human
***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 : The clinical relevancy of the 7-subtype classification of triple-negative breast cancer ( TNBC ) reported by Lehmann and colleagues is unknown . We investigated the clinical relevancy of TNBC heterogeneity by determining pathologic complete response ( pCR ) rates after neoadjuvant chemotherapy , based on TNBC subtypes . Experimental Design : We revali date d the Lehmann and colleagues experiments using Affymetrix CEL files from public data sets . We applied these methods to 146 patients with TNBC with gene expression microarrays obtained from June 2000 to March 2010 at our institution . Of those , 130 had received st and ard neoadjuvant chemotherapy and had evaluable pathologic response data . We classified the TNBC sample s by subtype and then correlated subtype and pCR status using Fisher exact test and a logistic regression model . We also assessed survival and compared the subtypes with PAM50 intrinsic subtypes and residual cancer burden ( RCB ) index . Results : TNBC subtype and pCR status were significantly associated ( P = 0.04379 ) . The basal-like 1 ( BL1 ) subtype had the highest pCR rate ( 52 % ) ; basal-like 2 ( BL2 ) and luminal and rogen receptor had the lowest ( 0 % and 10 % , respectively ) . TNBC subtype was an independent predictor of pCR status ( P = 0.022 ) by a likelihood ratio test . The subtypes better predicted pCR status than did the PAM50 intrinsic subtypes ( basal-like vs. non basal-like ) . Conclusions : Classifying TNBC by 7 subtypes predicts high versus low pCR rate . We confirm the clinical relevancy of the 7 subtypes of TNBC . We need to prospect ively vali date whether the pCR rate differences translate into long-term outcome differences . The 7-subtype classification may spur innovative personalized medicine strategies for patients with TNBC . Clin Cancer Res ; 19(19 ) ; 5533–40 . © 2013 AACR BACKGROUND The proliferation marker Ki67 has been suggested as a promising cancer biomarker . As Ki67 needs an exact quantification , this marker is a prototype of a new generation of tissue-based biomarkers . In this study , we have systematic ally evaluated different cut points for Ki67 using three different clinical end points in a large neoadjuvant study cohort . PATIENTS AND METHODS We have evaluated pretherapeutic Ki67 levels by immunohistochemistry in 1166 breast cancer core biopsies from the neoadjuvant GeparTrio trial . We used the st and ardized cutoff-finder algorithm for three end points [ response to neoadjuvant chemotherapy ( pCR ) , disease-free ( DFS ) and overall-survival ( OS ) ] . The analyses were stratified for hormone receptor ( HR ) and HER2 status by molecular subtype radar diagrams ( MSRDs ) . RESULTS A wide range of Ki67 cut points between 3%-94 % ( for pCR ) , 6%-46 % ( for DFS ) and 4%-58 % ( for OS ) were significant . The three groups of Ki67 ≤ 15 % versus 15.1%-35 % versus > 35 % had pCR-rates of 4.2 % , 12.8 % , and 29.0 % ( P < 0.0005 ) , this effect was also present in six of eight molecular subtypes . In MSRD , Ki67 was significantly linked to prognosis in uni- and multivariate analysis in the complete cohort and in HR-positive , but not triple-negative tumors . CONCLUSIONS Ki67 is a significant predictive and prognostic marker over a wide range of cut points suggesting that data -derived cut point optimization might not be possible . Ki67 could be used as a continuous marker ; in addition , the scientific community could define st and ardized cut points for Ki67 . Our analysis explains the variability observed for Ki67 cut points in previous studies ; however , this should not be seen as weakness , but as strength of this marker . MSRDs are an easy new approach for visualization of biomarker effects on outcome across molecular subtypes in breast cancer . The experience with Ki67 could provide important information regarding the development and implementation of other quantitative biomarkers BACKGROUND Studies with pertuzumab , a novel anti-HER2 antibody , show improved efficacy when combined with the established HER2-directed antibody trastuzumab in breast cancer therapy . We investigated the combination of pertuzumab or trastuzumab , or both , with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting . METHODS In this multicentre , open-label , phase 2 study , treatment-naive women with HER2-positive breast cancer were r and omly assigned ( 1:1:1:1 ) central ly and stratified by operable , locally advanced , and inflammatory breast cancer , and by hormone receptor expression to receive four neoadjuvant cycles of : trastuzumab ( 8 mg/kg loading dose , followed by 