- Email: [email protected]
A phase-III prevention trial of low-dose tamoxifen in postmenopausal hormone replacement therapy users: the HOT study
original articles
Annals of Oncology
Annals of Oncology 24: 2753–2760, 2013 doi:10.1093/annonc/mdt244 Published online 17 July 2013
A phase-III prevention trial of low-dose tamoxifen in postmenopausal hormone replacement therapy users: the HOT study A. DeCensi1*, B. Bonanni2, P. Maisonneuve3, D. Serrano2, U. Omodei4, C. Varricchio2, M. Cazzaniga2, M. Lazzeroni2, N. Rotmensz3, B. Santillo3, M. Sideri5, E. Cassano6, C. Belloni7, M. Muraca8, N. Segnan9, P. Masullo10, A. Costa11, N. Monti12, A. Vella13, L. Bisanti14, G. D’Aiuto15 & U. Veronesi16, for the Italian HOT Study Group†
Received 24 December 2012; revised 16 May 2013; accepted 28 May 2013
Background: Postmenopausal hormone replacement therapy (HRT) relieves menopausal symptoms and may decrease mortality in recently postmenopausal women, but increases breast cancer risk. Low-dose tamoxifen has shown retained activity in phase-II studies. Methods: We conducted a phase-III trial in 1884 recently postmenopausal women on HRT who were randomly assigned to either tamoxifen, 5 mg/day, or placebo for 5 years. The primary end point was breast cancer incidence. Results: After 6.2 ± 1.9 years mean follow-up, there were 24 breast cancers on placebo and 19 on tamoxifen (risk ratio, RR, 0.80; 95% CI 0.44–1.46). Tamoxifen showed favorable trends in luminal-A tumors (RR, 0.32; 95% CI 0.12–0.86), in HRT users <5 years (RR, 0.35; 95% CI 0.15–0.82) and in women completing at least 12 months of treatment (RR, 0.49; 95% CI 0.23–1.02). Serious adverse events did not differ between placebo and tamoxifen, including, respectively, coronary heart syndrome (6 versus 4), cerebrovascular events (2 versus 5), VTE (2 versus 5) and uterine cancers (3 versus 1). Vasomotor symptoms were 50% more frequent on tamoxifen. Conclusions: The addition of low-dose tamoxifen to HRT did not significantly reduce breast cancer risk and increased climacteric symptoms in recently postmenopausal women. However, we noted beneficial trends in some subgroups which may deserve a larger study. Key words: breast cancer, chemoprevention, hormone replacement therapy and low dose, tamoxifen
introduction Given the increase in life expectancy, the management of postmenopausal disorders is a public health issue. Two Women’s Health Initiative (WHI) trials testing hormone replacement therapy (HRT) in women with a mean age over 60 years showed a worsened global health index with HRT [1, 2]. The lack of benefit in coronary disease, in contrast to prior observational studies [3], and the increased risk of breast cancer in the combined conjugated equine estrogen (CEE) plus progestin therapy with the medroxyprogesterone acetate (MPA) *Correspondence to: Dr Andrea DeCensi, Division of Medical Oncology, E.O. Ospedali Galliera, Mura delle Cappuccine 14, 16128 Genoa, Italy. Tel: +39-0105634501; Fax: +39-01057481090; E-mail: [email protected] †
List of all investigators in appendix.
trial [1], led to a dramatic drop in HRT use also in recently postmenopausal women [4, 5], with a consequent decrease of breast cancer [6]. The timing of initiation of HRT after the menopause (gap-time) has been advocated as an important reason for the divergent findings on cardiovascular disease between observational studies and the WHI trials [7, 8], and subsequent analyses of both WHI trials indicated that total and cardiovascular mortality were reduced in women aged 50–59, particularly with CEE alone, in contrast to an increase in women who started HRT >20 years since menopause [9]. However, such a gap-time effect could not be detected on breast cancer in WHI trials as most participants started HRT after 10 years since menopause [9], whereas observational studies examining HRT use for menopausal symptoms showed a higher breast cancer risk in women starting HRT within 5 years from
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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1 Division of Medical Oncology, Ospedali Galliera, Genova; Divisions of; 2Cancer Prevention and Genetics; 3Epidemiology and Biostatistics; European Institute of Oncology, Milano; 4Gynecology Department Ospadali Civili Brescia Divisions of; 5Preventive Gynecology; 6Radiology; European Institute of Oncology, Milano; 7Division of Obstetricand Gynecology; Ospedale Valduce, Como; 8Oncology Prevention Center ISPO Firenze; 9CPO; Torino; 10Oncology Unit Ospedale S. Luca; Vallo della Lucania; 11Breast Unit Fondazione S. Maugeri; Pavia; 12Unit of Oncology; Ospedale S. Maria degli Angeli, Pordenone; 13Breast Unit; ASL Roma H, Albano Laziale; 14Epidemiology; Breast Unit ASL Città di Milano; 15Senology Fondazione Pascale; Napoli, Italy; 16European Institute of Oncology; Milano, Italy
original articles
methods subjects and treatment We conducted a phase-III, double-blind, placebo-controlled trial in recently postmenopausal women using HRT for menopausal symptom relief who were randomly allocated to either placebo or tamoxifen 5 mg/day for 5 years (trial IEO S51/200, HRT opposed by low-dose tamoxifen, HOT, Clinical Trials.gov NCT01579734). Eligibility criteria were current HRT use or de novo HRT use and negative mammography within 6 months. Toxicity was evaluated using the NCI toxicity criteria v2.0. Clinical examinations were repeated every 6 months and mammography was repeated annually. Transvaginal ultrasounds were carried out at baseline and repeated in case of atypical bleeding, followed by hysteroscopy on clinical judgment. At completion of the 5-year intervention, clinical visit and mammography were repeated annually up to 10 years. The use of venflaxine was allowed. The primary end point was the incidence of breast cancer, whereas the secondary end points included endometrial cancer, coronary heart syndrome, cerebrovascular events, venous thromboembolic events (VTEs), bone fractures, all cancers.
pathology and immunohistochemistry Central pathology assessment of breast cancer included histological type, grade, peritumoral vascular invasion, ER, PgR, HER2 and Ki-67, as previously described [23]. Molecular tumor subtypes were classified by immunohistochemistry (IHC) into four categories according to 2011 St Gallen criteria [24]: luminal-A, ER or PgR-positive and Ki-67 < 14%; luminal-B, ER or PgR-positive and either Ki-67 ≥ 14% with negative HER2 or HER2-positive regardless of the Ki-67 level; HER2-positive and ER/PgRnegative; triple negative, all receptors negative.
sample size and statistical analysis The study was designed to detect a 40% reduction of breast cancer with 80% power and two-sided 5% significance level. Using the log-rank test, 126 breast cancers had to be observed on 8500 subjects recruited over 5 years with 80% compliance and a background incidence rate of 4/1000. Recalculations based on a hazard ratio (HR) of 0.5, closer to the range observed in the Italian tamoxifen trial [14], and practical considerations based on the dramatic drop of HRT use after the first WHI trial results [1]
| DeCensi et al.
led to a total of 4500 women to be recruited to attain the pre-specified assumptions. The decision to stop recruitment was recommended by the Data Safety and Monitoring Committee (DSMC) after a limited recruitment in the last 24 months. Stratification factors were center, HRT use (current, de novo), route of estrogen administration (transdermal, oral) and prior hysterectomy (unopposed estrogen, combined estrogen-progestin therapy). An ad hoc computer program in Access was used to preserve the allocation ratio in each stratum through biased coin randomization and minimization. The data included are based on information received as of 30 November 2011. The main analysis was carried out on an intention-to-treat (ITT) basis. Incidence rates for breast cancer were calculated by dividing the number of events by the number of event-specific person-years of follow-up. For symptoms and adverse events, person-years were calculated from the date of randomization to treatment termination, development of the specific event or dropout, whichever came first. For other cancers and deaths, person-years were calculated from the date of randomization to the date of last follow-up or specific event. Event rates were compared by using risk ratios (RRs) and 95% confidence intervals (CIs), assuming that the events followed a Poisson distribution. Because healthy, middle-aged women were enrolled in the trial, mortality was not a major competing risk of failure. The two treatment groups were compared by the log-rank test. HRs and 95% CIs were obtained using a Cox proportional regression model after adjustment for age (in 5-year groups) and center. We tested the proportional hazards assumption by introducing a time-dependent variable and testing for its statistical significance. For breast cancer subtypes, follow-up was censored at diagnosis of any other breast cancer subtype. We carried out sensitivity analyses adjusted for nonadherence by censoring follow-up 6 months after women became nonadherent, i.e. took treatment for less than 80% of the planned intervention, or to women who completed at least 12 months of treatment. P-values were at <0.05 level for the main end points and at <0.01 level for secondary end points and subgroup analyses to account for multiple comparisons. Analyses were carried out with SAS software (version 8.2, Cary, NC).
results From 1 February 2002 to 31 July 2007, we randomly allocated 1884 women to either placebo (n = 946) or tamoxifen (n = 938). The participant flow diagram is reported in supplementary Figure S1, available at Annals of Oncology online. Compliance at the end of 5 years was 55.6% on placebo and 52.6% on tamoxifen (P = 0.19). At the end of follow-up, 1025 (54%) women were still on HRT; 88 (5%) had temporarily suspended HRT or were on HRT every other day and 584 (31%) had definitely stopped HRT. Information was missing for 187 (10%) women. A similar number of women stopped HRT in either arm (n = 289 on placebo and n = 295 on tamoxifen, P = 0.46). The main subject characteristics were evenly distributed by allocated arm (Table 1). The mean ± SD age was 53.1 ± 5.1 on placebo and 53.5 ± 5.0 on tamoxifen, and mean + SD BMI 24.0 ± 3.8. Approximately 20% were de novo HRT users, over 55% were on HRT for <5 years, <20% started HRT >5 years since menopause and only 4% started HRT >10 years since menopause (overall mean ± SD, 3.0 ± 3.5 years). Estrogen therapy at baseline included 92% on estradiol, of whom 10% at low dose (1 mg), CEE users were 8%, of whom 3% at low dose (0.3 mg).
