Evaluating CDK4/6 Inhibitor Therapy in Elderly Patients with Metastatic Hormone Receptor-Positive, HER2-Negative Breast Cancer: A Retrospective Real-World Multicenter Study.

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.

Metronomic chemotherapy and breast cancer: a critical evaluation of its role in the new landscape of therapeutics.

INTRODUCTION: Breast cancer (BC) remains a prevalent and challenging malignancy among women, with significant advancements in treatment strategies over the past decades. Traditional chemotherapy has been progressively supplemented by newer modalities, including Antibody-Drug Conjugates (ADCs), Immunotherapy (IO), and Targeted Therapies (TT). Despite these advancements, there remains a critical need for strategies that maintain efficacy while minimizing toxicity. AREAS COVERED: This review delves into metronomic chemotherapy (MC), a novel approach involving the frequent administration of low-dose chemotherapy without prolonged breaks. We explore MC's impact across various breast cancer subtypes, such as Estrogen Receptor-Positive (ER+), HER2-Positive, and Triple-Negative Breast Cancer (TNBC). The literature reviewed highlights MC's mechanisms, including its anti-angiogenic, immunomodulatory, and antiproliferative effects, and its potential to improve treatment tolerability and address drug resistance. EXPERT OPINION: MC represents a promising adjunct to existing therapies, particularly in advanced or resistant cases. Its unique dosing schedule could offer sustained antitumor activity with reduced toxicity, making it a viable option for long-term management. However, further research is warranted to establish optimal dosing regimens, identify predictive biomarkers, and delineate its role within combination treatment strategies. Clarifying these aspects could refine MC's application, potentially reshaping treatment paradigms and enhancing patient outcomes in breast cancer management.

Synergizing Immunotherapy and Antibody-Drug Conjugates: New Horizons in Breast Cancer Therapy.

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.

Safety evaluation of Datopotamab deruxtecan for triple-negative breast cancer: a meta-analysis.

BACKGROUND: TROP-2 is emerging as a valid and fruitful strategy in triple-negative breast cancer (TNBC) patients, and several agents are currently under evaluation, including Datopotamab deruxtecan (Dato-DXd). RESEARCH DESIGN AND METHODS: Herein, we performed a meta-analysis aimed to evaluate any grade adverse events, grade 3-4 adverse events, dose reduction, and serious adverse events in TNBC patients treated with Dato-DXd in clinical trials. RESULTS: The pooled results suggests that Dato-DXd is associated with a favorable safety profile: while any grade treatment-related toxicities were common, grade 3-4 events were not particularly frequent and mainly represented by stomatitis (13.88%; 95% CI, 10.68 - 17.09). CONCLUSIONS: These findings may help to comprehensively define the safety profile of Dato-DXd and to assist in the design of future clinical trials in this setting.

Immune-Based Combination Therapies for Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the fourth most frequent cause of cancer-related death worldwide. HCC frequently presents as advanced disease at diagnosis, and disease relapse following radical surgery is frequent. In recent years, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced HCC, particularly with the introduction of atezolizumab/bevacizumab as the new standard of care for first-line treatment. Recently, dual immune checkpoint blockade with durvalumab plus tremelimumab has also emerged as an effective first-line treatment for advanced HCC and most of the research is currently focused on developing combination treatments based mainly on ICIs. In this review, we will discuss the rationale and ongoing clinical trials of immune-based combination therapies for the treatment of advanced HCC, also focusing on new immunotherapy strategies such as chimeric antigen receptor T cells (CAR-T) and anti-cancer vaccines.

The Mediterranean Lifestyle to Contrast Low-Grade Inflammation Behavior in Cancer.

A healthy diet and an active lifestyle are both effective ways to prevent, manage, and treat many diseases, including cancer. A healthy, well-balanced diet not only ensures that the body gets the right amount of nutrients to meet its needs, but it also lets the body get substances that protect against and/or prevent certain diseases. It is now clear that obesity is linked to long-term diseases such as heart disease, diabetes, and cancer. The main reasons for people being overweight or obese are having bad eating habits and not moving around enough. Maintaining weight in the normal range may be one of the best things to avoid cancer. It has been scientifically proven that those who perform regular physical activity are less likely to develop cancer than those who lead a sedentary lifestyle. Moving regularly not only helps to maintain a normal body weight, avoiding the effects that favor tumor growth in overweight subjects, but also makes the immune system more resistant by counteracting the growth of tumor cells. Physical activity also helps prevent cardiovascular and metabolic diseases. In this review, it is highlighted that the association between the Mediterranean diet and physical activity triggers biological mechanisms capable of counteracting the low-grade chronic inflammation found in patients with cancer. This assumes that healthy lifestyles associated with cancer therapies can improve the expectations and quality of life of cancer patients.

