Intermittent Fasting in Breast Cancer: A Systematic Review And Critical Update Of Available Studies Part 1

Abstract: Breast cancer (BC) is the most frequent malignancy among women, whereas obesity and excess caloric consumption increase the risk of developing the disease. The objective of this systematic review was to examine the impact of intermittent fasting (IF) on previously diagnosed BC patients, regarding quality of life (QoL) scores during chemotherapy, chemotherapy-induced toxicity, radiological response and BC recurrence, endocrine-related outcomes, as well as IF-induced adverse effects in these populations. A comprehensive search was conducted between 31 December 2010 and 31 October 2022, using PubMed, CINAHL, Cochrane, Web of Science, and Scopus databases. Two investigators independently performed abstract screenings, full-text screenings, and data extraction, and the Mixed Method Appraisal Tool (MMAT) was used to evaluate the quality of the selected studies. We screened 468 papers, 10 of which were selected for data synthesis. All patients were female adults whose ages ranged between 27 and 78 years. Participants in all studies were women diagnosed with BC of one of the following stages: I, II (HER2−/+), III (HER2−/+), IV, LUMINAL-A, and LUMINAL-B (HER2−/+). Notably, IF during chemotherapy was found to be feasible, safe, and able to relieve chemotherapy-induced adverse effects and cytotoxicity. I seemed to improve QoL during chemotherapy, through the reduction of fatigue, nausea, and headaches,  however, data were characterized as low quality. I was found to reduce chemotherapy-induced DNA  damage and augmented optimal glycemic regulation, improving serum glucose, insulin, and IGF-1 concentrations. A remarkable heterogeneity in the duration of dietary patterns was observed among available studies. In conclusion, we failed to identify any IF-related beneficial effects on the QoL, response after chemotherapy, or related symptoms, as well as measures of tumor recurrence in BC  patients. We identified a potential beneficial effect of IF on chemotherapy-induced toxicity, based on markers of DNA and leukocyte damage; however, these results were derived from three studies and require further validation. Further studies with appropriate designs and larger sample sizes are warranted to elucidate its potential standard incorporation in daily clinical practice.

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Keywords: intermittent fasting; breast cancer; quality of life; recurrence; chemotherapy; toxicity

1. Introduction

Breast cancer (BC) is the most-frequent malignancy amongst women, after nonmelanoma skin neoplasms [1]. Approximately 25% of estimated new malignancy cases and 14% of estimated neoplasm-induced deaths in women are attributed to BC [1,2]. Previous epidemiological studies identified obesity as a risk factor for BC development and recurrence in BC patients, and strategies for optimal body weight are considered essential in the primary and secondary prevention of this clinical entity [2]. Caloric restriction (CR),  without malnutrition, has been considered one of the most-effective interventions for cancer prevention in mammals [3].

Continuous energy restriction (CER), in the form of a daily 30% reduction of the basic metabolic rate, while maintaining the required amounts of vitamins, minerals, and other necessary nutrients, combined with a less sedentary lifestyle, is a common strategy for weight loss [4,5]. Nevertheless, available studies indicate a moderate degree of adherence within 1–4 months after dietary intervention [4].

In this regard, alternative methods have been suggested as appropriate dietary regimens, including intermittent energy restriction (IER) as an umbrella term that includes two different subtypes of fasting: intermittent fasting (IF) and time-restricted feeding (TRF) [4]. Intermittent fasting (IF) involves short periods of marked energy restriction followed by periods of usual caloric intake [6].

IF dietary patterns consist of long periods (e.g., 16–48 h) of little to no caloric consumption, repeatedly alternating with periods of ad libitum intake (at one’s pleasure,  abbreviated to “ad lib”). IF variations include: (i) alternate day fasting (ADF), (ii) alternate day modified fasting (ADF), (iii) fasting 2 days per week (2DW), and (iv) periodic fasting (PF) lasting 2–21 days [4]. The ADF IF subtype consists of alternating the day when the energy limit is 75%, known as the “fast day”, and the day when food is eaten ad libitum [7]. Time-restricted feeding (TRF) is an IF diet that focuses on eating within a specific time frame, within a day (usually from 6–12 h) [7].

