bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world outcomes of long-term efficacy of T-DM1 after discontinuation due to limiting toxicity in patients with HER2-positive metastatic breast cancer.
Authors: Audi Blotta Daniella , Gomes Jessica Ribeiro , Moreira Shermann Brandão Rodrigues , Colosimo Danielle Fortes , Araujo Julio , Cavalcanti Gonçalves Ferreira Carolina , Forgiarini Elaine Aparecida , Buzaid Antonio C.
Published: June 2023

e13034

Background: Antibody-drug conjugates (ADC) are widely used in the treatment of breast cancer (BC). In our service, we observed that a significant number of patients (pts) with HER2-positive metastatic breast cancer (MBC) treated with T-DM1 had long-lasting response and survival rates, even after discontinuing T-DM1 due to limiting toxicity. However, data are scarce regarding its long-term benefit. We performed a retrospective study to evaluate the long-term efficacy of T-DM1 in the treatment of HER2-positive MBC. Methods: Medical records of pts with HER2-positive MBC treated with T-DM1 between September 2013 and January 2023 were reviewed. We analyzed data in the overall population and in the subgroup of pts who discontinued T-DM1 due to only limiting toxicity and did not have disease progression or death for at least 12 months, without receiving other subsequent lines of treatment. The primary endpoints were progression-free survival (PFS) and overall survival (OS) from the start of the treatment with T-DM1 to disease progression or death for the overall population, and from the time of T-DM1 discontinuation to disease progression or death for the aforementioned subgroup. Secondary endpoints were objective response rate (ORR) and toxicity. Results: A total of 73 pts were included. In the overall population, ORR was 82.6%, median PFS was 12.7 months (CI95% 8-16) and median OS was 53.9 months (CI95% 34-73). 10 (13.6%) pts had T-DM1 discontinued due to only limiting toxicity and had no disease progression or death for at least 12 months. In this specific subgroup, 2 pts received T-DM1 as first line, 6 pts as second line, and 2 as third or more lines. At the start of T-DM1, 5 pts had visceral metastasis (3 liver, 2 lung), and 2 had only leptomeningeal involvement. Median age was 57 years (IQR 49-70) and median T-DM1 duration was 30 months (IQR 12-45). At the time of T-DM1 discontinuation, 9 pts presented complete response (CR) and 1 presented partial response (PR). 5 pts maintained CR, with no evidence of disease progression or death throughout the analyzed period. The PFS of these 5 pts, from the time of T-DM1 discontinuation to the last evaluation, was 35.6, 37.9, 40.5, 42.7 and 68.5 months. In the entire subgroup, median PFS was 22.5 months, 5-year OS was 66.7% and median OS was not reached. The adverse events that led to the T-DM1 discontinuation were thrombocytopenia (10%), nausea, vomiting and fatigue (10%), pneumonitis (20%), hepatic pseudocirrhosis (20%) and peripheral neuropathy (40%). Conclusions: Our experience suggests that pts with HER2-positive MBC who had T-DM1 discontinued due to limiting toxicity may derive long-term benefit. Further prospective studies are warranted to evaluate our findings, also including other ADC.
Shifting trends in the usage of trastuzumab with its biosimilar inception in India.
Authors: Ramanjinappa Nagendra , Upveja Kunvar Harsh , Agarwal Jatin
Published: June 2023

e13037

Background: Biosimilars have the potential for cost savings and thus help increase access to treatment. The first trastuzumab biosimilar was introduced in 2014 in India. A qualitative study was conducted focusing on understanding the physicians’ perceptions on using trastuzumab biosimilars in HER2+ breast cancer (BC) and changes in trends from pre-biosimilar to post-biosimilar era in India. These study results were presented at ESMO Asia 2022 conference (https://www.annalsofoncology.org/article/S0923-7534(22)04219-3/fulltext). The current abstract utilizes sales data on trastuzumab to reexamine trends in biosimilar usage in this indication in India. Methods: Trends in patients treated with trastuzumab innovator or biosimilar were identified using data from Ipsos’ India Oncology Sales Audit (Jan 2014-Dec 2020), which reports Net Realized Value of all brands marketed by ~60 oncology companies across India. Data were collected using open-source intelligence and telephone interviews with sales/marketing personnel from pharmaceutical companies and distributors. The number of patients treated with trastuzumab was calculated using Microsoft Excel based on their body weight (assumed to be 60 kg), completing 6 months (9 cycles) of therapy and consuming 1 vial of 440 mg/cycle (8 mg/kg loading dose and 6mg/kg maintenance dose Q3W). Results: Approximately 68,000 HER2+ BC patients received trastuzumab from 2014-2020, out of which 46,000 received biosimilars and 22,000 innovators. Eighteen percent of patients were treated with biosimilars in 2014 which increased to 88% by end of 2020. There was a 17% decline in patients treated with innovator from the year 2017-2018, whereas patients treated with biosimilars grew by 229% in the same period, due to the launch of multiple biosimilars in this era. In the year 2020, there was a 15% decline (13% for biosimilar vs 30% for innovator) in the overall number of patients receiving trastuzumab which was primarily due to the impact of COVID-19. Similarly, pertuzumab usage increased 17 times from its introduction in 2015 till 2020. There has been decline in innovator trastuzumab patients and increase in the number of patients treated with biosimilar trastuzumab and pertuzumab in the last seven years; supporting our physician perception survey, wherein oncologists used pertuzumab with biosimilars in almost 45% of their patients. Conclusions: Findings from this data coincide with the physician perception survey suggesting increasing trend in usage of biosimilars in the last seven years. Biosimilars are preferred option amongst oncologists in India because of affordability and accessibility. The availability of quality biosimilars has the potential to reduce health care expenditure, and an effective supply also increase patient’s adherence to treatment.
Prognostic significance of estrogen receptor status in de novo metastatic breast cancer.
Authors: Chongxi Ren , Jianna Sun , Lingjun Kong , Ruizhen Luo , Kun Mu , Xiuzhen Jiang
Published: June 2023

