title: WSG ADAPT – adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early breast cancer: study protocol for a prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III trial Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. Very high quantitative tumor HER2 content and outcome in early breast cancer. Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial. Predictability of adjuvant trastuzumab benefit in N9831 patients using the ASCO/CAP HER2-positivity criteria. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial Health-related quality of life with adjuvant docetaxel- and trastuzumab-based regimens in patients with node-positive and high-risk node-negative, HER2-positive early breast cancer: results from the BCIRG 006 Study. C-MYC alterations and association with patient outcome in early-stage HER2-positive breast cancer from the north central cancer treatment group N9831 adjuvant trastuzumab trial. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. A phase III trial of adjuvant neratinib (NER) after trastuzumab (TRAS) in women with early-stage HER2+ breast cancer (BC). 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial Evaluation of trastuzumab without chemotherapy as a post-operative adjuvant therapy in HER2-positive elderly breast cancer patients: randomized controlled trial [RESPECT (N-SAS BC07)]. Adjuvant lapatinib for women with early-stage HER2-positive breast cancer: a randomised, controlled, phase 3 trial. Adjuvant trastuzumab in HER2-positive breast cancer. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. CNS relapses in patients with HER2-positive early breast cancer who have and have not received adjuvant trastuzumab: a retrospective substudy of the HERA trial (BIG 1-01). Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer Trial. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. Pattern of rash, diarrhea, and hepatic toxicities secondary to lapatinib and their association with age and response to neoadjuvant therapy: analysis from the NeoALTTO trial. Trastuzumab-associated cardiac events at 8 years of median follow-up in the Herceptin Adjuvant trial (BIG 1-01).
abstract: Background Adjuvant treatment decision-making based on conventional clinical /pathological and prognostic single molecular markers or genomic signatures is a therapeutic area in which over-/under-treatment are still key clinical problems even though substantial and continuous improvement of outcome has been achieved over the past decades . Response to therapy is currently not considered in the decision-making procedure . ADAPT is one of the first new generation (neo)adjuvant trials dealing with individualization of (neo)adjuvant decision-making in early breast cancer and aims to establish early predictive surrogate markers , e.g. , Ki-67 , for therapy response under a short induction treatment in order to maximally individualize therapy and avoid unnecessary toxicity by ineffective treatment . Methods / design The prospect i ve , multi-center , controlled , non-blinded , r and omized , investigator initiated phase II/III ADAPT trial has an innovative “ umbrella ” protocol design . The “ umbrella ” is common for all patients , consisting of dynamic testing of early therapy response .  ADAPT will recruit 4,936 patients according to their respective breast cancer subtype in four distinct sub-trials at 80 trial sites in Germany ; 4,000 patients with hormone receptor positive ( HR+ ) and HER2 negative disease will be included in the ADAPT HR+/HER2- sub-trial , where treatment decision is based on risk assessment and therapy response to induction therapy , and 380 patients will be included in ADAPT HER2+/HR+ . A further 220 patients will be included in ADAPT HER2+/HR- and 336 patients will be recruited for ADAPT Triple Negative . These three sub-trials focus on identification of early surrogate markers for therapy success in the neoadjuvant setting . Patients will be allocated to the respective sub-trial according to the result of their diagnostic core biopsy , as reported by local/ central pathology for HR and HER2 status . Discussion Recent trials , such as the GeparTrio , have shown that response-guided therapy using clinical response may improve outcome . For chemotherapy or HER2-targeted treatment , pathologic complete response in a neoadjuvant setting is an excellent predictor of outcome . For endocrine therapy , response to short induction treatment – as defined by decrease in tumor cell proliferation – strongly correlates with outcome . ADAPT now aims to combine static prognostic and dynamic predictive markers , focusing not just on single therapeutic targets , but also on general markers of proliferation and cell death . Biomarker analysis will help to optimize selection of subtype-specific treatment . Trial registration Clinical Trials.gov : ADAPT Umbrella : NCT01781338 ; ADAPT HR+/HER2- : NCT01779206 ; ADAPT HER2+/HR+ : NCT01745965 ; ADAPT HER2+/HR- : NCT01817452 ; ADAPT TN : NCT01815242 BACKGROUND Studies with pertuzumab , a novel anti-HER2 antibody , show improved efficacy when combined with the established HER2-directed antibody trastuzumab in breast cancer therapy . We investigated the combination of pertuzumab or trastuzumab , or both , with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting . METHODS In this multicentre , open-label , phase 2 study , treatment-naive women with HER2-positive breast cancer were r and omly assigned ( 1:1:1:1 ) central ly and stratified by operable , locally advanced , and inflammatory breast cancer , and by hormone receptor expression to receive four neoadjuvant cycles of : trastuzumab ( 8 mg/kg loading dose , followed by 6 mg/kg every 3 weeks ) plus docetaxel ( 75 mg/m(2 ) , escalating , if tolerated , to 100 mg/m(2 ) every 3 weeks ; group A ) or pertuzumab ( loading dose 840 mg , followed by 420 mg every 3 weeks ) and trastuzumab plus docetaxel ( group B ) or pertuzumab and trastuzumab ( group C ) or pertuzumab plus docetaxel ( group D ) . The primary endpoint , examined in the intention-to-treat population , was pathological complete response in the breast . Neither patients nor investigators were masked to treatment . This study is registered with Clinical Trials.gov , number NCT00545688 . FINDINGS Of 417 eligible patients , 107 were r and omly assigned to group A , 107 to group B , 107 to group C , and 96 to group D. Patients given pertuzumab and trastuzumab plus docetaxel ( group B ) had a significantly improved pathological complete response rate ( 49 of 107 patients ; 45·8 % [ 95 % CI 36·1 - 55·7 ] ) compared with those given trastuzumab plus docetaxel ( group A ; 31 of 107 ; 29·0 % [ 20·6 - 38·5 ] ; p=0·0141 ) . 23 of 96 ( 24·0 % [ 15·8 - 33·7 ] ) women given pertuzumab plus docetaxel ( group D ) had a pathological complete response , as did 18 of 107 ( 16·8 % [ 10·3 - 25·3 ] ) given pertuzumab and trastuzumab ( group C ) . The most common adverse events of grade 3 or higher were neutropenia ( 61 of 107 women in group A , 48 of 107 in group B , one of 108 in group C , and 52 of 94 in group D ) , febrile neutropenia ( eight , nine , none , and seven , respectively ) , and leucopenia ( 13 , five , none , and seven , respectively ) . The number of serious adverse events was similar in groups A , B , and D ( 15 - 20 serious adverse events per group in 10 - 17 % of patients ) but lower in group C ( four serious adverse events in 4 % of patients ) . INTERPRETATION Patients given pertuzumab and trastuzumab plus docetaxel ( group B ) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel , without substantial differences in tolerability .  Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile . These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer . FUNDING F Hoffmann-La Roche BACKGROUND We compared the efficacy and safety of the addition of lapatinib versus trastuzumab to anthracycline-taxane-based neoadjuvant chemotherapy . METHODS In the GeparQuinto r and omised phase 3 trial , patients with untreated HER2-positive operable or locally advanced breast cancer were enrolled between Nov 7 , 2007 , and July 9 , 2010 . Patients were eligible if their tumours were classified as cT3/4a-d , or hormone receptor (HR)-negative , HR-positive with clinical ly node-positive and cT2 disease ( cT2 cN+ ) , or HR-positive and pathologically node-positive in the sentinel lymph node for those with cT1 disease ( cT1 pN(SLN+ ) ) . Patients were r and omly assigned in a 1:1 ratio to receive neoadjuvant treatment with four cycles of EC ( epirubicin [ 90 mg/m(2 ) intravenously ] plus cyclophosphamide [ 600 mg/m(2 ) intravenously ] , every 3 weeks ) , and four cycles of docetaxel ( 100 mg/m(2 ) intravenously every 3 weeks ) with either trastuzumab ( 6 mg/kg intravenously , with a starting loading dose of 8 mg/kg , for eight cycles , every 3 weeks ) or lapatinib ( 1000 - 1250 mg per day orally ) throughout all cycles before surgery . R and omisation was done by dynamic allocation with the minimisation method of Pocock and patients were stratified by participating site , HR status , and extent of disease ( cT1 - 3 cN0 - 2 vs T4 or N3 ) . The primary endpoint was pathological complete response ( defined as ypT0 and ypN0 ) and was analysed in all patients who received at least one cycle of EC . Participants and investigators were not masked to treatment assignment . Pathologists in centres assessing surgery outcomes were masked to group assignment . This trial is registered with Clinical Trials.gov , number NCT00567554 . FINDINGS Of 620 eligible patients , 309 were r and omly assigned to chemotherapy with trastuzumab ( ECH-TH group ) and 311 to chemotherapy with lapatinib ( ECL-TL group ) . Two patients in the ECH-TH group and three patients in the ECL-TL group did not start treatment because of withdrawal of consent or immediate surgery . 93 ( 30·3 % ) of 307 patients in the ECH-TH group and 70 ( 22·7 % ) of 308 patients in the ECL-TL group had a pathological complete response ( odds ratio [ OR ] 0·68 [ 95%CI 0·47 - 0·97 ] ;  p=0·04 )  . Chemotherapy with trastuzumab was associated with more oedema ( 119 [ 39·1 % ] vs 88 [ 28·7 % ] ) and dyspnoea ( 90 [ 29·6 % ] vs 66 [ 21·4 % ] ) , and ECL-TL with more diarrhoea ( 231 [ 75·0 % ] vs 144 [ 47·4 % ] ) and skin rash ( 169 [ 54·9 % ] vs 97 [ 31·9 % ] ) . 43 ( 14·0 % ) patients discontinued in the ECH-TH group and 102 ( 33·1 % ) in the ECL-TL group . 70 serious adverse events were reported in the ECH-TH group and 87 in the ECL-TL group . INTERPRETATION This direct comparison of trastuzumab and lapatinib showed that pathological complete response rate  with chemotherapy and lapatinib was significantly lower than that with chemotherapy and trastuzumab . Unless long-term outcome data show different results , lapatinib should not be used outside of clinical trials as single anti-HER2-treatment in combination with neoadjuvant chemotherapy . FUNDING GlaxoSmithKline , Roche , and Sanofi-Aventis BACKGROUND Neoadjuvant chemotherapy with trastuzumab for patients with HER2-positive breast cancer can produce a pathological complete response in the breast in 30 - 65 % of patients . We investigated the effect of the timing of trastuzumab administration with anthracycline and taxane neoadjuvant chemotherapy . METHODS This r and omised trial was done at 36 centres in the USA and Puerto Rico . Women with operable HER2-positive invasive breast cancer were r and omly assigned ( 1:1 ) with a biased coin minimisation algorithm , stratified for age , tumour size , and hormone receptor status . Neither patients nor investigators ( except for a cardiac safety review panel ) were masked to treatment assignment . Patients r and omly assigned to sequential treatment received fluorouracil 500 mg/m(2 ) , epirubicin 75 mg/m(2 ) , and cyclophosphamide 500 mg/m(2 ) ( FEC-75 ) on day 1 of a 21-day cycle for four cycles followed by paclitaxel 80 mg/m(2 ) and trastuzumab 2 mg/kg ( after a 4 mg/kg loading dose ) once per week for 12 weeks , while those r and omly assigned to the concurrent treatment group received paclitaxel and trastuzumab once per week for 12 weeks followed by four cycles of FEC-75 ( on day 1 of each 21-day cycle ) and once-weekly trastuzumab , in the same doses as the sequential group . Surgery , including evaluation of the axilla , was done within 6 weeks of completion of neoadjuvant treatment . The primary outcome was the percentage of patients who had a pathological complete response in the intention-to-treat population . The study is registered with Clinical Trials.gov , number NCT00513292 . FINDINGS From Sept 15 , 2007 , to Dec 15 , 2011 , 282 women were enrolled ( 140 in the sequential group , 142 in the concurrent group ) . Two patients in the sequential group withdrew consent before starting treatment . 78 of 138 ( 56·5 % , 95 % CI 47·8 - 64·9 ) patients who received sequential treatment had a pathological complete response in the breast versus 77 of 142 ( 54·2 % , 95 % CI 45·7 - 62·6 ) who received concurrent treatment ( difference 2·3 % , 95 % CI -9·3 to 13·9 ) . No treatment-related deaths occurred . The most common severe toxic effects were neutropenia ( 35 [ 25·3 % ] of 138 patients in the sequential group vs 45 [ 31·7 % ] of 142 patients in the concurrent group ) and fatigue ( six [ 4·3 % ] vs 12 [ 8·5 % ] ) . Left ventricular ejection fraction dropped below the institutional lower limit of normal at week 12 in one ( 0·8 % ) of 130 patients who received sequential treatment and four ( 2·9 % ) of 137 patients who received concurrent treatment ; by week 24 , it had dropped below this limit in nine ( 7·1 % ) of 126 patients and in six ( 4·6 % ) of 130 patients , respectively . INTERPRETATION Concurrent administration of trastuzumab with anthracyclines offers no additional benefit and is not warranted . FUNDING US National Cancer Institute BACKGROUND We present the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer . METHODS The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks ( group 1 ) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel ( group 2 ) . The North Central Cancer Treatment Group trial N9831 compared three regimens : doxorubicin and cyclophosphamide followed by weekly paclitaxel ( group A ) , the same regimen followed by 52 weeks of trastuzumab after paclitaxel ( group B ) , and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel ( group C ) . The studies were amended to include a joint analysis comparing groups 1 and A ( the control group ) with groups 2 and C ( the trastuzumab group ) . Group B was excluded because trastuzumab was not given concurrently with paclitaxel . RESULTS By March 15 , 2005 , 394 events ( recurrent , second primary cancer , or death before recurrence ) had been reported , triggering the first scheduled interim analysis . Of these , 133 were in the trastuzumab group and 261 in the control group ( hazard ratio , 0.48 ; P<0.0001 ) . This result crossed the early stopping boundary . The absolute difference in disease-free survival between the trastuzumab group and the control group was 12 percent at three years . Trastuzumab therapy was associated with a 33 percent reduction in the risk of death ( P=0.015 ) . The three-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1 percent in trial B-31 and 2.9 percent in trial N9831 . CONCLUSIONS Trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer . ( Clinical Trials.gov numbers , NCT00004067 and NCT00005970 . BACKGROUND It is unknown how a very high tumor total HER2 ( human epidermal growth factor receptor-2 ) content ( H2 T ) influences outcome in early breast cancer treated with adjuvant trastuzumab plus chemotherapy .  