Adjuvant therapy in early breast cancer

Adjuvant therapy is systemic therapy following locoregional treatment (surgery) (1,2,3,4,5,6)

• more than 50% of women with operable breast cancer who receive only locoregional treatment die from metastatic disease
  • this is an indication of the presence of micrometastases at initial clinical presentation
  • major risk factors for the development of metastatic disease are:
    • involvement of axillary nodes
    • poor histological grade
    • large tumour size
    • histological evidence of lymphovascular invasion around the tumour site
    • absence of oestrogen and progestogen receptors, and the overexpression of the human epidermal growth factor receptor 2 (HER2), also carry an adverse prognosis
      
      
  • survival of these women can be improved by giving these women systemic medical treatment, including endocrine therapy, chemotherapy, or targeted therapy with trastuzumab along with surgery
    
    
  • various options for adjuvant therapy are available that have been shown to reduce the annual rates of tumour recurrence and death:
    • chemotherapy, oophorectomy (including the use of gonadotrophin releasing hormone analogues), tamoxifen, and aromatase inhibitors in postmenopausal women
    • adjuvant endocrine therapy is only effective only in patients with oestrogen receptor positive cancer or progesterone receptor positive cancer
    • the particular adjuvant treatment chosen depends on on risk of relapse, potential benefits of different treatments, oestrogen receptor status, age of the patient, and acceptability of treatment to the patient
    • important factors that influence choice of treatment include age and menopausal status
    • options for adjuvant therapy include:
      • tamoxifen
        • a partial oestrogen agonist (has antagonistic actions in breast cancers, but has agonist actions on endometrium, lipids, and bone)
        • more effective when given for five years rather than two, but no evidence shows that tamoxifen is of additional benefit if taken for more than five years, and it may be detrimental
        • leads to a reduction in risk of contralateral breast cancer by 40-50%
        • may be less effective against HER2 positive tumours
        • more effective when given after chemotherapy (when this is also indicated) rather than concurrently
      • aromatase inhibitors
        • acts via inhibition of oestrogen synthesis
        • agents include the non-steroidal agents anastrozole and letrozole, and the steroidal agent exemestane
        • effective only in postmenopausal women
        • leads to an improval in disease free and metastatic free survival better than tamoxifen
        • data suggest that more effective than tamoxifen against HER2 positive tumours
        • data from the ATAC trial (4):
          • show long-term safety findings and establish clearly the long-term efficacy of anastrozole compared with tamoxifen as initial adjuvant treatment for postmenopausal women with hormone-sensitive, early breast cancer, and provide statistically significant evidence of a larger carryover effect after 5 years of adjuvant treatment with anastrozole compared with tamoxifen
      • ophorectomy (including gonadotrophin releasing hormone analogues)
        • only of benefit only in premenopausal women
        • may be as effective as older cyclophosphamide, methotrexate, and fluorouracil chemotherapy (CMF) schedules against oestrogen receptor positive tumours
        • might result in further benefit after chemotherapy in premenopausal women who continue to menstruate
      • chemotherapy
        • benefits of chemotherapy are greatest in younger women but are still important up to 70 years
        • does not seem to produce substantial benefits in postmenopausal women with grade I or II breast cancer that is oestrogen receptor rich and HER2 negative, and who receive appropriate endocrine treatment
        • anthracycline-containing combinations using doxorubicin or epirubicin are more effective than traditional CMF chemotherapy combinations
        • adding taxanes (and particularly taxotere) to anthracyclines may further improves survival in women with node positive disease. Also accelerated (sometimes called dose dense) chemotherapy given every two weeks with haemopoietic support from granulocyte colony stimulating factor may improve survival further in node positive disease
        • if node positive cancer then
          • five year survival in women with node positive cancer has risen from around 65% without treatment, and from around 70% with CMF to around 85% with modern anthracycline-taxane combinations
        • adjuvant chemotherapy is of significant survival benefit in women aged < 70 years with moderate to high risk breast cancer
          • survival benefits seem to be greater in younger women
        • if oestrogen receptor positive cancer then data indicate that using chemotherapy and tamoxifen sequentially is more effective than using either alone
          • data incidates that efficacy is greater when tamoxifen is given after chemotherapy rather than concurrently
      • trastuzumab (Herceptin)
        • a humanised monoclonal antibody directed against the external domain of the receptor with clinical activity as a single agent in patients whose cancers overexpress HER2
        • reduces the risk of early recurrence by about 50% when given with or after chemotherapy for a year
        • there is an increase in risk of cardiotoxicity (mainly congestive heart failure) when given with chemotherapy, especially with anthracycline
      • bisphosphonates
        • inhibit osteoclast mediated bone resorption induced by tumours
• NICE (5,6) state that:
  • adjuvant therapy planning
    • with respect to postoperative assessment and adjuvant therapy planning
      • predictive factors
        • assess oestrogen receptor (ER) status of all invasive breast cancers
        • routine assessment of progesterone receptor status of tumours is not indicated
        • test human epidermal growth receptor 2 (HER2) status of all invasive breast cancers
        • ensure that the ER, PR and HER2 statuses are available and recorded at the preoperative and postoperative multidisciplinary team meetings when systemic treatment is discussed
      • offer genetic testing for BRCA1 and BRCA2 mutations to women under 50 years with triple negative breast cancer, including those with no family history of breast or ovarian cancer (6)
        
