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Adjuvant Therapy for Breast Cancer


Medical editor Bjørn Naume MD
Oncologist
Oslo University Hospital
Norway

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.

Treatment Plan

Recommended non-hormone treatment

When indicated, adjuvant chemotherapy is recommended up to 75 years. High age alone is not recommended for the omission of chemotherapy. This is especially relevant for triple negative and HER2 positive patients. For higher age chemotherapy application must be carefully evaluated in relation to comorbidity and survival expectancy – and customized treatment may be necessary. Cardiovascular morbidity must be especially scrutinized. MUGA or ECHO should be applied on liberal indications.

Cardiac MUGA and ECHO should be performed on all patients, independent of age, who are to be given high dose FEC (FEC100). This will optimally reveal the cardiac status and tolerability in the treatment.

Recommended hormone treatment

Premenopausal patients

  • Tamoxifen for 5 years

Extended hormonal treatment is recommended as follows:

  • Patients below 40 years of age at the initiation of the treatment may be offered 10 years of tamoxifen treatment if the tolerability/probable - absolute benefit supports this.
  • Patients > 40years of age who will be postmenopausal efter 5 years of tamoxifen treatment should be offered araomatase treatment for 3-5 years (monitoring the hormonal blood values should be performed bimonthly for half a year). For perimenopausal status tamoxifen should be applied, possibly followed by AI if the patient becomes menopausal.
  • Patients >40 years of age who are premenopausal after 5 years with tamoxifen may be further offered 5 years of tamoxifen treatment if the tolerability/probable - absolute benefit supports this.

Postmenopausal patients (≥ 55 (50) years) 

  • Aromatase inhibitor for 2 years followed by tamoxifen for 3 years, or
  • Aromatase inhibitor for 5 years
  • Women already given tamoxifen for 2 to 5 years are recommended to change to AI for 3 years.
  • Women already given tamoxifen for 5 years followed by treatment-free period should not change to AI. Those who are strongly motivated to take an aromatase inhibitor, should be informed of the effect and side effects of the treatment. If the patient still wishes to receive this treatment, this should be accommodated.
  • Women with an inclination to DVT or LE should have AI from immediately after surgery or chemotherapy.
  • Women having DVT or LE during ongoing tamoxifen should change to AI.
  • In cases where it is not relevant to apply AI for 2-3 years, extension of adjuvant treatment with tamoxifen for a total of 10 years should be considered.  

Calcium/Vitamin D (1000 mg/800 IU daily) should be given to all patients treated with aromatase inhibitors (AI), for instance Caligran Forte® chewing tablets.


Preparation

Cardiac MUGA and ECHO should be taken on patients who will have high-dose FEC100. This is to determine the cardiac status of the patient and tolerability for treatment.

The patient should be informed about the treatment and its consequences, and offered a customized wig.

Hormone treatment

Hormone receptor status, HER2 status and Ki67 expression should always be examined. Hormone receptor negative patients do not benefit from adjuvant endocrine treatment.

In connection with the start of treatment with aromatase inhibitor/inactivator (AI), bone density measurement (DEXA-scan) should also be performed.

Bone- density-measurement  (DEXA-scan) is required prior to treatment with aromatase inhibitors (AI). In patients receiving aromatase inhibitors with addition of zoledronic acid, the reason for monitoring the bone density disappears.

Chemotherapy

Neutropenia

During chemotherapy, neutropenia is the usual dose-limiting factor. G-CSF can effectively reduce complications of neutropenia.

For chemotherapy administered every third week (FEC, docetaxel), G-CSF is recommended as follows:

  • The lowest acceptable level for chemotherapy without G-CSF is a neutrophil count of 1.0 x 109/l.
  • For values below 1.0 x 109, the cytostatic treatment is most often applicable when combined with G-CSF. If there are contraindications to the administration of chemotherapy on schedule (very low neutrophils/uncertainty whether neutrophils are increasing), the patient is reassessed after 1-3 days with the goal of administering treatment with supporting G-CSF.
  • If there is a preceding episode of febrile neutropenia, the subsequent chemotherapy cycles is given in combination with G-CSF (secondary prophylaxis).

