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The COC Protocol™ in Breast Cancer

This document provides a brief summary of some of the current scientific evidence which supports the adjunctive use of the COC Protocol medications in breast cancer.

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Breast Cancer

Breast cancer is one of the most common types of cancer. Treatment can depend on the stage and type of cancer, and can include some or all of surgery, chemotherapy, radiation, hormone therapy, or targeted therapies.

Much current breast cancer research is also focused on introducing additional (adjunctive) treatments alongside standard treatments in the hope of improving results for patients. Scientific interest is growing in the use of treatments which target the metabolic pathways of cancer cells (i.e., the processes used by cells to generate energy) to slow or stop the growth of cancers.

Care Oncology specializes in using already-licensed (off-label) medications with known anti‑metabolic activity to help treat and control cancer. We have developed an adjunctive treatment called the COC Protocol, which combines what we believe to be the most effective metabolically-targeted off‑label medications available with standard of care. These metabolic medications are metformin, atorvastatin, doxycycline, and mebendazole. Each of these medications individually targets cancer using distinct mechanisms of action, and we believe that by combining these treatments, this multi-targeted approach can weaken cancer cells, helping to improve the effectiveness of standard cancer therapies.

Below is a brief summary of evidence supporting the combined use of these medications in breast cancer, in addition to a patient’s standard of care.

The COC Protocol as an adjunctive treatment for breast cancer


A wealth of evidence now supports the use of metformin as an adjunctive treatment for breast cancer. This evidence comes from a range of different studies, including laboratory studies, observational studies (which investigate links between taking metformin and breast cancer outcomes in groups of individuals), and early-stage clinical trials in humans. Below is a summary of just a few of these studies.

Metformin use linked to potential breast cancer benefits

Many observational studies now provide evidence supporting the use of metformin in breast cancer. Metformin is licensed to treat type 2 diabetes, and observational studies in groups of patients with diabetes tend to show that those who take metformin have reduced risk of developing breast cancer (1,2), and better chances of an improved outcome if they do develop breast cancer (3–5). These studies have also linked metformin use to improved survival in patients with breast cancer (6,7), improved response to breast cancer treatment (8), and less chance of breast cancer spreading and relapse (9,10). 

It is likely that some of the beneficial effect of metformin found in these studies is due to metformin’s ability to improve a patient’s diabetes and/or weight by reducing glucose levels, which can help reduce the risk of developing breast cancer can and improve a patient’s health and ability to tackle breast cancer if they do have it (11).

Laboratory studies also show that metformin is doing more than this. In fact, metformin can actively work directly against breast cancer cells, reducing their ability to take up and use energy, and blocking their ability to grow, spread, survive, and relapse (12–14).

Different types of breast cancer require different treatments. Trastuzumab, for example, is specifically used to treat human epidermal growth factor receptor 2 (HER2) positive breast cancer. Tamoxifen is effective against estrogen receptor (ER) positive breast cancer. Importantly, cancer cell studies in the laboratory demonstrate that metformin has anticancer activity against many different breast cancer cell types, including ER positive (15), HER2 positive (16), and potentially harder-to-treat subtypes such as triple-negative cancer cells (17–19). This means metformin has the potential to work effectively alongside standard treatments for breast cancer, regardless of the cancer subtype. 

Metformin targets breast cancer stem cells

Metformin has also been shown to target breast cancer stem cells (20–22). Cancer stem cells are a very resilient type of cancer cell which drive tumor development and growth. These cells can be very resistant to standard cancer treatments, and their regrowth following treatment can trigger disease relapse. Finding anticancer drugs which target cancer stem cells is a major current aim of breast cancer research (23).

Metformin’s activity against breast cancer stem cells, along with its ability to target different subtypes of breast cancer, help to explain why laboratory studies show it can work in combination with a number of standard treatments, including trastuzumab (21), tamoxifen (24), and standard chemotherapy agents (25). Animal and cell studies show that metformin both helps to improve the effectiveness of standard treatments (26–28) and delays relapse of cancers which have been treated with these therapies (25). In addition, laboratory studies also show that metformin can help to prevent breast cancer cells from becoming resistant to chemotherapy and improve the sensitivity of already resistant cancer cells to treatment (29). This could be because metformin is helping to target and ‘weaken’ the more treatment resistant breast cancer stem cells, making them more susceptible to the usual therapies.

Metformin improves markers of breast cancer in early clinical studies

As a result of the large amount of supportive data for metformin in breast cancer generated by observational and laboratory studies, various clinical trials investigating metformin in breast cancer are now underway (30).

A number of ‘window of opportunity’ trials are investigating if taking metformin for approximately two weeks prior to surgery can help to improve molecular markers of the disease in patients with operable early-stage breast cancer. Results from these studies generally suggest that taking metformin can lead to potentially positive changes in molecular markers of cancer, including those which regulate breast cancer cell growth and division (31–35), as well as potentially improving the regulation of hormones and other factors for some patients (34,35). These studies are now helping scientists understand exactly how and when metformin could help patients with breast cancer (31,36,37).

