Abstract
Breast cancer remains a global health challenge, prompting a search for preventive strategies beyond conventional approaches. This review explores the potential of specific micronutrients, including antioxidants, vitamins, and probiotics, in breast cancer prevention. Through an extensive literature search encompassing PubMed up to March 2024, 14 micronutrients emerged with promising roles in breast cancer prevention. These include five vitamins: folate, vitamin D, vitamin B6, beta carotene, and vitamin C and nine other micronutrients: curcumin, piperine, epigallocatechin-3-gallate, quercetin, sulforaphane, indole-3-carbinol, lactobacillus, n-3 polyunsaturated fatty acids and lycopene. Understanding the efficacy of these micronutrients could pave the way for personalized preventive interventions, offering new avenues for reducing breast cancer incidence and improving public health outcomes.
The incidence of breast cancer continues to rise, even in countries with established screening programs, with an estimated 2.3 million new cases diagnosed in 2020 (1). This increase can be attributed to changing reproductive habits, use of hormone replacement therapy and oral contraceptive pills, lifestyle, and environmental factors. Modifiable risk factors, such as elevated body mass index (BMI) post-menopause, lack of physical activity, and alcohol consumption are known contributors to breast cancer risk (2). Additionally, consumption of high-fat dairy products, red and processed meats, refined grains, sweets, caloric drinks, convenience foods, and sauces may elevate the risk of breast cancer (3).
Risk-reducing salpingo-oophorectomy has been demonstrated to lower the risk of breast cancer and its associated mortality among BRCA gene carriers only (4). However, risk-reducing mastectomies and chemoprevention with drugs have not been shown to significantly alter mortality or improve overall survival (OS) among healthy women with pathogenic BRCA mutations (5). While risk-reducing bilateral mastectomy is an option for high-risk individuals, it entails significant psychosexual and physical implications and has not been shown to enhance OS even in the presence of BRCA gene mutations (5).
In the pursuit of effective breast cancer prevention strategies, researchers have turned their attention to specific micronutrients (6). This review focuses on specific micronutrients, including antioxidants, vitamins, and probiotics, in breast cancer prevention,
We conducted a literature search up to March 2024 to identify micronutrients showing consistent evidence of potential efficacy in humans, using search terms like ‘breast cancer’ in conjunction with ‘nutrition’, ‘vitamins’, ‘diet’, ‘micronutrients’, or ‘supplements’. Preferential selection was given to meta-analyses over individual studies. Micronutrients with conflicting evidence, such as vitamin E, selenium, and vitamin B12, were excluded. The search yielded 9184 articles, identifying 14 micronutrients potentially involved in breast cancer prevention (7-57). These include 5 vitamins: folate, vitamin D, vitamin B6, beta carotene, and vitamin C, along with 9 other micronutrients: curcumin, piperine, epigallocatechin-3-gallate, quercetin, sulforaphane, Indole-3-carbinol, lactobacillus, n-3 polyunsaturated fatty acids, and lycopene.
Folate (Vitamin B9)
Vitamin B9, occurring naturally as folate, constitutes an essential nutrient. A comprehensive analysis of 23 prospective studies, incorporating 41,516 breast cancer cases and 1,171,048 individuals for meta-analysis, revealed that folate intake correlated with an 18% reduction in the risk of developing hormone receptor-negative breast cancer. Every 100-microgram increment in folate intake was associated with a 10% risk reduction among moderate alcohol consumers (7). A more recent meta-analysis of (n=49) observational studies examining dose-response relationships revealed an inverse association between folate intake and breast cancer risk, with the highest versus lowest intake categories showing reduced risk [odds ratio (OR)=0.85, 95% confidence interval (CI)=0.79-0.92]. The dose-response analysis indicated a linear correlation between folate intake and breast cancer risk. Furthermore, higher folate intake was associated with decreased breast cancer risk in premenopausal women (OR=0.80, 95% CI=0.66-0.97) but this was not statistically significant in postmenopausal women (OR=0.94, 95% CI=0.83-1.06) (36). A prospective nested case–control investigation comprising 712 cases and 712 controls examined the correlation between plasma folate and breast cancer. The study compared women in the highest quintile of plasma folate with those in the lowest, revealing a relative risk (RR) of 0.73 (95% CI=0.50-1.07; ptrend=0.06), suggesting that higher plasma levels of folate may reduce the risk of developing breast cancer (42).
