Comparison of <i>PIK3CA</i> Mutation Prevalence in Breast Cancer Across Predicted Ancestry Populations

Chen, Jessica W.; Murugesan, Karthikeyan; Newberg, Justin Y.; Sokol, Ethan S.; Savage, Heidi; Stout, Thomas J.; Maund, Sophia L.; Hutchinson, Katherine E.

doi:10.1200/po.22.00341

Cited by 4 publications

(1 citation statement)

References 73 publications

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“…Dysregulation of the PI3K/AKT/mTOR pathway is common in ER-dependent breast cancer, and activating mutations of PIK3CA , the catalytic subunit of class 1 PI3 Kinase, occur in 40% of these tumors 8 . The PI3K pathway enhances the proliferation, motility and invasiveness of these tumor cells and activation of the mTOR complex 1 (mTORC1) maintains high levels of eIF4E-dependent protein translation 9,10 11–14 .…”

Section: Introductionmentioning

confidence: 99%

eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer

Boyer,

Sharma,

Dorso

et al. 2024

Preprint

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The majority of human breast cancers are dependent on hormone stimulated estrogen receptor alpha (ER) and are sensitive to its inhibition. Treatment resistance arises in most advanced cancers due to genetic alterations that promote ligand independent activation of ER itself or ER target genes. Whereas re-targeting of the ER ligand binding domain (LBD) with newer ER antagonists can work in some cases, these drugs are largely ineffective in many genetic backgrounds including ER fusions that lose the LBD or in cancers that hyperactivate ER targets. By identifying the mechanism of ER translation, we herein present an alternative strategy to target ER and difficult to treat ER variants. We find that ER translation is cap independent and mTOR inhibitor insensitive, but dependent on 5'UTR elements and sensitive to pharmacologic inhibition of the translation initiation factor eIF4A, an mRNA helicase. EIF4A inhibition rapidly reduces expression of ER and short lived targets of ER such as cyclin D1 and other components of the cyclin D CDK complex in breast cancer cells. These effects translate into suppression of growth of a variety of ligand independent breast cancer models including those driven by ER fusion proteins that lack the ligand binding site. The efficacy of eIF4A inhibition is enhanced when it is combined with fulvestrant, an ER degrader. Concomitant inhibition of ER synthesis and induction of its degradation causes synergistic and durable inhibition of ER expression and tumor growth. The clinical importance of these findings is confirmed by results of an early clinical trial (NCT04092673) of the selective eIF4A inhibitor zotatifin in patients with estrogen receptor positive metastatic breast cancer. Multiple clinical responses have been observed on combination therapy including durable regressions. These data suggest that eIF4A inhibition could be a useful new strategy for treating advanced ER+ breast cancer.

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Section: Introductionmentioning

confidence: 99%

eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer

Boyer,

Sharma,

Dorso

et al. 2024

Preprint

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Disparities in Hormone Receptor-Positive Breast Cancer

Ogayo,

Mittendorf,

Kantor

2024

Curr Breast Cancer Rep

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Regional Variation in the Tumor Microenvironment, Immune Escape and Prognostic Factors in Breast Cancer in Sub-Saharan Africa

Bauer

Vetter

Stückrath

et al. 2023

Cancer Immunology Research

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The low overall survival rates of breast cancer (BC) patients in sub-Saharan Africa (SSA) are driven by regionally differing tumor biology, advanced tumor stages at diagnosis and limited access to therapy. However, it is not known whether regional differences in the composition of the tumor microenvironment (TME) exist and affect patients’ prognosis. In this international, multicentre cohort study, 1,237 formalin-fixed, paraffin-embedded BC samples, including samples of the ‘African Breast Cancer-Disparities in Outcomes (ABC-DO) Study’, were analyzed. The immune cell phenotypes, their spatial distribution in the TME and immune escape mechanisms of BC samples from SSA and Germany (n=117) were investigated using histomorphology, conventional and multiplex immunohistochemistry (IHC), and RNA expression analysis. The data revealed no regional differences in the number of tumor-infiltrating lymphocytes (TILs) in the 1,237 SSA BC samples, while the distribution of TILs in different BC IHC subtypes showed regional diversity, particularly when compared to German samples. Higher TIL densities were associated with better survival in the SSA cohort (n=400), but regional differences concerning the predictive value of TILs existed. High numbers of CD163+ macrophages and CD3+CD8+ T cells accompanied by reduced cytotoxicity, altered IL10 and IFNγ levels and downregulation of MHC class I components were predominantly detected in BC samples from Western SSA. Features of non-immunogenic BC phenotypes were associated with reduced patient survival (n=131). We therefore conclude that regional diversity in the distribution of BC subtypes, TME composition and immune escape mechanisms should be considered for therapy decisions in SSA and the design of personalized therapies.

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Comparison of PIK3CA Mutation Prevalence in Breast Cancer Across Predicted Ancestry Populations

Cited by 4 publications

References 73 publications

eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer

eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer

Disparities in Hormone Receptor-Positive Breast Cancer

Regional Variation in the Tumor Microenvironment, Immune Escape and Prognostic Factors in Breast Cancer in Sub-Saharan Africa

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