Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. Economic Analysis of Gene Expression Profile Data to Guide Adjuvant Treatment in Women with Early-Stage Breast Cancer Concurrent neoadjuvant chemotherapy and estrogen deprivation in patients with estrogen receptor–positive, human epidermal growth factor receptor 2–negative breast cancer (CBCSG‐036): A randomized, controlled, multicenter trial Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. 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. Endocrine therapy with or without inhibition of epidermal growth factor receptor and human epidermal growth factor receptor 2: a randomized, double-blind, placebo-controlled phase III trial of fulvestrant with or without lapatinib for postmenopausal women with hormone receptor-positive advanced brea SWOG S0221: a phase III trial comparing chemotherapy schedules in high-risk early-stage breast cancer. Absolute Benefit of Adjuvant Endocrine Therapies for Premenopausal Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer: TEXT and SOFT Trials. HER2 and response to paclitaxel in node-positive breast cancer. Short preoperative treatment with erlotinib inhibits tumor cell proliferation in hormone receptor-positive breast cancers. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Value of epidermal growth factor receptor, HER2, p53, and steroid receptors in predicting the efficacy of tamoxifen in high-risk postmenopausal breast cancer patients. Prospective Clinical Utility Study of the Use of the 21-Gene Assay in Adjuvant Clinical Decision Making in Women With Estrogen Receptor-Positive Early Invasive Breast Cancer: Results From the SWITCH Study. Phase II Study of Neoadjuvant Anthracycline-Based Regimens Combined With Nanoparticle Albumin-Bound Paclitaxel and Trastuzumab for Human Epidermal Growth Factor Receptor 2-Positive Operable Breast Cancer. Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial. Six cycles of doxorubicin and cyclophosphamide or Paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. A cohort analysis to identify eligible patients for intraoperative radiotherapy (IORT) of early breast cancer
PURPOSE To identify optimal chemo- and targeted therapy for women with human epidermal growth factor 2 (HER2)- negative ( or unknown ) advanced breast cancer . METHODS A systematic review of r and omized evidence ( including systematic review s and meta-analyses ) from 1993 through to current was completed . Outcomes of interest included survival , progression-free survival , response , quality of life , and adverse effects . Guideline recommendations were evidence based and were agreed on by the Expert Panel via consensus . RESULTS Seventy-nine studies met the inclusion criteria , comprising 20 systematic review s and /or meta-analyses , 30 trials on first-line treatment , and 29 trials on second-line and subsequent treatment . These trials form the evidence base for the guideline recommendations . RECOMMENDATIONS Endocrine therapy is preferable to chemotherapy as first-line treatment for patients with estrogen receptor-positive metastatic breast cancer unless improvement is medically necessary ( eg , immediately life-threatening disease ) . Single agent is preferable to combination chemotherapy , and longer planned duration improves outcome but must be balanced against toxicity . There is no single optimal first-line or subsequent line chemotherapy , and choice of treatment will be determined by multiple factors including prior therapy , toxicity , performance status , comorbid conditions , and patient preference . The role of bevacizumab remains controversial . Other targeted therapies have not so far been shown to enhance chemotherapy outcome in HER2-negative breast cancer Breast cancer is the second most common type of cancer among women in the United States with more than 200,000 women diagnosed with invasive disease and with approximately 40,000 dying annually from the disease ( 1 ) . As a result of early detection efforts , nearly half of these women present with lymph node negative hormone receptor positive disease . Current treatment for early-stage breast cancer ( ESBC ) with adjuvant hormonal therapy and /or chemotherapy is based on clinical and pathological criteria including the presence and number of involved lymph nodes , tumor size and grade , hormone receptor status , and the presence of HER2/neu overexpression among others . Treatment decisions may also take into consideration patient age or menopausal status due to the anticipated lower risk of cancer recurrence , and the potential for smaller benefit and greater toxicity