In this blog post, I will review the current recommendation of endocrine therapy for early non-metastatic breast cancer hormone positive breast cancer (Estrogen receptor positive ER + and/or Progesterone receptor positive PR +), this is most often referred to as Adjuvant hormonal or Adjuvant Endocrine therapy, for discussion regarding the use of endocrine therapy for metastatic breast cancer please refer to my earlier post by clicking here.
Hormone receptor-positive Breast cancer comprise 75% of all cases.
Endocrine therapy is of significant benefit and Generally well tolerated.
Why is adjuvant hormonal therapy recommended? Several large trials demonstrated that hormonal therapy following definitive surgery decreases the risk of recurrence and improve survival, also hormonal therapy is well tolerated, with low toxicity profile.
What are the agents used in such adjuvant hormonal therapy? The following is used alone or sometimes in combination,
- Selective estrogen receptor modulator the best example of that is Tamoxifen.
- Aromatase inhibitors (AI), for example Anastrazole.
- Ovarian suppression, this can be achieved by one of the following modalities
- Medical suppression by using agonist for GnRH for example Lupron.
- Surgical, by surgically removing the ovaries.
- Radiation, also called ovarian ablation.
The choice of hormonal therapy and duration will depend on several factors
- Patient menopausal status.
- Risk of recurrence, high vs. average risk.
- Presence of comorbidities.
As I go forward, it is clear that determining the patient menopausal status is the most pivotal step in determining the correct endocrine therapy. The following will help define the menopausal status, and it is adopted from NCCN.
A. Women 60-years and older are considered postmenopausal.
B. Women younger than 60-years are considered postmenopausal if one of the following is fulfilled.
- They previously had bilateral oophorectomy or ovarian ablation by radiation therapy.
- They have not had any menstrual periods for 12 months in the absence of tamoxifen, chemotherapy or ovarian suppression and the serum estradiol is in the postmenopausal range.
- They are amenorrheic on tamoxifen, and the follicle-stimulating hormone and serum estradiol are in the postmenopausal range.
All women who do not meet the definition of menopause must be treated as premenopausal.
On the other hand, there are no strict criteria for defining high-risk patients, it is generally accepted that in a premenopausal patient who received adjuvant chemotherapy should be considered a high risk as well as premenopausal patients diagnosed at age 35 or younger. The following slide will summarize the recommendation.
The above slide is my personal interpretation of the American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines which can be found here.
In the following table, I will list the most important trial that helped shape our current understanding of adjuvant endocrine therapy.
|SOFT||Adding ovarian suppression to tamoxifen did not provide a significant benefit in the overall study population, however for women who were at sufficient risk of recurrence and remained premenopausal adding ovarian suppression improved outcome.|
|TEXT||Premenopausal women with hormone receptor-positive, HER2-negative disease and high recurrence risk, as defined by clinicopathologic characteristics, may experience improvement of 10% to 15% in 5-year BCFI with exemestane plus OFS versus tamoxifen alone. An improvement of at least 5% may be achieved for women at intermediate risk, and improvement is minimal for those at lowest risk.|
|In this meta-analysis the addition of LHRH agonist to tamoxifen, chemotherapy, or both reduced recurrence by 12.7% (2.4-21.9, p=0.02); and death after recurrence by 15.1% (1.8-26.7, p=0.03)|
|BIG 1-98||For postmenopausal women with endocrine-responsive early breast cancer, a reduction in breast cancer recurrence and mortality is obtained by letrozole monotherapy when compared with tamoxifen montherapy. Sequential treatments involving tamoxifen and letrozole do not improve outcome compared with letrozole monotherapy, but might be useful strategies when considering an individual patient's risk of recurrence and treatment tolerability.|
Demonstrated a survival advantage with extended therapy with letrozole compared with placebo in women with ALN-positive (but not lymph node-negative), ER-positive breast cancer.
|MA.17R||The extension of treatment with an adjuvant aromatase inhibitor to 10 years resulted in significantly higher rates of disease-free survival and a lower incidence of contralateral breast cancer than those with placebo, but the rate of overall survival was not higher with the aromatase inhibitor than with placebo|
|ATAC||Demonstrated that anastrozole is superior to tamoxifen or the combination of tamoxifen and anastrozole in the adjuvant endocrine therapy of postmenopausal women with hormone receptor-positive breast cancer.|
|ATLAS||For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10.|
|IDEAL||This study showed no superiority of five years over 2.5 years of extended adjuvant letrozole after an initial five years of adjuvant endocrine therapy.|
Adjuvant endocrine therapy for non-metastatic breast cancer is far from being well defined with many decision-making challenges and treatment side effects management, next I will try to clarify some of such challenges.
Is there more side effects when ovarian suppression plus AI’s vs Tamoxifen in premenopausal women? the following was noted with higher frequency in women receiving AI’s
- Early discontinuation.
- Sexual issues such as vaginal dryness.
- Musculoskeletal complaints.
For a more detailed discussion regarding bone health issues with AI’s, please refer to my earlier blog post by clicking here.
What is the optimum duration of AI’s in postmenopausal women? unfortunately, there is conflicting data regarding this specific question. The NCCN guidelines recommend “consideration of additional AI’s” following the initial 5 years of adjuvant AI’s therapy. The MA.17R trial indicates a benefit of AI’s beyond five years, however, the recently published IDEAL trial did not show such benefit.
When to start adjuvant endocrine therapy?
a. For patients receiving adjuvant chemotherapy, it is a common practice to start endocrine therapy following the completion of chemotherapy.
b. For patients receiving radiation therapy? in my practice I favor starting adjuvant hormonal therapy following the completion of radiation therapy, however, there is some data showing that concomitant treatment with radiation therapy did not negatively affect the outcome.
c. For patients receiving anti Her2 therapy, endocrine therapy is started following the completion of the chemotherapy component fo the anti Her2 adjuvant regimen.