Phase 2 ‘neoadjuvant’ trials are generally longer and more complex trials which investigate metformin alongside courses of standard treatments to treat different types of breast cancer. The aim of these trials is to establish if metformin really does help improve the effectiveness of standard treatments, as laboratory studies suggest (38). Very recent results from one of these studies (the METTEN study) have just been reported, and results are encouraging (39). In this study in women with HER2 positive early-stage breast cancer, metformin was given alongside trastuzumab and chemotherapy cycles for 6 months prior to surgery. Metformin was generally well tolerated, and more patients taking metformin responded well to chemotherapy/targeted treatment (65.5%) compared to patients not taking metformin (58.6%). This difference was not statistically significant; which means this result could have been reached by chance. However, Phase 2 trials are generally underpowered for reaching statistical significance in this way, and the researchers called for progression to larger Phase 3 trials which can be properly designed to determine just how real this effect is (39).

In fact, a large Phase 3 trial is now underway to investigate metformin in breast cancer. This trial, with the clinicaltrials.gov number NCT01101438, is a huge, randomized, placebo-controlled study which has enrolled over 3,600 patients. The study is investigating how metformin, when added to standard therapy, impacts cancer relapse and patient survival in patients with early-stage breast cancer. Although the trial is not due to be completed until 2020, initial results from the first 6 months of the trial show that patients who started taking metformin immediately following completion of surgery and standard chemotherapy cycles have favorable changes in a molecular marker of breast cancer (40), and improved metabolic factors (41).


Observational studies link statins to better breast cancer outcomes

Statins are usually given to help manage cardiovascular disease. However, observational studies on large groups of people taking statins have also found that individuals with breast cancer who are taking statins may also have reduced risk of their cancer recurring following treatment, compared to patients who are not taking statins (42,43). For example, in one study in almost 2,000 survivors of breast cancer, those who started taking statins within three-years after diagnosis had a reduced chance of their cancer coming back (44). In another study, just 6 months of statin use post-diagnosis was linked to improved rates of relapse (45).

Importantly, the beneficial effect of statins in these and other studies was more strongly linked to more fat-soluble ‘lipophilic’ statins (like atorvastatin). In some laboratory studies, lipophilic statins have also been shown to have superior anticancer effects at the cellular level compared to less fat‑soluble statins (46).

Observational studies also link statin use to improved disease response to treatment and survival in patients with breast cancer, even for patients with breast cancer types which can be more aggressive (43,47,48). For example, in one study in patients with inflammatory breast cancer, patients taking atorvastatin while being treated for cancer had a longer period of time before their disease progressed, compared to those not taking a statin (49).

Statins target breast cancer cells

Statins, particularly fat-soluble lipophilic statins like atorvastatin, reduce growth and division of breast cancer cells and increase breast cancer cell death in laboratory studies (50–52). Studies also show that statins can potentially block the invasiveness of breast cancer cells in the laboratory, suggesting they can also help slow cancer spread to other parts of the body (metastasis) (53,54). In a mouse model of metastatic breast cancer, statin treatment delayed the growth of cancer which had already spread by up to 80%, with beneficial activity noted within a week of starting treatment (55).

Other studies also show that statins can help sensitize breast cancer cells to standard radiotherapy and chemotherapy treatments (56,57). One study found simvastatin could sensitize triple-negative or inflammatory breast cancer cells to radiotherapy in the laboratory. The same study went on to observe in a patient population that women with inflammatory breast cancer who took statins during their treatment had less chance of their cancer coming back within 3 years (58).

Similar to metformin, statins can produce these anticancer effects across different breast cancer types, including ER positive, HER2 positive, and triple-negative breast cancer. In fact, some laboratory studies show statins are particularly effective against triple-negative breast cancer cells (59,60).

Clinical trials investigating statins in breast cancer are now underway

A few early-stage clinical trials now show robustly positive results in terms of statins in breast cancer. Similar to metformin, early phase ‘window of opportunity’ trials have investigated if early, pre-surgical statins can help to improve molecular markers of the disease in patients with operable disease. So far, these studies show improved cancer molecular profiles in patients with statin treatment, suggesting atorvastatin and other statins in this context may have beneficial effects on cancer cell growth and division and cell death, even in women with high-grade more aggressive tumors (61–64)

Based on these promising results, a number of Phase 2 studies investigating adjunctive statins for a variety of different types of breast cancer, including triple-negative breast cancer, are now underway. These studies should help establish just how statins can help patients with breast cancer.


Interest in mebendazole as a potential anticancer treatment is relatively new and is mostly based on promising mechanistic studies and compelling reports from case studies in cancer patients (65,66).

Mebendazole is thought to kill cancer cells partly by disrupting special structures inside the cell, called microtubules (66). It works in a similar way to vincristine, a chemotherapy drug currently used for treatment of some types of cancer, including advanced-stage breast cancer (67).

