BREAST CANCER Updated June 2016 by Dr. Nixon (PGY-5 Medical Oncology Resident, University of Calgary)

Transcription

1 BREAST CANCER Updated June 2016 by Dr. Nixn (PGY-5 Medical Onclgy Resident, University f Calgary) Reviewed by Dr. Jan-Willem Henning (Staff Medical Onclgist, Tm Baker Cancer Centre, University f Calgary), Dr. Eitan Amir (Staff Medical Onclgist, Princess Margaret Cancer Centre, Trnt) and Dr. Christine Simmns (Staff Medical Onclgist, BC Cancer Agency Vancuver) DISCLAIMER: The fllwing are study ntes cmpiled by the abve PGY-5 medical nclgy residents and reviewed by a staff medical nclgist. They reflect what we feel is relevant knwledge fr graduating medical nclgy residents preparing fr their final examinatin. The infrmatin has nt been surveyed r ratified by the Ryal Cllege. A) PUBLIC HEALTH EPIDEMIOLOGY - Mst cmmn life threatening cancer amng wmen; secnd mst cmmn cause f cancer mrtality - Cmpared t white wmen, black wmen have lwer incidence f develping breast cancer but higher rate f breast cancer-related mrtality due t higher incidence f triple negative disease, and presenting with mre advanced disease - Incidence increasing in ecnmically develping cuntries pssibly due t lifestyle changes (besity, decreased physical activity), pssibly due t increased awareness and imprving diagnstic tls, and als changes t hrmnal risks such as increasing nulliparity and lder age at first pregnancy and reduced breast feeding. There is sme element f verdiagnsis in cuntries with screening prgrams. - Incidence decreasing in develped cuntries since 2002, likely as result f decreased HRT - Mrtality decreased 30% ver last 10 years in CA, US, UK mst likely related t increased screening and new therapies (als sme f this is stage migratin resulting frm verdiagnsis) RISK FACTORS - Risk Mdels Mdified Gail Mdel: mst widely used, calculates 5 year and lifetime risk f breast cancer based n varius variables: Age, age at menarche, age at first pregnancy, number f bipsies, presence f atypical hyperplasia, number f first-degree relatives w breast cancer, and race. Underestimates risk if significant genetic predispsitin BRCAPRO, IBIS (Tyrer-Cuzick), BOADICEA: calculate risk based n risk f harbring genetic mutatin and have als been validated as general risk calculatrs. - Weak (RR<2X) FMHX pst-menpausal cancer (excluding male r bilateral) Higher SES Nulliparity; later age f first birth (>30); late menpause (>55); early menarche (<15); pst-menpausal besity; ETOH; Diet; lng term HRT - Mderate (RR 2-4) Older age NA and N Eurpean residence FMHX Pre-menpausal BC Persnal HX BC: breast hyperplasia w/ut atypia; mammgraphic density >50% breast vlume - Strng (RR >4) FMHX f 3 (+) relatives with pre-menpausal bilateral BC r pre-menpausal in mther, grandmther, sister, daughterr varian cancer in grandmther, mther, sister, aunt r male breast cancer at any age

2 Evidence f genes (BRCA1/2; PTEN; TP53; CHD1; STK11; PALB2) BRCA1: Cumulative risk by age 70: Breast: ~65% Ovarian ~40% 2X increase risk pancreas 2-4X increase risk cln in patients <50y. Risk equivalent t ppulatin risk >50 y. BRCA2: Cumulative risk by age 70 Breast: ~45% Ovarian: ~11% 5-9X increase risk f prstate 3.51X increase risk pancreas Persnal HX lbular carcinma in situ Breast atypical hyperplasia Mammgraphic density >50% breast PREVENTION & SCREENING - Lifestyle Changes Physical activity: 3 prspective studies shwing recreatinal exercise can reduce incidence f breast cancer by 20-30%, especially amng pre-menpausal Diet and weight change: less alchl cnsumptin and maintain healthy weight - Risk-Reducing surgery: Ophrectmy: Recmmended fr BRCA carriers befre age 40 (decreased varian risk, breast cancer risk, all-cause AND varian cancer-specific mrtality) Bilateral mastectmy: decreases risk f breast CA >90% fr high risk/brca patients - Medical (Chempreventin):SERM and AI effective fr risk f ER psitive DCIS and IDC amng wmen with elevated risk using mdel (e.g. Gail) Tamxifen: EBCTCG trial shwed decreased risk f 39% fr cntralateral breast cancer in patients n 5 years adjuvant TAM at 15- years fllw up NSABP BCPT P-1: Wmen with 5 year risk (by Gail) >1.66% r LCIS received TAM fr 5 years vs. Placeb. 7-year FU shwed decrease risk f invasive breast CA 43% (62% hrmne psitive). NO effect n verall mrtality Ralxifene: MORE and CORE trial shwed decrease incidence f invasive breast cancer by 69-72% STAR cmpared TAM t Ralxifene: N difference at 4 years fllw up, hwever at 8 years fllw up Ralxifene retained 76% f effectiveness in reducing risk f invasive cancer with less txicity (VTE, endmetrial CA) Exemestane: NCIC CTC MAP.3 Exemastane vs. placeb 65% risk reductin fr invasive breast cancer (73% fr hrmne psitive) Anastrzle: IBIS-2 - ANA vs. placeb - The predicted cumulative incidence f all breast cancers after 7 years was 5.6% in the placeb grup and 2.8% in the anastrzle grup (significant) TRIAL PATIENTS (N) COMPARISON RR RR+ (hrmne +) STAR Ralxifine vs. TAM 1.24 NA MAP Exemestane vs. Placeb IBIS II Anastrazle vs. Placeb Italian TAM vs. Placeb Ryal Marsden TAM vs. Placeb IBIS TAM vs. Placeb BCPT P TAM vs. Placeb

