MAMA DISEMINADARAFAEL TRUJILLO VILCHEZPOST-ASCO 2013

Efficacy and safety of first-line pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer (CLEOPATRA) in patients previously exposed to trastuzumabEva Ciruelos,1 Adam Brufsky,2 Young-Hyuck Im,3 Sung-Bae Kim,4 Emma Clark,5 Adam Knott,5 Graham Ross,5 David Miles6

1University Hospital 12 de Octubre, Medical Oncology Department, Madrid, Spain; 2Division of Hematology and Oncology, University of Pittsburgh, Pittsburgh, PA; 3Division of Hematology and Medical Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 4Department of Oncology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea; 5Roche Products Limited, Welwyn, UK; 6Mount Vernon Cancer Centre, Middlesex, UK

Presented at the ASCO Annual Meeting, May 31June 4, 2013, Chicago, IL

Introduction to pertuzumab and trastuzumabThe humanized monoclonal antibodies trastuzumab and pertuzumab bind to different extracellular domains of HER2, a protein overexpressed in ~20% of breast cancers1Preclinical studies have shown that trastuzumab binds to subdomain IV of HER2,2 inhibiting ligand-independent signaling3 and preventing cleavage of the receptor and formation of the constitutively active p95 fragment4 Pertuzumab binds to the dimerization domain (subdomain II) of HER25 and inhibits ligand-dependent signaling6 Binding of trastuzumab and pertuzumab to HER2 also promotes antibody-dependent cell-mediated cytotoxicity7 Due to their complementary modes of action, the combination of these two HER2-targeted agents results in a more comprehensive blockade of HER2 signaling than either agent alone7 *HER2, human epidermal growth factor receptor 21. Wolff AC, et al. J Clin Oncol 2007; 25:118145;2. Cho HS, et al. Nature 2003; 421:756760;3. Junttila TT, et al. Cancer Cell 2009; 15:429440;4. Molina MA, et al. Cancer Res 2001; 61:47444749;5. Franklin MC, et al. Cancer Cell 2004; 5:317328;6. Agus DB, et al. Cancer Cell 2002; 2:127137;7. Scheuer W, et al. Cancer Res 2009; 69:93309336.

Mode of action of pertuzumab and trastuzumabHER2, human epidermal growth factor receptor 2HER2 binding sites of trastuzumab and pertuzumab*

Clinical efficacy of pertuzumab in combination with trastuzumabIt has been proposed that patients may progress on trastuzumab therapy due to the development of resistanceHowever, there is clinical evidence that pertuzumab in combination with trastuzumab is active when used to treat patients with HER2-positive MBC who have progressed during trastuzumab therapy1,2In the global Phase III clinical study CLEOPATRA, patients with HER2-positive MBC who received pertuzumab plus trastuzumab plus docetaxel as first-line treatment had significantly increased PFS3 and OS4 compared with those who received placebo plus trastuzumab plus docetaxelAdverse events reported at the primary analysis3 and after one additional year of follow-up4 were similar with respect to frequency, specificity, and severity. At this point, there is no evidence of late or cumulative toxicity with the study regimensOf note, cardiac adverse events were not increased in the pertuzumab arm compared with the placebo arm5*HER2, human epidermal growth factor receptor 2MBC, metastatic breast cancer; OS, overall survival; PFS, progression-free survival1. Baselga J, et al. J Clin Oncol 2010; 28:11381144;2. Cortes J, et al. J Clin Oncol 2012; 30:15941600;3. Baselga J, et al. N Engl J Med 2012; 366:109119;4. Swain SM, et al. Lancet Oncol 2013; 14:461471;5. Swain SM, et al. Oncologist 2013; 18:257264.

