Clinical trial NCT02947685: Randomized, Open Label, Clinical Study of the Targeted Therapy, Palbociclib, to Treat Metastatic Breast Cancer
Official title: A Randomized, Open Label, Phase III Trial to Evaluate the Efficacy and Safety of Palbociclib + Anti-HER2 Therapy + Endocrine Therapy vs. Anti-HER2 Therapy + Endocrine Therapy After Induction Treatment for Hormone Receptor Positive (HR+)/HER2-Positive Metastatic Breast Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: HER-2 Positive Breast Cancer
Estrogen Receptor Positive Breast Cancer
Keywords: breast cancer
malignant tumor of the breast
HER2+
HR+
metastatic breast cancer
Lead sponsor: Alliance Foundation Trials, LLC.
Sponsor class: OTHER
Collaborators: name: Pfizer
name: GBG Forschungs GmbH
name: Fondazione Michelangelo
name: PrECOG, LLC.
name: Breast Cancer Trials, Australia and New Zealand
name: Syneos Health
name: SOLTI Breast Cancer Research Group
name: UNICANCER
First posted: 2016-10-28
Enrollment: 518
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of this study is to demonstrate that the combination of palbociclib with anti-HER2 therapy plus endocrine therapy is superior to anti-HER2-based therapy plus endocrine therapy alone in improving the outcomes of subjects with hormone receptor-positive, HER2+ metastatic breast cancer.

Detailed description: Subjects will be randomized into one of two treatment arms following minimum of 4 and maximum of 8 cycles of induction treatment with anti-HER2 therapy. Arm A subjects will receive the experimental therapy, palbociclib, in addition to their current anti-HER2 therapy and endocrine therapy. Arm B subjects will continue to receive the anti-HER2 therapy. It is expected that the addition of palbociclib to the first-line treatment of HER2 disease will delay the onset of therapeutic resistance and ultimately prolong the survival of patients with metastatic breast cancer. The study is designed to treat the subset of patients with HER2+ disease who are also hormone receptor positive (HR+). It is also expected that palbociclib will modulate the endocrine resistance in HER2+/HR+ disease and potentiate the benefits of anti-HER2 therapy. Lastly, the current study includes a comprehensive molecular characterization of the disease at study entrance which will allow us to investigate the benefits of palbociclib in subsets of HER2+/HR+ disease such as PIK3CA mutant.

Eligibility criteria: Inclusion Criteria (Preliminary Screening)

1. Signed Preliminary Screening Informed Consent Form obtained prior to any study specific assessments and procedures
2. Age ≥18 years (or per national guidelines)
3. Patients must have histologically confirmed invasive breast cancer that is metastatic or not amenable for resection or radiation therapy with curative intent. Histological documentation of metastatic/recurrent breast cancer is not required if there is unequivocal evidence for recurrence of the breast cancer.
4. Patients must have histologically confirmed HER2+ and hormone receptor positive (ER+ and/or PR+), metastatic breast cancer. ER, PR and HER2 measurements should be performed according to institutional guidelines, in a CLIA-approved setting in the US or certified laboratories for Non-US regions. Cut-off values for positive/negative staining should be in accordance with current ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines.
5. Patients must agree to provide a representative formalin-fixed paraffin-embedded (FFPE) tumor tissue block (preferred) from primary breast or metastatic site (archival) OR at least 15 freshly cut unstained slides from such a block, along with a pathology report documenting HER2 positivity and hormone receptor positivity.
6. Patients should be willing to provide a representative tumor specimen obtained from recently biopsied metastatic disease if clinically feasible. This is recommended but optional tissue.

   Inclusion Criteria (Randomization Screening)
7. Signed Main Informed Consent Form obtained prior to any study specific assessments and procedures
8. Age ≥ 18 years (or per national guidelines)
9. ECOG performance status 0-1
10. Patients must be able and willing to swallow and retain oral medication without a condition that would interfere with enteric absorption.
