Serum C‐peptide levels and breast cancer risk: Results from the European prospective investigation into cancer and nutrition (EPIC)

Martijn Verheus, Petra H.M. Peeters, Sabina Rinaldi, Laure Dossus, Carine Biessy, Anja Olsen, Anne Tjønneland, Kim Overvad, Majbritt Jeppesen, Françoise Clavel‐Chapelon, Bertrand Téhard, Gabriele Nagel, Jakob Linseisen, Heiner Boeing, Petra H. Lahmann, Athina Arvaniti, Theodora Psaltopoulou, Antonia Trichopoulou, Domenico Palli, Rosario Tumino, Salvatore Panico, Carlotta Sacerdote, Sabina Sieri, Carla H. van Gils, Bas H. Bueno‐de‐Mesquita, Carlos A. González, Eva Ardanaz, Nera Larranaga, Carmen Martinez Garcia, Carmen Navarro, J. Ramón Quirós, Tim Key, Naomi Allen, Sheila Bingham, Kay‐Tee Khaw, Nadia Slimani, Elio Riboli, Rudolf Kaaks

It has been hypothesized that chronic hyperinsulinemia, a major metabolic consequence of physical inactivity and excess weight, might increase breast cancer risk by direct effects on breast tissue or indirectly by increasing bioavailable levels of testosterone and estradiol. Within the European Prospective Investigation into Cancer and Nutrition (EPIC), we measured serum levels of C-peptide--a marker for pancreatic insulin secretion--in a total of 1,141 incident cases of breast cancer and 2,204 matched control subjects. Additional measurements were made of serum sex hormone binding globulin (SHBG) and sex steroids. Conditional logistic regression models were used to estimate breast cancer risk for different levels of C-peptide. C-peptide was inversely correlated with SHBG and hence directly correlated with free testosterone among both pre and postmenopausal women. C-peptide and free estradiol also correlated positively, but only among postmenopausal women. Elevated serum C-peptide levels were associated with a nonsignificant reduced risk of breast cancer diagnosed up to the age of 50 years [odds ratio (OR)=0.70, (95% confidence interval (CI), 0.39-1.24); ptrend=0.05]. By contrast, higher levels of C-peptide were associated with an increase of breast cancer risk among women above 60 years of age, however only among those women who had provided a blood sample under nonfasting conditions [OR=2.03, (95% CI, 1.20-3.43); ptrend=0.01]. Our results do not support the hypothesis that chronic hyperinsulinemia generally increases breast cancer risk, independently of age. Nevertheless, among older, postmenopausal women, hyperinsulinemia might contribute to increasing breast cancer risk.