bluuebunny/crossref_metadata_2025 huggingface dataset:
CCT6A and triple-negative breast cancer metastasis: Activating the AKT/MDM2/P53 pathway.
Authors: Yang Mengdi , Cao Jianing , Guo Duancheng , Tao Zhonghua , Hu Xichun
Published: June 2023

e13087

Background: Triple-negative breast cancer (TNBC) patients are prone to distant recurrence and poorer prognosis. The key molecules and underlying mechanisms of TNBC's aggressive phenotype remain to be further clarified. Methods: First, using the Kaplan-Meier Plotter ( https://kmplot.com/analysis ) and analyzing our collected clinical samples, we established the expression pattern and clinical value of the chaperonin containing TCP1 subunit 6A (CCT6A) in TNBC. We carried out the Cell Counting Kit-8 (CCK8), Transwell, and flow cytometry assay in the TNBC cell lines including MDA-MB-231 and BT549 to assess the effects of knockdown and overexpress of CCT6A. The mechanism of CCT6A in TNBC was identified by using the RNA-seq, KEGG analysis and Co-Immunoprecipitation Mass Spectrometry. Rescue assays verified the role of the AKT Serine/Threonine Kinase 1 (AKT) / Mouse double minute 2 homolog (MDM2)/P53 pathway on CCT6A. Then, the effect of CCT6A on tumor progression and metastasis in vivo was evaluated by the mouse models of tumorigenesis in situ and caudal artery lung metastasis. APG115, a pharmacological p53 activator and immune stimulatory MDM2 inhibitor, combined with anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody Ipilimumab was found to prevent TNBC metastasis. Finally, we did a profiling of the tumor immune environment in mice. Results: CCT6A was highly expressed in TNBC ( p<0.0001), and patients with high expression of CCT6A had poor prognosis ( p=0.0053, HR=2.36 [1.27-4.39]). Of note, CCT6A was significantly associated with lymph node metastasis ( p<0.0001). CCT6A promoted cell proliferation, migration, and invasion while inhibiting cell apoptosis and achieving G1/S stage arrest through gain- and loss-of-function approaches. In terms of mechanism, Co-IP and Immunofluorescence assay verified that CCT6A interacted with Keratin 10 (KRT10) which can promote tumor metastasis. Compared with the control group, RNA-seq, and KEGG analysis suggested that AKT/MDM2/P53 signaling was inhibited after knockdown of CCT6A in MDA-MB-231. Furthermore, we found that the tumor volume and the number of lung metastasis sites were significantly reduced in the APG115 combined with Ipilimumab treatment group. Flow cytometry and multiple Immunofluorescence assay showed that TGF-β level from regulatory T cells decreased, while IFN-γ amount from CD8+T cells significantly increased with the combination (both p<0.05). Conclusions: Our research demonstrated that CCT6A can enhance metastasis of triple-negative breast cancer via up-regulating the AKT/MDM2/P53 pathway. These results provide rationales for MDM2 inhibitor combined with anti-CTLA-4 antibody for preventing TNBC metastasis.
Identifying the education, information and support needs of Canadians diagnosed with breast cancer: A Canadian Breast Cancer Network (CBCN) assessment project.
Authors: Ammendolea Cathy , Swiger Kathleen Dickerson , Richter Scott , Adegbembo Bukun
Published: June 2023

e13088

Background: Assessing the education, information and support needs of Canadians diagnosed with breast cancer involves categorizing and tailoring topics and methods of delivery but, most importantly, it must be rooted in an understating of the patient. In 2022, CBCN initiated a project to identify the needs of the Canadian breast cancer population and develop tailored, focused programs and materials. Methods: CBCN conducted a series of 45-minute key informant interviews (7) with patients and oncologists to determine needs, gaps, programs and materials. Five 90-minute patient focus groups (32 participants) were conducted to enhance the interviews. One group was specifically for metastatic patients. Findings from the interviews and focus groups were used to inform the questions for a survey which was fielded online May1/June 10, 2022. The data analysis began in September 2022 and is on-going. Results: A review of Canadian triple negative breast cancer (TNBC) patients’ responses (n=185 or 18.9% of respondents) showed that only 29.4% had heard the term TNBC before. When asked about educational resources on clinical, practical and support topics TNBC patients preferred them tailored to their breast cancer type (94.3%). TNBC patients reported difficulty locating resources (74.0%) and rated those available satisfactory to poor (44.6%). Sources included websites, social media and printed materials. Specific topics of interest were new treatments and latest research (66.2%), fear of recurrence (63.1%), prevention of illness after breast cancer (60.1%) and long term effects of treatment (57.4%). Conclusions: Public awareness of the types of breast cancer could promote a better understanding of the nature of the disease. Availability of multiple communication channels provides opportunities to disseminate and update resources and deliver them to the patients and providers. While information exists, identifying and increasing the availability of credible, reliable resources tailored to specific types of breast cancer that are easily accessible to both patients and clinicians could enhance the physician-patient dialogue, potentially improve adherence, promote trust and possibly contribute to improved outcomes.
Effect of doxorubicin on efficacy of immune checkpoint inhibitors through increasing infiltration of CD8-positive T cells and activating STAT1-IRF1-CXCL10 axis.
Authors: Xiaosu Qiao , Guo Duancheng , Tao Zhonghua , Hu Xichun
Published: June 2023

