bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic and predictive effects of circulating and disseminated tumor cells in breast cancer: A National Cancer Database (NCDB) analysis.
Authors: Bilani Nadeem , Elson Leah , Arteta-Bulos Rafael , Elimimian Elizabeth Blessing , Liang Hong , Nahleh Zeina A. 
Published: May 2020

1029 Background: Alongside other biomarkers, circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) could contribute to our growing understanding of the breast cancer (BC) “liquid biopsy”. This study evaluated 1) clinicopathologic factors associated with CTCs and DTCs, 2) the prognostic value of CTCs and DTCs by disease stage, 3), the efficacy of chemotherapy by CTC and DTC status. Methods: We conducted a retrospective analysis of BC using the 2004-2016 National Cancer Database (NCDB). The NCDB defines CTCs as isolated tumor cells (ITCs) found in the blood (using assays such as reverse transcriptase polymerase chain reaction or immunohistochemistry) distant from the breast. DTCs are ITCs found in the bone marrow or other non-regional tissues. To evaluate variables associated with CTCs or DTCs, we used chi-squared and Wilcoxon rank-sum tests (univariate), followed by multivariate logistic regression. Consequently, we included CTC or DTC status in a multivariate, stage-by-stage Cox regression analysis for overall survival (OS). After adjusting for receptor status and staging, we used the Kaplan-Meier method to explore chemotherapy efficacy in CTC- or DTC-positive vs. CTC- or DTC-negative subsets. Results: 4,846 cases reported CTC-status, 1,454 (21.1%) of which were positive. 4,993 cases reported DTC-status, 1,400 (20.3%) of which were positive. Factors associated with positive CTC status were HER2-positivity, progesterone receptor-positivity, lobular histology and N-staging. Factors associated with positive DTC status were being White, HER2-positivity, lobular histology and N-staging. Positive CTC-status was associated with poor OS overall in late-stage (III and IV) (HR 1.477, 95% CI: 1.129-1.931, p = 0.004) but not early-stage BC (0, I, II) (p = 0.110) disease. DTC-status was not associated with OS in early-stage or late-stage subsets. In hormone receptor (HR)-positive disease, chemotherapy was associated with better OS when CTC-status was also positive both in early-stage (p = 0.003) and late-stage (p = 0.023) disease. In a subset of the same BC subtype with negative CTC-status, however, chemotherapy conferred no survival benefit (p = 0.638 for early-stage, p = 0.501 for late-stage). DTC status was not a significant predictor of chemotherapy efficacy in early or late-stage, HR+ disease. Conclusions: This study suggests that CTC-status is a stronger prognostic factor at later stages of BC; yet it can also help guide management of early-stage disease as it appears predictive for chemotherapy benefit.
Identification of pathogenic ROS1 alterations in cell-free DNA (cfDNA) from patients with breast cancer.
Authors: Force Jeremy Meyer , Taylor Mary Love , Drusbosky Leylah , Yen Jennifer , Marcom Paul Kelly , Anders Carey K. , Marks Jeffrey R 
Published: May 2020

1031 Background: ROS1 is an important proto-oncogene involved in the development of various cancers for which we have FDA approved therapies. While activation of the ROS1 tyrosine kinase receptor has been reported in 1-2% of lung cancers, the frequency and type of ROS1 alterations in breast cancer have not been fully explored. We previously described the incidence of ROS1 alterations from breast cancer tissue. The purpose of this study was to identify the incidence of ROS1 genomic alterations occurring in cfDNA from patients with breast cancer. Methods: We queried 16,053 breast cancer samples from the Guardant Health breast cancer database between June 2015 - October 2019 to identify the incidence of ROS1 alterations detected in cfDNA in breast cancer. We identified fusion partner genes and classified each alteration type into the following categories: fusion, single nucleotide variants (SNVs), and indels. Radical amino acid changes occurring at conserved regions across the ROS1 gene were identified. In vitro analyses were used to investigate the effect of ROS1 nonsynonymous mutations on the ROS1 protein. We made associations with ROS1 alterations and co-occurring mutated genes. Results: Nonsynonymous ROS1 alterations from the Guardant Health breast cancer database were found in 162 samples from 142 patients in the 16,053-patient cohort (1%). Alterations found included: 1 (0.6%) ROS1-SLC35F1 fusion, 155 (95.7%) SNVs, and 6 (3.7%) indels. Of the 155 SNVs, we identified 23 (14.8%) mutations occurring in the ROS1 kinase, of which, 20 (12.9%) occurred at highly conserved regions and 15 (9.6%) harbored radical amino acid changes. The top 5 co-occurring mutations in samples with ROS1 alterations were TP53 (50%), PIK3CA (44%), ESR1 (27%), EGFR (21%), and FGFR1 (18%). Conclusions: A modest incidence of ROS1 genomic alterations occurs in cfDNA from patients with breast cancer. New somatic alterations in the ROS1 gene were identified from Guardant Health that were not detected in publicly available databases. A portion of mutations occurred at highly conserved regions across the ROS1 gene suggesting these may be more actionable than currently recognized. In vitro analyses of ROS1 gene activation from these newly discovered somatic alterations are being investigated with results to be reported. Co-occurring mutations reveal a unique genotype associated with ROS1 alterations that may play a biologic role in ROS1-mediated pathogenesis.
