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HORMONE RECEPTOR POSITIVE BREAST CANCER MANAGEMENT

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Sendhil Kumar

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ADJUVANT THERAPY IN HER 2 + BREAST CANCER
HER2 RECEPTOR HER2 is part of the epidermal growth factor family, along with 3 other receptors with no identifiable ligand The HER2 gene is located on the long arm of chromosome 17 and encodes a 185-kDa transmembrane protein It is present in an active conformation and can undergo ligand-independent dimerization with other EGF receptors HER2 overexpression is present in approximately 2030% of breast cancer tumors.
Gutierrez C, Schiff R. HER2: biology, detection, and clinical implications. Arch Pathol Lab Med. 2011
American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer
HER 3 RECEPTOR HER3 is a member of the HER family, which is composed of four homologous receptors tyrosine kinases The neuregulin also called the heregulin is the unique ligand of HER3 that activate HER3-ECD HER3 mostly heterodimerizes with HER2, and the HER2-HER3 heterodimer is the most active signaling dimer in this family HER3 is a potent activator for PI3K/AKT and other signaling pathways such as MEK/MAPK, PLC粒/PKC, Jak/Stat, and Src kinase, which have a crucial role in cellular growth, proliferation, and survival HER3 protein is overexpressed in about 5070 % of breast cancers with the HR+/HER2- subtype showing the highest expression (followed in order by HR+/HER2+ and HR-/HER2+ subtypes HER3 expression also plays a key role in developing metastases in specific organs, such as bone and brain HER3 upregulation is associated with acquired resistance to chemotherapy, endocrine therapy, and HER2- and PI3K/AKT/mTOR targeting therapy
TRANSTUZUMAB Trastuzumab, a humanized IgG1 monoclonal antibody that targets the extracellular domain of the HER2 protein It targets subdomain IV of the HER2 extracellular domain, exerting its antitumor effect by blocking HER2 cleavage, downstream proliferation pathways, and promoting apoptosis. Additionally, it stimulates endocytosis and prevents shedding of the extracellular domain of HER2. It also triggers antibody-dependent cellular cytotoxicity The most concerning adverse effect is cardiotoxicity which is increased when trastuzumab is combined with anthracyclines. Early studies demonstrated that New York Heart Association (NYHA) class III or IV heart failure occurred in up to 27% of patients treated with anthracycline, cyclophosphamide, and trastuzumab. Evaluation of left ventricular ejection fraction (LVEF) is recommended prior to initiation of adjuvant trastuzumab, every 3 months while on treatment, at completion, and every 6 months for 2 years after treatment is completed. Most cardiac toxicity is reversible with vigilant monitoring and early cessation of trastuzumab when it occurs
HORMONE RECEPTOR POSITIVE BREAST CANCER MANAGEMENT
NSABP-B-31 and NCCTG-N9831 Study Arms = doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q3wk x 4 = paclitaxel (P) 175 mg/m2 q3wk x 4 = paclitaxel (P) 80 mg/m2 qwk x 12 = trastuzumab (H) 4 mg/kg LD + 2 mg/kg qwk x 51 NSABP-B-31 NCCTG-N9831 Arm 1 Arm 2 Arm C Arm A Arm B
N9831/B-31 Disease-Free Survival DFS AC P + H (n = 2,028) AC P (n = 2,018) 10-year DFS* 73.7% 62.2% First DFS events Distant recurrence Local/regional recurrence Contralateral breast cancer Other second primary cancer Death without recurrence 11.2% 4.1% 2.3% 3.3% 1.9% 19.4% 6.1% 2.0% 3.7% 1.5% * Adjusted HR = 0.6, p < 0.0001
N9831/B-31 Overall Survival OS AC P+H (n = 2,028) AC P (n = 2,018) 10-year OS* 84.0% 75.2% OS events Deaths Due to this breast cancer Due to second primary cancer Due to other causes Cause unknown 14.1% 10.3% 1.2% 0.9% 1.6% 20.7% 16.8% 2.0% 0.7% 1.1% * Adjusted HR = 0.63, p < 0.0001
N9831/B-31 Conclusion
SEQUENTIAL TRANSTUZUMAB VS CONCURRENT TRANSTUZUMAB [ARM B vs ARM C (NCCTG N9981])
HORMONE RECEPTOR POSITIVE BREAST CANCER MANAGEMENT
HERA TRIAL
HORMONE RECEPTOR POSITIVE BREAST CANCER MANAGEMENT
HORMONE RECEPTOR POSITIVE BREAST CANCER MANAGEMENT
The combination of trastuzumab with anthracycline increases the risk of congestive heart failure by a factor of 4 to 5 and approximately 10% of patients treated with trastuzumab have a substantial decrease in their LVEF
10-year DFS was 74.6% with AC-DH (p < 0.0001), 73.0% with TCH (p= 0.0011), and 67.9% with AC-D. Overall survival at 10 years was 85.9% with AC-DH, 83.3% with TCH and 78.7% with AC-D, representing risk reductions of 27% (p < 0.0001) and 24% (p = 0.0075), respectively.
