Chemioprevenzione una nuova modalità di trattamento delle neoplasie prima della loro insorgenza Paolo Marchetti Oncologia Medica Università di L’Aquila CANCER CHEMOPREVENTION A New Way to Treat Cancer Before It Happens • Use of natural and/or synthetic compounds to prevent, inhibit or reverse carcinogenesis before the clinical event • Lessonfrom cardiology: drugs to correct risk factors have reduced mortality • The disease is carcinogenesis (a process) rather than cancer (an event) Neoplasia: Process vs Event • The recognition that carcinogenesis, not clinically evident cancer alone, is the disease of interest provides a compelling impetus – for more sensitive measures of risk in asymptomatic populations, – for identification and development of chemopreventive agents, and – for more accurate and reliable tests of preventive efficacy. • These elements can be combined to generate prevention trials that are more effective, efficient, and predictive of meaningful benefit. The target of the hormonal therapy Aromatase Activity Heart Breast Muscle Estradiol Adipose Liver Bone Ovaries Uterus Mechanisms of Action of Hormonal Therapies • Block oestrogen action – tamoxifen, other SERMs • Block oestrogen synthesis – ovarian ablation (premenopausal) – inhibition or inactivation of aromatase (postmenopausal) • Other mechanisms? – progestins – androgens – oestrogens Selective Estrogen Receptor Modulators (SERMs) – Estradiol Pure agonist – Tamoxifen – Toremiphene Mixed agonist/antagonist – Droloxifene – Idoxifene – Raloxifene – Faslodex (ICI 182,780) Pure antagonist Breast Cancer Initiation and Promotion NUMBER OF CELLS INITIATION PROMOTION PREINVASIVE INVASIVE DCIS ADH EH LIMIT OF CLINICAL HOST DETECTION DEATH Modified from Cavalieri et al., AACR 2002 Relative Risk of Breast Cancer in 238 Postmenopausal Women According to Serum Estradiol Concentration Reprinted from Clemons and Goss. N Engl J Med. 2001;344:276-285 Data from Thomas et al. Br J Cancer. 1997;76:401-405 ISSUES IN CANCER CHEMOPREVENTION • at-risk cohorts • surrogate biomarkers • effective agents AT-RISK SUBJECTS • Genetic (BRCA1 and 2, BRCA…?, p53) • Pre-invasive breast lesions (DCIS, LCIS, AH) • Previous breast cancer • Gail Model Breast Cancer Initiation and Promotion NUMBER OF CELLS INITIATION PROMOTION INVASIVE PREINVASIVE DCIS ADH EH LIMIT OF CLINICAL HOST DETECTION DEATH Modified from Cavalieri et al., AACR 2002 Breast Cancer Initiation and Promotion Pre-invasive breast lesions (DCIS, LCIS, AH)? Gene expression profiles of human breast cancer progression • One surprising result from this study was the remarkable similarity in the expression profiles of the distinct pathological stages. Xiao-Jun Ma et al., PNAS, 2003 Pre-invasive breast lesions (DCIS, LCIS, AH)? Gene expression profiles of human breast cancer progression • As compared with patient-matched normal epithelium, significant global alterations in gene expression occur at ADH, the earliest phenotypically recognized stage of progression, and such alterations are maintained in the later stages of DCIS and IDC. Xiao-Jun Ma et al., PNAS, 2003 NUMBER Breast Cancer Initiation and OF CELLS INITIATION Promotion PROMOTION INVASIVE PREINVASIVE DCIS ADH EH Xiao-Jun Ma et al., PNAS, 2003 LIMIT OF CLINICAL HOST DETECTION DEATH Modified from Cavalieri et al., AACR 2002 Breast cancer risk prediction Gail model • Age at menarche • Age at first live birth • Breast biopsies • Presence of atypical hyperplasia • Familial BC (mother/sisters) SURROGATE ENDPOINT BIOMARKERS • Precancerous lesions (LCIS,AH) • Cytological atypia • Circulating IGF-I • Mx density Plasma IGF- I and breast