PATIENTS AND METHODS H2 T was measured using a novel quantitative assay ( HERmark ( ® ) ) from formalin-fixed tumor tissue of 899 women who participated in the FinHer trial ( IS RCT N76560285 ) . In a chromogenic in situ hybridization ( CISH ) test , 197 ( 21.9 % ) patients had HER2-positive cancer and were r and omly assigned to receive trastuzumab or control .  RESULTS Cancer H2 T levels varied 1808-fold . High H2 T levels were correlated with a positive HER2 status by CISH ( P < 0.0001 ) . A nonlinear association was present between H2 T and the hazard of distant recurrence in a sub population treatment effect pattern plot analysis in CISH-positive disease . Patients with very high H2 T ( defined by ≥22-fold the median of HER2-negative cancers ; 13 % of CISH-positive cancers ) did not benefit from adjuvant trastuzumab [ hazard ratio ( HR ) 1.23 ; 95 % confidence interval ( CI ) 0.33 - 4.62 ; P = 0.75 ] , whereas the rest of the patients with HER2-positive disease by CISH ( 87 % ) did benefit ( HR 0.52 ; 95 % CI 0.28 - 1.00 ; P = 0.050 ) . CONCLUSION Patients with HER2-positive breast cancer with very high tumor HER2 content may benefit less from adjuvant trastuzumab compared with those whose cancer has more moderate HER2 content BACKGROUND Trastuzumab ( Herceptin(R ) ) improves disease-free survival ( DFS ) and overall survival for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer . We aim ed to assess the magnitude of its clinical benefit for sub population s defined by nodal and steroid hormone receptor status using data from the Herceptin Adjuvant ( HERA ) study . PATIENTS AND METHODS HERA is an international multicenter r and omized trial comparing 1 or 2 years of trastuzumab treatment with observation after st and ard chemotherapy in women with HER2-positive breast cancer . In total , 1703 women r and omized to 1-year trastuzumab and 1698 women r and omized to observation were included in these analyses . Median follow-up was 23.5 months . The primary endpoint was DFS . RESULTS The overall hazard ratio ( HR ) for trastuzumab versus observation was 0.64 [ 95 % confidence interval ( CI ) 0.54 - 0.76 ; P < 0.0001 ] , ranging from 0.46 to 0.82 for subgroups . Estimated improvement in 3-year DFS in subgroups ranged from + 11.3 % to + 0.6 % . Patients with the best prognosis ( those with node-negative disease and tumors 1.1 - 2.0 cm ) had benefit similar to the overall cohort ( HR 0.53 , 95 % CI 0.26 - 1.07 ; 3-year DFS improvement + 4.6 % , 95 % CI -4.0 % to 13.2 % ) . CONCLUSIONS Adjuvant trastuzumab therapy reduces the risk of relapse similarly across subgroups defined by nodal status and steroid hormone receptor status , even those at relatively low risk for relapse The 2007 American Society of Clinical Oncology and College of American Pathologists ( ASCO/CAP ) joint guidelines defined criteria for HER2 positivity of tumors that modified those of the US Food and Drug Administration ( FDA ) , causing some confusion and uncertainty among clinicians . Using data from the HER2-positive breast cancer adjuvant trial N9831 , we compared eligibility for patients who met both criteria , and disease-free survival ( DFS ) was assessed by Cox proportional hazards regression . The number of patients in the N9831 trial retrospectively eligible for trastuzumab therapy was decreased when ASCO/CAP criteria vs FDA criteria were applied to immunohistochemistry and /or fluorescence in situ hybridization results ( 107 [ 3.7 % ] of 2904 patients with immunohistochemistry results , 37 [ 1.3 % ] of 2809 patients with fluorescence in situ hybridization results , and 47 [ 1.7 % ] of 2809 patients with both results ) . Improvement in DFS was similar among patients treated with trastuzumab under either set of criteria ( concurrent trastuzumab and chemotherapy compared with chemotherapy alone : by ASCO/CAP criteria , hazard ratio of DFS = 0.59 , 95 % confidence interval = 0.48 to 0.73 ; by FDA criteria but not ASCO/CAP criteria , hazard ratio = 0.60 , 95 % confidence interval = 0.12 to 3.13 ; number needed to treat to prevent one additional DFS event at 5 years : 10 and 11.2 patients , respectively ) . Following the 2007 ASCO/CAP criteria for HER2 positivity would negate the option of potentially life-saving trastuzumab therapy for a small but meaningful group of patients . We recommend using FDA -approved HER2 criteria for therapeutic decision making BACKGROUND The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour activity in models of HER2-overexpressing breast cancer . We argue that the two anti-HER2 agents given together would be better than single-agent therapy . METHODS In this parallel groups , r and omised , open-label , phase 3 study undertaken between Jan 5 , 2008 , and May 27 , 2010 , women from 23 countries with HER2-positive primary breast cancer with tumours greater than 2 cm in diameter were r and omly assigned to oral lapatinib ( 1500 mg ) , intravenous trastuzumab ( loading dose 4 mg/kg [ DOSAGE ERROR CORRECTED ] , subsequent doses 2 mg/kg ) , or lapatinib ( 1000 mg ) plus trastuzumab . Treatment allocation was by stratified , permuted blocks r and omisation , with four stratification factors . Anti-HER2 therapy alone was given for the first 6 weeks ; weekly paclitaxel ( 80 mg/m(2 ) ) was then added to the regimen for a further 12 weeks , before definitive surgery was undertaken . After surgery , patients received adjuvant chemotherapy followed by the same targeted therapy as in the neoadjuvant phase to 52 weeks . The primary endpoint was the rate of pathological complete response ( pCR ) , analysed by intention to treat . This trial is registered with Clinical Trials.gov , NCT00553358 . FINDINGS 154 patients received lapatinib , 149 trastuzumab , and 152 the combination . pCR rate was significantly higher in the group given lapatinib and trastuzumab ( 78 of 152 patients [ 51·3 % ; 95 % CI 43·1 - 59·5 ] ) than in the group given trastuzumab alone ( 44 of 149 patients [ 29·5 % ; 22·4 - 37·5 ] ; difference 21·1 % , 9·1 - 34·2 , p=0·0001 ) . We recorded no significant difference in pCR between the lapatinib ( 38 of 154 patients [ 24·7 % , 18·1 - 32·3 ] ) and the trastuzumab ( difference -4·8 % , -17·6 to 8·2 , p=0·34 ) groups . No major cardiac dysfunctions occurred . Frequency of grade 3 diarrhoea was higher with lapatinib ( 36 patients [ 23·4 % ] ) and lapatinib plus trastuzumab ( 32 [ 21·1 % ] ) than with trastuzumab ( three [ 2·0 % ] ) . Similarly , grade 3 liver-enzyme alterations were more frequent with lapatinib ( 27 [ 17·5 % ] ) and lapatinib plus trastuzumab ( 15 [ 9·9 % ] ) than with trastuzumab ( 11 [ 7·4 % ] ) . INTERPRETATION Dual inhibition of HER2 might be a valid approach to treatment of HER2-positive breast cancer in the neoadjuvant setting . FUNDING GlaxoSmithKline BACKGROUND This study aims to describe and compare health-related quality of life ( HRQL ) in patients with node-positive and high-risk node-negative HER2-positive early breast cancer receiving adjuvant docetaxel and trastuzumab-based or docetaxel-based regimens alone . METHODS Eligible patients ( n = 3,222 ) were r and omly assigned to either four cycles of adjuvant doxorubicin and cyclophosphamide followed by four cycles of docetaxel ( AC→T ) or one of two trastuzumab-containing regimens : adjuvant doxorubicin and cyclophosphamide followed by docetaxel plus trastuzumab administered for 1 year ( AC→TH ) or six cycles of docetaxel plus carboplatin combined with trastuzumab administered for 1 year ( TCH ) . The European Organization for Research and Treatment of Cancer ( EORTC ) Quality of Life Question naire C30 and BR-23 were administered at baseline , the start of cycle 4 ( mid ) , and the end of chemotherapy ( EOC ) , as well as at 6 , 12 , and 24 months after chemotherapy . RESULTS Compliance rates for the EORTC question naires were acceptable at 72%-93 % of eligible patients out to the 12-month assessment . Systemic side effect ( SE ) change scores were significantly improved for TCH-treated patients compared with AC→TH and AC→T at EOC , suggesting improved tolerability . Physical functioning ( PF ) was only slightly worse at midpoint for those receiving TCH , compared with patients who were just starting on taxane in an AC→TH regimen , but was otherwise similar between arms . All treatment arms recovered from the deterioration in SE , PF , and Global Health Scale scores by 1 year and median future perspective change scores continued to improve throughout treatment and follow-up . CONCLUSION HRQL outcomes for adjuvant docetaxel and trastuzumab-based regimens are favorable and support TCH as a more tolerable treatment option PURPOSE Findings from the human epidermal growth factor receptor 2 ( HER2 ) -positive National Surgical Adjuvant Breast and Bowel Project ( NSABP ) B31 trial suggested that MYC/HER2 coamplification ( > 5.0 copies/nucleus ) was associated with additional benefit from adjuvant trastuzumab in patients with early-stage breast cancer . To further explore this relationship , we investigated associations between MYC amplification and disease-free survival ( DFS ) in a similar adjuvant trastuzumab HER2-positive breast cancer trial-North Central Cancer Treatment Group ( NCCTG ) N9831 . PATIENTS AND METHODS This analysis included 799 patients r and omly assigned to receive chemotherapy alone or with concurrent trastuzumab on N9831 . Fluorescence in situ hybridization ( FISH ) was performed by using a dual-probe mixture for MYC and centromere 8 ( MYC : CEP8 ) on tissue microarrays . MYC amplification was prespecified as MYC : CEP8 ratio > 2.2 or average MYC copies/nucleus > 5.0 . Exploratory variables included polysomy 8 . RESULTS In comparing DFS ( median follow-up , 4.0 years ) between treatments , patients with MYC : CEP8 ratio ≤ 2.2 ( n = 618 ; 77 % ) and > 2.2 ( n = 181 ; 23 % ) had hazard ratios ( HRs ) of 0.46 ( P < .001 ) and 0.67 ( P = .33 ) , respectively ( interaction P = .38 ) . Patients with MYC copies/nucleus ≤ 5.0 ( n = 534 ; 67 % ) and > 5.0 ( n = 265 ; 33 % ) had HRs of 0.52 ( P = .002 ) and 0.48 ( P = .02 ) , respectively ( interaction P = .94 ) . Patients with MYC : CEP8 ratio < 1.3 with normal chromosome 8 copy number ( n = 141 ; 18 % ) and ≥ 1.3 or < 1.3 with polysomy 8 ( n = 658 ; 82 % ) had HRs of 0.66 ( P = .28 ) and 0.44 ( P < .001 ) , respectively ( interaction P = .23 ) . Patients with MYC copies/nucleus < 2.5 ( n = 130 ; 16 % ) and ≥ 2.5 ( n = 669 ; 84 % ) had HRs of 1.07 ( P = .87 ) and 0.42 ( P < .001 ) , respectively ( interaction P = .05 ) . CONCLUSION We did not confirm the B31 association between MYC amplification and additional trastuzumab benefit . Exploratory analyses revealed potential associations between alternative MYC/chromosome 8 copy number alterations and differential benefit of adjuvant trastuzumab BACKGROUND Since 2005 , 12 months of adjuvant trastuzumab has been the st and ard treatment for patients with HER2-positive early-stage breast cancer . However , the optimum duration of treatment has been debated . We did a non-inferiority trial of a shorter exposure of 6 months versus the st and ard 12 months of trastuzumab for patients with early breast cancer . METHODS We did an open-label , r and omised , phase 3 trial in 156 centres in France . Patients with HER2-positive early breast cancer who had received at least four cycles of chemotherapy , had breast-axillary surgery , and had received up to 6 months of trastuzumab ( administered by intravenous infusions over 30 - 90 min every 3 weeks ; initial loading dose 8 mg/kg ; 6 mg/kg thereafter ) before r and omisation were eligible . Patients were r and omly assigned via central r and omisation procedure with web-based software to continue trastuzumab for another 6 months ( 12 months total duration ; control group ) or to discontinue trastuzumab at 6 months ( 6 months total duration ; experimental group ) . R and omisation was stratified by concomitant or sequential administration of trastuzumab with chemotherapy , oestrogen-receptor status , and centre using a minimisation algorithm . The primary endpoint was disease-free survival , with a prespecified non-inferiority margin of 1·15 . Analyses were done in the intention-to-treat population . This study is registered at Clinical Trials.gov , number NCT00381901 . FINDINGS 1691 patients were r and omly assigned to receive 12 months of trastuzumab and 1693 to receive 6 months of trastuzumab ;  1690 patients in each group were included in the intention-to-treat analyses . After a median follow-up of 42·5 months ( IQR 30·1 - 51·6 ) , 175 disease-free survival events were noted in the 12-month group and 219 in the 6-month group . 2-year disease-free survival was 93·8 % ( 95 % CI 92·6 - 94·9 ) in the 12-month group and 91·1 % ( 89·7 - 92·4 ) in the 6-month group ( hazard ratio 1·28 , 95 % CI 1·05 - 1·56 ; p=0·29 ) . 