e13095

Background: Immune checkpoint inhibitors (ICIs) generate an enduring clinical remission in metastatic cancers. However, the efficacy of ICIs monotherapy for triple negative breast cancer (TNBC) is limited. Strategies are urgently needed to enhance anticancer immune responses in TNBC to prolong survival of patients. Methods: BALB/c mice subcutaneous tumor experiments were done to evaluate the efficacy of doxorubicin combined with PD-1 inhibitor, compared with other chemotherapy including cisplatin and paclitaxel. RNA-seq and single-sample gene set enrichment analysis (ssGSEA) were done with our collected mice tumor tissue to observe changes of tumor immune environment in TNBC after chemotherapy combined with immunotherapy. Then, we performed coculture, Transwell assay and FACs in TNBC cell lines, including MDA-MB-231, BT549 and 4T1, and primary CD8+T cells, to assess effects of doxorubicin on CD8+T cell migration in vitro. Gene Ontology (GO) and Kyoto Encyclopedia of Genes, Genomes (KEGG) analysis were enriched from RNA-seq data to seek for a pathway. We analyzed the difference of CD8+T cell infiltration related gene expression, including CCL2, CCL3, CCL4, CCL5, CXCL9, CXCL10, CXCL11. Western blot, qPCR and ELISA were utilized to explore possible mechanism in stronger migration of CD8+T cells by doxorubicin. Rescue assays were used to confirm the involved mechanisms. Results: Subcutaneous tumor experiment showed that doxorubicin could enhance the efficacy of immune checkpoint inhibitors (p＜0.05),andthe immune microenvironment in TNBC transferred from "anti-inflammatory" to "proinflammatory" status after doxorubicin combined with immunotherapy, compared with other chemotherapy drugs combined with immunotherapy. Higher CD8+T cells infiltration occurred in TNBC treated with doxorubicin in vivo (p＜0.05). The CD8+T cells migration assay demonstrated a higher CD8+T cell migration with doxorubicin in vitro (p＜0.05). KEGG analysis revealed that the chemokine-related pathway was significantly activated after doxorubicin treatment, in which CXCL10 chemokine was most likely to be responsible for CD8+T cell infiltration based on its expression and secretion (both p<0.01). Further experiments demonstrated that the expression of the whole STAT1-IRF1-CXCL10 axis was up-regulated in TNBC mice treated with doxorubicin (p＜0.01), and the STAT1-IRF1-CXCL10 axis was also activated in doxorubicin-treated TNBC cell lines (p＜0.0001). Conclusions: This research demonstrated that doxorubicin can enhance efficacy of immune checkpoint inhibitors through increasing infiltration of CD8+T cells in triple-negative breast cancer via activating STAT1-IRF1-CXCL10 axis. These results provide rationales of doxorubicin combined with PD-1 inhibitor for extending survival of TNBC patients.
Effect of DUAL pharmacological blockade of AURKA and PD-L1 pathways on plasticity and metastasis for triple negative breast cancer.
Authors: Takchi Andrew , Haddad Tufia C.
Published: June 2023

e13100

Background: Aurora-A mitotic kinase (AURKA) plays a pivotal role in Triple Negative Breast Cancer (TNBC) progression through activation of epithelial to mesenchymal transition (EMT)-mediated cancer cell plasticity. Cancer cells that undergo EMT acquire a CD44high/CD24low and/or ALDHhigh cancer stem-like phenotype (Cancer Stem Cells) characterized by high self-renewal capacity and intrinsic drug resistance. Cancer Stem Cells (CSCs) also shows high PD-L1 expression that plays a critical role in inducing tumor immune escape through CD8+ T-cells exhaustion. For these reasons, molecular characterization of oncogenic pathways that promote stemness and intra-tumoral PD-L1 expression is essential to evaluate whether novel combinatorial therapeutic strategies aimed to inhibit cancer cell plasticity, immune evasion capacity and organ metastasis may impact cancer progression. Methods: (1) TNBC Models: MDA-MB 231 and variant MDA-MB 231/LM cells, and unique TNBC-M40 cells established from metastatic PDXs; (2) In Vitro Studies: TNBC cells were treated with the AURKA inhibitor alisertib (50nM). PD-L1 expression was evaluated by immunoblotting assay. Apoptosis was measured by immunofluorescence using Cleaved-PARP antibodies. To assess stemness capacity, TNBC cells were cultured under non-adherent conditions to form mammospheres. ALDH activity (functional stemness marker) was measured using the Aldefluor Kit. (3) In Vivo Studies: 1x106 MDA-MB 231/LM cells were injected into the mammary fat pad of humanized NSG-CD34+ female mice. Animals were randomized into four groups (5 mice per group) and treated with anti-PD-L1 ICI atezolizumab (20 mg/Kg) and alisertib (25 mg/Kg) as monotherapy or in combination. Control groups were treated with saline solution placebo. PD-L1, CD44, Vimentin expression and tumor infiltration of CD8+ T-cells were assessed by immunofluorescence. Results: Treatment of MDA-MB 231/LM xenografts with alisertib decreased the levels of CD44 and PD-L1 expression and increased CD8+ T-cells tumor infiltration. Because PD-L1 genetic targeting enhanced in vitro alisertib-induced apoptosis, MDA-MB 231/LM xenografts were treated with alisertib and the anti-PD-L1 ICI atezolizumab. Combination of atezolizumab and alisertib resulted in the reduced expression of the EMT marker vimentin that was linked to lack of organ metastasis. Remarkably, combination of atezolizumab and alisertib also induced a significant reduction of ALDHHigh CSC in ex-vivo 3D-Organoids established from TNBC-M40 cells. Conclusions: This study provides innovative pre-clinical rationale for combining AURKA inhibitors with ICIs to impair cancer cell plasticity, immune evasion capacity and halt the progression of metastatic TNBCs that currently has limited effective therapeutic options.
Efficacy and safety of eribulin plus gemcitabine in second-line or beyond for patients with HER2-negative metastatic breast cancer: A multi-center, open-label, single-arm, phase II study.
Authors: Peng Peijian , Xu Xiaolu , Zhong Jincai , Lin Hong , Wang Hong , Ye Jin-Hui , Du Caiwen , Wang Zhi-Hui , Yu Gengsheng , Zou Guorong , Ouyang Jie , Wang Yong-Xia , Li Lu-Zhen , Xu Fei , Cui Shi-En
Published: June 2023

