bluuebunny/crossref_metadata_2025 huggingface dataset:
AI-enabled digital test to predict disease recurrence for patients with early-stage invasive breast cancer and performance in a MammaPrint low-risk cohort from the Netherlands with a median 6-year follow-up.
Authors: Donovan Michael J. , Meurs Claudia , Fernandez Gerardo , Sainath Madduri Abishek , Feliz Aaron , Zeineh Jack , DeAngel Rebecca , Westenend Pieter
Published: June 2024

1569

Background: Traditional invasive breast cancer (IBC) grading, although useful, remains limited due to diagnostic subjectivity and absence of phenotypic diversity including the recently observed importance of tumor epithelial – stromal interactions and lymphocyte content-distribution. We developed and validated a clinical grade digital test (PreciseDx Breast, PDxBr) which combines image-derived Artificial Intelligent (AI)-grading features and clinical data (i.e. age, stage, tumor size, LN status) to predict recurrence in early-stage IBC and sought to understand performance in a MammaPrint cohort with outcome data. Methods: A MammaPrint cohort with median 6-year follow-up was identified at the Laboratory of Pathology, Dordrecht, the Netherlands (NTH). H&E stained images (digitized at Philips, Eindhoven, NTH) with clinical data (from the pathology and Dutch cancer registries) including demographics, pathology results, MammaPrint risk classification, treatment type and recurrence events were obtained. Performance of the PDxBr validated model (AI-grade + clinical) on the MammaPrint cohort was evaluated using the AUC/concordance index, along with NPV, PPV, Hazards ratio (HR), sensitivity, and specificity. Results: 250 patients, median age 57 years, majority stage 1-IIIa, 100% HR+ve, Her2-ve, 84% LN-ve, 67% grade 2 and 66% MammaPrint low risk. There were 15 events (6%: 7 deaths, 3 second primaries,4 metastases and 1 local regional). PDxBR model classified 134 patients as high risk and 116 as low with 10 of 15 (67%) events identified as high risk. The NPV for PDxBr was 96% with a HR 1.63, Se 70%, Sp 46% vs. MammaPrint with an NPV of 94%, HR of 0.96, Se 40%, Sp 66%; identifying only 5 of the 15 events (33%) as high risk while missing 10. Of note, the AI- grade/imaging model (without clinical features) yielded an NPV of 95% with a HR of 1.46, Se 70%, Sp 42% and correctly identified 10 of 15 events. Conclusions: The results from this observational study suggest that triaging patients with the PDxBr test could potentially be adjunctive to the management decision process of patients with early-stage IBC including the use and subsequent interpretation of genomic tests such as MammaPrint. Additional studies are underway to confirm these initial findings.
Inequities in timely treatment (Tx) initiation for patients (pts) with acute myeloid leukemia (AML) treated in a predominantly community setting in the United States (US).
Authors: Ma Esprit , Eisfeld Ann-Kathrin , Odenike Olatoyosi , Patel Achal , Wang Rongrong , Yellow-Duke Archibong , Montez Melissa , Xu Yanqing , Miu Kaylee , Hantel Andrew
Published: June 2024

1574

Background: AML is a highly morbid but treatable cancer with several novel Tx available. This study evaluates associations between race/ethnicity and socioeconomic status (SES) on timely Tx initiation in pts with newly diagnosed (ND) AML in a routine clinical setting. Methods: This retrospective cohort study uses the Flatiron Health electronic health record-derived, US nationwide, de-identified database. Pts aged ≥18 years, with AML diagnosis (Dx) Jan 2014–Dec 2022, had ≥2 visits recorded ≤3 months after Dx, and who received first line (1L) active Tx were included. 1L Tx was categorized as intensive chemotherapy (IC) or non-IC. Timely Tx was defined as initiation ≤14 days after Dx. Race/ethnicity was defined as White or People of Color (POC; including Black, Latinx, Asian, or Other). Logistic regression assessed associations between race/ethnicity and Yost Index-based SES on timely Tx initiation (adjusted for age at Dx, sex, practice type, hydroxyurea as part of 1L Tx [proxy of disease burden], European LeukemiaNet 2017 risk, and secondary AML), with adjusted odds ratios (aOR) reported. Results: Overall, 5981 pts with ND AML were included; 58% received non-IC and 42% received IC. Median ages were 76 and 60 years; 80% and 66% were treated in community settings; and median time from Dx to 1L initiation was 11 and 4 days. In the IC cohort, POC vs White pts had similar delays in Tx initiation (13.3% vs 13.8%, aOR 1.22, p=.2); significantly fewer POC vs White pts underwent stem cell transplant (SCT) post-remission (30.8% vs 47.7%, aOR 0.44, p<.001).In the non-IC cohort, numerically more POC had delayed Tx initiation vs White pts (40.6% vs 36.2%, aOR 1.19, p=.074). This disparity was larger in pts of low SES (POC vs White pts: 42.5% vs 34.4%, aOR 1.35, p=.077) vs high SES (38.7% vs 35.6%, aOR 1.16, p=.4) (Table). Conclusions: In a predominantly US community setting, numerical but non-significant race/ethnic disparities in timely 1L Tx initiation were observed for pts with ND AML. Fewer POC vs White pts receiving IC underwent SCT post-remission. Analyses are ongoing to assess mediators and impact on survival. [Table: see text]
ARC-9: A randomized study to evaluate etrumadenant based treatment combinations in previously treated metastatic colorectal cancer (mCRC).
Authors: Wainberg Zev A. , Han Sae-Won , Lee Soohyeon , Lee Keun-Wook , Kopetz Scott , Mizrahi Jonathan , Hong Yong Sang , Ghiringhelli François , Italiano Antoine , Tougeron David , Beagle Brandon , Boakye Mathew , Zhao Tingting , Rhee Joon , Nuyten Dimitry S. A. , Cecchini Michael
Published: June 2024

