bluuebunny/crossref_metadata_2025_split huggingface dataset:
TP53 pathogenic variants with low allele fraction in germline genetic testing.
Authors: Wu Yanqin , Fan Wenzhe , Xue Miao , Tang Yiyang , Peisu Suo , Yang Bo , Huang Tanxiao , Zhang Jing , Li Jiaping 
Published: June 2022

10600 Background: Blood or saliva DNA generally considered to be representative of germline genome in genetic cancer risk assessment. However white blood cells from these samples may also include somatic origin DNA due to postzygotic variation or, most commonly, clonal hematopoiesis (CH). Low variant allele fraction (VAF) found in germline genetic testing suggest the possibility of somatic variant and may lead to misinterpretation of genetic risk. TP53, of which germline pathogenic variants are associated with Li-Fraumeni syndrome (LFS), is frequently mutated in CH. This analysis investigated characteristics of TP53 pathogenic variants with low VAF. Methods: We reviewed the prevalence and distribution of TP53 pathogenic variants(PVs) detected in 11,277 advanced cancer patients who underwent clinical testing with a clinical NGS pan-cancer panel. Potential somatic PVs were defined as variants with low VAF from 10% to 35%. The VAF were evaluated in matched tumor tissue samples if available. Results: TP53 pathogenic variants were detected in 36 (0.32%) patients from blood or saliva samples, VAF between 10% and 35% were identified in 8(22.22%) patients and 7 of them were performed NGS sequencing in matched tumor tissue samples. The average VAF of tissue samples were 9.31times lower than blood or saliva samples(21.69% vs 3.88%). Conclusions: TP53 pathogenic variants with low allele fraction in blood or saliva samples indicate the possibility of somatic variant, a reduced VAF in matched tumor tissue samples may contribute to confirmation for suspicion of somatic origin.
Questioning a Li-Fraumeni Syndrome diagnosis: Characterization of a commonly observed germline TP53 variant, p.Arg156His.
Authors: Nehoray Bita , Schwartz Alison , Hyman Sophie , Stokes Samantha , Cervantes Aleck , Amos Christopher , Gruber Stephen B. , Garber Judy Ellen 
Published: June 2022

10612 Background: Germline pathogenic variants (PV) in the TP53 gene are associated with Li-Fraumeni syndrome (LFS). Increased use of multi-gene panel testing has identified TP53 variants suspected to have reduced penetrance, a departure from the significantly increased cancer risks expected with LFS, posing challenges in variant classification and clinical management. TP53 c.467G>A (p.Arg156His), R156H, is a variant with over 250 observations across multiple laboratories with prior discordant classification. R156H was recently downgraded by laboratories from likely pathogenic (VLP) to variant of uncertain significance (VUS). Characterization of R156H to clarify clinical significance has the potential to impact care for many. Methods: R156H carriers were identified through the Li-Fraumeni & TP53: Understanding & Progress (LiFT UP) study ( https://liftupstudy.org ) from 2019-2022. Clinical data were collected and reviewed for phenotypic characterization and to determine whether LFS Classic and/or Chompret criteria were met, and to assign Li-Fraumeni spectrum classification (Kratz et al.). Results: Proband/family characteristics are in the Table. Twenty R156H carriers were identified in 11 families. Seventeen carriers had a personal history of cancer; 8 had a LFS core cancer. All core cancers were breast except for an astrocytoma and a pediatric sarcoma. Two breast cancer cases also carried a BRCA2 PV. The average age at first cancer diagnosis was 40.5 years (range 6-71). No families met Classic LFS criteria. One proband met Chompret criteria due to breast cancer <31 years (who also carried a BRCA2 PV). Ten families were classified as attenuated LFS per Kratz et al. Conclusions: Most families in our case series did not meet LFS criteria, raising the question of appropriate clinical management and the willingness to de-escalate LFS surveillance. Our series supports the downgrade to VUS, but the presence of a few non-breast LFS core cancers warrants work to determine if R156H is a reduced penetrance PV. Recruitment of these families is ongoing through the LiFT UP study to perform segregation analyses and cancer risk estimations. This work may guide evaluation of other variants presenting similar challenges. [Table: see text]
Survival outcomes in metastatic HR-positive, HER2-negative invasive ductal carcinoma compared to invasive lobular carcinoma and mixed ductal/lobular treated with endocrine therapy in combination with CDK4/6 inhibitors, mTOR inhibitor, or PI3K inhibitor.
