Advanced / Metastatic Her2 positive Breast Cancer

📊 Management of Advanced/Metastatic HER2-Positive Breast Cancer

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🔹 HER2-Positive Definition

A tumor is HER2-positive if:

IHC 3+

FISH HER2/CEP17 ratio > 2 or HER2 gene copy number > 6

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🔹 First-Line Systemic Therapy Strategy (MABs)

📌 First-line regimen selection is based on the last adjuvant regimen and treatment-free interval (TFI):

TFI > 6 months → Use first-line regimens.

TFI ≤ 6 months → Move to second-line therapy (ADC-based).

✅ Trastuzumab + Chemotherapy (SLAMON et al. Trial)

PFS: 12 vs. 6 months (HR 0.49, p<0.001)

OS: 32 vs. 22 months (HR 0.78, p<0.001)

Significance: First proof of trastuzumab efficacy in HER2+ MBC

✅ Gold standard regimen Trastuzumab + Pertuzumab + Chemotherapy (CLEOPATRA Trial)

ORR: 80.2% vs. 69.3%

PFS: 18.5 vs. 12.4 months (HR 0.62, p<0.001)

OS: 56.5 vs. 40.8 months (HR 0.68, p<0.001)

Adverse Effects: Diarrhea, neutropenia, infusion reactions

📌 Chemo Backbone Options in First-Line

✅ Eribulin + HP vs. THP (EMERALD Trial – Phase III)

Eribulin met non-inferiority vs. taxane (PFS 14 vs. 12.9 months)

📌 Fixed-Dose Subcutaneous Option
✅ PHESGO (SC Pertuzumab + Trastuzumab) → Equivalent efficacy, faster administration

📌 Frail Patients

✅ HP + Oral Metronomic Chemotherapy (OMC) → Effective alternative in ECOG 2+

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🔹 First-Line Considerations for Specific Subgroups

📌 Triple-Positive MBC (HER2+/ER+/PR+)

Chemo-free approach: Trastuzumab + Pertuzumab + AI

✅ Trastuzumab + Pertuzumab + AI (PERTAIN Trial)

PFS: 18.9

Another option: Trastuzumab + endocrine therapy

✅ Lapatinib + Trastuzumab + AI (ALTERNATIVE Trial)

PFS: 11.0

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🔹 Second-Line Therapy (ADC-Based Approach)

✅ Trastuzumab Deruxtecan (T-DXd) – DESTINY-Breast03 Trial (ASCO 2024)

PFS: 29.0 vs. 7.2 months (HR 0.30, p<0.001)

36-month PFS rates: 45.7% vs. 12.4%

OS: 52.6 vs. 42.7 months (HR 0.73, p<0.001)

42-month OS rates: 62.5% vs. 50.1%

📌 ADC Post ADC Therapy
✅ T-DXd After T-DM1 – DESTINY-Breast02 Trial

PFS: 17.8 vs. 6.9 months (HR 0.36, p<0.001)

✅ Likewise T-DM1 May also Be Effective Post-T-DXd in Select Cases

✅ T-DM1 in Second Line – EMILIA Trial

PFS: 9.6 vs. 6.4 months (HR 0.65, p<0.001)

OS: 30.9 vs. 25.1 months (HR 0.68, p<0.001)

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🔹 Third-Line Therapy (TKIs & ADCs)

📌 T-DM1 in Third-Line – TH3RESA Trial

PFS: 6.2 vs. 3.3 months (HR 0.53, p<0.001)

OS: 22.7 vs. 15.8 months (HR 0.68, p<0.001)

📌 Tucatinib-Based Regimens – HER2CLIMB Trial (Preferred in brain metastases)
✅ Tucatinib + Trastuzumab + Capecitabine

PFS: 7.8 vs. 5.6 months (HR 0.54, p<0.001)

OS: 21.9 vs. 17.4 months (HR 0.66, p<0.001)

Intracranial PFS: 9.9 vs. 4.2 months (HR 0.48, p<0.001)

📌 Other Third-Line Options
✅ Neratinib + Capecitabine (NALA Trial)

Significantly improved PFS & time to CNS intervention vs. Lapatinib + Capecitabine

✅ Lapatinib + Capecitabine (LANDSCAPE Trial – For Brain Mets)

Intracranial ORR: 66%

✅ Lapatinib + Trastuzumab (Chemo-Free Option for Select Cases)

✅ Margetuximab + Chemotherapy (SOPHIA Trial)

CD16A-158FF patients (possible OS benefit vs trastuzumab):

OS 23.6 vs. 19.2 months (HR 0.72, p<0.001)

📌 TULIP Trial – New ADC Option
✅ Trastuzumab duocarmazine vs. Physician’s Choice

PFS: 7 vs. 4.9 months (HR 0.64, p<0.001)

📌 If ADCs and TKIs Are Unavailable

✅ Continue MABs with Chemotherapy Switch

Capecitabine, Eribulin, or Vinorelbine

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🔹 CNS Metastases – Optimized Approach

📌 First-Line Treatment for Active Brain Metastases
✅ Tucatinib + Trastuzumab + Capecitabine (HER2CLIMB) → Preferred approach

📌 Second-Line Treatment for Brain Mets
✅ T-DXd (DESTINY-Breast03, TUXEDO-1) → CNS activity, ILD monitoring required

📌 Later-Line CNS Options
✅ Lapatinib + Capecitabine (LANDSCAPE Trial – ORR 66%)
✅ Neratinib + Capecitabine (NALA Trial – Improved CNS outcomes)
✅TDM1

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🔹 Final Insight: Optimizing HER2+ MBC Treatment

📌 First-Line (MABs-Based)

✅ Trastuzumab + Pertuzumab + Taxane (CLEOPATRA) or Eribulin + HP (EMERALD)

📌 Second-Line (ADC-Based)

✅ T-DXd (DESTINY-Breast03, preferred) > T-DM1 (EMILIA)

📌 Third-Line (TKIs & ADCs)

✅ T-DM1 (TH3RESA), Tucatinib-based regimens (HER2CLIMB), or Neratinib + Capecitabine (NALA)

📌 Future of T-DXd in First-Line?

❗ Not yet standard, but ongoing trials (DESTINY-Breast09) may change practice