Studies on breast cancer cells grown in the laboratory show that mebendazole and related drugs from the same class (called benzimidazoles) can slow the growth and division of several different types of breast cancer cells, including cells resistant to chemotherapy (68–70). In one study, mebendazole potently reduced survival of chemotherapy-resistant breast cancer cells grown in the laboratory by as much as 63.1% (68). Studies using another type of benzimidazole, called flubendazole, also demonstrated anticancer activity against triple‑negative breast cancer (69,71). Importantly, in one study flubendazole was also shown to directly target breast cancer stem cells (69).

Emerging evidence also suggests that benzimidazoles can enhance the activity of standard breast cancer treatments such as doxorubicin and fluorouracil (69). In addition, a series of studies using chemotherapy-resistant ER/HER2 positive breast cancer cells grown in the laboratory, consistently showed that mebendazole not only reduced survival of cancer cells, it also helped to complement and enhance the activity of specially-developed targeted forms of breast cancer chemotherapy drugs epirubicin and gemcitabine (68,72,73).


Aside from being an effective antibiotic, doxycycline also possesses other extremely valuable properties, including anti-inflammatory and anticancer activity. This gives doxycycline real therapeutic potential in treating a range of other diseases, including cancer (74).

Laboratory and animal studies have long shown that doxycycline can block breast cancer cell growth, division, and movement (75–77). More recent studies also show that doxycycline can stop cancer cells from repairing their DNA when it becomes damaged, for example, by chemotherapy (78). Indeed, laboratory studies show that doxycycline can help improve the effectiveness of chemotherapy activity against breast cancer cells (79,80).

Most recently, focus has fallen on understanding how doxycycline can block breast cancer stem cell growth (81). Doxycycline can block a process, called mitochondrial biogenesis, which is used by cancer cells to generate the huge amount of energy they need to survive (82). Scientists now think this means doxycycline could potentially target any type of breast cancer stem cell, regardless of the molecular subtype (83). In support of this, a very recent study showed that doxycycline can block growth of HER2 positive and triple-negative breast cancer stem cells and helped to improve resistance-related changes induced by the standard chemotherapy paclitaxel (84).

Doxycycline has just reached early clinical trials in breast cancer patients and a number of trials are now ongoing, including one Phase 2 trial investigating doxycycline and metformin together (NCT02874430). Results from these studies are expected soon, and initial findings are already looking promising. In one study, breast cancer patients who took doxycycline for just 14 days before surgery showed an average of 40% reduction in levels of cancer stem cell molecular markers; with beneficial effects noted for all but one of the patients treated (8 out of 9 patients) (85). Larger clinical trials are now underway.

Important Disclaimer

Purpose of this article

This article is an overview of some of the scientific and medical published literature concerning the medications which comprise the patented Care Oncology protocol. Care has been taken to select relevant articles supporting the off-label use of these medicines in a clinical setting for the adjunct treatment of cancer. This article does not purport to be a comprehensive review of all the evidence, nor does it capture all of the potential side-effects of such treatment.

This article is for information purposes only and it does NOT constitute medical advice. The medicines discussed herein are available on prescription-only and should not be taken without consultation with your doctor or other professional healthcare provider. Care Oncology doctors will discuss the suitability of these medicines with you and will liaise with your doctor or oncologist to discuss their suitability for you.

You must NOT rely on the information in this article as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter you should consult your doctor or other professional healthcare provider. If you think you may be suffering from any medical condition you should seek immediate medical attention. You should never delay seeking medical advice, disregard medical advice, or discontinue medical treatment because of information contained in this article.


The copyright in this article is owned by Health Clinics LLC and its licensors.


The Care Oncology (“COC”) Protocol is protected by United States patent US9622982B2 and by various additional international patents.

Reading List

1.            Chlebowski RT, McTiernan A, Wactawski-Wende J, Manson JE, Aragaki AK, Rohan T, et al. Diabetes, metformin, and breast cancer in postmenopausal women. J Clin Oncol. 2012 Aug 10;30(23):2844–52.

2.            Gandini S, Puntoni M, Heckman-Stoddard BM, Dunn BK, Ford L, DeCensi A, et al. Metformin and Cancer Risk and Mortality: A Systematic Review and Meta-Analysis taking into account Biases and Confounders. Cancer Prev Res (Phila) [Internet]. 2014 Sep [cited 2018 Apr 27];7(9):867–85. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154969/

3.            Aksoy S, Sendur MAN, Altundag K. Demographic and clinico-pathological characteristics in patients with invasive breast cancer receiving metformin. Med Oncol. 2013;30(2):590.

4.            El-Benhawy SA, El-Sheredy HG. Metformin and survival in diabetic patients with breast cancer. J Egypt Public Health Assoc. 2014 Dec;89(3):148–53.