119 ( 93 % ) of the 128 cardiac events ( clinical or based on assessment of left ventricular ejection fraction ) occurred while patients were receiving trastuzumab . Significantly more patients in the 12-month group experienced a cardiac event than did those in the 6-month group ( 96 [ 5·7 % ] of 1690 patients vs 32 [ 1·9 % ] of 1690 patients , p<0·0001 ) . INTERPRETATION After 3·5 years follow-up , we failed to show that 6 months of treatment with trastuzumab was non-inferior to 12 months of trastuzumab . Despite the higher rates of cardiac events , 12 months of adjuvant trastuzmab should remain the st and ard of care . FUNDING French National Cancer Institute TPS137 Background : The human epidermal growth factor receptors ( HER1 - 4 ) are frequently overexpressed in human tumors . Increased HER receptor signaling is associated with increased resistance to st and ard therapies and poor prognosis . TRAS , an anti-HER2 monoclonal antibody , reduces recurrences and improves disease-free survival ( DFS ) in patients ( pts ) with HER2 + early BC . However , 15 % to 25 % of TRAS-treated pts still experience relapsed disease at 5 yrs . NER is a small molecule , irreversible tyrosine kinase inhibitor of HER2 as well as HER1 and HER4 . In a phase II study , orally administered NER 240 mg/d was well tolerated with significant antitumor activity in pts with HER2 + BC , with or without prior TRAS ( objective response rates of 24 % and 56 % ; median progression-free survival of 22 wks and 40 wks , respectively ) . The current study will evaluate the efficacy and safety of  NER in pts with early-stage HER2 + BC after adjuvant TRAS .  METHODS This double-blind , placebo-controlled , multicenter , phase III study will include approximately 3,300 women with early-stage HER2-overexpressing/amplified , node-positive BC ( or no pathologic complete response after neoadjuvant therapy ) at high risk for recurrence . Pts will be r and omized within 1 yr of prior adjuvant TRAS to oral NER 240 mg or placebo daily for 1 yr . Pts will be followed for up to 5 yrs post-r and omization for recurrence and /or survival . Primary endpoint is DFS ( time to disease recurrence or death ) , using a 1-sided log-rank test to compare treatment arms and a Cox proportional hazards regression model for hazard ratio estimation . Other efficacy endpoints include DFS including ductal carcinoma in situ , time to distant recurrence , distant DFS , incidence of central nervous system recurrence , and overall survival . Safety will be monitored , with particular attention to diarrhea . Biomarker analyses ( including HER2 confirmation from archived sample s ) and health-related quality of life ( FACT-B and EQ-5D ) will also be assessed . RESULTS As of Jan 25 , 2011 , a total of 2,050 pts have been r and omized , including 934 high-risk pts . CONCLUSIONS Recruitment is planned to continue until late 2013 . As of Nov 3 , 2010 , the IDMC recommended the trial to continue BACKGROUND Trastuzumab has established efficacy against breast cancer with overexpression or amplification of the HER2 oncogene . The st and ard of care is 1 year of adjuvant trastuzumab , but the optimum duration of treatment is unknown . We compared 2 years of treatment with trastuzumab with 1 year of treatment , and up date d the comparison of 1 year of trastuzumab versus observation at a median follow-up of 8 years , for patients enrolled in the HERceptin Adjuvant ( HERA ) trial . METHODS The HERA trial is an international , multicentre , r and omised , open-label , phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after st and ard neoadjuvant chemotherapy , adjuvant chemotherapy , or both in 5102 patients with HER2-positive early breast cancer . The primary endpoint was disease-free survival . The comparison of 2 years versus 1 year of trastuzumab treatment involved a l and mark analysis of 3105 patients who were disease-free 12 months after r and omisation to one of the trastuzumab groups , and was planned after observing at least 725 disease-free survival events . The up date d intention-to-treat comparison of 1 year trastuzumab treatment versus observation alone in 3399 patients at a median follow-up of 8 years ( range 0 - 10 ) is also reported . This study is registered with Clinical Trials.gov , number NCT00045032 . FINDINGS We recorded 367 events of disease-free survival in 1552 patients in the 1 year group and 367 events in 1553 patients in the 2 year group ( hazard ratio [ HR ] 0·99 , 95 % CI 0·85 - 1·14 , p=0·86 ) . Grade 3 - 4 adverse events and decreases in left ventricular ejection fraction during treatment were reported more frequently in the 2 year treatment group than in the 1 year group ( 342 [ 20·4 % ] vs 275 [ 16·3 % ] grade 3 - 4 adverse events , and 120 [ 7·2 % ] vs 69 [ 4·1 % ] decreases in left ventricular ejection fraction , respectively ) . HRs for a comparison of 1 year of trastuzumab treatment versus observation were 0·76 ( 95 % CI 0·67 - 0·86 , p<0·0001 ) for disease-free survival and 0·76 ( 0·65 - 0·88 , p=0·0005 ) for overall survival , despite crossover of 884 ( 52 % ) patients from the observation group to trastuzumab therapy . INTERPRETATION 2 years of adjuvant trastuzumab is not more effective than is 1 year of treatment for patients with HER2-positive early breast cancer . 1 year of treatment provides a significant disease-free and overall survival benefit compared with observation and remains the st and ard of care . FUNDING F Hoffmann-La Roche ( Roche ) PURPOSE To assess cardiac safety and potential cardiac risk factors associated with trastuzumab in the NCCTG N9831 Intergroup adjuvant breast cancer trial . PATIENTS AND METHODS Patients with HER2-positive operable breast cancer were r and omly assigned to doxorubicin plus cyclophosphamide ( AC ) followed by either weekly paclitaxel ( arm A ) ; paclitaxel then trastuzumab ( arm B ) ; or paclitaxel plus trastuzumab then trastuzumab alone ( arm C ) . Left ventricular ejection fraction ( LVEF ) was evaluated at registration and 3 , 6 , 9 , and 18 to 21 months . RESULTS Of 2,992 patients completing AC , 5.0 % had LVEF decreases disallowing trastuzumab ( decrease below normal : 2.4 % , decrease > 15 % : 2.6 % ) . There were 1,944 patients with satisfactory or no LVEF evaluation who proceeded to post-AC therapy . Cardiac events ( congestive heart failure [ CHF ] or cardiac death [ CD ] ) : arm A , n = 3 ( 2 CHF , 1 CD ) ; arm B , n = 19 ( 18 CHF , 1 CD ) ; arm C , n = 19 ( all CHF ) ; 3-year cumulative incidence : 0.3 % , 2.8 % , and 3.3 % , respectively . Cardiac function improved in most CHF cases following trastuzumab discontinuation and cardiac medication . Factors associated with increased risk of a cardiac event in arms B and C : older age ( P < .003 ) , prior/current antihypertensive agents ( P = .005 ) , and lower registration LVEF ( P = .033 ) . Incidence of asymptomatic LVEF decreases requiring holding trastuzumab was 8 % to 10 % ; LVEF recovered and trastuzumab was restarted in approximately 50 % . CONCLUSION The cumulative incidence of post-AC cardiac events at 3 years was higher in the trastuzumab-containing arms versus the control arm , but by less than 4 % . Older age , lower registration LVEF , and antihypertensive medications are associated with increased risk of cardiac dysfunction in patients receiving trastuzumab following AC PURPOSE Trastuzumab is a humanized monoclonal antibody against the human epidermal growth factor receptor 2 ( HER2 ) . The clinical benefits of adjuvant trastuzumab have been demonstrated in interim analyses of four large trials . Initial data of the combined analysis of the North Central Cancer Treatment Group ( NCCTG ) N9831 Intergroup trial and National Surgical Adjuvant Breast and Bowel Project ( NSABP ) B-31 trial were reported in 2005 . Long-term follow-up results on disease-free survival ( DFS ) and overall survival ( OS ) have been awaited . PATIENTS AND METHODS Patients with HER2-positive operable breast cancer were r and omly assigned to doxorubicin