Different Genomic Clusters Impact on Responses in Advanced Biliary Tract Cancer Treated with Cisplatin Plus Gemcitabine Plus Durvalumab.

BACKGROUND: The results reported in the TOPAZ-1 phase III trial led to the approval of the combination of cisplatin and gemcitabine with durvalumab as the new first-line standard of care for patients with locally advanced or metastatic cholangiocarcinoma. OBJECTIVE: We performed a clustering analysis to classify patients into different groups based on their mutation profile, correlating the results of the analysis with clinical outcomes. METHODS: We selected 51 patients with cholangiocarcinoma who were treated with the combination of chemotherapy and durvalumab and who were screened using the next-generation sequencing-based FoundationOne gene panel. We conducted mutation-based clustering of tumors and a survival analysis. RESULTS: Three main clusters were identified. Cluster 1 is mostly characterized by mutations in genes belonging to the chromatin modification pathway, altered in 100% of patients. Cluster 2 is characterized by the alteration of several pathways, among which DNA damage control, chromatin modification, RTK/RAS, cell-cycle apoptosis, TP53, and PI3K were the most affected. Finally, most altered pathways in cluster 3 were RTK/RAS and cell-cycle apoptosis. Overall response rate was 4/13 (31%), 12/24 (50%), and 0/10 (0%) in cluster 1, cluster 2, and cluster 3, respectively, and the difference between the three clusters was statistically significant (p = 0.0188). CONCLUSIONS: By grouping patients into three clusters with distinct molecular and genomic alterations, our analysis showed that patients included in cluster 2 had higher overall response rates, whereas patients included in cluster 3 had no objective response. Further investigations on larger and external cohorts are needed in order to validate our results.

Safety and Efficacy of Atezolizumab and Bevacizumab Combination as a First Line Treatment of Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common leading causes of cancer death worldwide. As most patients are diagnosed with advanced disease, systemic therapy remains the backbone of treatment. In recent years, we have witnessed the transformation of advanced HCC treatment landscapes from single-agent targeted therapies to immunotherapy combinations, with atezolizumab plus bevacizumab becoming the new first-line standard of care with an increase in overall survival, progression-free survival, and objective response rate compared to sorafenib, and a positive impact on quality of life. Although the efficacy and safety of this combination have been confirmed regardless of ethnicity, age, and etiology, only a subgroup of patients seems to benefit the most from this treatment. Currently, predictive serum and tissue biomarkers to select patients who are most likely to respond to atezolizumab plus bevacizumab are lacking. Moreover, the optimal subsequent therapy for patients who progress on first-line atezolizumab plus bevacizumab remains unknown, clinical trials are ongoing, and real-world data are needed to determine the most effective treatment sequence. Importantly, careful evaluation of bleeding risk and preservation of adequate liver function are fundamental to improve patients' prognosis, especially when subsequent treatments are administered.

Pancreatic Ductal Adenocarcinoma and Immune Checkpoint Inhibitors: The Gray Curtain of Immunotherapy and Spikes of Lights.

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a poor 5-year overall survival rate (~10%). The revolution of immunotherapy in clinical oncology has not substantially changed clinical outcome for patients with PDAC. Despite outstanding efforts, neither immune checkpoint inhibitors (ICIs) alone, nor in combination with chemotherapy or targeted therapies have shown encouraging results. This failure mirrors the lack of knowledge about the real key players of immune system senescence and the complexity of the tumor microenvironment in PDAC. However, some hope can be derived from PARP-inhibitor combinations, vaccines, and CAR-T-cells therapy. In this review, we comprehensively summarize the latest updates about the use of ICIs in PDAC, focusing on clinical evidence and ongoing studies highlighting explanations for the failure of immunotherapy and possible solutions.

Should patients on levothyroxine therapy be screened for pancreatic cancer?

