bluuebunny/crossref_metadata_2025 huggingface dataset:
Change in tumor microenvironment and PD-L1 expression with rucaparib treatment in triple-negative breast cancer.
Authors: Halder Ritika , Bhamidipati Nitish , Kiss Alexi , Aldhahri Walaa , Ehsani Sima , Segar Jennifer Margaret , Foster Nova , Chalasani Pavani
Published: June 2024

e12569

Background: Triple-Negative Breast Cancers (TNBCs) represent a diverse subset of tumors characterized by varied responses to therapies including immunotherapy (IO). While IO is approved in early-stage and advanced TNBC, responses are modest. Modulation of the tumor microenvironment to improve responses to IO is an active area of research. In-vitro and in-vivo studies have shown Poly-ADP Ribose Polymerase inhibitors (PARPi) to increase PD-L1 expression in sporadic, BRCA1 and BRCA2 mutated TNBC cell lines improving response to IO. In addition, TNBCs have diverse mechanisms leading to Homologous Recombination Deficiency and the role of PARPi in sporadic TNBCs is still unclear. Methods: To further investigate the role of PARPi in tumor immuno-modulation we conducted a single-arm, open-label, window of opportunity (WOO) trial in patients with early-stage TNBC (NCT03911453). This study was approved by our institutional review board. Patients with histologically documented stage I-III TNBC were eligible for definitive surgery were enrolled. Patients were treated with 600mg BID rucaparib for 21 days. Pre- and post-treatment tumor biopsies were collected. Post-treatment, patients went to surgery or proceeded with neoadjuvant chemotherapy (NAC) followed by definitive surgery. Our primary endpoint was to assess change in PD-L1 expression. In addition, change in tumor microenvironment was by evaluating change in percentage of B cells, T cells and macrophages was calculated. Results: Twenty patients were enrolled. Nineteen patients completed 21 days and 1 patient went on extended duration PARPi during the COVID19 pandemic. Almost 50% of patients went to surgery while the rest went onto NAC after PARPi therapy. Pre-treatment tumor samples were obtained from the diagnostic core biopsies while post-treatment, fresh frozen and Formalin Fixed Paraffin Embedded were obtained either at time of surgery or a research biopsy prior to NAC initiation. Primary biomarkers data was successfully done in 14 paired samples. Treatment with rucaparib has increased expression of PD-L1 from median of 15% in pre-treatment tumor samples to a median of 26% in post-treatment tumor samples. Table below summarizes our results. Conclusions: Our study revealed that treatment with PARPi, rucaparib, changed the tumor microenvironment as noted by changes in expression of PD-L1, and immune milieu in and around the tumor. This could lead to change in responsiveness to therapies including CKI. This strategy should be further investigated to evaluate improving responses to immunotherapies. Clinical trial information: NCT03911453 . [Table: see text]
Information and support needs of young Black women with early breast cancer to enable self-management and informed decisions during breast cancer treatment.
Authors: Weldon Christine B. , Steele Sue , Leach Virginia , Ravelo Arliene , Trosman Julia R.
Published: June 2024

e12587

Background: Black women with breast cancer are more likely to experience care delays and worse outcomes than White women (Emerson, Cancer ’20). Patient self-management contributes to more timely cancer care delivery and improved outcomes. We interviewed young black women with breast cancer to explore information needs related to their self-management interests and obtain feedback on the independent use of self-management tools developed within the 4R Oncology model. 4R (Right Info/Care/Patient/Time) is an approach to facilitate patient self-management using a Care Sequence plan- a care checklist with a visual depiction of timing and sequence of care, as well as a side effect self-care tool. These tools are typically provided in the clinic, but we aimed to explore if they could be used independently by patients. Methods: The interviewee cohort (N=20) was recruited from the Tigerlily Foundation ANGEL (Advocate Now to Grow, Empower and Lead) patient program. The cohort included Black women, average age 36 (21 to 46), stage I-III breast cancer. The framework approach of qualitative research was used. Results: All women reported information needs not addressed by their providers. Mental wellness and social support information were lacking for 70% (“I never worked with a social worker or anyone to support my mental health”). Most women (65%) wanted more information about breast cancer surgery options and post-surgery drains, bras, pain, and tingling (“before I had my surgery, my doctor didn't tell me all the options I had”). 40% mentioned a lack of reconstructive option information, including how radiation affects implants, “risk of encapsulation” and the long-term impact of having implants “changing them out every 10 years.” A slight majority (55%) desired nutrition and integrative medicine information. About one-third (35%) of women mentioned considerable skin issues during radiation treatment (“I needed skin care, for people with darker skin”). When reviewing a Care Sequence and a side-effect self-care tool, 95% reported they would use them independently if their clinic did not provide them ("I just got general information about breast cancer, I would have preferred a step-by-step process like this"; “This describes what services each role provides, and links to more support”). Most (95%) would have used the side-effect tool ("My chemo education was overwhelming, just a bunch of info thrown at me all at once, having a resource to look at would have been helpful"). Conclusions: In interviews with young Black women with breast cancer we found several information needs and a preference for tools to support self-management during treatment. These indicate considerable improvements are needed in this area. Using the input from the interviews, we are enhancing the 4R Oncology tools to better support the needs of Black patients with breast cancer.
The relationship between PIK3CA mutations and survival in patients with human epidermal growth factor receptor 2–positive breast cancer receiving pyrotinib combined with trastuzumab for neoadjuvant treatment.
Authors: Shi Qiyun , Tian Hao , Ma Dandan , Xuhong Juncheng , Ge Jia , Liu Feng , Lan Yang , Tang Peng , Liang Yan , Chen Li , Fan Linjun , Zhang Yi , Luo Tao , Bian Xiuwu , Jiang Jun , Qi Xiaowei
Published: June 2024