3 - Screening: Data frm evaluatin f RCT published in 2002 suggests 23% reductin in breast cancer mrtality in wmen ages 50-70, and 15% reductin fr ages Updated evaluatin in 2009 shwed 14% fr wmen aged 50-59, and 32% (Nelsn et al 2009) n verall mrtality reductin (Cchrane Database) Mdalities Digital Mammgraphic Imaging Screening Trial (DMIST): cmpared digital images with film screen images. Overall, n difference in diagnstic accuracy, hwever digital was superir in detectin f malignancy amng pre- r peri-menpausal wmen, wmen <50, and wmen with dense breast tissue Ppulatin based study f tw-view film-screening mammgraphy vs. digital in Osl fund sensitivity f 77% with digital vs. 62% with film screening. Digital breast screening tmsynthesis: 3D imaging similar t CT >90% sensitivity, slightly greater radiatin N trial w direct cmparisn with DBT and rutine screening Ultrasund (US): Detects and defines ambiguus lesins n mammgraphy; characterizes palpable masses NOT useful alne; increased sensitivity f mammgram by 25% in a study by ACRIN in select ppulatin (dense breast). Als had increased false psitive rate Clinical Breast exam: In 2015, Canadian Task Frce n Preventive Health Care and ACS recmmend nt perfrming clinical breast examinatin, given ptential fr false psitive and lack f evidence fr imprved utcmes Breast self exam: has NOT been shwn t increase detectin f early-stage breast CA n ppulatin basis MRI: Utility in high risk ppulatin (see belw) Recmmendatins Average risk age Mammgram q2 years Age discuss w patient, q1 year if decide t screen. Decisin based n ther individual risk factrs (see abve) (Canadian TOP guidelines). Age 75 (+): cnsider individual health factrs/life expectancy and patient preference High Risk Grups BRCA mutatin: Wh t screen: Varies prvincially Diagnsis f breast cancer befre age 50, especially triple negative Bilateral breast cancer Breast and varian cancer in same patient One (+) male family members with breast cancer Multiple family members with breast r varian cancer One family member wh is psitive fr BRCA Ashkenazi Jew with diagnsis f breast cancer In general, screening begins at age 25 with annual mammgraphy and MRI (usually 6 mnth alternating with mammgram) PLUS biannual clinical breast exam MRI when added t mammgram increases sensitivity frm 25-59% t % (als decreased specificity frm 93 t 73%) Adding MRI t mammgram is assciated with a 70% reductin in lymph nde psitive r large invasive breast cancer Annual MRI als ffered t untested first degree relatives f BRCA patient Other: Annual MRI is als recmmended fr Li-Fraumeni, Cwden, histry f mantle radiatin fr treatment f lymphma prir t age 30 based n extraplatin frm data frm BRCA studies

4 Cnsider annual MRI fr wmen with lifetime risk >20-25% based n risk mdels that depend n family histry NOT Gail. B) PRESENTATION & DIAGNOSIS SYMPTOMS & SIGNS - SYMPTOMS:Palpable mass, unilateral nipple discharge, inflammatry breast cancer (uncmmn; see belw), SX frm metastatic disease (bne pain, RUQ pain) - Cmmn Presentatins: Often with psitive screening examinatin r palpable mass. INVESTIGATIONS - Labratry (pre-treatment): Basic bldwrk (CBC, electrlytes, Creat) Liver Enzymes (including ALP) - Diagnstic Prcedures: All patients with a palpable area f cncern shuld underg triple diagnstic investigatin (clinical, radilgical and pathlgical). Screen-detected abnrmalities can be simply fllwed up if appear benign r subjected t tissue diagnsis. Abnrmal screening mammgram shuld have diagnstic mammgram (mre views than standard 2 views in screening mammgram) +/- US Nrmal mammgram shuld NOT delay DX if palpable mass Bipsy nn-palpable using fine wire lcalizatin Bipsy fr diagnsis: Cre BX > FNA (des nt prvide enugh tissue t differentiate invasive frm nn-invasive r t d receptr testing) PATHOLOGY & MOLECULAR BIOLOGY - Cmmn Histlgy: Majrity is either infiltrating ductal carcinma (IDC; 75%) r infiltrating lbular carcinma (ILC; 10%) r a cmbinatin IDC easier t see mammgraphically vs. ILC ILC has increased frequency f multifcality and higher incidence f bilateral invlvement and ndal invlvement at time f diagnsis Prgnsis similar - Cmmn Metastatic Sites (de-nv metastatic disease rare except in nde psitive wmen): Bne: Mre cmmn first site f mets fr ER+, pst-menpausal cancer (but 75% f all metastatic breast cancer patients develp bne metastases at sme pint in the natural histry f their disease) Liver Lung Brain - Relevant Mlecular Bilgy: Tumr size: greatest diameter. If multifcal use largest lesin nt summatin Grade (based n nuclear size; tubule frmatin; #mitsis/hpf) I-III Lymphvascular invasin Margins (less f an issue than befre; ASCO/ASTRO guideline) LN (# resected, # psitive) Extrandal extensin ER/PR: IHC n cre BX; may be dne n surgical if results incngruent w histlgy 0 (Allred 0-2); 1+ (Allred 3-4); 2+ (Allred 5-6); 3+ (Allred 7-8)l; als cmmnly reprted as % nly HER2/neu: verexpressed in ~15-20% Initial IHC: 3+ psitive; 2+ intermediate; 1+ negative If 2+: mve n t in-situ hybridizatin(lk at rati f HER2 signal t chrmsme 17 centrmere) - can be flurescent, silver, dual-clur r chrmphbe.

