1. Breast cancer chemoprevention in the high-risk patient
Pharmacological compounds to prevent the development of breast cancer
An update
Patrick Neven, MD, PhD
UZ Leuven
2nd Belgian Breast Meeting 2008 1

2. Being Diagnosed Means:
Transformation to a patient
You become a survivor
End of treatment does not mean end of disease
I suppose that you are familiar with the common reactions after being diagnosed: denial, fear, anger, rage are just a few of them.
Some .women get so afraid that they want to undergo radical mastectomy on both sides just to minimize risk of getting breast cancer again.
My experience is that most patients overestimate their risk of dying and it’s important that they get correct information.
Sometimes you are more ill after operation during treatment than before operation.
The greatest trauma is that nobody can tell you if you are cured.
The option of reconstruction is not available to all patient for different reasons. In some countries patients don’t even get a free prostheses to wear in the bra .
To most patients mastectomy means a loss of femininity.
After recovery you still have scars on your body and scars in your mind but many survivors find they have a much richer life with new meaning.
Can we avoid this? 2

3. Breast cancer: Important enough to prevent it
Probability of developing invasive breast cancer during selected age intervals
X 50
Untill recently the incidence was increasing
X 5

4. Breast Cancer Evolving Model of 2 Diseases
ER - Negative
Decreases w/ age
Genetic Factors
BRCA 1 & 2
Hormonally insensitive???
Worse prognosis
ER - Positive
Increases w/ age
Weak link to genetic factors
NOT BRCA - 1
BRCA 2
Hormonally sensitive
Better prognosis
We are/will be more succesfull in prevention of ER+ breast cancer

5. Prevention does work there is less heart disease & stroke
Identification of high-risk individuals by measuring BP and cholesterol levels,
and offering them targeted preventive treatment
Cholesterol lowering drugs, antihypertensives
…breast density lowering drugs

6. High-risk factors for breast cancer: relative risk
Not including BRCA mutation risk- has ~ 10x RR, and not including untested people in a family with known BRCA mutation
Also not including calculated 5-yr risk of 1.75 or greater
Use of HRT after 10 yrs (estrogen/progesterone > risk than estrogen alone)
Study of atomic bomb survivors-- higher RR if exposed before age 20, sig decline if exposed after age 35
Study of Hodgkins disease-- if XRT between puberty and age 30, increased RR; if exposure after age 30, much lower risk
Radiation exposure from mammograms does not increase breast cancer risk
Alcohol
Obesity
Sedentary lifestyle
High levels of postmenopausal oestradiol
Willey et al. Screening and follow-up of the patient at high risk for breast cancer. Obstet Gynecol 2007;110: 6

7. Primary prevention = Stop promotion
How safely and effectively “arrest” the progression
of subclinical (pre) malignant disease?
Stopping (pre-malignant) subclinical lesions is the key to effective prevention methods
Primary prevention = Stop promotion
Initiation starts earlier
Which individuals are at risk and for what type of cancer?
Risk calculation = SOC
Information on 1ary (chemo)prevention= SOC

8. Breast Cancer Disease Course Long Window of Opportunity
0 5 10
Years of growth*
1012
1010
108
106
104
102
Prevention
10 cm
Very early breast cancer (undetectable)
Clinical breast cancer
Number of cells
1 cm
1 mm
Compared to several other cancers, breast cancer is a relatively indolent disease and particularly its hormone-dependent subtype. This graph represents the rate of growth and natural history of the tumor. Until recently, breast cancer has been diagnosed relatively late in its natural history; thus, any therapeutic intervention was relatively late. In recent years, however, increasing attention has been given to therapeutic intervention at earlier stages of this process.
Number of cell doublings
*Note: 90-day doubling x 20 doublings = 1800 days (~ 5 years).
**Can vary from days
Harris et al, eds. Breast Diseases, 2nd ed. Philadelphia PA: JB Lippincott; 2000 8

9. ▼ Preventing breast cancer disease before invasion develops
Eliminate or prevent pre-invasive
disease before invasion develops
General health maintenance
Eat a healthy diet
Reproductive issues
Don’t drink too much
Exercise/ maintain optimal weight
Prophylactic surgery ▼
Chemoprevention 9

10. Chemoprevention of Breast Cancer Options for High Risk Women
Chemoprevention with SERMs (e.g. tamoxifen (EMEA not approved)
Participation in trials using aromatase inhibitors (IBIS-II)
Others
NSAIDs, Cox 2 inhibitors
Vit A derivatives
Statins
Metformine
For women at high risk of developing breast cancer, the options for chemoprevention include:
Tamoxifen which is FDA approved for that indication. Raloxifene was compared to tamoxifen in the follow-up STAR trial. This trial is now closed for recruitment and results are anticipated in 2008.
Alternatively postmenopausal women have the opportunity to participate in chemoprevention trials evaluating aromatase inhibitors. Some of which have breast cancer as an endpoint or
participate in early phase trials using Cox-2 inhibitors to assess biomarker modulation.