ObjectiveAnalysis of the efficacy of the combination of pertuzumab, trastuzumab, and docetaxel compared with placebo, trastuzumab, and docetaxel in the subgroup of patients who had previously received trastuzumab in the (neo)adjuvant setting in CLEOPATRA*

Study treatmentPatients were randomized to receive pertuzumab plus trastuzumab plus docetaxel or placebo plus trastuzumab plus docetaxelStudy drugs:Pertuzumab: 840 mg initial dose, followed by 420 mg q3wTrastuzumab: 8 mg/kg initial dose, followed by 6 mg/kg q3wDocetaxel: 75 mg/m2 q3w (with escalation to 100 mg/m2 at the investigators discretion)Pertuzumab and trastuzumab were administered until investigator-assessed disease progression, unmanageable toxicity, or withdrawal of consentDocetaxel was administered for a recommended 6 cycles, and then continuation was at the investigators discretion, or until disease progression, unmanageable toxicity, or withdrawal of consent*

Key eligibility criteriaCentrally confirmed HER2-positive MBC or locally recurrent, unresectable breast cancerNo prior biologic or chemotherapy in the metastatic setting, with the exception of one previous hormonal regimen for MBC, which had to be stopped prior to randomizationNo prior approved or investigative tyrosine kinase/HER inhibitors for breast cancer in any treatment setting, with the exception of (neo)adjuvant trastuzumabPatients who received (neo)adjuvant therapy for breast cancer were eligible if they had a disease-free interval of 12 monthsBaseline LVEF 50% and no LVEF decline to

Statistical analysesThe primary endpoint was independently assessed PFS, and secondary endpoints included OS and safetyThe study was designed to have 80% power to detect a 33% improvement in median PFS in the pertuzumab arm (HR = 0.75) at a two-sided significance level of 5%Post-hoc analyses of PFS and OS were conducted in the subgroup of patients who received prior (neo)adjuvant therapy with trastuzumab*HR, hazard ratio; OS, overall survival; PFS, progression-free survival

Baseline demographics and disease characteristics*ECOG PS, Eastern Cooperative Oncology Group performance status; ER, estrogen receptor; PgR, progesterone receptor* Protocol violation

Baseline demographics and disease characteristics** In patients with (neo)adjuvant treatment; some patients had missing data Only in patients with target lesions

Baseline demographics and disease characteristicsIn the overall study population, 47.3% and 45.8% of patients in the placebo and pertuzumab arms, respectively, had received (neo)adjuvant chemotherapy10.1% and 11.7% of patients in the placebo and pertuzumab arms, respectively, had received (neo)adjuvant trastuzumabThe demographics of the subgroup of patients with (neo)adjuvant trastuzumab exposure were generally balanced between arms and similar to the overall study populationOf patients with prior trastuzumab exposure, 82% came from Europe or North America, reflecting the timing of adjuvant trastuzumab approval in these regions compared with the rest of the worldThere was a shorter median treatment-free interval in the subgroup of patients with prior trastuzumab exposure compared with the overall study populationIn the prior trastuzumab subgroup, more patients in the pertuzumab arm had bone and soft tissue metastases and positive lymph nodes at baseline compared with the placebo arm*

Progression-free survivalD, docetaxel; Pla, placebo; Ptz, pertuzumab; T, trastuzumabn at risk4739291284100Ptz + T + D: Prior T413422543200Pla + T + D: Prior TTime (months)Ptz + T + D: Prior TPtz + T + D: No prior TPla + T + D: Prior TPla + T + D: No prior T13712099523114400Ptz + T + D: No prior T1511198039206200Pla + T + D: No prior TProgression-freesurvival (%)*

Progression-free survival*CI, confidence interval; HR, hazard ratio

Progression-free survival by independent assessmentPlacebo + trastuzumab + docetaxelPertuzumab + trastuzumab + docetaxelOverall population (N = 808)Median (months)HR (95% CI)p-value12.418.50.62 (0.51, 0.75)p < 0.0001Patients with (neo)adjuvant therapy without trastuzumab (n = 288)Median (months)HR (95% CI)

12.6

21.60.60 (0.43, 0.83)Patients with (neo)adjuvant therapy with trastuzumab (n = 88)Median (months)HR (95% CI)

10.4

16.90.62 (0.35, 1.07)

Overall survival The PFS and OS HR 95% CIs are wide for patients who received (neo)adjuvant therapy with trastuzumab due to the small number of patients in this subgroup

*CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival

Overall survivalOverall study population (N = 808)HR (95% CI)p-value0.66 (0.52, 0.84)p = 0.0008Patients without (neo)adjuvant therapy (n = 432)HR (95% CI)0.66 (0.47, 0.93)Patients with (neo)adjuvant therapy (n = 376)HR (95% CI)0.66 (0.46, 0.94)Patients with (neo)adjuvant therapy with trastuzumab (n = 88)HR (95% CI)0.68 (0.30, 1.55)