5 FISH rati f >/=2 is cnsidered psitive (this was the cut-ff used in clinical trials lking at Herceptin) - Intrinsic Mlecular Subtypes Have very limited effect n clinical practice, but prvide infrmatin n tumur bilgy/ Require availability f a gene expressin assay r use immunhistchemical surrgate. Specific gene expressin signature with clinical characteristics; subtypes characterized by IHC have >1 IHC prfile IHC used as surrgate t define mlecular subtypes since genmic prfiling n all patients nt practical Ki67 used as alternative marker f prliferatin hwever has less clinical validity than mlecular testing; n cntinuus distributin therefre challenge t define useful cutpint Luminal A: ER/PR+; ften lw grade, lw incidence f p53 mutatin, assciated with best verall prgnsis Luminal B: ER+, PR+/-, with mre expressin f prliferatin and HER2 related genes; ften higher grade and less favrably prgnsis cmpared w luminal A HER2: Demnstrates verexpressin f genes within the ERBB2 amplicn. Frequently HER2+; ER/PR- r lw; mre ften high grade and assciated with mre p53 mutatins (40-80%) Basal-like: mimic basal epithelial cells by nt expressing HR r HER2 related genes. Assciated with the least favrable prgnsis. BRCA1 assciated cancers are ften basal-like (BRCA2 include entire spectrum, ften EGFR ver-expressing and may express CK5/6.). STAGING - Investigatins Fr stage I IIB: cnsider additinal studies nly if directed by signs r symptms If clinical stage IIIA (T3, N1, M0) cnsider: Chest CT, abdminal +/-pelvic diagnstic CT r MRI, bne scan r PET/CT - Uses TNM staging system Tumur T1 mic: <0.1mm T cm (T1a: cm, T1b: cm, T1c: cm) T cm T3 >5 cm Ndes Ni+ <0.2mm metasteses (single cells r islated tumr cell clustering) N1mi: micrmetasteses 0.2- <2mm N1 1-3 ndes N2 4-9 nes N3 >10 Metastases MX unknwn M0 nne M1 present - Stage IA: T1N0M0; IB: T0-1N1micM0 IIA: T0-1N1M0; T2N0M0; IIB: T2N1M0; T3N0M0 IIIA: T0-2N2M0; T3N1-2M0; IIIB T4N1-2M0 IV: any M1

6 C) TREATMENT Stage 0: Ductal Carcinma in Situ (DCIS) - Cmplete replacement f nrmal cells with spectrum f abnrmal cells cnfined t the duct withut invasin % will ultimately prgress t invasive disease if nt remved - Management: Detailed mammgram t btain preperative extent f disease Surgery fr lcal cntrl RT if DCIS >1cm treated with BCS, and ALL with margins <5mm Mastectmy recmmended fr DCIS >5cm - NSABP: Tamxifen shwn t decrease ccurrence f invasive and in situ disease when cmbined with RT(Allred et al, 2012) Cntributes an additinal 32% RRR in lcal recurrence and 53% fr risk f cntralateral disease 15 years after DX Nt yet assciated with imprved OS LOCALIZED / ADJUVANT Lcal disease cntrl Stage I, II and III disease - Ttal mastectmy Adjuvant RT shuld be added if 4 (+) axillary ndes psitive; clinical evidence fr internal mammary invlvement; psitive surgical margins; tumur >5cm Cnsider if 1-3 LN+, r fr tumur>5cm, especially with adverse pathlgy - Breast cnservatin therapy (BCT): Demnstrated in NSABP B-06 t be equivalent OS t mastectmy RT: reduces abslute risk f ipsilateral breast recurrence by 30-40% dwn t 5-7% Cntraindicatins t BCT + RT: prir RT and cnnective tissue disease invlving the skin (i.e. sclerderma) - Clinically Nde psitive that are dwn-staged after NAT: SLN apprpriateness cntrversial False negative rate remain >10% unless 3 (+) ndes examined - SLND fr clinically negative disease AMAROS trial: Patients with T1-2 primary breast cancer and n palpable LAN were randmized t receive either ALND r axillary RT in case f psitive SLN 5y axillary recurrence 0.43 after ALND vs. 1.19% after axillary RT. Axillary RT resulted in significantly less mrbidity ACOSOG Z011: Clinically nde negative patients wh underwent SN BX and had 1 r SN with metastases were randmized t ALND r n further axillaryspecific treatment All patients were treated with lumectmy and ppsing tangential field irradiatin SNB alne had median 2 LN remved; ALND had median 17 5 y breast recurrence 3.7% (ALND) vs. 2.1% SLNB alne 5y ndal recurrence 0.6% vs1.3% 5yOS 91.9% vs 92.5% (ALND vs. SLNB) ADJUVANT SYSTEMIC THERAPY General Apprach: 3 Brad categries: HR+; HER2+; Triple negative Decisin t add is based n the risk f distant metastasis and the benefit f therapies t reduce the risk Gene expressin prfiles risk f recurrence, +/- benefit f chemtherapy (e.g.mammaprint r ONCOTYPE DX: belw)

