Immunotherapy is one of the most recent systemic treatments to emerge for use in oncology, and is based on the blocking of inhibitory immune checkpoints to potentiate the immune response to cancer. The anti‑cytotoxic T lymphocyte‑associated antigen‑4 antibody ipilimumab and anti‑programmed cell death protein 1 antibodies, including nivolumab and pembrolizumab, are currently available and widely used, and other immune‑inhibiting antibodies are now under intensive investigation. These antibodies have shown efficacy in a growing number of tumor types, following initial observations of their notable effects in melanoma treatment. Despite the efficacy of these antibodies, their novel mechanisms of action are also associated with a new class of side effects called immune‑related adverse events (IRAEs). These side effects do not share a common pathophysiology with other anticancer treatments and, therefore, they often require specific therapies. When detected early and correctly treated, IRAEs are reversible; however, they can become severe and life‑threatening if underestimated or inappropriately treated. This review aims to revisit the pathogenesis of IRAEs, with attention to gastrointestinal manifestations, since these are common and potentially dangerous complications of immunotherapy and represent a major cause of treatment discontinuation. Recommendations and guidelines for the management of IRAEs are also presented, in order to provide a clear and applicable algorithm for use by clinicians.

The advent of immunotherapy and antibody–drug conjugates (ADCs) have revolutionized breast cancer treatment, offering new hope to patients. However, challenges, such as resistance and limited efficacy in certain cases, remain. Recently, the combination of these therapies has emerged as a promising approach to address these challenges. ADCs play a crucial role by delivering cytotoxic agents directly to breast cancer cells, minimizing damage to healthy tissue and enhancing the tumor-killing effect. Concurrently, immunotherapies harness the body’s immune system to recognize and eliminate cancer cells. This integration offers potential to overcome resistance mechanisms and significantly improve therapeutic outcomes. This review explores the rationale behind combining immunotherapies with ADCs, recent advances in this field, and the potential implications for breast cancer treatment.

Background: Metastatic HR+/HER2- breast cancer is commonly treated with CDK4/6 inhibitors in combination with endocrine therapy. However, the efficacy and safety of this approach in elderly patients (≥70 years) remain unclear, particularly in the context of real-world clinical practice. This study aims to evaluate the clinical outcomes and tolerability of CDK4/6 inhibitor treatments in this fragile population, which is often under-represented in randomized clinical trials. Patients and methods: This retrospective multicenter study included elderly patients with metastatic HR+/HER2-negative breast cancer receiving first-line CDK4/6 inhibitors. The primary endpoint was progression-free survival (PFS). The secondary endpoints focused on the overall survival (OS), safety, and tolerability, considering variables such as tumor subtype, age, comorbidities, and treatment specifics. Results: The median PFS and OS were slightly lower than those reported in clinical trials, reflecting the inclusion of a more fragile population. The luminal B subtype was linked to a poorer PFS, while other factors like age, BMI, and ECOG status did not significantly affect the outcomes. A safety analysis indicated a higher incidence of grade 3 or higher toxicities, especially in frail patients, leading to dose reductions. Despite these challenges, CDK4/6 inhibitors were generally well-tolerated, allowing most patients to continue therapy. Conclusions: CDK4/6 inhibitors with endocrine therapy are effective in elderly patients with metastatic HR+/HER2- breast cancer, though careful management is crucial to balance efficacy and minimize adverse events.

Background: Pembrolizumab has reshaped the neoadjuvant treatment landscape for triple-negative breast cancer (TNBC). However, the influence of BRCA1/2 mutational status on the efficacy of chemo-immunotherapy remains unclear, particularly in real-world settings. Since BRCA-mutated tumors exhibit homologous recombination deficiency (HRD) and high genomic instability, they may be more immunogenic and responsive to immune checkpoint inhibitors. This multicenter study investigated the association between BRCA1/2 mutations and pathologic complete response (pCR) in TNBC patients treated with pembrolizumab-based neoadjuvant chemotherapy (NACT). Methods: We retrospectively analyzed 184 patients with stage II–III TNBC treated between 2021 and 2024 across eleven Italian oncology centers. All received pembrolizumab combined with platinum- and taxane-based NACT followed by anthracyclines, according to the KEYNOTE-522 regimen. Germline BRCA1/2 status was determined by next-generation sequencing. The primary endpoint was pCR, defined as ypT0/is ypN0. Fisher’s exact test and logistic regression models were used to assess associations between clinical–pathological variables and pCR. Results: Among 184 patients, 25 (13.6%) harbored BRCA1 mutations, 12 (6.5%) BRCA2 mutations, and 147 (79.9%) were wild-type. pCR was achieved in 80.0% of BRCA1-mutated, 75.0% of BRCA2-mutated, and 61.1% of wild-type tumors. When pooled, BRCA1/2-mutated cases showed a higher likelihood of achieving pCR (78.4% vs. 61.1%; odds ratio [OR] = 2.17; 95% CI 1.01–4.97; p = 0.056). High tumor-infiltrating lymphocytes (≥30%) were also associated with increased pCR rates. The frequency of BRCA mutations (20.1%) was consistent with that reported in major TNBC series. No comparative analysis of toxicity or survival outcomes was performed due to the retrospective design and limited follow-up. Conclusions: In this multicenter real-world cohort, TNBC patients carrying BRCA1/2 mutations exhibited a trend toward higher pCR rates with pembrolizumab-based NACT compared with wild-type tumors. These findings suggest enhanced chemosensitivity and immune responsiveness in BRCA-deficient disease, warranting further validation in larger prospective studies with survival endpoints.

Background: Pembrolizumab combined with neoadjuvant chemotherapy significantly improves pCR in early TNBC, but the effect of treatment intensity and baseline clinical factors has been insufficiently explored in real-world settings. Methods: We retrospectively included 169 consecutive patients with stage II–III TNBC treated across 11 Italian oncology centers (January 2022–January 2025) with the KEYNOTE-522 regimen. Clinical, pathological, and treatment data were collected, including relative dose intensity (RDI), dose modifications, and toxicities. The primary endpoint was pCR (ypT0/is ypN0). Results: The overall pCR rate was 65.7%, which is consistent with clinical trial data. Dose reductions occurred in 40% of patients and chemotherapy was discontinued in 18%. Patients maintaining RDI ≥85% achieved higher pCR (79.3% vs. 51.2%, p < 0.001). Similarly, patients without dose reductions (72.5% vs. 55.2%, p = 0.031) and those completing all cycles (73.1% vs. 41.0%, p < 0.001) had superior outcomes. Dose modifications occurred mainly during the taxane/carboplatin phase and were predominantly due to hematological toxicities (anemia 44%, neutropenia 30%, and thrombocytopenia 15%), neuropathy (18%), and gastrointestinal events (36%). Higher TILs correlated with increased pCR (70.6% vs. 60.7%, p = 0.049), while BRCA mutations showed a favorable trend. ECOG, BMI, pregnancy history, and comorbidities were not significantly associated with pCR. Conclusions: In this multicenter real-world cohort, maintaining chemotherapy dose intensity (RDI ≥ 85%) and completing all planned cycles were strongly associated with higher pCR rates, reinforcing the clinical importance of minimizing dose reductions and discontinuations during pembrolizumab-based neoadjuvant therapy for TNBC.

Metaplastic breast cancer (MPBC) is a rare and aggressive tumor type in great need of satisfactory therapies. Although most cases of MPBC are ‘triple negative’, they are nonetheless related to wors...