Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Adjuvant Pertuzumab and Trastuzumab in Early HER2‐Positive Breast Cancer Trastuzumab or lapatinib with standard chemotherapy for HER2-positive breast cancer: results from the GEICAM/2006-14 trial Predictive value of HER2 serum levels in patients treated with lapatinib or trastuzumab – a translational project in the neoadjuvant GeparQuinto trial Predictive value of PET-CT for pathological response in stages II and III breast cancer patients following neoadjuvant chemotherapy with docetaxel. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial Molecular Heterogeneity and Response to Neoadjuvant Human Epidermal Growth Factor Receptor 2 Targeting in CALGB 40601, a Randomized Phase III Trial of Paclitaxel Plus Trastuzumab With or Without Lapatinib. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2-positive operable breast cancer: results of the randomized phase II CHER-LOB study. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups.
BACKGROUND Findings from the r and omised phase 3 NeoALTTO trial in women with HER2-positive early breast cancer showed that the combination of lapatinib and trastuzumab significantly improved rates of pathological complete response compared with either drug alone . Here , we report data for the prespecified secondary endpoints of event-free and overall survival , and assess the association between these outcomes and pathological complete response . METHODS We enrolled women with HER2-positive early breast cancer and r and omly assigned them to receive oral lapatinib ( 1500 mg ) , intravenous trastuzumab ( 4 mg/kg loading dose followed by 2 mg/kg ) , or lapatinib ( 1000 mg ) plus trastuzumab ( same dose as for single agent ) in combination for 6 weeks , followed by an additional 12 weeks of the assigned anti-HER2 therapy in combination with weekly paclitaxel ( 80 mg/m(2 ) ) . Definitive surgery was done 4 weeks after the last dose of paclitaxel . After surgery , women received three cycles of FEC ( fluorouracil 500 mg/m(2 ) plus epirubicin 100 mg/m(2 ) plus cyclophosphamide 500 mg/m(2 ) ) given intravenously every 3 weeks , followed by 34 weeks of the same assigned neoadjuvant anti-HER2 therapy . The primary endpoint was pathological complete response . Secondary endpoints included event-free and overall survival ( intention-to-treat analysis ) , and the association between pathological complete response and event-free or overall survival ( analysed by l and mark analysis at 30 weeks after r and omisation ) . Follow-up is ongoing , and the trial is registered with Clinical Trials.gov , number NCT00553358 . FINDINGS 455 patients were enrolled : 154 ( 34 % ) were assigned to the lapatinib group , 149 ( 33 % ) to the trastuzumab group , and 152 ( 33 % ) to the lapatinib plus trastuzumab group . At an event follow-up of 3·77 years ( IQR 3·50 - 4·22 ) , 3-year event-free survival was 78 % ( 95 % CI 70 - 84 ) in the lapatinib group , 76 % ( 68 - 82 ) in the trastuzumab group , and 84 % ( 77 - 89 ) in the combination group . Event-free survival did not differ between the lapatinib and trastuzumab groups ( HR 1·06 , 95 % CI 0·66 - 1·69 , p=0·81 ) , nor between the combination and trastuzumab groups ( 0·78 , 0·47 - 1·28 , p=0·33 ) . Median survival follow-up was 3·84 years ( IQR 3·60 - 4·24 ) , and 3-year overall survival was 93 % ( 95 % CI 87 - 96 ) for lapatinib , 90 % ( 84 - 94 ) for trastuzumab , and 95 % ( 90 - 98 ) for combination therapy . Overall survival did not significantly differ between the lapatinib and trastuzumab groups ( HR 0·86 , 95 % CI 0·45 - 1·63 , p=0·65 ) , nor between the combination and trastuzumab groups ( 0·62 , 0·30 - 1·25 , p=0·19 ) . L and mark analyses showed that 3-year event-free survival was significantly improved for women who achieved pathological complete response compared with those who did not ( HR 0·38 , 95 % CI 0·22 - 0·63 , p=0·0003 ) , as was 3-year overall survival ( 0·35 , 0·15 - 0·70 , p=0·005 ) . Adverse events occurred in 149 ( 99 % ) patients receiving lapatinib , 142 ( 96 % ) patients receiving trastuzumab , and 147 ( 99 % ) patients receiving combination therapy . The most common adverse events were diarrhoea , rash or erythema , hepatic