The Role of KRAS Mutation in Colorectal Cancer-Associated Thrombosis.

Venous thromboembolic events (VTE) are common in patients with colorectal cancer (CRC) and represent a significant contributor to morbidity and mortality. Risk stratification is paramount in deciding the initiation of thromboprophylaxis and is calculated using scores that include tumor location, laboratory values, patient clinical characteristics, and tumor burden. Commonly used risk scores do not include the presence of molecular aberrations as a variable. This retrospective study aims to confirm the link between KRAS-activating mutations and the development of VTE in CRC. A total of 166 patients were included in this study. They were split into two cohorts based on KRAS mutational status. We evaluated the frequency and mean time to VTE development stratified by the presence of KRAS mutations. Patients with mutant KRAS had an odds ratio (OR) of 2.758 for VTE compared to KRAS wild-type patients, with an increased risk of thrombosis being maintained in KRAS mutant patients even after adjusting for other known VTE risk factors. Taking into account the results of this study, KRAS mutation represents an independent risk factor for VTE.

Does the Rechallenge with Another CDK 4/6 Inhibitor in Breast Cancer Work? A Case Report and Literature Review.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors and endocrine therapy are the gold standards for systemic therapy for patients with hormone-positive (HR+)/human epidermal growth factor receptor-2-negative (HER2-) metastatic breast cancer. Following progression, no prospective randomized data exist to help guide second-line treatment. Moreover, there is a scarcity of data on rechallenge treatment strategies with another CDK4/6 inhibitor after prior limiting toxicity. We report a real-world experience of rechallenging with abemaciclib after the prior reaction of grade 4 liver toxicity to ribociclib, with high transaminases values of more than 27 times the upper limit of normal (ULN) and unexpected grade 3 neutropenia and diarrhea after a few months of abemaciclib. After two years of treatment, the patient had stable oncological disease, with normal complete blood count, hepatic enzymes, and a very good performance status. We believe that our clinical case, along with others gathered from all around the world, will help with the consolidation of an unmet clinical need to readjust the treatment after experiencing toxicity to CDK4/6 inhibitors.

Metastatic Kidney Cancer: Does the Location of the Metastases Matter? Moving towards Personalized Therapy for Metastatic Renal Cell Carcinoma.

The management of renal cell carcinoma (RCC) has been revolutionized over the past two decades with several practice-changing treatments. Treatment for RCC often requires a multimodal approach: Local treatment, such as surgery or ablation, is typically recommended for patients with localized tumors, while stage IV cancers often require both local and systemic therapy. The treatment of advanced RCC heavily relies on immunotherapy and targeted therapy, which are highly contingent upon histological subtypes. Despite years of research on biomarkers for RCC, the standard of care is to choose systemic therapy based on the risk profile according to the International Metastatic RCC Database Consortium and Memorial Sloan Kettering Cancer Centre models. However, many questions still need to be answered. Should we consider metastatic sites when deciding on treatment options for metastatic RCC? How do we choose between dual immunotherapy and combinations of immunotherapy and tyrosine kinase inhibitors? This review article aims to answer these unresolved questions surrounding the concept of personalized medicine.

Tumor-to-Tumor Metastasis of Lung Cancer to Kidney Cancer: A Review of the Literature and Our Experience.

Tumor-to-tumor metastasis (TTM) is a rare phenomenon documented in patients with multiple primary cancers. This condition is defined as a metastasis between two true primary tumors. The most frequently reported recipient tumor is renal cell carcinoma (RCC), and the lung carcinomas are the most common metastatic tumor donors. Therefore, this paper attempts to address the current gap in knowledge about this rare phenomenon. The first part of this review outlines the recently proposed models and mechanisms involved in the TTM process. The second part then summarizes and analyzes previous case reports in the literature. We also present our experience with the case of lung cancer that metastasized into RCC. Given the sporadic incidence of TTM, no specific management guidelines exist. Therefore, considering TTM in patients with multiple primary tumors is important as it could potentially modify the oncological management offered.