11. Serum or urine pregnancy test must be negative within 7 days of randomization in women of childbearing potential. Pregnancy testing does not need to be pursued in patients who are judged as postmenopausal before randomization, as determined by local practice, or who have undergone bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation. Women of childbearing potential and male patients randomized into the study must use adequate contraception for the duration of protocol treatment which is 6 months after the last treatment with palbociclib if they are in Arm A and for 7 months after last treatment with trastuzumab if in either Arm A or Arm B Adequate contraception is defined as one highly effective form (i.e. abstinence, (fe)male sterilization OR two effective forms (e.g. non-hormonal IUD and condom / occlusive cap with spermicidal foam / gel / film / cream / suppository).
12. Resolution of all acute toxic effects of prior induction anti-HER2-based chemotherapy regimen to NCI CTCAE version 4.0 Grade ≤1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion) 12 weeks between last dose of chemotherapy-anti-HER2therapy and randomization are allowed. Endocrine therapy could start before study randomization.
13. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures

    Prior Treatment Specifics
14. Patients may or may not have received neo/adjuvant therapy, but must have a disease-free interval from completion of anti-HER2 therapy to metastatic diagnosis ≥6 months.
15. Patients must have received an acceptable, standard, chemotherapy containing anti-HER2 based induction therapy for the treatment of metastatic breast cancer prior to study enrollment. For this study, chemotherapy is limited to a taxane or vinorelbine (only for trastuzumab-based regimen). Eligible patients are expected to have completed 6 cycles of chemotherapy containing anti-HER2-therapy treatment. A minimum of 4 cycles of treatment is acceptable for patients experiencing significant toxicity associated with treatment as long as they are without evidence of disease progression (i.e. CR, PR or SD). The maximum number of cycles is 8. Patients can randomize immediately following completion of their induction therapy, or for those who have already completed induction, a gap of 12 weeks between their last infusion/dose of induction therapy and the C1D1 visit is permitted. Patients are eligible provided they are without evidence of disease progression by local assessment (i.e. CR, PR or SD).
16. Patients with a history or presence of asymptomatic CNS metastases are eligible, provided they meet all of the following criteria:

    * Disease outside the CNS is present.
    * No evidence of interim progression between the completion of induction therapy and the screening radiographic study
    * No history of intracranial hemorrhage or spinal cord hemorrhage
    * Not requiring anti-convulsants for symptomatic control
    * Minimum of 3 weeks between completion of CNS radiotherapy and Cycle 1 Day 1 and recovery from significant (Grade ≥ 3) acute toxicity with no ongoing requirement for corticosteroid

    Baseline Body Function Specifics
17. Absolute neutrophil count ≥ 1,000/mm3
18. Platelets ≥ 100,000/mm3
19. Hemoglobin ≥ 10g/dL
20. Total serum bilirubin ≤ ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin within normal range in patients with documented Gilbert's Syndrome.
21. Aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) ≤ 3 × institutional ULN (≤5 x ULN if liver metastases are present).
22. Serum creatinine below the upper limit of normal (ULN) of the institutional normal range or creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with serum creatinine levels above institutional ULN.
23. Left ventricular ejection fraction (LVEF) ≥ 50% at baseline as determined by either ECHO or MUGA

Exclusion Criteria (Randomization)

1. Concurrent therapy with other Investigational Products.
2. Prior therapy with any CDK 4/6 inhibitor.
3. History of allergic reactions attributed to compounds of chemical or biologic composition similar to palbociclib.
4. Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A isoenzymes within 7 days of randomization (see Section 8.6.3 for list of strong inhibitors or inducers of CYP3A isoenzymes).
5. Uncontrolled current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, diabetes, or psychiatric illness/social situations that would limit compliance with study requirements. Ability to comply with study requirements is to be assessed by each investigator at the time of screening for study participation.