with aggressive systemic chemotherapy in older women . These considerations form the basis for clinical practice guidelines for the management of patients with ESBC ( 2 , 3 ) . Current guidelines recommend adjuvant systemic chemotherapy and endocrine therapy for most women with lymph node negative , hormone receptor positive , ESBC . Unfortunately , such systemic chemotherapy is associated with considerable cost , proximal morbidity , as well as increasing evidence for serious delayed toxicities including neurocognitive dysfunction and secondary malignancies . The risk of distant recurrence is generally low among ESBC patients with lymph node negative , hormone receptor positive disease regardless of treatment with adjuvant chemotherapy . However , several r and omized controlled trials of adjuvant chemotherapy and meta-analyses have shown the value of adjuvant chemotherapy in reducing the risk of disease The current r and omized , controlled , multicenter clinical trial was conducted to investigate the efficacy of concurrent neoadjuvant chemotherapy ( NCT ) and estrogen deprivation in patients with estrogen receptor (ER)–positive , human epidermal growth factor receptor 2 (HER2)–negative breast cancer PURPOSE We previously reported the eradication of human epidermal growth factor receptor 2 (HER2)- amplified human xenografts in mice by inhibition of the HER2 pathway with lapatinib and trastuzumab to block all homo- and heterodimer signaling as well as by blockade of estrogen receptor ( ER ) when expressed . In this clinical trial , we sought to translate these findings to patients using targeted therapy without chemotherapy . PATIENTS AND METHOD Women with stages II to III HER2-positive breast cancers were eligible . They received trastuzumab once per week ( 4 mg/kg loading , then 2 mg/kg ) and lapatinib 1000 mg once per day for 12 weeks . Women with ER-positive tumors also received letrozole ( plus a luteinizing hormone-releasing hormone [ LHRH ] agonist if premenopausal ) .  Pathologic response was assessed by ER status . Biopsies were obtained at baseline , weeks 2 and 8 , and time of surgery . RESULTS Sixty-six patients were enrolled , and 64 were eligible and evaluable for response .  Median tumor size was 6 cm ( range , 1.5 to 30 cm ) . Adverse events were mainly grade s 1 to 2 ( GI , 63 % ; skin , 46 % ) . Grade 3 metabolic , GI , and liver ( 18 % ; 12 patients ) and grade 4 liver toxicities ( one patient ) were also observed . Overall , in-breast pathologic complete response ( pCR ; ypT0-is ) was 27 % ( ER positive , 21 % ; ER negative , 36 % ) . The rate of low-volume residual disease ( ypT1a-b ) was 22 % ( ER positive , 33 % ; ER negative , 4 % ) . CONCLUSION In patients with locally advanced HER2-positive breast cancer , our approach of targeted therapy only result ed in a high pCR rate without chemotherapy . Our data support the hypothesis that selected patients with HER2-positive tumors may not need chemotherapy , and more-complete blockade of HER receptors and ER is an effective strategy worthy of further study 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 CALGB 40302 sought to determine whether lapatinib would improve progression-free survival ( PFS ) among women with hormone receptor-positive metastatic breast cancer treated with fulvestrant . PATIENTS AND METHODS Eligible women had estrogen receptor-positive and /or progesterone receptor-positive tumors , regardless of human epidermal growth factor receptor 2 ( HER2 ) status , and prior aromatase inhibitor treatment . Patients received fulvestrant 500 mg intramuscularly on day 1 , followed by 250 mg on days 15 and 28 and every 4 weeks thereafter , and either lapatinib 1,500 mg or placebo daily . The study planned to accrue 324 patients and was powered for a 50 % improvement in PFS with lapatinib from 5 to 7.5 months . RESULTS At the third planned interim analysis , the futility boundary was crossed , and the data and safety monitoring board recommend study closure , having accrued 295 patients . At the final analysis , there was no difference in PFS ( hazard ratio [ HR ] of placebo to lapatinib , 1.04 ; 95 % CI , 0.82 to 1.33 ; P = .37 ) ; median PFS was 4.7 months for fulvestrant plus lapatinib versus 3.8 months for fulvestrant plus placebo . There was no difference in overall survival ( OS ) ( HR , 0.91 ; 95 % CI , 0.68 to 1.21 ; P = .25 ) . For HER2-normal tumors , median PFS did not differ by treatment arm ( 4.1 v 3.8 months ) . For HER2-positive tumors , lapatinib was associated with longer median PFS ( 5.9 v 3.3 months ) , but the differential treatment effect by HER2 status