Enhancing Chemotherapy Response via Dietary Interventions in Breast Cancer

In a conversation with CancerNetwork®, Ifeoma Dikeocha, a PhD candidate from Adelaide University, explored the findings of a comprehensive review titled “Dietary interventions and tumor response to chemotherapy in breast cancer: a comprehensive review of preclinical and clinical data.” The discussion focused on how specific dietary strategies such as fasting-mimicking diets (FMD) and ketogenic protocols may sensitize tumors to cytotoxic therapy and improve treatment adherence by mitigating toxicity. Dikeocha emphasized the metabolic vulnerabilities of triple-negative breast cancer (TNBC) and the necessity for standardized dietary protocols within clinical oncology workflows to ensure measurable and reproducible patient outcomes.

CancerNetwork: Can you provide a brief background of your study?

Dikeocha: The study [evaluated] breast cancer and the [varying] responses to chemotherapy during treatment, specifically how nutrition and diet influence these responses. The review was designed to evaluate whether dietary interventions used alongside chemotherapy can directly sensitize tumors to cytotoxic therapy or improve treatment adherence by reducing toxicity, thereby improving tumor control.

The study highlighted that fasting-mimicking diets (FMD) may be particularly effective against TNBC. Why does this subtype appear more sensitive to metabolic restriction than other breast cancer subtypes?

In our synthesis, TNBC repeatedly showed strong sensitization signals under metabolic restriction, particularly when combined with chemotherapy. Preclinical studies showed that FMD, when combined with agents like doxorubicin and cyclophosphamide, reduces tumor growth and improves survival. TNBC models appeared more pronounced for cyclophosphamide compared with doxorubicin. Mechanistically, TNBC may be more responsive because it aligns with the vulnerabilities that FMD is designed to exploit, reducing circulating glucose, insulin, and insulin-like growth factor 1 (IGF-1), which reduces apoptosis and slows systemic inflammation. TNBC appears to be a metabolically vulnerable subtype, and dietary interventions like FMD or caloric restriction can exploit this vulnerability to enhance treatment responses.

Weight loss can be a cause of concern for oncologists, especially for patients who may be at risk of sarcopenia and cachexia. How does your research address the balance between therapeutic fasting restriction and maintaining the nutritional reserve needed for recovery?

Weight loss is a significant concern because chemotherapy itself often causes weight loss. We address this by distinguishing between caloric restriction and FMD. Caloric restriction is defined as reduced energy intake without malnutrition, whereas FMD is typically a short, cyclical, structured, low-calorie, and low-protein approach lasting 3 to 5 days. The intent is not chronic weight loss but a time-limited metabolic pause to modify insulin-glucose signaling, aligned with the pre-chemotherapy period or the waiting period between rounds. If the primary advantage is improved tolerance, we should prioritize diets that support body composition while achieving metabolic goals, such as a eucaloric ketogenic approach. The study wasn’t designed to restrict calories, but it just reduced the amount of glucose and carbohydrates, and this led to reduction in inflammatory markers and tumor size reduction during chemotherapy as well. We are not advocating for uncontrolled weight loss; the more clinical plausible approaches are structured. With the FMD, or the calorie restriction or eucaloric strategies like the ketogenic diet, they are time-limited cycles. This approach reduces inflammatory markers and tumor size without designed calorie restriction. These are structured, time-limited cycles requiring careful monitoring by a dietitian or oncologist to ensure metabolic reprogramming without depleting body reserves.

One finding in the review was that heterogeneity in approaches leads to a minimally impactful evidence base. From a clinical workflow perspective, how can oncology teams better standardize dietary protocols to ensure that data are measurable?

This is one of the most actionable points from the review. Comparability collapses when diets vary in duration, composition, timing, and adherence measurements. Oncology teams must first protocolize and standardize the diet “dose,” including the timing [by starting a specific number of days before and stopping hours after infusion], duration [by standardizing to a set 3-to-5-day window], and composition [via kilocalories and whether the diet is plant-based]. Second, clinicians should standardize what they measure, including adherence, to correlate it with pathological responses. We should also standardize the intended vs delivered chemotherapy dose, tumor response end points [whether they are radiologic or pathologic], and key metabolic markers like glucose and insulin levels. To make the evidence base clinically meaningful, dietary protocols need to look more like drug protocols.

How significant is the role of the gut microbiota in mediating the success where dietary interventions occur?

The microbiota emerged as a credible mechanistic mediator, although current evidence is primarily preclinical. Several studies showed that interventions like probiotics, whey protein, or milk diets improve chemotherapy response through immune and inflammatory modulation. We noted a particularly interesting signal regarding ginsenosides given during cyclophosphamide treatment, which restored gut microbial diversity and increased genera associated with anticancer immunity. However, these findings require stronger human validation. The microbiota is part of the story regarding immune tone and mucosal resilience, but we need standardized clinical studies to measure microbiome changes alongside metabolic and tumor end points.

What biomarkers should clinicians look for to determine which patient is a candidate for a ketogenic diet vs FMD?

There is currently no definitive, validated selection of biomarkers, but a pragmatic framework can be based on what these diets consistently modify. FMD works by reducing glucose, insulin, and IGF-1 markers. The ketogenic diet emphasizes lowering blood glucose and insulin while affecting signaling pathways like mTOR to reduce cancer cell proliferation. If the objective is a short metabolic reduction around chemotherapy, FMD may be beneficial. If a patient is at high risk of weight loss with limited reserve, a ketogenic diet might be better, as it maintains body reserve while reducing blood glucose. Inflammatory and immune biomarkers, such as TNF-alpha and interleukin-10, may also serve as useful pharmacodynamic readouts. Emerging tools include measuring the microbiota before chemotherapy to predict resilience. Ultimately, the strategy should pair metabolic markers with the cancer subtype and treatment setting.

What do you hope your colleagues take away from this conversation?

I hope researchers are motivated to design studies that explicitly measure how diet influences chemotherapy response in diverse cancer settings and groups. Standardizing diet content and outcomes in a large clinical trial would be ideal. Researchers should begin designing studies to measure these effects across different cancer types, not just breast cancer.

Is there anything else you would like to highlight?

I want to highlight the importance of dietary support from diagnosis until the end of treatment. Many patients with cancer do not receive support until they are already malnourished or underweight. We need tailored dietary support rather than a “one-size-fits-all” approach. This focused support is essential not only for better chemotherapy response but also for the patient's mental and physical well-being.

Reference

Dikeocha IJ, Wardill HR, Coller JK, Bowen JM. Dietary interventions and tumor response to chemotherapy in breast cancer: a comprehensive review of preclinical and clinical data. Clin Nutr ESPEN. 2024;63:462-475. doi:10.1016/j.clnesp.2024.06.048