Authors: Mouabbi Jason A , Raghavendra Akshara Singareeka , Bassett Roland L. , Hassan Amy Aida , Tripathy Debu , Layman Rachel M. 
Published: June 2022

1067 Background: The majority of invasive lobular breast cancers (ILC) are hormone receptor (HR)-positive, HER2-negative and are clinically treated similarly to HR+ HER2-negative invasive ductal cancers (IDC). However, ILC differs distinctly from IDC in its clinicopathologic characteristics and molecular alterations. ILC also differs in response to systemic therapy, with studies showing ILC as less sensitive to chemotherapy. It is currently unknown if patients with ILC or mixed ductal/lobular (MDL) histologies derive similar benefits as IDC from endocrine therapy (ET) in combination with cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), mTOR inhibitor everolimus or PI3K inhibitor alpelisib. Methods: We retrospectively searched for patients treated at MD Anderson Cancer Center with a diagnosis of HR+, HER2-negative metastatic breast cancer (MBC) with ET in combination with CDK4/6is, everolimus or alpelisib. Patients were divided into 3 groups based on their histology: ILC, IDC and mixed. We obtained data on demographics, estrogen (ER) and progesterone (PR) receptor status, menopausal status, treatment duration and survival status. The Kaplan-Meier product-limit method was used to compare progression-free survival (PFS) and overall survival (OS) between the three different groups stratified by the treatment received. Results: We identified 2,971 patients (2,432 IDC [82%], 427 ILC [14%], 112 Mixed [4%]) with HR+ HER2-negative MBC treated with ET in combination with CDK4/6is, everolimus and/or alpelisib between 2010 and 2021. Median age was around 50 years in all groups. Around 80% of patients were white, 10% Hispanic and 5% black. Around 55% of patients were post-menopausal, 99% had ER+ and 88% PR+ tumors; 1,895 patients (81% IDC, 15% ILC, 4% mixed) received CDK4/6is, 1,027 (82% IDC, 14% ILC, 4% mixed) received everolimus and 49 (81% IDC, 19% ILC) received alpelisib. PFS and OS were not statistically different between the 3 groups (Table). Conclusions: HR+ HER2-negative MBC patients with IDC, ILC and MDL benefited from ET in combination with CDK4/6is, everolimus or alpelisib similarly with no significant differences in PFS and OS. [Table: see text]
Safety and clinical activity of MEDI5752, a PD-1/CTLA-4 bispecific checkpoint inhibitor, as monotherapy in patients (pts) with advanced renal cell carcinoma (RCC): Preliminary results from an FTIH trial.
Authors: Albiges Laurence , Medina Rodriguez Laura , Kim Sang-We , Im Seock-Ah , Carcereny Enric , Rha Sun Young , Tran Ben , Oliveira Julio , Maroto-Rey Pablo , Su Wu-Chou , Voskoboynik Mark , Rodriguez-Vida Alejo , Costa Luis , Ascierto Paolo Antonio , Insa Molla Maria Amelia , Wang Yi , Gainer Shelby D. , Subramaniam Deepa S , Voss Martin H 
Published: June 2022

107 Background: MEDI5752 is a monovalent bispecific antibody targeting PD-1 and CTLA-4. A phase I, open-label study (NCT03530397) of MEDI5752 monotherapy 2.25–2500 mg IV Q3W showed encouraging antitumor activity in advanced solid tumors. Maximum tolerated dose was not reached; doses <1500 mg were better tolerated than doses ≥1500 mg. Here we present preliminary results in pts with advanced RCC in the escalation (ESC) and expansion (EXP) cohorts. Methods: Eligible pts were ≥18 yrs old (ECOG PS 0–1). In ESC and EXP, pts could be treatment-naïve (1L) or refractory. Eligible EXP pts had clear cell component (ccRCC), were immunotherapy-naïve (IO-naïve) and limited to ≤2 prior lines of therapy. Pts were treated until progression or unacceptable toxicity. Primary objectives were safety and tolerability (ESC), and antitumor activity by objective response per RECIST v1.1 (EXP). Results: Overall, 46 RCC pts were treated: 19 ESC, 27 EXP. In ESC, pts (all IO-naïve, 73.7% prior nephrectomy, 26.3% 1L, 89.5% clear cell histology) were treated across 3 dose levels: 750 mg (n=1), 2000 mg (n=16) and 2500 mg (n=2). Seven pts (36.8%) had objective responses (all PRs); 4 of these were 1L, including 1 each with papillary and sarcomatoid histology. In EXP, pts (all IO-naïve, 