Borstkliniek Voorkempen

Borstkliniek Voorkempen Borstkliniek Voorkempen Update handboek senologie «Associatie Borstkliniek Voorkempen» Malle, 1-9-2010

Materiaal SABCC, dec 2009, San Antonio EBCC, maart 2010, Barcelona ASCO, juni 2010, Chicago Algemene vergadering Borstkliniek Voorkempen, 23 juni 2010: initiatief te herhalen? Praktical clinical guideliness, ESMO =>Weinig «echte wijzigingen» voor handboek in 2010, SG consensus 2009 blijft geldig

Inhoud Diagnostiek Stadiëring en registratie Beeldvorming Pathologie Registratie Behandeling Heelkunde Radiotherapie Systeemtherapie Revalidatie Gemetastaseerd borstcarcinoom Klinische studies Publicaties en abstracts

Borstkankerscreening Erkenningsnormen mammoscreening! Wachttijden beperken tussen 1ste en 2de lezing Niet zinvol tussen 40 en 50 jaar (KCE) 24 gevallen extra opsporen en sterfgevallen voorkomen Doch Stralingsrisico Ongerustheid, vals positieve gezien «densere borsten» Kostprijs Zinloze behandelingen, biopsies, nodeloze mastectomies, overdiagnostiek Evolutie DCIS, gezien vroegdiagnostiek nog onduidelijk

Diagnostiek Radiologie Beeldvorming bij tepelverlies Radiologie verslagen Belang introductie nieuwe techniek voor het nemen van stuk-rx na tumorectomie

Dr. I. Biltjes Dr. P. Naudts Dienst Medische Beeldvorming AZ Klina

Beeldvorming bij (bloederig)tepelverlies Pre-operatief synthese verslag Peroperatieve standarisatie van rx Tumorectomiestukken Post-operatief

tepelverlies Vroeger rx galactografie Nu 1:echografie 2: mr mammografie

Mammo-echo

15/06/1960 F A mr mammo met contrast T1w_VISTA 2 dyn 30/08/2010 12:58:50 10113174 15/06/1960 F A mr mammo met contrast 30/08/2010 13:09:28 10113174 LOC: : 46,80 THK: 0,65 SP: 0,65 HFP THK: R L R L SENSE-Flex-M EC: 1 SE FA: 90 TR: 350 TE: 16,11 ACQ:152\152 Z: 3,20 C: 997 W: 1733 DFOV:10x10cm SE TR: 350 TE: Z: 3,82 C : 1464 W: 1364 DFOV:8,38x8,31cm Page: 145 of 200 P cm IM: 145 SE: 801 Page: 73 of 100 P cm IM: 73 SE: 851

15/06/1960 F A mr mammo met contrast 30/08/2010 13:09:28 10113174 THK: R L SE TR: 350 TE: Z: 4,41 C: C : 1525 W: 1562 DFOV:7,25x7,19cm Page: 1 of 2 Page: 73 of 100 P cm IM: 73 SE: 851

Pre-operatief syntheseverslag 1/omschrijving van de uitgebreidheid van een mammatumor aan de hand van beeldvorming en ap-resultaat van punctiebiopten 2/betere communicatie door standarisatie 3/geen dwingend advies

Schaal C1: unifocale tumorale pathologie met diameter kleiner dan 3 cm C2: tumorale pathologie groter dan 3 cm of multifocaal, maar kleiner dan kwadrant of segment C3: tumor groter dan kwadrant of segment

Post-operatief follow-up verslag Datum ingreep Ap, uitgebreidheid, Chirurgische techniek Beschrijving van borst, oksel, m pectoralis

Post-operatief verslag Beoordeling litteken: B2: goed beoordeelbaar litteken B3: moeilijk beoordeelbaar litteken (rx niet zichtbaar, slagschaduwen, holtevorming, vetnecrose)

Post-operatief verslag B2: normale post operatieve bevindingen B3: verhoogd risico, moeilijk beoordeelbaar Aanvullend mr mammografie