e12637

Background: Our previous study suggested that HER2-positive breast cancer patients with activated mutations in PIK3CA are less likely to achieve a pathological complete response (pCR) from pyrotinib combined with trastuzumab in the neoadjuvant setting. The relationship of PIK3CA mutations and survival remains unknown. Methods: The genomic characteristics of 425 cancer-related genes from the archived tumour blocks of 50 patients enrolled in a prospective neoadjuvant pyrotinib and trastuzumab plus chemotherapy clinical trial (ChiCTR1900022293) were assessed by next-generation sequencing (NGS). The relationship between PIK3CA mutations and event-free survival (EFS) and overall survival (OS) were explored. Results: Among the cohort of 50 cases, five patients dropped out during treatment due to various reasons, whereas the other 45 patients were followed up until August 31, 2023. The median follow-up was 36.1 months, and mEFS and mOS were not reached yet. Kaplan-Meier estimated 3-year EFS rate and OS rate were 91.1% (95% confidence interval [CI]=83.2%-99.8%) and 97.1% (95% CI=91.8%-100%), respectively. Patients with wild-type PIK3CA tended to achieve a better 3-year EFS rate (96.2% vs 63.2%, hazard ratio [HR]=0.18, 95% CI=0.02-1.59, log-rank P = 0.081) compared with the patients with mutated PIK3CA. Besides, patients with pCR showed a better 3-year EFS rate (96.2% vs 84.2%, HR=0.16,95% CI=0.02-1.45, log-rank P = 0.063) compared with the patients without pCR. Conclusions: HER2-positive breast cancer patients with activated mutations in PIK3CA are less likely to benefit from pyrotinib combined with trastuzumab in the neoadjuvant setting, but this conclusion still needs to be confirmed by large-sample studies and long-term follow-up results. Clinical trial information: 1900022293.
Effect of HER2-low expression on the efficacy of CDK4/6 inhibitors in breast cancer: A meta-analysis.
Authors: Ye Lingling , Dai Yan , Chen Liushan , Liang Yuqi , He Jiafa , Chen Shenying , Song Xue , Luo Wei , Xu Rui , Chen Qianjun
Published: June 2024

e13034

Background: The effect of human epidermal growth factor receptor 2 (HER2)-low expression on the efficacy of CDK4/6 inhibitors in breast cancer is unclear. Therefore, the aim of this meta-analysis was to determine the effect of HER2-low on the efficacy of CDK4/6 inhibitors in advanced breast cancer. Methods: We searched 10 databases and meeting minutes up to July 15, 2023, to identify studies that reported median progression-free survival (mPFS) and overall survival (OS) among HR+/HER2-low breast cancer patients and HER2-zero breast cancer patients receiving treatment with CDK4/6 inhibitors. We calculated pooled hazard ratios (HRs) and 95% confidence intervals (CIs). Results: A total of 9 retrospective studies involving 1494 patients were included. HER2-low breast cancer patients accounted for 52.48% of the sample, and HER2-zero breast cancer patients accounted for 47.52% of the sample. The mPFS was significantly worse for HR+/HER2-low breast cancer patients treated with CDK4/6 inhibitors combined with endocrine therapy than for HER2-zero breast cancer patients (risk ratio = 1.29, 95% CI: 1.15-1.44, p < 0.00001). There was no significant difference in the median overall survival (mOS) between patients with HER2-low breast cancer and patients with HER2-zero breast cancer (risk ratio = 1.07, 95% CI: 0.69-1.66%, p = 0.78). The mPFS was significantly worse for HR+/HER2-low breast cancer patients receiving first-line treatment with CDK4/6 inhibitors combined with endocrine therapy (risk ratio = 1.25, 95% CI: 1.07-1.47, p = 0.0002). Conclusions: The mPFS of patients with advanced HER2-low breast cancer and first-line salvage patients receiving CDK4/6 inhibitors combined with endocrine therapy was significantly inferior to that observed in HER2-zero breast cancer patients. However, there were no discernible differences in the mOS between the two patient groups.
Real-world experience with CDK4/6 inhibitors in the first-line palliative setting for HR+/HER2- advanced breast cancer.
Authors: Patel Ram , Nasser Abdullah
Published: June 2024

e13066

Background: CDK4/6 inhibitors paired with aromatase inhibitors (AIs) have redefined the first-line treatment for metastatic breast cancer, as evidenced by several pivotal trials. Although progression-free survival (PFS) has been consistent across these studies, notable differences in overall survival (OS) have been observed. Our study evaluates the real-world efficacy of palbociclib and ribociclib, in combination with AIs, for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer at our institution. Methods: We retrospectively reviewed charts of adult patients with advanced metastatic breast cancer at a single academic center from January 1, 2015, to December 1, 2022. We extracted relevant clinical data to estimate the median PFS and OS associated with palbociclib and ribociclib. Results: Among 75 patients analyzed, the majority were female (98.7%) and postmenopausal (77.3%). Palbociclib was prescribed to 74.7%, while 52.0% presented with de novo stage IV disease. Those on ribociclib were significantly younger (median age 57.6 vs. 67.5 years; p = 0.013) and more likely premenopausal (42.1% vs. 5.4%; p < 0.001). Median PFS for palbociclib was 20.3 months (95% CI: 14.8-46.0), with an OS of 37.2 months (20.3 months to not reached). Median PFS and OS for ribociclib were not reached. The differences in PFS and OS between the drugs were not statistically significant (PFS log-rank p = 0.1; OS log-rank p = 0.2). Conclusions: Our real-world analysis suggests a non-significant trend towards improved PFS and OS for ribociclib over palbociclib when used with AIs for treating HR+/HER2- advanced breast cancer, potentially influenced by the younger age of patients on ribociclib. Further research with larger cohorts and extended follow-up is warranted to substantiate these observations.
Clinical utility of an ultra-sensitive ctDNA NGS assay for the detection and monitoring in HR-positive, HER2-negative breast cancer.
Authors: Liao Hao , Zhong Jianxin , Liu Xiao-ran , Bin Shao , Tang Haoran , Jia Cancan , Xie Feng , Zhang Yue , Jia Shidong , Li Huiping
Published: June 2024

