Not just chemotherapy for breast cancer

Introduction

Breast cancer remains one of the most common malignancies and a leading cause of cancer death worldwide. The latest global cancer statistics show that breast cancer in females constituted about 2.3 million new cancer cases and 666,000 deaths in 2022 (1). Breast cancer consists of different subtypes depending on the expression of hormone receptors (estrogen and/or progesterone), human epidermal growth factor receptor 2 (HER2), and the lack of such antigens (triple-negative). Notably, most breast cancers are hormone receptor-positive (HR+). Although such neoplastic diseases are highly sensitive to hormonal therapy, patients with advanced and/or metastatic HR+/luminal breast cancers inevitably become refractory. Despite recent therapeutic advances (e.g. CDK4/6 inhibitors) that have extended survival (2), HR+ breast cancer with extensive metastasis remains essentially incurable, with a median overall survival of only a few years (3). Thus, there is an urgent demand for new novel therapeutic approaches, especially when conventional treatment options have been exhausted.

The conventional management of malignant breast cancer is driven by cancer subtype and stage, with a combination of surgery, radiotherapy, systemic endocrine therapy for HR+ disease, HER2-directed therapies for HER2+ cancers, and chemotherapy. Endocrine therapy, such as aromatase inhibitors or selective estrogen receptor modulators, forms the foundation for HR+ breast cancer, frequently combined with targeted therapies like CDK4/6 inhibitors in metastatic disease. These interventions can prolong disease control, but resistance invariably emerges (4). Once tumors become refractory to hormonal therapy, treatment options are limited to sequential chemotherapies which confer diminishing benefits and cumulative toxicities. As a result, there is growing interest in metabolism-based therapies and repurposed drug approaches that target cancer cell vulnerabilities beyond those addressed by standard cytotoxic or hormonal agents.

An emerging therapeutic strategy is to target the distinct metabolic phenotype of cancer cells. All major cancers, including breast cancer, exhibit a dependency on elevated cytosolic substrate-level phosphorylation (glycolysis) to drive both biomass synthesis and oxygen-independent ATP production (5–7). This metabolic reprogramming is associated with mitochondrial dysfunction (8). Consequently, strategies that restrict glucose availability or force a reliance on oxidative metabolism can selectively pressure cancer cells while sparing normal cells. Calorie restriction and ketogenic diets (KD) are being explored in this context (9). Nutritionally balanced diets that are high in fats and very low in carbohydrates will lower circulating glucose and insulin levels while elevating circulating ketone bodies (β-hydroxybutyrate and acetoacetate) thus inducing a state of nutritional ketosis. The glucose ketone index (GKI) was developed as a quantitative blood biomarker for assessing the state of therapeutic ketosis where values of 2.0 or below induce metabolic stress on tumor cells (10, 11). Normal cells can adapt by utilizing ketone bodies and fatty acids as alternative fuels to glucose, but cancers exhibit reduced ketolytic capacity due to insufficiency of OxPhos linked to mitochondrial dysfunction (11–13). Preclinical studies and early clinical trials indicate that ketogenic metabolic therapy may slow tumor growth and enhance the effects of other cytotoxic treatments (14, 15). Fasting or fasting-mimicking diets can have similar effects; even short-term fasting has been shown to reduce blood glucose and insulin-like growth factor-1 (IGF-1) levels, which are critical growth factors for cancer cells (16). Such metabolic interventions create an unfavorable environment for cancer cells that induce cellular stress responses like autophagy, making tumor cells more susceptible to cytotoxic therapy. However, while early data is promising, the broader clinical evidence surrounding standalone ketogenic diets in cancer remains mixed; such inconsistencies may stem from dietary formulations that fail to adequately and consistently lower GKI values into a therapeutic range, or from the concurrent use of treatments that have not been temporally or mechanistically adjusted to synergize with metabolic interventions (e.g., corticosteroids) (17, 18).

Building on these insights, we developed metabolically-supported chemotherapy (MSCT) protocols to enhance treatment efficacy. MSCT refers to the use of the patient’s metabolic condition to exploit cancer cell vulnerability. In our case, MSCT specifically involves fasting for 14 hours and low-dose insulin potentiation therapy (19, 20), which are performed prior to chemotherapy. Cancer cells, which are highly dependent on glucose, experience acute metabolic stress under these conditions, potentially increasing their uptake of chemotherapeutic agents and amplifying drug-induced cytotoxicity. This concept—described as a “press-pulse” therapeutic strategy—has shown encouraging results in several cancers (11). For example, a recent publication in patients with metastatic lung cancer found that combining a ketogenic diet with MSCT significantly improved response rates and survival compared to standard of care outcomes (21). Similarly, other case reports and case series in advanced cancers have documented significantly improved responses using protocols that integrate fasting, low dose insulin-induced mild hypoglycemia, chemotherapy, ketogenic diet, hyperthermia and hyperbaric oxygen therapy (21–28). A ketogenic diet is often maintained during therapy to induce a relative reduction in glycolytic fuel supply and insulin signaling to the tumor. Collectively, these interventions aim to exploit the metabolic flexibility of normal cells vs. the metabolic inflexibility of cancer cells, thereby sensitizing the tumor to treatment while protecting healthy tissues (11).

