Neoadjuvant immunotherapy in gastrointestinal cancers - The new standard of care?

The development of immune checkpoint inhibitors (ICI) offers novel treatment possibilities for solid cancers, with the crucial benefit of providing higher cure rates. These agents have become part of standard treatments in the metastatic and adjuvant setting for select cancers, such as melanoma, non-small cell lung cancer (NSCLC) or urological malignancies. Currently, there is ample clinical interest in employing ICI in a neoadjuvant setting with a curative intent. This approach is especially supported by the scientific rationale that ICI primarily stimulate the host immune system to eradicate tumor cells, rather than being inherently cytotoxic. Aside from tumor downstaging, neoadjuvant immunotherapy offers the potential of an in situ cancer vaccination, leading to a systemic adjuvant immunological effect after tumor resection. Moreover, preclinical data clearly demonstrate a synergistic effect of ICI with radiotherapy (RT), chemoradiotherapy (CRT) or chemotherapy (ChT). This review harmonizes preclinical concepts with real world data (RWD) in the field of neoadjuvant ICI in gastrointestinal (GI) cancers and discusses their limitations. We believe this is a crucial approach, since up to now, neoadjuvant strategies have been primarily developed by clinicians, whereas the advances in immunotherapy primarily originate from preclinical research. Currently there is limited published data on neoadjuvant ICI in GI cancers, even though neoadjuvant treatments including RT, CRT or ChT are frequently employed in locally advanced/oligometastatic GI cancers (i.e. rectal, pancreatic, esophagus, stomach, etc.). Utilizing established therapies in combination with ICI provides an abundance of opportunities for innovative treatment regimens to further improve survival rates.

Next-Generation Sequencing of Circulating Tumor DNA Can Optimize Second-Line Treatment in RAS Wild-Type Metastatic Colorectal Cancer after Progression on anti-EGFR Therapy: Time to Rethink Our Approach.

BACKGROUND: Management of Ras wild-type colorectal cancer (CRC) patients upon disease progression after the successful use of targeted treatment with anti-EGFR monoclonal antibodies and backbone chemotherapy remains a clinical challenge. SUMMARY: Development of treatment resistance with prevalence of preexisting RAS mutated clones, RAS mutation conversion, truncation of extracellular receptor domains as well as HER2 and MET amplification are molecular events that can be difficult to follow without the use of sophisticated laboratory techniques. The clinical hurdle of re-biopsy and tumor heterogeneity can be overcome by the implementation of next-generation sequencing (NGS) to analyze circulating tumor DNA (ctDNA) and identify druggable mutations or recovery of RAS-wildness. In this opinion paper, we summarize with critical thinking the clinical approach to be followed after the failure of first-line treatment in Ras wild-type CRC tumors with the use of NGS. Rechallenge with anti-EGFR inhibitors, in case of persistent or recovery of RAS-wildness, and targeted approach of specific mutations (BRAF inhibitors), amplifications (anti-Her2 treatment), or fusion proteins (NTRK inhibitors) can by guided by the use of NGS. The use of NGS platforms for serial analysis of ctDNA is an important step to better understand the molecular landscape of metastatic CRC and guide clinical decisions. KEY MESSAGES: NGS should be considered a mainstay in clinical practice for the management of CRC patients and health authorities should consider reimbursing its use in the appropriate clinical settings.

COVID-19 Vaccinations: Summary Guidance for Cancer Patients in 28 Languages: Breaking Barriers to Cancer Patient Information.

BACKGROUND: Covid-19 vaccination has started in the majority of the countries at the global level. Cancer patients are at high risk for infection, serious illness, and death from COVID-19 and need vaccination guidance and support. Guidance availability in the English language only is a major limit for recommendations' delivery and their application in the world's population and generates information inequalities across the different populations. METHODS: Most of the available COVID-19 vaccination guidance for cancer patients was screened and scrutinized by the European Cancer Patients Coalition (ECPC) and an international oncology panel of 52 physicians from 33 countries. RESULTS: A summary guidance was developed and provided in 28 languages in order to reach more than 70 percent of the global population. CONCLUSION: Language barrier and e-guidance availability in the native language are the most important barriers when communicating with patients. E-guidance availability in various native languages should be considered a major priority by international medical and health organizations that are communicating with patients at the global level.