e13076

Background: Breast cancer is the most diagnosed cancer in women globally, mainly as hormone receptor HR-positive, HER2-negative. While endocrine therapies have markedly improved clinical outcomes, the threat of disease progression persists. This study introduces an ultra-sensitive circulating tumor DNA (ctDNA) Next-Generation Sequencing (NGS) assay that was designed for in-depth genomic profiling of breast cancer patients undergoing endocrine therapy, aimed at detecting treatment resistance and monitoring disease progression. Methods: In this ongoing investigation, 46 patients with advanced HR-positive, HER2-negative breast cancer were enrolled, and plasma samples were collected subsequent to first-line aromatase inhibitor (AI) treatment and before the initiation of second-line treatment with fulvestrant. The study employed the PredicineCARE ULTRA, an ultra-sensitive liquid biopsy assay with a proprietary NGS panel and exceeds 100,000x coverage, allowing for the ultra-sensitive identification of genomic alterations, surpassing the detection capabilities of standard ctDNA NGS assays with approximately 20,000x coverage. Results: Within the cohort of 46 patients, the ultra-sensitive assay detected 193 somatic mutations, 95 gene copy number variants (CNVs), and a gene fusion involving FGFR3. The most commonly mutated genes, with a prevalence of 20% or more, were TP53 (33%), PIK3CA (26%), ATM (24%), ESR1 (22%), and BRCA2 (20%). These findings were benchmarked against results from a down-sampling algorithm designed to emulate ctDNA assays with 20,000x coverage. The ultra-sensitive assay revealed 31.3% more mutations (193 vs. 147) and 30.1% more CNVs. It was especially proficient in detecting mutations with allele frequencies (MAF) below 0.1%, identifying 10 additional mutations not observed at the standard ctDNA assay sensitivity, with the lowest MAF detected being 0.03% compared to the 0.1% threshold of the standard assay. This heightened sensitivity was evident in genes associated with targeted therapies and drug resistance, identifying 30.7% more variations in PIK3CA and 11.1% more in ESR1, with the lowest MAFs of 0.08% and 0.06%, respectively. The FGFR3-BAIAP2L1 gene fusion was also uniquely detected by the ultra-sensitive assay, with a MAF of 0.09%. Conclusions: The ultra-sensitive ctDNA NGS assay demonstrated superior detection of low-frequency mutations in HR-positive, HER2-negative breast cancer, significantly outperforming standard liquid biopsy assays. This enhanced sensitivity may offer profound implications for identifying more diagnostically positive patients who may benefit from targeted therapy such as PIK3CA and ESR1 inhibitors. This ultra-sensitive ctDNA assay will also enable early detection of treatment resistance and refined disease monitoring, potentially guiding more effective personalized therapies.
Single institution retrospective review of patients with metastatic hormone receptor positive breast cancer receiving first line therapy of CDK4/6 inhibitors.
Authors: Bhargava Anika , Tavcar Michelle , Dong Brian
Published: June 2024

e13090

Background: Breast cancer continues to be the most commonly diagnosed cancer in women. The majority of these cancers are estrogen positive (ER+) and about 6% of new cases are stage 4 at time of diagnosis. The current standard of care for postmenopausal women with stage 4 ER+ breast cancer is a combination of an aromatase inhibitor (AI) with a cyclin-dependent kinase (CDK) 4/6 inhibitor. Based on Medicare data claim analysis from IQVIA, CDK 4/6 inhibitors are being used nationally in the first line setting in 56% of cases where 24% of cases were treated with AI monotherapy. The state of Kentucky currently lies below this national average by using this treatment regimen in 38% of cases where 47% of cases are treated with AI monotherapy. The reason for this discrepancy between the national average and Kentucky is currently unknown. To further understanding, we have conducted an internal review of adherence to the guidelines. Methods: This is a single center retrospective study done at University of Louisville, Brown Cancer Center. Data was collected on patients who had biopsy proven metastatic hormone positive breast cancer from July 2021 until May 2023 (n=41). Collected characteristics include age on diagnosis, tumor grade, sites of metastatic disease, first line treatment received, choice of CDK4/6 inhibitor if received, and prior exposure to chemotherapy or anti-estrogen therapy. Results: In our cohort of 41 patients, we found that 63.4% (n=26) of patients received an AI and CDK4/6 inhibitor in the first line. There were 4.88% (n=2) of patients who received AI monotherapy, 21.9% (n=9) received Fulvestrant and CDK4/6 inhibitor, 4.88 % (n=2) received AI and Fulvestrant and 4.88% (n=2) received Fulvestrant alone. In total, patients who received estrogen therapy plus CDK4/6 inhibitor totaled 85% of new patients (n=35). Conclusions: This internal review showed our institution to be compliant with endocrine therapy and CDK 4/6 inhibitor in front-line treatment for the majority of metastatic ER+ patients. Given the supportive data for use of CDK 4/6 inhibitors in front-line treatment, the compliance is expected to be much higher. We recommend continued discussion amongst oncology providers to help identify barriers to treatment and determine the causes for poor compliance in the state of Kentucky.
Fulvestrant and elacestrant utilization on prognostic outcome of patients with HR+ve/HER2-ve MBC.
Authors: Dawood Shaheenah S. , Hernández Gema , Segovia Alba
Published: June 2024