cancer risk Cases/controls: 397 breast cancers /620 age-matched controls Time from blood collection to diagnosis: 28 months (range 1-57) • All, top vs bottom quintile of IGF-I: RR=0.99 (0.65-1.50) • Postmenopause, t vs b quintile: RR=0.85 (0.53-1.39) • Premenopause, t vs b tertile: RR=2.88* (1.21-6.85) • Premenopause <50 yrs, t vs b tertile: RR=7.28* (2.40-22.0) *adjusted for IGFBP-3 Hankinson SE et al, Lancet 1998 Effect of % mammographic density on breast cancer risk in prospective studies Author N. N. % Adjusted 95% CI cases control density OR Saftlas 1991 67 58 45-65 3.8 2.1-3.6 45 33 >65 4.3 2.1-8.8 Boyd 1995 66 31 >75 6.1 2.8-13 Byrne 1995 194 136 >75 4.4 3.1-6.1 576 554 50-74 2.8 2.1-3.6 Kato 1995 37 99 (pre) >66 3.6 1.7-7.9 48 81 (post) >66 2.1 1.1-3.8 SERMs in Breast Cancer Prevention: Proven Efficacy Trial Outcome NSABP B-14 Contralateral cancers NSABP P1 invasive/preinvasive breast cancer Royal Marsden No in risk Italian Study Risk in HRT users only MORE Study Invasive cancers IBIS 1 invasive/preinvasive breast cancer STAR Ongoing IBIS 2 Ongoing Chemoprevention trials N. pts Reduction Reference BC (%) NSABP-P1 13,388 49 Fisher, JNCI’98 ER+ 69 ER- NS RMH 2,471 NS Powles, Lancet’98 ITPT 5,408 NS Veronesi, Lancet’98 Breast cancer incidence Surveillance and Chemoprevention Selection Surveillance TMX Criteria (BC/100/y) (BC/100/y) NSABP-P1 Gail 0.46 0.23 Fisher, JNCI’98 F+ 0.48 0.25 F+ >3BC 0.64 0.35 RMH Claus 0.48 0.46 Powles, Lancet’98 FCC BRCA1+ 3.3 ? Brekelmans, JCO’01 Rotterdam DISCREPANCY OF RESULTS • Compliance (26% women dropped out in ITPT). • Study population. • Duration of follow-up (average follow-up for NSABP-P1 was only 3.5 years compared with the median of nearly 6 years. • Duration of tamoxifen treatment. Controversial results of published prevention studies. • The two trials give insights concerning the rate of BC incidence in women selected according to epidemiological risk and familial risk, respectively, and it is equivalent in the placebo arms (0.46 and 0.48/100 women/y, respectively); • Apparently, TAM shows beneficial effects in women selected mostly according to epidemiological criteria of risk than according to familial risk (0.23 and 0.46 /100 women/y, respectively); • In the NSABP-P1 trial, mostly characterized by postmenopausal women, the advantage of the TAM is significant also in the subset of selected women showing familial risk of BC (0.48 vs 0.25 BCs/ 100 women/y in placebo and TAM arm, respectively); Controversial results of published prevention studies (ii). • The TAM effect is clear also in the cohort with more consistent risk (>3 familial BCs) of genetic predisposition (0.64 vs 0.35 BCs/ 100 women/y in placebo and TAM arm, respectively). • The preliminary evaluation of the BRCA1/2 status of the 70 incidental BCs in RMH trial showed 7 BRCA1/2 mutations only (10%) in this very high-risk group due to FH+ and the occurrence of BC (Powles, 2nd European Breast Cancer Conference, Bruxelles’00). NSABP-P1 Adverse effects of TMX • Endometrial cancer (RR 2.5) • Thromboembolic events pulmonary embolus deep vein thrombosis cerebral vascular accident IBIS 1: Number of Breast Cancers and Characteristics by Treatment Allocation Discrepancies between P1 and IBIS 1 • The compliance rate in P-1 was 76% compared with 64% in IBIS-1. • The median follow-up in IBIS-1 was shorter (50 vs 55 months) and a smaller proportion of patients (25% vs 37%) reached the 5-year treatment threshold, creating a narrower window for observed effect. • Whereas P-1 excluded women who were treated with hormone replacement therapy (HRT) within 3 months of the study, in