Nieuwe techniek voor het nemen van stukrx (specimenradiologie) na tumorectomie

Preoperatieve mx - us 7/05/1954 56 YEAR F rx mammografie rechts 18/05/2010 8:44:55 RML Pressure (mm): 51 Pressure (N): 90 ESE (mgy): 4,43 AGD (dgy): 0.01048 mas: 44 kvp: 29 spot (mm): 0,3 thickness (mm): 51 Page: 1 of 1 cm Z: 0,45 C: 2761 W: 900 Compressed 27:1 IM:1 100556 Page: 1 o

Preoperatieve MR: solitair letsel 7/05/1954 F mr mammo met contrast New 17/05/2010 12:36:48 10052663 7/05/1954 F A mr mammo met contrast ethrive_hr SENSE 17/05/2010 12:41:30 10052663 LOC : 51 THK: 3 SP: 1,5 HFP R L Page: 1 of 3 Z: 1 C C: : 777 W: 2136 Compressed C 25:1 IM: 1 SENSE-Body EC: : 1 GR FA: 12 TR: 6,03 TE: 3,01 Page: 35 of 100 P cm Z: 1 C: 113 W: 197 Compressed 7:1 IM: 35 SE: 401 mr mammo

Lokalisatie op RX

harpoen RML

Tumorectomie OK

Stuk rx Klinitray

Klinitray op OK

Klinitray op RX Face

Klinitray op RX Profiel

Stuk rx face en profiel 7/05/1954 56 YEAR F rx mammografie rechts 25/05/2010 17:35:12 RCC rx mammografie rechts 25/05/2010 17:36:10 RCC Pressure (mm): 198 Pressure (N): 0 ESE (mgy): 14,04 AGD (dgy): 0.09079 mas: 45 kvp: 25 spot (mm): 0,1 thickness (mm): 198 Page: 2 of 3 cm* Z: 0,45 C: 2822 W: 2761 Compressed 25:1 IM:2

Klinitray naar APD

Klinitray op APD

Meten op APD

Inkten oppervlakken

Cutting APD

Diagnostiek Pathologie Introductie systematisch pathologie protocol voor de borstkliniek ( richtlijnen in BJMO ) Systematische beschrijving ook belangrijk in registratie!

Dr G.Jacomen Patholoog anatoom

Reporting BreastCa Pathology report = important tool Way of communication between pathologist and clinician Needed for treatment decisions Needed for cancer registration Should be clear and structured, complete and concise

Optimalisation = joint effort VVOG invited their pathologists with interest in breast pathology No official mandate Only Flemish pathologists Only gynecologists and pathologists Liesbeth Van Eyken (Belgian Cancer Registry)

Participants Gynaecologists - Pathologists Patrick Berteloot (Duffel) Jan Decloedt (Dendermonde) Carine De Rop (Bonheiden) Patrick Neven (Leuven) Gracienne Staelens(Kortrijk) Chris Vereecke (Ghent) Liesbeth Bekaert / Joke Van Aken (Ghent) Cecile Colpaert (Antwerp) Ria Drijkoningen (Hasselt) Romaric Croes (Dendermonde) Gerd Jacomen (Duffel) Kathleen Lambein (Ghent) Philippe Moerman (Leuven) Erwin Pierre (Bonheiden) Anne-Marie Schelfhout (Aalst) Heidi Woestenborghs (St Niklaas)

Optimalisation on 2 fronts Standardisation of request form Generating minimal requirements for pathology report

Fixation 1. Type 2. Duration 3. Delay

Type of fixation Is fresh tissue indicated? Neutral buffered formalin Use of a fixative other than what is used in routine in your team can affect result of IHC,... Check with your pathologist!!! Specify on request form!!!

Duration of fixation Ideal 6-48 Hr Prolonged fixation: weekend Rarely a problem Minimal fixation: rapid turn around times

Duration of fixation Tumour has to be fixed for at least 6 Hr Shorter: ER CNB also needs 6 Hr! Minimum Formalin Fixation Time for Consistent Estrogen Receptor Immunohistochemical Staining of Invasive Breast Carcinoma Goldstein NS, Am J ClinPathol 2003

Consequence Tissue obtained after 13.00 Hr may not be processed the same day If processed same day: neg/low ER is not conclusive

Is 6 Hr sufficient? Formalin: few mm/hr Tumour 1 cm from section margin: fixation starts after 5 hours!!! Immediate incision is necessary

How to report fixation time? Unknown < 6 Hr 6-48 Hr > 48 Hr

Delay of fixation ER begins to diminish with delay to fixation of 2Hr PgR 1 Hr HER2 ISH begins after 1 Hr, significant after 2 Hr Khoury T, ModPathol 2009

How to report delay of fixation? Unknown < 1Hr 1-2 Hr > 2 Hr

What should be in report? Number of tumours Localisation Largest diameter Distance to nearest section margin Which section margin?

