Paul E Goss 如何合理的选择乳腺癌辅助内分泌治疗.ppt
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Endocrine Responsive Breast Cancer
* > 1 M diagnoses of breast cancer and 375,000 deaths annually worldwide
* Approximately 75% of tumors in postmenopausal women are hormone receptor positive
* ~ 400,000 US women are currently on endocrine therapy
Aromatase Inhibitors in
Treatment and Prevention
Chronic Relapses in Endocrine Responsive Breast Cancer: Post - Tamoxifen
Chronic Relapses post-anthracycline chemo Receptor Positive Breast Cancer
* Late recurrences (>5 years) > in ER+ and/or PgR+ tumors
* 15 year mortality equivalent in ER+ and ER- disease
Aromatase Inhibitor Trials
SUMMARY: AI upfront, after 2 yrs and after 5yr tamoxifen beneficial
4 Year DFSHR
ATACAnastrozole Up Front2.4%0.83
BIG 1-98Letrozole Up Front 2.7%*0.81
IESExemestane 2yr4.7% 0.73
ARNO/ABCSG A 2yr3.1%** 0.60
MA-17Letrozole 5yr4.9%0.58
MA.17: Trial Design
MA.17: Efficacy Conclusions
Post - Unblinding of MA.17
* First Interim Analysis:p = 0.00008 for DFS (HR0.57) (O'Brien Flemming stopping p = 0.0008)
* Trial unblinded on advice of DSMC to offer women who had been on placebo for 1-5 years (6 to 10 yrs post-diagnosis) an opportunity to take letrozole for an additional 5 yrs (11 - 15 yrs post-diagnosis )
* Regardless of early stopping, MA17 like other recent AI trials was not designed to address optimal duration
MA.17 Post-Unblinding Cohorts
Different Baseline Characteristics (All p<0.01)
MA.17 Post-Unblinding Cohorts
Different Baseline Characteristics (All p<0.01)
MA.17 Post-Unblinding Cohorts
Percentage of Patients with Recurrence
MA.17 Post-Unblinding Cohorts
Percentage of Breast Cancer and Other Cause Mortality
MA.17 Post-Unblinding Cohorts
Adjusted HR (PLAC-LET to PLAC) for Efficacy Outcomes
Aromatase Inhibitors in Early Breast Cancer
Efficacy and Toxicity
MA.17: Incidence of Adverse Events*
(All Grades)
MA.17:% Patients Whose Overall SF- 36 QOL "Response" Was Worse*
Conclusions:
First Generation AI Trials
* TOXICITIES AND TOLERABILITY
- Mild symptoms - estrogen depletion
- Tam and AI different- QOL largely unaltered
- Estrogen suppressionBMD
? Prior tamoxifen BMD
? Monitoring necessary and bisphosphonates as required
? Substantial BMD recovery post - AI
? Exemestane (androgenic) maybone strength
- Cardiovascular toxicity is unlikely (MA17) -adjudication
- Gynecologic interventions from tamoxifen underestimated
Endocrine Therapies: Unresolved Questions
* Aromatase Inhibitor: Up-front or in sequence with Tamoxifen
* Optimal Duration of Endocrine Therapy
* Optimal Aromatase inhibitor
* How to select a patient for specific endocrine therapy
* Identifying and overcoming Mechanisms of Resistance
* AI + other Standard Endocrine therapy
* AI + new targeted therapies
Peto Overview 1998: ER+ Patients
Most Breast Cancer Recurrences
Are Distant Metastases
Distant Recurrences Are Associated With High Risk of Death
* All breast cancer recurrences are associated with some increased risk of mortality1
* Substantially higher risk of death in patients with distant recurrences compared with locoregional recurrences and new contralateral breast cancers1
Locoregional Recurrence: Substantial Annual Risk of Distant Metastasis
Cuzick Model (ATAC): ? Up-front AI
Years lost to recurrence in ER+/PgR- subset
Summary AI up-front versus Sequence
* Cross Trial Comparisons are problematic
* Both Models assume a 5 year "carry-over" effect AI
* Tamoxifen does have a carry-over effect
* BIG 1-98 and ATAC - Median Absolute DFS advantage at 4 yrs is 2.7 and 2.4 % repectively
