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. 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. 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. SWOG S0221: a phase III trial comparing chemotherapy schedules in high-risk early-stage breast cancer. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. Tumor-specific expression of vascular endothelial growth factor receptor 2 but not vascular endothelial growth factor or human epidermal growth factor receptor 2 is associated with impaired response to adjuvant tamoxifen in premenopausal breast cancer. Double-blind, placebo-controlled, multicenter, randomized, phase IIb neoadjuvant study of letrozole-lapatinib in postmenopausal hormone receptor-positive, human epidermal growth factor receptor 2-negative, operable breast cancer. Value of epidermal growth factor receptor, HER2, p53, and steroid receptors in predicting the efficacy of tamoxifen in high-risk postmenopausal breast cancer patients. Evaluation of serum HER2 extracellular domain in early breast cancer patients: correlation with clinicopathological parameters and survival. 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 Preoperative therapy with trastuzumab and paclitaxel followed by sequential adjuvant doxorubicin/cyclophosphamide for HER2 overexpressing stage II or III breast cancer: a pilot study. Predictors of Resistance to Preoperative Trastuzumab and Vinorelbine for HER2-Positive Early Breast Cancer Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. 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. 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 Prospective study of the impact of the Prosigna assay on adjuvant clinical decision-making in unselected patients with estrogen receptor positive, human epidermal growth factor receptor negative, node negative early-stage breast cancer Neoadjuvant chemotherapy of breast cancer: tumor markers as predictors of pathologic response, recurrence, and survival. Trastuzumab Emtansine With or Without Pertuzumab Versus Trastuzumab Plus Taxane for Human Epidermal Growth Factor Receptor 2–Positive, Advanced Breast Cancer: Primary Results From the Phase III MARIANNE Study Pilot trial of paclitaxel-trastuzumab adjuvant therapy for early stage breast cancer: a trial of the ECOG-ACRIN cancer research group (E2198) Impact of PTEN protein expression on benefit from adjuvant trastuzumab in early-stage human epidermal growth factor receptor 2-positive breast cancer in the North Central Cancer Treatment Group N9831 trial. Efficacy and safety of neoadjuvant chemotherapy with concurrent liposomal-encapsulated doxorubicin, paclitaxel and trastuzumab for human epidermal growth factor receptor 2-positive breast cancer in clinical practice
 PIK3CA mutations, phosphatase and tensin homolog, human epidermal growth factor receptor 2, and insulin-like growth factor 1 receptor and adjuvant tamoxifen resistance in postmenopausal breast cancer patients Pilot neoadjuvant trial in HER2 positive breast cancer with combination of nab-paclitaxel and lapatinib
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 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 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 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 BACKGROUND Lapatinib , a tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 ( HER2 , also referred to as HER2/neu ) and epidermal growth factor receptor ( EGFR ) , is active in combination with capecitabine in women with HER2-positive metastatic breast cancer that has progressed after trastuzumab-based therapy . In this trial , we compared lapatinib plus capecitabine with capecitabine alone in such patients . METHODS Women with HER2-positive , locally advanced or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline , a taxane , and trastuzumab  were r and omly assigned to receive either combination therapy ( lapatinib at a dose of 1250 mg per day continuously plus capecitabine at a dose of 2000 mg per square meter of body-surface area on days 1 through 14 of a 21-day cycle ) or monotherapy ( capecitabine alone at a dose of 2500 mg per square meter on days 1 through 14 of a 21-day cycle ) . The primary end point was time to progression , based on an evaluation by independent review ers under blinded conditions . RESULTS The interim analysis of time to progression met specified criteria for early reporting on the basis of superiority in the combination-therapy group . The hazard ratio for the independently assessed time to progression was 0.49 ( 95 % confidence interval , 0.34 to 0.71 ; P<0.001 ) , with 49 events in the combination-therapy group and 72 events in the monotherapy