63.0% prior nephrectomy, 48.1% 1L [of whom 69.2% had IMDC intermediate/poor risk], 96.3% clear cell histology) received MEDI5752 1500 mg IV Q3W. Ten (38.5%) had objective responses (2 CRs, 8 PRs). In 1L EXP pts, 58.3% had objective responses (1 CR and 6 PRs); disease control rate (DCR) was 91.7% (Table). Grade 3/4 treatment-related adverse events (TRAEs) were seen in 68.4% of ESC and 74.1% of EXP pts. In EXP, treatment-emergent AEs (TEAEs), particularly hepatotoxicity, were the most common cause of treatment discontinuation (D/C). At a median duration of follow-up of 14.6 mo, median duration of response (DOR; including in those who discontinued MEDI5752 due to AEs), median PFS and OS were NR in 1L EXP pts. Conclusions: MEDI5752 monotherapy showed deep and durable antitumor activity in pts with advanced RCC, despite high rates of treatment D/C, particularly in the 1L setting. To better characterize the risk-benefit profile, MEDI5752 is now being explored at doses <1500 mg in 1L ccRCC expansion cohorts. Clinical trial information: NCT03530397. [Table: see text]
The safety, tolerability, and preliminary antitumor activity of sitravatinib plus tislelizumab in patients with locally recurrent or metastatic triple-negative breast cancer.
Authors: Fan Lei , Liu Xiyu , Jin Xi , Yang Yunsong , Chen Li , Hu Xin , Wang Zhonghua , Jiang Yizhou , Shao Zhimin 
Published: June 2022

1070 Background: Anti-PD-1 antibody plus chemotherapy has been demonstrated promising anti-tumor activity in patients with locally recurrent or metastatic triple negative breast cancer (TNBC). However, this regime only limited to TNBC patients with PD-L1 positive. As antiangiogenic agents could enhance the response to immune checkpoint inhibitors, we conducted this phase 2 study to assess the efficacy and safety of novel chemotherapy-free regimen of sitravatinib (targets receptor TKI against TYRO3, AXL, MERTK and VEGF family of receptors) in combination with tislelizumab (anti-PD-1 antibody) in patients with locally recurrent or metastatic TNBC regardless of PD-L1 status. Methods: Patients with locally recurrent or metastatic TNBC were included and divided into two cohorts. Patients received 70 mg (cohort A) or 100 mg (cohort B) sitravatinib QD PO and 200 mg tislelizumab IV Q3W until disease progression or intolerable toxicity. The primary endpoints included overall response rate (ORR) (cohort A and B) and rate of grade ≥3 treatment-related adverse events (AEs) (cohort B). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), 1-year overall survival rate and safety/tolerability. In cohort A, the first statistical analysis would be performed when 12 patients were enrolled; if ≥1 of 12 patients were with confirmed response during the first stage, additional 9 patients would be enrolled to the second stage based on Simon's two-stage design. We would deem cohort A to be statistically superior to a historical control of 8% under the settings if > 3 of 21 patients responded (one-sided a = 0.1 and power of 80%). Patients’ recruitment in cohort B would begin after completing the recruitment in cohort A. Results: Herein we reported the preliminary results in cohort A. Four patients were with confirmed response during the first stage, and additional nine patients were enrolled to the second stage. A total of 21 patients with 0-3 lines of prior chemotherapy were included from April 2021 to September 2021. The median age was 51 (32-66) years and 20 (95%) patients had ECOG PS 0. At data cut off 13 Jan 2022, 19 patients were alive, 11 are still on treatment. The confirmed ORR was 38.1% (95% CI, 18.1%-61.6%) based on current 21 efficacy evaluable patients. DCR was 95.2% (95% CI, 76.2%-99.9%), and median PFS was 7.0 (95% CI, 3.7 - not reached) months. 4/21 (19%) of patients experienced grade 3 treatment-related AEs. Grade 3 AEs reported in ≥5% of patients were aspartate aminotransferase increased (9.5%) and palmar-plantar erythrodysaesthesia syndrome (9.5%). No patients experienced grade 4 AEs. Conclusions: Sitravatinib combined with tislelizumab demonstrated clinically meaningful anti-tumor activity and had a manageable safety profile. Clinical trial information: NCT04734262.