e13094

Background: OS of pts with HR+ve/HER2-ve MBC has improved with CDK4/6i and endocrine therapy. Fulvestrant (FUL) works post progression on aromatase inhibitors in an endocrine resistant cohort. Ealcestrant (ELA) improves PFS compared to FUL in pts with an ESR1 mutation. This retrospective analysis looks at the trends in use of and associated outcome with FUL and ELA among pts with HR+ve/HER2-ve MBC. Methods: We utilized a federated network of de-identified health data representing approximately 135 million pt lives available through the TriNetX Research Network. We identified 14,387pts with HR+ve/HER2-ve MBC treated with endocrine therapy and CDK4/6i diagnosed between Nov 2018 - Nov 2023. OS was computed using the Kaplan Meier product limit method. Results: Mean age was 66 yrs. 5,736(39.9%) pts received FUL and 143(1%) pts ELA. In 2023 median time to use of FUL was 16m to 18m from metastases and median time to use of ELA decreased with time from 50m to 28m. Among pts who received ELA 65% received CDK4/6i for > 12m, 47% received FUL prior ELA, 7% received FUL after ELA. 5-yr OS of the whole cohort was 56.9%. 5-yr OS among pts who did and did not receive ELA was 85.4% and 60.0% respectively (HR 0.28, 95%CI 0.15-0.49, p<0.0001). 5-yr OS among pts who did and did not receive FUL w/o ELA was 61.5% and 60.9% respectively (HR 0.87, 95% CI 0.81-0.94, p<0.0001). 5-yr OS was 85.4% and 52.4% among pts who received ELA and FUL w/o ELA respectively (HR0.23, 95% CI0.14-0.41, p<0.0001). 5-yr OS was 88.7% and 67.9% among pts who received ELA and FUL w/o ELA respectively for > 3m (HR 0.29, 95% CI 0.05-1.145, p=0.11). Among pts who received CDK4/6i > 12m 5-yr OS was 86.0% and 64.9% among pts who received ELA and FUL w/o ELA respectively (HR 0.36, 95% 0.20-0.67, p = 0.0007). Among pts who received ELA 1-yr OS from the start of ELA was 86.0% and 33.3% among pts who received CDK4/6i>12m and < 12m respectively (p=0.72). Conclusions: To our knowledge this is the first real world data set to show the efficacy of ELA among pts with HR+ve/HER2-ve MBC who had progressed on endocrine therapy and CDK4/6i. Our results show decreasing time to use of ELA with improved outcome compared to FUL especially among pts who received CDK4/6i for > 12m. We continue to collect data among pts who are receiving ELA and expect over 200pts at the time of the presentation.
Real-world outcomes of sacituzumab govitecan in breast cancer.
Authors: Singh Vaishnavi , Dhaibar Hemangini , Peddi Prakash
Published: June 2024

e13137

Background: Sacituzumab govitecan (Trodelvy), a novel antibody-drug conjugate, has emerged as a promising treatment option, in patients with metastatic triple-negative breast cancer (mTNBC). It gained FDA approval for unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies based on ASCENT trial which demonstrated that progression-free survival (PFS) and overall survival (OS) was significantly longer with sacituzumab govitecan than with single-agent chemotherapy. Hence, here in our current study, we further explore the outcomes of patients on sacituzumab govitecan in the setting of mTNBC. Methods: A single-center retrospective analysis was conducted on 21 women (aged 30-80 years old) with mTNBC breast cancer treated with sacituzumab govitecan over a span of 4 years. Baseline characteristics, pre-sacituzumab govitecan treatment PFS correlations, PFS and OS of sacituzumab govitecan were assessed and compared with the ASCENT trial. Results: A total of 21 women, comprising 10 African American, 10 Caucasian, and 1 Asian were evaluated over a span of 4 years. In our study with an average population of 50.6 years, the overall mean (± standard error of the mean) observed was 5.00 months (SEM 1.02) for PFS and 8.33 months (SEM 1.62) for OS. Patients with brain metastasis (n=8) and without brain metastasis (n=13) exhibited a mean of 5.99 months (SEM 2.23) and 4.40 months (SEM 0.97) for PFS respectively whereas 8.34 months (SEM 2.28) and 8.33 months (SEM 2.29) for OS respectively. The average number of previous treatment exposures in this subset was 5.6, with a mean PFS of 11.33 months (SEM 3.64) for prior treatment before initiation of sacituzumab govitecan. Conclusions: Our data reflects a similar interpretation with ASCENT trial study for mean PFS, however with a lower mean OS. In our study, the mean PFS from 8 patients who had brain metastasis closely matched with the patients without brain metastasis and the median PFS of the trial, thus suggesting potential consideration of sacituzumab govitecan in patients with active brain metastasis, as the patients with brain metastasis were excluded from the primary endpoint analysis in the ASCENT trial. No correlation was observed between the mean PFS of the prior line of therapy before sacituzumab govitecan and sacituzumab govitecan’s mean PFS. Overall, sacituzumab govitecan represents a significant advancement in breast cancer treatment and offers hope for patients with mTNBC.
A phase II trial of anlotinib combined chemotherapy as second-line and above therapy in HER2-negative advanced breast cancer.
Authors: Yuan Yuan , Zhang Lili , Xu Ting , Xiong Weili , Hu Sainan , Huang Jiayuan , Dong Min , Xu Xinyu , Lou Kexin
Published: June 2024

