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11.1 How do changes in signalling pathways influence the change from benign adenomas to malignant colorectal tumours?
The accumulation of molecular changes in signalling pathways leads to the progression from benign to malignant states. Using the chromosomal instability pathway as an example this begins with mutation and loss of function of the APC tumour suppressor gene followed by mutation of the KRAS gene that regulate cell proliferation and then progresses via loss of heterozygosity affecting genes located in chromosome 18 and the TP53 gene, another tumour suppressor gene.
11.2 Up to 40-60% of wild-type KRAS colorectal tumours do not respond to anti-EGFR therapy. What other mechanisms can explain the resistance to anti-EGFR in these tumours?
Mutations downstream in the pathway can lead to lack of response to anti-EGFR therapy in the absence of KRAS mutation. Although the data is controversial BRAF mutations or other alterations in the MEK/ERK/MAPK pathway (PIK3CA mutations and loss of PTEN) can lead to resistance to anti-EGFR monoclonal antibodies. Although less frequent, EGFR mutations have been described in CRC patients treated with cetuximab and panitumumab
11.3 Which infective agents have been associated with gastric cancer?
Helicobacter pylori has been associated with gastric carcinoma, but on its own it does not cause its development as only 5% of infected individuals develop gastric cancer.
EBV-associated gastric carcinoma (EBVaGC), defined by the presence of EBV positive cells is a distinct disease recognised by the Cancer Genomic Consortium, characterized by lymphoepithelioma-like carcinoma (very rich accompanying lymphoid population) and conventional adenocarcinoma. EBVaGC is more frequently seen in males, proximal location in the stomach and associated with favourable prognosis. These tumours are characterized by PIK3CA somatic mutations and amplification of PD-L1/L2 among other alterations.
11.4 Cancer progression and resistance to anti-EGFR mutations has been reported in up to 50-70% of lung adenocarcinoma patients. Please describe any mechanism leading to anti-EGFR resistance. Is there any role in ctDNA to monitor response to monoclonal antibodies?
A significant number of EGFR-mutant lung cancer treated with TKIs develop resistance within 9–14 months. The main mechanisms of acquired resistance is the presence of the TT90M substitution, a secondary EGFR kinase domain mutation in exon 20. The substitution can be detected in circulating tumour DNA (ctDNA) from plasma in patients with NSCLC. New EGFR TKIs (e.g., osimertinib) have been approved for locally advanced or metastatic EGFR T790M mutation –positive non-small cell lung cancers.
11.5 Immune checkpoint blockade has provided durable responses across several tumour types and is particularly successful in melanoma. Describe possible mechanisms in the pathogenesis of melanoma which can explain the response to immuno-checkpoint inhibitors?
Environmental exposure to ultraviolet light (similar to tobacco in lung cancer) lead to high mutational load in melanomas resulting in high number of neoantigens. Some of these mutated proteins can be specifically expressed on the cell surface and subsequently recognized by T cells. There is evidence that a high mutational burden increases the likelihood of the development of specific neoepitopes and it is associated with clinical benefit from CTLA-4 blockade in melanoma patients
11.6 Tumours with microsatellite instability tend to respond better to immuno-checkpoint inhibitors. Please explain the possible mechanisms to explain this response?
MMR deficiency leads to accumulation of somatic mutations due to its role in contributing to genomic stability. In addition, dMMR contributes to upregulation of a large number of genes involved in the immune response resulting in production of mediators in the tumour microenvironment, finally leading the activation of the PD-1 pathway. As in melanoma patients the high mutation burden in MMR deficient tumours is associated with high number of tumour neoantigens which contribute to the recruitment and activation of cytotoxic T-cells. Mismatch Repair Deficiency is a well-recognised predictive biomarker for response to immunotherapy. The FDA has approved the use of PD-1 inhibitors in paediatric and adult patients with microsatellite instability (MSI)-high or mismatch repair (MMR)-deficient solid tumours.