Disclosure Information Relationships Relevant to this Session

Transcription

1 Disclosure Information Relationships Relevant to this Session DeCensi, Andrea No relevant relationships to disclose. Please note, all disclosures are reported as submitted to ASCO, and are always available at chicago2012.asco.org

2 PHASE-III PREVENTION TRIAL OF LOW-DOSE TAMOXIFEN IN HRT USERS. THE H.O.T. STUDY. B. Bonanni, P. Maisonneuve, D. Serrano, U. Omodei, C. Varricchio, M. Cazzaniga, M. Lazzeroni, N. Rotmensz, B. Santillo, M. Sideri, E. Cassano, C. Belloni, M. Rosselli Del Turco, N. Segnan, P. Masullo, A. Costa, N. Monti, A. Vella, L. Bisanti, G. D Aiuto, U. Veronesi, and A. DeCensi, for the Italian HOT Study Group

3 BACKGROUND A basic principle of medicine indicates that hormone deficiency should be replaced when it is clinically relevant Life expectancy has dramatically increased over the last century, whereas age at menopause showed little increase HRT can relieve menopausal symptoms and prevent bone fractures The results of the WHI trials have decreased HRT prescriptions by 80% also in recently postmenopausal women despite the different indications for HRT (prevention of chronic diseases vs menopausal symptom relief)

4 HRT decreased overall mortality in women aged in a pooled analysis of the WHI trials! y y y HT n 4476 Plac n 4356 HR (95% CI) HT n 6240 Plac n 6122 HR (95% CI) HT n 3100 Plac n 3053 HR (95% CI) P Tre nd ( ) ( ) ( ).06 CEE n 1637 Plac n 1673 HR (95% CI) CEE n 2387 Plac n 2465 HR (95% CI) CEE n 1286 Plac n 1291 HR (95% CI) ( ) ( ) ( ).18 CEE+MP A n 2839 Plac n 2683 HR (95% CI) CEE+MP A n 3853 Plac n 3657 HR (95% CI) CEE+MPA n 1814 Plac n 1762 HR (95% CI) ( ) ( ) ( ).19 Rossouw et al. JAMA, 2007; 297

5 BREAST CANCER RıSK AND ınterval FROM MENOPAUSE TO HRT START (GAP TıME) Years of Hormone Therapy No. Cases RR (95% CI) <5 years (1.36 to 1.49) >5 years (0.89 to 1.23) Estrogen Only Estrogen + Progestin <5 years (1.97 to 2.12) >5 years (1.38 to 1.69) Beral et al. J Natl Cancer Inst 2011

6 Subgroup effect in the Italian Tamoxifen trial at 20 mg/day Veronesi et al. JNCI 2007 On ERT at some point (n=1580) HR=0.35, 95% CI,

7 Median % change and 95% CI TAMOXIFEN AT LOWER DOSES HAS SIMILAR EFFECTS ON KI67 CHANGE IN A 4-WEEK PRESURGICAL TRIAL Tam vs Control Dose-response P<.0001 P= Tamoxifen Control 1 mg 5 mg 20 mg ER+ ERn=39 n=40 n=35 n=29 n=34 DeCensi et al. JNCI 2003

8 HRT users THE HOT STUDY (HRT Opposed by low-dose Tamoxifen) Study design R PRIMARY ENDPOINT Tamoxifen 5 mg/day 5 yrs+ 5yrs follow-up Placebo/day Incidence of invasive breast cancer and DCIS Recruitment time: Feb 1, 2002-July 31, 2007 After first WHI release letter from the CMO to all GPs of the Milan district to invite them to quit HRT prescriptions!

9 STRATIFICATION FACTORS: Center; HRT timing (current versus de novo); Transdermal versus oral estrogen; ERT vs combined EPT STUDY PROCEDURES Baseline Clinical Visit Mammography Tranvaginal Ultrasound Every 6 months * Every year ** *** (*) for the first 5 yrs; (**) up to 5 yrs; (***) in women with bleeding

10 SAMPLE SIZE The study was initially designed to detect 126 events in 8500 subjects over 5 years for a 40% reduction of breast cancer with a 80% power, twosided 5% significance level, 80% compliance and background incidence rate of 4/1000. Subsequent re-calculations based on a HR=0.5, within the range of the Italian tamoxifen trial in hysterectomized women, and practical considerations based on the dramatic drop of HRT use after the initial WHI trial results, led to a sample of 4500 women to be recruited.

11 Assessed for eligibility (n=4618) Allocated to Placebo (n=946) Ineligible (n=1) Completed the 5 year intervention (n=526, 52.6%) Lost to Follow up (n=12) Discontinued intervention (n=407) Adverse events (n=58) Loss of interest/too long (n=128) Complaints (n=72) Advised by family doctor (n=64) Other (n=85) Randomized (n=1884) Excluded (n=2734) Not meeting inclusion criteria (n=1166) Refused to participate n=1568) Allocated to Tamoxifen (n=938) Ineligible (n=4) Completed the 5 year intervention (n=493, 56.6%) Lost to Follow up (n=10) Discontinued intervention (n=430) Adverse events (n=62) Loss of interest/too long (n=113) Complaints (n=108) Advised by family doctor (n=58) Other (n=89) Died during intervention (n=1) Average (+ SD) duration of intervention, months: 43.5 (+ 22.7) Average (+ SD) follow-up until last contact, months: 73.8 (+ 23.4) Average (+ SD) duration of intervention, months: 41.8 (+ 23.6) Average (+ SD) follow-up until last contact, months: 73.6 (+ 23.3)