IBIS-1, 40% of participants received HRT during the course of the trial. Samuel Cykert, Lancet 2004 IBIS 1: a comment. • Tamoxifen for breast-cancer prevention is a limited intervention that requires thoughtful decision-making. However, because of methodological and follow-up constraints, the benefits of this approach are probably underestimated and harms exaggerated in this report. Samuel Cykert, Lancet 2004 SERMs in Breast Cancer Prevention: Proven Efficacy Overview of the four tamoxifen breast cancer prevention trials (Lancet, 2003) • The combined data showed a 38% reduction in breast cancer incidence (95% CI 28–46%, P=0.001). • There was an increase in endometrial cancer events (Relative Risk (RR) 2.4, CI 1.5–4.0) and thromboembolic events (RR 1.9, CI 1.4–2.6), but not in cardiovascular events. • Overall, there was no significant effect on mortality (RR 0.91, CI 0.70–1.18). • The data, together with the data from the Oxford metanalysis, indicate that it is very unlikely that mortality is increased by tamoxifen. Low-dose tamoxifen and fenretinide Placebo + Placebo Premenopausal women DCIS, LCIS TAM 5mg + P R 2y Gail > 1.3% in 5 yrs 4-HPR 200mg + P TAM + 4-HPR I endpoint: IGFs and Mx density II endpoint: endometrial and ovarian effects breast FNA (image analysis) Sample size: 300 subjects The HOT (Hormone Replacement Therapy and Tamoxifen) Study HRT users Placebo/day R (de novo or Tamoxifen 5 mg/day current users) Sample size: 8500 subjects (4250 per arm) Endpoint: Breast cancer incidence (IBC and DCIS) Breast Cancer Prevention Trials: Unanswered Questions. • Type of preventive treatment • Durability of the preventive effect • Influence on mortality • Subsets who benefit from treatment • Interaction with HRT • Preventive effect in BRCA1/2 carriers Randomized phase III studies of anti-Aromatase Agents vs Tamoxifen as Initial Therapy of Metastatic Breast Cancer Anastrozole Anastrozole Letrozole Exemestane Patients, N 170 vs 182 340 vs 328 453 vs 454 182 vs 189 OR, % 21 vs 17 33 vs 33 30 vs 20* 46 vs 31* Clin. Benefit, % 59 vs 46* 56 vs 56 49 vs 38* 66 vs 49* Med. PFS, mo 11 vs 6* 8 vs 8 9 vs 6* 10 vs 6* ER unknown, % 11 vs 11 56 vs 54 34 vs 33 15 vs 11 Significantly different from Tamoxifen (*) Nabholtz et al. J Clin Oncol. 2000;18:3758-3767; Bonneterre et al. J Clin Oncol. 2000;18:3748-3757; Mouridsen et al. J Clin Oncol. 2001;19:2596-2606; Mouridsen et al. Breast Cancer Res Treat. 2001;69:211, abst 9; From EORTC 10951, ASCO 2004 Adjuvant Therapy Trials: What They’ll Tell Us About Anti-Aromatase Agents • Efficacy in the adjuvant setting • Long-term tolerability – adverse events – bone and lipid metabolism – quality of life – menopausal function • Efficacy in prevention of contralateral breast cancer Estimated reduction in contralateral breast cancer in the ATAC trial Women per year of follow- up in each treatment group 8.600 women\year = 3.100 x 2.8 Expected incidence of contralateral tumors in women surgically treated for 7/1000 women\year breast cancer in the absence of TAM Extimated number of contralateral tumors 61 in 2.8 years of follow- up 33 Tumors observed with Reduction of Tamoxifen 46% 14 Tumors observed with anastrozole Reduction of 77% FINAL RESULTS OF A RANDOMIZED PHASE III TRIAL COMPARING EXEMESTANE WITH TAMOXIFEN AS FIRST-LINE HORMONE THERAPY FOR POSTMENOPAUSAL WOMEN WITH METASTATIC BREAST CANCER EORTC 10951 CONDUCTED BY THE EORTC BREAST GROUP in collaboration with THE EXEMESTANE WORKING GROUP AND THE NCIC CLINICAL TRIALS GROUP ASCO - New Orleans - june 5-8, 2004 PFS by Treatment Arm 100 90 80 70 Primary test: Logrank p=0.121 60 Sensitivity test: Wilcoxon