Role of Etiology in Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Counterfactual Event-Based Mediation Analysis.

Background: Whether the etiology of underlying liver disease represents a prognostic factor in patients with hepatocellular carcinoma (HCC) treated with lenvatinib is still a matter of debate. This study investigates whether the viral etiology of HCC plays a prognostic role in overall survival (OS). Methods: Data derived from a multicenter series of 313 HCC patients treated with lenvatinib between 2019 and 2022 were analyzed. Actuarial survival estimates were computed using the Kaplan−Meier method and compared with the log-rank test. We performed an event-based counterfactual mediation analysis to estimate direct (chronic inflammation and immunosuppression), indirect (tobacco smoking, alcohol use, illicit drug abuse with injections), and the total effect of viral etiology on OS. Results were expressed as hazard ratio (HR) and 95% CI. Results: Median OS was 21 months (95% CI: 20−23) in the group with other etiologies and 15 months (14−16) in the group with viral etiology (p < 0.0001). The total effect of viral etiology was associated with OS (HR 2.76, 1.32−5.21), and it was mainly explained by the pure direct effect of viral etiology (HR 2.74, 1.15−4.45). By contrast, its total indirect effect was not associated with poorer survival (HR 1.05, 0.82−2.13). These results were confirmed when considering tobacco, alcohol consumption, or injection drug abuse as potential mediators. Median progression-free survival was 9 months (8−10) in patients with other etiologies and 6 months (5−7) in patients with viral etiology (p < 0.0001). No difference in terms of adverse event rate was observed between the two groups. Conclusions: Patients affected by HCC with nonviral etiology treated with lenvatinib exhibit longer survival than those with viral etiology. This finding may have relevance in the treatment decision-making process.

Second-Line Chemotherapy in Elderly Patients with Advanced Biliary Tract Cancer: A Multicenter Real-World Study.

Objectives: The ABC-06 and the NIFTY trials recently established the role of second-line chemotherapy (2L) in patients with advanced biliary tract cancer (BTC). Our real-world study aimed to explore 2L in BTC patients aged ≥ 70 years old and to compare their outcomes with younger subjects. Methods: Institutional registries across three academic medical centers were retrospectively reviewed. The Kaplan−Meier methods were used to estimate survival, and the log-rank test was used to make comparisons. Results: A total of 190 BTC patients treated with 2L were identified and included in the analysis. Among them, 52 (27.3%) were aged ≥ 70 years (range 70−87 years). No statistically significant differences in both median overall survival (mOS) and median progression-free survival (mPFS) were recorded between the elderly and younger patients. Absolute lymphocyte count < 1000/mmc (p < 0.001) and albumin level < 3 g/dL (p < 0.001) were independently associated with worse prognoses. Conclusions: The results of this real-world study suggest that for patients aged ≥ 70 years, 2L could be equally effective for younger patients with survival outcomes aligned to those from the ABC-06 and NIFTY trials. The delivery of 2L should be carefully evaluated and monitored in this patient subset.

Pemigatinib in Intrahepatic Cholangiocarcinoma: A Work in Progress.

Cholangiocarcinoma (CCA) is the second most frequent primary liver cancer, following hepatocellular carcinoma (HCC). Progress in the molecular understanding of CCA has led to the development of several agents, including FGFR inhibitors, such as pemigatinib, whose approval has marked a new era in this hepatobiliary malignancy. However, a number of questions remain unanswered, including the development of secondary resistance and the role of combination therapies, including FGFR inhibitors. Herein, we specifically focus on the current challenges and future research directions of pemigatinib use in CCA patients.

Pathological Complete Response to Neoadjuvant Chemoimmunotherapy for Early Triple-Negative Breast Cancer: An Updated Meta-Analysis.

Immune checkpoint inhibitors (ICIs) have made a breakthrough in the systemic treatment for metastatic triple-negative breast cancer (TNBC) patients. However, results of phase II and III clinical trials assessing ICIs plus chemotherapy as neoadjuvant treatment were controversial and conflicting. We performed a meta-analysis aimed at assessing the Odds Ratio (OR) of the pathological complete response (pCR) rate in trials assessing neoadjuvant chemoimmunotherapy in TNBC. According to our results, the use of neoadjuvant chemoimmunotherapy was associated with higher pCR (OR 1.95; 95% Confidence Intervals, 1.27-2.99). In addition, we highlighted that this benefit was observed regardless of PD-L1 status since the analysis reported a statistically significant and clinically meaningful benefit in both PD-L1 positive and PD-L1 negative patients. These findings further support the exploration of the role of ICIs plus chemotherapy in early-stage TNBC, given the potentially meaningful clinical impact of these agents. Further studies aimed at more deeply investigating this emerging topic in breast cancer immunotherapy are warranted.

