Studies presented at the ESMO Gastrointestinal Cancers Congress 2024 could improve outcomes through better patient selection and optimised use of available therapies
Treatment of gastrointestinal (GI) cancers is catching up with other areas of oncology and offering patients better prospects for survival and quality of life, but a significant uptick in early-onset cases is raising new questions about effective prevention, diagnosis and treatment. That was the subject of much discussion at the ESMO Gastrointestinal Cancers Congress 2024 which took place in Munich, Germany, 26-29 June.
Early-onset GI cancers: A growing concern
GI malignancies account for a quarter of cancer cases and for one in three cancer-related deaths globally, with colorectal cancer being among the three most common tumour types and causing over 900,000 fatalities each year.
Annual new cases of early-onset disease, ie, in individuals below the age of 50, have risen by 51 per cent in high-income regions since the 1990s, and if this trend continues colorectal cancer could become the deadliest cancer in the 20-49 years demographic by 2030.
Research presented at the ESMO Gastrointestinal Cancers Congress 2024 tends to confirm that young GI cancer patients are more likely to be diagnosed at an advanced stage, a possible explanation for the poorer outcomes seen in this age group.
Similarly, one study found that pancreatic cancer displays more aggressive behaviour in younger individuals, with lower rates of curative surgery and a higher risk of relapse.
In the area of biliary tract cancers, by contrast, young patients appeared to have a better prognosis than their older counterparts in the advanced setting thanks to a higher prevalence of actionable molecular alterations such as FGFR2 fusions making them eligible for personalised therapies.
With almost 455,000 new cases of colorectal cancer diagnosed in Europe in 2022, including 20,000 patients aged between 18 and 49 years, ESMO President Prof Andrés Cervantes, Professor of Medicine at the University of Valencia and Head of the Medical Oncology Department at Hospital Clínico Universitario de Valencia, Spain, highlighted the importance of better understanding the characteristics of this young patient demographic as well as the risk factors they are exposed to in order to help design effective strategies for prevention and early detection.
Hereditary cancer risks such as Lynch syndrome make early-onset disease more likely, but these only account for a minority of the cases diagnosed. As the age shift is observed for different gastrointestinal cancers and across high-income countries globally, there is good reason to suspect lifestyle-related factors that affect the composition of the gut microbiome are playing a role, such as the Western diet, low physical activity or use of antibiotics, but these hypotheses still need to be scientifically confirmed.
Data from two presentations at the Congress highlighted the clinical utility of liquid biopsies detecting circulating tumour DNA (ctDNA) in guiding treatment for patients with metastatic colorectal cancer (mCRC) and providing prognostic information post-surgery for patients with stage 3 colon cancer.
In the first study, the phase 2 CAPRI 2-GOIM trial, molecular assessments were performed at baseline using next-generation sequencing (NGS) on tumour tissue and plasma ctDNA in patients with RAS/BRAF wild-type mCRC (Abstract 6MO). Plasma ctDNA results were available for 206 patients, of whom 19 had molecular alterations associated with resistance to anti-EGFR therapies (18 patients with alterations in RAS and one patient with alterations in BRAF). Overall, 166 patients had both tissue and ctDNA results available. Among RAS-mutated tumours, high (94.6%) concordance was reported between tissue and ctDNA, except for mutations found in nine patients: three mutations found only in tissue and six mutations found only in ctDNA.
Remarking on these results, Dr Pashtoon Murtaza Kasifrom Weill Cornell Medicine, New York, NY, USA, says, “This trial contributes to a growing body of evidence supporting the use of ctDNA in patients with mCRC. It shows the clinical value of baseline plasma NGS, not only in guiding the selection of patients for anti-EGFR therapy but also in detecting other genetic aberrations that may otherwise have been missed.” However, he also highlighted that, “Liquid biopsy is not necessarily a replacement for tissue biopsy but should instead be considered as a complementary tool.”