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menopause, including unopposed estrogen therapy [10–12]. Since HRT use in recently postmenopausal women alleviates menopausal symptoms and decreases bone fracture risk [8] and, possibly, overall mortality in estrogen-alone users [9, 13], a reduction of breast cancer risk would further ameliorate HRT cost–benefit ratio. Subgroup analyses of breast cancer prevention trials showed fewer breast cancers in current or past HRT users allocated to either tamoxifen [14, 15] or raloxifene [16] versus placebo. The increased risk of breast cancer associated with HRT is linked to higher expression of estrogen receptors in normal breast tissue [17], thus leading to enhanced antiestrogen sensitivity. Conversely, the use of a progestin may attenuate the endometrial effects of tamoxifen [18]. Recent dose-ranging trials defined 5 mg/day of tamoxifen as the optimal biological dose based upon a retained activity on surrogate biomarkers [19–21] and the lack of endometrial proliferation in HRT users [22]. We therefore conducted a phase-III prevention trial to determine the efficacy of low-dose tamoxifen in reducing breast cancer risk in recently postmenopausal women on HRT.
Annals of Oncology
original articles
Annals of Oncology Table 1. Main subjects characteristics by allocated arm Placebo No. %
Tamoxifen No. %
All women Age at entry (years) <50 50–54 ≥55 Body mass index Underweight (<18.5) Normal weight (18.5–24.9) Overweight (25–29.9) Obese (≥ 30) Duration of HRT at entry De Novo <5 years ≥5 years Unknown Route of HRT Oral Transdermal Type of HRTa Estrogen alone Combined continuous Combined sequential Tibolone Unknown Type of progestin Progesterone, dydrogesterone Medroxyprogesterone acetate Cyproterone acetate NETA, levonorgestrel Nomegestrol acetate Trimegestone Other (drospirenone, medrogestone, OC) Unknown Time since menopause to HRT 0–1 year 2–4 years ≥5 years Unknown 5-year Gail breast cancer risk (%) <1 1–1.49 ≥1.5
946
100.0
938
100.0
219 360 367
23.2 38.1 38.8
182 372 384
19.4 39.7 40.9
26 598 243 79
2.7 63.2 25.7 8.4
28 623 227 60
3.0 66.4 24.2 6.4
183 545 213 5
19.3 57.6 22.5 0.5
183 521 219 15
19.5 55.5 23.3 1.6
445 501
47.0 53.0
439 499
46.8 53.2
169 252 473 28 24
17.9 26.6 50.0 3.0 2.5
177 265 444 36 16
18.9 28.3 47.3 3.8 1.7
197 140 48 183 88 39 13 39
20.9 15.0 5.1 19.3 9.3 4.1 1.4 4.1
190 142 36 189 91 26 13 40
20.3 14.9 3.8 20.2 9.7 2.8 1.4 4.3
391 387 163 5
41.3 40.9 17.2 0.5
401 347 180 10
42.8 37.0 19.2 1.1
287 416 243
30.3 44.0 25.7
240 422 276
25.6 45.0 29.4
a Hormone Replacement Therapy. NETA, Norethisterone acetate; OC, oral contraceptive.
Table 2 summarizes breast cancer events by allocated arm and selected characteristics. After a mean ± SD follow-up of 6.2 ± 1.9 years, we observed 24 breast cancers on placebo (annual rate 4.1/1000) and 19 on tamoxifen (annual rate 3.3/1000), with rate ratio (RR) = 0.80 (95% CI 0.44–1.46). Tamoxifen showed favorable trends in women on HRT for <5 years (unadjusted RR, 0.35; 95% CI 0.15–0.82; RR = 0.35; 95% CI 0.15–0.85, after adjustment for age, family history of breast cancer, BMI, hysterectomy, duration of HRT use at baseline, route and type
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discussion A basic principle of clinical endocrinology indicates that hormone deficiency should be replaced when it is clinically relevant [8]. Although life expectancy has dramatically increased over the last century, age at menopause has shown only a small increase [25]. The aim of this pragmatic trial was to assess the efficacy of 5 mg/day of tamoxifen in reducing breast cancer in recently postmenopausal women treated with different HRT forms for menopausal symptom relief. We found a nonsignificant 20% reduction of breast cancer with low-dose tamoxifen, a figure similar to that obtained with 20 mg/day in hysterectomized women [14]. Unfortunately, the negative impact of the WHI findings on HRT prescriptions in recently doi:10.1093/annonc/mdt244 |
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Characteristic
of HRT, and Gail breast cancer risk) and in estrogen-alone users (RR = 0.26, 95% CI 0.05–1.28), but had no effect in the combined HRT subgroup (16 versus 16 tumors) or according to the Gail risk. A lower number of luminal-A tumors (RR, 0.32; 95% CI 0.12–0.86) and PgR-positive tumors (RR 0.43; 95% CI 0.19–0.97) were observed on tamoxifen, whereas additional tumor characteristics did not differ, including stage pT1 tumors (86.4% versus 80.0%) and pN + tumors (22.7% versus 31.3%), respectively (supplementary Table S1, available at Annals of Oncology online). The cumulative incidence of breast cancer, overall and by molecular subtypes is illustrated in Figure 1. In sensitivity analyses shown in Figure 2, censoring follow-up 6 months after women became nonadherent (i.e. took treatment for <4 years), tamoxifen showed a greater risk reduction of breast cancer, with 24 events on placebo versus 13 on tamoxifen (age adjusted HR 0.59; 95% CI 0.30–1.17). Similarly, in women who completed at least 12 months of treatment, the number of events was 23 versus 14 (HR, 0.65; 95% CI 0.33–1.26). In an efficacy analysis restricted to women who completed at least 12 months of treatment and censoring follow-up 6 months after women became nonadherent, the number of events was 23 versus 10 (HR, 0.49; 95% CI 0.23–1.02). Table 3 summarizes protocol pre-specified menopausal symptoms and adverse events by allocated arm. Moderate or severe (grade 2 or higher) hot flashes, night sweats, vaginal dryness and discharge were significantly more frequent on tamoxifen than on placebo, whereas headache was significantly less frequent on tamoxifen. Pre-specified serious adverse events were not different between placebo and tamoxifen, including coronary heart syndrome (6 versus 4), cerebrovascular events (2 versus 5, including four TIA on tamoxifen) and VTE (2 versus 5, including one superficial VTE on tamoxifen), respectively. There were six cases of endometrial polyps on placebo and 27 on tamoxifen, leading to drug withdrawal in 2 versus 10 cases, respectively (P = 0.016). There was no increase of uterine cancer on tamoxifen (3 on placebo versus 1 on tamoxifen). No clinical bone fractures were recorded. The cumulative incidence of pre-specified adverse events is illustrated in supplementary Figure S2, available at Annals of Oncology online. The rate of grade 2–3 menopausal symptoms was 50%–80% higher on tamoxifen versus placebo. There were 15 cancers other than breast on placebo and 14 on tamoxifen, and 2 versus 6 deaths (supplementary Table S2, available at Annals of Oncology online).