p=0.028 50 HR 0.84 95% CI (0.67, 1.05) 40 30 20 10 0 (years) 0 1 2 3 4 5 6 7 O N Number of patients at risk : Treatment 161 189 56 17 6 2 0 0 Tamoxifen 158 182 75 25 9 2 1 1 Exemestane EORTC 10951 - PFS estimates EXE TAM 182 patients 189 patients 158 events (87%) 161 events (85%) Median PFS (months) 9.9 5.8 (95% CI) (8.7 - 11.8) (5.3 - 8.1) % PFS at 6 months 66% 49% (95% CI) (59% - 73%) (42% - 57%) % PFS at 12 months 42% 31% (95% CI) (35% - 49%) (24% - 38%) Considerations in the Selection of an Anti- Aromatase Agent for Long-Term Therapy • Efficacy – there are no published direct comparisons of anti-aromatase agents, but trials are ongoing – there is no evidence, to date, that one anti- aromatase agent is superior to another in efficacy • Tolerability –? Anti-aromatase Agents: They Are Not All the Same • Different estrogen-suppression potencies? • Enzyme inactivation vs inhibition? • Different effects or PK profile on tumour aromatase? • Additional action though androgen receptor? Working Mechanism of Action for Anti-aromatase Agents Type I inactivators (steroidal) (target the substrate-binding site, formestane, exemestane) Androgen Oestrogen Cytochrome P450 Aromatase molecule Type II inhibitors (nonsteroidal) (target the NADP+ cytochrome P450 ‘aromatase’, NADPH aminoglutetimide, fadrozole, anastrozole, letrozole) From Textbook of Breast Cancer. A Clinical Guide to Therapy London, England. Martin Dunitz Ltd; 1997:281–304 Bone Effects of Antiaromatase Agents: Summary Biomarker Biomarker of Bone of Bone Formation Resorption BMD Fractures Nonsteroidal Agents Anastozole1,2 Letrozole3,4 / NA NA Steroidal Agent Exemestane5 / / NA NA Bisphosphonates6 1. ATAC Trialists Group, Lancet 2002. Vol 259; 2131-39; 2. Eastell et al. Annals of Oncology, 2002. 13 (Suppl. 5): page 32, Abs 113PD; 3. Harper-Wynne et al. Breast Cancer Res Treat. 2001;69:225, #136; 4. Heshmati et al. J Bone Mineral Res. 2002; 17: 172-178; 5. Goss et al. Breast Cancer Res Treat. 2002 vol. 76, sup 1, S76, Abs 267 (updated); 6. Johnell et al. J Clin Endocrinol Metab 2002 Mar;87(3):985-92 Effects of steroidal and nonsteroidal aromatase inhibitors (AIs) on markers of bone turnover and lipid metabolism in healthy volunteers. M. Subar, P. E. Goss, T. Thomsen, J. Banke-Bochita. AI Effects on Estrogens Estradiol Median with 1st and 3rd Quartiles •There were no significant differences noted in baseline estrogens among the 4 study arms. 8.00 7.00 •All 3 AIs effectively suppressed serum estrone. 6.00 5.00 •All 3 AIs effectively suppressed serum estradiol. 4.00 Baseline Week 24 3.00 2.00 Estrone 1.00 Median with 1st and 3rd Quartiles 0.00 Anastrozole Exemestane Letrozole Placebo 45.00 Treatment 40.00 35.00 30.00 Baseline 25.00 Week 24 20.00 15.00 10.00 5.00 0.00 Anastrozole Exemestane Letrozole Placebo Treatment Effects of steroidal and nonsteroidal aromatase inhibitors (AIs) on markers of bone turnover and lipid metabolism in healthy volunteers. M. Subar, P. E. Goss, T. Thomsen, J. Banke-Bochita. Bone Resorption Marker: Baseline-Adjusted AUC- Baseline to Week 24 Serum CTX-I (Median with 95% CI) 3.00 2.50 2.00 1.50 1.00 0.50 0.00 -0.50 -1.00 Anastrozole Exemestane Letrozole Placebo Treatment *p = 0.070 Samples obtained at multiple time points and *Difference across active treatment groups area under the curve (AUC) was calculated using a published method. Effects of steroidal and nonsteroidal aromatase inhibitors (AIs) on markers of bone turnover and lipid metabolism in healthy volunteers. M. Subar, P. E. Goss, T. Thomsen, J. Banke-Bochita. Bone Resorption Marker: Baseline-Adjusted AUC- Baseline to Week 24 Serum CTX-I (Median with 95% CI) 3.00 2.50 2.00 1.50 1.00 0.50 0.00 Bone Formation Marker Baseline-Adjusted AUC- -0.50 Baseline to Week 24 Serum PINP (Median with 95% CI) -1.00 350.00 Anastrozole Exemestane Letrozole Placebo 300.00 Treatment 250.00 200.00 *p = 0.070 Samples obtained at multiple time points and area under the curve (AUC) was calculated 150.00 *Difference across active treatment groups using a published method. 