tbuckley/cabot-search huggingface dataset:
CENP-E inhibition induces chromosomal instability and synergizes with diverse microtubule-targeting agents in breast cancer
Authors: John B. Tucker, Caleb L. Carlsen, Christina M. Scribano, Srishrika M. Pattaswamy, Mark E. Burkard, Beth A. Weaver
Journal: Cancer Research (2024)

Abstract Drugs that perturb microtubules are commonly used to treat breast cancers of all subtypes in both early stage and metastatic disease, but they are effective in only approximately 50% of patients. High concentrations of microtubule-targeting agents can elicit mitotic arrest in cell culture models; however, recent evidence from primary and metastatic breast cancers has revealed that these agents only accumulate at intratumoral levels capable of inducing abnormal multipolar mitotic spindles, not mitotic arrest. Although the maintenance of multipolar spindles can generate cytotoxic rates of chromosomal instability (CIN), focusing of aberrant multipolar spindles into normal bipolar spindles can dramatically reduce CIN and confer resistance to microtubule poisons. Here, we showed that inhibition of the mitotic kinesin centromeric-associated protein-E (CENP-E) overcomes resistance caused by focusing multipolar spindles. Clinically relevant microtubule-targeting agents used a mechanistically conserved pathway to induce multipolar spindles without requiring centrosome amplification. Focusing could occur at any point in mitosis, with earlier focusing conferring greater resistance to antimicrotubule agents. CENP-E inhibition increased CIN on focused spindles by generating chromosomes that remained misaligned at spindle poles during anaphase, which substantially increased death in the resulting daughter cells. CENP-E inhibition synergized with diverse, clinically relevant microtubule poisons to potentiate cell death in cell lines and suppress tumor growth in orthotopic tumor models. These results suggest that primary resistance to microtubule-targeting drugs can be overcome by simultaneous inhibition of CENP-E. Significance: The increased incidence of polar chromosomes induced by inhibition of the mitotic kinesin CENP-E exacerbates chromosomal instability, reduces daughter cell viability, and improves sensitivity to microtubule-targeting therapies.
How overall survival is conditioned in the progression to treatment with cyclin inhibitors plus endocrine treatment in metastatic breast cancer with luminal phenotype.
Authors: ANA Prieto Garcia, Serafin Morales Murillo, Noemí Tuset Der-abrain, Gara Rodriguez Gonzalez, Ariadna Gasol Cudos
Journal: Journal of Clinical Oncology (2024)

e13079 Background: CDK4/6 inhibitors plus endocrinotherapy (ET) is the standard first-line treatment for metastatic breast cancer with a luminal phenotype. However, the response to this treatment is highly dependent on its previous efficacy. Methods: We analyzed the overall survival in a cohort of 127 patients with metastatic luminal breast cancer in progression after treatment with CDK4/6 inhibitors plus ET. Results: The median age of the group was 67 years (41-96), the interval time between initial diagnosis and first recurrence was 0 in 41 (32%), 1-60 months in 37 (29%) and more than 60 months in 39 (38%). The first line in the metastatic setting was CDK4/6 plus ET in 81 patients (64%), ET in 15 (12%) and 31 (24%) were treated with chemotherapy. The status of HER2 expression was HER2 low in 77% and 43 % had visceral metastases disease. The median progression-free survival for the patients treated with CDK4/6 inhibitors plus ET was 9 months, with a total of deaths of 69 (55%). Overall survival after progression on CDK4/6 plus ET was 38 months (28 – 47) and the most important factor for overall survival was the response time to treatment with CDK4/6 inhibitors plus ET. Conclusions: The most important factor for overall survival is the duration of treatment with CDK4/6 inhibitors plus ET. Patients with a response time of less than 6 months had a median overall survival after progression of 11 months (3 – 19), while the 6- to 12-month group had a median of 39 months (19 – 59) and the group with more than 12 months had the best prognosis with a median overall survival of 53 months (37 – 68). We need to improve the new treatment options for patients who respond for less than 6 months to treatment with CDK4/6 plus ET.
Activation of dendritic cells by a synthesized small molecule for breast cancer vaccination.
Authors: Yuxuan Wu, Yu-wen Yeh, Zou Xiang
Journal: Journal of Clinical Oncology (2024)

