Charting the Course in Sequencing Antibody-Drug Conjugates in Breast Cancer.

Based on the unprecedented results observed in recent clinical trials, antibody-drug conjugates (ADCs) have revolutionized the treatment algorithm of metastatic breast cancer (mBC). The strategy of sequencing different ADCs in other lines of therapy is highly attractive, but the proportion of patients who have undergone such a strategy in the context of published clinical trials is still limited, especially for modern ADCs. HER2-positive disease is primarily managed with a sequence of different ADCs. Historically, trastuzumab emtansine (T-DM1) has been the most commonly used ADC for both early and metastatic HER2-positive disease. Considering the recent evidence related to trastuzumab deruxtecan (T-DXd), it is expected to assume the role of the main ADC in our clinical practice. Herein, we report a retrospective analysis of the sequence of different ADCs relying on available published data from clinical trials.

Cyclin-dependent kinase 2 (CDK2) inhibitors and others novel CDK inhibitors (CDKi) in breast cancer: clinical trials, current impact, and future directions.

Aberrant cyclin-dependent kinase 2 (CDK2) activation has been identified as a main resistance mechanism to CDK4/6 inhibition in hormone-receptor positive (HR+) breast cancer. Additionally, consistent preclinical evidence states its crucial role in MYC and CCNE1 overexpressed cancer survival, such as triple-negative breast cancers (TNBC), thus representing an appealing and relatively unexplored target treatment opportunity. Despite emerging initial results of novel CDK2 inhibitors (CDK2i) activity, a comprehensive outcomes collection is currently absent from the scientific literature. We aim to provide an overview of ongoing clinical trials involving CDK2i in the context of metastatic breast cancer (mBC), either as monotherapy or in combination with other agents. The review extends beyond CDK2i to encompass novel emerging CDK4 inhibitors, combined CDK2/4/6 inhibitors, and the well-known pan-CDK inhibitors including those specifically directed at CDK2. Delving into the results, we critically appraise the observed clinical efficacy and offer valuable insights into their potential impact and future applications.

Identification of a Panel of miRNAs Associated with Resistance to Palbociclib and Endocrine Therapy.

We investigated whether we could identify a panel of miRNAs associated with response to treatment in tumor tissues of patients with Hormone Receptor-positive/HER2-negative metastatic breast cancer treated with endocrine therapy (ET) and the CDK4/6 inhibitor (CDK4/6i)i palbociclib. In total, 52 patients were evaluated, with 41 receiving treatment as the first line. The overall median PFS was 20.8 months (range 2.5-66.6). In total, 23% of patients experienced early progression (<6 months). Seven miRNAs (miR-378e, miR-1233, miR-99b-5p, miR-1260b, miR-448, -miR-1252-5p, miR-324-3p, miR-1233-3p) showed a statistically significant negative association with PFS. When we considered PFS < 6 months, miR-378e, miR-99b-5p, miR-877-5p, miR-1297, miR-455-5p, and miR-4536-5p were statistically associated with a poor outcome. In the multivariate analysis, the first three miRNAs confirmed a significant and independent impact on PFS. The literature data and bioinformatic tools provide an underlying molecular rationale for most of these miRNAs, mainly involving the PI3K/AKT/mTOR pathway and cell-cycle machinery as cyclin D1, CDKN1B, and protein p27Kip1 and autophagy. Our findings propose a novel panel of miRNAs associated with a higher likelihood of early progression in patients treated with ET and Palbociclib and may contribute to shed some light on the mechanisms of de novo resistance to CDK4/6i, but this should be considered exploratory and evaluated in larger cohorts.

Efficacy and activity of treatments after progression from palbociclib plus endocrine therapy in patients with HR+/HER2- metastatic breast cancer: a prospective, monocentric study.

Background: Breast cancer is the most frequent tumour worldwide, and the HR+/HER2- subtype is the most common. For this tumour type, endocrine therapy (ET) is the mainstay of treatment. The association of ET and CDK4/6 inhibitors (CDK4/6i) represents the gold standard for first-line or second-line therapies. However, the optimal therapeutic strategy after CDK4/6i progression is still a matter of debate, with several randomized clinical trials still ongoing. Patients and methods: This is an observational, prospective, real-world study including women with HR+/HER2- metastatic breast cancer progressing to palbociclib plus ET. Patients received either ET or chemotherapy (CT). The primary objective was the evaluation of efficacy of the different therapeutic strategies after palbociclib in terms of median progression-free survival 2. Secondary objectives were the activity of therapeutic strategies measured with the clinical benefit rate, evaluation of the parameters used for the treatment choice, and progression-free survival 1 related to palbociclib plus ET treatment. Results: Overall, 48 patients (median age 53, range 33-78 years) were included. The median progression-free survival 2 was of 5 months in the overall cohort (95% CI 4-48 months) with a statistically significant difference between the two therapeutic strategies adopted (ET versus CT, 10 months versus 5 months, respectively). Regarding secondary objectives, the clinical benefit rate was 55.2% in the CT cohort and 50% in ET. Moreover, women treated with CT had a greater number of visceral metastases and a shorter median progression-free survival 1 than patients who received ET. Conclusions: ET and CT represent two possible therapeutic alternatives for patients progressing on CDK4/6i plus ET. The choice is based on clinical parameters, with a potential preference for ET.

