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Exploring Pembro vs. Placebo for Aggressive Breast Cancer
Breast Cancer

Impact of COVID-19 on BC Treatment Delays: PHIRI Study

KEY TAKEAWAYS The PHIRI study aimed to investigate the changes in the time to 1 treatment for patients with BC during the COVID-19 pandemic. Researchers noticed that delays in Aragon and Wales were significant but not clinically relevant, suggesting structural...

Jul 2, 2024

Alveoli in Lungs Tiny Air Spaces
Lung Cancer

L-Theanine Enhances DDP Chemoresistance in Lung Cancer

KEY TAKEAWAYS The study aimed to assess the effects of L-Theanine over chemoresistance in patients with lung cancer. L-Theanine improves DDP chemoresistance by regulating STAT3/NOTCH1/BMAL1, reducing stemness, and inhibiting migration. L-Theanine- an amino acid...

Jul 2, 2024

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Neddylation Suppression Improves PTX Sensitivity in TNBC

KEY TAKEAWAYS

  • The study aimed to assess the differential expression of UBC12 and NEDD8 among PTX-sensitive and PTX-insensitive TNBC tissues.
  • The neddylation downregulation with PTX treatment demonstrated enhanced tumor suppression in TNBC.

In the poor prognosis of triple-negative breast cancer (TNBC), Paclitaxel (PTX) treatment resistance is a considerable factor. There is a need to identify new targets for designing therapeutic combinations for the treatment. Neddylation is a post-translational process that introduces a ubiquitin-like protein called neural precursor cell expressed developmentally downregulated protein 8 (NEDD8).

Past studies have established that neddylation is activated in various tumor conditions but its association with PTX chemotherapy sensitivity has yet to be reported.

Bowen Zheng and the team investigated the differences in UBC12 and NEDD8 expression levels between PTX-sensitive and PTX-insensitive TNBC.

Researchers conducted a differential expression analysis, to confirm variations in UBC12 and NEDD8 expression levels among PTX-sensitive and PTX-insensitive TNBC tissues samples, that were further validated through public databases and immunohistochemistry.

In vitro and in vivo functional experiments were employed to assess the impact of neddylation inhibition combined with PTX therapy on tumor progression. Molecular mechanisms were investigated using Co-IP, western blot, and PCR assays.

Molecular docking simulated the protein binding interactions of UBC12 with tripartite motif containing 25 (TRIM25), while molecular dynamics (MD) simulations observed changes in TRIM25 protein conformation.

Results revealed that in PTX-insensitive TNBC samples, there was an increased expression of NEDD8 and its conjugating enzyme UBC12. Treatment with the NEDD8-activating enzyme (NAE) inhibitor mln4924 or knockdown of UBC12 significantly increased tumor sensitivity to PTX. This increased sensitivity was linked to UBC12-mediated activation of autophagy. Mechanistically, UBC12 transfers NEDD8 to the E3 ubiquitin ligase TRIM25 at K117.

MD simulations indicated that neddylation modification of TRIM25 alleviates steric hindrance in its RING domain, facilitating TRIM25’s binding to ubiquitylated substrates.

Subsequently, TRIM25 promotes nuclear translocation of transcription factor EB (TFEB) and transcription of autophagy-related genes through increased K63-polyubiquitination of TFEB, thereby reducing tumor sensitivity to PTX.

The study concluded that neddylation is enhanced in PTX-insensitive TNBC. In particular, autophagy gene transcriptional activation mediated by the UBC12/TRIM25/TFEB axis reduced TNBC sensitivity to PTX. Downregulation of neddylation in combination with PTX treatment showed a synergistic effect in tumor suppression.

The study was supported by grants from the National Natural Science Foundation of China (no. 82073204), the Shanghai Municipal Health Commission (no. 202040157), and the Shanghai Tenth People’s Hospital (No. YNCR2B008).

Source: https://pubmed.ncbi.nlm.nih.gov/38926803/

Zheng B., Qian F., Wang X., et al. (2024). “Neddylation activated TRIM25 desensitizes triple-negative breast cancer to paclitaxel via TFEB-mediated autophagy.” J Exp Clin Cancer Res. 2024 Jun 26;43(1):177. doi: 10.1186/s13046-024-03085-w. PMID: 38926803.

SNPs Contribute to Palpitations in BC Before Surgery

KEY TAKEAWAYS

  • The study aimed to identify associations between palpitations in women with BC before surgery and SNPs in neurotransmitter genes.
  • The alterations in the neurotransmitter levels were contributing to palpitations.

Ying Sheng and the team aimed to identify associations between the palpitations encountered by women before breast cancer (BC) surgery and single nucleotide polymorphisms (SNPs) for neurotransmitter genes.