Apatinib combined with chemotherapy versus single chemotherapy in HER-2 negative advanced breast cancer: A randomized, controlled, open-label phase II study.
Authors: Chen Zhanhong , Wang Xiaojia , Huang Jian , Zheng Yabing , Shao Xiying , Cao Wenming , Chen Junqing , Ye Weiwu , Ping Huang , Li Guangliang , Lei Lei , Shi Lei , Huang Yuan , Zou Weibin , Wang Rong , Shen Xia-Bo , Lou Caijin 
Published: June 2022

1072 Background: Apatinib is an oral, highly potent tyrosine-kinase inhibitor targeting VEGFR2. A series of clinical studies have shown that anti-angiogenic drugs combined with chemotherapy enable to improve the efficacy of HER2-negative advanced/metastatic breast cancer(MBC). Methods: Patients with HER2-negative MBC with less than two lines of systemic therapy were enrolled in this open-label, controlled, phase II trial. Patients with measurable disease were randomly assigned, in a 1:1 ratio, to receive oral apatinib (250 mg once daily) combined with chemotherapy(A+CT) or chemotherapy(CT) alone (the physician’s choice) until disease progression or intolerable toxicity. The primary end point was progression-free survival(PFS), which was assessed by investigator and was analyzed on an intention-to-treat basis. Results: Between August 2017 and January 2021, of the 80 patients who underwent randomization, 40 were assigned to receive apatinib plus chemotherapy(A+CT) and 40 were assigned to receive standard therapy(CT). As of January 2022, 10 patient had not undergone response evaluation or dropout, 70 patients(36 patients in A+CT, 34 patients in CT were finally included with PFS events and 72 patients were included in safety set. Median PFS was significantly longer in A+CT than in CT (182 days vs 63 days; P = 0.043);The median PFS of TNBC subgroup (11 in A+CT group, 14 in CT) was longer in the aptinib group than in CT group (167 days vs 63 days; P = 0.637);The median PFS of HR+ subgroup(25 in apatinib group, 20 in chemotherapy group) was longer in the aptinib group than in CT group (259 days vs 56 days; P = 0.054);The median PFS of patients with liver metastases(19 in apatinib group, 17 in chemotherapy group) was longer in the aptinib group than in the CT group (151 days vs 54 days; P = 0.191); The severe adverse reactions (grade 3/4) were neutropenia(22.2% vs 13.9%), hypertension(11.1% vs 0.0%), leukopenia(8.3% vs 8,3%), hypokalemia(8.3% vs 2.8%), anemia(5.6% vs 11.1%), ALT(2.8% vs 8.3%), AST(0.0% vs 5.6%) in the apatinib group and the CT, respectively. Proteinuria did not occur in both groups. Treatment delay or dose reduction owing to adverse event was 16.7% and 11.1%, respectively. Treatment discontinuation owing to adverse event was 23.5% and 8.8%, respectively. Conclusions: Apatinib combined with chemotherapy showed a significant improvements in PFS and a manageable safety profile in HER2 negative MBC.
Leveraging patient engagement to optimize a phase 3 clinical trial design, study participation and recruitment for women diagnosed with triple-negative breast cancer (TNBC).
Authors: Elmer Mary E. , Karantza Vassiliki , Vichnin Michelle , Aktan Gursel , Powell Valerie J. 