3508

Background: Adenosine mediated signaling via A2a and A2b receptors impairs activation, proliferation, and cytotoxic activity of effector T cells resulting in inhibition of antitumor activity. Adenosine receptor blockade may therefore enhance therapeutic efficacy of chemo/immunotherapy regimens. Etrumadenant (E) is an orally bioavailable, selective, A2a and A2b receptor antagonist that has demonstrated safety and clinical activity in solid tumors when combined with chemo/immunotherapy. ARC-9 (NCT04660812), a Phase Ib/II trial evaluating the safety and efficacy of E combined with zimberelimab (Z) (anti-PD-1 antibody), and FOLFOX/bevacizumab (bev) regimens or novel therapies in 3 cohorts of patients (pts) with mCRC. While FOLFOX rechallenge is frequently used in the management of mCRC, no prospective trials have been performed to date. Methods: Cohort B enrolled pts who previously progressed on both oxaliplatin and irinotecan containing regimens.Pts were randomized 2:1 to EZFB: E (150 mg orally [PO] once daily [QD]) + Z (240 mg intravenous [IV] once every 2 weeks [Q2W]) + mFOLFOX-6 + bev (5 mg/kg IV Q2W), or regorafenib (rego) (160 mg PO QD [days 1-21 every 4 weeks]). Pts who progressed on rego were allowed to crossover to EZFB. The primary endpoint is progression-free survival (PFS) per RECIST 1.1 and overall survival (OS) is a key secondary endpoint. Results: In Cohort B, 112 pts were randomized. Baseline characteristics are comparable between arms. As of 13 Nov 2023, with median follow-up of 20.4 months (mo), EZFB demonstrated statistically significant improvement in PFS (HR 0.27, 95% CI 0.17-0.43, p < 0.0001) and OS (HR 0.37, 95% CI 0.22-0.63, p = 0.0003) vs rego (Table). EZFB had an acceptable safety profile, consistent with the known FOLFOX/bev toxicity profile with no deaths related to study treatment in either arm. Conclusions: In this randomized phase II clinical trial, EZFBsignificantlyimproved efficacy outcomes compared to rego in refractory mCRC pts previously treated with 5-FU, oxaliplatin and irinotecan regimens with no unexpected toxicities. Further investigation of this promising regimen is warranted given the clinically meaningful PFS and OS improvement. Table Clinical trial information: NCT04660812 . [Table: see text]
First-in-human study of ABBV-400, a novel c-Met–targeting antibody-drug conjugate, in advanced solid tumors: Results in colorectal cancer.
Authors: Sharma Manish , Strickler John H , Sommerhalder David , Kuboki Yasutoshi , Perets Ruth , Cohen Jonathan , Raimbourg Judith , Nakajima Takako Eguchi , Yamamoto Noboru , Cruz-Correa Marcia , O'Neil Bert , Ghiringhelli François , Raghav Kanwal Pratap Singh , Li Rui , Morrison Thiele Gladys , Neagu Aristide Martha Raluca , Freise Kevin Jay , Biesdorf de Almeida Carla , Vasilopoulos Athanasios , Powderly John D.
Published: June 2024

3515

Background: c-Met (MET protein) is frequently overexpressed in several advanced solid tumors including colorectal cancer (CRC). There are no approved therapies specific for c-Met–overexpressing tumors in CRC. The antibody-drug conjugate ABBV-400 comprises c-Met–targeting antibody telisotuzumab conjugated to a novel topoisomerase 1 inhibitor payload. A phase 1 study of ABBV-400 was initiated for adults with advanced solid tumors and progression on standard therapies (NCT05029882); results from dose escalation (ESC) at doses 1.6–6.0 mg/kg once every 3 weeks (Q3W) were previously presented and showed preliminary efficacy (Sharma et al. ASCO 2023. Abstract 3015). We present data from dose ESC and expansion (EXP) cohorts in CRC. Methods: During EXP, patients (pts) with CRC were randomized to receive ABBV-400 at 1.6, 2.4, or 3.0 mg/kg Q3W. Primary objectives were to evaluate the safety, tolerability, pharmacokinetics, preliminary efficacy, and the recommended phase 2 dose of ABBV-400. Results: As of Oct 2023, 122 pts (ESC: 29; EXP: 93) were included. Median age: 56 years; 65 (53%) males. Median prior treatments was 4. Follow-up was longer in ESC vs EXP (14.8 vs 3.8 months). Seventy-eight (64%) pts had a grade (G)≥3 treatment-emergent adverse event (TEAE); 41% had a serious TEAE. Most frequent hematologic TEAEs were anemia (52%; G≥3: 30%), neutropenia (37%; G≥3: 25%), leukopenia (25%; G≥3: 12%), and thrombocytopenia (23%; G≥3: 12%); nonhematologic TEAEs were nausea (57%, G≥3: 3%), fatigue (43%; G≥3: 2%), and vomiting (39%, G≥3: 4%). G≥3 diarrhea was < 1%. Unadjudicated interstitial lung disease/pneumonitis rate was 7% (G≥3: 2%). Treatment-related AEs leading to discontinuation occurred in 11 (9%) pts. Preliminary efficacy outcomes are shown in the Table. The majority of tissues expressed c-Met. In pts with higher c-Met expression, an increased ORR of > 30% was observed at efficacious doses (≥2.4 mg/kg). Activity was also seen at lower c-Met expression levels (10–15% ORR). Conclusions: ABBV-400 at 2.4 and 3.0 mg/kg Q3W has a tolerable and manageable safety profile, with promising antitumor activity. Long-term tolerability appears improved at 2.4 relative to 3.0 mg/kg, with higher relative dose intensity and generally lower TEAEs. The study is also evaluating ABBV-400 with bevacizumab in pts with CRC. Clinical trial information: NCT05029882 . [Table: see text]
Three-year disease-free survival after transanal vs. laparoscopic total mesorectal excision for rectal cancer (TaLaR): A randomized clinical trial.
Authors: Kang Liang , Zeng Ziwei , Liu Huashan ,   Chinese Transanal Endoscopic Surgery Collaborative (CTESC) Group
Published: June 2024