Researchers enrolled 398 women, scheduled for unilateral BC surgery, and provided detailed information on demographic and clinical characteristics and the occurrence of palpitations before BC surgery.

They evaluated the palpitation using a single item: “heart races/pounds” in the past week, answered with “yes” or “no.” Blood samples were collected for genomic analyses. Multiple logistic regression analyses were conducted to identify associations between the occurrence of palpitations and variations in neurotransmitter genes.

The results revealed that 9 SNPs and 2 haplotypes within 11 candidate genes demonstrated associations with the encounter of palpitations in women with BC. These genes encode various neurotransmitters and/or their receptors, such as serotonin, norepinephrine, dopamine, gamma-aminobutyric acid (GABA), Substance P, and neurokinin.

The study concluded that alterations in a variety of neurotransmitter-encoding genes contributed to the development of palpitations.

The funding information was not provided.

Source: https://pubmed.ncbi.nlm.nih.gov/38950091/

Sheng Y., Conley Y.P., Paul S.M., et al. (2024). “Palpitations in Women With Breast Cancer Are Associated With Polymorphisms for Neurotransmitter Genes.” Oncol Nurs Forum. 2024 Jun 14;51(4):332-348. doi: 10.1188/24.ONF.332-348. PMID: 38950091.

BUB1: Novel Target for Radiosensitization in TNBC

KEY TAKEAWAYS

  • The study aimed to elucidates BUB1’s role in TNBC radioresistance, proposing a novel strategy to enhance TNBC treatment efficacy.
  • The results indicated BUB1 ablation sensitizes TNBC to radiotherapy, suggesting it as a novel molecular target for treatment.

Triple-negative breast cancer (TNBC), a highly aggressive subtype often treated with radiotherapy (RT), lacks effective targets, necessitating the identification of novel molecular targets to enhance RT efficacy.

Sushmitha Sriramulu and the team aimed to elucidate the involvement of BUB1 (a cell cycle Ser/Thr kinase) in TNBC radioresistance and proposes a novel treatment strategy for TNBC enhancement.

Gene expression analysis compared TNBC patient samples to other subtypes. Cell proliferation and clonogenic survival assays determined BUB1 inhibitor (BAY1816032) IC50 and radiation enhancement ratio (rER) with pharmacological and genomic BUB1 inhibition.

Mammary fat pad xenograft experiments were conducted in CB17/SCID mice. Mechanistic insights into how BUB1 inhibitor sensitizes TNBC cells to radiotherapy were obtained through γ-H2AX foci assays, BLRR, Immunoblotting, qPCR, CHX chase, and cell fractionation assays.

The results revealed that BUB1 is overexpressed in breast cancer, particularly in TNBC, where its elevated expression correlates with poor survival outcomes. Pharmacological or genomic ablation of BUB1 sensitized multiple TNBC cell lines to radiation-induced cell killing, while breast epithelial cells showed no radiosensitization with BUB1 inhibition. The kinase function of BUB1 primarily accounted for this radiosensitization phenotype.

Moreover, BUB1 ablation led to radiosensitization in TNBC tumor xenografts, significantly delaying tumor growth and improving overall survival. Mechanistically, BUB1 ablation inhibited the repair of radiation-induced DNA double-strand breaks (DSBs). Furthermore, BUB1 ablation stabilized phospho-DNAPKcs (S2056) following radiation, while pre-treatment with BUB1 inhibitor prevented this stabilization (t1/2, ~8 h).

Nuclear and chromatin-enriched fractionations revealed an increase in recruitment of phospho- and total-DNAPK, and KAP1 to chromatin, indicating BUB1’s crucial role in the activation and recruitment of non-homologous end joining (NHEJ) proteins to DSBs. Additionally, BUB1 staining of TNBC tissue microarrays demonstrated a significant correlation of BUB1 protein expression with tumor grade.

The study concluded that BUB1 ablation enhances the sensitivity of TNBC cell lines and xenografts to radiotherapy. Additionally, it suggests that BUB1-mediated radiosensitization may occur through non-homologous end NHEJ. These findings collectively underscore BUB1 as a promising molecular target for radiosensitization in women with TNBC.

This work was supported by the NCI R21, HFHS Research Administration Start up, HFHS Proposal Development Award, HFHS-Radiation Oncology Start Up, and Game on Cancer award to SN.

Source: https://pubmed.ncbi.nlm.nih.gov/38863037/

Sriramulu S, Thoidingjam S, Chen WM, et al. (2024). “BUB1 regulates non-homologous end joining pathway to mediate radioresistance in triple-negative breast cancer.” J Exp Clin Cancer Res. 2024 Jun 11;43(1):163. doi: 10.1186/s13046-024-03086-9. PMID: 38863037.