original articles
Annals of Oncology
Table 2. Numbers and rates of breast cancer by allocated arm and selected characteristics No. of events Placebo Tamoxifen
RR (95% CI)b
P value for heterogeneity
a
Difference
19
4.12
3.30
0.82
0.80 (0.44–1.46)
0 5 14
5.35 3.65 3.88
0.00 2.16 5.98
5.35 1.49 −2.10
0.00 Ne 0.59 (0.19–1.81) 1.54 (0.67–3.57)
0.14
1 7 11
0.00 6.19 2.30
0.90 2.17 8.20
−0.90 4.03 −5.90
Ne Ne 0.35 (0.15–0.82) 3.56 (0.99–12.8)
0.002
10 9
4.03 4.20
3.75 2.92
0.28 1.29
0.93 (0.39–2.19) 0.69 (0.30–1.63)
0.66
2 8 8 1
6.78 2.59 4.03 6.37
1.80 5.14 2.84 5.59
4.98 −2.56 1.20 0.78
0.26 (0.05–1.28) 1.99 (0.60–6.62) 0.70 (0.29–1.72) 0.88 (0.05–14.1)
0.21
9 7 3
5.03 3.69 3.05
3.61 3.30 2.74
1.42 0.40 0.31
0.72 (0.30–1.71) 0.89 (0.33–2.40) 0.90 (0.18–4.46)
0.90
2 10 7
2.91 3.90 5.86
1.38 3.89 4.03
1.52 0.02 1.82
0.48 (0.09–2.46) 1.00 (0.41–2.40) 0.69 (0.26–1.85)
0.76
5 7 1 5
2.75 0.69 0.00 0.34
0.87 1.22 0.17 0.87
1.88 −0.53 −0.17 −0.53
0.32 (0.12–0.86) 1.77 (0.52–6.05) Ne Ne 2.53 (0.49–13.0)
0.034
a
Rate in the placebo group minus rate in the tamoxifen group. Risk ratio (RR) for women in the tamoxifen group relative to women in the placebo group. c Classified by IHC according to 2011 St Gallen criteria [26]. CI, confidence interval; Ne, non-estimable. b
postmenopausal women [4, 5, 8] despite the different indications and age range heavily hampered our recruitment capability. Subgroup analyses showed that tamoxifen exhibited a favorable trend on luminal-A tumors and tumors expressing PgR, which are known to be associated with HRT use [26] and to be highly endocrine responsive [24]. Tamoxifen also showed a lower breast cancer risk in women on HRT <5 years, who had the highest risk among HRT users, consistent with the gap-time effect [10–12], and among ERT-alone users, where the longterm risk of breast cancer incidence and death is decreased, at least with CEE [27]. In contrast, tamoxifen had no effect in the combined HRT subgroup, where the risk of breast cancer incidence and mortality is increased [28, 29].Sensitivity analysis adjusted for nonadherence and restricted to women who took treatment for more than 1 year yielded a 50%, borderline significant reduction of breast cancer by low-dose tamoxifen. All these subgroup analyses have limited power, however, and none were significant at P < 0.01, so the results should be interpreted with caution.
| DeCensi et al.
We found no excess of cardiovascular events and VTE on tamoxifen, in line with the observation that the risk of VTE under tamoxifen is attenuated by concomitant ERT use [30] and in premenopausal women [31]. Also, the rates of serious adverse events seem to be lower with 5 mg/day than with 20 mg/day in a similar population [14], possibly because tamoxifen estrogenicity is attenuated by a lower dose [20]. Although significantly more endometrial polyps were noted on tamoxifen, no increase of endometrial cancer was observed, again suggesting a protective effect of progestins against tamoxifen endometrial effects [18, 32]. However, a clear relationship between endometrial polyps and subsequent endometrial cancer under tamoxifen has not been established [33]. Despite the concomitant use of HRT, low-dose tamoxifen increased the rate of grade 2–3 hot flashes by ∼50% (from 64/ 1000 to 97/1000 per year). An indirect comparison suggests that this rate is lower than that observed with tamoxifen at 20 mg/ day in our prior trial in hysterectomized women (from 67/1000 on placebo to 119/1000 on tamoxifen [14]), but it is still of
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All women 24 Age at entry (years) <50 7 50–54 8 ≥55 9 Duration of HRT De Novo 0 <5 years 21 ≥5 years 3 Route of HRT Oral 11 Transdermal 13 Type of HRTa Estrogen alone 7 Combined continuous 4 Combined sequential 12 Tibolone 1 Time since menopause to HRT 0–1 year 12 2–4 years 9 ≥5 years 3 5-year Gail breast cancer risk (%) <1 5 1–1.49 10 ≥1.5 9 Tumor molecular subtypec Luminal-A 16 Luminal-B 4 HER2+ 0 Triple negative 2
Rate per 1000 women-year Placebo Tamoxifen
Annals of Oncology
original articles
Figure 2. Cumulative incidence of breast cancer by intention-to-treat (ITT) (A), and after adjustment for adherence (B), efficacy (C) and adherence and efficacy (D). Adherence analysis includes follow-up censored 6 months after last treatment assumption for women who did not complete 80% (4 years) of treatment. Efficacy analysis includes women who completed 12 months of therapy.
concern given the notion that hot flashes are a major reason for dropout in prevention trials [14, 31]. In both the studies, women were on HRT because of menopausal symptoms or early surgical menopause [14], and thus represent a selected
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population with a higher rate of symptoms than the average population treated with tamoxifen. An increase of hot flashes under 20 mg tamoxifen in HRT users has also been reported in the IBIS trial [34]. Because women were not randomly assigned
doi:10.1093/annonc/mdt244 |
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Figure 1. Cumulative incidence of breast cancer overall, by PgR-positive tumors and molecular subtypes by allocated arm. Hazards ratio (HR) and 95% confidence intervals (CIs) were obtained from a Cox regression model adjusted for age and center.
original articles
Annals of Oncology
Table 3. Numbers and rates of selected adverse events by the allocated arm RR (95% CI)b
Tamoxifen
Rate per 1000 women Placebo Tamoxifen
Difference
245 147 223 113 134 23 108 24 286 71 89 35 6
305 200 269 181 241 58 129 28 356 93 105 48 27
178.18 63.61 141.68 46.60 52.30 7.43 37.50 7.73 153.52 24.64 36.90 12.18 1.89
317.38 96.76 229.91 83.56 111.42 20.49 47.58 9.53 228.06 35.20 46.44 17.72 8.98
−139.20 −33.15 −88.24 −36.97 −59.12 −13.06 −10.08 −1.80 −74.54 −10.56 −9.54 −5.54 −7.09
1.78 (1.48–2.15) 1.52 (1.22–1.90) 1.62 (1.34–1.97) 1.79 (1.41–2.28) 2.13 (1.71–2.65) 2.76 (1.70–4.48) 1.27 (0.98–1.65) 1.23 (0.71–2.13) 1.49 (1.25–1.76) 1.43 (1.04–1.95) 1.26 (0.94–1.68) 1.45 (0.94–2.26) 4.74 (1.96–11.5)
6 2 2 7 3
4 4 5 18 1
1.89 0.63 0.63 0.63 0.51
1.33 1.33 1.67 3.33 0.17
0.56 −0.70 −1.03 −2.70 0.34
0.70 (0.20–2.50) 2.11 (0.39–11.5) 2.64 (0.51–13.6) 5.27 (1.15–24.1) 0.34 (0.04–3.25)
a
a
Rate in the placebo group minus rate in the tamoxifen group. Risk ratio (RR) for women in the tamoxifen group relative to women in the placebo group. CI = confidence interval. c Among women who were free of symptoms at baseline. d Coronary heart syndrome includes: myocardial infarction (1P/3T), coronary stenting (1P/0T), cardiac arrhythmia (0P/1T), coronary ischemia (4P/0T). e Cerebrovascular events includes four TIA on tamoxifen. f Two endometrial cancers (2P/0T) were diagnosed during treatment, and two (1P/1T) were diagnosed after treatment. b
to HRT, however, we cannot determine the magnitude of the effect of HRT on tamoxifen-induced menopausal symptoms. The 5-year compliance was slightly over 50% in our trial, in line with most breast cancer prevention trials [1, 2, 14, 15, 31]. Yet the high dropout rate remains an important issue that may jeopardize efficacy, as suggested by our sensitivity analyses. Although our study cannot directly apply to different categories such as gene mutation carriers undergoing risk reduction salpingo-oophorectomy, our findings seem to provide safety reassurance on the addition of low-dose tamoxifen to estrogen-alone therapy for menopausal symptom relief in these specific women’s populations where there is a clear unmet medical need [35, 36]. A properly designed clinical trial may be warranted. Our population was mostly composed of recently postmenopausal women undergoing HRT for menopausal symptoms, in contrast to the WHI trials which addressed the preventive effect of HRT in a much older and asymptomatic population. Moreover, only a minority of our participants used oral CEE (8%) and MPA (15%), reflecting the limited prescription of both the drugs in Europe. Admittedly, the lower risk of breast cancer death associated with estrogen therapy alone [27] versus the increased risk in the combined HRT [28, 29] may have contributed to the heterogeneity of our findings. Since subgroup analyses of the WHI trials indicated that estrogen therapy alone has an overall health benefit in women aged <60 years [9, 13], it is possible that the use of most
| DeCensi et al.
recent forms of HRT that avoid the systemic effects of MPA will regain consensus in the treatment of recently postmenopausal women [8]. If this is the case, our results are useful as they provide a clue to reduce breast cancer, the major risk associated with HRT use, in a broad population composed of recently postmenopausal women. Although tamoxifen is currently not available as 5 mg tablet in the market, its prolonged half-life allows for alternative schedules with retained activity, such as 10 mg every other day [37, 38]. Our findings in primary prevention cannot be compared with the HABITS [39] and Stockholm trial [40], which assessed the effect of HRT in breast cancer survivors, some of whom were being treated with tamoxifen as an adjuvant treatment. The Stockholm trial did not show any difference between HRT arms in tamoxifen users (5 versus 4), whereas in the HABITS trial there was a higher risk of recurrence in the HRT arm among tamoxifen users. However, the proportion of tamoxifen users was lower in HABITS (33% versus 52%). Moreover, because tamoxifen use was not randomized, women may have received the anti-estrogen tamoxifen because of their higher risk of recurrence. Our study has several important limitations, including the limited statistical power and the marked heterogeneity of HRT types having different risks of breast cancer. For these reasons, reliable conclusions cannot be drawn. However, our trial suggests that the addition of low-dose tamoxifen to HRT may reduce the risk of breast cancer in recently
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Symptom/Event Hot flashesc (moderate or severe) Night sweatsc (moderate or severe) Vaginal dischargec (moderate or severe) Vaginal bleedingc (moderate or severe) Vaginal dryness, pruritusc (moderate or severe) Dyspareunia c (moderate or severe) Endometrial polyps Serious adverse events Coronary heart syndromed Cerebrovascular eventse VTEs Hysterectomy for benign disorders Endometrial cancersf
No. of events Placebo
Annals of Oncology
postmenopausal women. This hypothesis should be assessed in a larger study.