e13140

Background: The group of HER2-negative accounts for about 75% of breast cancer and has limited response to chemotherapy. Anlotinib is a novel multitarget tyrosine kinase inhibitor targeting VEGFR, PDGFR, FGFR, and c-Kit. In this study, we assessed the efficacy and safety of anlotinib plus chemotherapy in second-line and above treatment of HER-2 negative advanced breast cancer. Methods: This open-label, single-arm, phase II study enrolled women aged 18-75 years with HER2-negative breast cancer who underwent at least one-line chemotherapy. All patients were treated with anlotinib (12mg, qd, administered orally on Days 1-14 of each 21 day cycle) in combination with investigator-selected chemotherapy. The primary endpoint evaluated in this study was the median progression-free survival (PFS). Secondary endpoints included the objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR) and safety. Results: From August 2022 to August 2023, 33 patients were enrolled in this study including 22(66.7%) HR+/HER2- patients and 11(33.3%) TNBC patients. After a median follow-up time of 11 months (95% CI, 5.8-16.2), the median PFS (mPFS) of the all patients was 8.6 months (95% CI 7.3-NA). In the HR+ and HR- populations, mPFS was 7.6 months versus 9.5 months (HR,0.376 [95%CI 0.12-1.13], p=0.072), respectively. All the patients had the confirmed best overall response assessments, no patient achieved complete response (CR); 11(33.3%) patients got partial response (PR) and 19(57.6%) patients achieved stable disease (SD). ORR was 33.3% (95% CI 18.0-51.8), DCR was 90.9% (95% CI 75.7-98.1) and CBR was 60.6% (95% CI 42.1-77.1). The most frequently observed adverse events were elevated triglycerides (78.8%), elevated blood sugar (63.6%), anemia (60.6%), elevated cholesterol (51.5%), elevated alanine aminotransferase (48.5%), and leukopenia (48.5%). Dose reductions due to adverse events occurred in 7 (21.2%) patients. Conclusions: Anlotinib combined with chemotherapy showed a promising efficacy with an acceptable safety profile for second-line and above patients with HER2-negative metastatic breast cancer. Further studies enrolling more patients are still needed.
Cryptolepine: A naturally derived alkaloid inhibits breast cancer progression by blocking cell cycle progression and inducing apoptosis.
Authors: Mir Manzoor Ahmad , Qayoom Hina
Published: June 2024

e13151

Background: Triple Negative Breast cancer is an aggressive breast cancer subtype. TNBC has a more aggressive clinical course, an earlier age of beginning, a larger propensity for metastasis, and worse clinical outcomes as evidenced by a higher risk of recurrence and a shorter survival rate when compared to hormone receptor-positive or HER2-positive illness. Currently, the primary options for TNBC treatment are surgery, radiation, and chemotherapy. These treatments, however, remain ineffective due to recurrence. However, given that p53 mutations have been identified in more than 60–88% of TNBC, translating p53 into the clinical situation is particularly important in TNBC. Given the scope that some natural drugs can be used as specifically targeting prospective therapeutic in TNBC and to sensitize this aggressive malignancy while reducing side effects. In this study, we screened and evaluated the therapeutic potential of CRP in TNBC in-vitro models being an anti-malarial drug it could be repurposed as an anti-cancer therapeutic in TNBC. Moreover, the cytotoxicity activity of cryptolepine to TNBC cells and a detailed anti-tumor mechanism in mutant P53 has not been reported. Methods: MTT assays were used to examine the cytotoxicity and cell viability activity of Cryptolepine in TNBC, non-TNBC T47D and MCF-7 and non-malignant MCF10A cells. Scratch wound and clonogenic assay was used to evaluate cryptolepine’s effect on migration and colony forming ability of TNBC cells. Flow cytometry, MMP and DAPI was used to assess cell cycle arrest and cell apoptosis. The expression of proteins was detected by western blots. The differential expression of RNAs was evaluated by RT-PCR and the interaction between P53 and drug was evaluated computationally using in-silico approach and in-vitro using ChIP assay. Results: In this study, we found that cryptolepine has more preferential cytotoxicity in TNBC than non-TNBC cells. Notably, our studies revealed the mechanism that cryptolepine can induce intrinsic apoptosis and inhibit migration, colony formation ability, induce cell cycle arrest by inducing conformational change in the mutant P53 thereby increasing its DNA binding ability and also inducing its own transcriptional activation to synthesize new P53 protein and hence activating its tumor suppressing potential significantly. Conclusions: Our study revealed that CRP significantly reduced the proliferation, migration and colony forming ability of TNBC cells lines. Moreover, it was revealed that CRP induces cell cycle arrest and apoptosis by activating mutant P53 and enhancing its DNA binding ability to induce its tumor suppressing ability.
Impact of aromatase inhibitors on mortality and hospitalization costs in patients with breast cancer: A National Inpatient Sample analysis 2020.
Authors: Kasire Sripada Preetham , Mylavarapu Maneeth
Published: June 2024