group . The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group . This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events . CONCLUSIONS Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline , a taxane , and trastuzumab . ( Clinical Trials.gov number , NCT00078572 [ Clinical Trials.gov ] . ) PURPOSE Vascular endothelial growth factor A ( VEGF-A ) and vascular endothelial growth factor receptor 2 ( VEGFR2 ) are often coexpressed in breast cancer , and potentially affect cellular pathways and key proteins such as the estrogen receptor ( ER ) targeted by endocrine treatment . We therefore explored the association between adjuvant tamoxifen treatment in breast cancer and expression of VEGF-A and VEGFR2 , as well as human epidermal growth factor receptor 2 ( HER2 ) , which represents a c and i date gene product involved in tamoxifen resistance . PATIENTS AND METHODS Immunohistochemical expression of tumor-specific VEGF-A , VEGFR2 , and HER2 was evaluated in tumor specimens from premenopausal breast cancer patients r and omly assigned to 2 years of tamoxifen or no treatment ( n = 564 ) , with 14 years of follow-up .  Hormone receptor status was determined in 96 % of the tumors . RESULTS VEGF-A , VEGFR2 , and HER2 were assessable in 460 , 472 , and 428 of the tumors , respectively . In patients with ER-positive and VEGFR2-low tumors , adjuvant tamoxifen significantly increased recurrence-free survival ( RFS ; [ HR ] hazard ratio for RFS , 0.53 ; P = .001 ) . In contrast , tamoxifen treatment had no effect in patients with VEGFR2-high tumors ( HR for RFS , 2.44 ; P = .2 ) . When multivariate interaction analyses were used , this difference in treatment efficacy relative to VEGFR2 expression status was statistically significant for both ER-positive ( P = .04 ) plus ER-positive and progesterone receptor-positive tumors . We found no significant difference in  tamoxifen treatment effects in relation to VEGF-A or HER2 status . CONCLUSION Tumor-specific expression of VEGFR2 was associated with an impaired  tamoxifen effect in hormone receptor-positive premenopausal breast cancer .  Tamoxifen in combination with VEGFR2 inhibitors might be a novel treatment approach for VEGFR2-expressing breast cancer , and such a treatment might restore the  tamoxifen  response PURPOSE This is a r and omized , double-blind , placebo-controlled study aim ed to evaluate the clinical and biologic effects of letrozole plus lapatinib or placebo as neoadjuvant therapy in hormone receptor ( HR ) -positive/human epidermal growth factor receptor 2 ( HER2 ) -negative operable breast cancer . METHODS Ninety-two postmenopausal women with stage II to IIIA primary breast cancer were r and omly assigned to preoperative therapy consisting of 6 months of letrozole 2.5 mg orally daily plus lapatinib 1,500 mg orally daily or placebo . Surgery was performed within 2 weeks from the last study medication . Clinical response was assessed by ultrasonography . Pre- and post-treatment sample s were evaluated for selected biomarkers . Fresh-frozen tissue sample s were collected for genomic analyses . RESULTS Numerically similar clinical response rates ( partial + complete response ) were observed ( 70 % for letrozole-lapatinib and 63 % for letrozole-placebo ) . Toxicities were generally mild and manageable . A significant decrease in Ki-67 and pAKT expression from baseline to surgery was observed in both arms . Overall , 34 patients ( 37 % ) had a mutation in PIK3CA exon 9 or  20 . In the letrozole-lapatinib arm , the probability of achieving a clinical response was significantly higher in the presence of PIK3CA mutation ( objective response rate , 93 % v 63 % in PIK3CA wild type ; P = .040 ) . CONCLUSION The combination of letrozole-lapatinib in early breast cancer was feasible , with expected and manageable toxicities . In unselected estrogen receptor-positive/HER2-negative patients , letrozole-lapatinib and letrozole-placebo result ed in a similar overall clinical response rate and similar effect on Ki-67 and pAKT . Our secondary end point findings of a significant correlation between PIK3CA mutation and response to letrozole-lapatinib in HR-positive/HER2-negative early breast cancer must now be independently confirmed 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 We explored the correlation between serum human epidermal growth factor receptor-2 ( HER2 ) extracellular domain ( ECD ) and tissue HER2 status , their relationship with clinicopathological parameters and their impact on disease-free survival ( DFS ) and overall survival in early breast cancer patients . PATIENTS AND METHODS This prospect i ve trial included patients with stage I-III breast cancer .  