endocrine therapies are effective in improving disease-free and overall survival.
(ii) Endocrine response uncertain: some expression of steroid hormone receptors either quantitatively low or qualitatively insufficient to indicate a substantial chance for response to endocrine therapies alone, thus suggesting the need for chemotherapy.
(iii) Endocrine non-responsive : cells have no detectable expression of steroid hormone receptors.
Nodal status remains the most important feature for defining risk category.
Involvement of four or more nodes in the axilla by itself indicated high risk, but patients with one to three nodes involved required significant HER2/neu verexpression or amplification to be included in the high-risk group.
Tumors larger than 2 cm indicated intermediate or high-risk, even in the absence of other adverse prognostic features.
Node negative AND all of the following features: Low risk T ≤2 cm & Grade 1, & Absence of peritumoral vascular invasion, & HER2/neu gene neither overexpressed nor amplified, & Age≥ 35 Node negative & at least one of the following features: Intermediate risk T >2 cm, OR Grade 2-3, OR Presence of peritumoral vascular invasion, OR HER2/neu gene overexpressed or amplified, OR Age <35 years Node positive (1-3 involved nodes) & HER2/neu gene neither overexpressed nor amplified Node positive (1-3 involved nodes) AND HER2/neu gene overexpressed or amplified High risk Node positive (4 or more involved nodes)
low levels of steroid hormone receptor immunoreactivity
( usually considered as <10% of cells positive ).
progesterone receptors (PgR) negative
irrespective of (ER)
features suggesting potential resistance to particular endocrine therapies
(e.g. HER2/neu over expression and tamoxifen), a high number of involved lymph nodes
high tumor levels of urokinase-type plasminogen (uPA/PAI-1 )
and increased proliferation markers.
Endocrine nonresponsive Endocrine response uncertain Endocrine responsive Risk category Not applicable ET or Nil ET or Nil Low risk CT CT -> ET ET alone, or CT -> ET Intermediate risk CT CT -> ET CT -> ET High risk
tamoxifen for 2 to 3 years followed by an aromatase inhibitor for up to 5 years.
Patients who crossed over to aromatase inhibitors
statistically significant reduction in the risk of breast cancer recurrence by one-quarter to one-third.
MA.17: Trial Design Adjuvant Letrozole (Femara ® ) vs Placebo in Postmenopausal Women With Primary Breast Cancer Completing 5 Years of Tamoxifen Primary end point: DFS Secondary end points: OS/safety/QOL *n=2575 (efficacy); 2154 (safety) in the FEMARA arm. † n=2582 (efficacy); 2145 (safety) in the placebo arm. Goss et al. N Engl J Med . 2003;349:TBD. Randomization (Disease-free) Tamoxifen Placebo qd † FEMARA (Letrozole) 2.5 mg qd* 5 years early adjuvant 5 years extended adjuvant
Tamoxifen as a standard adjuvant treatment for premenopausal women with endocrine responsive disease.
Ovarian function suppression (OFS) was accepted as an alternative where tamoxifen was contraindicated.
tamoxifen ovarian function suppression:
for very young patients, especially in intermediate- and high-risk groups.
and for premenopausal patients of any age at high risk, especially if chemotherapy did not induce OFS.
Optimal duration of ovarian function suppression is unknown. Patients with tumors overexpressing HER2/neu] may benefit if the entire period of tamoxifen were covered with a GnRH analog.
tamoxifen should be given sequentially after a djuvant chemotherapy.
timing of OFS in relation to chemotherapy was less clearly defined.
Patients who received adjuvant tamoxifen when they were premenopausal for node positive, endocrine responsive disease, might consider later continuation of the adjuvant endocrine treatment with letrozole if they become postmenopausal.
Aromatase inhibitor either as initial therapy or after treatment with tamoxifen.
Adjuvant tamoxifen has a long-lasting (‘carry-over’) benefit well beyond 5 years after its cessation.
(i) an aromatase inhibitor (anastrozole, letrozole) alone for 5 years
(ii) tamoxifen for 2– 3 years followed by an aromatase inhibitor to complete 5 years of therapy.
(iii) switch to an aromatase inhibitor (letrozole) after completing 5 years of tamoxifen.
(iv) Finally, selected patients at low risk or with comorbid musculo-skeletal or cardiovascular risk factors may be considered suitable for tamoxifen alone, and this may be the only option available on economic grounds in many cases
Five years of tamoxifen is still the reference standard.
Five years of tamoxifen therapy has proven at least as effective as 10 years.
AI(ATAC & BIG 1-98) superior to tamoxifen (DFS but may overall survival).
Sequential tamoxifen for 2 to 3 years, followed by an aromatase inhibitor for up to 5 years:
crossed over to aromatase inhibitors experienced a statistically significant reduction in the risk of breast cancer recurrence by one-quarter to one-third.