bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of pretreatment chest CT abnormalities with trastuzumab deruxtecan–associated pneumonitis.
Authors: Abelman Rachel Occhiogrosso , Hartley-Blossom Zachary , Fell Geoffrey G. , Ryan Phoebe , Nakajima Erika , Moy Beverly , Ellisen Leif W. , Bardia Aditya , Fintelmann Florian J. , Spring Laura 
Published: June 2023

1106 Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate approved for HER2+ metastatic breast cancer (MBC) and HER2-low (IHC 1+ or 2+ with FISH-) MBC . Pneumonitis with T-DXd has been observed in 13.6% of patients (pts) on DESTINY-Breast 01 (including 2.2% fatal events) and 12.1% in pts on DESTINY-BREAST 04 (including 0.8% fatal events). There is an unmet need to determine if pts with baseline lung abnormalities are at increased risk for development of pneumonitis from T-DXd. Methods: This retrospective cohort study included all pts treated with T-DXd for MBC at an academic institution from 1/2020 to 2/2023 for more than 1 cycle (>21 days). Outcomes were evaluated from treatment initiation until 2/1/2023. Two board-certified radiologists blinded to outcomes reviewed staging chest CTs performed before initiating T-DXd and graded each scan on 16 parenchymal abnormalities, including presence of interstitial lung abnormalities (ILA). Pneumonitis was retrospectively adjudicated by an independent oncologist using chart review and graded according to CTCAE v5.0 and compared to the treating physician’s assessment. The difference of proportions was analyzed with the Pearson Chi-Square test. Significance was declared at the 0.05 type I error threshold. Results: A total of 68 pts (median age 57.3 years) were included (30 = HER2+, 24 = HR+/HER2 low, 14 = TNBC/HER2 low). By independent assessment, 16 pts (23.5%) had grade 1 pneumonitis and 3 pts (4.4%) grade 2 pneumonitis. Median time from treatment initiation to pneumonitis was 83 days (range 35-266). By treating physician assessment, 5 pts (7.4%) developed grade 1 pneumonitis and 3 pts (4.4%) developed grade 2 pneumonitis. 16 of 68 pts (23.5%) had baseline ILA and 62 pts (91.2%) had at least one other parenchymal abnormality. As assessed by an independent oncologist, of pts with baseline ILA (N = 16), 12.5% developed T-DXd related pneumonitis, compared to 32.7% of pts without pre-existing ILA (N=52), p=0.16. There was no statistical difference in T-DXd related pneumonitis assessed by treating physician between pts with baseline ILA (2/16 patients, 12.5%) compared to pts without baseline ILA (7/52 pts, 13.5%), p=0.68. Conclusions: In this study, presence of baseline ILA was not associated with subsequent pneumonitis from T-DXd. Notably, the rate of independently assessed pneumonitis was higher than treatment-attributed pneumonitis as defined by the treating physician. Further research is needed to validate these findings and define predictors of treatment-associated pneumonitis. [Table: see text]
Distribution and outcomes of HER2-low and HER2-zero metastatic breast cancer in Black and younger women.
Authors: Zagami Paola , Abdou Yara , Wardell Alexis Caroline , Deal Allison Mary , Wheless Amy , Dees Elizabeth Claire , Carey Lisa A. 