Synthesis of Recommendations From 25 Countries and 31 Oncology Societies: How to Navigate Through Covid-19 Labyrinth.

INTRODUCTION: Pandemic COVID-19 is an unexpected challenge for the oncological community, indicating potential detrimental effects on cancer patients. Our aim was to summarize the converging key points providing a general guidance in order to support decision making, pertaining to the oncologic care in the middle of a global outbreak. METHODS: We did an international online search in twenty five countries that have managed a surge in cancer patient numbers. We collected the recommendations from thirty one medical oncology societies. RESULTS: By synthesizing guidelines for a) oncology service delivery adjustments, b) general and specific treatment adaptations, and c) discrepancies from guidelines comparison, we present a clinical synopsis with the forty more crucial statements. A Covid-19 risk stratification base was also created in order to obtain a quick, objective patient assessment and a risk-benefit evaluation on a case-by-case basis. CONCLUSIONS: In an attempt to face these complex needs and due to limited understanding of COVID-19, a variability of recommendations based on general epidemiological and infectious disease principles rather than definite cancer-related evidence has evolved. Additionally, the absence of an effective treatment or vaccine requires the development of cancer management guidance, capitalizing on comprehensive COVID-19 oncology experience globally.

Trastuzumab mediates antibody-dependent cell-mediated cytotoxicity and phagocytosis to the same extent in both adjuvant and metastatic HER2/neu breast cancer patients.

BACKGROUND: Monoclonal antibodies (mAb), such as trastuzumab are a valuable addition to breast cancer therapy. Data obtained from neoadjuvant settings revealed that antibody-dependent cell-mediated cytotoxicity (ADCC) is a major mechanism of action for the mAb trastuzumab. Conflicting results still call into question whether disease progression, prolonged treatment or concomitant chemotherapy influences ADCC and related immunological phenomena. METHODS: We analyzed the activity of ADCC and antibody-dependent cell-mediated phagocytosis (ADCP) of peripheral blood mononuclear cells (PBMCs) from human epidermal growth factor receptor 2 (HER2/neu) positive breast cancer patients receiving trastuzumab therapy either in an adjuvant (n = 13) or metastatic (n = 15) setting as well as from trastuzumab treatment-naive (t-naive) HER2/neu negative patients (n = 15). PBMCs from healthy volunteers (n = 24) were used as controls. ADCC and ADCP activity was correlated with the expression of antibody binding Fc-gamma receptor (FcγR)I (CD64), FcγRII (CD32) and FcγRIII (CD16) on CD14+ (monocytes) and CD56+ (NK) cells, as well as the expression of CD107a+ (LAMP-1) on CD56+ cells and the total amount of CD4+CD25+FOXP3+ (Treg) cells. In metastatic patients, markers were correlated with progression-free survival (PFS). RESULTS: ADCC activity was significantly down regulated in metastatic, adjuvant and t-naive patient cohorts as compared to healthy controls. Reduced ADCC activity was inversely correlated with the expression of CD107a on CD56+ cells in adjuvant patients. ADCC and ADCP activity of the patient cohorts were similar, regardless of treatment duration or additional chemotherapy. PFS in metastatic patients inversely correlated with the number of peripheral Treg cells. CONCLUSION: The reduction of ADCC in patients as compared to healthy controls calls for adjuvant strategies, such as immune-enhancing agents, to improve the activity of trastuzumab. However, efficacy of trastuzumab-specific ADCC and ADCP appears not to be affected by treatment duration, disease progression or concomitant chemotherapy. This finding supports the application of trastuzumab at any stage of the disease.

Heterozygous carriage of a dysfunctional Toll-like receptor 9 allele affects CpG oligonucleotide responses in B cells.

