Randomized comparison of adjuvant aromatase inhibitor exemestane plus ovarian function suppression vs tamoxifen plus ovarian function suppression in premenopausal women with hormone receptor positive early breast cancer: joint analysis of ibcsg text and soft

Endocrine Management of
Premenopausal Early Breast Cancer:
Current and Future Practice
A/Professor Prue Francis
Peter MacCallum Cancer Centre
EBCTCG: Adjuvant Tamoxifen Effective in Premenopausal age group Breast Cancer Recurrence
Breast Cancer Specific Mortality
Overall Survival
ITT -OS • Any death 0.93 (0.89-1.1) • ER-pos 0.87, p=0.01 • Death without recurrence= not significant between arms Death without recurrence= not significant between arms Premenopausal HR+ Early Breast Cancer
• Adjuvant tamoxifen for ≥ 5 years is recommended • The value of ovarian function suppression or ablation (OFS) for women who receive tamoxifen (T) is uncertain • Value of aromatase inhibitor with OFS is uncertain • Women who develop chemotherapy-induced ovarian suppression (amenorrhea) have a reduced risk of relapse • Likelihood of chemotherapy-induced amenorrhea correlated with older age; less likely in women < 35 years age

Outcomes from Premenopausal Adjuvant
Chemotherapy Trials with no Hormonal Rx
Goldhirsch A et al. JNCI Monogr 2001;30:44-51 Hazard Ratio of Rela Hazard Ratio of R

TEXT and SOFT Adjuvant Breast Cancer Trials • Trials coordinated by IBCSG • Collaboration of the Breast International Group (BIG) and North American Breast Cancer Group (NABCG) • Financial support/drug supply: Pfizer, Ipsen, US NCI, NHMRC SOFT and TEXT: Questions in Premenopausal
Hormone Receptor Positive Early Breast Cancer
• Does addition of ovarian function suppression (OFS) to tamoxifen improve outcomes compared with tamoxifen ? • Does the aromatase inhibitor (AI) exemestane improve outcomes compared with tamoxifen, in premenopausal women treated with ovarian function suppression (OFS)? TEXT and SOFT Designs
Enrolled: Nov03-Apr11 TAMOXIFEN AND EXEMESTANE TRIAL (N=2672)
• Premenopausal Tamoxifen+OFS x 5y
• ≤12 wks after surgery Exemestane+OFS x 5y
• No planned chemo
OR planned chemo
SUPPRESSION OF OVARIAN FUNCTION TRIAL (N=3066)
• Premenopausal • ≤12 wks after surgery Tamoxifen x 5y
• No chemo
OR
Tamoxifen+OFS x 5y
• Remain premenopausal Z
Exemestane+OFS x 5y
≤ 8 mos after chemo
OFS=ovarian function suppression • Premenopausal women with HR+ (ER and/or PgR≥10%) invasive breast cancer confined to breast +/- axillary nodes • Proper local-regional treatment with no residual disease • Women in SOFT who received prior (neo)adjuvant
chemotherapy randomized ≤8 months from chemotherapy completion once premenopausal status demonstrated –These patients were permitted to receive oral endocrine therapy prior to randomization Protocol treatment for 5 years from randomization
• Ovarian Function Suppression
• Women started with GnRH agonist triptorelin (IM q28d) • Triptorelin initiated concurrently with chemotherapy, if chemo given • Oophorectomy or irradiation alternatives to triptorelin after 6 months • Choice of any OFS method • Oral endocrine therapy
• Exemestane 25 mg daily, or • Tamoxifen 20 mg daily • In TEXT started 6 to 8 weeks after initiation of OFS if no chemotherapy or after chemotherapy if given Primary Disease-free survival (DFS) – Invasive recurrence (local, regional, distant) – Invasive contralateral breast cancer – Second (non-breast) invasive malignancy – Death without prior cancer event Secondary Breast cancer-free interval (BCFI) – Invasive recurrence or contralateral breast cancer Distant recurrence-free interval (DRFI) – Distant recurrence Overall survival (OS) Suppression of Ovarian Function Trial
Premenopausal ER+ve and/or PR+ve Breast Cancer 3047 Patients Randomized in ITT, Dec 2003 - Jan 2011
Primary Analysis (n= 2033)
