HER-2 Positive Breast CancerPhase 3PATINANCT02947685
Randomized, Open Label, Clinical Study of the Targeted Therapy, Palbociclib, to Treat Metastatic Breast Cancer
A Phase 3 study testing palbociclib, trastuzumab and pertuzumab in people with HER-2 Positive Breast Cancer and Estrogen Receptor Positive Breast Cancer, run by Alliance Foundation Trials, LLC. at 108 sites in 8 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- HER-2 Positive Breast Cancer, Estrogen Receptor Positive Breast Cancer
- What is being tested?
- palbociclib, trastuzumab and pertuzumab
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 518 participants
- Where
- 108 sitesin 8 countries
- Study dates
- 21 Jun 2017to 31 Dec 2030
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Signed Preliminary Screening Informed Consent Form obtained prior to any study specific assessments and procedures
- Age ≥18 years (or per national guidelines)
- 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.
- 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.
- 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.
- 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.
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- Signed Main Informed Consent Form obtained prior to any study specific assessments and procedures
- Age ≥ 18 years (or per national guidelines)
- ECOG performance status 0-1
- Patients must be able and willing to swallow and retain oral medication without a condition that would interfere with enteric absorption.
- 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).
- 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.
- Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
- Prior Treatment Specifics
- 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.
- 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).
- 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
- Absolute neutrophil count ≥ 1,000/mm3
- Platelets ≥ 100,000/mm3
- Hemoglobin ≥ 10g/dL
- Total serum bilirubin ≤ ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin within normal range in patients with documented Gilbert's Syndrome.
- Aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) ≤ 3 × institutional ULN (≤5 x ULN if liver metastases are present).
- 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.
- Left ventricular ejection fraction (LVEF) ≥ 50% at baseline as determined by either ECHO or MUGA
Who cannot join
- Concurrent therapy with other Investigational Products.
- Prior therapy with any CDK 4/6 inhibitor.
- History of allergic reactions attributed to compounds of chemical or biologic composition similar to palbociclib.
- 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).
- 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.
- 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.
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- 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.
- QTc interval >480 msec, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes.
- Patients with clinically significant history of liver disease, including viral or other known hepatitis, current alcohol abuse, or cirrhosis
Trial locations and contacts
108 sites in 8 countries.
108 sites in 8 countries
United States35 sites
New Mexico Cancer Care Alliance
Albuquerque, New Mexico, 87131
Michigan Cancer Research Consortium (St. Joseph Mercy Hospital
Ann Arbor, Michigan, 48106
Emory University
Atlanta, Georgia, 30322
University of Maryland - Greenebaum Comprehensive Cancer Center
Baltimore, Maryland, 21201
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, 21287
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215
University of Illinois at Chicago
Chicago, Illinois, 60612
Baycare Healthcare (Morton Plant Mease)
Clearwater, Florida, 33756
Ohio State University
Columbus, Ohio, 43210
Duke Cancer Institute
Durham, North Carolina, 27710
West Michigan Cancer Center
Grand Rapids, Michigan, 49503
Hackensack Medical Center
Hackensack, New Jersey, 07601
Ingalls Memorial Hospital
Harvey, Illinois, 60426
Memorial Healthcare System
Hollywood, Florida, 33021
MD Anderson
Houston, Texas, 77030
Lowell General Hospital
Lowell, Massachusetts, 01854
University of Miami
Miami, Florida, 33136