e13149 Background: Dendritic cell-based vaccination is a promising immunotherapy for treating various types of cancer. However, tumor-loaded dendritic cells alone have limited treatment efficacy. We have designed a small molecule mimicking the action of damage-associated molecular pattern molecules as an adjuvant for activating dendritic cells in vitro, which demonstrated augmented treatment efficacy. Methods: We aimed at exploring the roles of the synthesized small molecule in augmenting the efficacy of dendritic cell-based cancer vaccination to target triple negative breast cancer. Breast cancer mouse model is constructed using a 4T1 tumor cell line. Data were analyzed using a two-tailed unpaired t-test. Results: Mouse dendritic cells could be activated in vitro by the small molecule as an adjuvant evidenced by increased expression of MHC-I, MHC-II and CD40. Augmented motility of dendritic cells was also observed after treatment with the adjuvant. The signaling of NFkB is remarkably activated in dendritic cells by the adjuvant, which facilitates the maturation of dendritic cells. Engraftment of adjuvant-primed dendritic cells loaded with 4T1 tumor antigen into 4T1 tumor-bearing mice efficiently reduced the tumor size and improved survival, compared with the group treated with dendritic cells only. After injection of adjuvant-activated dendritic cells, both CD4 T cell and CD8 T cell populations were expanded in the spleen and lymph nodes draining the tumor sites. Furthermore, the adjuvant could promote the production of IFN-γ and IL-2, cytokines required for T cell activation and expansion. Next, splenocytes were obtained from individual mice after dendritic cell-based treatment. Upon re-encounter with the tumor antigen in vitro, remarkable expansion of T cell populations with a memory cell feature was confirmed in splenocytes derived from mice that received adjuvant-treated dendritic cells. Consistently, production of TNF-α, IFN-γ and granzyme B, was profoundly increased in these T cells associated with the adjuvant treatment. Conclusions: Our work suggests a novel dendritic cell-based cancer immunotherapy by using a small molecule mimicking the action of damage-associated molecular pattern molecules, which have documented immune potentiation activities.
Real-world outcomes of sacituzumab govitecan in breast cancer.
Authors: Vaishnavi Singh, Hemangini Dhaibar, Prakash Peddi
Journal: Journal of Clinical Oncology (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.
Efficacy and safety of abemaciclib in combination with endocrine therapy for HR+/HER2- advanced or metastatic breast cancer: A systematic review and meta-analysis.
Authors: Faryal Altaf, Zaheer Qureshi, Abdur Jamil, Rimsha Siddique, Eeshal Fatima
Journal: Journal of Clinical Oncology (2024)

e13096 Background: Breast cancer, particularly the HR+/HER2- subtype, remains a major global health concern. Abemaciclib, a CDK4/6 inhibitor, has shown promise in treating advanced cases. This study comprehensively assesses the efficacy and safety of Abemaciclib in combination with endocrine therapy for HR+/HER2- advanced or metastatic breast cancer. Methods: Following PRISMA guidelines, a systematic review and meta-analysis were conducted. A thorough literature search spanning PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov identified 22 studies. Inclusion criteria encompassed RCTs and retrospective cohort studies reporting on Abemaciclib in approved doses, either as monotherapy or in combination. Outcome assessments included PFS, ORR, SE/AE, and OS. Quality assessment utilized ROB II and NOS tools. Results: Analysis of 22 studies involving 14,010 patients revealed that Abemaciclib significantly improved PFS and ORR, with a 47% and 46% reduction in risk, respectively. A noteworthy 24% reduction in the risk of death was observed in the Fulvestrant combination group. However, Abemaciclib increased the risk of SE/AE by 104% and 304% in the Fulvestrant and NSAI combinations, respectively. Conclusions: Abemaciclib, particularly in combination with Fulvestrant, emerges as an effective therapeutic option for HR+/HER2- advanced or metastatic breast cancer, improving PFS and OS. The higher toxicity profile warrants cautious use, especially in treatment-naïve patients. This review informs future research directions and offers insights for clinical decision-making in the evolving landscape of breast cancer treatment.
Analysis of risk factors for recurrence within 12 months after surgery in patients with breast cancer receiving neoadjuvant therapy at a Brazilian cancer center.
Authors: Guilherme Rossato de Almeida, Marcelle Goldner Cesca, Débora Guilherme de Albuquerque e Rodrigues de Sousa, Flavia Cavalcanti Balint, Luciana de Moura Leite, Vladmir Cordeiro Lima, Solange Moraes Sanches, Monique Celeste Tavares
Journal: Journal of Clinical Oncology (2024)