Trastuzumab deruxtecan for HER2-positive metastatic breast cancer: DESTINY-Breast01 subgroup analysis.
Authors: Modi Shanu , Andre Fabrice , Krop Ian E. , Saura Cristina , Yamashita Toshinari , Kim Sung-Bae , Tamura Kenji , Chen Shuquan , Suto Fumitaka , Kuwahara Yusuke , Lee Caleb C. , Park Yeon Hee 
Published: May 2020

1036 Background: Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable linker, and a cytotoxic topoisomerase I inhibitor. In the pivotal DESTINY-Breast01 trial, efficacy of T-DXd in HER2-positive metastatic breast cancer (mBC) was demonstrated, with an objective response rate (ORR) of 60.9% and median progression-free survival (mPFS) of 16.4 months. Methods: DESTINY-Breast01 was a single-group, open-label, multicenter, phase II trial of 184 patients with HER2-positive mBC previously treated with trastuzumab emtansine (T-DM1) who received T-DXd at 5.4 mg/kg. Multivariate analysis using logistic regression models (ORR) and Cox proportional hazards models (duration of response [DOR], mPFS) explored 15 relevant clinical predictor variables. Circulating tumor DNA (ctDNA) was collected prior to the first dose, every 3 cycles of treatment, and at the end of treatment. Sequencing was done via GuardantOMNI (Guardant Health) for single-nucleotide variation/insertion and deletion, amplification, and fusion of ≈ 500 genes. Results: Efficacy in all evaluated clinical subgroups was similar to the overall ORR 60.9% and mPFS 16.4 months with ranges from ORR 46.4%-74.5% and mPFS 12.3-18.1 months. Variables associated with improved ORR, DOR, or mPFS included hormone receptor positive status, fewer prior treatment regimens (continuous variable), pertuzumab given in the first or second line, and normal renal and hepatic function. Variables that did not impact efficacy outcomes compared to the overall population include age, race, region, ECOG PS, HER2 IHC 3+ status, progesterone receptor status, best response to T-DM1, time since diagnosis, and history of brain metastases. In 48 subjects with progression as of data cut date, metastases were most commonly observed in the liver, lung, and lymph nodes. Only 8% (4 of 48) had progression involvement in the brain upon disease progression. Decrease of ERBB2 copy number in ctDNA was seen on treatment and correlated with clinical response. Additional changes in molecular markers on treatment and following progression will be described. Conclusions: T-DXd demonstrated strong efficacy in all clinical subgroups analyzed. Further exploration of both clinical and molecular variables to determine biomarkers of efficacy may be warranted. Clinical trial information: NCT03248492 .
Clinical activity of MCLA-128 (zenocutuzumab) in combination with endocrine therapy (ET) in ER+/HER2-low, non-amplified metastatic breast cancer (MBC) patients (pts) with ET-resistant disease who had progressed on a CDK4/6 inhibitor (CDK4/6i).