Metro-Minnesota NCI Community Oncology Research Program
Minneapolis, Minnesota, 55416
Vanderbilt University Medical Center
Nashville, Tennessee, 37204
Ochsner Medical Center Jefferson
New Orleans, Louisiana, 70121
Nebraska Methodist Hospital
Omaha, Nebraska, 68114
University of Nebraska Medical Center
Omaha, Nebraska, 68198
Florida Hospital
Orlando, Florida, 32804
The Valley Hospital, Okonite Research Center
Paramus, New Jersey, 07652
University of Pennsylvania
Philadelphia, Pennsylvania, 19106
First Health of the Carolinas Cancer Center
Pinehurst, North Carolina, 28374
Legacy Good Samaritan Hospital
Portland, Oregon, 97210
Mayo Clinic, Rochester, MN
Rochester, Minnesota, 55905
Huntsman Cancer Institute, University of Utah
Salt Lake City, Utah, 84112
UCSF
San Francisco, California, 94115
New England Cancer Specialists
Scarborough, Maine, 04074
Washington University School of Medicine
St Louis, Missouri, 63110
Georgetown University Medical Center
Washington D.C., District of Columbia, 20007
Lexington Medical Center
West Columbia, South Carolina, 29169
Cancer Center of Kansas
Wichita, Kansas, 67214
France25 sites
Institut de Cancérologie de l'Ouest, site Paul Papin
Angers
Institut Sainte Catherine
Avignon
Institut Bergonié
Bordeaux
Centre Francois Baclesse
Caen
Centre Hospitalier Cholet
Cholet
Centre Jean Perrin
Clermont-Ferrand
Centre Georges François Leclerc
Dijon
Centre Oscar Lambret
Lille
CHU de Limoges
Limoges
Centre Léon Bérard
Lyon
Institut Paoli Calmettes
Marseille
Institut de Cancerologie de Montpellier
Montpellier
Centre Azureen de Cancerologie
Mougins
Centre Antoine Lacassagne
Nice
Institut Curie Site Paris
Paris
Tenon Oncologie Médicale - APHP
Paris
Centre CARIO-HPCA
Plérin
Institut Jean Godinot
Reims
Centre Eugene Marquis
Rennes
Centre Henri Becquerel
Rouen
Institut Curie Site Saint Cloud
Saint-Cloud
Institut de Cancérologie Lucien Neuwirth
Saint-Priest-en-Jarez
Centre Paul Strauss
Strasbourg
Intitut Claudius Regaud
Toulouse
Gustave Roussy
Villejuif
Spain17 sites
Hospital Clínic de Barcelona
Barcelona
Hospital General de Catalunya
Barcelona
Hospital Universitari Vall d'Hebron
Barcelona
ICO L'Hospitalet
Barcelona
Hospital Universitario 12 de Octubre
Madrid
Hospital Universitario de Fuenlabrada
Madrid
Hospital Universitario Fundación Jiménez Díaz
Madrid
Hospital Universitario La Paz
Madrid
MD Anderson Cancer Center Spain
Madrid
Hospital Regional Universitario de Málaga
Málaga
Hospital Universitario Virgen de la Arrixaca
Murcia
Complejo Hospitalario de Navarra
Navarro
Hospital Universitario de Salamanca
Salamanca
Complejo Hospitalario Univ. De Santiago
Santiago
Hospital Quirón Sagrado Corazón
Seville
Hospital Sant Joan de Reus
Tarragona
Hospital Clínico Universitario de Valencia
Valencia
Germany12 sites
Klinikum Bayreuth GmbH
Bayreuth, 95445
Marienhospital Bottrop
Bottrop
St. Elisabeth Krankenhaus
Cologne
Kliniken Essen-Mitte, Evang. Huyssens-Stiftung/Knappschaft GmbH
Essen
Agaplesion Markus Krankenhaus
Frankfurt
Universitasklinikum Freiburg
Freiburg im Breisgau, 79106
Diakovere Henriettenstift Frauenklinik
Hanover
UKSH, Klinik für Gynäkologie und Geburtshilfe
Kiel
Praxis Prof. Nitz im Brustzentrum Niederrhein
Münster
Universitätsklinikum Münster
Münster
Univ. Klinikum Oldenburg AÖR Hämatologie/Onkologie
Oldenburg
Leopoldina-Krankenhaus Schweinfurt
Schweinfurt
Australia9 sites
Monash Health
Clayton
St. Vincent's Hospital, Sydney Kinghorn Cancer Centre
Darlinghurst
The Canberra Hospital
Garran
Peter MacCallum Cancer Centre, Royal Melbourne Hospital
Melbourne
Breast Cancer Research Centre-WA
Nedlands
Icon Cancer Care
South Brisbane
Mater Cancer Care Centre
South Brisbane
Calvary Mater Newcastle Hospital
Waratah
Westmead Hospital
Westmead
Italy5 sites
Policlinico Sant'Orsola-Malpighi
Bologna
U.O. Oncologia AOU Arcispedale Sant'Anna
Cona
Istituto Europeo di Oncologia
Milan
Ospedale San Raffaele
Segrate
Ospedale Santa Maria della Misericordia
Udine
Portugal4 sites
Hospital Champalimaud
Lisbon
Hospital Da Luz
Lisbon
Hospital Beatriz Angelo
Loures
IPO Porto
Porto
New Zealand1 site
Auckland City Hospital Cancer and Blood Research
Auckland
About this study
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
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.
