Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma or a Metaphor for Heterogeneity: From Single-Cell Analysis to Whole-Body Imaging.

Pancreatic ductal adenocarcinoma (PDAC) represents a formidable challenge due to its aggressive nature and poor prognosis. The tumor microenvironment (TME) in PDAC, characterized by intense stromal desmoplastic reactions and a dominant presence of cancer-associated fibroblasts (CAFs), significantly contributes to therapeutic resistance. However, within the heterogeneous CAF population, fibroblast activation protein (FAP) emerges as a promising target for Gallium-68 FAP inhibitor positron emission tomography (Ga68FAPI-PET) imaging. Notably, 68Ga-FAPI-PET demonstrates promising diagnostic sensitivity and specificity, especially in conjunction with low tracer uptake in non-tumoral tissues. Moreover, it provides valuable insights into tumor-stroma interactions, a critical aspect of PDAC tumorigenesis not adequately visualized through conventional methods. The clinical implications of this innovative imaging modality extend to its potential to reshape treatment strategies by offering a deeper understanding of the dynamic TME. However, while the potential of 68Ga-FAPI-PET is evident, ongoing correlative studies are essential to elucidate the full spectrum of CAF heterogeneity and to validate its impact on PDAC management. This article provides a comprehensive review of CAF heterogeneity in PDAC and explores the potential impact of 68Ga-FAPI-PET on disease management.

Prognostic Value of Circulating Cytokines in Chemorefractory Colorectal Cancer.

Circulating cytokines could be optimal biomarkers for prognostication and management decisions in colorectal cancer (CRC). Chemorefractory CRC patients with available plasma samples were included in this study. In the discovery cohort (n = 85), 182 circulating cytokines were tested with a semi-quantitative multiplex assay, and prognostic cytokines were analyzed in the validation cohort (n = 111) by ELISA. Overall survival (OS) was the primary outcome measure, with the false discovery rate (FDR) method (significance level of <0.01) being used to correct for multiple comparisons. Four cytokines were associated with OS in the discovery cohort: insulin-like growth factor-binding protein 1 (IGFBP-1) (HR 2.1 [95%CI: 1.58-2.79], FDR < 0.001), insulin-like growth factor-binding protein 2 (IGFBP-2) (HR 1.65 [95%CI: 1.28-2.13], FDR = 0.006), serum amyloid A (SAA) (HR 1.84 [95%CI: 1.39-2.43], FDR < 0.001), and angiotensin II (HR 1.65 [95%CI: 1.29-2.1], FDR = 0.006). Of these, IGFBP-1 (HR 2.70 [95%CI: 1.56-4.76], FDR = 0.007) and IGFBP-2 (HR 3.33 [95%CI: 1.64-6.67], FDR = 0.008) were confirmed to be independently associated with OS in the validation cohort. Patients with high concentrations of IGFBP-1 and/or IGFBP-2 had a median OS of 3.0 months as compared with 6.9 months for those with low concentrations of both cytokines (HR 2.44 [95%CI: 1.52-4.0], FDR = 0.002) Validation of circulating IGFBP-1 and IGFBP-2 as independent prognostic biomarkers for chemorefractory CRC in larger, independent series is warranted.

Immunotherapies in non-metastatic gastrointestinal cancers.

PURPOSE: Over the last decade, immune checkpoint inhibitors (ICI) have emerged as cornerstone in the treatment of many metastatic tumour types, including gastrointestinal cancers. In many solid tumours, the effective therapies in the metastatic field are progressively brought into the curative setting. Consequently, earlier tumoural settings have become a field of experiment for immunotherapies. In melanoma, lung, and bladder cancers, excellent results were recorded, possibly explained by differences in the tumour microenvironment between metastatic and non-metastatic settings. In gastrointestinal (GI) Oncology, nivolumab is the first immune checkpoint inhibitor to become a standard-of-care adjuvant treatment after curative surgery for oesophagal or gastroesophageal junction cancer. RECENT FINDINGS: We herein discuss the results of a selection of the most relevant studies presented/published over the last 18 months testing immunotherapies in non-metastatic GI cancers. Among immunotherapies, ICI have been investigated in pre-, peri- and postoperative setting across tumour types, alone or in combination with chemo- and/or radiotherapy. Vaccines are also a new field of investigation. SUMMARY: Promising results from two studies (NCT04165772 and NICHE-2 study) demonstrating never-seen-before responses to neoadjuvant immunotherapy in MMR deficient (dMMR) colorectal cancers raise hope for improving the patients' outcome and developing organ-sparing strategies in this situation.

