Presentation on theme: "Breast cancer chemoprevention in the high-risk patient"— Presentation transcript:
1Breast cancer chemoprevention in the high-risk patient Pharmacological compounds to prevent the development of breast cancerAn updatePatrick Neven, MD, PhDUZ Leuven2nd Belgian Breast Meeting 20081
2Being Diagnosed Means: Transformation to a patientYou become a survivorEnd of treatment does not mean end of diseaseI 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
3Breast cancer: Important enough to prevent it Probability of developing invasive breast cancer during selected age intervalsX 50Untill recently the incidence was increasingX 5
4Breast Cancer Evolving Model of 2 Diseases ER - NegativeDecreases w/ ageGenetic FactorsBRCA 1 & 2Hormonally insensitive???Worse prognosisER - PositiveIncreases w/ ageWeak link to genetic factorsNOT BRCA - 1BRCA 2Hormonally sensitiveBetter prognosisWe are/will be more succesfull in prevention of ER+ breast cancer
5Prevention does work there is less heart disease & stroke Identification of high-risk individuals by measuring BP and cholesterol levels,and offering them targeted preventive treatmentCholesterol lowering drugs, antihypertensives…breast density lowering drugs
6High-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 mutationAlso not including calculated 5-yr risk of 1.75 or greaterUse 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 35Study of Hodgkins disease-- if XRT between puberty and age 30, increased RR; if exposure after age 30, much lower riskRadiation exposure from mammograms does not increase breast cancer riskAlcoholObesitySedentary lifestyleHigh levels of postmenopausal oestradiolWilley et al. Screening and follow-up of the patient at high risk for breast cancer. Obstet Gynecol 2007;110:6
7Primary prevention = Stop promotion How safely and effectively “arrest” the progressionof subclinical (pre) malignant disease?Stopping (pre-malignant) subclinical lesions is the key to effective prevention methodsPrimary prevention = Stop promotionInitiation starts earlierWhich individuals are at risk and for what type of cancer?Risk calculation = SOCInformation on 1ary (chemo)prevention= SOC
8Breast Cancer Disease Course Long Window of Opportunity 0 5 10Years of growth*10121010108106104102Prevention10 cmVery early breast cancer (undetectable)Clinical breast cancerNumber of cells1 cm1 mmCompared 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 daysHarris et al, eds. Breast Diseases, 2nd ed. Philadelphia PA: JB Lippincott; 20008
9▼ Preventing breast cancer disease before invasion develops Eliminate or prevent pre-invasivedisease before invasion developsGeneral health maintenanceEat a healthy dietReproductive issuesDon’t drink too muchExercise/ maintain optimal weightProphylactic surgery▼Chemoprevention9
10Chemoprevention 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)OthersNSAIDs, Cox 2 inhibitorsVit A derivativesStatinsMetformineFor 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 orparticipate in early phase trials using Cox-2 inhibitors to assess biomarker modulation.
11Block pre- and postmenopausal oestrogens…risk/benefit AITamTam
12Estrogen-Receptor Action SERM-ER interactions: Complex and Ligand DependentBreasttamoxifenoestradiolFigure 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 genesSERMs initiate or suppress target genes leading them to their actionsSERM activity ~ relative levels or coregulators in target cellsRiggs BL and Hartmann LC in N Engl J Med 2003;348:1192
13Tamoxifen for breast cancer prevention IBIS-I Overall 4 tamoxifen prevention trialsRisk reduction : 38%
14Tamoxifen NSABP-P1 tam / placebo trial Tamoxifen lowered invasive breast cancer risk by 50%For ER+ cancersNo reduction in ER- cancersStatistically significant(95% CI )The trial was unblinded earlyRR = 3X //3-4% over next 5 yearsPlaceboTamoxifenIncidence of invasive breast cancer per 1000 women42.524.8-17/1000/5 yearsNNT 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 mortality14
15Comparison of relative risks (with 95% confidence intervals) of benefits and undesirable effects of tamoxifen from the initial and updated results of NSABP P-1Fisher, B. et al. J. Natl. Cancer Inst : ; doi: /jnci/dji372Copyright restrictions may apply.