BACKGROUND: Pancreatic ductal adenocarcinoma is an aggressive disease with increasing incidence. Thyroid hormones play different roles in development and physiological processes of the entire digestive system, including pancreas. Therefore, many have hypothesized that thyroid hormone supplementation for hypothyroidism disorders might increase the risk of malignancy. PATIENTS AND METHODS: We conducted retrospective observational mono-centre study. The aim was to examine the prevalence of thyroid disorders among patients with pancreatic cancer. Moreover, we investigated the impact of thyroid hormone supplementation in pancreatic cancer patients' outcome and the correlation with various clinicopathologic parameters. RESULTS: A total of 92 consecutive pancreatic cancer patients were retrospectively reviewed: 18.5% patients had a history of hypothyroidism and all received a replacement hormone therapy with levothyroxine, in particular 20% in metastatic group and 11% in radically resected PDAC patients' group. Nor in radically resected neither in metastatic group, we did not observe any statistically significant difference in outcome between the group with or without thyroid disorders. On multivariate analyses, cox proportional hazards model analysis showed that only the presence of perineural invasion was associated with a significantly higher hazard ratio for overall survival in metastatic PDAC patients (HR=2.7; 95%CI=1.029-6.925; p=0.009). CONCLUSIONS: We observed higher prevalence of thyroid disorders in PDAC patients. Further studies are warranted to explore the impact of levothyroxine therapy on outcome in PDAC patients.

Long-Term Effects of Breast Cancer Therapy and Care: Calm after the Storm?

Breast cancer is still a lethal disease and the leading cause of death in women, undermining patients' survival and quality of life. Modern techniques of surgery and radiotherapy allow for the obtaining of good results in terms of survival, however they cause long-term side effects that persist over time, such as lymphedema and neuropathy. Similarly, the advent of new therapies such as endocrine therapy revolutionized breast cancer outcomes, but side effects are still present even in years of follow-up after cure. Besides the side effects of medical and surgical therapy, breast cancer is a real disruption in patients' lives considering quality of life-related aspects such as the distortion of body image, the psychological consequences of the diagnosis, and the impact on family dynamics. Therefore, the doctor-patient relationship is central to providing the best support both during treatment and afterwards. The aim of this review is to summarize the consequences of medical and surgical treatment on breast cancer patients and to emphasize the importance of early prevention of side effects to improve patients' quality of life.

Olaparib as a single agent treatment in pre-treated metastatic pancreatic cancer patient harboring BRCA2 mutation: What could we expect?

BACKGROUND: Despite ongoing developments, pancreatic cancer remains one of the most difficult tumors to treat. Even the most effective chemotherapy regimens, only marginally improve the outcome of Pancreatic cancer patients, which rarely exceeds one year. A small subset of Pancreatic cancer patients, carriers of germline variants of BRCA1/2, are clinically relevant as therapeutic targets in pancreatic cancer, both for the first-line and maintenance therapy, as they are more responsive to platinum-based chemotherapy agents and PARP inhibitors. Though, a little is known about the efficacy of olaparib monotherapy in later lines, or in poor responders to platinum-based regimens. METHODS: We describe a case of a patient with pancreatic cancer harboring BRCA2 mutation, treated with radical surgery, adjuvant treatment and three different palliative chemotherapy regimens at disease recurrence (FOLFOX in first line with progression-free survival of five months, gemcitabine and nab-paclitaxel in the second line with progression-free survival of six months and FOLFIRI in the third line with progression-free survival of three months) before olaparib off-label treatment. RESULTS: Interestingly, the patient remained 10 months on olaparib treatment, without disease progression, and without any side effects from the treatment. CONCLUSION: In conclusion, this case highlights the clinically relevant progression-free survival with olaparib treatment in later line and the potential of better health-related quality of life in this small subset of Pancreatic cancer patients.

Transforming Growth Factor-Beta Signaling in Cancer-Induced Cachexia: From Molecular Pathways to the Clinics.