Preexisting evidence and outcome of phase III trials in gastrointestinal oncology: a systematic review.

BACKGROUND: A minority of phase III trials in gastrointestinal oncology are positive. We assessed the association between their outcome and the level and characteristics of preexisting evidence. METHODS: EMBASE, PubMed, and proceedings from international meetings were searched for phase III gastrointestinal cancer trials (gastroesophageal, hepatocellular, biliary tract, pancreatic, small bowel, colorectal, anal, stromal, and neuroendocrine) between January 2000 and June 2020. Trials investigating anticancer drugs for advanced disease, with superiority design and standard treatments as control were eligible. The highest level of preexisting evidence was retrieved from the main study report. RESULTS: A total of 193 phase III trials were included, and 69 (35.8%) met their primary endpoint. Positivity rates were as follows: gastroesophageal 37%, colorectal 48%, pancreatic 17.1%, hepatocellular 20%, neuroendocrine 75%, and both biliary tract and GIST 60%. No information about preexisting evidence was found for 44 trials (22.8%). For the remaining 149, preexisting evidence consisted of phase II studies in 123 cases (82.6%) and phase I studies in 26 cases (17.4%). The probability of success was 34.1%, 35.8%, and 35.7%, respectively (P = .934). No parameter from prior studies predicted the outcome of phase III trials except ß < .2 (P = .048). A numerically increased success rate was observed for phase III trials preceded by positive phase II studies (41.9% vs 18.5%, P = .2). CONCLUSIONS: There does not appear to be an association between level of prior evidence and success of phase III gastrointestinal cancer trials. These data, along with the high phase III failure rate, highlight the need to improve the drug development process in this setting.

The emerging role of immunotherapy in the treatment of anal cancer.

For decades, chemoradiotherapy for early-stage disease and systemic chemotherapy for advanced disease have represented the mainstay of treatment for anal cancer. Over the last few years, however, the advent of immunotherapy has opened interesting therapeutic perspectives, with the establishment of new standards of care, and the development of clinical trials that may further shape the treatment algorithm for this tumour. In this review article, we discuss the rationale behind the use of immunotherapy for anal cancer and provide an overview of the available clinical data and ongoing efforts to build on these.

Regorafenib in combination with immune checkpoint inhibitors for mismatch repair proficient (pMMR)/microsatellite stable (MSS) colorectal cancer.

Immune checkpoint inhibitors (ICIs) have marked a new era of cancer treatment, showing remarkable efficacy in a wide range of solid malignancies. In colorectal cancer (CRC), however, the therapeutic potential of ICIs is limited to the small group (≈5%) of patients with mismatch repair deficient (dMMR)/high microsatellite instable (MSI-H) tumours, which are characterised by high mutational/neo-antigen burden, and an inflammatory tumour microenvironment with abundant tumour-infiltrating lymphocytes. Over the last few years, research has focused on immuno-modulatory strategies that could overcome the inherent resistance to ICIs that is observed in the vast group (≈95%) of patients with mismatch repair proficient (pMMR)/microsatellite stable (MSS) tumours. Among these, the combination of ICIs with multi-kinase inhibitors has gained traction in preclinical studies and clinical trials. Thanks to their multiple targets and mechanisms of action, generally involving key cancer pathways such as oncogenesis, angiogenesis, metastasis, and tumour immunity, these agents can exert synergistic effects with ICIs, eventually turning inherently cold cancers into hot tumours, that can be efficiently recognised and targeted by an activated immune system. Regorafenib is routinely used for chemorefractory CRC with limited efficacy. Preliminary evidence, however, suggests that this multi-kinase inhibitor could be an optimal combination partner for ICIs. In this review article, we explain the biological rationale underlying the synergism between regorafenib and ICIs, discuss the available clinical data in CRC, and take a glance into future perspectives by presenting ongoing trials and possible research developments in this setting.

Mind the target: human epidermal growth factor receptor 2 in colorectal cancer.