Authors: Pistilli Barbara , Wildiers Hans , Hamilton Erika Paige , Ferreira Ana Alexandra , Dalenc Florence , Vidal Maria , Gavilá Joaquín , Goncalves Anthony , Murias Carmen , Mouret-Reynier Marie-Ange , Canon Jean-Luc Re , Bazan Fernando , Ladoire Sylvain , Sirulnik L. Andres , Bekradda Mohamed , Bol Kees , Stalbovskaya Viktoriya , Murat Anastasia , Ford Jim , Bidard Francois Clement 
Published: May 2020

1037 Background: MCLA-128 (zenocutuzumab) is an ADCC-enhanced humanized bispecific antibody targeting HER2 and HER3 and potently blocking HER3-ligand induced receptor dimerization. Upregulation of Her2:Her 3 pathway is a means of resistance to ET in HR+ breast cancer, indicating a potential role for MCLA-128. In preclinical studies, the combination of MCLA-128 with ET in breast cancer xenografts outperformed single drug treatments. The current study explores the use of MCLA-128 to rescue pts with ET-resistant MBC who have progressed on a CDK4/6i. Methods: This phase II, open-label trial planned for up to 40 evaluable women with HR+, HER2 low (IHC 1+/IHC 2+ with negative FISH) MBC, who had progressed on a CDK4/6i and up to 3 lines of ET, who had received ≤ 2 chemotherapy regimens in the metastatic setting. Pts received MCLA-128 (750 mg, 2h IV, flat dose) q3w combined with last ET on which the pt had previously progressed immediately prior to study entry. Disease control rate (DCR; RECIST 1.1, per investigator), best overall response (BOR), overall response rate (ORR), safety, and PK, are evaluated. Data cut off was 14Nov2019. Results: 48 pts were treated, all of whom had progressed on a CDK4/6i. Pts had received a median 2 prior ET lines (range 1-5) and 1 line (range 1-3) of chemotherapy. Pts had a median number of 3 metastatic sites (range 1-6) and 42 (88%) had visceral involvement. Among 42 pts evaluable for efficacy, DCR was 45% (90% CI 32-59) with 2 pts having unconfirmed PR and 19 pts SD as BOR. Common related AEs (all grades; G3-4) were asthenia/fatigue (27%; 2%), diarrhea (25%; 0), nausea (21%; 0). No clinically significant LVEF decline was seen. At the end of cycle 1, mean trough level of MCLA-128 was 15.5 µg/mL, and mean terminal half-live was 102 h (n = 19-21). Data on the primary endpoint, clinical benefit rate at 24 weeks, and biomarkers will be provided. Conclusions: The addition of MCLA-128 to the last line of ET showed clinical activity after ET+CDK4/6i failure and a favorable safety profile. Clinical trial information: NCT03321981 .
Targeted next generation sequencing to expand HER2 status detection: Implication for newer HER2-directed agents.
Authors: Liao Ning , Song RongFeng , Xue FangQin , Zhang Shuirong , Klempner Samuel J , Chen Lijuan , Wang Kai , Wang Wenjing 
Published: May 2020

1047 Background: Establishment of ERBB2 ( HER2) amplification status in breast carcinoma (BC) and gastric carcinoma (GC) is essential for treatment selection, but no anti- HER2 therapies have been approved for tumors with low level of HER2 expression. The clinical trial ( NCT02564900 ) was initiated to evaluate the safety and efficacy of trastuzumab deruxtecan (DS-8201a) in BC patients with lower HER2 expression by current methods. This study aims to validate NGS-based detection for HER2 low expression. Methods: 275 BC and 425 GC were collected and subjected to NGS for genomic alteration detection. The testing was carried out by a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory, Shanghai, China. Protein expression was analyzed by using IHC. FISH was carried out on 108 samples, including 63 BC and 45 GC. To set up NGS cutoff, FISH was performed on additional 34 samples. Sensitivity, specificity and accuracy were evaluated based on FISH as a gold-standard reference. Results: In BC, the expression level of HER2 protein detected by IHC was overall IHC 0 in 28.7%, 1+ in 18.9%, 2+ in 27.3% and 3+ in 25.1%, respectively, while in GC, the expression level was 60.7%, 18.6%, 14.8% and 5.9%, respectively. Log2ratio was used to assess ERBB2 amplification status detected by NGS. According to the FISH results of 34 other samples with high sensitivity (98%) and specificity (100%), the threshold was determined as 0.5. 8 and 10 samples of IHC 1+/2+ met the cutoff in BC and GC, respectively. In 63 BC, there were 17 positive and 46 negative by FISH. According to the threshold, the sensitivity and specificity of NGS detection was 94.1% and 97.8%, respectively. The proportion of samples with IHC 2+ that couldn't determine NGS ERBB2 status was 49.2%. However, except for false positive and false negative, the NGS results were concordant with FISH. In 45 GC, there were 5 positive and 40 negative by FISH. The specificity and sensitivity was 97.5% and 40%, respectively. In 4 samples with IHC 2+, 2 of them were discordant with the results of NGS and FISH. All IHC 1+ didn't meet the cutoff of NGS and was FISH negative in 108 samples. The accuracy of NGS in ERBB2 detection was 96.8% and 91.1% for BC and GC, respectively. Conclusions: Our data indicated that the NGS-based detection of ERBB2 amplification had high sensitivity, specificity and accuracy. In samples with IHC 1+/2+, the results of NGS detection were high concordant with FISH detection.
