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Nomilin Targets PI3K/Akt Pathway in TNBC

KEY TAKEAWAYS

  • The study aimed to explore how nomilin combats TNBC and to uncover its molecular mechanisms.
  • The results showed that nomilin inhibits TNBC progression by targeting core proteins in the PI3K/Akt pathway.

Zhixuan Wu and their team aimed to investigate the therapeutic potential of nomilin, a limonoid compound, in treating triple-negative breast cancer (TNBC). Despite its known biological activities, nomilin’s effects on TNBC remain unclear. This study explored the mechanisms behind nomilin’s action to provide insights into potential treatments for TNBC.

Researchers applied weighted gene co-expression network analysis (WGCNA), differential expression analysis, and the GeneCards database to identify TNBC-related targets.

Additionally, they used Swiss Target Prediction, ChEMBL, and STITCH databases to identify nomilin’s potential targets.

They constructed a protein-protein interaction (PPI) network to identify core targets of nomilin against TNBC, followed by molecular docking, molecular dynamics simulations, and enrichment analyses to predict mechanisms. The results were verified through in vitro and in vivo experiments.

The results demonstrated that 17,204 TNBC targets were identified, while 301 potential targets were linked to nomilin. About 8 core targets—BCL2, Caspase3, CyclinD1, EGFR, HSP90AA1, KRAS, PARP1, and TNF—were identified from the PPI network.

Molecular docking revealed strong binding activity between nomilin and these proteins. Enrichment analysis indicated that nomilin’s effects are mediated through the PI3K/Akt pathway. Experimental results confirmed that nomilin inhibits TNBC cell proliferation, promotes apoptosis, and reduces migration.

The study concluded that nomilin targets key proteins in the PI3K/Akt pathway, suggesting its potential as a novel therapeutic agent for TNBC.

Funding was not applicable.

Source: https://pubmed.ncbi.nlm.nih.gov/39342122/

Wu Z, Xiang H, Wang X, et al. (2024). “Integrating network pharmacology, molecular docking and experimental verification to explore the therapeutic effect and potential mechanism of nomilin against triple-negative breast cancer.” Mol Med. 2024;30(1):166. Published 2024 Sep 28. doi:10.1186/s10020-024-00928-2

Low CD247 and CD4 Expression Predicts Poor TNBC Prognosis

KEY TAKEAWAYS

  • The study aimed to investigate the role of CD247 and CD4 expression in TNBC prognosis.
  • The results showed low CD247 and CD4 expression predicts poor outcomes in patients with TNBC.

Ankit Pateriya and the team aimed to evaluate the prognostic significance of CD247 and CD4 expression in triple-negative breast cancer (TNBC), an aggressive form of breast cancer with a poor prognosis. The tumor microenvironment of TNBC includes various cell types, such as tumor-infiltrating lymphocytes (TILs), which play a crucial role in cancer progression and resistance to chemotherapy.

Researchers used online computational tools to evaluate the prognostic significance of CD247 and CD4 expression in patients with TNBC. They analyzed the correlation between these markers and immune cell infiltration, including dendritic cells, B-cells, CD4+ cells, CD8+ cells, and neutrophils.

The results demonstrated that patients with TNBC having lower CD247 and CD4 expression had significantly shorter relapse-free survival and overall survival (OS) than those with higher expression levels. The expression of CD247 and CD4 showed a strong positive correlation with tumor-infiltrating dendritic cells, B-cells, CD4+, CD8+, and neutrophils.

The study concluded that low levels of CD247 and CD4 may impair immune cell infiltration in the tumor microenvironment, hindering cancer cell elimination and leading to poor patient outcomes. CD247 and CD4 could serve as useful biomarkers and potential therapeutic targets in TNBC.

No funding information was given.

Source: https://pubmed.ncbi.nlm.nih.gov/39342598/

Pateriya A, Nema R, Mishra AK, et al. (2024). “Decreased Expression of CD247 and CD4 Immune Marker Predicts Poor Prognosis in Triple Negative Breast Cancer.” Asian Pac J Cancer Prev. 2024;25(9):3187-3197. Published 2024 Sep 1. doi:10.31557/APJCP.2024.25.9.3187

Predicting pCR and Therapy Adjustments in Invasive BC

KEY TAKEAWAYS

  • The study aimed to explore if on-treatment biopsies could predict pCR and DFS in invasive BC.
  • The results showed that on-treatment biopsies can identify patients unlikely to achieve pCR, aiding therapy adjustments.