6 mg/kg every 3 weeks ) plus docetaxel ( 75 mg/m(2 ) , escalating , if tolerated , to 100 mg/m(2 ) every 3 weeks ; group A ) or pertuzumab ( loading dose 840 mg , followed by 420 mg every 3 weeks ) and trastuzumab plus docetaxel ( group B ) or pertuzumab and trastuzumab ( group C ) or pertuzumab plus docetaxel ( group D ) . The primary endpoint , examined in the intention-to-treat population , was pathological complete response in the breast . Neither patients nor investigators were masked to treatment . This study is registered with Clinical Trials.gov , number NCT00545688 . FINDINGS Of 417 eligible patients , 107 were r and omly assigned to group A , 107 to group B , 107 to group C , and 96 to group D. Patients given pertuzumab and trastuzumab plus docetaxel ( group B ) had a significantly improved pathological complete response rate ( 49 of 107 patients ; 45·8 % [ 95 % CI 36·1 - 55·7 ] ) compared with those given trastuzumab plus docetaxel ( group A ; 31 of 107 ; 29·0 % [ 20·6 - 38·5 ] ; p=0·0141 ) . 23 of 96 ( 24·0 % [ 15·8 - 33·7 ] ) women given pertuzumab plus docetaxel ( group D ) had a pathological complete response , as did 18 of 107 ( 16·8 % [ 10·3 - 25·3 ] ) given pertuzumab and trastuzumab ( group C ) . The most common adverse events of grade 3 or higher were neutropenia ( 61 of 107 women in group A , 48 of 107 in group B , one of 108 in group C , and 52 of 94 in group D ) , febrile neutropenia ( eight , nine , none , and seven , respectively ) , and leucopenia ( 13 , five , none , and seven , respectively ) . The number of serious adverse events was similar in groups A , B , and D ( 15 - 20 serious adverse events per group in 10 - 17 % of patients ) but lower in group C ( four serious adverse events in 4 % of patients ) . INTERPRETATION Patients given pertuzumab and trastuzumab plus docetaxel ( group B ) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel , without substantial differences in tolerability .  Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile . These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer . FUNDING F Hoffmann-La Roche Purpose : Gene expression analysis identifies several breast cancer subtypes . We examined the relationship of neoadjuvant chemotherapy response to outcome among these breast cancer subtypes . Experimental Design : We used immunohistochemical profiles [ human epidermal growth factor receptor 2–positive (HER2+)/hormone receptor – negative for HER2+/estrogen receptor – negative ( ER− ) , hormone receptor and HER2− for basal-like , hormone receptor – positive for luminal ] to subtype a prospect ively maintained data set of patients with breast cancer treated with neoadjuvant anthracycline-based ( doxorubicin plus cyclophosphamide , AC ) chemotherapy .  We analyzed each subtype for clinical and pathologic response to neoadjuvant chemotherapy and examined the relationship of response to distant disease – free survival and overall survival . Results : Of the 107 patients tested , 34 ( 32 % ) were basal-like , 11 ( 10 % ) were HER2+/ER− , and 62 ( 58 % ) were luminal . After neoadjuvant AC , 75 % received subsequent chemotherapy and all received endocrine therapy if hormone receptor – positive . The chemotherapy regimen and pretreatment stage did not differ by subtype . Clinical response to AC  was higher among the HER2+/ER− ( 70 % ) and basal-like ( 85 % ) than the luminal subtypes ( 47 % ; P < 0.0001 ) . Pathologic complete response occurred in 36 % of HER2+/ER− , 27 % of basal-like , and 7 % of luminal subtypes ( P = 0.01 ) . Despite initial chemosensitivity , patients with the basal-like and HER2+/ER− subtypes had worse distant disease – free survival ( P = 0.04 ) and overall survival ( P = 0.02 ) than those with the luminal subtypes . Regardless of subtype , only 2 of 17 patients with pathologic complete response relapsed . The worse outcome among basal-like and HER+/ER− subtypes was due to higher relapse among those with residual disease ( P = 0.003 ) . Conclusions : Basal-like and HER2+/ER− subtypes are more sensitive to anthracycline-based neoadjuvant chemotherapy than luminal breast cancers . Patients that had pathologic complete response to chemotherapy had a good prognosis regardless of subtype . The poorer prognosis of basal-like and HER2+/ER− breast cancers could be explained by a higher likelihood of relapse in those patients in whom pathologic complete response was not achieved This study examined the pathological complete response ( pCR ) rate and safety of sequential gemcitabine-based combinations in breast cancer . We also examined gene expression profiles from tumour biopsies to identify biomarkers predictive