Immunotherapy around the Clock: Impact of Infusion Timing on Stage IV Melanoma Outcomes.

Although the impact of circadian timing on immunotherapy has yet to be integrated into clinical practice, chronoimmunotherapy is an emerging and promising field as circadian oscillations are observed in immune cell numbers as well as the expression of immunotherapy targets, e.g., programmed cell death protein-1 and its ligand programmed death ligand 1. Concurrent retrospective studies suggest that morning infusions may lead to higher effectiveness of immune checkpoint inhibitors in melanoma, non-small cell lung cancer, and kidney cancer. This paper discusses the results of a retrospective study (2016-2022) exploring the impact of infusion timing on the outcomes of all 73 patients with stage IV melanoma receiving immunotherapy at a particular medical center. While the median overall survival (OS) was 24.2 months (95% confidence interval [CI] 9.04-39.8), for a median follow-up of 15.3 months, our results show that having more than 75% of infusions in the afternoon results in shorter median OS (14.9 vs. 38.1 months; hazard ratio 0.45 [CI 0.23-0.86]; p < 0.01) with more expressive impacts on particular subgroups: women, older patients, and patients with a lower tumor burden at the outset of immunotherapy. Our findings highlight the potential benefits of follow-up validation in prospective and translational randomized studies.

Avelumab as First-Line Maintenance Treatment in Locally Advanced or Metastatic Urothelial Carcinoma.

This work provides a summary of guideline recommendations and an expert position on the use of maintenance avelumab therapy based on a review of current international clinical practice guidelines for locally advanced or metastatic urothelial carcinoma (UC). A PubMed literature search was conducted in March 2022 (updated in July 2023) to identify guidelines for locally advanced or metastatic UC. An expert panel (four oncologists and one urologist) reviewed the guidelines and clinical evidence, and discussed practical questions regarding the use of avelumab maintenance therapy in this clinical setting. The National Comprehensive Cancer Network, European Association of Urology and European Society for Medical Oncology guidelines recommend first-line cisplatin-containing chemotherapy for cisplatin-eligible patients, carboplatin-gemcitabine for cisplatin-ineligible patients who are fit for carboplatin, or immunotherapy with programmed death ligand-1 (PD-L1) inhibitors (e.g. atezolizumab) in platinum-ineligible patients. Maintenance avelumab is recommended in patients with response/stable disease following chemotherapy (regardless of PD-L1 status). In patients who relapse after/during chemotherapy, options include immunotherapy, erdafitinib [in those with fibroblast growth factor receptor (FGFR) mutations], enfortumab vedotin or further chemotherapy. The expert panel provided the following practical guidance: (1) consider maintenance avelumab in all eligible patients; (2) continue avelumab until disease progression/unacceptable toxicity; (3) ideally, administer six cycles of platinum-based chemotherapy prior to maintenance avelumab; (4) perform radiological evaluation after four chemotherapy cycles and prior to maintenance avelumab; (5) carboplatin-gemcitabine followed by maintenance avelumab is preferred in cisplatin-ineligible patients (regardless of PD-L1 expression), but consider first-line immunotherapy in PD-L1-positive patients and platinum-ineligible patients (regardless of PD-L1 status); and (6) for patients who relapse on avelumab, second-line options include enfortumab vedotin, FGFR inhibitors (in those with FGFR mutations) or clinical trial inclusion. In conclusion, avelumab maintenance therapy is recommended following platinum-based chemotherapy in all eligible patients with locally advanced or metastatic UC, continued until disease progression or unacceptable toxicity.

Co-targeting RANK pathway treats and prevents acquired resistance to CDK4/6 inhibitors in luminal breast cancer.

The combination of endocrine therapy (ET) and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (CDK4/6i) was a hallmark in metastatic luminal breast cancer (BC). However, intrinsic and acquired resistance affects long-term efficacy. Here, we study the role of the receptor activator of nuclear factor-κB (RANK) pathway in CDK4/6i resistance. We find that RANK overexpression in luminal BC is associated with intrinsic resistance to CDK4/6i, both in vitro and in mouse xenografts, and decreased proliferation rate and chronic interferon (IFN) γ response are highlighted as resistance drivers. Gene expression data from the NeoPalAna CDK4/6i clinical trial, and studies with palbociclib-resistant cell lines, show that RANK is upregulated after treatment with CDK4/6i, supporting a role in acquired resistance. Our study shows that RANK ligand (RANKL) inhibitors can restore sensitivity to CDK4/6i and prevent acquired resistance. On the basis of these findings, we conclude that pharmacological inhibition of the RANK pathway through RANKL blocking could represent an add-on to ET + CDK4/6i, warranting further clinical studies.