5.            Sonnenblick A, Agbor-Tarh D, Bradbury I, Di Cosimo S, Azim HA, Fumagalli D, et al. Impact of Diabetes, Insulin, and Metformin Use on the Outcome of Patients With Human Epidermal Growth Factor Receptor 2–Positive Primary Breast Cancer: Analysis From the ALTTO Phase III Randomized Trial. J Clin Oncol [Internet]. 2017 May 1 [cited 2018 Oct 29];35(13):1421–9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455460/

6.            Kim HJ, Kwon H, Lee JW, Kim HJ, Lee SB, Park HS, et al. Metformin increases survival in hormone receptor-positive, HER2-positive breast cancer patients with diabetes. Breast Cancer Res. 2015 May 3;17:64.

7.            Xu H, Chen K, Jia X, Tian Y, Dai Y, Li D, et al. Metformin Use Is Associated With Better Survival of Breast Cancer Patients With Diabetes: A Meta-Analysis. Oncologist. 2015 Nov;20(11):1236–44.

8.            Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, et al. Metformin and Pathologic Complete Responses to Neoadjuvant Chemotherapy in Diabetic Patients With Breast Cancer. J Clin Oncol [Internet]. 2009 Jul 10 [cited 2018 Apr 27];27(20):3297–302. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2736070/

9.            Jacob L, Kostev K, Rathmann W, Kalder M. Impact of metformin on metastases in patients with breast cancer and type 2 diabetes. J Diabetes Complicat. 2016;30(6):1056–9.

10.          Chen L, Chubak J, Boudreau DM, Barlow WE, Weiss NS, Li CI. Diabetes Treatments and Risks of Adverse Breast Cancer Outcomes among Early-Stage Breast Cancer Patients: A SEER-Medicare Analysis. Cancer Res [Internet]. 2017 Nov 1 [cited 2018 Dec 18];77(21):6033–41. Available from: http://cancerres.aacrjournals.org/content/77/21/6033

11.          Hatoum D, McGowan EM. Recent advances in the use of metformin: can treating diabetes prevent breast cancer? Biomed Res Int. 2015;2015:548436.

12.          Alimova IN, Liu B, Fan Z, Edgerton SM, Dillon T, Lind SE, et al. Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle [Internet]. 2009 Mar 15 [cited 2018 Apr 27];8(6):909–15. Available from: http://www.tandfonline.com/doi/abs/10.4161/cc.8.6.7933

13.          Hadad SM, Hardie DG, Appleyard V, Thompson AM. Effects of metformin on breast cancer cell proliferation, the AMPK pathway and the cell cycle. Clin Transl Oncol. 2014 Aug;16(8):746–52.

14.          Orecchioni S, Reggiani F, Talarico G, Mancuso P, Calleri A, Gregato G, et al. The biguanides metformin and phenformin inhibit angiogenesis, local and metastatic growth of breast cancer by targeting both neoplastic and microenvironment cells. Int J Cancer. 2015 Mar 15;136(6):E534-544.

15.          Giles ED, Jindal S, Wellberg EA, Schedin T, Anderson SM, Thor AD, et al. Metformin inhibits stromal aromatase expression and tumor progression in a rodent model of postmenopausal breast cancer. Breast Cancer Res [Internet]. 2018 [cited 2018 Oct 29];20. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6000949/

16.          Chen T, Liang Y, Feng D, Tao L, Qi K, Zhang H, et al. Metformin inhibits proliferation and promotes apoptosis of HER2 positive breast cancer cells by downregulating HSP90. J BUON. 2013 Mar;18(1):51–6.

17.          Deng X-S, Wang S, Deng A, Liu B, Edgerton SM, Lind SE, et al. Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers. Cell Cycle. 2012 Jan 15;11(2):367–76.

18.          Vazquez-Martin A, Oliveras-Ferraros C, Cufí S, Del Barco S, Martin-Castillo B, Lopez-Bonet E, et al. The anti-diabetic drug metformin suppresses the metastasis-associated protein CD24 in MDA-MB-468 triple-negative breast cancer cells. Oncol Rep. 2011 Jan;25(1):135–40.

19.          Wahdan-Alaswad RS, Cochrane DR, Spoelstra NS, Howe EN, Edgerton SM, Anderson SM, et al. Metformin-induced killing of triple-negative breast cancer cells is mediated by reduction in fatty acid synthase via miRNA-193b. Horm Cancer. 2014 Dec;5(6):374–89.

20.          Bao B, Azmi AS, Ali S, Zaiem F, Sarkar FH. Metformin may function as anti-cancer agent via targeting cancer stem cells: the potential biological significance of tumor-associated miRNAs in breast and pancreatic cancers. Ann Transl Med [Internet]. 2014 Jun [cited 2018 Oct 29];2(6). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200664/

21.          Cufi S, Corominas-Faja B, Vazquez-Martin A, Oliveras-Ferraros C, Dorca J, Bosch-Barrera J, et al. Metformin-induced preferential killing of breast cancer initiating CD44+CD24-/low cells is sufficient to overcome primary resistance to trastuzumab in HER2+ human breast cancer xenografts. Oncotarget. 2012 Apr;3(4):395–8.