acknowledgements Tamoxifen and placebo were gifted by FIDIA FarmaceuticiS.p.a, AbanoTerme, Italy. We are grateful to the study participants for their heart and energy.
funding The study was supported by the Italian Foundation for Cancer Research, Avon Italia, LegaItaliana per la Lottacontro i Tumori (LILT project number 51/2005), American Italian Cancer Foundation, ASL Città di Milano, RegionePiemonte.
disclosure
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16. Lippman ME, Krueger KA, Eckert S et al. Indicators of lifetime estrogen exposure: effect on breast cancer incidence and interaction with raloxifene therapy in the multiple outcomes of raloxifene evaluation study participants. J Clin Oncol 2001; 19: 3111–3116. 17. Khan SA, Rogers MA, Khurana KK et al. Estrogen receptor expression in benign breast epithelium and breast cancer risk. J Natl Cancer Inst 1998; 90: 37–42. 18. Gardner FJ, Konje JC, Abrams KR et al. Endometrial protection from tamoxifenstimulated changes by a levonorgestrel-releasing intrauterine system: a randomised controlled trial. Lancet 2000; 356: 1711–1717. 19. Decensi A, Gandini S, Guerrieri-Gonzaga A et al. Effect of blood tamoxifen concentrations on surrogate biomarkers in a trial of dose reduction in healthy women. J Clin Oncol 1999; 17: 2633–2638. 20. Decensi A, Robertson C, Viale G et al. A randomized trial of low-dose tamoxifen on breast cancer proliferation and blood estrogenic biomarkers. J Natl Cancer Inst 2003; 95: 779–790. 21. Decensi A, Gandini S, Serrano D et al. Randomized dose-ranging trial of tamoxifen at low doses in hormone replacement therapy users. J Clin Oncol 2007; 25: 4201–4209. 22. Haugan Moi LL, Hauglid FM, Gandini S et al. Effect of low-dose tamoxifen on steroid receptor coactivator 3/amplified in breast cancer 1 in normal and malignant human breast tissue. Clin Cancer Res 2010; 16: 2176–2186. 23. Viale G, Giobbie-Hurder A, Regan MM et al. Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial 1–98 comparing adjuvant tamoxifen with letrozole. J Clin Oncol 2008; 26: 5569–5575. 24. Goldhirsch A, Wood WC, Coates AS et al. Strategies for subtypes—dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2011. Ann Oncol 2011; 22: 1736–1747. 25. Nichols HB, Trentham-Dietz A, Hampton JM et al. From menarche to menopause: trends among US Women born from 1912 to 1969. Am J Epidemiol 2006; 164: 1003–1011. 26. Reeves GK, Beral V, Green J et al. Hormonal therapy for menopause and breastcancer risk by histological type: a cohort study and meta-analysis. Lancet Oncol 2006; 7: 910–918. 27. Anderson GL, Chlebowski RT, Aragaki AK et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol 2012; 13: 476–486. 28. Chlebowski RT, Anderson GL. Changing concepts: menopausal hormone therapy and breast cancer. J Natl Cancer Inst 2012; 104: 517–527. 29. Chlebowski RT, Anderson GL, Gass M et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 2010; 304: 1684–1692. 30. Decensi A, Maisonneuve P, Rotmensz N et al. Effect of tamoxifen on venous thromboembolic events in a breast cancer prevention trial. Circulation 2005; 111: 650–656. 31. Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 1998; 90: 1371–1388. 32. Gardner FJ, Konje JC, Bell SC et al. Prevention of tamoxifen induced endometrial polyps using a levonorgestrel releasing intrauterine system long-term follow-up of a randomised control trial. Gynecol Oncol 2009; 114: 452–456. 33. Chalas E, Costantino JP, Wickerham DL et al. Benign gynecologic conditions among participants in the Breast Cancer Prevention Trial. Am J Obstet Gynecol 2005; 192: 1230–1237. 34. Sestak I, Kealy R, Edwards R et al. Influence of hormone replacement therapy on tamoxifen-induced vasomotor symptoms. J Clin Oncol 2006; 24: 3991–3996. 35. Rebbeck TR, Friebel T, Wagner T et al. Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol 2005; 23: 7804–7810. 36. Domchek SM, Friebel T, Neuhausen SL et al. Is hormone replacement therapy (HRT) following risk-reducing salpingo-oophorectomy (RRSO) in BRCA1 (B1)- and
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The authors have declared no conflicts of interest.
original articles
original articles 37. 38.
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BRCA2 (B2)-mutation carriers associated with an increased risk of breast cancer? ASCO Annu Meeting Proc 2011; 29: 1501. Decensi A, Bonanni B, Guerrieri-Gonzaga A et al. Biologic activity of tamoxifen at low doses in healthy women. J Natl Cancer Inst 1998; 90: 1461–1467. Guerrieri-Gonzaga A, Baglietto L, Johansson H et al. Correlation between tamoxifen elimination and biomarker recovery in a primary prevention trial. Cancer Epidemiol Biomarkers Prev 2001; 10: 967–970. Holmberg L, Iversen OE, Rudenstam CM et al. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J Natl Cancer Inst 2008; 100: 475–482. von Schoultz E, Rutqvist LE. Menopausal hormone therapy after breast cancer: the Stockholm randomized trial. J Natl Cancer Inst 2005; 97: 533–535.
appendix
| DeCensi et al.
Istituto Europeo di Oncologia, Milan: Veronesi Umberto, Bonanni Bernardo, CazzanigaMassimiliamo, Lazzeroni Matteo, Serrano Davide, Varricchio Maria Clara, Feroce Irene, Rotmensz Nicole, Maisonneuve Patrick, Santillo Barbara, Bazolli Barbara, Goldhirsch Aron, Sideri Mario, Di Pace Raffaella, Moroni Simona, Zamperini Paola, Viale Giuseppe, Cassano Enrico, Latronico Antuono, Meneghetti Lorenza, Di Nubila Brunella, Pizzamiglio Maria; Fondazione Pascale, Naples: D’Aiuto Giuseppe, Oliviero Pasquale, Oliviero Giovanna, Riccone Giuseppina; Istituto Nazionale per la Ricerca sul Cancro, Genoa: Gustavino Claudio, Centurioni Maria Grazia, Ferrando Liliana; Ospedale Civile di Leganano, Presidio di Magenta, Magenta: De Maria Enrica; Zandonini Gianfranco; Ospedale S. Gerardo, Monza: Mangioni Costantino, Giussani Maria Elena; Universita degli Studi di Napoli Federico II, Naples: Di Carlo Costantino, Nappi Carmine; Ospedale Niguarda, Milan: Mapelli Carlo; Consultorio Famigliare, Palmi: Infantino Carmelo; Clinica Ostetrica Ginecologica, Parma: Bacchi Modena Alberto, Sgarabotto Maria Paola, Valitutto Simona; Fondazione Salvatore Maugeri, Pavia: Costa Alberto; Scoccia Elisabetta; Policlinico Santa Chiara, Pisa: Genazzani Andrea, Gambacciani Marco, Pepe Antonia, Vacca Francesca; Azienda Ospedaliera Santa Maria degli Angeli, Pordenone: Monti Nadia, Tumolo Salvatore; Ospedale Maggiore, Parma: Cascinu Stefano, Michiara Maria; Ospedale Infermi, Rimini: Ravaioli Alberto, Desiderio Franco, Fabbri Carla, Pini Emanuela; ASL Roma H, Albano Laziale: Vella Alessandro, Fabi Linda Maria, Corrado Nunziata; Policlinico Umberto I, Rome: Bastianelli Carlo, Rapiti Stefania, Colafrancesco Francesca; Ospedale Luigi Sacco, Milan: Ferrazzi Enrico, Bombelli Maria Vittoria, Ciminera Nadia, Cetin Irene; Ospedale San Carlo Borromeo, Milan: Quaranta Stefano; Ospedale San Giuliano, Giugliano: Incoronato Pasquale; Policlinico Le Scotte, Siena: Gioffré Walter, Tripodi Alessia; Ospedale Az.San. 6, Soveria Mannelli: Vescio Filippo; Ospedale S.S. Antonio e Margherita, Tortona: Pacquola Maria Grazia; Policlinico Tor Vergata, Rome: Piccione Emilio, Pietropolli Adalgisa; Ospedale Valduce, Como: Belloni Carlo, Piol Francesca; Ospedale Civile, Vasto: Sangiorgi Barbara; Ospedale San Luca, Vallo di Lucania: Masullo Pietro, Di Feo Gemma, Speranza Mariangela, Ronsini Salvatore; ASL Milano, Milan: Bisanti Luigi. Data safety and Monitoring Committee: Giuseppe Benagiano (Chairman, Rome, Italy), Aron Goldhirsch (Lugano, CH), Chris Robertson (Glasgow, UK).