7

8 *Recurrence scres may help with decisin-making in apprpriate patients (see ONCOTYPE belw) ADJUVANT HORMONE - Bttm Line General Apprach: IHC 1+ (Allred 3-4) debatable benefit, usually ffered treatment; IHC 2+ (Allred 5-6) and 3+ (Allred 7-8) shuld get treatment PRE-MENOPAUSAL

9 Standard 5 years f TAM; if still pre-menpausal additinal 5y TAM (ATLAS); if pst-menpausal, cnsider AI In ATLAS: nly 8% f patients were pre-menpausal therefre must cnsider generalizability f results. Ovarian suppressin (Surgery vs. LHRHa) +AI SOFT/TEXT Pagani O, et al2014 JCO(32:5s) Regimen Primary Endpint Inclusin/Exclusin Criteria Size (N) Results Txicity Cnclusin Other Cmments 5y TAM 5y TAM vs. Placeb DFS (invasive recurrence lcal/reginal/distant; invasive CL BC; Secnd nn-breast invasive malignancy; Death w/ut prir cancer event) Prtcl amended in 2011 (befre efficacy data available) fr jint analysis with SOFT and TEXT Pre-MP; <12w after surgery; planned OFS; +/- CTX 4690 (cmbined w SOFT) DFS: 91.1 vs. 85.3% at 5 y (3.8% difference) EX+OFS vs. TAM+OFS AE cmparable with pst-mp wmen; early cessatin f all assigned TX mre frequent w EX+OFS EX+OFS vs TAM+OFS Greater difference bserved in wmen wh received chemtherapy (higher risk disease) as utcmes in lwer risk very gd regardless Study nt designed initially t be cmbined therefre slightly different inclusin criteria (in SOFT had t remain pre-mp <8 m. after CTX Greater benefit seen in pts under age 35 EX+OFS vs. Tam imprved utcme by 5-7% but fr thse under age 35 imprved utcme by 12% N Tamxifen alne arm included in final analysis POST-MENOPAUSAL 5y ttal primary (AI r TAM) EBCTC TAM 5y (HR recurrence 0.61) ATAC Anastrazle (ANA) v TAM (HR 0.9) BIG 1-98 Letrzle (LET) v TAM (HR 0.88) ABCSG-12 *3 years treatment ANA+OFS v TAM+OFS (HR 1.1) Switch ttal 5y ABCSG-8 TAM/ANA v TAM (HR 0.85) BIG 1-98 TAM/LET v LET (1.05) LET/TAM v LET (0.96) ITA TAM/ANA v TAM (0.57) TEAM TAM/Exemestane (EXE) vs EXE (HR 0.97) IES TAM/EXE vs TAM

10 FIRST and nly STUDY TO SHOW IMPROVEMENT IN OS until ATAC AND ATLAS NSAS BC-03 TAM/ANA vs TAM (clsed early) ARNO 95 Extended Adjuvant attom (2013) TAM X5y Cntinue vs. stp ATLAS Regimen Primary Endpint Inclusin/Exclusin Criteria Size (N) ATLAS Davies C. et allancet(2013) 381: y TAM 5y TAM vs. Placeb Recurrence, BC mrtality, verall mrtality Early breast cancer (surgically resected); Tamxifen (current r stpped within past year); clinically free f disease ER negative r unknwn nt included in final analysis f utcmes; were included fr txicity 12894; 6048 with ER unknwn r ER negative were included, but subgrup analysis f 6846 wmen with ER + were reprted n Results Recurrence (10y pst entry) 25.1 vs. 21.4% (5 vs. 10y) BC mrtality (10y pst entry) 15 vs. 12% Overall mrtality (10y pst-entry) 18.6 vs. 21.1% Txicity Cnclusin Other Cmments Fr wmen with ER+ disease 10 vs. 5 years f TAM further reduces recurrence and mrtality, particularly after year 10 Accrual stpped early due t benefit seen in MA.17 MA. 17 5yTAM LET vs Placeb (0.68) Mdest imprvement in OS that was statistically significant fr nde psitive wmen ABCSG-6a 5yTAM ANA vs Placeb (0.62) NSABP B-33 5y TAM EXE vs Placeb (0.68) Overall: Additin f AI (either 5y r switch) is assciated w 3% fewer DFS events (CL breast cancer, relapse, death frm any cause)