e13102

Background: Eribulin is a non-taxane microtubule inhibitor approved in China for the treatment of patients with advanced breast cancer who progress after ≥2 lines of chemotherapy. Eribulin was shown to improve overall survival (OS) in various subgroups of patients with metastatic breast cancer (MBC) who were pretreated with an anthracycline and taxane. Furthermore, combination chemotherapy with eribulin plus gemcitabine led to a similar progression free-survival (PFS) benefit, with less neurotoxicity, as paclitaxel plus gemcitabine in patients with MBC who had not received prior cytotoxic chemotherapy for metastatic disease. However, the effect of eribulin plus gemcitabine on PFS in second-line or beyond remain unclear. Methods: This phase II, open-label, single-arm study was conducted at 13 institutions in China (NCT05263882). Patients with histologically confirmed HER2-negative MBC who had received at ≥1 prior taxane-containing chemotherapeutic regimen for advanced disease and had received anthracycline-containing regimens in the adjuvant setting, were enrolled between Nov 2021 and Oct 2022. Eligible patients received eribulin 1.4 mg/m2 and gemcitabine 1.0 g/m2 intravenously on days 1 and 8 of a 21-day cycle. Efficacy outcomes included PFS, objective response rate (ORR), and disease control rate (DCR), evaluated using RECIST v1.1. Adverse events (AEs) were graded according to The National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 5.0. Results: In total, 54 patients were included; 39 (72.2 %) were HR+/HER2- and 15 (27.8 %) were triple negative, the median age was 49.5 years (range: 31-70) and sites of metastasis were the liver (57.4%), lung (37.0%), bone (59.3%), brain (11.1%) and lymph nodes (53.7%). The median number of previous chemotherapy lines was 3 (range: 2-7): eribulin plus gemcitabine was used in second-line for 15 (27.8%) patients, third-line for 20 (37.0%) patients, fourth-line for 7 (13.0%) patients and ≥fifth-line in 12 (22.2%) patients. The median PFS was 7.7 months. The ORR was 40.7% and the DCR was 66.7%. Best overall responses and PFS rates at 3 and 6 months are shown. The most common grade 3-4 AEs were hematological: Leukopenia (35.2%), anemia (18.6%) and thrombocytopenia (9.4%). No treatment-related death was reported. Conclusions: Eribulin plus gemcitabine is effective in heavily pretreated patients with HER2-negative MBC with a predictable, manageable safety profile. Clinical trial information: NCT05263882 . [Table: see text]
Incidence and outcomes of cardiac tamponade in patients with breast cancer.
Authors: Ilerhunmwuwa Nosakhare Paul , Wasifuddin Mustafa , Hakobyan Narek , Tahir Muhammad , Avezbakiyev Boris
Published: June 2023

e13108

Background: Cardiac tamponade (CT) is a cardio-oncological emergency reported to be associated with poor outcomes in some solid tumors, such as lung cancers. There is a paucity of literary evidence on CT in patients with breast cancer. We sought to examine the Nationwide Inpatient Sample (NIS) -the largest inpatient database in the United States- to determine the incidence and factors associated with CT, and the in-hospital outcomes in patients with breast cancer. Methods: We retrospectively explored the NIS database collected from 2016 to 2020. Patients aged ≥ 18 with breast cancer and CT were selected using ICD-10 diagnostic codes. Univariate, multivariate logistic, and negative binomial regression models were used to assess the annual incidence trends, determine factors associated with cardiac tamponade and in-hospital outcomes among patients with breast cancer. Results: A total of 144,405 breast cancer patients (weighted n= 722,025) were examined, of which 345 (0.24%) had CT. The incidence of CT rose from 25 per 10 000 in 2016 to 27.3 per 10 000 cases of breast cancer in 2020 though this was not statistically significant (p=0.409). Patients with CT were more likely to be younger (60 ± 13 vs 66 ± 14, p<0.001), with comorbidity index ≥ 5 (90.72% vs 9.28%, p<0.0001), history of chemotherapy (18.84% vs 12.46%, p=0.0004), history of radiation therapy (17.97% vs 10.80%, p<0.0001), and had Medicare (50.43% vs 49.57%, p<0.001). After multivariate adjustment, comorbidity index ≥ 5 (aOR=5.16, 95% CI: 3.03 - 8.78; p<0.001), and history of irradiation (aOR=1.45, 95% CI: 1.08 - 1.96; p=0.014), were found to be independent predictors of CT. However, the risk of CT was less with age > 65 years (aOR=0.64, 95% CI: 0.47 - 0.87; p=0.004). Regarding in-hospital outcomes, after controlling for other covariates, CT was associated with an increased risk of mortality (aOR=1.71, 95% CI: 1.16 - 2.52; p=0.07) and longer hospital stay (7.25 ± 5.77 vs 4.78 ± 5.45; incidence risk ratio [IRR]:1.49, 95% CI: 1.36 - 1.63; p <0.001). Conclusions: Cardiac tamponade is rare in breast cancer and tends to occur more in patients who are younger, have comorbidities, and prior radiation therapy. It is associated with increased risk of in-hospital mortality and longer stay. Risk stratification of patients with breast cancer when deciding treatment is relevant to reduce the likelihood of CT and improve outcomes. Further studies are needed to establish the optimal management of CT in patients with breast cancer.
A prospective, single-arm, single-center, exploratory clinical study of anlotinib combined with irinotecan in second-line and above treatment of HER-2–negative advanced breast cancer.
Authors: Zhang Ying , Xu Wenhuan , Zhao Yutian , Guo Xuedan , Hong Tingting , Yan Yidan , Wu Xiaohong
Published: June 2023