Additionally, BRCA1 mutation carriers who used folic acid-containing supplements experienced a notable decrease in breast cancer risk (55% risk reduction) compared to non-users (8). Similarly, A systematic review of 25 articles that examined the safety and efficacy of Vitamin B supplementation in oncology contexts concluded that B9 vitamin supplementation significantly reduced the risk of breast cancer among BRCA1-positive patients (n=400) (35). Notably, a relatively high dietary folate intake exhibited an inverse association with the risk of uterine (48% risk reduction) and ovarian cancers (61% risk reduction) (19). Therefore, it is prudent for women to incorporate a daily folate supplement (400 micrograms daily), as it represents a healthier form of vitamin B9 compared to folic acid.
Folate naturally occurs in a diverse range of foods, such as vegetables (particularly dark green leafy ones), fruits, nuts, beans, peas, seafood, eggs, dairy, meat, poultry, and grains. Spinach, liver, asparagus, and Brussels sprouts are notable for their high folate content.
Vitamin D
Treating breast cancer cells with 1,25(OH)D3 demonstrates two beneficial effects: an anti-proliferative effect, suppressing cell growth (30), and a pro-apoptotic effect, encouraging natural cell death (41).
Vitamin D undergoes enzymatic conversion in the liver to 25-hydroxyvitamin D (25[OH]D), the primary circulating form, and subsequently in the kidney to 1,25-dihydroxyvitamin D, the active form. A recent meta-analysis of 68 studies published in 2018 revealed a protective association between 25(OH) vitamin D and breast cancer, with a 35% reduction in risk observed in case-control studies and a 15% risk reduction in cohort studies. The secondary analysis of the Women’s Health Initiative CaD trial, spanning approximately 20 years, involved 36,282 postmenopausal women randomly assigned to calcium plus vitamin D or placebo. Supplementation significantly reduced DCIS risk in the CaD group throughout follow-up and during the post-intervention phase. Furthermore, combining CaD trial intervention (400 international units: IU) with personal supplementation (up to 1,000 IU) significantly lowered DCIS risk compared to the placebo group. These findings suggest that consistent CaD supplementation may offer long-term protection against DCIS, a non-obligate precursor of invasive malignancy in postmenopausal women (52). However, it was not feasible to separate the potential impact of vitamin D from that of calcium in the trial.
A systematic review and meta-analysis of 25 studies investigating vitamin D baseline levels upon breast cancer diagnosis unveiled a notable prevalence of vitamin D insufficiency among newly diagnosed breast cancer patients (37). In a multicenter case-control study involving 411 breast cancer cases and 784 controls, researchers examined the association between vitamin D levels and breast cancer risk. Those with serum vitamin D deficiency (<20 ng/ml) had a heightened risk of breast cancer compared to individuals with sufficient serum vitamin D (>30 ng/ml) (OR=1.65, 95% CI=1.10-2.50). Additionally, women who reported a history of vitamin D supplementation one year before enrolment demonstrated a significant protective effect against breast cancer (OR=0.32, 95% CI=0.24-0.43) (39). Another recent meta-analysis indicated that vitamin D deficiency directly correlated with breast cancer risk, while total blood vitamin D levels and supplemental vitamin D intakes exerted a protective effect (54). Lastly, a meta-analysis encompassing five studies, with 4413 breast cancer patients, highlighted that higher 25(OH) vitamin D levels (>75 nmol/l) correlated with a 42% reduction in the odds of breast cancer mortality (55).
A systematic assessment of eight studies involving 2503 patients, investigated the link between vitamin D receptor (VDR) expression and prognosis of breast cancer patients through meta-analysis (38). While the combined analysis indicated that VDR expression generally lacked a statistically significant correlation with OS, disease-free survival (DFS), and progression-free survival (PFS) in breast cancer patients, a subgroup of studies utilizing threshold values demonstrated that high VDR expression was associated with improved OS (pooled HR=0.47; 95% CI=0.30-0.74; p=0.001). Moreover, elevated total VDR expression in both the nucleus and cytoplasm was linked to improved OS (pooled HR=0.41; 95% CI=0.18-0.95; p=0.038).