For weekly treatment, evaluation of the lowest acceptable level for repeated treatment is based on the rate of improvement after a possible fall in neutrophil granulocytes. It is often possible to continue treatment when neutrophil granulocyte values are > 0.7 x 109/l. G-CSF is not given for weekly cycles. If a treatment must be postponed, the patient should be reassessed after 1-3 days.  

Thrombocytopenia

Thrombocytopenia is rarely a problem during adjuvant chemotherapy, but treatment should generally not be given with values < 50.

Other side effects

All the relevant regimens for adjuvant chemotherapy for breast cancer will cause loss of hair in most patients. The patients should be informed about this and that the hair will regrow after the termination of the treatment.

Cyclophosphamide and 5-fluorouracil give rise to nausea and vomiting in at least 50% of the patients. The symptoms may appear from 1 to several hours after the infusion. 5HT3-receptor blockers are at present standard antiemetic treatment  for FEC courses. Usually this is given in combination with dexamethasone. Further reactions/medication should be considered according to individual tolerance. Docetaxel and paclitaxel will usually cause no or slight nausea.

Docetaxel/paclitaxel can cause hypersensitivity/anaphylactic reactions. Monitoring of the patient is therefore necessary, particularly at the initial courses. Specific schedule is prepared (National Register for Medical Cancer Treatment or Cytodose). The risk for serious reactions is minimal if glucocorticoid is combined with the courses, as given in the schemes above. If reactions appear, the infusion is temporarily paused and relevant treatment given. When the symptoms have disappeared, the infusion is started with reduced rate, gradually increasing if the symptoms do not reappear.

If sepsis or hemorrhage has occurred, individual considerations are needed before the next course is given. ECG must be performed in cases of suspect cardiac disease. Epirubicin is highly tissue toxic and must only be given with secure intravenous access to avoid extravasation.

Trastuzumab

The most serious side effect caused by trastuzumab is cardiotoxicity.

Necessary examinations before treatment are:

  • Hematological testing  (ASAT, ALAT, ALP, creatinine, and bilirubin) before starting treatment. After this no blood samples are routinely required. Before starting trastuzumab, blood tests must be within the following limits: 
    • Bilirubin ≤ 2.0 x upper normal limit (ULN)
    • ALAT or ASAT ≤ 2.5 x ULN
    • ALP ≤ 2.5 x ULN
    • Creatinine ≤ 2 ULN
    • Neutrophil ≥ 1.0 x 109/L
    • Thrombocytes ≥ 100 x 109/L
  • ECG
  • Assessment of left ventricular ejection fraction (LVEF) with MUGA-scan or ECHO. LVEF should be ≥ 55% to start with trastuzumab.
  • Previous cumulative epirubicin dose must not be >720 mg/m2
  • The patient must not have serious heart disease such as documented heart failure, high risk for uncontrolled arrhythmia, severe chest pain requiring medical treatment, valve disorder, transmural cardiac infarction, or poorly controlled hypertension (systolic > 180, diastolic > 100).
  • The patient should not have serious lung disease.
  • The patient should not be pregnant.

Implementation

Hormone treatment

Premenopausal women

Treatment starts after adjuvant chemotherapy is terminated. Treatment with tamoxifen daily for five years is recommended in premenopausal women. If recurrence occurs during the treatment, the medication is stopped.

In the event that the patient does not want chemotherapy, an alternative is goserelin injections for three years in combination with tamoxifen for 5 years. There still is insufficient data of the effect of this combination compared to chemotherapy followed by tamoxifen.

Postmenopausal women

If adjuvant chemotherapy is relevant, hormone treatment is started after completion of chemotherapy. 

It is usually recommended to start with aromatase inhibitors, as this has shown improved survival compared to tamoxifen.