11. Block pre- and postmenopausal oestrogens…risk/benefitAI
Tam
Tam

12. Estrogen-Receptor Action
SERM-ER interactions: Complex and Ligand Dependent
Breast
tamoxifen
oestradiol
Figure 2. Estrogen-Receptor Action. Each class of SERMs (orange symbols) has a slightly different shape, although all will bind to the estrogen receptor. When it binds to an estrogen, antiestrogen, or SERM, the estrogen receptor undergoes a conformational change that permits its spontaneous dimerization and facilitates the subsequent interaction of the dimer with estrogen response elements (EREs) located within target genes. The estrogen-receptor-ligand complex also leads to binding of various coregulator proteins that vary with its conformational structure. Some estrogen-receptor-SERM complexes favor corepressor recruitment (red) that, in a given target cell, increases its antagonist activity, and others favor coactivator recruitment (blue) that increases its agonist activity. Some SERMs may also facilitate the interaction of the estrogen receptor with yet-to-be-identified coactivators (green) with which estrogens or antiestrogens would not normally couple. It has now been determined that estrogen facilitates the interaction of the estrogen receptor with coactivators. The antagonist-activated estrogen receptor, on the other hand, interacts preferentially with corepressors. The binding of different SERMs to the receptor permits the receptor to adopt conformational states that are different from each other and also distinct from that induced by classic estrogen agonists or antagonists.The implication of this model is that SERM activity will be influenced by the relative levels of expression of the coregulator proteins (corepressors and coactivators) that are expressed in different target cells.
Target genes
SERMs initiate or suppress target genes leading them to their actions
SERM activity ~ relative levels or coregulators in target cells
Riggs BL and Hartmann LC in N Engl J Med 2003;348:1192

13. Tamoxifen for breast cancer prevention IBIS-I
Overall 4 tamoxifen prevention trials
Risk reduction : 38%

14. Tamoxifen NSABP-P1 tam / placebo trial
Tamoxifen lowered invasive breast cancer risk by 50%
For ER+ cancers
No reduction in ER- cancers
Statistically significant
(95% CI )
The trial was unblinded early
RR = 3X //3-4% over next 5 years
Placebo
Tamoxifen
Incidence of invasive breast cancer per 1000 women
42.5
24.8
-17/1000/5 years
NNT over 5 years: 1/80 ‘high risk’ cases
=Aclasta 3 years to prevent a hip fracture in osteoporosis
=ASA taken for 5 years reduced myocardial infarction (ARR, 0.5%, NNT 200 for 5 years),
increased major haemorrhage (ARI, 0.7%, NNT 154), and did not reduce all cause mortality or cardiovascular mortality 14

15. Comparison of relative risks (with 95% confidence intervals) of benefits and undesirable effects of tamoxifen from the initial and updated results of NSABP P-1
Fisher, B. et al. J. Natl. Cancer Inst : ; doi: /jnci/dji372
Copyright restrictions may apply.

16. Predicted benefits vs harms for 5 years of tamoxifen per 1000 women: 74/12 FU
Age 45
Age 55
Age 65
Age 75
5 yr breast cancer risk
No FH
0.7
1.6
1.1
2.3
1.5
3.2
3.4 FH
# of invasive breast cancers avoided 4 8 6 12 16 17
Hip fractures avoided
<1 3 5 15
Endometrial cancer caused 2 21 22
Strokes caused 1 9 20
PE caused 18
DVT caused
Total adverse events 7 42 64
Based on the Gail model, using estimates from the Breast Cancer Prevention Trial 1999; Gail et al, Weighing the risks and benefits of tamoxifen for preventing breast cancer, J Natl Cancer Inst, 1999.
2- No family history means no first degree relative, Family history means one first degree relative
3- based on Gail model, menarche age 12, first birth age 22, and no breast biopsies
USPSTF 2007
Less side effects <50 years
Hot flushes and night leg cramps not considered 16

17. Tamoxifen FDA Approved
But ...
Less than 3% of eligible candidates for primary prevention of breast cancer are taking tamoxifen
10 million women meet high risk status
2 million would derive an overall benefit, especially year olds
>28,000 invasive breast cancers prevented / 5 years
J Natl Cancer Inst. 2003;95(7):

