Teaching pack: Triple-negative breast cancer (TNBC)

TNBC is defined by what it lacks: ER <1%, PR <1%, HER2 0-1+ (or 2+/ISH-negative). It is biologically heterogeneous (basal-like 1 and 2, mesenchymal, luminal androgen receptor, immunomodulatory subtypes), nearly always TP53-mutant, frequently HRD-positive (~20% germline BRCA1/2), and has the highest TROP2 expression and the most immune infiltration of any breast subtype. Relapses cluster in the first three years and favour visceral and brain metastases.

The standard of care changed three times in six years. KEYNOTE-522 (2020-21) made pembrolizumab plus carboplatin-containing chemotherapy before surgery, continued after, the standard for stage II-III disease, with a 7.9-point overall survival gain at seven years. OlympiA (2021) added adjuvant olaparib for germline BRCA carriers with residual disease. In metastatic disease, pembrolizumab-chemotherapy (CPS ≥10) was joined by the TROP2 ADCs: sacituzumab govitecan (ASCENT, second line 2020; first-line ASCENT-03/04 2026) and datopotamab deruxtecan (TROPION-Breast02, first-line PD-1-ineligible, 2026, with an overall survival benefit), while T-DXd covers the ~35% of TNBC that is HER2-low. The EGFR×HER3 bispecific ADC iza-bren posted the first positive phase 3 for a bispecific ADC in pretreated TNBC in February 2026.

• Curative-intent: chemo-immunotherapy (KEYNOTE-522) cures more patients than ever; pCR ~65%. Adjuvant PARP inhibitor for BRCA carriers.
• Metastatic: ADCs first line (sacituzumab, Dato-DXd), ADC + IO for PD-L1+ disease; median OS in first-line trials now approaches two years, roughly double the 2015 figure.
• HER2-low reclassification gives a third of TNBC patients access to T-DXd.
• De-escalation is real: TIL-guided omission of chemotherapy in stage I; anthracycline-free and pembrolizumab-omission trials in stage II-III.

1. 2000Molecular portraits define the basal-like subtype
2. 2007'Triple-negative' enters clinical vocabulary
3. 2014Carboplatin raises pCR
4. 2018First immunotherapy signal
5. 2018PARP inhibitors in BRCA breast cancer
6. 2020Sacituzumab govitecan approved
7. 2020Pembrolizumab + chemotherapy first line
8. 2021KEYNOTE-522 changes early-stage care
9. 2021OlympiA: adjuvant olaparib
10. 2022HER2-low: T-DXd works in 'HER2-negative' disease

• Sacituzumab tirumotecan (product)
• Izalontamab brengitecan (product)
• TROPION-Breast05 (trial)
• IZABRIGHT-Breast01 (trial)
• OptimICE-pCR (A012103) (trial)
• SCARLET (SWOG S2212) (trial)
• TROP2 PET (technology)
• Patritumab deruxtecan (product)
• Puxitatug samrotecan (product)
• Dual-payload ADC (technology)
• Personalised neoantigen (mRNA) vaccines (technology)
• MRD / molecular residual disease testing (technology)

• KEYNOTE-355 (phase 3, n=847): Overall survival, PD-L1 CPS ≥10: 23 months vs 16.1 months, HR 0.73
• ASCENT (phase 3, n=529): Progression-free survival (patients without brain metastases): 5.6 months vs 1.7 months, HR 0.41
• ASCENT-03 (phase 3, n=558): Progression-free survival (BICR): 9.7 months vs 6.9 months, HR 0.62
• DESTINY-Breast04 (phase 3, n=557): Progression-free survival, HR+ cohort (BICR): 10.1 months vs 5.4 months, HR 0.51
• TROPION-Breast02 (phase 3, n=644): Progression-free survival (BICR): 10.8 months vs 5.6 months, HR 0.57
• ASCENT-04 / KEYNOTE-D19 (phase 3, n=443): Progression-free survival (BICR): 11.2 months vs 7.8 months, HR 0.65

• Residual disease after KEYNOTE-522: no approved escalation beyond capecitabine/olaparib; ctDNA-guided trials needed.
• ADC sequencing: does a second TOP1-payload ADC work after the first? SATEEN/BRE-354 suggest limited efficacy; chemotherapy interposition debated.
• Patient selection for TROP2 ADCs: IHC does not predict; TROP2 PET and ctDNA are candidates.
• PD-L1-negative early disease has no immunotherapy option and no ADC yet in the curative setting.
• Brain metastases (up to 30-45% of metastatic TNBC) remain undertreated; ADC CNS activity is emerging but unproven.
• Mesenchymal/claudin-low biology (EMT, efflux pumps) resists chemotherapy, ADC payloads, and immunotherapy alike.

1. What does 'triple-negative' mean in breast cancer?
   Answer

   The tumour lacks the three receptors other breast cancers can be treated through: oestrogen receptor, progesterone receptor, and HER2 (IHC 0-1+ or 2+/ISH-negative).
2. 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.
3. What is pathologic complete response and why does it matter in TNBC?
   Answer

   pCR means no invasive cancer is left in the breast and lymph nodes when the surgeon removes the tissue after pre-surgery treatment. In TNBC patients with pCR have around 90% five-year event-free survival, and trials now test giving less treatment after pCR.
4. What questions should someone newly diagnosed with triple-negative breast cancer ask before surgery?
   Answer

   Whether chemo-immunotherapy before surgery (KEYNOTE-522) is planned and why; germline BRCA testing; PD-L1 and HER2-low status; TIL score; clinical trial options; fertility preservation; breast-conserving versus mastectomy and sentinel node approach; what response (pCR/RCB) will mean for treatment afterwards.
5. Who should have germline genetic testing when diagnosed with cancer?
   Answer

   All patients with TNBC, ovarian, pancreatic, or metastatic prostate cancer, increasingly all breast cancer, and anyone with suggestive family history; results change surgery, drug choice (PARP inhibitors), and family screening.
6. Why are mesenchymal or claudin-low triple-negative tumours hard to treat with any class of drug?
   Answer

   EMT programmes (ZEB1/2, SNAIL) confer stemness, apoptosis resistance, immune exclusion, and high ABC efflux transporters that pump out chemotherapy and ADC payloads (MMAE, DXd, SN-38), so efflux-independent approaches (radiation, radioligands, immune killing) are proposed.

• Wikipedia: https://en.wikipedia.org/wiki/Triple-negative_breast_cancer
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419
• Guideline: https://pmc.ncbi.nlm.nih.gov/articles/PMC13114725/
• Guideline: https://www.pharmacytimes.com/view/a-new-era-in-first-line-metastatic-tnbc-nccn-guidelines-elevate-sacituzumab-govitecan-to-category-1-status