Targeting Immune-Related Biological Processes in Solid Tumors: We do Need Biomarkers

Pagni, Fabio; Guerini-Rocco, Elena; Schultheis, Anne M.; Grazia, Giulia; Rijavec, Erika; Ghidini, Michele; Lopez, Gianluca; Venetis, Konstantinos; Croci, Giorgio Alberto; Malapelle, Umberto; Fusco, Nicola

doi:10.3390/ijms20215452

Cited by 50 publications

(44 citation statements)

References 138 publications

(159 reference statements)

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“…Therefore, no companion diagnostic test came with FDA approval. Whether the predictive diagnostic algorithms should be histology-agnostic remains a matter of controversy [23]. In this respect, the loss of the MMR proteins is not necessarily linked to an underlying MMR deficiency in breast neoplasms [7,24].…”

Section: Discussionmentioning

confidence: 99%

PTEN Expression as a Complementary Biomarker for Mismatch Repair Testing in Breast Cancer

Lopez

Noale

Corti

et al. 2020

IJMS

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Mismatch repair (MMR) analysis in breast cancer may help to inform immunotherapy decisions but it lacks breast-specific guidelines. Unlike in other neoplasms, MMR protein loss shows intra-tumor heterogeneity and it is not mirrored by microsatellite instability in the breast. Additional biomarkers can improve MMR clinical testing. Phosphatase and tensin homolog (PTEN) inactivation is an early oncogenic event that is associated with MMR deficiency (dMMR) in several tumors. Here, we sought to characterize the diagnostic utility of PTEN expression analysis for MMR status assessment in breast cancer. A total of 608 breast cancers were profiled for their MMR and PTEN status. Proteins expression and distribution were analyzed by immunohistochemistry (IHC) on tissue microarrays and confirmed on full sections; PTEN copy number alterations were detected using a real-time PCR assay. Overall, 78 (12.8%) cases were MMR-heterogeneous (hMMR), while all patterns of PTEN expression showed no intra-tumor heterogeneity. Wild-type PTEN expression was observed in 15 (18.5%) dMMR tumors (p < 0.0001). Survival analyses revealed significant correlations between MMR-proficient (pMMR), PTEN expression, and a better outcome. The positive predictive value of PTEN-retained status for pMMR ranged from 94.6% in estrogen receptor (ER)+/HER2- tumors to 100% in HER2-amplified and ER-/HER2- cases. We propose a novel diagnostic algorithm where PTEN expression analysis can be employed to identify pMMR breast cancers.

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Section: Discussionmentioning

confidence: 99%

PTEN Expression as a Complementary Biomarker for Mismatch Repair Testing in Breast Cancer

Lopez

Noale

Corti

et al. 2020

IJMS

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“…The lymphatic system is composed of a complex network of vessels and organs complementary to the cardiovascular system (16). It plays a crucial role in several biological events, including immune response and homeostasis of interstitial fluids, cells, molecules, and tissue debris (17,18). At early stages of embryogenesis, the lymphatic vessels develop from the embryonic veins through the stepwise expression of numerous molecules, including prospero-related homeobox domain 1 (PROX1) and nuclear receptor subfamily 2, group F, member 2 (NR2F2) (17,19).…”

Section: Ontogenesis Of the Lymphatic Systemmentioning

confidence: 99%

Integrating Biological Advances Into the Clinical Management of Breast Cancer Related Lymphedema

et al. 2020

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Breast cancer-related lymphedema (BCRL) occurs in a significant number of breast cancer survivors as a consequence of the axillary lymphatics' impairment after therapy (mainly axillary surgery and irradiation). Despite the recent achievements in the clinical management of these patients, BCRL is often diagnosed at its occurrence. In most cases, it remains a progressive and irreversible condition, with dramatic consequences in terms of quality of life and on sanitary costs. There are still no validated pre-surgical strategies to identify individuals that harbor an increased risk of BCRL. However, clinical, therapeutic, and tumor-specific traits are recurrent in these patients. Over the past few years, many studies have unraveled the complexity of the molecular and transcriptional events leading to the lymphatic system ontogenesis. Additionally, molecular insights are coming from the study of the germline alterations involved at variable levels in BCRL models. Regrettably, there is a substantial lack of predictive biomarkers for BCRL, given that our knowledge of its molecular milieu remains extremely puzzled. The purposes of this review were (i) to outline the biology underpinning the ontogenesis of the lymphatic system; (ii) to assess the current state of knowledge of the molecular alterations that can be involved in BCRL pathogenesis and progression; (iii) to discuss the present and shortterm future perspectives in biomarker-based patients' risk stratification; and (iv) to provide practical information that can be employed to improve the quality of life of these patients.

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“…It is not surprising that dMMR GECs, in comparison to MMR wild-type cases, show higher tumor-infiltrating lymphocytes (TILs) and overexpression of immune checkpoint molecules, such as programmed death-ligand 1 (PD-L1) [20]. Of note, MSI-H and PD-L1 POS phenotype are major prognostic factors as well as predictive biomarkers for ICI efficacy in GEC [21][22][23]. Multiregion exome sequencing revealed > 20-fold levels of intratumor heterogeneity in dMMR GEC compared to other cancer types, and also long phylogenetic trunks [24].…”

Section: Clinicopathologic and Molecular Features Of Mmr-deficient Gamentioning

confidence: 99%

Mismatch Repair System Genomic Scars in Gastroesophageal Cancers: Biology and Clinical Testing

et al. 2020

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Alterations in the mismatch repair (MMR) system result in genomic instability, neoantigen production, and immune response in cancer. There is evidence that gastroesophageal tumors with MMR deficiency may be susceptible to immune-checkpoint inhibitors treatment, especially in those presenting at advanced-stage disease. Although a number of biomarkers have been developed in histology-agnostic settings to assess MMR status, there is evidence that a tumor-specific testing approach would improve the selection of patients for immunotherapy. However, no testing methods have been developed specifically for gastroesophageal cancers so far. Here, we discuss the state of the art, current advances, and future perspectives of MMR-related biomarkers’ biologic and clinical role in gastroesophageal cancers.

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Targeting Immune-Related Biological Processes in Solid Tumors: We do Need Biomarkers

Cited by 50 publications

References 138 publications

PTEN Expression as a Complementary Biomarker for Mismatch Repair Testing in Breast Cancer

PTEN Expression as a Complementary Biomarker for Mismatch Repair Testing in Breast Cancer

Integrating Biological Advances Into the Clinical Management of Breast Cancer Related Lymphedema

Mismatch Repair System Genomic Scars in Gastroesophageal Cancers: Biology and Clinical Testing

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