Published: June 2023

1109 Background: Black and younger patients with breast cancer (BC) have higher mortality. This racial disparity has been attributed to different BC biology, access to care, and treatment. With the advent of new antibody-drug conjugates (ADC) for metastatic BC (MBC), “HER2-negative” has been subdivided into HER2-low (IHC 1+ or 2+/ISH-negative) and HER2-0 (IHC 0). Little is known about these subcategories among Black and younger women with MBC. Methods: Clinical characteristics, treatment, and outcomes of patients diagnosed with HER2-negative MBC between 2011-2022 and with follow-up through a progression-free survival event on first-line therapy (PFS1) were retrieved from the UNC Metastatic Breast Cancer Database; hormone receptor (HR) and HER2 categories were by clinical criteria from the pathology report. Analyses were limited to HER2-negative BC and stratified/controlled by HR status. Fisher’s exact tests were used to compare HER2 status across race and age. The Kaplan Meier method and log-rank tests, as well as Cox proportional hazards models estimated PFS1. Results: The cohort included 772 MBC patients (56% HER2-low and 44% HER2-0), 22% Black women and 30% < 50 years old at MBC diagnosis. There were no differences in proportion with HER2-low by race or age (p>0.5). Patients with HER2-low had better observed median PFS1 compared to HER2-0, however, most of these differences were non-significant: overall (HR+ 12.2 vs 9.8m, p=0.11, HR- 4.3 v 3.3m, p=0.29) and within race and age categories (see table). In Cox modeling, Black women had worse PFS1 (p=0.03), that was no longer apparent after adjusting for HR status (p=0.1), there was no difference by age. Patients with HER2-0 had worse PFS1 (p=0.0005), which remained after adjusting for HR status (p=0.05). In a multivariable model comparing HER2-0 to HER2-low, adjusting for race and HR status, PFS1 remained shorter in the HER2-0 group (hazard ratio: 0.84, CI 0.692 – 1.015, p=0.07). Among those treated with uniform first-line therapy, better PFS1 was observed in HER2-low disease. This included 137 HR+ MBC treated with ET + CDK4/6i (mPFS1 14.3 v 10.3m, p=0.33) and 170 HR- MBC treated with chemotherapy (mPFS1 4.0 v 3.1m, p=0.22) with no variation by race or age. Conclusions: Within HER2-negative MBC, distribution of HER2-low and HER2-0 cancers does not differ by race and age. The clinical benefit of first-line therapy is strongly driven by HR status regardless of race and age, and is greater in HER2-low cancers although this cohort did not include HER2-directed ADCs. [Table: see text]
Imbalance in treatment discontinuation without progression between experimental and control arms among randomized trials in advanced breast cancer.
Authors: Tamimi Faris , Mittal Abhenil , Molto Consolacion , Malon Gimenez Diego , Nadler Michelle B. , Amir Eitan 
Published: June 2023

1110 Background: In Randomized Controlled Trials (RCT), treatment discontinuation (TD) can result in censoring. Imbalanced frequency of TD between arms could impact interpretation of results. Here, we quantify TD between the experimental and control arms among RCT supporting registration of drugs for advanced breast cancer. Methods: We identified RCT supporting US Food and Drug Administration's approval of drugs for advanced breast cancer between 2013 and 2023. We extracted data for the number of participants with TD for reasons other than disease progression (PD), death, or completion of treatment. Odds ratio (OR) for TD comparing experimental to control arms were determined for each trial. To assess progression-free survival (PFS) translation into an overall survival (OS) benefit, we calculated hazard ratio (HR) for PFS/OS. Then we assessed whether there was quantitative association between the OR for TD and the ratio of HR for PFS/OS. Quantitative significance was defined according to the criteria of Burnand. Results: Analysis included 22 RCT comprising 13853 participants and supporting approval for 18 distinct drugs. TD was reported in 2212 (16.0%) participants. Among these participants, the leading causes of TD were withdrawal of consent (27.8%), site termination (20.7%), adverse events (17.2%), and loss of follow-up (10.9%). There was a statistically significant imbalance in the experimental arm in 4 RCT (18%) (Table), which was observed for everolimus, ribociclib (with fulvestrant), alpelisib, and neratinib. The OR for TD showed quantitative, but not statistically significant negative association with the ratio of the HR for PFS/OS (Beta -0.393; p=0.18). Conclusions: TD without PD, death, or completion of treatment occurs in a substantial proportion of participants of several RCT supporting approval of drugs for advanced breast cancer. all the statistically significant imbalanced TD in the RCT were in experimental arms. Quantitative association between imbalanced TD and the ratio of HR for PFS/OS suggests imbalanced TD may impact ability to translate improvements in PFS to OS. Results of RCT with imbalance in TD should be interpreted cautiously. [Table: see text]
Efficacy of combination lurbinectedin (LURBI) + doxorubicin (DOX) from the phase 1B soft-tissue sarcoma (STS) lead-in to a randomized phase 2 trial in leiomyosarcoma (LMS).