11 Armatase inhibitrs versus tamxifen in early breast cancer: patient-level meta-analysis f the randmized trials Lancet. 2015;386: Regimen Meta-analysis n individual patient data Mechanism f. Actin f Experimental Drug Primary Endpint Any recurrence f BC, BC mrtality, death withut recurrence and all-cause mrtality Inclusin/Exclusin pst MP wmen with ER+ early breast cancer in trials f 5y AI vs 5y Criteria TAM; f 5y AI versus 2-3y TAM plus AI t 5y Size (N) Results 5y TAM vs. 5y AI: recurrence RR favred AI significantly during years 0-1(RR0.64) and 2-4 (RR0.88); ns thereafter 10y BC mrtality lwer w AI (12.1 vs 14.2% 2p = 0.009) 5y AI vs. switch: RR favred AIwhile patients were n AI, but nt after switch. Breast cancer mrtality reductin was ns 5y TAM vs. switch: RR favred AI during years 2-4 (RR0.56) but nt thereafter, and 10-y BC mrtality was lwer with switch (8.7 vs p = 0.015) Txicity Cmpared t Tamxifen, AIs are assciated with greater risk f ischemic heart disease and bne fracture, but lwer risk f venus thrmbsis and endmetrial carcinma. Risk f cerebrvascular disease is similar. (Amir et al JNCI 2011) Cnclusin Recurrence RR favrs AI during time when treatment differs but nt significantly thereafter. BC mrtality was reduced bth when treatment differed (RR0.79) and subsequently (RR0.89) and fr all perids cmbined (RR0.86) Interpretatin AI reduce recurrence rates by abut 30% (prprtinately) cmpared with TAM while treatment differs but nt thereafter 5y f AI reduced 10y BC mrtality rates by abut 15% cmpared w TAM, hence by abut 40% (prprtinately) t n endcrine TX Fr patients at risk f early relapse (large tumur, high grade, ndal invlvement and n chem) upfrnt AI is the preferred apprach. Fr ther patients, a sequencing strategy may be the best balance between benefits and risks.

12 ADJUVANT CHEMOTHERAPY Adjuvant nline: Recurrence risk assessment tl, last updated 2006 Criteria fr cnsideratin f chemtherapy (any r all f) Tumr >3cm LVI Grade III Weak/lw ER/PR Nde psitive HORMONE POSITIVE CTX fr luminal A disease has little evidence fr anthracycline/taxane ver AC, CMF Onctype DX: Recurrence scre generated based n mrna level f several genes within the tumur Patients must be: Nde negative, fit fr chemtherapy, PLUS higher risk (varies by prvince)

13 Gene Expressin and Benefit f Chemtherapy in Wmen With Nde-Negative, Estrgen Receptr-Psitive Breast Cancer Paik et al 2006 JCO ( ) Purpse Fllw up t 21-gene recurrence scre assay (Paik et al 2004) that quantified likelihd f distant recurrence t determine benefit f chemtherapy Methds RS was measured in tumrs frm TAM treated and TAM plus chemtherapy frm NSABP B20 trial Cx prprtinal hazards mdels utilized t test interactin between chemtherapy and the RS Primary Endpint DFS Inclusin/Exclusin Nde negative, ER psitive, HER2 negative breast cancer treated Criteria with TAM Size (N) 651 Results Patients with high-rs (>/=31) had large benefit frm chemtherapy (RR 0.26 CI ) Patients with lw RS (<18) derived minimal if any benefit (RR1.31 CI ) Txicity NA Cnclusin RS bth quantifies likelihd f breast cancer recurrence with nde-negative ER+ BC, and als predicts the magnitude f CTX benefit Other Cmments Based n this trial high (>/=31), intermediate, and lw (<18) scres were determined; all patients w high scre receive cmbinatin chemtherapy, lw shuld nt, and intermediate t discretin f physician Fllw up t the riginal article defining the RS: Paik et al 2004; NEJM 351:

14 TailRx (Trial Assigning Individualized Optins fr Treatment) NEMJ 2015; 373: Purpse T lk at intermediate RS patients Methds P3 RCT Wmen with Onctype DX recurrence scre randmized 1:1 receive cmbinatin chemtherapy fllwed by hrmnal therapy Primary Endpint DFS Inclusin/Exclusin Nde negative, ER+, HER2-, breast cancer receiving hrmnes Criteria Results Of the 10,253 eligible wmen enrlled, 1626 wmen (15.9%) wh had a recurrence scre f 0 t 10 were assigned t receive endcrine therapy alne withut chemtherapy. At 5 years, in this patient ppulatin, the rate f invasive disease free survival was 93.8% (95% cnfidence interval [CI], 92.4 t 94.9), the rate f freedm frm recurrence f breast cancer at a distant site was 99.3% (95% CI, 98.7 t 99.6), the rate f freedm frm recurrence f breast cancer at a distant r lcal reginal site was 98.7% (95% CI, 97.9 t 99.2), and the rate f verall survival was 98.0% (95% CI, 97.1 t 98.6). Cnclusin Amng patients with hrmne-receptr psitive, HER2-negative, axillary nde negative breast cancer wh met established guidelines fr the recmmendatin f adjuvant chemtherapy n the basis f clinicpathlgic features, thse with tumrs that had a favrable gene-expressin prfile had very lw rates f recurrence at 5 years with endcrine therapy alne. The secnd part f the trial t be reprted later RxPnder Purpse T lk at lw vlume (1-3) nde psitive disease with the aim f aviding vertreatment fr all nde psitive patients Primary Endpint DFS Inclusin/Exclusin ER+, HER2-, lw vlume (1-3) ndes psitive Criteria Cmments Study difficult accrual due t discmfrt with t giving CTX t nde psitive patients Cnclusin Results still pending CHEMOTHERAPY PROTOCOLS Principles Mst studies invlve wmen yunger than 70y, therefre administratin in elderly patients is based upn risk/benefit There is n apparent benefit in dse escalatin with standard dse CTX in adjuvant chemtherapy Plychemtherapy is preferred and assciated with greater benefits in wmen yunger than age 50, with higher risk (nde psitive) and hrmne negative disease