e13039 Background: Early recurrence following treatment for localized breast cancer typically occurs within 5 years, and is commonly linked to high-risk clinicopathologic factors. However, literature focusing on risk factors for earlier recurrence timeframes is scarce, particularly within the neoadjuvant treatment population. Therefore, this study aims to investigate potential predictors for recurrence within 12 months post-surgery in breast cancer patients submitted to neoadjuvant therapy. Methods: This is an observational, descriptive, retrospective study involving 310 patients with recurrent breast cancer who received neoadjuvant therapy between January 2007 and March 2022, at AC Camargo Cancer Center in São Paulo, Brazil. Patients were compared based on relapse time after surgery (&lt;12 months or ≥12 months), and risk factors were analyzed using the Chi-Square test or Fisher’s Exact test. Results: From 310 patients analyzed, 108 relapsed within 12 months and 202 after this period. Factors predicting recurrence in less than 12 months included: Histologic grade (HG) III ( p &lt; 0.01); nuclear grade (NG) III ( p &lt; 0.001); mitotic counts &gt;20/mm2 ( p = 0.02); Ki67 &gt; 20% ( p = 0.010); triple negative breast cancer (TNBC) and HER2+/HR- subtypes ( p &lt; 0.001); interruption of neoadjuvant therapy due to disease progression or toxicity ( p &lt; 0.001); chemotherapy dose reduction or delay ( p = 0.001); omission of adjuvant radiotherapy ( p &lt; 0.001) and interruption of adjuvant HER2 targeted therapy ( p &lt; 0.001). Menopausal status, Residual Cancer Burden (RCB) index, type of surgery and clinical stage showed no significant correlation with the outcome. Conclusions: Recurrence in less than 12 months was associated with intrinsic factors, such as HG III, NG III, high mitotic counts, Ki67 &gt; 20%, TNBC, as well as interruption or delay of neoadjuvant therapy, omission of adjuvant radiotherapy and interruption or delay of HER2 targeted therapy, pointing out potential risk factors in this population.
Mechanisms of mammalian orthoreovirus-induced cell death and NF-kB activation in ER+ breast cancer.
Authors: Syrena Hilgendorf, Julie Ostrander, Natasha Roman Ortiz
Journal: Journal of Clinical Oncology (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.
Transcriptomic analysis of the tumor immune microenvironment (TIME) in patients with breast cancer with liver metastasis (BCLM).
Authors: Weihua Guo, Jiayi Tan, Bryan Chan, Cynthia Mark, Jin Sun Bitar, Shikha Bose, Vivek Pujara, Moray Campbell, Stephen Lawrence Shiao, Yuan Yuan
Journal: Journal of Clinical Oncology (2024)