Common Misconceptions about Diet and Breast Cancer: An Unclear Issue to Dispel.

Breast cancer (BC) constitutes a prevalent health condition among women. Recent years have witnessed the identification of dietary proto-oncogenic factors that deserve attention. Besides the well-known role of alcohol and red and processed meat in BC development, the impact of other dietary components remains unclear. Our narrative review aims to explore the diet-BC relationship, focusing on sugar, dairy, and soy consumption. We conducted a PubMed literature search covering the last decade (2013-2023) and included 35 papers. We found limited evidence on the association between high sugar intake and BC incidence. On the other hand, dairy and soy consumption displayed a protective effect in the majority of the analyzed papers. However, a significant degree of heterogeneity was reported among the results. Menopausal status and the specific BC molecular subtypes were the main factors influencing the interpretation of the results. Exploring dietary factors and BC revealed inconsistencies: high glycemic index post-menopause may be a risk factor, while sugar-sweetened drinks and artificial sweeteners yielded conflicting results; fermented dairy showed potential benefits, non-fermented dairy presented inconsistent findings; soy impact on BC varied according to molecular subtype, with some studies suggesting a positive association in luminal-like BC. Hence, further investigation is crucial to obtain a uniform consensus on the diet-BC relationship.

Opportunities and Challenges of Synthetic Data Generation in Oncology.

Widespread interest in artificial intelligence (AI) in health care has focused mainly on deductive systems that analyze available real-world data to discover patterns not otherwise visible. Generative adversarial network, a new type of inductive AI, has recently evolved to generate high-fidelity virtual synthetic data (SD) trained on relatively limited real-world information. The AI system is fed with a collection of real data, and it learns to generate new augmented data while maintaining the general characteristics of the original data set. The use of SD to enhance clinical research and protect patient privacy has drawn a lot of interest in medicine and in the complex field of oncology. This article summarizes the main characteristics of this innovative technology and critically discusses how it can be used to accelerate data access for secondary purposes, providing an overview of the opportunities and challenges of SD generation for clinical cancer research and health care.

Unlocking the Potential of Circulating miRNAs in the Breast Cancer Neoadjuvant Setting: A Systematic Review and Meta-Analysis.

The potential role of circulating microRNAs (miRNAs) as biomarkers in breast cancer (BC) management has been widely reported. However, the numerous discrepancies between studies in this regard hinders the implementation of circulating miRNAs in routine clinical practice. In the context of BC patients undergoing neoadjuvant chemotherapy (NAC), the possibility of predicting NAC response may lead to prognostic improvements by individualizing post-neoadjuvant therapy. In this context, the present meta-analysis aims to clarify circulating miRNAs' predictive role with respect to NAC response among BC patients. We conducted a comprehensive literature search on five medical databases until 16 February 2023. We pooled the effect sizes of each study by applying a random-effects model. Cochran's Q test (p-level of significance set at 0.05) scores and I2 values were assessed to determine between-study heterogeneity. The PROBAST (Prediction Model Risk of Bias Assessment Tool) tool was used to evaluate the selected studies' risk of bias. Overall, our findings support the hypothesis that circulating miRNAs, specifically miR-21-5p and miR-155-5p, may act as predictive biomarkers in the neoadjuvant setting among BC patients. However, due to the limited number of studies included in this meta-analysis and the high degrees of clinical and statistical heterogeneity, further research is required to confirm the predictive power of circulating miR-21-5p and miR-155-5p.

Clinical Review on the Management of Breast Cancer Visceral Crisis.

Visceral crisis is a life-threatening clinical condition requiring urgent treatment and accounts for 10-15% of new advanced breast cancer diagnoses, mainly hormone receptor-positive/human epidermal growth factor 2 negative. As its clinical definition is an open topic with nebulous criteria and much room for subjective interpretation, it poses a challenge for daily clinical practice. International guidelines recommend combined chemotherapy as first-line treatment for patients with visceral crisis, but with modest results and a very poor prognosis. Visceral crisis has always been a common exclusion criterion in breast cancer trials, and the available evidence mainly comes from limited retrospective studies which are not sufficient to draw solid conclusions. The outstanding efficacy of innovative drugs, such as CDK4/6 inhibitors, questions the role of chemotherapy in this setting. In the lack of clinical reviews, we aim to critically discuss the management of visceral crisis, advocating future treatment perspectives for this challenging condition.