Activity of front-line window therapy with temozolomide plus irinotecan in patients with primary multifocal Ewing sarcoma: ISG/AIEOP EW-2 protocol.
Authors: Sebastian Asaftei Dorin , Puma Nadia , Paioli Anna , Petraz Marco , Morosi Carlo , Podda Marta Giorgia , Tamburini Angela , Coccoli Luca , Grignani Giovanni , Manzitti Carla , Bertulli Rossella , De Leonardis Francesco , Rabusin Marco , Picci Piero , Prete Arcangelo , Longhi Alessandra , Fagioli Franca , Luksch Roberto 
Published: May 2020

10516 Background: The prognosis of patients with primary multifocal metastatic Ewing sarcoma (PMES) remains dismal. So far, combination with temozolomide and irinotecan (TEMIRI) was tested in patients with refractory or relapsed disease. This study evaluates the activity and the tolerability of TEMIRI as front-line treatment in PMES. Methods: In the study-period 2012-2018, a front-line window therapy with 2 courses TEMIRI (temozolomide 100 mg/sqm/day + irinotecan 50 mg/sqm/day for 5 days every three weeks) was introduced as amendment to the ISG/AIEOP EW-2 protocol ( EUDRACT#2009-011197-15, Vers. 1.02 ) for patients with PMES. Main objective was to test the activity of TEMIRI evaluated by RECIST 1.1 criteria, with centralized revision of the radiological response. Secondary objectives included assessment of the toxicity profile and clinical benefit of the combination. A two-step study design by Simon was planned. Results: Thirty-four patients were enrolled. Median age at diagnosis was 19 years (range 3-55); males/females ratio was 2.4. Primary axial tumour was present in 24 (70%). After TEMIRI, RECIST response was as follows: partial response -20 (59%), stable disease -11 (32%), progression disease -3 (9%). After TEMIRI, amelioration in ECOG/Lansky score was achieved in 25/34 (73,5%), and reduction or disappearance of pain was observed in 31/34 patients (91%). TEMIRI toxicity was manageable: incidence of grade 3-4 nonhaematological and haematological toxicity was 3% and 3%, respectively (67/68 evaluable courses). At the time of the present analysis, 11 patients are alive; 7 of them are in complete remission and completed their treatment program (5-drug standard chemotherapy). With a median follow-up of 31 months (range 23-75), the 3-year survival estimate is 36,5%±0.09. Conclusions: Upfront TEMIRI x 2 courses showed an encouraging activity, with response rate 59% and deserves further evaluation combined with conventional treatments also in non-metastatic patients. In PMES new treatment strategies are urgently needed. Clinical trial information: NCT02727387.
Tisagenlecleucel (Tisa) for relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL): B2001X study focusing on prior exposure to blinatumomab (BLINA) and inotuzumab (INO).