Median follow-up 5.6 years
Two Patient Cohorts (stratified)
Tamoxifen x 5y
(n=1018)
No Chemotherapy (47%)
Premenopausal, within 12 weeks of surgery
(Median time since surgery = 1.8 months)
Tamoxifen+OFS x 5y
(n=1015)
Prior Chemotherapy (53%)
Premenopausal* after completing chemotherapy; Randomization within 8 months of completion Exemestane+OFS x 5y (n=1014)
(Median time since surgery = 8.0 months)
OFS=ovarian function suppression
(GnRH triptorelin, oophorectomy or irradiation)
*According to locally-determined E level in premenopausal range Statistical Considerations
• DFS event rate much lower than anticipated • Protocols amended in 2011 (before efficacy data available) • Primary analysis: T+OFS vs T • After median follow-up of at least 5 years • Anticipated 186 DFS events, power 80% for HR=0.665 comparing T+OFS vs T (two sided α=0.05) • Analysis according to use of prior chemotherapy (no/yes) prospectively planned • E+OFS vs T became secondary objective • E+OFS vs T+OFS by combined analysis with TEXT Primary Analysis: Patient Characteristics
Prior Chemo
47% (n=949) 53% (n=1084)
(n=2033)
Median time since surgery Primary Analysis: Disease-free Survival
5.6 years median follow-up
Primary analysis in overall population not significant (p=0.10) Multivariable Cox model HR=0.78 (95% CI 0.62-0.98) p=0.03 Secondary Objectives
T+OFS v T: 19% relative reduction in BC recurrence, p=0.09 E+OFS v T: 36% relative reduction in BC recurrence, 5y BCFI >90% Events in Primary Analysis
and by Chemotherapy Stratum
5.6 years median follow-up
Primary Analysis
Prior Chemo
T+OFS vs T (n=2033)
(n=1084)
2nd non-breast ca 36 as DFS event Deaths Premenopausal No Chemotherapy
Cohort selected for low risk clinicopathologic features 90% ≥ age 40yr, 91% node negative, 85% tumor ≤ 2cm, 41% grade 1 Premenopausal after Prior Chemotherapy
T+OFS v T: Absolute improvement in 5-yr BCFI of 4.5% E+OFS v T: Absolute improvement in 5-yr BCFI of 7.7% and 5-yr DRFI of 4.2% SOFT: All women < 35 years of age
350 patients (11.5%) under age 35 94% received chemotherapy in this age group SOFT: Conclusions
• The overall premenopausal population did not benefit from the addition of OFS -- some do very well with tamoxifen alone. • For women at sufficient risk of recurrence to warrant adjuvant chemotherapy and who retained premenopausal estradiol, addition of OFS to tamoxifen reduced recurrence. • OFS enables treatment with an aromatase inhibitor which further reduced recurrence in the higher-risk cohort. • Addition of OFS increases menopausal symptoms, depression, hypertension, diabetes and osteoporosis. SOFT: Conclusions
• Benefit from OFS is most striking in women under age 35. • Long-term follow-up in SOFT is crucial to assess overall survival and late toxicities -- future analyses planned. • Published in New England Journal of Medicine (Francis P. et al, January 2015) Joint Analysis of TEXT and SOFT
TEXT and SOFT Designs
TAMOXIFEN A
T EXEMESTANE TRIAL (N=2672)
Enrolled: Nov03-Apr11 • Premenopausal Tamoxifen+OFS x 5y
• ≤12 wks after surgery Exemestane+OFS x 5y
Joint Analysis
No planned chemo OR planned chemo (N=4690)
Tamoxifen+OFS x 5y

SOFT OF OVARIAN FUNCTION TRIAL (N=3066)
Exemestane+OFS x 5y
• Premenopausal • ≤12 wks after surgery Tamoxifen x 5y
Median follow-up 5.7 years Tamoxifen+OFS x 5y
• Remain premenopausal Z
Exemestane+OFS x 5y
≤ 8 mos after chemo OFS=ovarian function suppression Presented by: Olivia Pagani, MD Statistical Considerations • DFS event rate much lower than anticipated • Protocols amended in 2011 (before efficacy data available): – For the E+OFS vs T+OFS comparison, a planned secondary joint analysis of TEXT & SOFT was promoted to the primary analysis – With data cut-off in late-2013 (>5 years median follow-up), power 84% for HR=0.75 (2-sided α=0.05) in the combined analysis – No interim analyses • ITT analysis; stratified by trial, chemotherapy use, nodal Exemestane+OFS Improved DFS Difference 3.8% at 5 years 5.7 years median follow-up Sites of First Failure TEXT+SOFT: AI Question