Read the 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.
- Being tested
- palbociclib, trastuzumab, pertuzumab, letrozole, Anastrozole
- Keywords
- breast cancer, malignant tumor of the breast, HER2+, HR+, metastatic breast cancer
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
palbociclibDrug
Also called Ibrance
- Starting dose: 125 mg capsule taken orally once per day for 21 days followed by 7 days off to complete 28 day cycle. Dose reductions: 100 mg, 75 mg. allowed. Number of Cycles: until progression or unacceptable toxicity develops
trastuzumabDrug
Also called Herceptin
Patients must have received a minimum of 4 and maximum of 8 cycles of induction therapy prior to randomization to Arm A or B, at which point they will continue on antiHER2 therapy and endocrine therapy, with or without palbociclib. Trastuzumab dosing will be determined based on a loading dose of 8mg trastuzumab/kg body weight for Q3WK dosing schedules or a maintenance dose of 6mg/kg trastuzumab/kg dosing weight for Q3WK dosing schedules. Loading dose will be administered on Cycle 1, Day 1.
pertuzumabDrug
Also called Perjeta
Patients must have received a minimum of 4 and maximum of 8 cycles of induction therapy prior to randomization to Arm A or B, at which point they will continue on antiHER2 therapy and endocrine therapy, with or without palbociclib.Pertuzumab will be administered at a loading dose of 840 mg infusion and then at a maintenance dose of 420 mg q3wks. If patient is within 5 weeks of receiving loading dose at Cycle 1, Day 1, patient may start with maintenance dose of 420 mg.
letrozoleDrug
Also called Femara
There are several allowed endocrine treatment agents for Arm A and Arm B of this study. Administration is performed on an outpatient, self-administration basis according to local requirements and local standard practice. Endocrine treatment may have started before the patient enters the study. Agents will be administered at the discretion of principal investigator as well as according to standard institutional or regional practice. Recommended dosing regimen for letrozole oral therapy is 2.5 mg orally, once a day.
AnastrozoleDrug
Also called Arimidex
There are several allowed endocrine treatment agents for Arm A and Arm B of this study. Administration is performed on an outpatient, self-administration basis according to local requirements and local standard practice. Endocrine treatment may have started before the patient enters the study. Agents will be administered at the discretion of principal investigator as well as according to standard institutional or regional practice. Recommended dosing regimen for anastrozole is 1 mg orally, once a day.
ExemestaneDrug
Also called Aromasin
There are several allowed endocrine treatment agents for Arm A and Arm B of this study. Administration is performed on an outpatient, self-administration basis according to local requirements and local standard practice. Endocrine treatment may have started before the patient enters the study. Agents will be administered at the discretion of principal investigator as well as according to standard institutional or regional practice. Recommended dosing regimen for exemestane is 25 mg orally, once a day.