Nonetheless, an analysis combining data from seven RCTs involving 19,137 females revealed no significant impact of vitamin D on breast cancer risk, implying that the perceived protective effect of vitamin D observed in observational studies might have been overstated (40). However, the lack of significant findings in these trials could be attributed to low serum 25(OH) levels at the endpoint in some instances. Furthermore, the relatively short durations of four out of seven studies, lasting less than 12 months, may not adequately capture the progression of cancer. Moreover, since all RCTs were conducted in developed countries, the generalizability of these findings may be limited.
Besides exposure to sunlight, excellent sources of vitamin D include fatty fish and fish liver oils. The recommended vitamin D analog for daily supplementation is cholecalciferol (vitamin D3; 400-1,000 iU), with its active form being 1,25-dihydroxy-vitamin D3.
Vitamin B6
Vitamin B6 participates in numerous biochemical reactions and may play a role in carcinogenesis. A pooled analysis of data from five studies conducted in the United States, involving 2509 breast cancer cases, demonstrated that high serum pyridoxal 5’-phosphate levels (PLP, the active form of vitamin B6) were associated with a 20% reduction in breast cancer risk among postmenopausal women compared with low levels RR=0.80 (95% CI=0.66-0.98, p=0.03) (34). A more extensive analysis in 2017, incorporating 121 observational studies (participants= 1,924,506; cancer cases=96,436) and nine randomized controlled trials (RCTs; participants, n=34,911; cases, n=2539), examining 19 tumor sites, revealed that high intake of dietary (food only) vitamin B6 correlated significantly with a 22% lower risk of all cancers (56). A more recent systematic review comprising 25 articles demonstrated a notable association between B6 vitamin supplementation and a diminished risk of breast cancer among middle-aged women (n=27,853 patients) (35). A prospective nested case–control investigation involving 712 cases and 712 controls explored the link between vitamin B6 and breast cancer. Comparing women in the highest quintile of plasma vitamin B6 with those in the lowest quintile yielded a relative risk of 0.70 (95% CI=0.48-1.02; ptrend=0.09), suggesting that higher plasma levels of vitamin B6 may reduce the risk of developing breast cancer (42). The richest sources of vitamin B6 comprise fish, beef liver, other organ meats, potatoes, starchy vegetables, and non-citrus fruits.
β-Carotene and Lycopene
Beta carotene, a precursor for vitamin A, predominantly found in carrots, mangoes, maize, lentils, dark green leaves, amaranth, and spinach, exhibits notable properties in reducing breast cancer risk. Research was undertaken to explore the impact of lycopene and beta-carotene on the cell cycle and survival of human breast cancer cells (43). The results revealed a significant reduction in the number of viable breast cancer cells when treated with lycopene and beta-carotene, which led to cell-cycle arrest and enhanced apoptosis in comparison to the controls. A systematic review of epidemiological studies on β-carotenoids and breast cancer found a confirmed association, suggesting that dietary intake of β-carotenoids may reduce the risk of breast cancer (44). A pooled analysis of eight cohort studies, incorporating over 80% of the world’s published prospective data on plasma or serum carotenoids and breast cancer, comprising 3055 case subjects and 3956 matched control subjects, indicated that high serum levels of beta carotene correlated with a 17% reduction in breast cancer risk (57). Furthermore, a meta-analysis involving 10 studies (eight cohort, one clinical trial, and one pooled studies), with 19,450 breast cancer cases, demonstrated a significant association between dietary intake of β-carotene and enhanced breast cancer survival, with a 30% reduction in the odds of breast cancer mortality (9).
Lycopene, a carotenoid nutraceutical, bolsters defenses against cancer, cardiovascular disease, hypertension, and neurodegenerative and inflammatory conditions. In vivo, Lycopene mechanisms involve regulating oxidative and inflammatory processes, inducing apoptosis, and inhibiting cell division, angiogenesis, and metastasis formation (31). The efficacy of lycopene in diminishing viable breast cancer cells was substantiated, leading to cell-cycle arrest and an increase in apoptosis (43). A recent meta-analysis comprising 13 effect sizes from 11 publications involved 18,854 participants and 6630 breast cancer cases. The pooled RR was 0.86 (95% CI=0.76-0.98) for the highest compared to the lowest category of circulating lycopene. Notably, between-study heterogeneity was not significant (I2=0.0%; p=0.46) (32). Key dietary sources of lycopene encompass red fruits and vegetables, notably tomatoes and watermelons.