Health outcomes and budget impact projection of anti-PD-(L)1s in cancer care in Portugal.

Introduction: PD-[L]1 inhibitors revolutionized cancer treatment but challenge the affordability of health systems. This policy-focused model aimed to estimate the health and budget impact of anti-PD-(L)1s in Portugal and inform current discussions. Materials and methods: The Health Impact Projection (HIP) model estimates clinical (life years, progression-free survival [PFS] years, and quality-adjusted life years [QALY] gained and adverse events [AEs] incurred) and economic (direct and indirect costs) outcomes in a world where cancer patients are initiating treatment with standard-of-care (SOC) versus SOC plus anti-PD-(L)1s over a 3-year time horizon. Indications included adjuvant and metastatic melanoma, non-small cell lung cancer (first and second line), metastatic triple-negative breast cancer, head and neck cancer, urothelial carcinoma, and renal cell carcinoma. Model inputs were based on publicly available literature data and expert opinion. Results: The model estimated that, over 3 years, 7,773 patients would be treated with anti-PD-(L)1s, realizing a gain of 4,787 life years, 6,901 PFS years, and 4,214 QALYs and avoiding 399 AEs. The introduction of anti-PD-(L)1s had a projected average annual impact of ≈ €108 million and a share of 20% of total cancer medicines expenditure and 0.6% of total healthcare expenditure in 2021. Although higher disease management costs are expected for patients living longer with anti-PD-(L)1s and drug acquisition costs are considerable, that is partially offset by a reduction in end-of-life costs (€611,092/year) and costs associated with patient productivity lost to cancer (€9,128,142/year). Discussion: This model highlights the significant survival and QoL benefit of anti-PD-(L)1s for cancer patients in Portugal, with a relatively low increased cost in total healthcare expenditure.

Identification of biomarkers predictive of metastasis development in early-stage colorectal cancer using network-based regularization.

Colorectal cancer (CRC) is the third most common cancer and the second most deathly worldwide. It is a very heterogeneous disease that can develop via distinct pathways where metastasis is the primary cause of death. Therefore, it is crucial to understand the molecular mechanisms underlying metastasis. RNA-sequencing is an essential tool used for studying the transcriptional landscape. However, the high-dimensionality of gene expression data makes selecting novel metastatic biomarkers problematic. To distinguish early-stage CRC patients at risk of developing metastasis from those that are not, three types of binary classification approaches were used: (1) classification methods (decision trees, linear and radial kernel support vector machines, logistic regression, and random forest) using differentially expressed genes (DEGs) as input features; (2) regularized logistic regression based on the Elastic Net penalty and the proposed iTwiner-a network-based regularizer accounting for gene correlation information; and (3) classification methods based on the genes pre-selected using regularized logistic regression. Classifiers using the DEGs as features showed similar results, with random forest showing the highest accuracy. Using regularized logistic regression on the full dataset yielded no improvement in the methods' accuracy. Further classification using the pre-selected genes found by different penalty factors, instead of the DEGs, significantly improved the accuracy of the binary classifiers. Moreover, the use of network-based correlation information (iTwiner) for gene selection produced the best classification results and the identification of more stable and robust gene sets. Some are known to be tumor suppressor genes (OPCML-IT2), to be related to resistance to cancer therapies (RAC1P3), or to be involved in several cancer processes such as genome stability (XRCC6P2), tumor growth and metastasis (MIR602) and regulation of gene transcription (NME2P2). We show that the classification of CRC patients based on pre-selected features by regularized logistic regression is a valuable alternative to using DEGs, significantly increasing the models' predictive performance. Moreover, the use of correlation-based penalization for biomarker selection stands as a promising strategy for predicting patients' groups based on RNA-seq data.

Histology-Agnostic Drugs: A Paradigm Shift-A Narrative Review.