plus cyclophosphamide followed by paclitaxel with or without trastuzumab in the NCCTG N9831 and NSABP B-31 trials . The similar design of both trials allowed data from the control and trastuzumab-containing arms to be combined in a joint analysis . RESULTS At 3.9 years of median follow-up , there continues to be a highly statistically significant reduction in DFS event rate in favor of the trastuzumab-containing arm ( P < .001 ) . Similarly , there continues to be a statistically significant 39 % reduction in death rate in favor of the trastuzumab-containing arm ( P < .001 ) . CONCLUSION These data demonstrate consistent DFS and OS advantages of adjuvant trastuzumab over time , with the longest follow-up reported to date . The clinical benefits continue to outweigh the risks of adverse effects BACKGROUND Trastuzumab -- a humanised monoclonal antibody against HER2 - -has been shown to improve disease-free survival after chemotherapy in women with HER2-positive early breast cancer . We investigated the drug 's effect on overall survival after a median follow-up of 2 years in the Herceptin Adjuvant ( HERA ) study . METHODS HERA is an international multicentre r and omised trial that compared 1 or 2 years of trastuzumab treatment with observation alone after st and ard neoadjuvant or adjuvant chemotherapy in women with HER2-positive node positive or high-risk node negative breast cancer . 5102 women participated in the trial ; we analysed data from 1703 women who had been r and omised for treatment with trastuzumab for 1 year and 1698 women from the control group , with median follow-up of 23.5 months ( range 0 - 48 months ) . The primary endpoint of the trial was disease-free survival . Here , we assess overall survival , a secondary endpoint . Analyses were done on an intent-to-treat basis . This trial is registered with the European Clinical Trials Data base , number 2005 - 002385 - 11 . FINDINGS 97 ( 5.7 % ) patients r and omised to observation alone and 58 ( 3.4 % ) patients r and omised to 1 year of treatment with trastuzumab were lost to follow-up . 172 women stopped trastuzumab prematurely . 59 deaths were reported for trastuzumab and 90 in the control group . The unadjusted hazard ratio ( HR ) for the risk of death with trastuzumab compared with observation alone was 0.66 ( 95 % CI 0.47 - 0.91 ; p=0.0115 ) . 218 disease-free survival events were reported with trastuzumab compared with 321 in the control group . The unadjusted HR for the risk of an event with trastuzumab compared with observation alone was 0.64 ( 0.54 - 0.76 ; p<0.0001 ) . INTERPRETATION Our results show that 1 year of treatment with trastuzumab after adjuvant chemotherapy has a significant overall survival benefit after a median follow-up of 2 years . The emergence of this benefit after only 2 years reinforces the importance of trastuzumab in the treatment of women with HER2-positive early breast cancer OBJECTIVE This trial is conducted to investigate the benefit of trastuzumab monotherapy compared with a combination therapy of trastuzumab and chemotherapy in women over 70 years with human epidermal growth factor receptor type-2-positive primary breast cancer . METHODS Inclusion criteria are the following : histologically diagnosed as invasive breast cancer and received curative operation for primary breast cancer ; Stage I , IIA , IIB or IIIA/M0 ; and baseline left ventricular ejection fraction is ≥55 % . Patients are r and omized to receive either trastuzumab ( 8 mg/kg loading dose , 6 mg/kg every 3 weeks for 1 year ) plus chemotherapy selected from regimens specified on the protocol or trastuzumab monotherapy . The primary endpoint is disease-free survival . Secondary endpoints are overall survival , relapse-free survival , safety , health-related quality of life , comprehensive geriatric assessment and cost effectiveness . RESULTS Patients recruitment has been commenced in October 2009 . Enrollment of 300 patients is planned during the 4-year recruitment period . CONCLUSIONS We hereby report the study concept BACKGROUND Worldwide , many patients with HER2-positive early stage breast cancer do not receive trastuzumab-the st and ard adjuvant treatment . We investigated the efficacy and safety of adjuvant lapatinib for patients with trastuzumab-naive HER2-positive early-stage breast cancer , started at any time after diagnosis . METHODS This study was a placebo-controlled , multicentre , r and omised phase 3 trial . Women out patients from 405 [ corrected ] centres in 33 countries [ corrected ] with HER2-positive early-breast cancer who had previously received adjuvant chemotherapy but not trastuzumab were r and omly assigned ( 1:1 ) to receive daily lapatinib ( 1500 mg ) or daily placebo for 12 months . R and omisation was done with a computer-generated sequence , stratified by time since diagnosis , lymph node involvement at diagnosis , and tumour hormone-receptor status . Investigators , site staff , and patients were masked to treatment assignment . The primary endpoint was disease-free survival in the intention-to-treat population . This study is registered with Clinical Trials.gov , number NCT00374322 . FINDINGS Between August , 2006 , and May , 2008 , 3161 women were enrolled and 3147 were assigned to lapatinib ( n=1571 ) or placebo ( n=1576 ) . After a median follow-up of 47·4 months ( range 0·4 - 60·0 ) in the lapatinib group and 48·3 ( 0·7 - 61·3 ) in the placebo group , 210 ( 13 % ) disease-free survival events had occurred in the lapatinib group versus 264 ( 17 % ) in the placebo group ( hazard ratio [ HR ] 0·83 , 95 % CI 0·70 - 1·00 ; p=0·053 ) . Central review of HER2 status showed that only 2490 ( 79 % ) of the r and omised women were HER2-positive . 157 ( 13 % ) of 1230 confirmed HER2-positive patients in the lapatinib group and in 208 ( 17 % ) of 1260 in the placebo group had a disease-free survival event ( HR 0·82 , 95 % 0·67 - 1·00 ; p=0·04 ) . Serious adverse events occurred in 99 ( 6 % ) of 1573 patients taking lapatinib and 77 ( 5 % ) of 1574 patients taking placebo , with higher incidences of grade 3 - 4 diarrhoea ( 97 [ 6 % ] vs nine [ < 1 % ] ) , rash ( 72 [ 5 % ] vs three [ < 1 % ] ) , and hepatobiliary disorders ( 36 [ 2 % ] vs one [ < 1 % ] ) . INTERPRETATION Our data show that there was no significant difference in disease-free survival between groups when analysed in the intention-to-treat population . However , exploratory analyses restricted to patients who had HER2-positive disease confirmed by central fluorescence in-situ hybridisation review suggested marginal benefit with lapatinib in terms of disease-free survival . Thus lapatinib might be an option for women with HER2-positive breast cancer who do not or can not receive adjuvant trastuzumab . FUNDING GlaxoSmithKline BACKGROUND Trastuzumab improves survival in the adjuvant treatment of HER-positive breast cancer , although combined therapy with anthracycline-based regimens has been associated with cardiac toxicity . We wanted to evaluate the efficacy and safety of a new nonanthracycline regimen with trastuzumab . METHODS We r and omly assigned 3222 women with HER2-positive early-stage breast cancer to receive doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks ( AC-T ) , the same regimen plus 52 weeks of trastuzumab ( AC-T plus