From prevention to early diagnosis: New approaches to GI cancer screening
As a very heterogeneous group of diseases, gastrointestinal cancers remain overall an area with high unmet need and in which late diagnosis remains a common issue leading to poor outcomes. “We have a problem with prevention and screening in the GI field, where compliance with invitations to undergo stool testing or colonoscopies is lower than 30 per cent across Europe, compared to adherence to breast cancer screening which is two to three times higher,” Prof Cervantes emphasised, calling for educational efforts and collaboration with primary care physicians to improve awareness and acceptance.
Opening up new perspectives in this area are technologies that were previously used in the advanced disease setting, now being used to screen for cancers that are not yet clinically detectable. “Multi-cancer early detection tests, mainly in the form of blood tests, are drawing a lot of interest to allow diagnosis of cancer patients at an earlier stage and increase their chances of being cured,” said Dr Benedikt Westphalen, Comprehensive Cancer Centre Munich, Germany, Chair of the ESMO Translational Research and Precision Medicine Working Group, who saw potential for these non-invasive methods to extend the reach of GI cancer screening both in the general population and particularly in younger age groups.
Research highlights from the ESMO GI Congress programme
Growing interest and scientific activity in the field of GI oncology are putting an end to the time when treatment of GI cancers was lagging behind other areas of oncology that saw successive waves of innovation with targeted agents and immunotherapy. “We had difficulties integrating these new therapies in gastrointestinal oncology in the past because we had to identify patient subgroups who could really benefit from them, but this is now changing,” Prof Florian Lordick, Professor of Medicine, University of Leipzig, Germany, and Editor-in-Chief of the journal ESMO Gastrointestinal Oncology, explained, citing the example of GI tumours with microsatellite instability, the management of which has been transformed by immunotherapy, now allowing some patients to be spared major surgery.
Progress is increasingly coming from multidisciplinary approaches to managing gastrointestinal cancers, with research presented at the ESMO Gastrointestinal Cancers Congress spanning the fields of medical oncology, surgery, radiotherapy, genetics and immunology. One such breakthrough is being achieved with liver transplants in patients with advanced colorectal cancer that has metastasised to the liver, with data presented for the first time in Europe during the Congress.
Another promising area of research is focusing on making better use of existing therapies to optimise outcomes for patients. “For example, final analysis of long-term data from the KEYNOTE-585 trial integrating immunotherapy in the treatment of advanced gastro-oesophageal cancer reveals that this works very well for some patients with high PD-L1 expression in the tumour tissue, but not for those with a negative biomarker,” Prof Lordick explained. “It is interesting to look at these data in detail because we have to make decisions on a daily basis about who to give these drugs to.” Similarly, an update from the TOPAZ-1 study of durvalumab in biliary tract cancer shows the long-term survival achieved with this immunotherapy and offers insights into the specific results achieved within different patient subgroups.
A further study with potential practical implications showed that a subset of gastric cancer patients who are negative for all currently actionable biomarkers (HER2, PD-L1 and DNA mismatch repair deficiency) and thus have limited options could benefit from the integration of an old chemotherapy agent, paclitaxel, into their course of treatment. For a rare category of gastroenteropancreatic neuroendocrine tumours, data from a prospective randomised trial for the first time confirms the efficacy of a form of targeted treatment by intravenous radiotherapy across patient subgroups.
In colorectal cancer, too, new combinations of immunotherapy with chemotherapy or of immunotherapy with targeted agents in different settings are attempting to optimise the benefit for specific subgroups of patients. Existing diagnostic tools are also being used in complementary ways to further improve the identification of patients for treatments from which they are most likely to benefit.
Updated results from the randomised TRANSMET trial showed that chemotherapy combined with liver transplantation in highly selected patients with colorectal cancer quadrupled the 5-year overall survival (OS) rate compared with chemotherapy alone.
Meanwhile, phase 3 data on immune-based combination therapies fo first-line treatment of hepatocellular carcinoma (HCC), presented at the Congress, confirmed the benefits of the combination of ipilimumab and nivolumab, which further expand alternative therapeutic options for patients with unresected advanced disease.
For more information on the Congress, check out www.esmo.org
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