e13114

Background: The group of HER2-negative accounts for 70-80% of breast cancer and effective treatments for heavily pretreated patients with HER2-negative metastatic breast cancer are urgently needed. Irinotecan is a semi-synthetic water-soluble camptothecin derivative which can be used as a chemotherapeutic agent for HER2-negative breast cancer after failure of anthracycline and taxanes treatments. Anlotinib is a novel multitarget tyrosine kinase inhibitor targeting VEGFR, PDGFR, FGFR, and c-Kit. This study aimed to evaluate the efficacy and safety of irinotecan combined with anlotinib in second-line and above treatment of HER-2 negative advanced breast cancer. (ChiCTR2000037448) Methods: This open-label, single-arm, phase II study enrolled women aged 18 years and older with HER2-negative breast cancer who underwent ≥1 line chemotherapy, All patients were treated with irinotecan (60mg/m2, administered intravenously on Days 1 and 8 of each 21 day cycle) and anlotinib (12mg, qd, administered orally on Days 1-14 of each 21 day cycle). The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), disease control rate (DCR), overall survival (OS) and safety. Results: From November 2020 to November 2022, 14 patients were enrolled in this study. Median follow-up was 10.8 months (95% CI 4.3-17.3). Median PFS was 5.9 months (95% CI 2.0-9.8). Of all the patients whose efficacy could be evaluated (13/14), no patient achieved complete response (CR); 3(23.07%) and 8(61.54%) patients got partial response (PR) and stable disease (SD), respectively. ORR was 23.1% (95% CI 5.0-53.8) and DCR was 84.6% (95% CI 54.6-98.1). OS has not reached. The major treatment-related adverse events (incidence≥10%) were fatigue (42.86%), hypertension (42.86%), neutropenia (28.57%), hand foot syndrome (21.43%) and myelosuppression (14.29%). There is no grade 3/4 adverse events occurred.28.57% (4/14) of patients had dose reductions. Conclusions: The combination of irinotecan and anlotinib showed better treatment response and tolerable toxicity in the treatment of second-line and above patients with HER2-negative metastatic breast cancer. Further studies enrolling more patients are still needed. Clinical trial information: ChiCTR2000037448 .
Optimization of protein extraction for proteomic analysis of formalin-fixed and paraffin-embedding (FFPE) biopsy specimens from males with breast cancer.
Authors: Bezerra Maria Júlia Barbosa , Silva Jackeline Almeida , Sant'Ana Rosane Oliveira , Picanço-Albuquerque Clarissa Gondim , Luciano Maria Claudia dos Santos , Bastos Jose Fernando , Barbosa Oliveira Francisca Fernanda , Freire Italo Aguiar , Bitencourt Flávio da Silveira , Hirth Carlos Gustavo , Silva Paulo Goberlanio de Barros , Silva-Fernandes Isabelle Joyce de Lima
Published: June 2023

e13119

Background: Male breast cancer corresponds to 1% of breast cancer diagnoses. Given this low incidence, the tumors detected have a worse prognosis and lethality. Formalin fixation and paraffin-embedding (FFPE) methods are the most common to maintain biopsied samples. It is a low-cost procedure and is a valuable resource for the study of pathological molecular mechanisms and research of potential biomarkers and therapeutic target molecules. However, in this technique cross-links are formed compromising protein extraction, resulting in low yield and quality for mass spectrometry analysis. Objective: To present an optimized method of protein extraction from male breast FFPE samples for proteomic analysis. Methods: Four protein extraction protocols were optimized and tested in female breast cancer FFPE samples from Haroldo Juaçaba Hospital/Cancer Institute of Ceará to preserve the male sample. Each protocol was performed using a total of eight 5uM tumor slides. Different deparaffinization processes were tested followed by distinct extraction buffers and variable incubation time. The characteristics of each of the protocols and optimizations are presented in the table. The quantification of the protein profile was carried out in nanodrop 2000. The protocol with the highest yield was used in the male breast cancer sample FFPE. Analysis of the protein profile in polyacrylamide gel (SDS PAGE) was performed. Results: Protocol IV presented the highest yield of protein (16.9 mg/mL) and protocols I, II, and III presented, 0.46 mg/mL and 0.28 mg/ml, and 2.3 mg/mL, respectively. Protocol IV was selected to be used in the male breast cancer sample and the yield was 14.26 mg/mL, similar to the female sample. Protein bands from male and female samples using protocol IV were detected on the SDS-PAGE gel. Conclusions: Protocol IV performed a satisfactory protein yield in breast cancer samples FFPE. [Table: see text]
Clinical and molecular characterization of a cohort with breast cancer brain metastases.
Authors: Oyogoa Emmanuella , Chun Brie , Sandow Lyndsey , Rice Douglas , Goodyear Shaun , Zimmer Alexandra Dos Santos
Published: June 2023