Cancer diagnosis and therapeutics have been traditionally based on pathologic classification at the organ of origin. The availability of an unprecedented amount of clinical and biologic data provides a unique window of opportunity for the development of new drugs. What was once treated as a homogeneous disease with a one-size-fits-all approach was shown to be a rather heterogeneous condition, with multiple targetable mutations that can vary during the course of the disease. Clinical trial designs have had to adapt to the exponential growth of targetable mechanisms and new agents, with ensuing challenges that are closer to those experienced with rare diseases and orphan medicines. To face these problems, precision/enrichment and other novel trial designs have been developed, and the concept of histology-agnostic targeted therapeutic agents has emerged. Patients are selected for a specific agent based on specific genomic or molecular alterations, with the same compound used to potentially treat a multiplicity of cancers, granted that the actionable driver alteration is present. There are currently approved drugs for such indications, but this approach has raised issues on multiple levels. This review aims to address the challenges of this new concept and provide insights into possible solutions and frameworks on how to tackle them.

Genetic and microenvironmental intra-tumor heterogeneity impacts colorectal cancer evolution and metastatic development.

Colorectal cancer (CRC) is a highly diverse disease, where different genomic instability pathways shape genetic clonal diversity and tumor microenvironment. Although intra-tumor heterogeneity has been characterized in primary tumors, its origin and consequences in CRC outcome is not fully understood. Therefore, we assessed intra- and inter-tumor heterogeneity of a prospective cohort of 136 CRC samples. We demonstrate that CRC diversity is forged by asynchronous forms of molecular alterations, where mutational and chromosomal instability collectively boost CRC genetic and microenvironment intra-tumor heterogeneity. We were able to depict predictor signatures of cancer-related genes that can foresee heterogeneity levels across the different tumor consensus molecular subtypes (CMS) and primary tumor location. Finally, we show that high genetic and microenvironment heterogeneity are associated with lower metastatic potential, whereas late-emerging copy number variations favor metastasis development and polyclonal seeding. This study provides an exhaustive portrait of the interplay between genetic and microenvironment intra-tumor heterogeneity across CMS subtypes, depicting molecular events with predictive value of CRC progression and metastasis development.

Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer.

PURPOSE: Cetuximab is an EGFR-targeted therapy approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, about 60% of these patients show innate resistance to cetuximab. To increase cetuximab efficacy, it is crucial to successfully identify responder patients, as well as to develop new therapeutic approaches to overcome cetuximab resistance. EXPERIMENTAL DESIGN: We evaluated the value of EGFR effector phospholipase C gamma 1 (PLCγ1) in predicting cetuximab responses, by analyzing progression-free survival (PFS) of a multicentric retrospective cohort of 94 treated patients with mCRC (log-rank test and Cox regression model). Furthermore, we used in vitro and zebrafish xenotransplant models to identify and target the mechanism behind PLCγ1-mediated resistance to cetuximab. RESULTS: In this study, levels of PLCγ1 were found increased in RAS WT tumors and were able to predict cetuximab responses in clinical samples and in vitro and in vivo models. Mechanistically, PLCγ1 expression was found to bypass cetuximab-dependent EGFR inhibition by activating ERK and AKT pathways. This novel resistance mechanism involves a noncatalytic role of PLCγ1 SH2 tandem domains in the propagation of downstream signaling via SH2-containing protein tyrosine phosphatase 2 (SHP2). Accordingly, SHP2 inhibition sensitizes PLCγ1-resistant cells to cetuximab. CONCLUSIONS: Our discoveries reveal the potential of PLCγ1 as a predictive biomarker for cetuximab responses and suggest an alternative therapeutic approach to circumvent PLCγ1-mediated resistance to cetuximab in patients with RAS WT mCRC. In this way, this work contributes to the development of novel strategies in the medical management and treatment of patients with mCRC.

Immunotherapy in Metastatic Mucosal Melanoma with Disseminated Intravascular Coagulation: A Case of Success.