TCH is an acceptable adjuvant regimen that may lessen the risk of cardiotoxicity
HORMONE RECEPTOR POSITIVE BREAST CANCER MANAGEMENT
Trastuzumab emtansine (T-DM1), an antibodydrug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy.
HORMONE RECEPTOR POSITIVE BREAST CANCER MANAGEMENT
APHINITY TRIAL
HORMONE RECEPTOR POSITIVE BREAST CANCER MANAGEMENT
The 6-year OS difference remains insignificant with 95% in the pertuzumab group compared to 94% in the placebo group Toxicity was increased with dual HER2-blockade particularly in the form of diarrhea with a 9.8% rate of grade 3 or higher diarrhea in the pertuzumab group compared to 3.7% in the placebo group. The risk of diarrhea was even greater among patients treated with the docetaxel and carboplatin regimen at 18%. Cardiac toxicity was similar between treatment arms.
HORMONE RECEPTOR POSITIVE BREAST CANCER MANAGEMENT
Neratinib significantly improved iDFS in the HER2+ /HR+ / 1-year population, and a similar trend was observed in patients with residual disease following neoadjuvant treatment. Numerical improvements in central nervous system events and OS were consistent with iDFS benefits and suggest long-term benefit for neratinib in this population. Diarrhoea was the important side effect.

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HORMONE RECEPTOR POSITIVE BREAST CANCER MANAGEMENT

  • 1. ADJUVANT THERAPY IN HER 2 + BREAST CANCER
  • 2. HER2 RECEPTOR HER2 is part of the epidermal growth factor family, along with 3 other receptors with no identifiable ligand The HER2 gene is located on the long arm of chromosome 17 and encodes a 185-kDa transmembrane protein It is present in an active conformation and can undergo ligand-independent dimerization with other EGF receptors HER2 overexpression is present in approximately 2030% of breast cancer tumors.