16Predicted benefits vs harms for 5 years of tamoxifen per 1000 women: 74/12 FU Age 45Age 55Age 65Age 755 yr breast cancer riskNo FH0.71.61.12.18.104.22.168FH# of invasive breast cancers avoided486121617Hip fractures avoided<13515Endometrial cancer caused22122Strokes caused1920PE caused18DVT causedTotal adverse events74264Based 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 relative3- based on Gail model, menarche age 12, first birth age 22, and no breast biopsiesUSPSTF 2007Less side effects <50 yearsHot flushes and night leg cramps not considered16
17Tamoxifen FDA Approved But ...Less than 3% of eligible candidates for primary prevention of breast cancer are taking tamoxifen10 million women meet high risk status2 million would derive an overall benefit, especially year olds>28,000 invasive breast cancers prevented / 5 yearsJ Natl Cancer Inst. 2003;95(7):
18Tamoxifen and LCIS or ADH in P1 trial First, do not Harm! Menopausal women are at risk for toxicity! Lower NNTTamoxifen and LCIS or ADH in P1 trialLCIS829 women included:Events at 7 yrs FU:Incidence of event n/1000/YADH1196 women included:Events at 7 yrs FU:Incidence of events n/1000/YNNT: 30NNT: 15Circulating oestrogens do not predict benefit from tamoxifen
19Raloxifene More Trials Multiple Outcomes of Raloxifene Evaluation (MORE trial)7705 postmenopausal with osteoporosisRaloxifene vs placebo, 3 yearsIncreased bone density; reduced risk of vertebral (not hip) w/o risk of uterine caDecreased risk of invasive BC (RRR 76%)For ER + tumors, RRR 90%But did increase risk of VTE, RR 3.1Breast Cancer Res Treat. 2001;65:
20Raloxifene and ER+ Breast Cancer in Low Risk Women 56%71%44%High risk population
21NSABP P2 Breast Cancer Prevention STAR Schema Risk-EligiblePost-Menopausal WomenAge 35 +No history of:CancerClottingDM & HTNSTRATIFICATIONAgeRelative RiskRaceHistory of LCISTAMOXIFEN20 mg/dayx 5 yearsRALOXIFENE60 mg/dayx 5 years21
22P-2 STAR: raloxifene vs tamoxifen Primary endpoint: Breast cancer prevention Baseline Characteristics19474 women randomized (risk = NASBP-P1)47.3 months follow-upMean age, 58.5 yearsMean 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 hyperplasiaTamoxifen: 22.5% Raloxifene: 23.0%55% hysterectomy*Women with history of ductal carcinoma in situ (DCIS) were excludedVogel VG et al. JAMA 2006;295:
23P-2 STAR Age Distribution of Participants 9%9%70+<4960-6932%50-5950%Vogel VG et al. JAMA 2006;295:
24P-2 STAR First-Degree Relatives with Breast Cancer None29%3+3%152%216%Vogel VG et al. JAMA 2006;295:
25STAR Average Annual Rate & Number of Invasive Breast Cancers 246810Gail ModelProjectionTAMN= 9726RaloxifeneN= 9745Av Ann Rate per 1000312*163*168** # of eventsPopulation: 4 % over 5 yrs will get breast cancer (normal: 2%)
26Tamoxifen vs Raloxifene Comparable efficacy to prevent invasive breast cancer and osteoporotic fracturesRaloxifene had fewer thromboembolic events, endometrial hyperplasia hysterectomies, cataracts, and less uterine cancerSimilar risk of MI, stroke, hot flashes, leg cramps26
27Clear Winner? Tamoxifen not widely accepted Raloxifene as effective Primary care physicians less familiar with its useSerious adverse effectsRaloxifene as effectiveMore widespread use by primary physiciansLess adverse effects