18. Tamoxifen and LCIS or ADH in P1 trial
First, do not Harm! Menopausal women are at risk for toxicity! Lower NNT
Tamoxifen and LCIS or ADH in P1 trial
LCIS
829 women included:
Events at 7 yrs FU:
Incidence of event n/1000/Y
ADH
1196 women included:
Events at 7 yrs FU:
Incidence of events n/1000/Y
NNT: 30
NNT: 15
Circulating oestrogens do not predict benefit from tamoxifen

19. Raloxifene More Trials
Multiple Outcomes of Raloxifene Evaluation (MORE trial)
7705 postmenopausal with osteoporosis
Raloxifene vs placebo, 3 years
Increased bone density; reduced risk of vertebral (not hip) w/o risk of uterine ca
Decreased risk of invasive BC (RRR 76%)
For ER + tumors, RRR 90%
But did increase risk of VTE, RR 3.1
Breast Cancer Res Treat. 2001;65:

20. Raloxifene and ER+ Breast Cancer in Low Risk Women
56%
71%
44%
High risk population

21. NSABP P2 Breast Cancer Prevention STAR Schema
Risk-Eligible
Post-Menopausal Women
Age 35 +
No history of:
Cancer
Clotting
DM & HTN
STRATIFICATION
Age
Relative Risk
Race
History of LCIS
TAMOXIFEN
20 mg/day
x 5 years
RALOXIFENE
60 mg/day
x 5 years 21

22. P-2 STAR: raloxifene vs tamoxifen Primary endpoint: Breast cancer prevention Baseline Characteristics
19474 women randomized (risk = NASBP-P1)
47.3 months follow-up
Mean age, 58.5 years
Mean 5-year predicted risk of breast cancer, 4.03%
History of lobular carcinoma in situ (LCIS)*
Tamoxifen: 9.2% Raloxifene: 9.2%
History of breast atypical hyperplasia
Tamoxifen: 22.5% Raloxifene: 23.0%
55% hysterectomy
*Women with history of ductal carcinoma in situ (DCIS) were excluded
Vogel VG et al. JAMA 2006;295:

23. P-2 STAR Age Distribution of Participants9% 9%
70+
<49
60-69
32%
50-59
50%
Vogel VG et al. JAMA 2006;295:

24. P-2 STAR First-Degree Relatives with Breast Cancer
None
29% 3+ 3% 1
52% 2
16%
Vogel VG et al. JAMA 2006;295:

25. STAR Average Annual Rate & Number of Invasive Breast Cancers2 4 6 8 10
Gail Model
Projection
TAM
N= 9726
Raloxifene
N= 9745
Av Ann Rate per 1000
312*
163*
168*
* # of events
Population: 4 % over 5 yrs will get breast cancer (normal: 2%)

26. Tamoxifen vs Raloxifene
Comparable efficacy to prevent invasive breast cancer and osteoporotic fractures
Raloxifene had fewer thromboembolic events, endometrial hyperplasia hysterectomies, cataracts, and less uterine cancer
Similar risk of MI, stroke, hot flashes, leg cramps 26

27. Clear Winner? Tamoxifen not widely accepted Raloxifene as effective
Primary care physicians less familiar with its use
Serious adverse effects
Raloxifene as effective
More widespread use by primary physicians
Less adverse effects

28. Raloxifene is an excellent Osteoporosis drug
DVT / PE
Stroke if CVD!
Hot Flashes
Raloxifene is an excellent chemopreventive agent for the
very high breast cancer risk patient
But, osteoporotic women probably not at high breast cancer risk

29. The ideal treatment for postmenopausal women would:
Decrease vertebral fractures
Decrease non-vertebral fractures
Decrease CHD
Decrease Stroke
Decrease Breast Cancer
Decrease Vulvo-Vaginal Atrophy
Decrease hot Flashes
No increase in DVT / Endometrial Cancer
The New SERMs
No current therapy meets these needs but…
Lasofoxifene is not far from being the ideal SERM

30. Lasofoxifene High affinity for the estrogen receptor
Previous clinical studies
Decreases bone turnover
Decreases bone loss
Decreases LDL-cholesterol
Relieves vulvovaginal atrophy
Indication: Treatment of osteoporosis and vaginal atrophy
with breast cancer reduction as a consequence
Presented at FDA & ASBMR-Canada Sept 2008

31. The PEARL Trial – 5 year results Double Blind RCT: Plac vs Laso
Randomized placebo-controlled trial
Two daily doses (0.25 mg or 0.5 mg)
All received Vit D3 and calcium daily
5 year results
8,556 women 59 to 80 years old
BMD T-score ≤ -2.5 and ≥ -4.5 at the femoral neck or spine
< 4 radiographic vertebral fractures
* Postmenopausal Evaluation and Risk-reduction with Lasofoxifene

