What is the recommended treatment approach for a patient with FISH (Fluorescence In Situ Hybridization) test positive breast cancer, indicating HER2 (Human Epidermal growth factor Receptor 2)-positive status?

Treatment Approach for FISH-Positive (HER2-Positive) Breast Cancer

For patients with FISH-positive breast cancer, indicating HER2-positive status, the recommended first-line treatment is trastuzumab, pertuzumab, and a taxane combination, which should be continued until disease progression or unacceptable toxicity. 1

Confirmation of HER2 Status

• HER2 testing should be performed on every primary invasive breast cancer (and on metastatic sites if available) to guide treatment decisions 2
• Patients are considered HER2-positive if their tumors are either positive for HER2 by FISH or 3+ by IHC 2
• For IHC 2+ results, reflex FISH testing is necessary to confirm HER2 status, as concordance between IHC 2+ and FISH positivity is only about 31.1% 3
• For IHC 3+ results, FISH confirmation may not be necessary as concordance is approximately 84.1% 3

First-Line Treatment for Metastatic HER2-Positive Breast Cancer

• The standard first-line treatment is the combination of trastuzumab, pertuzumab, and a taxane (docetaxel or paclitaxel) 1, 2
• Chemotherapy should continue for approximately 4-6 months or until maximal response, while HER2-targeted therapy should be continued until disease progression 1
• Alternative first-line regimens include trastuzumab with other chemotherapy agents such as vinorelbine or capecitabine 2
• The combination of trastuzumab with doxorubicin/cyclophosphamide should be avoided due to high risk (27%) of cardiac dysfunction 2

Second-Line Treatment and Beyond

• For patients who progress during or after first-line HER2-targeted therapy, trastuzumab deruxtecan (T-DXd) is recommended as the preferred second-line treatment 1, 4
• If T-DXd is not available, trastuzumab emtansine (T-DM1) should be offered 1, 4
• For third-line and beyond, options include:
  • Lapatinib plus capecitabine 2
  • Tucatinib plus trastuzumab and capecitabine (especially beneficial for patients with brain metastases) 4, 5
  • Continuation of trastuzumab with different chemotherapy partners 1, 2

Special Considerations for Early Recurrence

• For patients who relapse within 6 months after completing adjuvant therapy, T-DXd is recommended as the preferred first-line option 4
• For those relapsing between 6-12 months after non-pertuzumab-based adjuvant treatment, first-line trastuzumab, pertuzumab, and a taxane is recommended 4
• For patients relapsing within 12 months of pertuzumab-based adjuvant treatment, second-line HER2-targeted therapy recommendations should be followed 1

Treatment for Hormone Receptor-Positive and HER2-Positive Disease

• For patients with both hormone receptor-positive and HER2-positive disease, HER2-targeted therapy plus chemotherapy is the approach with strongest evidence 1
• After completing chemotherapy, endocrine therapy may be added while continuing HER2-targeted therapy 1
• In selected cases with low disease burden or significant comorbidities, endocrine therapy plus trastuzumab or lapatinib may be considered 1

Monitoring and Follow-up

• Cardiac monitoring should be performed before and during trastuzumab therapy due to risk of cardiotoxicity 2
• Response evaluation is recommended after 2-3 cycles of chemotherapy through clinical assessment, imaging, and tumor markers 2
• After completing chemotherapy in combination regimens, HER2-targeted therapy should be continued until disease progression or unacceptable toxicity 1

Common Pitfalls and Caveats

• Failure to re-biopsy accessible metastatic lesions to confirm HER2 status, as receptor status can change during disease progression 1
• Discontinuing HER2-targeted therapy prematurely after chemotherapy completion instead of continuing until disease progression 1
• Using trastuzumab in combination with anthracyclines outside of clinical trials due to high risk of cardiac toxicity 2
• Inadequate standardization and validation of HER2 assays, which can lead to false-positive determinations 2

By following this treatment algorithm based on the latest guidelines, patients with FISH-positive (HER2-positive) breast cancer can receive optimal therapy that significantly improves their outcomes in terms of morbidity, mortality, and quality of life.