of response . Indian women with large or locally advanced breast cancer received 4 cycles of gemcitabine 1200 mg m−2 plus doxorubicin 60 mg m−2 ( Gem+Dox ) , then 4 cycles of gemcitabine 1000 mg m−2 plus cisplatin 70 mg m−2 ( Gem+Cis ) , and surgery . Three alternate dosing sequences were used during cycle 1 to examine dynamic changes in molecular profiles . Of 65 women treated , 13 ( 24.5 % of 53 patients with surgery ) had a pCR and 22 ( 33.8 % ) had a complete clinical response . Patients administered Gem d1 , 8 and Dox d2 in cycle 1 ( 20 of 65 ) reported more toxicities , with G3/4 neutropenic infection/febrile neutropenia ( 7 of 20 ) as the most common cycle-1 event . Four drug-related deaths occurred . In 46 of 65 patients , 10-fold cross vali date d supervised analyses identified gene expression patterns that predicted with ⩾73 % accuracy ( 1 ) clinical complete response after eight cycles , ( 2 ) overall clinical complete response , and ( 3 ) pCR . This regimen shows strong activity . Patients receiving Gem d1 , 8 and Dox d2  experienced unacceptable toxicity , whereas patients on other sequences had manageable safety profiles . Gene expression patterns may predict benefit from gemcitabine-containing neoadjuvant therapy Background No specific treatment guidelines are available for triple-negative breast cancers , defined by a lack of expression of estrogen ( ER ) , progesterone ( PgR ) , and HER2 receptors . Patients and methods We investigated in patients with T2–T3 N0 - 3 ER , PgR < 10 % and HER2 negative breast cancers the activity both in terms of pathological ( pCR ) and objective responses of four courses of cisplatin containing chemotherapy ( ECF , epirubicin , cisplatin , and fluorouracil as continuous infusion ) followed by three courses of weekly paclitaxel . Adjuvant metronomic chemotherapy including cyclophosphamide and methotrexate for 4–6 months was administered . Results Thirty patients are evaluable . Median age was 41 years ( 28–64 years ) . Twenty-three of 25 evaluable tumors stained positively for epidermal growth factor receptor . An objective response , either complete and partial , was observed in 26 patients ( 86 , 95 % CI 69.3–96.2 % ) . and a pCR was obtained in 12 patients ( 40 , 95 % CI 22.7–59.4 % ) . Two patients progressed during paclitaxel . 
    Output:
    
agent
***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 : The clinical relevancy of the 7-subtype classification of triple-negative breast cancer ( TNBC ) reported by Lehmann and colleagues is unknown . We investigated the clinical relevancy of TNBC heterogeneity by determining pathologic complete response ( pCR ) rates after neoadjuvant chemotherapy , based on TNBC subtypes . Experimental Design : We revali date d the Lehmann and colleagues experiments using Affymetrix CEL files from public data sets . We applied these methods to 146 patients with TNBC with gene expression microarrays obtained from June 2000 to March 2010 at our institution . Of those , 130 had received st and ard neoadjuvant chemotherapy and had evaluable pathologic response data . We classified the TNBC sample s by subtype and then correlated subtype and pCR status using Fisher exact test and a logistic regression model . We also assessed survival and compared the subtypes with PAM50 intrinsic subtypes and residual cancer burden ( RCB ) index . Results : TNBC subtype and pCR status were significantly associated ( P = 0.04379 ) . The basal-like 1 ( BL1 ) subtype had the highest pCR rate ( 52 % ) ; basal-like 2 ( BL2 ) and luminal and rogen receptor had the lowest ( 0 % and 10 % , respectively ) . TNBC subtype was an independent predictor of pCR status ( P = 0.022 ) by a likelihood ratio test . The subtypes better predicted pCR status than did the PAM50 intrinsic subtypes ( basal-like vs. non basal-like ) . Conclusions : Classifying TNBC by 7 subtypes predicts high versus low pCR rate . We confirm the clinical relevancy of the 7 subtypes of TNBC . We need to prospect ively vali date whether the pCR rate differences translate into long-term outcome differences . The 7-subtype classification may spur innovative personalized medicine strategies for patients with TNBC . Clin Cancer Res ; 19(19 ) ; 5533–40 . © 2013 AACR BACKGROUND The proliferation marker Ki67 has been suggested as a promising cancer biomarker . As Ki67 needs an exact quantification , this marker is a prototype of a new generation of tissue-based biomarkers . In this study , we have systematic ally evaluated different cut points for Ki67 using three different clinical end points in a large neoadjuvant study cohort . PATIENTS AND METHODS We have evaluated