32. Endpoint Adjudication committees (blinded):
Fractures: Vertebral, Non-vertebral, Hip
Breast cancer (ER+ cancer co-1° at 5 yrs)
Gynecologic: endometrial cancer, hyperplasia
Cardiovascular
Stroke, TIA, VTE, major CHD events*
Cause of death
*Composite of coronary death, non-fatal MI, new ischemic heart disease, hospitalization for unstable angina, revascularization procedures

33. Nonvertebral Fracture at 5 Years
0.90
(0.76, 1.06)
0.76
(0.64, 0.91)
24%
(p < 0.01)
Lasofoxifene
10%
(P = 0.19)
n = 296
n =269
n = 230
First SERM with
Non-vertebral fracture
Risk reduction

34. ER+ Breast Cancer at 5 years
0.19
(0.07, 0.56)
0.52
(0.25, 1.08)
48%
(p = 0.073)
n = 21
Incidence Rate per 1000 Patient Years (95% CI)
81%
(p < 0.001)
n = 11
n = 4
Placebo
0.25 mg
0.5 mg
Lasofoxifene

35. Major CHD Events Through 5 Years
HR % CI p-value
Laso 0.25 mg (0.56, 1.03)
Laso 0.5 mg (0.50, 0.93) *
Placebo – – 4% 3%
Cumulative Incidence 2% 1%
+ less stroke 0% 1 2 3 4 5
Baseline
Time (years)

36. Adverse Events: VTE / Flushes
Placebo
Lasofoxifene, mg/d
0.25
0.5
EndCan
3 (0.1%)
2 (0.1%)
Endhyperpl
Vaginal Bleeding
Hot Flushes
VTE
36 (0.3%)
70 (0.5%)
90 (0.7%)
158 (1.2) 372 (2.9) 365 (2.8)
18 (0.6%) 48 (1.7%) 37 (1.3%)
Endometrial Texture = Tam Like ( 20%)
Subepithelial changes and More Atrophic E-Polyps

37. Arzoxifene, Lasophoxifene, Bazedoxifene Much more data to come
The Ideal SERM?
Tamoxifen, Raloxifene
Arzoxifene, Lasophoxifene, Bazedoxifene
Much more data to come
Agonist
Antagonist
Bone
CVS
Breast
Uterus
More evidence than before
Cell of Positive Thinking, SG, age 75
Time is ripe for reassessment of the rapidly changing SERM concept

38. Barriers To Chemoprevention
Women and physicians perceptions
89 of 345 w/ breast lump were high risk
Counseled on increased risk and prevention
Encouraged to discuss with family physician
Physicians educated on chemoprevention
F/U by telephone interviews
< 3% of eligible women take pills to prevent breast cancer!
Ann Fam Med.2005 May-June;3(3):242-7.

39. Results 1/89 decided to take Tamoxifen for prevention of breast cancer
Only 49% discussed with MD
MD recommended T for only 3 (3.4%)
MD made NO recs for 8 (9.1%)
MD advised against use for 37 (42%)
Reasons against use
Fear of adverse events (47%), MD’s recommendation (34%), perceived low breast cancer risk (34%)
Ann Fam Med.2005 May-June;3(3):242-7.

40. And Physicians?… Survey 822 primary care docs
Six patient scenarios with varying breast cancer risks ( 0.7% - 8.2%)
Almost all endorse mammography and lifestyle behavior counseling
Many underestimate the BC risk
Overemphasize FH but neglect other factors
Under-use genetic counseling or primary chemoprevention
J Gen Intern Med (4):302-9

41. Conclusions SERMs
Physicians must become more familiar with breast cancer risk assessment
Both tamoxifen and raloxifene decrease breast cancer risk in high risk women
Both have adverse effects which must be weighed against benefits
We must improve communication of risk and benefits to patients and be aware of their perceptions, especially for minority patients
New SERMs: Laso, Basedoxifene, Arzoxifene

42. Breast Cancer Prevention Combining SERMs with other agent
Clinical trials with retinoids for breast cancer chemoprevention. Fenretinide
Tamoxifen + Vit A analogue in premenopausals
DCIS, LCIS, 4 arm trial
Hot trial, 2 arm trial
LHRH-agonist + Tibolone/Raloxifene
Raloxifene + Omega – 3 FA
STEAR: Tibolone

43. Aromatase Inhibitoren Tamoxifen
Postmenopausal patients
Aromatase Inhibitoren Tamoxifen
Arimidex
Femara
Aromasin A
Reduce Estrogen
Aromatase
Inhibitors
NO OESTROGENS AT ALL! ER E
Block Estrogen
SERMs
(Tamoxifen)
Nolvadex D
Tamoplex
Tamoxifen ….