28Raloxifene is an excellent Osteoporosis drug DVT / PEStroke if CVD!Hot FlashesRaloxifene is an excellent chemopreventive agent for thevery high breast cancer risk patientBut, osteoporotic women probably not at high breast cancer risk
29The ideal treatment for postmenopausal women would: Decrease vertebral fracturesDecrease non-vertebral fracturesDecrease CHDDecrease StrokeDecrease Breast CancerDecrease Vulvo-Vaginal AtrophyDecrease hot FlashesNo increase in DVT / Endometrial CancerThe New SERMsNo current therapy meets these needs but…Lasofoxifene is not far from being the ideal SERM
30Lasofoxifene High affinity for the estrogen receptor Previous clinical studiesDecreases bone turnoverDecreases bone lossDecreases LDL-cholesterolRelieves vulvovaginal atrophyIndication: Treatment of osteoporosis and vaginal atrophywith breast cancer reduction as a consequencePresented at FDA & ASBMR-Canada Sept 2008
31The PEARL Trial – 5 year results Double Blind RCT: Plac vs Laso Randomized placebo-controlled trialTwo daily doses (0.25 mg or 0.5 mg)All received Vit D3 and calcium daily5 year results8,556 women 59 to 80 years oldBMD T-score ≤ -2.5 and ≥ -4.5 at the femoral neck or spine< 4 radiographic vertebral fractures* Postmenopausal Evaluation and Risk-reduction with Lasofoxifene
32Endpoint Adjudication committees (blinded): Fractures: Vertebral, Non-vertebral, HipBreast cancer (ER+ cancer co-1° at 5 yrs)Gynecologic: endometrial cancer, hyperplasiaCardiovascularStroke, 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
34ER+ Breast Cancer at 5 years 0.19(0.07, 0.56)0.52(0.25, 1.08)48%(p = 0.073)n = 21Incidence Rate per 1000 Patient Years (95% CI)81%(p < 0.001)n = 11n = 4Placebo0.25 mg0.5 mgLasofoxifene
35Major CHD Events Through 5 Years HR % CI p-valueLaso 0.25 mg (0.56, 1.03)Laso 0.5 mg (0.50, 0.93) *Placebo – –4%3%Cumulative Incidence2%1%+ less stroke0%12345BaselineTime (years)
36Adverse Events: VTE / Flushes PlaceboLasofoxifene, mg/d0.250.5EndCan3 (0.1%)2 (0.1%)EndhyperplVaginal BleedingHot FlushesVTE36 (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
37Arzoxifene, Lasophoxifene, Bazedoxifene Much more data to come The Ideal SERM?Tamoxifen, RaloxifeneArzoxifene, Lasophoxifene, BazedoxifeneMuch more data to comeAgonistAntagonistBoneCVSBreastUterusMore evidence than beforeCell of Positive Thinking, SG, age 75Time is ripe for reassessment of the rapidly changing SERM concept
38Barriers To Chemoprevention Women and physicians perceptions89 of 345 w/ breast lump were high riskCounseled on increased risk and preventionEncouraged to discuss with family physicianPhysicians educated on chemopreventionF/U by telephone interviews< 3% of eligible women take pills to prevent breast cancer!Ann Fam Med.2005 May-June;3(3):242-7.
39Results 1/89 decided to take Tamoxifen for prevention of breast cancer Only 49% discussed with MDMD recommended T for only 3 (3.4%)MD made NO recs for 8 (9.1%)MD advised against use for 37 (42%)Reasons against useFear of adverse events (47%), MD’s recommendation (34%), perceived low breast cancer risk (34%)Ann Fam Med.2005 May-June;3(3):242-7.