adverse events , and neutropenia ( not related to FEC administration ) , and were consistent with known safety profiles of lapatinib and trastuzumab . Three primary and eight secondary cardiac events occurred , with no significant difference in incidence between treatment groups for primary or any cardiac events . INTERPRETATION Although event-free survival or overall survival did not differ between treatment groups , findings from our study confirm that patients who achieve pathological complete response after neoadjuvant anti-HER2 therapy have longer event-free and overall survival than do patients without pathological complete response . FUNDING GlaxoSmithKline 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 We studied the effect on tumour response to neoadjuvant therapy of the substitution of lapatinib for trastuzumab in combination with weekly paclitaxel after doxorubicin plus cyclophosphamide treatment , and of the addition of lapatinib and trastuzumab combined after doxorubicin plus cyclophosphamide treatment in patients with HER2-positive operable breast cancer to determine whether there would be a benefit of dual HER2 blockade in these patients . METHODS For this open-label , r and omised phase 3 trial we recruited women aged 18 years or older with an ECOG performance status of 0 or 1 with operable HER2-positive breast cancer . Each received four cycles of st and ard doxorubicin 60 mg/m(2 ) and cyclophosphamide 600 mg/m(2 ) intravenously on day 1 every 3 weeks followed by four cycles of weekly paclitaxel ( 80 mg/m(2 ) ) intravenously on days 1 , 8 , and 15 , every 4 weeks . Concurrently with weekly paclitaxel , patients received either trastuzumab ( 4 mg/kg load , then 2 mg/kg intravenously ) weekly until surgery , lapatinib ( 1250 mg orally ) daily until surgery , or weekly trastuzumab plus lapatinib ( 750 mg orally ) daily until surgery . After surgery , all patients received trastuzumab to complete 52 weeks of HER2-targeted therapy . R and omisation ( ratio 1:1:1 ) was done central ly with stratification by clinical tumour size , clinical nodal status , hormone-receptor status , and age . The primary endpoint was the pathological complete response in the breast , and analysis was performed on an intention-to-treat population . FINDINGS Patient accrual started on July 16 , 2007 , and was completed on June 30 , 2011 ; 529 women were enrolled in the trial . 519 patients had their pathological response determined .  Breast pathological complete response was noted in 93 ( 52·5 % , 95 % CI 44·9 - 59·5 ) of 177 patients in the trastuzumab group , 91 ( 53·2 % , 45·4 - 60·3 ) of 171 patients in the lapatinib group ( p=0·9852 ) ; and 106 ( 62·0 % , 54·3 - 68·8 ) of 171 patients in the combination group ( p=0·095 ) . The most common grade 3 and 4 toxic effects were neutropenia ( 29 [ 16 % ] patients in the trastuzumab group [ grade 4 in five patients ( 3 % ) , 28 [ 16 % ] in the lapatinib group [ grade 4 in eight patients ( 5 % ) ] , and 29 [ 17 % ] in the combination group [ grade 4 in nine patients ( 5 % ) ] ) and grade 3 diarrhoea ( four [ 2 % ] patients in the trastuzumab group , 35 [ 20 % ] in the lapatinib group , and 46 [ 27 % ] in the combination group ; p<0·0001 ) . Symptomatic congestive heart failure defined as New York Heart Association Class III or IV events occurred in seven ( 4 % ) patients in the trastuzumab group , seven ( 4 % ) in the lapatinib group , and one ( < 1 % ) in the combination group ; p=0·185 ) . INTERPRETATION Substitution of lapatinib for trastuzumab in combination with chemotherapy result ed in similar high percentages of pathological complete response . Combined HER2-targeted therapy produced a numerically but insignificantly higher pathological complete response percentage than single-agent HER2-directed therapy ; these findings are consistent with results from other studies . Trials are being undertaken to further assess these findings in the adjuvant setting BACKGROUND Pertuzumab increases the rate of pathological complete response in the preoperative context and increases overall survival among patients with metastatic disease when it is added to  trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (HER2)–positive