Characteristics of tumour Type (WHO 2003) Grade (Nottingham, Ellis&Elston) Optional: mitotic activity Lymphovascular invasion

Prognostic and predictive markers ER PgR Allred score: % and intensity HER2 IHC USCAP guidelines HER2 ISH Amplification or not HER2/CEP17

Associated lesions DCIS Diameter of WHOLE lesion Distance to section margin (which?) Nuclear grade (according to ECWGBSP) LCIS Morbus Paget of the nipple

Pure DCIS Diameter Distance to section margin (which?) Nucleargrade (according to ECWGBSP) Optional: Van NuysPrognostic Index Optional: architectural pattern ER, PgR: % positive nuclei

Lymph nodes Total number Number of LN with metastasis Largest diameter Number of LN with extracapsular invasion

Sentinelnodes Total number Number of LN with metastasis Largest diameter Number of LN with extra capsular invasion

TNM ptn(m): 7th edition Is missing in 50%!!!

Ingediend Belgian J MedOncol Standardisation of the breast pathology request form and the breast pathology report: a proposal by the VVOG, BIG Senologie. Cecile Colpaert, Gracienne Staelens, Gerd Jacomen, Patrick Neven and Philippe Moerman on behalf of the BIG Senologie of the VVOG (subgroup with special interest in breast pathology of the Flemish Society of Obstetrics and Gynaecology)

Nieuwe classificatie borstkanker Op basis van anatomische oorsprongcellen, IHC eigenschappen en microrooster profielen Basal-like (triple-negatief ; BRCA-like ):15% Nieuw : Claudin-low subtype (triple neg, non-basal like) Luminal A : 70% Luminal B : 8% Her-2 positief (rec.neg) : 6%

1. Luminal A Meerderheid borstca > 70% Kenmerken Receptoren Oe : +, sterk Prog : +/- Ki 67 < 14%, lage proliferatie-index Her2 : neg EGFR : - Gunstige prognose

2. Luminal B Minderheid (rec. Pos) : 8% Kenmerken Receptoren Oe : + Prog :: +/- Ki 67 > 14 % Soms Her2 + Mindere prognose Jongere leeftijd

3. Triple negative(tnbc)and basal-like breast cancer(blbc) Triple negative immunohistochemical profiling ER PR HER2 Cyclin D1, CK5/6/17, EGFR, Vimentin, Basal like CK5/6 positive high grade poor prognosis Non Basal like CK5/14 negative better prognosis Oakman C et al, Breast, 2010, epub Perez E et al, Breast Cancer Res Treat, 2010, epub

Triple negative (TNBC) and basal-like breast cancer (BLBC) TNBC Phenotype* based on Negative estrogen receptor Negative progesterone receptor Negative HER2 receptor as assessed by immunohistochemistry (IHC) or FISH for HER2 * The phenotype is the demonstration of the hereditary patrimony existing at the genes level BLBC Basal membrane Mature myoepithelial cells Mature luminal cells Breast cancer subtype originating from the basal layer of mammary epithelium (also known as the myoepithelial cells) 1 ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ Adapted from M. Smalley 2 1 Hamperl H et al, Curr Top Pathol, 1970, 53: 161 220 2 Smalley M et al, Nat Rev Cancer, 2003, 3: 832 44

Prognosis of TNBC/BLBC in comparison with other BC TNBC/BLBC have a poor prognosis in the first 5 years after diagnosis compared to other breast cancer subtypes A significant proportion of patients (about 60%), even without adjuvant treatment, do not relapse. After about 8 years of follow-up, these patients have a high chance to be cured. URGENT NEED for USEFUL PROGNOSTIC MARKERS! Linn SC et al, Eur J Cancer, 2009, 45, Suppl 1, 11-26

