Predictive value and clinical utility of centrally assessed ER, PgR, and Ki-67 to select adjuvant endocrine therapy for premenopausal women with hormone receptor-positive, HER2-negative early breast cancer: TEXT and SOFT trials.
The SOFT and TEXT randomized phase III trials investigated adjuvant endocrine therapies for premenopausal women with hormone receptor-positive (HR+) early breast cancer. We investigated the prognostic and predictive value of centrally assessed levels of estrogen receptor (ER), progesterone receptor (PgR), and Ki-67 expression in women with HER2-negative disease. Of 5707 women enrolled, 4115 with HER2-negative (HR+/HER2-) disease had ER, PgR, and Ki-67 centrally assessed by immunohistochemistry. Breast cancer-free interval (BCFI) was defined from randomization to first invasive local, regional, or distant recurrence or contralateral breast cancer. The prognostic and predictive values of ER, PgR and Ki-67 expression levels were assessed using Cox modeling and STEPP methodology. In this HR+/HER2- population, the median ER, PgR, and Ki-67 expressions were 95, 90, and 18 % immunostained cells. As most patients had strongly ER-positive tumors, the predictive value of ER levels could not be investigated. Lower PgR and higher Ki-67 expression were associated with reduced BCFI. There was no consistent evidence of heterogeneity of the relative treatment effects according to PgR or Ki-67 expression levels, though there was a greater 5-year absolute benefit of exemestane + ovarian function suppression (OFS) versus tamoxifen with or without OFS at lower levels of PgR and higher levels of Ki-67. Women with poor prognostic features of low PgR and/or high Ki-67 have greater absolute benefit from exemestane + OFS versus tamoxifen + OFS or tamoxifen alone, but individually PgR and Ki-67 are of limited predictive value for selecting adjuvant endocrine therapy for premenopausal women with HR+/HER2- early breast cancer.
Department of Biostatistics and Computational Biology, International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Mailstop CLS-11007, Boston, MA, 02215, USA. mregan@jimmy.harvard.edu.
Meredith M
MM
Regan
Institute of Oncology of Southern Switzerland, Swiss Group for Clinical Cancer Research (SAKK), Lugano Viganello, Switzerland. olivia.pagani@ibcsg.org.
Olivia
O
Pagani
Peter MacCallum Cancer Center, St Vincent's Hospital, University of Melbourne, Melbourne, VIC, Australia. prue.francis@petermac.org.|Australia & New Zealand Breast Cancer Trials Group (ANZBCTG), University of Newcastle, Callaghan, NSW, Australia. prue.francis@petermac.org.
Prudence A
PA
Francis
The University of Chicago Medical Center and Alliance for Clinical Trials in Oncology, Chicago, IL, USA. gfleming@medicine.bsd.uchicago.edu.
Gini F
GF
Fleming
Tom Baker Cancer Centre and NCIC Clinical Trials Group, Calgary, AB, Canada. Barbara.Walley@albertahealthservices.ca.
Barbara A
BA
Walley
International Breast Cancer Study Group Coordinating Center and Central Pathology Office, Bern, Switzerland. Rosita.Kammler@ibcsg.org.
Roswitha
R
Kammler
International Breast Cancer Study Group Central Pathology Office, Department of Pathology, European Institute of Oncology, Milan, Italy. patrizia.dellorto@ieo.it.
Patrizia
P
Dell'Orto
International Breast Cancer Study Group Central Pathology Office, Department of Pathology, European Institute of Oncology, Milan, Italy. leila.russo@ieo.it.
Leila
L
Russo
Pathological Department, National Institute of Oncology, Budapest, Hungary. szoke.j@oncol.hu.
János
J
Szőke
Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru. fdoimi@inen.sld.pe.
Franco
F
Doimi
Division of Pathology, Salvatore Maugeri Foundation, Pavia, Italy. laura.villani@fsm.it.
Laura
L
Villani
Struttura Operativa Complessa di Anatomia Patologica, Azienda Ospedaliero-Universitaria di Udine, Udine, Italy. pizzolitto.stefano@aoud.sanita.fvg.it.
Stefano
S
Pizzolitto
Kantonsspital St. Gallen, Swiss Group for Clinical Cancer Research (SAKK), St. Gallen, Switzerland. christian.oehlschlegel@kssg.ch.
Christian
C
Öhlschlegel
University of Insubria-Ospedale di Circolo and Fondazione Macchi, Varese, Italy. fausto.sessa@ospedale.varese.it.
Fausto
F
Sessa
Department of Pathology, Vall d'Hebron University Hospital, SOLTI Group, Barcelona, Spain. vpeg@vhebron.net.
Vicente
V
Peg Cámara
Pathology Department, Hospital Universitario «12 de Octubre», i+12, Universidad Complutense Madrid, SOLTI Group, Madrid, Spain. jrperalto@salud.madrid.org.
José Luis
JL
Rodríguez Peralto
Laboratoire Anatomopathologie, Institut Bergonié, Bordeaux, France. g.macgrogan@bordeaux.unicancer.fr.|EORTC, Brussels, Belgium. g.macgrogan@bordeaux.unicancer.fr.
Gaëtan
G
MacGrogan
Division of Medical Senology, European Institute of Oncology, Milan, Italy. marco.colleoni@ieo.it.
Marco
M
Colleoni
Program for Breast Health, European Institute of Oncology, Milan, Italy. aron.goldhirsch@ibcsg.org.
Aron
A
Goldhirsch
International Breast Cancer Study Group Statistical Center, Frontier Science and Technology Research Foundation, Boston, MA, USA. price@jimmy.harvard.edu.
Karen N
KN
Price
University of Sydney, Sydney, Australia. alan.coates@ibcsg.org.
Alan S
AS
Coates
International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. gelber@jimmy.harvard.edu.|Harvard T.H. Chan School of Public Health, Boston, MA, USA. gelber@jimmy.harvard.edu.|Frontier Science and Technology Research Foundation, Boston, MA, USA. gelber@jimmy.harvard.edu.
Richard D
RD
Gelber
International Breast Cancer Study Group Central Pathology Office, European Institute of Oncology, University of Milan, Milan, Italy. giuseppe.viale@ieo.it.
Giuseppe
G
Viale
D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality*; D017024:Chemotherapy, Adjuvant; D017326:Clinical Trials, Phase III as Topic; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000378:metabolism*; D008207:Lymphatic Metastasis; D008875:Middle Aged; D060787:Neoplasm Grading; D017697:Premenopause; D011379:Prognosis; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D047368:Tumor Burden; D055815:Young Adult
D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone
Estrogen receptor; Exemestane; Ki-67; Ovarian function suppression; Progesterone receptor; Tamoxifen