40And 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 counselingMany underestimate the BC riskOveremphasize FH but neglect other factorsUnder-use genetic counseling or primary chemopreventionJ Gen Intern Med (4):302-9
41Conclusions SERMsPhysicians must become more familiar with breast cancer risk assessmentBoth tamoxifen and raloxifene decrease breast cancer risk in high risk womenBoth have adverse effects which must be weighed against benefitsWe must improve communication of risk and benefits to patients and be aware of their perceptions, especially for minority patientsNew SERMs: Laso, Basedoxifene, Arzoxifene
42Breast Cancer Prevention Combining SERMs with other agent Clinical trials with retinoids for breast cancer chemoprevention. FenretinideTamoxifen + Vit A analogue in premenopausalsDCIS, LCIS, 4 arm trialHot trial, 2 arm trialLHRH-agonist + Tibolone/RaloxifeneRaloxifene + Omega – 3 FASTEAR: Tibolone
44Each AI has developed its own prevention programme Incidence of Contralateral Breast CancersTamoxifen versus Oral Aromatase InhibitorNumber of casesATAC IES MA BIG 1-9850403048In 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.202126262810121416A(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
46IBIS-II: 5 years anti-E therapy Current status 6yrs recruitementPrevention: Anastrozole versus PlaceboN= 2284/6000ER+ DCIS: Anastrozole versus TamoxifenN= 1686/400019 countriesUK: 1764Germany: 511ANZ: 390Italy: 357France: 298Belgium: 124Manuscripts/Abstracts:Cognitive function studyBone studyMainly DCIS
47Preventing 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: 40–7Harris 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, statinsTriple-negative breast cancers express receptors for GHRH andrespond to GHRH antagonists with growth inhibition.
48Three potential mechanisms through which growth-hormone-releasing hormone (GHRH) antagonists mediate the inhibition of tumor growthSchally A V et al. (2008) Antagonists of growth-hormone-releasing hormone:an emerging new therapy for cancerNat Clin Pract Endocrinol Metab 4: 33–43 doi: /ncpendmet0677
49Life style changes Physical activity Weight Loss Diet Girl Before a Mirror. Picasso.
50Premenopausal breast cancer She is not “yet” at risk Anovulatory cycle and less progestinsbut once in the menopause
51J 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 LevelsJ 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: , 2005Metformin and reduced risk of cancer in diabetic patients.Galega officinalis has been known since theMiddle Ages for relieving the symptoms of diabetesMetformine
53Case #1A 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 mutationIs 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 obeseIBIS-II trial?Or do you already give tamoxifen?
54Case #2A 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 55IBIS-II prevention trial?Or do you already give tamoxifen?If osteoporosis: Raloxifene54
55Case #3A 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 MRIsShould she be offered chemoprophylaxis?
56Breast Cancer Prevention Trials: Unanswered Questions. Type of preventive treatment:Which tumor do we want to prevent:Durability of the preventive effect:Influence on mortalitySubsets who really benefit from treatmentInteraction with HRPreventive effect in BRCA1/2 carriersData 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.
57Breast cancer chemoprevention in the high-risk patient Pharmacological compounds to prevent the development of breast cancerAn updateBelgian Breast Meeting 2008Thanks for your attention!57
59Highest risk factor for breast cancer-- BRCA mutation The highest risk factor for breast cancer is having a gene mutation in either BRCA1 or BRCA2Both are autosomal dominant, high-penetrance genesNormally function as a tumor suppressorOver 30 known mutations35% to 85% lifetime risk of breast cancer10% to 50% lifetime risk of ovarian cancerAlso increased risk of other cancers-- colon, melanoma, prostateNormal lifetime risk of breast cancer is 13%Normal lifetime risk of ovarian cancer is 1%
60Hormonal 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
61Study participants who developed BC in 288 genotyped cases (NSABP-P1, JAMA, Nov 14, 2001) PlaceboTAMRisk Ratio (95% C.I.)BRCA1 mut.351.67( )BRCA2 mut.80.38( )BRCA WT182870.48( )All participants*2111090.52( )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
62Preventive 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.
63Chemopreventive trials in BRCA mutated carriers Which treatment?Tamoxifen.LH-RH agonists & aromatase inhibitors (premenopausal women).Aromatase inhibitors (postmenopausal women).
64Exemestane: 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.
