Nuove strategie nella chemioprevenzione e nella terapia ormonale del carcinoma mammario

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Claribel Bailey
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1 University of L Aquila Nuove strategie nella chemioprevenzione e nella terapia ormonale del carcinoma mammario Paolo Marchetti

2 Issues of chemoprevention A New Way to Treat Cancer Before It Happens Prevention: Process vs Event The recognition that carcinogenesis (a( a process), not clinically evident cancer (an( event), 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.

3 The target of the hormonal therapy Aromatase Activity Breast Heart Muscle Liver Estradiol Adipose Bone Ovaries Uterus Effect of % mammographic density on breast cancer risk in prospective studies Author N. N. % Adjusted cases control density OR 95% CI Saftlas > Boyd > Reprinted from Clemons and Goss. N Engl J Med. 2001;344: Data from Thomas et al. Br J Cancer. 1997;76: Byrne > Kato (pre( pre) > (post) >

4 Breast Cancer Initiation and Promotion NUMBER OF CELLS INITIATION PROMOTION PREINVASIVE INVASIVE Xiao-Jun Ma et al., PNAS, 2003 DCIS EH ADH Modified from Cavalieri et al., AACR 2002 LIMIT OF CLINICAL DETECTION HOST DEATH

5 Chemoprevention in the 21st Century Selective estrogen receptor modulators (SERMs), to prevent multiple diseases in women. Aromatase inhibitors, to reduce the risk of breast cancer by removing all estrogen. V. C. Jordan, JCO, 2005

6 Trials in Breast Cancer Prevention Trial NSABP B-14 NSABP P1 Royal Marsden Italian Study MORE Study IBIS 1 CORE Study STAR IBIS 2 MP3 Outcome Contralateral cancers invasive/preinvasive breast cancer (TAM vs PL) No in risk (TAM vs PL) Risk in HRT users only (TAM vs Placebo) Invasive cancers (RAL vs Placebo) invasive/preinvasive breast cancer (TAM vs PL) Invasive cancers (RAL vs Placebo) Closed (TAM vs RAL) Ongoing (ANA vs Placebo) Ongoing (EXE + CELECOXIB vs Placebo)

7 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 ) and thromboembolic events (RR 1.9, CI ), but not in cardiovascular events. Overall, there was no significant effect on mortality (RR 0.91, CI ). The data, together with the data from the Oxford metanalysis,, indicate that it is very unlikely that mortality is increased by tamoxifen..

8 DISCREPANCY OF RESULTS Compliance (26% women dropped out in ITPT). Study population. Duration of follow-up (average follow-up for NSABP-P1 P1 was only 3.5 years compared with the median of nearly 6 years. Duration of tamoxifen treatment.

9 The use of tamoxifen for risk reduction is limited! Out of 43 potential risk eligible women, only two (4.7%) accepted to start TAM treatment (Port( et al., Ann Surg Oncol,, 2001). Out of 137 women offered preventive tamoxifen therapy, only 57 (42%) accepted TAM treatment (Tchou( et al., Cancer,, 2004). Fear of both major and minor side effects and uncertainty over who will benefit often make tamoxifen unattractive to healthy women.

10 Trials in Breast Cancer Prevention Trial NSABP B-14 NSABP P1 Royal Marsden Italian Study MORE Study IBIS 1 CORE Study STAR IBIS 2 MP3 Outcome Contralateral cancers invasive/preinvasive breast cancer (TAM vs PL) No in risk (TAM vs PL) Risk in HRT users only (TAM vs Placebo) Invasive cancers (RAL vs Placebo) invasive/preinvasive breast cancer (TAM vs PL) Invasive cancers (RAL vs Placebo) Closed (TAM vs RAL) Ongoing (ANA vs Placebo) Ongoing (EXE + CELECOXIB vs Placebo)

11 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

12 BRCA1/2 carriers Prevention strategies and risk reduction Surveillance Prophylactic Surgery in BRCA1/2 mut.. carriers Hartmann et al., NEJM, 1999: bpm 90% risk reduction. Meijers-Heijboer et al., NEJM, 2001 & JCO, 2003: surveillance alone 8 BC/63 bpm 0 BC/76 PROSE Study Group, Rebbeck et al., JCO 2004 bpm 90% risk reduction. Rebbeck et al., JNCI, 1999: PO 53% risk reduction. Breast Cancer Prevention

13 Adjuvant Therapy Trials: What They ll Tell Us About TAM? Five years of Tamoxifen in HR+ Early Breast Cancer Effective for treating breast cancer 41% reduction in risk of recurrence 32% reduction in risk of death 40% reduction in risk of secondary breast cancer 45% reduction in risk of BC in primary prevention The effect is largely independent of nodal status, age, or prior chemotherapy Limitation Endometrial cancer, VTE s,, side effects (hot flushes, ), efficacy in subgroups of pts (HER2 pos? ER+ PgR-?)