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Steering committee: Veronesi Umberto (studychair), DeCensi Andrea (Principal Investigator), Bonanni Bernardo, Maisonneuve Patrick, Omodei Umberto, Rotmensz Nicole, Sideri Mario and Bisanti Luigi. The HOT Study Group also includes the following physicians and scientists who contributed to this trial: Istituto Oncologico, Bari: Schitulli Francesco, DeLiso Maria; Spedali Civili di Brescia, Brescia: Omodei Umberto, Ramazzotto Francesca, Corini Silvia, Pecorelli Sergio, Daldos Cristina; Ospedale San Giovanni di Dio, Cagliari: Melis Gianbenedetto, Pilloni Monica; Ospedale B. Ramazzini, Carpi: Artioli Fabrizio, Guerzoni Roberta; Azienda Ospedaliera Vittorio Emanuele, Catania: Sciacchitano Salvatore, Grasso Daniela; Ospedale Città di Castello, Citta’ di Castello: Torrioli Donatello, Bravi Stefano; Presidio Ospedaliero di Cerignola, Cerignola: Corrado Gemma; Ospedale Mariano Santo, Cosenza: BiamonteRosalbino; Centro di Riferimento per l’Epidemiologia e la Prevenzione Oncologica - Piemonte, Turin: Segnan Nereo, Ponti Antonio, Marti Elvira, Gonzales Galina; Ospedale S. Anna, Turin: Campagnoli Carlo, Massobrio Marco, Ambrogio Simona, Gallo Mario; Ospedale Mauriziano, Turin: Sismondi Piero, Biglia Nicoletta, Utcic E.; Istituti Ospitalieri, Cremona: Bottini Alberto, Allevi Giovanni, Andreis Daniele; Istituto per lo Studio e la Prevenzione Oncologica, Florence: Rosselli del Turco Marco, MuracaMariaGrazia, Zeccarelli Maurizia, Iossa Anna, Brancato Beniamino; Gino, Belluardo Donatella; Ospedale San Martino, Genoa: Valenzano Mario, Bogliolo Stefano, Fortunato Tiziana; Ospedale San Paolo, Milan e successivamente al 2004 Istituto Ostetrico ginecologico L. Mangiagalli: Pardi Giorgio, Ferrari Maria, Waldis Francesca;
Annals of Oncology
Annals of Oncology
Annals of Oncology 24: 2753–2760, 2013 doi:10.1093/annonc/mdt244 Published online 17 July 2013
A phase-III prevention trial of low-dose tamoxifen in postmenopausal hormone replacement therapy users: the HOT study A. DeCensi1*, B. Bonanni2, P. Maisonneuve3, D. Serrano2, U. Omodei4, C. Varricchio2, M. Cazzaniga2, M. Lazzeroni2, N. Rotmensz3, B. Santillo3, M. Sideri5, E. Cassano6, C. Belloni7, M. Muraca8, N. Segnan9, P. Masullo10, A. Costa11, N. Monti12, A. Vella13, L. Bisanti14, G. D’Aiuto15 & U. Veronesi16, for the Italian HOT Study Group†
Received 24 December 2012; revised 16 May 2013; accepted 28 May 2013
Background: Postmenopausal hormone replacement therapy (HRT) relieves menopausal symptoms and may decrease mortality in recently postmenopausal women, but increases breast cancer risk. Low-dose tamoxifen has shown retained activity in phase-II studies. Methods: We conducted a phase-III trial in 1884 recently postmenopausal women on HRT who were randomly assigned to either tamoxifen, 5 mg/day, or placebo for 5 years. The primary end point was breast cancer incidence. Results: After 6.2 ± 1.9 years mean follow-up, there were 24 breast cancers on placebo and 19 on tamoxifen (risk ratio, RR, 0.80; 95% CI 0.44–1.46). Tamoxifen showed favorable trends in luminal-A tumors (RR, 0.32; 95% CI 0.12–0.86), in HRT users <5 years (RR, 0.35; 95% CI 0.15–0.82) and in women completing at least 12 months of treatment (RR, 0.49; 95% CI 0.23–1.02). Serious adverse events did not differ between placebo and tamoxifen, including, respectively, coronary heart syndrome (6 versus 4), cerebrovascular events (2 versus 5), VTE (2 versus 5) and uterine cancers (3 versus 1). Vasomotor symptoms were 50% more frequent on tamoxifen. Conclusions: The addition of low-dose tamoxifen to HRT did not significantly reduce breast cancer risk and increased climacteric symptoms in recently postmenopausal women. However, we noted beneficial trends in some subgroups which may deserve a larger study. Key words: breast cancer, chemoprevention, hormone replacement therapy and low dose, tamoxifen
introduction Given the increase in life expectancy, the management of postmenopausal disorders is a public health issue. Two Women’s Health Initiative (WHI) trials testing hormone replacement therapy (HRT) in women with a mean age over 60 years showed a worsened global health index with HRT [1, 2]. The lack of benefit in coronary disease, in contrast to prior observational studies [3], and the increased risk of breast cancer in the combined conjugated equine estrogen (CEE) plus progestin therapy with the medroxyprogesterone acetate (MPA) *Correspondence to: Dr Andrea DeCensi, Division of Medical Oncology, E.O. Ospedali Galliera, Mura delle Cappuccine 14, 16128 Genoa, Italy. Tel: +39-0105634501; Fax: +39-01057481090; E-mail: [email protected] †
List of all investigators in appendix.
trial [1], led to a dramatic drop in HRT use also in recently postmenopausal women [4, 5], with a consequent decrease of breast cancer [6]. The timing of initiation of HRT after the menopause (gap-time) has been advocated as an important reason for the divergent findings on cardiovascular disease between observational studies and the WHI trials [7, 8], and subsequent analyses of both WHI trials indicated that total and cardiovascular mortality were reduced in women aged 50–59, particularly with CEE alone, in contrast to an increase in women who started HRT >20 years since menopause [9]. However, such a gap-time effect could not be detected on breast cancer in WHI trials as most participants started HRT after 10 years since menopause [9], whereas observational studies examining HRT use for menopausal symptoms showed a higher breast cancer risk in women starting HRT within 5 years from
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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1 Division of Medical Oncology, Ospedali Galliera, Genova; Divisions of; 2Cancer Prevention and Genetics; 3Epidemiology and Biostatistics; European Institute of Oncology, Milano; 4Gynecology Department Ospadali Civili Brescia Divisions of; 5Preventive Gynecology; 6Radiology; European Institute of Oncology, Milano; 7Division of Obstetricand Gynecology; Ospedale Valduce, Como; 8Oncology Prevention Center ISPO Firenze; 9CPO; Torino; 10Oncology Unit Ospedale S. Luca; Vallo della Lucania; 11Breast Unit Fondazione S. Maugeri; Pavia; 12Unit of Oncology; Ospedale S. Maria degli Angeli, Pordenone; 13Breast Unit; ASL Roma H, Albano Laziale; 14Epidemiology; Breast Unit ASL Città di Milano; 15Senology Fondazione Pascale; Napoli, Italy; 16European Institute of Oncology; Milano, Italy
original articles
methods subjects and treatment We conducted a phase-III, double-blind, placebo-controlled trial in recently postmenopausal women using HRT for menopausal symptom relief who were randomly allocated to either placebo or tamoxifen 5 mg/day for 5 years (trial IEO S51/200, HRT opposed by low-dose tamoxifen, HOT, Clinical Trials.gov NCT01579734). Eligibility criteria were current HRT use or de novo HRT use and negative mammography within 6 months. Toxicity was evaluated using the NCI toxicity criteria v2.0. Clinical examinations were repeated every 6 months and mammography was repeated annually. Transvaginal ultrasounds were carried out at baseline and repeated in case of atypical bleeding, followed by hysteroscopy on clinical judgment. At completion of the 5-year intervention, clinical visit and mammography were repeated annually up to 10 years. The use of venflaxine was allowed. The primary end point was the incidence of breast cancer, whereas the secondary end points included endometrial cancer, coronary heart syndrome, cerebrovascular events, venous thromboembolic events (VTEs), bone fractures, all cancers.
pathology and immunohistochemistry Central pathology assessment of breast cancer included histological type, grade, peritumoral vascular invasion, ER, PgR, HER2 and Ki-67, as previously described [23]. Molecular tumor subtypes were classified by immunohistochemistry (IHC) into four categories according to 2011 St Gallen criteria [24]: luminal-A, ER or PgR-positive and Ki-67 < 14%; luminal-B, ER or PgR-positive and either Ki-67 ≥ 14% with negative HER2 or HER2-positive regardless of the Ki-67 level; HER2-positive and ER/PgRnegative; triple negative, all receptors negative.
sample size and statistical analysis The study was designed to detect a 40% reduction of breast cancer with 80% power and two-sided 5% significance level. Using the log-rank test, 126 breast cancers had to be observed on 8500 subjects recruited over 5 years with 80% compliance and a background incidence rate of 4/1000. Recalculations based on a hazard ratio (HR) of 0.5, closer to the range observed in the Italian tamoxifen trial [14], and practical considerations based on the dramatic drop of HRT use after the first WHI trial results [1]
| DeCensi et al.