e13160

Background: Breast cancer is a significant public health concern globally, affecting millions of individuals each year. Aromatase inhibitors are a class of medications commonly used in the treatment of hormone receptor-positive breast cancer. The significance of the study lies in the impact of aromatase inhibitors on mortality and also healthcare-related costs for the treatment of breast cancer. Methods: The National Inpatient Sample database (2020) was used to identify adult patients with breast cancer using ICD-10 codes. Demographics (age, race, sex, region, and hospital size), co-morbidities, and hospitalization costs were compared between the two groups of patients: those who are on aromatase inhibitors and those who are not. The odds of mortality were analyzed. A p<0.05 was considered statistically significant. Results: Out of 166870 patients who had breast cancer, 12975(7.7%) were on aromatase inhibitors. The aromatase inhibitors group was relatively older (median age, 69.4 years vs 64 years) and predominantly white (71.50% vs 66%) compared to the non-aromatase inhibitors group. The prevalence of heart failure and osteoporosis was greater in the aromatase inhibitors group than in the non-aromatase inhibitors group. The adjusted odds ratio of mortality in the aromatase inhibitors group was 0.45, 95% CI (0.39-0.50, p<0.0001). Furthermore, the average total cost of hospitalization in the aromatase inhibitor group was $6426 less than the non-aromatase inhibitor group. Conclusions: Our study findings indicate that breast cancer patients treated with aromatase inhibitors experienced lower odds of mortality and lesser costs of hospitalization. However, the aromatase inhibitor group was found to have a higher prevalence of heart failure and osteoporosis. Hence, further research needs to be done on potential adverse effects and long-term effects of the aromatase inhibitors treatment.
Mechanisms of mammalian orthoreovirus-induced cell death and NF-kB activation in ER+ breast cancer.
Authors: Hilgendorf Syrena , Ostrander Julie , Roman Ortiz Natasha
Published: June 2024

e13171

Background: Estrogen receptor positive (ER+) breast cancer is one of the most commonly diagnosed types of breast cancer in the United States. Although the five-year survival rate of ER+ breast cancer is 90% or higher, ER+ breast cancer can recur and metastasize 10-20+ years after initial diagnosis. Novel therapeutic strategies are needed to prevent and treat breast cancer recurrence and metastasis. A possible solution is mammalian orthoreovirus (MRV), a replication-competent natural oncolytic virus. The strain T3D (Reolysin) is in current clinical trials to treat metastatic breast cancer; however, the mechanisms of MRV-induced death are not well elucidated. Furthermore, other MRV strains have not been well studied for their oncolytic potential in ER+ breast cancer. Our studies aim to explore the different cell death pathways elicited by MRV. Prior studies have reported that MRV induces cell death in L929 cells (murine fibroblasts, permissive to MRV infection) by activating apoptosis, necroptosis, and inhibiting the NFκB pathway to enhance viral replication. Methods: Our goal is to compare the effects of MRV in L929 cells and ER+ breast cancer cell line MCF7 using chemical inhibitors of necroptosis, apoptosis, and the NFκB pathway. Results: Our results indicate that necroptosis inhibitors do not impact cell viability in response to MRV infection, but apoptosis inhibitors increase cell viability, suggesting that MRV-induces apoptotic cell death in ER+ breast cancer cells. Previous work has shown that the NFκB pathway may be activated or inhibited by MRV. Our cell viability studies in MCF7 cells with the IKK inhibitor BAY-11-7082 indicate that several MRV strains likely activate the NFκB pathway to potentially enhance viral replication. Conclusions: Future studies are aimed at further defining mechanisms of MRV-induced cell death in ER+ breast cancer. We anticipate future studies will lead to an improved MRV virotherapeutic that may be combined with clinically relevant treatments, such as CDK4/6 inhibitors and anti-estrogens, to prevent and treat therapy-resistant ER+ breast cancer.
Characteristics of hospital admission during checkpoint-inhibition therapy.
Authors: Fröhlich Tabea Constanze , Wiegmann Jonas Paul , Möhn Nora , Mahjoub Susann , Duzzi Laura , Narte Emily , Aurich Johanna , Berliner Dominik , Wirth Thomas , Golpon Heiko , von Wasielewski Imke , Heidel Florian , Skripuletz Thomas , Gutzmer Ralf , Beutel Gernot , Ivanyi Philipp
Published: June 2024

e14510

Background: Immune checkpoint inhibitors (ICI) have enriched the therapeutic armamentarium in outpatient oncology care; however, data on necessity of hospitalizations associated with immune-related adverse event (irAEs) are scarce. Here, we retrospectively characterize hospitalizations of patients (pts) undergoing ICI. Methods: Between 12/2019 and 06/2022, 237 pts were included. Clinical data and characteristics of ICI were collected during a 6-month observation period after the initiation of therapy. Descriptive Statistics and Kaplan-Meier statistics were administered. Results: 30 out of 237 pts were hospitalized (HA+). Most common underlying tumor entities in the overall cohort were malignant melanoma (59.5%), renal cell carcinoma (13.1%), and non-small cell lung carcinoma (12.7%). Hospitalized pts exhibited an increased rate of pulmonary and cerebral metastases. We observed a significantly higher hospitalization rate during dual ICI with Nivolumab and Ipilimumab. The predominant irAEs for hospitalization were colitis (26.7), followed by hypophysitis (13.3%), leading to a median hospitalization of 7 days (range 1-34). Most pts were treated on the general ward (76.7%). Interdisciplinary consultations were frequent, especially to gastroenterology (46.7%) and neurology (26.7%). Although a trend towards an overall survival in the HA+ subgroup was identified, no statistically significant difference was found among the subgroups. Conclusions: The hospitalization rate of 12.6% is comparable to the literature. There was a disproportionate admission of patients with immune-related colitis and hypophysitis compared to the prevalence described under ICI. We observed a high need for interdisciplinary consults in line with the heterogeneity of immune-mediated side effects. When compared to non-hospitalized pts, there was no survival disadvantage in the cohort of hospitalized patients.
Example of a simple and scalable manufacturing process for immunomodulatory alpha neutrophils, a specifically designed immuno-cell therapy with direct and indirect anti-cancer activity for solid tumour indications.
Authors: Patel Durva , Florence Samuel , McGinley Aoife , Lich Jakub , Thacker Urvi , Blyth Alex , Willis Andrew , Quintas-Cardama Alfonso , Polyakova Oxana
Published: June 2024