e13049

Background: The clinical behaviors of de novo metastatic breast cancer (dnMBC) differ according to hormone receptor (HR) status, but an association between estrogen receptor (ER) expression and clinical outcomes has not been established. Our study aimed to investigate the influence of different ER status on survival outcomes for patients with dnMBC. This study was the Medical Science Research Project of Hebei Province and approved by the Ethics Committee of the Ethics Committee of Cangzhou Clinical College of Integrated Traditional Chinese and Western Medicine of Hebei Medical University (NO. 2017-AF29-058). Methods: Using hospital-based database, we identified patients with dnMBC diagnosed between 2010 and 2017, retrospectively collecting demographic data, tumor characteristics, treatment types and survival data. According to ER status, the patients were divided into ER-negative and ER-positive groups, and the propensity score matching (PSM) was used to balance the mixed bias. Overall survival (OS) was estimated by Kaplan-Meier method and log rank test. Univariable and multivariable analyses were performed using the Cox proportional hazard model to identify statistically significant prognostic factors. Results: A total of 322 patients were included. The median age was 53 (21-82) years, and the median follow-up was 8.5 years. The median OS for the PSM cohort was 29 months (95% confidence interval [CI], 26-35 months), and 5-year OS was 18.9%. OS differed significantly between the two groups (p = 0.0012), with a median OS of 36 months (95% CI, 32-41 months) in ER-positive group and 24 months (95% CI, 19-27 months) in ER-negative group. Multivariate analysis showed that clinical T-stage and initial metastatic sites were independent prognostic factors for survival in patients focused on ER status, with Ki-67 index, endocrine therapy and radiotherapy added to the ER-positive group, while initial and advanced chemotherapy added to the ER-negative group. Conclusions: For patients with dnMBC, there were substantial differences in OS according to ER status. ER-negative subtype is clinically different from ER-positive subtype, showing unfavorable tumor characteristics and poorer OS. We identified several prognostic factors that could guide therapy selection in this patient population. Clinical trial information: 20210957 .
Efficacy of abemaciclib versus tucidinostat after progression on palbociclib in patients with HR+/HER2− MBC: A multicenter retrospective cohort study.
Authors: Yuan Yang , Zhang Shaohua , Wang Tao , Wang Biyun , Wang Shusen , Shi Jing , Sun Tao , Yin Yongmei , Ouyang Quchang , Li Jianbin , Wen Yi , Zhang Lijun , Jiang Zefei
Published: June 2023

e13056

Background: For patients with hormone receptor-positive HER2-negeative metastatic breast cancer (HR+HER2-MBC), switching to another cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) or target drug with different mechanism are reasonable treatment strategies post-CDK4/6i. However, no clinical data has been reported on which of the two strategies is more effective. We performed a retrospective cohort study to evaluate the efficacy of abemaciclib-based therapy versus tucidinostat-based therapy after progression on palbociclib. Methods: We identified patients with HR+/HER2- MBC who received abemaciclib-based therapy or tucidinostat-based therapy after progression on palbociclib from seven research centers in China. The primary endpoint was progression-free survival (PFS), the secondary endpoints were objective response rate (ORR), clinical benefit rate (CBR), PFS in patients with PIK3CA-mutant and PIK3CA wild-type, and safety. Results: Between Apr 1st 2020 and September 30th 2022, a total of 149 patients were included, of whom 73 patients received abemaciclib plus endocrine therapy(ET), and 76 patients received tucidinostat plus ET. The majority of patients had visceral disease (124/149, 83.2%) and ≥3 metastatic sites (76/149, 51.0%) at baseline, one third of patients (48/149, 32.2%) had previously been treated ≥3 lines of endocrine therapy in MBC setting. More patients received sequential therapy after palbociclib in abemaciclib group(49.3%) than that in tucidinostat group(30.3%). There were no statistically significant differences in other baseline characteristics between the two groups. Clinical benefit rate (CBR) was 38.4% (28/73) in abemaciclib group and 17.1% (13/76) in ET plus tucidinostat group (p=0.0037). There was significant difference in PFS between abemaciclib group and tucidinostat group in both the whole population (5.0 months vs. 2.0 months; HR 0.44; 95%CI 0.31-0.64; P＜0.001) and propensity score matched population. PIK3CA mutations occurred in 44.20% of patients who had undergone multigene sequencing. PIK3CA-mutant showed a negative effect on PFS of abemaciclib-based therapy. The most common any grade and grade 3-4 adverse events was neutropenia in either group. Common non-hematological toxicity occurred in abemaciclib group was diarrhea, and were increased AST, nausea, vomiting in tucidinostat group. Conclusions: Abemaciclib-based therapy improved clinical benefit rate and prolonged PFS compared with tucidinostat-based therapy, providing a superior treatment option in patients progressed on palbociclib.
Comprehensive molecular profiling from liquid and tissue for analysing the somatic mutational landscape in an Indian breast cancer cohort.
Authors: Rohatgi Nitesh , Limaye Sewanti Atul , Bahl Ankur , Sirohi Bhawna , Sahni Sidharth , Patil Darshana , Datta Vineet , Limited Datar , Crook Tim , Kurzrock Razelle , Cristofanilli Massimo
Published: June 2023