Toll-like receptors (TLR) are employed by the innate immune system to detect microbial pathogens based on conserved microbial pathogen molecules. For example, TLR9 is a receptor for CpG-containing microbial DNA, and its activation results in the production of cytokines and type I interferons from human B cells and plasmacytoid dendritic cells, respectively. Both are required for mounting an efficient antibacterial or antiviral immune response. These effects are mimicked by synthetic CpG oligodeoxynucleotides (ODN). Although several hyporesponsive TLR9 variants have been reported, their functional relevance in human primary cells has not been addressed. Here we report a novel TLR9 allele, R892W, which is hyporesponsive to CpG ODN and acts as a dominant-negative in a cellular model system. The R892W variant is characterized by increased MyD88 binding and defective co-localization with CpG ODN. Whereas primary plasmacytoid dendritic cells isolated from a heterozygous R892W carrier responded normally to CpG by interferon-α production, carrier B cells showed impaired IL-6 and IL-10 production. This suggests that heterozygous carriage of a hyporesponsive TLR9 allele is not associated with complete loss of TLR9 function but that TLR9 signals elicited in different cell types are regulated differently in human primary cells.

[Consensus guidelines for diagnosis, treatment and follow-up of patients with gastrointestinal stromal tumors]. / Prijedlog postupnika za dijagnostiku, lijecenje i pracénje oboljelih od gastrointestinalnih stromalnih tumora.

Gastrointestinal stromal tumors are the most common mesenchymal tumors in gastrointestinal tract. They are often asymptomatic and discovered incidentally during endoscopic or barium studies. About 80% GISTs have a KIT (CD 117 antigen) gene mutation. Most affect exon 11, less commonly exon 9,13 or 17, that results in uncontrolled KIT signaling. This led to effective systemic therapies in the form of small molecule inhibitors of the receptor tyrosine kinase such as imatinib mesylat. With the purpose of providing standardized approach to rational and effective diagnostic and treatment algorithm in Croatia, a multidisciplinary session was organized. Results of the session are given in the form of Consensus guidelines.

Single-nucleotide polymorphisms in genes encoding toll-like receptor -2, -3, -4, and -9 in case-control study with breast cancer.

BACKGROUND: Genetic susceptibility to cancer is multifactorial, and it is known that impairment of the immune system could contribute to risk for getting cancer. AIM OF THE STUDY: Single-nucleotide polymorphisms (SNPs) of Toll-like receptor (TLR) 2, TLR3, TLR4, and TLR9 genes, which are important for innate immunity, were analyzed for the association with breast cancer. METHODS: The SNPs comprised TLR2 (c.597T>C), TLR2 (c.1350T>C), TLR3 (c.1377C>T), TLR4 (c.896A>G), and TLR9 (c.1635A>G). The allelic and genotypic frequencies of these TLR SNPs were compared between patients (n = 130) and controls (n = 101) in a case-control study from Croatia. RESULTS: TLR SNPs were not significantly different. From the population genetics viewpoint, we found that a hypomorphic variant of TLR4 (p.Asp299Gly) allele has no specific allelic frequency (8.4%) in the Croatian population (n = 496) compared to other Caucasians (6.5-10%). CONCLUSION: These results suggest that polymorphisms in tested TLR genes are not likely to be associated with increased risk for developing breast cancer.

CL097, a TLR7/8 ligand, inhibits TLR-4--dependent activation of IRAK-M and BCL-3 expression.

Prolonged or repeated stimulation of Toll-like receptor (TLR) 4 leads to hyporesponsiveness of monocyte-derived macrophages, which seems to be a hallmark of immunosuppression related to sepsis and cancer. Two negative regulators of TLR-4 signaling are IL-1 receptor-associated kinase M and B-cell leukemia 3. Here, we demonstrate that the expression of both proteins is inhibited when the TLR-7/TLR-8 agonist CL097 is added to monocyte cultures despite costimulation with the TLR-4 agonist LPS or hyaluronic acid. Reduction of IL-1 receptor-associated kinase M and B-cell leukemia 3 was paralleled by a significant increased cytokine induction of TNF-alpha, IL-10, and IL-12 observed after intracellular and extracellular TLR stimulation. In ex vivo stimulated whole blood of patients who have prolonged sepsis or metastatic cancer, TLR-7/TLR-8 agonists retained their ability of increased stimulation of TNF-alpha. These data might add to the understanding of sepsis and cancer-associated immune suppression in men.