was not significant ( P = .53 ) . The most frequent toxicities were diarrhea , fatigue , and rash associated with lapatinib . CONCLUSION Adding lapatinib to fulvestrant does not improve PFS or OS in advanced ER-positive breast cancer and is more toxic PURPOSE To determine the optimal dose and schedule of anthracycline and taxane administration as adjuvant therapy for early-stage breast cancer . PATIENTS AND METHODS A 2 × 2 factorial design was used to test two hypotheses : ( 1 ) that a novel continuous schedule of doxorubicin-cyclophosphamide was superior to six cycles of doxorubicin-cyclophosphamide once every 2 weeks and ( 2 ) that paclitaxel once per week was superior to six cycles of paclitaxel once every 2 weeks in patients with node-positive or high-risk node-negative early-stage breast cancer . With 3,250 patients , a disease-free survival ( DFS ) hazard ratio of 0.82 for each r and omization could be detected with 90 % power with two-sided α = .05 . Overall survival ( OS ) was a secondary outcome . RESULTS Interim analyses crossed the futility boundaries for demonstrating superiority of both once-per-week regimens and once-every-2-weeks regimens . After a median follow-up of 6 years , a significant interaction developed between the two r and omization factors ( DFS P = .024 ; OS P = .010 ) in the 2,716 patients r and omly assigned in the original design , which precluded interpretation of the two factors separately . Comparing all four arms showed a significant difference in OS ( P = .040 ) but not in DFS ( P = .11 ) , with all treatments given once every 2 weeks associated with the highest OS . This difference in OS seemed confined to patients with hormone receptor-negative/human epidermal growth factor receptor 2 ( HER2 ) -negative tumors ( P = .067 ) , with no differences seen with hormone receptor-positive/HER2-negative ( P = .90 ) or HER2-positive tumors ( P = .40 ) . CONCLUSION Patients achieved a similar DFS with any of these regimens . Subset analysis suggests the hypothesis that once-every-2-weeks dosing may be best for patients with hormone receptor-negative/HER2-negative tumors PURPOSE Risk of recurrence is the primary consideration in breast cancer adjuvant therapy recommendations . The TEXT ( Tamoxifen and Exemestane Trial ) and SOFT ( Suppression of Ovarian Function Trial ) trials investigated adjuvant endocrine therapies for premenopausal women with hormone receptor-positive breast cancer , testing exemestane plus ovarian function suppression ( OFS ) , tamoxifen plus OFS , and tamoxifen alone . We examined absolute treatment effect across a continuum of recurrence risk to individualize endocrine therapy decision making for premenopausal women with human epidermal growth factor receptor 2 ( HER2 ) -negative disease . PATIENTS AND METHODS The TEXT and SOFT hormone receptor-positive , HER2-negative analysis population included 4,891 women . The end point was breast cancer-free interval ( BCFI ) , defined as time from r and om assignment to first occurrence of invasive locoregional , distant , or contralateral breast cancer . A continuous , composite measure of recurrence risk for each patient was determined from a Cox model incorporating age , nodal status , tumor size and grade , and estrogen receptor , progesterone receptor , and Ki-67 expression levels . Sub population treatment effect pattern plot methodology revealed differential treatment effects on 5-year BCFI according to composite risk . RESULTS SOFT patients who remained premenopausal after chemotherapy experienced absolute improvement of 5 % or more in 5-year BCFI with exemestane plus OFS versus tamoxifen plus OFS or tamoxifen alone , reaching 10 % to 15 % at intermediate to high composite risk ; the benefit of tamoxifen plus OFS versus tamoxifen alone was apparent at the highest composite risk . The SOFT no-chemotherapy cohort-for whom composite risk was lowest on average-did well with all endocrine therapies . For TEXT patients , the benefit of exemestane plus OFS versus tamoxifen plus OFS in 5-year BCFI ranged from 5 % to 15 % ; patients not receiving chemotherapy and with lowest composite risk did well with both treatments . CONCLUSION Premenopausal women with hormone receptor-positive , HER2-negative disease and high recurrence risk , as defined by clinicopathologic characteristics , may experience improvement of 10 % to 15 % in 5-year BCFI with exemestane plus OFS versus tamoxifen alone . An improvement of at least 5 % may be achieved for women at intermediate risk , and improvement is minimal for those at lowest risk BACKGROUND The status of human epidermal growth factor receptor type 2 ( HER2 ) in breast-cancer cells predicts clinical outcomes in women who receive adjuvant anthracycline-based chemotherapy .  