Biomarker Associations with Efficacy of Abiraterone Acetate and Exemestane in Postmenopausal Patients with Estrogen Receptor-Positive Metastatic Breast Cancer.
OBJECTIVE
Abiraterone may suppress androgens that stimulate breast cancer growth. We conducted a biomarker analysis of circulating tumor cells (CTCs), formalin-fixed paraffin-embedded tissues (FFPETs), and serum samples from postmenopausal estrogen receptor (ER)+breast cancer patients to identify subgroups with differential abiraterone sensitivity.


METHODS
Patients (randomized 1:1:1) were treated with 1,000 mg/d abiraterone acetate + 5 mg/d prednisone (AA), AA + 25 mg/d exemestane (AAE), or exemestane. The biomarker population included treated patients (n = 293). The CTC population included patients with ≥3 baseline CTCs (n = 104). Biomarker [e.g., androgen receptor (AR), ER, Ki-67, CYP17] expression was evaluated. Cox regression stratified by prior therapies in the metastatic setting (0/1 vs. 2) and setting of letrozole/anastrozole (adjuvant vs. metastatic) was used to assess biomarker associations with progression-free survival (PFS).


RESULTS
Serum testosterone and estrogen levels were lowered and progesterone increased with AA. Baseline AR or ER expression was not associated with PFS in CTCs or FFPETs for AAE versus exemestane, but dual positivity of AR and ER expression was associated with improved PFS [HR, 0.41; 95% confidence interval (CI), 0.16-1.07; P = 0.070]. For AR expression in FFPETs obtained <1 year prior to first dose (n = 67), a trend for improved PFS was noted for AAE versus exemestane (HR, 0.56; 95% CI, 0.24-1.33; P = 0.19).


CONCLUSIONS
An AA pharmacodynamic effect was shown by decreased serum androgen and estrogen levels and increased progesterone. AR and ER dual expression in CTCs and newly obtained FFPETs may predict AA sensitivity. Clin Cancer Res; 22(24); 6002-9. ©2016 AACR.
Janssen Research & Development, Spring House, Pennsylvania. wli78@its.jnj.com.
Weimin
W
Li
US Oncology, Dallas, Texas.
Joyce
J
O'Shaughnessy
The University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
Daniel
D
Hayes
Institut de Cancérologie de l'Ouest, Nantes, France.
Mario
M
Campone
Dnepropetrovsk Medical Academy, Municipal Clinical Hospital #4, Dnepropetrovsk, Ukraine.
Igor
I
Bondarenko
Leningrad Regional Oncology Dispensary, Saint Petersburg, Russia.
Irina
I
Zbarskaya
Hôpital René Huguenin, Saint-Cloud, France.
Etienne
E
Brain
N.N. Blokhin Cancer Research Center, Moscow, Russia.
Marina
M
Stenina
Research Institute of Oncology, Saint Petersburg, Russia.
Olga
O
Ivanova
CHC, Liège, Belgium.
Marie-Pascale
MP
Graas
University Hospitals Leuven, Leuven, Belgium.
Patrick
P
Neven
Janssen Research & Development, Raritan, New Jersey.
Deborah
D
Ricci
Janssen Research & Development, Los Angeles, California.
Thomas
T
Griffin
Janssen Research & Development, San Diego, California.
Thian
T
Kheoh
Janssen Research & Development, Los Angeles, California.
Margaret
M
Yu
Janssen Research & Development, Spring House, Pennsylvania.
Michael
M
Gormley
Janssen Research & Development, High Wycombe, United Kingdom.
Jason
J
Martin
Janssen Research & Development, Spring House, Pennsylvania.
Michael
M
Schaffer
Janssen Research & Development, Spring House, Pennsylvania.
Kathy
K
Zelinsky
Janssen Research & Development, Beerse, Belgium.
Peter
P
De Porre
The Royal Marsden Hospital and The Institute of Cancer Research, London, United Kingdom.
Stephen R D
SR
Johnston
D000069501:Abiraterone Acetate / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000730:Androstadienes / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000378:metabolism; D017698:Postmenopause / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism
D000730:Androstadienes; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D013254:Steroid 17-alpha-Hydroxylase; D000069501:Abiraterone Acetate; C056516:exemestane