Original Article. Breast Care 2016;11: DOI: /

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1 Originl Article Brest Cre 2016;11: DOI: / Published online: October 24, 2016 Neodjuvnt Chemotherpy with Docetxel, Crbopltin nd Weekly Trstuzumb Is Active in HER2-Positive Erly Brest Cncer: Results fter Medin Follow-Up of over 4 Yers Hns-Christin Kolberg Leyl Akpolt-Bsci Miltides Stephnou Bhriye Akts b c Crl Veren Hnnig Corneli Liedtke d Klinik für Gynäkologie und Geburtshilfe, Mrienhospitl Bottrop, Bottrop, Germny; b Klinik für Fruenheilkunde und Geburtshilfe, Universitätsklinikum Essen, Essen, Germny; c Schwerpunktprxis für Hämtologie und Onkologie, Bottrop, Germny; d Klinik für Fruenheilkunde und Geburtshilfe, Universitätsklinikum Schleswig-Holstein Cmpus Lübeck, Lübeck, Germny Keywords Neodjuvnt therpy HER2 positive Brest cncer Anthrcycline free TCH Summry Introduction: Most ptients with HER2-positive brest cncer receive chemotherpy nd trstuzumb. Dt from djuvnt trils hve shown tht the combintion of docetxel, crbopltin nd weekly trstuzumb (TCH) is well tolerted nd s effective s nthrcycline-contining regimes. Previous investigtions on neodjuvnt tretment with txnes, pltinum slts nd trstuzumb showed pthologicl complete remission (pcr) rtes between 43.3 nd 76%. To dte, the longest published follow-up in this indiction is 3 yers. Here we present 4-yer follow-up dt for cohort of 78 ptients treted with neodjuvnt TCH. Methods: Between 2009 nd 2014 we treted 78 ptients with operble HER2- positive brest cncer with neodjuvnt schedule of docetxel (75 mg/m 2 ) nd crbopltin (AUC 6) every 3 weeks (q3w) nd trstuzumb (4 mg/kg loding dose then 2 mg/kg) q1w. Lymph node involvement ws verified by sentinel lymph node or core-cut biopsy. Ptients were dignosed t men ge of 55.5 yers; 65.4% hd hormone receptor-positive tumors, 34.6% presented with grde 3 disese nd 51.3% of ptients were node positive. Ptients were monitored every 2 cycles by ul- trsound. After 6 cycles of chemo therpy ll ptients hd surgery. Axillry dissection ws performed in cse of positive lymph node sttus prior to TCH. After surgery, trstuzumb ws continued q3w up to 1 yer. Results: No grde III/IV toxicities occurred nd no cse of congestive hert filure ws observed. Neither dose modifictions nor dose delys were necessry. 34 of the 78 ptients (43.6%) chieved pcr, 27 of the 40 node-positive ptients (67.5%) experienced nodl conversion. After medin follow up of 48.5 months the disese-free survivl (DFS) ws 84.6%, the distnt disese-free survivl (DDFS) ws 87.2% nd the overll survivl (OS) ws 91%. Only T stge nd nodl sttus t bseline were found to be significntly ssocited with survivl estimtes. Conclusion: The nthrcycline-free regimen TCH is effective nd sfe in the neodjuvnt therpy of HER2-positive brest cncer, yielding DFS, DDFS nd OS probbilities comprble to the results of djuvnt trils. Our dt support the use of TCH s neodjuvnt therpy regimen for ptients with HER2- positive brest cncer. They lso strongly encourge the use of txnes nd pltinum slts s the chemotherpy bckbone in studies investigting dul blockde with trstuzumb nd pertuzumb in the neodjuvnt setting S. Krger GmbH, Freiburg Fx Informtion@Krger.com S. Krger GmbH, Freiburg Accessible online t: Dr. med. Hns-Christin Kolberg Klinik für Gynäkologie und Geburtshilfe Mrienhospitl Bottrop ggmbh Josef-Albers-Str. 70, Bottrop, Germny hns-christin.kolberg@mhb-bottrop.de

