Teaching pack: Salivary gland cancers

Salivary gland carcinomas are defined increasingly by fusion genes: MYB-NFIB in adenoid cystic carcinoma (ACC), CRTC1-MAML2 in mucoepidermoid carcinoma, ETV6-NTRK3 in secretory carcinoma, PLAG1/HMGA2 fusions in carcinoma ex pleomorphic adenoma, and androgen receptor and HER2 in salivary duct carcinoma (SDC). Adenoid cystic carcinoma is the archetype of slow but relentless disease with perineural spread and late lung metastases; salivary duct carcinoma is aggressive and resembles apocrine breast cancer.

Surgery with post-operative radiotherapy (or neutron/carbon-ion therapy for unresectable ACC) is standard for localised disease; RTOG 1008 tested adding cisplatin. Systemic therapy is subtype-directed: trastuzumab-docetaxel or T-DXd for HER2-positive SDC; androgen deprivation (leuprorelin ± bicalutamide, enzalutamide) for AR-positive SDC; larotrectinib or entrectinib for ETV6-NTRK3 secretory carcinoma; lenvatinib, axitinib or rivoceranib for progressive ACC (~10-15% response, high disease control); and chemotherapy (CAP, carboplatin-paclitaxel) for others. Checkpoint inhibitors have low activity except in a minority with high TMB or PD-L1. Notch-mutant ACC (~15%, aggressive) is a target for gamma-secretase inhibitors.

• Salivary gland cancer is where fusion-defined pathology has most changed practice: ETV6-NTRK3 secretory carcinoma responds to NTRK inhibitors in ~90%.
• Salivary duct carcinoma is treated like a HER2+/AR+ breast cancer, with T-DXd giving durable responses.
• VEGFR inhibitors stabilise adenoid cystic carcinoma but rarely shrink it; NOTCH inhibition targets its worst subset.
• Carbon-ion therapy for unresectable ACC is an example of particle therapy with a clear niche.

1. 1859Billroth describes 'cylindroma' (adenoid cystic carcinoma)
2. 1994Neutron therapy trial (RTOG-MRC) in unresectable salivary cancer
3. 2003CRTC1-MAML2 fusion in mucoepidermoid carcinoma (Tonon)
4. 2009MYB-NFIB fusion in adenoid cystic carcinoma (Persson, PNAS)
5. 2010Mammary analogue secretory carcinoma with ETV6-NTRK3 described (Skálová)
6. 2018Larotrectinib approved tumour-agnostically, including secretory carcinoma
7. 2019Trastuzumab-docetaxel in HER2+ salivary duct carcinoma (Takahashi, JCO); lenvatinib in ACC (Tchekmedyian, JCO)
8. 2022ESMO-EURACAN salivary gland guideline

• Trastuzumab deruxtecan (product)
• Lenvatinib (product)
• Larotrectinib (product)
• Carbon-ion therapy (technology)

• Adenoid cystic carcinoma: no drug induces meaningful shrinkage; 20-year survival remains poor.
• Trials are tiny; most evidence is phase 2 or retrospective.
• Facial nerve sacrifice and disfigurement in surgery.
• Immunotherapy largely inactive.

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. 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.
3. 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.
4. What is the bystander effect in ADCs?
   Answer

   A released, membrane-permeable payload diffuses out of the targeted cell and kills neighbouring cells that lack the antigen; requires a cleavable linker and permeable payload (DXd, MMAE, SN-38), explaining T-DXd's activity in HER2-low disease and T-DM1's lack of it.
5. What should I ask before starting an ADC such as Enhertu?
   Answer

   How lung inflammation (ILD) will be monitored and what symptoms to report immediately; HER2 status and how it was scored; expected nausea, hair loss, and blood counts; dosing schedule (every three weeks); how response will be assessed and when; what comes next if it stops working.
6. A patient with HER2-low, hormone-positive metastatic breast cancer has progressed on a CDK4/6 inhibitor and one chemotherapy. What are the ADC options and how would you order them?
   Answer

   T-DXd (DESTINY-Breast04/06) is generally first among ADCs for HER2-low disease; sacituzumab govitecan (TROPiCS-02) or Dato-DXd (TROPION-Breast01) later. Both classes carry TOP1 payloads, so cross-resistance is a concern and interposing chemotherapy is debated; consider ESR1/PIK3CA-directed options if endocrine-sensitive.

• NCCN Guidelines: Head and Neck Cancers: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437
• ESMO-EURACAN salivary gland guideline (2022): https://doi.org/10.1016/j.annonc.2022.04.073
• Adenoid Cystic Carcinoma Research Foundation: https://www.accrf.org/
• Wikipedia: https://en.wikipedia.org/wiki/Salivary_gland_tumour
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437