e14512

Background: Recent findings have demonstrated neutrophils play a key role in tumour control and in facilitating successful responses to cancer immunotherapy. At LIfT Biosciences we have developed the first-in-class, allogeneic, off-the-shelf, stem cell-derived immuno-cell therapy with anti-cancer neutrophil properties. Immunomodulatory Alpha Neutrophils (IMANs) exert their anti-cancer activity via multiple direct and indirect mechanisms, ensuring direct antigen-independent tumour cell killing, as well as impacting anti-cancer function of other direct acting cells such as NK and gamma delta T cells, and further immunomodulation of the environment to boost adaptive immune responses ensuring maximal T cell activity can be achieved. IMANs have the potential to provide major clinical benefits in the treatment of multiple solid tumours. Methods: We present a patent-pending, GMP-compliant manufacturing process starting with CD34+ cells isolated from mobilized peripheral blood of healthy donors. Extensive characterisation of starting material in combination with in-process and raw material controls results in a simple, consistent, scalable manufacturing process using known and established manufacturing platforms. IMANs are granulopoietic myeloid progenitors derived from the expansion of CD34+ cells followed by differentiation in proprietary media compositions, composed of critical priming agents which are known to promote anti-cancer neutrophil phenotype and function. Neutrophil functional heterogeneity is becoming increasingly appreciated and we have designed our manufacturing process to produce activated, committed, persistent IMANs with multimodal mechanisms of action. IMANs are composed of distinct neutrophil progenitor populations. IMANs are cytotoxic towards numerous solid tumour cell lines, expressing tumour-ablating Neutrophil elastase. Furthermore, IMANs exert immunomodulatory properties through cytokine and chemokine secretion, and expression of ligands for T and NK cell co-stimulatory receptors. Results: The manufacturing process has been optimised with vast expansion capacity, showing up to 1000-fold increase from starting cell populations and efficient cryopreservation with exceptional post-thaw recovery. Conclusions: Cryopreserved IMANs offer a cost-effective and globally accessible cell therapy with the potential for long term clinical benefit.
Immunomodulatory alpha neutrophils: The first-in-class neutrophil progenitor-based allogeneic immuno-cell therapy with cytotoxic and immunomodulatory functionality for the treatment of solid tumours.
Authors: McGinley Aoife , Florence Samuel , Woodward Martin James , Patel Durva , Willis Andrew , Blyth Alex , Quintas-Cardama Alfonso , Polyakova Oxana
Published: June 2024

e14523

Background: Adoptive cell therapy for the treatment of cancer has largely focused on the administration of autologous engineered αβ T cells. Although successful in some haematological malignancies, the solid tumour microenvironment (TME) poses significant challenges to the efficacy of CAR-T cells, including physical barriers, heterogeneous antigen expression or antigen escape and immunosuppressive mediators. Remodeling the immunosuppressive solid TME is pivotal to the success of immunotherapies. Recent studies have highlighted key roles for neutrophils in tumour control and in facilitating successful responses to cancer immunotherapy, with neutrophil functional heterogeneity within the TME becoming increasingly appreciated. Methods: At LIfT Biosciences we have developed the first-in-class, stem cell-derived immuno-cell therapy with anti-cancer neutrophil properties called Immunomodulatory Alpha Neutrophils (IMANs). IMANs are derived from CD34+ stem cells expanded and differentiated in proprietary media compositions in a simple and scalable GMP-compliant manufacturing process. IMANs are designed to recapitulate those neutrophil states that are both cytotoxic and capable of immunomodulating the solid TME for long-lasting tumour control. Off-the-shelf, allogeneic, innate IMANs have the potential to provide major clinical benefits in the treatment of multiple solid tumours. Results: IMANs multimodal mechanisms of action (MoA) have been demonstrated in different state-of-the-art solid tumour models, including co-culture with patient-derived xenograft organoids (PDX-O) and with 3D ex vivo patient tissues (tumour-on-a-chip). Direct antigen-independent cytotoxicity towards PDX-O from a range of solid tumour indications has been demonstrated. Additionally, and fundamental to IMANs MoA is their ability to migrate to the solid TME and recruit and activate recipients’ anti-tumour immune responses. We have demonstrated IMANs ability to rapidly migrate into the solid TME and promote recruitment of patients’ immune cells leading to enhanced tumour cell death using tumour-on-a-chip technology accompanied by daily live cell imaging. Mechanistically, co-culture with IMANs enhanced expression of co-stimulatory receptors on T and NK cells, such as OX40 and 4-1BB, as well as promoting secretion of TME-modulating factors, such as CXCL10. Furthermore, co-culture with IMANs enhanced secretion of IFN-γ by activated tumour-infiltrating lymphocytes. Conclusions: These cytotoxic and immunomodulatory functions enable IMANs to remodel the TME, leaving the solid tumour more susceptible to host immune responses.
Influence of gender on acute kidney injury among patients undergoing chimeric antigen receptor T-cell (CAR-T cell) therapy: Insights from National Inpatient Sample.
Authors: Zakhour Joud , Akkawi Abdul Rahman , Alqam Anas , Karam Wissam , Shah Raj N , Mattar Bassam Ibrahim
Published: June 2024