Avelumab Improves Survival in High-Risk TNBC: A-Brave

Avelumab Improves Survival in High-Risk TNBC: A-Brave

KEY TAKEAWAYS

  • The A-Brave phase 3 trial aimed to investigate the efficacy of avelumab as an adjuvant treatment for high-risk early TNBC.
  • The Co-primary endpoint was to determine DFS, and the secondary endpoint was OS.
  • Researchers noticed that Avelumab shows improved OS in high-risk TNBC; further investigation is ongoing.

Prognosis of patients with early triple-negative breast cancer (TNBC), characterized by its poor outcomes, necessitates the exploration of novel therapies. TNBC’s high immunogenicity suggests potential sensitivity to immune checkpoint inhibitors. The A-BRAVE trial was initiated to evaluate avelumab, an anti-PD-L1 antibody, as adjuvant therapy for patients with early TNBC at high risk.

Pier Franco Conte and the team aimed to assess the efficacy of avelumab in this context.

They performed an inclusive analysis for a phase III, multicentric, randomized adjuvant study comparing 1 year of treatment with the anti-PD-L1 avelumab versus observation for patients with TNBC considered at high risk of relapse.

Patients were enrolled following completion of standard curative-intent treatment, including surgery and neoadjuvant/adjuvant chemotherapy. High risk was defined as invasive residual disease after neoadjuvant chemotherapy (Stratum A), 2) >pN2/any pT, pN1/pT2, or pN0/pT3 after primary surgery (Stratum B).

Patients were randomly assigned (1:1, balanced for strata A and B) to receive Avelumab 10 mg/kg I.V. every 2 weeks for 1 year or observation. Co-primary endpoints were disease-free survival (DFS) in the total population and Stratum A. The study aimed to detect an improvement in the 3-year DFS rate (HR 0.6; 90% power, 1-sided test, alfa 2%) from 60% to 73.6% with 474 patients, with 172 DFS events required for event-driven analysis. Overall survival (OS) was a secondary endpoint.

From June 2016 to October 2020, 477 patients were randomly assigned from 64 Italian and 6 UK centers. After that, about 11 patients (3 receiving avelumab, 8 in the control group) withdrew consent immediately after randomization and were excluded from further analyses. Three hundred seventy-eight patients entered Stratum A (83%), with 99 (57 receiving avelumab, 42 in the control group) receiving additional chemotherapy after surgery prior to trial enrollment.

The study concluded that 1 year of adjuvant avelumab versus control did not significantly improve DFS in patients with high-risk TNBC. However, the secondary endpoint of OS was significantly improved with avelumab compared to the control. Results for relapse-free survival (RFS) and distant metastasis-free survival (DMFS) will also be reported. Additionally, a centralized collection of tumor tissue, plasma, and feces has been conducted, enabling various correlative studies.

The study was sponsored by the Istituto Oncologico Veneto IRCCS.

Source: https://meetings.asco.org/abstracts-presentations/232429

Clinical Trial: https://clinicaltrials.gov/study/NCT02926196

Conte P F, Dieci M V, Bisagni G. et al. (2024). “A-BRAVE trial: A phase III randomized trial with avelumab in early triple-negative breast cancer with residual disease after neoadjuvant chemotherapy or at high risk after primary surgery and adjuvant chemotherapy.” Presented at ASCO 2024. J Clin Oncol 42, 2024 (suppl 17; abstr LBA500), 10.1200/JCO.2024.42.17_suppl.LBA500

ZNF680-Driven REG3A: A Novel Breast Cancer Target

KEY TAKEAWAYS

  • The study aimed to explore REG3A’s expression and functions in TNBC, identifying potential new targets.
  • The results revealed that ZNF680-triggered REG3A overexpression promotes breast cancer tumorigenesis via Akt-mTOR activation, suggesting a promising therapeutic target.

In the quest to uncover fresh targets for triple-negative breast cancer (TNBC), thorough scrutiny has been directed towards REG3A (regenerating islet-derived protein 3 A), a lectin protein reliant on calcium. Its expression and roles in breast cancer have been extensively examined.

Xiaoxia Jin and the team aimed to investigate REG3A expression and functions in TNBC to identify potential therapeutic targets.

Bioinformatics and local tissue analyses were used to detect REG3A expression in breast cancer. Researchers employed genetic techniques to modify REG3A expression and observed its effects on breast cancer cell behavior. Subcutaneous xenograft models were established to explore REG3A’s role in breast cancer cell growth in vivo.

