Study Design Open, three arm-stratified, non-randomized, prospective, multicentric study

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PONS Study Synpsis Title f the Study Subtype-Stratified Fllw-up Care Study f Breast Cancer Patients with Cmbined In Vitr and In Viv Diagnstics Plus Early Target-Oriented Interventin Gals Imprve and

1 PONS Study Synpsis Title f the Study Subtype-Stratified Fllw-up Care Study f Breast Cancer Patients with Cmbined In Vitr and In Viv Diagnstics Plus Early Target-Oriented Interventin Gals Imprve and individualize breast cancer aftercare thrugh a subtype-adapted cmbinatin f mlecular tissue diagnstics, regular serlgical bimarker measurements, sensitive whle-bdy imaging and individualized therapy management. Ratinale Tumr bilgy determines the risk f metastasis and time f metastasis (Kennecke et al. JCO 2010) Current guidelines recmmend minr fllw-up care in general irrespective f particular subtypes (Janni et al. 2009) Current fllw-up care guidelines are based n data ver 25 years ld (Rsselli del Turc and GIVIO et al. JAMA 1994) Since this time, sensitive and specific diagnstic parameters (tumr markers such as CEA, CA 15-3 and CA 125, and whle bdy imaging like PET-CT) have benefitted the detectin f recurrence (Mlina et al. Tumr Bil 2005; Ertl et al., abstract ISOBM 2009; Stieber et al. ASCO 2006; Veit-Haibach et al. Br J Radil 2007; Radan L et al. Cancer 2006) Diagnstic apparatuses are recmmended nly fr symptms, s that an early detectin f relapse is n lnger pssible New lc-reginal prcedures such as RFA, resectin and CyberKnife are rarely used, since the prprtin f ligmetastatis is < 3% (Tait et al. JCO 2005) A delay in starting treatment f > 12 weeks results already in symptmatic metastatic disease in reduced survival (Jung SY et al. BCRT2011) Study Design Open, three arm-stratified, nn-randmized, prspective, multicentric study 1 Duratin f the Study Duratin f the cmplete study (frm the admissin f the first patient until the final patient s exit): 84 mnths. Admissin perid fr patients: 24 mnths.

2 Duratin fr an Individual Patient: The bservatin perid lasts up t 60 mnths after admissin int the study Number f Patients Planned: Ttal: 1000 HER2-neu: 150 Triple-Negative: 150 Luminal: 700 The number f patients planned can be increased by an amendment, if necessary, which wuld be indicated by a subsequent change. Primary Objective f the Study: T find a prprtin > 20% f ligmetastatic patients amng all patients detected with metastatic disease during the study. 2 Secndary Study Gals: - Evaluatin f diagnstic sensitivity: Serlgical bimarkers: time and frequency f disease at detectin f the appearance f metastases in the cntext f a subtype-specific relapse-risk Whle-bdy imaging: time, frequency, lcatin, and extent f disease at detectin f the appearance f metastases in the cntext f a subtype-specific relapse-risk - Evaluatin f diagnstic specificity: Serlgical bimarkers: number and descriptin f false-psitive findings Whle-bdy Imaging: number and descriptin f false-psitive findings - Evaluatin f subtype specificity: Evaluatin f the time, lcatin, frequency and magnitude with relatins t the subgrups Luminal A, Luminal B, triple-negative and HER2 - Evaluatin f ECOG-status: Detectin f ECOG status at the time f the first metastasis: average imprved ECOG status due t the extensin f the lead-time fr symptmatic disease and an enlarged range f pssible treatment

3 mdalities - Prprtin f patients in whm an imaging and/r bichemical remissin can be achieved (curative apprach) - Perid f time withut symptms and/r bichemical remissin, with respect t the subtype specific behavir f prgressive disease - Length f the interval withut treatment after metastasis ccured, with respect t subgrup-specific therapeutic ptins - Imprved cancer-specific verall survival: Detectin f cancer-specific verall survival frm time f primary diagnsis t death: average imprved survival, independent f the "lead time" - Increased adherence t recmmended therapy due t increased awareness abut the individual risk fr relapse - Detectin f the frequency, timing, and extent f use f alternative and cmplementary treatments and therapies - Detectin f the frequency, timing, and extent f use f additinal diagnstic prcedures utside f the study prtcl - Measurement f quality f life by reductin f anxiety and increase f "perceived" security thrugh a practive and transparent apprach t the patient, with regard t her subtype-specific disease during the fllw-up (under the PO-BADO BK-LQ-curve). - Evidence f cst-effectiveness f a subtype-specific aftercare vs. an uncntrlled "gray" aftercare - Health-ecnmic cmparisn f csts relating t subtype-specific aftercare study arms - Effects f subtype-specific aftercare n the practice f the "5-year cure prbatin" in the Disabilities Act Evaluatin f Safety: Nt applicable Admissin Criteria: 3 - Fully resected ( 1 mm) histpathlgically secure unilateral r bilateral primary breast cancer

