Emerging Mechanism of Action

Emerging Mechanisms of Action for Breast Cancer Treatment

Combination Immunotherapy Approaches

Recent preclinical data has guided the development of a tetratherapy approach for breast cancer treatment, particularly for HER2 breast cancer. This novel combination includes BN-Brachyury (a poxvirus vaccine), Bintrafusp alfa (a bifunctional anti-PD-L1 protein with TGFβ "trap"), Entinostat (a histone deacetylase inhibitor), and T-DM1 (ado-trastuzumab emtansine). This approach addresses challenges of breast tumors with low mutational burden, low PD-L1 expression, defective antigen processing/presentation, and an immunosuppressive tumor microenvironment.

The tetratherapy induces a robust immune response by expanding tumor antigen-specific effector T cells, natural killer cells, and immunostimulatory dendritic cells, while improving antigen presentation and decreasing inhibitory cytokines. A phase 1b clinical trial (NCT04296942) is currently evaluating this approach.

Antibody-Drug Conjugates (ADCs)

Antibody-drug conjugates represent a promising drug class with significant efficacy across all breast cancer subtypes. Trastuzumab emtansine (T-DM1) combines trastuzumab with the cytotoxic maytansine derivative DM1, showing effectiveness in breast cancer cell lines resistant to trastuzumab. ADCs targeting HER2 are approved for both HER2-positive and HER2-low expressing tumors. Novel targets in HER2-negative disease have expanded therapeutic capabilities, including Trop-2 targeted therapies for triple-negative breast cancer.

CDK4/6 Inhibition

CDK4/6 inhibitors are effective for treating advanced HR+/HER2- breast cancer. Research shows that palbociclib-sensitive cell types are also sensitive to Cyclin D1, CDK4, and CDK6 knockout/knockdown, whereas palbociclib-resistant lines are sensitive to Cyclin E1, CDK2, and SKP2 knockout/knockdown. Potential biomarkers include increased expression of CCND1 and RB1, and reduced expression of CCNE1 and CDKN2A.

A phase 1b study combining ribociclib (CDK4/6 inhibitor) with T-DM1 in advanced/metastatic HER2-positive breast cancer showed a median PFS of 10.4 months, demonstrating the potential of combination approaches.

Novel Targeted Approaches

Several novel targets are emerging: - CD44 receptor targeting with RG7356, a humanized antibody showing antitumor efficacy in CD44-expressing tumors - Tyrosine Kinase Inhibitors like lapatinib for HER2+ metastatic breast cancer - Oral taxanes as a new type of oral chemotherapy - ICY-5, a novel arylidene analogue targeting c-MET/STAT3-mediated mitochondrial apoptosis - RXR receptors and vitamin D receptors for ER-negative breast cancers - PARP inhibitors for breast cancers in BRCA-1 or -2 mutation carriers - Protein kinase C (PKC) signaling pathway - Cap43/NDRG1/Drg-1 (metastasis-suppressor gene) modulated by estrogen/anti-estrogens - Y-box binding protein-1 (YB-1) which plays a role in breast cancer malignancy through HER2-Akt-dependent pathways

Biomarker-Driven Approaches

Liquid biopsy analysis using the Plasma-SeqSensei (PQS) panel demonstrates strong sensitivity in detecting mutations for monitoring disease and treatment response in HR+/HER2- breast cancer patients. Among patients with disease progression on CDK4/6 inhibitors, PIK3CA mutations were common, highlighting the importance of molecular profiling for treatment selection.

Emerging End Points

Key Unmet Needs and Target Populations in Breast Cancer

Aggressive Subtypes with Limited Options

Triple-negative breast cancer (TNBC) remains a leading cause of cancer-associated deaths in women due to its highly metastatic potential and limited treatment options. Despite advances, TNBC presents significant challenges with median overall survival less than 18 months with standard chemotherapy for metastatic disease. These cancers are immunogenic but exhibit resistance to chemotherapy and have a poor prognosis.

Metaplastic carcinoma of breast (MCB), a rare histological subtype accounting for less than 1 percent of cases, has no specific treatment guidelines and poor prognosis. Similarly, metaplastic breast cancer (MPBC) is typically treated based on triple-negative breast cancer guidelines.

Treatment Resistance and Metastasis

The biggest challenges in breast cancer treatment are metastasis and drug resistance. Chemotherapy resistance remains a clinical problem, particularly with anthracyclines like doxorubicin. Cellular senescence has been observed in models of doxorubicin resistance, requiring novel combinations to eliminate senescent cells.

For HER2-positive breast cancer with leptomeningeal metastases (LM), which represents a turning point in prognosis and quality of life, more prospective studies on intrathecal trastuzumab treatment are needed. Despite therapeutic success of existing HER2-targeted therapies, tumors invariably relapse, requiring new strategies to overcome resistance.

Biomarker-Defined Populations

Patients with aberrant Tissue Factor (TF) expression have poor prognosis and low immune effector cell infiltration, characterizing as "cold tumor". TP53 mutations, mostly seen in triple-negative breast cancer, are linked to a more aggressive course and worse overall survival rates.

HER2-low disease is associated with worse systemic progression-free survival compared to HER2+ disease. Two FDA-approved companion diagnostic PD-L1 assays are available to identify TNBC patients eligible for immunotherapy, but other biomarkers of response are still being examined.

Personalized Treatment Approaches

Current breast cancer follow-up policies use a "one size fits all" approach that does not account for differences in subtypes, individual prognosis, and treatments received. There is a need to re-evaluate current breast cancer follow-up strategies based on recent advances in breast cancer treatments.

For small HER2-positive breast tumors (pT1a,b N0M0), there is limited evidence that adjuvant chemotherapy with or without trastuzumab is effective, suggesting these patients may benefit from tailored treatment decisions.

Emerging Therapeutic Targets

Research has identified potential therapeutic approaches including: * Blocking the interleukin-1/interleukin-1 receptor system and its signaling cascades * Targeting super-enhancers involved in the overactivation of oncogenes * Moderating transcript levels of NSMCE2 to improve patients' response to standard chemotherapy * Combination treatment with ABL allosteric inhibitors and EZH2 inhibitors for TNBC * Anti-TF antibodies to improve tumor immunoenvironment

There is a continued need for targeted drugs that are less toxic and more effective against breast cancer, particularly for ERBB2-positive breast cancer where current chemotherapy regimens are associated with considerable morbidity.