Serum HER2 ECD levels  were measured by two enzyme-linked immunosorbent assays before surgical treatment .  Tissue HER2 status was analyzed by immunohistochemistry ( IHC ) in all tumors ; FISH assay was utilized in HER2 2 + tumors by IHC . RESULTS From May 2000 to July 2005 , 256 consecutive stage I-III breast cancer patients were included in this study . High serum HER2 ECD levels ( > or=15 ng/ml ) were reported in 23 patients ( 9.0 % ) and HER2-positive status in tumor tissue was observed in 42 patients ( 16.4 % ) with a concordance of 87.1 % . High HER2 ECD levels were significantly associated with high histological grade ( P = 0.003 ) , stage III ( P = 0.008 ) , lymph node involvement ( P = 0.035 ) and negativity of both estrogen ( P = 0.016 ) and progesterone ( P = 0.007 ) receptors . At multivariate analysis , high serum HER2 ECD levels were a significant independent prognostic factor of worse DFS ( P = 0.009 ) . CONCLUSIONS A statistically significant association was observed between high serum HER2 ECD levels and worse DFS in early breast cancer patients 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 Trastuzumab combined with chemotherapy improves outcomes for women with human epidermal growth factor receptor 2 ( HER2 ) overexpressing advanced breast cancer . We conducted a pilot study of preoperative trastuzumab and paclitaxel , followed by surgery and adjuvant doxorubicin and cyclophosphamide chemotherapy in earlier stage breast cancer . PATIENTS AND METHODS Patients with HER2-positive ( 2 + or 3 + by immunohistochemistry ) stage II or III breast cancer received preoperative trastuzumab ( 4 mg/kg x 1 , then 2 mg/kg/wk x 11 ) in combination with paclitaxel ( 175 mg/m(2 ) every 3 weeks x 4 ) . Patients received adjuvant doxorubicin and cyclophosphamide chemotherapy following definitive breast surgery .  Clinical and pathologic response rates were determined after preoperative therapy . Left ventricular ejection fraction and circulating levels of HER2 extracellular domain were measured serially . RESULTS Preoperative trastuzumab and paclitaxel achieved clinical response in 75 % and complete pathologic response in 18 % of the 40 women on study . HER2 3 + tumors were more likely to respond than 2 + tumors ( 84 % v 38 % ) . No unexpected treatment-related noncardiac toxicity was encountered . Four patients developed grade 2 cardiotoxicity ( asymptomatic declines in left ventricular ejection fraction ) . Baseline HER2 extracellular domain was elevated in 24 % of patients and declined with preoperative therapy . Immunohistochemical analyses of posttherapy tumor specimens indicated varying patterns of HER2 expression following trastuzumab-based treatment . CONCLUSION Preoperative trastuzumab and paclitaxel is active against HER2 overexpressing early-stage breast cancer and may be feasible as part of a sequential treatment program including anthracyclines . The observed changes in cardiac function merit further investigation . Correlative analyses of HER2 status may facilitate underst and ing of tumor response and resistance to targeted therapy Purpose : To assess pathologic complete response ( pCR ) , clinical response , feasibility , safety , and potential predictors of response to preoperative trastuzumab plus vinorelbine in patients with operable , human epidermal growth factor receptor 2 (HER2)–positive breast cancer . Experimental Design : Forty-eight patients received preoperative trastuzumab and vinorelbine weekly for 12 weeks . Single and multigene biomarker studies were done in an attempt to identify predictors of response . Results : Eight of 40 ( 20 % ) patients achieved pCR ( 95 % confidence interval , 9 - 36 % ) . Of 9 additional patients recruited for protocol -defined toxicity analysis , 8 were evaluable ; 42 of 48 ( 88 % ) patients had clinical response ( 16 patients , clinical complete response ; 26 patients , clinical partial response ) . T1 tumors more frequently exhibited clinical complete response ( P = 0.05 ) and showed a trend to exhibit pCR ( P = 0.07 ) . Five ( 13 % ) patients experienced grade 1 cardiac dysfunction during preoperative treatment . Neither HER2 nor estrogen receptor status changed significantly after exposure to trastuzumab and vinorelbine . RNA profiling identified three top-level clusters by unsupervised analysis . Tumors with extremes of response [ pCR ( n = 3 ) versus nonresponse ( n = 3 ) ] fell into separate groups by hierarchical clustering . No predictive genes were identified in pCR tumors . Nonresponding tumors were more likely to be T4 stage ( P = 0.02 ) and express basal markers ( P < 0.00001 ) , growth factors , and