Curcumin and Piperine
Turmeric, a yellow spice renowned for flavoring Asian cuisine, contains curcumin, a polyphenolic compound isolated from turmeric, which exhibits notable anti-breast-cancer effects, primarily elucidated through animal and laboratory studies. Curcumin influences breast cancer development and progression via its modulation of the cell cycle, natural cell death, cancer spread, and angiogenesis to support tumor progression. Key signaling pathways implicated include NFkB, PI3K/Akt/mTOR, MAPK, and JAK/STAT (10). Despite the scarcity of evidence from human clinical studies, utilizing curcumin as a therapeutic and preventive agent in breast cancer garners support from extensive evidence derived from laboratory and animal studies demonstrating diverse biological activity against breast cancer cells and tumors, much of which remains unexplained (10).
Preclinical studies have explored the impact of curcumin on breast cancer cell proliferation, viability, apoptosis, and tumor volume. Turmeric’s anticancer effects in breast cancer cells were validated, with curcuminoids primarily causing antiproliferation through cell cycle arrest, senescence, and apoptosis induction via p53/p21 activation (46). In another report, curcumin, particularly combined with aminonaphthoquinone derivatives, was found to induce marked anti-angiogenic effects in breast cancer cells and significantly decrease their metastatic capability (45). A recent systematic review of 60 articles (10) found that curcumin, administered through various concentrations and routes, effectively inhibited proliferation, decreased viability, and induced apoptosis in both human and animal breast cancer cells. Nanoformulations of curcumin, delivered orally, via implant, and intraperitoneally, demonstrated a significant reduction in tumor volume for both human and murine mammary cells in vivo. Additionally, curcumin nanoformulations showed promising results in inhibiting tumor growth in animal models of breast cancer. These findings suggest that regular consumption of curcuminoids could help prevent and support treatment in combating breast cancer. Further randomized clinical trials are necessary to evaluate the efficacy and safety of curcumin formulations for potential clinical applications.
The bioavailability of curcumin significantly improves when combined with piperine, which also exhibits anti-breast cancer properties (11). Notably, a white form of turmeric known as C3® Reduct has emerged, overcoming the bioavailability limitation of parent curcuminoids by directly providing the active metabolite. Research has indicated that C3® Reduct serves as a remarkable antioxidant, even surpassing curcumin itself in this regard. Although curcumin has been extensively investigated at a preclinical level, there remains a scarcity of clinical trials involving humans.
Green Tea Polyphenols
Scientific literature provides compelling evidence that green tea exerts protective effects against tumorigenesis, attributed to its principal polyphenol, epigallocatechin-3-gallate (EGCG) (12). A population-based case-control study involving 3454 incident cases and 3474 controls aged 20-74 over a 9-year period revealed that drinking green tea was associated with a decreased risk of breast cancer. Regular green tea drinkers had a reduced risk (OR=0.88; 95% CI=0.79-0.98) compared to non-drinkers. Among premenopausal women, a lower risk was linked to the duration of green tea consumption (ptrend=0.02), and a statistically significant dose-response relationship was observed with the amount consumed per month (ptrend=0.046) (48). A meta-analysis involving breast cancer incidence and recurrence, encompassing 5,617 cases of breast cancer, highlighted an inverse association between green tea consumption and the risk of breast cancer recurrence (RRpooled=0.73, 95%CI=0.56-0.96). Even when solely considering case-control studies of breast cancer incidence, the inverse association persisted (RRpooled=0.81, 95%CI=0.75-0.88) (13). Consistent with prior meta-analyses, a recent systematic review and meta-analysis of various observational studies, involving 163,810 individuals, reported a statistically significant inverse correlation between green tea consumption and breast cancer risk, with a 15% risk reduction (OR=0.85, 95%CI=0.80-0.92, p<0.001). Notably, when focusing solely on case-control studies, the observed protective effect was more pronounced, with a 19% reduction in breast cancer risk (OR=0.81, 95%CI=0.74-0.88, p<0.001). The significance of case-control studies in establishing the causal link between exposure and event cannot be overstated. Moreover, in a sensitivity analysis of studies featuring high-quality scores included in this meta-analysis, the reported reduction in breast cancer risk was even more pronounced, at 27% (14). A more recent meta-analysis of 16 studies revealed that consuming green tea may decrease the risk of breast cancer, particularly with long-term and high doses. The pooled relative risk for breast cancer at the highest versus lowest levels of green tea consumption was 0.86 (95% CI=0.75-0.99) (47).