44. Each AI has developed its own prevention programme
Incidence of Contralateral Breast Cancers
Tamoxifen versus Oral Aromatase Inhibitor
Number of cases
ATAC IES MA BIG 1-98 50 40 30 48
In the hormone receptor-positive population there was a 53% reduction in all contralateral breast cancers in the anastrozole group and a 57% reduction in invasive contralateral breast cancer. 20 21 26 26 28 10 12 14 16 A
(n=3125) T
(n=3116) E
(n=2352) T
(n=2372) L
(n=2582) T
(n=2575) L
(n=4003) T
(n=4007)
Each AI has developed its own prevention programme

45. Comparing tamoxifen with anastrozole
Completion analysis (%)
P value A T
Hot flushes
35.7
40.9
<0.0001
Vaginal bleeding
5.4
10.2
Vaginal discharge
3.5
13.2
Endometrial cancera
0.2
0.8
0.02
Ischaemic cerebrovascular event
2.0
2.8
0.03
Venous thromboembolic events
4.5
0.0004
Deep venous thromboembolic events
1.6
2.4
Joint symptoms
35.6
29.4
Total fracturesb
11.0
7.7
ATAC Lancet 2005; 365: 60–2.

46. IBIS-II: 5 years anti-E therapy Current status
6yrs recruitement
Prevention: Anastrozole versus Placebo
N= 2284/6000
ER+ DCIS: Anastrozole versus Tamoxifen
N= 1686/4000
19 countries
UK: 1764
Germany: 511
ANZ: 390
Italy: 357
France: 298
Belgium: 124
Manuscripts/Abstracts:
Cognitive function study
Bone study
Mainly DCIS

47. Preventing ER- Breast Cancers ?
Rahme E, et al. Association between frequent use of NSAIDs and breast cancer. BMC Cancer 2005;5:159.
Swede H, et al. Association of regular aspirin use and breast cancer risk. Oncology 2005;68: 40–7
Harris RE, et al. Reduction in the risk of human breast cancer by selective cyclooxygenase-2 (COX-2) inhibitors. BMC Cancer 2006;6:27.
Mazhar D, et al. COX inhibitors and breast cancer. Br J Cancer 2006;94:346–50.
Wu K, et al. The retinoid X receptor-selective retinoid, LGD1069, prevents the development of estrogen receptor-negative mammary tumors in transgenic mice. Cancer Res 2002;62(22):6376–80.
Bonovas S et al. Use of statins and breast cancer: a meta-analysis of seven randomized clinical trials and nine observational studies. J Clin Oncol 2005;23(34):8606–12.
Eliassen AH, Colditz GA, Rosner B, et al. Serum lipids, lipid-lowering drugs, and the risk of breast cancer. Arch Intern Med 2005;165: 2264–71.
NSAIDs, COX-2 inhibitors, retinoids, statins
Triple-negative breast cancers express receptors for GHRH and
respond to GHRH antagonists with growth inhibition.

48. Three potential mechanisms through which growth-hormone-releasing hormone (GHRH) antagonists mediate the inhibition of tumor growth
Schally A V et al. (2008) Antagonists of growth-hormone-releasing hormone:
an emerging new therapy for cancer
Nat Clin Pract Endocrinol Metab 4: 33–43 doi: /ncpendmet0677

49. Life style changes Physical activity Weight Loss Diet
Girl Before a Mirror. Picasso.

50. Premenopausal breast cancer She is not “yet” at risk
Anovulatory cycle and less progestins
but once in the menopause

51. J Natl Cancer Inst. 2008 Apr 16;100(8):530-2
J Natl Cancer Inst Apr 16;100(8): Doctors Seek To Prevent Breast Cancer Recurrence by Lowering Insulin Levels
J Clin Oncol 2008 Feb 20;26(6):833-4.
Insulin in the adjuvant breast cancer setting: a novel therapeutic target for lifestyle and pharmacologic interventions?
BMJ 330: , 2005
Metformin and reduced risk of cancer in diabetic patients.
Galega officinalis has been known since the
Middle Ages for relieving the symptoms of diabetes
Metformine

52. On-going trials for chemoprevention
Phyto-Oestrogens, Omega-3 FA, …
Weight bearing exercises,…
Letrozole, Exemestane
Celecoxib
LHRH + Raloxifene
Atorvastin
cHCG

53. Case #1
A 40 yrs patient presents for her annual physical exam. Last year she had a wide excision for LCIS right breast. On her history, she has a paternal grandmother, and two paternal aunts who had breast cancer, all after age 50. Her father has had prostate cancer at 55 years and he tested negative for the BRCA mutation
Is she a high breast cancer risk patient?
Would you suggest 5 years of tamoxifen?
What if she is 55, has no uterus and if she is not obese
IBIS-II trial?
Or do you already give tamoxifen?