3516

Background: Transanal total mesorectal excision (taTME) has gained significant traction as an effective approach for treating rectal cancer. Many previous studies reported positive relevant short-term results, histopathological results and associated complications of taTME compared to laparoscopic total mesorectal excision (laTME). Nonetheless, long-term oncological outcomes of taTME remain controversial. This study aimed to compare the 3-year DFS of taTME with laTME. Methods: We conducted a phase 3, randomized, open-label, noninferiority trial to compare the survival outcomes of taTME versus laTME in patients with rectal cancer located below the peritoneal reflection. This trial encompassed 16 hospitals across 10 provinces in China, with a total enrollment of 1,115 patients. We set the 3-year disease-free survival (DFS) and 5-year overall survival (OS) as the primary endpoints for analysis. The analysis of the 3-year DFS was conducted following a predefined modified intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT02966483. Results: The taTME group exhibited a 3-year DFS rate of 83.42%, and the laTME group achieved a 3-year DFS rate of 82.86%. The marginal difference of 0.56% between the DFS rates of the two groups (97.5% CI, −4.83 to 5.95, P < 0.0001 for noninferiority) suggests comparable outcomes. Moreover, the rates of local recurrence were 3.90% in the taTME group and 3.62% in the laTME group, indicating similar degrees of localized tumor control. Regarding overall survival, the taTME group demonstrated a rate of 94.50% compared to 92.01% in the laTME group. In the taTME group, patients who are male or underwent neoadjuvant showed a higher 3-year OS than that in the laTME group. Conclusions: In patients with mid-low rectal cancer, the 3-year DFS of taTME is not inferior to that of laTME. This study provides evidence supporting the clinical effectiveness of taTME in the treatment of rectal cancer. Clinical trial information: NCT02966483 .
Factors associated with benefit of adjuvant chemotherapy in patients with T1b/T1c HR-positive/HER2-negative breast cancer and high multigene recurrence score.
Authors: Herran Maria , Sabbagh Saad , Hijazi Ali , Mohanna Mohamed , Sarna Kaylee , Dominguez Barbara , Nahleh Zeina A.
Published: June 2024

e12540

Background: Patients diagnosed with early-stage HR-positive/HER2-negative Breast Cancer (BC) and high Oncotype DX Recurrence Score (RS ≥26) are offered adjuvant chemotherapy and endocrine therapy compared (CET) to endocrine therapy alone (ET). We sought to investigate if additional clinical factors that could further determine benefit from chemotherapy in patients with T1b/T1c and N0 tumors with high Oncotype DX to help deescalate treatment by avoiding chemotherapy induced toxicity. Methods: The purpose of this study is to determine the clinical factors associated with a survival difference from CET compared to ET alone in T1b/T1c and N0 BC. We analyzed the record of patients diagnosed with T1b/T1cN0M0 HR-positive/HER2-negativeBC and RS ≥26 between 2006 and 2020 from the National Cancer Database. Patients were separated into two groups based on their treatment: CET or ET and the following characteristics were assessed: age, grade, histology, and RS (26-30, 31-40, 41-100) to determine overall survival differences among the two groups. Chi-square was performed to evaluate the association between baseline categorical characteristic variable and chemotherapy treatment. Survival analysis of treatment modalities using Kaplan Meier curves and univariate Cox regression. Multivariate Cox regression with backwards elimination was performed for subgroup analyses. Results: A total of N=19,373 eligible patients were identified, n=14,422 (74.4%) received CET and the rest ET alone. The mean age at diagnosis was 59.6 years (SD=10.3); 86.6% presented with invasive ductal carcinoma and 83.3% had a Charlson-Deyo Comorbidity Score of 0. In the overall group, patients who received CET had a higher median overall survival than endocrine therapy alone (65.7 versus 52.1 months, log-rank p-value<.0001). However, further analysis noted that treatment with CET showed better outcome compared to ET alone in the following subgroups of patients: invasive ductal histology (95% OS 65.5 versus 52.7 months, log-rank p-value<.0001) and RS >30 (95% OS 63.6 versus 40.5 months, log-rank p-value<.0001). Importantly, multivariable cox regression subgroup analysis revealed no significant overall survival difference among the subgroup of patients with T1b/T1c and low grade (p=0.286) or RS 26-30 (p=0.200) with CET compared to ET alone. Conclusions: This large database confirms the heterogeneity of BC in patients with low burden disease despite high Oncotype.While patients diagnosed with T1b/T1cN0M0 and high RS (>30) could benefit from CET compared to ET alone as per standard practice, additional criteria could be considered in this group including low grade or RS 26-30 to better determine which population of patients do not benefit from the addition of chemotherapy and accordingly individualized chemotherapy decision might be made to minimize toxicity.
PRE-ISPY phase I/Ib oncology platform program (PRE-I-SPY-P1).
Authors: Pohlmann Paula R , Potter David Alexander , Chen Nan , Mouabbi Jason A , Rampurwala Murtuza , Rayani Shayan , Tan Antoinette R. , Leon-Ferre Roberto Antonio , Giridhar Karthik , Boughey Judy Caroline , Han Hyo S. , Kennedy Laura Carpin , Walsh Elaine M. , Tripathy Debashish , Jafari Shabnam , Eklund Martin , Nanda Rita , Meric-Bernstam Funda , Yee Douglas , Esserman Laura
Published: June 2024