100.00 50.00 0.00 -50.00 -100.00 -150.00 Anastrozole Exemestane Letrozole Placebo Treatment *p = 0.003 Samples obtained at multiple time points and area under the curve (AUC) was calculated *Difference across active treatment groups using a published method. Antiaromatase agents. Lipids Exemestane (n = 76, not all evaluable) – TG – TC/HDL risk ratio unchanged – HDL stable – ApoA1/ApoB risk ratio unchanged – TC stable Data from ATAC trial (Anastrozole arm 3092 patients) demostrate a higher incidence of hypercholesterolemia in women treated with anastrozole vs tamoxifen (7% vs 3%) Letrozole (n = 20) – TC – HDL – LDL – TC/ HDL risk ratio – Apo B – LDL/HDL risk ratio – Apo A1 – ApoA1/ApoB risk ratio TG = triglycerides; TC = total cholesterol; HDL = high=density lipoprotein; LDL = low-density lipoprotein. Lohrisch et al. Proc Am Soc Clin Oncol. 2001;20:83a. Abs 167; Arimidex (anastrozole) vs Product Information. Wilmington DE: Astra Zeneca Spt. 2002; Elisaf et al. Eur J Cancer. 2001;37:1510-1513. Clinical implications of familial breast cancer screening The problem. • Women carrying BRCA1/2 mutations have a lifetime risk of BC of 56 and 80%, respectively (Easton et , Am J H Gen’95; Ford et al, Am J Hum Gen ’98; Struewing et al, NEJM ’97). • Both genes also confer an increased risk of ovarian cancer: 60% for BRCA1 and 27% for BRCA2 by the age of 80 years, respectively. • Furthermore, it is now clear that both genes also confer an increased risk to develop different other cancer, equating to an absolute risk of 6-14% (Ford, Lancet ’94; Breast cancer Linkage Consortium, JNCI ’99). BRCA1/2 Breast Cancer Risk 1 0,9 0,8 0,7 Cumulative Risk 0,6 BRCA1 0,5 BRCA2 0,4 0,3 0,2 0,1 0 30 40 50 60 70 Age Eeles and Powles, JCO Vol 18, 2000: pp93s-99s BRCA1/2 Ovarian Cancer Risk 1 0,9 0,8 0,7 Cumulative Risk 0,6 BRCA1 0,5 BRCA2 0,4 0,3 0,2 0,1 0 30 40 50 60 70 Age Eeles and Powles, JCO Vol 18, 2000: pp93s-99s BRCA1/2 carriers Prevention strategies and risk reduction • Surveillance • Prophylactic Surgery – Hartmann et al., NEJM, 1999: • bPM 90% risk reduction. – Meijers-Heijboer et al., NEJM, 2001: • in pts with BRCA1/2 mutations: – surveillance alone 8 BC/63 – bPM 0 BC/76 – Rebbeck et al., JNCI, 1999: PO 53% risk reduction. • Breast Cancer Prevention SECONDARY PREVENTION • Although there were no significant differences between women with BRCA-associated breast cancer and those with non- BRCA-associated cancers in – 5-year relapse-free survival (65% versus 69%, P = NS), – 5-year event-free survival (57% versus 68%, P = NS), – 5-year overall survival, • women with germline BRCA mutations were significantly more likely to develop contralateral breast cancer at 5 years (31% versus 4%, P = 0.0007). Robson et al, JCO 1998. SECONDARY PREVENTION • Breast cancer survivors who carry BRCA mutations remain at risk for second primary malignancies because of inherited susceptibility. – What is the optimal clinical management for a young woman with a strong family history and a new diagnosis of unilateral breast cancer? – Is breast conservation therapy an option? – Is OOX necessary? – What are the risks for secondary cancers? BRCA1/2 carriers Prevention strategies and risk reduction • Surveillance • Prophylactic Surgery – Hartmann et al., NEJM, 1999: • bPM 90% risk reduction. – Meijers-Heijboer et al., NEJM, 2001: • in pts with BRCA1/2 mutations: – surveillance alone 8 BC/63 – bPM 0 BC/76 – Rebbeck et al., JCO, 2004: • BPM reduces the risk of BC in women with BRCA1/2 mutations by approximately 90%. – Rebbeck et al., JNCI, 1999: PO 53% risk reduction. • Breast Cancer Prevention Time to breast cancer diagnosis in female BRCA1 mutation carriers with and without bilateral prophylactic mastectomy (BPM). • Kaplan-Meier analysis of breast cancer events by postsurgery follow-up time in cases compared with controls. (Rebbeck et al., JCO, 2004) Bilateral prophylactic mastectomy • We cannot make strong inferences about optimal type and timing of surgery or about risk factors that may influence post-bilateral prophylactic mastectomy breast cancers. Bilateral prophylactic mastectomy • Subcutaneous bilateral prophylactic mastectomy leaves substantial residual breast tissue intact, including the nipple-areolar complex and, therefore, is not optimal for a prophylactic procedure. • Total mastectomy requires more extensive reconstruction and may result in an inferior cosmetic result, but it removes substantially more breast tissue. • However, the recently developed skin-sparing mastectomy with immediate reconstruction combines adequate tissue removal with excellent Bilateral prophylactic mastectomy • Regardless of the selected procedure, care should be taken to remove as much breast tissue as possible to maximize risk reduction. • There are surgical and anesthetic risks that should be considered when offering prophylactic surgery to a healthy individual. Bilateral prophylactic mastectomy: risks • In a recent series of 112 high-risk women (79 with a BRCA1/2 mutation) who underwent prophylactic mastectomy (103 with immediate reconstruction), 21% had complications, including hematoma, infection, contracture, or implant rupture. • Use of autologous tissue, such as with transverse rectus abdominis musculocutaneous (TRAM) or latissimus dorsi reconstruction, may eliminate the need for silicone implants, but complication rates may be even higher. • In one series of 147 breast cancer patients with TRAM reconstruction after mastectomy, follow-up operations were necessary in 71% of patients, including intervention for complications such as abdominal hernia, full or partial TRAM ischemic loss, and fat necrosis. BRCA1/2 carriers Prevention strategies and risk reduction • Surveillance • Prophylactic Surgery – Hartmann et al., NEJM, 1999: • bPM 90% risk reduction. – Meijers-Heijboer et al., NEJM, 2001: • in pts with BRCA1/2 mutations: – surveillance alone 8 BC/63 – bPM 0 BC/76 – Rebbeck et al., JNCI, 1999: PO 53% risk reduction. • Breast Cancer Prevention Hormonal Preventive Effect in BRCA1/2 Carriers • Early reports suggested that there is a loss of ER and PgR in tumors with BRCA1 mutations, whereas tumors with BRCA2 mutations are often ER positive1. • The critical question is whether breast cancer prevention, specifically hormone-therapy, would also reduce incidence of invasive BC among cancer-free women with inherited BRCA1 or BRCA2 mutations. 