15 In general, 4-6 mnths f chemtherapy with bth Anthracycline and Taxane is preferred fr nde-psitive wmen Nde-negative but large and/r grade 3 cancers, cnsider shrter regimens (e.g. DC) Pst-Menpausal: Relatively yung and fit cnsider fr same as premenpausal with similar stage and grade Older (>60), less fit may derive less benefit and mre txicity (13) In general, trials cnducted in patients <70 y therefre this must be taken int cnsideratin Cardiac C-mrbidities: Cnsider nn-anythacycline if lw LVEF Cumulative lifetime expsure shuld nt exceed 480mg/m2 TRIPLE NEGATIVE Assciated with higher recurrence risk than HR+ CTX strngly recmmended fr all T1cN0r higher stage Yunger, fit patients may als benefit fr T1a and T1b tumrs, althugh abslute benefits are smaller There is apparent benefit frm dse dense therapy in this grup. HER2+ Cmbinatin chemtherapy plus Trastuzumab (preferably given cncurrently with taxane-based chemtherapy) fr T1cN0 r higher Ideally chemtherapy regimen cnsists f taxane + anthracycline r TCH (BCIRG 006) Cnsider fr T1bN0M0 especially if HR- given recurrence >25% and dramatically reduced w treatment Adjuvant r Neadjuvant chemtherapy regimens HER2 NEGATIVE HER2 POSITIVE Dxrubicin/Cyclphsphamide X4 (Fisher et al 1990) AC Dcetaxel/Cyclphsphamide X 4 (Jnes et al 2009) DC dd Dxrubicin/Cyclphsphamide X4 dd Paclitaxel X 4 (Citrn et al 2003) ddac-t Dxrubicin/cyclphsphamide X 4 Paclitaxel weekly X 12 (Sparanet al 2008) AC- T Flururacil/Epirubicin/Cyclphsphamide Dcetaxel FEC-D (PACS01) Dcetaxel/Dxrubicin/Cyclphsphamide X 6 (Martin et al, 2005) TAC Adjuvant chemtherapy (varius) 1 year Trastuzumab (Piccart-Gebhartet al 2005 (HERA)) Dcetaxel/carbplatin/trastuzumab X 6 Trastuzumab1y ttal(slamnet al 2011) Dxrubicin/cyclphsphamide X4 Paclitaxel weekly X 12 + Trastuzumab X 1y ttal (Perez et al 2011) Paclitaxel/Trastuzumab weekly X 12 weeks Trastuzumab 1y ttal (Tlanyet al 2013) Neadjuvant nly: Pertuzumab/Trastuzumab/Taxane X 12 weeks Dxrubicin/Cyclphsphamide X 4 Trastuzumab 1y ttal (Gianni et al 2012)

16 Taxane-Based Cmbinatins as Adjuvant Chemtherapy f Early Breast Cancer: A Meta- Analysis f Randmized Trials De Laurentiiset al (2008) JCO 26:44-53 Methds Studies were retrieved by searching the PubMEd database and prceedings f majr cnferences. HR and 95% CI were extracted fr DFSand OS frm each trial Inclusin/Exclusin Early breast cancer; adjuvant therapy; RCT cmparing taxaneanthracycline based t anthracycline based alne Criteria Size (N) 13 studies incuded Results Survival: (HR 0.85; 5-yr risk reductin 5% abslute) DFS:HR 0.83; 5yr risk reductin 3% abslute Cmbinatin anthracycline/taxane was nt superir t sequence Txicity (e.g. cmmn txicities verall, cmmn grade 3/4 txicities) Cnclusin Additin f taxane t anthracycine imprves DFS and OS f high risk early breast cancer patients Other Cmments Benefit was independent f ER status, degree f ndal invlvement, type f taxane, age/menpausal status and administratin schedule Weekly Paclitaxel in the Adjuvant Treatment f Breast Ca Sparan et al NEJM (2008) 358: Methds 2 X2 trial design fllwing 4 cycles f DC; paclitaxel q 3 weekly X4 vs. paclitaxel weekly X12 vs. dcetaxel q 3 weekly X4 vs. dcetaxel weekly X12 Primary endpint OS Inclusin/Exclusin T1-3N1-2, r high risk nde negative (T2-3) within 3 mnths f surgery, Criteria any HER2 Size (N) 4950 Results Weekly paclitaxel and q3 weekly dcetaxel prvided superir DFS Weekly paclitaxel imprved OS cmpared t q3 weekly paclitaxel Txicity Grade 2, 3, 4 neurpathy was mre frequent with weekly paclitaxel than with paclitaxel every 3 weeks Cnclusin Weekly paclitaxel after standard adjuvant chemtherapy with DC imprves DFS and OS in wmen with breast cancer

