ApreS _Aromasin_ Prevention Study_ Double-Blind_ Placebo by hcj

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									             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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