Outcomes of TNBC TNBC Others p Probability of local relapse (%) 13% 12% 0.77 Mean time to local relapse (y) 2.8 4.2 0.02 Probability of distant relapse (%) 33.9 20.4 < 0.0001 Mean time to distant relapse (y) 2.6 5.0 < 0.0001 Probability to die from BC (%) 42.2 28 < 0.0001 Median time to 4.2 6 < 0.0001 death (y) Dent R et al, Breast Cancer Res Treat, 2007, 13: 4429-34

Time of recurrence Risk of any recurrence rose sharply from date of diagnosis, peaked 1 to 3 years and dropped quickly after Short post-recurrence survival TNBC/BLBC are at increased risk of developing visceral and brain metastases Dent R et al, Breast Cancer Res Treat, 2007, 13: 4429-34 Linn SC et al, Eur J Cancer, 2009, 45, Suppl 1, 11-26

Luminal subtypes Mucineus Tubulair Neuro-endocrien Klassiek lobulair Moleculaire subtypes met microroosters Basal subtypes : dissectie mogelijk in klinisch relevante subtypes : good versus poor prognosis! Medullair Metaplastisch Adenoic cystic Apocien Pleiomorf lobulair

Immunohistochemie Oestrogeenreceptoren Progesteronreceptoren C-erbB-2 oncogenproteine Indien 2+ of 3+ => FISH (resultaat verhouding!) <1.8 => negatief Tussen 1.8 en 2.2 => herhalen IHC >2.2 => positief Herceptine terugbetaald indien tumor >1cm CK (5,6), belang voor «basal cell like» Ki-67 altijd of bij twijfel over chemo-indicatie? EGFR?

SamenvattingT1-NO-N1 pt1 tumor < of = 2 cm pt1mic micro-invasiviteit < of = 0.1 cm pt1a > 0.1 cm en < of = 0.5 cm pt1b > 0.5 cm en < of = 1.0 cm pt1c > 1.0 cm en < of = 2.0 cm pn0 LN tumorvrij en geen aanvullend onderzoek naar geïsoleerde tumorcellen (ITC: unieke cel of klompje < of = 0.2mm ) pn0(i+)of (i-) ITC + of - bij middel van IHC pn0(mol+) of (mol-) ITC + of - bij middel van RT-PCR (Reverse Transcription-Polymerase Chain Reaction) pn1 pn1mi pn1a pn1b pn1c micrometastasen (> 0.2 mm en < of = 2.0 mm) metastasen in 1-3 axillaire LN (met minstens 1 > 2.0 mm) metastasen in MI LN volgens sn-procedure, maar klinisch niet verdacht metastasen in 1-3 axillaire LN + metastasen in MI LN volgens sn-procedure en klinisch niet verdacht

Stadiëring PET scan? Enkel in studieverband, manier om antwoord op chemo te volgen Sentinel node! Belang micrometastase en geïsoleerde tumorcellen? Geen associatie IHC-SN en BM BM meta heeft prognostisch belang, IHC-SN niet! CTC gebruiken in prognose en follow-up van de therapie? tailoring lengte chemotherapie?

EUSOMA registratie SenoNetwork Meeting, 1-10 in Wenen Topics Trends in mastectomie Eusoma database : «QT» Eusoma certification process for quality in comprehensive and multidisciplinary breast care

QT QT is a public domain oncological database designed for multidisciplinary Breast Units Breast Units can use QT to manage Q = Quality T = Treatment But also screening, assessment, pathology and FU Adopted as EUSOMA data base QT calculates, also surgical outcome

QT allows the use of the system by different specialists involved in breast cancer assessment and management: radiologists, surgeons, pathologists, radiotherapists, medical oncologists Data can be stored runtime on a PC network in the Breast Unit Radiologist Pathologist QT Surgeon Radiotherapist, Oncologist

QT includes: 22 data-entry forms 25 Outcome measures 1 Trim. 2 Trim. 3 Trim. 4 Trim. 5 automatic reports (History, Assessment, Surgery) EpiInfo 6 Emulator (for complex statistical analysis)

Guided data-entry: colors help to distinguish minimum set fields (white) from other less important items (green). Not pertinent fields are grey

