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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

Metformin

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).

Statins

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.

Mebendazole

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).

Doxycycline

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.

Copyright

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

Patent

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

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