6. Pregnant women, or women of childbearing potential without a negative pregnancy test (serum or urine) within 7 days prior to randomization, irrespective of the method of contraception used, are excluded from this study because the effect of palbociclib on a developing fetus is unknown. Breastfeeding must be discontinued prior to study entry.
7. Patients on combination antiretroviral therapy, i.e. those who are HIV-positive, are ineligible because of the potential for pharmacokinetic interactions or increased immunosuppression with palbociclib.
8. QTc interval \>480 msec, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes.
9. Patients with clinically significant history of liver disease, including viral or other known hepatitis, current alcohol abuse, or cirrhosis

Primary outcomes:
measure: Progression-free survival (PFS) as assessed by Investigator
timeFrame: 24 months
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: 24 months
measure: 3 and 5 year survival probabilities
timeFrame: 24 months
measure: Objective Response Rate (OR: CR or PR)
timeFrame: 24 months
measure: Duration of Response (DOR)
timeFrame: 24 months
measure: Clinical Benefit Rate (CBR: CR or PR or SD ≥ 24 weeks
timeFrame: 24 months
measure: Safety: Type incidence and severity (as graded by NCI CTCAE v 4.0)
timeFrame: 24 months
measure: Patient Reported Outcomes
timeFrame: 24 months
measure: Incidence of CNS Metastasis
timeFrame: 24 months
Other outcomes:
measure: Trough Plasma concentration of palbociclib, trastuzumab and pertuzumab
timeFrame: Palbociclib PK assessment: Day 22, Cycle 1, No; Pertuzumab, Trastuzumab PK assessment: Day 1, Cycle 4
measure: PIK3CA genotype assessed in circulating cfDNA
timeFrame: Day 1, Cycle 1, Day 1, Cycle 4, End of Treatment, approx 24 months
measure: Tumor tissue biomarkers including genes, proteins, and RNA expression
timeFrame: Baseline
Locations:
city: San Francisco
country: United States
facility: UCSF
state: California
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Clearwater
country: United States
facility: Baycare Healthcare (Morton Plant Mease)
state: Florida
city: Hollywood
country: United States
facility: Memorial Healthcare System
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Orlando
country: United States
facility: Florida Hospital
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: University of Illinois at Chicago
state: Illinois
city: Harvey
country: United States
facility: Ingalls Memorial Hospital
state: Illinois
city: Wichita
country: United States
facility: Cancer Center of Kansas
state: Kansas
city: New Orleans
country: United States
facility: Ochsner Medical Center Jefferson
state: Louisiana
city: Scarborough
country: United States
facility: New England Cancer Specialists
state: Maine
city: Baltimore
country: United States
facility: University of Maryland - Greenebaum Comprehensive Cancer Center
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University/Sidney Kimmel Cancer Center
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Lowell
country: United States
facility: Lowell General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: Michigan Cancer Research Consortium (St. Joseph Mercy Hospital
state: Michigan
city: Grand Rapids
country: United States
facility: West Michigan Cancer Center
state: Michigan
city: Minneapolis
country: United States
facility: Metro-Minnesota NCI Community Oncology Research Program
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic, Rochester, MN
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: Nebraska Methodist Hospital
state: Nebraska
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack Medical Center
state: New Jersey
city: Paramus
country: United States
facility: The Valley Hospital, Okonite Research Center
state: New Jersey
city: Albuquerque
country: United States
facility: New Mexico Cancer Care Alliance
state: New Mexico
city: Durham
country: United States
facility: Duke Cancer Institute
state: North Carolina
city: Pinehurst
country: United States
facility: First Health of the Carolinas Cancer Center
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Legacy Good Samaritan Hospital
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: West Columbia
country: United States
facility: Lexington Medical Center
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: MD Anderson
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute, University of Utah
state: Utah
city: Clayton
country: Australia
facility: Monash Health
city: Darlinghurst
country: Australia
facility: St. Vincent's Hospital, Sydney Kinghorn Cancer Centre
city: Garran
country: Australia
facility: The Canberra Hospital