12 MAIN SUBJECTS CHARACTERISTICS BY ALLOCATED ARM-1 Placebo Tamoxifen Characteristic No. % No. % All women Mean (±SD) age at entry 53.3±5 53.3±5 < 50 years years years Body Mass Index Underweight (< 18.5) Normal weight ( ) Overweight ( ) Obese ( 30) year Gail breast cancer risk <1% % %

13 MAIN SUBJECTS CHARACTERISTICS BY ALLOCATED ARM-2 Placebo Tamoxifen CHARACTERISTIC % % Duration of HRT at entry De Novo < 5 years years Unknown Type of HRT* Estrogen alone Combined continuous Combined sequential Tibolone Unknown Type of progestin Progesterone, dydrogesterone Medroxyprogesterone acetate Cyproterone acetate NETA, levonorgestrel Nomegestrol acetate Trimegestone Other/unknown Time since menopause to HRT 0-1 year years years Unknown

14 Numbers and rates of breast cancer by allocated arm Selected Characteristics Rate per 1000 women-year Placebo Tamoxifen RR (95% CI) All women ( ) Age at entry < 50 years 5.35 N= years ( ) 55 years ( ) Body Mass Index Underweight (< 18.5) Normal weight ( ) ( ) Overweight (25-29) ( ) Obese ( 30) ( ) Tumor stage pt1 19 (86%) 12 (80%) pt2 3 (13%) 3 (20%) Nodal status pnx 1 (5%) 1 (6%) pn0 16 (73%) 10 (63%) pn+ 5 (23%) 5 (31%)

15 NUMBERS AND RATES OF BREAST CANCER BY ARM Rate per 1000 women-year Placebo Tamoxifen RR (95% CI) Selected Characteristics All women ( ) Duration of HRT De Novo Ne Ne < 5 years ( ) 5 years ( ) Type of HRT Estrogen alone ( ) Combined continuous ( ) Combined sequential ( ) Tibolone ( ) Type of progestin Progesterone, dydrogesterone ( ) Medroxyprogesterone acetate ( ) Cyproterone acetate ( ) NETA, levonorgestrel ( ) Nomegestrol acetate Ne Ne Trimegestone ( ) Time since menopause to HRT 0-1 year ( ) 2-4 years ( ) 5 years ( )

16 RATES OF BREAST CANCER BY ALLOCATED ARM Selected Characteristics All women ( ) Tumor invasion DIN/LIN ( ) Invasive ( ) ER Absent ( ) 1% ( ) PgR Absent ( ) 1% ( ) Molecular subtype Rate per 1000 women-year Placebo Tamoxifen RR (95% CI) Luminal A ( ) Luminal B ( ) HER Ne Ne Triple Negative ( )

17 CUMULATIVE INCIDENCE OF BREAST CANCER

18 SENSITIVITY ANALYSIS Censored 6 months after last treatment <4 years At least 12 months of therapy

19 NUMBER AND RATE OF SERıOUS ADVERSE EVENTS BY ALLOCATED ARM No. events Rate per 1000 women Serious Adverse Events Plac Tam Plac Tam RR (95% CI) Coronary heart syndrome ( ) Cerebrovascular events ( ) VTE ( ) Endometrial polyps ( ) Endometrial cancers ( )

20 RATE OF SELECTED G2-G3 ADVERSE EVENTS BY ALLOCATED ARM Rate per 1000 women Symptoms Placebo Tamoxifen 5 mg/d RR (95% CI) Hot flashes ( ) Hot flashes 20 mg/d* ( ) Night sweats ( ) Vaginal discharge ( ) Vaginal bleeding ( ) Vaginal dryness ( ) Dyspareunia ( ) Headache ( ) *Veronesi et al. JNCI 2007

21 CONCLUSIONS: It s been a good study, it could be a great study! Tamoxifen at 5 mg/day decreased breast cancer by 20% in recently postmenopausal HRT users. The magnitude of the reduction is similar to our prior study of 20 mg/d in hysterectomized women. Unplanned subgroup analyses showed specific inhibition in luminal A tumors and in women on HRT<5 years, consistent with the gap time effect. Sensitivity analysis adjusted for non adherence and efficacy yielded to a 50%, borderline significant reduction of breast cancer on tamoxifen. The combination of HRT and low-dose tamoxifen is safe and may retain the benefits while reducing the risks of either agent in recently postmenopausal women. Our findings require confirmation in larger studies. PRESENTED BY: Andrea DeCensi

22 ACKNOWLEDGMENTS Supported by the Italian Foundation for Cancer Research, Lega Italiana per la Lotta contro i Tumori (LILT), American Italian Cancer Foundation, AVON Italia, ASL Città di Milano, Regione Piemonte. Tamoxifen and placebo were gifted by FIDIA Farmaceutici S.p.a, Abano Terme, Italy. PRESENTED BY: Andrea DeCensi