* Absolute 4 yr DFS benefit of sequence is 4.7%
BIG 1-98: Design
BIG 1-98 Compared With ATAC: Summary of Key Efficacy Results
Clinical Implications
* Breast cancer recurrence remains a significant and ongoing risk throughout the entire treatment of breast cancer regardless of lymph node status
* Recurrence at distant sites leads to poor and often fatal outcomes
* Letrozole demonstrates an improvement in risk of distant recurrence
* Letrozole is effective as initial adjuvant therapy. Further follow-up needed to determine if sequential therapy is superior to initial letrozole therapy
Endocrine Therapies: Unresolved Questions
* Aromatase Inhibitor: Up-front or in sequence with Tamoxifen
* Optimal Duration of Endocrine Therapy
* Optimal Aromatase inhibitor
* How to select a patient for specific endocrine therapy
* Identifying and overcoming Mechanisms of Resistance
* AI + other Standard Endocrine therapy
* AI + new targeted therapies
Optimum Duration of Endocrine Therapy
MCF-7arom Nude Mouse Model
Aromatase Inhibitors in
Treatment and Prevention
NCIC CTG MA.17R
ProposedAmendment: >5 versus 5 years of adjuvant AI
Endocrine Therapies: Unresolved Questions
* Aromatase Inhibitor: Up-front or in sequence with Tamoxifen
* Optimal Duration of Endocrine Therapy
* Optimal Aromatase inhibitor
* How to select a patient for specific endocrine therapy
* Identifying and overcoming Mechanisms of Resistance
* AI + other Standard Endocrine therapy
* AI + new targeted therapies
Aromatase Inhibitors in
Treatment and Prevention
Peripheral Aromatase Inhibition: Postmenopausal Women
Inhibition of Whole Body Aromatization by Letrozole and Anastrozole
FACE
Adjuvant Femara(r) vs Anastrozole-Phase IIIb Trial Design......（后略) ......
Endocrine Responsive Breast Cancer
* > 1 M diagnoses of breast cancer and 375,000 deaths annually worldwide
* Approximately 75% of tumors in postmenopausal women are hormone receptor positive
* ~ 400,000 US women are currently on endocrine therapy
Aromatase Inhibitors in
Treatment and Prevention
Chronic Relapses in Endocrine Responsive Breast Cancer: Post - Tamoxifen
Chronic Relapses post-anthracycline chemo Receptor Positive Breast Cancer
* Late recurrences (>5 years) > in ER+ and/or PgR+ tumors
* 15 year mortality equivalent in ER+ and ER- disease
Aromatase Inhibitor Trials
SUMMARY: AI upfront, after 2 yrs and after 5yr tamoxifen beneficial
4 Year DFSHR
ATACAnastrozole Up Front2.4%0.83
BIG 1-98Letrozole Up Front 2.7%*0.81
IESExemestane 2yr4.7% 0.73
ARNO/ABCSG A 2yr3.1%** 0.60
MA-17Letrozole 5yr4.9%0.58
MA.17: Trial Design
MA.17: Efficacy Conclusions
Post - Unblinding of MA.17
* First Interim Analysis:p = 0.00008 for DFS (HR0.57) (O'Brien Flemming stopping p = 0.0008)
* Trial unblinded on advice of DSMC to offer women who had been on placebo for 1-5 years (6 to 10 yrs post-diagnosis) an opportunity to take letrozole for an additional 5 yrs (11 - 15 yrs post-diagnosis )
* Regardless of early stopping, MA17 like other recent AI trials was not designed to address optimal duration
MA.17 Post-Unblinding Cohorts
Different Baseline Characteristics (All p<0.01)
MA.17 Post-Unblinding Cohorts
Different Baseline Characteristics (All p<0.01)
MA.17 Post-Unblinding Cohorts
Percentage of Patients with Recurrence
MA.17 Post-Unblinding Cohorts
Percentage of Breast Cancer and Other Cause Mortality
MA.17 Post-Unblinding Cohorts
Adjusted HR (PLAC-LET to PLAC) for Efficacy Outcomes
Aromatase Inhibitors in Early Breast Cancer
