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Breast cancer chemoprevention in the high-risk patient

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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/benefit
AI 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 Participants
9% 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 Cancers
2 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 Events
5 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)

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