Potential risk factors for the development of LVSDA univariate Cox regression analysis was performed to assess the influence of the predefined potential risk factors: prior anthracycline exposure, prior radiotherapy, prior trastuzumab therapy, age, smoking history, diabetes mellitus, and hypertension, on the time to development of asymptomatic or symptomatic LVSDPrior anthracycline exposure (HR = 2.21; 95% CI 1.27, 3.86; p = 0.0053) and prior radiotherapy (HR = 2.43; 95% CI 1.37, 4.31; p = 0.0025) were identified as potentially important risk factors for developing LVSDPrior trastuzumab therapy was not associated with the development of LVSD*CI, confidence interval; HR, hazard ratio; LVSD, left ventricular systolic dysfunction

DiscussionThe proportion of patients in CLEOPATRA who had prior trastuzumab exposure was lower than would be expected based on current clinical practiceHowever, this proportion was consistent with that expected during the trial recruitment periodRecruitment into CLEOPATRA began in February 2008, less than 2 years after the first approval of trastuzumab in the adjuvant setting (May 2006)The standard duration of adjuvant trastuzumab treatment is 1 year, and a disease-free interval of 12 months was mandatory for CLEOPATRA, limiting the number of eligible patients who had previously received trastuzumab*

ConclusionsThis post-hoc analysis demonstrates that patients with HER2-positive MBC in the first-line setting who had received prior trastuzumab in the (neo)adjuvant setting derive similar benefit in terms of PFS and OS from the combination of pertuzumab, trastuzumab, and docetaxel when compared with the whole study population or patients who are trastuzumab-naive.There is further evidence of the benefit from pertuzumab plus trastuzumab in patients with HER2-positive MBC whose disease had progressed on trastuzumab-based therapy,1,2 and more data including patients previously exposed to trastuzumab are anticipated from the randomized study PHEREXA (NCT01026142),3 and from the single-arm global safety study PERUSE (NCT01572038).4*HER2, human epidermal growth factor receptor 2;MBC, metastatic breast cancer; OS, overall survival;PFS, progression-free survival1. Baselga J, et al. J Clin Oncol 2010; 28:11381144;2. Cortes J, et al. J Clin Oncol 2012; 30:15941600;3. Urruticoechea A, et al. Eur J Cancer 2012; 48(suppl. 1):194;4. Bachelot T, et al. Cancer Res 2012; 72(suppl. 3):OT1-1-02.

Enfermedad HER2-positivaAbstract 505. Oral abstract session. Phase III, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and vinorelbine in trastuzumab-resistant, advanced breast cancer (BOLERO-3).Abstract 517. Poster discussion session. Phase III trial of non-pegylated liposomal doxorubicin (M) in combination with trastuzumab (T) and paclitaxel (P) in HER2+ metastatic breast cancer (MBC).

R. M. ORegan, M. Ozguroglu, F. Andr, M. Toi, G. Jerusalem, S. Wilks, C. Isaacs, B. Xu, N. Masuda, F. Arena, D. Yardley, Y. S. Yap, Y. Zhang, S. Douma, M. El-Hashimy, T. Taran, T. Sahmoud, D. Lebwohl, L. GianniOn behalf of the BOLERO-3 Investigators Phase 3, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and vinorelbine in trastuzumab-resistant, advanced breast cancer (BOLERO-3)

BOLERO-3: Study Design* Actual enrollment was 569.Following a 4-mg/kg loading dose on day 1, cycle 1 (1 cycle = every 21 days). Abbreviations: CBR, clinical benefit rate; DoR, Duration of response; ECOG, Eastern Cooperative Oncology Group; HER2, human epidermal growth factor receptor 2; ORR, overall response rate; OS overall survival; PD, progressive disease; PFS, progressive-free survival; PO, oral; PS, performance status; QoL, quality of life.Stratification by prior lapatinib use (yes/no)1:1 randomization

BOLERO-3: Primary Endpoint Progression-Free Survival by Local AssessmentAbbreviations: CI, confidence interval.2852532021771381098564493826231916121074PlaceboHazard ratio = 0.78; 95% CI [0.65, 0.95]Log-rank P value = .0067

Median PFSEverolimus: 7.00 months; 95% CI [6.74, 8.18] Placebo: 5.78 months; 95% CI [5.49, 6.90]

Everolimus (n/N = 196/284)Placebo (n/N = 219/285)Censoring times1008060402000612182430364248546066727884Time, weeks9096102284259233200161126987854403526181414954EverolimusNumber of Patients Still at RiskProbability, %

BOLERO-3: PFS Subgroup Analyses by Local AssessmentFavors PBOFavors EVEAbbreviations: CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status.