e13045 Background: Breast cancer with liver metastasis (BCLM) is a significant predictor of worse prognosis and poor overall survival. Liver specific homing of breast cancer is not well understood, and the tumor immune microenvironment (TIME) likely plays a critical role in the process of forming BCLM. This retrospective study was conducted to determine the clinical risk factors and transcriptomic biomarkers associated with BCLM. Methods: A retrospective single institute chart review was conducted. Patient, disease characteristics and treatment variables were reviewed. Liver metastasis specific survival (defined by overall survival time from the diagnosis of liver metastasis) were compared across three breast subtypes (i.e., ER+/HER2-, HER2+, and triple-negative (TN) breast cancer) using Kaplan-Meier curves. Next generation sequencing (NGS) via commercial platforms were then used to obtain transcriptomic data. Transcriptomic analysis including differential gene expression analysis, gene set enrichment analysis (GSEA), as well as gene deconvolution analysis with TIMER2.0 were conducted for comparison of transcriptomic profiles and immune compositions across the three breast cancer subtypes. Results: 176 patients with BCLM and available liver metastasis biopsy were identified through retrospective chart review. Liver metastasis specific survival was compared, HER2+ BCLM patients (n = 17) had the best outcome and TN BCLM patients (n = 46) had the worst outcome with ER+ BCLM patients (n = 112) in the middle (p &lt; 0.0001, ER+ vs TNBC p &lt; 0.0001, ER+ vs HER2+ p = 0.038, HER2+ vs TNBC p = 0.00011). Principle component analysis on the transcriptomic data of 30 liver metastatic samples revealed different expression profiles between ER+ (n = 20) and TN (n = 7) BCLM, while HER2+ (n = 3) BCLM did not shown statistical differences with either group. B cell mediated immunity was upregulated in TN BCLM compared to ER+HER2- BCLM by GSEA (normalized enrichment score = 2.35, adjusted P-value = 0.19). Consistently, plasma cells were relatively enriched in TN BCLM compared to ER+ and HER2+ BCLM (p = 0.037) based on CIBERSORT estimation. In contrast, monocytes and neutrophils were enriched in ER+ BCLM (p = 0.0093 &amp; 0.018) based on TIMER2.0 estimation. Additional NGS analysis is currently underway for increased sample size. Conclusions: BCLM in TNBC was associated with significantly worse overall survival. TIME in TN BCLM enriched for genes associated with B cell mediated immunity while ER+ BCLM had more monocyte/neutrophil mediated immunity.
The long noncoding RNA MANCR to promote and stabilize triple negative breast cancer.
Authors: Janine Warren, Bodhisattwa Banerjee, Janet Stein, Gary Stein, Jane Lian
Journal: Journal of Clinical Oncology (2024)

e13150 Background: Cancer remains a leading cause of death worldwide, despite many advances in cancer treatment over the past decade. Triple Negative Breast Cancer (TNBC) is among the highest with a poor prognosis. Early diagnosis and modern treatment regimens for breast cancer (BC) have led to a high disease-free survival rate. Still, survival decreases significantly for patients with metastatic disease. Long non-coding RNAs are among a recent class of epigenetic regulators that function in the nucleus to support the stability of the cells and maintain the fidelity of chromatin interactions. Our laboratory discovered the long noncoding RNA MANCR (LINC00704) as being upregulated in human BC tumors and this is indicative of a worse survival rate than in patients with low MANCR-expressing tumors. MANCR is aberrantly expressed in TNBC cells, and these cells are highly dependent on MANCR to retain their tumorigenic characteristics. Methods: Our functional in vitro studies in MDA-MB-231 TNBC cells used GapmerRs to knockdown MANCR. For in vivo studies, TNBC cells were injected into the 4 th mammary fat pad of mice, allowed initial tumor formation, and then treated the animals with 2 nmol/g of a negative control or MANCR targeting GapmeR. We also identified genome interaction sites at single nucleotide resolution by chromatin isolation by RNA purification (ChIRP)-seq to determine the mechanism of MANCR activity in TNBC cells. Results: We found that MANCR knockdown promotes DNA damage and decreases cell proliferation, migration, anchorage-independent colony formation, transwell invasion, and overall survival. Additionally, targeting MANCR in animals with existing tumors drastically inhibited tumor growth and the end-point tumor mass over time. The MANCR GapmeR treatment also inhibited the ability of TNBC cells to circulate and disseminate to distant organs. After performing ChIRP-seq in the MDA-MB-231 cells, we identified 988 genome-wide binding sites that exhibit MANCR interactions, of which 79% are intergenic and 21% are genic regions. Furthermore, 127 MANCR ChIRP peaks were found to overlap with fragile sites in the genome, indicating MANCR provides stability to these sites. Conclusions: These data suggest that targeting MANCR has therapeutic potential for patients with “MANCR-high” TNBC tumors by disrupting genome stability. Indeed, our in vivo studies demonstrate that “MANCR-high” TNBC tumors require MANCR to rapidly grow and promote disease progression. Lastly, many of the MANCR-chromatin interactions identified were found in intergenic regions and overlap with fragile sites within the genome. Collectively these data strongly indicate that MANCR stabilizes the TNBC genome, and disrupting genome stability by targeting MANCR has therapeutic potential.