BREAST JOURNAL CLUB LONG-TERM OUTCOME RESULTS OF THE PHASE III PROMISE- GIM6 STUDY EVALUATING THE ROLE OF LHRH ANALOG

Transcription

1 BREAST JOURNAL CLUB LONG-TERM OUTCOME RESULTS OF THE PHASE III PROMISE- GIM6 STUDY EVALUATING THE ROLE OF LHRH ANALOG (LHRHa) DURING CHEMOTHERAPY AS A STRATEGY TO REDUCE OVARIAN FAILURE IN EARLY BREAST CANCER PATIENTS Matteo Lambertini, Luca Boni, Andrea Michelotti, Teresa Gamucci, Tiziana Scotto, Stefania Gori, Monica Giordano, Ornella Garrone, Alessia Levaggi, Francesca Poggio, Sara Giraudi, Claudia Bighin, Carlo Vecchio, Mario Roberto Sertoli, Simona Pastorino, Paolo Pronzato, Lucia Del Mastro November21 st, 2015 Trieste

2 Study Background Approximately 11% of breast cancer occur in women younger than 45 years with 6% in women under Most of these patients will receive chemotherapy and are at risk for premature ovarian failure and infertility 2,3. Available options for fertility preservation in breast cancer patients: 1. cryopreservation of embryos or oocytes (St); 2. cryopreservation of ovarian tissue (Ex); 3. temporary ovarian suppression with luteinizing hormone-releasing hormone (LHRHa) during chemotherapy (Ex). 1. SEER data PartridgeAH et al, Breast2014; 23(3): TriversKF et al, Oncologist 2014; 19(8):

3 Study Background: LHRHa Temporary ovarian suppression with LHRHa during chemotherapy: no delay, widely availability, preservation of both ovarian function and fertility 1. The 2013 ASCO and ESMO guidelines consider the use of LHRHa as an experimental strategy to preserve fertility 2,3. Paucity of data is available on long-term outcomes (longterm ovarian function and pregnancies). Some concerns exist about the safety of the procedure, especially in patients with endocrine sensitive disease. 1. Lambertini M et al, CurrOpinObstetGynecol 2015; 27(1): Loren AW et al, J ClinOncol 2013; 31(19): Peccatori FA et al, AnnOncol 2013; 24(Suppl6):vi

4 PROMISE-GIM6 Study Design Premenopausal stage I-III ER+ or ERbreastcancerpatientscandidatesfor (neo)adjuvant chemotherapy RANDOMIZATION Stratified by center (neo)adjuvant chemotherapyalone (neo)adjuvant chemotherapy + triptorelin ClinicalTrial.gov: NCT

5 Study Objectives and Endpoints Primary objective: To evaluate the incidence of chemotherapy-induced premature ovarian failure between treatment arms Defined as no resumption of menstrual activity and postmenopausal levels of both follicle-stimulating hormone (FSH) and estradiol (E2) 1 year after the end of chemotherapy. Secondary objective: To compare the toxicity of the addition of triptorelin to chemotherapy.

6 Study Objectives and Endpoints Current analysis: post-hoc extension of the original study design to investigate the association between treatment groups and long-term outcomes: long-term ovarian function; pregnancies; disease-free survival (DFS). Systematic data collection was based on the annual followup visit, including physical examination and mammography, performed by each patient according to clinical practice.

7 Consort Diagram 281 patients randomized 133 chemotherapy alone 148 chemotherapy + triptorelin 127 completedfollowup for the primary analysis 13 patients lost to follow-up 141 completedfollowup for the primary analysis 115 completedfollowup for the current analysis (long-term outcomes) 22 patients lost to follow-up 131 completedfollowup for the current analysis (long-term outcomes) 35 (12.5%) patients lost to follow-up

8 Baseline Characteristics Chemotherapy alone arm (n=133) No. (%) Chemotherapy + triptorelin arm (n=148) No. (%) Age, median (range), years 39 (25-45) 39 (24-45) Age 40 years 88 (66) 99 (67) Full-term pregnancies before breast cancer diagnosis 0 1 Unknown 51 (38) 78 (58) 4 (4) 49 (33) 96 (65) 3 (2) Hormone receptor status ER-positive and/or PR-positive ER-negative and PR-negative Unknown Timing of chemotherapy Adjuvant therapy Neoadjuvant therapy Not begun Type of chemotherapy Anthracycline-based Anthracycline and taxane-based CMF-based 109 (82) 22 (17) 2 (1) 117 (88.0) 10 (7.5) 6 (4.5) 117 (79) 29 (20) 2 (1) 133 (89.9) 13 (8.8) 2 (1.4) 57 (42.9) 62 (46.6) 8 (6.0) 56 (37.8) 86 (58.1) 4 (2.7) Duration of chemotherapy, median (IQR) weeks 16.9 ( ) 17.8 ( ) Treatment completed as planned Chemotherapy Triptorelin during chemotherapy 121 (91.0) NA 143 (96.6) 142 (95.9)

9 Baseline Characteristics Patients with Endocrine Sensitive Disease Type of adjuvant endocrine therapy in hormone receptor positive patients, No. (%) No treatment LHRHa alone LHRHa + tamoxifen LHRHa + aromatase inhibitor Tamoxifen Tamoxifen followed by aromatase inhibitor Chemotherapy alone arm (n=109) No. (%) 6 (5.5) 3 (2.8) 65 (59.6) 11 (10.1) 22 (20.2) 2 (1.8) Chemotherapy + triptorelin arm (n=117) No. (%) 10 (8.6) 4 (3.4) 65 (55.6) 10 (8.6) 28 (23.9) 0 (0.0) Median duration of endocrine therapy (IQR range), y 5.00 ( ) 5.00 ( ) Median duration of adjuvant LHRHa (IQR range), y 4.10 ( ) 4.08 ( )