The results revealed elevated REG3A levels in human breast cancer tissues, as uncovered by analysis of the TCGA database. Furthermore, both REG3A mRNA and protein levels were heightened in locally treated TNBC tissues compared to adjacent normal tissues.

In primary human TNBC cells, REG3A knockdown significantly impeded cell proliferation, migration, and invasion while promoting caspase-mediated apoptosis. Similarly, utilizing CRISPR-sgRNA for REG3A knockout demonstrated notable anti-TNBC cell activity.

Conversely, REG3A overexpression enhanced cell proliferation and migration. REG3A was found to be crucial for activating the Akt-mTOR cascade, evidenced by reduced Akt-S6K1 phosphorylation upon REG3A silencing or knockout, which was reversed by REG3A overexpression.

A constitutively active mutant S473D Akt1 (caAkt1) restored Akt-mTOR activation and counteracted the inhibition of proliferation and induction of apoptosis induced by REG3A knockdown in breast cancer cells. Additionally, REG3A played a pivotal role in maintaining mTOR complex integrity. Bioinformatics analysis identified zinc finger protein 680 (ZNF680) as a potential transcription factor for REG3A.

Knockdown or knockout of ZNF680 reduced REG3A expression, while its overexpression increased it in primary breast cancer cells. Enhanced binding between ZNF680 protein and the REG3A promoter was observed in breast cancer tissues and cells.

In vivo experiments demonstrated that REG3A knockdown significantly inhibited primary TNBC cell xenograft growth. Reduced REG3A levels, Akt-mTOR inhibition, and activated apoptosis were evident in REG3A-silenced xenograft tissues.

The study concluded that ZNF680-induced REG3A overexpression may contribute to breast cancer tumorigenesis by potentially stimulating Akt-mTOR activation, highlighting its promise as an innovative cancer target.

Funding was provided by the Science and Technology Project of NanTong.

Source: https://pubmed.ncbi.nlm.nih.gov/38840145/

Jin X, Yang S, Lu X, et al. (2024). “Increased expression of REG3A promotes tumorigenic behavior in triple negative breast cancer cells.” Breast Cancer Res. 2024 Jun 5;26(1):92. doi: 10.1186/s13058-024-01845-2. PMID: 38840145.

EV in Heavily Treated TNBC: Manageable Safety & Antitumor Activity

KEY TAKEAWAYS

  • The EV-202 phase 2 trial aimed to evaluate EV monotherapy in TNBC and HR+/HER2- BC, expanding its approved use beyond urothelial cancer.
  • The primary endpoint was confirmed ORR.
  • EV demonstrated antitumor activity in heavily treated TNBC, with manageable safety profiles consistent with prior reports.

The Nectin–4–directed antibody-drug conjugate enfortumab vedotin (EV) is approved for urothelial cancer treatment. It targets Nectin-4 expressed in various solid tumors, including breast cancer (BC).

Antonio Giordano and the team aimed to assess EV monotherapy in triple-negative breast cancer (TNBC) and HR+/HER2- BC, expanding its approved use beyond urothelial cancer.

In this open-label, multicohort, phase 2 trial, eligible adults with locally advanced or metastatic solid tumors, measurable disease, and ECOG PS 0–1 were enrolled. BC cohorts required prior taxanes or anthracyclines, ≥1 standard-of-care cytotoxic regimen, and ≤2 lines of cytotoxic therapy for locally advanced or metastatic breast cancer. Patients also had prior PD-1/L1 inhibitor (TNBC) or endocrine treatment with a CDK4/6 inhibitor (HR+/HER2- BC).

Nectin-4 expression was not mandatory but assessed retrospectively. Participants received EV 1.25 mg/kg intravenously on days 1, 8, and 15 of each 28-day cycle until meeting discontinuation criteria such as disease progression or unacceptable toxicity.

The primary endpoint was confirmed objective response rate (ORR), with ≥10 responders needed for TNBC and ≥12 for HR+/HER2- BC out of 40 evaluable patients to claim promising antitumor activity. Secondary endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety/tolerability. Investigator-assessed antitumor activity was evaluated per RECIST v1.1.

In the TNBC cohort, 42 female patients had received EV as of March 3, 2023, with a median follow-up of 11.8 months. Their median age was 53 years, 64% had undergone at least 2 lines of systemic treatment for metastatic BC, and 33% had prior sacituzumab govitecan therapy. ORR was 19.0%.