The Impact of Concomitant Proton Pump Inhibitors on Immunotherapy Efficacy among Patients with Urothelial Carcinoma: A Meta-Analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have recently represented a breakthrough in urothelial carcinoma (UC). Proton pump inhibitors (PPIs) are routinely used for extended time periods in UC patients, with these agents having potentially and frequently undervalued effects on ICIs efficacy. METHODS: We performed a meta-analysis aimed at investigating the impact of concomitant PPI administration on progression-free survival (PFS) and overall survival (OS) among patients receiving immunotherapy for metastatic UC. RESULTS: Two studies encompassing a total of 1015 patients were included. The pooled Hazard Ratios (HRs) for OS and PFS were 1.55 (95% CI, 1.31-1.84) and 1.43 (95% CI, 1.23-1.66), respectively, suggesting that the administration of PPIs was negatively associated with PFS and with OS in UC patients treated with ICIs. CONCLUSIONS: The current meta-analysis represents the first study to provide a systematic evaluation of the impact of concomitant PPI use in UC patients treated with ICIs. Further studies are warranted on this topic to clarify the relationship between gut microbiome, antiacid exposure, and cancer immunotherapy. In the current era of medical oncology, progress in this setting will require the collaboration of basic science and clinical research to optimize systemic treatment and to improve the outcomes of UC patients receiving ICIs.

Current and Future Role of Neoadjuvant Chemoimmunotherapy for Early Triple-Negative Breast Cancer: Which Way to Go Forward.

Immunotherapy has revolutionized previous triple-negative breast cancer (TNBC) treatment algorithms, prompting researchers and clinicians to consider the expansion of the role of immunotherapy in other settings, including the earlier stage of the disease (e.g., as neoadjuvant and adjuvant therapy). The role of chemoimmunotherapy have been assessed in some recently presented and published clinical trials, including the KEYNOTE-522, the IMpassion031, and the GeparNUEVO. In the current Editorial, we will provide a critical snapshot of these studies, exploring strengths and limitations of neoadjuvant chemotherapy in early TNBC.

Adenosine pathway inhibitors: novel investigational agents for the treatment of metastatic breast cancer.

INTRODUCTION: The adenosine pathway has been suggested to play a key role in several carcinogenetic processes, with the metabolism of adenosine-5'-triphosphate (ATP) and its derivatives reported to be dysregulated in breast cancer. Preclinical evidence has supported the role of adenosine in the pathogenesis of this malignancy as well as the development of selective adenosine pathway inhibitors. AREAS COVERED: The paper overviews the evidence regarding the use of adenosine pathway inhibitors in breast cancer; a literature search was conducted in January 2022 of Pubmed/Medline, Cochrane library, and Scopus databases. EXPERT OPINION: The adenosine pathway regulates inflammation, apoptosis, metastasis, and cell proliferation in breast cancer cells, and adenosine pathway inhibitors have yielded encouraging results in early-phase clinical trials. Well-designed, multicenter studies focused on monotherapies and combination therapies (which include immune checkpoint inhibitors) are warranted in this setting.

Chronic Inflammation in Obesity and Cancer Cachexia.

Chronic inflammation has long been linked to obesity and related conditions such as type 2 diabetes and metabolic syndrome. According to current research, the increased risk of cancer in people with certain metabolic diseases may be due to chronic inflammation. Adipocytokines, which are pro-inflammatory cytokines secreted in excess, are elevated in many chronic metabolic diseases. Cytokines and inflammatory mediators, which are not directly linked to DNA, are important in tumorigenesis. Cachexia, a type of metabolic syndrome linked to the disease, is associated with a dysregulation of metabolic pathways. Obesity and cachexia have distinct metabolic characteristics, such as insulin resistance, increased lipolysis, elevated free fatty acids (FFA), and ceramide levels, which are discussed in this section. The goal of this research project is to create a framework for bringing together our knowledge of inflammation-mediated insulin resistance.

Which role for predictors of response to immune checkpoint inhibitors in hepatocellular carcinoma?

INTRODUCTION: Hepatocellular carcinoma (HCC) remains a frequently diagnosed malignancy worldwide, still representing an important cause of cancer-related death. Recent years have seen the emergence of novel systemic treatments for HCC patients, including immune checkpoint inhibitors (ICIs). Nonetheless, several questions regarding HCC immunotherapy remain unanswered, especially in terms of biochemical predictors of response. AREAS COVERED: In the current paper, we will discuss available evidence regarding predictive biomarkers of response to HCC immunotherapy. A literature search was conducted in January 2022 of Pubmed/Medline, Cochrane library, and Scopus databases. EXPERT OPINION: The identification of predictive biomarkers represents an unmet need in HCC patients receiving ICIs. The HCC medical community is called to further efforts aimed to elucidate the effective role of PD-L1 expression, TMB, MSI, gut microbiota, and other emerging biomarkers.

