-L1 inhibitors naïve) were randomized 1:1 to receive ATEZO (1200 mg IV Q3W) + ENT (5 mg PO QW) or ATEZO+P. Treatment continued until unequivocal progressive disease or unacceptable toxicity. The primary endpoint was PFS as determined by the investigators using RECIST 1.1. The hypothesis was that the combination would improve median PFS by 3 months (hazard ratio = 0.57). Sixty events (from 70 pts.) would provide 80% power with 1-sided significance level of 0.1. Secondary endpoints were PFS per immune-related RECIST (irRECIST), ORR, clinical benefit rate (CBR), Overall Survival (OS), and safety. Results: 81 pts. were enrolled, median age 56 years (range 29-87), 69% received 1 prior line of therapy and 31% > 1 line. No significant difference in PFS per RECIST 1.1 was observed between ATEZO+ENT and ATEZO+P (median PFS 1.68 and 1.51 months, respectively [p = 0.64; HR 0.89, 95% CI: 0.53-1.48]), nor in any of the secondary efficacy endpoints (median PFS per irRECIST 1.68 vs 1.54 months; ORR 10.0% vs 2.4%; CBR 37.5% vs 31.7%; median OS 9.8 vs 12.4 months, respectively). Frequency of treatment-emergent adverse events (TEAEs), SAEs, discontinuations due to TEAE and TEAE with outcome death were higher in the ENT+ATEZO arm. Conclusions: In pts. with previously treated aTNBC, median PFS was not prolonged when ENT was added to ATEZO compared to ATEZO and placebo, and the combination resulted in greater toxicity. Clinical trial information: NCT02708680 .
International retrospective cohort study of locoregional and systemic therapy in oligometastatic breast cancer (OLIGO-BC1).
Authors: Ueno Takayuki , Bi XiWen , Liu Guangyu , Sim Sung Hoon , Im Seock-Ah , Takao Shintaro , Wang Kun , Im Young-Hyuck , Futamura Manabu , Ahn Sung Gwe , Lee Jeong Eon , Park Yeon Hee , Toi Masakazu , Fujiwara Yasuhiro , Saito-Oba Mari , Kitagawa Yuko , Nishiyama Masahiko , Imoto Shigeru 
Published: May 2020

1025 Background: Systemic therapy is the standard care in metastatic breast cancer (BC). However, retrospective studies demonstrated survival benefits of locoregional and systemic (combination) therapy in oligometastatic BC. To clarify it, the Federation of Asian Clinical Oncology conducted an international retrospective cohort study (OLIGO-BC1) (UMIN No.000030047). Methods: Oligometastatic BC patients diagnosed from 2007 to 2012 were registered. “Oligometastases” is defined as low volume metastatic disease with limited number and size of metastatic lesions up to five and not necessarily in the same organ by the ABC guidelines. Overall survival (OS) from the diagnosis of oligometastases was the primary endpoint and compared between combination and systemic therapy using a log-rank test. Assuming the 5-year OS of 50% and 40%, respectively, 698 patients were required to achieve 80% power to detect the superiority of combination therapy, at a two-sided significance level. A multivariable Cox regression model with stratification by country was performed to estimate hazard ratio (HR) for therapy and other risk factors. Results: While 1,262 cases had been registered from February 2018 to May 2019, 1,200 remained for analysis after exclusion of unavailable cases. Among them, 573, 529 and 98 cases were registered from China, Japan and Korea, respectively. Luminal BC was recorded in 526 cases (44%), luminal-HER2 BC in 189 (16%), HER2 BC in 154 (13%), triple-negative BC in 166 (14%) and others in 165 (13%). One oligometastatic BC was found in 578 cases, 2 in 289, 3 in 154, 4 in 102 and 5 in 77. Bone metastases were recorded in 301 cases, visceral metastases in 387, locoregional recurrence in 25, local recurrence in 83 and multiple metastatic sites in 404. Combination therapy was performed in 595 cases and systemic therapy in 404. At median follow-up of 4.9 years, 5-year OS was 59.6% and 41.9%, respectively (p < 0.01). An adjusted HR was 0.61 (95% CI: 0.51, 0.74). Type of systemic therapy, younger age, ECOG performance status 0, stage I BC, non-triple negative subtype, fewer metastatic sites, local recurrence and longer disease-free interval were significantly favorable prognostic factors. Discussions: Oligometastatic BC under some conditions seems to be curable. Taken together with recent molecular targeted therapy, locoregional therapy will be advantageous to conquer it. Conclusions: Combination therapy is a promising strategy for patients with oligometastatic BC.
Circulating tumor DNA (ctDNA) to evaluate stage III and stage IV metastatic breast cancer (MBC), describe tumor heterogeneity, and outcome.