e13080

Background: Breast cancer is a genetically and clinically heterogeneous entity, with high prevalence in the Indian population. The primary objective of this study was to characterize the somatic mutational landscape of metastatic breast cancer in Indian patients from tumor and liquid specimens. Methods: We performed molecular profiling of 341 tumor tissue specimens and 901 blood specimens from individual breast cancer patients, with paired tissue and blood processing in a sub cohort (n=101). Targeted NGS evaluating single nucleotide alterations, copy number alterations, and fusions was performed on these specimens. Results: In the cohort with tissue-based sequencing (n = 341), TP53 was the prevalently altered gene (55%). PIK3CA and ESR1 mutations were detected in 32% and 9%, respectively. BRCA1/2 alterations were detected in 10.8%, ARID1A in 7%, KEAP1 in 6%, NF1 in 6%, and ATR in 6%. ERBB2 amplification was observed in 10% of the cases. ESR1 gene fusions were detected in 3.7%. This is clinically relevant as along with other ESR1 resistance mutations, ESR1 fusions are also known as recurrent drivers of endocrine therapy resistance and are impervious to ER-targeted therapies. In a sub cohort comprising 255 specimens, TMB analysis showed a median TMB of 5 mut/Mb (range 1 - 88 mut/Mb), and 15.3% specimens with TMB-High (≥10 mut/mb). The ctDNA analysis (n = 901) revealed TP53 being the most altered (41%) gene, followed by PIK3CA (23%), ESR1(11%), EGFR (6%) and GNAS (4%). Acquired resistance mutations in ERBB2 were identified in ctDNA analysis liquid biopsy from two patients treated with HER2-targeted therapy and were absent in corresponding tissue samples. Mutations in ESR1 were more commonly seen in liquid biopsy than paired tissue, indicating this acquired resistance alteration being better captured in ctDNA than tissue due to tumor heterogeneity and tumor evolution. This indicates causative role for ESR1 mutations in endocrine resistance but not in disease pathogenesis. Conclusions: We report the largest liquid biopsy study reporting the genomic landscape from breast cancer cases of Indian origin along with tissue based molecular landscape. High concordance of liquid for PIK3CA alteration and higher sensitivity for detection of resistance conferring alterations like ESR1 and ERBB2 shows utility of liquid biopsy profiling. It reinforces the utility of liquid biopsy as effective tool that reveal clinically relevant information including mutational status and therapeutic options and seem more relevant in acquired resistance settings. [Table: see text]
Exploring the effects of inhibiting miR-10b on breast cancer stemness and metastasis.
Authors: Al-Qadi Nasreen , Halim Alan , Mackie Hussein , Sempere Lorenzo , Moore Anna
Published: June 2023

e13084

Background: There are currently limited effective therapeutic options for metastatic breast cancer, and none target the metastatic process. MiR-10b is a major driver of breast cancer cell invasion and migration. Our lab has demonstrated its importance in metastatic cell viability, positioning miR-10b as a target for metastatic breast cancer. Our previous studies demonstrated that delivery of a novel therapeutic consisting of antisense anti-miR-10b oligomers conjugated to magnetic nanoparticles (termed MN-anti-miR10b) prevented metastases in vivo. These studies led us to hypothesize that MN-anti-miR10b affects the viability of a stem cell-like population of cells within primary tumors that otherwise would have formed metastases. Here, we investigate the relationship between miR-10b and breast cancer cell stemness and the effects of miR-10b inhibition by MN-anti-miR10b on breast cancer cell stemness. Methods: MDA-MB-231 breast cancer cells were sorted based on surface markers into stem-like (CD44+/CD24-) and non-stem-like (CD44-/CD24-) populations, and their miR-10b expression levels were quantitated. Then, unsorted MDA-MB-231 cells were treated with MN-anti-miR10b to determine the effects of miR-10b inhibition on the expression of EPCAM, a marker for cancer cell stemness. Lastly, MCF-7 breast cancer cells were cultured in mammosphere medium (which selects for stem-like cells and induces spheroid formation) and treated with MN-anti-miR10b to establish the phenotypic effect of miR-10b inhibition on cancer cell stemness. Results: We found that stem-like MDA-MB-231 cells displayed >2-fold miR-10b expression compared to non-stem-like cells. Accordingly, alongside a 70% reduction in miR-10b expression, treatment of MDA-MB-231 cells with MN-anti-miR10b reduced EPCAM expression by 65%. Treatment of MCF-7 spheroids with MN-anti-miR10b resulted in significantly greater cell dissociation from the spheroid compared to controls. Conclusions: These results support the hypothesis that inhibition of miR-10b with MN-anti-miR10b inhibits breast cancer cell stemness. This provides an explanation for the therapeutic efficacy of MN-anti-miR10b observed in mouse breast cancer metastasis models. Future studies will further investigate this relationship and shed light on how miR-10b can be optimally targeted to treat metastatic breast cancer in humans.
Correlation analysis to assess surrogate endpoints for overall survival (OS) in triple-negative breast cancer (TNBC).
Authors: Pérez-Granado Judith , Kalucha Ankit , Gala Kinisha , Bodriagova Olga , Vidal Laura , Larvol Bruno , Gramling Mark , Saini Kamal S.
Published: June 2023

