Teaching pack: HR-positive / HER2-negative breast cancer

Hormone receptor-positive, HER2-negative breast cancer is about 70% of all breast cancers and the archetype of a hormone-driven, slow-evolving disease. Oestrogen receptor signalling drives proliferation, so endocrine therapy has been the backbone since tamoxifen (1977) and aromatase inhibitors (1990s); because recurrences can occur 10-20 years after diagnosis, therapy lasts 5-10 years and adherence is a major real-world determinant of outcome. Gene-expression assays (Oncotype DX, MammaPrint) now spare roughly 70% of node-negative and most postmenopausal node-positive patients chemotherapy, while adjuvant CDK4/6 inhibitors (abemaciclib, ribociclib) reduce recurrence in the high-risk minority.

Metastatic disease is treated as a sequence of endocrine-based combinations. First line is a CDK4/6 inhibitor plus endocrine therapy, with ribociclib and abemaciclib showing overall survival gains that palbociclib did not. Progression is increasingly managed by genotype: ESR1 mutations detected in ctDNA (30-40% after aromatase inhibitors) call for oral SERDs (elacestrant, imlunestrant) or the PROTAC vepdegestrant, and since September 2026 for camizestrant switched in at molecular progression; PIK3CA/AKT1/PTEN alterations (about 50%) call for inavolisib, capivasertib, or alpelisib; gedatolisib (2026) works in PIK3CA-wild-type disease. After endocrine options are exhausted, antibody-drug conjugates precede chemotherapy: T-DXd for the ~60% with HER2-low or ultralow expression, and the TROP2 ADCs sacituzumab govitecan and datopotamab deruxtecan.

• Adjuvant CDK4/6 inhibitors reduce recurrence in high-risk early disease.
• ctDNA-guided ESR1 switching and first PROTAC approval (2026).
• ADCs before chemotherapy in HER2-low/ultralow disease.
• Chemotherapy omission for ~70% of node-negative and most postmenopausal node-positive patients using genomic assays (TAILORx, RxPONDER, MINDACT).
• Adjuvant CDK4/6 inhibitors (abemaciclib, ribociclib) cut recurrence in high-risk early disease; the first adjuvant oral SERD (giredestrant, lidERA) is positive and awaiting approval.
• First-line CDK4/6 + endocrine therapy with median OS beyond five years (MONALEESA-2: 63.9 months).

1. 1896Beatson removes ovaries to treat breast cancer
2. 1896Beatson removes ovaries to treat advanced breast cancer
3. 1958Oestrogen receptor discovered (Jensen)
4. 1977Tamoxifen approved
5. 1977Tamoxifen approved
6. 1998Anastrozole and letrozole approved; tamoxifen for prevention
7. 2002Fulvestrant: first SERD
8. 2004Oncotype DX launched
9. 2012Everolimus + exemestane (BOLERO-2)
10. 2014SOFT/TEXT: ovarian suppression in premenopausal women

• Vepdegestrant (product)
• Sacituzumab tirumotecan (product)
• Datopotamab deruxtecan (product)
• ArteraAI Breast (product)
• Patritumab deruxtecan (product)
• Camizestrant (product)
• Giredestrant (product)
• Atirmociclib (product)
• CAMBRIA-1 & CAMBRIA-2 (trial)
• FOURLIGHT-1 (trial)
• lidERA (trial)
• evERA (trial)

• monarchE (phase 3, n=5,637): Invasive disease-free survival at 2 years: 92.2% vs 88.7%, HR 0.75
• NATALEE (phase 3, n=5,101): Invasive disease-free survival at 3 years: 90.4% vs 87.1%, HR 0.75
• SOFT & TEXT (phase 3, n=5,738): 12-year disease-free survival (TEXT+SOFT): 80.5% vs 75.9%, HR 0.79
• DESTINY-Breast06 (phase 3, n=866): Progression-free survival, HER2-low (BICR): 13.2 months vs 8.1 months, HR 0.62
• EMBER-3 (phase 3, n=874): Progression-free survival, ESR1-mutant (imlunestrant vs standard ET): 5.5 months vs 3.8 months, HR 0.62
• TAILORx (phase 3, n=10,273): Invasive disease-free survival at 9 years (RS 11-25): 83.3% vs 84.3%, HR 1.08

• Late recurrence (up to 20+ years) with no predictive test.
• CDK4/6 resistance mechanisms and sequencing.
• Endocrine therapy adherence and toxicity.
• Late recurrence: half of relapses occur after year 5 and no test reliably identifies who needs extended or intensified therapy.
• Adherence: a third of women stop adjuvant endocrine therapy early because of arthralgia, hot flushes, and sexual side effects.
• Sequencing after CDK4/6: no head-to-head trials among oral SERDs, PI3K/AKT agents, everolimus combinations, and ADCs.

1. What can a 21-gene test tell a woman with early hormone-positive breast cancer?
   Answer

   Oncotype DX gives a recurrence score; TAILORx showed women with a score of 25 or below (over 50) get no benefit from chemotherapy and can safely skip it; RxPONDER extended this to 1-3 positive nodes in postmenopausal women.
2. 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.
3. Which TROP2 ADCs are approved for first-line metastatic triple-negative breast cancer?
   Answer

   Sacituzumab govitecan (Trodelvy), as monotherapy for PD-1-ineligible patients (ASCENT-03) and with pembrolizumab for PD-L1 CPS ≥10 disease (ASCENT-04), and datopotamab deruxtecan (Datroway) for PD-1/PD-L1-ineligible patients (TROPION-Breast02), both approved in 2026.
4. 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.
5. Which trial showed the first overall survival benefit for a first-line ADC in triple-negative breast cancer?
   Answer

   TROPION-Breast02: datopotamab deruxtecan vs chemotherapy in first-line PD-1/PD-L1-ineligible metastatic TNBC, OS 23.7 vs 18.7 months.
6. 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.

• Wikipedia: https://en.wikipedia.org/wiki/Breast_cancer
• Guideline: https://pmc.ncbi.nlm.nih.gov/articles/PMC13114725/
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419