Quercetin
Quercetin, a bioactive flavonoid pigment found in various fruits, vegetables, and leaves, has been reported to possess potent anti-tumoral properties alongside its antioxidant activity. A meta-analysis of twelve studies, including 9,513 cases and 181,906 controls, found that a high intake of flavonols including quercetin, was associated with a 12% decrease in breast cancer risk (RR=0.88, 95% CI=0.80-0.98) (15). The authors found that consuming flavonols and flavones, rather than other flavonoid subclasses or total flavonoids, was linked to a reduced risk of developing breast cancer, particularly among post-menopausal women. Furthermore, in a network of multicentric Italian case-control studies involving 10,000 cancer cases and 16,000 controls, individuals with a high flavonol intake, such as quercetin, exhibited a reduced risk of breast cancer by 20% and ovarian cancer by 37% (ORs for the highest vs. the lowest quintile were 0.80 and 0.63, respectively) (16, 17). Primary dietary sources of quercetin encompass onions, grapes, berries, cherries, broccoli, and citrus fruits.
Sulforaphane and Indole-3-carbinol
Sulforaphane, an isothiocyanate phytochemical from cruciferous vegetables, possesses multiple molecular targets and exhibits anti-inflammatory, antioxidant, and anti-cancer properties. Several studies have demonstrated the chemo-preventive benefits of sulforaphane consumption, influencing human cancer development and progression through the modulation of key cellular mechanisms (18, 20). Indole-3-carbinol, another phytochemical derived from cruciferous vegetables, has been shown to be a potent chemo-preventive agent for hormone-dependent breast cancer, inducing apoptosis and altering estrogen metabolism (21). Interestingly, a study in transgenic mouse models suggests that timing of exposure to epigenetic-modulating dietary components like cruciferous vegetables could enhance chemopreventive effects against breast cancer. Prenatal or maternal intake of sulforaphane-based broccoli sprout diet may influence early gene expression, impacting breast cancer susceptibility later in life. Prenatal or maternal treatment showed the strongest preventive effects, with postnatal treatment before puberty onset also providing some protection, albeit less effective than prenatal or maternal treatment (49). A meta-analysis of thirteen epidemiologic studies indicated a significant association between high consumption of cruciferous vegetables and a 15% reduction in breast cancer risk (RR=0.85, 95% CI=0.77-0.94) (22). Key sources of sulforaphane and indole-3-carbinol encompass cruciferous vegetables like broccoli, kale, cabbage, and Brussels sprouts.
Lactobacillus
Recent research suggests a potential link between bacterial imbalances in the gut microbiota and breast tissue, contributing to the development of breast cancer. Alterations in the composition and function of bacteria in both the gut and breast may play a role in the growth and progression of breast cancer through various mechanisms. Specifically, the gut microbiota’s role in metabolizing steroid hormones like estrogen is highlighted, potentially increasing the risk of breast cancer, particularly in menopausal women (23).
Probiotics, such as Lactobacillus, may offer protection against breast cancer due to their systemic immunomodulatory effects and influence on intestinal microbiota. In vitro studies have demonstrated that probiotic intervention induces apoptosis in cancer cells and inhibits their proliferation. Animal models have shown that probiotic treatment can inhibit tumor growth, reduce tumor size, and exhibit various beneficial properties (24). Animal studies demonstrated evidence that Lactobacillus acidophilus could modulate the immune response against breast cancer (25).
