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Hormone Thearpy Early Breast Cancer Farshad Modified 2003
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Hormone Thearpy Early Breast Cancer Farshad Modified 2003

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last update in breast cancer hormone therapy.

last update in breast cancer hormone therapy.

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Hormone Thearpy Early Breast Cancer Farshad Modified 2003 Hormone Thearpy Early Breast Cancer Farshad Modified 2003 Presentation Transcript

  • Hormone therapy in early breast cancer Farshad seyednejad ,M.D Radiation oncologist Tabriz medical science university Jan2009
  • Early Breast Cancer The Good News Majority cured with optimal therapy
  • Positive Proof of Progress in Early Breast Cancer
    • Progressive reduction in surgery needed.
    • Progressive reduction in risk of relapse.
    • 2001 risk were based upon nodal status.
    • 2003 add endocrine responsiveness to define both risk & treatment choice.
    • 2005 endocrine responsiveness is removed from determination since it is primary factor determining treatment choice.
    • 2008 target therapy.
  • We know that……..
    • 50% to 80% early breast cancer have tumors that express estrogen or progesterone receptors.
    • Adjuvant endocrine therapy is a major contributor to decrease in breast ca. mortality.
  • 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
  • Endocrine responsiveness
    • Three disease responsiveness categories were defined :
      • (i) Endocrine responsive: cells express steroid hormone receptors
        • 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.
  • Risk categories
    • 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)
    • endocrine therapies may be offered alone to selected patients with clearly endocrine responsive disease.
    • while chemotherapy alone is offered to patients with endocrine non-responsive disease.
    • The newly defined category of uncertain endocrine responsiveness is suited to combintions of chemotherapy and endocrine therapy.
      • the absolute magnitude of clinical benefit from chemotherapy is smaller in hormone receptor-positive as compared to hormone receptor-negative breast cancer.
    Valued classification .... why ?
  • uncertainty of endocrine responsiveness
    • 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
  • Premenopausal: principals
    • Adjuvant hormone therapy:
      •  risk of recurrence & mortality with estrogen receptor-positive early-stage breast cancer.
    • ovarian ablation
      • surgery or radiation
      • recent  gonadotropin-releasing hormone (GnRH) agonists have become more popular.
    • Ovarian ablation and chemotherapy without adjuvant hormone therapy achieve the same reduction in the risk of breast cancer recurrence.
    • patients who retain the function of the ovaries after chemotherapy may profit from adjuvant GnRH analogs
  • Premenopausal : Tamoxifen
    • effective adjuvant therapy.
    • its action does not depend on the age of patients or on menstrual status after chemotherapy.
      • Important : no single trial or metaanalysis has demonstrated that ovarian suppression is beneficial in the presence of tamoxifen.
      • 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).
  • Premenopausal Aromatase inhibitors ( Anastrozole, letrozole, exemestane )
    • Aromatase inhibitors are inactive in premenopausal patients if the ovarian function is not suppressed.
    • AI + GnRH injections (to suppress ovaries)
    • Trials SOFT and TEXT
    • the worth of adjuvant therapy with aromatase inhibitors, in conjunction with GnRH analogs, is not known .
    • caution !!!! …BEWARE
      • AI with chemotherapy-induced amenorrhea :may promote the recovery of ovarian function..
      • Effectiveness in women < 45 years who “seem” postmenopausal after chemotherapy is uncertain (unless ovaries removed).
    • classic CMF (6 months) --> 69% become menopausal
    • AC x 4 (3 months) --> 34% become menopausal
  • summary
    • Adjuvant GnRH (or ovarian ablation) may replace chemotherapy in premenopausal patients with estrogen receptor-positive early breast cancer.
    • Tamoxifen is the standard of care after chemotherapy and adds to the efficacy of GnRH analogs.
    • In contrast, it is not known whether GnRH analogs provide added benefit in the presence of tamoxifen