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre, Royal Melbourne Hospital
city: Nedlands
country: Australia
facility: Breast Cancer Research Centre-WA
city: South Brisbane
country: Australia
facility: Icon Cancer Care
city: South Brisbane
country: Australia
facility: Mater Cancer Care Centre
city: Waratah
country: Australia
facility: Calvary Mater Newcastle Hospital
city: Westmead
country: Australia
facility: Westmead Hospital
city: Angers
country: France
facility: Institut de Cancérologie de l'Ouest, site Paul Papin
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Bordeaux
country: France
facility: Institut Bergonié
city: Caen
country: France
facility: Centre Francois Baclesse
city: Cholet
country: France
facility: Centre Hospitalier Cholet
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Dijon
country: France
facility: Centre Georges François Leclerc
city: Lille
country: France
facility: Centre Oscar Lambret
city: Limoges
country: France
facility: CHU de Limoges
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Montpellier
country: France
facility: Institut de Cancerologie de Montpellier
city: Mougins
country: France
facility: Centre Azureen de Cancerologie
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Institut Curie Site Paris
city: Paris
country: France
facility: Tenon Oncologie Médicale - APHP
city: Plerin Cedex
country: France
facility: Centre CARIO-HPCA
city: Reims
country: France
facility: Institut Jean Godinot
city: Rennes
country: France
facility: Centre Eugene Marquis
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint-Cloud
country: France
facility: Institut Curie Site Saint Cloud
city: Saint-Priest-en-Jarez
country: France
facility: Institut de Cancérologie Lucien Neuwirth
city: Strasbourg
country: France
facility: Centre Paul Strauss
city: Toulouse
country: France
facility: Intitut Claudius Regaud
city: Villejuif
country: France
facility: Gustave Roussy
city: Bottrop
country: Germany
facility: Marienhospital Bottrop
city: Essen
country: Germany
facility: Kliniken Essen-Mitte, Evang. Huyssens-Stiftung/Knappschaft GmbH
city: Frankfurt
country: Germany
facility: Agaplesion Markus Krankenhaus
city: Hannover
country: Germany
facility: Diakovere Henriettenstift Frauenklinik
city: Kiel
country: Germany
facility: UKSH, Klinik für Gynäkologie und Geburtshilfe
city: Köln
country: Germany
facility: St. Elisabeth Krankenhaus
city: Munster
country: Germany
facility: Praxis Prof. Nitz im Brustzentrum Niederrhein
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Schweinfurt
country: Germany
facility: Leopoldina-Krankenhaus Schweinfurt
city: Bologna
country: Italy
facility: Policlinico Sant'Orsola-Malpighi
city: Cona
country: Italy
facility: U.O. Oncologia AOU Arcispedale Sant'Anna
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia
city: Segrate
country: Italy
facility: Ospedale San Raffaele
city: Udine
country: Italy
facility: Ospedale Santa Maria della Misericordia
city: Auckland
country: New Zealand
facility: Auckland City Hospital Cancer and Blood Research
city: Lisboa
country: Portugal
facility: Hospital Champalimaud
city: Lisboa
country: Portugal
facility: Hospital Da Luz
city: Loures
country: Portugal
facility: Hospital Beatriz Angelo
city: Porto
country: Portugal
facility: IPO Porto
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Barcelona
country: Spain
facility: Hospital General de Catalunya
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: ICO L'Hospitalet
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario de Fuenlabrada
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Alcorcón
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Madrid
country: Spain
facility: MD Anderson Cancer Center Spain
city: Murcia
country: Spain
facility: Hospital Universitario Virgen de la Arrixaca
city: Málaga
country: Spain
facility: Hospital Regional Universitario de Málaga
city: Navarro
country: Spain
facility: Complejo Hospitalario de Navarra
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Santiago
country: Spain
facility: Complejo Hospitalario Univ. De Santiago
city: Seville
country: Spain
facility: Hospital Quirón Sagrado Corazón
city: Tarragona
country: Spain
facility: Hospital Sant Joan de Reus
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
Study officials:
References:
citation: Early Breast Cancer Trialists' Collaborative Group (EBCTCG); Peto R, Davies C, Godwin J, Gray R, Pan HC, Clarke M, Cutter D, Darby S, McGale P, Taylor C, Wang YC, Bergh J, Di Leo A, Albain K, Swain S, Piccart M, Pritchard K. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012 Feb 4;379(9814):432-44. doi: 10.1016/S0140-6736(11)61625-5. Epub 2011 Dec 5.