Site of First Failure All DFS events N (%) 216 (9.2) 298 (12.7) 160 (15.7) 139 (13.7) Contralateral breast Regional ± above Soft tissue/distant LN± Viscera ± above Second (non-breast) ca 15% of first failures Death, no cancer Death, recur. suspected 5.7 yr median follow-up Exemestane+OFS Reduced Recurrence • 4% absolute improvement in 5-yr freedom from breast cancer for exemestane+OFS • No significant difference in overall survival Women Who Did Not Receive Chemotherapy 16% <40 years; 19% T-size >2cm; 21% N+ 9% <40 years; 15% T-size >2cm; 8% N+ Some women have excellent prognosis with highly-effective endocrine therapy alone >97% breast cancer-free at 5 years when treated with exemestane+OFS Women Who Received Chemotherapy 66% N+; 53% T-size >2cm; 30% <40 years
57% N+; 47% T-size >2cm; 49% <40 years
Absolute improvement with exemestane+OFS 5-yr freedom from breast cancer: 5.5% in TEXT and 3.9% in SOFT 5-yr freedom from distant recurrence: 2.6% in TEXT and 3.4% in SOFT • Exemestane+OFS, as compared with tamoxifen+OFS, significantly improves DFS, BCFI and DRFI and is a new treatment option for premenopausal women with HR+ early breast cancer • No significant difference in overall survival, conclusions premature at this early point in follow-up of HR+ breast cancer • Side effect profile of exemestane+OFS mirrors that seen with AIs in postmenopausal women • Some premenopausal women diagnosed with HR+ breast cancer have an excellent prognosis with highly-effective endocrine therapy alone • Long-term follow-up needed. Published NEJM (Pagani et al, 2014) Do other trial results support findings from SOFT and TEXT Trials? For premenopausal women at low risk of recurrence, adjuvant tamoxifen alone is an appropriate treatment (SOFT). ECOG 3193: Premenopausal Node negative HR+ve (n=345) Tamoxifen v Tamoxifen + Ovarian Function Suppression J Clin Oncol 2015 Some premenopausal women have an excellent prognosis with highly-effective endocrine therapy alone, including some with node-positive disease Women Who Did Not Receive Chemotherapy 16% <40 years; 19% T-size >2cm; 21% N+ 9% <40 years; 15% T-size >2cm; 8% N+ Some women have excellent prognosis with highly-effective endocrine therapy alone >97% breast cancer-free at 5 years when treated with exemestane+OFS Does Chemotherapy Add to Combined Endocrine Rx? IBCSG 11: Premenopausal Node+ve ER+ve Breast Cancer Res Treat 2009 For premenopausal women at significant risk for recurrence, Exemestane + OFS is a more effective adjuvant endocrine treatment option than tamoxifen ABCSG 12: Premenopausal HR+ve Final Results: ANA+OFS vs Tam+OFS x 3 yrs +/- Zol 8 yr DFS: T+OFS+Zol 88.4% T+OFS 85.6% 8yr OS all pts 95.2% 8 yr DFS: A+OFS+Zol 86.9% A+OFS 83.4% OS worse for ANA than Tam Differences between TEXT-SOFT (NEJM 2014) and ABCSG 12 (Ann Oncol 2015) Trials • ABCSG 12 smaller trial (251 DFS/86 OS events in final analysis vs. 514 DFS/194 OS events in TEXT-SOFT) • ABCSG12 pts < 40 yrs: ANA (25.2%) vs.Tam (20.6%) p<0.02 • ABCSG 12: no chemotherapy predominantly • ABCSG 12: endocrine Rx 3 years • ABCSG12: Zoledronate randomization • ABCSG 12 anastrozole / TEXT-SOFT exemestane • Exemestane slightly greater suppression of E2 levels than Anastrozole in postmenopausal – difference might be clinically relevant in young women undergoing OFS • Anastrozole less effective in high BMI (ATAC, ABCSG12, ABCSG6) - no similar data for exemestane. SOFT and TEXT : Summary of Results
Trend to improved DFS with T+OFS in SOFT HR= 0.83 p = 0.10 (p =0.03 multivariate) E+OFS: significantly improved DFS in joint Exemestane + OFS analysis of TEXT-SOFT HR=0.72 p < 0.001 Francis et al, NEJM 2015 Pagani et al, NEJM 2014 SOFT : Breast Cancer Free Interval (BCFI)
