bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying the optimal therapeutics for patients with hormone receptor-positive, HER2-positive advanced breast cancer: A systematic review and network meta-analysis.
Authors: Wang Yan , Xu Hangcheng , Han Yiqun , Wu Yun , Sa Qiang , Xu Binghe , Wang Jiayu 
Published: June 2023

e13023 Background: Hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-positive breast cancer is a distinct subtype with different prognosis and response to treatment. HER2-targeted therapy is currently recommended for patients with HR+/HER2+ advanced breast cancer. However, there is debate over which drugs to add on the basis of HER2 blockade yields the optimal efficacy. Moreover, the research on replacing chemotherapy with endocrine therapy in the regimens are under way. This systematic review and network meta-analysis was conducted to find the optimal treatment for this subtype. Methods: Eligible randomized controlled trials (RCTs) comparing different interventions in metastatic HR+/HER2+ breast cancer were included by comprehensively searching PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, and abstracts of oncology conferences before September 5th, 2022. The outcomes of interest included progression free survival (PFS), overall survival (OS) and treatment-related adverse events (TRAEs). Pooled hazard ratios (HRs) or odds ratios (ORs) with credible intervals (CrIs) were calculated to estimate the predefined outcomes based on the data type. The optimal therapeutics were identified by utilizing the cumulative ranking curves (SUCRA). Results: In total, 23 pieces of literature of 20 RCTs were included. Regarding PFS, significant differences were detected between dual HER2 blockade plus endocrine therapy versus endocrine therapy alone (HR 0.45, 95% CrI 0.25-0.83; HR 0.47, 95% CrI 0.27-0.87), and trastuzumab, pertuzumab plus chemotherapy versus trastuzumab plus chemotherapy (HR 0.69, 95% CrI 0.47-0.96). The SUCRA values suggested the relatively better efficacy of dual HER2-targeted therapy plus endocrine therapy (86% to 91%) or chemotherapy (62% to 81%) in prolonging PFS and OS. The HER2 blockade-containing regimens showed similar safety profiles in eight documented TRAEs. Conclusions: Prominent status of dual-targeted therapy for patients with HR+/HER2+ metastatic breast cancer was revealed. Compared with chemotherapy-containing regimens, the endocrine therapy-containing regimens showed better efficacy and similar safety profile, which could be recommended in practice.
Preliminary analysis of pyrotinib and dalpiciclib-based therapy in HER2-positive advanced breast cancer (ABC).
Authors: Wang Yongsheng , Yuan Peng , Yang Hua , Liu Yanbing , Yue Jian , Yang Yang , Li Huajun , Yu Jinming 
Published: June 2023

e13027 Background: The efficacy of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) and HER2 target agents combined with endocrine treatment (ET) has been demonstrated in hormone receptor (HR)-positive and HER2+ ABC, while little was known about the role of CDK4/6i in HR-/HER2+ ABC. In this prospective, multi-center, multi-cohort, phase 2 study (NCT04095390), we assessed the efficacy and safety of pyrotinib (P) and a CDK4/6i, dalpiciclib (D)-based therapy in HER2+ ABC with disparate HR statuses. Methods: HER2+ ABC females with known HR status were eligible if previously treated with trastuzumab (T). No more than one prior systemic regimen in advanced setting was allowed. Cohort A: HR+ pts received P (320 mg QD) and D (125 mg QD, 21 days on and 7 days off) combined with letrozole (2.5 mg QD). Cohort B or C: HR- pts were randomized to receive P and D combined with or without capecitabine (500 mg TID). Pts were treated until progression or unaccepted toxicity. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: As of Jan. 16, 2023, 33 pts were enrolled. We describe pts' distribution and characteristics. 