Outcome measures easily calculated with just one click

Automatic reports available: Diagnostic rep. Surgical rep. Histological rep. History rep. Surgery description rep. Date 06/11/2000 Mrs. Jenny Smith Diagnostic report First Screening Centre S.John Hospital Bourbon Street, 31 LT160, Caribbean Borough Screening mammogram carried out on 02/08/2001. Assessment session carried out on 14/08/2001. Palpable lesion of 15 mm. measured by ultrasound located in inferior-internal area of right breast. At mammography is an abnormality of indeterminate significance (R3)(06/08/2001). Microcalcifications state is unknown. Ultrasound result is lesion presenting malignant features (U5) (14/08/2001). FNA has not been performed. Core biopsy guided by ultrasound has been performed (15/08/2001) with the following hystological result: "B5-Malignant". Recommendation (15/08/2001): exeresis. The following axillary operation was performed: sentinel lymphnode. Histopathological diagnosis: Invasive carcinoma.

Multidimensional analysis up to 4 variables and graphical reports

QT can be used: by specialists during multidisciplinary meetings and patients management for summarising and evaluating the activity of the Breast Unit for specialist training in breast cancer by screening programs to monitor quality of diagnosis and treatment of screen detected cancers by Cancer Registries for high definition registration of breast cancer at the population level

Behandeling Heelkunde Trend mastectomie AND after SNB Radiotherapie Tamoxifen «enkel» bij oudere patiënten Targitt - IOR Systeemtherapie Chemotherapie Eribulin Triple negatief Hormonotherapie Round-up - LHRH agonisten en AI! Kleine molecules- Antistoffen- Angiogeneseremmers Herceptine-lapatinib : studieprotocol! Avastin te overwegen bij Triple negatieve tumoren?

Heelkunde : mastectomie Stijgende trend mastectomies? In vraag gesteld JCO «Are mastectomy really increasing in the united states?» B.Habermann et al. Borstcarcinomen, stadium DCIS tot III, dalende trend van 2000 tot 2006 : 40,8 naar 37% (SEER data base, 26% USA ): 233.754 patiënten Verder onderzoek en follow-up blijft noodzakelijk Mastectomie registratie en bewustwording! Ook introduceren in Malle Wenen, Eusoma 1-10

Heelkunde Duidelijke marge noodzakelijk: > of = 1mm: 5% recidief 15% indien + marge BCS nog overwegen indien multifocaal en of multicentrisch in geselecteerde gevallen Volledig risicoprofiel te bekijken!

Heelkunde : axilla Indien SN negatief, geen AND! geen verschil in OS, DFS na 8 jaar ; Krag,et al. NSABP B-32 Zelf indien 1 of 2 SN positief, bij T1-2, AND in vraag te stellen geen verschil na 5 jaar recurrence of OS, studie echter probleem met accrual ; Giuliano, et al. ACOSOG Z0011

Radiotherapie BCS en Tamoxifen is verantwoord bij oudere vrouwen, >70j met kleine, N0, endocrien gevoelige borstcarcinomen!, bovendien is OS na 10 jaar : 98 versus 96% (Hughes et al.) TARGIT trial, Baum et al.: na twee jaar geen verschil in herval : 0,3% ( Externe RT versus IORT ) : N:2232, vrouwen meer dan 45j, T<2cm, meestal N- Te korte FU, te gunstige groep? Introduktie in KLINA? Borstkliniek Voorkempen?

Chemotherapie Geen belangrijke evoluties in adjuvante setting Consensus over incorporatie Taxanen adjuverend ( drie meta-analyses ) 3-5% DFS 2-3% OS Geen selectie van subgroep mogelijk Richtlijnen Sankt-Gallen ( 2009 )

St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2009 Table 2: Thresholds for treatment modalities Treatment modality Indication Comments Endocrine therapy Any ER staining ER negative and PgR positive are probably artefactual Anti-HER2 therapy Chemotherapy ASCO/CAP HER2 positive (>30% intense and complete staining (IHC) or FISH>2.2+) May use clinical trial definitions In HER2-positive disease (with anti-her2 therapy) Trial evidence for trastuzumab is limited to use with or following chemotherapy Combined endocrine therapy + anti-her2 therapy without chemotherapy in strongly ERpositive, HER2-positive is logical but unproven In triple-negative disease Most patients No proven alternative; most at elevated risk In ER-positive, HER2- negative disease (with endocrine therapy) Variable according to risk See tabel 3