e12641

Background: Many promising agents or combinations regimens relevant to breast cancer lack sufficient clinical information for use in the neoadjuvant setting. To enable acceleration of drug development by reducing time and cost of clinical trial planning and conduct, the Phase I initiative PRE-ISPY Program was created. Methods: The PRE-ISPY Program is built within the I-SPY network, with the overall aim to streamline the regulatory pathway and the processes of trial design, contracting, activation, enrollment, execution, data gathering and analysis, as well as reporting of new therapeutic agents or combinations of relevance to breast cancer. Results: The PRE-ISPY trial is an open-label platform phase IB study designed to evaluate compelling single agent or combination regimens with the overall goal of moving promising drug regimens into I-SPY2 Trial and/or into other oncology-based trials in a timely manner. Graduation of a PRE-ISPY regimen to I-SPY2 is not mandatory. The primary objectives in each study Arm are to determine safety and to obtain preliminary efficacy data of the new regimen in patients with metastatic cancer, including a cohort of breast cancer patients. Each Arm may contain a Part 1 (dose finding) and a Part 2 (dose expansion). The new treatment can be tested also in patients with other solid malignancies than breast cancer, in which the treatment may be applicable, as specified in the design of the Arm. A breast cancer specific cohort is required in Part 2. Candidate treatment regimens are selected with advice from the I-SPY2 Agent Selection Working Group. The PRE-ISPY/Phase IB trial has multiple ongoing drug regimen Arms subsequently added as new protocol appendices through amendments to a Master protocol. There is no randomization; participants are enrolled, and treatment selected according to the relevance of therapy to their disease. Prospective companion biomarkers are evaluated. The current arms under study are PRE1: ALX-148 combined with trastuzumab deruxtecan; PRE2: tucatinib combined with zanidatamab; and PRE3: vidutolimod combined with cemiplimab. Selected agents or therapeutic combinations are tested through this protocol in the I-SPY Network Centers that participate in the PRE-ISPY Program. Toxicities are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). Clinical responses are evaluated based on RECIST v1.1 criteria. Conclusions: Once safety is established, promising regimens can be rapidly transitioned to I-SPY 2.2 or other phase 2/3 trials. The first patient was enrolled on 2/1/2023. Clinical trial information: NCT05868226 .
Efficacy and safety of dalpiciclib, fulvestrant, and pyrotinib in HR+ HER2-low advanced breast cancer following cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors and aromatase inhibitors (AIs): A Bayesian optimal phase II trial.
Authors: Hao Chunfang , Shi Jing , Zhang Jie , Meng Wenjing
Published: June 2024

e13056

Background: Cross-line treatment with CDK4/6 inhibitors is a challenging topic. Currently, the MAINTAIN study, which involves switching CDK4/6 inhibitors and endocrine therapy, is the only one with positive results. Additionally, in vitro studies have demonstrated that the combination of anti-HER2 agents with CDK4/6 inhibitors, along with fulvestrant, can synergistically enhance inhibition in cell lines with low HER2 expression. The present study aims to assess the efficacy and safety of dalpiciclib, fulvestrant, and pyrotinib in patients with HR-positive and HER2-low advanced breast cancer (BC), who have experienced disease progression after treatment with CDK4/6 inhibitors and AIs. Methods: We propose a single-arm Bayesian optimal phase II design with a time-to-event endpoint. Key eligibility criteria include patients over 18 years of age with HR+, HER2-low advanced BC, disease progression following treatment with CDK4/6 inhibitors and AIs, no more than one line of chemotherapy. Patients who meet these criteria will receive oral dalpiciclib at a dose of 125 mg/day (three weeks on and one week off), intramuscular fulvestrant at a dose of 500 mg every four weeks, and oral pyrotinib at a dose of 320 mg/day until intolerance or disease progression. The primary endpoint of the study is progression-free survival (PFS), and the secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival, safety, and biomarker analysis. The study aims to enroll up to 30 patients, and an interim analysis will be conducted after the enrollment of 15 patients to make a go/no-go decision based on the stopping boundaries of the total observation time (TOT). Results: From May 2023 to November 2023, a total of 15 patients were enrolled in the study. The median age of the patients was 50 years (range: 36-72). Among these patients, 7 (46.7%) had visceral metastasis, 11 (73.3%) had undergone previous chemotherapy, 12 (80.0%) received abemaciclib, and 3 (20%) received palbociclib. The median duration of prior treatment with CDK4/6 inhibitors was 14 months (range: 5-33). As of January 24, 2024, a total of 9 patients underwent efficacy evaluation, revealing an ORR of 44.44% (4/9) and a DCR of 66.67% (6/9), 4 patients experienced disease progression. The TOT was 49.50 months, exceeding the predetermined stopping boundary of 22.54 months. Currently, the survival data are immature. The median follow-up period is 3.20 months (95% CI: 2.33-NA), and the median PFS has not been reached. Grade 3 and above treatment-related adverse events were reported in 40% (6/15) of the patients. Conclusions: The preliminary results indicate a certain level of efficacy and manageable safety. Based on these findings, the study will continue to enroll up to 30 participants. Clinical trial information: NCT05806671 .
Results of a retrospective study on the efficacy and safety of alpelisib in patients with HR+/HER2- metastatic breast cancer in real-world clinical practice.
Authors: Sultanbaev Alexander Valerievich , Kolyadina Irina Vladimirovna , Menshikov Konstantin , Musin Shamil , Sultanbaeva Nadezda , Lipatov Danila
Published: June 2024