Whilst chronic caloric deficit cannot be practically implemented for cancer patients,  short fasting periods could comprise an alternative approach as a candidate adjunctive tool for cancer prevention and treatment. Results from available studies, however, are conflicting, particularly on certain types of malignancy, including BC. This is mainly due to a scarcity of high-quality evidence, despite available preclinical data suggesting the beneficial effects of IF in chemotherapy-related toxicity and tumor growth [8]. We aimed to systematically review available evidence regarding the implementation of IF in BC  patients, in a secondary prevention setting, with a discourse on current knowledge gaps and the future research agenda. This systematic review aimed to explore the effect of intermittent fasting (IF) on already diagnosed BC patients, regarding the QoL during chemotherapy, chemotherapy-induced toxicity, radiological response and BC recurrence,  endocrine-related outcomes, and IF-induced adverse effects. This analysis addressed the potential effects of IF implementation on the secondary prevention of BC. The rationale behind this analysis is based on a plethora of earlier studies [9–14] that demonstrated that short periods of very low caloric intake, including either period of short-term fasting (2–4 days)  or dietary manipulation of specific macronutrients, can be effective at delaying primary tumor growth. Conversely, excess consumption of animal-derived protein is linked with increased cancer risk and all-cause mortality. Different forms of intermittent fasting (IF)  and time-restricted feeding (TRF) are broadly characterized by cyclical periods of low caloric intake or complete fasting interspersed between periods of ad libitum (AL) feeding. IF and TRF results in a dramatic reduction in tumor growth and have garnered traction both as an adjuvant to chemotherapy and as a tool for cancer prevention with promising translational applications.

2. Methods 

2.1. Data Sources and Search Strategy 

We conducted a systematic review regarding the safety and efficacy of IF among BC  patients in the reduction of chemotherapy-related side effects and the prevention of disease recurrence. A comprehensive literature search was carried out, using the following search strategy. We combined the terms ‘’intermittent fasting”, OR ‘’alternate day fasting”, OR ‘’time-restricted fasting”, OR ‘’fasting” to identify the fasting component and ‘’breast cancer”, OR ‘’breast malignancy” to identify the BC component. PubMed, CINAHL, Cochrane, Web of Science, and Scopus databases were used as the search platforms. The search was performed in the fields of the article title, abstract, and Medical Sub-Heading (MeSH)  terms in PubMed and the fields of the article title, abstract, and keywords in CINAHL and Scopus. Reference lists of the selected articles were searched to identify additional articles. This review protocol was developed, but not registered; therefore, a complete copy of the Systematic Reviews and Meta-Analyses checklist (PRISMA Checklist 2020) is given in the Supporting Information (Table S2).

2.2. Eligibility Criteria

Original studies that were published between 31 December 2010 and 31 October 2022  and investigated IF in BC patients were included. The selected studies either reported the association between IF and BC-related outcomes or provided sufficient data to calculate relevant measures of association. We included cross-sectional, longitudinal, case–control,  and cohort studies.

We included outcomes related to quality of life (QoL), chemotherapy-induced toxicity, response after chemotherapy, radiological disease recurrence, adverse effects, and endocrine-related outcomes of IF, in previously diagnosed BC patients. The literature search was limited to articles published in English and solely included BC survivors over the age of 18. Duplicate articles were removed.

We excluded studies not published in English, not performed in humans, as well as those performed on a healthy population and that included humans younger than the age of 18. The titles and abstracts of the remaining articles were screened to select publications for the full-paper review. The full papers were then assessed to determine their eligibility using predetermined inclusion and exclusion criteria.