e13089

Background: The use of surrogate endpoints can help reduce the trial duration and cost which is important for aggressive diseases such as TNBC. Previous studies suggest progression-free survival (PFS) may serve as a surrogate for OS in metastatic TNBC. We aim to evaluate PFS and additional surrogate endpoints for their correlation with OS in localized and advanced TNBC. Methods: TNBC phase 3 trials and pooled analysis as well as trials including TNBC subgroups, were identified through a systematic search using LARVOL CLIN, PubMed, clinicaltrials.gov, and conference proceedings. Out of these, trials reporting median survival and hazard ratios (HR) for both OS and surrogate endpoints were considered for further statistical analysis. Surrogate endpoints reported by fewer than 4 trials were excluded from the study. Pearson correlation (r) and determination coefficient (R2) were calculated to assess surrogacy between Median OS and Median PFS, HR OS and HR PFS, HR disease-free survival (DFS), and invasive disease-free survival (IDFS). Weighted regression analysis was conducted controlling for sample size among trial arms. Results: 26 TNBC cohorts and 2 pooled analyses evaluating PARP, PD-1, PD-L1 inhibitors, and chemotherapies were included. The association analysis results are shown. There was a significant correlation between median OS and median PFS (r = 0.73, p value = 1.026×10−6) as well as between HR OS and HR PFS (r = 0.61, p value = 0.009). There was also a significant correlation between HR DFS and HR IDFS with HR OS (r = 0.92, p value = 0.003; r = 0.99, p value = 0.014). Conclusions: PFS is significantly correlated with OS in TNBC across diverse therapies. Also, HR PFS, HR DFS, and HR IDFS are significantly correlated with HR OS. Overall, these results illustrate that PFS could be used as a surrogate for OS in TNBC. Subsequent studies should include early-phase trials to increase association robustness and enable correlation comparison between the diverse mechanism of actions and other surrogate endpoints. [Table: see text]
A real-world study of immune checkpoint inhibitors in advanced triple-negative breast cancer.
Authors: Zhao Weihong , Zhang Zheng , Zhang Yadi , Chen Yimeng , Zhu Yimin , Liu Chuanling , Shao Jiakang , Zhang Li , Liu Mei
Published: June 2023

e13090

Background: Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer. The lack of specific targets leads in fewer effective treatments and poor prognosis. Immunotherapy has become a new generation of treatment approach in addition to surgery, radiotherapy, chemotherapy, endocrine therapy and targeted therapy. Immune checkpoint inhibitors (ICIs) have been widely used in the clinical treatment of various tumors and changed the landscape of tumor treatment, but the data from real-world studies of ICIs for TNBC remain limited. Methods: Clinical data of patients with advanced TNBC treated with ICIs in Chinese People’s Liberation Army General Hospital were collected from January 2004 to December 2022. The effect of different factors on patient response and prognosis was analyzed using Kaplan-Meier survival curves. The relationship between clinical, pathological characteristics, hematological indicators, and efficiency were analyzed using univariate and multifactorial Cox regressions. Objective Response Rate (ORR), Disease Control Rate (DCR), Progression-free Survival (PFS), Overall survival (OS), and adverse events (AEs) were assessed. Results: Eighty-one patients were enrolled in the study. Median follow-up was 26.3 months (range, 16.0 - 36.6 months). Confirmed ORR was 32.1% and DCR was 64.2%. The median PFS was 4.2 months and the median OS was 11.0 months. Eastern Cooperative Oncology Group (ECOG) performance status score ≥ 1, applying ICIs in 2nd and later lines, with liver metastases, with more than two sites of metastases, lactate dehydrogenase (LDH) ≥ 194.3 U/L, alkaline phosphatase (ALP) ≥ 104.7 U/L, neutrophil-to-lymphocyte ratio at baseline (bNLR) ≥ 2.7, NLR before the second dose of immunotherapy (NLR2) ≥ 2.2, platelet to lymphocyte ratio before the second dose of immunotherapy (PLR2) ≥ 165.6 were associated with a poorer prognosis. Patients with effective initial treatment, tumor - infiltrating lymphocytes (TIL) ≥ 20%, derived neutrophil-to-lymphocyte ratio (dNLR) ≤ 1.9, LDH < 194.3 U/L and bNLR < 2.5 prior to ICI treatment have a better prognosis. Conclusions: ICIs were effective in advanced TNBC with tolerable adverse effects, and we have identified a series of biomarkers associated with PFS and OS. Randomized controlled clinical trials are warranted to validate our findings.
Lactate-induced lactylation circularly regulates glucose metabolism enzymes in breast cancer.
Authors: Xu Jia-lin , Shen Hong-yu , Zhu Zhen , Tang Jinhai
Published: June 2023

