ESMO Gastrointestinal Cancers Congress 2024 (Munich, 26-29 June)

Biomarkers to predict recurrence in hepatocellular carcinoma

While there has been progress in the development of treatment for hepatocellular carcinoma (HCC) over the last decade, there is still a need for specific biomarkers to guide management. Studies presented at the European Society for Medical Oncology (ESMO) Gastrointestinal Cancers Congress 2024 (Munich, 26-29 June) reveal how advances in technology may improve patient care.

Predicting which patients with cirrhosis will develop HCC is a key challenge. The capacity of regular ultrasound and alpha-fetoprotein (aFP) testing to predict cancer is limited.

A retrospective study from Hong Kong, presented at the Congress, reported that artificial intelligence (AI) analysis of routine blood tests revealed HCC signatures up to a year before the clinical diagnosis of cancer (Abstract 165MO).

The AI classifier has shown impressive sensitivity and specificity. In a previous study by the same team, AI analysis achieved a sensitivity of 0.80 and specificity of 0.81 for HCC detection (AUROC 0.894 at cutoff).

The new research presented at the Congress examined how effective AI would be at detecting HCC early.

Using the results of blood tests, including full blood counts, liver and renal function tests, and clotting profiles from 3,415 patients with HCC, the researchers showed that AI-associated screening had sensitivity of 61.3 per cent at one to three months, 50.1 per cent at three to six months, 44.2 per cent at six to nine months and 41.3 per cent at nine to 12 months before diagnosis. AI sensitivity was superior to aFP testing, which remained under 45 per cent at all intervals.

It should be noted that this is a study from Asia, where HCC may have a different aetiology compared with Western countries. Large-cohort confirmatory studies are required to give a better insight into the global utility of this AI model.

In another retrospective study presented at the Congress, serial ctDNA testing was shown to be effective in identifying early recurrence in patients with HCC undergoing curative-intent surgery (Abstract 181P).

The researchers retrospectively analysed 672 plasma samples from 120 patients with HCC. The curative-intent treatments were liver transplantation (56%), hepatectomy (40%), or liver directed/systemic therapy (4%) for inoperable patients.

Patients were divided into four cohorts. Cohort A (n=64) were monitored for recurrence after liver transplant. Cohort B (n=47) were monitored for recurrence after hepatectomy. Cohort C (n=4): monitored for treatment response after known recurrence. Cohort D (n=5) were monitored for treatment response in patients with inoperable disease.

A personalised, tumour-informed 16-plex PCR-NGS assay (SignateraTM, Natera, Inc.) was used for ctDNA testing.

The minimal residual disease (MRD) window was defined as up to 12 weeks post liver transplant or resection, before starting adjuvant therapy.

Among 64 patients who underwent liver transplantation and subsequent recurrence monitoring (Cohort A), all 36 patients with testing available in the MRD window were ctDNA negative. One patient turned ctDNA positive upon serial testing and had disease-related death 340 days after ctDNA positivity. Longitudinally, among 61 patients with imaging available within six months of ctDNA testing, sample level specificity of 99.5 per cent was observed.

In Cohort B, ctDNA was detected in 22.5 per cent of patients within the MRD window. Four experienced clinical recurrence. Three had short follow-up. Among 42 patients with imaging available within six months of a ctDNA test, ctDNA positivity was prognostic for recurrence.

In Cohorts C and D, on-treatment ctDNA dynamics were concordant with treatment response, as measured by imaging.

The findings suggest serial ctDNA testing is a valuable tool to identify recurrence early post-resection and liver transplant. ctDNA is also useful for treatment response monitoring in the recurrence setting and can help resolve ambiguous imaging results. The ability to detect patients who are inevitably going to relapse could be useful in tailoring treatment.

A new treatment for heavily pre-treated metastatic colorectal cancer

Dr Grainne O’Kane, Consultant Medical Oncologist, St James’s Hospital, Dublin, and Director of the Cancer Clinical Trials Unit at the Trinity St James’s Cancer Institute, presented data which suggest a possible new treatment for heavily pre-treated metastatic colorectal cancer (mCRC).

BOLD-100 is a novel ruthenium-based small molecule targeting GRP78 to modulate the unfolded protein response and generate reactive oxygen species, leading to DNA damage and cell cycle arrest. This dual action triggers cell death across a spectrum of cancer types, including many that are resistant to current treatments.

Dr O’Kane presented the latest data from the prospective, phase 2 BOLD-100-001 study which is evaluating BOLD-100 + FOLFOX in patients with mCRC (n=38) who have received prior standard treatment, including FOLFOX or CAPOX.

This was a heavily pre-treated population. The median number of prior systemic therapies was four, ranging from two to eight. All but one participant had stage IV disease.

Patients received 625mg/m² of BOLD-100 + FOLFOX on day one of each 14-day cycle. Treatment continued until disease progression or unacceptable toxicity. Participants received a median of six cycles of BOLD-100 + FOLFOX, ranging from one to 18.

As of 14 March 2024, median progression-free survival (PFS) was 4.2 months (95% credible interval [CrI] 3.0-6.0). Median overall survival (OS) was 8.3 months (95% CrI 5.7-13). Disease control rate (DCR) was 77 per cent in 31 evaluable patients.

Three participants achieved a partial response and two achieved target tumour lesion decreases between 20 and 29 per cent.