FulvestrantDrug
Also called Faslodex
There are several allowed endocrine treatment agents for Arm A and Arm B of this study. Administration is performed on an outpatient, self-administration basis according to local requirements and local standard practice. Endocrine treatment may have started before the patient enters the study. Agents will be administered at the discretion of principal investigator as well as according to standard institutional or regional practice. Recommended dosing regimen for Fulvestrant is 250 mg injections on Day 1 and Day 15 of Cycle 1, and q4weeks thereafter.
| Study group | Role | What they receive |
|---|---|---|
| Arm A | Experimental | Palbociclib 125 mg daily + AntiHER2 Therapy (trastuzumab/pertuzumab) q3wks + Endocrine Therapy (letrozole, anastrozole, exemstane OR fulvestratnt) until confirmed disease progression Receives: Drug: palbociclib; Drug: trastuzumab; Drug: pertuzumab; Drug: letrozole; Drug: Anastrozole; Drug: Exemestane; Drug: Fulvestrant |
| Arm B | Active comparator | AntiHER2 Therapy (trastuzumab/pertuzumab) q3wks + Endocrine Therapy (letrozole, anastrozole, exemstane OR fulvestrant) until confirmed disease progression Receives: Drug: pertuzumab; Drug: letrozole; Drug: Anastrozole; Drug: Exemestane; Drug: Fulvestrant |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression-free Survival (PFS) as Assessed by Investigator
The time from registration to disease progression or death.
Measured: 7 years 3 months
Secondary outcomes (8)
Overall Survival (OS)
Defined as time from date of randomization to date of death due to any cause
Measured: 7 years 3 months
3 and 5 Year Survival Probabilities
Defined as the percentage of patients still alive and followed at 3 and 5 years post beginning of treatment.
Measured: 5 years
Objective Response Rate (OR: CR or PR)
Defined as proportion of patients that achieve complete response (CR) or partial response (PR) according to RECIST v1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Measured: 24 months
Duration of Response (DOR)
Defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of objective tumor progression or to death from any cause, whichever occurs first
Measured: 72 months
Clinical Benefit Rate
The Clinical Benefit Rate (CBR) on each treatment arm will be estimated by dividing the number of patients with CR, PR, or SD/Non-CR and Non-PD (for patients with measurable disease) for ≥ 24 weeks by the number of patients randomized to the treatment arm.
Measured: 24 months
Incidence of Grade 3 or Higher Adverse Events (as Graded by NCI CTCAE v 4.0)
The proportion of patient by arm that experienced grade 3 or higher adverse events will be reported
Measured: 24 months
Patient Reported Outcomes
Time to symptom progression (FACT-B PFB-TOI), breast cancer specific health treatment related quality of life and general health status
Measured: 24 months
Incidence of CNS Metastasis
Compare the incidence of CNS metastasis between treatment arms
Measured: 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Oct 2016 (estimated)
- Study start21 Jun 2017
- Primary completion15 Oct 2024
- Study completion31 Dec 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (40)Papers the sponsor has linked to this study.
- Other trials for HER-2 Positive Breast CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 518 participants (actual)
Sponsor and investigators
- Lead sponsor
- Alliance Foundation Trials, LLC.
- Sponsor type
- University, hospital or other
- Collaborators
- Pfizer, GBG Forschungs GmbH, Fondazione Michelangelo, PrECOG, LLC., Breast Cancer Trials, Australia and New Zealand, Syneos Health, SOLTI Breast Cancer Research Group, UNICANCER
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02947685
- Sponsor's protocol ID
- AFT-38
- Acronym
- PATINA
- Status last verified
- Feb 2026
- First submitted
- 26 Oct 2016
- Last updated
- 22 Oct 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 22152853Welch 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.
PubMed 26510017Baselga 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.
PubMed 22149875Swain 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.
PubMed 25693012Ferlay 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.
PubMed 23485231Sherr 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.
PubMed 10385618van 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.
PubMed 8266103Weinberg 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.
PubMed 7736585Harper 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.
PubMed 8242751Koff 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.
PubMed 8475385Polyak 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.
PubMed 8288131Sherr CJ. D-type cyclins. Trends Biochem Sci. 1995 May;20(5):187-90. doi: 10.1016/s0968-0004(00)89005-2.
PubMed 7610482Toyoshima 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.
PubMed 8033213Lukas 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.
PubMed 7777060Medema 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.
PubMed 7603984