trastuzumab ) , or docetaxel and carboplatin plus 52 weeks of trastuzumab ( TCH ) . The primary study end point was disease-free survival . Secondary end points were overall survival and safety . RESULTS At a median follow-up of 65 months , 656 events triggered this protocol -specified analysis . The estimated disease-free survival rates at 5 years were 75 % among patients receiving AC-T , 84 % among those receiving AC-T plus trastuzumab , and 81 % among those receiving TCH . Estimated rates of overall survival were 87 % , 92 % , and 91 % , respectively . No significant differences in efficacy ( disease-free or overall survival ) were found between the two trastuzumab regimens , whereas both were superior to AC-T. The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group ( P<0.001 ) . Eight cases of acute leukemia were reported : seven in the groups receiving the anthracycline-based regimens and one in the TCH group subsequent to receiving an anthracycline outside the study . CONCLUSIONS The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer . The risk-benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab , given its similar efficacy , fewer acute toxic effects , and lower risks of cardiotoxicity and leukemia . ( Funded by Sanofi-Aventis and Genentech ; BCIRG-006 Clinical Trials.gov number , NCT00021255 . ) BACKGROUND Treatment with adjuvant trastuzumab for 1 year improves disease-free survival and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer . We aim ed to assess disease-free survival and overall survival after a median follow-up of 4 years for patients enrolled on the Herceptin Adjuvant ( HERA ) trial . METHODS The HERA trial is an international , multicentre , r and omised , open-label , phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after st and ard neoadjuvant , adjuvant chemotherapy , or both in patients with HER2-positive early breast cancer . The primary endpoint was disease-free survival . After a positive first interim analysis at a median follow-up of 1 year for the comparison of treatment with trastuzumab for 1 year with observation , event-free patients in the observation group were allowed to cross over to receive trastuzumab . We report trial outcomes for the 1-year trastuzumab and observation groups at a median follow-up of 48·4 months ( IQR 42·0 - 56·5 ) and assess the effect of the extensive crossover to trastuzumab . Our analysis was by intention-to-treat . The HERA trial is registered with the European Clinical Trials Data base , number 2005 - 002385 - 11 . FINDINGS The HERA trial population comprised 1698 patients r and omly assigned to the observation group and 1703 to the 1-year trastuzumab group . Intention-to-treat analysis of disease-free survival showed a significant benefit in favour of patients in the 1-year trastuzumab group ( 4-year disease-free survival 78·6 % ) compared with the observation group ( 4-year disease-free survival 72·2 % ; hazard ratio [ HR ] 0·76 ; 95 % CI 0·66 - 0·87 ; p<0·0001 ) . Intention-to-treat analysis of overall survival showed no significant difference in the risk of death ( 4-year overall survival 89·3%vs 87·7 % , respectively ; HR 0·85 ; 95 % CI 0·70 - 1·04 ; p=0·11 ) . Overall , 885 patients ( 52 % ) of the 1698 patients in the observation group crossed over to receive trastuzumab , and began treatment at median 22·8 months ( range 4·5 - 52·7 ) from r and omisation . In a non-r and omised comparison , patients in the selective-crossover cohort had fewer disease-free survival events than patients remaining in the observation group ( adjusted HR 0·68 ; 95 % CI 0·51 - 0·90 ; p=0·0077 ) . Higher incidences of grade 3 - 4 and fatal adverse events were noted on 1-year trastuzumab than in the observation group . The most common grade 3 or 4 adverse events , each in less than 1 % of patients , were congestive cardiac failure , hypertension , arthralgia , back pain , central -line infection , hot flush , headache , and diarrhoea . INTERPRETATION Treatment with adjuvant trastuzumab for 1 year after chemotherapy is associated with significant clinical benefit at 4-year median follow-up . The substantial selective crossover of patients in the observation group to trastuzumab was associated with improved outcomes for this cohort . FUNDING F Hoffmann-La Roche , Michelangelo Foundation BACKGROUND Several r and omised trials have confirmed the benefit of adjuvant trastuzumab for patients with HER2-positive early breast cancer . However , concern has been expressed that adjuvant trastuzumab might be associated with an increased frequency of CNS relapses . We assessed the frequency and course of CNS relapses , either as first event or at any time , using data from the HERA trial . METHODS We estimated the cumulative incidence of first disease-free survival ( DFS ) events in the CNS versus other sites by competing risks analysis in patients with HER2-positive early breast cancer who had been r and omly assigned to receive 1 year of trastuzumab or to observation in the HERA trial after a median follow-up of 4 years ( IQR 3·5 - 4·8 ) . To obtain further information about CNS relapse at any time before death , we circulated a data collection form to investigators to obtain st and ardised information about CNS events that occurred in all patients who had died before July , 2009 . We estimated the cumulative incidence of CNS relapse at any time with a competing risks analysis . RESULTS Of 3401 patients who had been assigned to receive 1 year of trastuzumab or to observation , 69 ( 2 % ) had a CNS relapse as first DFS event and 747 ( 22 % ) had a first DFS event not in the CNS . The frequency of CNS relapses as first DFS event did not differ between the group given 1 year of trastuzumab ( 37 [ 2 % ] of 1703 patients ) and the observation group ( 32 [ 2 % ] of 1698 ; p=0·55 [ Gray 's test ] ) . 481 data collection forms were distributed , of which 413 ( 86 % ) were returned . The proportion of patients who had died and experienced a CNS relapse was numerically higher in the observation group ( 129 [ 57 % ] of 227 ) than in the group given trastuzumab for 1 year ( 88 [ 47 % ] of 186 ; p=0·06 [ Gray 's test ] ) . Most CNS relapses were symptomatic ( 189 [ 87 % ] of 217 ) . CONCLUSION Adjuvant trastuzumab does not increase the risk of CNS relapse in patients with HER2-positive early breast cancer . FUNDING None PURPOSE Docetaxel has not been compared with vinorelbine as adjuvant treatment of early breast cancer .  Efficacy and long-term safety of a short course of adjuvant trastuzumab administered concomitantly with chemotherapy for human epidermal growth factor receptor 2 ( HER2 ) -positive cancer are unknown . PATIENTS AND METHODS One thous and ten women with axillary node-positive or high-risk node-negative breast cancer were r and omly assigned to receive three cycles of docetaxel or vinorelbine , followed in both groups by three cycles of fluorouracil , epirubicin , and cyclophosphamide ( FEC ) .  