Patients who achieve a pathologic complete response (pCR) to neoadjuvant chemotherapy for invasive breast cancer (BC) tend to have better outcomes, including improved disease-free survival (DFS). Predicting early treatment response can be crucial in adapting therapies and reducing unnecessary surgical and systemic treatments.

On-treatment biopsies may provide an opportunity to assess treatment effectiveness before completion of therapy, especially in specific subtypes like triple-negative breast cancer (TNBC) and HER2-positive BC.

Bruno Valentin Sinn and the team aimed to investigate if on-treatment biopsies could predict pCR and assess their correlation with tumor-infiltrating lymphocytes (TILs), Ki-67 levels, and residual cancer presence.

The study involved 297 patients with invasive BC enrolled in 3 randomized, prospective neoadjuvant trials that were GeparQuattro, GeparQuinto, and GeparSixto. Participants had biopsies taken during treatment, and the amount of residual cancer, TILs, and the proliferation marker Ki-67 were compared to pre-treatment samples.

Researchers assessed the relationship between these factors and their impact on achieving pCR and DFS. Tumor subtypes included HR+/human epidermal growth factor receptor 2-negative (HER2-), TNBC, and HER2-positive.

Among the 297 samples, 138 (46%) were hormone receptor-positive (HR+)/human epidermal growth factor 2-negative (HER2-), 87 (29%) were TNBC, and 72 (24%) were HER2-positive.

Invasive tumor cells were detected in 70% of on-treatment biopsies, with varying rates across subtypes (HR+/HER2-: 84%, TNBC: 62%, HER2+: 51%; P< 0.001). Patients with residual tumor during treatment had an 8% pCR rate post-treatment (HR+/HER2-: 3%, TNBC: 19%, HER2+: 11%), while those without any invasive tumor achieved a 50% pCR rate (HR+/HER2-: 27%; TNBC: 48%, HER2+: 66%).

The sensitivity for predicting residual disease was 0.81, with positive and negative predictive values of 0.92 and 0.50, respectively. Increasing TILs from baseline to on-treatment biopsy (if residual tumor was present) were associated with a higher likelihood of achieving pCR in the overall cohort (OR 1.034, 95% CI 1.013-1.056 per % increase; P= 0.001) and a longer DFS in TNBC (HR 0.980, 95% CI 0.963-0.997 per % increase; P= 0.026). Persisting or increased Ki-67 levels were linked to a lower probability of pCR in the overall cohort (OR 0.957, 95% CI 0.928-0.986; P= 0.004) and shorter DFS in TNBC (HR 1.023, 95% CI 1.001-1.047; P= 0.04).

The study concluded that on-treatment biopsies can help predict patients unlikely to achieve pCR, which could enable therapy adjustments for TNBC and HER2-positive BC.

These biopsies may also offer insights into mechanisms of treatment resistance. Future research should focus on refining the accuracy of on-treatment biopsy procedures and expanding their use in clinical practice.

Open Access funding enabled and organized by Projekt DEAL. This analysis was funded by GBG. The GeparQuattro trial received funding support from Roche and Sanofi-Aventis, GlaxoSmithKline, Novartis, Roche, Sanofi Aventis, and Cephalon.

Source: https://pubmed.ncbi.nlm.nih.gov/39317942/

Sinn BV, Sychra K, Untch M, et al. (2024). “On-treatment biopsies to predict response to neoadjuvant chemotherapy for breast cancer.” Breast Cancer Res. 2024;26(1):138. Published 2024 Sep 24. doi:10.1186/s13058-024-01883-w

Efficacy of Multi-Peptide T Cells in TNBC Treatment

Efficacy of Multi-Peptide T Cells in TNBC Treatment

KEY TAKEAWAYS

  • The study aimed to evaluate the effectiveness of multi-peptide pulsing to generate T cells targeting TNBC.
  • The results showed that multi-peptide-pulsed T cells effectively kill TNBC cells through cytotoxic mechanisms.