breast cancer . In this trial , we investigated whether pertuzumab , when added to adjuvant trastuzumab and chemotherapy , improves outcomes among patients with HER2‐positive early breast cancer . METHODS We r and omly assigned patients with node‐positive or high‐risk node‐negative HER2‐positive , operable breast cancer to receive either pertuzumab or placebo added to st and ard adjuvant chemotherapy plus 1 year of treatment with trastuzumab . We assumed a 3‐year invasive‐disease – free survival rate of 91.8 % with pertuzumab and 89.2 % with placebo . RESULTS In the trial population , 63 % of the patients who were r and omly assigned to receive pertuzumab ( 2400 patients ) or placebo ( 2405 patients ) had node‐positive disease and 36 % had hormone‐receptor – negative disease  . Disease recurrence occurred in 171 patients ( 7.1 % ) in the pertuzumab group and 210 patients ( 8.7 % ) in the placebo group ( hazard ratio , 0.81 ; 95 % confidence interval [ CI ] , 0.66 to 1.00 ; P=0.045 ) . The estimates of the 3‐year rates of invasive‐disease – free survival were 94.1 % in the pertuzumab group and 93.2 % in the placebo group . In the cohort of patients with node‐positive disease , the 3‐year rate of invasive‐disease – free survival was 92.0 % in the pertuzumab group , as compared with 90.2 % in the placebo group ( hazard ratio for an invasive‐disease event , 0.77 ; 95 % CI , 0.62 to 0.96 ; P=0.02 ) . In the cohort of patients with node‐negative disease , the 3‐year rate of invasive‐disease – free survival was 97.5 % in the pertuzumab group and 98.4 % in the placebo group ( hazard ratio for an invasive‐disease event , 1.13 ; 95 % CI , 0.68 to 1.86 ; P=0.64 ) . Heart failure , cardiac death , and cardiac dysfunction were infrequent in both treatment groups . Diarrhea of grade 3 or higher occurred almost exclusively during chemotherapy and was more frequent with pertuzumab than with placebo ( 9.8 % vs. 3.7 % ) . CONCLUSIONS Pertuzumab significantly improved the rates of invasive‐disease – free survival among patients with HER2‐positive , operable breast cancer when it was added to trastuzumab and chemotherapy .  Diarrhea was more common with pertuzumab than with placebo . ( Funded by F. Hoffmann – La Roche/Genentech ; APHINITY Clinical Trials.gov number , NCT01358877 . Background : The addition of trastuzumab ( T ) and lapatinib ( L ) to neoadjuvant chemotherapy increases the pathological complete response ( pCR ) rate in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer . We investigated the efficacy of T or L with neoadjuvant chemotherapy and specific efficacy biomarkers . Methods : Patients with stages I – III ( including inflammatory ) HER2-positive breast cancer were r and omised to receive epirubicin ( E ) plus cyclophosphamide ( C ) × 4 cycles followed by docetaxel ( D ) plus either T ( EC-DT ) or L ( EC-DL ) . End points included pCR ( primary ) , clinical response , toxicity , and pCR-predictive biomarkers . Results : We r and omised 102 patients to EC-DT ( 50 ) and EC-DL ( 52 ) . Median age was 48 , 56 % were premenopausal and 58 % had oestrogen receptor (ER)-positive tumours . Pathological complete response in breast was 52.1 % ( 95 % CI:38.0–66.2 % ) for EC-DT and 25.5 % ( 95 % CI:13.5–37.5 % ) for EC-DL ( P=0.0065 ) . Pathological complete response in breast and axilla was 47.9 % for EC-DT and 23.5 % for EC-DL ( P=0.011 ) . Grade 3–4 toxicity did not differ across treatments , except for diarrhoea ( 2 % in EC-DT vs 13.5 % in EC-DL , P=0.030 ) . Multivariate analyses showed that treatment ( P=0.036 ) and ER ( P=0.014 ) were the only predictors of pCR in both groups . Conclusion : EC-DT  exhibited higher efficacy and lower toxicity than EC-DL . Of the different biomarkers studied , only the absence of ER expression was associated with increased pCR Background : We were able to demonstrate a predictive value of serum HER2 ( sHER2 ) in patients receiving trastuzumab in the neoadjuvant GeparQuattro trial . However , the role of sHER2 in patients receiving neoadjuvant therapy ( NT ) with lapatinib is still unclear . Methods : The neoadjuvant GeparQuinto trial compared trastuzumab vs lapatinib in addition to chemotherapy in HER2-positive primary breast cancer patients .  