1Johannsson et al., Eur J Cancer 33: 362-371; 1997 Study participants who developed BC in 288 genotyped cases (NSABP-P1, JAMA, Nov 14, 2001) Placebo TAM Risk Ratio (95% C.I.) 1.67 BRCA1 mut. 3 5 (0.32-10.70) 0.38 BRCA2 mut. 8 3 (0.06-1.56) 0.48 BRCA WT 182 87 (0.37-0.61) All 0.52 211 109 participants* (0.41-0.65) Includes 288 genotyped cases and 32 cases without DNA available ER status of tumors (NSABP-P1, JAMA, Nov 14, 2001) ER positive ER negative Placebo Tamoxifen Placebo Tamoxifen BRCA1 mut 0 1 3 3 BRCA2 mut 4 2 2 1 BRCA wt 132 41 32 36 ER status unknown for 1 BRCA1 tumor, 2 BRCA2 tumors, and 28 wild-type tumors. Preventive effect in BRCA1/2 carriers • In BC treatment oophorectomy, tamoxifen, or anti- aromatase agents are effective. • If oophorectomy, performed before 35 years, is effective in reducing BC incidence among women with BRCA1 mutations (Rebbeck et al., JNCI, 1999), then TAM or anti-aromatase agents might be effective in cancer-free women with BRCA1 mutations. • It is possible that early in the course of BRCA1 tumors, hormone-therapy might still have a role to play. Chemopreventive trials in BRCA mutated carriers. • Which treatment? – Tamoxifen. – LH-RH agonists & aromatase inhibitors (premenopausal women). – Aromatase inhibitors (postmenopausal women). Treatment • Substantial evidence support the concept that oestrogens contribute to cause BC by stimulating proliferation of breast cells. • Either high oestrogen levels or enhanced aromatase activity associate with increased susceptibility to BC. • The rationale of the BC preventive treatment with SERMs is to antagonize estrogen receptor activity, thus inhibiting the proliferative hormonal stimula. Treatment (ii) • In presence of a mutation of an oncosuppressor gene, as BRCA 1 or 2, is the ER activation, even if partial, safe? • It seems reasonable to prevent the estrogen production with aromatase inhibitors than antagonize estrogen effect. Exemestane: Rationale for Use in BC Prevention • Exemestane inhibits in situ aromatase by more than 95%. • It also reduces endogenous oestrogen concentrations in BC. The treatment with irreversible aromatase inhibitors has been demonstrated to completely abrogate estrogen production, at the level of mammary gland. • Suppressing local estrogen production may be important, as suggested by the discovery of a unique transcriptional promoter of aromatase gene expression in breast adipose tissue. Exemestane: Rationale for Use in BC Prevention • Preventive effect in preclinical models • Decreased levels of aromatase enzyme (instead of the increase observed after non-steroidal anti-aromatase agents) • Activity in advanced breast cancer • Improved tolerability vs TAM • No negative effects on lipids • Preclinical and clinical favourable bone data ApreS (Aromasin® Prevention Study) • Double-Blind, Placebo-Controlled Study of Exemestane for the Prevention of Breast Cancer in Postmenopausal Unaffected Carriers of BRCA1/2 Mutations • Participating Italian Institutions (partial list): – Italian Consortium HB/OC (G. Bevilacqua) – Cooperative group for the identification of families at BC risk in Italy (V. Silingardi, S. Venuta) – IRE Rome (F. Cognetti, M. Lopez, E. Terzoli), University of Napoli (A.R. Bianco, S. De Placido, A. Contegiacomo), University of Modena (M. Federico), University of L’Aquila (C. Ficorella, P. Marchetti), University of Chieti (S. Iacobelli, R. Mariani Costantini), University of Padova (Chieco Bianchi, E. D'Andrea, Monfardini), University of Messina (M. Mesiti), University of Ancona (R. Cellerino, A. Piga), University of Torino (P. Sismondi), Catholic University, Roma (G. Scambia, D. Terribile), Medical Oncology, Terni (F. Di Costanzo). – Participation of 4 more European cooperative groups is pending. ApreS Primary End-Point The efficacy of the irreversible aromatase inhibitor exemestane in preventing breast cancer by significantly reducing the incidence rate of invasive breast cancer in unaffected postmenopausal women carriers of BRCA1/BRCA2 inactivation.
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