Efficacy and Toxicity
MA.17: Incidence of Adverse Events*
(All Grades)
MA.17:% Patients Whose Overall SF- 36 QOL "Response" Was Worse*
Conclusions:
First Generation AI Trials
* TOXICITIES AND TOLERABILITY
- Mild symptoms - estrogen depletion
- Tam and AI different- QOL largely unaltered
- Estrogen suppressionBMD
? Prior tamoxifen BMD
? Monitoring necessary and bisphosphonates as required
? Substantial BMD recovery post - AI
? Exemestane (androgenic) maybone strength
- Cardiovascular toxicity is unlikely (MA17) -adjudication
- Gynecologic interventions from tamoxifen underestimated
Endocrine Therapies: Unresolved Questions
* Aromatase Inhibitor: Up-front or in sequence with Tamoxifen
* Optimal Duration of Endocrine Therapy
* Optimal Aromatase inhibitor
* How to select a patient for specific endocrine therapy
* Identifying and overcoming Mechanisms of Resistance
* AI + other Standard Endocrine therapy
* AI + new targeted therapies
Peto Overview 1998: ER+ Patients
Most Breast Cancer Recurrences
Are Distant Metastases
Distant Recurrences Are Associated With High Risk of Death
* All breast cancer recurrences are associated with some increased risk of mortality1
* Substantially higher risk of death in patients with distant recurrences compared with locoregional recurrences and new contralateral breast cancers1
Locoregional Recurrence: Substantial Annual Risk of Distant Metastasis
Cuzick Model (ATAC): ? Up-front AI
Years lost to recurrence in ER+/PgR- subset
Summary AI up-front versus Sequence
* Cross Trial Comparisons are problematic
* Both Models assume a 5 year "carry-over" effect AI
* Tamoxifen does have a carry-over effect
* BIG 1-98 and ATAC - Median Absolute DFS advantage at 4 yrs is 2.7 and 2.4 % repectively
* Absolute 4 yr DFS benefit of sequence is 4.7%
BIG 1-98: Design
BIG 1-98 Compared With ATAC: Summary of Key Efficacy Results
Clinical Implications
* Breast cancer recurrence remains a significant and ongoing risk throughout the entire treatment of breast cancer regardless of lymph node status
* Recurrence at distant sites leads to poor and often fatal outcomes
* Letrozole demonstrates an improvement in risk of distant recurrence
* Letrozole is effective as initial adjuvant therapy. Further follow-up needed to determine if sequential therapy is superior to initial letrozole therapy
Endocrine Therapies: Unresolved Questions
* Aromatase Inhibitor: Up-front or in sequence with Tamoxifen
* Optimal Duration of Endocrine Therapy
* Optimal Aromatase inhibitor
* How to select a patient for specific endocrine therapy
* Identifying and overcoming Mechanisms of Resistance
* AI + other Standard Endocrine therapy
* AI + new targeted therapies
Optimum Duration of Endocrine Therapy
MCF-7arom Nude Mouse Model
Aromatase Inhibitors in
Treatment and Prevention
NCIC CTG MA.17R
ProposedAmendment: >5 versus 5 years of adjuvant AI
Endocrine Therapies: Unresolved Questions
* Aromatase Inhibitor: Up-front or in sequence with Tamoxifen
* Optimal Duration of Endocrine Therapy
* Optimal Aromatase inhibitor
* How to select a patient for specific endocrine therapy
* Identifying and overcoming Mechanisms of Resistance
* AI + other Standard Endocrine therapy
* AI + new targeted therapies
Aromatase Inhibitors in
Treatment and Prevention
Peripheral Aromatase Inhibition: Postmenopausal Women
Inhibition of Whole Body Aromatization by Letrozole and Anastrozole
FACE
Adjuvant Femara(r) vs Anastrozole-Phase IIIb Trial Design......（后略) ......
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