***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: Background Palbociclib is an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6 . In the r and omized , open-label , phase II PALOMA-1/TRIO-18 trial , palbociclib in combination with letrozole improved progression-free survival ( PFS ) compared with letrozole alone as first-line treatment of estrogen receptor (ER)-positive , human epidermal growth factor receptor 2 (HER2)-negative , advanced breast cancer ( 20.2 months versus 10.2 months ; hazard ratio ( HR ) = 0.488 , 95 % confidence interval ( CI ) 0.319–0.748 ; one-sided p = 0.0004 ) . Grade 3–4 neutropenia was the most common adverse event ( AE ) in the palbociclib + letrozole arm . We now present efficacy and safety analyses based on several specific patient and tumor characteristics , and present in detail the clinical patterns of neutropenia observed in the palbociclib + letrozole arm of the overall safety population . Methods Postmenopausal women ( n = 165 ) with ER+ , HER2-negative , advanced breast cancer who had not received any systemic treatment for their advanced disease were r and omized 1:1 to receive either palbociclib in combination with letrozole or letrozole alone . Treatment continued until disease progression , unacceptable toxicity , consent withdrawal , or death . The primary endpoint was PFS . We now analyze the difference in PFS for the treatment population s by subgroups , including age , histological type , history of prior neoadjuvant/adjuvant systemic treatment , and sites of distant metastasis , using the Kaplan-Meier method . HR and 95 % CI are derived from a Cox proportional hazards regression model . Results A clinical ly meaningful improvement in median PFS and clinical benefit response ( CBR ) rate was seen with palbociclib + letrozole in every subgroup evaluated . Grade 3–4 neutropenia was the most common AE with palbociclib + letrozole in all subgroups . Analysis of the frequency of neutropenia by grade during the first six cycles of treatment showed that there was a downward trend in Grade 3–4 neutropenia over time . Among those who experienced Grade 3–4 neutropenia , 71.7 % had no overlapping infections of any grade and none had overlapping Grade 3–4 infections . Conclusion The magnitude of clinical benefit seen with the addition of palbociclib to letrozole in improving both median PFS and CBR rate is consistent in nearly all subgroups analyzed , and consistent with that seen in the overall study population . The safety profile of the combination treatment in all subgroups was also comparable to that in the overall safety population of the study Purpose Abemaciclib , a cyclin-dependent kinase 4 and 6 inhibitor , demonstrated efficacy as monotherapy and in combination with fulvestrant in women with hormone receptor (HR)-positive , human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer previously treated with endocrine therapy . Methods MONARCH 3 is a double-blind , r and omized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with HR-positive , HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting . Patients received abemaciclib or placebo ( 150 mg twice daily continuous schedule ) plus either 1 mg anastrozole or 2.5 mg letrozole , daily . The primary objective was investigator-assessed progression-free survival . Secondary objectives included response evaluation and safety . A planned interim analysis occurred after 189 events . Results Median progression-free survival was significantly prolonged in the abemaciclib arm ( hazard ratio , 0.54 ; 95 % CI , 0.41 to 0.72 ; P = .000021 ; median : not reached in the abemaciclib arm , 14.7 months in the placebo arm ) . In patients with measurable disease , the objective response rate was 59 % in the abemaciclib arm and 44 % in the placebo arm ( P = .004 ) . In the abemaciclib arm , diarrhea was the most frequent adverse effect ( 81.3 % ) but was mainly grade 1 ( 44.6 % ) . Comparing abemaciclib and placebo , the most frequent grade 3 or 4 adverse events were neutropenia ( 21.1 % v 1.2 % ) , diarrhea ( 9.5 % v 1.2 % ) , and leukopenia ( 7.6 % v 0.6 % ) . Conclusion Abemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy , significantly improving progression-free survival and objective response rate and demonstrating a tolerable safety profile in women with HR-positive , HER2-negative advanced breast cancer OBJECTIVES Cyclin D-cyclin-dependent kinase ( CDK ) 4/6-inhibitor of CDK4/6-retinoblastoma ( Rb ) pathway hyperactivation is associated with hormone receptor-positive ( HR+ ) breast cancer ( BC ) . This study assessed the biological activity of ribociclib ( LEE011 ; CDK4/6 inhibitor ) plus letrozole compared with single-agent letrozole in the presurgical setting . MATERIAL S AND METHODS Postmenopausal women ( N = 14 ) with resectable , HR+ , human epidermal growth factor receptor 2-negative ( HER2- ) early BC were r and omized 1:1:1 to receive 2.5 mg/day letrozole alone ( Arm 1 ) , or with 400 or 600 mg/day ribociclib ( Arm 2 or 3 ) . Circulating tumor DNA and tumor biopsies were collected at baseline and , following 14 days of treatment , prior to or during surgery . The primary objective was to assess antiproliferative response per Ki67 levels in Arms 2 and 3 compared with Arm 1 . Additional assessment s included safety , pharmacokinetics , and genetic profiling . RESULTS Mean decreases in the Ki67-positive cell fraction from baseline were : Arm 1 69 % ( range 38 - 100 % ; n = 2 ) , Arm 2 96 % ( range 78 - 100 % ; n = 6 ) , Arm 3 92 % ( range 75 - 100 % ; n = 3 ) . Decreased phosphorylated Rb levels and CDK4 , CDK6 , CCND2 , CCND3 , and CCNE1 gene expression were observed following ribociclib treatment . Ribociclib and letrozole pharmacokinetic parameters were consistent with single-agent data . The ribociclib plus letrozole combination was well tolerated , with no Grade 3/4 adverse events over the treatment . CONCLUSION The results suggest absence of a drug-drug interaction between ribociclib and letrozole and indicate ribociclib plus letrozole may reduce Ki67 expression in HR+ , HER2- BC ( NCT01919229 ) Purpose MONARCH 2 ( Clinical Trials.gov identifier : NCT02107703 ) compared the efficacy and safety of abemaciclib , a selective cyclin-dependent kinase 4 and 6 inhibitor , plus fulvestrant with fulvestrant alone in patients with advanced breast cancer ( ABC ) . Patients and Methods MONARCH 2 was a global , double-blind , phase III study of women with hormone receptor-positive and human epidermal growth factor receptor 2-negative ABC who had progressed while receiving neoadjuvant or adjuvant endocrine therapy ( ET ) , ≤ 12 months from the end of adjuvant ET , or while receiving first-line ET for metastatic disease . Patients were r and omly assigned 2:1 to receive abemaciclib or placebo ( 150 mg twice daily ) on a continuous schedule and fulvestrant ( 500 mg , per label ) . The primary end point was investigator-assessed progression-free survival ( PFS ) , and key secondary end points included overall survival , objective response rate ( ORR ) , duration of response , clinical benefit rate , quality of life , and safety . Results Between August 2014 and December 2015 , 669 patients were r and omly assigned to receive abemaciclib plus fulvestrant ( n = 446 ) or placebo plus fulvestrant ( n = 223 ) . Abemaciclib plus fulvestrant significantly extended PFS versus fulvestrant alone ( median , 16.4 v 9.3 months ; hazard ratio , 0.553 ; 95 % CI , 0.449 to 0.681 ; P < .001 ) . In patients with measurable disease , abemaciclib plus fulvestrant achieved an ORR of 48.1 % ( 95 % CI , 42.6 % to 53.6 % ) compared with 21.3 % ( 95 % CI , 15.1 % to 27.6 % ) in the control arm . The most common adverse events in the abemaciclib versus placebo arms were diarrhea ( 86.4 % v 24.7 % ) , neutropenia ( 46.0 % v 4.0 % ) , nausea ( 45.1 % v 22.9 % ) , and fatigue ( 39.9 % v 26.9 % ) . Conclusions Abemaciclib at 150 mg twice daily plus fulvestrant was effective , significantly improving PFS and ORR and demonstrating a tolerable safety profile in women with hormone receptor-positive and human epidermal growth factor receptor 2-negative ABC who progressed while receiving ET thous and s of false-positive findings and strain health care re sources . Though reluctant to rule out that a protein biomarker could reveal new pancreatic tumors , Goggins questions whether proteins in general are selective enough to avoid diagnostic overlap with other , noncancerous problems . Such proteins include the initial 28 in the M. D. And erson study , he said , most of which are elevated under multiple setting s. Goggins 's views on biomarker c and i date s lean more toward circulating tumor DNA snippets in blood , or circulating tumor cells , which he said could be more specific to pancreatic cancer . However , Firpo maintains that protein-based panels can be continually improved . " Each biomarker is individually a weak classifier , so our goal is to combine them into stronger classifier panels , " he said . " That approach has mathematical validity , and this latest study shows that we 're making progress , even though we 're not there yet . " According to Taguchi , the next step will be to vali date current results and then investigate the panel in prediagnostic blood sample s , which will help ensure its predic-tive value . professor and pancreatic cancer specialist at Cold Spring Harbor Laboratory in New York , and a program chair at the American Association for Cancer Research conference , agrees that 's the right approach . Emphasizing optimism over pessimism is important , he said . " However , we now need to substantiate the panel on retrospective cases , and perhaps also with a new prospect i ve series from the general population or from patients who are at high risk . " Sources for this story all agreed that the panel is not ready for the clinic . Screening high-risk individuals is now performed exclusively with imaging , as described in P albociclib , the first in a new class of drugs to complete phase II testing , doubled progression-free survival ( PFS ) in women with metastatic estro-gen receptor – positive ( ER + ) and HER2-negative ( HER2 – ) breast cancer when given with st and ard hormone therapy , compared with hormone therapy alone . In the 47-patient r and omized study , those taking palbociclib and the aromatase inhibitor letrozole had a median PFS of 20.2 months , compared with 10.2 months for those taking letrozole alone . Women taking the combination lived a mean of 4 months longer ( 37.5 vs. 33.3 months ) . But increased survival did not reach statistical significance , said at April 's American Association of Cancer Research meeting in San Diego . The Food and Drug Administration design ated palbociclib a breakthrough therapy in April 2013 . Palbociclib targets two cell cycle enzymes , cyclin-dependent Purpose : To identify the dose-limiting toxicity ( DLT ) and maximum tolerated dose ( MTD ) of the first-in-class , oral CDK4/6 inhibitor PD 0332991 administered once daily for 21 of 28 days ( 3/1 schedule ) in patients with retinoblastoma protein (Rb)-positive advanced solid tumors and to describe pharmacokinetic – pharmacodynamic relationships relative to drug effects . Experimental Design : This open-label phase I study ( NCT00141297 ) enrolled patients who received PD 0332991 orally in six dose-escalation cohorts in a st and ard 3 + 3 design . Results : Forty-one patients were enrolled .  DLTs were observed in five patients ( 12 % ) overall ; at the 75 , 125 , and 150 mg once daily dose levels . The MTD and recommended phase II dose of PD 0332991 was 125 mg once daily . Neutropenia was the only dose-limiting effect . After cycle 1 , grade 3 neutropenia , anemia , and leukopenia occurred in five ( 12 % ) , three ( 7 % ) , and one ( 2 % ) patient(s ) , respectively . The most common non-hematologic adverse 
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Conclusion Our analysis provides evidence that the use of CDK 4/6 inhibitors is associated with an increased risk of all- grade and high- grade hematological adverse events , which seems to be a class-effect , but not of febrile neutropenia compared with hormonal therapy alone