Triple-negative breast cancer (TNBC) is characterized by its aggressiveness and limited treatment options, making it a significant challenge for patients.

Suyanee Thongchot and the team aimed to investigate the potential of adoptive cell transfer, which involves generating antigen-specific T cells from peripheral blood mononuclear cells (PBMCs). The overexpression of mesothelin (MSLN) and nucleolin (NCL) in TNBC highlights their viability as targets for T cell therapy.

The study confirmed the expression of MSLN and NCL in patient samples of TNBC through immunohistochemistry. They synthesized MSLN and NCL peptides, which were combined and administered to activate PBMCs from healthy donors. The cancer-killing ability of the resulting T cells was assessed using crystal violet staining, while their subtypes and cytokine production were characterized using flow cytometry and cytokine bead array.

The results demonstrated that 85.3% (127/149) of TNBC cases were positive for either MSLN or NCL, or both, with single positivity rates of 14.1% for MSLN and 28.9% for NCL. MSLN and NCL peptides, which showed high binding affinity for HLA-A*02, were combined and introduced to activated PBMCs from healthy donors.

The co-pulsed PBMCs significantly increased the production of TEM and TEMRA CD3+/CD8+ T cells and IFN-γ compared to single-peptide pulsed or unpulsed conditions. Importantly, MSLN/NCL-specific T cells induced cell death in MSLN+/NCL+ MDA-MB-231 cells, releasing critical cytotoxic factors such as perforin, granzymes A and B, Fas ligand, IFN-γ, and granulysin.

The study concluded that using multiple immunogenic peptides represents a promising therapeutic strategy for treating patients with TNBC.

Open access funding provided by Mahidol University. The current study was supported by the Siriraj Research Fund, Faculty of Medicine Siriraj Hospital, Mahidol University (R016334002 and R016737004).

Source: https://pubmed.ncbi.nlm.nih.gov/39294656/

Thongchot S, Aksonnam K, Prasopsiri J, et al. (2024). “Mesothelin- and nucleolin-specific T cells from combined short peptides effectively kill triple-negative breast cancer cells.” BMC Med. 2024;22(1):400. Published 2024 Sep 18. doi:10.1186/s12916-024-03625-3

Improved OS with Neoadjuvant Pembrolizumab in Early TNBC

KEY TAKEAWAYS

  • The KEYNOTE-522 phase 3 trial aimed to investigate the OS benefit of adding pembrolizumab to chemotherapy in patients with high-risk early-stage TNBC.
  • The primary endpoints were pCR & EFS and the secondary endpoint was OS.
  • Researchers observed a significant OS improvement with pembrolizumab plus chemotherapy in high-risk early-stage TNBC.

KEYNOTE-522 (NCT03036488) demonstrated statistically significant and clinically meaningful improvements in pathologic complete response (pCR) and event-free survival (EFS) with the addition of pembrolizumab to chemotherapy in patients with early-stage triple-negative breast cancer (TNBC). The study focused on assessing the long-term impact of this treatment combination.

Peter Schmid and the team aimed to assess the final overall survival (OS) results to further evaluate the benefits of pembrolizumab in this high-risk population.

They performed an inclusive analysis on eligible patients with previously untreated, non-metastatic, centrally confirmed TNBC at stage T1c N1-2 or T2-4 N0-2 according to AJCC criteria. Patients were randomized in a 2:1 ratio to receive either neoadjuvant pembrolizumab (200 mg Q3W) or placebo (pbo).

Both groups were treated with 4 cycles of paclitaxel and carboplatin, followed by 4 cycles of doxorubicin or epirubicin combined with cyclophosphamide. Following definitive surgery, patients received adjuvant pembrolizumab or pbo for up to 9 cycles or until recurrence or unacceptable toxicity occurred.

The study’s dual primary endpoints were (pCR; ypT0/Tis ypN0) and EFS, measured as the time from randomization to disease progression preventing definitive surgery, local or distant recurrence, second primary cancer, or death from any cause. OS was defined as the key secondary endpoint.