An Overview of the Safety Profile and Clinical Impact of CDK4/6 Inhibitors in Breast Cancer-A Systematic Review of Randomized Phase II and III Clinical Trials.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have transformed the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer over the last decade. These inhibitors are currently established as first- and second-line systemic treatment choices for both endocrine-sensitive and -resistant breast cancer populations alongside endocrine therapy (ET) or monotherapy. Data on targeted therapy continue to mature, and the number of publications has been constantly rising. Although these drugs have been demonstrated to prolong overall survival (as well as progression-free survival (PFS) in breast cancer patients), changing the paradigm of all current knowledge, they also cause important adverse events (AEs). This review provides the latest summary and update on the safety profile of the three CDK4/6 inhibitors, as it appears from all major phase II and III randomized clinical trials regarding palbociclib, ribociclib, and abemaciclib, including the most relevant 15 clinical trials.

Second-Line Treatment of Metastatic Renal Cell Carcinoma in the Era of Predictive Biomarkers.

BACKGROUND: Over the past few years, significant advancements have been achieved in the front-line treatment of metastatic renal cell carcinomas (mRCCs). However, most patients will eventually encounter disease progression during this front-line treatment and require further therapeutic options. While treatment choices for mRCCs patients are determined by established risk classification models, knowledge of prognostic factors in subsequent line therapy is essential in patient care. METHODS: In this retrospective, single-center study, patients diagnosed with mRCCs who experienced progression after first-line therapy were enrolled. Fifteen factors were analyzed for their prognostic impact on survival using the Kaplan-Meier method and the Cox proportional hazards model. RESULTS: Poor International Metastatic RCCs Database Consortium (IMDC) and Memorial Sloan-Kettering Cancer Center (MSKCC) risk scores, NLR value > 3, clinical benefit < 3 months from a therapeutic line, and the presence of sarcomatoid differentiation were found to be poor independent prognostic factors for shortened overall survival. CONCLUSIONS: This study provided new insights into the identification of potential prognostic parameters for late-line treatment in mRCCs. The results indicated that good IMDC and MSKCC prognostic scores are effective in second-line therapy. Moreover, patients with NLR < 3, no sarcomatoid differentiation, and clinical benefit > 3 months experienced significantly longer overall survival.

Mechanisms of Resistance to CDK4/6 Inhibitors and Predictive Biomarkers of Response in HR+/HER2-Metastatic Breast Cancer-A Review of the Literature.

The latest and newest discoveries for advanced and metastatic hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer are the three cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) in association with endocrine therapy (ET). However, even if this treatment revolutionized the world and continued to be the first-line treatment choice for these patients, it also has its limitations, caused by de novo or acquired drug resistance which leads to inevitable progression after some time. Thus, an understanding of the overview of the targeted therapy which represents the gold therapy for this subtype of cancer is essential. The full potential of CDK4/6i is yet to be known, with many trials ongoing to expand their utility to other breast cancer subtypes, such as early breast cancer, and even to other cancers. Our research establishes the important idea that resistance to combined therapy (CDK4/6i + ET) can be due to resistance to endocrine therapy, to treatment with CDK4/6i, or to both. Individuals' responses to treatment are based mostly on genetic features and molecular markers, as well as the tumor's hallmarks; therefore, a future perspective is represented by personalized treatment based on the development of new biomarkers, and strategies to overcome drug resistance to combinations of ET and CDK4/6 inhibitors. The aim of our study was to centralize the mechanisms of resistance, and we believe that our work will have utility for everyone in the medical field who wants to deepen their knowledge about ET + CDK4/6 inhibitors resistance.

The Prognostic Value of Neutrophil-to-Lymphocyte Ratio in Patients with Metastatic Renal Cell Carcinoma.