The sHER2 levels were measured by enzyme-linked immunosorbant assay in 210 patients , of whom 109 ( 52 % ) patients received trastuzumab and 101 ( 48 % ) lapatinib at three different time points . Results : Twenty-two percent of patients had elevated baseline sHER2 levels ( > 15 ng ml−1 ) . A decrease of sHER2 levels ( > 20 % ) in the trastuzumab and lapatinib-treated group during NT was seen in 44 % and 24 % of the patients , an increase of sHER2 levels ( > 20 % ) was seen in 6 % and 41 % of patients , respectively . Higher pre-chemotherapy sHER2 levels were associated with higher pathological complete remission ( pCR ) rates in the entire study cohort ( OR 1.8 , 95 % CI 1.02–3.2 , P=0.043 ) . A decline of sHER2 levels ( > 20 % ) during NT was a predictor for pCR in the lapatinib-treated patient group ( OR : 11.7 , 95 % CI 1.3–110 , P=0.031 ) . Conclusion : Results of this study demonstrate that sHER2 levels change differently during NT depending on the anti-HER2 treatment strategy . Elevated baseline sHER2 levels ( > 15 ng ml−1 ) and a decrease of sHER2 levels ( > 20 % ) early after therapy initiation are both relevant criteria to predict response to lapatinib-based treatment PURPOSE To prospect ively study the value of PET-CT with fluorine-18 fluorodeoxyglucose ( FDG ) to predict neoadjuvant chemotherapy ( NAC ) response of locoregional disease of stages II and III breast cancer patients . MATERIAL AND METHODS A written informed consent and approval were obtained from the Ethics Committee . PET-CT accuracy in the prediction of pathologic complete response ( pCR ) after NAC was studied in primary tumors and lymph node metastasis in 43 women ( mean age : 50 years : range : 27 - 71 years ) with histologically proven breast cancer between December 2009 and January 2011 .  PET-CT was performed at baseline and after NAC .  SUV(max ) percentage changes ( ΔSUV(max ) ) were compared with pathology findings at surgery . Receiver-operator characteristic ( ROC ) analysis was used to discriminate between locoregional pCR and non-pCR . In patients not achieving pCR , it was investigated if ΔSUV(max ) could accurately identify the residual cancer burden ( RCB ) classes : RCB-I ( minimal residual disease ( MRD ) ) , RCB-II ( moderate RD ) , and RCB-III ( extensive RD ) . RESULTS pCR was obtained in 11 patients ( 25.6 % ) . Residual disease was found in 32 patients ( 74.4 % ) : 16 ( 37.2 % ) RCB-I , 15 ( 35.6 % ) RCB-II and 2 ( 4.7 % ) RCB-III . Sensitivity , specificity , and accuracy to predict pCR were 90.9 % , 90.6 % , and 90.7 % , respectively . Specificity was 94.1 % in the identification of a subset of patients who had either pCR or MRD . CONCLUSION Accuracy of ΔSUV(max ) in the locoregional disease of stages II and III breast cancer patients after NAC is high for the identification of pCR cases . Its specificity is potentially sufficient to identify a subgroup of patients who could be managed with conservative surgery 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 PURPOSE Dual human epidermal growth factor receptor 2 ( HER2 ) targeting can increase pathologic complete response rates ( pCRs ) to neoadjuvant therapy and improve progression-free survival in metastatic disease . CALGB 40601 examined the impact of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel , considering tumor and microenvironment molecular features . PATIENTS AND METHODS Patients with stage II to III HER2-positive breast cancer underwent tumor biopsy followed by r and om assignment to paclitaxel plus trastuzumab alone ( TH ) or with the addition of lapatinib ( THL ) for 16 weeks before surgery . An investigational arm of paclitaxel plus lapatinib ( TL ) was closed early . The primary end point was pCR in the breast ; correlative end points focused on molecular features identified by gene expression-based assays . RESULTS Among 305 r and omly assigned patients ( THL , n = 118 ; TH , n = 120 ; TL , n = 67 ) , the pCR rate was 56 % ( 95 % CI , 47 % to 65 % ) with THL and 46 % ( 95 % CI , 37 % to 55 % ) with TH ( P = .13 ) , with no effect of dual therapy in the hormone receptor-positive subset but a significant increase in pCR with dual therapy in those with hormone receptor-negative