St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2009 Table 3: Chemoendocrine therapy in patients with ER-positive, HER-negative disease Clinicopathological features Relative indications for chemoendocrine therapy Factors not useful for decision Relative indications for endocrine therapy alone ER and PgR Lower ER and PgR level Higher ER and PgR level Histological grade Grade 3 Grade 2 Grade 1 Proliferation High Intermediate Low Nodes Node positive (four or more involved nodes) Node positive (one to three involved nodes) Node negative PVI Presence of extensive PVI pt size >5 cm 2.1 5 cm 2 cm Patient preference Use all available treatments Absence of extensive PVI Avoid chemotherapyrelated side-effects Multigene assays Gene signature High score Intermediate score Low score

Hormonotherapie Situering verschillen DFS, OS Hormono en chemo Hormonotherapie hoeksteen bij sterk receptor positieve tumoren Chemo beperkte meerwaarde! AI : benefit Belangrijke drop-out, 20 à 40%! Motivatie voor inname! Weinig evidentie voor «combined approach» Ovarian suppression + TAM Chemo + LHRH + TAM

Gain in the adjuvant setting : tamoxifen and chemotherapy versus control Lancet 2005; 365: 1687 1717

Lancet 2005; 365: 1687 1717

Gain in the adjuvant setting : tamoxifen versus AI Ingle J et al. SABCS 2008

. Heterogeneity of our patients Oe 100% Ki 67 low Oe 20% Oe 100% Ki 67 High

Efficacy end-points DFS TTDR TTR RR PFS TTP CB OS

Cost-benefit analyse!

AIs and Tamoxifen: Potential Risks and Benefits Contralateral BC Osteoporosis risk Myalgia Hyperlipidemia Tamoxifen Neurocognition? Sexual function? Cardiovascular disease? Contralateral BC Deep vein thrombosis Endometrial cancer Hot flashes AI Hot flashes Thromboemboli Endometrial cancer Genitourinary adverse effects Arthralgia/myalgia Osteoporosis risk Goss P CCO Oncology

Is progress in hormonal manipulation still possible? The working room of Antonio Gaudi

Estrogen Carcinogenesis in Breast Cancer Yager JD et al. N Engl J Med 2006;354:270-82.

Different future with new opportunities!

Hormonotherapie : adj-premenopause ABCSG-12 Goserilin + Tamoxifen versus Goserilin + Anastrozole Overgewicht nadeling voor ANA ( 9 % versus 5% distale meta s ) OS zeker niet beter met ANA => geen LHRH +AI adjuvant zeker indien obese patient!

Optie neoadjuvante hormonotherapie Fase II studie met drie AI Postmenopausaal bij stadium II-III borstca Neo-adjuvante respons bij ER ++ carcinomen na 16 weken : 60-70% Optioneel om borstsparend te werken

Revalidatie Update noodzakelijk sessie Borstchirurg, Med. oncoloog en Plastisch chirurg: één presentatie noodzakelijk tegen dec. 2010 MO: Situering prognose, erfelijkheid en follow-up, bespreking drop-out hormonotherapie! MO-BC: - Neveneffecten behandeling, soms langdurige hormonotherapie (hormonot = anticonceptie) - Vermoeidheid, depressie, slaapproblemen, geheugen stoornissen, lymfoedeem, seksuele stoornissen, fertiliteit, «body image» BC: - Behandeling symptomen - Belang informatie met mogelijke aternatieven PC: Rekonstruktie mogelijkheden Introduktie relaxatiesessie fysio! Updating website! Met deze informatie!