22.          Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin Selectively Targets Cancer Stem Cells, and Acts Together with Chemotherapy to Block Tumor Growth and Prolong Remission. Cancer Res [Internet]. 2009 Oct 1 [cited 2018 Oct 29];69(19):7507–11. Available from: http://cancerres.aacrjournals.org/content/69/19/7507

23.          Economopoulou P, Kaklamani VG, Siziopikou K. The Role of Cancer Stem Cells in Breast Cancer Initiation and Progression: Potential Cancer Stem Cell-Directed Therapies. Oncologist [Internet]. 2012 Nov [cited 2018 Oct 29];17(11):1394–401. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3500359/

24.          Ma J, Guo Y, Chen S, Zhong C, Xue Y, Zhang Y, et al. Metformin enhances tamoxifen-mediated tumor growth inhibition in ER-positive breast carcinoma. BMC Cancer. 2014 Mar 11;14:172.

25.          Iliopoulos D, Hirsch HA, Struhl K. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res. 2011 May 1;71(9):3196–201.

26.          Bradford SA, Khan A. Individualizing Chemotherapy using the Anti-Diabetic Drug, Metformin, as an “Adjuvant”: An Exploratory Study. Journal of Cancer Science & Therapy [Internet]. 2013 Mar 13 [cited 2018 Sep 5];5(3). Available from: https://www.omicsonline.org/individualizing-chemotherapy-using-the-antidiabetic-drug-metformin-as-an-adjuvant-1948-5956.1000197.php?aid=11581

27.          Liu H, Scholz C, Zang C, Schefe JH, Habbel P, Regierer A-C, et al. Metformin and the mTOR inhibitor everolimus (RAD001) sensitize breast cancer cells to the cytotoxic effect of chemotherapeutic drugs in vitro. Anticancer Res. 2012 May;32(5):1627–37.

28.          Zhang Y, Storr SJ, Johnson K, Green AR, Rakha EA, Ellis IO, et al. Involvement of metformin and AMPK in the radioresponse and prognosis of luminal versus basal-like breast cancer treated with radiotherapy. Oncotarget. 2014 Dec 30;5(24):12936–49.

29.          Davies G, Lobanova L, Dawicki W, Groot G, Gordon JR, Bowen M, et al. Metformin inhibits the development, and promotes the resensitization, of treatment-resistant breast cancer. PLoS One [Internet]. 2017 Dec 6 [cited 2018 Oct 29];12(12). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718420/

30.          Camacho L, Dasgupta A, Jiralerspong S. Metformin in breast cancer – an evolving mystery. Breast Cancer Res. 2015 Jun 26;17:88.

31.          Bonanni B, Puntoni M, Cazzaniga M, Pruneri G, Serrano D, Guerrieri-Gonzaga A, et al. Dual effect of metformin on breast cancer proliferation in a randomized presurgical trial. J Clin Oncol. 2012 Jul 20;30(21):2593–600.

32.          Cazzaniga M, DeCensi A, Pruneri G, Puntoni M, Bottiglieri L, Varricchio C, et al. The effect of metformin on apoptosis in a breast cancer presurgical trial. Br J Cancer [Internet]. 2013 Nov 26 [cited 2018 May 21];109(11):2792–7. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844911/

33.          Hadad S, Iwamoto T, Jordan L, Purdie C, Bray S, Baker L, et al. Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial. Breast Cancer Res Treat [Internet]. 2011 Aug 1 [cited 2018 Apr 27];128(3):783–94. Available from: https://link.springer.com/article/10.1007/s10549-011-1612-1

34.          Kalinsky K, Crew KD, Refice S, Xiao T, Wang A, Feldman SM, et al. Presurgical trial of metformin in overweight and obese patients with newly diagnosed breast cancer. Cancer Invest. 2014 May;32(4):150–7.

35.          Niraula S, Dowling RJO, Ennis M, Chang MC, Done SJ, Hood N, et al. Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study. Breast Cancer Res Treat [Internet]. 2012 Oct 1 [cited 2018 Apr 27];135(3):821–30. Available from: https://link.springer.com/article/10.1007/s10549-012-2223-1

36.          DeCensi A, Puntoni M, Gandini S, Guerrieri-Gonzaga A, Johansson HA, Cazzaniga M, et al. Differential effects of metformin on breast cancer proliferation according to markers of insulin resistance and tumor subtype in a randomized presurgical trial. Breast Cancer Res Treat [Internet]. 2014 [cited 2018 Oct 29];148(1):81–90. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196136/

37.          DeCensi A, Puntoni M, Guerrieri-Gonzaga A, Cazzaniga M, Serrano D, Lazzeroni M, et al. Effect of Metformin on Breast Ductal Carcinoma In Situ Proliferation in a Randomized Presurgical Trial. Cancer Prev Res (Phila). 2015 Oct;8(10):888–94.