26 pts had at least one efficacy assessment, and 17 (65.4%) achieved confirmed objective responses. ORR was 66.7% (10/15), 80% (4/5), and 50% (3/6) in cohort A, B, and C, respectively. Among the ITT population, the estimated median PFS was 24.9 mo. (24.9 mo., NR, and 20.2 mo. in cohort A, B, and C, respectively). 32 (97.0%) pts experienced treatment-related adverse events (TRAEs). Grade (G) 3-4 TRAEs occurred in 81.8% of pts, and the most frequent (≥ 10%) ones were neutropenia (72.7%), leukopenia (57.6%), diarrhea (21.2%), and mucositis (12.1%). Safety profiles were similar among cohorts, except more G3-4 mucositis, hand-foot syndrome and thrombocytopenia in cohort B. Two in cohort B discontinued due to toxicity (1 rash, and 1 neutropenia). One death was reported after withdrawal and unrelated to the study. Median OS was not reached. Conclusions: Our study shows P and D combined with ET is effective in HR+/HER2+ ABC, providing a chemo-free option to these pts. In HR-/HER2+ ABC, we preliminarily observed that the addition of chemotherapy could improve effectiveness of P and D, but also increase toxicities. Due to the limited sample, the findings need further confirmation. Clinical trial information: NCT04095390 . [Table: see text]
Incidence of interstitial lung disease and cardiotoxicity with trastuzumab-deruxtecan in patients with breast cancer: A systematic review and single-arm meta-analysis.
Authors: Soares Leonardo Ribeiro , Rosa Victor Domingos Lisita , Vilbert Maysa , Oliveira Jessica Lopes , Deus Mariana Moreira , Freitas-Junior Ruffo 
Published: June 2023

e13033 Background: The new antibody-drug conjugated directed to HER2, Trastuzumab-Deruxtecan (T-DXd), has shown the benefit of progression-free survival and overall survival in metastatic breast cancer (mBC) patients after progression to ≥1 HER2 targeted therapies. Interstitial lung disease (ILD) and cardiotoxicity are the most significant and concerning toxicities related to T-DXd. We performed a systematic review and meta-analysis to assess the incidence and severity of those adverse events (AE) in mBC patients treated with T-DXd. Methods: We comprehensively searched Pubmed, Cochrane, and Scopus databases for randomized clinical trials (RCT) and observational cohort studies, including mBC patients with HER2-low or -positive expression who have received at least one dose of T-DXd. The DESTINY-Breast02 study was also included after its presentation at the SABCS 2022. The statistical analysis was performed using R software, and the results are presented as pooled analysis in forest plots. Results: We included nine studies: three phase III RCTs, three phase II and two phase I non-RCTs, and one retrospective cohort comprising 1,443 patients with a mean follow-up of 14.9 months. The median age of our population ranged from 53 to 59 years. Most were non-Asian (40.5%) and presented with hormone-receptor positive mBC (66.8%). In a pooled analysis, the incidence of ILD was 13.0% (179 patients; 95%CI 11.0 to 13.0). Patients enrolled in phase III clinical trials had an ILD rate of 12.0%, while the observational cohort reported a numerically higher rate of 18.0%. Most ILD cases, 84.9% (152 patients), were mild (grade 1 or 2). Grade 3 or 4 AE were reported in 13 patients (7,3%), and grade 5 in 14 patients (7,8%). Decreased left ventricular ejection fraction (LVEF) was seen in 3.6% (95%CI 3.0 – 5.0%), and most patients were asymptomatic. Eleven patients developed prolonged QT interval, and four had left ventricular dysfunction and cardiac failure. Conclusions: Our meta-analysis reinforces the importance of close vigilance for pulmonary and cardiac toxicities in mBC patients on treatment with T-DXd. Early detection and management by a multidisciplinary team following the most recent guidelines may improve the patient outcomes. [Table: see text]
Safety and efficacy study of oral metronomic capecitabine in combination with pyrotinib for HER2-positive metastatic breast cancer: A phase II trial.
