Background
Breast cancer is the most frequent cancer in women and in 2018 was the leading cause of cancer-related death in women worldwide [
1]. In Germany, breast cancer is the third leading cause of cancer-related deaths and poses a relevant economic burden on the healthcare system [
2]. As a result, there is burgeoning interest in researching modifiable factors that causally impact the treatment outcome and prognosis of breast cancer patients. Besides well-known prognostic factors such as age, stage of disease, HER2-Neu expression, and estrogen and progesterone receptor status, factors relating to the cancer patient’s metabolism such as obesity [
3,
4], sarcopenia [
5,
6], insulin levels [
7,
8], and chronic hyperglycemia [
9‐
11] have been shown to possess a prognostic role. Evidence for a causal influence of these metabolic factors comes from preclinical data showing that breast cancer cells are stimulated by insulin [
12] and certain adipokines [
13] and are vulnerable to glucose restriction [
14,
15]. Unfortunately, a large proportion of newly diagnosed breast cancer patients exhibit high fasting blood glucose levels [
16], obesity, and low muscle mass [
5,
6]. These phenomena may be exacerbated during radio- and chemotherapy, worsening the health and fitness of patients. In fact, many women tend to gain weight during therapy, which by itself has been associated with negative treatment outcomes [
17]. Thus, research into interventions that improve the body composition and metabolic health of women is necessary as it could potentially improve the prognosis of these patients. Lifestyle modifications are of particular interest since they allow patients to take self-responsibility during their treatment.
Along these lines, a large percentage of women are interested in receiving recommendations for a “healthy diet” during treatment. For example, out of 37 breast cancer patients undergoing curative radiotherapy in a Swiss study, 70% were extremely interested in receiving dietary advice [
18]. However, current dietary guidelines may be suboptimal for halting weight gain and improving body composition and metabolic health of breast cancer patients during and after their therapy [
17]. Furthermore, current recommendations vary widely [
19], further illustrating the need for evidence-based guidelines supported by dietary research. A high-fat ketogenic diet (KD) has been proposed by some authors, as it appears to not only promote weight loss comparable to a low-fat diet, but also favorably impact metabolic parameters associated with cancer treatment outcomes [
17,
20,
21]. A KD induces a state of physiological ketosis, which is defined as β-hydroxybutyrate (β-OHB) levels ≥ 0.5 mmol/l [
22].
To test the hypothesis that a KD during radiotherapy can positively influence body composition and metabolic parameters, we have launched a prospective, non-randomized, controlled phase I clinical trial, the KETOCOMP study [
23]. This study has been approved by the ethics committee of the Bavarian Medical Association (Landesaerztekammer Bayern) and registered under ClinicalTrials.gov identifier NCT02516501. In a first interim analysis, we have reported favorable effects on body composition of seven breast cancer, eight rectal cancer, and five head and neck cancer patients following a KD during radiotherapy compared to control patients on a standard diet (SD) [
24]. Here, we report the final results of the KETOCOMP study for the subgroup of breast cancer patients.
Discussion
In this work, we illustrate that an individualized KD for breast cancer patients undergoing curative radiotherapy was safe and led to significant changes in body composition compared to an unspecified SD. The KD induced weight loss, primarily by reducing ICW and FM. These results are in line with, and thus confirm, our interim analysis that already revealed these effects [
24].
Obesity is known to correlate with the risk of breast cancer development and recurrence, and several adipose tissue-mediated mechanisms including immune dysregulation, chronic systemic inflammation, and elevated growth factors may account for a causal correlation [
38,
39]. While undesired weight loss is common in a broad variety of cancer entities, the opposite is generally true for breast cancer patients who tend to gain more weight during and after treatment [
17]. Some data suggest that being overweight (BMI > 25 kg/m
2) and having excess adipose tissue mass and low muscle mass at breast cancer diagnosis are associated with lower disease-free and overall survival [
40]. Furthermore, there is evidence suggesting that post-diagnosis weight gain adversely affects disease-free survival [
41]. For this reason, we focused on body composition outcomes in addition to BMI and BW, hoping to identify a practical diet regimen that would prevent both weight gain and muscle loss.
Comparing the body composition changes of patients on a KD and unspecified SD during radiotherapy (over a median of 35 days for both groups), we found that the KD intervention was associated with an average reduction of both BW and FM by 0.4 kg/week (Table
2). Additionally, body composition measurements revealed that FFM and SMM generally dropped in the KD group (Fig.
3 and Table
4), in parallel with decreases of TBW and ICW. Most of these changes had occurred already at the second measurement, soon after initiation of the KD, and in contrast to BW and FM, there was no indication for any further gradual decrease of FFM, SMM, TBW, or ICW. We believe that this general and rapid effect of the KD on FFM and SMM could be accounted for by a rapid loss of TBW and ICW occurring within the first days after diet onset. Accordingly, the decline of FFM and SMM was tightly correlated with that of TBW and ICW. Such water loss is a natural and expected consequence of the KD-induced depletion of glycogen stores, since each gram of muscle or liver glycogen is stored with at least 3 g of water [
42‐
44]. In addition, because insulin increases the reabsorption of sodium in the kidneys [
45], KDs typically exert a rapid diuretic effect by lowering average insulin levels which could have contributed to water loss in the KD group.
