***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Purpose : Mutations associated with resistance to kinase inhibition are an important mechanism of intrinsic or acquired loss of clinical efficacy for kinase-targeted therapeutics . We report the prospect i ve discovery of ErbB2 mutations that confer resistance to the small-molecule inhibitor lapatinib . Experimental Design : We did in vitro screening using a r and omly mutagenized ErbB2 expression library in Ba/F3 cells , which were dependent on ErbB2 activity for survival and growth . Results : Lapatinib resistance screens identified mutations at 16 different ErbB2 amino acid residues , with 12 mutated amino acids mapping to the kinase domain . Mutations conferring the greatest lapatinib resistance cluster in the NH2-terminal kinase lobe and hinge region . Structural computer modeling studies suggest that lapatinib resistance is caused by multiple mechanisms ; including direct steric interference and restriction of conformational flexibility ( the inactive state required for lapatinib binding is energetically unfavorable ) . ErbB2 T798I imparts the strongest lapatinib resistance effect and is analogous to the epidermal growth factor receptor T790 M , ABL T315I , and cKIT T670I gatekeeper mutations that are associated with clinical drug resistance . ErbB2 mutants associated with lapatinib resistance transformed NIH-3T3 cells , including L755S and T733I mutations known to occur in human breast and gastric carcinomas , supporting a direct mechanism for lapatinib resistance in ErbB2-driven human cancers . The epidermal growth factor receptor/ErbB2/vascular endothelial growth factor receptor inhibitor EXEL-7647 was found to inhibit almost all lapatinib resistance-associated mutations . Furthermore , no ErbB2 mutations were found to be associated with EXEL-7647 resistance and lapatinib sensitivity . Conclusions : Taken together , these data suggest potential target-based mechanisms of resistance to lapatinib and suggest that EXEL-7647 may be able to circumvent these effects BACKGROUND Trastuzumab , a recombinant monoclonal antibody against HER2 , has clinical activity in advanced breast cancer that overexpresses HER2 . We investigated its efficacy and safety after excision of early-stage breast cancer and completion of chemotherapy . METHODS This international , multicenter , r and omized trial compared one or two years of trastuzumab given every three weeks with observation in patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy .  RESULTS Data were available for 1694 women r and omly assigned to two years of treatment with trastuzumab , 1694 women assigned to one year of trastuzumab , and 1693 women assigned to observation .  We report here the results only of treatment with trastuzumab for one year or observation . At the first planned interim analysis ( median follow-up of one year ) , 347 events ( recurrence of breast cancer , contralateral breast cancer , second nonbreast malignant disease , or death ) were observed : 127 events in the trastuzumab group and 220 in the observation group . The unadjusted hazard ratio for an event in the trastuzumab group , as compared with the observation group , was 0.54 ( 95 percent confidence interval , 0.43 to 0.67 ; P<0.0001 by the log-rank test , crossing the interim analysis boundary ) , representing an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points . Overall survival in the two groups was not significantly different ( 29 deaths with trastuzumab vs. 37 with observation ) . Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab . CONCLUSIONS One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer . ( Clinical Trials.gov number , NCT00045032 . PURPOSE Human epidermal growth factor ( HER ) -mediated signaling is critical in many cancers , including subsets of breast and lung cancer . HER family members signal via the phosphatidylinositide 3-kinase ( PI3 K ) -AKT/protein kinase B-mammalian target of rapamycin ( mTOR ) cascade ; mTOR activation is critical for the expression of multiple contributors to tumor growth and invasion . On the basis of pre clinical data suggesting synergy of HER2 inhibition and mTOR inhibition in breast and lung cancer models , we conducted a phase I combination study of neratinib , a small-molecule irreversible pan-HER tyrosine kinase inhibitor , and temsirolimus , an mTOR inhibitor , in patients with advanced solid tumors . PATIENTS AND METHODS This study enrolled patients to dosing combinations of neratinib and temsirolimus . The primary objective was to estimate the toxicity contour of the combination and establish recommended phase II doses . RESULTS Sixty patients were treated on 12 of 16 possible dosing combinations .  Diarrhea was the most common drug-related ( 93 % ) and dose-limiting toxicity ( DLT ) , constituting four of 10 DLTs . Dose-limiting grade 3 metabolic abnormalities were also observed . Other frequent drug-related toxicities included nausea , stomatitis ( both 53 % ) , and anemia ( 48 % ) . Two maximum-tolerated dose combinations were identified : 200 mg of neratinib/25 mg of temsirolimus and 160 mg of neratinib/50 mg of temsirolimus . Responses were noted in patients with HER2-amplified breast cancer resistant to trastuzumab , HER2-mutant non-small-cell lung cancer , and tumor types without identified mutations in the HER-PI3K-mTOR pathway . CONCLUSION The combination of neratinib and temsirolimus was tolerable and demonstrated antitumor activity in multiple tumor types , warranting further evaluation 
    Output:
    
These genic alterations are independently associated with HER2 amplification status , occurring in both ER-positive/HER2-negative diseases or HER2-enriched cancers .