Background: Breast cancer (BrC) is the most frequent neoplasm in women. New biomarkers, including aberrant DNA methylation, may improve BrC management. Herein, we evaluated the detection and prognostic performance of seven genes’ promoter methylation (APC, BRCA1, CCND2, FOXA1, PSAT1, RASSF1A and SCGB3A1). Methods: Methylation levels were assessed in primary BrC tissues by quantitative methylation-specific polymerase chain reaction (QMSP) and in circulating cell-free DNA (ccfDNA) by multiplex QMSP from two independent cohorts of patients (Cohort #1, n = 137; and Cohort #2, n = 44). Receiver operating characteristic (ROC) curves were constructed, and log-rank test and Cox regression were performed to assess the prognostic value of genes’ methylation levels. Results: The gene-panel APC, FOXA1, RASSF1A, SCGB3A1 discriminated normal from cancerous tissue with high accuracy (95.55%). In multivariable analysis, high PSAT1-methylation levels [>percentile 75 (P75)] associated with longer disease-free survival, whereas higher FOXA1-methylation levels (>P75) associated with shorter disease-specific survival. The best performing panel in ccfDNA (APC, FOXA1 and RASSF1A) disclosed a sensitivity, specificity and accuracy over 70%. Conclusions: This approach enables BrC accurate diagnosis and prognostic stratification in tissue samples, and allows for early detection in liquid biopsies, thus suggesting a putative value for patient management.

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Breast cancer (BrC) is the most frequent malignancy and the leading cause of cancer death among women worldwide. Approximately 70% of BrC are classified as luminal-like subtype, expressing the estrogen receptor. One of the most common and effective adjuvant therapies for this BrC subtype is endocrine therapy. However, its effectiveness is limited, with relapse occurring in up to 40% of patients. Because microRNAs have been associated with several mechanisms underlying endocrine resistance and sensitivity, they may serve as predictive and/or prognostic biomarkers in this setting. Hence, the main goal of this study was to investigate whether miRNAs deregulated in endocrine-resistant BrC may be clinically relevant as prognostic and predictive biomarkers in patients treated with adjuvant endocrine therapy. A global expression assay allowed for the identification of microRNAs differentially expressed between luminal BrC patients with or without recurrence after endocrine adjuvant therapy. Then, six microRNAs were chosen for validation using quantitative reverse transcription polymerase chain reaction in a larger set of tissue samples. Thus, miR-30c-5p, miR-30b-5p, miR-182-5p, and miR-200b-3p were found to be independent predictors of clinical benefit from endocrine therapy. Moreover, miR-182-5p and miR-200b-3p displayed independent prognostic value for disease recurrence in luminal BrC patients after endocrine therapy. Our results indicate that selected miRNAs’ panels may constitute clinically useful ancillary tools for management of luminal BrC patients. Nevertheless, additional validation, ideally in a multicentric setting, is required to confirm our findings.

Gastric cancer (GC) remains a public health problem, being the fifth most common cancer worldwide. In the western countries, the majority of patients present with advanced disease. Additionally, 65 to 75% of patients treated with curative intent will relapse and develop systemic disease. In metastatic disease, systemic treatment still represents the state of the art, with less than a year of median overall survival. The new molecular classification of GC was published in 2014, identifying four distinct major subtypes of gastric cancer, and has encouraged the investigation of new and more personalized treatment strategies. This paper will review the current evidence of immunotherapy in advanced gastric cancer.

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Notwithstanding the marked progress in breast cancer (BC) management, it still constitutes the most common malignancy in women and a major cause of morbidity and mortality, thus remaining a major health issue worldwide. Most BC cases are hormone receptor (HR) positive (luminal A or B molecular subtypes) and endocrine treatment (ET) is an important therapeutic modality at all disease stages. Nevertheless, despite substantial improvements in BC patient outcome, effectiveness of ET is limited, as up to 40% of patients eventually relapse or progress and endocrine resistant BC has a less favorable prognosis and constitutes a therapeutic challenge. The biological mechanisms underlying endocrine resistance are, however, still poorly understood. In this review, we focused on data regarding the main epigenetic mechanisms associated with the development of endocrine treated-resistant BC described so far, including alterations in DNA methylation, non-coding RNAs, chromatin remodeling, post-translational histone modifications and histone variants. Notably, specific epigenetic alterations have been characterized in this subset of breast tumors and may be of clinical value for individualized patient management in the future. Contents 1. Introduction 2. Evidence acquisition 3. Conclusion

