Dr. Weeks Comment: The cancer TUMOR is not a disease. It is the result of a diseased process which manifests as a tumor but the process is where we need to intervene and not solely at the final stage, i.e removing or killing the tumor. Remove the tumor while ignoring the cancer process and you will be just as frustrated as the diligent gardener, who, the day after weeding her garden, discovers even more weeds the next day. The terrain is more important than the pathogen. Even the discoverer of bacteria Louis Pasteur admitted his mistake on his deathbed by exclaiming: “Bacteria are nothing the terrain is everything”
No researcher is doing more important work in this area of cancerous process than my friend Thomas Seyfried, professor of biology at Boston College. When I visited him a couple months ago, I was thrilled to discover the wisdom he was teaching his students. I was sore tempted to go back to college after 40 years and study under him! But that was not necessary as he has generously shared his insights with me since then and today sent me this newly published revolutionary article.
Efficacy of Metabolically Supported Chemotherapy Combined with Ketogenic Diet, Hyperthermia, and Hyperbaric Oxygen Therapy for Stage IV Triple-Negative Breast Cancer
Abstract
Triple-negative breast cancer (TNBC) is more aggressive and metastatic than other breast cancer types. Cytotoxic chemotherapy is presently the predominant systemic therapy for TNBC patients. This case report highlights the influence of metabolically supported chemotherapy (MSCT), ketogenic diet (KD), hyperthermia (HT), and hyperbaric oxygen therapy (HBOT) in an overweight 29-year-old woman with stage IV (T4N3M1) triple-negative invasive ductal carcinoma of the breast. The patient presented with an observable mass in her left breast detected during a physical examination in December 2015. Magnetic resonance imaging revealed a Breast Imaging Reporting and Data System Category 5 tumor and multiple lymphadenomegaly in the left axilla. A Tru-Cut biopsy led to the diagnosis of a triple-negative nuclear grade 2 invasive ductal carcinoma. The patient was admitted to ChemoThermia Oncology Center, Istanbul, Turkey in October 2016, and a whole body (18F)-fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography (PET-CT) scan revealed a 77 mm x 55 mm primary tumor in her left breast, multiple left pectoral and axillary lymph nodes, multiple widespread liver masses, and an upper left nodular abdominal lesion. The patient received a treatment protocol consisting of MSCT, KD, HT, and HBOT. A follow-up whole body 18F-FDG PET-CT scan in February 2017 showed a complete therapeutic response with no evidence of abnormal FDG uptake. The patient continued to receive this treatment protocol and in April 2017 underwent a mastectomy, which revealed a complete pathological response consistent with the response indicated by her PET-CT imaging. This single case study presents evidence of a complete clinical, radiological, and pathological response following a six-month treatment period using a combination of MSCT and a novel metabolic therapy in a patient with stage IV TNBC.
Introduction
Breast cancer is the most frequently diagnosed cancer among women, with nearly 1.7 million new cases diagnosed worldwide in 2012. It ranks as the fifth cause of death from cancer overall (522,000 deaths) and is the leading cause of cancer death in women [1]. Breast cancer is a heterogeneous disease with several biologically distinct subtypes. Triple-negative breast cancer (TNBC) is defined by the absence of immunohistochemical expression of the estrogen (ER) and progesterone (PgR) receptors and a lack of amplification of the human epidermal growth factor receptor 2 (HER2)/Neu gene, accounting for approximately 20% of breast cancer cases. TNBC has a highly aggressive nature, develops among younger women, and has a higher risk of distant metastasis than other types of breast cancers. Its lack of molecular targets has contributed in part to the difficulty in managing TNBC. Cytotoxic chemotherapy is the only systemic therapy available for these patients. In the treatment of early-stage disease, chemotherapy is effective and pathologic complete response (pCR) rates exceed those of hormonal receptor-positive subtypes [2]. However, patients with metastatic disease experience rapid progression through several lines of chemotherapy. No prior studies have evaluated the influence of metabolically supported chemotherapy (MSCT), ketogenic diet (KD), hyperthermia (HT), and hyperbaric oxygen therapy (HBOT) as a therapeutic strategy for managing TNBC.
The rationale for MSCT is based on Warburg’s hypothesis that “cancer is a disease of metabolic dysregulation” where aerobic fermentation compensates for insufficient oxidative phosphorylation for energy generation [3]. In practice, MSCT initiates with a 12-hour fast, the application of pharmacological doses of regular insulin, and the development of mild hypoglycemia prior to the administration of chemotherapy. As was previously demonstrated in a case report of rectal cancer and a case series in pancreatic cancer, MSCT may enhance the cytotoxic effects of chemotherapy [4-5].