Mucosal melanoma accounts for 1% of all melanomas. It is more aggressive than cutaneous melanoma, and local excision provides the best disease-free survival. The vast majority of patients eventually develop metastases, with a metastatic pattern independent of the primary tumor site. While studies show that BRAF and KIT inhibitors have a role in the management of these patients, the actual treatment focus is on immunotherapy. Herein is described the case of a 79-year-old woman with metastatic mucosal melanoma and bone marrow infiltration causing disseminated intravascular coagulation, who was treated with an immunotherapy combination (anti-CTLA-4 and anti-PD-1 antibodies), achieving complete disease remission. This is the third case of melanoma with disseminated intravascular coagulation at presentation and the second case treated with immunotherapy in the literature, but the only one achieving disease remission.

HERVs establish a distinct molecular subtype in stage II/III colorectal cancer with poor outcome.

Colorectal cancer (CRC) is one of the most lethal malignancies. The extreme heterogeneity in survival rate is driving the need for new prognostic biomarkers. Human endogenous retroviruses (hERVs) have been suggested to influence tumor progression, oncogenesis and elicit an immune response. We examined multiple next-generation sequencing (NGS)-derived biomarkers in 114 CRC patients with paired whole-exome and whole-transcriptome sequencing (WES and WTS, respectively). First, we demonstrate that the median expression of hERVs can serve as a potential biomarker for prognosis, relapse, and resistance to chemotherapy in stage II and III CRC. We show that hERV expression and CD8+ tumor-infiltrating T-lymphocytes (TILs) synergistically stratify overall and relapse-free survival (OS and RFS): the median OS of the CD8-/hERV+ subgroup was 29.8 months compared with 37.5 months for other subgroups (HR = 4.4, log-rank P < 0.001). Combing NGS-based biomarkers (hERV/CD8 status) with clinicopathological factors provided a better prediction of patient survival compared to clinicopathological factors alone. Moreover, we explored the association between genomic and transcriptomic features of tumors with high hERV expression and establish this subtype as distinct from previously described consensus molecular subtypes of CRC. Overall, our results underscore a previously unknown role for hERVs in leading to a more aggressive subtype of CRC.

BRAF L597K mutation: an opportunity to treat.

The outcomes of patients with metastatic melanoma (MM) have significantly improved after the introduction of BRAF-specific inhibitors. Herein is reported a patient with MM and non-V600-BRAF mutation who responded to iBRAF/iMEK therapy. In July 2014, a 63-year-old man presented with a 4.1mm-thick V600E-BRAF wild type melanoma on the back. Metastases were identified in one sentinel node and two of 11 subsequently excised lymph nodes, with no signs of distant metastatic disease. In September 2017, lung metastasis was observed and pembrolizumab was started. Progressive disease was apparent at cycle 10 and therapy was switched to ipilimumab. After four cycles, an asymmetric response was observed. In November 2017, next generation sequencing genomic profiling disclosed a rare L597K-BRAF mutation and vemurafenib plus cobimetinib therapy was initiated in January 2018. Seven days after treatment start, a remarkable clinical improvement was observed. In April 2018, the patient achieved partial response, which was sustained until October 2018. Cases of patients with non-V600-BRAF mutations responding to iBRAF/iMEK therapy have been reported over the last years. To the best of our knowledge, this is the first case reporting response to combined iBRAF/iMEK therapy in a patient with metastatic melanoma harboring L597K mutation.

Impact of Extraskeletal Metastases on Skeletal-Related Events in Metastatic Castration-Resistant Prostate Cancer with Bone Metastases.

The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has substantially evolved over the last decade. Nonetheless, a better understanding of bone-targeted agents (BTAs) action in mCRPC remains an unmet need. Theuse of BTAs aims to reduce the incidence of skeletal-related events (SREs) in patients with mCRPC. Less frequent BTA schedules are currently being studied to minimize adverse events. In this study, the impact of metastatic compartment (bone and extraskeletal metastases (BESM) vs. bone-only metastases (BOM)) on bone biomarker kinetics, time to first on-study SRE, and symptomatic skeletal events (SSEs) is evaluated. This is a retrospective analysis of the prospective, randomized, multicenter clinical trial of denosumab vs. zoledronic acid in patients with mCRPC and bone metastases. A total of 1901 patients were included, 1559 (82.0%) with BOM and 342 with BESM (18.0%). Bone metastases burden was balanced between groups. Baseline levels and normalization rates of corrected urinary N-terminal telopeptide and bone alkaline phosphatase did not differ between groups. However, BESM patients had a higher risk of SREs (adjusted HR 1.21; 95% CI 1.01-1.46; p = 0.043) and SSEs (adjusted HR 1.30; 95% CI 1.06-1.61; p = 0.014). This difference was more pronounced in the first 12 months of BTA treatment.In mCRPC, strategies of BTA schedule de-escalation may take into account presence of extraskeletal metastases.

