Bernardo Bonanni of the European Institute of Oncology (IEO) in Milan is one of those investigators who are trying out different strategies to get a better insight into cancer.

As one of the keynote speakers of the “Emerging targets in cancer prevention” session at the AACR-NCI-EORTC conference in Boston (http://www.aacr.org/home/scientists/meetings--workshops/molecular-targets-and-cancer-therapeutics.aspx), he presented the preliminary results of a two arm Phase II clinical trial testing metformin against placebo in women with early brest cancer. Metformin is a biguanide derivate, and a cheap generic drug. It works by increasing the sensitivity of peripheral tissue to insulin and by inhibiting  hepatic glucose production, and it is used very widely in patients with non insulin dependent diabeted mellitus and non diabetic women with polycistic ovaric syndrome (PCOS).

But, insuline resistance is not a unique feature of diabetes or PCOS. Indeed, insuline resistance interferes more in general with metabolic pathways and energy imbalnce, and gives rise to dislypedemia, glucose intolerance, hyperuricemia, and hypertension.

Recently, it has been demonstrated that the breast cancer prognosis is indeed modulated by insuline levels (Goodwin PJ et al, JCO 2008, 2009). Moreover, a number of observational studies suggest that metformin may be useful in cancer treatment and prevention, while other initial clinical data show that metformin is associated with enhanced response to neoadjuvant therapy in breast cancer.

Elaborating on these studies, Bonanni presented the preliminary result of a presurgical window opportunity trial of metformin against placebo in a randomized, double-blinded, placebo controlled phase II trial conducted at the IEO. The change in tumor and dysplastic/ hyperplastic cell proliferation, as measured by the percentageof Ki67 positive cells, is the primary endpoint of the study. The plan is to enroll 200 patients with early breast cancer, who did not receive previous treatment. The other main exclusion criteria is the presence of diabetes mellitus.

The results of the trial are not yet published, but a few meaningful conclusions can already be drawn. First of all, such a trial appears to be feasible in terms of recruiting patients during the presurgical window. This also demonstrates that a 'clean' sample of non-pretreated patients can be obtained. The compliance was high, and the toxicity low.

While the analysis of the primary endpoint is currently ongoing, the rationale of the study and the importance of the trial in terms of timeliness of the presurgical window, and of studying the correlation of the Ki67 proliferation marker -and possibly other markers- with the prognosis of the tumor has been demonstrated.

But probably the most important take home message from Bonanni's talk was that the application of metformin, a drug usually used in contexts other than cancer, represents one of the first and most promising examples of a paradigm shift of the drug development process, where the current 'one drug one disease model', where a single agent is used only for a single disease, would not be valid anymore. Indeed, molecularly targeted agents, which target pathways instead of diseases, reshape the drug development process. The same pathway may be involved in different tumors, and in different diseases, as in the case of the Notch pathway, which is deregulated in different cancers, Alzheimer's disease and potentially other neurodenerative disorders, and cardiovascular diseases.

The administration of metformin to early breast cancer patient could represent also an excellent case-study of a multiple approach to tackle a disease. A multiple strategy would integrate the administration of one or more drugs with changes in life style (eg exercise) and diet. The approach envisaged by Bonanni would therefore shed a broader outlook on the concept of disease and health, while aiming not only at cancer prevention, but at a more holistic perspective of global health promotion.

References

Goodwin PJ. Insulin in the adjuvant breast cancer setting: a novel therapeutic target for lifestyle and pharmacologic interventions? J Clin Oncol. 2008:26(6):833-4.

Goodwin PJ, Ligibel JA, Stambolic V. Metformin in breast cancer: time for action. J Clin Oncol. 2009:27(20):3271-3.