65Exemestane: Rationale for Use in BC Prevention Preventive effect in preclinical modelsDecreased levels of aromatase enzyme (instead of the increase observed after non-steroidal anti-aromatase agents)Activity in advanced breast cancerImproved tolerability vs TAMNo negative effects on lipidsPreclinical and clinical favourable bone dataThere 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.
66ApreS (Aromasin® Prevention Study) Double-Blind, Placebo-Controlled Study of Exemestane for the Prevention of Breast Cancer in Postmenopausal Unaffected Carriers of BRCA1/2 MutationsParticipating 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.
67ApreS 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.
68Defining the target: Lowering NNT 5408; hysterectomy; 11 j FU; 136 events:2,48/1000/j 2,07/1000/j702; 2 ovaries; tall; menarche; P0: 6,26/1000/j1,50/1000/jJ Natl Cancer Inst May 2;99(9):
69LCIS/ADH IBIS I (n=7152): NSABP-P1: (n=13338) 88/201 Vrouwen Geen stratificatieNSABP-P1: (n=13338)826/1193 pre- en postmenopauzale vrouwen56% en 75% Vermindering ER+ BorstkankerIBIS-II: 6000 postmenopauzale vrouwen met hoog risicoLCIS/ ADH/ DCIS and mastectomyFamilial historyAnastrazole versus Placebo
70Low-dose tamoxifen and fenretinide Placebo + PlaceboPremenopausal womenDCIS, LCISTAM 5mg + PR2yGail > 1.3% in 5 yrs4-HPR 200mg + PTAM + 4-HPRI endpoint: IGFs and Mx densityII endpoint: endometrial and ovarian effects breast FNA (image analysis)Sample size:300 subjects
71The HOT (Hormone Replacement Therapy and Tamoxifen) StudyHRT users Placebo/dayR(de novo or Tamoxifen 5 mg/daycurrent users)Sample size: subjects (4250 per arm)Endpoint: Breast cancer incidence (IBC and DCIS)
72Proportion of disease prevalence attributable to obesity Type 2 diabetesHypertensionCoronary heart diseaseGallbladder diseaseOsteoarthritisBreast cancerUterine cancerColon cancer57%17%30%14%11%Wolf et al. Obes Res. 1998;6:
73Approach to the high-risk patient Increased surveillanceRecommended for all patientsReferral to genetic counseling if high-risk due to family historyBRCA testingPreventionProphylactic medication (chemoprevention)Selective estrogen receptor modulators (SERMs)TamoxifenRaloxifeneAromatase inhibitorsProphylactic surgeryBilateral mastectomyBilateral oophorectomy
74Risk assessment tools Gail model Claus model Tyrer-Cuzick model Uses predominantly clinical historyEstimates 5-yr and lifetime breast cancer riskNational Surgical Adjuvant Breast and Bowel ProjectNational Cancer InstituteClaus modelUses family history onlyTyrer-Cuzick modelBRCAPROBoth Gail and Claus also available as Palm OS PDA softwareLast two more accurate, but not easily available74
75Risk assessment tools-- Gail model Most commonly used by cliniciansLeast accurateBased onNational Surgical Adjuvant Breast and Bowel ProjectBreast Cancer Detection and Demonstration ProjectLooks atCurrent age, age at menarche, age at first live birth, number of prior breast biopsies, biopsy results, # of first degree relatives with breast cancer, and raceLimitationsDoes not account for extended family history, history of chest radiation, breast densityA calculated 5-year risk of breast cancer of ≥ 1.67% is high-riskWomen age 35 or older with a 5-yr breast cancer risk of 1.67% or more were included in the first breast cancer chemoprevention trial75
76Sample Gail model calculation Hx of breast cancer, DCIS, or LCIS: NoWoman’s age: 36Age of menarche: 12 to 13Age at first birth of child: >30First-degree relatives with breast cancer: 0Hx of breast biopsy: NoRace: White5 year riskThis patient: 0.5%Average patient: 0.3%Lifetime riskThis patient: 13.8%Average patient: 12.5%5 yr risk age 46: 1.17%5 yr risk age 56: 1.7%76