BACKGROUND: Metastatic renal cell carcinoma (mRCC) is an aggressive cancer characterised by an increased recurrence rate and an inadequate response to treatment. This study aimed to investigate the importance of the neutrophil-to-lymphocyte ratio (NLR) as a prognostic marker for long-term survival in patients with mRCC. METHODS: We retrospectively analysed data from 74 patients with mRCC treated at our medical centre with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). We evaluated the predictive value of NLR for overall survival (OS) in these patients. RESULTS: The median OS was 5.1 months in the higher NLR group (≥3) and 13.3 months in the lower NLR group (<3) (p < 0.0001). There was no significant difference in the OS between the TKI and ICI therapies in the low NLR group (12.9 vs. 13.6 months, p = 0.411) or in the high NLR group (4.7 vs. 5.5 months, p = 0.32). Both univariate and multivariate analyses revealed that a higher NLR was an independent prognostic factor of long-term survival in patients with mRCC treated with first-line therapy. CONCLUSIONS: This retrospective study showed that adding NLR to other Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) variables might improve the prognostic and predictive power of these models.

Infection and reinfection with SARS-CoV-2 in cancer patients: A cohort study.

COVID-19 reinfection, although a controversial issue, is an important clinical problem in cancer patients and beyond. The present study aimed to identify the risk factors associated with worse outcomes in cancer patients with Covid-19 in both first infection and reinfection and to describe the involvement of vaccines in reinfection outcome. The present study enrolled 85 patients with solid tumors who had Covid-19 infection and had not been previously vaccinated. Classical risk factors associated with worse outcomes in cancer patients with second SARS-Cov infection were considered. The patients were followed up retrospectively, measuring mortality at the first and second infection and the vaccination rate after the first infection. The factors associated with the highest risk of mortality at the first infection were, in order of importance: intensive care unit (ICU) admission, unfavorable performance status, radiologically quantifiable presence of oncological disease, and administration of cytotoxic chemotherapy in the period immediately before infection. The risk factors associated with higher mortality from reinfection were ECOG 3-4 performance status and administration of cytotoxic chemotherapy in the period immediately before infection. In the studied patients, mortality from reinfection was not affected by prior vaccination. Thus, bearing in mind all of these risk factors for poor outcomes in cancer patients with solid tumors presenting with Covid-19 can help the treating oncologists make personalized decisions about patient care during the pandemic.

Clinical Impact of the Administration of FOLFIRINOX Beyond Six Months in Advanced Pancreatic Adenocarcinoma: A Cohort Study.

Background Although a toxic regimen, FOLFIRINOX is one of the most efficient chemotherapy regimens in advanced pancreatic adenocarcinoma. There is no standard number of cycles in locally advanced or metastatic stages. Materials and method The present retrospective study reports the experience of a single center with this regimen administered until disease progression or unacceptable toxicity. The authors of this retrospective study analyzed the data on patients with this diagnosis treated in our clinic during 2017-2021. Forty-two patients were included in the study, 21 who received six courses or less and 21 who received more than six courses. Progression-free survival (PFS) and overall survival (OS) were analyzed according to this stratification. The oncological response was also reported according to dose reduction and treatment delay, irrespective of the number of courses administered. Results Median PFS was 7.5 months, and median OS was 13.6 months in the entire studied population. When patients were compared according to the number of courses received (under six vs. over six), there were obvious differences (PFS: 5.17 months vs. 11.2, p = 0.8, OS: 8 months vs. 17.3 months, p = 0.6). However, when stratifying survival by treatment delay and the presence or absence of dose reduction, better results were seen with lower doses (p<0.001) and treatment temporization (p=0.03). The general incidence of hematologic and neurologic toxicity was higher than the ones reported in the literature. Conclusion The study revealed that patients benefit from the administration of FOLFIRINOX for more than six months, but that the administration of full dose and the maintaining dose intensity does not necessarily favor the patient.