4 - Availability f representative frmalin-fixed, paraffin-embedded tissue blcks f the untreated primary tumr (bipsy r resected tissue) t the main pathlgy department - Written infrmed cnsent prir t the study, authrizing prcedures including genetic testing f the primary tumr tissue - Wmen with an age at the time f diagnsis 18 years - N evidence f distant metastases after cmplete diagnstic examinatins including PET-CT r PET-MR - General cnditin ECOG < 2 - The patient must be accessible fr diagnstic fllw-up - In the event f the ccurrence f relapse in the perid f the study, patients must be cntrlled by a principle investigatr - The study admissin is subgrup specific accrding t the fllwing scheme: Luminal A > 48 mnths after primary surgery Luminal B > 18 mnths after primary surgery HER2-psitive < 9 mnths after primary surgery Triple-negative < 9 mnths after primary surgery Exclusin Criteria: - Inperable breast cancer - Any earlier r parallel malignant tumr disease in additin t the nnmetastasized primary breast cancer disease - Knwn hypersensitivity reactins, r lack f cmpliance regarding planned diagnstic and lgistic prcesses 4 Statistical Analyses: Dr. Christine Windemuth-Kieselbach Effectiveness: Increased frequency f ligmetastatic lesins in asymptmatic patients due t subtype-specific cmbinatin f in vitr and in viv diagnstics Descriptin f the primary analysis f efficacy and ppulatin: The fllwing assumptins underlie: A 10-year survival is significantly different between the subgrups (Kennecke et al. JCO 2010)

5 5 - Luminal A: 70% - Luminal B: 54.4% - HER2: 48.1% - TNT: 62.6% Within the subgrups, there are significant differences with respect t the timing f metastases (Kennecke et al. JCO 2010): - Luminal B/TNT/HER2 within the first 5 years - Luminal A shws a cntinuus relapse between 5-15 years 15% f patients with breast cancer experience a distant metastasis (empirical value f the Munich fllw-up study) The rate f patients with ligmetastatic disease (defined as < 3 lesins limited t ne rgan except the bnes) must be < 3% within the first five years, independent f tumr subtype The rate f patients with ligmetastatic disease demnstrated by regular serum analyzes within the first three years will be < 10% within the nnsubtypical grup f all study participants The margin f errr fr a false psitive utput (alpha) is set t 5% using tw-tailed significance tests. The margin f errr fr a false negative utput (beta) is set t 20%, e.g. the study s pwer is specified as 80% fr the differentiatin f clinical interest The general expnential failure rate is 10% Patients will be enrlled in the study fr 24 mnths The fllw-up perid frm the end f the admissin perid until data analysis is 84 mnths Assumptins: 15% f patients with breast cancer suffer frm a distant metastasis The rate f patients with ligmetastasis is 10% α = 5%, tw-sided Pwer = 80% Failure rate = 10% With the cmbined methd, the rate f patients with ligmetastatic disease is 20% Assuming a prbability f less than 10% fr the early detectin f metastases in a ligmetastatic state (histrical cntrl) and at least 20% using a cmbined diagnstic apprach f mlecular testing and serum testing at determined intervals, 78 patients are needed. Of this patient grup, 13 must be identified in rder t demnstrate the difference f the A'Hern methd in a tw-sided significance level f 0.05 and a pwer f 80%. Since nly 15% f patients suffer frm breast cancer distant metastasis, 572 patients shuld be admitted in this study n the assumptin f a 10% failure rate.

6 Evaluatin f safety Nt applicable Primary endpint: Mre than 20% f ligmetastatic patients within the patients fund with distant metastases during the study Secndary endpints: Refer t secndary bjectives Sample size calculatin: T attain reliability: n=573 Assignatin f n: n=1000 T analyze: n=1000 The number f planned patients may be increased by an amendment. Cntrl Check-ups Basic investigatins = Admissin time (fr all patients) Mlecular analysis (RNA expressin prfile) with kpcr f an mrna which was extracted frm frmalin-fixed and paraffin-embedded tumr tissue Entrance PET/CT Central lab analysis f tumr marker CEA, CA 15-3, CA 125 (determinatin f individual base value) Additinal riginal investigatins (nly fr TNT and HER2): Mlecular analysis thrugh immune cell testing Every 8 weeks (fr all patients): Central lab analysis f tumr markers CEA, CA 15-3, CA-125 Every 3 mnths (fr TN, HER2 and Luminal B) Anamnestic and physical examinatin findings Every 6 mnths (fr Luminal A) Anamnestic and physical examinatin findings Every 6 mnths (fr patients with BCS in the first 3 years after primary OP): Mammgraphy f the affected side Every 12 mnths (als 18, 30 and 42 mnths after R0-resectin f the primary tumr; nly fr high-risk patient grups: TN + HER2): PET/CT 6

7 Every 12 mnths (fr all patients): Mammgraphy f the healthy side; mammgraphy f the affected side fr patients with BCS after the 4th year fllwing primary surgery In general (fr all patients): In the case f a reprducible pathlgical increase f tumr markers accrding t defined criteria! immediate PET/CT In the case f a tumr s detectin, individualized therapeutic cncept (with serlgic fllw-up every 4 weeks) as determined by the interdisciplinary tumr bard In the absence f tumr detectin: cntinuatin f the tumr marker determinatin every 4 weeks, repeated whle-bdy imaging after 3 mnths Planned accmpanying scientific prject: Circulating tumr cells (Fr. Prf. K. Pachmann) 7

Commissioning Policy: South Warwickshire CCG (SWCCG)

Commissioning Policy: South Warwickshire CCG (SWCCG) Cmmissining Plicy: Suth Warwickshire CCG (SWCCG) Treatment Indicatin Criteria FreeStyle Libre Flash Cntinuus Glucse Mnitring System Type I Diabetes Prir apprval must be requested frm the Individual Funding