Other metabolic therapies may be integrated into the MSCT and KD combination to increase stress to cancer cells. Hyperthermia (HT), the therapeutic application of heat, exploits the fact that cancer cells are more sensitive to high temperatures than normal cells. Local or regional HT (raising tumor temperature to ~42 °C) can damage cancer cell proteins and membranes, induce direct cell death, and improve perfusion, thereby enhancing delivery of oxygen and drugs to the tumor. Clinically, HT can synergize with chemotherapy and radiotherapy, increasing tumor response rates in several trials (29). Hyperbaric oxygen therapy (HBOT) is another modality used to counteract tumor hypoxia, a common feature of aggressive cancers that contributes to treatment resistance. By having patients breathe high concentration oxygen under elevated atmospheric pressure, HBOT significantly increases the amount of dissolved oxygen in the blood and tissues (15, 30). Elevated oxygen tension in the tumor microenvironment can generate reactive oxygen species (ROS) in hypoxic cancer cells and re-sensitize tumors to therapies like radiation or chemotherapy. Indeed, HBOT is an effective method for overcoming tumor hypoxia and has been shown to improve drug penetration and radiation response in preclinical models (31, 32). Neither hyperthermia nor HBOT used alone are curative, but as adjuncts they target the vulnerabilities of cancer cells (heat sensitivity and tumor hypoxia, respectively) and have demonstrated safety and feasibility in integrative treatment protocols.

In addition to dietary and physical therapies, there is growing interest in repurposing well-known non-oncology drugs as anticancer adjuvants. Metformin, one of the first-line oral therapies for type 2 diabetes treatment, has been related to improved cancer outcomes in observational studies. In preclinical models and clinical data, metformin acts as an activator of AMP-activated protein kinase (AMPK) and a mitochondrial complex I inhibitor in the liver, which can suppress the PI3K/Akt/mTOR signaling pathway and lower blood insulin and glucose concentrations, creating unfavorable conditions for tumor growth (33). Aspirin is a widely used nonsteroidal anti-inflammatory medication (NSAID) that has been recognized to exhibit good anticancer properties in preclinical in vitro and in vivo studies (34). At low doses, aspirin’s antiplatelet activity may prevent circulating tumor cells from evading immune surveillance and forming metastases while high-dose aspirin exerts inhibitory effects on cyclooxygenase-2 (COX-2) and the PI3K/Akt oncogenic pathway. A comprehensive 2025 meta-analysis confirmed that regular post-diagnostic aspirin use is associated with a significant reduction in breast cancer-specific mortality rate by 23% compared with controls (34). Another repurposed drug, doxycycline, is a tetracycline antibiotic that reaches high intratumoral concentrations and inhibits mitochondrial protein synthesis. In cell culture studies, doxycycline has been shown to decrease cancer cell invasive potential by downregulating matrix metalloproteinases (MMP-2/9) and reverse epithelial-to-mesenchymal transition (EMT) markers in various cancers (35). In preclinical in vivo murine breast cancer models, doxycycline decreased the tumor burden in bone metastases with reduced proliferation indices, especially in combination with bone-targeted therapies (36). Recent studies show that the antiparasitic drug, mebendazole, has inhibitory effects on both glucose-driven glycolysis and glutamine-driven glutaminolysis, the two metabolic pathways necessary and sufficient for tumor cell proliferation (37, 38). Mebendazole has broad anti-tumor activity across cancer types; notably, it inhibited metastatic spread in preclinical thyroid and colon cancer models and produced regression of lung and lymph node metastases in refractory colorectal cancer in case studies (39). Another antiparasitic, ivermectin, has shown multiple mechanism-oriented activities in cancer treatment. In vitro, ivermectin inhibits the Wnt/β-catenin pathways with downregulation in oncogenic cyclin D1 in cancerous cells (40). It also inhibits the PAK1 kinase and AKT/mTOR signaling, which are involved in cancer cell proliferation and drug resistance, including in breast cancer (40). Recent research in endocrine-resistant breast cancer cell lines showed that ivermectin can suppress invasiveness by inhibiting Wnt pathway components, effectively slowing the progression of hormonally resistant tumor cells (40). Finally, H2 histamine receptor antagonists, such as famotidine, show potential in modulating immune response in cancer treatment. Tumor-derived histamine acting on H2 receptors can dampen T-cell and natural killer (NK) cell activity, so blocking these receptors may enhance anti-tumor immunity. In fact, early clinical studies found that short-term famotidine treatment before surgery increased tumor-infiltrating lymphocytes in breast tumors, and patients who developed robust lymphocytic infiltration showed improved disease-free survival (41). This suggests H2 blockers might improve immune responses against cancer when used as adjuncts.

Individually and in combination, these metabolic therapies and repurposed drug strategies aim to target multiple hallmarks of cancer (metabolic dysregulation, evasion of cell death, invasiveness, and immune suppression) in a comprehensive manner. There is emerging clinical evidence that suggests that a combination of nutritional ketosis, fasting/insulin-induced mild hypoglycemia before chemotherapy, hyperthermia, HBOT, and repurposed drugs are clinically feasible and may have efficacy when combined with standard of care (21). Based on this rationale, we implemented an integrative protocol for a patient with advanced HR+ breast cancer. This is a report of a single patient that underwent metabolically supported chemotherapy, in combination with a ketogenic diet, hyperthermia, HBOT, and a regimen of repurposed drugs (metformin, aspirin, doxycycline, mebendazole, ivermectin, and famotidine). This multimodal approach was associated with a complete response with three years of disease management in this patient with end-stage breast cancer. The results from this case report may inform further research into metabolic therapies as a complementary strategy for managing advanced breast cancers.