77Tamoxifen Selective Estrogen Receptor Modulator (SERM) Competes with estrogen for estrogen receptors on breast cancer cellsBlocks estrogen uptakePrevents cell growthFDA-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 years77
78Tamoxifen Only acts on estrogen receptor positive tumors (ER+) BRCA2 gene mutation carriers can have estrogen receptor positive or negative tumorsTamoxifen is effective only in the subset of patients who are ER+BRCA1 gene mutation carriers are usually estrogen receptor negativeTamoxifen is ineffective for most of these patientsOophorectomy is effective …78
79Tamoxifen Increased risks of Decreased risks of Side effects Uterine cancerStrokeMyocardial infarctionThromboemboli (DVT, PE)CataractsDecreased risks ofOsteoporosisHyperlipidemiaSide effectsHot flashes, night sweats, irregular mensesBlack box warning: some women have had fatal adverse effects using tamoxifen for breast cancer prevention79
80Chemoprophylaxis of breast cancer Best forWomen in their 40s who are at increased risk for breast cancer and have no predisposition to thromboembolismWomen in their 50s who are at increased risk for breast cancer, have no predisposition to thromboembolism, and do not have a uterus.Less beneficial forWomen in their 30s (less risk of breast cancer)Women > age 60 (increased risk of thromboembolism)80
81Aromatase inhibitorsBlock the peripheral conversion of androstenedione to estrone and testosterone to estradiolNot yet approved for prophylaxisAnastrazole, Tamoxifen, Alone or in Combination (ATAC) trial (Lancet 2002)Multicenter, international, double-blind, RCT9,366 postmenopausal women with early stage breast cancerAfter 33 months statistically significant >50% reduction in contralateral primary invasive breast cancers in the anastrazole alone groupAnastrazole is an aromatase inhibitorPromising for prophylaxisFinal results of this trial still coming outLess side effects than SERMs, except worse bone density scores81
82Prophylactic 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 benefitAdverse effectsPremature menopauseIncreased risks of osteoporosis, cardiovascular disease82
83Identifying 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
84Summary--Management options for high-risk women SurveillanceSBE?CBE yearly (? or q 6 mos)Annual mammogram (? age to start)Once determined high-risk10 years younger than age of youngest affected first degree relativeAge 25 if BRCA mutation carrierAnnual MRIStarting at age 30 if they meet the ACS criteriaKnown BRCA mutation1º relative with a BRCA mutation, and patient untested20% or greater lifetime risk of breast cancerChest radiation exposure between ages 10 and 30 yrsAnd consider even if they don’t meet ACS criteria…Lifetme breast cancer risk 15-20%Mammographically dense breastsPersonal history of atypia, LCIS, breast cancer84
85Summary--Management options for high-risk women Genetic testingIf high-risk based on family historyTo help guide surveillance and prophylaxisChemoprophylaxisIf BRCA mutation carrierIf Gail 5-yr risk ≥ 1.67%Use of tamoxifen or raloxifeneSurgical prophylaxisMastectomy and/or oophorectomy
86ReferencesACS Recommendations on MRI and mammography for breast cancer screening. Am Fam Phys 2007;5:Breast cancer facts and figures. ACSGuide 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 CenterWilley S, Costanza C. Screening and follow-up of the patient at high-risk for breast cancer. Obstet gynecol 2007;110:86
87P-2 STAR Annual Rate and Number of Invasive Breast Cancers by 5-year Predicted Risk* 32†6170444777*Determined using Gail Model†No. of eventsVogel VG et al. JAMA 2006;295:
88STAR: Thromboembolic Events 510152025303540612182436424854606672At Risk by Year # of Rate/1000Treatment Events at 6 yrs. RRTamoxifenRaloxifeneP-value= 0.01Cumulative Incidence (per 1000)Time Since Randomization (months)