citation: Welch HG, Gorski DH, Albertsen PC. Trends in Metastatic Breast and Prostate Cancer--Lessons in Cancer Dynamics. N Engl J Med. 2015 Oct 29;373(18):1685-7. doi: 10.1056/NEJMp1510443. No abstract available.
citation: Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. doi: 10.1056/NEJMoa1113216. Epub 2011 Dec 7.
citation: Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortes J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. doi: 10.1056/NEJMoa1413513.
citation: Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, Forman D, Bray F. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013 Apr;49(6):1374-403. doi: 10.1016/j.ejca.2012.12.027. Epub 2013 Feb 26.
citation: Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999 Jun 15;13(12):1501-12. doi: 10.1101/gad.13.12.1501. No abstract available.
citation: van den Heuvel S, Harlow E. Distinct roles for cyclin-dependent kinases in cell cycle control. Science. 1993 Dec 24;262(5142):2050-4. doi: 10.1126/science.8266103.
citation: Weinberg RA. The retinoblastoma protein and cell cycle control. Cell. 1995 May 5;81(3):323-30. doi: 10.1016/0092-8674(95)90385-2. No abstract available.
citation: Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993 Nov 19;75(4):805-16. doi: 10.1016/0092-8674(93)90499-g.
citation: Koff A, Ohtsuki M, Polyak K, Roberts JM, Massague J. Negative regulation of G1 in mammalian cells: inhibition of cyclin E-dependent kinase by TGF-beta. Science. 1993 Apr 23;260(5107):536-9. doi: 10.1126/science.8475385.
citation: Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev. 1994 Jan;8(1):9-22. doi: 10.1101/gad.8.1.9.
citation: Sherr CJ. D-type cyclins. Trends Biochem Sci. 1995 May;20(5):187-90. doi: 10.1016/s0968-0004(00)89005-2.
citation: Toyoshima H, Hunter T. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell. 1994 Jul 15;78(1):67-74. doi: 10.1016/0092-8674(94)90573-8.
citation: Lukas J, Parry D, Aagaard L, Mann DJ, Bartkova J, Strauss M, Peters G, Bartek J. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature. 1995 Jun 8;375(6531):503-6. doi: 10.1038/375503a0.
citation: Medema RH, Herrera RE, Lam F, Weinberg RA. Growth suppression by p16ink4 requires functional retinoblastoma protein. Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6289-93. doi: 10.1073/pnas.92.14.6289.
citation: Lee RJ, Albanese C, Fu M, D'Amico M, Lin B, Watanabe G, Haines GK 3rd, Siegel PM, Hung MC, Yarden Y, Horowitz JM, Muller WJ, Pestell RG. Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway. Mol Cell Biol. 2000 Jan;20(2):672-83. doi: 10.1128/MCB.20.2.672-683.2000.
citation: Lane HA, Beuvink I, Motoyama AB, Daly JM, Neve RM, Hynes NE. ErbB2 potentiates breast tumor proliferation through modulation of p27(Kip1)-Cdk2 complex formation: receptor overexpression does not determine growth dependency. Mol Cell Biol. 2000 May;20(9):3210-23. doi: 10.1128/MCB.20.9.3210-3223.2000.