led to a total of 4500 women to be recruited to attain the pre-specified assumptions. The decision to stop recruitment was recommended by the Data Safety and Monitoring Committee (DSMC) after a limited recruitment in the last 24 months. Stratification factors were center, HRT use (current, de novo), route of estrogen administration (transdermal, oral) and prior hysterectomy (unopposed estrogen, combined estrogen-progestin therapy). An ad hoc computer program in Access was used to preserve the allocation ratio in each stratum through biased coin randomization and minimization. The data included are based on information received as of 30 November 2011. The main analysis was carried out on an intention-to-treat (ITT) basis. Incidence rates for breast cancer were calculated by dividing the number of events by the number of event-specific person-years of follow-up. For symptoms and adverse events, person-years were calculated from the date of randomization to treatment termination, development of the specific event or dropout, whichever came first. For other cancers and deaths, person-years were calculated from the date of randomization to the date of last follow-up or specific event. Event rates were compared by using risk ratios (RRs) and 95% confidence intervals (CIs), assuming that the events followed a Poisson distribution. Because healthy, middle-aged women were enrolled in the trial, mortality was not a major competing risk of failure. The two treatment groups were compared by the log-rank test. HRs and 95% CIs were obtained using a Cox proportional regression model after adjustment for age (in 5-year groups) and center. We tested the proportional hazards assumption by introducing a time-dependent variable and testing for its statistical significance. For breast cancer subtypes, follow-up was censored at diagnosis of any other breast cancer subtype. We carried out sensitivity analyses adjusted for nonadherence by censoring follow-up 6 months after women became nonadherent, i.e. took treatment for less than 80% of the planned intervention, or to women who completed at least 12 months of treatment. P-values were at <0.05 level for the main end points and at <0.01 level for secondary end points and subgroup analyses to account for multiple comparisons. Analyses were carried out with SAS software (version 8.2, Cary, NC).
results From 1 February 2002 to 31 July 2007, we randomly allocated 1884 women to either placebo (n = 946) or tamoxifen (n = 938). The participant flow diagram is reported in supplementary Figure S1, available at Annals of Oncology online. Compliance at the end of 5 years was 55.6% on placebo and 52.6% on tamoxifen (P = 0.19). At the end of follow-up, 1025 (54%) women were still on HRT; 88 (5%) had temporarily suspended HRT or were on HRT every other day and 584 (31%) had definitely stopped HRT. Information was missing for 187 (10%) women. A similar number of women stopped HRT in either arm (n = 289 on placebo and n = 295 on tamoxifen, P = 0.46). The main subject characteristics were evenly distributed by allocated arm (Table 1). The mean ± SD age was 53.1 ± 5.1 on placebo and 53.5 ± 5.0 on tamoxifen, and mean + SD BMI 24.0 ± 3.8. Approximately 20% were de novo HRT users, over 55% were on HRT for <5 years, <20% started HRT >5 years since menopause and only 4% started HRT >10 years since menopause (overall mean ± SD, 3.0 ± 3.5 years). Estrogen therapy at baseline included 92% on estradiol, of whom 10% at low dose (1 mg), CEE users were 8%, of whom 3% at low dose (0.3 mg).
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menopause, including unopposed estrogen therapy [10–12]. Since HRT use in recently postmenopausal women alleviates menopausal symptoms and decreases bone fracture risk [8] and, possibly, overall mortality in estrogen-alone users [9, 13], a reduction of breast cancer risk would further ameliorate HRT cost–benefit ratio. Subgroup analyses of breast cancer prevention trials showed fewer breast cancers in current or past HRT users allocated to either tamoxifen [14, 15] or raloxifene [16] versus placebo. The increased risk of breast cancer associated with HRT is linked to higher expression of estrogen receptors in normal breast tissue [17], thus leading to enhanced antiestrogen sensitivity. Conversely, the use of a progestin may attenuate the endometrial effects of tamoxifen [18]. Recent dose-ranging trials defined 5 mg/day of tamoxifen as the optimal biological dose based upon a retained activity on surrogate biomarkers [19–21] and the lack of endometrial proliferation in HRT users [22]. We therefore conducted a phase-III prevention trial to determine the efficacy of low-dose tamoxifen in reducing breast cancer risk in recently postmenopausal women on HRT.
Annals of Oncology
original articles
Annals of Oncology Table 1. Main subjects characteristics by allocated arm Placebo No. %
Tamoxifen No. %
All women Age at entry (years) <50 50–54 ≥55 Body mass index Underweight (<18.5) Normal weight (18.5–24.9) Overweight (25–29.9) Obese (≥ 30) Duration of HRT at entry De Novo <5 years ≥5 years Unknown Route of HRT Oral Transdermal Type of HRTa Estrogen alone Combined continuous Combined sequential Tibolone Unknown Type of progestin Progesterone, dydrogesterone Medroxyprogesterone acetate Cyproterone acetate NETA, levonorgestrel Nomegestrol acetate Trimegestone Other (drospirenone, medrogestone, OC) Unknown Time since menopause to HRT 0–1 year 2–4 years ≥5 years Unknown 5-year Gail breast cancer risk (%) <1 1–1.49 ≥1.5
946
100.0
938
100.0
219 360 367
23.2 38.1 38.8
182 372 384
19.4 39.7 40.9
26 598 243 79
2.7 63.2 25.7 8.4
28 623 227 60
3.0 66.4 24.2 6.4
183 545 213 5
19.3 57.6 22.5 0.5
183 521 219 15
19.5 55.5 23.3 1.6
445 501
47.0 53.0
439 499
46.8 53.2
169 252 473 28 24
17.9 26.6 50.0 3.0 2.5
177 265 444 36 16
18.9 28.3 47.3 3.8 1.7
197 140 48 183 88 39 13 39
20.9 15.0 5.1 19.3 9.3 4.1 1.4 4.1
190 142 36 189 91 26 13 40
20.3 14.9 3.8 20.2 9.7 2.8 1.4 4.3
391 387 163 5
41.3 40.9 17.2 0.5
401 347 180 10
42.8 37.0 19.2 1.1
287 416 243
30.3 44.0 25.7
240 422 276
25.6 45.0 29.4
a Hormone Replacement Therapy. NETA, Norethisterone acetate; OC, oral contraceptive.
Table 2 summarizes breast cancer events by allocated arm and selected characteristics. After a mean ± SD follow-up of 6.2 ± 1.9 years, we observed 24 breast cancers on placebo (annual rate 4.1/1000) and 19 on tamoxifen (annual rate 3.3/1000), with rate ratio (RR) = 0.80 (95% CI 0.44–1.46). Tamoxifen showed favorable trends in women on HRT for <5 years (unadjusted RR, 0.35; 95% CI 0.15–0.82; RR = 0.35; 95% CI 0.15–0.85, after adjustment for age, family history of breast cancer, BMI, hysterectomy, duration of HRT use at baseline, route and type
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discussion A basic principle of clinical endocrinology indicates that hormone deficiency should be replaced when it is clinically relevant [8]. Although life expectancy has dramatically increased over the last century, age at menopause has shown only a small increase [25]. The aim of this pragmatic trial was to assess the efficacy of 5 mg/day of tamoxifen in reducing breast cancer in recently postmenopausal women treated with different HRT forms for menopausal symptom relief. We found a nonsignificant 20% reduction of breast cancer with low-dose tamoxifen, a figure similar to that obtained with 20 mg/day in hysterectomized women [14]. Unfortunately, the negative impact of the WHI findings on HRT prescriptions in recently doi:10.1093/annonc/mdt244 |
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Characteristic
of HRT, and Gail breast cancer risk) and in estrogen-alone users (RR = 0.26, 95% CI 0.05–1.28), but had no effect in the combined HRT subgroup (16 versus 16 tumors) or according to the Gail risk. A lower number of luminal-A tumors (RR, 0.32; 95% CI 0.12–0.86) and PgR-positive tumors (RR 0.43; 95% CI 0.19–0.97) were observed on tamoxifen, whereas additional tumor characteristics did not differ, including stage pT1 tumors (86.4% versus 80.0%) and pN + tumors (22.7% versus 31.3%), respectively (supplementary Table S1, available at Annals of Oncology online). The cumulative incidence of breast cancer, overall and by molecular subtypes is illustrated in Figure 1. In sensitivity analyses shown in Figure 2, censoring follow-up 6 months after women became nonadherent (i.e. took treatment for <4 years), tamoxifen showed a greater risk reduction of breast cancer, with 24 events on placebo versus 13 on tamoxifen (age adjusted HR 0.59; 95% CI 0.30–1.17). Similarly, in women who completed at least 12 months of treatment, the number of events was 23 versus 14 (HR, 0.65; 95% CI 0.33–1.26). In an efficacy analysis restricted to women who completed at least 12 months of treatment and censoring follow-up 6 months after women became nonadherent, the number of events was 23 versus 10 (HR, 0.49; 95% CI 0.23–1.02). Table 3 summarizes protocol pre-specified menopausal symptoms and adverse events by allocated arm. Moderate or severe (grade 2 or higher) hot flashes, night sweats, vaginal dryness and discharge were significantly more frequent on tamoxifen than on placebo, whereas headache was significantly less frequent on tamoxifen. Pre-specified serious adverse events were not different between placebo and tamoxifen, including coronary heart syndrome (6 versus 4), cerebrovascular events (2 versus 5, including four TIA on tamoxifen) and VTE (2 versus 5, including one superficial VTE on tamoxifen), respectively. There were six cases of endometrial polyps on placebo and 27 on tamoxifen, leading to drug withdrawal in 2 versus 10 cases, respectively (P = 0.016). There was no increase of uterine cancer on tamoxifen (3 on placebo versus 1 on tamoxifen). No clinical bone fractures were recorded. The cumulative incidence of pre-specified adverse events is illustrated in supplementary Figure S2, available at Annals of Oncology online. The rate of grade 2–3 menopausal symptoms was 50%–80% higher on tamoxifen versus placebo. There were 15 cancers other than breast on placebo and 14 on tamoxifen, and 2 versus 6 deaths (supplementary Table S2, available at Annals of Oncology online).