38.          Kim J, Lim W, Kim E-K, Kim M-K, Paik N-S, Jeong S-S, et al. Phase II randomized trial of neoadjuvant metformin plus letrozole versus placebo plus letrozole for estrogen receptor positive postmenopausal breast cancer (METEOR). BMC Cancer. 2014 Mar 10;14:170.

39.          Martin-Castillo B, Pernas S, Dorca J, Álvarez I, Martínez S, Pérez-Garcia JM, et al. A phase 2 trial of neoadjuvant metformin in combination with trastuzumab and chemotherapy in women with early HER2-positive breast cancer: the METTEN study. Oncotarget [Internet]. 2018 Oct 26 [cited 2018 Dec 4];9(86):35687–704. Available from: http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=26286

40.          Dowling RJ, Parulekar WR, Gelmon KA, Shepherd LE, Virk S, Ennis M, et al. CA15-3/MUC1 in CCTG MA-32 (NCT01101438): A phase III RCT of the effect of metformin vs. placebo on invasive disease free and overall survival in early stage breast cancer (BC). Journal of Clinical Oncology [Internet]. 2018 Jun 1 [cited 2018 Dec 18]; Available from: http://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.557

41.          Goodwin PJ, Parulekar WR, Gelmon KA, Shepherd LE, Ligibel JA, Hershman DL, et al. Effect of metformin vs placebo on and metabolic factors in NCIC CTG MA.32. J Natl Cancer Inst. 2015 Mar;107(3).

42.          Ahern TP, Lash TL, Damkier P, Christiansen PM, Cronin-Fenton DP. Statins and breast cancer prognosis: evidence and opportunities. Lancet Oncol. 2014 Sep;15(10):e461-468.

43.          Manthravadi S, Shrestha A, Madhusudhana S. Impact of statin use on cancer recurrence and mortality in breast cancer: A systematic review and meta-analysis. Int J Cancer. 2016 Sep 15;139(6):1281–8.

44.          Kwan ML, Habel LA, Flick ED, Quesenberry CP, Caan B. Post-diagnosis statin use and breast cancer recurrence in a prospective cohort study of early stage breast cancer survivors. Breast Cancer Res Treat. 2008 Jun;109(3):573–9.

45.          Chae YK, Valsecchi ME, Kim J, Bianchi AL, Khemasuwan D, Desai A, et al. Reduced Risk of Breast Cancer Recurrence in Patients Using ACE Inhibitors, ARBs, and/or Statins. Cancer Investigation [Internet]. 2011 Oct 24 [cited 2018 Dec 5];29(9):585–93. Available from: http://www.tandfonline.com/doi/full/10.3109/07357907.2011.616252

46.          Liu B, Yi Z, Guan X, Zeng Y-X, Ma F. The relationship between statins and breast cancer prognosis varies by statin type and exposure time: a meta-analysis. Breast Cancer Res Treat. 2017 Jul;164(1):1–11.

47.          Murtola TJ, Visvanathan K, Artama M, Vainio H, Pukkala E. Statin use and breast cancer survival: a nationwide cohort study from Finland. PLoS ONE. 2014;9(10):e110231.

48.          Zhong S, Zhang X, Chen L, Ma T, Tang J, Zhao J. Statin use and mortality in cancer patients: Systematic review and meta-analysis of observational studies. Cancer Treatment Reviews [Internet]. 2015 Jun 1 [cited 2018 Apr 27];41(6):554–67. Available from: https://www.cancertreatmentreviews.com/article/S0305-7372(15)00074-2/fulltext

49.          Brewer TM, Masuda H, Liu DD, Shen Y, Liu P, Iwamoto T, et al. Statin use in primary inflammatory breast cancer: a cohort study. Br J Cancer. 2013 Jul 23;109(2):318–24.

50.          Alarcon Martinez T, Zeybek ND, Müftüoğlu S. Evaluation of the Cytotoxic and Autophagic Effects of Atorvastatin on MCF-7 Breast Cancer Cells. Balkan Med J. 2018 29;35(3):256–62.

51.          Mück AO, Seeger H, Wallwiener D. Inhibitory effect of statins on the proliferation of human breast cancer cells. Int J Clin Pharmacol Ther. 2004 Dec;42(12):695–700.

52.          Seeger H, Wallwiener D, Mueck AO. Statins can inhibit proliferation of human breast cancer cells in vitro. Exp Clin Endocrinol Diabetes. 2003 Feb;111(1):47–8.

53.          Kanugula AK, Gollavilli PN, Vasamsetti SB, Karnewar S, Gopoju R, Ummanni R, et al. Statin-induced inhibition of breast cancer proliferation and invasion involves attenuation of iron transport: intermediacy of nitric oxide and antioxidant defence mechanisms. FEBS J. 2014 Aug;281(16):3719–38.

