***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 G1–S checkpoint of the cell cycle is frequently dysregulated in breast cancer .  Palbociclib ( PD0332991 ) is an oral inhibitor of CDK4/6 . Based upon pre clinical /phase I activity , we performed a phase II , single-arm trial of palbociclib in advanced breast cancer . Experimental Design : Eligible patients had histologically confirmed , metastatic breast cancer positive for retinoblastoma ( Rb ) protein and measureable disease .  Palbociclib was given at 125 mg orally on days 1 to 21 of a 28-day cycle . Primary objectives were tumor response and tolerability . Secondary objectives included progression-free survival ( PFS ) and assessment of Rb expression/localization , KI-67 , p16 loss , and CCND1 amplification . Results : Thirty-seven patients were enrolled ; 84 % hormone-receptor (HR)+/Her2− , 5 % HR+/Her2 + , and 11 % HR−/Her2− , with a median of 2 prior cytotoxic regimens . Two patients had partial response ( PR ) and 5 had stable disease ≥ 6 months for a clinical benefit rate ( CBR = PR + 6moSD ) of 19 % overall , 21 % in HR+ , and 29 % in HR+/Her2− who had progressed through ≥2 prior lines of hormonal therapy . Median PFS overall was 3.7 months [ 95 % confidence interval ( CI ) , 1.9–5.1 ] , but significantly longer for those with HR+ versus HR− disease ( P = 0.03 ) and those who had previously progressed through endocrine therapy for advanced disease ( P = 0.02 ) . Grade 3/4 toxicities included neutropenia ( 51 % ) , anemia ( 5 % ) , and thrombocytopenia ( 22 % ) . Twenty-four percent had treatment interruption and 51 % had dose reduction , all for cytopenias . No biomarker identified a sensitive tumor population . Conclusions : Single-agent palbociclib is well tolerated and active in patients with endocrine-resistant , HR+ , Rb-positive breast cancer . Cytopenias were uncomplicated and easily managed with dose reduction . Clin Cancer Res ; 21(5 ) ; 995–1001 . © 2014 AACR BACKGROUND Triple-negative breast cancer ( TNBC ) is an aggressive disease , nevertheless exhibiting a high response rate to chemotherapy . Since the retinoblastoma protein ( pRb ) loss confers a high sensitivity to chemotherapy regimens , we evaluated the prevalence of pRb loss in TNBCs and its relevance on the clinical outcome of patients treated with adjuvant chemotherapy .  PATIENTS AND METHODS  pRb status was prospect ively evaluated by immunocytochemistry in 518 consecutive patients with complete receptor information . The predictive value of pRb status in TNBCs was determined according to the adjuvant therapeutic treatments . RESULTS Fifty-three tumors were identified as TNBCs . The prevalence of pRb loss was significantly higher in TNBCs than in the other cancer subtypes . All patients with TNBCs lacking pRb and treated with systemic chemotherapy ( cyclophosphamide , methotrexate and 5-fluorouracil ) were disease free at a medium follow-up time of 109 months , whereas the clinical outcome of those expressing pRb was significantly poorer ( P = 0.008 ) . Analysis of disease-free survival including the established anatomo- clinical prognostic parameters indicated pRb loss as the only significant predictive factor . CONCLUSIONS pRb loss is much more frequent in TNBCs than in the other breast cancer subtypes . Patients with TNBCs lacking pRb had a very favorable clinical outcome if treated with conventional adjuvant chemotherapy BACKGROUND Palbociclib ( PD-0332991 ) is an oral , small-molecule inhibitor of cyclin-dependent kinases ( CDKs ) 4 and 6 with pre clinical evidence of growth-inhibitory activity in oestrogen receptor-positive breast cancer cells and synergy with anti-oestrogens . We aim ed to assess the safety and efficacy of palbociclib in combination with letrozole as first-line treatment of patients with advanced , oestrogen receptor-positive , HER2-negative breast cancer . METHODS In this open-label , r and omised phase 2 study , postmenopausal women with advanced oestrogen receptor-positive and HER2-negative breast cancer who had not