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Adjuvant Therapy for Breast Cancer

General

Depending on age, estrogen, and progesterone receptor status, HER2 status and Ki67 expression, systemic adjuvant treatment varies. 

Hormonal treatment

The presence of estrogen and progesterone receptors in tumor indicates the probability for response of hormonal treatment.

Anti-estrogen (tamoxifen - TAM)

Adjuvant tamoxifen for 5 years has shown considerable effects on survival and is the most important single treatment drug. Tamoxifen also has additional estrogenic effects, especially in postmenopausal women. This has proven to give positive side effects on bone and lipid metabolism. Tamoxifen also reduces the risk for contralateral breast cancer. 

Aromatase inhibitors/inactivators

Aromatase inhibitors (AI) are only appropriate for postmenopausal women. Multiple large studies have shown that AI give longer disease-free survival than tamoxifen (6).

Chemotherapy

A series of chemotherapy regimens are used for adjuvant treatment. Use of several cytostatic drugs (polychemotherapy) has been shown to be more effective than use of one drug alone.

Today most often antracyclin- containing treatment regimens (moderate or high dosage (AC, FEC, FAC, EC) and regimens including taxanes(paclitaxel, docetaxel) either simultaneously with or in sequence with antracyclin containing chemotherapy. Different dosages and length of treatment are used within these main treatment groups.

Adjuvant chemotherapy for 4-6 months are considered adequate.

Antracyclin-containing regimens with higher dosage of epirubicin or more frequent administration (14 days interval  instead of 3 weeks) improves survival in high-risk groups. Difference in benefit from more intensive chemotherapy in hormone receptor positive and negative are reported. Hormone receptor positive patients have little or no effect of more intensive chemotherapy while hormone negative patients of high-risk groups can experience considerable improvement of the prognosis.

The last EBCTCG overview shows an average 1/3 reduction in death from breast cancer during optimal use of the presently available chemotherapy. Application of taxan in sequence with antracyclin containing chemotherapy gives 14% reduction in breast cancer deaths (RR 0.86) compared to regimens with lower doses of antracyclin containing regimens while it is not found significant differences if the regimen is compared to non-taxan regimes (including antracyclin) where  an identical number of cycles as in the taxan arm is given.

Chemotherapy and subgroups:

On patients analyzed on subgroups including HER2 / Ki67 in addition to hormonereceptors, the following effects can be achieved by adding taxanes to antracyclin containing thereapy:

Improved survival:

  • For hormonereceptor negative patients
  • For HER2 positive patients (borderline significant)
  • For hormonereceptor positive patients with Ki67 > 14% Ki67 positive cells in tumor (BCIRG001) or ≥ 20% Ki67 positive cells (PACS01) in tumor.

No difference in survival:   

  • For HER2 negative ER positive patients with Ki67 < 14% Ki67 positive cells (BCIRG001) or ER positive patients with <20% Ki67 positive cells (PACS01) in tumor

The indications for application of chemotherapy depends on the actual subtype of cancer (best classified by means of molecular geneprofiles):  

  • Luminal A (HR intensively positive HER2 positive with low proliferation)
  • Luminal B (HR positive HER2 positive or HR positive HER2 negative  Ki67 high/PgR negative/low)
  • ErB2 overexpression type (HER2 positive non luminal; HR negative HER2 positive)
  • Basal like (Tripple negative: HR negative HER2 negative)

Chemotherapy is not recommended to patients with Luminal A subtype. Application of chemotherapy should be considered in relation to tumor volume, other risk factors and patients preference. Analyses suggest that there is very little effect of chemotherapy in Luminal A like breast cancer with low tumor volume.

Antracyclin containing chemotherapy (commonly FEC) is the general basis for adjuvant chemotherapy in Norway. Enhanced dosage of antracyclin should be given to HER2 positive patients. There is also special reason for adding taxans to patients with HER2 positive tumors, triple negative or Luminal B tumors with high proliferation or large tumor volume.

At present the two available taxans seem equally effective and it is not clear whether these should be given in sequence or simultaneously with the antracyclin. A recent study (BIG 02-98) suggests that in sequence can improve DFS compared to synchronous application.