  • 3. Gutierrez C, Schiff R. HER2: biology, detection, and clinical implications. Arch Pathol Lab Med. 2011
  • 4. American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer
  • 5. HER 3 RECEPTOR HER3 is a member of the HER family, which is composed of four homologous receptors tyrosine kinases The neuregulin also called the heregulin is the unique ligand of HER3 that activate HER3-ECD HER3 mostly heterodimerizes with HER2, and the HER2-HER3 heterodimer is the most active signaling dimer in this family HER3 is a potent activator for PI3K/AKT and other signaling pathways such as MEK/MAPK, PLC粒/PKC, Jak/Stat, and Src kinase, which have a crucial role in cellular growth, proliferation, and survival HER3 protein is overexpressed in about 5070 % of breast cancers with the HR+/HER2- subtype showing the highest expression (followed in order by HR+/HER2+ and HR-/HER2+ subtypes HER3 expression also plays a key role in developing metastases in specific organs, such as bone and brain HER3 upregulation is associated with acquired resistance to chemotherapy, endocrine therapy, and HER2- and PI3K/AKT/mTOR targeting therapy
  • 6. TRANSTUZUMAB Trastuzumab, a humanized IgG1 monoclonal antibody that targets the extracellular domain of the HER2 protein It targets subdomain IV of the HER2 extracellular domain, exerting its antitumor effect by blocking HER2 cleavage, downstream proliferation pathways, and promoting apoptosis. Additionally, it stimulates endocytosis and prevents shedding of the extracellular domain of HER2. It also triggers antibody-dependent cellular cytotoxicity The most concerning adverse effect is cardiotoxicity which is increased when trastuzumab is combined with anthracyclines. Early studies demonstrated that New York Heart Association (NYHA) class III or IV heart failure occurred in up to 27% of patients treated with anthracycline, cyclophosphamide, and trastuzumab. Evaluation of left ventricular ejection fraction (LVEF) is recommended prior to initiation of adjuvant trastuzumab, every 3 months while on treatment, at completion, and every 6 months for 2 years after treatment is completed. Most cardiac toxicity is reversible with vigilant monitoring and early cessation of trastuzumab when it occurs
  • 8. NSABP-B-31 and NCCTG-N9831 Study Arms = doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q3wk x 4 = paclitaxel (P) 175 mg/m2 q3wk x 4 = paclitaxel (P) 80 mg/m2 qwk x 12 = trastuzumab (H) 4 mg/kg LD + 2 mg/kg qwk x 51 NSABP-B-31 NCCTG-N9831 Arm 1 Arm 2 Arm C Arm A Arm B
  • 9. N9831/B-31 Disease-Free Survival DFS AC P + H (n = 2,028) AC P (n = 2,018) 10-year DFS* 73.7% 62.2% First DFS events Distant recurrence Local/regional recurrence Contralateral breast cancer Other second primary cancer Death without recurrence 11.2% 4.1% 2.3% 3.3% 1.9% 19.4% 6.1% 2.0% 3.7% 1.5% * Adjusted HR = 0.6, p < 0.0001
  • 10. N9831/B-31 Overall Survival OS AC P+H (n = 2,028) AC P (n = 2,018) 10-year OS* 84.0% 75.2% OS events Deaths Due to this breast cancer Due to second primary cancer Due to other causes Cause unknown 14.1% 10.3% 1.2% 0.9% 1.6% 20.7% 16.8% 2.0% 0.7% 1.1% * Adjusted HR = 0.63, p < 0.0001
  • 12. SEQUENTIAL TRANSTUZUMAB VS CONCURRENT TRANSTUZUMAB [ARM B vs ARM C (NCCTG N9981])
  • 17. The combination of trastuzumab with anthracycline increases the risk of congestive heart failure by a factor of 4 to 5 and approximately 10% of patients treated with trastuzumab have a substantial decrease in their LVEF
  • 18. 10-year DFS was 74.6% with AC-DH (p < 0.0001), 73.0% with TCH (p= 0.0011), and 67.9% with AC-D. Overall survival at 10 years was 85.9% with AC-DH, 83.3% with TCH and 78.7% with AC-D, representing risk reductions of 27% (p < 0.0001) and 24% (p = 0.0075), respectively.
  • 19. TCH is an acceptable adjuvant regimen that may lessen the risk of cardiotoxicity
  • 21. Trastuzumab emtansine (T-DM1), an antibodydrug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy.
  • 25. The 6-year OS difference remains insignificant with 95% in the pertuzumab group compared to 94% in the placebo group Toxicity was increased with dual HER2-blockade particularly in the form of diarrhea with a 9.8% rate of grade 3 or higher diarrhea in the pertuzumab group compared to 3.7% in the placebo group. The risk of diarrhea was even greater among patients treated with the docetaxel and carboplatin regimen at 18%. Cardiac toxicity was similar between treatment arms.
  • 27. Neratinib significantly improved iDFS in the HER2+ /HR+ / 1-year population, and a similar trend was observed in patients with residual disease following neoadjuvant treatment. Numerical improvements in central nervous system events and OS were consistent with iDFS benefits and suggest long-term benefit for neratinib in this population. Diarrhoea was the important side effect.