e13058

Background: The combination of alpelisib and fulvestrant is an optimal therapy option for patients with hormone receptor-positive (HR+), HER2-negative (HER2–) metastatic breast cancer with PIK3CA gene mutations. The aim of this work to retrospectively analyze the efficacy and safety of alpelisib in real-world clinical practice in patients with pre-treated luminal HER2– negative metastatic breast cancer. Methods: The study included an analysis of 33 patients with widespread luminal HER2- negative breast cancer with detected PIK3CA gene mutation. The median age was 57 ± 13 months (95% CI 52-62). In 12 (36.4%) patients, the PIK3CA gene mutation was detected in exon 9, and in 21 (63.6%) – in exon 20. Alpelisib was prescribed to pre-treated patients in different lines. Most women (32/33; 97%) had received ET combined regimens with CDK4/6 inhibitors before starting alpelisib therapy: 14 (42.4%) patients underwent palbociclib therapy in combination with fulvestrant; 4 (12.1%) – palbociclib with aromatase inhibitors; 13 (39.5%) – ribociclib in combination with fulvestrant; 1 (3.0%) – ribociclib with aromatase inhibitors. It is important to note that 63.6% of patients had previous progression on fulvestrant monotherapy and 72.7% on aromatase inhibitor therapy. Patients with luminal B-subtype of breast cancer dominated - 72.7% (24/33). Results: The median overall survival (OS) in this study was 14 ± 2.5 months (95% CI: 9-18.9), and the median progression-free survival (PFS) was 6 ± 2.7 months (95% CI: 0.7-11.3). The rate of objective response was 30.3%, and prolonged disease stabilization was observed in 24.2% of cases. Prognostic factors were brain metastases (increasing the risk of death by 18 times) and discontinuation of the drug for any reason (increasing the risk of death by 8 times). It should be noted that the main reason for discontinuation or disruption of the drug's timing was unmanageable toxicity. All patients registered adverse events of varying degrees, with 21 (63.6%) patients experiencing hyperglycemia (grade 3-4 – 30.3%) and 14 (42.4%) patients experiencing skin toxicity (grade 3-4 – 15.2%). In the SOLAR-1 study, the frequency of hyperglycemia was comparable (64.8%), and rash was noted in a third of all patients, which is comparable to our data. Conclusions: The results of using alpelisib with fulvestrant confirm its effectiveness in real-world clinical practice in patients with pre-treated HR+HER2- negative widespread breast cancer with the presence of somatic PIK3CA gene mutation. Brain involvement is an unfavorable prognostic factor in patients with PIK3CA mutation and increases the risk of death by 18 times, requiring the need to optimize the therapeutic algorithm, including through radiation methods. Discontinuation of the drug, which increases the risk of death by 8 times.
Acceptance and usability testing of a visual care-navigation tool for patients, survivors, caregivers, nurses, and oncologists.
Authors: Daswani Samira , Blayney Douglas W. , Lindquist Molly , Dasgupta Arko , Finley Stephanie , Leung Celeste
Published: June 2024

e13064

Background: Breast cancer patients (BCP) and family caregivers (CG) describe their experience as a difficult hike, without access to a map, relevant gear, or a guide. The shrinking oncologist workforce has ~24 minutes per patient to communicate the condition, treatment plan and answer questions. Many use hand-drawn visuals – analogous to a map or process flow diagrams. 97% of BCP use Dr. Google™, which results in “Cancer Information Overload” and non-evidence-based activities. A team of survivors, cartographers, and oncologists developed an interactive cancer map and self-management platform to coach BCP to navigate treatment. Using equitable design, features include: (a) 7th grade reading level; (b) written content and audio/video assets; (c) supporting the user from diagnosis through survivorship to make the platform accessible to a diverse population. After acceptance testing showed high willingness to use & recommend (ASCO Quality 2023;552), we tested the platform’s usability through observed use and task-analysis. Methods: A convenience sample of BCP, CG and oncology HCP [including advanced practice providers (APP)] underwent a usability test in two waves. We defined a set of tasks the users should be able to accomplish. We observed the users during a 30-minute virtual session and recorded the session, noted the task accomplishments, and any issues. Issues from wave 1 were addressed and incorporated into the test for wave 2. Results: We tested two waves of users between November 30, 2023 and February 1, 2024. The results are shown in the table. After wave 1, we modified the platform and tested the maps with wave 2 users. Two core usability features were added between waves: (a) user drill down to access a more detailed level of the map; (b) a product tour guiding the user through the tool, which addressed qualitative user observations that showed initial confusion as to how to begin navigation. Conclusions: Cartographically represented maps of the cancer journey and the self-management tools are acceptable to BCP, survivors, and CG and are usable. Per the ASCO Quality 2023;552 poster, the platform is acceptable to HCPs and not perceived to increase work, and APPs found value in the platform to enable education. Features have been added to ensure a diverse population can easily use the platform including guided walk through and welcome videos. [Table: see text]
ESR1 mutations kit performance with SensID ESR1 reference set 1% AF.
Authors: Paveley Jack , Nana Ryan , Read Ava , Howard Kimberly Jane , Astley Lucy , Hoy Christine , Gasior Anna , Rollinson Sara , Whitfield Colette , Gorniak Joanna
Published: June 2024

