Teaching pack: Oesophageal cancer

Oesophageal cancer causes about 510,000 new cases and 445,000 deaths a year, making it the seventh most common cancer and sixth leading cause of cancer death. It is two diseases: squamous cell carcinoma (ESCC, ~85% globally, driven by tobacco, alcohol, hot beverages, and nutritional factors along a belt from Iran through Central Asia to China) and adenocarcinoma (EAC, dominant in the West, arising from Barrett's oesophagus through reflux and obesity). Most patients present with dysphagia and locally advanced or metastatic disease; five-year survival is about 20%. Japan and parts of China screen high-risk populations endoscopically and cure early squamous cancers with endoscopic resection.

Localised disease is treated with multimodality therapy. CROSS chemoradiation followed by oesophagectomy gives 10-year survival of 38% versus 25% for surgery alone; perioperative FLOT is the alternative for adenocarcinoma (ESOPEC favoured it). Definitive chemoradiation is used for cervical tumours and unfit patients. CheckMate 577 added a year of adjuvant nivolumab for residual disease after chemoradiation (DFS 22.4 vs 11.0 months), and SANO showed that patients with a clinical complete response can be watched rather than operated on with non-inferior survival. Advanced disease is treated with chemotherapy plus PD-1 blockade: pembrolizumab (KEYNOTE-590, both histologies), nivolumab ± ipilimumab (CheckMate 648, squamous), tislelizumab (RATIONALE-306, squamous PD-L1 ≥1%), and camrelizumab or sintilimab in China. HER2-positive adenocarcinoma follows the gastric pathway (trastuzumab, zanidatamab after HERIZON-GEA-01, T-DXd second line). In 2026 the EGFR×HER3 bispecific ADC izalontamab brengitecan became the first agent to improve overall survival in second-line ESCC after immunotherapy (PANKU-Esophagus01).

• Immunotherapy in first line and adjuvant.
• First bispecific ADC phase 3 success in ESCC.
• Chemoradiation before surgery (CROSS) has a durable 13-point 10-year survival gain; organ preservation after complete response is non-inferior (SANO).
• Adjuvant nivolumab doubles disease-free survival after incomplete response to chemoradiation (CheckMate 577), though OS was not significantly improved.
• Chemo-immunotherapy is first-line standard in both histologies, replicated in five phase 3 trials; PD-L1 defines the size of benefit.
• A chemotherapy-free immunotherapy doublet (nivolumab + ipilimumab) is an option in squamous disease.

1. 1913Torek performs the first successful oesophagectomy for cancer
2. 1980Cisplatin/5-FU chemoradiation defined (RTOG 85-01 reported 1992)
3. 1990Endoscopic mucosal resection for early oesophageal cancer (Japan)
4. 2006MAGIC: perioperative chemotherapy for GEJ adenocarcinoma
5. 2010ToGA includes GEJ adenocarcinoma: trastuzumab for HER2-positive disease
6. 2012CROSS: neoadjuvant chemoradiation
7. 2012CROSS: neoadjuvant chemoradiation becomes standard
8. 2019PD-1 blockade second line: pembrolizumab (KEYNOTE-181) and nivolumab (ATTRACTION-3)
9. 2021Checkpoint inhibitors first line
10. 2021CROSS 10-year data; CheckMate 577 adjuvant nivolumab; KEYNOTE-590 and ESCORT-1st first-line chemo-IO

• Izalontamab brengitecan (product)
• PANKU-Esophagus01 (BL-B01D1-305) (trial)
• SANO (trial)
• Organ preservation as the default after complete response in oesophageal cancer (idea)
• Non-endoscopic screening for Barrett's oesophagus and early adenocarcinoma (idea)
• HERIZON-GEA-01 (trial)
• Zanidatamab (product)
• Tislelizumab (product)
• CLARITY-Gastric 01 (trial)
• MRD / molecular residual disease testing (technology)
• FAPI PET (technology)
• CROSS chemoradiation → surgery → adjuvant nivolumab if residual disease (pairing)

