Plasma Biomarker May Be Independent Risk Predictor of Breast Cancer In Women Without Family History

Karla M. Gonye, MBA President, sphingotec LLC Cambridge, Interview with:
Karla M. Gonye, MBA
President, sphingotec LLC
Cambridge, Massachusetts

MedicalResearch: What is the background for this study?

  • Met- and Leu-Enkephalin: are endogenous pentapeptides of the family of opioid peptides known as opiod-growth factors (OGF)
  • Enkephalins have been widely studied and play a major role in a variety of physiological processes
    • Perception of pain
    • Regulation of stress
    • Regulation of cardiovascular function
    • Regulation of bone formation
    • Regulation of immune responses
  • Alcohol and pain relievers reduce synthesis of Enkephalins
  • Met-Enkephalin (opioid growth factor) inhibits tumor progression and metastasis and enhances natural killer cell activity1,2
  • Mechanisms3-7:
    • Opioids can directly interact with tumor cells to cause a cytotoxic or antiproliferative effect
    • Opioids can modulate host antitumor immune mechanisms
  • Opiods can also induce apoptosis
  • We need enkephalins to help inhibit tumor progression
  • At sphingotec, it was hypothesized that disease progression begins earlier than symptoms are present and that reduced enkephalins in the blood would be an indicator of future breast cancer; measurement of this hormone peptide was possible with the company’s expertise, and that test could be developed to precisely measure enkephalin.
  • This method is published in a separate publication by Ernst et al (2006) in Peptides.
  • To test this hypothesis, Sphingotec measured enkephalin levels in the MDC and MPP study populations to determine if an association could be made between lower enkephalins and risk of breast cancer: We related proenkephalin (P-ENK) in fasting plasma from 1929 healthy women (mean age 58±5.9 years) of the population based Malmö Diet and Cancer Study (MDCS) to incidence of breast cancer (n=123) using multivariate Cox proportional hazards models during 14.8 years of follow-up. For replication, P-ENK was related to risk of breast cancer (n=130) in an older independent sample from the Malmö Preventive Project (MPP) consisting of 1569 women (mean age 70.0±4.4 years), using multivariate logistic regression.

MedicalResearch: What are the main findings?


  • In the MDCS, P-ENK was inversely related to risk of incident breast cancer [hazard ratio per each standard deviation increment of LN-transformed P-ENK (95% confidence interval)] of [0.72 (0.62-0.85), P<0.001)]
  • As seen with pro-NT, there was a linear increase in risk over P-ENK quartiles 3, 2 and 1 (4th quartile as reference “normal”) of 1.38 (0.73-2.64), 2.29 (1.26-4.15) and 3.16 (1.78-5.60) (P for trend <0.001).
  • These results were replicated in the MPP, where the continuous odds ratio for incident breast cancer (95% confidence interval) was 0.63 (0.52-0.75), P<0.001 and the risk over P-ENK quartiles 3, 2 and 1 (4th quartile as reference) was 2.48 (1.25-4.94), 2.94 (1.50-5.77) and 4.81 (2.52-9.18) (P for trend <0.001).
  • We show for the first time that low fasting plasma concentration of the opioid precursor peptide P-ENK strongly associates with, and thus may contribute to prediction of, increased future breast cancer risk in middle aged and post-menopausal women.

MedicalResearch: What should clinicians and patients take away from your report?


  • Plasma enkenphalin is an independent risk predictor of future breast cancer in women without a family history of the disease.
  • When put in the context of other known risk factors that clinicians utilize today to counsel patients, such as age, smoking, age of menarche, menopausal status, an encephalin level is a much stronger and independent predictor of future breast cancer particularly in the group of women do not have a family history of breast cancer
  • Understanding factors related to disease progression can allow a woman and her clinician to understand her risk and allow for such interventions may be to control modifiable risk factors
  • Given the annual incidence of breast cancer, clinicians should be eager and excited to learn what more they can do identify women at highest risk women for breast cancer and discuss treatment/interventions with their patients.

MedicalResearch: please see:


[1]Faith RE et al., Brain Behav Immun. 1988 Jun;2(2):114-22.,
2 Schäfer et al., Adv. Pall. Med. 2009; 8, 2: 53–56
3 Murgo AJ et al.,in Stress and the Immune System, Plotnikoff NP et al. Eds., Plenum Press, New York, 1986, 221.a
4 Zagon IS et al., in Stress and Immunity, Plotnikoff NP et al., Eds., CRC Press, Boca Raton, FL, 1991, 343.
5 Murgo AJ et al., in Stress and Immunity, Plotnikoff NP et al., Eds., CRC Press, Boca Raton, FL, 1999, 143.
6 Mernenko OA et al.,FEBS Lett. 1996 Apr 1;383(3):230-2.
7 Maneckjee, R et al., Cell Growth Differ. 1994 Oct;5(10):1033-40.


Stable Peptide of the Endogenous Opioid Enkephalin Precursor and Breast Cancer Risk

Olle Melander, Marju Orho-Melander, Jonas Manjer, Thomas Svensson, Peter Almgren, Peter M. Nilsson, Gunnar Engström, Bo Hedblad, Signe Borgquist, Oliver Hartmann, Joachim Struck, Andreas Bergmann, and Mattias Belting

JCO JCO.2014.59.7682; published online on July 13, 2015;

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Karla M. Gonye, MBA (2015). Plasma Biomarker May Be Independent Risk Predictor of Breast Cancer In Women Without Family History 

Last Updated on July 30, 2015 by Marie Benz MD FAAD