Prognostic Role of Pathological Complete Response in Early Stage Epithelial Solid Tumors.

Neoadjuvant chemotherapy was originally designed to convert inoperable cancer. Nowadays, this concept has expanded since it can also offer the possibility to evaluate markers of response such as pathological complete response (pCR) with possible implications in long-term prognostic outcomes. A substantial body of literature tried to evaluate the ability of pCR to fulfill the conditions required to establish a preliminary endpoint, such as pCR, as a surrogate for the final endpoint, the overall survival (OS) but no systematic reviews have been performed yet. In this review we systematically analyzed the prognostic role of pCR in various cancers (breast, gastro-oesophageal, rectal, ovarian, bladder, lung) in which neoadjuvant treatment is a standard of care, evaluating articles published in the English language of phase III or phase II randomized controlled trials and meta-analyses. Since the continue development of immunotherapy in earlier stage, it has also been considered the impact of tumor-infiltrating lymphocyte on pCR.

Potential Role of Circulating miRNAs for Breast Cancer Management in the Neoadjuvant Setting: A Road to Pave.

Recently, circulating microRNAs (miRNAs) have emerged as potential non-invasive biomarkers for breast cancer (BC) management. In the context of BC patients undergoing neoadjuvant chemotherapy (NAC), the possibility of obtaining repeated, non-invasive biological samples from patients before, during, and after treatment is incredibly convenient and provides the opportunity to investigate circulating miRNAs as diagnostic, predictive, and prognostic tools. The present review aims to summarize major findings in this setting, thus highlighting their potential applicability in daily clinical practice and their possible limitations. In all the contexts (diagnostic, predictive, and prognostic), circulating miR-21-5p and miR-34a-5p have emerged as the most promising non-invasive biomarkers for BC patients undergoing NAC. Specifically, their high baseline level could discriminate between BC patients and healthy controls. On the other hand, in predictive and prognostic investigations, low circulating miR-21-5p and miR-34a-5p levels may identify patients with better outcomes, in terms of both treatment response and invasive disease-free survival. However, the findings in this field have been very heterogeneous. Indeed, pre-analytical and analytical variables, as well as factors related to patients, may explain the inconsistency among different study results. Thus, further clinical trials, with more precise patient inclusion criteria and more standardized methodological approaches, are definitely needed to better define the potential role of these promising non-invasive biomarkers.

Clinical and Biological Variables Influencing Outcome in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) Treated with Anti-PD-1/PD-L1 Antibodies: A Prospective Multicentre Study.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have become the standard of treatment for patients with non-small cell lung cancer (NSCLC). However, there are still many uncertainties regarding the selection of the patient who could benefit more from this treatment. This study aims to evaluate the prognostic and predictive role of clinical and biological variables in unselected patients with advanced NSCLC candidates to receive ICIs. METHODS: This is an observational and prospective study. The primary objective is the evaluation of the relationship between clinical and biological variables and the response to ICIs. Secondary objectives included: safety; assessment of the relationship between clinical and biological parameters/concomitant treatments and progression-free survival at 6 months and overall survival at 6 and 12 months. Nomograms to predict these outcomes have been generated. RESULTS: A total of 166 patients were included. An association with response was found in the presence of the high immunohistochemical PD-L1 expression, squamous cell histotype, and early line of treatment, whereas a higher probability of progression was seen in the presence of anemia, high LDH values and neutrophil/lymphocyte ratio (NLR), pleural involvement, and thrombosis before treatment. The nomogram showed that anemia, PD-L1 expression, NLR, and LDH represented the most informative predictor as regards the three parameters of interest. CONCLUSIONS: In the era of personalized medicine, the results are useful for stratifying the patients and tailoring the treatments, considering both the histological findings and the clinical features of the patients.

Patterns of treatment and outcome of palbociclib plus endocrine therapy in hormone receptor-positive/HER2 receptor-negative metastatic breast cancer: a real-world multicentre Italian study.