Authors: Cote Gregory Michael , Haddox Candace L. , Choy Edwin , Merriam Priscilla , Mazzola Emanuele , Wagner Andrew J. , Siontis Brittany L. , Attia Steven , Seetharam Mahesh , Demetri George D. , George Suzanne 
Published: June 2023

11507 Background: Single agent or combination chemotherapy, typically Dox- or gemcitabine-based, are standard 1st- and 2nd-line therapies in patients (pts) with metastatic LMS; however, objective response rates (ORR), progression-free, and overall survival (PFS/OS) remain inadequate. Lurbi (PharmaMar S.A. / Jazz Pharmaceuticals) binds to DNA inhibiting transcription and inducing double strand breaks leading to apoptosis and delaying S/G2 progression. In a prior pilot study, we showed Lurbi+Dox is well-tolerated, with signs of activity, particularly in LMS. We designed this phase 1b to optimize dosing to lead into a randomized (1:1) phase 2 trial of Dox+/-Lurbi in anthracycline-naïve LMS. Herein we provide updated efficacy and tolerability data for this Phase 1b cohort. Methods: Pts > 18 yrs with locally advanced/metastatic, unresectable non-GIST STS (Phase 1b only) w/o prior anthracycline or Lurbi/trabectedin, ECOG PS < 3, RECIST 1.1 measurable, and normal organ function were eligible. The phase 1b followed a 3+3 design. Dosing included fixed Lurbi (3.2 mg/m2 d1) with two Dox dose levels (DL; DL1: 25 mg/m2 d1; DL2 25 mg/m2 d1+8). All pts received GCSF prophylaxis. Tumor assessments were every 2 cycles. DL1 was chosen as RP2D and the phase 2 trial began accrual in Aug 2022 aiming to enroll 50 LMS pts randomized 1:1 (stratified by uterine LMS [uLMS]] v. other LMS) with PFS as primary endpoint. Pts progressing on Dox are allowed to cross to Lurbi monotherapy. Results: 10 patients were enrolled in Phase 1b. Histologies included 5 LMS (4 uLMS) and 1 each of myxofibrosarcoma (myxFS), undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (DDLPS), endometrial stromal sarcoma (ESS), and solitary fibrous tumor (SFT). With a median follow-up of 344 days, 5/10 pts remain on treatment with median PFS of 357 days (95%CI 175-ND). 6 pts demonstrated partial response (PR; 5 confirmed), 3 with stable disease (SD), and 1 with progressive disease (PD, Table). Median time to PR was 81 days (range 46-207). Duration of response was over 132 days in all responders with 3 still on treatment. Treatment-related AEs were typical for Dox/Lurbi, including nausea, fatigue, and reversible LFT elevations/cytopenias. Updated safety and response data will be provided at the time of the meeting. Conclusions: Lurbi+Dox is well-tolerated with efficacy in STS including 6/10 pts achieving PR, 9/10 pts staying on treatment for >120d, and 6/10 pts >200d. The randomized phase 2 study is currently enrolling. Clinical trial information: NCT05099666 . [Table: see text]
Histopathological response (HR) after neoadjuvant chemotherapy (ChT) for high-risk soft tissue sarcomas (STS): A planned analysis of the ISG-STS-1001 trial.