citation: Yu Q, Sicinska E, Geng Y, Ahnstrom M, Zagozdzon A, Kong Y, Gardner H, Kiyokawa H, Harris LN, Stal O, Sicinski P. Requirement for CDK4 kinase function in breast cancer. Cancer Cell. 2006 Jan;9(1):23-32. doi: 10.1016/j.ccr.2005.12.012.
citation: Nahta R, Iglehart JD, Kempkes B, Schmidt EV. Rate-limiting effects of Cyclin D1 in transformation by ErbB2 predicts synergy between herceptin and flavopiridol. Cancer Res. 2002 Apr 15;62(8):2267-71.
citation: Reddy HK, Mettus RV, Rane SG, Grana X, Litvin J, Reddy EP. Cyclin-dependent kinase 4 expression is essential for neu-induced breast tumorigenesis. Cancer Res. 2005 Nov 15;65(22):10174-8. doi: 10.1158/0008-5472.CAN-05-2639.
citation: Yang C, Ionescu-Tiba V, Burns K, Gadd M, Zukerberg L, Louis DN, Sgroi D, Schmidt EV. The role of the cyclin D1-dependent kinases in ErbB2-mediated breast cancer. Am J Pathol. 2004 Mar;164(3):1031-8. doi: 10.1016/S0002-9440(10)63190-2.
citation: Landis MW, Pawlyk BS, Li T, Sicinski P, Hinds PW. Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis. Cancer Cell. 2006 Jan;9(1):13-22. doi: 10.1016/j.ccr.2005.12.019.
citation: Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, Ginther C, Atefi M, Chen I, Fowst C, Los G, Slamon DJ. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11(5):R77. doi: 10.1186/bcr2419.
citation: Witkiewicz AK, Cox DW, Rivadeneira D, Ertel AE, Fortina P, Schwartz GF, Knudsen ES. The retinoblastoma tumor suppressor pathway modulates the invasiveness of ErbB2-positive breast cancer. Oncogene. 2014 Jul 24;33(30):3980-91. doi: 10.1038/onc.2013.367. Epub 2013 Oct 14.
citation: Roberts PJ, Bisi JE, Strum JC, Combest AJ, Darr DB, Usary JE, Zamboni WC, Wong KK, Perou CM, Sharpless NE. Multiple roles of cyclin-dependent kinase 4/6 inhibitors in cancer therapy. J Natl Cancer Inst. 2012 Mar 21;104(6):476-87. doi: 10.1093/jnci/djs002. Epub 2012 Feb 1.
citation: Goel S, Wang Q, Watt AC, Tolaney SM, Dillon DA, Li W, Ramm S, Palmer AC, Yuzugullu H, Varadan V, Tuck D, Harris LN, Wong KK, Liu XS, Sicinski P, Winer EP, Krop IE, Zhao JJ. Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors. Cancer Cell. 2016 Mar 14;29(3):255-269. doi: 10.1016/j.ccell.2016.02.006.
citation: Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Zhang K, Theall KP, Jiang Y, Bartlett CH, Koehler M, Slamon D. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016 Apr;17(4):425-439. doi: 10.1016/S1470-2045(15)00613-0. Epub 2016 Mar 3.
citation: Ramakrishna N, Temin S, Chandarlapaty S, Crews JR, Davidson NE, Esteva FJ, Giordano SH, Gonzalez-Angulo AM, Kirshner JJ, Krop I, Levinson J, Modi S, Patt DA, Perez EA, Perlmutter J, Winer EP, Lin NU. Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014 Jul 1;32(19):2100-8. doi: 10.1200/JCO.2013.54.0955. Epub 2014 May 5.