There is international consensus that adjuvant endocrine treatment in most cases should include aromatase inhibitor. The BIG 1-98 study supports the indication for initially giving aromatase inhibitor the first 2 years, and thereafter considering switch to tamoxifen. This is comparable in effect to aromatase inhibitor for 5 years (3). Decision on an individual basis depends on the side effects, economy, or other conditions. 

Osteoporosis and marked osteopenia while being treated with AI, requires bisphosphonate treatment.

Mild to moderate osteopenia at the beginning requires a new reassessment of bone density monitoring after one year. With a fall of bone density (BMD) of ≥ 10%, bisphosphonate treatment should be started. Vitamin D/calcium (1000 mg/800IE daily) should be given to all that receive AI adjuvant treatment, regardless of bone density, for instance Calcigran forte, chewing tablets 1 tablet x 2 daily. 

Chemotherapy

Adequate duration of adjuvant chemotherapy is four to six months.

Trastuzumab

The treatment usually starts 3 weeks after the last adjuvant FEC course, and is given simultaneously with the taxane treatment as a combination therapy. If  LVEF < 50%, the trastuzumab treatment is postponed and a new MUGA- or Echo-examination is performed after 3-6 weeks.

After completed taxane treatment, trastuzumab monotherapy is given, regardless of whether the patient receives radiation therapy.

The first infusion with trastuzumab is given as a loading dose of 8 mg/kg. Thereafter, one dose of 6 mg/kg is given every three weeks until 17 courses. The treatment lasts for about one year.

Treatment with trastuzumab does not require blood tests except for prior to the first infusion. The neutrophil granulocyte count should then be  ≥ 1.0 x 109/l.

MUGA- or Echo- examination is performed every 12th. week. Adjustment of the treatment due to this monitoring will be according to the following treatment algorithm:

http://www.nbcg.net/filer/57.ppt.

References

  1. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial.Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists' Group, Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M.  Lancet Oncol. 2008 Jan;9(1):45-53.
  2. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. Coates AS, Keshaviah A, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, et al. J Clin Oncol. 2007 Feb 10;25(5):486-92.
  3. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. BIG 1-98 Collaborative Group, Mouridsen H, Giobbie-Hurder A, Goldhirsch A, Thürlimann B, Paridaens R, Smith I, et al. N Engl J Med. 2009 Aug 20;361(8):766-76.

Follow-up

Hormone treatment

Many women will stop menstruating. This will be depending on the woman’s age; younger women will have a higher propensity to maintain menstruation than women who are near menopause.  Pregnancy must be avoided.

The side effects of endocrine treatment are usually mild to moderate.

The most common side effects are hot flashes. Other side effects, which may occur are:

  • Mild nausea
  • Abdominal discomfort
  • Vaginal symptoms
  • Joint problems, especially with aromatase inhibitors
  • Bone density changes, especially with aromatase inhibitors

Tamoxifen causes a small increased risk for deep vein thrombosis (DVT) and lung embolism (LE) and endometrial cancer.  Women who are predisposed for DVT or LE under tamoxifen treatment should change to AI.

An annual gynecological examination is recommended during tamoxifen treatment.

Chemotherapy

Some side effects of adjuvant cytostatic treatment (1)

(frequent > 1/100, rare < 1/1000)

  FEC    
  Fluorouracil Epirubicin Cyclophosphamide Paclitaxel Docetaxel
Bone marrow depression frequent frequent frequent frequent frequent
Nausea/vomiting low moderate high/moderate low low
Hair loss frequent frequent with high doses frequent frequent
Diarrhea/constipation diarrhea diarrhea dose-dependent diarrhea diarrhea/constipation
Mucositis/stomatitis stomatitis mucositis dose-dependent mucositis stomatitis
Allergic reactions rare rare frequent rare sometimes
Cardiotoxicity rare yes rare rare rare
Neurologic symptoms rare not reported not reported frequent frequent
Nail changes not reported not reported rare frequent frequent
Liver dysfunction rare not reported frequent rare/serious frequent
Skin reaction frequent frequent rare not reported less frequent

*Cardiac failure combined with trastuzumab (comprises 2.2 %)(1).


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