Authors: Pasquali Sandro , Collini Paola , Romagosa Cleofe , Coindre Jean Michel , Pizzamiglio Sara , Verderio Paolo , Barisella Marta , Palmerini Emanuela , Quagliuolo Vittorio , Martin Broto Javier , Lopez-Pousa Antonio , Grignani Giovanni , Blay Jean-Yves , Lugowska Iwona A. , Fontana Valeria , Sbaraglia Marta , Bague Silvia , De Tos Paolo , Casali Paolo G , Gronchi Alessandro 
Published: June 2023

11511 Background: HR after neoadjuvant ChT for high-risk STS has not been prospectively characterized and the prognostic implications remain unclear. This planned analysis of the ISG-STS-1001 trial, which compared neoadjuvant anthracycline plus ifosfamide (AI) and a histology-tailored (HT) ChT, was aimed at characterizing HR after neoadjuvant ChT and investigating association with the risk of recurrence. Methods: Patients registered in the ISG-STS-1001 study (ID: NCT01710176) were included if they had the per-protocol assessment of HR in surgical specimens. The following morphological post-treatment changes were considered: residual stainable tumor cells, necrosis, hemorrhage, sclerosis, sclerohyalinosis, and fibrohistiocytic reaction with haemosiderin. Pathologists at each study site analyzed and expressed each of these changes as a rate within each tumor. Disease-free survival (DFS), which was the trial primary end-point, was the outcome variable. Results: HR was assessed in 201 of 287 randomized patients (47 had re-excision, 7 did not have surgery, and 32 were not evaluable after wide excision), who were followed up for a median of 89 months (IQR 75-102 months). Presence (>1%) of stainable tumor cells (N=194, 96%) was not associated with DFS (HR=1.47, 95%CI 0.36–5.98, P= 0.591). Conversely, presence (≥1%) of necrosis (N=169, 84%) was associated with shorter DFS (HR=3.11, 95%CI 1.36–7.14, P=0.007) and sclerohyalinosis >20% (N=42, 21%) was associated with a lower risk of recurrence (HR=0.51, 95%CI 0.28–0.94, P=0.031). These findings were confirmed when patients who had preoperative radiotherapy (N=32) were excluded. In patients randomized to AI with tumors evaluable for HR (N=98), sclerohyalinosis >20% (N=24, 24.5%) maintained the association with a lower risk of recurrence (HR=0.24, 95%CI 0.09 – 0.67, P=0.007). Finally, the prognostic value of necrosis and sclerohyalinosis for DFS held also when patients registered in the study (187/361 evaluable for HR) were selected in addition to randomized patients. Conclusions: This is the first study that prospectively evaluated HR after neoadjuvant ChT in high-risk STS. Previous classifications of HR were based on expert consensus and had limited prognostic relevance. In this study residual stainable tumor cells, which is often considered the most relevant post-treatment change, did not stratify patient risk, while sclerohyalinosis (>20%) singled out patients with the best outcome after neoadjuvant ChT. Clinical trial information: NCT01710176 .
Impact of pregnancy in women with desmoid fibromatosis: An international retrospective observational study.