2 Introduction The prognosis for HER2-positive brest cncer is worse thn the prognosis for HER2-negtive tumors. In the djuvnt setting, this poor prognosis hs been significntly improved by nti-her2 therpy with trstuzumb [1, 2]. In the neodjuvnt setting, the ddition of HER2-trgeted therpy to chemotherpy hs resulted in n incresed rte of pthologicl complete remission (pcr), indicting tht positive HER2 sttus is predictive mrker for response to neodjuvnt chemotherpy. The Germn GeprQuttro tril demonstrted tht the ddition of trstuzumb to neodjuvnt chemotherpy for HER2-positive brest cncer ws ssocited with n increse in pcr rte from 15.7 to 31.7% [3]. These beneficil pcr rtes re trnslting into improved survivl probbilities. A recently published pooled nlysis of 12 neodjuvnt studies [4] showed tht pcr (defined s ypt0 ypn0 or yptis ypn0) is ssocited with improved overll survivl (OS). In the nlysis of the totl cohort, irrespective of biologicl subtypes, significnt benefit for event-free survivl (EFS) (hzrd rtio (HR) 0.48) nd OS (HR 0.36) ws seen. In the HER2-positive/hormone receptor-negtive subgroup, chieving pcr ws ssocited with significnt dvntge in terms of EFS (HR 0.25). Bsed upon concerns regrding crdiotoxicity, nthrcyclinefree chemotherpy bckbones for trstuzumb hve been explored. In the djuvnt setting, the BCIRG-006 tril compred n nthrcycline-contining regime with or without the ddition of trstuzumb with the nthrcycline-free combintion of docetxel, crbopltin nd trstuzumb (TCH). As expected, ptients in the study rm without trstuzumb did worse thn in the 2 rms contining trstuzumb. However, there ws no significnt difference between the 2 groups receiving trstuzumb, no mtter whether they received n nthrcycline nd txne or crbopltin nd txne, wheres the rtes of serious congestive hert filures fvored the TCH rm [2]. The pcr rtes chieved in the neodjuvnt setting by combintions of txnes, pltinum slts nd trstuzumb rnged from 43.3 to 76% [5 8]. Our own workgroup presented pcr of 64% in cohort treted with TCH, the regimen used in the BCIRG-006 tril [9]. To dte, the longest published follow-up for ptients receiving the combintion of txne, pltinum slt nd trstuzumb s neodjuvnt therpy for HER2neu-positive brest cncer hs been 3 yers nd tht study showed recurrence-free survivl rte of 71% nd n OS rte of 86% [10]. Here we report the survivl vribles of cohort with medin follow-up of over 4 yers in this indiction. Mteril nd Methods Ptient Chrcteristics Between 2009 nd 2014 we treted 78 ptients with operble HER2-positive brest cncer with neodjuvnt schedule of docetxel (75 mg/m 2 ) every 3 weeks (q3w), crbopltin (AUC 6) q3w nd trstuzumb (4 mg/kg loding dose then 2 mg/kg) q1w, i.e. the regimen used in the BCIRG-006 tril [2]. The men ge of the ptients ws 55.5 yers (rnge yers). Tble 1. Ptient chrcteristics t bseline (n = 78) n (%) Grding G1 1 (1.3) G2 50 (64.1) G3 27 (34.6) Hormone receptor sttus Positive 51 (65.4) Negtive 27 (34.6) T stge t dignosis T1 38 (48.7) T2 33 (42.3) T3 1 (1.3) T4 6 (7.7) Nodl sttus t dignosis Negtive 38 (48.7) Positive 40 (51.3) Menopusl sttus Premenopusl 21 (26.9) Postmenopusl 57 (73.1) Tble 2. Ptient chrcteristics with sttisticlly significnt ssocition with survivl vribles Survivl vrible DDFS DFS OS Tumor stge t bseline T1, % Other, % Log rnk p Nodl sttus t bseline Negtive, % Positive, % Log rnk p DDFS = Distnt disese-free survivl, DFS = disese-free survivl, OS = overll survivl. All ptients received stging prior to the strt of neodjuvnt therpy for lung, liver nd bone metstses nd were ll found to be negtive. Ptients with cliniclly negtive lymph nodes received sentinel lymph node biopsy (SLNB) prior to neodjuvnt therpy. Lymph node involvement ws verified by SLNB or core-cut biopsy. All tumors were mrked with titnium clips before neodjuvnt therpy. Ptient chrcteristics re shown in tble 1. Ptients were monitored every 2 cycles by ultrsound. After 6 cycles of chemotherpy ll ptients hd surgery. In cses of clinicl complete remission, the clips were wire-mrked using mmmogrphic control. Intropertive specimen rdiogrphy ws performed irrespective