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Annals of Oncology
Table 2. Numbers and rates of breast cancer by allocated arm and selected characteristics No. of events Placebo Tamoxifen
RR (95% CI)b
P value for heterogeneity
a
Difference
19
4.12
3.30
0.82
0.80 (0.44–1.46)
0 5 14
5.35 3.65 3.88
0.00 2.16 5.98
5.35 1.49 −2.10
0.00 Ne 0.59 (0.19–1.81) 1.54 (0.67–3.57)
0.14
1 7 11
0.00 6.19 2.30
0.90 2.17 8.20
−0.90 4.03 −5.90
Ne Ne 0.35 (0.15–0.82) 3.56 (0.99–12.8)
0.002
10 9
4.03 4.20
3.75 2.92
0.28 1.29
0.93 (0.39–2.19) 0.69 (0.30–1.63)
0.66
2 8 8 1
6.78 2.59 4.03 6.37
1.80 5.14 2.84 5.59
4.98 −2.56 1.20 0.78
0.26 (0.05–1.28) 1.99 (0.60–6.62) 0.70 (0.29–1.72) 0.88 (0.05–14.1)
0.21
9 7 3
5.03 3.69 3.05
3.61 3.30 2.74
1.42 0.40 0.31
0.72 (0.30–1.71) 0.89 (0.33–2.40) 0.90 (0.18–4.46)
0.90
2 10 7
2.91 3.90 5.86
1.38 3.89 4.03
1.52 0.02 1.82
0.48 (0.09–2.46) 1.00 (0.41–2.40) 0.69 (0.26–1.85)
0.76
5 7 1 5
2.75 0.69 0.00 0.34
0.87 1.22 0.17 0.87
1.88 −0.53 −0.17 −0.53
0.32 (0.12–0.86) 1.77 (0.52–6.05) Ne Ne 2.53 (0.49–13.0)
0.034
a
Rate in the placebo group minus rate in the tamoxifen group. Risk ratio (RR) for women in the tamoxifen group relative to women in the placebo group. c Classified by IHC according to 2011 St Gallen criteria [26]. CI, confidence interval; Ne, non-estimable. b
postmenopausal women [4, 5, 8] despite the different indications and age range heavily hampered our recruitment capability. Subgroup analyses showed that tamoxifen exhibited a favorable trend on luminal-A tumors and tumors expressing PgR, which are known to be associated with HRT use [26] and to be highly endocrine responsive [24]. Tamoxifen also showed a lower breast cancer risk in women on HRT <5 years, who had the highest risk among HRT users, consistent with the gap-time effect [10–12], and among ERT-alone users, where the longterm risk of breast cancer incidence and death is decreased, at least with CEE [27]. In contrast, tamoxifen had no effect in the combined HRT subgroup, where the risk of breast cancer incidence and mortality is increased [28, 29].Sensitivity analysis adjusted for nonadherence and restricted to women who took treatment for more than 1 year yielded a 50%, borderline significant reduction of breast cancer by low-dose tamoxifen. All these subgroup analyses have limited power, however, and none were significant at P < 0.01, so the results should be interpreted with caution.
| DeCensi et al.
We found no excess of cardiovascular events and VTE on tamoxifen, in line with the observation that the risk of VTE under tamoxifen is attenuated by concomitant ERT use [30] and in premenopausal women [31]. Also, the rates of serious adverse events seem to be lower with 5 mg/day than with 20 mg/day in a similar population [14], possibly because tamoxifen estrogenicity is attenuated by a lower dose [20]. Although significantly more endometrial polyps were noted on tamoxifen, no increase of endometrial cancer was observed, again suggesting a protective effect of progestins against tamoxifen endometrial effects [18, 32]. However, a clear relationship between endometrial polyps and subsequent endometrial cancer under tamoxifen has not been established [33]. Despite the concomitant use of HRT, low-dose tamoxifen increased the rate of grade 2–3 hot flashes by ∼50% (from 64/ 1000 to 97/1000 per year). An indirect comparison suggests that this rate is lower than that observed with tamoxifen at 20 mg/ day in our prior trial in hysterectomized women (from 67/1000 on placebo to 119/1000 on tamoxifen [14]), but it is still of
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All women 24 Age at entry (years) <50 7 50–54 8 ≥55 9 Duration of HRT De Novo 0 <5 years 21 ≥5 years 3 Route of HRT Oral 11 Transdermal 13 Type of HRTa Estrogen alone 7 Combined continuous 4 Combined sequential 12 Tibolone 1 Time since menopause to HRT 0–1 year 12 2–4 years 9 ≥5 years 3 5-year Gail breast cancer risk (%) <1 5 1–1.49 10 ≥1.5 9 Tumor molecular subtypec Luminal-A 16 Luminal-B 4 HER2+ 0 Triple negative 2
Rate per 1000 women-year Placebo Tamoxifen
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original articles
Figure 2. Cumulative incidence of breast cancer by intention-to-treat (ITT) (A), and after adjustment for adherence (B), efficacy (C) and adherence and efficacy (D). Adherence analysis includes follow-up censored 6 months after last treatment assumption for women who did not complete 80% (4 years) of treatment. Efficacy analysis includes women who completed 12 months of therapy.
concern given the notion that hot flashes are a major reason for dropout in prevention trials [14, 31]. In both the studies, women were on HRT because of menopausal symptoms or early surgical menopause [14], and thus represent a selected
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population with a higher rate of symptoms than the average population treated with tamoxifen. An increase of hot flashes under 20 mg tamoxifen in HRT users has also been reported in the IBIS trial [34]. Because women were not randomly assigned
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Figure 1. Cumulative incidence of breast cancer overall, by PgR-positive tumors and molecular subtypes by allocated arm. Hazards ratio (HR) and 95% confidence intervals (CIs) were obtained from a Cox regression model adjusted for age and center.
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Annals of Oncology
Table 3. Numbers and rates of selected adverse events by the allocated arm RR (95% CI)b
Tamoxifen
Rate per 1000 women Placebo Tamoxifen
Difference
245 147 223 113 134 23 108 24 286 71 89 35 6
305 200 269 181 241 58 129 28 356 93 105 48 27
178.18 63.61 141.68 46.60 52.30 7.43 37.50 7.73 153.52 24.64 36.90 12.18 1.89
317.38 96.76 229.91 83.56 111.42 20.49 47.58 9.53 228.06 35.20 46.44 17.72 8.98
−139.20 −33.15 −88.24 −36.97 −59.12 −13.06 −10.08 −1.80 −74.54 −10.56 −9.54 −5.54 −7.09
1.78 (1.48–2.15) 1.52 (1.22–1.90) 1.62 (1.34–1.97) 1.79 (1.41–2.28) 2.13 (1.71–2.65) 2.76 (1.70–4.48) 1.27 (0.98–1.65) 1.23 (0.71–2.13) 1.49 (1.25–1.76) 1.43 (1.04–1.95) 1.26 (0.94–1.68) 1.45 (0.94–2.26) 4.74 (1.96–11.5)
6 2 2 7 3
4 4 5 18 1
1.89 0.63 0.63 0.63 0.51
1.33 1.33 1.67 3.33 0.17
0.56 −0.70 −1.03 −2.70 0.34
0.70 (0.20–2.50) 2.11 (0.39–11.5) 2.64 (0.51–13.6) 5.27 (1.15–24.1) 0.34 (0.04–3.25)
a
a
Rate in the placebo group minus rate in the tamoxifen group. Risk ratio (RR) for women in the tamoxifen group relative to women in the placebo group. CI = confidence interval. c Among women who were free of symptoms at baseline. d Coronary heart syndrome includes: myocardial infarction (1P/3T), coronary stenting (1P/0T), cardiac arrhythmia (0P/1T), coronary ischemia (4P/0T). e Cerebrovascular events includes four TIA on tamoxifen. f Two endometrial cancers (2P/0T) were diagnosed during treatment, and two (1P/1T) were diagnosed after treatment. b
to HRT, however, we cannot determine the magnitude of the effect of HRT on tamoxifen-induced menopausal symptoms. The 5-year compliance was slightly over 50% in our trial, in line with most breast cancer prevention trials [1, 2, 14, 15, 31]. Yet the high dropout rate remains an important issue that may jeopardize efficacy, as suggested by our sensitivity analyses. Although our study cannot directly apply to different categories such as gene mutation carriers undergoing risk reduction salpingo-oophorectomy, our findings seem to provide safety reassurance on the addition of low-dose tamoxifen to estrogen-alone therapy for menopausal symptom relief in these specific women’s populations where there is a clear unmet medical need [35, 36]. A properly designed clinical trial may be warranted. Our population was mostly composed of recently postmenopausal women undergoing HRT for menopausal symptoms, in contrast to the WHI trials which addressed the preventive effect of HRT in a much older and asymptomatic population. Moreover, only a minority of our participants used oral CEE (8%) and MPA (15%), reflecting the limited prescription of both the drugs in Europe. Admittedly, the lower risk of breast cancer death associated with estrogen therapy alone [27] versus the increased risk in the combined HRT [28, 29] may have contributed to the heterogeneity of our findings. Since subgroup analyses of the WHI trials indicated that estrogen therapy alone has an overall health benefit in women aged <60 years [9, 13], it is possible that the use of most
| DeCensi et al.