• CheckMate 649 (phase 3, n=1,581): Overall survival, PD-L1 CPS ≥5: 14.4 months vs 11.1 months, HR 0.71
• CheckMate 648 (phase 3, n=970): Overall survival, PD-L1 ≥1% (nivolumab + chemotherapy): 15.4 months vs 9.1 months, HR 0.54
• ESCORT-1st (phase 3, n=596): Overall survival: 15.3 months vs 12 months, HR 0.7
• KEYNOTE-590 (phase 3, n=749): Overall survival, all patients: 12.4 months vs 9.8 months, HR 0.73
• RATIONALE-306 (phase 3, n=649): Overall survival, all patients: 17.2 months vs 10.6 months, HR 0.66
• ToGA (phase 3, n=594): Overall survival: 13.8 months vs 11.1 months, HR 0.74

• Late presentation.
• Squamous cell carcinoma lacks targets beyond EGFR/HER3.
• Most patients present with advanced disease; no Western screening for squamous cancer and only trial-stage non-endoscopic screening for Barrett's.
• Adjuvant nivolumab improves DFS but not significantly OS; who truly needs it (PD-L1, ctDNA) is unknown.
• Squamous cell carcinoma has no validated molecular targets beyond PD-1 and, since 2026, EGFR/HER3 antigen delivery.
• PD-L1-negative tumours derive little from chemo-immunotherapy; alternatives are lacking.

1. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.
2. What is the first bispecific ADC to succeed in a phase 3 trial, and in which cancer?
   Answer

   Izalontamab brengitecan (iza-bren, BL-B01D1), an EGFR×HER3 bispecific ADC from SystImmune/BMS, met PFS and OS in previously treated TNBC (BL-B01D1-307, February 2026) and also in oesophageal squamous cell carcinoma.
3. Why does trastuzumab deruxtecan work in 'HER2-low' breast cancers that older HER2 drugs ignored?
   Answer

   Its cleavable linker releases a membrane-permeable topoisomerase-I payload (DXd) at high DAR, so a small amount of HER2 is enough to deliver drug and the payload diffuses to kill neighbouring cells (bystander effect); HER2-low is a delivery address, not a driver. DESTINY-Breast04 and -06 proved it.
4. In what setting did T-DXd move into early-stage HER2-positive breast cancer in 2026?
   Answer

   Neoadjuvant (DESTINY-Breast11, T-DXd followed by THP, pCR 67.3% vs 56.3%) and post-neoadjuvant residual disease (DESTINY-Breast05, beating T-DM1), both approved Q2 2026.
5. What was the first cancer drug approved on the basis of a blood test for leftover disease?
   Answer

   Atezolizumab for ctDNA-positive muscle-invasive bladder cancer after cystectomy (IMvigor011, using Signatera), approved Q2 2026; DFS HR 0.64, OS HR 0.59.
6. Can a blood test decide who needs chemotherapy after colon cancer surgery?
   Answer

   Yes in stage II: the DYNAMIC trial used ctDNA to guide adjuvant chemotherapy, halving its use (15% vs 28%) with non-inferior recurrence-free survival (93.5% vs 92.4% at two years).

• NCCN Esophageal and EGJ Cancers guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1433
• ESMO oesophageal cancer guideline: https://www.esmo.org/guidelines/guidelines-by-topic/esmo-clinical-practice-guidelines-gastrointestinal-cancers/oesophageal-cancer
• NCI PDQ esophageal cancer treatment: https://www.cancer.gov/types/esophageal/hp/esophageal-treatment-pdq
• Wikipedia: https://en.wikipedia.org/wiki/Esophageal_cancer
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1433
• Guideline: https://www.esmo.org/guidelines/guidelines-by-topic/esmo-clinical-practice-guidelines-gastrointestinal-cancers/oesophageal-cancer