54. Case #2
A 45 yrs female patient had a mastectomy and breast reconstruction for ER-positive right breast.
Is she a high-risk patient for CL breast cancer?
Would you suggest 5 years of tamoxifen?
What if she is 55
IBIS-II prevention trial?
Or do you already give tamoxifen?
If osteoporosis: Raloxifene 54

55. Case #3
A 40 yrs patient presents for her check up. On family history, her mother died at age 35 from breast cancer. She is BRCA-2 positive. The patient has already seen a genetic counselor, and informs she does not want prophylactic surgery and opts for self examination, a yearly mammogram, breast ultrasound and MRIs
Should she be offered chemoprophylaxis?

56. Breast Cancer Prevention Trials: Unanswered Questions.
Type of preventive treatment:
Which tumor do we want to prevent:
Durability of the preventive effect:
Influence on mortality
Subsets who really benefit from treatment
Interaction with HR
Preventive effect in BRCA1/2 carriers
Data available from the chemoprevention trial unanswered some important questions about the best kind of preventive treatment, the durability of the preventive effect, the subsets who can benefit from the treatment, the interaction with hormone replacement therapy and, in particular, the efficacy of the hormono-therapy in BRCA1 e 2 carriers.

57. Breast cancer chemoprevention in the high-risk patient
Pharmacological compounds to prevent the development of breast cancer
An update
Belgian Breast Meeting 2008
Thanks for your attention! 57

58. + other pathways AI
Tam
Targeted therapies

59. Highest risk factor for breast cancer-- BRCA mutation
The highest risk factor for breast cancer is having a gene mutation in either BRCA1 or BRCA2
Both are autosomal dominant, high-penetrance genes
Normally function as a tumor suppressor
Over 30 known mutations
35% to 85% lifetime risk of breast cancer
10% to 50% lifetime risk of ovarian cancer
Also increased risk of other cancers-- colon, melanoma, prostate
Normal lifetime risk of breast cancer is 13%
Normal lifetime risk of ovarian cancer is 1%

60. 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.
The critical question is whether chemoprevention, specifically hormone-therapy, would also reduce incidence of invasive BC among cancer-free women with inherited BRCA1 or BRCA2 mutations.
In fact BRCA1 tumors seem to be ER negative, even if we cannot exclude that this characteristic, frequently reported in observational studies, might be a covariating feature, related, for example, to the age of the patients or to a more aggressive phenotype of the tumor.
On the contrary, in BRCA2 women there is a prevalence of ER positive tumors, confirming the opportunity of an hormonal preventive approach.
1Johannsson et al., Eur J Cancer 33: ; 1997

61. Study participants who developed BC in 288 genotyped cases (NSABP-P1, JAMA, Nov 14, 2001)
Placebo
TAM
Risk Ratio (95% C.I.)
BRCA1 mut. 3 5
1.67
( )
BRCA2 mut. 8
0.38
( )
BRCA WT
182 87
0.48
( )
All participants*
211
109
0.52
( )
The recently published data from P1, obtained after genotyping almost all the women presenting BC, confirm that Tam is able to reduce BC incidence only in patients carring a BRCA2 mutation.
Although not significant, in BRCA1 women there was an increase of BC incidence.
Includes 288 genotyped cases and 32 cases without DNA available

62. 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.
We can conclude that BRCA1 women present more frequently ER negative tumors and then they appear to be not eligible for an hormonal preventive treatment.
But we known that hormonal treatments in advanced or early BC are effective, independently from the kind of treatment, I mean oophorectomy, tam or anti aromatase agents.
Considering that oophorectomy, performed early in reproductive life, is effective in reducing BC incidence, it is possible to think that in an early stage of cancer progression, cells, even BRCA1 mutated, maintain a certain level of hormone-sensitivity. On the contrary the results observed by Rebbeck and collaborators cannot be explained. Therefore, it is possible that also other hormonal manipulations such as TAM or anti aromatase agents might be useful in reducing breast cancer risk in BRCA1 mutated carriers as well.

63. Chemopreventive trials in BRCA mutated carriers
Which treatment?
Tamoxifen.
LH-RH agonists & aromatase inhibitors (premenopausal women).
Aromatase inhibitors (postmenopausal women).

64. 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.

65. 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
There are several reasons to use exemestane in a breast cancer prevention study. Exemestane showed a preventive effect in preclinical models, it is able to induce a progressive reduction of the aromatase levels, it is effective in advanced breast cancer, it have a better safety profile with respect to TAM, it do not present negative effects on lipids while preclinical data show a favourable effect on the bone.