2.3. Quality Assessment 

We used the Mixed Method Appraisal Tool (MMAT) [15] to evaluate the quality of the selected studies. The MMAT is a critical appraisal tool, designed for the appraisal stage of systematic mixed studies (Table S1). It allows the appraising of the methodological quality of qualitative research, randomized controlled trials, non-randomized studies, quantitative descriptive studies, and mixed methods studies. The MMAT checks for selection bias, the appropriateness of the measurement for expected exposure, the completeness of outcome data, and the intended exposure. Five core criteria are the most relevant to appraise the methodological quality of studies. Each item was rated on a categorical scale (yes, no, and cannot tell); if the details of any quality assessment criteria were not reported in the reviewed papers, each item was categorized as “cannot tell”.

2.4. Data Extraction

A template was designed for the data extraction. This included fields for methods (design, sample characteristics, type of IF, exclusion, and inclusion criteria, reported BCrelated outcomes, and/or adverse effects of IF of (if reported)). The literature search,  title/abstract screening, full-paper assessment, quality assessment of the papers, and data extraction were performed independently by M.A., A.V., and V.K. Any differences in these outcomes were discussed, and the consensus was reached and referred to S.K. for resolution and/or confirmation.

3. Results 

We identified 468 articles, excluding duplicates. The title/abstract screening excluded 344 articles. In total, 10 out of the 67 remaining articles were included. The reasons for exclusion are given in Figure 1. The selected studies used various study designs, namely cohort (n = 2), clinical trial (n = 1), case series (n = 1), qualitative study (n = 1), controlled cross-over (n = 1), randomized cross-over pilot study (n = 2), randomized controlled observer-blind study (n = 1), and non-randomized cross-over pilot study (n = 1). The sample characteristics are presented in Table 1.

Most studies (n = 7) were hospital-based; two studies recruited participants from both the hospital and the community (n = 2), while one study recruited participants from an unidentified source (n = 1). Sample sizes ranged from 4 to 2413 female patients. All patients were female adults, and their ages ranged from 27–78 years. The participants in all studies were women diagnosed with BC of the following stages: I, II (HER2−/+), III (HER2−/+), IV, LUMINAL-A, and LUMINAL-B (HER2−/+).

3.1. Health Outcomes 

3.1.1. Quality of Life: Chemotherapy-Induced Side Effects

A positive effect of IF on QoL scores of BC patients undergoing chemotherapy was reported in four studies. The QoL was assessed through The Functional Assessment Of Cancer Therapy-General (FACT-G), the Functional Assessment of Chronic Illness Therapy (FACIT-F), the Big Five Inventory (BFI) scale, as well as the score based on the Common Terminology Criteria for Adverse Events of The National Cancer Institute [16]. Overall, BC patients displayed higher tolerance to chemotherapy and fewer chemotherapy-induced side effects whilst following an IF regimen.

In detail, Kleckner et al. assessed 4–60 months post-cancer treatment BC survivors,  who already reported a fatigue level ≥ 3 on a scale between 0 and 10 [17]. Women followed a 2-week 14: 10 h TRF dietary regimen (this dietary pattern includes 14 h of fasting within the same day) with no inclusion of a control group in the study [17]. Fatigue symptoms were assessed using the FACIT-F and BFI scales pre-and post-intervention. The FACIT-F is divided into five subscales: physical well-being, social wellbeing, emotional well-being,  functional well-being, and fatigue [16]. The BFI is a self-reported scale that is designed to measure the major personality traits (extraversion, agreeableness, conscientiousness,  neuroticism, and openness) and is comprised of a 10-item fatigue questionnaire, which is also validated and commonly used in the cancer population [18].

A significant improvement in fatigue scale symptoms was evident, as well as high adherence of BC survivors to this TRF regimen. The authors reported a reduction in fatigue severity after 2 weeks of the TRF regimen [17]. Specifically, fatigue scores improved 5.3 ± 8.1 points on the FACIT-F fatigue subscale (p < 0.001, effect size (ES) = 0.55), 30.6 ± 35.9 points for the FACIT-F total score (p < 0.001, ES = 0.50), and −1.0 ± 1.7 points on the BFI scale (p < 0.001, ES = −0.58) [17].