Dual immune checkpoint blockade in hepatocellular carcinoma: where do we stand?

Hepatocellular carcinoma (HCC) represents the fourth most common cause of cancer-related death. Surgery, local ablative therapies and liver transplantation are the only potentially curative strategies, but the majority of patients present with advanced disease at diagnosis or develop recurrence after surgery. In recent years, immunotherapy for HCC has received growing interest, and one of the most promising strategies is the association of two immune checkpoint inhibitors (ICIs), which has already demonstrated its potential in other solid tumors such as melanoma and renal cell carcinoma. Herein, we discuss the role and the biologic rationale of dual immune checkpoint blockade in HCC patients, focusing on the two ICI combinations: nivolumab plus ipilimumab and durvalumab plus tremelimumab.

Impact of clinicopathological features on immune-based combinations for advanced urothelial carcinoma: a meta-analysis.

Aims: Immune checkpoint inhibitors (ICIs) have recently revolutionized the treatment landscape of metastatic urothelial carcinoma. The authors performed a meta-analysis aiming to evaluate the predictive value of Eastern Cooperative Oncology Group performance status, age, sex, liver metastasis and histology in trials comparing first-line ICI-based combinations with chemotherapy in metastatic urothelial carcinoma patients. Methods: Hazard ratios were analyzed. Results: ICI-based combinations significantly decreased the risk of death in several clinicopathological subgroups, including patients with no liver metastases (hazard ratio: 0.84; 95% CI: 0.74-0.95) and those with an Eastern Cooperative Oncology Group performance status of 0 (hazard ratio: 0.84; 95% CI: 0.72-0.97). Conclusion: The benefit of ICI-based combinations over chemotherapy in metastatic urothelial carcinoma was consistent across several clinicopathological subgroups, although a proportion of patients responded to chemotherapy alone.

Immune-based combinations for metastatic triple negative breast cancer in clinical trials: current knowledge and therapeutic prospects.

INTRODUCTION: Immune checkpoint inhibitor (ICI) monotherapy appears to be effective in a small cohort of patients with metastatic triple negative breast cancer (mTNBC). This supports the exploration of strategies for increasing the efficacy of immunotherapy. To enhance overall response and clinical outcomes, several immune-based combinations are being investigated. AREAS COVERED: The authors present a synopsis of current, state-of-art immune-based combinations in this setting and reflect on future possibilities. They shed light on recently presented and published clinical trials and ongoing studies. A literature search was conducted in October 2021; in addition, abstracts of international cancer meetings were reviewed. EXPERT OPINION: Clinical trials suggest that ICI monotherapy could be beneficial in a minority of mTNBC patients; conversely, several immune-based combinations have reported notable results in recently presented or published studies. Some of these combination strategies have been approved for mTNBC - as in the case of chemoimmunotherapy in PD-L1 positive patients. Numerous trials are investigating novel ICI-based combinations and their results are eagerly awaited.

Lenvatinib plus pembrolizumab: the next frontier for the treatment of hepatocellular carcinoma?

INTRODUCTION: While sorafenib monotherapy represented the mainstay of medical treatment for advanced hepatocellular carcinoma (HCC) patients for more than a decade, novel agents and combination therapies have recently produced unprecedented paradigm shifts. The combination of lenvatinib plus pembrolizumab is now being evaluated as a front-line treatment in advanced HCC patients; early phase clinical trials have already reported promising results. AREAS COVERED: This paper reviews the combination of lenvatinib plus pembrolizumab for the treatment of advanced HCC. The preclinical rationale and completed and ongoing trials are examined and later, the authors reflect on biomarkers of predictive of response to immune-based combinations and future treatment decision-making on the basis of tolerability and clinical benefits provided by these novel therapeutics. A literature search was conducted in April 2021 of Pubmed/Medline, Cochrane library and Scopus databases; moreover, abstracts of international cancer meetings were reviewed. EXPERT OPINION: The landscape of new agents and combinations continues to expand. Recently, immune-based combinations have reported important results in advanced HCC, as witnessed by the landmark IMbrave150 trial. Based on the promising results of early phase clinical trials, lenvatinib plus pembrolizumab has the potential to represent a novel treatment option in this setting.

Ampullary Carcinoma: An Overview of a Rare Entity and Discussion of Current and Future Therapeutic Challenges.

Ampullary carcinomas (ACs) represent a rare entity, accounting for approximately 0.2% of all gastrointestinal solid tumors and 20% of all periampullary cancers (PACs). Unfortunately, few data are available regarding the optimal therapeutic strategy for ACs due to their rarity, and physicians frequently encounter significant difficulties in the management of these malignancies. In this review, we will provide an overview of current evidence on AC, especially focusing on biological features, histological characteristics, and available data guiding present and future therapeutic strategies for these rare, and still barely known, tumors.