Prior Chemo patients ↑ 5year BCFI= 4.5% Exemestane + OFS Prior Chemo patients ↑ 5 year BCFI = 7.7% NB: Patients who did not receive chemotherapy in SOFT did as well with tamoxifen alone, as compared with other endocrine treatments SOFT: Distant Recurrence Free Interval (DRFI)
Prior Chemo patients ↑ 5 year DRFI= 1.2% Prior Chemo patients ↑ 5 year DRFI = 4.2% Exemestane + OFS Overall survival data not mature at 5 years in HR+ve SOFT and TEXT Conclusions: Premenopausal
Hormone Receptor Positive Early Breast Cancer
For women at significant risk for recurrence, Exemestane + OFS is a more effective adjuvant endocrine treatment option than tamoxifen. For women at low risk of recurrence, adjuvant tamoxifen alone is an appropriate treatment. Prevention of Early Menopause Study (POEMS) - NEJM 2015 Phase III trial of LHRH analog during chemotherapy to reduce ovarian failure in early stage, hormone receptor-negative breast cancer: an international Intergroup trial Halle C.F. Moore, Joseph M. Unger, Kelly-Anne Phillips, Frances Boyle,
Erika Hitre, David Porter, Prudence A. Francis, Lori Minasian,
Richard D. Gelber, Lori J. Goldstein, Henry L. Gomez, Carlos S. Vallejos, Ann H. Partridge, Shaker R. Dakhil, Silvana Martino, William E. Barlow, Carol J. Fabian, Frank L. Meyskens, Gabriel N. Hortobagyi, Kathy S. Albain Premenopausal Stage I, II, IIIA ER-/PR- Breast Cancer chemotherapy regimen cyclophosphamide cyclophosphamide containing (neo)adjuvant containing (neo)adjuvant chemotherapy + goserelin Goserelin Administration • Goserelin 3.6 mg sc every 4 weeks • Started at least 1 week prior to first chemotherapy dose • Continued for duration of chemotherapy – Last goserelin administered within 2 weeks of (before or after) the final chemotherapy dose POEMS Objectives and Endpoints – Ovarian Failure at 2 years Defined as amenorrhea for the prior 6 months and FSH in the postmenopausal range – Ovarian dysfunction at 1 and 2 years – Pregnancy Outcomes POEMS Consort Diagram POEMS Patients
Standard
Chemotherapy +
Goserelin
Age in years: median
38.7 (25-49)
37.6 (26-49)
Age <40 years
3-4 month/cycle
6-8 month/cycle
3-4 month/cycle non-anthra. 4%
6-8 month/cycle non-anthra. 6%
POEMS Ovarian Failure Standard
Chemotherapy + Goserelin
Ovarian failure at 2 y 15/69 = 22%
Analysis
0.10 – 0.87 p=.01 Stratified*
0.09 – 0.97 p=.02
Multivariate* 0.36 0.11 – 1.14 p=.04 *Accounting for age and regimen through stratification ("Stratified") or covariate ("Multivariate") adjustment, respectively Standard
Adjusted Adjusted
+ Goserelin
Attempted pregnancy
Achieved pregnancy
Patients with > 1 delivery
8 (7%)
Delivery or ongoing
10 (9%)
pregnancy
Total number of babies
Ongoing pregnancies
Total adverse events
Miscarriages
Elective termination
Delivery complication
POEMS Disease Free Survival
Goserelin
O R (95% CI)
Standard
Covariates
0.47 (0.24-0.95) Relapse 4-Year
0.49 (0.24-0.97) At Risk or Death Estimate
age, regimen, & p=.04 Goserelin 105
Standard
Years from Randomization
POEMS Overall Survival
Goserelin
Standard
Regression
OR (95% CI)
Covariates
Adjusted for age 0.45 (0.19-1.04) At Risk Deaths Estimate
0.43 (0.18-1.00) Goserelin
Standard
Years from Randomization
• Goserelin use led to consistent evidence of better preserved
ovarian function across multiple endpoints
• First demonstration of improved fertility prospects and more
successful pregnancies when goserelin was used with
chemotherapy
• Findings of favorable DFS and OS with goserelin are
intriguing, and are reassuring regarding the safety of this
approach
• Premenopausal women beginning curative intent
chemotherapy should consider this new option to prevent
premature ovarian failure

Acknowledgements

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