54.          Wolfe AR, Debeb BG, Lacerda L, Larson R, Bambhroliya A, Huang X, et al. Simvastatin prevents triple-negative breast cancer metastasis in pre-clinical models through regulation of FOXO3a. Breast Cancer Res Treat. 2015 Dec;154(3):495–508.

55.          Vintonenko N, Jais J-P, Kassis N, Abdelkarim M, Perret G-Y, Lecouvey M, et al. Transcriptome analysis and in vivo activity of fluvastatin versus zoledronic acid in a murine breast cancer metastasis model. Mol Pharmacol. 2012 Sep;82(3):521–8.

56.          Kozar K, Kaminski R, Legat M, Kopec M, Nowis D, Skierski J, et al. Cerivastatin demonstrates enhanced antitumor activity against human breast cancer cell lines when used in combination with doxorubicin or cisplatin. International Journal of Oncology [Internet]. 2004 May 1 [cited 2018 Dec 11]; Available from: http://www.spandidos-publications.com/10.3892/ijo.24.5.1149

57.          Van Wyhe RD, Rahal OM, Woodward WA. Effect of statins on breast cancer recurrence and mortality: a review. Breast Cancer (Dove Med Press) [Internet]. 2017 Dec 1 [cited 2018 Apr 27];9:559–65. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716320/

58.          Lacerda L, Reddy JP, Liu D, Larson R, Li L, Masuda H, et al. Simvastatin radiosensitizes differentiated and stem-like breast cancer cell lines and is associated with improved local control in inflammatory breast cancer patients treated with postmastectomy radiation. Stem Cells Transl Med. 2014 Jul;3(7):849–56.

59.          Campbell MJ, Esserman LJ, Zhou Y, Shoemaker M, Lobo M, Borman E, et al. Breast cancer growth prevention by statins. Cancer Res. 2006 Sep 1;66(17):8707–14.

60.          Yao H, He G, Yan S, Chen C, Song L, Rosol TJ, et al. Triple-negative breast cancer: is there a treatment on the horizon? Oncotarget. 2017 Jan 3;8(1):1913–24.

61.          Bjarnadottir O, Romero Q, Bendahl P-O, Jirström K, Rydén L, Loman N, et al. Targeting HMG-CoA reductase with statins in a window-of-opportunity breast cancer trial. Breast Cancer Res Treat. 2013 Apr;138(2):499–508.

62.          Bjarnadottir O, Kimbung S, Johansson I, Veerla S, Jönsson M, Bendahl P-O, et al. Global Transcriptional Changes Following Statin Treatment in Breast Cancer. Clin Cancer Res. 2015 Aug 1;21(15):3402–11.

63.          Feldt M, Bjarnadottir O, Kimbung S, Jirström K, Bendahl P-O, Veerla S, et al. Statin-induced anti-proliferative effects via cyclin D1 and p27 in a window-of-opportunity breast cancer trial. J Transl Med. 2015 Apr 29;13:133.

64.          Garwood ER, Kumar AS, Baehner FL, Moore DH, Au A, Hylton N, et al. Fluvastatin reduces proliferation and increases apoptosis  in women with high grade breast cancer. Breast Cancer Res Treat. 2010 Jan;119(1):137–44.

65.          Nygren P, Larsson R. Drug repositioning from bench to bedside: Tumour remission by the antihelmintic drug mebendazole in refractory metastatic colon cancer. Acta Oncologica [Internet]. 2014 Mar

[cited 2018 Apr 27]

;53(3):427–8. Available from: http://www.tandfonline.com/doi/full/10.3109/0284186X.2013.844359

66.          Pantziarka P, Bouche G, Meheus L, Sukhatme V, Sukhatme VP. Repurposing Drugs in Oncology (ReDO)—mebendazole as an anti-cancer agent. Ecancermedicalscience [Internet]. 2014 Jul 10 [cited 2018 Apr 27];8. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096024/

67.          De Witt M, Gamble A, Hanson D, Markowitz D, Powell C, Al Dimassi S, et al. Repurposing Mebendazole as a Replacement for Vincristine for the Treatment of Brain Tumors. Mol Med [Internet]. 2017 Apr 5 [cited 2018 Apr 27];23:50–6. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403762/

68.          Coyne CP, Jones T, Bear R. Gemcitabine-(C4-amide)-[anti-HER2/neu] Anti-Neoplastic Cytotoxicity in Dual Combination with Mebendazole against Chemotherapeutic-Resistant Mammary Adenocarcinoma. J Clin Exp Oncol [Internet]. 2013 [cited 2018 Oct 29];2(2). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531380/

69.          Hou Z-J, Luo X, Zhang W, Peng F, Cui B, Wu S-J, et al. Flubendazole, FDA-approved anthelmintic, targets breast cancer stem-like cells. Oncotarget [Internet]. 2015 Jan 21 [cited 2018 Oct 29];6(8):6326–40. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467440/

70.          Mukhopadhyay T, Sasaki J, Ramesh R, Roth JA. Mebendazole Elicits a Potent Antitumor Effect on Human Cancer Cell Lines Both in Vitro and in Vivo. Clin Cancer Res [Internet]. 2002 Sep 1 [cited 2018 Dec 3];8(9):2963–9. Available from: http://clincancerres.aacrjournals.org/content/8/9/2963

71.          Zhang L, Guo M, Li J, Zheng Y, Zhang S, Xie T, et al. Systems biology-based discovery of a potential Atg4B agonist (Flubendazole) that induces autophagy in breast cancer. Mol Biosyst. 2015 Nov;11(11):2860–6.