SubgroupNAll569Age< 65 years472 6597RegionEurope223North America123Asia166Latin America36Other21Prior lapatinibYes161No408Prior adj/neo trastuzumabYes251No318Baseline ECOG PS03821 or 2186Hormonal statusER/PgR250ER+/PgR+317Visceral involvementYes439No130

Hazard Ratio [95% CI]0.78 [0.65-0.95]0.77 [0.62-0.95]0.93 [0.56-1.57]0.72 [0.53-0.99]0.86 [0.55-1.32]0.83 [0.59-1.18]0.61 [0.27-1.38]1.28 [0.48-3.45]0.79 [0.56-1.11]0.78 [0.62-0.99]0.65 [0.48-0.87]0.92 [0.71-1.18]0.79 [0.63-1.00]0.75 [0.53-1.05]0.65 [0.48-0.87]0.93 [0.72-1.20]0.89 [0.72-1.10]0.48 [0.30-0.76]

Grfico1

5690.170.14

4720.180.15

970.640.37

2230.270.19

1230.460.31

1660.350.24

360.770.34

212.170.8

1610.320.23

4080.210.16

2510.220.17

3180.260.21

3820.210.16

1860.30.22

2500.220.17

3170.270.21

4390.210.17

1300.280.18

Y-Values

Sheet1

X-ValuesY-ValuesSizeSubgroupNlowerupperlow barhigh bar

0.7921569All5690.650.960.140.17

0.7720472Age< 65 years4720.620.950.150.18

0.931997 65970.561.570.370.64

0.7218223RegionEurope2230.530.990.190.27

0.8617123NA1230.551.320.310.46

0.8316166Asia1660.591.180.240.35

0.611536LA360.271.380.340.77

1.281421Other210.483.450.82.17

0.7913161Prior use of lapatinibYes1610.561.110.230.32

0.7812408No4080.620.990.160.21

0.6511251Prior trastuzumab useYes2510.480.870.170.22

0.9210318No3180.711.180.210.26

0.799382Baseline ECOG PS03820.6310.160.21

0.7581861 or 21860.531.050.220.3

0.657250ER-/PgR-2500.480.870.170.22

0.936317ER+/PgR+3170.721.20.210.27

0.895439VisceralYes4390.721.10.170.21

0.484130No1300.30.760.180.28

BOLERO-3: Overall ResponseAbbreviation: CI, confidence interval.

Everolimus + Trastuzumab + Vinorelbine (N = 284)P valuePlacebo + Trastuzumab + Vinorelbine (N = 285) Best Overall Response, %Complete response (CR) 3.22.5Partial response (PR)37.734.7Stable disease (SD)48.241.4Progressive disease (PD)4.913.0Unknown6.08.4Overall response rate (CR or PR) 95% CI40.8 35.1, 46.80.210837.2 31.6, 43.1Clinical benefit rate (Objective response or SD 24 wks) 95% CI59.2 53.2, 64.9 0.094553.3 47.4, 59.2

BOLERO-3: Most Common Adverse Events

Adverse Event, %Everolimus Arm (N = 280)Placebo Arm (N = 282)All GradesGrade 3Grade 4All GradesGrade 3Grade 4Stomatitis631302810Fatigue4312

Prior (neo)adjuvant anthra, taxanes, or trastuzumab permitted, if completed >1 year beforeIf prior HT, it had to be discontinued before study entryOne measurable lesion per RECISTNormal LVEF, no history of cardiac diseaseTrastuzumab 4 mg/kg loading dose, followed by 2 mg/kg qwPaclitaxel 80 mg/m2 qwTrastuzumab 4 mg/kg loading dose, followed by 2 mg/kg qwPaclitaxel 80 mg/m2 qwMyocet 50 mg/m2 q3w x 6STRATIFICATIONPrior anthracycline: yes/noER/PgR: yes/noAge: 50, >50Geographic region: NA, EU, ROWPRIMARY EFFICACY ENDPOINTPFS by independent review