Authors: Zhang Qiang , Cai Zheng , Gerratana Lorenzo , Davis Andrew A. , Jacob Saya , D’Amico Paolo , Vagia Elena , Zhang Youbin , Qiang Wenan , Wehbe Firas , Kerby Katy Lucretia , Flaum Lisa E. , Shah Ami N. , Behdad Amir , Gradishar William John , Platanias Leonidas C. , Cristofanilli Massimo 
Published: May 2020

1028 Background: MBC is a challenging clinical condition treated with palliative intent due to tumor heterogeneity. We reported in 2019 ASCO that the correlation of HER2 and ESR1 mutations of ctDNA with CTCs results in worse prognosis in MBC. Here we reported that ctDNA mutations is a key point which is different between Stage III and Stage IV, and it would be helpful to evaluate the MBC metastasis and outcome. Methods: This study included 33 Stage III and 204 Stage IV MBC patients who received systemic treatments at NMH (2016-2019). Plasma ctDNA before treatment was isolated from patients and then was analyzed by Guardant 360 Health NGS-based assay for a 73 genes panel for genomic alterations including single nucleotide variants, insertions/deletions, gene fusions/rearrangements and copy number variations. Causal Inference with Ensembel Learning was used for statistical analyses. Results: Among stage III patients, 40% are luminal, 44% are HER2+ and 16% are TNBC, while in stage IV 50% patients are luminal, 20% are HER2+ and 30% are TNBC. The major differences in ctDNA between two stages lie in several genes including PIK3CA, ERBB2 and KRAS. On the top of the list is PIK3CA, which is detected in 2 out of 33 stage III patients (1 luminal, 1 HER2+) (6.06%) in baseline, each of them carries 1 mutation on PIK3CA (E542K, E545G). In 43 out of 204 stage IV patients (21.57%) who carry this gene, 15 show 1 amplification, 34 have 1 mutation (mainly H1047R, E542K, E545K and H1047L), 11 have 2 mutations (E542K/E726K, D454N/D1029N, E545K/D1017H, E545K/L287L, H1047R/E453K, H1047R/N426S and P539R/H1047R), and 1 has 3 mutations (E542Q/D454N/D1029N and E545K/E726K/R93Q). On treatment effects, PIK3CA is found to be very detrimental on prognosis and on its effects on the treatment outcome. Patients without any mutation in PIK3CA live 2.65 times longer than those with more than one mutations on PIK3CA ( p-value = 4.47e-06, CI = [1.731, 3.926]). PIK3CA, ESR1, TP53 and ARID1A are found to significantly affect liver metastasis when RET, FBXW7, ERBB2, CCND2, BRAF and MET are found to be associated with lung metastasis for both stages. EGFR, KIT and ARID1A are associated with CNS metastasis. Conclusions: We elucidated that ctDNA mutations on PIK3CA and other genes dramatically increased in Stage IV patients compared to Stage III patients which provides a new insight on the Stage III and Stage IV MBC determination. New set of genes especially PIK3CA are identified to correlate with metastasis and affect the outcome which may also be reliably used to monitor the response to therapy.
Detection of actionable gene mutations in breast cancer by amplicon-based next-generation sequencing liquid biopsy.
Authors: Lim Jing Shan , Choudhury Yukti , Phyo Wai Min , Gupta Chaitanya , Ho Yiliang , Tay Carina , Sim Yuki , Ng Wei Shuen , Tan Min-Han , Tsang Janice , See Hui Ti 
Published: May 2020

1035 Background: The PI3K-inhibitor, alpelisib, was approved for the treatment of hormone receptor (HR)-positive, HER2-negative breast cancers with PIK3CA mutations based on findings from the SOLAR-1 trial. PIK3CA-positivity in tumor tissue was 29% (341/1172), but was only 15% (177/1172) in plasma cell-free DNA (cfDNA). The lower mutation detection rate observed in cfDNA may limit the clinical application of liquid biopsy in breast cancer. Amplicon-based next-generation sequencing (NGS) approach may confer improved sensitivity, allowing more effective profiling. We conducted a study to evaluate the use of this technology. Methods: Plasma cfDNA from 113 breast cancer patients (82.3% metastatic) underwent real-world testing in a CAP and ISO15189 accredited central laboratory. We analysed genetic alterations in cfDNA using an amplicon-based NGS technology. The presence of PIK3CA and other mutations relevant to breast cancer were correlated to molecular subtypes and treatment histories. Results: At least one mutation was detected in 70.8% of cases. Mutations were more frequent in metastatic cases (77.4%) compared to non-metastatic cases (27.3%). Across all patients, mutations in PIK3CA (33.6%), TP53 (32.7%), ESR1 (22.1%), GATA3 (7.1%) and ERBB2 (7.1%) were most frequently detected, in accordance with tumor tissue genotyping studies. PIK3CA mutations were more common in HR+ HER2- patients (44.4% vs 28.6% of other patients). Among PIK3CA-mutant cases, multiple PIK3CA mutations were present in 18.4% of cases, and hotspot mutations H1047R (34.2%), E542K (26.3%) and E545K (15.8%) were most frequent. An association was seen between PIK3CA mutation and prior treatment with CDK4/6 inhibitors (palbociclib, ribociclib) or mTOR inhibitor (everolimus), with 58% of PIK3CA-mutant cases having received these treatment previously compared to only 20% of PIK3CA-wild type (wt) cases. In addition, 75% of previously treated ESR1-mutant cases had specifically received hormonal treatment, compared to 60 % of ESR1-wt cases that received any treatment. Conclusions: We report similar PIK3CA mutation frequencies (~30%) with amplicon-based NGS on cfDNA compared to tumor tissue testing in breast cancer. Importantly, other driver mutations were also observed at similar frequencies as external tissue studies, implying high sensitivity as the primary reason for performance. This supports the clinical utility of an amplicon-based NGS-based approach to liquid biopsy for the sensitive detection of actionable mutations in breast cancer.