Authors: Li Qiao , He Maiyue , Liu Jiaxuan , Wang Zijing 
Published: June 2023

e13038 Background: A single-arm prospective phase II trial to was conducted evaluate the efficacy and safety of oral metronomic capecitabine combined with pyrotinib in human epidermal growth factor receptor 2-positive (HER2 positive) metastatic breast cancer (MBC) patients. Methods: HER2-positive patients received oral metronomic capecitabine 500 mg three times daily and pyrotinib 400 mg. The primary endpoint was progression-free survival (PFS). Other endpoints included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and safety. Results: 50 patients with HER2-positive MBC were enrolled, and one was excluded due to medication irregularities. The median PFS and OS were 11.9 months (95%CI 8.8-14.6) and 29.3 months (95%CI 24.4-34.8) respectively. ORR was 34.7%, and CBR was 81.6% with 2 CR (4.1%), 15 PR (30.6%) and 23 SD (46.9%). The mPFS in first- or second-line treatment was 12.2 months. The most frequent treatment-related adverse complications included hand-foot syndrome, diarrhea, vomiting and nausea. Grade 3 adverse events occurred in 15 (30.6%) patients and included hand-foot syndrome (12.2%), diarrhea (12.2%), vomiting (4.1%), and nausea (2.0%). Grade 4 adverse event of diarrhea (2.0%) was observed in one case. Conclusions: The combination of metronomic capecitabine and pyrotinib is a promising regimen with competitive efficacy and improved tolerability in HER2-positive metastatic breast cancer patients. Clinical trial information: NCT03923166 .
Use of PARPi among patients with HER2+ve MBC: Results from a real world dataset.
Authors: Dawood Shaheenah S. , Brzozowski Kaylen 
Published: June 2023

e13044 Background: Among individuals with germline mutations in BRCA1/ BRCA2 genes, life-time risk of developing breast cancer is approximately 50%. The majority of these cancers are HER2-ve with a low frequency of HER2+ve breast cancer (2.1%-10% in pts with BRCA1 mutations and 6.8%-13% of pts with BRCA2 mutations) with co-occurrence of BRCA mutation and HER2+ve status being a poor prognostic factor. PARPi have been shown in phase III trials to be effective in HER2-ve BRCA mutation MBC. The objective of this retrospective analysis was to look at the prognostic outcome associated with use of PARPi among pts with HER2 +ve BRCA mutated MBC in the real-world setting. Methods: We utilized a federated network of de-identified health data representing approximately 107 million pt lives available through the TriNetX Research Network. We identified patients with MBC who were treated with PARPi, and pts were assumed to have BRCA mutated MBC if they were recorded with a PARPi. Overall survival (OS) was computed using the Kaplan Meier product limit method. Pts with MBC were defined as having HER2+ve status if they received an anti-HER2 therapy after metastasis, HR+ve if they received endocrine therapy after metatstasis, and triple negative (TNBC) if they did not receive anti-HER2 therapy or endocrine therapy. Results: 1369pts with MBC were treated with PARPi, of whom 77.9%received olaparib. Mean age of pts was 57ys. 546(39.9%), 521(38.1%) and 73(5.3%) pts had TNBC, HR+ve/HER2-ve, and HER2+ve MBC, respectively. Among pts with HER2+ve disease, 35.2% and 74.0% had HR-ve and HR+ve MBC, respectively. Median time to use of PARPi was 7.1m, 15.1m, and 24.0m among pts with TNBC, HR+ve/HER2-ve, and HER2 +ve MBC respectively. Median OS was 44.4m, 47.0m, and 46.7m among pts with TNBC, HR+ve/HER2-ve and HER2+ve MBC respectively. Among pts with HER2+ve disease, median OS was 74.5m and 31.5m among pts with HR+ve and HER-ve disease, respectively (HR=0.27, p=0.0001). 321(23.4%) pts had brain metastases of whom 36.8%, 36.4% and 8.1% had TNBC, HR+ve/HER2-ve and HER2+ve MBC respectively. Among pts with HER2+ve MBC,38.3% received anti HER2 therapy before PARPi, 24.7% received anti HER2 therapy after PARPi and 37.0% received PARPi and anti HER2 therapy concurrently. Among pts with HER2+ve disease, median OS was 44.4m among those who received anti -HER2 therapy on or before PARPi and 93.8m among those who received anti-HER2 therapy after PARPi (HR 0.83, p=0.64).Among pts with brain metastases, median OS was 23.9m, 40.0m and 40.2m among pts with TNBC, HR+ve/HER-ve and HER2+ve MBC respectively. Conclusions: To our knowledge this is the first real world data set to report on the prognostic outcome of pts with HER2+ve BRCA mutated MBC. When PARPi inhibitors are given median OS is similar among the three subtypes of breast cancer. Although not significant, there appears to be a trend towards improved OS with earlier use of PARPi among patients with HER2+ve BRCA mutated MBC.