A study on breast tissue samples from 403 cancer-free women and 76 breast cancer patients investigated breast tissue microbial composition and its association with breast cancer risk factors, highlighting the significant impact of lifestyle factors on normal breast microbial composition (50). The study identified Lactobacillaceae (mainly Lactobacillus vini and Lactobacillus paracasei) as one of the most abundant families in healthy breasts. Transcriptome analysis of normal breast tissues also showed an enrichment in metabolism- and immune-related genes in tissues with abundant Lactobacillus vini. Human studies suggest that consumption of Lactobacillus casei shirota reduced breast cancer incidence, and intake of fermented milk products and yogurt was inversely associated with breast cancer incidence. However, the curative role of probiotics in breast cancer remains uncertain, and further research is needed (26). Key sources of lactobacillus include fermented foods, like yogurt, kefir, cheese, and pickles.
Vitamin C
Vitamin C is of growing interest for its potential health benefits, including the reduction cancer risk by neutralizing free radicals and reducing oxidative DNA damage. A study examining the association between vitamin C intake and survival in 3,405 women diagnosed with invasive breast cancer found that those in the highest quartile of pre-diagnosis vitamin C intake had a significantly lower adjusted HR for breast cancer death (HR=0.75, 95% CI=0.57-0.99) compared to those in the lowest quartile (ptrend=0.03). However, post-diagnosis vitamin C supplementation did not show an association with breast cancer-specific mortality, suggesting that only dietary vitamin C intake before breast cancer diagnosis may be beneficial for breast cancer survival (51). A meta-analysis by Harris et al. indicates that post-diagnosis vitamin C supplement use may reduce mortality risk, with dietary vitamin C intake also linked to decreased total mortality and breast cancer-specific mortality (28). A more recent meta-analysis of observational studies suggests that higher vitamin C intake is significantly associated with a lower risk (14%) of breast cancer incidence (RR=0.86; 95% CI=0.81-0.92) (27).
The sources of vitamin C include citrus fruits, such as oranges, grapefruit, and lemons, as well as kiwi fruit, blackcurrants, strawberries, and guava. Additionally, vegetables like broccoli, cauliflower, cabbage, cooked kale, and Brussels sprouts are rich in this nutrient.
n-3 Polyunsaturated Fatty Acids
A hospital-based case-control study involving 1,589 cases and 1,621 controls found that a higher intake of n-3 PUFAs, including marine and total n-3 PUFAs, was associated with a reduced risk of breast cancer, especially among premenopausal women and those with ER+ and/or PR+ tumors. The OR [4th quartile versus 1st quartile] was 0.68 (0.55-0.84) for marine n-3 PUFAs and 0.56 (0.42-0.75) for total n-3 PUFAs (53). Dietary intake of alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid was inversely associated with breast cancer risk, with adjusted ORs (95%CIs) ranging from 0.51 to 0.76. These associations were more pronounced in premenopausal women and those with ER+, PR+, and ER+PR+ tumors (53). A recent meta-analysis involving nearly 1.5 million participants revealed that consuming marine n-3 PUFAs was linked to a statistically significant 30% decrease in breast cancer risk (RR=0.70, 95% CI=0.55-0.91) (29). Experimental studies suggest that the ratio of n-3/n-6 PUFAs can inhibit the growth of breast cancer cells through various mechanisms, including competition for metabolic pathways. Multiple animal experiments and in vitro studies have supported the protective effect of polyunsaturated fatty acids against breast carcinogenesis (58-61). However, further research is needed to fully understand the molecular mechanisms underlying the influence of marine PUFAs on breast cancer carcinogenesis and angiogenesis. Marine fish and fish oil are widely recognized as primary sources of n-3 polyunsaturated fatty acids (PUFAs), specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
Discussion
Most of the micronutrients highlighted in this review possess antioxidant properties, countering reactive oxygen species (ROS) and averting DNA damage and cellular mutations, thus diminishing the likelihood of cancer cell proliferation. Additionally, each class exhibits specific molecular mechanisms, as discussed earlier, which could facilitate their anti-cancer effects, in addition to their anti-inflammatory and immune system-boosting properties.