        
    • adjuvant chemotherapy for invasive breast cancer
      • for people with breast cancer where chemotherapy is indicated, offer a regimen that contains both a taxane and an anthracycline. Refer to the summaries of product characteristics for individual taxanes and anthracyclines to check for differences in licensed indications
        
        
    • adjuvant endocrine therapy for invasive breast cancer
      • tamoxifen - initial adjuvant endocrine therapy for men and premenopausal women with ER-positive invasive breast cancer
      • an aromatase inhibitor - initial adjuvant endocrine therapy for postmenopausal women with ER-positive invasive breast cancer who are at medium or high risk of disease recurrence. Offer tamoxifen to women who are at low risk of disease recurrence, or if aromatase inhibitors are not tolerated or are contraindicated
        
        
    • ovarian function suppression
      • ovarian function suppression should be considered in addition to endocrine therapy for premenopausal women with ER-positive invasive breast cancer
        
        
    • extended endocrine therapy
      • extended therapy (total duration of endocrine therapy of more than 5 years) should be offered with an aromatase inhibitor for postmenopausal women with ER-positive invasive breast cancer who are at medium or high risk of disease recurrence and who have been taking tamoxifen for 2 to 5 years
      • consider extended therapy (total duration of endocrine therapy of more than 5 years) with an aromatase inhibitor[4] for postmenopausal women with ER-positive invasive breast cancer who are at low risk of disease recurrence and who have been taking tamoxifen for 2 to 5 years
      • consider extending the duration of tamoxifen therapy for longer than 5 years for both premenopausal and postmenopausal women with ER-positive invasive breast cancer
      • endocrine therapy
      • ovarian suppression/ablation for early invasive breast cancer
        • adjuvant ovarian ablation/suppression should not be offered to premenopausal women with ER-positive early invasive breast cancer who are being treated with tamoxifen and, if indicated, chemotherapy
        • adjuvant ovarian ablation/suppression should be offered in addition to tamoxifen to premenopausal women with ER-positive early invasive breast cancer who have been offered chemotherapy but have chosen not to have it
          
          
    • biological therapy
      • offer adjuvant trastuzumab for people with T1c and above HER2-positive invasive breast cancer. Give this at 3-week intervals for 1 year in combination with surgery, chemotherapy, endocrine therapy and radiotherapy, as appropriate
      • consider adjuvant trastuzumab for people with T1a/T1b HER2-positive invasive breast cancer, taking into account any comorbidities, prognostic features and possible toxicity of chemotherapy

Notes:

• a prospective trial randomly assigned postmenopausal women with hormone-receptor-positive breast cancer who had received 5 years of adjuvant endocrine therapy to receive the aromatase inhibitor anastrozole for an additional 2 years (2-year group, receiving a total of 7 years) or an additional 5 years (5-year group, receiving a total of 10 years) (7)
  • postmenopausal women with hormone-receptor-positive breast cancer who had received 5 years of adjuvant endocrine therapy, extending hormone therapy by 5 years provided no benefit over a 2-year extension but was associated with a greater risk of bone fracture
• trastuzumab
  • review of 7 RCTs (n=13,864) found risks of breast cancer recurrence (RR 0.66, 95% CI 0.62- 0.71) and death from breast cancer (0.67, 0.61-0.73) were lower with trastuzumab plus chemotherapy vs chemotherapy alone. Absolute risk reductions were 9.0% & 6.4% at 10 years respectively (8)
    • adding trastuzumab to chemotherapy for early-stage, HER2-positive breast cancer reduces recurrence of, and mortality from, breast cancer by a third

Reference:

• (1) BMJ. 2006 Jan 28;332(7535):223-4.
• (2) BMJ 2006;332:34-37.
• (3) BMJ 2006;332:101-103.
• (4) Forbes JF et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol. 2008 Jan;9(1):45-53.
• (5) NICE (March 2017).Early and locally advanced breast cancer - dagnosis and treatment
• (6) NICE (June 2023).Early and locally advanced breast cancer: diagnosis and management
• (7) Gnant M et al. Duration of Adjuvant Aromatase-Inhibitor Therapy in Postmenopausal Breast Cancer. N Engl J Med 2021; 385:395-405
• (8) Early Breast Cancer Trialists' Collaborative group (EBCTCG).Trastuzumab for early-stage, HER2-positive breast cancer: a meta-analysis of 13864 women in seven randomised trials. Lancet Oncology 22(8):1139-1150, August 01, 2021