e13092

Background: Breast cancer is the most common malignant tumor in the female population worldwide and has become the disease with the highest cancer-related mortality. Among the molecular subtypes of breast cancer, triple-negative breast cancer accounts for only 15% of primary malignancies, but due to its increasing recurrence, metastasis, and mortality, we need to find new therapeutic targets to address this phenomenon. Analysis from the field of metabolism found that the level of glycolysis in triple-negative breast cancer was significantly higher than that in other cancers. Glycolysis is a common malignant phenotype of cancer, namely the famous Warburg effect. LDHA is the last metabolic enzyme in the glycolytic pathway, and its expression is increased in triple-negative breast cancer. Lactate is the final product of glycolysis, which converts pyruvate to lactate and NADH to NAD+ under the catalysis of LDHA. The acidic tumor microenvironment formed by the accumulation of lactate will not only affect the progression of tumors and the therapeutic effect of anticancer drugs, but also inhibit the function of immune cells. Lactic acid groups can bind to histones and non-histone proteins to produce a new post-translational modification, lactylation. Methods: Breast cancer cells were infected with lentivirus vectors overexpressing or knocking down LDHA, and cell proliferation and cytotoxicity assay, transwell assay and Lactic Acid Content Assay were performed. To further explore the presence of lactylation of LDHA, immunoprecipitation experiments were performed and the modification sites were mutated to examine the enzymatic activity and function of LDHA. Results: In triple negative breast cancer with strong glycolytic metabolic phenotype, altering LDHA level can affect the biological function of breast cancer cells. Secondly, RNA-seq sequencing results showed that LDHA can affect the protein and transcription levels of MEST and CSTA. Finally, the lactylation of histones was also significantly changed after LDHA dysregulated. Reduced levels of LDHA were accompanied by reduced levels of MEST, CSTA, and histone lactylation. In addition, LDHA itself also has lactic acid modification, and mutations in the modification sites can change the enzymatic activity and function of LDHA. Conclusions: The regulatory axis of LDHA-lactate-lactylation has important value and function in the occurrence and development of breast cancer. LDHA regulates the function of some genes by lactate-induced lactylation of histones. In addition, the lactylation of LDHA can alter the enzyme activity, which may be a new therapeutic target for breast cancer.
Effect of microRNA-21 blockade in human triple negative breast cancer allografts on progression and immune checkpoint proteins.
Authors: Jin Yuan-Yuan , Desai Vilas Shivaji , Castro Miguel M. , Mitchell Edith P. , Wickstrom Eric
Published: June 2023

e13097

Background: Triple negative breast cancer (TNBC) is an orphan disease that attacks > 46,000 US women every year. TNBC recurs after standard-of-care surgery, chemotherapy and radiation, killing half its victims within 4 years. Poly(ADP-ribose) polymerase (PARP) inhibitors, topoisomerase inhibitors, immune checkpoint inhibitors, and antibody-drug conjugates extend the survival of a fraction of TNBC patients for a few months. Thus, TNBC shows a critical need for molecularly-targeted therapy. Most TNBC cells show high microRNA 21 (miR-21), identical in humans and mice, which decreases tumor suppressor proteins that keep cell growth in check. Hypothesis: Short anti-miR-21 RNA analogs conjugated to a receptor ligand will direct TNBC cell uptake and slow the growth of TNBC orthotopic allografts with immune activation and minimal toxicity. Methods: We designed an anti-miR-21 RNA analog using aminomethyl bridged nucleic acid (BNA), exhibiting low toxicity, and serum stability. We lipofected a concentration ramp of the anti-miR-21 RNA analog into human TNBC cell lines (MDA-MB-231, MDA-MB-157, MDA-MB-436, MDA-MB-468, BT-20, BT-549, HCC1806, HCC1937, HCC1806) representing a spectrum of TNBC subtypes, then measured proliferation and biochemical markers. We also conjugated a peptide analog for endocytosis by the insulin-like growth factor 1 receptor (IGF1R), overexpressed in most TNBC lesions. The peptide ligand for IGF1R provides a unique strategy for delivering the anti-miR-21 RNA analog preferentially into TNBC cells. We administered 5 mg/kg of the anti-miR-21 RNA-peptide analog in sterile saline intraperitoneally twice a week for 14 days into immunocompetent female Balb/c mice bearing syngeneic EMT6 TNBC tumors in their mammary fat pads. Results: The anti-miR-21 RNA analog slowed proliferation, increased apoptosis, elevated tumor suppressor proteins, and suppressed immune checkpoint gene expression in multiple human TNBC lines. IC50 for inhibiting cell proliferation correlated with miR-21 copies/cell in 7 TNBC cell lines, but not in the non-tumorigenic breast epithelial cell line MCF-10A. The anti-miR-21 RNA-peptide analog stopped orthotopic TNBC allograft growth in syngeneic immunocompetent female Balb/c mice during 14 days of therapy, with apparent safety. Conclusions: This strategy optimizes cancer cell-specific delivery to block proliferation and immune checkpoints. The results support further preclinical proof-of-concept studies to enable an eIND submission for the anti-miR-21 RNA-peptide analog.
Circulating methylated-HOXA9 tumor DNA as a biomarker for mortality in recurrent breast cancer.
Authors: Hansen Torben , Bakkensen Bruun Stine Bakkensen , Andersen Rikke Fredslund , Madsen Jonna Skov , Tabor Tomasz Piotr , Bechmann Troels , Kjær Ina Mathilde
Published: June 2023