Bauersfeld et al. (2018) focused on the effects of IF on the impact of chemotherapy (six cycles) on BC patients who started fasting 36 h before chemotherapy and stopped fasting 24 h post-chemotherapy (60 h fasting period) [19]. Overall, 34 BC patients were instructed to follow an IF dietary pattern, in the first half of the chemotherapy cycles, followed by a noncaloric diet (Group A; n = 18) or vice versa (Group B; n = 16) [19]. The authors assessed the QoL scores through the Functional Assessment of Cancer Therapy-General (FACT-G) [16]. This is a 27-item questionnaire assessing health-related quality of life, as far as physical, social, emotional, and functional welfare is concerned [16]. Chemotherapy-induced reduction of the QoL was less than the minimally important difference (MID; FACT-G = 5) with short-term fasting (STF), but greater than the MID for non-fasting periods, during Chemotherapy Cycles c1–c3 in comparison to Chemotherapy Cycles c4–  c6 [19]. Finally, IF improved chemotherapy-induced fatigue, weakness, and gastrointestinal side effects [19].

Badar et al. [20] recruited four BC patients at Stage IIB/IIIB/IV treated with docetaxel. In their study, Ramadan-fasting patients first received chemotherapy (20 min after sunset)  and, then, continued their fasting routine for the rest of the month. During the fasting period, the patients fasted daily from dawn to sunset and permitted food access from sunset to dawn. For a minimum of 2 weeks of “wash out” after the end of Ramadan, patients underwent the same chemotherapy while not fasting.

All patients were monitored daily by phone, regarding chemotherapy-induced adverse effects (assessed through the score-based Common Terminology Criteria for Adverse Events of National Cancer), and a complete blood count, as well as renal and liver function assessment, were performed once a week. A total of 12.5% of patients noted nausea improvement during fasting; 50% reported fatigue improvement during fasting; in 62.5% of patients, fasting made them feel better as was demonstrated by The Common Terminology Criteria for Adverse Events of The National Cancer Institute Questionnaire [20].

Mas et al. included 16 semi-structured interviews of BC patients who had been previously (within the last year) treated with chemotherapy [21]. Participants were not instructed according to a specific dietary regimen, but rather, followed nutritional advice from healthcare general practitioners. Patients mainly fasted to alleviate chemotherapeutic adverse effects, as well as to cope with treatment-induced anxiety, through obtaining a sense of control over their remedy [21]. The authors reported that fasting improved nausea and vomiting, as well as appetite, satiation, and fatigue between chemotherapy sessions [21]. A  case series conducted by Safdie et al. [22] reported on the side effects of fasting among four BC patients, by utilizing a non-validated questionnaire that used items from the Common Terminology Criteria for Adverse Events of The National Cancer Institute. The authors revealed that nausea, vomiting, diarrhea, abdominal cramps, and mucositis were not reported during fasting, and fatigue and weakness were reduced [22]. Finally, Marinac et al. reported that patients undergoing an FMD manifested a greater duration of night sleep for more hours per night compared to those who followed a noncaloric diet (β = 0.20; 95% CI, 0.14–0.26) [23].

3.1.2. Chemotherapy-Induced Toxicity

A positive effect of IF on chemotherapy-induced toxicity was reported in 4 out of 10 studies.

Deoxyribonucleic acid (DNA) damage was evaluated through the COMET assay,  which was used for the quantification of leukocytic oxidative stress and γ-H2AX phosphorylation (formed by the phosphorylation of the Ser-139 residue of the histone variant H2AX) [24] as a marker of chemotherapy-induced double-stranded DNA breaks. Frequency and toxicity scores were used for the evaluation of individual toxicities.