72.          Coyne C, Jones T, Bear R. Anti-Neoplastic Cytotoxicity of Gemcitabine-(C4-amide)-[anti-EGFR] in Dual-combination with Epirubicin-(C3-amide)-[anti-HER2/neu] against Chemotherapeutic-Resistant Mammary Adenocarcinoma (SKBr-3) and the Complementary Effect of Mebendazole. J Cancer Res Ther Oncol [Internet]. 2014 Apr 9 [cited 2018 Apr 27];2(1). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381351/

73.          Coyne CP, Jones T, Bear R. Influence of Alternative Tubulin Inhibitors on the Potency of a Epirubicin-Immunochemotherapeutic Synthesized with an Ultra Violet Light-Activated Intermediate. Cancer Clin Oncol [Internet]. 2012 Nov [cited 2018 Oct 29];1(2):49–80. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516052/

74.          Bahrami F, Morris DL, Pourgholami MH. Tetracyclines: drugs with huge therapeutic potential. Mini Rev Med Chem. 2012 Jan;12(1):44–52.

75.          Duivenvoorden WCM, Popović SV, Lhoták S, Seidlitz E, Hirte HW, Tozer RG, et al. Doxycycline decreases tumor burden in a bone metastasis model of human breast cancer. Cancer Res. 2002 Mar 15;62(6):1588–91.

76.          Fife RS, Sledge GW. Effects of doxycycline on in vitro growth, migration, and gelatinase activity of breast carcinoma cells. J Lab Clin Med. 1995 Mar;125(3):407–11.

77.          Fife RS, Sledge GW. Effects of doxycycline on cancer cells in vitro and in vivo. Adv Dent Res. 1998 Nov;12(2):94–6.

78.          Peiris-Pagès M, Sotgia F, Lisanti MP. Doxycycline and therapeutic targeting of the DNA damage response in cancer cells: old drug, new purpose. Oncoscience [Internet]. 2015 Aug 24 [cited 2018 Apr 27];2(8):696–9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580062/

79.          Foroodi F, Duivenvoorden WC, Singh G. Interactions of doxycycline with chemotherapeutic agents in human breast adenocarcinoma MDA-MB-231 cells. Anticancer Drugs. 2009 Feb;20(2):115–22.

80.          Lamb R, Fiorillo M, Chadwick A, Ozsvari B, Reeves KJ, Smith DL, et al. Doxycycline down-regulates DNA-PK and radiosensitizes tumor initiating cells: Implications for more effective radiation therapy. Oncotarget [Internet]. 2015 Jun 13 [cited 2018 Oct 8];6(16):14005–25. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546447/

81.          Zhang L, Xu L, Zhang F, Vlashi E. Doxycycline inhibits the cancer stem cell phenotype and epithelial-to-mesenchymal transition in breast cancer. Cell Cycle. 2017 Apr 18;16(8):737–45.

82.          Lamb R, Ozsvari B, Lisanti CL, Tanowitz HB, Howell A, Martinez-Outschoorn UE, et al. Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease. Oncotarget [Internet]. 2015 Jan 22 [cited 2018 Apr 27];6(7):4569–84. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467100/

83.          Ozsvari B, Sotgia F, Lisanti MP. A new mutation-independent approach to cancer therapy: Inhibiting oncogenic RAS and MYC, by targeting mitochondrial biogenesis. Aging (Albany NY) [Internet]. 2017 Oct 27 [cited 2018 Apr 27];9(10):2098–116. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680558/

84.          Lin C, Lo M, Moody R, Stevers N, Tinsley S, Sun D. Doxycycline targets aldehyde dehydrogenase‑positive breast cancer stem cells. Oncology Reports [Internet]. 2018 Mar 27 [cited 2018 Dec 3]; Available from: http://www.spandidos-publications.com/10.3892/or.2018.6337

85.          Scatena C, Roncella M, Di Paolo A, Aretini P, Menicagli M, Fanelli G, et al. Doxycycline, an Inhibitor of Mitochondrial Biogenesis, Effectively Reduces Cancer Stem Cells (CSCs) in Early Breast Cancer Patients: A Clinical Pilot Study. Front Oncol [Internet]. 2018

[cited 2018 Oct 15]

;8. Available from: https://www.frontiersin.org/articles/10.3389/fonc.2018.00452/full