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.

• 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).
• Genotype-directed second line: ESR1-mutant → oral SERDs or the first approved PROTAC (vepdegestrant); PIK3CA/AKT/PTEN → inavolisib (OS benefit), capivasertib.
• The first ctDNA-triggered treatment switch approved by the FDA (camizestrant, SERENA-6, September 2026), over a negative advisory vote.
• ADCs before chemotherapy in endocrine-resistant disease: T-DXd for HER2-low and ultralow (DESTINY-Breast06), TROP2 ADCs for the rest.

1. 1896Beatson removes ovaries to treat advanced breast cancer
2. 1958Oestrogen receptor discovered (Jensen)
3. 1977Tamoxifen approved
4. 1998Anastrozole and letrozole approved; tamoxifen for prevention
5. 2002Fulvestrant: first SERD
6. 2004Oncotype DX launched
7. 2012Everolimus + exemestane (BOLERO-2)
8. 2014SOFT/TEXT: ovarian suppression in premenopausal women
9. 2015Palbociclib: first CDK4/6 inhibitor
10. 2018TAILORx: most women can skip chemotherapy

• Vepdegestrant (treatment)
• Sacituzumab tirumotecan (treatment)
• Datopotamab deruxtecan (treatment)
• ArteraAI Breast (treatment)
• Patritumab deruxtecan (treatment)
• TQB2102 (treatment)
• HRS-8080 (treatment)
• Ipatasertib (treatment)
• RC148 (treatment)
• SPH4336 (treatment)
• YL202 (treatment)
• TQB3616 (treatment)

• NSABP B-32 (phase 3, n=5,611): Overall survival at 8 years (sentinel node-negative patients): 90.3% vs 91.8%, HR 1.2
• 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
• ACOSOG Z0011 (Alliance) (phase 3, n=891): Overall survival at 10 years: 86.3% vs 83.6%, HR 0.85
• CREATE-X (phase 3, n=910): Disease-free survival at 5 years: 74.1% vs 67.6%, HR 0.7

• 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.
• Does acting on ctDNA improve survival? SERENA-6 improved PFS; OS and patient-reported outcomes are unresolved, as the ODAC vote showed.
• Palbociclib versus ribociclib versus abemaciclib: different survival results without a randomised comparison.
• HER2-low scoring reproducibility at IHC 0/1+ determines T-DXd eligibility for millions of patients.

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
• NCCN Guidelines for Patients and the NCCN breast cancer guideline summary (PMC): https://pmc.ncbi.nlm.nih.gov/articles/PMC13114725/
• SEER Cancer Stat Facts: female breast cancer subtypes (share of cases and five-year relative survival by receptor subtype and stage, SEER 21): https://seer.cancer.gov/statfacts/html/breast-subtypes.html
• Royal College of Pathologists G148: dataset for histopathological reporting of breast disease in surgical excision specimens of breast cancer, version 3, November 2024 (full review due November 2026): https://www.rcpath.org/resourceLibrary/g148-dataset-for-histopathological-reporting-of-breast-disease-in-surgical-excision-specimens-of-breast-cancer.html
• NICE NG101: early and locally advanced breast cancer, diagnosis and management (published 18 July 2018, last updated 14 April 2025): https://www.nice.org.uk/guidance/ng101/chapter/recommendations
• GLOBOCAN breast fact sheet (IARC Global Cancer Observatory, 2024 estimates): https://gco.iarc.who.int/media/globocan/factsheets/cancers/20-breast-fact-sheet.pdf
• Wikipedia: https://en.wikipedia.org/wiki/Breast_cancer
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419