When there is indication for taxan treatment this should be given in sequence with 4 FEC cycles followed by 12 weeks taxan treatment (combined with trastuzumad for HER2 positive)

Influence of Ki67 on the chemotherapy decision:

  • For hotspot Ki67 > 30% (analyzed on the surgical specimen) provides the basis for giving chemotherapy as 4 FEC cycles should be given followed by 12 weeks of taxan medication.
  • For hotspot Ki67 value < 30% the decision for treatment should be based on other tumorcaracteristics and stage of the cancer. For HR positive HER2 negative patients with otherwise reason for chemotherapy, addition of taxans will primarily be appropriate for patients with grade 3 tumors with more extensive spread to the axilla (pN2-3).
  • Hotspot Ki67 value < 15% in HR positive >50% HER2 negative Grade 1-2 pN0-1 patients identifies a subgroup where application of adjuvant chemotherapy may be avoided.
  • Ki67 is usually not used for evaluation of treatment for HER2 positive cancer.

Trastuzumab

Blocking of the activity transferred through HER2 has been successfully attempted by use of the humanized monoclonal antibody trastuzumab. Chemotherapy in combination with trastuzumab is presently being tested.

Trastuzumab added to chemotherapy show a definite effect on disease free survival, and survival without metastases compared to chemotherapy alone (1). Studies show around 50% reduction of risk for recurrence, most recurrences are distant metastases.

Bisphosfanates

For postmenopausal patients comprehensive documentation has shown that zoledronic acid gives rise to additional effects. These patients are also regularly treated with aromatase inhibitors (AI). AI reduces bone density. NBCG therefore recommends:

  • Zoledronic acid 4 mg is given i.v. every 6 months for 5 years in definite postmenopausal women ≥ 55 years with indication for systemic adjuvant treatment The treatment is supervised by an oncologist in with the departments giving adjuvant chemotherapy.   
  • Zoledronic acid treatment for patients with primary operable breast cancer should be initiated within 6 months postoperatively (pragmatic starting point). There is no recommendable absolute upper age limit for the use of zoledronic acid, and it should be applied till the age of minimum 75 years. For age above 70-75 years treatment should be evaluated in regard to comorbidity and expected length of survival.
This treatment ensures optimal bone health and reduces recurrence. Routine bone density measurements are not required in patients receiving zoledronic acid as part of adjuvant therapy. Dental health must be resolved before the treatment starts. Zoledronic acid is not recommended if there are dental problems or dental surgery is planned.
Blood tests are recommended at least once a year. Zoledronic acid is not recommended if creatinine exceeds more than 1.5 times the upper normal limit.

Indications

Indication for chemotherapy and selection of regimen should be based on sybtype classification of the breast cancer in addition to histologic grade and pTpN stage. Even if the best suclassification is performed with geneprofile analyses, these are not generally available yet, and the combination of hormone reseptor status, Ki 67 status and HER2 status may be used as surrogate. When in doubt about application of chemotherapy, Oncotype Dx for instance can help in estimating a possible effect.

Patients with the following tumor caracteristics are candidates for adjuvant systemic treatment:

  • Lymph node positive patients (greatest tumor dimension > 0.2 mm, (pN1-3)
  • Lymph node negative patients (pN0) with the following primary tumor characteristics

    • pT2 (tumor dimension > 20 mm) independent of grade
    • pT1c (tumor dimension 11-20 mm) and simultaneous grade 2 or 3
    • pT1a-c (tumor size 1-20 mm) and simultaneously HER2 positive and/or hormone receptor negative and/or high Ki67. Hormone receptor negative and/or HER2 positive patients are found almost exclusively with histology grade 2-3.
  • Lymph node negative patients (pN0) with age < 35 years or the following primary tumor characteristics:

    • pT1a-b and simultaneous Grade 2 or 3

Goal

  • Cure the disease

Referances

  1. Bouchardy et al. J Clin Oncol. 2007 10;25(14):1858-69
  2. Crivellari et al, J Clin Oncol. 2007 25(14):1882-90
  3. Muss et al., J Clin Oncol. 2007 25(14):1870-5
  4. Goldhirsch et al. Meeting Highlights: International Expert Consensus on the primary therapy of early breast cancer 2005. Annals of Oncology 2005; 16:1569-1583
  5. Goldhirsch et al. Meeting Highlights: International Expert Consensus on the primary therapy of early breast cancer 2005. Annals of Oncology 2005; 16:1569-1583
  6. Ny medikamentell behandling av brystkreft - Adjuvant behandling med trastuzumab ved tidlig stadium brystkreft. Rapport fra Kunnskapssenteret Nr. 2 2006.
  7. Goldhirsch et al. Strategies for subtypes--dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol. 2011 Aug;22(8):1736-47. Epub 2011 Jun 27.

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