growth factor receptors . Insulin-like growth factor-I receptor membrane expression was associated with a lower response rate ( 50 % versus 97 % ; P = 0.001 ) . Conclusions : Preoperative trastuzumab plus vinorelbine is active and well tolerated in patients with HER2-positive , operable , stage II/III breast cancer . HER2-overexpressing tumors with a basal-like phenotype , or with expression of insulin-like growth factor-I receptor and other proteins involved in growth factor pathways , are more likely to be resistant to this regimen BACKGROUND Bevacizumab , a monoclonal antibody against vascular endothelial growth factor A , has shown clinical efficacy in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer . We evaluated the efficacy , measured according to the rate of pathological complete response ( absence of invasive and intraductal disease in the breast and the axillary lymph nodes ) , and the safety of adding bevacizumab to neoadjuvant chemotherapy in patients with early-stage breast cancer . METHODS We r and omly assigned 1948 patients with a median tumor size of 40 mm on palpation to receive neoadjuvant epirubicin and cyclophosphamide followed by docetaxel , with or without concomitant bevacizumab .  Patients with untreated HER2-negative breast cancer were eligible if they had large tumors , hormone-receptor-negative disease , or hormone-receptor-positive disease with palpable nodes or positive findings on sentinel-node biopsy , and no increased cardiovascular or bleeding risk . RESULTS Overall , the rates of pathological complete response were 14.9 % with epirubicin and cyclophosphamide followed by docetaxel and 18.4 % with epirubicin and cyclophosphamide followed by docetaxel plus bevacizumab ( odds ratio with addition of bevacizumab , 1.29 ; 95 % confidence interval , 1.02 to 1.65 ; P=0.04 ) ; the corresponding rates of pathological complete response were 27.9 % and 39.3 % among 663 patients with triple-negative tumors ( P=0.003 ) and 7.8 % and 7.7 % among 1262 patients with hormone-receptor-positive tumors ( P=1.00 ) . Breast-conserving surgery was possible in 66.6 % of the patients in both groups . The addition of bevacizumab , as compared with neoadjuvant therapy alone , was associated with a higher incidence of grade 3 or 4 toxic effects ( febrile neutropenia , mucositis , the h and -foot syndrome , infection , and hypertension ) but with a similar incidence of surgical complications . CONCLUSIONS The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response among patients with HER2-negative early-stage breast cancer . Efficacy was restricted primarily to patients with triple-negative tumors , in whom the pathological complete response is considered to be a reliable predictor of long-term outcome . ( Funded by Sanofi-Aventis and Roche , Germany ; Clinical Trials.gov number , NCT00567554 . ) 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 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 Abstract Purpose : Improved underst and ing of risk of recurrence ( ROR ) is needed to reduce cases of recurrence and more effectively treat breast cancer patients . The purpose of this study was to examine how a gene-expression profile ( GEP ) , identified by Prosigna , influences physician adjuvant treatment selection for early breast cancer ( EBC ) and the effects of this influence on optimizing adjuvant treatment recommendations in clinical practice . Methods : A prospect i ve , observational , multicenter study was carried out in 15 hospitals across Spain . Participating medical oncologists completed pre- assessment , post- assessment , and follow-up question naires recording their treatment recommendations and confidence in these recommendations , before and after knowing the patient ’s ROR . Patients completed question naires on decision-making , anxiety , and health status . Results : Between June 2013 and January 2014 , 217 patients enrolled and a final 200 were included in the study . Patients were postmenopausal , estrogen receptor positive , human epidermal growth hormone factor negative , and node negative with either stage 1 or stage 2 tumors . After receiving the GEP results , treatment recommendations were changed for 40 patients ( 20 % ) . The confidence of medical oncologists in their treatment recommendations increased in 41.6 % and decreased in 6.5 % of total cases . Patients reported lower anxiety after physicians made treatment recommendations based on the GEP results ( p < 0.05 ) . Conclusions : Though this study does not include evaluation of the impact of GEP on long-term outcomes , it was found that GEP results influenced the treatment decisions of medical oncologists