of the wy of preopertive locliztion to detect the clip. Axillry dissection ws performed if pre-therpeutic lymph node sttus ws positive. pcr ws defined s no invsive tumor in brest or lymph nodes fter neodjuvnt tretment. Nodl conversion ws defined s histologiclly negtive lymph nodes fter neodjuvnt therpy in ptients with positive lymph nodes (SLNB or core-cut biopsy) t bseline. After surgery trstuzumb ws continued q3w up to 1 yer. Rdiotherpy ws pplied ccording to the stndrd in our center. All hormone receptor-positive ptients received endocrine therpy. All postmenopusl ptients received zoledronte q6m for 60 months. 324 Brest Cre 2016;11: Kolberg/Akpolt-Bsci/Stephnou/Akts/Hnnig/ Liedtke

3 Fig. 1. Kpln-Meier estimte for disese-free survivl (DFS). Fig. 3. Kpln-Meier estimte for overll survivl (OS). Meier method. Correltion nlysis between T sttus, hormone receptor sttus, lymph node sttus, grding, pcr, nodl conversion nd survivl vribles ws performed using univrite semi-prmetric Cox regression with SPSS Sttistics softwre version A 2-sided p vlue of < 0.05 ws considered significnt. Fig. 2. Kpln-Meier estimte for distnt DFS (DDFS). Toxicity ws ssessed every 3-week cycle on therpy. Screening for congestive hert filure ws performed by echocrdiogrphy t bseline, fter 3 nd 6 cycles nd 12 months fter surgery. Survivl vribles were collected from the dtbse of our center where the complete follow-up of our ptients is on file. Sttisticl Methods In this retrospective nlysis we report the medin disese-free survivl (DFS, defined s locl or distnt recurrence or deth from ny cuse), distnt disese-free survivl (DDFS, defined s distnt recurrence or deth from ny cuse) nd the OS (defined s deth from ny cuse) intervls fter medin follow up of 48.5 months. Survivl estimtes were plotted using the Kpln- Results No grde III/IV toxicities occurred nd no cse of congestive hert filure ws observed. Neither dose modifictions nor dose delys were necessry. 34 of the 78 ptients (43.6%) chieved pcr, 27 of the 40 node-positive ptients (67.5%) experienced nodl conversion. After medin follow-up of 48.5 months the DFS ws 84.6%, the DDFS ws 87.2% nd the OS ws 91%. Figures 1 3 demonstrte Kpln-Meier curves for the 3 survivl vribles. Hormone receptor sttus, grding, menopusl sttus, nodl conversion nd pcr hd no significnt influence on the survivl vribles, wheres T stge nd nodl sttus t bseline were found to be significntly ssocited with survivl estimtes. Significnt results for the subgroups re shown in tble 2. Discussion The dtset presented in this nlysis represents the longest published follow-up to dte for cohort treted with neodjuvnt TCH. Outcome in our nlysis fter medin follow up of 48.5 months compres well to outcome dt observed in djuvnt trstuzumb trils looking t the trstuzumb-contining rms fter the sme or shorter period of observtion, such s the HERA NAT with TCH for HER2-Positive Brest Cncer Brest Cre 2016;11:

4 Fig. 4. Design of the FREE tril. Inclusion criteri: HER2neu-positive, non-metsttic brest cncer; tumor bord recommendtion for neodjuvnt therpy with docetxel/crbopltin/trstuzumb/ pertuzumb. tril (4-yer DFS 78.6%, 4-yer OS 89.3%) [11], the BCIRG-006 tril (3-yer DFS 82%, 3-yer OS 91% in the TCH rm) [12] nd the joint nlysis of NCCTG N9831 nd NSABP B-31 (4-yer DFS 85.9%, 4-yer OS 92.6%) [13]. The comprble efficcy of nthrcycline-contining nd nthrcycline-free regimens in the djuvnt therpy of HER2-positive brest cncer hs recently been demonstrted bsed upon the 10-yer follow-up of the BCIRG-006 tril. In this tril, HRs for DFS for drimycin/cyclophosphmide (60/600 mg/m 2 q3w 4) followed by docetxel (100 mg/m 2 q3w 4) nd trstuzumb 1 yer (AC-TH) or docetxel/crbopltin (75 mg/m 2 /AUC 6 q3w 6) nd trstuzumb 1 yer (TCH) were reported to be 0.70 