disease ( P = .01 ) . The tumors were molecularly heterogeneous by gene expression analysis using mRNA sequencing ( mRNAseq ) . pCR rates significantly differed by intrinsic subtype ( HER2 enriched , 70 % ; luminal A , 34 % ; luminal B , 36 % ; P < .001 ) . In multivariable analysis treatment arm , intrinsic subtype , HER2 amplicon gene expression , p53 mutation signature , and immune cell signatures were independently associated with pCR . Post-treatment residual disease was largely luminal A ( 69 % ) . CONCLUSION pCR to dual HER2-targeted therapy was not significantly higher than single HER2 targeting . Tissue analysis demonstrated a high degree of intertumoral heterogeneity with respect to both tumor genomics and tumor microenvironment that significantly affected pCR rates . These factors should be considered when interpreting and design ing trials in HER2-positive disease Purpose Lapatinib is a small molecule , dual tyrosine kinase inhibitor of epidermal growth factor receptor ( EGFR ) and human epidermal growth factor receptor type 2 ( HER2 ) . Initial results of a phase III trial demonstrated that lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that progressed following prior therapy including trastuzumab . Up date d efficacy and initial biomarker results from this trial are reported . Methods Women with HER2-positive , locally advanced or metastatic breast cancer previously treated with anthracycline- , taxane- , and trastuzumab-containing regimens were r and omized to lapatinib 1,250 mg/day continuously plus capecitabine 2,000 mg/m2 days 1–14 of a 21-day cycle or capecitabine 2,500 mg/m2 on the same schedule . The primary endpoint was time to progression ( TTP ) as determined by an independent review panel . Relationship between progression-free survival ( PFS ) and tumor HER2 expression and serum levels of HER2 extracellular domain ( ECD ) were assessed . Results 399 women were r and omized . The addition of lapatinib prolonged TTP with a hazard ratio ( HR ) of 0.57 ( 95 % CI , 0.43–0.77 ; P < 0.001 ) and provided a trend toward improved overall survival ( HR : 0.78 , 95 % CI : 0.55–1.12 , P = 0.177 ) , and fewer cases with CNS involvement at first progression ( 4 vs. 13 , P = 0.045 ) . Baseline serum HER2 ECD did not predict for benefit from lapatinib . Conclusion The addition of lapatinib to capecitabine provides superior efficacy for women with HER2-positive , advanced breast cancer progressing after treatment with anthracycline- ,  taxane- , and trastuzumab-based therapy . Biomarker studies could not identify a subgroup of patients who failed to benefit from the addition of lapatinib to capecitabine PURPOSE This is a noncomparative , r and omized , phase II trial of preoperative taxane-anthracycline in combination with trastuzumab , lapatinib , or combined trastuzumab plus lapatinib in patients with human epidermal growth factor receptor 2 ( HER2 ) -positive , stage II to IIIA operable breast cancer . The primary aim was to estimate the percentage of pathologic complete response ( pCR ; no invasive tumor in breast and axillary nodes ) . PATIENTS AND METHODS In the three arms , chemotherapy consisted of weekly paclitaxel ( 80 mg/m(2 ) ) for 12 weeks followed by fluorouracil , epirubicin , and cyclophosphamide for four courses every 3 weeks . The patients r and omly assigned to arm A received a 4-mg loading dose of trastuzumab followed by 2 mg weekly ; in arm B patients received lapatinib 1,500 mg orally ( PO ) daily ; and in arm C , patients received trastuzumab and lapatinib 1,000 mg PO daily . RESULTS A total of 121 patients were r and omly assigned .  