and their confidence in adjuvant therapy selection . Patients ’ anxiety about the selected adjuvant therapy decreased with use of the GEP This study reports the value of the tumor markers estrogen receptor ( ER ) , progesterone receptor ( PR ) , and human epidermal growth factor receptor 2 ( HER2 ) in predicting the response of breast cancer to neoadjuvant chemotherapy . A community cancer center prospect ively maintained breast cancer data base containing over 8,000 patient records was used . Since 1989 , 464 patients were treated with neoadjuvant chemotherapy followed by surgical resection  and were tested for ER and PR . Estrogen receptor and /or PR positive patients were considered hormone receptor ( HR ) positive . Human epidermal growth factor receptor 2 status was available on 368 patients .  Total , breast , and nodal pathologic complete response ( pCR ) rates , recurrence , and overall survival were assessed . Total and breast pCR rates were higher in HR negative ( HR- ) patients ( 26 % and 32 % , respectively ) than in HR positive ( HR+ ) patients ( 4 % and 7 % , respectively ; p < 0.001 ) . Compared to HR+ patients , HR- patients had higher recurrence rates ( 38 % versus 22 % ; p < 0.001 ) , a shorter time to recurrence ( 1.28 versus 2.14 years ; p < 0.001 ) , and decreased overall survival ( 67 % versus 81 % ; p < 0.001 ) . Human epidermal growth factor receptor 2 positive patients treated with neoadjuvant trastuzumab ( NAT ) demonstrated higher total pCR ( 34 % versus 13 % ; p = 0.008 ) , breast pCR ( 37 % versus 17 % ; p = 0.02 ) , and nodal pCR rates ( 47 % versus 23 % ; p = 0.05 ) compared to HER2 + patients not treated with NAT . Furthermore , HER2 + patients who received NAT had lower recurrence rates ( 5 % versus 42 % ; p < 0.001 ) and increased overall survival ( 97 % versus 68 % ; p < 0.001 ) . In conclusion , breast cancer HR status is predictive of total and breast pCR rates after neoadjuvant chemotherapy . Although HR- patients derive greater benefit from neoadjuvant chemotherapy in terms of pathologic response , they have worse outcomes in terms of recurrence and survival . Hormone receptor positive patients demonstrate significantly less response to neoadjuvant chemotherapy , but significantly better overall outcome . For both HR- and HR+ , addition of NAT for HER2 + tumors results in both a superior response and outcome Purpose Trastuzumab and pertuzumab are human epidermal growth factor receptor 2 ( HER2 ) –targeted monoclonal antibodies , and trastuzumab emtansine ( T-DM1 ) is an antibody – drug conjugate that combines the properties of trastuzumab with the cytotoxic activity of DM1 . T-DM1 demonstrated encouraging efficacy and safety in a phase II study of patients with previously untreated HER2-positive metastatic breast cancer .  Combination T-DM1 and pertuzumab showed synergistic activity in cell culture models and had an acceptable safety profile in a phase Ib and II study . Methods In the MARIANNE study , 1,095 patients with central ly assessed , HER2-positive , advanced breast cancer and no prior therapy for advanced disease were r and omly assigned 1:1:1 to control ( trastuzumab plus taxane ) , T-DM1 plus placebo , hereafter T-DM1 , or T-DM1 plus pertuzumab at st and ard doses . Primary end point was progression-free survival ( PFS ) , as assessed by independent review . Results T-DM1 and T-DM1 plus pertuzumab showed noninferior PFS compared with trastuzumab plus taxane ( median PFS : 13.7 months with trastuzumab plus taxane , 14.1 months with T-DM1 , and 15.2 months with T-DM1 plus pertuzumab ) . Neither experimental arm showed PFS superiority to trastuzumab plus taxane . Response rate was 67.9 % in patients who were treated with trastuzumab plus taxane , 59.7 % with T-DM1 , and 64.2 % with T-DM1 plus pertuzumab ; median response duration was 12.5 months , 20.7 months , and 21.2 months , respectively . The incidence of grade ≥ 3 adverse events was numerically higher in the control arm ( 54.1 % ) versus the T-DM1 arm ( 45.4 % ) and T-DM1 plus pertuzumab arm ( 46.2 % ) . Numerically fewer patients discontinued treatment because of adverse events in the T-DM1 arms , and health-related quality of life was maintained for longer in the T-DM1 arms . Conclusion T-DM1 showed noninferior , but not superior , efficacy and better tolerability than did taxane plus trastuzumab for first-line treatment of HER2-positive , advanced breast cancer Background : Blockade of human epidermal growth factor receptor type 2 ( HER2 ) has dramatically improved outcome for patients with HER2-positive breast cancer .  