nd 0.76, respectively, compred to the trstuzumb-free rm of the tril. HRs for OS were 0.64 nd 0.76 for AC-TH nd TCH, respectively, nd were sttisticlly significnt in both rms. Of prticulr interest is the significnt reduction of crdiotoxicity in the TCH rm compred to AC-TH in the long-term follow-up. The rte of symptomtic congestive hert filure events ws 5-fold lower following TCH (n = 4; 0.4%) compred to AC-TH (n = 21; 2.0%) (p = ). The number of ptients suffering from left ventriculr ejection frction decline of > 10% fter AC-TH (n = 206) ws double tht fter TCH (n = 97) (p < ) [14]. These dt led to the estblishment of TCH s 1 of the stndrds in the djuvnt tretment of HER2-positive brest cncer. Our dt presented here support the use of this regimen lso in the neodjuvnt setting. Our sttisticl nlysis could not identify ny subgroup not benefitting from TCH. Although we hve only reported significnt ssocitions of survivl vribles with tumor size nd nodl sttus t bseline, the other nlyses on hormone receptor sttus, grding, menopusl sttus, nodl conversion nd pcr showed similr trends, but lcked sttisticl significnce in these nlyses. This is probbly being due to our comprbly smll cohort. The better outcome in ptients with fvorble prognostic prmeters ws not surprising nd confirmed tht the impct of prognostic prmeters does not get lost during follow-up fter neodjuvnt TCH. In 2012, the results of the Neo Sphere tril showed pcr rte of 45.8%, estblishing the combintion of trstuzumb nd pertuzumb with chemotherpy (in the tril monochemotherpy with docetxel) s the new neodjuvnt stndrd therpy for HER2-positive brest cncer [15]. The TRYPHAENA tril, published 1 yer lter, compred 2 nthrcycline-contining regimens (5-fluorourcil, epirubicin, cyclophosphmide (FEC) + pertuzumb + trstuzumb followed by docetxel + pertuzumb + trstuzumb; nd FEC followed by docetxel + pertuzumb + trstuzumb) to the nthrcycline-free regimen docetxel + crbopltin + pertuzumb + trstuzumb using the sme chemotherpy bckbone s TCH. pcr rtes in the 2 nthrcycline-contining rms were 61.6% nd 57.3%, respectively, wheres ptients in the nthrcycline-free rm chieved pcr rte of 66.2% [16]. These dt impressively underline the high efficcy of nthrcycline-free regimens in the neodjuvnt therpy of HER2-positive brest cncer using chemotherpy bckbone contining of txne nd pltinum slt. Bsed on the results of the TRYPHAENA tril, nd encourged by our results in the 4 yer follow up of neodjuvnt TCH, we re plnning follow-up tril on neodjuvnt TCPH (docetxel/crbopltin/ pertuzumb nd trstuzumb in nlogy to the regimen used in the TRYPHAENA tril) tht is momentrily in the process of chieving the pprovl of our ethicl committee. The design of the tril is shown in figure 4. In conclusion, the nthrcycline-free TCH regimen is effective nd sfe in the neodjuvnt therpy of HER2-positive brest cncer, yielding DFS, DDFS nd OS probbilities comprble to the results of djuvnt trils. Our dt support the use of TCH s neodjuvnt therpy regimen for ptients with HER2-positive brest cncer. They lso strongly encourge the use of txnes nd pltinum slts s the chemotherpy bckbone in studies investigting dul blockde with trstuzumb nd pertuzumb in the neodjuvnt setting. Disclosure Sttement Dr. Kolberg reports personl fees from Crl Zeiss meditec, Therclion, Novrtis, Amgen, Jnssen, GSK, LIV Phrm, nd Genomic Helth. Dr. Akpolt-Bsci, Dr. Stephnou nd Dr. Akts hve nothing to disclose. Dr. Hnnig reports personl fees from BMS, Boehringer Ingelheim, Novrtis, Roche, Celgene, nd Hexl. Dr. Liedtke reports personl fees from Celgene, TEVA, Pierre Fbre, Novrtis, Amgen, Eisi, GSK, Roche, nd Genomic Helth. 326 Brest Cre 2016;11: Kolberg/Akpolt-Bsci/Stephnou/Akts/Hnnig/ Liedtke

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