Diarrhea and dermatologic and hepatic toxicities were observed more frequently in patients receiving lapatinib . No episodes of congestive heart failure were observed . The rates of breast-conserving surgery were 66.7 % , 57.9 % , and 68.9 % in arms A , B and C , respectively . The pCR rates were 25 % ( 90 % CI , 13.1 % to 36.9 % ) in arm A , 26.3 % ( 90 % CI , 14.5 % to 38.1 % ) in arm B , and 46.7 % ( 90 % CI , 34.4 % to 58.9 % ) in arm C ( exploratory P = .019 ) . CONCLUSION The primary end point of the study was met , with a relative increase of 80 % in the pCR rate achieved with chemotherapy plus trastuzumab and lapatinib compared with chemotherapy plus either trastuzumab or lapatinib . These data add further evidence supporting the superiority of a dual-HER2 inhibition for the treatment of HER2-positive breast cancer PURPOSE To determine whether preoperative doxorubicin and cyclophosphamide ( AC ) permits more lumpectomies to be performed and decreases the incidence of positive nodes in women with primary breast cancer . PATIENTS AND METHODS Women ( n = 1,523 ) were r and omized to National Surgical Adjuvant Breast and Bowel Project ( NSABP ) B-18 ; 759 eligible patients received postoperative AC and 747 , preoperative AC . The clinical size of breast and axillary tumors was determined before each of four cycles of AC and before surgery . Tumor response to preoperative therapy was clinical ly complete ( cCR ) , partial ( cPR ) , stable ( cSD ) , or progressive disease ( cPD ) . Tissue from patients with a cCR was evaluated for a pathologic complete response ( pCR ) . RESULTS Breast tumor size was reduced in 80 % of patients after preoperative therapy ; 36 % had a cCR . Tumor size and clinical nodal status were independent predictors of cCR . Twenty-six percent of women with a cCR had a pCR . Clinical nodal response occurred in 89 % of node-positive patients : 73 % had a cCR and 44 % of those had a pCR . There was a 37 % increase in the incidence of pathologically negative nodes . Before r and omization ,  lumpectomy  was proposed for 86 % of women with tumors < or = 2 cm , 70 % with tumors 2.1 to 5.0 cm , and 3 % with tumors > or = 5.1 cm . Clinical tumor size and nodal status influenced the physician 's decision . Overall , 12 % more lumpectomies were performed in the preoperative group ; in women with tumors > or = 5.1 cm , there was a 175 % increase . CONCLUSION Preoperative therapy reduced the size of most breast tumors and decreased the incidence of positive nodes . The greatest increase in lumpectomy after preoperative therapy occurred in women with tumors > or = 5 cm , since women with tumors less than 5 cm were already lumpectomy c and i date s. Preoperative therapy should be considered for the initial management of breast tumors judged too large for lumpectomy PURPOSE To evaluate efficacy and safety of epirubicin and cyclophosphamide followed by paclitaxel and trastuzumab as neoadjuvant treatment in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer . PATIENTS AND METHODS Patients with central ly confirmed HER2-overexpressing breast cancer ( ≥ 2 cm or inflammatory ) received four 3-week cycles epirubicin and cyclophosphamide ( 90/600 mg/m(2 ) ) followed by four 3-week cycles paclitaxel ( 175 mg/m(2 ) ) and trastuzumab ( 6 mg/kg ) before surgery . Trastuzumab was continued after surgery to complete 1 year of treatment . Primary end point was pathologic complete response ( pCR ) defined as no residual invasive tumor in breast and lymphatic tissue . RESULTS Thirty-nine percent of 217 enrolled patients achieved a pCR . Breast conservation was possible in 64 % of patients . Three-year disease-free survival ( DFS ) was 88 % in patients with pCR compared to 73 % in patients without pCR ( P = .01 ) . Three-year overall survival ( OS ) was 96 % in patients with pCR compared to 86 % in patients without pCR ( P = .025 ) . pCR was the only significant prognostic factor for DFS ( hazard ratio [ HR ] 2.5 ; 95 % CI , 1.2 to 5.1 ; P = .013 ) and OS ( HR , 4.9 ; 95 % CI , 1.4 to 17.4 ; P = .012 ) in multivariable analysis . Cardiac toxicity was reported in eight patients ( 3.7 % ) of whom six presented with an asymptomatic left ventricular ejection fraction decrease and two with symptomatic chronic heart failure . CONCLUSION Neoadjuvant combination of trastuzumab and chemotherapy result ed in a high pCR rate in HER2-overexpressing primary breast cancer . Patients with a pCR after neoadjuvant anti-HER2 therapy in combination with chemotherapy followed by maintenance trastuzumab have an improved long-term outcome . Patients without a pCR had an increased risk for relapse and death
Aim To evaluate efficacy and safety of lapatinib or trastuzumab alone or both plus chemotherapy for the treatment of breast cancer patients with positive HER-2 expression .