The reduction in circulating glucose can exploit the dependency of cancer cells reliant on glycolytic fermentation. The KD, a high-fat, carbohydrate-restricted diet, decreases blood glucose levels and elevates blood ketone levels, thus slowing the progression of cancer [6]. HT exposes body temperature to 42°C or higher and exploits the heat sensitivity of cancer cells [7]. Tumor hypoxia increases the glycolytic dependency of cancer cells, and hypoxic environments have cancer-promoting effects. HBOT increases oxidative stress specifically in tumor cells and reverses the cancer-promoting effects of hypoxia [8]. We report here a case of stage IV TNBC in a patient that achieved a complete clinical, radiological, and pathological response after receiving a combination of MSCT, KD, HT, and HBOT…..
…. Discussion
We have described a complete response to MSCT, KD, HT, and HBOT in a 29-year-old woman with stage IV (T4N3M1) TNBC that had metastasized to the lymph nodes, liver, and abdomen. There are, currently, no specific treatment guidelines for managing TNBC, and the lack of identifiable molecular targets makes management even more challenging. However, pCR is strongly correlated with a favorable long-term prognosis [10]. We proposed that the effect of standard chemotherapy drugs would be enhanced when combined with therapies that also target the metabolic weaknesses of cancer cells with the goal of achieving pCR. MSCT is a therapeutic strategy that builds on Warburg’s theory that tumor cells lack metabolic flexibility and become dependent on the aerobic fermentation of glucose due to impaired respiration [3-5, 9]. In the case presented here, this therapeutic strategy included the induction of mild hypoglycemia achieved through a 12-hour fast and pharmacological doses of insulin prior to each administration of chemotherapy.
The strong dependence of cancer cells on glucose makes them vulnerable to KDs that lower blood glucose levels while elevating levels of circulating ketone bodies. Ketone bodies are water-soluble energy substrates derived from fatty acid metabolism. They cannot be utilized for energy in cancer cell mitochondria due to respiratory defects [9]. Although the KD has been used for decades as a treatment for intractable pediatric epilepsy, its potential as a therapy for targeting energy metabolism in cancer cells has only recently been explored [6]. The reduced blood glucose levels with elevated urinary ketone levels observed in this patient are theorized to have contributed in part to the patient’s pCR.
In addition to the KD, HT and HBOT also targeted the defective energy metabolism of tumor cells. HT contributes to a therapeutic effect by aiding the uptake of drugs, increasing oxygen radical production, and inhibiting DNA repair in cancer cells, which leads to cancer cell death [7]. HBOT targets tumor hypoxia, which is associated with tumor aggressiveness and resistance to chemotherapy and radiotherapy [8]. Both HT and HBOT also exploit the reliance of tumor cells on glycolysis, a major contributor to the upregulation of antioxidant activity responsible for the tumor’s increased resistance to pro-oxidant chemotherapy and radiation therapies [9]. Consequently, HT and HBOT will selectively increase oxidative stress in the tumor cells. Ketone bodies protect normal cells from this stress while also providing a substrate for energy production. We suggest that the synergistic effect of targeting cancer cell metabolism concurrent with the standard chemotherapy drugs contributed to the patient’s pCR. Moreover, it is important to emphasize that the patient tolerated this treatment well and reported no discomfort or adverse event. This underscores the need to determine if our patient’s response to this treatment was an isolated occurrence or if this response might also be seen in a larger cohort of patients with TNBC.
Despite the advanced stage of this disease, the therapeutic strategy of combining MSCT, KD, HT, and HBOT achieved a clinical and radiological complete response in this patient within four months. The treatment regimen was continued for an additional two months when pCR was further documented in tissue following her mastectomy.
Conclusions
TNBC is more aggressive and metastatic than other types of breast cancer and has a lack of molecular targets making it more difficult to manage than other cancers. Given the poor prognosis and adverse effects, women with advanced TNBC may be counseled to forgo conventional chemotherapy. This single case study presents evidence of a complete clinical, radiological, and pathological response following a six-month treatment period using a combination of MSCT and a novel metabolic therapy in a patient with stage IV TNBC. Given this patient’s remarkable favorable outcomes, further research and randomized clinical trials exploring add-on therapies (such as KD, HT, and HBOT) that may enhance the efficacy of traditional cancer treatments by exploiting the metabolic weaknesses in cancer cells are warranted, especially for patients with poor prognosis of high grade and/or late-stage cancer that is not expected to respond to treatment. Furthermore, this patient did not experience the adverse effects that are commonly associated with the current standard of care and this improved quality of life should also be considered when designing research that compares outcomes of MSCT, KD, HT, and HBOT to traditional treatment. In conclusion, this combined metabolic approach appears effective in treating advanced TNBC, given this patient’s complete response with a good quality of life.
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