Cachexia is a metabolic syndrome consisting of massive loss of muscle mass and function that has a severe impact on the quality of life and survival of cancer patients. Up to 20% of lung cancer patients and up to 80% of pancreatic cancer patients are diagnosed with cachexia, leading to death in 20% of them. The main drivers of cachexia are cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), macrophage inhibitory cytokine 1 (MIC-1/GDF15) and transforming growth factor-beta (TGF-ß). Besides its double-edged role as a tumor suppressor and activator, TGF-ß causes muscle loss through myostatin-based signaling, involved in the reduction in protein synthesis and enhanced protein degradation. Additionally, TGF-ß induces inhibin and activin, causing weight loss and muscle depletion, while MIC-1/GDF15, a member of the TGF-ß superfamily, leads to anorexia and so, indirectly, to muscle wasting, acting on the hypothalamus center. Against this background, the blockade of TGF-ß is tested as a potential mechanism to revert cachexia, and antibodies against TGF-ß reduced weight and muscle loss in murine models of pancreatic cancer. This article reviews the role of the TGF-ß pathway and to a minor extent of other molecules including microRNA in cancer onset and progression with a special focus on their involvement in cachexia, to enlighten whether TGF-ß and such other players could be potential targets for therapy.

It Takes Two to Tango: Potential Prognostic Impact of Circulating TGF-Beta and PD-L1 in Pancreatic Cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with rising incidence and poor prognosis. The lack of reliable prognostic biomarkers hampers the individual evaluation of the survival and recurrence potential. Methods: Here, we investigate the value of plasma levels of two potential key players in molecular mechanisms underlying PDAC aggressiveness and immune evasion, soluble TGF-beta (sTGF-beta) and sPD-L1, in both metastatic and radically-resected PDAC. To this aim we prospectively enrolled 38 PDAC patients and performed appropriate statistical analyses in order to evaluate their correlation, and role in the prediction of disease relapse/progression, and patients' outcome. Results: Metastatic patients showed lower levels of circulating sTGF-beta and higher levels of sPD-L1 compared to radically-resected patients. Moreover, a decrease in sTGF-beta levels (but not sPD-L1) was significantly associated with disease relapse in radically-resected patients. We also observed lower sTGF-beta at disease progression after first-line chemotherapy in metastatic patients, though this change was not statistically significant. We found a significant correlation between the levels of sTGF-beta and sPD-L1 before first-line chemotherapy. Conclusions: These findings support the possible interaction of TGF-beta and PD-L1 pathways and suggest that sTGF-beta and sPD-L1 might synergize and be new potential blood-based biomarkers.

"Depart from evil, and do good": Turning Axl from uncontrolled tumorigenic gene to biomarker for early detection of pancreatic cancer.

Attempts to achieve early diagnosis are crucial to improve the outcome of patients with pancreatic ductal adenocarcinoma (PDAC). Here we present a critical evaluation of a recent study unraveling the potential of circulating AXL as a novel blood marker for early detection of PDAC and differential diagnosis from chronic pancreatitis (CP).

Potential Role of Exosomes in the Chemoresistance to Gemcitabine and Nab-Paclitaxel in Pancreatic Cancer.

In recent years, a growing number of studies have evaluated the role of exosomes in pancreatic ductal adenocarcinoma cancer (PDAC) demonstrating their involvement in a multitude of pathways, including the induction of chemoresistance. The aim of this review is to present an overview of the current knowledge on the role of exosomes in the resistance to gemcitabine and nab-paclitaxel, which are two of the most commonly used drugs for the treatment of PDAC patients. Exosomes are vesicular cargos that transport multiple miRNAs, mRNAs and proteins from one cell to another cell and some of these factors can influence specific determinants of gemcitabine activity, such as the nucleoside transporter hENT1, or multidrug resistance proteins involved in the resistance to paclitaxel. Additional mechanisms underlying exosome-mediated resistance include the modulation of apoptotic pathways, cellular metabolism, or the modulation of oncogenic miRNA, such as miR-21 and miR-155. The current status of studies on circulating exosomal miRNA and their possible role as biomarkers are also discussed. Finally, we integrated the preclinical data with emerging clinical evidence, showing how the study of exosomes could help to predict the resistance of individual tumors, and guide the clinicians in the selection of innovative therapeutic strategies to overcome drug resistance.