We therefore conclude that the KD initially induced a rapid reduction of BW through water loss, followed by a further gradual decrease consisting almost entirely of FM reduction, while FFM was preserved. In contrast, the average time trend for the SD group only indicated very small gains in BW and FM (0.04 and 0.08 kg/week, respectively) and very small decreases in FFM (− 0.05 kg/week). Given the large standard errors of these estimates (Table
2), we conclude that the SD did not change body composition substantially during radiotherapy. These results are consistent with the few studies that have investigated longitudinal body composition changes in early stage breast cancer patients undergoing radiotherapy. In a prospective Brazilian study including 23 breast cancer patients, there was a small, but insignificant increase of BW of 0.4 kg during radiotherapy, and no significant change in phase angle. In a Swiss study of 37 breast cancer patients, BW and FM increased from 64.4 ± 8.5 kg and 23.3 ± 5.8 kg, respectively, at radiotherapy start to 64.9 ± 8.6 kg and 23.7 ± 5.8 kg at radiotherapy end, while FFM remained stable [
18]. This average weight gain of 0.5 kg is similar to our data, in which patients on a SD gained 0.7 ± 1.2 and 0.4 ± 1.3 kg, respectively, after hypo- and normofractionated radiotherapy (Table
4). In the cited study by Genton et al. [
18], patients also reported increased fatigue levels associated with less appetite and less physical activity, and other data confirm a small, but significant decrease in activity levels during radiotherapy [
46]. Thus, decreased physical activity during radiotherapy could be one explanation for the small gradual weight gain generally observed in patients who do not receive a dietary intervention, although we did not track changes in physical activity of our patients to further confirm this hypothesis. However, we asked each patient about the amount and type of physical activity they engaged in during radiotherapy. With a total of seven patients in each group who did exercise for at least 3 h per week, there was no apparent difference in physical activity between both groups that would confound the effects on body composition associated with the KD.
Our results are in line with a study in women with endometrial or ovarian cancer in which a KD based on whole foods resulted in significantly greater reductions of total, android, and visceral fat mass over 12 weeks than a diet recommended by the American Cancer Society, whereas total lean mass remained constant on both diets [
36].
Of interest is the finding that intake of 10 g MAP to each radiotherapy fraction was not associated with any increase in FFM or SMM. An explanation for the general lack of beneficial effects of the MAP supplement on body composition might be that patients consumed sufficient amounts of high-quality protein as emphasized by our dietary guidelines, so that the additional amino acids were not utilized for further muscle anabolism.
In addition to body composition, we looked at breast cancer patients’ hormone profiles before, during, and at the end of the study to identify any significant or desired changes from adhering to a KD. Insulin and IGF-1 are of particular oncological interest, since both are known as growth factors for tumor cells [
39] and might provide a mechanistic link between the increased risk of obesity and breast cancer incidence and recurrence. Overall, the KD had no significant effects on insulin and IGF-1 levels compared to the SD, although both hormones gradually decreased to a slightly greater extent in the KD group (Supplementary Table
3). This decrease may have been more pronounced with longer diet duration as is indicated by the greater absolute change in insulin and IGF-1 in patients who received 26–31 fractions compared to only 16 or 19 fractions (Table
4). The relatively short diet duration is a limitation of this study, but was determined by the duration of radiotherapy.
There was also a significant drop in T3 hormone by 0.06 ± 0.01 pg/ml/week (
p = 6.3 × 10
−5) associated with the KD. This association remained stable when restricting the analysis to 22 KD and 21 SD patients who did not take thyroxin medication (coefficient − 0.06 ± 0.02 pg/ml/week,
p = 5.0 × 10
−4). This is an interesting, yet not unexpected, finding for weight loss and KDs [
37].
This analysis focused on the primary study outcome of body composition changes. Another potential benefit of a KD during radiotherapy that is mainly supported by preclinical data could be a synergistic anti-tumor effect mediated through the ketogenic state and its effect on a variety of molecular signaling pathways [
47‐
51]. A randomized controlled trial conducted by Khodabakhshi and colleagues found an overall survival benefit (
p = 0.046) for 25 locally advanced or metastatic breast cancer patients eating a KD during neoadjuvant chemotherapy compared to 18 control patients who received chemotherapy without dietary intervention [
52]. With a median follow-up of 4.4 months (range, 0.7–65.1), our data are currently not adequate to address the question about the efficacy of the KD as a complementary, synergistic adjunct to radiotherapy. With longer follow-up data that we will collect, we may be able to address this question in the future.
The major limitation of this study is that patients self-selected to enter the KD group and that the KD food composition was not standardized, but highly individual. Although we tried to account for self-selection bias to some extent by our consecutive recruitment scheme and by adjusting for several putative confounders in the linear regression model analysis, there might have been some residual confounders that remained unaccounted for. Apart from macronutrient prescriptions, our KD protocol was not standardized, but rather provided a framework for designing personalized diets that would allow each individual to achieve and remain in nutritional ketosis. This lowers the degree to which the study outcome truly measures the effect of the intervention on the outcome in the study population (internal validity) [
53]. It could be argued, however, that such an “ad lib” prescription better reflects the real world clinical situation and therefore increases the degree to which our results apply to any “real world” breast cancer population (external validity). Finally, we mention the limitation that the original patient number estimation for the KETOCOMP study was based on measuring the absolute change in PA between intervention group 1 and the control group across all three tumor entity cohorts [
23]. This resulted in a minimum number of 35 patients needed in each group to detect a 0.3° increase in PA, which might imply that this breast cancer study has been underpowered. However, with the closure of intervention group 1 and focusing on longitudinal body composition changes instead of PA, our analysis was able to detect highly significant effects of a KD consumed during radiotherapy.
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