10 Results: Primary Analyses Chemotherapy alone arm Chemotherapy+ triptorelin arm Absolute difference (95% CI) Pvalue N=133 N=148 Ovarian failure at1 year 25.9% 8.9% -17% (from -26% to -7.9%) <.001 Highly significant reduction in the risk of the treatment-related early menopause (OR = 0.28; 95% CI, ; P <.001) No significant difference in triptorelin-related toxicities (hot flushes, headache, sweating, mood modification, vaginal dryness) Del Mastro L et al, JAMA 2011; 306(3):

11 Current Analysis: Long-term Ovarian Function Median follow-up time: 7.3 years (IQR, years) CT alone arm CT + T arm n Events 5-year CIMR 95% CI CT alone arm % CT + T arm % UnadjustedHR = 1.28 (95% CI, ); P=.07 Age-adjustedHR = 1.48 (95% CI, ); P=.006

12 Current Analysis: Pregnancies Cumulative Incidence of Pregnancy, % CT alone arm Control group LHRHa CT + T arm group n Events 5-year CIP 95% CI CT alone arm % CT + T arm % UnadjustedHR = 2.56 (95% CI, ); P=.14 Age-adjustedHR = 2.40 (95% CI, ); P=.20 0 Gray's test P = No. at risk Control group LHRHa group Follow-up, yrs

13 Current Analysis: Pregnancies Chemotherapy alone arm (n=133) Chemotherapy + triptorelin arm (n=148) No. pregnancies 3 8 Incidence rate per ( ) 0.9 ( ) person-years (range) No. abortions (type) - 1 (induced abortion) 2 (miscarriages) No. live births 3 5 Interval from randomization to first pregnancy: between 1.0 and 6.6 years Patients with hormone receptor positive disease: 4 pregnancies Interval from randomization to first pregnancy: between 6.2 and 6.6 years Patients with hormone receptor negative disease: 7 pregnancies Interval from randomization to first pregnancy: between 1.0 and 6.5 years

14 Current Analysis: Disease-Free Survival CT alone arm CT + T arm n Events 5-year DFS 95% CI CT alone arm % CT + T arm % HR = 1.17 (95% CI, ); P =.52

15 Current Analysis: Disease-Free Survival CT alone arm CT + T arm n Events 5-year DFS 95% CI CT alone arm % CT + T arm % HR = 1.17 (95% CI, ); P =.52 Subgroup Numberof patients Numberof events HR (95% CI) Pfor interaction Hormone-receptor negative ( ) Hormone-receptor positive ( ).19

16 Current Analysis: Disease-Free Survival CoxProportionalHazardModel: Effect of Temporary Ovarian Suppression, Tumor Size, Axillary Nodes, and Hormone Receptor Status on Disease-free Survival Variable Patients/Events HR (95% CI) P Value Random assignment CT alone arm CT + T arm Tumor size (T) pt1 pt2-4 Axillary nodes (N) pn0 pn1-2 Hormone receptor status ER negative and PR negative ER positive and/or PR positive 133/29 148/36 167/33 114/32 133/22 148/43 53/17 228/48 1 [Reference] 1.10 ( ) 1 [Reference] 1.25 ( ) 1 [Reference] 1.80 ( ) 1 [Reference] 0.56 ( )

17 Conclusions Concurrent administration of triptorelin and chemotherapy compared with chemotherapy alone, was associated with higher long-term probability of menstrual resumption. A higher but not statistically significant different number of pregnancies was observed in the chemotherapy plus triptorelin arm as compared to the chemotherapy alone arm. Disease-free survival was not statistically significantly different between the two treatment arms.

18 PROMISE-GIM6 and POEMS-S0230 Studies ThePROMISE-GIM6 study 1,2 The POEMS-S0230 study 3 Median age, years No. patients (ER pos/er neg) Ovarian disfunction (CT + LHRHavs CT alone) Pregnancies (CT + LHRHavs CT alone) Disease-free survival (CT + LHRHavs CT alone) 281 (226/51) 8.9* vs 25.9%* OR = 0.28, P < vs 3 age-adjusted HR = 2.40, P= % vs 83.7% HR = 1.17, P = (0/218) 8%** vs 22%** stratified OR = 0.30, P = vs 12 adjusted OR = 2.45, P=.03 89% vs 78% adjusted HR = 0.49, P =.04 * Evaluated1 year after the end of chemotherapy ** Evaluated 2 years after the end of chemotherapy # 5-year disease-free survival ## 4-year disease-free survival 1. Del Mastro L et al, JAMA 2011; 306(3): Lambertini M et al, submitted. 3. Moore HCF et al, NEJM 2015; 372(10):

19 Lambertini M et al, AnnOncol 2015; [Epubaheadof print] Meta-Analysis of RCT

20 Meta-Analysis of RCT Premature Ovarian Failure One-year Amenorrhea Patientswith Pregnancy Disease-Free Survival Events No. studies No. patients Result LHRHa vs control 12 1, % vs 33.5% OR= % vs 42.9% OR= vs 19 OR= % vs 18.8% HR=1.00 Pvalue I 2 < % < % % % Lambertini M et al, AnnOncol 2015; [Epubaheadof print]

21 Conclusions Linee Guida AIOM Fertilità 2015

22 Acknowledgements All the patients enrolled in the study and their families Investigators and research teams IRCCS AOU San Martino IST in Genova (Italy) Associazione Italianaper la Ricercasul Cancro (AIRC): for supplemental funding Gruppo Italiano Mammella (GIM) IPSEN: for drug supply

23