Tumor Infiltrating Lymphocytes across Breast Cancer Subtypes: Current Issues for Biomarker Assessment

Tumor-infiltrating lymphocytes (TILs) represent a surrogate biomarker of anti-tumor, lymphocyte-mediated immunity. In early, triple-negative breast cancer, TILs have level 1B of evidence to predict clinical outcomes. TILs represent a promising biomarker to select patients who can experience a better prognosis with de-intensified cancer treatments and derive larger benefits from immune checkpoint inhibitors. However, the assessment and the validation of TILs as a biomarker require a prospective and rigorous demonstration of its clinical validity and utility, provided reproducible analytical performance. With pending data about the prospective validation of TILs’ clinical validity to modulate treatments in early breast cancer, this review summarizes the most important current issues and future challenges related to the implementation of TILs assessments across all breast cancer subtypes and their potential integration into clinical practice

Tumor Infiltrating Lymphocytes across Breast Cancer Subtypes: Current Issues for Biomarker Assessment

Tumor-infiltrating lymphocytes (TILs) represent a surrogate biomarker of anti-tumor, lymphocyte-mediated immunity. In early, triple-negative breast cancer, TILs have level 1B of evidence to predict clinical outcomes. TILs represent a promising biomarker to select patients who can experience a better prognosis with de-intensified cancer treatments and derive larger benefits from immune checkpoint inhibitors. However, the assessment and the validation of TILs as a biomarker require a prospective and rigorous demonstration of its clinical validity and utility, provided reproducible analytical performance. With pending data about the prospective validation of TILs’ clinical validity to modulate treatments in early breast cancer, this review summarizes the most important current issues and future challenges related to the implementation of TILs assessments across all breast cancer subtypes and their potential integration into clinical practice

Future potential targets of antibody-drug conjugates in breast cancer

Metastatic breast cancer (BC) remains an incurable disease. Besides endocrine and targeted agents, chemotherapy is still a relevant therapeutic option for this disease. Recently, antibody-drug conjugates (ADCs) have shown to overcome the lack of tumor specificity and systemic toxicity typically associated with traditional chemotherapies, thus improving the therapeutic index. To effectively exploit this technological breakthrough, identification of optimal target antigens (Ags) is of utmost importance. To make the ideal target, differential expression of target Ags between healthy and cancer tissues, as well as specific mechanisms of ADC internalization after Ag-antibody interaction are required.Therefore, several in silico strategies to identify and characterize new promising candidate Ags have been developed. If initial in vitro and in vivo positive data are documented, thus providing a biological rationale for further Ag investigation, early phase clinical trials are designed. In BC, these strategies have already led to the development of effective ADCs, namely trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG), primarily targeting HER2 and TROP-2. However, promising new Ags are currently under investigation, with encouraging results especially coming from targeting HER3, FRα, Tissue Factor, LIV-1, ROR1-2, and B7–H4.In this review, we describe the landscape of emergent and future potential targets (i.e., other than HER2 and TROP-2) investigated in BC for ADC development. Predominant target expression, function, preclinical rationale, potential clinical implication, as well as preliminary clinical trial results are provided

ESR1 mutations in HR+/HER2-metastatic breast cancer: Enhancing the accuracy of ctDNA testing

: Activating mutations of the estrogen receptor alpha gene (ESR1) are common mechanisms of endocrine therapy (ET) resistance in hormone receptor-positive (HR + )/Human Epidermal Growth Factor Receptor 2 (HER2)-negative metastatic breast cancer (MBC). Recent clinical findings emphasize that both old and new generations of selective ER degraders (SERDs) demonstrate enhanced clinical effectiveness in patients with MBC who have detectable ESR1 mutations via liquid biopsy. This stands in contrast to individuals with MBC carrying these mutations and undergoing conventional endocrine monotherapies like aromatase inhibitors (AIs). Liquid biopsy, particularly the analysis of circulating tumor DNA (ctDNA), has emerged as a promising, minimally invasive alternative to conventional tissue-based testing for identifying ESR1 mutations. Within the context of the PADA-1 and EMERALD trials, distinct molecular methodologies and assays, specifically digital droplet PCR (ddPCR) and next-generation sequencing (NGS), have been employed to evaluate the mutational status of ESR1 within ctDNA. This manuscript critically examines the advantages and indications of various ctDNA testing methods on liquid biopsy for HR+/HER2-negative MBC. Specifically, we delve into the capabilities of ddPCR and NGS in identifying ESR1 mutations. Each methodology boasts unique strengths and limitations: ddPCR excels in its analytical sensitivity for pinpointing hotspot mutations, while NGS offers comprehensive coverage of the spectrum of ESR1 mutations. The significance of meticulous sample handling and timely analysis is emphasized, acknowledging the transient nature of cfDNA. Furthermore, we underscore the importance of detecting sub-clonal ESR1 mutations, as these variants can exert a pivotal influence on predicting both endocrine therapy resistance and responsiveness to SERDs. In essence, this work discusses the role of ctDNA analysis for detecting ESR1 mutations and their implications in tailoring effective therapeutic strategies for HR+/HER2- MBC