Expression of receptor activator of NFkB (RANK) drives stemness and resistance to therapy in ER+HER2- breast cancer.

The role of RANKL-RANK pathway in progesterone-driven mammary carcinogenesis and triple negative breast cancer tumorigenesis has been well characterized. However, and despite evidences of the existence of RANK-positive hormone receptor (HR)-positive breast tumors, the implication of RANK expression in HR-positive breast cancers has not been addressed before. Here, we report that RANK pathway affects the expression of cell cycle regulators and decreases sensitivity to fulvestrant of estrogen receptor (ER)-positive (ER+)/HER2- breast cancer cells, MCF-7 and T47D. Moreover, RANK overexpressing cells had a staminal and mesenchymal phenotype, with decreased proliferation rate and decreased susceptibility to chemotherapy, but were more invasive in vivo. In silico analysis of the transcriptome of human breast tumors, confirmed the association between RANK expression and stem cell and mesenchymal markers in ER+HER2- tumors. Importantly, exposure of ER+HER2- cells to continuous RANK pathway activation by exogenous RANKL, in vitro and in vivo, induced a negative feedback effect, independent of RANK levels, leading to the downregulation of HR and increased resistance to hormone therapy. These results suggest that ER+HER2- RANK-positive cells may constitute an important reservoir of slow cycling, therapy-resistance cancer cells; and that RANK pathway activation is deleterious in all ER+HER2- breast cancer cells, independently of RANK levels.

Levels of Circulating Fibroblast Growth Factor 23 (FGF23) and Prognosis in Cancer Patients with Bone Metastases.

The fibroblast growth factor (FGF) signaling pathway plays a key role in tumorigenesis and is recognized as a potential therapeutic target. In this study, the authors aimed to assess the impact of serum FGF23 levels in the prognosis of patients with cancer and bone metastases from solid tumors. A cohort of 112 patients with cancer and metastatic bone disease were treated with bone-targeted agents (BTA). Serum baseline FGF23 was quantified by ELISA and dichotomized in FGF23high and FGF23low groups. Additionally, the association between FGF23 and overall survival (OS) and time to skeletal-related events (TTSRE) was investigated. Baseline characteristics were balanced between groups, except for the median urinary N-terminal telopeptide (uNTX) level. After a median follow-up of 26.0 months, a median OS of 34.4 and 12.2 months was found in the FGF23low and FGF23high groups, respectively (multivariate HR 0.18, 95% CI 0.07⁻0.44, p = 0.001; univariate HR 0.27, p = 0.001). Additionally, TTSRE was significantly longer for patients with FGF23low (13.0 vs 2.0 months, p = 0.04). Overall, this study found that patients with FGF23low at baseline had longer OS and TTSRE. Further studies are warranted to define its role as a prognostic biomarker and in the use of drugs targeting the FGF axis.

Clinical and translational pharmacology of drugs for the prevention and treatment of bone metastases and cancer-induced bone loss.

Bone disease is a frequent event in cancer patients, both due to cancer spread to bone and to cancer therapies. Bone is the organ most frequently affected by metastatic disease when considering the two most frequent cancers in the Western world (breast and prostate cancers). Bone metastases can have a substantial detrimental effect on patients' quality of life, as well as significant morbidity due to complications collectively known as skeletal-related events (SREs), which include hypercalcaemia, pathological fractures, spinal cord compression, and need of radiotherapy or surgery to the bone. These have been successfully mitigated with the development of bone-targeted agents (BTAs; bisphosphonates and denosumab), focused on inhibiting osteoclast activity. The potential direct antitumour effect of bisphosphonates, as well as the impact of osteoclast inhibition with subsequent decrease in bone metabolism, have also propelled investigation on the role of BTAs in preventing cancer relapse in bone. In this review, the authors aimed to discuss the role of BTAs in the treatment and prevention of bone metastases, as well as their potential value in preventing cancer treatment-induced bone loss (CTIBL). The review will focus on breast and prostate cancers, with the aim of providing the most relevant clinical data emerging from bench to bedside translational research in the field of cancer-induced bone disease.

