Hormone Thearpy Early Breast Cancer Farshad Modified 2003


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  • Hormone Thearpy Early Breast Cancer Farshad Modified 2003

    1. 1. Hormone therapy in early breast cancer Farshad seyednejad ,M.D Radiation oncologist Tabriz medical science university Jan2009
    2. 2. Early Breast Cancer The Good News Majority cured with optimal therapy
    3. 3. Positive Proof of Progress in Early Breast Cancer <ul><li>Progressive reduction in surgery needed. </li></ul><ul><li>Progressive reduction in risk of relapse. </li></ul><ul><li>2001 risk were based upon nodal status. </li></ul><ul><li>2003 add endocrine responsiveness to define both risk & treatment choice. </li></ul><ul><li>2005 endocrine responsiveness is removed from determination since it is primary factor determining treatment choice. </li></ul><ul><li>2008 target therapy. </li></ul>
    4. 4. We know that…….. <ul><li>50% to 80% early breast cancer have tumors that express estrogen or progesterone receptors. </li></ul><ul><li>Adjuvant endocrine therapy is a major contributor to decrease in breast ca. mortality. </li></ul>
    5. 5. Hypothalamus Gonadotropins (FSH + LH) Ovary Estrogens Progesterone Prolactin Growth Hormone Pituitary gland Postmenopausal and Premenopausal Adrenal gland Progesterone Androgens Estrogens Corticosteroids Premenopausal Adrenocorticotropic hormone (ACTH) Estrogen Production in Premenopausal and Postmenopausal
    6. 6. Endocrine responsiveness <ul><li>Three disease responsiveness categories were defined : </li></ul><ul><ul><li>(i) Endocrine responsive: cells express steroid hormone receptors </li></ul></ul><ul><ul><ul><li>endocrine therapies are effective in improving disease-free and overall survival. </li></ul></ul></ul><ul><ul><li>(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. </li></ul></ul><ul><ul><li>(iii) Endocrine non-responsive : cells have no detectable expression of steroid hormone receptors. </li></ul></ul>
    7. 7. Risk categories <ul><li>Nodal status remains the most important feature for defining risk category. </li></ul><ul><li>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. </li></ul><ul><li>Tumors larger than 2 cm indicated intermediate or high-risk, even in the absence of other adverse prognostic features. </li></ul>
    8. 8. 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)
    9. 9. <ul><li>endocrine therapies may be offered alone to selected patients with clearly endocrine responsive disease. </li></ul><ul><li>while chemotherapy alone is offered to patients with endocrine non-responsive disease. </li></ul><ul><li>The newly defined category of uncertain endocrine responsiveness is suited to combintions of chemotherapy and endocrine therapy. </li></ul><ul><ul><li>the absolute magnitude of clinical benefit from chemotherapy is smaller in hormone receptor-positive as compared to hormone receptor-negative breast cancer. </li></ul></ul>Valued classification .... why ?
    10. 10. uncertainty of endocrine responsiveness <ul><li>low levels of steroid hormone receptor immunoreactivity </li></ul><ul><ul><li>( usually considered as <10% of cells positive ). </li></ul></ul><ul><li>progesterone receptors (PgR) negative </li></ul><ul><ul><li>irrespective of (ER) </li></ul></ul><ul><li>features suggesting potential resistance to particular endocrine therapies </li></ul><ul><ul><li>(e.g. HER2/neu over expression and tamoxifen), a high number of involved lymph nodes </li></ul></ul><ul><li>high tumor levels of urokinase-type plasminogen (uPA/PAI-1 ) </li></ul><ul><ul><li>and increased proliferation markers. </li></ul></ul>
    11. 11. 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
    12. 12. Premenopausal: principals <ul><li>Adjuvant hormone therapy: </li></ul><ul><ul><li> risk of recurrence & mortality with estrogen receptor-positive early-stage breast cancer. </li></ul></ul><ul><li>ovarian ablation </li></ul><ul><ul><li>surgery or radiation </li></ul></ul><ul><ul><li>recent  gonadotropin-releasing hormone (GnRH) agonists have become more popular. </li></ul></ul><ul><li>Ovarian ablation and chemotherapy without adjuvant hormone therapy achieve the same reduction in the risk of breast cancer recurrence. </li></ul><ul><li>patients who retain the function of the ovaries after chemotherapy may profit from adjuvant GnRH analogs </li></ul>
    13. 13. Premenopausal : Tamoxifen <ul><li>effective adjuvant therapy. </li></ul><ul><li>its action does not depend on the age of patients or on menstrual status after chemotherapy. </li></ul><ul><ul><li>Important : no single trial or metaanalysis has demonstrated that ovarian suppression is beneficial in the presence of tamoxifen. </li></ul></ul><ul><ul><li>the efficacy of adjuvant therapy with a GnRH, in addition to tamoxifen, is being investigated in the multinational intergroup Suppression of Ovarian Function trial (SOFT). </li></ul></ul>