66. 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.

67. 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.

68. Defining the target: Lowering NNT
5408; hysterectomy; 11 j FU; 136 events:2,48/1000/j 2,07/1000/j
702; 2 ovaries; tall; menarche; P0: 6,26/1000/j1,50/1000/j
J Natl Cancer Inst May 2;99(9):

69. LCIS/ADH IBIS I (n=7152): NSABP-P1: (n=13338) 88/201 Vrouwen
Geen stratificatie
NSABP-P1: (n=13338)
826/1193 pre- en postmenopauzale vrouwen
56% en 75% Vermindering ER+ Borstkanker
IBIS-II: 6000 postmenopauzale vrouwen met hoog risico
LCIS/ ADH/ DCIS and mastectomy
Familial history
Anastrazole versus Placebo

70. 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

71. The HOT (Hormone Replacement Therapy
and Tamoxifen) Study
HRT users Placebo/day R
(de novo or Tamoxifen 5 mg/day
current users)
Sample size: subjects (4250 per arm)
Endpoint: Breast cancer incidence (IBC and DCIS)

72. Proportion of disease prevalence attributable to obesity
Type 2 diabetes
Hypertension
Coronary heart disease
Gallbladder disease
Osteoarthritis
Breast cancer
Uterine cancer
Colon cancer
57%
17%
30%
14%
11%
Wolf et al. Obes Res. 1998;6:

73. Approach to the high-risk patient
Increased surveillance
Recommended for all patients
Referral to genetic counseling if high-risk due to family history
BRCA testing
Prevention
Prophylactic medication (chemoprevention)
Selective estrogen receptor modulators (SERMs)
Tamoxifen
Raloxifene
Aromatase inhibitors
Prophylactic surgery
Bilateral mastectomy
Bilateral oophorectomy

74. Risk assessment tools Gail model Claus model Tyrer-Cuzick model
Uses predominantly clinical history
Estimates 5-yr and lifetime breast cancer risk
National Surgical Adjuvant Breast and Bowel Project
National Cancer Institute
Claus model
Uses family history only
Tyrer-Cuzick model
BRCAPRO
Both Gail and Claus also available as Palm OS PDA software
Last two more accurate, but not easily available 74

75. Risk assessment tools-- Gail model
Most commonly used by clinicians
Least accurate
Based on
National Surgical Adjuvant Breast and Bowel Project
Breast Cancer Detection and Demonstration Project
Looks at
Current age, age at menarche, age at first live birth, number of prior breast biopsies, biopsy results, # of first degree relatives with breast cancer, and race
Limitations
Does not account for extended family history, history of chest radiation, breast density
A calculated 5-year risk of breast cancer of ≥ 1.67% is high-risk
Women age 35 or older with a 5-yr breast cancer risk of 1.67% or more were included in the first breast cancer chemoprevention trial 75

76. Sample Gail model calculation
Hx of breast cancer, DCIS, or LCIS: No
Woman’s age: 36
Age of menarche: 12 to 13
Age at first birth of child: >30
First-degree relatives with breast cancer: 0
Hx of breast biopsy: No
Race: White
5 year risk
This patient: 0.5%
Average patient: 0.3%
Lifetime risk
This patient: 13.8%
Average patient: 12.5%
5 yr risk age 46: 1.17%
5 yr risk age 56: 1.7% 76

77. Tamoxifen Selective Estrogen Receptor Modulator (SERM)
Competes with estrogen for estrogen receptors on breast cancer cells
Blocks estrogen uptake
Prevents cell growth
FDA-labeled for breast cancer prophylaxis in high-risk patients
>35 yo with a Gail model 5-yr risk of ≥1.67%
Dose 20 mg orally daily for 5 years 77

78. Tamoxifen Only acts on estrogen receptor positive tumors (ER+)
BRCA2 gene mutation carriers can have estrogen receptor positive or negative tumors
Tamoxifen is effective only in the subset of patients who are ER+
BRCA1 gene mutation carriers are usually estrogen receptor negative
Tamoxifen is ineffective for most of these patients
Oophorectomy is effective … 78

79. Tamoxifen Increased risks of Decreased risks of Side effects
Uterine cancer
Stroke
Myocardial infarction
Thromboemboli (DVT, PE)
Cataracts
Decreased risks of
Osteoporosis
Hyperlipidemia
Side effects
Hot flashes, night sweats, irregular menses
Black box warning: some women have had fatal adverse effects using tamoxifen for breast cancer prevention 79