Trastuzumab , an anti-HER2 monoclonal antibody , has previously demonstrated improvement in overall survival ( OS ) in patients with metastatic and early stage HER2-positive breast cancer . However , trastuzumab can cause congestive heart failure ( CHF ) with an increased frequency for patients who have also received an anthracycline . The current trial was design ed to evaluate the impact of the duration of trastuzumab on CHF . Methods : E2198 included 227 eligible women with histologically confirmed stage II or IIIA HER2-positive breast cancer . The patients were r and omised to receive 12 weeks of paclitaxel and trastuzumab followed by four cycles of doxorubicin and cyclophosphamide ( abbreviated Arm ) or the aforementioned treatment with additional 1 year of trastuzumab ( conventional Arm ) . The primary end point was to evaluate the safety of this variable duration of  trastuzumab therapy , particularly cardiac toxicity defined as CHF or left ventricular ejection fraction decrease > 10 % . Secondary end points included disease-free survival ( DFS ) and OS . Results : Compared with 12-week treatment with trastuzumab , 1 year of trastuzumab-based therapy did not increase the frequency or severity of cardiac toxicity : three patients on the abbreviated Arm and four on the conventional Arm experienced CHF . The 5-year DFS was 76 % and 73 % for the abbreviated and conventional Arms , respectively , with a hazard ratio ( HR ) of 1.3 ( 95 % CI : 0.8–2.1 ; P=0.3 ) . There was also no statistically significance difference in OS ( HR , 1.4 ; P=0.3 ) . Conclusions : Compared with 12 weeks of treatment , 1 year of treatment with trastuzumab did not significantly increase the risk of cardiac toxicity . Although not powered for efficacy comparisons , the longer duration of trastuzumab therapy did not demonstrate a signal for marked superiority PURPOSE It has been suggested that PTEN , a negative regulator of PI3K/AKT signaling , is involved in tumor sensitivity to trastuzumab . We investigated the association between tumor PTEN protein expression and disease-free survival ( DFS ) of patients r and omly assigned to receive chemotherapy alone ( arm A ) or chemotherapy with sequential ( arm B ) or concurrent trastuzumab ( arm C ) in the phase III early-stage human epidermal growth factor receptor 2 ( HER2 ) -positive trial-North Central Cancer Treatment Group ( NCCTG ) N9831 . PATIENTS AND METHODS The intensity and percentage of invasive cells with cytoplasmic PTEN staining were determined in tissue microarray sections containing three cores per block ( n = 1,286 ) or in whole tissue sections ( WS ; n = 516 ) by using st and ard immunohistochemistry ( 138G6 monoclonal antibody ) . Tumors were considered positive for PTEN ( PTEN-positive ) if any core or WS had any invasive cells with ≥ 1 + staining . Median follow-up was 6.0 years . RESULTS Of 1,802 patients included in this analysis ( of 3,505 patients registered to N9831 ) , 1,342 ( 74 % ) had PTEN-positive tumors . PTEN positivity was associated with hormone receptor negativity ( χ(2 ) P < .001 ) and nodal positivity ( χ(2 ) P = .04 ) . PTEN did not have an impact on DFS within the various arms . Comparing DFS of arm C to arm A , patients with PTEN-positive and PTEN-negative tumors had hazard ratios ( HRs ) of 0.65 ( P = .003 ) and 0.47 ( P = .005 ) , respectively ( interaction P = .16 ) . For arm B versus arm A , patients with PTEN-positive and PTEN-negative tumors had HRs of 0.70 ( P = .009 ) and 0.85 ( P = .44 ) , respectively ( interaction P = .47 ) . CONCLUSION In contrast to selected pre clinical and limited clinical studies suggesting a decrease in trastuzumab sensitivity in patients with PTEN-negative tumors , our data show benefit of adjuvant trastuzumab for patients with HER2-positive breast cancer , independent of tumor PTEN status Abstract Background Based on previous results obtained with non-pegylated liposomal-encapsulated doxorubicin ( TLC-D99 ) together with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer ( BC ) , a similar regimen was evaluated in the neoadjuvant setting in a prospect ively selected series of consecutive patients with clinical stage II – III BC . Primary and secondary objectives included the rate of pathologic complete response ( pCR ) , safety , and predictive factors of pCR . Methods Patients received six cycles of TLC-D99 ( 50 mg/m2 every 3 weeks ) , paclitaxel ( 80 mg/m2 weekly ) and trastuzumab ( 4 mg/kg initial dose and 2 mg/kg weekly ) . All patients underwent surgery after treatment . pCR was defined as the absence of invasive cancer cells in the breast and the axilla . Results Sixty-two patients with a median age of 46.6 years were analyzed . Stage IIIA was diagnosed in 43.5 % of patients