Authors: Fiore Marco , Bonvalot Sylvie , Personeni Giulia , Raut Chandrajit P , Mercier Kelly , Gladdy Rebecca , Ljevar Silva , Tzanis Dimitrios , Rossi Enrica , Sulciner Megan , Suraweera Harini , Colombo Chiara , Rabih Mikhael , Coppola Marianna , Sarre-Lazcano Catherine , Iadecola Sara , Figura Costanza , Salvatore Daniela , Gronchi Alessandro 
Published: June 2023

11513 Background: Desmoid fibromatosis (DF) often occurs during pregnancy/peripartum. Guidance for planning new pregnancies during active surveillance or following DF resection has been limited. Thus, we sought to evaluate outcomes and decision making in the peripartum. Methods: Women of child-bearing age with DF diagnosed between 2000 and 2020 were interviewed about procreation decisions, in a multicenter retrospective observational study (NCT05284305). Pregnancies simultaneous or after diagnosis were analyzed. Primary outcome was DF progression/recurrence within 1 yr postpartum. Secondary outcomes were spontaneous regression, switch to active treatment, and obstetric risks. To estimate probability of progression, a random intercept logistic model was fit to account for correlation of progression in multiple pregnancies in the same patient. Results: Of 483 pts interviewed, 120 (24.8%) postponed, 32 (6.6%) interrupted, and/or 232 (48%) avoided pregnancy (in 93.3%, 50%, and 72.9% of cases because of DF), respectively. 147 pregnancies in 131 pts were concurrent with or after diagnosis: 26 (17.7%, Group A) concurrent with diagnosis, 48 (32.7%, B) after DF resection, and 73 (49.7%, C) with DF on surveillance. Estimated probability of progression was 12.0% (CI 2.0 – 48.4) during pregnancy and 15.8% (5.6 – 37.5) postpartum; for pregnancies after diagnosis (Groups B and C), these rates were 5.1% (0.4 – 40.0) and 9.0% (1.8 – 35.0). On multivariate analysis, age at pregnancy and size of primary DF were significant risk factors for progression (Table). Estimated probability of spontaneous regression was 3.6% (CI 0.2-40.7) during pregnancy and 7.1% (CI 0.3 – 67.2) postpartum. 7/38 (18.4%) spontaneously regressed after pregnancy-related PD, 4/23 (17.4%) in Groups B and C. Treatment for progression was needed in 9/79 (11.4%) postpartum, in 4/63 (6.3%) in Groups B and C. Obstetric complications were comparable to population data in developed countries. Conclusions: After DF diagnosis, pregnancy is safe with a risk of progression of 5% during pregnancy and 9% postpartum. Treatment is needed in only 6%. Spontaneous regression is less common but occurs even after initial progression. Patients decision making about procreation appeared to be influenced by their DF diagnosis. This study supports counseling that fertility options should be fully explored with expert guidance as intervention rates are low. [Table: see text]
Tumor volume and T2 hyperintensity changes from DeFi: A phase 3, randomized, controlled trial of nirogacestat in patients with desmoid tumors.
Authors: Alcindor Thierry , Kasper Bernd , Gounder Mrinal M. , Ratan Ravin , Van Der Graaf Winette T.A. , Wilky Breelyn A. , Riedel Richard F. , Federman Noah , Peruzzi Agnese , Moody Stephanie , Lim Allison , Tumminello Brad , Kummar Shivaani , Schöffski Patrick 
Published: June 2023

11514 Background: MRI tumor volume or T2 signal intensity changes may represent novel imaging techniques that could have a prognostic or predictive value for assessing response in desmoid tumors (DT). For example, hyperintense areas on T2-weighted images have been associated with active fibroblastic proliferation and ≥90% hyperintensity is associated with DT disease progression, whereas iso- or hypo-intense areas are associated with inactive sites of disease. In DeFi (NCT03785964), the novel gamma secretase inhibitor nirogacestat (n=70 patients) significantly improved the primary endpoint of PFS compared with placebo (n=72 patients; hazard ratio, 0.29 [95% CI, 0.15, 0.55; P<0.001]) and significantly improved the secondary endpoint of ORR per blinded, independent central review (41% vs 8%; P<0.001). Complete responses were achieved in 7% with nirogacestat and 0% with placebo. Here, we present an exploratory analysis of MRI tumor volume and T2 signal intensity changes in DeFi. Methods: Eligible adults had histologically confirmed DT that had progressed ≥20% per RECIST v1.1 within 12 months of screening. Patients were randomized 1:1 to receive nirogacestat 150 mg or placebo twice daily taken continuously in 28-day cycles. Volumetric MRI and T2 hyperintensity of the largest target tumor were evaluated at screening and every 6 cycles during the double-blind phase. MRI T2 signal intensity is represented as the ratio of hyperintensity in total tumor volume to muscle background. A blinded, independent, central radiologist reviewed all MRI scans. Results: Nirogacestat treatment led to more substantial reductions versus placebo in tumor volume and T2 hyperintensity ratio (Table). At baseline, similar proportions of patients in each arm had a T2 hyperintensity ratio ≥90% (95% vs 97%). This ratio changed from ≥90% at baseline to <90% at any time after baseline in 34% of patients in the nirogacestat arm and 15% of those on placebo. Conclusions: In DeFi, nirogacestat demonstrated substantial reduction of tumor volume and T2 hyperintensity of the largest target tumors by MRI compared with placebo in adults with DT. These results are consistent with the significant improvement in ORR achieved with nirogacestat. These data suggest that volumetric MRI and T2 hyperintensity might provide additional information in the evaluation of treatment response in DT. The prognostic or predictive value of these imaging techniques in DT should be further studied. Clinical trial information: NCT03785964 . [Table: see text]
SARC037: Results of phase I study of trabectedin given as a 1-hour (h) infusion in combination with low dose irinotecan in relapsed/refractory Ewing sarcoma (ES).