e13106

Background: The Homeobox A9 (HOXA9) gene may act as a tumor suppressor in carcinomas and induce breast cancer progression. The clinical potential of methylated HOXA9 (meth-HOXA9) as a biomarker is unclear. Therefore, this study aims to examine the association between meth-HOXA9 in tumor tissue, meth-HOXA9 in plasma, and mortality. Additionally, the study examines the association between meth-HOXA9 in metastatic tissue and plasma at the time of recurrence. Methods: The study enrolled 51 patients with recurrent breast cancer between 2011 and 2015 recruited at the Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark. Tissue samples were obtained from the primary tumor at the time of primary surgery between 1993 and 2013. Tissue samples from the metastases and plasma samples were obtained at the time of recurrence. The study follow-up period ran until death or January 2019. All samples were analyzed for meth-HOXA9 using droplet digital PCR. The optimal cut-off for meth-HOXA9 in tissue was established at ≥7.4% using tissue specimens from independent breast cancer patients and healthy controls. In plasma samples, the detection of ≥5 meth-HOXA9-containing droplets resulted in a positive test. Using Cox regression, we estimated crude and age-adjusted hazard ratios (HR) for mortality with 95% confidence intervals (CI) comparing patients with detectable and undetectable meth-HOXA9 in both tumor tissue and plasma. Fischer’s exact test was used to compare plasma and metastasis meth-HOXA9 status. Results: Among the 50 patients with data on tumor tissue meth-HOXA9, 80% had detectable meth-HOXA9 in the primary tumor, but there was no increased mortality when comparing patients with detectable and undetectable meth-HOXA9 (HR 1.09; CI 0.47-2.52). Only 34 patients had data on plasma meth-HOXA9 and 62% of these had detectable meth-HOXA9 at the time of recurrence. Patients with detectable meth-HOXA9 in plasma had higher mortality than those without (HR 3.95; CI 1.50-10.37). Among the 20 patients with data on plasma and metastatic tissue meth-HOXA9, there was no significant association between meth-HOXA9 in plasma and metastatic tissue (p = 1.00). Conclusions: These results indicate that detectable plasma meth-HOXA9 at the time of breast cancer recurrence is associated with increased mortality. However, there is no association between tumor tissue meth-HOXA9 and mortality. Metastatic tissue and plasma meth-HOXA9 are not associated. Our data support the potential relevance of plasma meth-HOXA9 as a biomarker for prognosis and mortality in recurrent breast cancer, which calls for further investigation.
Efficacy of antibody-drug conjugates in breast cancer: A systematic review and meta-analysis of randomized clinical trials.
Authors: Ali Muhammad Ashar , Aiman Wajeeha , Afzal Fatima , Zahoor Hafsa , Kazmi Syeda Hafsa , Anwar Aqsa , Bajwa Ayfa Riaz , Maroules Michael , Guron Gunwant K. , Shaaban Hamid Salim
Published: June 2023

e13113

Background: Breast cancer (BC) is the 2nd most common cause of cancer related deaths in women. Antibody-drug conjugates are monoclonal antibodies conjugated to the cytotoxic payload and are directed towards cell surface proteins specific to tumor cells. This systematic review and meta-analysis aims to assess the efficacy of ADCs in breast cancer and comparison of different ADCs. Methods: A literature search was performed on PubMed, Embase, WOS, and clinicaltrials.gov with key words “breast neoplasms,” and “immunoconjugates” from the inception of data till 6/6/2022. Cochrane and PRISMA guidelines were followed to establish guidelines registered on Prospero (CRD42022329529). Out of 4,570 articles, seven randomized clinical trials (RCTs, N=5,302) were included. R programming language software with “meta” package was used for this meta-analysis. Results: In 7 RCTs (N=5,302), 4,834 patients had HER-2 positive disease while 468 patients were triple negative BC (TNBC). 1,486 patients had residual invasive disease while 3,816 patients had metastatic breast cancer (mBC). 3,389 patients were treated with ADC (235 with sacituzumab govitecan (saci-gov), 2,339 with trastuzumab emtansine (T-DM1) and 261 trastuzumab deruxtecan (T-der)), 2,105 patients were treated with chemotherapy regimens. In 4 RCTs on HER-2 patients (N=2,825), pooled HR of PFS and OS were 0.72 (95% CI=0.61-0.84, I2=71%) and 0.73 (95% CI=0.64-0.84, I2=20%), respectively, in favor of ADC. Risk of ORR was 1.48 (95% CI=0.84-2.60, I2=91%) in favor of ADC. In RCT on TNBC (N=468), HR of PFS and OS were 0.55 (95% CI=0.51-0.61) and 0.59 (95% CI=0.54-0.66), respectively, in favor of saci-gov (ADC). In RCT on HER-2 positive residual invasive breast cancer, HR of recurrence/death was 0.61 (95% CI=0.54-0.69) in favor of T-DM1. In an RCT by Cortes et al. (N=524) comparing two ADCs in HER-2 mBC, the HR of PFS and OS were 0.28 (95% CI= 0.22-0.37) and 0.55 (95% CI=0.36-0.86), respectively, in favor of T-der as compared to T-DM1. The RR of ORR and CR were 2.33 and 1.28, respectively, in favor of T-der. Conclusions: ADCs are significantly more effective than chemotherapy in patients with HER-2 positive mBC, HER-2 positive residually invasive BC, and metastatic TNBC in terms of improving survival and response rates. Among ADCs, T-der was significantly more effective than T-DM1 in patients with HER-2 positive mBC. More double blinded multicenter RCTs are needed to confirm these results.
Treatment (Tx) patterns, efficacy and safety of eribulin for advanced and heavily pretreated breast cancer (ABC): A single-center, real-world study.
Authors: Yang Jin , Yang Jiao , Wang Guangxi , Zhang Haochen , Zhao Shidi , Zhao Xiaoai , Dong Danfeng , Wang Le
Published: June 2023