PRIMARY CARDIAC ENDPOINTNYHA Class III or IV CHF and cardiac death by independent, blinded CSMC

SECONDARY ENDPOINTSOSORRAsymptomatic LVEF Composite cardiac endpoint (death, CHF, grade 3-4 myocardial ischemia/infarction, grade 3-4 arrhythmia)Other AEs

1:1 randomizationPhase III trial of non-pegylated liposomal doxorubicin (M) in combination with trastuzumab (T) and paclitaxel (P) in HER2+ metastatic breast cancer (MBC)First-Line HER2+ MBCN = 363De la Pena et al.

No significant benefit in PFS, but a trend to longer OS was detectedMTP = non-pegylated liposomal doxorubicin + trastuzumab + paclitaxel, TP = trastuzumab + paclitaxel, HR = hazard ratio, RR = response rate.In terms of RR, the benefit was comparable in the two treatment arms (67% vs. 62%), while response duration was numerically longer in the MTP arm (18.1 months vs. 15.3 months).A significant benefit in PFS and OS was observed in an exploratory analysis of the ER/PR-negative population

The MTP combination demonstrated a favorable cardiac safety profileIncidence of NYHA Class III/IV CHF per the blinded review of the CSMC: 3% in the MTP arm1% in the control arm

No cardiac deaths in the MTP group per blinded central assessment

No reports of grade 3-4 myocardial ischemia/infarction, or grade 3-4 arrhythmia in either treatment armCSMC = cardiac safety monitoring committee

QT adyuvante

Time trends in the use of chemotherapy and outcomes in women with T1a,b N0 M0 BC in the NCCNMediana de seguimiento: 5,5 aos.

Time trends in the use of chemotherapy and outcomes in women with T1a,b N0 M0 BC in the NCCN

QT Neoadyuvante

CALGB 40601: Phase III Trial of Lapatinib Added to Neoadjuvant Therapy of HER2+ Breast Cancer

ACOSOG Z1041 (Alliance): Definitive Analysis of a Randomized Neoadjuvant Trial Comparing FEC Followed by Paclitaxel Plus Trastuzumab with Paclitaxel Plus Trastuzumab Followed by FEC Plus Trastuzumab in HER2+ Operable Breast Cancer

ACOSOG Z1041 (Alliance): Definitive Analysis of a Randomized Neoadjuvant Trial Comparing FEC Followed by Paclitaxel Plus Trastuzumab with Paclitaxel Plus Trastuzumab Followed by FEC Plus Trastuzumab in HER2+ Operable Breast Cancer

Follow-up results of NOAH, a randomized phase III trial evaluating neoadjuvant chemotherapy with trastuzumab followed by adjuvant H versus CT alone, in patients with HER2-positive locally advanced breast cancer

*BOLERO-3: Study Design1.2BOLERO-3 is a phase 3, randomized, double-blind, placebo-controlled, multicenter, international, clinical trial designed to compare the efficacy of EVE + vinorelbine + TRAS versus placebo + vinorelbine + TRAS patients with HER2+ advanced breast cancer resistance to TRAS and who have been previously treated with a taxane. A total of 569 patients have been enrolled at 159 sites worldwide. Eligible patients were randomized in a 1:1 ratio to either arm and stratified by prior lapatinib use (yes or no).Key endpoints of the study include:Primary: Progression-free survivalSecondary: Overall survival, ORR, time to deterioration of ECOG PS, safety, duration of response, clinical benefit rate, time to response, and QoLStudy treatment is continued until progressive disease or intolerable toxicity. As described earlier, the rationale for using EVE at 5mg/day in combination with vinorelbine and TRAS was based on results from the phase 1b/2 study, J2102.

Reference:http://www.clinicaltrials.gov/ct2/show/NCT01007942?term=BOLERO3&rank=1ORegan RM, et al. ASCO 2013. Abstract 505.