and 14.5 % had inflammatory BC . Conservative surgery was performed in 46.8 % of the patients and pCR was achieved in 63 % ( 95 % CI 50.5–75.5 ) . Patients with estrogen receptor (ER)-negative tumors presented a significantly higher pCR rate than patients with ER-positive tumors ( 74.4 vs 43.5 % ; P = 0.028 ) . Forty-five patients ( 72.6 % ) completed study treatment and 80.6 % received at least five treatment cycles . No patients developed congestive heart failure and 14.5 % of patients showed a ≥10 % decrease in the left ventricular ejection fraction . Conclusion The triple combination therapy assessed is effective and safe , offering a high pCR rate in patients with HER2-positive BC Introduction Inhibitors of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin ( PI3K/AKT/mTOR ) pathway can overcome endocrine resistance in estrogen receptor ( ER ) α-positive breast cancer , but companion diagnostics indicating PI3K/AKT/mTOR activation and consequently endocrine resistance are lacking . PIK3CA mutations frequently occur in ERα-positive breast cancer and result in PI3K/AKT/mTOR activation in vitro . Nevertheless , the prognostic and treatment-predictive value of these mutations in ERα-positive breast cancer is contradictive . We tested the clinical validity of PIK3CA mutations and other canonic pathway drivers to predict intrinsic resistance to adjuvant tamoxifen . In addition , we tested the association between these drivers and downstream activated proteins . Methods Primary tumors from 563 ERα-positive postmenopausal patients , r and omized between adjuvant tamoxifen ( 1 to 3 years ) versus observation were recollected . PIK3CA hotspot mutations in exon 9 and exon 20 were assessed with Sequenom Mass Spectometry . Immunohistochemistry was performed for human epidermal growth factor receptor 2 ( HER2 ) , phosphatase and tensin homolog ( PTEN ) , and insulin-like growth factor 1 receptor ( IGF-1R ) . We tested the association between these molecular alterations and downstream activated proteins ( like phospho-protein kinase B ( p-AKT ) , phospho-mammalian target of rapamycin ( p-mTOR ) , p-ERK1/2 , and p-p70S6 K ) . Recurrence-free interval improvement with tamoxifen versus control was assessed according to the presence or absence of canonic pathway drivers , by using Cox proportional hazard models , including a test for interaction . Results PIK3CA mutations ( both exon 9 and exon 20 ) were associated with low tumor grade . An enrichment of PIK3CA exon 20 mutations was observed in progesterone receptor- positive tumors . PIK3CA exon 20 mutations were not associated with downstream-activated proteins . No significant interaction between PIK3CA mutations or any of the other canonic pathway drivers and tamoxifen-treatment benefit was found . Conclusion PIK3CA mutations do not have clinical validity to predict intrinsic resistance to adjuvant tamoxifen and may therefore be unsuitable as companion diagnostic for PI3K/AKT/mTOR inhibitors in ERα- positive , postmenopausal , early breast cancer patients Lapatinib , a dual kinase inhibitor against epidermal growth factor receptor ( EGFR ) and human epidermal receptor two ( HER2 ) has shown efficacy in treating HER2 positive breast cancer . Nanoparticle albumin bound ( nab ) paclitaxel was developed to reduce toxicities from paclitaxel and improve its efficacy . Thirty patients with stage I – III HER2 positive breast cancer were treated in the neoadjuvant setting with lapatinib 1,000 mg/day and nab-paclitaxel 260 mg/m2 every 3 weeks for four cycles . The primary end point of the trial was clinical response rate ( cRR ) with secondary end points including pathologic complete response rate ( pCR ) , tolerability of the combination , and marker response . The cRR was 82.8 % ( 24 patients ) with six ( 20.7 % ) patients having complete clinical response , 18 ( 62.1 % ) having partial clinical response , and five ( 17.2 % ) stable disease . A pCR was observed in five of the 28 patients ( 17.9 % ) . The most frequent grade 2 toxicities were neuropathy in nine patients ( 30 % ) , fatigue in seven patients ( 23.3 % ) , rash in 11 patients ( 36.7 % ) , and bone pain in 10 patients ( 33.3 % ) . There was no significant drop in the left ventricular ejection fraction ( LVEF ) . Of the tissue markers examined , we were not able to find a predictor of response . The combination of lapatinib and nab-paclitaxel was well tolerated and provided good efficacy in women with HER2 positive breast cancer . This combination offers an alternative non-anthracycline-containing regimen for women with HER2 positive breast cancer
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 ? "