    14. 14. Premenopausal Aromatase inhibitors ( Anastrozole, letrozole, exemestane ) <ul><li>Aromatase inhibitors are inactive in premenopausal patients if the ovarian function is not suppressed. </li></ul><ul><li>AI + GnRH injections (to suppress ovaries) </li></ul><ul><li>Trials SOFT and TEXT </li></ul><ul><li>the worth of adjuvant therapy with aromatase inhibitors, in conjunction with GnRH analogs, is not known . </li></ul><ul><li>caution !!!! …BEWARE </li></ul><ul><ul><li>AI with chemotherapy-induced amenorrhea :may promote the recovery of ovarian function.. </li></ul></ul><ul><ul><li>Effectiveness in women < 45 years who “seem” postmenopausal after chemotherapy is uncertain (unless ovaries removed). </li></ul></ul><ul><li>classic CMF (6 months) --> 69% become menopausal </li></ul><ul><li>AC x 4 (3 months) --> 34% become menopausal </li></ul>
    15. 15. summary <ul><li>Adjuvant GnRH (or ovarian ablation) may replace chemotherapy in premenopausal patients with estrogen receptor-positive early breast cancer. </li></ul><ul><li>Tamoxifen is the standard of care after chemotherapy and adds to the efficacy of GnRH analogs. </li></ul><ul><li>In contrast, it is not known whether GnRH analogs provide added benefit in the presence of tamoxifen </li></ul>
    16. 16. Postmenopausal <ul><li>Menopause: </li></ul><ul><li>Permanent cessation of menstruation caused by failure of ovarian follicular development and estradiol production in the presence of elevated gonadotrophin levels. </li></ul><ul><li>5 years of tamoxifen is still the reference standard against which newer adjuvant treatments must be compared. </li></ul><ul><ul><li>tamoxifen reduces the risk of recurrence on average by 41% and breast cancer mortality by 34%. </li></ul></ul><ul><ul><li>Five years of tamoxifen therapy has proven at least as effective as 10 years in two trials for patients with node-negative breast cancer. </li></ul></ul><ul><ul><li>(ATLAS) trial </li></ul></ul>
    17. 17. OVARIAN FUNCTION SUPPRESSION <ul><li>OFS when?????? </li></ul><ul><ul><li>is less clearly defined-> waiting until after the completion of chemotherapy -> allows assessment of chemotherapy-associated amenorrhea. </li></ul></ul><ul><ul><li>An alternative approach :ovarian function suppression. </li></ul></ul><ul><ul><li>The optimal duration of OFS is unknown. </li></ul></ul><ul><ul><ul><li>goserelin is chosen, at least three years. </li></ul></ul></ul>
    18. 18. Role of Aromatase in Estrogen Biosynthesis and Tumor Growth Aromatase Aromatase Adrenal gland Peripheral tissues Postmenopausal women Tumor = Estrogen = Androstenedione Receptor
    19. 19. The Role of Aromatase in Estrogen Biosynthesis and Tumor Growth Aromatase Aromatase Adrenal gland Peripheral tissues Postmenopausal women Tumor = Estrogen = Androstenedione Receptor AI AI
    20. 20. ATAC Trial Design      + Postmenopausal women with invasive breast cancer Surgery  radiotherapy  chemotherapy Randomization 1:1:1 for 5 years Anastrozole 1mg qd + Tamoxifen placebo Anastrozole placebo + Tamoxifen 20mg qd Anastrozole 1mg qd + Tamoxifen 20mg qd  Regular follow-up  <ul><li>Primary trial endpoints </li></ul><ul><li>Disease-free survival </li></ul><ul><li>Safety/tolerability </li></ul><ul><li>Secondary trial endpoints </li></ul><ul><li>Incidence of contralateral breast cancer </li></ul><ul><li>Time to distant recurrence </li></ul><ul><li>Survival (data will be mature in 18 months) </li></ul>
    21. 21. Postmenopausal <ul><li>AI proved superior to tamoxifen in terms of disease-free survival, but both failed to demonstrate a statistically significant difference in overall survival. </li></ul><ul><ul><li>letrozole was particularly effective in patients : </li></ul></ul><ul><ul><ul><li>1/with more than four axillary lymph node metastases </li></ul></ul></ul><ul><ul><ul><li>2/ those with highly proliferative breast cancer </li></ul></ul></ul><ul><ul><ul><li>whereas no differential effect was observed in relation to the expression of the progesterone receptor and of the HER2 protein in ATAC and in BIG 1–98 </li></ul></ul></ul>
    22. 22. Summary II ( Safety ) <ul><li>Anastrozole </li></ul><ul><li>significantly better tolerated with respect to: </li></ul><ul><ul><li>Endometrial cancer </li></ul></ul><ul><ul><li>Vaginal bleeding </li></ul></ul><ul><ul><li>Vaginal discharge </li></ul></ul><ul><ul><li>Ischaemic cerebrovascular </li></ul></ul><ul><ul><li>Venous thromboembolic </li></ul></ul><ul><ul><li>Hot flushes </li></ul></ul><ul><li>Tamoxifen </li></ul><ul><li>better tolerated with respect to: </li></ul><ul><ul><li>Musculoskeletal disorders </li></ul></ul><ul><ul><li>Fractures </li></ul></ul>
    23. 23. Sequence <ul><li>tamoxifen for 2 to 3 years  followed by an aromatase inhibitor for up to 5 years. </li></ul><ul><li>RESULT: </li></ul><ul><ul><li>Patients who crossed over to aromatase inhibitors </li></ul></ul><ul><ul><ul><li>statistically significant reduction in the risk of breast cancer recurrence by one-quarter to one-third. </li></ul></ul></ul><ul><ul><ul><li>MA.17 </li></ul></ul></ul>
    24. 24. 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
    25. 25. MA.17: Summary of Efficacy Results <ul><li>FEMARA lowers the risk of recurrence by 43% vs placebo </li></ul><ul><li>FEMARA improves the estimated 4-year DFS rate by 6% vs placebo (93% vs 87%) </li></ul><ul><li>FEMARA improves estimated 4-year OS rate by 2% vs placebo (96% vs 94%) </li></ul><ul><li>FEMARA decreases incidence of contralateral breast cancer by 46% </li></ul>Goss et al. N Engl J Med . 2003;349:TBD.