e13122

Background: Breast cancer (BC) is the most common cancer in Women in the United States, it is the second most frequent cause of brain metastases (BM). Despite steady improvement in BC treatment (tx) and prognosis, BM continues to be an unmet need. With most BM patients excluded from clinical trials, the study of cohorts remains an important source of information regarding this aspect of the disease. We aim to characterize incidence, disease course, tx, and molecular profile of BM for BC subtypes. Methods: In this single-center retrospective analysis, we identified all adult patients (>18 years) diagnosed (dx) with BC as well as secondary malignant neoplasm of the brain from 1/1/15 to 10/1/22 using database query from EMR. Baseline characteristics were obtained through chart review. Molecular profiling was performed in a total of 41 patients, 8 of which was from brain tissue. Next generation sequencing (NGS) was the most used method. Results were generated using descriptive statistics. Results: We identified 304 BC patients with BM (median age = 60 years [range: 24 to 88]). Baseline characteristics are described in table 1. Hormone receptor positive/HER2-neu negative (HR+/HER2-) was the most commonly observed BC subtype (41.4%), and triple negative BC (TNBC) was the least frequent (16.8%). On primary tissue biopsy, five patients with recurrent BC had a subtype shift that differed from their initial disease: 2 patients with HR +/HER2 – BC subtype recurred with TNBC, 2 patients with a HR+/HER2- recurred with HR+/HER2+ BC, and 1 patient with TNBC at initial dx had their disease shift to HR+/HER 2- BC at first metastatic recurrence then back to TNBC 4 years after initial dx. NGS was available for 41 patients, with TP53, MSS, PIK3CA and ERBB2 being the most frequently observed mutations. On average, 3 lines of therapy were used before dx of BM. In the metastatic setting, capecitabine was one the most commonly used drugs. Targeted central nervous system (CNS) tx used in this study population include WBRT, SRS, SBRT and surgical resection. Conclusions: Studying patterns of disease presentation, progression during standard tx, and the molecular characteristics accompanying BM will enable us to develop more effective tx for patients. Our cohort includes a spectrum of BC subtypes and natural histories. Further characterization of this cohort with tx interactions, progression and survival timeline is ongoing and will be reported at the meeting. [Table: see text]
Clinical outcomes of patients with metastatic breast cancer treated with eribulin: A real-world evidence study from China.
Authors: Yan Xi , Chen Lan , He Ping , Tian Ting-Lun , Zhong Xiaorong , Luo Ting
Published: June 2023

e13126

Background: Eribulin is a novel synthetic analog of halichondrin B that acts as a microtubule inhibitor and inhibits the G2-M growth phase. Eribulin was approved for metastatic breast cancer (MBC) based on the landmark phase 3 EMBRACE trial (Cortes et al, Lancet 2011; NCT00388726); however, only a small number of Asian patients were included in that trial. Therefore, in this real-world study, we retrospectively assessed the clinical outcomes of Chinese patients with MBC who received eribulin. Methods: Adult patients with MBC who received eribulin as several lines of therapy were retrospectively analyzed. Socio-demographic, clinical, pathology, imaging, and therapy records were reviewed. Progression-free survival (PFS) and tumor response were evaluated. Results: A total of 85 patients were included. The median age was 45 years (range, 21–63). Eribulin was used as a first, second, third, and fourth or more chemotherapy agent in 13 (15.3%), 16 (18.8%), 11 (12.9%) and 45 (52.9%) of patients with MBC, respectively. Eribulin was monotherapy in 32.9% of patients; eribulin plus anti-HER2 targeted therapy was used in 9.4% of patients; eribulin plus immunotherapy was used in 5.9% of patients; eribulin plus other chemotherapy was used in 36.5% of patients, and eribulin plus antiangiogenic therapy was used in 9.4% of patients. The objective response rate (ORR) was 28.2% overall. By number of lines of therapy, the first-line ORR was 38.5% and the second-line ORR was 37.5%. On subgroup analysis, ORR of patients with liver metastasis and lung metastasis was 43.9% and 38.6 %, respectively. By molecular classification, the ORR of patients with HR+/HER2− disease was 66.7%; among patients with HER2+ disease, 32.6%; and among patients with triple-negative BC, 13.3%. The 6-month PFS rate was 33.6% overall. By number of lines of therapy, the 6-month PFS rate among patients who received eribulin as first-line treatment was 67.7% and among patients who received eribulin as second-line treatment, 38.3%. Among patients who received eribulin monotherapy, the 6-month PFS rate was 21.4% and among patients who received eribulin combination therapy, 41.2%. No adverse reactions related to neutrophils were reported. Conclusions: This real-world retrospective study suggests that eribulin was effective in Chinese patients with MBC with a range of prior lines of chemotherapy, supporting the use of eribulin in the treatment of Chinese patients with MBC.
Therapeutic strategies for metaplastic breast cancer: A clinicopathologic analysis of a single institution cohort.
Authors: Batra-Sharma Hemali , Yeung Kay T , Shatsky Rebecca Arielle
Published: June 2023