pretherapeutic Ki67 levels by immunohistochemistry in 1166 breast cancer core biopsies from the neoadjuvant GeparTrio trial . We used the st and ardized cutoff-finder algorithm for three end points [ response to neoadjuvant chemotherapy ( pCR ) , disease-free ( DFS ) and overall-survival ( OS ) ] . The analyses were stratified for hormone receptor ( HR ) and HER2 status by molecular subtype radar diagrams ( MSRDs ) . RESULTS A wide range of Ki67 cut points between 3%-94 % ( for pCR ) , 6%-46 % ( for DFS ) and 4%-58 % ( for OS ) were significant . The three groups of Ki67 ≤ 15 % versus 15.1%-35 % versus > 35 % had pCR-rates of 4.2 % , 12.8 % , and 29.0 % ( P < 0.0005 ) , this effect was also present in six of eight molecular subtypes . In MSRD , Ki67 was significantly linked to prognosis in uni- and multivariate analysis in the complete cohort and in HR-positive , but not triple-negative tumors . CONCLUSIONS Ki67 is a significant predictive and prognostic marker over a wide range of cut points suggesting that data -derived cut point optimization might not be possible . Ki67 could be used as a continuous marker ; in addition , the scientific community could define st and ardized cut points for Ki67 . Our analysis explains the variability observed for Ki67 cut points in previous studies ; however , this should not be seen as weakness , but as strength of this marker . MSRDs are an easy new approach for visualization of biomarker effects on outcome across molecular subtypes in breast cancer . The experience with Ki67 could provide important information regarding the development and implementation of other quantitative biomarkers BACKGROUND Studies with pertuzumab , a novel anti-HER2 antibody , show improved efficacy when combined with the established HER2-directed antibody trastuzumab in breast cancer therapy . We investigated the combination of pertuzumab or trastuzumab , or both , with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting . METHODS In this multicentre , open-label , phase 2 study , treatment-naive women with HER2-positive breast cancer were r and omly assigned ( 1:1:1:1 ) central ly and stratified by operable , locally advanced , and inflammatory breast cancer , and by hormone receptor expression to receive four neoadjuvant cycles of : trastuzumab ( 8 mg/kg loading dose , followed by 6 mg/kg every 3 weeks ) plus docetaxel ( 75 mg/m(2 ) , escalating , if tolerated , to 100 mg/m(2 ) every 3 weeks ; group A ) or pertuzumab ( loading dose 840 mg , followed by 420 mg every 3 weeks ) and trastuzumab plus docetaxel ( group B ) or pertuzumab and trastuzumab ( group C ) or pertuzumab plus docetaxel ( group D ) . The primary endpoint , examined in the intention-to-treat population , was pathological complete response in the breast . Neither patients nor investigators were masked to treatment . This study is registered with Clinical Trials.gov , number NCT00545688 . FINDINGS Of 417 eligible patients , 107 were r and omly assigned to group A , 107 to group B , 107 to group C , and 96 to group D. Patients given pertuzumab and trastuzumab plus docetaxel ( group B ) had a significantly improved pathological complete response rate ( 49 of 107 patients ; 45·8 % [ 95 % CI 36·1 - 55·7 ] ) compared with those given trastuzumab plus docetaxel ( group A ; 31 of 107 ; 29·0 % [ 20·6 - 38·5 ] ; p=0·0141 ) . 23 of 96 ( 24·0 % [ 15·8 - 33·7 ] ) women given pertuzumab plus docetaxel ( group D ) had a pathological complete response , as did 18 of 107 ( 16·8 % [ 10·3 - 25·3 ] ) given pertuzumab and trastuzumab ( group C ) . The most common adverse events of grade 3 or higher were neutropenia ( 61 of 107 women in group A , 48 of 107 in group B , one of 108 in group C , and 52 of 94 in group D ) , febrile neutropenia ( eight , nine , none , and seven , respectively ) , and leucopenia ( 13 , five , none , and seven , respectively ) . The number of serious adverse events was similar in groups A , B , and D ( 15 - 20 serious adverse events per group in 10 - 17 % of patients ) but lower in group C ( four serious adverse events in 4 % of patients ) . INTERPRETATION Patients given pertuzumab and trastuzumab plus docetaxel ( group B ) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel , without substantial differences in tolerability .  Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile . These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer . FUNDING F Hoffmann-La Roche Purpose : Gene expression analysis identifies several breast cancer subtypes . We examined the relationship of neoadjuvant chemotherapy response to outcome among these breast cancer subtypes . Experimental Design : We used immunohistochemical profiles [ human epidermal growth factor receptor 2–positive (HER2+)/hormone receptor – negative for HER2+/estrogen receptor – negative ( ER− ) , hormone receptor and HER2− for basal-like , hormone receptor – positive for luminal ] to subtype a prospect ively maintained data set of patients with breast cancer treated with neoadjuvant anthracycline-based ( doxorubicin plus cyclophosphamide , AC ) chemotherapy .  We analyzed each subtype for clinical and pathologic response to neoadjuvant chemotherapy and examined the relationship of response to distant disease – free survival and overall survival . Results : Of the 107 patients tested , 34 ( 32 % ) were basal-like , 11 ( 10 % ) were HER2+/ER− , and 62 ( 58 % ) were luminal . After neoadjuvant AC , 75 % received subsequent chemotherapy and all received endocrine therapy if hormone receptor – positive . The chemotherapy regimen and pretreatment stage did not differ by subtype . Clinical response to AC  was higher among the HER2+/ER− ( 70 % ) and basal-like ( 85 % ) than the luminal subtypes ( 47 % ; P < 0.0001 ) . Pathologic complete response occurred in 36 % of HER2+/ER− , 27 % of basal-like , and 7 % of luminal subtypes ( P = 0.01 ) . Despite initial chemosensitivity , patients with the basal-like and HER2+/ER− subtypes had worse distant disease – free survival ( P = 0.04 ) and overall survival ( P = 0.02 ) than those with the luminal subtypes . Regardless of subtype , only 2 of 17 patients with pathologic complete response relapsed . The worse outcome among basal-like and HER+/ER− subtypes was due to higher relapse among those with residual disease ( P = 0.003 ) . Conclusions : Basal-like and HER2+/ER− subtypes are more sensitive to anthracycline-based neoadjuvant chemotherapy than luminal breast cancers . Patients that had pathologic complete response to chemotherapy had a good prognosis regardless of subtype . The poorer prognosis of basal-like and HER2+/ER− breast cancers could be explained by a higher likelihood of relapse in those patients in whom pathologic complete response was not achieved This study examined the pathological complete response ( pCR ) rate and safety of sequential gemcitabine-based combinations in breast cancer . We also examined gene expression profiles from tumour biopsies to identify biomarkers predictive of response . Indian women with large or locally advanced breast cancer received 4 cycles of gemcitabine 1200 mg m−2 plus doxorubicin 60 mg m−2 ( Gem+Dox ) , then 4 cycles of gemcitabine 1000 mg m−2 plus cisplatin 70 mg m−2 ( Gem+Cis ) , and surgery . Three alternate dosing sequences were used during cycle 1 to examine dynamic changes in molecular profiles . Of 65 women treated , 13 ( 24.5 % of 53 patients with surgery ) had a pCR and 22 ( 33.8 % ) had a complete clinical response . Patients administered Gem d1 , 8 and Dox d2 in cycle 1 ( 20 of 65 ) reported more toxicities , with G3/4 neutropenic infection/febrile neutropenia ( 7 of 20 ) as the most common cycle-1 event . Four drug-related deaths occurred . In 46 of 65 patients , 10-fold cross vali date d supervised analyses identified gene expression patterns that predicted with ⩾73 % accuracy ( 1 ) clinical complete response after eight cycles , ( 2 ) overall clinical complete response , and ( 3 ) pCR . This regimen shows strong activity . Patients receiving Gem d1 , 8 and Dox d2  experienced unacceptable toxicity , whereas patients on other sequences had manageable safety profiles . Gene expression patterns may predict benefit from gemcitabine-containing neoadjuvant therapy Background No specific treatment guidelines are available for triple-negative breast cancers , defined by a lack of expression of estrogen ( ER ) , progesterone ( PgR ) , and HER2 receptors . Patients and methods We investigated in patients with T2–T3 N0 - 3 ER , PgR < 10 % and HER2 negative breast cancers the activity both in terms of pathological ( pCR ) and objective responses of four courses of cisplatin containing chemotherapy ( ECF , epirubicin , cisplatin , and fluorouracil as continuous infusion ) followed by three courses of weekly paclitaxel . Adjuvant metronomic chemotherapy including cyclophosphamide and methotrexate for 4–6 months was administered . Results Thirty patients are evaluable . Median age was 41 years ( 28–64 years ) . Twenty-three of 25 evaluable tumors stained positively for epidermal growth factor receptor . An objective response , either complete and partial , was observed in 26 patients ( 86 , 95 % CI 69.3–96.2 % ) . and a pCR was obtained in 12 patients ( 40 , 95 % CI 22.7–59.4 % ) . Two patients progressed during paclitaxel . 
    Output:
    