received any systemic treatment for their advanced disease were eligible to participate . Patients were enrolled in two separate cohorts that accrued sequentially : in cohort 1 , patients were enrolled on the basis of their oestrogen receptor-positive and HER2-negative biomarker status alone , whereas in cohort 2 they were also required to have cancers with amplification of cyclin D1 ( CCND1 ) , loss of p16 ( INK4A or CDKN2A ) , or both . In both cohorts , patients were r and omly assigned 1:1 via an interactive web-based r and omisation system , stratified by disease site and disease-free interval , to receive continuous oral letrozole 2.5 mg daily or continuous oral letrozole 2.5 mg daily plus oral palbociclib 125 mg , given once daily for 3 weeks followed by 1 week off over 28-day cycles . The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population . Accrual to cohort 2 was stopped after an unplanned interim analysis of cohort 1 and the statistical analysis plan for the primary endpoint was amended to a combined analysis of cohorts 1 and 2 ( instead of cohort 2 alone ) . The study is ongoing but closed to accrual ; these are the results of the final analysis of progression-free survival . The study is registered with the Clinical Trials.gov , number NCT00721409 . FINDINGS Between Dec 22 , 2009 , and May 12 , 2012 , we r and omly assigned 165 patients , 84 to palbociclib plus letrozole and 81 to letrozole alone . At the time of the final analysis for progression-free survival ( median follow-up 29.6 months [ 95 % CI 27.9 - 36.0 ] for the palbociclib plus letrozole group and 27.9 months [ 25.5 - 31.1 ] for the letrozole group ) , 41 progression-free survival events had occurred in the palbociclib plus letrozole group and 59 in the letrozole group . Median progression-free survival was 10.2 months ( 95 % CI 5.7 - 12.6 ) for the letrozole group and 20.2 months ( 13.8 - 27.5 ) for the palbociclib plus letrozole group ( HR 0.488 , 95 % CI 0.319 - 0.748 ; one-sided p=0.0004 ) . In cohort 1 ( n=66 ) , median progression-free survival was 5.7 months ( 2.6 - 10.5 ) for the letrozole group and 26.1 months ( 11.2-not estimable ) for the palbociclib plus letrozole group ( HR 0.299 , 0.156 - 0.572 ; one-sided p<0.0001 ) ; in cohort 2 ( n=99 ) , median progression-free survival was 11.1 months ( 7.1 - 16.4 ) for the letrozole group and 18.1 months ( 13.1 - 27.5 ) for the palbociclib plus letrozole group ( HR 0.508 , 0.303 - 0.853 ; one-sided p=0.0046 ) . Grade 3 - 4 neutropenia was reported in 45 ( 54 % ) of 83 patients in the palbociclib plus letrozole group versus one ( 1 % ) of 77 patients in the letrozole group , leucopenia in 16 ( 19 % ) versus none , and fatigue in four ( 4 % ) versus one ( 1 % ) . Serious adverse events that occurred in more than one patient in the palbociclib plus letrozole group were pulmonary embolism ( three [ 4 % ] patients ) , back pain ( two [ 2 % ] ) , and diarrhoea ( two [ 2 % ] ) . No cases of febrile neutropenia or neutropenia-related infections were reported during the study . 11 ( 13 % ) patients in the palbociclib plus letrozole group and two ( 2 % ) in the letrozole group discontinued the study because of adverse events . INTERPRETATION The addition of palbociclib to letrozole in this phase 2 study significantly improved progression-free survival in women with advanced oestrogen receptor-positive and HER2-negative breast cancer . A phase 3 trial is currently underway . FUNDING Pfizer 
    Output:
    
A r and omised phase II trial of palbociclib plus letrozole versus letrozole and a phase III of palbociclib plus fulvestrant versus fulvestrant showed significantly increased progression-free survival when compared with endocrine therapy alone in first-line and second-line treatment for advanced hormone receptor-positive HER2-negative BC .
The predominant toxicity of agents was limited neutropenia .
The toxicities seemed manageable .
CDK4/6 inhibition might represent a substantial advance for patients with hormone receptor-positive HER2-negative BC .