e13128

Background: Metaplastic breast cancer (MpBC) is a rare, aggressive, and histologically diverse subtype, which is associated with worse survival outcomes than other triple-negative breast cancers. Methods: This study is a single-institution retrospective analysis of 30 patients with MpBC, focused on response to therapies in the context of histologic subtype, molecular alterations, and PD-L1 expression. Patients with MpBC who received treatment at our institution consented to share clinical information with a research biorepository. Clinicopathologic and next generation sequencing (NGS) data were obtained from patients’ electronic health records. The primary outcomes are overall survival (OS) and event-free survival (EFS), and the secondary outcomes are responses to neoadjuvant therapy, tumor growth on taxane and/or anthracycline, and responses to systemic therapy in the relapsed/metastatic setting. Results: Among the 30 MpBC patients, the median age at diagnosis was 47.5 years. 86.7% were diagnosed with early-stage disease, 36.7% with squamous cell MpBC, 93.3% with triple-negative disease, and 30% with HER2-low disease. Of the patients diagnosed with early-stage disease, 88.5% received neoadjuvant systemic therapy, 96.2% underwent breast surgery, 92.3% received definitive/adjuvant radiation, and 76.9% received adjuvant systemic therapy. 61.5% of patients with localized disease experienced local and/or distant relapse. Median EFS was 14.0 months (95% CI, 10 to 20 months). Median OS was 26.5 months (95% CI, 20 to 32 months). There was no clearly superior neoadjuvant regimen based on MpBC subtype, but more patients with squamous MpBC experienced tumor growth on taxane-containing therapy compared to those with growth on anthracycline-containing regimens. In the relapsed/metastatic setting, patients with squamous cell MpBC and somatic mutations in the PI3K/Akt/mTOR pathway had prolonged partial responses to combination treatment with an anthracycline, mTOR inhibitor, and VEGF inhibitor. Median treatment duration with sacituzumab govitecan in the 1st or 2nd line metastatic setting was 1.5 months (95% CI, 1 to 4 months) before disease progression. Low tumor mutational burden was seen across all MpBC subtypes (median 2.1, 95% CI 1.6-4.0). 75% of the cases were PD-L1 positive by Immune Cell expression. There was no clear association between PD-L1 expression and response to immunotherapy-containing treatments in the neoadjuvant or relapsed/metastatic setting. Conclusions: Our findings on the presentation of MpBC correlate with other clinicopathologic studies. For squamous MpBC, we noted trends on the utility of anthracycline-containing regimens. Chemoimmunotherapy and antibody-drug conjugates have changed management of triple-negative and HER2-low breast cancer, but more prospective data are needed to determine the optimal therapeutic strategies for MpBC.
Validation of a 56 gene panel for the detection of somatic variants in metastatic breast cancer.
Authors: Blankfard Martin , Christiansen Jason H. , Dharajiya Nilesh , Lam Ernest , Wenstrup Rick
Published: June 2023

e13131

Background: The use of ctDNA and next generation sequencing has unprecedented potential to improve genomic profiling and predicting actionable drug treatment in patients with metastatic breast cancer (MBC). Liquid biopsy is uniquely suited for patients where tissue biopsy is not feasible. We specifically focus on actionable variants found in liquid biopsy for MBC including bTMB and MSI. Here we report on the validation of a 56 gene sub panel for the determination of somatic mutations in MBC. Methods: Commercially available, well-characterized, biological ctDNA reference samples with allele frequency ranging from 0.5 -2.5% and bTMB scores (7 – 20) were obtained to analytically evaluate sensitivity, specificity and precision of a range of clinically significant variants (SNV, indels, fusions and copy number variants) in the TSO-500 ctDNA NGS assay. Additionally, 48 Whole blood samples from well characterized metastatic breast cancer patients and 13 healthy donors were obtained from commercial sources. cfDNA was extracted from the plasma separated from whole blood and analyzed on both TS0-500 ctDNA assay and PGDx Elio Complete. TSO-500 ctDNA sequencing data was further analyzed with the DRAGEN pipeline for variant calling and all variants were annotated and curated with the Clinical Genomic Workspace from PierianDx. PGDx utilized a proprietary pipeline and reporting of all variants detected. Results: Analytical validation determined excellent sensitivity (PPA: 99.4 – 100%), specificity (NPA: 99.6 -99.8%) and reproducibility (95 – 98.6%) for SNV, indels, fusions and Copy number variants. bTMB, with a cutoff for bTMB high as >20 mut/Mb, exhibited a sensitivity of 75% and specificity of 93.3%. Limit of detection (LOD) was established at 0.5 % VAF for SNV, Indels and fusions at a minimum read depth of 1000x. LOD for Copy number amplifications was established at 1.26-fold change or 3 copies. Clinical samples also exhibited excellent concordance across both TS0-500 ctDNA and PGDx Elo Complete. SNV, indels and copy number variants exhibited 100% (PPA) sensitivity and 99-100% Specificity (NPA). bTMB exhibited 87.5 % sensitivity and 96.22% specificity. As expected, fusions and microsatellite instability were observed in the clinical population but were rare. No reportable mutations were found in the healthy donors. Actionable mutations were reported for PIK3CA, ESR1, BRCA1 and BRCA2, TP53 and ERBB2 variants. Rare mutations in ATM, CHEC2, PALB2, FGFR1 and CCND1 were also observed. Conclusions: Clinical utility of liquid biopsy assays requires excellent sensitivity, specificity and precision. The Epic 56 gene panel has established clinical validity and high sensitivity and specificity across all relevant variants including bTMB in MBC. This clinically available NGS panel for metastatic breast cancer allows for routine genomic profiling, specifically in patients where tissue biopsy cannot be obtained.
Improving multidisciplinary patient-centered care for adolescents and young adults with cancer.
Authors: Elliott Leighton Andrew , Lagmay Joanne P. , Scott Daimian Holiday , Staley Lauren
Published: June 2023