Metastase Herbiopsieren eerste metastase! Hormonotherapie Nieuw cytostatica: Eribulin Triple negatief tumoren! PARP inhibitor : Veliparib BSI-201 Her2 positief Continueren Herceptin bij progressie! Of «Lapatinb»? Angiogenese-inhibitie in vraag SUTENT AVASTIN bij Triple negatieve tumoren terugbetaald

Herbiopsieren van metastase letsel Klinisch belangrijk en wijzigingen mogelijk : drie studies! Discordantie tussen primaire tumor en meta Weefsel fixatie Biologisch : genomische heterogeniteit Selectie subpopulatie door therapie Tot 15% klinisch relevante wijziging

Hormonotherapy :Gain in the Palliative situation As first-line treatment vs tamoxifen Overview of efficacy data from randomised trials Time to Progression Trials 0027&0030 combined Arimidex tamoxifen p value ER+ and/or PgR+ tumors 10.7 mths 6.4 mths 0.022 (2-sided) letrozole tamoxifen Study 025 9.4 mths 6.0 mths 0.0001 (2-sided) Phase II trial exemestane tamoxifen N.A. 9,9 mths 5,8 mths Bonneterre J et al Cancer 2001;92:2247 58 Mouridsen H et al J Clin Oncol 21, (11) 2003: 2101-2109 Paridaens R et al. J Clin Oncol 26 (30) 2008: 4883-4890

EMBRACE study : fase III ERIBULIN ( synthetisch analoog halichondrin B= nieuw, niet taxaan antimicrotubuli product ) Bij sterk voorbehandelde pt ( N:762 ), minstens taxaan en antracycline Eribulin versus chemo keuze onderzoeker Verbeterde overleving ( 2,5 maanden ) Toxiciteit acceptabel: moeheid, neutropenie, neuropathie

PARP Inhibitor Mechanism of Action PAR chains are degraded via PARG Repair enzyme DNA damage PARP PAR PAR Binding to DNA PARP modifies itself, producing large chain of PAR Rationale for PARP inhibition in TNBC/BLBC Numerous chemotherapy (alkylating agents, platinum salts, antimetabolites) and ionizing radiation induced DNA damages repaired by DNA repair mechanisms inhibition of this pathway would increase the cytotoxicity Fong PC et al, NEJM, 2009, 361: 123-34 (appendix)

PARP Inhibitor Mechanism of Action BSI-201 C C G T C A G T G A C 1 Cancer Chemo DNA strand break Tumor growth inhibition Small molecule PARP inhibitor C C G T C A G T G A C G 3 2 PARP upregulation + BSI-201 DNA repair Enhance tumor response to chemotherapy Potentiates effects of chemotherapy-induced DNA damage

Phase II TNBC Study: Treatment Schema Metastatic TNBC N = 120 RANDOMIZE Gemcitabine (1000 mg/m 2, IV, d 1, 8) Carboplatin (AUC 2, IV, d 1, 8) 21-Day Cycle BSI-201 (5.6 mg/kg, IV, d 1, 4, 8, 11) Gemcitabine (1000 mg/m 2, IV, d 1, 8) Carboplatin (AUC 2, IV, d 1, 8) RESTAGING Post-Cycle 2 & every 6-8 wks * Patients randomized to gem/carbo alone could crossover to receive gem/carbo + BSI-201 at disease progression J O Shaughnessy, JCO, 2009, 27 (15S): abstr 3

Efficacy Summary* Gem/Carbo (n = 59) BSI-201 + Gem/Carbo (n = 57) P-value Objective Response Rate, n (%) **Clinical Benefit Rate, n (%) 7/44 (16%) 20/42 (48%) 0.002 9/44 (21%) 26/42 (62%) 0.0002 *Includes patients enrolled before September 30, 2008 and patients who had a confirmed response or disease progression **Clinical Benefit Rate = CR + PR + SD 6 months J O Shaughnessy, JCO, 2009, 27 (15S): abstr 3

Progression-Free Survival BSI-201 + Gem/Carbo (n = 57) Median PFS = 6.9 months Gem/Carbo (n = 59) Median PFS = 3.3 months P < 0.0001 HR = 0.342 (95% CI, 0.200-0.584) J O Shaughnessy, JCO, 2009, 27 (15S): abstr 3