Authors: Grohar Patrick , Ballman Karla V. , Heise Rachel , Glod John , Wedekind Mary Frances , Mascarenhas Leo , Gedminas Jenna Marie , DuBois Steven G. , Maki Robert G. , Crompton Brian D. , Hayashi Masanori , Peer Cody J. , Figg William Douglas , Lindenberg Maria Liza , Mena Gonzalez Esther , Bagatell Rochelle , Laetsch Theodore Willis , Widemann Brigitte C. , Reinke Denise K. , Chugh Rashmi 
Published: June 2023

11519 Background: Recurrent ES carries a poor prognosis, and systemic therapies have limited efficacy. Preclinical models suggested that trabectedin (T) could achieve serum concentrations high enough to suppress the dominant oncogene of ES (i.e. EWS::FLI1 transcription factor), and that this effect is sustained by subsequent administration of low dose irinotecan (I). We conducted a phase I study of T+I in patients (pts) with ES. Methods: This multicenter dose escalation study employed a standard 3+3 design. T was given as a 1-h infusion on day (D)1 with low dose I intravenously on D2 and 4 of a 21D cycle. Dose limiting toxicities (DLTs) were evaluated in cycle one. Eligibility required confirmed EWS::FLI1 fusion transcript, age ≥10 years, ECOG performance status ≤2, adequate organ function and willing to have a research biopsy if safely accessible. Primary objectives were to determine the recommended dose (RD) and safety of T+I. Secondary objectives comprised efficacy of T+I and avidity of ES for 3'-Deoxy-3'-18F Fluorothymidine (18F-FLT) PET. Results: 20 pts enrolled from 1/2021-12/2022 across 5 sites, 5F/15M, median age 18 years (range 10-59). Pts had received a median of 4 (range 2-9) prior therapy lines including irinotecan in 60% of pts. Grade (G) 3/4 treatment-emergent adverse events (TEAEs) occurring in ≥10% of pts were: elevated ALT/AST, elevated creatinine phosphokinase, febrile neutropenia, anemia, lymphopenia, neutropenia, and thrombocytopenia. There were 2 G5 respiratory TEAEs. 18F-FLT PET scans were obtained in 5 pts. ES tumors were 18F-FLT PET avid. Dose level (DL)2 was the RD. At DL 2 and above, there were 4 PRs, 6 SD in 14 evaluable pts (Table). Conclusions: T+I can be safely administered to heavily pretreated pts with ES, demonstrating activity at the RD with 3 PRs (n=5 evaluable). The 18F-FLT PET may be useful to understand patterns of disease progression in ES. Correlative studies will be critical to understanding the mechanism of drug activity. Given the clinical benefit seen with T+I at RD, a phase II portion in pts with ES ≥6 years old is actively accruing. Clinical trial information: NCT04067115 . [Table: see text]