About 1174 patients were randomized to the pembrolizumab group (n=784) or the pbo group (n=390). The data cutoff (March 22, 2024), median follow-up duration was 75.1 months (range: 65.9-84.0 months). A total of 115 patients (14.7%) in the pembrolizumab group and 85 patients (21.8%) in the pbo group had died, with a hazard ratio (HR) of 0.66 (95% CI, 0.50-0.87; P=0.0015), meeting the prespecified significance boundary of 0.00503.

The 5-year OS rate (95% CI) was 86.6% (84.0-88.8) in the pembrolizumab group compared to 81.7% (77.5-85.2) in the pbo group. The benefit of pembrolizumab on OS was generally consistent across the prespecified subgroups, including those defined by PD-L1 expression and nodal status.

The 5-year EFS rate (95% CI) was 81.2% (78.3-83.8) for the pembrolizumab group versus 72.2% (67.4-76.4) for the pbo group (HR 0.65 [95% CI, 0.51-0.83]). Grade ≥3 treatment-related adverse event (TRAEs) rates were 77.1% in the pembrolizumab group and 73.3% in the pbo group, with a death incidence of 0.5% versus 0.3%, respectively. Immune-mediated AEs of any grade were reported in 35.0% of the pembrolizumab group compared to 13.1% in the pbo group.

The study concluded that neoadjuvant pembrolizumab combined with chemotherapy, followed by adjuvant pembrolizumab, resulted in a statistically significant and clinically meaningful improvement in OS compared with neoadjuvant chemotherapy alone in patients with high-risk early-stage TNBC.

The trial was sponsored by the Merck Sharp & Dohme LLC.

Source: https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/show/session/170

Clinical Trial: https://clinicaltrials.gov/study/NCT03036488

Schmid P, Cortés J, Dent R.A, et al. (2024). “Neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for high-risk early-stage TNBC: Overall survival results from the phase III KEYNOTE-522 study.” Presented at ESMO 2024 (Abstract LBA4).

T-DXd Combo Shows Promise in HER2+ GEJA Treatment

KEY TAKEAWAYS

  • The DG-03 phase 2 trial aimed to assess the efficacy and safety of T-DXd with FP, platinum, and anti-PD-1 in 1L HER2+ esophageal/gastric/GEJA.
  • The primary endpoints were to determine ORR, safety, and tolerability.
  • Researchers noticed T-DXd with FP and pembrolizumab showed promising efficacy in HER2+ esophageal/gastric/GEJA.

The study investigates trastuzumab deruxtecan (T-DXd), a HER2-directed antibody-drug conjugate, which is approved at a dose of 6.4 mg/kg for patients with metastatic HER2-positive (HER2+) gastric/gastroesophageal junction adenocarcinoma (GEJA) who have previously undergone trastuzumab-based treatment.

Recent advances in first-line (1L) treatment for HER2+ gastric/GEJA have demonstrated that combining dual PD-1 and HER2 blockade with fluoropyrimidine (FP; 5-fluorouracil or capecitabine) and platinum-based regimens yields improved outcomes compared to traditional chemotherapy and trastuzumab.

Yelena Y. Janjigian and the team aimed to explore the efficacy of T-DXd in combination with FP and an anti-PD-1 agent in the 1L setting for esophageal/gastric/GEJA.

They performed an inclusive analysis of patients enrolled in DG-03 Part 2 (NCT04379596), who had 1L HER2+ esophageal, gastric, or gastroesophageal junction adenocarcinoma. Patients were globally enrolled, regardless of PD-L1 status and were randomized to receive standard of care, T-DXd monotherapy, or T-DXd-based combinations, with randomization except for arm F.

The study stratified patients by HER2 status. The primary endpoint was an investigator-assessed confirmed objective response rate (ORR) per RECIST 1.1, with safety and tolerability also evaluated.

About 307 patients were enrolled, with 229 receiving treatment. Baseline and disease characteristics were not balanced across arms. Combining T-DXd with FP/pembrolizumab (pembro) 200 mg demonstrated durable clinical benefit in patients with HER2+ central PD-L1 CPS ≥1 esophageal/gastric/GEJA.

Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis occurred in 21 (11%) T-DXd-treated patients (arm B [6.4 mg/kg], n=4; arm C [6.4 mg/kg + FP], n=4; arm D [6.4 mg/kg + FP + pembro], n=8; arm E [6.4 mg/kg + pembro], n=5), with 3 deaths (arm D, n=2; arm E, n=1).

The study concluded that the combination of T-DXd + FP + pembro showed promising antitumor activity in esophageal/gastric/GEJA, warranting further investigation. Although tolerability was lower with T-DXd 6.4 mg/kg + FP + pembro, the overall safety profile was manageable.

The trial was sponsored by the AstraZeneca.

Source: https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/show/session/43

Clinical Trial: https://clinicaltrials.gov/study/NCT04379596

Janjigian Y.Y, Van Laarhoven H.W, Young Rha S, et al. (2024). “Trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients (pts) with advanced/metastatic HER2-positive (HER2+) esophageal, gastric or gastroesophageal junction adenocarcinoma (GEJA): DESTINY-Gastric03 (DG-03).” Presented at ESMO 2024 (Abstract 1401O).

Efficacy and Safety of T-DXd in HER2+ mBC ± BM

KEY TAKEAWAYS

  • The DESTINY-B12 phase III trial aimed to evaluate T-DXd efficacy in HER2-positive mBC ± BM.
  • The primary endpoints were to determine PFS and ORR.
  • T-DXd showed significant and durable clinical activity in patients with HER2+ mBC and ± BM.

Intracranial activity of trastuzumab deruxtecan (T-DXd) has been noted in small or retrospective patient cohorts with HER2-positive metastatic breast cancer (mBC) and brain metastases (BM), either stable or active (untreated/treated and progressing).

Nancy Lin and the team aimed to provide the most extensive prospective evaluation of T-DXd efficacy in patients with HER2-positive mBC and BM.

They performed an inclusive analysis on adults with HER2+ mBC who experienced progression on ≤2 prior lines of therapy in the metastatic setting. Patients were enrolled into either a BM cohort, which included those with stable or active (untreated/treated progressing) BM not requiring immediate local therapy or a non-BM cohort. Patients in the BM cohort were allowed to use dexamethasone (≤3 mg daily) or an equivalent for symptom control.

The study design did not permit cross-cohort comparison. Patients received T-DXd at a dose of 5.4 mg/kg intravenously every 3 weeks. The primary endpoints were progression-free survival (PFS) in the BM cohort and objective response rate (ORR) in the non-BM cohort, assessed per RECIST 1.1 by an independent central review.

Additional endpoints included CNS PFS, CNS ORR, ORR (BM cohort), and safety. Interstitial lung disease (ILD) and pneumonitis were reported by investigators, with no adjudication committee involved.

A total of 504 patients were treated (263 in the BM cohort and 241 in the non-BM cohort). A median follow-up of 15.4 (range: 0.1-30.0) months was observed for the BM cohort and 16.1 (0.8-28.4) months for the non-BM cohort.

The 12-month PFS for the BM cohort was 61.6% (95% CI: 54.9-67.6), and CNS PFS was 58.9% (95% CI: 51.9-65.3). This was similar in patients with stable (57.8% 95% CI 48.2, 66.1) and active (60.1% 95% CI 49.2, 69.4) BM. CNS ORR was 79.2% (95% CI: 70.2-88.3) in patients with stable BM and 62.3% (95% CI: 50.1-74.5) in patients with active BM.

Pneumonitis/ILD occurred in 16.0% of patients (n=42) with BM and 12.9% (n=31) among non-BM cohorts. Of these 5 ILD/pneumonitis events were reported as co-occurring with opportunistic infection (1.9% BM cohort).

The study concluded that T-DXd demonstrated significant and lasting overall and intracranial clinical activity in patients with HER2+ mBC, including those with stable or active BM, with no new safety concerns observed.

The trial was supported by AstraZeneca and Daiichi Sankyo.

Source: https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/show/session/23

Clinical Trial: https://clinicaltrials.gov/study/NCT04739761

Lin N, Ciruelos EM, Jerusalem G, et al. (2024). “Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2+ advanced/metastatic breast cancer (mBC) with or without brain metastases (BM): DESTINYBreast-12 primary results.” Presented at ESMO-2024 (Abstract LBA18).

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