e13118

Background: We evaluated the Tx patterns, efficacy and safety of eribulin for heavily pretreated ABC in real-world practice. Methods: Patients (pts) with ABC who had progression on anthracycline/taxane Tx and received eribulin (1.4 mg/m2 IV on Days 1 and 8 of a 21-day cycle) between April 2020 and August 2022 were enrolled. Response was evaluated using RECIST v1.1. Results: 73 pts were enrolled. Median (range) age was 54 (30–79) years; 78.1% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1, and pts had a median of 3 prior lines of chemotherapy. 69.9% of pts had Ki67 >30% and 52.1% had HR+/HER2− disease. 90.4% of pts had visceral metastasis. Eribulin was monotherapy in 28.8% of pts, and combined with bevacizumab, capecitabine, bevacizumab + capecitabine, and anti-HER2 agents in 28.8%, 10.9%, 4.1%, and 27.4%, respectively. The objective response rate was 24.7%; disease control rate was 75.3%. Median progression-free survival (PFS) overall was 6.0 (95% CI, [3.8–8.2]) months (mo). Univariate analysis indicated pts with HER2+ disease had longer PFS than pts with HR+/HER2− or triple-negative BC (median, 8.0, 6.0, and 3.0 mo, respectively; P = 0.049). Pts with Ki67 expression ≤30% had longer PFS than pts with Ki67 >30% (median, 8.0 vs. 4.0 mo; P = 0.024). Pts with late relapse (disease-free survival [DFS] >24 mo) had longer PFS than pts with early recurrence (DFS 6–24 mo) or de novo disease (DFS <6 mo; median PFS, 9.0, 4.5, and 3.6 mo, respectively; P = 0.026). Among 38 pts with HR+/HER2− ABC, pts who received eribulin plus capecitabine had longer PFS than pts who received eribulin monotherapy (median 11.4 vs. 4.0 mo, P = 0.021). Among the 18 pts with a partial response, median PFS was 9.5 mo. Multivariate analysis indicated line of Tx predicted PFS; pts who received eribulin as line 1–3 had longer PFS than pts who received eribulin as line >3 (HR=0.42 [95% CI, 0.19–0.93]; P = 0.034). The most common adverse events were leukopenia (43.2%), anemia (37.9%), and neutropenia (37.8%). Neurotoxicity was rare (2.7%). Conclusions: In this single-center study of pts with heavily pre-treated ABC in China, eribulin Tx resulted in favorable PFS irrespective of molecular subtype, with a manageable safety profile. In pts with a large tumor burden and a good PS, eribulin-based combinations may further improve outcomes. [Table: see text]
In-hospital outcomes of patients with breast cancer and venous thromboembolism.
Authors: Sanghvi Ankushi , Nanavaty Dhairya , Bansal Kannu , Narayan Gayatri , Shah Shailja
Published: June 2023

e13133

Background: Breast cancer is the most common cause of cancer in women in the USA after skin cancer. About 264000 cases of breast cancer are diagnosed in women each year in the USA. 42000 women die from this cancer each year. Less is known regarding the association of venous thromboembolism (VTE) in breast cancer. We aim to study the prevalence of VTE in breast cancer and its effect on healthcare utilization using a national database. Methods: We used the National Inpatient Sample (NIS) to collect data for all adult patients >18 years with a diagnosis of breast cancer from 2017-2019 using appropriate ICD 10 codes. These patients were further classified into patients with and without DVT/PE. Multivariate regression analysis was performed to study the effect of DVT/PE in patients with breast cancer taking mortality as primary outcome and total cost and length of hospital stay as secondary outcomes. Results: There were a total of 855494 admissions with a diagnosis of breast cancer. The mean age was 63.87 years and 98.8% of them were females. Acute DVT was found in 1.87% of patients and acute PE was found in 3.01% of patients with breast cancer. A total of 7.36% of breast cancer patients who had acute DVT and 8.04% with acute PE died during the hospital stay. The odds of all-cause mortality for DVT (OR 1.58; 95% CI 1.38-1.82, p<0.001) and PE (OR 1.71, 95% CI 1.52-1.94, p<0.001) were significantly higher in patients with breast cancer than those without. The total cost of hospital stay was 26099 USD ($21814-$30383, p<0.001) higher and LOS was 2.51 days higher (2.22-2.81; P<0.001) when patients developed acute DVT however there was no significant difference in these parameters with PE hospitalizations. Conclusions: Our study concludes that patients with breast cancer who develop acute DVT or PE tend to have worse outcomes in terms of mortality. Length of hospital stay and total hospital charge are also increased in patients developing DVT. Current guidelines (2020) recommend against offering thromboprophylaxis to patients with any cancer. Given the worse outcomes, this study reflects the need to formulate risk assessment models for role of primary thromboprophylaxis in breast cancer.
Virtual nutrition services in oncology.
Authors: Lammersfeld Carolyn , Sonntag Kara , Dahlk Sadie , Schober Nathan , Morgiewicz Kayla , Gupta Digant , Markman Maurie
Published: June 2023

e13504

Background: In 2016, the National Academy of Sciences, Engineering and Medicine convened a workshop to examine challenges patients experience accessing specialized nutrition care in outpatient cancer treatment settings. Inadequate Registered Dietitian Nutritionist (RDN) staffing and reimbursement were identified as barriers to timely care. Staffing challenges at our three destination community cancer centers led to a backlogged queue of nutrition consults resulting in a ≥ 4-week wait time for an appointment. A quality improvement project to address delays in care for patients at risk for malnutrition, resulted in implementation of a hybrid model utilizing remote RDNs to provide virtual Medical Nutrition Therapy (MNT) to supplement onsite RDNs. Methods: After approved in June 2022, two remote RDNs were hired to provide virtual patient care. Nationwide recruitment allowed for hiring rare talent. A project team was created to assure we followed all regulatory guidelines related to licensing and billing. RDNs were individually licensed in 14 states to cover where ≥ 70% of our patients reside. System-wide criteria and licensure alerts for appointments were established between scheduling and nutrition leaders. The first patients were seen virtually on October 14, 2022, with units of service (uos) logged in 15-minute increments. Results: Appointments were tracked from October 14, 2022, through February 3, 2023. 69.2% of 302 scheduled appointments were successfully delivered virtually via telehealth platform with a mean of 1.7 uos. The main reasons for nonuse of the platform were no shows (52.7%) and the need to convert to a phone call (32.3%). The mean uos was significantly higher in new patients compared to returning patients (2.23 versus 1.53; p<0.001). Conclusions: A hybrid model of onsite and virtual care RDNs has potential to improve access to nutrition care. New patient appointments averaged > 30 minutes, and follow-ups averaged < 30 minutes. This may help inform future scheduling of virtual MNT appointments. This model may allow for recruitment from a wider pool of RDNs. It may also help avoid delays in care for patients at risk for malnutrition and gaps in their cancer treatment. [Table: see text]
Implementation of an early-stage lung cancer survivorship clinic in a comprehensive cancer center.
Authors: Wentworth Stacy , Willis Alana , Hensley Amy E. , Hyson Jill , Sohl Stephanie Jean , D'Agostino Ralph , de Hoyos Alberto , Petty William J. , Blackstock A. William
Published: June 2023