Published: June 2022

1073 Background: The importance of Patient Engagement (PE) on clinical trial design is well established. PE in oncology medicines development can serve many purposes including obtaining input on trial design/procedures, identifying recruitment challenges and barriers to participation, and understanding retention strategies. Designing a clinical trial with procedures that have been confirmed as acceptable to participants is also likely to improve patient adherence to treatments. Triple-Negative Breast Cancer (TNBC) is a virulent subtype associated with early onset and increased risk of early recurrence and accounts for 15% to 20% of breast cancers. In addition, a higher risk exists in premenopausal and Black women. Chemotherapy is the mainstay of curative therapy recommended by guidelines. The aim was to obtain insights from patients to inform key aspects of a clinical study design including choice of chemotherapy regimen, study feasibility and recruitment strategies. Methods: Two groups of US women (N = 20) ages 28-54; (race 55% Caucasian, 30% African American, 10% Hispanic, 5% Native American) diagnosed with Stage IIb-IV TNBC and in active or completed treatment were recruited to participate in two in person IRB approved sessions. Trained 3rd party facilitators used qualitative methods to elicit patient feedback. Preliminary research included interviews with key stakeholders, including TNBC advocacy group leaders and a review of online patient communities. Patients reviewed a study design with an investigational agent every 3 weeks plus chemotherapy (nab-paclitaxel; paclitaxel) or placebo plus chemotherapy. Results: Patient reaction to the choice of taxane chemotherapy in the standard of care arm was neutral to negative. Approximately 50% of the patients identified taxane treatment as a barrier to participation. All patients requested flexibility in treatment choices, clear information about required tests and visits, and more diversity in recruitment materials. Black and Hispanic women impacted by TNBC did not feel they had equal access to clinical trials due to race, rural location, and other factors. Patient insights reinforced the decision to add another standard-of-care option (carboplatin plus gemcitabine) as a treatment arm to the trial design and was confirmed with investigators. Patient feedback was incorporated into the trial along with additional strategies to support recruitment of diverse patients in the clinical study. Conclusions: On November 13, 2020 the FDA approved this regimen in the label for pembrolizumab in combination with chemotherapy, as the 1st line treatment in women with locally recurrent or metastatic TNBC. Both patients and physicians perceived that a flexible chemotherapy backbone was a benefit.
Genomic landscape and peripheral blood biomarkers of advanced triple-negative breast cancer treated with immune checkpoint blockade: An exploratory analysis of the TQB2450-Ib-07 trial.
Authors: Han Yiqun , Wang Jiayu , Sun Tao , Ouyang Quchang , Li Jianwen , Xu Binghe 
Published: June 2022

1080 Background: Immune checkpoint inhibitor (ICI) has emerged as a novel therapeutic option for advanced triple-negative breast cancer (aTNBC). However, no robust biomarker indicative of clinical outcomes has been identified. Herein, we portraited the genomic landscape and explored the biomarkers for patients with aTNBC receiving ICI-based therapy. Methods: This is a prospective, multicenter, phase 1b clinical trial (NCT03855358) to assess the efficacy and safety profiles of TQB2450, a humanized monoclonal PD-L1 antibody, plus anlotinib in pretreated TNBC. Eligible patients undergo liquid biopsy at baseline and the timepoint of disease progression. NGS-based assay was performed based on circulating tumor DNA (ctDNA) in the bloodstream. Meanwhile, results of laboratory blood tests were dynamically collected and blood markers, including neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), and platelet to lymphocyte ratio (PLR), were successively evaluated. The primary endpoints were progression-free survival (PFS) and clinical efficacy assigned via guidelines for response criteria for use in trials testing immunotherapies (iRECIST). Results: Between May 29, 2019, and December 31, 2020, 34 patients with aTNBC were enrolled. Gene alternations primarily comprised mutation, amplification, or deletion of TP53, MLL3, DNMT3A, PI3KCA, EP300, PTEN, LRP1B, MDM2, and NCOR1. The median maximum somatic allele frequency (MSAF) was 9.97% significantly indicative of PFS, which was 3.58 months for the MSAF-high group and 13.34 months for the MSAF-low group (P = 3e-04), respectively. Else, a strong association was also signified between MSAF and tumor shrinkage (CR/PR vs. SD/PD, P = 0.012). For blood tumor mutation burden (bTMB), the median was 6.72 muts/Mb, which the bTMB-low group was suggestive of a better PFS (11.09 months vs. 5.52 months, P = 0.007), yet no obvious association existing in terms of clinical response. Dynamic analysis revealed that a decline in MSAF was significantly associated with a better PFS (7.10 months vs. 2.74 months, P = 0.018), while no correlations were detected between bTMB and PFS. Based on NLR week 2/0 of 0.95, PFS was significantly worse in the NLR-low group (11.0 months vs. 3.5 months, P = 0.006) and likely distinguished the clinical response (CR/PR vs. SD vs. PD, P = 0.049; non-PD vs. PD, P = 0.022). Moreover, NLR week 2/0 could notably foretell the clinical response for patients with aTNBC with the AUC of 0.82 (0.61-1.00). No comparable utilities were identified regarding LMR and PLR. Conclusions: For aTNBC treated with ICI, MSAF tended to be a robust indicator for both PFS and clinical response. NLR week 2/0 presented a favorable profile indicative of PFS as well as a strong predictor for clinical responsiveness of patients with aTNBC receiving immune checkpoint blockade. Clinical trial information: NCT03855358.