e13503

Background: Approximately 90,000 adolescents and young adults (AYA) are diagnosed with cancer annually. Poor outcomes are associated with decreased access to specialized care, limited opportunities for clinical trial participation, treatment protocol variations, and limited psychosocial resources. Fortunately, there has been an increased awareness of the unique challenges faced by AYA patients with the establishment of AYA programs around the world. In order to maximize management opportunities for this marginalized population, our academic healthcare system embarked to establish an effective AYA Oncology Program to serve within the continuum of Pediatric and Medical Oncology and survivorship. Herein, we report the outcomes from this important quality improvement initiative. Methods: In May 2018, the AYA program was established within Pediatric Oncology. We were able to hire a dedicated social worker in March 2020. At this time, growth of the program was limited due to the COVID pandemic. In January 2021, the consult order was updated to enhance tracking metrics. We aimed to increase AYA program consult orders by 20% from 2021 to 2022. In June 2021, we presented the AYA program to Medical Oncology and Malignant Hematology to increase program awareness. We implemented several other educational activities with the Department of Pediatrics, Department of Medicine (including Medical Oncology and Malignant Hematology), and the community via multiple Plan-Do-Study-Act (PDSA) cycles. Results: Since 2020, the AYA program has tracked 91 answered consults – 86 in the last 2 years. In 2022, there were 50 total consults placed compared to 36 in 2021, a 38.9% increase. Since 2021, the AYA program was consulted on 17.2% of newly diagnosed AYA patients. Inpatient consults were more common at 62.6%. Thirteen total consults were ordered for patients ≥30yo, of which only 2 were for patients older than 32. The AYA program was consulted on only 3.5% of newly diagnosed adults ≥30yo compared to 28.7% for the younger AYA patients. Upon surveying medical oncologists at our institution, most providers simply forget to order consults to the AYA program. Conclusions: Total AYA program consult numbers are increasing, however, there is opportunity for growth, especially in reaching the older AYA patients. Our healthcare system has recently approved the establishment of a Best Practice Advisory (BPA) in our electronic medical record to remind providers to order AYA program consults, if appropriate. Once the BPA is established, subsequent PDSA cycles will emphasize reaching older AYA patients by re-circulating educational resources and activities to providers and social workers in Medical Oncology and Malignant Hematology. Future objectives will evaluate outcomes in quality of life, overall survival, healthcare utilization, and clinical trial enrollment amongst other metrics.
Clinical pathways utilization and characteristics of non-adherence at Sidney Kimmel Cancer Center.
Authors: Houtmann Sarah , Manobianco Steven , Hansinger Emily , Binder Adam F.
Published: June 2023

e13505

Background: Clinical pathways are utilized by many oncology practices with goal to deliver high quality, consistent care across health systems. In pathway tools, evidence-based treatments are recommended using the following hierarchy 1) efficacy, 2) adverse events, 3) cost. Previous research has shown that increasing adherence to pathways delivers evidenced based care at reduced cost. However, this comes at the expense of increased “clicks” and inefficiencies in workflow. We hypothesized that at a large academic center with subspecialty oncologists that lack of adherence to pathway utilization did not result in decrease adherence to evidence-based medicine. Methods: At our institution’s main academic hub, all breast, genitourinary (GU), and gastrointestinal (GI) chemotherapy encounters ordered from July 2020 through June 2021 were identified. A subset of these encounters, those ordered without use of Elsevier’s ClinPath, “pathway-independent,” were identified. Chart review was performed to identify clinical characteristics, ordering physicians, and line of treatment. Treatment choice was compared to ClinPath pathways to determine if treatment was “on-pathway” or “off-pathway.” Treatment was also compared to NCCN guidelines, to determine if aligns with standard of care. Results: 1,111 breast, GU, and GI total chemotherapy ordering encounters were identified. Only 103 (9.3%) were pathway-independent orders. 41 were hepatobiliary orders, which do not have a ClinPath pathway at our institution, leaving 62 pathway-independent orders despite a pathway available. 87% of the pathway-independent encounters were on-pathway, just not utilizing the ClinPath tool, and 91.9% align with standard of care. Only 8 of the 62 (12.9%) pathway-independent encounters were off-pathway. Of these 8 encounters, 4 (50%) were GI and 4 (50%) GU chemotherapy. 5 were 1st line treatment, 2 were 2nd line, and 1 was 3rd line. 3 of 8 off-pathway encounters were in accordance with NCCN guidelines. There were justifications for 2 of the 8 off-pathway treatments: prohibitive hepatic dysfunction and patient preference to continue treatment ordered by outside institution. The remainder were by physician preference. Conclusions: At our academic institution, there was high utilization of ClinPath when ordering GI, GU, and breast chemotherapy, with 94.4% total encounters utilizing ClinPath. The vast majority of chemotherapy ordered at our center, even when ordered without ClinPath, aligns with standard of care. While the number of pathway-independent decisions was very small in this sample, it suggests that the clinical pathway tool may not influence clinical decision making as much as suggested in other studies, but likely adds administrative burden to physicians who practice in highly subspecialized areas.
Overcoming barriers to adoption of precision medicine in community oncology centers in the rural southeastern United States using novel informatics tools and academic collaborations.
Authors: Caughey Bennett Adam , Kumar Anivarya , Owen Jennifer R. , Sloat Nicholette , Maynard Elizabeth , Hill Vanessa , Hubbard Christopher , Neely Benjamin , McKinney Matthew Stuart , Sutton Linda , McCall Shannon J. , Datto Michael , Strickler John H. , Green Michelle
Published: June 2023

e13514

Background: Comprehensive genomic profiling (CGP) is an important tool to identify actionable biomarkers and guide cancer therapy. However, patient (pt) race, socioeconomic status, and clinical setting are associated with lower access to CGP, targeted therapies, and clinical trials. To address this, we expanded a novel framework for genomic data management and clinical decision support developed at a large academic medical center to a network of affiliated community cancer centers located in rural, traditionally underserved communities. Methods: The Duke Precision Cancer Medicine Initiative (PCMI) developed a centralized database to aggregate and normalize CGP results. This database enables CGP review by a multi-disciplinary Molecular Tumor Board (MTB). PCMI established a protocol that allows the MTB to review CGP results and relevant clinical data for consented patients. This protocol opened enrollment at four DCN-affiliated cancer centers in rural North Carolina. Clinical recommendations are captured in a standard note and returned to DCN providers following each review. Our protocol also includes an anonymous survey sent to oncology providers asking about barriers to access and utilization of CGP. Results: Between Jan 2022 and Jan 2023, 62 pts were enrolled and had CGP results reviewed by the MTB; 13 pts (21.0%) were Native American and 20 (32.3%) were Black. 61 actionable genomic alterations were identified from 38 pts, including 16 (25.6%) that molecularly matched clinical trial inclusion criteria. Most DCN providers reported being comfortable ordering (14/20) CGP though fewer expressed comfort with interpretation (9/20) CGP; provider-reported barriers included cost/insurance for targeted therapies (12/20) and distance to clinical trials (14/20). Conclusions: Successful academic-community partnerships to expand access to CGP, clinical trials, and targeted therapies are feasible when supported by fit-for-purpose informatics tools and scalable workflows. Additional work is required to develop comprehensive solutions that ensure equal access to CGP and precision medicine for all patients. [Table: see text]
Improvement of the timeliness to lung cancer diagnosis and treatment with the Rapid Access Lung Lesion Clinic in regional Australia.
Authors: Yeoh Hui Ling , Malsem Eve , Harrap Benjamin , McCann Katherine , Faisal Wasek
Published: June 2023