H-Ras gene takes part to the host immune response to COVID-19

I membri della famiglia del gene Ras svolgono un ruolo rilevante nel cancro, specialmente quando sono mutati. Tuttavia, possono svolgere ruoli aggiuntivi in ​​altre condizioni oltre al cancro. Abbiamo eseguito l'analisi dell'espressione genica utilizzando il pannello NanoString PanCancer IO 360 nelle cellule mononucleate del sangue periferico (PBMC) di sei pazienti COVID-19 e abbiamo scoperto che il gene H-Ras era significativamente sovraregolato, mentre entrambi i geni K-Ras e N-Ras erano sottoregolato. In particolare, l'upregulation del gene H-Ras era più evidente nei pazienti COVID-19 con una malattia più grave. Abbiamo confrontato i nostri risultati con quelli ottenuti analizzando due set di dati diversi e indipendenti, tra cui un totale di 53 pazienti COVID-19, in cui l'analisi dell'espressione genica è stata eseguita utilizzando il pannello Immunology_V2. L'analisi comparativa dell'espressione del gene H-Ras in questi pazienti ha confermato i nostri risultati preliminari. In entrambi, infatti, abbiamo potuto confermare la sovraregolazione dell'espressione del gene H-Ras. Il ruolo esatto di questa specifica sovraregolazione del gene H-Ras in risposta all'infezione da SARS-CoV-2 e il suo possibile ruolo nel cancro devono ancora essere chiariti. In conclusione, il gene H-Ras partecipa alla risposta immunitaria dell'ospite all'infezione da virus SARS-CoV-2, specialmente nei pazienti affetti dalla forma più grave del COVID-19.Ras gene family members play a relevant role in cancer, especially when they are mutated. However, they may play additional roles in other conditions beside cancer. We performed gene expression analysis using the NanoString PanCancer IO 360 panel in the peripheral blood mononuclear cell (PBMC) of six COVID-19 patients and we found that H-Ras gene was significantly upregulated, while both K-Ras and N-Ras genes were downregulated. In particular, H-Ras gene upregulation was more evident in COVID-19 patients with a more severe disease. We compared our results with those obtained by analyzing two different and independent datasets, including a total of 53 COVID-19 patients, in which the gene expression analysis was performed using the Immunology_V2 panel. Comparative analysis of the H-Ras gene expression in these patients confirmed our preliminary results. In both of them, in fact, we were able to confirm the upregulation of the expression of the H-Ras gene. The exact role of this specific upregulation of the H-Ras gene in response to SARS-CoV-2 infection and its possible role in cancer still remains to be elucidated. In conclusion, H-Ras gene participates to the host immune response to SARS-CoV-2 virus infection, especially in patients affected by the most severe form of the COVID-19

Clinical impact of drug-drug interactions on abemaciclib in the real-world experience of AB-ITALY study

Abstract Abemaciclib demonstrated clinical benefit in women affected by HR+/HER2− advanced breast cancer (aBC). Drug-drug interactions (DDIs) can lead to reduced treatment efficacy or increased toxicity. This retro-prospective study aimed to evaluate outcomes, DDIs’ impact, and toxicities of abemaciclib combined with endocrine therapy in a real-world setting. Patients from 12 referral Italian hospitals with HR+/HER2− aBC who received abemaciclib were included. Clinical data about comorbidities, concurrent medications, outcomes, and adverse events (AE) were collected. Drug-PIN® (Personalized Interactions Network) is a tool recognizing the role of multiple interactions between active and/or pro-drug forms combined with biochemical and demographic patient data. The software was used to define the Drug-PIN score and Drug-PIN tier (green, yellow, dark yellow, and red) for each patient. Univariate and multivariate analyses were performed to identify predictors of patients’ PFS or toxicity. One hundred seventy-three patients were included. 13% of patients had >75years. The overall response rate (ORR) was 63%. The general population’s median PFS (mPFS) was 22 months (mo), while mOS were not reached. Patients treated with abemaciclib in combination with AI and fulvestrant had a mPFS of 36 and 19 mo, respectively. The most common toxicities were diarrhea, asthenia, and neutropenia detected in 63%,49%, and 49% of patients. The number of concomitant medications and comorbidities were not associated with survival outcomes (22 vs 17 mo, p = 0.068, p = 0.99). Drug-PIN tier from dark yellow to red and Drug-PIN score >12 were associated with shorter PFS compared to no/low-risk DDIs and score <12 (15 vs 23, p = 0.005, p = 0.0017). Drug interaction was confirmed as an independent biomarker in a multivariate model (p = 0.02). No difference in any grade AE, severe toxicities, and diarrhea were detected among different age subgroups. No association was found between Drug-PIN score or Drug-PIN tier and overall toxicity (p = 0.44), severe AEs (p = 0.11), or drug reduction (p = 0.27). The efficacy and safety of abemaciclib plus ET were confirmed in a real-world setting, even in the elderly population and patients with comorbidities. Evaluation of DDIs with Drug-PIN appears to be an independent predictor of PFS