e13087

Background: Oestrogen receptor 1 (ER/ ESR1) mutations have arisen as crucial biomarkers for endocrine therapy resistance in ER positive metastatic breast cancer. Detecting these mutations is key for understanding acquired resistance during treatment. Current clinical trials, exploring ESR1 mutation prevalence during various treatments, often use expensive and time-consuming next-generation sequencing (NGS)-based assays or digital PCR (dPCR) assays that require specialist equipment. The APIS ESR1 Mutations Kit offers a cost effective, rapid, and highly sensitive (≤ 1% MAF) alternative to NGS, and dPCR assays. This targeted, qPCR-based assay detects eleven ESR1 mutations across ESR1 exons 5 (E380Q), 7 (S463P) and 8 (P535H, L536R/Q/H/P, Y537C/S/N and D538G). Designed for circulating-free DNA (cfDNA) samples, it reduces the need for invasive procedures in clinical settings, providing researchers in both centralised and decentralised laboratory settings the flexibility to explore ESR1 mutations with precision. Here, we demonstrate the performance of the APIS ESR1 Mutations Kit using the first commercially available cfDNA reference set (SensID ESR1 Reference Set 1% AF cfDNA) for nine ESR1 mutations (Table). Methods: The SensID ESR1 standards were assessed with the APIS ESR1 Mutations Kit. All vials were diluted with nuclease-free water to 3 ng/µL, resulting in 15 ng total input per reaction. Samples were run according to the APIS ESR1 Mutations Kit handbook. All PCR runs were performed using a QuantStudio 5 Dx (ThermoFisher) instrument. Results: The APIS ESR1 Mutations Kit successfully detected all ESR1 mutations, with expected target calls for the nine mutations at 1% MAF. No false positive results for the remaining mutation targets were observed. Similarly, no false positives for any mutation targets were reported for vial 5, containing the wildtype (WT) sample, reaffirming the kit’s accuracy in distinguishing WT and mutant samples. Conclusions: The ESR1 Mutations Kit demonstrated highly sensitive and specific detection of the SensID ESR1 Reference Set 1% AF cfDNA, confirming the kit’s LoD of ≤ 1% MAF with externally validated samples. [Table: see text]
Real-world treatment patterns and clinical outcomes among patients with HR+/HER2- advanced/metastatic breast cancer receiving palbociclib in Brazil: IRIS study.
Authors: Simon Patricia , Guarin Alexandra , Jain Ankita , Piton Luciana , Lima Julia , Carvalho Carla Fabrine , Nazareth Felipe
Published: June 2024

e13088

Background: Palbociclib was approved for hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced/metastatic breast cancer (aBC/mBC) in Brazil in 2018. Worldwide studies explore palbociclib's real-world use and outcomes; however, this data is not available for Brazilian patients. IRIS Brazil study aimed to describe demographic/clinical characteristics, treatment and clinical outcomes of adult female patients who have received palbociclib as first-line treatment for HR+/HER2- aBC/mBC in private healthcare institutions in Brazil. Methods: This retrospective descriptive study included females aged 18 years or older diagnosed with HR+/HER2- aBC/mBC and those who had received palbociclib as their initial line of therapy. The study analyzed variables such as demographics, clinical characteristics, treatment history, palbociclib combinations, and clinical outcomes. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier estimates at 6- and 12-month time points. Results: A total of 121 patients were included in the study. The mean age was 54.4 years, and 82 (67.7%) were menopausal at diagnosis. A total of 51 patients (42.1%) were treated with palbociclib + fulvestrant, while 67 (55.8%) were treated with palbociclib + aromatase inhibitors. The majority of patients (n = 79; 65.3%) did not require any dose adjustments. Among the 40 patients (33.1%) who required dose adjustments, the main reason was adverse events/toxicity (n = 36; 90%). The PFS rates at 6 and 12 months were 78% and 60%, respectively. The OS rates at 6 and 12 months were 86% and 70%, respectively. Conclusions: Results from this initial real-world assessment of clinical outcomes in Brazil suggest that Palbociclib combinations exhibit favorable effectiveness in treating HR+/HER2- aBC/mBC disease, as measured by PFS and OS rates.
Comparative analysis of genomic tests for the prediction for late recurrence risk in hormone receptor–positive invasive breast cancer in a sample of Colombian patients.
Authors: Caicedo Jose Joaquin
Published: June 2024

e13092

Background: Approximately 70% of invasive breast cancers are hormone receptor-positive, requiring 5 years of endocrine therapy as the gold standard treatment. However, extended endocrine therapy (EET) may be needed, considering the late recurrence risk up to 15 years post-diagnosis. Different genomic tests predict the risk of recurrence. The 70-gene signature classifies patients as low or high risk during the first 5-years after diagnosis. The 12-gene test identifies high and low-risk patients for distant relapse up to 15 years, while a third test, based on 7-gene expression, assesses distant relapse risk up to 10 years. These tests assist clinicians in defining the need for EET. This study aims to compare the results of these genomic tests to determine late recurrence and distant relapse risks after 5 years, guiding EET indications. Methods: This is a retrospective descriptive transversal study involving 27 female patients diagnosed with hormone receptor-positive invasive breast cancer, treated in the same oncologic center in Colombia. All patients were first tested with the 70-gene genomic profile, with 15 patients undergoing the 12-gene test and 12 cases undergoing the 7-gene assay approximately 5 years later. Concordance between test results was assessed, and socio-demographic variables were descriptively analyzed. Results: The mean age was 54.4 years (SD=11.7). Invasive ductal carcinoma comprised 77.7% and invasive lobular carcinoma 22.22%. The 70-gene profile identified 21 cases (77.7%) as low-risk. Among those, 87.5% had a high-risk result with the 12-gene test, and 60% had a high-risk score with the 7-gene test. Conclusions: The findings support the utility observed in the sub-analysis of the NSABP-B42 study, showing that a low-risk result in the 70-genes signature, means high risk of late recurrence and the need for EET, emphasizing the importance of further evaluation and validation of genomic tests in predicting breast cancer recurrence risks. Larger sample sizes are necessary to confirm these results and establish their clinical relevance in oncology practice.
Switching from nonsteroidal aromatase inhibitors to exemestane and its impact on menopausal symptoms.
Authors: Blanter Julia , Ezratty Charlotte , McIntyre Anahi , Sheng Tianxiang , Tiersten Amy
Published: June 2024