    26. 26. MA.17: Conclusions <ul><li>FEMARA is the first and only treatment to achieve a significant DFS benefit in the extended adjuvant setting beyond early adjuvant tamoxifen . </li></ul><ul><li>FEMARA reduces the risk of contralateral breast cancer </li></ul><ul><li>FEMARA reduces risk of distant metastases, and based on these results, will provide considerable benefit to women with early stage breast cancer </li></ul>Goss et al. N Engl J Med . 2003;349:TBD.
    27. 27. Result…… <ul><li>In summary, postmenopausal patients with early-stage breast cancer should be treated with an aromatase inhibitor as part of the adjuvant therapy. </li></ul><ul><ul><li>Adjuvant hormone therapy for postmenopausal women with ER+ breast cancer should include an AI. </li></ul></ul><ul><li>An AI is a reasonable alternative to tamoxifen for initial treatment in postmenopausal women with ER+ breast cancer. </li></ul><ul><li>Postmenopausal women who complete five years of tamoxifen should consider taking an AI for up to 5 years. </li></ul><ul><li>Alternatively, postmenopausal women completing two to three years of tamoxifen could consider crossover to an AI, for a total of five years of therapy. </li></ul><ul><li>adjuvant tamoxifen be limited to 5 years. </li></ul>
    28. 28. <ul><li>Tamoxifen as a standard adjuvant treatment for premenopausal women with endocrine responsive disease. </li></ul><ul><li>Ovarian function suppression (OFS) was accepted as an alternative where tamoxifen was contraindicated. </li></ul><ul><li>tamoxifen  ovarian function suppression: </li></ul><ul><ul><li>for very young patients, especially in intermediate- and high-risk groups. </li></ul></ul><ul><ul><li>and for premenopausal patients of any age at high risk, especially if chemotherapy did not induce OFS. </li></ul></ul><ul><li>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. </li></ul><ul><li>tamoxifen should be given sequentially after a djuvant chemotherapy. </li></ul><ul><li>timing of OFS in relation to chemotherapy was less clearly defined. </li></ul><ul><li>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. </li></ul>
    29. 29. Key points Postmenopausal <ul><li>St Gallen </li></ul><ul><li>ASCO2008 </li></ul><ul><li>Aromatase inhibitor either as initial therapy or after treatment with tamoxifen. </li></ul><ul><li>Adjuvant tamoxifen has a long-lasting (‘carry-over’) benefit well beyond 5 years after its cessation. </li></ul><ul><li>(i) an aromatase inhibitor (anastrozole, letrozole) alone for 5 years </li></ul><ul><li>(ii) tamoxifen for 2– 3 years followed by an aromatase inhibitor to complete 5 years of therapy. </li></ul><ul><li>(iii) switch to an aromatase inhibitor (letrozole) after completing 5 years of tamoxifen. </li></ul><ul><li>(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 </li></ul><ul><li>Five years of tamoxifen is still the reference standard. </li></ul><ul><ul><li>Five years of tamoxifen therapy has proven at least as effective as 10 years. </li></ul></ul><ul><li>AI(ATAC & BIG 1-98) superior to tamoxifen (DFS but may  overall survival). </li></ul><ul><li>Sequential tamoxifen for 2 to 3 years, followed by an aromatase inhibitor for up to 5 years: </li></ul><ul><li>crossed over to aromatase inhibitors experienced a statistically significant reduction in the risk of breast cancer recurrence by one-quarter to one-third. </li></ul>