De novo metastatic Her2+ breast cancer in a diverse population of women under age 40.
Authors: Chung Victoria , Sheen Melanie Anne , Henry Marcia , Alberti Matthew , Peeples James , Yuan Helen , Saxena Raina , Olet Susan , Taylor Caitlin , Cattie Rabia 
Published: June 2023

e13045 Background: Breast cancer (BC) is the most common malignancy among women. Her2 mutation has historically been associated with more aggressive disease and worse prognosis, however this paradigm is changing with Her2-directed therapies. Her2 positive BC presents with de novo metastatic disease more often than other subtypes. Young women are more likely to be diagnosed with Her2 positive BC, however previous studies have not had adequate representation of Black/African American women. We evaluated a diverse group of young women under the age of 40 to determine if Her2+ disease was more likely to present with de novo metastatic disease. Methods: We performed a retrospective chart review and collected data on 746 women diagnosed with BC under the age of 40 from 2012 to 2022. We collected age at diagnosis, Her2 receptor status, self-identified race, and stage at diagnosis. 187 of these patients were Her2 positive, and 276 patients were Black. We stratified patients as Black versus White, and as stage IV at diagnosis versus stages I to III at diagnosis. We performed Fisher's exact test to determine if Her2 positive BC was more or less likely to present as de novo metastatic disease compared to Her2 negative BC. Results: In our population of 746 young women under the age of 40 presenting to our health system in a 10-year period, 48 (6.4%) presented with de novo metastatic BC, and 19 (39.6%) of these were Her2 positive. 36% of our study population was Black, which is representative of the demographics of our region. We performed Fisher's exact test, and found that Her2 positive BC was more likely to present as de novo metastatic disease compared to Her2 negative BC. This was statistically significant (p = 0.024). When divided for race, this was not statistically significant for White patients alone (p = 0.052) or Black patients alone (p = 0.234). Conclusions: Our data shows that Her2 positive BC in women under the age of 40 is statistically more likely to present with de novo metastatic disease. Previous research in this area has not been inclusive of Black patients. Current guidelines only recommend staging imaging among patients with systemic symptoms. Based on this data, consideration should be made for staging scans for young women presenting with new HER2+ breast cancer diagnoses. There is limited data available for breast cancer subtype incidence and prognosis among Black patients, and this study underscores the need for more inclusive study populations.[Table: see text]
Impact of use of CDK4/6i and neratinib among patients with HER2 +ve MBC: Results from a real world dataset.