e13515

Background: Early-stage lung cancer survivors are a growing population. A comprehensive plan to address needs relevant to longer survival (e.g., psychological distress, persistent symptoms, physical function) and clinic capacity is necessary. How to deliver comprehensive survivorship care that meets national standards and results in improved patient outcomes is a challenge. Survivorship clinics staffed by advanced practice providers (APP) are an option to address these needs. Methods: In June 2019, Atrium Health Wake Forest Baptist Comprehensive Cancer Center (AHWFB-CCC) opened a dedicated survivorship clinic. Stakeholders from the lung cancer disease-oriented team developed a standard referral pathway for patients to survivorship. A standard workflow was developed in the electronic medical record (EPIC). Eligible lung cancer survivors were referred to the Lung Cancer Survivorship Clinic for a survivorship orientation visit (SOV) with a lung cancer specific APP. Prior to the SOV, a welcome video, disease-specific questionnaire, and electronic patient reported outcome (ePRO) tools (i.e., PROMIS-29 and Distress Thermometer) were sent to the patients’ electronic chart. At the SOV, the ePRO responses and survivorship care plan were reviewed. Analysis of survivor demographic and clinical characteristics (i.e., age, gender, race, residence according to rural-urban commuting area (RUCA) codes, treatment modality, and method used to complete ePROs) and ePRO responses was performed using several regression methods. Patients were offered a post visit survey. Results: From January 2020 to December 2022, 285 lung cancer patients completed a SOV. Most patients were able to complete the pre-visit questions via the electronic chart. AHWFB-CCC survivors reported improved PROMIS-29 T-Scores compared to the average United States (US) early-stage lung cancer survivor, with meaningfully better scores (≥ 3 pts) in five of the seven health-related domains measured. We found no significant interactions between T-Scores and a survivor’s demographic or clinical characteristic, except for gender (p < .001). Most notably, we found a lack of interaction between PROMIS-29 T-Scores and treatment modality (p=.27). Most patients found the SOV helpful and expressed better understanding of their cancer treatment and side effects after the SOV. Conclusions: Our model of an optimized electronic medical record pathway paired with an APP led survivorship visit is feasible and can address current challenges in providing survivorship care to early-stage lung cancer survivors. Survivors had similar ePRO regardless of treatment modality, indicating their survivorship care could be consolidated. Future evaluation is needed to establish if this care model improves outcomes over subsequent visits, minimizes the effect of health disparities, or enhances care capacity.
Evidence supporting innovative cancer care delivery model for overcoming health disparity.
Authors: Pendharkar Dinesh , Tripathi Chandramauli , Srivastav Kalpana , Kumar Uttam , Nagar Ashok Kumar
Published: June 2023

e13521

Background: Disparity in cancer care is the biggest challenge faced by the health systems. The solution could be brought out by new models of service delivery. To mitigate the challenge, an innovative district cancer care model was launched across 6 states of India. A cancer care unit has been established in government district hospitals, which constitute pivot of health systems in all low- and middle-income countries of the world . It assists cancer patients in complete care continuum from diagnosis to end of life care. Here, we report how a district cancer care model (Pendharkar model) proved its validity during the covid pandemic, by providing relentless cancer care, when specialized cancer services were paralyzed in the country. Methods: Patient data were collected from four government district hospitals of Ujjain (Madhya Pradesh) Bhilwara, Jhalawar and Churu (Rajasthan), over three years, including period of Covid pandemic and lockdown. The numbers were analyzed for attendance in outpatient and inpatient services, numbers of chemotherapy sessions administered, from January 2019 to December 2021. Standard statistical calculations were done. Results: A total of 4873 new patients were registered in the cancer units (1614,1678,1581 per year), over the period of three years: 2019, 2020, 2021. Annually, there were 695,643 and 609, new patients registered in the Ujjain district, 190,252 and 204 in Churu, 349. 276.and 276 in Jhalawar, and 380,507 and 442 in Bhilwara. Over a three-year period, there were 37183 outpatient visits in total (11416, 13665, and 12102 in 2019, 2020, and 2021 respectively). The number of inpatient admissions were 18593 (5047,7077,6469 respectively). A total of 17639 sessions of chemotherapy were performed during this period (5133,6361,8745 in 2019, 2020, and 2021 respectively). The data showed no change despite pandemic lockdown. Conclusions: Utilization of outpatient and inpatient services, as well procedures rendered, did not change despite covid and lockdown in caner units of government district hospitals. The data clearly demonstrates the robustness and resilience of this health care model of system strengthening, using alternate oncology workforce, task sharing and capacity building. It worked equally efficiently in different parts of India and maintained its effectiveness even during pandemic, when complete collapse of healthcare was noticed around the world. The oncology societies and international organizations could take more interest in analyzing and improving this delivery model, which has immense capability of reducing health disparities.[Table: see text]