Zorn et al. studied patients subjected to a minimum of four cycles of chemotherapy,  and they fasted for 96 h during half of their chemotherapy cycles and followed a noncaloric diet during the rest of the chemotherapy cycles. IF (periodic fasting subtype STF) was found to significantly moderate (p=0.023) the frequency and severity score of stomatitis (p = 0.013), headaches (p=0.002), weakness (p=0.024), and total toxicity score [25]. Moreover, after the implementation of IF, there was chemotherapeutic endurance improvement (p=0.034), and chemotherapy was notably less frequently postponed [21]. Groot et al. randomized 131 patients with HER2-negative Stage II/III breast cancer, without previously diagnosed diabetes and BMI ≥ 18 kg m2, to receive either a fasting-mimicking diet (FMD) or their regular diet for 3 days before and during neoadjuvant chemotherapy. Moreover, they reported that an ad libitum dietary pattern significantly increased CD45 + CD3 + T-lymphocytic DNA damage post-chemotherapy, in comparison to patients who underwent an FMD (p = 0.045) [26].

In a previous study by Groot et al. [27], 13 HER2-negative BC patients at Stage II/III  were recruited, of whom 7 were randomized to IF (fasting 24 h before and after neoadjuvant TAC regimen: docetaxel/doxorubicin/cyclophosphamide). In general, IF was well tolerated, whereas the authors reported remarkably higher mean erythrocyte and thrombocyte concentrations 7 days post-chemotherapy, in patients undergoing IF compared with those randomized to the non-IF group (95% CI, p = 0.007 and 95% CI, p = 0.00007, respectively) [27]. Moreover, in patients adhering to IF, protection from chemotherapy-attributed bone marrow and cellular toxicity was evident, as well as improvement in DNA damage in peripheral blood mononuclear cells (PBMCs), quantified by the level of γ-H2AX analyzed by flow cytometry [27], particularly at 30 min post-chemotherapy.

At baseline (upon chemotherapy initiation), γ-H2AX phosphorylation increased in both the IF and non-IF groups, but 7 days after chemotherapy, it solely declined in the IF  group [27].

Dorff et al. [28] studied three cohorts, and they evaluated leukocytic oxidative stress through the COMET assay (single-cell gel electrophoresis) and peripheral blood mononuclear cells. DNA damage increased in all cohorts after chemotherapy; however, there was a decrease in Olive tail moment (OTM) (describes heterogeneity within a cell population and can pick up variations in DNA distribution within the tail) in the 48 h and the 72 h  cohorts (range 0.9–20.7) [28]. A positive effect of IF on platinum-induced toxicity (fasting for ≥48 h (p = 0.08)) in minimizing DNA damage in leukocytes [28] was also reported. It was concluded that peri-chemotherapeutic fasting for 72 h is safe and achievable for BC  patients [28].

3.1.3. Chemotherapeutic or Radiological Response/Tumor Recurrence 

We identified two studies that reported results on therapeutic response and tumor recurrence.

De Groot et al. [26] studied the effects of FMD on tumor growth and response according to the Miller and Payne scores (a grading system comparing tumor cellularity between pre-neoadjuvant core biopsy and the definitive surgical specimen). A radiologically complete or partial response was found to occur more regularly in patients using the FMD (OR 3.168, p = 0.039). Furthermore, the per-protocol analysis showed that the Miller and Payne 4/5 pathological response, indicating 90–100% tumor cell loss, was more likely to occur in patients using the FMD (OR 4.109, p = 0.016) [26]. Marinac et al. (2016) utilized data derived from 2413 women with early-stage invasive BC (semiannual telephone calls) and studied tumor recurrence, during a mean of 7.3 years [23]. Overnight fasting for ≤13 h revealed a higher risk of BC mortality (hazards ratio, 1.21; 95% CI, 0.91–1.60) or a higher risk of all-cause mortality (hazards ratio, 1.22; 95% CI, 0.95–1.56) [23]. It should be emphasized that fasting per night ≤ 13 h, was associated with a 36% higher risk for BC recurrence, in contrast to fasting ≥ 13 h (hazards ratio, 1.36; 95% CI, 1.05–1.76) [23].

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