J O Shaughnessy, SABCS, 2009: abstr 3122 Overall Survival

Conclusions PARP1 was upregulated in most evaluated TNBC patients BSI-201 + gemcitabine/carboplatin was well tolerated and did not potentiate chemotherapy-related toxicities BSI-201 (Iniparib ) improved patients clinical outcomes Clinical Benefit Rate (62% vs. 21%; p = 0.0002) ORR (48% vs. 16%; p = 0.002) Median PFS (6.9 months vs. 3.3 months; p < 0.0001) Median OS (12.2 months vs. 7.7 months; p = 0.005) J O Shaughnessy, JCO, 2009, 27 (15S): abstr 3 and SABCS, 2009, abstr 3122

Update Triple negatieve op ASCO Betere respons op Taxaan bij BRCA-2 drager Responders op Temozolomide en Velaparib (ABT-888 ; fase 2 ) enkel bij BRCA dragers

Target-therapie, Herceptine resistentie! Verderzetten Herceptine bij progressie Trial Beyond progression met andere chemotherapie Nieuw antistof Pertuzumab ( ander anti-her 2 antistof ) Nieuwe en oud STI Lapatinb en capecitabine voordeel tegenover capecitabine HKI-272

Angiogeneseremmers ter discussie? Negatieve studies met SUTENT! (fase III met capecitabine en docetaxel ) Geen effect op overleving met bevacuzimabtaxol, wel effect op RR 6 maanden verschil in PFS ECOG 2100 Twee andere studies (AVADO-RIBBON ) slechts 1 maand verschil in PFS, en niet in OS Belang subgroep te selecteren? Terugbetaling enkel bij Triple negatieve is niet gebaseerd op biologisch correlaat!

Klinische studies DATA management Gwen Colfs Caroline De Smet Sofie Herman 7 studies open voor inclusie: Aantal inclusies: 86

PACS Adjuvant Chemotherapie : open label, fase III Inclusie: N+ of N- (indien T>2cm of SBR 2 of 3 Triple neg of enkel ER + als N+ Exclusie: mastitis Twee armen A B :3 X CEF 3 X Taxotere :3 X CEF 3 X Ixabepilone Aantal inclusies : 15

Adjuvant Hormoontherapie SOLE : open label, fase III Inclusie Postmenopausaal ER en/of PR +, N+ Exclusie osteoporosefraktuur Twee armen : na 5 jaar adjuvante hormonotherapie ( elke vorm! ) A :continu letrozole 2.5 mg gedurende 5 jaar B :intermittent letrozole 2.5 mg gedurende 9 maanden, 3 maanden rust Aantal incusies : 28 Studie van IBCSG? Lidmaatschap einde jaar

Adjuvant Antistoffen BETH: adj. Herceptine +/- Avastin Inclusies: 14 OHERA: observatief cardiotoxiciteit met Herceptine Inclusies: 24 Worden afgesloten in september 2010

Metastase: eerste lijn chemotherapie Neu - TRIO 012: double-blind fase III Inclusie :eerste lijn meta, chemo Exclusie :hersenmetastase Twee armen A :Taxotere + IMC B :Taxotere + placebo IMC 1121 B : monoclonaal Ab tegen VEGFR2 Gestart juli 09: 1 inclusie!

Metastase: progressie op hormonor/ AI Neu BIIB: open label, fase IIA, Hormonotherapie, tweede lijn na AI Inclusie: Progressie tijdens of binnen de 12 mnd na beeindiging van adj. hormonotherapie Progressie tijdens AI voor gemetast. Borst Exclusie: Exemestane, Neu +, hersenm+ Twee armen: A B :25mg Exemestane+ 100mg BIIB021 BID :450mg BIIB021 TIW Heat shock proteine

Metastase: progressie op hecerptine eerste lijn PHEREXA: Inclusie: Reeds taxanen gehad Progressie na herceptine Exclusie: Neu + reeds Xeloda gehad insuline-dependente diabetes Twee armen A :Capecitabine +Herceptine B :Capecitabine +Herceptine +Pherexa Inclusies : 1

Publicaties en abstracts Lapatinib en hersenmeta s: «The Oncologist» - ESMO abstract Actual indications for mastectomy: how to cope with the increasing trend? D. Verhoeven, I. Biltjes, W. Demey, P. Naudts, J. Teuwen (BJMO 2009;Vol 3;6:236-242) Faslodex 500 mg: JCO - publication accepted for publication