We hypothesized that HER2 positivity predicts a benefit from adjuvant doxorubicin doses above st and ard levels , from the addition of paclitaxel after adjuvant chemotherapy with doxorubicin plus cyclophosphamide , or from both . METHODS We r and omly selected 1500 women from 3121 women with node-positive breast cancer who had been r and omly assigned to receive doxorubicin ( 60 , 75 , or 90 mg per square meter of body-surface area ) plus cyclophosphamide ( 600 mg per square meter ) for four cycles , followed by four cycles of paclitaxel ( 175 mg per square meter ) or observation . Tissue blocks from 1322 of these 1500 women were available . Immunohistochemical analyses of these tissue specimens for HER2 with the CB11 monoclonal antibody against HER2 or with a polyclonal-antibody assay kit and fluorescence in situ hybridization for HER2 amplification were performed . RESULTS No interaction was observed between HER2 positivity and doxorubicin doses above 60 mg per square meter . HER2 positivity was , however , associated with a significant benefit from paclitaxel . The interaction between HER2 positivity and the addition of  paclitaxel to the treatment was associated with a hazard ratio for recurrence of 0.59 ( P=0.01 ) . Patients with a HER2-positive breast cancer benefited from paclitaxel , regardless of estrogen-receptor status , but paclitaxel did not benefit patients with HER2-negative , estrogen-receptor-positive cancers . CONCLUSIONS The expression or amplification , or both , of HER2 by a breast cancer is associated with a benefit from the addition of paclitaxel after adjuvant treatment with doxorubicin ( < 60 mg per square meter ) plus cyclophosphamide in node-positive breast cancer , regardless of estrogen-receptor status . Patients with HER2-negative , estrogen-receptor-positive , node-positive breast cancer may gain little benefit from the administration of paclitaxel after adjuvant chemotherapy with doxorubicin plus cyclophosphamide PURPOSE To administer the epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitor erlotinib to patients with operable untreated breast cancer during the immediate preoperative period and to measure an antiproliferative and /or a proapoptotic effect in the post-therapy specimen and determine a biomarker profile associated with evidence of erlotinib-mediated cellular activity . PATIENTS AND METHODS Newly diagnosed patients with stages I to IIIA invasive breast cancer were treated with erlotinib 150 mg/d orally for 6 to 14 days until the day before surgery . Erlotinib plasma levels were measured by t and em mass spectrometry the day of surgery . Drug-induced changes in tumor cell proliferation and apoptosis were assessed by Ki67 immunohistochemistry and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling analysis , respectively , in biopsies from the pretherapy and surgical specimens . Biopsies were also evaluated for P-EGFR , P-HER-2 , P-MAPK , P-Akt , P-S6 , and S118 P-ER alpha . RESULTS In drug-sensitive PC9 xenografts , 5 days of treatment with erlotinib were enough to induce a maximal inhibition of cell proliferation and induction of apoptosis .  Forty-one patients completed preoperative treatment with erlotinib .  Grade < or= 2 rash and diarrhea were the main toxicities . Erlotinib inhibited tumor cell proliferation ( Ki67 ) , P-EGFR , and P-HER-2 . The inhibition of proliferation occurred in estrogen receptor ( ER ) -positive but not in human epidermal growth factor receptor 2 ( HER-2 ) -positive or triple-negative cancers . Treatment was associated with a significant reduction of P-MAPK , P-Akt , P-S6 , and S118 P-ER alpha in hormone receptor-positive cancers . CONCLUSION A presurgical approach to evaluate cellular responses to new drugs is feasible in breast cancer . EGFR inhibitors are worthy of testing against ER-positive breast cancers but are unlikely to have clinical activity against HER-2-positive or triple-negative breast cancers BACKGROUND Neratinib , an irreversible tyrosine-kinase inhibitor of HER1 , HER2 , and HER4 , has clinical activity in patients with HER2-positive metastatic breast cancer . We aim ed to investigate the efficacy and safety of 12 months of neratinib after trastuzumab-based adjuvant therapy in patients with early-stage HER2-positive breast cancer . METHODS We did this multicentre , r and omised , double-blind , placebo-controlled , phase 3 trial at 495 centres in Europe , Asia , Australia , New Zeal and , and North and