  • Postmenopausal
    • Menopause:
    • Permanent cessation of menstruation caused by failure of ovarian follicular development and estradiol production in the presence of elevated gonadotrophin levels.
    • 5 years of tamoxifen is still the reference standard against which newer adjuvant treatments must be compared.
      • tamoxifen reduces the risk of recurrence on average by 41% and breast cancer mortality by 34%.
      • Five years of tamoxifen therapy has proven at least as effective as 10 years in two trials for patients with node-negative breast cancer.
      • (ATLAS) trial
  • OVARIAN FUNCTION SUPPRESSION
    • OFS when??????
      • is less clearly defined-> waiting until after the completion of chemotherapy -> allows assessment of chemotherapy-associated amenorrhea.
      • An alternative approach :ovarian function suppression.
      • The optimal duration of OFS is unknown.
        • goserelin is chosen, at least three years.
  • Role of Aromatase in Estrogen Biosynthesis and Tumor Growth Aromatase Aromatase Adrenal gland Peripheral tissues Postmenopausal women Tumor = Estrogen = Androstenedione Receptor
  • The Role of Aromatase in Estrogen Biosynthesis and Tumor Growth Aromatase Aromatase Adrenal gland Peripheral tissues Postmenopausal women Tumor = Estrogen = Androstenedione Receptor AI AI
  • 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 
    • Primary trial endpoints
    • Disease-free survival
    • Safety/tolerability
    • Secondary trial endpoints
    • Incidence of contralateral breast cancer
    • Time to distant recurrence
    • Survival (data will be mature in 18 months)
  • Postmenopausal
    • AI proved superior to tamoxifen in terms of disease-free survival, but both failed to demonstrate a statistically significant difference in overall survival.
      • letrozole was particularly effective in patients :
        • 1/with more than four axillary lymph node metastases
        • 2/ those with highly proliferative breast cancer
        • 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
  • Summary II ( Safety )
    • Anastrozole
    • significantly better tolerated with respect to:
      • Endometrial cancer
      • Vaginal bleeding
      • Vaginal discharge
      • Ischaemic cerebrovascular
      • Venous thromboembolic
      • Hot flushes
    • Tamoxifen
    • better tolerated with respect to:
      • Musculoskeletal disorders
      • Fractures
  • Sequence
    • tamoxifen for 2 to 3 years  followed by an aromatase inhibitor for up to 5 years.
    • RESULT:
      • 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
  • 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
  • MA.17: Summary of Efficacy Results
    • FEMARA lowers the risk of recurrence by 43% vs placebo
    • FEMARA improves the estimated 4-year DFS rate by 6% vs placebo (93% vs 87%)
    • FEMARA improves estimated 4-year OS rate by 2% vs placebo (96% vs 94%)
    • FEMARA decreases incidence of contralateral breast cancer by 46%
    Goss et al. N Engl J Med . 2003;349:TBD.
  • MA.17: Conclusions
    • FEMARA is the first and only treatment to achieve a significant DFS benefit in the extended adjuvant setting beyond early adjuvant tamoxifen .
    • FEMARA reduces the risk of contralateral breast cancer
    • FEMARA reduces risk of distant metastases, and based on these results, will provide considerable benefit to women with early stage breast cancer
    Goss et al. N Engl J Med . 2003;349:TBD.
  • Result……
    • In summary, postmenopausal patients with early-stage breast cancer should be treated with an aromatase inhibitor as part of the adjuvant therapy.
      • Adjuvant hormone therapy for postmenopausal women with ER+ breast cancer should include an AI.
    • An AI is a reasonable alternative to tamoxifen for initial treatment in postmenopausal women with ER+ breast cancer.
    • Postmenopausal women who complete five years of tamoxifen should consider taking an AI for up to 5 years.
    • Alternatively, postmenopausal women completing two to three years of tamoxifen could consider crossover to an AI, for a total of five years of therapy.
    • adjuvant tamoxifen be limited to 5 years.
    • 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.
  • Key points Postmenopausal
    • St Gallen
    • ASCO2008
    • 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.