What is the recommended treatment for a patient with well-differentiated adenocarcinoma of the esophagus that is Human Epidermal growth factor Receptor 2 (HER2) positive?

Treatment of HER2-Positive Well-Differentiated Esophageal Adenocarcinoma

For HER2-positive esophageal adenocarcinoma, treatment depends critically on disease stage: localized disease requires perioperative chemotherapy or neoadjuvant chemoradiotherapy followed by surgery, while metastatic/unresectable disease mandates trastuzumab plus chemotherapy (cisplatin/fluoropyrimidine) as first-line therapy. 1

Disease Staging Determines Treatment Pathway

Localized Resectable Disease (M0)

• Perioperative chemotherapy with cisplatin and 5-FU is the standard approach for locally advanced adenocarcinoma 1
• Preoperative chemoradiotherapy (cisplatin/5-FU with 40 Gy) represents an alternative option, particularly for high-risk patients with locally advanced tumors 1
• Surgery with curative intent should follow neoadjuvant therapy in appropriate candidates 1, 2
• Multimodal therapy (chemotherapy, radiotherapy, and surgery) demonstrates superior survival compared to surgery alone, with median survival of 16 months versus 11 months (P=0.01) 2

Critical caveat: While trastuzumab is established for metastatic HER2-positive disease, neoadjuvant chemoradiotherapy plus perioperative trastuzumab has not demonstrated survival benefit in resectable esophageal cancer patients 3. Therefore, do not routinely add trastuzumab to neoadjuvant regimens outside clinical trials for localized disease.

Metastatic or Unresectable Disease (M1)

Trastuzumab combined with cisplatin and a fluoropyrimidine (5-FU or capecitabine) is the mandatory first-line treatment for HER2-positive metastatic esophageal adenocarcinoma 1:

• This regimen achieved level-1 evidence for overall survival advantage based on the ToGA trial 1
• FDA and European Medicines Agency approved this combination in 2010 1
• The combination improves quality of life with extended quality-adjusted time without symptoms (Q-TWiST of 2.42 months) 1

Treatment algorithm for metastatic disease:

1. Confirm HER2 positivity before initiating trastuzumab - do not start HER2-targeted therapy on presumption 1
2. Start cytotoxic chemotherapy immediately if patient is symptomatic while awaiting HER2 results 1
3. Add trastuzumab once HER2 positivity is confirmed 1
4. Standard dosing: trastuzumab loading dose 8 mg/kg, then 6 mg/kg every 3 weeks with chemotherapy 1
5. For biweekly regimens (e.g., oxaliplatin/fluoropyrimidine): loading dose 8 mg/kg, then 4 mg/kg every 2 weeks 1

Alternative chemotherapy backbones: While cisplatin/fluoropyrimidine is FDA-approved, NCCN guidelines recommend adding trastuzumab to any active chemotherapy combination 1. Oxaliplatin/fluoropyrimidine combinations are acceptable alternatives to cisplatin-based regimens 1

Second-Line Therapy After Progression

For HER2-positive patients who progress after first-line trastuzumab plus chemotherapy, trastuzumab deruxtecan (antibody-drug conjugate) is the recommended second-line agent 1, 3:

• This represents a newer, more effective anti-HER2 strategy after trastuzumab failure 3
• Ramucirumab plus paclitaxel is an alternative for any gastroesophageal adenocarcinoma after first-line progression 1

Emerging Immunotherapy Considerations

For HER2-positive patients, the 2023 ASCO guidelines now recommend trastuzumab plus pembrolizumab in combination with chemotherapy as first-line therapy 1:

• This triple combination (anti-HER2 + immunotherapy + chemotherapy) represents the most recent guideline update 1
• This recommendation applies specifically to HER2-positive gastric or gastroesophageal junction adenocarcinoma 1

Important distinction: The immunotherapy recommendations for HER2-negative esophageal adenocarcinoma (nivolumab or pembrolizumab plus chemotherapy based on PD-L1 status) do not replace HER2-targeted therapy in HER2-positive disease 1

HER2 Testing Requirements

All patients with advanced esophageal adenocarcinoma who are potential candidates for HER2-targeted therapy must undergo HER2 testing 1:

• Test on resection specimens (primary or metastasis) preferably before initiating trastuzumab 1
• FNA specimens (cell blocks) are acceptable alternatives if resection specimens unavailable 1
• Perform IHC testing first, followed by ISH only if IHC result is 2+ (equivocal) 1
• Use Ruschoff/Hofmann scoring method for gastroesophageal adenocarcinoma 1

Critical pitfall: Do not repeat HER2 testing after progression on trastuzumab - there is no evidence supporting this practice and no established benefit for re-testing 1. However, if initial testing was negative and no tissue was available, attempt to collect additional tissue for testing 1

Palliative Interventions

For symptomatic dysphagia in metastatic disease:

• Single-dose brachytherapy provides better long-term dysphagia relief with fewer complications than metal stent placement 1
• This applies even after percutaneous radiochemotherapy 1

Do not delay systemic therapy for local palliative procedures - chemotherapy with trastuzumab takes priority for survival benefit in HER2-positive disease 1.