Women with HER2-positive cancer ( n = 232 ) were further assigned to either receive or not receive trastuzumab for 9 weeks with docetaxel or vinorelbine . The median follow-up time was 62 months after r and om assignment . RESULTS Women assigned to docetaxel had better distant disease-free survival ( DDFS ) than those assigned to vinorelbine ( hazard ratio [ HR ] = 0.66 ; 95 % CI , 0.49 to 0.91 ; P = .010 ) . In the subgroup of HER2-positive disease , patients treated with trastuzumab tended to have better DDFS than those treated with chemotherapy only ( HR = 0.65 ; 95 % CI , 0.38 to 1.12 ; P = .12 ; with adjustment for presence of axillary nodal metastases , HR = 0.57 ; P = .047 ) . In exploratory analyses , docetaxel , trastuzumab , and FEC improved DDFS compared with docetaxel plus FEC ( HR = 0.32 ; P = .029 ) and vinorelbine , trastuzumab , and FEC ( HR = 0.31 ; P = .020 ) . The median left ventricular ejection fraction of trastuzumab-treated patients remained unaltered during the 5-year follow-up ; only one woman treated with trastuzumab was diagnosed with a heart failure . CONCLUSION Adjuvant treatment with docetaxel improves DDFS compared with vinorelbine . A brief course of trastuzumab administered concomitantly with docetaxel is safe and effective and warrants further evaluation PURPOSE NCCTG ( North Central Cancer Treatment Group ) N9831 is the only r and omized phase III trial evaluating trastuzumab added sequentially or used concurrently with chemotherapy in resected stages I to III invasive human epidermal growth factor receptor 2-positive breast cancer . PATIENTS AND METHODS Patients received doxorubicin and cyclophosphamide every 3 weeks for four cycles , followed by paclitaxel weekly for 12 weeks ( arm A ) , paclitaxel plus sequential trastuzumab weekly for 52 weeks ( arm B ) , or paclitaxel plus concurrent trastuzumab for 12 weeks followed by trastuzumab for 40 weeks ( arm C ) . The primary end point was disease-free survival ( DFS ) . RESULTS Comparison of arm A ( n = 1,087 ) and arm B ( n = 1,097 ) , with 6-year median follow-up and 390 events , revealed 5-year DFS rates of 71.8 % and 80.1 % , respectively . DFS was significantly increased with trastuzumab added sequentially to paclitaxel ( log-rank P < .001 ; arm B/arm A hazard ratio [ HR ] , 0.69 ; 95 % CI , 0.57 to 0.85 ) . Comparison of arm B ( n = 954 ) and arm C ( n = 949 ) , with 6-year median follow-up and 313 events , revealed 5-year DFS rates of 80.1 % and 84.4 % , respectively . There was an increase in DFS with concurrent trastuzumab and paclitaxel relative to sequential administration ( arm C/arm B HR , 0.77 ; 99.9 % CI , 0.53 to 1.11 ) , but the P value ( .02 ) did not cross the prespecified O'Brien-Fleming boundary ( .00116 ) for the interim analysis . CONCLUSION DFS was significantly improved with 52 weeks of trastuzumab added to adjuvant chemotherapy . On the basis of a positive risk-benefit ratio , we recommend that trastuzumab be incorporated into a concurrent regimen with taxane chemotherapy as an important st and ard-of-care treatment alternative to a sequential regimen PURPOSE We investigated the pattern of rash , diarrhea , and hepatic adverse events ( AEs ) secondary to lapatinib and their association with age and pathologic complete response ( pCR ) in the Neoadjuvant Lapatinib and /or Trastuzumab Treatment Optimisation ( NeoALLTO ) phase III trial . PATIENTS AND METHODS Patients with HER2-positive early breast cancer were r and omly assigned to receive lapatinib ( Arm A ) , trastuzumab ( Arm B ) , or their combination ( Arm C ) for 6 weeks followed by the addition of paclitaxel for 12 weeks before surgery . We investigated the frequency and time to developing each AE according to age ( ≤ 50 v > 50 years ) and their association with pCR in a logistic regression model adjusted for age , hormone receptors , tumor size , nodal status , planned breast surgery , completion of lapatinib administration , and treatment arm . RESULTS Only patients r and omly assigned to arms A and C were eligible ( n = 306 ) . Younger patients ( ≤ 50 years ) experienced significantly more rash compared with older patients ( 74.4 % v 47.9 % ; P < .0001 ) . Diarrhea and hepatic AEs were observed in 78.8 % and 41.2 % of patients , respectively , with no differences in rate or severity or time of onset according to age . Early rash ( ie , before starting paclitaxel ) was independently associated with a higher chance of pCR , mainly in patients older than 50 years ( odds ratio [ OR ] = 3.76 ; 95 % CI , 1.69 to 8.34 ) but not in those ≤ 50 years ( OR = 0.92 ; 95 % CI , 0.45 to 1.88 ; P for interaction = .01 ) . No significant association was observed between pCR and diarrhea or hepatic AEs . CONCLUSION Our results indicate that the frequency and clinical relevance of lapatinib-related rash is largely dependent on patient age PURPOSE To document the rate and outcome of trastuzumab-associated cardiac dysfunction in patients following 1 or 2 years of adjuvant therapy .  PATIENTS AND METHODS The Herceptin Adjuvant ( HERA ) trial is a three-arm , r and omized trial comparing 2 years or 1 year of trastuzumab with observation in 5,102 patients with human epidermal growth factor receptor 2 ( HER2 ) -positive early-stage breast cancer . Cardiac function was closely monitored . Eligible patients had left ventricular ejection fraction ( LVEF ) ≥ 55 % at study entry following neoadjuvant chemotherapy with or without radiotherapy .  This 8-year median follow-up analysis considered patients r and omly assigned to 2 years or 1 year of trastuzumab or observation . RESULTS The as-treated safety population for 2 years of trastuzumab ( n = 1,673 ) , 1 year of trastuzumab ( n = 1,682 ) , and observation ( n = 1,744 ) is reported . Cardiac adverse events leading to discontinuation of trastuzumab occurred in 9.4 % of patients in the 2-year arm and 5.2 % of patients in the 1-year arm . Cardiac death , severe congestive heart failure ( CHF ) , and confirmed significant LVEF decrease remained low in all three arms . The incidence of severe CHF ( 0.8 % , 0.8 % , and 0.0 % , respectively ) and confirmed significant LVEF decrease ( 7.2 % , 4.1 % , and 0.9 % , respectively ) was significantly higher in the 2-year and 1-year trastuzumab arms compared with the observation arm . Severe CHF was the same for 2-year and 1-year trastuzumab . Of patients with confirmed LVEF decrease receiving 2-year trastuzumab , 87.5 % reached acute recovery . Of patients with confirmed LVEF decrease receiving 1-year trastuzumab , 81.2 % reached acute recovery . CONCLUSION Long-term assessment at 8-year median follow-up confirms the low incidence of cardiac events for trastuzumab given sequentially after chemotherapy and radiotherapy , and cardiac events were reversible in the vast majority of patients
target: Longer trastuzumab duration ( hera : 2 years vs. 1 year ) showed no improvement in dfs or os and a higher rate of cardiac events .
  In the neoadjuvant setting ( neoaltto , GeparQuinto , Neosphere ) , trastuzumab alone or in combination with another anti-her2 agent ( lapatinib , pertuzumab ) was compared with either lapatinib or pertuzumab alone and showed superior or equivalent rates of pathologic complete response .
  In the adjuvant setting , lapatinib alone or in combination with trastuzumab , compared with trastuzumab alone ( altto ) or with placebo ( teach ) , was not superior in dfs .
background: BACKGROUND This systematic review addresses the question " What is the optimal targeted therapy for female patients with early-stage human epidermal growth factor receptor 2 (her2)-positive breast cancer ? "