BACKGROUND: The CDK4/6 inhibitor palbociclib combined with endocrine therapy (ET) has proven to prolong progression-free survival (PFS) in women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Few data are available regarding the efficacy of such a regimen outside the clinical trials. PATIENTS AND METHODS: This is a multicentre prospective real-world experience aimed at verifying the outcome of palbociclib plus ET in an unselected population of MBC patients. The primary aim was the clinical benefit rate (CBR); secondary aims were the median PFS, overall survival (OS) and safety. Patients received palbociclib plus letrozole 2.5 mg (cohort A) or fulvestrant 500 mg (cohort B). RESULTS: In total, 191 patients (92 in cohort A, 99 in cohort B) were enrolled and treated, and 182 were evaluable for the analysis. Median age was 62 years (range 47-79); 54% had visceral involvement; 28% of patients had previously performed one treatment line (including chemotherapy and ET), 22.6% two lines and 15.9% three. An overall response rate of 34.6% was observed with 11 (6.0%) complete responses and 52 (28.6%) partial responses. Stable disease was achieved by 78 patients (42.9%) with an overall CBR of 59.8%. At a median follow-up of 24 months (range 6-32), median PFS was 13 months without significant differences between the cohorts. When analysed according to treatment line, PFS values were significantly prolonged when palbociclib-based therapy was administered as first-line treatment (14.0 months), to decrease progressively in second and subsequent lines (11.7 and 6.7 months, respectively). Median OS was 25 months, ranging from 28.0 months in 1st line to 18.0 and 13.0 months in 2nd and subsequent lines, respectively. CONCLUSIONS: Our data indicate that palbociclib plus ET is active and safe in HR+/HER2- MBC, also suggesting a better performance of the combinations in earlier treatment lines.

Impact of COVID-19 Outbreak on Cancer Patient Care and Treatment: Data from an Outpatient Oncology Clinic in Lombardy (Italy).

Lombardy was the first area in Italy to have an outbreak of coronavirus disease 19 (COVID-19) at the beginning of 2020. In this context, cancer has been reported as a major risk factor for adverse outcomes and death, so oncology societies have quickly released guidelines on cancer care during the pandemic. The aim of this study was to investigate the management of cancer patients and oncological treatments during the COVID-19 pandemic and to describe the containment measures performed in our outpatient clinic at Pavia (Lombardy). A comparison with the same period of the four previous years (2019, 2018, 2017, and 2016) was also performed. Using our electronic databases, we evaluated the number and characteristics of patients accessing the hospital for anticancer drug infusion from 24 February, 2020 to 30 April, 2020 and the number of radiological exams performed. Although a significant reduction in access for therapy was seen when compared with 2019 (2590 versus 2974, access rate ratio (ARR) = 0.85, p < 0.001), no significant differences in access numbers and ARR was evident between 2020 and 2018, 2017, or 2016 (2590 versus 2626 (ARR = 0.07), 2660 (ARR = 0.99), and 2694 (ARR = 0.96), respectively, p > 0.05). In 2020, 63 patients delayed treatment: 38% for "pandemic fear", 18% for travel restrictions, 13% for quarantine, 18% for flu syndrome other than COVID-19, and 13% for worsening of clinical conditions and death. Only 7/469 patients developed COVID-19. A significant reduction in radiological exams was found in 2020 versus all the other years considered (211 versus 360, 355, 385, 390 for the years 2020, 2019, 2018, 2017, and 2016, respectively, p < 0.001). The low incidence of COVID-19 among our cancer patients, along with the hospital policy to control infection, enabled safe cancer treatment and a continuum of care in most patients, while a small fraction of patients experienced a therapeutic delay due to patient-related reasons.

Renal and Cardiovascular Toxicities by New Systemic Treatments for Prostate Cancer.

Prostate cancer (PC) is the most common male cancer in Western Countries. In recent years, the treatment of relapsed or metastatic disease had benefited by the introduction of a variety of new different drugs. In consideration of the relative long survival of PC patients, side effects of these drugs must be considered and monitored. In this review, we analyzed the newly developed therapies for PC treatment, describing the mechanism of action, the metabolism and latest clinical trials that led to the approval of these drugs in clinical practice. We then evaluated the cardiovascular and renal side effects from pivotal phase III and II studies and meta-analyses. Cardiovascular side effects are the most frequent, in particular hypertension, while renal toxicity is rarer and not well described in literature. Therefore, there is a need to better define the effects of these therapies, in order to personalize patient treatment on the basis of their comorbidities and preferences, in addition to their symptoms and disease load.

Targeting angiogenesis in metastatic renal cell carcinoma.

INTRODUCTION: Renal cell carcinoma (RCC), and particularly its clear cell histological subtype, is commonly characterized by genetic alterations in the Von Hippel Lindau (VHL) tumor suppressor gene, leading to a typically exasperated angiogenesis. However, other biological and genetic peculiarities contribute to differentiate this malignancy from other solid tumors, including its immunogenicity. Areas covered: This review focuses on the present and future role of antiangiogenic drugs, administered either alone (as it has been in the past few years), or in combination with other agents (e.g. immune checkpoint inhibitors), in the treatment of metastatic RCC. Expert commentary: Due to its peculiar pathogenesis, it is unrealistic to expect to be able to get rid of antiangiogenic agents for the treatment of this disease; however, we do expect that combinations of VEGF/VEGFRs-targeting agents with immune checkpoint inhibitors will gradually replace antiangiogenic monotherapies as the standard of care, at least in the first line setting of metastatic RCC patients. Biomarkers discovery remains the highest priority in order to further improve the percentage of patients benefitting of our treatment.