Authors: Dawood Shaheenah S. , Brzozowski Kaylen 
Published: June 2023

e13046 Background: The introduction of anti-HER2 therapy has improved the prognostic outcome of pts with HER2+ve MBC. A phase II trial revealed that among pts with HR+ve/HER2+ve MBC the use of CDK4/6i with anti-HER2 and endocrine therapy was associated with a survival advantage compared to anti-HER2 therapy and chemotherapy. A phase III trial showed that neratinib + capecitabine improved OS compared to lapatinib and capecitabine. With a plethora of new and efficacious anti-HER2 therapy now available the true clinical utility of CDK4/6i and neratinib are undetermined. The objective of this retrospective analysis was to look at the prognostic outcome associated with use of CDK4/6i and neratinib among pts with HER2+ve MBC in the real-world setting. Methods: We utilized a federated network of de-identified health data representing approximately 107 million pt lives available through the TriNetX Research Network. We identified pts with 6511pts with HER2+ve MBC diagnosed since 2015 who were treated with ant-HER2 therapy including trastuzumab, pertuzumab, neratinib, lapatinib, TDM-1 and margetuximab. OS was computed using the Kaplan Meier product limit method. HR+ve status was defined by treatment with endocrine therapy after metastasis, and triple negative (TNBC) status was identified if they did not receive anti-HER2 therapy or endocrine therapy. Results: Mean age was 57.0 yrs. 3679(57.2%) and 2832(42.8%) pts had HR+ve and HR-ve disease, respectively. 2-year OS among pts diagnosed prior to 2015 and during or after 2015 was 79.7% and 82.8%, respectively (p=0.0041). 2-year OS among pts with HR+ve and HR-ve MBC was 87.0% and 75.4%, respectively (p<0.0001). Among pts with HR+ve MBC, 592(16.1%) received a CDK4/6i. Median time to use of CDK4/6i was 4.7m. 2-year OS among pts who did and did not receive a CDK4/6i was 85.1% and 87.5%, respectively (p=0.1844). Median OS among pts who received CDK4/6i within the first year of MBC diagnosis compared to those who received it after the first year of diagnosis was 71.0m and 69.4m, respectively (p=0.0679). No difference in OS was observed among pts with HR+ve disease who had brain mets who did and did not receive CDK4/6i(49.5m vs 54.5m p=0.7335). 327(5.0%) pts received neratinib, of whom 63.9% had HR+ve MBC. 2-year OS among pts who did and did not receive neratinib was 85.1% and 82.6%, respectively(p=0.2366). No difference in 2-year OS was observed among pts who did and did not receive neratinib stratified by HR status and presence of brain metastasis. Conclusions: OS among pts with HER2+ve MBC has significantly improved over time. The use of CDK4/6i among pts with HR+ve/HER2+ve MBC and use of neratinib among pts with HER2+ve MBC did not impact OS.
BPI-16350, a novel promising CDK4/6 inhibitor for HR+/HER2- metastatic breast cancer (MBC): Results from a phase I study.
Authors: Zhang Jian , Liu Rujiao , Gao Shuiping , Chen Wenyan , Han Xinghua , Ma Yanjie , Ding Lieming , Wang Jiabing , Lan Hong , Hu Xichun 
Published: June 2023

e13051 Background: BPI-16350 is a highly potent CDK4/6 inhibitor, and has a similar structure to abemaciclib but with less inhibition of CDK9 in pre-clinical experiments. This is an open-label, dose-escalation and -expansion phase I study to evaluate the safety, pharmacokinetics, and preliminary antitumor activity of BPI-16350 as monotherapy (Part A) and combined treatment with fulvestrant (FUL) in pts with HR+/HER2- MBC (Part B). Methods: In Part A, patients (pts) who had failed standard therapies were eligible to receive BPI-16350 in a standard 3+3 pattern at doses ranging from 50−500 mg QD. In Part B, BPI-16350 (300 mg or 400 mg QD) plus intramuscular FUL was administered in pts who had experienced secondary endocrine resistance. Pts in this part should have received no more than one line of chemotherapy for metastatic disease and no prior therapies with other CDK4/6 inhibitors, FUL or everolimus. Results: As of 13 November 2022, 24 pts were enrolled in Part A (50 mg, n=4; 100 mg, n=4; 200 mg, n=3; 300 mg, n=3; 400 mg, n=4; 500 mg, n=6), including 23 pts with MBC and one pt with abdominal liposarcoma. 