e13098

Background: Aromatase inhibitors (AIs) are the most used adjuvant treatment in post-menopausal women with favorable oncotype, hormone receptor-positive (HR+) early breast cancer. Nonsteroidal AIs, such as anastrozole and letrozole, are associated with menopausal side effects including arthralgias, vaginal dryness, and hot flashes. Steroidal AIs, such as exemestane, however, have mild androgenic activity, thus minimizing the risk for these side effects. While studies show exemestane exhibits less bone toxicity compared to anastrozole, there has not yet been a proven significant difference in all menopausal symptoms. Nevertheless, switching from nonsteroidal to steroidal AI is still commonly seen in clinical practice. In this study, we aimed to examine the impact of switching from nonsteroidal to steroidal AI on menopausal side effects. Methods: We performed a retrospective review of patients diagnosed with HR+ breast cancer managed at an urban academic center from 2010-2023. Patients initially treated with anastrozole or letrozole and switched to exemestane were identified. Pathology records, treatment plans, and documented side effects were abstracted from medical records, as were baseline demographics. Symptoms were graded based on severity before and after each hormone therapy: mild grade described intermittent symptoms that did not require intervention; moderate grade described persistent daily symptoms or those that improved with additional intervention; severe grade described persistent disabling symptoms that required change in hormone therapy. Wilcoxon signed-rank tests were used to compare severity of menopausal symptoms before and after switching to exemestane. Results: There were 128 patients included in the study. Median age at diagnosis was 62.5 years; 13% pre-menopausal, 80% post-menopausal, 4% perimenopausal, and 3% unknown. Most patients were diagnosed with invasive ductal carcinoma (80%) and 45% were found to have stage IA breast cancer. The median amount of time on first and second lines of endocrine therapy were 11 and 25 months, respectively. Ninety-six patients (75%) reported menopausal symptoms on nonsteroidal AI, and 66% subsequently switched to exemestane due to severity of these symptoms. The most reported symptoms were arthralgias (79%), hot flashes (27%), body aches (25%), fatigue (10%), and vaginal dryness (9%). Of those with menopausal symptoms, 51% noted a decrease in symptom severity after switching to exemestane: 4 improved from moderate to mild, 21 from severe to moderate, and 24 from severe to mild. This decrease in severity was statistically significant across all menopausal symptoms (p<0.001). Conclusions: HR+ breast cancer patients exhibited a significant decrease in all menopausal symptoms when switching from nonsteroidal to steroidal AI. Further research is needed to examine the impact of this switch on a wider range of symptoms.
The role of stress in modulating AIPB expression and estradiol synthesis in triple-negative breast tumors.
Authors: Patrawala Mahjabin , Bose Himangshu
Published: June 2024

e13146

Background: In the United States, invasive breast cancer affects 1 in 8 women during their lifetime, with over 3.8 million individuals living as survivors. Breast cancers vary, with some being hormone-responsive and categorized on the presence or absence of estrogen (ER), progesterone (PR), and HER2 receptors. While targeted therapies exist for Estrogen Receptor positive (Er+) and Progesterone Receptor positive (PR+) cancers, triple-negative breast cancer (TNBC), which lacks all three receptors, affects about 15% of patients and is unresponsive to effective molecular treatments. Only a fraction of the cases respond to chemotherapy which emphasizes a need for new prognostic markers and treatments. Aromatase is the key enzyme in converting testosterone to estradiol which plays a crucial role in tumor growth, especially after menopause. Our research lab has identified the “Aromatase Interacting Partner in Breast or AIPB, whose overexpression inhibits aromatase, leading to a reduction in estradiol levels. However, in triple-negative breast cancer, there is an increase in AIPB expression when compared to ER+/PR+/Her2- breast tumors or unaffected women. This devastating prognosis and low survival rates can contribute to a considerable amount of stress in the diagnosed patients, in turn leading to an increase in cortisol production. Our hypothesis suggests that this stress or increase in cortisol could alter AIPB production in the tumorigenic cells which could potentially lead to a decrease in estradiol synthesis. Methods: Stress stimulation was achieved in a lab setting by subjecting engineered triple-negative breast cancer cells, capable of conditional AIPB overexpression upon tetracycline addition, to a 42 °C heat shock for various durations (0,15, 30, 45 minutes). Results: Following the 45 minutes of stress, MDA-MMD-231 cells exhibited a significant reduction in estradiol levels, decreasing from 160ng/ml to 100ng/ml. MDA-MD-231 cells engineered to overexpress AIPB produced only 62ng/ml of estradiol, marking an 18.75% decrease. The introduction of doxycycline led to a further reduction in estradiol levels to 47ng/ml, which is approximately a 29.4% drop. Western blot analysis using a CT antibody revealed heightened AIPB expression in MDA-MD-231-AIPB cells when stress and doxycycline treatments were combined. Conclusions: Given the absence of aromatase in triple-negative breast cancer, our findings suggest that AIPB’s role in estradiol production is independent of aromatase, highlighting its significance in these cancer cells. The data supports the hypothesis that enhancing AIPB expression could potentially improve patient outcomes by reducing estradiol synthesis.
Interim analysis of a phase I study using cryopreserved non-genetically modified allogeneic natural killer cells with enhanced cytotoxicity (SNK02) in patients with advanced solid tumors without lymphodepletion.
Authors: Chua Victoria , Chawla Sant P. , Gordon Erlinda Maria , Feske William , Hui Lucia , Lee Hank , Kang Yoonmi , Mata Juan , Betito Katia , Chang Paul Y. , Song Paul Y.
Published: June 2024