Estrogen and progesterone receptor status in primary breast cancer--a study of 11,273 patients from the year 1990 to 2002.

The aim of this study was to gain insight of the breast cancer hormone receptor status of our patients, its stratification according to age as well as its changes during the period of 13 years. 11,273 patients with primary breast cancer from several towns in Croatia were included in this study. Patients' tumour specimens were collected from 1990 to 2002 and were analysed on estrogen (ER) and progesterone (PR) receptors in the Laboratory of the Department of Medical Oncology, University Hospital Centre Zagreb. More than half of our breast cancer patients had ER positive tumours (54.3%). We observed ER + tumours increased with age continuously, with highest percentage in the age group of 70 to 79 years (68.1%). Similarly, proportion of PR + tumours was higher in the older age groups, being the highest between 40 and 49 years (55.9%). During 13 years of the study, the increase in frequency and proportion of ER + tumours was observed (from 52% in 1990 to 62% in 2002) and decrease of PR + tumours (56% to 53%). We confirm previous findings that the risk of hormone dependent breast cancer increases with aging. Risk of ER + breast cancer increased for 10% from 1990 to 2002 and PR + tumours decreased for 3.5% in the same period.

[Imatinib in gastrointestinal stromal tumor treatment--results from University Hospital Centre Zagreb]. / Imatinib u lijecenju gastrointestinalnih stromalnih tumora--Iskustva KBC-a Zagreb.

Gastrointestinal stromal tumours (GIST) may be defined as intraabdominal mesenchymal tumours that express KIT protein or have an activating mutation in class III receptor tyrosine kinase gene (KIT or PDGFRalpha). Most GISTs respond to imatinib mesylate, which selectively inhibits both KIT and PDGFRalpha, and is now considered standard systemic therapy for advanced GIST. We assessed the antitumour response of patients treated with imatinib mesylate who had advanced and/or metastatic (GIST). In the Department of Medical Oncology fourteen (14) patients with advanced GIST were treated in the period from year 2002 to 2004. Imatinib mesylate was applied at the dose of 400 mg daily. Only two patients required dose enlargement up to 800 mg. All tumours had positive immunohystochemical expression of KIT. Median age of patients was 56 years. 12 male patients and 2 female patient was treated. Considering primary site of tumour we had 6 small intestine, 4 mesenterium and 4 gastric tumours. Mean duration of the treatment was 14 months (5 to 30 months). Six patients had partial remission, six had stable disease and two progression. Complete remission has not been achieved in any patient. Side-effects were mild and no patient required dose reduction or treatment discontinuation. Our results show the effectivness of targeted antitumour therapy with imatinib mesylate in advanced and/or metastatic GIST, and correspond to those in literature.

[Gastrointestinal stromal tumors (GIST)--a paradigm of successful targeted therapy of solid tumors]. / Gastrointestinalni stromalni tumori (GIST)--paradigma uspjesnog ciljanog lijecenja solidnih tumora.

Gastrointestinal stromal tumors (GIST) have attracted basic scientists as well as clinicians in the last 10 years. The reason for this is explanation of the pathogenetic mechanism of tumor growth by activation of c-Kit protein, followed by a rationally designed suppressor, a drug named imatinib. It is the first successful therapy for solid tumors to date, although there are other ongoing studies of agents with targeted action on different molecules in different tumors. In 80% of patients there is a clinical benefit from imatinib trreatment. GIST shows great diversity in clinical presentation and some questions still remain, such as malignant potential and prognostic criteria in these tumors. Imatinib therapy demonstrates many favorable effects such as acceptable toxicity and relative mild side effects, excellent quality of life, good patient compliance, etc. There are ongoing trials of new agents designated for target molecules, which would hopefully show benefit after developing resistance to imatinib.