South America . Eligible women ( aged ≥18 years , or ≥20 years in Japan ) had stage 1 - 3 HER2-positive breast cancer and had completed neoadjuvant and adjuvant trastuzumab therapy up to 2 years before r and omisation . Inclusion criteria were amended on Feb 25 , 2010 , to include patients with stage 2 - 3 HER2-positive breast cancer who had completed trastuzumab therapy up to 1 year previously . Patients were r and omly assigned ( 1:1 ) to receive oral neratinib 240 mg per day or matching placebo . The r and omisation sequence was generated with permuted blocks stratified by hormone receptor status ( hormone receptor-positive [ oestrogen or progesterone receptor-positive or both ] vs hormone receptor-negative [ oestrogen and progesterone receptor-negative ] ) , nodal status ( 0 , 1 - 3 , or ≥4 ) , and trastuzumab adjuvant regimen ( sequentially vs concurrently with chemotherapy ) , then implemented central ly via an interactive voice and web-response system . Patients , investigators , and trial sponsors were masked to treatment allocation . The primary outcome was invasive disease-free survival , as defined in the original protocol , at 2 years after r and omisation . Analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00878709 . FINDINGS Between July 9 , 2009 , and Oct 24 , 2011 , we r and omly assigned 2840 women to receive neratinib ( n=1420 ) or placebo ( n=1420 ) . Median follow-up time was 24 months ( IQR 20 - 25 ) in the neratinib group and 24 months ( 22 - 25 ) in the placebo group . At 2 year follow-up , 70 invasive disease-free survival events had occurred in patients in the neratinib group versus 109 events in those in the placebo group ( stratified hazard ratio 0·67 , 95 % CI 0·50 - 0·91 ; p=0·0091 ) . The 2-year invasive disease-free survival rate was 93·9 % ( 95 % CI 92·4 - 95·2 ) in the neratinib group and 91·6 % ( 90·0 - 93·0 ) in the placebo group . The most common grade 3 - 4 adverse events in patients in the neratinib group were diarrhoea ( grade 3 , n=561 [ 40 % ] and grade 4 , n=1 [ < 1 % ] vs grade 3 , n=23 [ 2 % ] in the placebo group ) , vomiting ( grade 3 , n=47 [ 3 % ] vs n=5 [ < 1 % ] ) , and nausea ( grade 3 , n=26 [ 2 % ] vs n=2 [ < 1 % ] ) . QT prolongation occurred in 49 ( 3 % ) patients given neratinib and 93 ( 7 % ) patients given placebo , and decreases in left ventricular ejection fraction ( ≥ grade 2 ) in 19 ( 1 % ) and 15 ( 1 % ) patients , respectively . We recorded serious adverse events in 103 ( 7 % ) patients in the neratinib group and 85 ( 6 % ) patients in the placebo group . Seven ( < 1 % ) deaths ( four patients in the neratinib group and three patients in the placebo group ) unrelated to disease progression occurred after study drug discontinuation . The causes of death in the neratinib group were unknown ( n=2 ) , a second primary brain tumour ( n=1 ) , and acute myeloid leukaemia ( n=1 ) , and in the placebo group were a brain haemorrhage ( n=1 ) , myocardial infa rct ion ( n=1 ) , and gastric cancer ( n=1 ) . None of the deaths were attributed to study treatment in either group . INTERPRETATION Neratinib for 12 months significantly improved 2-year invasive disease-free survival when given after chemotherapy and trastuzumab-based adjuvant therapy to women with HER2-positive breast cancer . Longer follow-up is needed to ensure that the improvement in breast cancer outcome is maintained . FUNDING Wyeth , Pfizer , Puma Biotechnology PURPOSE Few studies have examined the possible importance of biologic prognostic factors in breast cancer connected with differentiation and growth in predicting response to a specific adjuvant treatment . HER2 , epidermal growth factor receptor ( EGFR ) , and p53 have all been suggested as possible markers of tamoxifen resistance . The aim of this study was to investigate interactions between adjuvant treatment with tamoxifen and the content of EGFR , HER2 , and p53 in steroid receptor-positive patients . PATIENTS AND METHODS A total of 1,716 high-risk postmenopausal breast cancer patients were r and omly assigned to treatment with tamoxifen ( 868 women ) or to observation ( 848 women ) in a prospect i ve trial ( Danish Breast Cancer Cooperative Group 's 77c protocol ) . The content of the steroid receptors and expression of p53 , EGFR , and HER2 were determined by immunohistochemical analysis of paraffin-embedded tissue . The length of follow-up was 10 years . The end point for this analysis was disease-free survival . RESULTS Multivariate analysis demonstrated no increased risk of recurrence after treatment with tamoxifen for HER2- , EGFR- , and p53-positive , high-risk , steroid receptor-positive patients . Patients with steroid receptor-positive tumors and positive immunohistochemical staining for HER2 , EGFR or p53 benefited from treatment with tamoxifen for 1 year , although the latter variable contained independent prognostic information by itself . CONCLUSION With the statistical power of the present r and omized study , we did not find support for the hypothesis that HER2/EGFR or p53 status predicts benefit from tamoxifen treatment in estrogen receptor-positive patients with early-stage breast cancer . Thus , neither HER2 , EGFR , nor p53 overexpression/accumulation should be used as a contraindication for giving tamoxifen BACKGROUND The 21-gene Oncotype DX Recurrence Score assay is a vali date d assay to help decide the appropriate treatment for estrogen receptor-positive ( ER+ ) , early-stage breast cancer ( EBC ) in the adjuvant setting . The choice of adjuvant treatments might vary considerably in different countries according to various treatment guidelines . This prospect i ve multicenter study is the first to assess the impact of the Oncotype DX assay in the French clinical setting . METHODS A total of 100 patients with ER+ , human epidermal growth factor receptor 2-negative EBC , and node-negative ( pN0 ) disease or micrometastases in up to 3 lymph nodes ( pN1mi ) were enrolled . Treatment recommendations , physicians ' confidence before and after knowing the Recurrence Score value , and physicians ' perception of the assay were recorded . RESULTS Of the 100 patients , 95 were evaluable ( 83 pN0 , 12 pN1mi ) . Treatment recommendations changed in 37 % of patients , predominantly from chemoendocrine to endocrine treatment alone . The proportion of patients recommended chemotherapy  decreased from 52 % pretest to 25 % post-test . Of patients originally recommended chemotherapy , 61 % were recommended endocrine treatment alone after receiving the Recurrence Score result . For both pN0 and pN1mi patients , post-test recommendations appeared to follow the Recurrence Score result for low and high values . Physicians ' confidence improved significantly . CONCLUSION These are the first prospect i ve data on the impact of the Oncotype DX assay on adjuvant treatment decisions in France . Using the assay was associated with a significant change in treatment decisions and an overall reduction in chemotherapy use . These data are consistent with those presented from European and non-European studies UNLABELLED We treated patients with operable human epidermal growth factor receptor 2-positive breast cancer with neoadjuvant anthracycline regimens followed by nanoparticle albumin-bound paclitaxel plus trastuzumab . Of the 44 patients , 49 % achieved a pathologic complete response ( pCR ) . The pCR rate was 36 % and 71 % in the patients with estrogen receptor-positive and -negative cancer , respectively . Neoadjuvant therapy using this combination appears to be effective and safe . Introduction : Neoadjuvant chemotherapy plus trastuzumab . INTRODUCTION Neoadjuvant chemotherapy plus trastuzumab results in a 30 % to 50 % pathologic complete response ( pCR ) rate in human epidermal growth factor receptor 2 (HER2)-positive breast cancer and has been associated with improved therapeutic outcomes . Thus , the pCR rate can be useful in evaluating novel agents in this patient population . Nanoparticle albumin-bound (nab)-paclitaxel ( PTX ) can reduce the toxicity of PTX while maintaining its efficacy . The present study evaluated the activity and safety of nab-PTX as a neoadjuvant treatment of HER2(+ ) breast cancer . PATIENTS AND METHODS We treated patients with stage I to IIIA breast cancer using neoadjuvant epirubicin/cyclophosphamide ( EC ) or 5-fluorouracil/epirubicin/cyclophosphamide every 3 weeks ( q3w ) for 4 cycles , followed by nab-PTX ( 260 mg/m(2 ) ) plus trastuzumab q3w for 4 cycles . The primary endpoint was the pCR rate . The secondary endpoints included the clinical response rate , disease-free survival , pathologic response rate ( defined as pCR or minimal residual invasive disease only in the breast ) , breast-conserving surgery rate , and safety . RESULTS Forty-six patients were enrolled . One patient met the exclusion criteria because of the coexistence of another malignant disease ; therefore , we evaluated 45 patients in the entire study . One patient experienced rapid disease progression during EC therapy , leaving 44 patients evaluable for nab-PTX treatment . Of the 45 patients , 49 % achieved a pCR . The pCR rate was 36 % and 71 % in those with estrogen receptor-positive and -negative cancer , respectively . Of all the study treatments , the most frequent reason for delay or dose reduction was hematologic toxicity ; only 1 patient required a dose reduction for nab-PTX because of peripheral neuropathy . CONCLUSION Neoadjuvant therapy using this combination appears to be effective and safe 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 PURPOSE The ideal duration of adjuvant chemotherapy for patients with lower risk primary breast cancer is not known . Cancer and Leukemia Group B trial 40101 was conducted using a phase III factorial design to define whether six cycles of a chemotherapy regimen are superior to four cycles . We also sought to determine whether paclitaxel ( T ) is as efficacious as doxorubicin/cyclophosphamide ( AC ) , but with reduced toxicity . PATIENTS AND METHODS Between 2002 and 2008 , the study enrolled women with operable breast cancer and zero to three positive nodes . Patients were r and omly assigned to either four or six cycles of either AC or T. Study stratifiers were estrogen receptor/progesterone receptor ( ER/PgR ) , human epidermal growth factor receptor 2 ( HER2 ) , and menopausal status . After 2003 , all treatment was administered in dose-dense fashion . The primary efficacy end point was relapse-free survival ( RFS ) . RESULTS A total of 3,171 patients were enrolled ; 94 % were node-negative and 6 % had one to three positive nodes . At a median follow-up of 5.3 years , the 4-year RFS was 90.9 % and 91.8 % for six and four cycles , respectively . The adjusted hazard ratio ( HR ) of six to four cycles regarding RFS was 1.03 ( 95 % CI , 0.84 to 1.28 ; P=.77 ) . The 4-year OS was 95.3 % and 96.3 % for six and four cycles , respectively , with an HR of six to four cycles of 1.12 ( 95 % CI , 0.84 to 1.49 ; P=.44 ) . There was no interaction between treatment duration and chemotherapy regimen , ER/PgR , or HER2 status on RFS or OS . CONCLUSION For women with resected primary breast cancer and zero to three positive nodes , we found no evidence that extending chemotherapy regimens of AC or single-agent T from four to six cycles improves clinical outcome Background Since the results from the r and omized TARGIT A trial were published , intraoperative radiotherapy ( IORT ) is used more often . IORT can be provided as accelerated partial breast irradiation ( APBI ) or as a boost . The definition of suitable patients for IORT as APBI differs between different national societies ( e.g. ESTRO and ASTRO ) and different inclusion criteria of trials and so does the eligibility of patients . This analysis identifies eligible patients for  IORT according to available consensus statements and inclusion criteria of the ongoing TARGIT trials . Methods Between 01/03 – 12/09 , 1505 breast cancer cases were treated at the breast cancer center at the University Medical Center Mannheim . Complete data sets for age , stage ( T , N , and M ) , histology and hormone receptor status were available in 1108 cases . Parameters to identify eligible patients are as follows : ESTRO : > 50 years , invasive ductal carcinoma/other favorable histology ( IDC ) , T1 - 2 ( ≤3 cm ) , N0 , any hormone receptor status , M0 ; ASTRO : ≥60 years , IDC , T1 , N0 , positive estrogen hormone receptor status , M0 ; TARGIT E “ elderly ” , risk adapted radiotherapy with IORT followed by external beam radiotherapy in case of risk factors in final histopathology , phase II : ≥70 years , IDC , T1 , N0 , any hormone receptor status , M0 ; TARGIT C “ consolidation ” , risk adapted radiotherapy , phase IV : ≥50 years , IDC , T1 , N0 , positive hormone receptor status , M0 ; TARGIT BQR “ boost quality registry ” : every age , every histology , T1 - 2 ( max . 3.5 cm ) , any hormone receptor status , N0/+ , M0/+ . Results Out of the 1108 cases , 379 cases ( 34.2 % ) were suitable for IORT as APBI regarding the ESTRO and 175 ( 15.8 % ) regarding the ASTRO consensus statements . 82 ( 7.4 % ) patients were eligible for the TARGIT E trial , 258 ( 23.3 % ) for the TARGIT C trial and 671 ( 60.6 % ) for the TARGIT BQR registry . According to the consensus statements of ASTRO ( 45.1 % ) and ESTRO ( 41.4 % ) about half of the eligible patients were treated with IORT as APBI . From the eligible patients fulfilling the criteria for IORT boost ( 35 % ) about one third was eventually treated . Conclusions Patient selection for IORT should be restrictive . For IORT as APBI the TARGIT trials are even more restrictive including patients than the ESTRO and ASTRO consensus statements
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 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 ? "