17 Trastuzumab after Adjuvant Chemtherapy in HER2-Psitive Breast Cancer (HERA) Piccart-Gebhartet al (2005) NEJM 353: Regimen Randmized t ne r tw years f trastuzumab, q3wk vs. bservatin fllwing physician chice chemtherapy Blus 8mg/kg nce, 6mg/kg each subsequent treatment Mechanism f Actin f Experimental Drug Primary Endpint DFS Inclusin/Exclusin Criteria Mnclnal antibdy t extracellular dmain f HER2neu (transmembrane tyrsine kinase)) HER2+ Early stage invasive BC; nde psitive r nde negative with T >1cm Cmpleted lcreginal therapy with minimum f 4 curses f chemtherapy either neadjuvant r adjuvant Nrmal LVEF (>55) Size (N) 5081 Results Survival: 2 yr OS nt statistically significant (96% vs 95.1%) DFS:2 yr DFS fr 1yrtrastuzumab 85.8 vs fr bservatin (HR 0.54) Txicity (e.g. cmmn txicities verall, cmmn grade 3/4 txicities) Cnclusin Additin f trastuzumabfr 1 year after adjuvant chemtherapy significantly imprves DFS amng wmen with HER2+ breast cacer Other Cmments This trial did nt lk at cncurrent administratin with Taxane (addressed in Rmndet al 2005 NEJM 353: ) Small fllw up perid unable t detect OS difference since OS was s high in bth grups NEOADJUVANT THERAPY (NAT) - Principle Outcmes f neadjuvant = adjuvant fr DFS and OS (NSABP B18) with higher chance f achieving breast cnservatin. - Advantages Allws immediate assessment f tumur respnse Allws evaluatin f new and nvel agents May allw fr earlier cntrl f micrmetastases May allw fr ptin f BCS May render inperable disease perable May imprve chances f btaining clear surgical margins with 1 st peratin - Bttm Line General Apprach: Chemtherapy regimens the same neadjuvant as fr adjuvant - Candidates fr NAT: Inflammatry BC Clinical DX; at a minimum the fllwing are required Rapid nset f erythema, edema and/r peaud range with r withut underlying mass; Duratin f HX < 6m; Erythema at least 1/3 f breast; pathlgic cnfirmatin f invasive carcinma Lcally advanced: Definitin varies amng trials. Canadian Cnsensus definitin: T3 r T4 with any clinical N status Any size tumr (T) with N2 r N3 disease

18 Other: May be cnsidered in any patient wh has clinical features that make it certain they will need systemic therapy. Especially if it may mean BCS vs. mastectmy - Wrk Up: Histlgy (ER, PR, HER2 n cre; breast imaging; imaging f the ipsilateral axilla with FNA f any suspicius ndes; clinical staging In clinically stage IIB (+) get metastatic imaging (CXR, US) NSABP-B18 Fisher et al (1997) JCO 15: Regimen Pst-perative AC vs pre-perative AC Primary Endpint Clinical cmplete respnse (ccr); Pathlgic cmplete respnse (pcr) Size (N) 1523 Results Respnse Rate:Breast tumr size reduced in 80%; 36% had ccr; 26% with ccr had pcr Clinical Decisin making: 12% mre lumpectmies perfrmed in the pre-surgery grup Txicity NA Cnclusin Pre-perative therapy reduced the size f mst breast tumrs and decreased the incidence f psitive ndes Greatest increase in lumpectmy after NAT ccurred in wmen with tumrs > r = 5cm Other Cmments 9 yr fllw up (Wlmark et al 2001) Demnstrated patients with pcr had better OS vs. thse wh did nt NSABP-B27 Bear J Clin Oncl 21: , 2003, J Clin Oncl 24: , 2006 Regimen Either fur cycles f preperative AC fllwed by surgery (grup I), r fur cycles f AC fllwed by fur cycles f dcetaxel, fllwed by surgery (grup II), r fur cycles f AC fllwed by surgery and then fur cycles f dcetaxel (grup III). Primary Endpint DFS (OS secndary) Size (N) Wmen (N = 2,411) with perable primary breast cancer Results Additin f T t AC did nt significantly impact DFS r OS. There were trends tward imprved DFS with additin f T. The additin f T reduced the incidence f lcal recurrences as first events (P =.0034). Preperative T, but nt pstperative T, significantly imprved DFS in patients wh had a clinical partial respnse after AC (hazard rati [HR] = 0.71; 95% CI, 0.55 t 0.91; P =.007). Pathlgic cmplete respnse, which was dubled by additin f preperative T, was a significant predictr f OS regardless f treatment (HR = 0.33; 95% CI, 0.23 t 0.47; P <.0001). Pathlgic ndal status after chemtherapy was a significant predictr f OS (P <.0001). Cnclusin The additin f preperative r pstperative T after preperative AC did nt significantly affect OS, slightly imprved DFS, and decreased the incidence f lcal recurrences. The sample size f this study was nt sufficient t yield significance fr the mderate DFS imprvement. Cncurrent use f tamxifen may have limited

19 the impact f adding T.