e14515

Background: Natural killer (NK) cells play a key role as the main effector cells toward cancer in innate immunity. A leading approach to boost NK cell-mediated anti-tumor activity is via the adoptive transfer of ex vivo activated NK cells. Current allogeneic donor-derived products require lymphodepletion to prevent immunologic rejection of donor cells by the recipient and ensure adequate cell delivery of the product cells to the target. However, lymphodepletion can negatively impact combination therapies where a robust T cell response is desired. SNK02 is a first-in-kind, cryopreserved allogeneic non-genetically modified NK cell product with significant anti-tumor cytotoxicity and over 90% expression of CD16, NKG2D, NKp46, and DNAM-1, that can be consistently produced on a large commercial scale. We hypothesized that higher doses of SNK02 (to overcome autodigestion) could be delivered frequently without the need for lymphodepletion and that it might demonstrate activity against solid tumors that have failed multiple prior standard-of-care treatment options. Methods: In this Phase 1 dose escalation study (NCT05990920), SNK02 was administered intravenously (IV) weekly for 8 consecutive weeks in patients with advanced solid tumors. The starting dose was 6 x 109 SNK02 cells. The primary endpoint was safety based on adverse events (AEs), vitals, laboratory tests, and physical exams. Results: As of Feb 1, 2023, 5 patients with advanced refractory solid tumors have been enrolled. Median age was 64 (range 44 – 71) and 3 were male. The subtypes were 1 leiomyosarcoma, 1 angiosarcoma, 1 endometrial adenocarcinoma, 1 undifferentiated pleomorphic sarcoma, and 1 colorectal adenocarcinoma. Four of five patients completed 8 cycles of SNK02. There was 1 death on study, which was deemed unrelated to the investigational product (IP). Out of the 36 doses administered through Cycle 8, there were 17 Grade 1, 3 Grade 2, and 1 Grade 3 adverse AEs related to IP. The Grade 3 AE of increased fatigue resolved after 1 day with no intervention required. Antibodies appeared to develop around cycle 5 and appeared to correlate with AEs. The best objective response of SD was demonstrated in 100% of patients that completed the 8 cycles. Conclusions: SNK02 was well tolerated as a monotherapy and appears to have some clinical activity against pretreated solid tumors despite the lack of lymphodepletion. SNK02 will continue to be studied as a monotherapy and in potential combination treatment regimens with monoclonal antibodies and immune checkpoint inhibitors. Clinical trial information: NCT05990920 .
Impact of urolithin A supplementation, a mitophagy activator on mitochondrial health of immune cells (MitoIMMUNE): A randomized, double-blind, placebo-controlled trial in healthy adults.
Authors: Denk Dominic , Singh Anurag , Kasler Herbert , Alcober Boquet Lucia , D'Amico Davide , Gorol Johanna , Greten Florian
Published: June 2024

e14562

Background: Mitochondrial dysfunction and stem cell exhaustion are hallmarks of aging, driving inflammation and limiting immune function. Likewise, cancer is characterized by repression of mitochondrial dynamics in tumor-infiltrating leukocytes that fosters terminal T cell exhaustion. Yet, interventions to reliably improve immune function are still lacking. Urolithin A (UA) is a postbiotic known to improve muscle function in aged adults upon oral intake. We have recently shown that UA induces mitophagy in human CD8+ cells to induce formation of T memory stem cells, while sensitizing murine cancer to immunotherapy. Methods: In this double-blind, prospective, placebo-controlled trial (NCT05735886) we sought to characterize for the first time the effects of UA on the human immune system. Fifty healthy participants aged 45-70 years were randomized (1:1) to an intervention of single-dose (1000mg) UA or placebo per day for a study duration of 28 days. Randomization was performed based on age, gender and BMI. Exclusion criteria were prior medical conditions, BMI >35 kg/m2, smoking, and intake of prescription medication or other dietary supplements. The primary end points of the study were changes in peripheral CD3+ cells, as well as alterations in mitochondrial activity in select immune populations of the peripheral blood as assessed by flow cytometry. Results: Intake of UA was safe and well-tolerated in the intervention cohort of 25 participants. After the study period, total peripheral lymphocytes and circulating NK cells were expanded in the UA group. Performing a complete immunophenotyping via spectral flow cytometry, we found that UA elicits immune remodeling characterized by broad changes of immune surface markers and mitochondrial measurements. CD8+ cells of participants in the intervention arm displayed greater mitochondrial mass, while preferably taking on a naive phenotype and expressing more Ki67. In addition, circulating monocytes exhibited a less inflammatory signature. UA intake reduced plasma levels of several proinflammatory cytokines. Conclusions: Collectively, our study constitutes an unprecedented intervention-based assessment of immune aging that globally characterizes the effect of UA on the immune system, proposing validation in future confirmatory studies and potential combination with cancer immunotherapy. Clinical trial information: NCT05735886 .