Prognostic factors for patients treated with abiraterone.

AIM: To evaluate prostate-specific antigen response (PSAr) defined as a ≥50% decrease in PSA concentration from the pretreatment value, as a prognostic factor in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA). METHODS: Retrospective evaluation of patients with mCRPC treated with AA. RESULTS: 124 patients were identified. Median overall survival and progression-free survival for patients achieving PSAr versus patients without PSAr were 29.3 versus 9.7 months and 17.0 versus 5.2 months, respectively. Multivariate analysis confirmed that PSAr correlated with better overall survival (hazard ratio: 0.19; 95% CI: 0.10-0.38; p < 0.001) and progression-free survival (hazard ratio: 0.24; 95% CI: 0.14-0.41; p < 0.001). CONCLUSION: PSAr can be utilized as prognostic and predictive factors in mCRPC patients treated with AA.

Castration-Resistant Prostate Cancer: Mechanisms, Targets and Treatment.

Prostate cancer is the most common malignancy in men, and remains the second leading cause of cancer-related death in this gender [1]. Data suggests that 10-20% of patients with prostate cancer metastasis develop castration-resistant prostate cancer (CRPC) within 5 years of follow-up, and that the median survival since development of castration resistance is approximately 14 months (range 9-30) [2]. Additionally, patients with non-metastatic CRPC are at higher risk of disease progression. Approximately 15-33% of patients develop metastasis within 2 years, increasing the mortality burden in this population [3, 4].

Anti-EGFR Therapy to Treat Metastatic Colorectal Cancer: Not for All.

The development of monoclonal antibodies (mAbs) cetuximab and panitumumab, which target the transmembrane protein epidermal growth factor receptor (EGFR), mark a major step forward in the treatment of metastatic colorectal cancer (mCRC). However, this therapeutic progress proved to be effective only in a very restricted subset of patients. Although several mechanisms of resistance, both primary and acquired, have been identified, the only established predictive tumour biomarker for the treatment of mCRC patients is the RAS mutational status. RAS activating mutations predict a lack of response to these therapies while low levels of primary resistance characterize RAS wild type (WT) patients (only about 15%). However, even WT patients that initially respond to anti-EGFR therapy, eventually undergo tumour progression. In this context, there is still more to be done in the search for effective predictive markers with therapeutic applicability. In this chapter, we provide an overview on the mechanisms that contribute to resistance to EGFR-targeted therapy and highlight what is still missing in our understanding of these molecular mechanisms and approaches to overcome them.

Radionuclides in oncology clinical practice - review of the literature.

Radionuclide therapy is a type of targeted therapy that can be useful in the treatment of several malignant tumors. Compared with other forms of systemic therapy used in cancer - including chemotherapy - it has the advantage of sparing biological structures adjacent to the tumor cells. This treatment modality has registered significant advances since its first use for the treatment of tuberculous skin lesions in the 1900s. This paper reviews the characteristics and clinical applications of therapeutic radionuclides commonly used in the oncology clinical practice, and discusses future potential applications.

Immunotherapy-based combinations: current status and perspectives.

PURPOSE OF REVIEW: Since the approval of ipilimumab, different immune checkpoint inhibitors, vaccines and costimulatory agonists have been developed with success, improving patient's survival in a number of different tumour types. However, immunotherapy results in durable responses but only in a fraction of patients. In order to improve this, combination of different immune agents is currently being attempted in the clinic with the potential of becoming one day the next wave of immune treatments available for our cancer patients. RECENT FINDINGS: Combinatory regimens may have synergistic effects by acting at different points of the cancer immune cycle, from initiation and propagation of anticancer immunity, to stimulation of neoantigen presentation and priming, promotion of trafficking of immune cells to access the tumour and, finally, cancer-cell recognition and killing. SUMMARY: In this article, the most relevant combination strategies that are currently under research are reviewed, as they are expected to become a new standard of care in the near future.