TPS579 Background: The standard management of MIBC involves neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy and pelvic lymph node dissection. Approximately 40% of patients with MIBC are cisplatin ineligible, the standard of care (SoC) for these patients is to proceed directly to cystectomy as there are no effective or approved neoadjuvant therapies in this setting. Only nivolumab has been approved as adjuvant treatment for patients who are at high risk of recurrence after radical resection. Given this, there remains an unmet need. D (anti–PD-L1 antibody) +T (anti–CTLA-4 antibody) have demonstrated a manageable safety profile with clinical activity in metastatic urothelial carcinoma and in a phase 2 neoadjuvant trial, D+T showed anti-tumor activity, including meaningful pathologic complete responses (pCR), in cisplatin-ineligible MIBC with high-risk features. Targeted cytotoxic antibody drug conjugates (ADCs) are known to have the potential to induce immunogenic tumor cell death, which promotes activation and recruitment of immune cells. EV is a vedotin ADC comprising an antibody against Nectin-4 linked to a microtubule-disrupting agent MMAE that has demonstrated efficacy in, and is approved for, advanced urothelial cancer. Thus, we hypothesize that EV in combination with PD-L1 inhibition, with or without CTLA-4 inhibition, may improve outcomes in patients with MIBC by downstaging of disease before cystectomy and that adjuvant therapy with D or D+T may further improve time to disease relapse. Methods: VOLGA (NCT04960709) is a phase 3, randomized, open-label, multicenter, international trial that will enroll ̃830 patients with MIBC. Eligible patients include those aged ³18 years with histologically or cytologically documented MIBC (transitional and mixed transitional cell histology), who are cisplatin ineligible and with a clinical stage of T2-4aN0-N1M0. Patients will be randomized to 3 arms to receive 3 cycles of neoadjuvant therapy Q3W as follows: (Arm 1) D (1500 mg day 1) +T (75 mg day 1) +EV (1.25 mg/kg Days 1 & 8); (Arm 2) D (1500 mg day 1) +EV (1.25 mg/kg Days 1 & 8); or (Arm 3) no neoadjuvant treatment (SoC). A safety run-in study is included. Following radical cystectomy, patients will then receive: (Arm 1) 1 cycle of T on Day 1 plus 9 cycles of D Q4W; (Arm 2) 9 cycles of D Q4W; or (Arm 3) either no adjuvant treatment (observation only) or adjuvant nivolumab in high-risk patients where available and approved (planned amendment). The dual primary endpoints are pCR and event-free survival. Secondary endpoints include overall survival, disease-free survival, pathologic downstaging rate to < pT2, disease-specific survival, quality of life, immunogenicity, and pharmacokinetics. The study is actively enrolling. Clinical trial information: NCT04960709.

Renal cell carcinoma (RCC) comprises a highly heterogeneous group of kidney tumours built upon distinct genetic-and epigenetic-driven mechanisms and molecular pathways. Therefore, responsiveness to treatment is considerably variable across patients, adding an extra layer of complexity to the already challenging therapeutic decision process. The last decade brought an unprecedented shift in the medical approach to advanced or metastatic RCC; in fact, immunotherapy-based combinations have significantly transformed the therapeutic arsenal and clinical outcomes of these patients. These strategies were quickly adopted by international guidelines committees as the new standards of care. However, this enhanced efficacy comes at the expense of tolerability, with a predictable negative impact on patients' quality of life. Moreover, subgroup and post hoc analyses of the major clinical trials have shown that not all patients benefit equally from these innovative approaches. In this context, a group of experts on kidney cancer met and discussed the state of the art in the field, with a special emphasis on the appropriateness of using monotherapy with an anti-angiogenesis tyrosine kinase inhibitor (TKI) to treat specific subgroups of patients with RCC. This article reviews the main topics that were