20 Efficacy and safety f neadjuvant pertuzumab and trastuzumab in wmen with lcally advanced, inflammatry, r early HER2-psitive breast cancer (NeSphere) Gianni L et al (2012) Lancet Oncl. 13:25-32 Regimen Open label P2 study; 1:1:1:1 randmizatin t 4 neadjuvant cycles f trastuzumab/dcetaxe (Gup A)l vs. pertuzumab/trastuzumab/dcetaxel (B) vs. pertuzumab/trastuzumab (C) vs. pertzumab/dcetaxel(d) Primary Endpint Pathlgic cmplete respnse (pcr) Size (N) 417 Results pcr: 45.8% (Grup B); 29% (A); 24% (D); 17% (C) Txicity Mst cmmn AE grade 3 (+) were neutrpenia, febrile neutrpenia, and leucpenia. Serius AE were similar in all grups with the exceptin f Grup C with fewer serius adverse events. Cnclusin Cmbinatin f pertuzumab + trastuzumab + dcetaxel achieved the highest pcr Other Cmments Based n results f this trial US FDA issed accelerated apprval fr neadjuvant HER2 disease, stage II r III. In general, patients shuld als receive pst-perative anthracycline and cmplete 1 year f trastuzumab T date, n evidence fr DFS r OS Pertuzumab and trastuzumab withut chemtherapy eradicated tumurs in a prprtin f wmen with favrable safety prfile LOCAL RECURRENCE Chemtherapy fr islated lcreginal recurrence f breast cancer (CALOR) Aebiet al Lancet Oncl 2014;15: Regimen Primary Endpint Inclusin/Exclusin Criteria Size (N) Results Txicity Cnclusin Other Cmments Open label randmized trial cmparing chemtherapy (physician chice) vs. n chemtherapy DFS Open label randmized trial cmparing chemtherapy (physician chice) vs. n chemtherapy 162 patients (85 randmized t CTX; 77 t n chemtherapy) Median fllw up 4.9 years 28% (CTX) vs. 44% (n CTX) had DFS events 5y DFS was 69% (CTX) vs 57%%; HR 0.59 (p=0.046) Analysis f DFS accrding t ER status were nt statistically significant (p=0.43); ER psitive patients did nt have significant benefit fr DFS 15% f CTX grup had serius AE: mst cmmn neutrpenia, febrile neutrpenia and intestinal infectin Adjuvant CTX shuld be recmmended fr patients with cmpletely resected ILRR f breast cancer, especially if the recurrence is ER negative Data has nt matured yet t analyze OS (underpwered t perfrm this analysis.)

21

22 D) REFERENCES - ASCO-SEP Medical Onclgy Self-Evaluatin Prgram. Furth Editin BC Cancer Agency Treatment Guidelines - Alberta Health Services Cancer Treatment Guidelines - Twards Optimized Practice - Oeffinger KC, GOntham ET, Etzini R, et al. Breast Cancer Screening fr Wmen at Average Risk: 2015 Guideline Update frm the American Cancer Sciety. JAMA 2015;314(15): Canadian Task Frce n Preventive Health Care. Recmmendatins n screening fr breast cancer in average-risk wmen aged years. CMAJ. 2011;183 (17): Antniu A, Pharah PD, Nard S et al. Average risk f breast and varian cancer assciated with BRCA 1 r BRCA2 mutatins detected in case Series unselected fr family histry: a cmbined analysis f 22 studies. Am J Hum Genet. 2003; 72(5): Nelsn HD, Tyne K, Naik A, et al. Screening fr breast cancer: an update fr the US preventive Services Task Frce. Ann Intern Med. 2009;151: Fisher B, Brwn AM, Dimitrv NV, et al. Tw mnths f dxrubicin-cyclphsphamide with and withut interval reinductin therapy cmpared with 6 mnths f cyclphsphamide, methtrexate, and flurcuracil in nde-psitive breast cancer patients with tamxifen nnrespnsive tumrs: results frm the NSABP B-15. J ClinOncl. 1990;8: Citrn ML, Berry DA, Cirrincine C, et al. Randmized trial f dse-dense versus cnventinally scheduled and sequential versus cncurrent cmbinatin chemtherapy as pst-perative adjuvant treatment f nde-psitive primary breast cancer: First reprt f Intergrup Trial C9471/Cancer and Leukemia Grup B Trial J ClinOncl. 2003;2: Martin M, Pienkwski T, Mackey J et al. Adjuvant dcetaxel fr nde-psitive breast cancer. N Engl J Med 2005;352: Sparan JA, Wang M, Martin S et al. Weekly paclitaxel in the adjuvant treatment f breast cancer. N Engl J Med. 2008;358: Jnes S, Hlmes FA, O Shaughnessy J, et al. Dcetaxel With Cyclphsphamide is Assciated With an Overall Survival Benefit Cmpared with Dxrubicin and Cyclphsphamide: 7 year fllw up f US Onclcgy Research Trial J ClinOncl. 2009; 27: Slamn D, Eiermann W, Rbert N, et al. Adjuvant trastuzumab in HER2 psitive breast cancer. N Engl J Med. 2011;365: Perez EA, Rmnd EH, Suman VJ, et al. Fur-year fllw-up f trastuzumab plus adjuvant chemtherapy fr perable human epidermal grwth factr receptr 2-psitive breast cancer: jint analysis f data frm NCCTG N9831 and NSABP B-31. J ClinOncl. 2011;29: Allred DC, Andersn SJ, Paik S, et al. Adjuvant tamxifen reduces subsequent breast cancer in wmen with estrgen receptr-psitive ductal carcinma in situ: A study based n NSABP prtcl B-24. J ClinOncl 2012;30: Tlaney SM, Barry WT, Dang C, et al. A phase II study f adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) fr nde-negative, HER2-psitive breast cancer. Paper presented at 36 th annual San Antni Breast Cancer Sympsium; December 2013; San Antni TX. - Hart CD, Di Le A. Defining ptimal duratin and predicting benefit frm chemtherapy in patients with luminal-like subtypes. The Breast 24 Supp. E) ABBREVIATIONS ALND: Axillary Lymph Nde Dissectin BC: Breast Cancer BCT: Breast Cnserving Treatment BSE: Breast Self-Exam BX: Bipsy FMHX: Family Histry HRT: Hrmne Replacement Therapy

23 HX: Histry IDC: Invasive Ductal Carcinma LN: Lymph Nde RT: Radiatin therapy SLN: Sentinal Lymph Nde SLND: Sentinal Lymph Nde Dissectin SX: Symptm TAM: Tamxifen