Grade ≥3 treatment-related adverse events (TRAEs) occurring in more than 1 patient included decreased neutrophil count (n=3, 7%), decreased white blood cell count (n=2, 5%), and increased aspartate aminotransferase (n=2, 5%). Selected TRAEs of special interest were skin reactions (n=25, 60%), peripheral neuropathy (n=11, 26%), and hyperglycemia (n=2, 5%). In the HR+/HER2- BC cohort (median age, 57.0 years), 45 female patients had received EV as of December 3, 2022, with a median follow-up of 11.2 months.

Most (73%) had undergone at least three lines of systemic treatment for metastatic breast cancer. The ORR was 15.6%. Grade ≥3 TRAEs occurring in more than one patient were maculopapular rash (n=7, 16%), pruritus and increased aspartate aminotransferase (both n=3, 7%), and abdominal pain and erythema (both n=2, 4%). Selected TRAEs of special interest were skin reactions (n=28, 62%), peripheral neuropathy (n=12, 27%), and hyperglycemia (n=5, 11%).

The study concluded that EV demonstrated antitumor activity in heavily pretreated TNBC, with safety profiles consistent with prior reports in both cohorts.

The trial was sponsored by Astellas Pharma Global Development, Inc.

Source: https://meetings.asco.org/abstracts-presentations/233643

Clinical Trial: https://clinicaltrials.gov/study/NCT04225117

Giordano A, Ali AA, Bruce JY, et al. (2024). “Enfortumab vedotin (EV) in triple-negative breast cancer (TNBC) and HR+/HER2- breast cancer (BC) cohorts of EV-202.” Presented at ASCO 2024, J Clin Oncol 42, 2024 (suppl 16; abstr 1005), DOI: 10.1200/JCO.2024.42.16_suppl.1005 (1005)

Predicting CD8+ TIL Levels in HER2+ BC Using US and MRI

KEY TAKEAWAYS

  • The study aimed to investigate the correlation between US and MRI features and CD8+-TIL levels in HER2+ BC.
  • Researchers noticed that US features and ADC values can estimate CD8+-TIL levels in HER2+ BC, aiding clinical decisions.

The level of tumor-infiltrating lymphocytes (TILs) in human epidermal growth factor receptor type 2 (HER2)-positive (+) breast cancer (BC) is positively correlated with pathological complete response.

Yuhong Fan and the team aimed to assess the correlation between these imaging features and CD8+-TIL levels to develop a reliable, non-invasive predictive tool.

They performed an inclusive analysis of 155 consecutive women with HER2+ BC in this retrospective study. Patients were divided into two groups based on CD8+-TIL levels: CD8+-TILlow (< 35%) and CD8+-TILhigh (≥ 35%). Ultrasound (US) and magnetic resonance imaging (MRI) features were evaluated using the BI-RADS lexicon, and the apparent diffusion coefficient (ADC) value was calculated with RadiAnt software.

Univariate and multivariate analyses identified the optimal US and MRI features for predicting CD8+-TIL levels. The diagnostic performance of US and MRI features was compared using receiver operating characteristic analysis and the Delong test. Additionally, the implementation of a nomogram was proposed to enhance clinical utility.

The univariate analysis of US features showed significant differences in shape, orientation, and posterior echo between the 2 groups; however, there were no significant differences in margins, internal echo, and microcalcification. Multifactorial analysis revealed that shape, orientation, and posterior echo were independent risk factors, with odds ratios of 11.62, 2.70, and 0.16, respectively.

In terms of MRI features, ADC was an independent predictor of CD8+-TIL levels. These 3 US features and the ADC performed well, with area under the curve (AUC) values of 0.802 and 0.705, respectively. The combination of US and ADC values had higher predictive efficacy (AUC = 0.888) than either US or ADC alone (P = 0.009, US_ADC vs. US; P < 0.001, US_ADC vs. ADC).

The study concluded that US features (shape, orientation, and posterior echo) and ADC value may be valuable tools for estimating CD8+-TIL levels in HER2+ BC. The nomogram developed from these imaging features could assist clinicians in making more informed treatment decisions.

This study was supported by the Innovation Ability Enhancement Project of Daping Hospital – Multimodal ultrasound in BI-RADS category 4 breast mass grading diagnosis and prognostic assessment of breast cancer and the Natural Science Foundation of Chongqing, China.

Source: https://pubmed.ncbi.nlm.nih.gov/38700366/

Fan Y, Li X, Zhong P, et al. (2024). “Radiological Features for Predicting the Status of CD8-Positive Lymphocytes in HER2 Positive Breast Cancer.” Balkan Med J. 2024 May 3;41(3):213-221. doi: 10.4274/balkanmedj.galenos.2024.2024-2-64. PMID: 38700366; PMCID: PMC11077930.

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