80. Chemoprophylaxis of breast cancer
Best for
Women in their 40s who are at increased risk for breast cancer and have no predisposition to thromboembolism
Women in their 50s who are at increased risk for breast cancer, have no predisposition to thromboembolism, and do not have a uterus.
Less beneficial for
Women in their 30s (less risk of breast cancer)
Women > age 60 (increased risk of thromboembolism) 80

81. Aromatase inhibitors
Block the peripheral conversion of androstenedione to estrone and testosterone to estradiol
Not yet approved for prophylaxis
Anastrazole, Tamoxifen, Alone or in Combination (ATAC) trial (Lancet 2002)
Multicenter, international, double-blind, RCT
9,366 postmenopausal women with early stage breast cancer
After 33 months statistically significant >50% reduction in contralateral primary invasive breast cancers in the anastrazole alone group
Anastrazole is an aromatase inhibitor
Promising for prophylaxis
Final results of this trial still coming out
Less side effects than SERMs, except worse bone density scores 81

82. Prophylactic oophorectomy
In women who have a known BRCA mutation, prophylactic oophorectomy can decrease breast cancer incidence by 50%
Rebbeck et al. Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers, J Natl cancer Inst 1999;91(17):
Insufficient evidence regarding mortality benefit
Adverse effects
Premature menopause
Increased risks of osteoporosis, cardiovascular disease 82

83. Identifying high-risk patients in clinic
Any FH of breast or ovarian cancer?
Any 1º or 2º relative with both breast and ovarian cancer?
Any male relatives with breast cancer?
Any 1º relative with cancer in both breasts?
Two or more 1º relatives?
Three or more 1º or 2º relatives?
Both breast and ovarian cancer in 1º or 2º relatives?
Two or more 1º or 2º relatives with ovarian cancer?
Has a relative tested positive for a BRCA gene mutation?
Has the patient tested positive for a BRCA gene mutation?
Gail model 5-yr risk ≥ 1.67%?
Lifetime risk ≥ 20%
Therapeutic chest radiation ages 10-30?
HRT ≥ 10 yrs?
Dense breast tissue?
Atypical hyperplasia, LCIS, or prior breast cancer? 83

84. Summary--Management options for high-risk women
Surveillance
SBE?
CBE yearly (? or q 6 mos)
Annual mammogram (? age to start)
Once determined high-risk
10 years younger than age of youngest affected first degree relative
Age 25 if BRCA mutation carrier
Annual MRI
Starting at age 30 if they meet the ACS criteria
Known BRCA mutation
1º relative with a BRCA mutation, and patient untested
20% or greater lifetime risk of breast cancer
Chest radiation exposure between ages 10 and 30 yrs
And consider even if they don’t meet ACS criteria…
Lifetme breast cancer risk 15-20%
Mammographically dense breasts
Personal history of atypia, LCIS, breast cancer 84

85. Summary--Management options for high-risk women
Genetic testing
If high-risk based on family history
To help guide surveillance and prophylaxis
Chemoprophylaxis
If BRCA mutation carrier
If Gail 5-yr risk ≥ 1.67%
Use of tamoxifen or raloxifene
Surgical prophylaxis
Mastectomy and/or oophorectomy

86. References
ACS Recommendations on MRI and mammography for breast cancer screening. Am Fam Phys 2007;5:
Breast cancer facts and figures. ACS
Guide to Clinical Preventive Services. USPSTF 2007.
Harris, R. Screening for breast cancer: what to do with the evidence. Am Fam Phys 2007;5:
Kutson D, Steiner E. Screening for breast cancer: Current Recommendations and Future Directions. Am Fam Phys 2007;5:
Newman LA, Vogel VG. Breast Cancer Risk Assessment and Risk Reduction. Surg Clin N Am 87 (2007)
Saslow D et al. American Cancer Society Guideline for Breast Screening with MRI as an adjunt to mammography. CA Cancer J Clin 2007: 57:75-89.
Update on Breast Cancer Risk Reduction. Cedars Sinai Medical Center
Willey S, Costanza C. Screening and follow-up of the patient at high-risk for breast cancer. Obstet gynecol 2007;110: 86

87. P-2 STAR Annual Rate and Number of Invasive Breast Cancers by 5-year Predicted Risk*
32† 61 70 44 47 77
*Determined using Gail Model
†No. of events
Vogel VG et al. JAMA 2006;295:

88. STAR: Thromboembolic Events5 10 15 20 25 30 35 40 6 12 18 24 36 42 48 54 60 66 72
At Risk by Year # of Rate/1000
Treatment Events at 6 yrs. RR
Tamoxifen
Raloxifene
P-value= 0.01
Cumulative Incidence (per 1000)
Time Since Randomization (months)