Treatment was well tolerated. Of the 38 participants, 35 experienced at least one treatment-related adverse events (AEs). The most common AEs were neutropaenia (47%), nausea (42%), vomiting (21%), fatigue (21%), infusion-related reaction (21%), and pruritus (16%). Most AEs were grade 1-2, although 16 patients developed grade 3/4 neutropaenia.

Despite previous oxaliplatin treatment, fewer than 5 per cent of patients reported peripheral neuropathy and those cases that were reported were grade 1/2.

The data suggest BOLD-100 + FOLFOX is an active and well-tolerated treatment for heavily pretreated patients with advance mCRC, demonstrating clinical benefit with minimal neuropathy or significant toxicities. Further study is needed to confirm and expand the current evidence.

Call for new staging system for appendiceal goblet cell adenocarcinoma

New research led by the University of Texas MD Anderson Cancer Centre has identified the clinical features that predict survival in appendiceal goblet cell adenocarcinoma (GCA) and suggests a new staging system is needed in GCA.

Of the 414 patients included in the study, 143 (44%) had lymph node involvement, while lymphovascular invasion (LVI) was noted in 241 (74%). Perineural invasion was present in 275 (87%), and signet ring cells (SRC) were observed in 183 (44%).

On multivariable analysis, stage IV disease, LVI, and SRC were independently associated with overall survival (OS).

Forty patients received first-line chemotherapy, with radiological response in 12 (30%) and PFS of 11 months. Fifty-nine patients had cytoreductive surgery (CRS).

Median OS was 32 months, mean peritoneal cancer index was 15 and complete cytoreduction (CCR=0/1)
was achieved in 42 (71%).

Somatic gene mutation testing was conducted on 116 tumours. TP53 was mutated in 22 of these (27%). Whole-exome sequencing (WES) analysis of 15 tumours identified recurrent deletion at 19q, 19p, and 22q chromosomal regions in eight (53%) cases, leading to loss of apoptosis-inducing genes, such as WTIP and PDCD2L.

Presenting the findings at ESMO GI 2024, Abdelrahman Yousef from the University of Texas MD Anderson Cancer Center said the study suggests a new staging system is needed in GCA to better stratify patient outcomes.

Delving into young-onset GI cancers

The increasing rates of young-onset (YO) gastrointestinal (GI) cancers is a cause for concern. Research is ongoing to understand this phenomenon and inform prevention and management strategies for these young patients.

A dedicated session at ESMO GI 2024 highlighted emerging data on the features and outcomes of these patients.

One study, conducted at two institutions in Greece and Cyprus, found that the clinical and molecular characteristics of colorectal cancer (CRC) are generally similar across patient age groups (Abstract 139P).

The retrospective study included a total of 334 patients aged 18 to 50 years. The proportion with colon cancer was 68 per cent, while the remaining 32 per cent had rectal cancer. The most common presenting symptoms were bleeding per rectum (37.4%), weight loss (36.2%), change in bowel habit (27.5%) and bloating (19.5%).

Molecular testing was carried out on patients with available tissue either prospectively or retrospectively. Pathogenic mutation patterns were comparable between patients with YO colon cancer and their older counterparts. Almost half (48.4%) had RAS mutations – 44.4 per cent in right-sided tumours and 50 per cent in left-sided tumours. The overall rate of BRAF mutations was 8.3 per cent – 13.4 and 6.1 per cent in right- and left-sided tumours, respectively.

However, more YO-CRC patients were diagnosed with metastatic disease at presentation. Approximately 38 per cent presented with stage III disease and 29.5 per cent were stage IV at presentation. For stage IV patients, median progression-free survival (PFS) was seven months and five-year overall survival (OS) was 20.5 per cent.

Early-onset pancreatic cancer similarly appears to be associated with more aggressive disease.

In a study of 238 patients with pancreatic cancer being treated at a medical oncology department in Tunisia between 2021 and 2023, preserved general status (PS 0-1) was more common in patients aged ≥45 years compared to those less than 45 years old (61.5 vs 53.5%).

Relapse after curative surgery was more common in younger patients (69.3 vs 67.9%). A higher proportion of radiologic progression was noted in older patients after first-line palliative chemotherapy (90.9 vs 100%).

All young patients progressed after second line treatment (100 vs 71.6%). PFS was five months for YO patients and six months for older patients.

Although the results did not meet statistical significance, they suggest that more aggressive treatments should be recommended for young patients with pancreatic cancer.

In contrast, however, patients diagnosed with YO biliary tract cancer (BTC) may have a better prognosis in the metastatic setting than their elders, with more opportunities to receive personalised therapies (Abstract 291P).

In a study of 1,023 patients with histologically confirmed BTC treated at two cancer centres in France and Spain from 2011 to 2021, median OS was 22 months in patients ≤50 years old vs 18 months in 51 to 69 year-olds and 15 months in patients aged ≥70 years. This was despite a higher tumoral burden with more bilobar liver involvement.

FGFR2 fusions were more frequent in YO-BTC, which opens up opportunities for precision oncology-based approaches. The rates of IDH1, HER2, BRAFV600E, NTRK, and MSI did not differ by age categories.

Further epidemiological studies are required to uncover the specific features of early-onset gastrointestinal tumours in order to develop targeted effective prevention and treatment, particularly given that GI cancers account for a quarter of all new cancer cases and a third of cancer deaths worldwide.