e14524

Background: Chimeric antigen receptor T-cell (CAR-T Cell) immunotherapy has shown promising results in patients with B-cell leukemia and lymphoma and multiple myeloma. The side effect profile is still being studied and acute kidney injury (AKI) following treatment has been a commonly reported outcome in the context of cytokine release syndrome. In most cases, the kidney injury is reversible with adequate hydration and treatment of the underlying cytokine release syndrome when needed. This study aimed to investigate the outcomes of gender in patients undergoing CAR-T cell therapy along with the protective variables and independent predictors of AKI in this patient population. Methods: This was a retrospective analysis of data the National Inpatient Sample (NIS) between January 2019 and December 2020 to identify patients who underwent CAR-T cell therapy. We stratified the data based on gender and studied the incidence of AKI in patient admitted to the hospital primarily for CAR-T cell treatment. The primary endpoint was in-hospital mortality, AKI, average age, length of stay (LOS), and total charge by hospital. Additionally, we explored independent predictors and protective variables for AKI in patients receiving the treatment. Results: A total of 4010 patients underwent CAR-T Cell therapy from January 2019 to December 2020. Among these patients, females comprised 41.1% (n=1650). The mean age at the time of CAR-T cell treatment for males was 57.5 and for females 56.9. The inpatient mortality rates for both groups were 3% (p=0.97). The total incidence of AKI in patients undergoing CAR-T cell therapy was 14.9%, with rates of 19% in males and 9% in females (p<0.01). LOS for males and females was 19 days, and 20 days respectively (p=0.4). Average total hospital charge for males was 958,345 and 1,017,685 for females (p=0.3642). Interestingly, there was no difference between genders in relation to the incidence of cytokine release syndrome (p=0.3). Notably, CKD, obesity, liver disease, and electrolyte imbalances were independent predictors of AKI with an adjusted odds ratio of 4.26 (p<0.01; 95% confidence interval [CI]: 1.7-10.6), 2.7 (p=0.015; 95% CI: 1.2-6.06), 2.7 (p=0.045; 95% CI: 1.02-7.23), 2.5 (p<0.01; 95% CI: 1.67-3.81). Importantly, gender was a protective variable for females when it came to AKI after CAR-T cell therapy with an adjusted odds ratio of 0.38 (p<0.01; 95% CI: 0.23-0.63). Conclusions: AKI has been documented as a common side effect in patients undergoing CAR-T cell therapy. In most cases the kidney injury is reversible with adequate hydration and CRS treatment when necessary. Our study highlights CKD, obesity, liver disease, and electrolyte imbalance as independent predictors of AKI after CAR-T cell therapy and female gender as a predictive variable against developing AKI.
Intracellular retention of TCRαβ/CD3 and CD7 to generate novel allogeneic CAR-T cells targeting CD7 for treating T-cell malignancies.
Authors: Li Jun , Liu Kaichun , Fu Jianmin , Chen Shanshan , Zhang Yinhang , Xu Guanggui
Published: June 2024

e14531

Background: The treatment for patients with T-ALL/LBL who relapse after hematopoietic stem cell transplantation (HSCT) are currently restricted. CD7 is highly expressed on the surface of T-ALL/LBL T cells and CAR-T cell therapy provides a promising avenue towards remission. However, CD7-targeting immunotherapies may be compromised by T-cell fratricide. Furthermore, in addition to the long production time, high cost, and high risk of production failure, the biggest challenges of autologous CAR-T cell therapy are how to isolate a sufficient number of healthy T cells from malignant T cells. Thus, allogeneic CAR-T cells can overcome these hurdles. Methods: A novel non-gene-editing allogeneic CAR-T platform was developed on the base of intracellular retention of membrane proteins, and named ThisCART (TCR and/or HLA-I intracellular sequestered). CD7-directed ThisCART cells are readily produced with a single lentiviral vector, encoding both a CD7-targeting CAR, an anti-CD7and anti-CD3 single chain antibody with the KDEL peptide fused to its C-termini. The surface expression of CAR, TCRαβ/CD3 and CD7 was measured by flow cytometer. Specific tumor cytotoxicity was evaluated both in vitro and in vivo. Furthermore, the safety of donor derived ThisCART cells were tested in a xenogeneic GvHD model. Results: The manufacturing platform of CD7 ThisCART was able to achieve over 130-folds of ex vivo CAR-T expansion in all batches, with the purity of products (CAR-positive/CD7-negative/TCRαβ-negative) above 99%. In preclinical models, CD7 ThisCART did not induce GvHD, and exhibited superior antitumor function compared to Control T. CD7 ThisCART cells were readily produced to a quantity and quality supporting clinical investigation. Conclusions: CD7 ThisCART cells based on intracellular retention of TCRαβ/CD3 complex and CD7 demonstrated superior CD7-dependent cytotoxicity and no xenogeneic GvHD in murine models. With streamlined single-vector-based production and potent cytotoxicity and favored preclinical safety profile, CD7 ThisCART warrant clinical investigation.