A phase Ib study of pembrolizumab (pembro) plus trastuzumab emtansine (T-DM1) for metastatic HER2+ breast cancer (MBC).
Authors: Waks Adrienne Gropper , Keenan Tanya , Li Tianyu , Tayob Nabihah , Wulf Gerburg M. , Richardson Edward T. , Mittendorf Elizabeth A. , Overmoyer Beth , Krop Ian E. , Winer Eric P. , Van Allen Eliezer Mendel , Agudo Judith , Tolaney Sara M. 
Published: May 2020

1046 Background: Preclinical evidence suggests treatment (tx) with T-DM1 plus an anti-PD1 antibody triggers antitumor immunity. We conducted a phase 1 trial to determine the safety and explore the efficacy of T-DM1 plus pembro. Methods: Eligible patients (pts) had MBC previously treated with trastuzumab (H) and taxane (T), were T-DM1-naïve, and received >1 prior line of tx for MBC or developed recurrence within 6 months (mo) of adjuvant tx. A dose de-escalation (esc) design was used with 6 pts in the dose-finding cohort, followed by an expansion (exp) cohort at the recommended phase 2 dose (RP2D), with mandatory baseline biopsies (bx). The primary endpoint was safety and tolerability. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and clinical benefit rate (CBR: complete response + partial response + stable disease >24 weeks). Associations between immune biomarkers and tx response were explored. Results: 20 pts started protocol tx (6 in dose de-esc cohort; 14 in exp cohort). Median follow-up was 23.5 mo. Pts had median age 54 yrs and median 1 line of prior MBC tx (range 0-2); 100% had received prior T, H, and pertuzumab. There were no dose-limiting toxicities in the dose de-esc cohort; thus full doses of T-DM1 (3.6 mg/kg q21 days) and pembro (200 mg q21 days) were the RP2D. 85% of pts experienced tx-related adverse events (AEs) > grade (gr) 1; 20% of pts experienced gr3 AEs. There were no gr>4 AEs. Gr3 AEs were fatigue; AST increase; ALT increase; pneumonia; pneumonitis; oral mucositis; and vomiting, each in 1 pt. 17 pts had baseline bx; 6 pts had repeat bx after 1 tx cycle. Efficacy results, overall and by PD-L1 Combined Positive Score (CPS; 22C3 staining) and tumor-infiltrating lymphocyte (TIL) status, are shown in the table. Tumors’ antigen presentation will be explored through HLA/dendritic cell marker staining and immune signatures by RNA sequencing. Conclusions: T-DM1 plus pembro was safe and tolerable. The regimen demonstrated clinical activity. Further exploration of immune-related predictive biomarkers is warranted. Clinical trial information: NCT03032107 . [Table: see text]
Utility of circulating cell-free DNA (cfDNA) analysis in patients with carcinoma of unknown primary (CUP) in identifying alterations with strong evidence for response or resistance to targeted therapy.