*BOLERO-3: Primary Endpoint Progression-free Survival by Local AssessmentThe trial met its primary endpoint.The primary efficacy analysis based on local radiologic assessment resulted in an estimated 22% risk reduction for PFS (HR = 0.78; 95% CI, 0.65-0.95; P < .0067)This risk reduction corresponds to a 1.22-month prolongation in median PFS, from 5.78 months in the placebo arm to 7.00 months in the everolimus arm At the time of data cut-off, 415 PFS events had accrued

*BOLERO-3: PFS Subgroup AnalysesOverall, the PFS benefit of everolimus was observed across patient subgroups defined by demographic characteristics (eg, age, region), prior therapy (eg, lapatinib, adjuvant/neoadjuvant TRAS), and disease characteristics (eg, hormone receptor status, liver involvement)Notably, patients with negative hormone receptor status (ER or PR) had better PFS outcomes with everolimus; that is consistent with the data previously reported in the HER2-positive advanced breast cancer population

*BOLERO-3: Tumor ResponseThe overall response rate (ORR) was similar between treatment arms (EVE 40%; Placebo 37%).

The percentage of patients with disease progression as best response was more than doubled in the placebo arm compared with the everolimus arm (13% vs 5%).

The clinical benefit rate (ORR + SD 24 weeks) was slightly higher with everolimus compared with placebo (59% vs 53%), albeit the difference was not statistically significant (P = .0945).

**Kaplan-Meier estimates of progression-free survival based on independent central review, and overall survival (intent-to-treat population). The trial failed to detect a statistically significant difference in the primary endpoint. The median PFS by IRC (237 events) was 16.1 months in the MTP arm vs. 14.5 months in the TP arm (p=0.174). The interim OS analysis by the cut-off date of June 30, 2010 was based on 175 events, 82 (45%) in the MTP arm and 93 (51%) in the control arm. A total of 30 patients were lost to follow-up for survival, 13 (7.2%) in the MTP group and 17 (9.3%) in the control group. The median survival was 32.3 months in the MTP group and 29.0 months in the TP group (=0.195). The final OS analysis, with 225 events, pointed to a trend in OS favoring the MTP arm over the TP arm, with corresponding medians of 33.6 months vs. 29.0 months, respectively (p= 0.083)

*The incidence of NYHA Class III/IV CHF or cardiac death per the blinded review of the CSMC, the primary cardiac toxicity endpoint, was 3% in the MTP arm and 1% in the control arm. There were no cardiac deaths in the MTP group per that blinded central assessment. The CSMC re-assessed LVEF changes in 297/360 patients (82.5%). The proportion of patients meeting the criteria for treatment discontinuation was 6% in the MTP arm and 4% in the control arm. There were no reports of Grade 3-4 myocardial ischemia, Grade 3-4 MI, or Grade 3-4 arrhythmia in either treatment arm.Myelosuppression was the most frequent adverse reaction associated with the MTP arm (Table 3). It consisted of severe leucopenia and neutropenia as well as mild to moderate anemia and thrombocytopenia. The higher degree of myelosuppression in the MTP arm led to more transfusions, more febrile neutropenia and more anti-infective therapy, although the incidence of infective episodes was similar in both arms. There was also a higher incidence of predominantly mild to moderate stomatitis and gastrointestinal intolerance in the MTP arm as well as more mild to moderate LFT alterations. Of note, hand-foot syndrome occurred in 8 patients (4.5%) in the MTP arm and 3 patients (1.7%) in the TP arm, with severe manifestations in a single patient in both arms (Grade 3 in both cases). AEs, including treatment-related toxicities and deaths, led to more treatment discontinuations (23% vs. 15%, Fig. 1) and hospitalizations (23% vs. 15%) in the MTP arm. The incidence of deaths within 30 days of last study therapy was similar in both treatment arms (5% vs. 6%). *Estudio retrospectivo de NCCN database que estudia las tendencias de indicacin de tratamiento de ms de 4000 pacientes incluidas en el registro y con un seguimiento de 5.5 aos. Aqu en la grfica podemos observar la probabilidad de DRFS en pacientes NO TRATADAS con QT adyuvante a los 5 aos.*La tercera rama se cerr prematuramente tras anlisis interim per ser la menos eficaz y ms txicaLa primare rama tambin sufri una variacin significativa en la dosis inicialmente electa.*TL se lleva la peor parte en el perfil de toxicidad, sobre todo en cuanto a diarreas, rash y neutropenia*Las diferencias son ostensibles, y quizs clinicamente relevantes, pero no significativas. Las diferencias a favor del doble bloqueo son ms evidentes en HR-.*