Small Bowel Adenocarcinoma: From Molecular Insights to Clinical Management.

Small bowel adenocarcinoma (SBA) is a rare malignancy, with a rising incidence in recent decades, and accounts for roughly 40% of all cancers of the small bowel. The majority of SBAs arise in the duodenum and are associated with a dismal prognosis. Surgery remains the mainstay of treatment for localized disease, while systemic treatments parallel those used in colorectal cancer (CRC), both in the adjuvant and palliative setting. In fact, owing to the lack of prospective data supporting its optimal management, SBA has historically been treated in the same way as CRC. However, recent genetic and molecular data suggest a distinct profile from other gastrointestinal malignancies and support a more nuanced approach to its management. Herein, we briefly review the state-of-the-art in the clinical management of early-stage and advanced disease and recent discoveries of potentially actionable genetic alterations or pathways along with the most promising ongoing clinical trials, which will hopefully revolutionize the treatment landscape of this orphan disease in the foreseeable future.

Biological Hallmarks and New Therapeutic Approaches for the Treatment of PDAC.

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest solid tumors and is estimated to become a leading cause of cancer-related death in coming years. Despite advances in surgical approaches and the emergence of new chemotherapy options, its poor prognosis has not improved in the last decades. The current treatment for PDAC is the combination of cytotoxic chemotherapy agents. However, PDAC shows resistance to many antineoplastic therapies with rapid progression. Although PDAC represents a heterogeneous disease, there are common alterations including oncogenic mutations of KRAS, and the frequent inactivation of different cell cycle regulators including the CDKN2A tumor suppressor gene. An emerging field of investigation focuses on inhibiting the function of proteins that suppress the immune checkpoint PD-1/PD-L1, with activation of the endogenous immune response. To date, all conventional immunotherapies have been less successful in patients with PDAC compared to other tumors. The need for new targets, associated with an extended molecular analysis of tumor samples could give new pharmacological options for the treatment of PDAC. It is, therefore, important to push for a broader molecular approach in PDAC research. Here, we provide a selected summary of emerging strategy options for targeting PDAC using CDK4/6 inhibitors, RAS inhibitors, and new drug combinations with immune checkpoint agents.

The Growing Skyline of Advanced Hepatocellular Carcinoma Treatment: A Review.

Hepatocellular carcinoma (HCC) is the main type of liver cancer. In the majority of cases, HCC is diagnosed at the advanced stage, leading to poor prognosis. In recent years, many efforts have been devoted to investigating potential new and more effective drugs and, indeed, the treatment armamentarium for advanced HCC has broadened tremendously, with targeted- and immune-therapies, and probably the combination of both, playing pivotal roles. Together with new established knowledge, many issues are emerging, with the role of neoadjuvant/adjuvant settings, the definition of the best transitioning time from loco-regional treatments to systemic therapy, the identification of potential predictive biomarkers, and radiomics being just some of the topics that will have to be further explored in the next future. Clearly, the current COVID-19 pandemic has influenced the management of HCC patients and some considerations about this topic will be elucidated.

The implication of liquid biopsies to predict chemoresistance in pancreatic cancer.

Pancreatic cancer is one of the most aggressive diseases among solid tumors. Most patients are diagnosed with advanced or metastatic disease and are characterized by poor chemosensitivity. Therefore, earlier diagnosis and novel therapeutic possibilities for pancreatic cancer patients are urgently needed. Liquid biopsy is an emerging technology that allows the noninvasive sampling of tumor material. Nowadays, liquid biopsy has shown promising results as diagnostic, prognostic and predictive biomarkers, but it has not yet been universally adopted into regular use by clinicians. In this review, we describe different components of liquid biopsy, especially circulating tumor cells, circulating tumor DNA and exosomes and their potential clinical utility for pancreatic cancer patients.

The role of the microbiome in drug resistance in gastrointestinal cancers.