citation: Cardoso F, Costa A, Norton L, Senkus E, Aapro M, Andre F, Barrios CH, Bergh J, Biganzoli L, Blackwell KL, Cardoso MJ, Cufer T, El Saghir N, Fallowfield L, Fenech D, Francis P, Gelmon K, Giordano SH, Gligorov J, Goldhirsch A, Harbeck N, Houssami N, Hudis C, Kaufman B, Krop I, Kyriakides S, Lin UN, Mayer M, Merjaver SD, Nordstrom EB, Pagani O, Partridge A, Penault-Llorca F, Piccart MJ, Rugo H, Sledge G, Thomssen C, Van't Veer L, Vorobiof D, Vrieling C, West N, Xu B, Winer E. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2)dagger. Ann Oncol. 2014 Oct;25(10):1871-1888. doi: 10.1093/annonc/mdu385. Epub 2014 Sep 18. No abstract available.
citation: Lipton A, Ali SM, Leitzel K, Demers L, Harvey HA, Chaudri-Ross HA, Brady C, Wyld P, Carney W. Serum HER-2/neu and response to the aromatase inhibitor letrozole versus tamoxifen. J Clin Oncol. 2003 May 15;21(10):1967-72. doi: 10.1200/JCO.2003.09.098.
citation: Burstein HJ, Harris LN, Marcom PK, Lambert-Falls R, Havlin K, Overmoyer B, Friedlander RJ Jr, Gargiulo J, Strenger R, Vogel CL, Ryan PD, Ellis MJ, Nunes RA, Bunnell CA, Campos SM, Hallor M, Gelman R, Winer EP. Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol. 2003 Aug 1;21(15):2889-95. doi: 10.1200/JCO.2003.02.018.
citation: Chan A, Martin M, Untch M, Gil MG, Guillem-Porta V, Wojtukiewicz M, Kellokumpu-Lehtinen P, Sommer HL, Georgoulias V, Battelli N, Pawlicki M, Aubert D, Bourlard T, Gasmi J, Villanova G, Petruzelka L; Navelbine Herceptin Project. Vinorelbine plus trastuzumab combination as first-line therapy for HER 2-positive metastatic breast cancer patients: an international phase II trial. Br J Cancer. 2006 Oct 9;95(7):788-93. doi: 10.1038/sj.bjc.6603351. Epub 2006 Sep 12.
citation: Brady MJ, Cella DF, Mo F, Bonomi AE, Tulsky DS, Lloyd SR, Deasy S, Cobleigh M, Shiomoto G. Reliability and validity of the Functional Assessment of Cancer Therapy-Breast quality-of-life instrument. J Clin Oncol. 1997 Mar;15(3):974-86. doi: 10.1200/JCO.1997.15.3.974.
citation: EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of life. Health Policy. 1990 Dec;16(3):199-208. doi: 10.1016/0168-8510(90)90421-9.
citation: Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015 Jan;16(1):25-35. doi: 10.1016/S1470-2045(14)71159-3. Epub 2014 Dec 16.
citation: Finn, R.S., et al., PALOMA-2: Primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2- advanced breast cancer (ABC). ASCO Meeting Abstracts, 2016. 34(15_suppl): p. 507.
citation: Paridaens R, Dirix L, Lohrisch C, Beex L, Nooij M, Cameron D, Biganzoli L, Cufer T, Duchateau L, Hamilton A, Lobelle JP, Piccart M; European Organization for the Research and Treatment of Cancer (EORTC)- Investigational Drug Branch for Breast Cancer (IDBBC). Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer. Ann Oncol. 2003 Sep;14(9):1391-8. doi: 10.1093/annonc/mdg362.
citation: Pfizer, Inc. Palbociclib (PD-0332991): Investigator's Brochure. N.p.: Pfizer, 2015. Print.
citation: Peddi PF, Slamon DJ. Frontiers in HER2-positive breast cancer in 2020. Curr Opin Obstet Gynecol. 2021 Feb 1;33(1):48-52. doi: 10.1097/GCO.0000000000000677.