PURPOSE OF REVIEW: In this article, we briefly summarise the current knowledge about human epidermal growth factor receptor 2 (HER2) alterations in colorectal cancer (CRC) and provide an overview of the latest published evidence especially regarding standardisation of detection methods/diagnostic criteria, prognostication, prediction and targeted treatments. RECENT FINDINGS: Over the last 18 months, the results of many studies have been presented confirming the therapeutic potential of established anti-HER2 agents either as a monotherapy or in combination, as well as new anti-HER2 agents like antibody-drug-conjugates and tyrosine kinase inhibitors. Also, we have seen confirmation of the utility of liquid biopsy and ctDNA analyses as tool for HER2 detection and patient selection. SUMMARY: Despite concerning only 5% of metastatic CRC, HER2 represents a valuable target for emerging anti-HER2 therapies that might significantly improve the outcome of these patients. Standardising HER2 detection methods/diagnostic criteria, and producing high-quality, randomised evidence are the next challenges to meet the standards of regulatory authorities and ultimately have anti-HER2 agents available for use in routine practice.

The Exciting New Field of HER2-Low Breast Cancer Treatment.

Since human epidermal growth factor receptor-2 (HER2) characterization, going through clinical research and regulatory approval of HER2-targeted therapies, much has elapsed and is still unfolding. Hitherto, only breast cancer (BC) patients with HER2 immunohistochemistry 3+ or with HER2 gene fluorescence in-situ hybridization (FISH) amplification (a.k.a., HER2-positive BC) have benefited from anti-HER2 agents. In recent years, however, much of the research effort has been expanded, with positive outcomes being reached for formerly known HER2-negative BC that yet express HER2 to some degree (HER2 immunohistochemistry 1+ or 2+, but FISH negative) and are currently being classified as HER2-low BC for the purpose of trial enrollment. In this sense, our aim is to review the body of evidence of HER2-low BC that led to the study of first-generation anti-HER2 agents, like trastuzumab, and how they have failed to achieve any clinical applicability in this setting. In addition, we review new data that is leading to the growing success of the new generation of drugs, especially the promising HER2-directed antibody-drug conjugates. A narrative review is also performed regarding the rationale behind the consolidated and ongoing clinical trials studying anti-HER2 agents in combination with unrelated agents, such as immunotherapy, endocrine therapy, and CDK4/6 inhibitors. Hopefully, all this ongoing research effort will be able to extend the survival benefits seen with anti-HER2 agents in HER2-positive disease, at least to some degree, to the greater proportion of patients with HER2-low BC.

Clinical outcomes of platinum-based chemotherapy in patients with advanced breast cancer: An 11-year single institutional experience.

BACKGROUND/METHODS: Although the prognosis of metastatic breast cancer (BC) has improved, some patients still develop high burden metastases or visceral crisis (VC) and polychemotherapy is commonly used in these cases. Data reporting the real effectiveness of this strategy are scanty. Therefore, the outcomes of patients with metastatic BC treated with platinum-based chemotherapy (P-ChT) at the Jules Bordet Institute during the period of January 2008 and December 2018 were retrospectively reviewed. The presence of VC was defined according to ABC 4 criteria. RESULTS: 441 patients were identified: visceral metastases were observed in 430 (97.5%) while 261 (59.2%) presented VC. As for metastatic BC subtype, 255 (57.8%) had ER-positive/HER2-negative, 41 (9.3%) ER-positive/HER2-positive, 34 (7.7%) ER-negative/HER2-positive and 111 (25.1%) triple-negative BC. Median number of prior treatment lines was 3.8 (0-12). Median OS with P-ChT in the entire cohort was 6.13 months. Patients with VC had lower OS than patients without VC (8.6 vs 3.7 months; p < 0.001). On multivariate analysis, the variables correlated with worse OS were hyperbilirubinemia (HR 1.90; 95% CI 1.34-2.75), ECOG ≥2 (HR 1.77; 95% CI 1.13-2.78) and ECOG ≥3 (HR 2.52; 95% CI 1.48-4.28), and >3 previous treatment lines (HR 2.27; 95% CI 1.53-3.21). Of the 261 patients with VC, 106 (40.5%) presented a resolution of the VC which correlated with better OS (9.3 vs 2.0 months, HR 0.27; 95% CI 0.21-0.36). CONCLUSION: Patients who overcome VC benefit from P-ChT with OS similar to patients without VC. In this analysis, hyperbilirubinemia, poor ECOG and >3 previous treatment lines were significant prognostic factors in the overall study population.