14 Adjuvant Therapy Trials: What They ll Tell Us About Anti-Aromatase 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

15 Phase III Randomized Adjuvant Trials Comparing Third- Generation Aromatase Inhibitors to Tamoxifen or Placebo Trial ATAC MA17 ITA IES ARNO 95 ABCSG 8 Design T vs A (vs T+A) in newly diagnosed patients Letrozole vs placebo in patients after 5 years of tamoxifen T vs A in patients after 2 to 3 years of tamoxifen T vs E in patients after 2 to 3 years of tamoxifen T vs A in patients after 2 years of tamoxifen N 6,241(+3,125) 5, ,742 3,123 Jakesz R. Presentation. SABCS 2004; Winer EP et al. J Clin Oncol 2005;23(3):

$8 Expected incidence of contralateral tumors in women surgically treated for breast cancer in the absence of TAM 8.600 women\year 7/1000 women\year Extimated number of contralateral tumors in 2.$

16 Estimated reduction in contralateral breast cancer in the ATAC trial Women per year of follow-up in each treatment group = x 2.8 Expected incidence of contralateral tumors in women surgically treated for breast cancer in the absence of TAM women\year 7/1000 women\year Extimated number of contralateral tumors in 2.8 years of follow-up Tumors observed with Tamoxifen Tumors observed with anastrozole Reduction of 46% 14 Reduction of 77%

18 Considerations in the Selection of an Anti- Aromatase Agent for Long-Term Therapy Efficacy there are no published direct comparisons of anti-aromatase aromatase agents, but trials are ongoing there is no evidence, to date, that one anti- aromatase agent is superior to another in efficacy Tolerability?

19 Anti-aromatase Agents: They Are Not All the Same Different estrogen-suppression suppression potencies? Enzyme inactivation vs inhibition? Different effects or PK profile on tumour aromatase? Additional action though androgen receptor?

20 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.

21 Exemestane: Rationale for Use in BC Prevention Preventive effect in preclinical models Decreased levels l of aromatase enzyme (instead of the increase observed after non-steroidal anti-aromatase aromatase agents) Activity in advanced breast cancer Improved tolerability vs TAM No negative effects on lipids Preclinical and clinical favourable bone data

22 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.

23 Aromatase Inhbitors design of Adjuvant Trials THESE ARE ALL DIFFERENT QUESTIONS! Upfront Sequential Extended Schema T vs AI T 2/3 y AI T 5y AI Reported (6/2005) ATAC BIG IES ABCSG/ARNO MA 17 Awaited TEAM BIG 1/98 NSABP B-33B TEAM ATTOM- ATLAS

24 Early BC: for a newly diagnosed patient, which treatment would be best? No data at present comparing different strategies No data at present comparing different AIs Trial results not expected for several years Long-term outcomes not expected for many years and may be confounded by changing practice patterns

25 BIG 1-981

BIG 1-98: 1 consequences of the inclusion of pts from arm C & D The inclusion of Arms C and D reduces the percentage of patients treated for more than 2 years.

26 BIG 1-98: 1 consequences of the inclusion of pts from arm C & D The inclusion of Arms C and D reduces the percentage of patients treated for more than 2 years. Then, we have more than 50% of pts treated with LET for a shorter time (<2 y), with unpredictable effects on toxicity evaluation with respect to other AIs trials.

27 Early Breast Cancer AIs Trials: Unanswered Questions. The results of the reported trials to date do not adequately answer a number of questions Are there efficacy and long-term toxicity differences among the AIs in the adjuvant setting? Which AI is better? What is the optimal sequence for a newly diagnosed patient: AI alone, a tamoxifen followed by AI, or AI followed by tamoxifen? Which treatment strategy would be best in a patient already treated ted with TAM (from <2 y or 2/3 y or >3 y?) What is the optimal duration of AI therapy (2/3 y or 5 y or 10 y)? y What are the long-term therapy toxicities of the AIs (after 2/3 y or 5 y or 10 y)? Should we offer our patients AIs in the presence of tumors ER+PgR PgR- or over-expressing expressing Her2? Do the bisphosphonates decrease the risk of fracture associated with some AIs? Should premenopausal women consider ovarian ablation or suppression in combination with an AI as adjuvant endocrine therapy?

28 Do Molecular markers predict when to implement aromatase inhibitor therapy in invasive breast cancer? S. Tovey et al., ASC Data from the ATAC & IES trials suggest that differences exist in the molecular profile of patients who response to early or delayed treatment with aromatase inhibitors. PR- ve patients derived greater benefit from initial anastrozole treatment compared to tamoxifen (ATAC) The results obtained with exemestane after years tamoxifen (IES) seems to be unrelated to PgR status.

29 Anti-Aromatase Aromatase Agents for Initial Therapy of MBC: Results Anti-Aromatase Agent vs Tamoxifen Phase III Studies Randomized Phase II Study Anastrozole Anastrozole Letrozole Exemestane Patients, N 170 vs vs vs vs 59 OR, % 21 vs vs vs 20* 41 vs 14 Clinical Benefit, % 59 vs 46* 56 vs vs 38* 56 vs 42 TTP, mo 11 vs 6* 8 vs 8 9 vs 6* 9 vs 5 TTF, mo 8 vs 5 6 vs 6 9 vs 6* Not reported *Difference is statistically significant; Non-protocol analysis. Nabholtz et al. J Clin Oncol. 2000;18: ; Bonneterre et al. J Clin Oncol. 2000;18: ; Mourisden et al. J Clin Oncol. 2001;19: ; Paridaens et al. Proc Am Soc Clin Oncol. 2004;19:83a; Dirix et al. Proc Am Soc Clin Oncol. 2001;20:29a

William J. Gradishar MD

Northwestern University Feinberg School of Medicine Adjuvant Endocrine Therapy For Postmenopausal Women SOBO 2013 William J. Gradishar MD Betsy Bramsen Professor of Breast Oncology Director, Maggie Daley