Authors: Weipert Caroline , Kato Shumei , Saam Jennifer , Kurzrock Razelle 
Published: May 2020

105 Background: CUP is a rare, heterogeneous group of cancers with an overall poor prognosis; the standard treatment remains chemotherapy. The OncoKB database is a curated list of somatic molecular alterations. Alterations with the highest classification must be an FDA-recognized biomarker associated with response to an FDA-approved drug (Level 1), be recommended by major guidelines or expert panels as predictive of response to an FDA-approved drug (Level 2) or be predictive of resistance to an FDA-approved drug (R1). We explored the landscape of alterations classified as Level 1, 2 or R1 based on the OncoKB scale in a large cohort of CUP patients tested via a well-validated cfDNA assay. Methods: We queried consecutive samples from advanced cancer patients with a listed diagnosis of CUP who underwent testing via a commercially available liquid biopsy assay (Guardant360) between November 2016 and November 2019. The cfDNA assay included targeted next-generation sequencing of 73- to 74-genes specifically curated to include genes with potential targeted therapy options. Alterations were classified based on their ranking in the OncoKB database as of January 2020. Results: In total we identified 2,022 samples with a diagnosis of CUP, and 90.0% of these samples had >1 cfDNA alteration detected. The median age of patients was 68 years and 51% were female. Overall, 20.7% of patients had a Level 1 alteration, 9.5% had a Level 2 alteration, and 23.9% had an R1 alteration (select alterations outlined in Table). Conclusions: cfDNA analysis of patients with advanced CUP identified a significant number of patients with alterations associated with strong evidence for either response or resistance to treatment based on the OncoKB classification schema. While many of these alterations are associated with approvals in specific cancer types, the identification of these alterations suggests many CUP patients may have targeted therapy options. We will present case examples illustrating patient outcomes from CUP patients who received targeting therapy based on cfDNA results. [Table: see text]
Phase I trial of lorlatinib in patients with ALK-driven refractory or relapsed neuroblastoma: A New Approaches to Neuroblastoma Consortium study.
Authors: Goldsmith Kelly C. , Kayser Kimberly , Groshen Susan G. , Chioda Marc , Thurm Holger C. , Chen Joseph , Peltz Gerson , Granger Meaghan , Maris John , Matthay Katherine K. , Ghazarian Suzy , Park Julie R. , Berko Esther , Marachelian Araz , Mosse Yael P. 
Published: May 2020

10504 Background: Lorlatinib, a potent ALK inhibitor, exerts unprecedented activity against neuroblastoma (NB) derived xenografts harboring common crizotinib-resistant ALK mutations, leading to a first in child phase I study. Methods: R/R NB patients (pts) > 12 months, with ALK mutations/amplification and prior ALK inhibitor (ALKi) treatment were eligible. Lorlatinib was administered in 28-day courses (C). For pts < 18 years, 5 dose levels (DL) (45, 60, 75, 95, 115 mg/m2/day) were assessed. DL5 (115 mg/m2/day) expansion is enrolling (cohort A1). For patients > 18 years, two DL (DL3a the adult RP2D of 100 mg/day and DL4a at 150mg/day) were assessed (cohort A2). Primary endpoint was dose-limiting toxicity (DLT) during C1 and neurocognitive toxicity through C2. Blood samples for circulating tumor DNA (ctDNA) were matched to radiologic restaging. Results: From 9/2017 to 1/2019, 33 eligible patients enrolled (13 with prior ALKi therapy), with median age (range) 5.5 years (2-17) on A1, 21.5 years (15-50) on A2. In A1, 3 pts each enrolled onto DL1-3, with no DLT’s. 5/10 pts enrolled on DL4, with no DLT’s. 1/3 on DL5 had a DLT of grade 3 diarrhea, with expansion ongoing. In cohort A2, 5 patients enrolled at 100 mg/day with no DLT’s; 6 enrolled at 150 mg/day, with one DLT (grade 4 reversible psychosis). Most common treatment-related adverse events were weight gain (90%, grade 1-3), hyperlipidemia (90%, grade 1-3), concentration/memory impairment (23%, grade 1-2), peripheral neuropathy (13%; grade 1-2, A2 only), and peripheral edema (10%; grade 1, A2 only). Lorlatinib steady state exposure at DL3 and DL4 was in the range of exposures seen in adult lung cancer patients at the 100 mg and 200 mg DLs. In A1, 1/18 had partial response (PR), 3/18 had minor responses (MR), and 4/18 had stable disease (SD). Of pts with MR, 2/3 had PR of soft tissue and 1/3 had complete response (CR) by MIBG. In A2 pts, 1/10 had CR, 3/10 PR, and 3/10 MR; Notably, 2/3 with PR had CR by MIBG. Of the pts with MR, one had PR and one CR by MIBG. Responses occurred across dose levels, ALK mutations, and in ALKi pre-treated pts with median courses of 2 (1-24) on A1 and 10.5 (2-28) on A2. Serial ctDNA results showed mutant ALK variant allele frequency trajectories that correlated with clinical response and emergence of novel ALK mutations in cis that corresponded with disease progression. Conclusions: Inhibition of ALK-driven NB with lorlatinib occurs with manageable toxicity and objective anti-tumor activity. Prospective ctDNA allows for monitoring of disease and evolution of resistance. Clinical trial information: NCT03107988.