66.7% (16/24) of pts had received ≥ 2 lines of chemotherapies and 70.8% (17/24) had received ≥ 2 lines of endocrine therapies. Only one dose-limiting toxicity event (i.e. Grade 3 blood creatinine increased) was observed at 500 mg dose, and the maximum tolerated dose was not reached. Grade ≥ 3 AEs occurred in 45.8% (11/24) of pts, with the most common being diarrhea (4/24), anemia (3/24), and neutropenia (2/24). The median time to peak concentration for BPI-16350 was 2.0-17.0 hours, and the mean half-life was 35.6-51.0 hours, supporting once-daily dosing. After a single oral dose of 50–500 mg of BPI-16350, the drug exposure was dose-proportional. With a QD dosing regimen, accumulation was 2.1–3.3 fold. The disease control rate (DCR) was 70.8% (17/24, 95% CI: 48.9%-87.4%). One pt (4.2%) achieved a partial response at 500 mg dose. In Part B, 46 pts with HR+/HER2- MBC were enrolled (300 mg, n=9; 400 mg, n=37), and 63.0% (29/46) of pts were still on treatment. Grade ≥ 3 AEs occurred in 42.5% (20/46) of pts, with the most common being anemia (8/46), leukopenia (6/46), hypokalemia (6/46), and neutropenia (5/46). Among the 46 pts, 43 pts were evaluable for efficacy. The DCR was 97.7% (42/43, 95% CI: 87.7%-99.9%). The confirmed overall response rate was as high as 60.5% (26/43, 95% CI: 44.4%-75%). The median progression-free survival has not been reached (95% CI: 11.1 months–not reached). Conclusions: To our knowledge, BPI-16350 plus FUL demonstrated numerically highest antitumor activity compared with the already approved CDK4/6 inhibitors and less Grade ≥ 3 diarrhea than abemaciclib. A phase III study (NCT05433480) comparing BPI-16350 plus FUL versus placebo plus FUL in pts with MBC is ongoing. Clinical trial information: NCT03791112 .
Outcome of second-line treatment after CDK4/6 inhibitors in hormonal-positive HER-2 negative metastatic breast cancer: Single institution experience.
Authors: Alghanmi Hosam , Elsamany Shereef Ahmed , Elnaghi Khaled 
Published: June 2023

e13053 Background: In patients with metastatic hormonal receptors (HR)-positive, HER2-negative breast cancer, CDK 4/6 inhibitors with hormonal therapy is the current standard first line therapy in patients without visceral crisis. Limited data is available about the outcome of second line therapy after CDK 4/6 inhibitors. In this study, we reported the survival outcome of second line systemic therapy after CDK 4/6 inhibitors in a single institute in Saudi Arabia. Methods: We retrospectively checked patients with metastatic HR-positive, HER2-negative breast cancer who received first line therapy with palbociclib in addition to an aromatase inhibitor in King Abdullah Medical City, Saudi Arabia. Patients who received second line systemic therapy were recruited. Different clinicopathological data were checked in addition to type of second line therapy, dates of starting 1st and second lines therapy and dates of progression. We check progression-free survival (PFS) with second line therapy in relation to the type of second line therapy, duration of 1st line therapy and other potential prognostic factors. Results: We recruited 59 eligible patients. Median PFS of the study group was 4 months (95% CI 2.9-5.1). No significant difference in PFS according to type of second line systemic therapy (chemotherapy: 4 months, everolimus with hormonal therapy: 6 months, hormonal monotherapy: 3 months, p=0.17). In addition, there was no significance difference in second line therapy PFS according to duration of 1st line palbociclib-hormonal therapy (≤ 12 months: 4 months vs. >12 months: 5 months, HR 0.97, 95% CI: 0.55-1.7, p=0.92). Similarly, taking 6 months as a cutoff, no significant difference in PFS (≤ 6 months: 4 months, >6 months: 6 months, HR 0.73, 95% CI: 0.43-1.24, p=0.25). Similarly, no difference in second line PFS according to menopausal status, age at diagnosis (≤ 50 vs >50) or ER-Allred score (≤ 6 vs >6). Conclusions: Outcome of 2nd line systemic therapy following first line palbociclib with hormonal therapy was poor in the study cohort. No significant difference in PFS according to type of systemic therapy, duration of first line therapy, or other clinicopathological factors.