Introduction: The microbiota is recognized for its impact on both human health and disease. The human microbiota is made up of trillions of cells, including bacteria, viruses, and fungi. The largest population of microbes reside in the gut, prompting research for better understanding of the impact of gastrointestinal microbiota in different diseases. Evidence from numerous studies has pointed out the role of commensal microbes as key determinants of cancer pathogenesis. Moreover, gut microbiota may play an important role in chemoresistance; consequently, this knowledge might be important for novel strategies to improve anticancer treatment efficacy.Areas covered: We describe the role of microbiota in different gastrointestinal cancer types (esophageal, gastric, colorectal, hepatocellular and pancreatic-biliary tract cancers). Moreover, we analyzed the impact of the microbiota on resistance to anticancer therapies, and, lastly, we focused on possibilities of microbiota modulation to enhance anticancer therapy efficacy.Expert opinion: Increasing evidence shows that gut microbiota might influence resistance to anticancer treatment, including conventional chemotherapy, immunotherapy, radiotherapy, and surgery. Therefore, a better knowledge of gut microbiota and its interactions with anticancer drugs will enable us to develop novel anticancer treatment strategies and subsequently improve the cancer patients' outcome.

Synchronous and metachronous colorectal liver metastases: impact of primary tumor location on patterns of recurrence and survival after hepatic resection.

BACKGROUND: Considerable differences in terms of prognosis exist between the right-sided (RCC) and the left-sided colon cancer (LCC). Aim of the work: In this study, we evaluated prognostic implications of primary tumor location (PTL) among patients who underwent curative-intent hepatectomy for synchronous (SM) and metachronous (MM) colorectal liver metastases (CRLM). METHODS: The study population included all consecutive patients affected by CRLM scheduled for first liver resection at three Italian oncological centers. RESULTS: A total of 204 patients who underwent CRLM resection were included, 50% with RCC. Synchronous lesions were prevalent (n=133, 65%). Median OS was respectively 40.3 months for SM-RCC, 53.5 months for SM-LCC, 64.5 months for MM-RCC and 81.6 months for MM-LCC. Patients with MM-LCC showed an OS better than patients with SM-RCC (p=0.008) and SM-LCC (p=0.002). PTL had no influence on RFS. RCC group had less recurrences (75% vs 86.5%), though further surgery with curative-intent was possible more in LCC group (29.3% vs 32.5%). Cox proportional hazards model analysis showed that age and the presence of SM vs MM was associated with a significantly higher hazard ratio (HR) for death (HR=1.024; 95%CI=1.005-1.043; p=0.011 and HR=2.010; 95%CI=1.328-3.043; p=0.001, respectively). CONCLUSIONS: We confirmed that patients with CRLM and right-sided primary colon cancer experience worse survival after hepatic resection. The timing of metastasis has been revealed as important prognostic factor.

State of the Art for Metastatic Pancreatic Cancer Treatment: Where Are We Now?

The prognosis of metastatic pancreatic cancer remains poor despite the recent progress on modern chemotherapeutic regimens, such as FOLFIRINOX, gemcitabine and nab-paclitaxel. A better understanding of the altered signalling pathways and the importance of stroma and the immune environment in pancreatic cancer have led to the development of new clinical trials with promising results. In the present review, a general outline of current first- and second-line therapies is provided. Further, new therapeutic possibilities are reviewed, in particular EGFR and VEGF inhibitors, immunotherapy and PARP inhibitors.

Noncoding Rnas Emerging as Novel Biomarkers in Pancreatic Cancer.

Noncoding RNAs play important regulatory roles in diverse biological processes and their misregulation might lead to different diseases, including cancer. Previous studies have reported the evolving role of miRNAs as new potential biomarkers in cancer diagnosis, prognosis, as well as predictive biomarkers of chemotherapy response or therapeutic targets. In this review, we outline the involvement of noncoding RNA in pancreatic cancer, providing an overview of known miRNAs in its diagnosis, prognosis and chemoresistance. In addition, we discuss the influence of non-coding RNAs in the metastatic behavior of pancreatic cancer, as well as the role of diet in epigenetic regulation of non-coding RNAs in cancer, which can, in turn, lead the development of new prevention's techniques or novel targets for cancer therapy.