recent forms of HRT that avoid the systemic effects of MPA will regain consensus in the treatment of recently postmenopausal women [8]. If this is the case, our results are useful as they provide a clue to reduce breast cancer, the major risk associated with HRT use, in a broad population composed of recently postmenopausal women. Although tamoxifen is currently not available as 5 mg tablet in the market, its prolonged half-life allows for alternative schedules with retained activity, such as 10 mg every other day [37, 38]. Our findings in primary prevention cannot be compared with the HABITS [39] and Stockholm trial [40], which assessed the effect of HRT in breast cancer survivors, some of whom were being treated with tamoxifen as an adjuvant treatment. The Stockholm trial did not show any difference between HRT arms in tamoxifen users (5 versus 4), whereas in the HABITS trial there was a higher risk of recurrence in the HRT arm among tamoxifen users. However, the proportion of tamoxifen users was lower in HABITS (33% versus 52%). Moreover, because tamoxifen use was not randomized, women may have received the anti-estrogen tamoxifen because of their higher risk of recurrence. Our study has several important limitations, including the limited statistical power and the marked heterogeneity of HRT types having different risks of breast cancer. For these reasons, reliable conclusions cannot be drawn. However, our trial suggests that the addition of low-dose tamoxifen to HRT may reduce the risk of breast cancer in recently
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Symptom/Event Hot flashesc (moderate or severe) Night sweatsc (moderate or severe) Vaginal dischargec (moderate or severe) Vaginal bleedingc (moderate or severe) Vaginal dryness, pruritusc (moderate or severe) Dyspareunia c (moderate or severe) Endometrial polyps Serious adverse events Coronary heart syndromed Cerebrovascular eventse VTEs Hysterectomy for benign disorders Endometrial cancersf
No. of events Placebo
Annals of Oncology
postmenopausal women. This hypothesis should be assessed in a larger study.
acknowledgements Tamoxifen and placebo were gifted by FIDIA FarmaceuticiS.p.a, AbanoTerme, Italy. We are grateful to the study participants for their heart and energy.
funding The study was supported by the Italian Foundation for Cancer Research, Avon Italia, LegaItaliana per la Lottacontro i Tumori (LILT project number 51/2005), American Italian Cancer Foundation, ASL Città di Milano, RegionePiemonte.
disclosure
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The authors have declared no conflicts of interest.
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appendix
| DeCensi et al.
Istituto Europeo di Oncologia, Milan: Veronesi Umberto, Bonanni Bernardo, CazzanigaMassimiliamo, Lazzeroni Matteo, Serrano Davide, Varricchio Maria Clara, Feroce Irene, Rotmensz Nicole, Maisonneuve Patrick, Santillo Barbara, Bazolli Barbara, Goldhirsch Aron, Sideri Mario, Di Pace Raffaella, Moroni Simona, Zamperini Paola, Viale Giuseppe, Cassano Enrico, Latronico Antuono, Meneghetti Lorenza, Di Nubila Brunella, Pizzamiglio Maria; Fondazione Pascale, Naples: D’Aiuto Giuseppe, Oliviero Pasquale, Oliviero Giovanna, Riccone Giuseppina; Istituto Nazionale per la Ricerca sul Cancro, Genoa: Gustavino Claudio, Centurioni Maria Grazia, Ferrando Liliana; Ospedale Civile di Leganano, Presidio di Magenta, Magenta: De Maria Enrica; Zandonini Gianfranco; Ospedale S. Gerardo, Monza: Mangioni Costantino, Giussani Maria Elena; Universita degli Studi di Napoli Federico II, Naples: Di Carlo Costantino, Nappi Carmine; Ospedale Niguarda, Milan: Mapelli Carlo; Consultorio Famigliare, Palmi: Infantino Carmelo; Clinica Ostetrica Ginecologica, Parma: Bacchi Modena Alberto, Sgarabotto Maria Paola, Valitutto Simona; Fondazione Salvatore Maugeri, Pavia: Costa Alberto; Scoccia Elisabetta; Policlinico Santa Chiara, Pisa: Genazzani Andrea, Gambacciani Marco, Pepe Antonia, Vacca Francesca; Azienda Ospedaliera Santa Maria degli Angeli, Pordenone: Monti Nadia, Tumolo Salvatore; Ospedale Maggiore, Parma: Cascinu Stefano, Michiara Maria; Ospedale Infermi, Rimini: Ravaioli Alberto, Desiderio Franco, Fabbri Carla, Pini Emanuela; ASL Roma H, Albano Laziale: Vella Alessandro, Fabi Linda Maria, Corrado Nunziata; Policlinico Umberto I, Rome: Bastianelli Carlo, Rapiti Stefania, Colafrancesco Francesca; Ospedale Luigi Sacco, Milan: Ferrazzi Enrico, Bombelli Maria Vittoria, Ciminera Nadia, Cetin Irene; Ospedale San Carlo Borromeo, Milan: Quaranta Stefano; Ospedale San Giuliano, Giugliano: Incoronato Pasquale; Policlinico Le Scotte, Siena: Gioffré Walter, Tripodi Alessia; Ospedale Az.San. 6, Soveria Mannelli: Vescio Filippo; Ospedale S.S. Antonio e Margherita, Tortona: Pacquola Maria Grazia; Policlinico Tor Vergata, Rome: Piccione Emilio, Pietropolli Adalgisa; Ospedale Valduce, Como: Belloni Carlo, Piol Francesca; Ospedale Civile, Vasto: Sangiorgi Barbara; Ospedale San Luca, Vallo di Lucania: Masullo Pietro, Di Feo Gemma, Speranza Mariangela, Ronsini Salvatore; ASL Milano, Milan: Bisanti Luigi. Data safety and Monitoring Committee: Giuseppe Benagiano (Chairman, Rome, Italy), Aron Goldhirsch (Lugano, CH), Chris Robertson (Glasgow, UK).
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Steering committee: Veronesi Umberto (studychair), DeCensi Andrea (Principal Investigator), Bonanni Bernardo, Maisonneuve Patrick, Omodei Umberto, Rotmensz Nicole, Sideri Mario and Bisanti Luigi. The HOT Study Group also includes the following physicians and scientists who contributed to this trial: Istituto Oncologico, Bari: Schitulli Francesco, DeLiso Maria; Spedali Civili di Brescia, Brescia: Omodei Umberto, Ramazzotto Francesca, Corini Silvia, Pecorelli Sergio, Daldos Cristina; Ospedale San Giovanni di Dio, Cagliari: Melis Gianbenedetto, Pilloni Monica; Ospedale B. Ramazzini, Carpi: Artioli Fabrizio, Guerzoni Roberta; Azienda Ospedaliera Vittorio Emanuele, Catania: Sciacchitano Salvatore, Grasso Daniela; Ospedale Città di Castello, Citta’ di Castello: Torrioli Donatello, Bravi Stefano; Presidio Ospedaliero di Cerignola, Cerignola: Corrado Gemma; Ospedale Mariano Santo, Cosenza: BiamonteRosalbino; Centro di Riferimento per l’Epidemiologia e la Prevenzione Oncologica - Piemonte, Turin: Segnan Nereo, Ponti Antonio, Marti Elvira, Gonzales Galina; Ospedale S. Anna, Turin: Campagnoli Carlo, Massobrio Marco, Ambrogio Simona, Gallo Mario; Ospedale Mauriziano, Turin: Sismondi Piero, Biglia Nicoletta, Utcic E.; Istituti Ospitalieri, Cremona: Bottini Alberto, Allevi Giovanni, Andreis Daniele; Istituto per lo Studio e la Prevenzione Oncologica, Florence: Rosselli del Turco Marco, MuracaMariaGrazia, Zeccarelli Maurizia, Iossa Anna, Brancato Beniamino; Gino, Belluardo Donatella; Ospedale San Martino, Genoa: Valenzano Mario, Bogliolo Stefano, Fortunato Tiziana; Ospedale San Paolo, Milan e successivamente al 2004 Istituto Ostetrico ginecologico L. Mangiagalli: Pardi Giorgio, Ferrari Maria, Waldis Francesca;
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