Authors: Krueger Joerg , Bittencourt Henrique N. S. , Rives Susana , Baruchel Andre , De Moerloose Barbara , Peters Christina , Bader Peter , Buechner Jochen , Boissel Nicolas , Hiramatsu Hidefumi , Thudium Karen , Sanjeevi Prasanthi , White Marina , Eldjerou Lamis K. , Balduzzi Adriana 
Published: May 2020

10518 Background: B2001X (NCT03123939) is a multicenter global study of tisa to provide access to patients (pts) with r/r ALL including prior anti-CD19 therapy after enrollment ended in the pivotal ELIANA (NCT02435849) study. We report clinical outcomes and cellular kinetics in B2001X including pts with prior BLINA exposure or INO as bridging therapy (BT). Methods: Eligible pts ≤21 y at diagnosis with ≥2 relapse, refractory or post allogeneic transplant (alloSCT) relapse were enrolled globally. Results: As of Nov 4, 2019, 73 pts were enrolled; 67 received tisa. 91% received lymphodepletion. Among 65 pts ≥3 mo follow up (FU) or discontinued earlier (efficacy analysis set [EAS]) median FU was 9.6 mo (range [R] 0.2-16.5). Median age 10 y (R 2-33); prior alloSCT 61%; 15 pts had prior BLINA and 9 pts had INO as BT. Efficacy is summarized in Table. 13/14 relapsed pts were medullary (isolated or combined with extramedullary [EM]) and 1 EM; 9 within 6 mo including 4/5 who were CD19(+). 64% had CRS (G 3/4 13%/15%; Penn scale); 24% had neurologic events (G 3/4 9%/2%; CTCAE v4.03). 4 deaths ≤30 d: 2 early ALL progression, 1 fatal CRS with refractory ALL, 1 infection with multiorgan failure. Transgene level in peripheral blood: limited to no in vivo expansion in nonresponders (n=8) vs responders (n=42). Median duration of persistence (T last) of tisa was 272 d (R 27-379) in responders. In pts with CR/CRi, Cmax (geo-mean [CV%]) and median T last were 9260 (124) copies/µg DNA and 154 d (R 28-349), respectively, in pts who received INO as BT (n=6) vs 38,500 (215) and 273 d (R 27-379), respectively, in pts with no INO as BT (n=36). Conclusions: Outcomes in B2001X remain consistent with ELIANA. In pts with prior BLINA or INO as BT, a trend toward suboptimal outcomes was observed but should be interpreted with caution due to small n, short FU and potential confounding factors. Clinical trial information: NCT03123939. [Table: see text]
Biomarker analysis from a phase I study using gedatolisib+palbociclib+hormone therapy in ER+/HER2- metastatic breast cancer (mBC).
Authors: Wesolowski Robert , Pathan Nuzhat , Zhu Zhou , Stringer-Reasor Erica Michelle , Han Hyo S. , Dees Elizabeth Claire , Bardia Aditya , Layman Rachel M. , Weise Amy , Kabos Peter , Lu Janice M. , Kern Kenneth Alan , Pierce Kristen J. , Rugo Hope S. 
Published: May 2020

1052 Background: Endocrine therapy with a CDK4/6 inhibitor (CDKi) is standard of care (SOC) for patients (pts) with estrogen-receptor-positive (ER+) metastatic breast cancer (mBC). Resistance to therapy may arise from mutations in ESR1, PIK3CA, and activation of receptor tyrosine kinase signaling pathways. In this study, gedatolisib (G), a PI3KCA/mTOR inhibitor, was added to a CDKi (palbociclib, P) + letrozole (L) or fulvestrant (F) for treatment of pts with ER+/HER2- mBC. Methods: This phase 1b study (NCT02684032) comprises a dose escalation phase evaluating the dose-limiting toxicity and maximum tolerated dose of G+P+L/F and a dose expansion phase assessing the objective response rate of G+P+L/F, compared with historical data for P+L or P+F. Response was assessed using RECIST v1.1. Genomic and transcriptomic analyses were performed on archival pt tumor biopsies. Longitudinal plasma ctDNA analysis was performed on samples taken at baseline, on-treatment, and end-of-treatment. Unsupervised data analysis was conducted. Results: Genomic information was available for 25 of 35 pts with measurable disease (G+P+L: 11; G+P+F: 14). No relationship was observed between responses (1 complete response [CR] and 11 partial responses [PR]) and baseline PIK3CA pathway alterations. Pt tumor tissue analysis (n = 25) confirmed pts with FGF3/4/19 amplification (n = 4) had larger changes in tumor size in response to G+P+L/F (p = 0.029). Of the 6 pts with an ESR1 mutation, 1 pt with an ESR1 Y537S mutation exhibited a partial response (PR) to G+P+L. Longitudinal plasma ctDNA analysis (73-gene panel) revealed that decreases in PIK3CA and PTEN were most associated with clinical response. Plasma sample analysis (n = 21) showed that pts with somatic alterations in EGFR (n = 4) had a greater response to therapy (p = 0.066), compared with pts without somatic EGFR alterations. Transcriptomic profiling also revealed responsive patients had higher levels of EGFR expression. Pts exhibiting CR/PR had a lower somatic tumor mutation burden at Cycle 5 Day 1 compared with baseline (p = 0.0013). Conclusions: The addition of G to SOC endocrine + CDKi therapy may help overcome resistance due to activation of FGFR or EGFR signaling pathways and the ESR1 Y537S mutation. Somatic frequency changes of PI3K pathway alterations were most correlated with clinical response. Genomic data analysis from dose expansion samples is currently ongoing. Clinical trial information: NCT02684032 .