e13519

Background: The Rapid Access Lung Lesion Clinic (RALLC) was implemented to expedite the multidisciplinary diagnostic pathway of suspected lung cancer in a regional tertiary centre in Victoria, Australia. The aim of this study was to audit the performance of this clinic against the recommended timeframes of the Victorian Optimal Care Pathway for People with Lung Cancer. Methods: Data of all patients referred to the RALLC clinic between July 2017 and December 2021 was prospectively collected, and compared with patients with lung lesions referred to Ballarat Hospital between 2014 to 2015. Information was collected regarding these cohorts’ demographics, cancer care pathway and diagnosis. Results: 302 patients were analysed in this study, of whom, 266 were managed by the RALLC between 2017 to 2021, and 36 patients were managed pre-RALLC between 2014 and 2015. In this cohort, 161 (53%) were males, 256 (85%) were ECOG 0-1 and 251 (83%) had non-small cell lung cancer (NSCLC). 184 (61%) referrals were from general practitioners and 161 (53%) patients received curative-intent treatment. The median time between referral to appointment was 8 days for the RALLC cohort vs. 11 days for the pre-RALLC cohort. The median time between referral to diagnosis was 20 days for the RALLC cohort vs. 36 days for the pre-RALLC cohort. The median time between referral to treatment was 45 days for the RALLC cohort vs. 62 days for the pre-RALLC cohort. The median time between specialist appointment to diagnosis was 11 days for the RALLC cohort vs. 24 days for the pre-RALLC cohort. Conclusions: Although the RALLC did not significantly reduce time between referral to specialist appointment, the clinic did reduce time between referral and specialist appointment to diagnosis, and the time between referral to treatment. The clinic has achieved a marked improvement in meeting the standards of the Optimal Care Pathway for this regional tertiary centre in Australia and demonstrates the benefits of coordinated multidisciplinary service provision especially where specialist access may be limited. Future research is being undertaken to investigate its impact on the clinical outcomes for patients. [Table: see text]
Barriers in the identification and diagnosis of hereditary colon cancer.
Authors: Usry Benjamin , Graf Kevin , Raman Rohith , Allen Caitlin , Meeder Kiersten , Hughes Kevin S. , Donahue Colleen
Published: June 2023

e13524

Background: Lynch Syndrome (LS), the most common form of hereditary colorectal cancer (CRC), is due to germline pathogenic variant (PV) in mismatch repair genes (MMR). Since 2009, the National Comprehensive Cancer Network (NCCN) recommends MMR screening for LS for all CRCs regardless of age. The American College of Medical Genetics and Genomics recommends patients with MMR deficiency or microsatellite instability (MSI) be referred for genetic testing. Despite these recommendations, compliance is low. The aim of this study was to evaluate compliance with LS screening and genetic testing in CRC. Methods: A single institution retrospective review of patients diagnosed with CRC from 2018-2021 was performed. A chart review of those diagnosed in 2018 and 2021 was analyzed and combined as a single population from pre and post COVID periods. A student’s T-Test was used to compare continuous variables and chi square for categorical variables within the two populations. The compliance with either MSI or MMR screening was calculated. Meeting criteria for genetic testing was defined as age less than 50, MSI-L/H or MMR deficient. These patients were then analyzed to determine the proportion of genetic referrals, genetic counseling, genetic testing and identification of LS. Results: 276 patients with CRC were reviewed, 153 in 2018, 123 in 2021. 71.2% were Caucasian and 58% male. There was no statistically significant difference in gender, race or ethnicity, however, there was a difference in age, with a younger average age in 2021 (67, 63; p = 0.014). 146 (53%) patients were screened for LS. 44 (16%) with MSI, 19 (7%) MMR and 82 (30%) with both. 78 patients met criteria for genetic testing; 47 due to age alone, 6 age and positive LS screening and 25 screening alone. 35% (27/78) of those meeting criteria were referred to genetics, of which 63% (17/27) completed their appointment, 63% (17/27) were tested, and 37% (10/27) had a PV identified. Conclusions: Despite guidelines for LS screening, compliance is low with only half of CRC patients appropriately screened at our institution. Even patients with positive screening and those less than 50 were not referred for genetic testing. However, of referred patients, 63% completed their appointment and all those were tested. This supports the idea that poor compliance with genetic testing is not due to patient compliance, but shows a systems issue at a higher level. To improve LS identification, reflex screening and genetic referrals are paramount. In our study, 59% of patients with germline testing had a PV, however 65% of those meeting criteria were never referred, which could reflect a proportion of patients with LS going unidentified. This validates the 2022 NCCN guidelines recommending genetic testing for all CRCs despite age or MSI/MMR status. By removing the barrier of MMR testing, more genetic testing will likely be done. [Table: see text]