Moreover, these micronutrients are abundantly found in fruits and vegetables. Analysis of data from two prospective studies involving 182,145 women over 30 years revealed that a higher intake of fruits and vegetables, especially cruciferous and yellow/orange vegetables, could potentially reduce the risk of breast cancer, particularly aggressive phenotypes (33). This underscores the potential efficacy of these micronutrients, advocating for their sufficient intake to maintain adequate serum levels as a precautionary measure against breast cancer. For women unable to meet their intake requirements through diet alone, considering supplements containing these micronutrients may be beneficial. However, it’s important to note that such dietary supplements lack approval from the Food and Drug Administration (FDA).
FDA-approved cancer therapies like paclitaxel and vinblastine are derived from plants, while dietary supplements lack FDA approval for cancer treatment efficacy despite the fact that approximately half of cancer patients in the United States begin using new dietary supplements upon receiving their cancer diagnosis (62). Oncologists face challenges advising patients on safe supplement use, as FDA has not approved any to prevent, treat, or mitigate cancer or its treatment side effects. FDA approval requires conducting phase 3 randomized clinical trials meeting specific endpoints, such as incidence, overall survival, disease-free survival, and progression-free survival, at a predetermined level of statistical significance.
Basic scientists discovering antitumor activity in compounds seek clinical counterparts for human trials, yet positive preclinical outcomes often fail to translate into positive clinical outcomes. In vitro preclinical studies involve high concentrations of natural products, not replicable in humans, especially with oral medications and limited bioavailability. Clinical trials are considerably costlier than preclinical studies and lack of patent protection restricts financial incentives for funding phase 3 trials. Clinical researchers face other challenges, such as the lack of standardized manufacturing and composition of supplements, coupled with heterogeneous intake of other natural dietary sources of the supplement in question by individuals who could be eligible candidates for clinical trials.
Micronutrients and breast cancer outcomes. In women with a history of breast cancer, most studies have focused on antioxidants, yet many suffer from serious sample size and study design issues, yielding mixed results (63, 64). The largest and most rigorous study to date is a prospective study of 4,877 breast cancer survivors in Shanghai, China, which reported that antioxidant use (including vitamin C, vitamin E, and/or multivitamins) during the first six months post-diagnosis was associated with a decreased risk of recurrence (HR=0.78; 95% CI=0.63-0.95) and overall mortality (HR=0.82; 95% CI=0.65-1.02) (65). In a meta-analysis comprising five studies involving 4413 breast cancer patients, it was found that higher levels of 25(OH) vitamin D (>75 nmol/l) were associated with a 42% reduction in the odds of breast cancer mortality (55).
Furthermore, statistically significant associations were found between dietary vitamin C intake and decreased risks of both total mortality and breast cancer-specific mortality (28). While vitamin E consumption wasn’t linked to a reduced risk of developing breast cancer, it was observed to significantly decrease the risk of breast cancer recurrence (66). Finally, consumption of green tea was observed to be associated with a 27% reduction of breast cancer recurrence in meta-analysis (13). These observations suggest that micronutrients may have the potential to eliminate dormant and stem breast cancer cells or inhibit their awakening. Additionally, recent preclinical research indicates that phytochemicals, such as curcumin, tea polyphenols (epigallocatechin-3-gallate, epigallocatechin), sulforaphane, indole-3-carbinol, vitamin E, retinoic acid (a beta-carotene derivative), and quercetin have demonstrated the ability to combat breast cancer stem cells. This suggests they could serve as promising therapeutic agents for breast cancer treatment and potential candidates for drug development (67).
Limitation of the review. Despite the large number of individuals included in the various observational studies, finding an inverse association between serum levels of a specific micronutrient and breast cancer risk is not considered high-level evidence and does not necessarily prove causality. Therefore, randomized controlled trials are required to substantiate these observed associations. Furthermore, many studies did not stratify the risk according to tumor type and were unable to conduct dose-response analysis due to insufficient data. Additionally, it was not feasible to include all confounding factors, such as dietary habits, genetic predisposition, and lifestyle factors like physical activity, BMI, and alcohol consumption. Finally, evidence derived from pre-clinical studies often fails to translate into clinical benefits in the real-world setting.
Conclusion
The absence of patentability-related financial incentives and the challenge of ensuring the purity and consistency of naturally occurring micronutrients, coupled with the difficulty in accounting for all confounding factors, have constrained the evidence derived from phase 3 randomized control trials. However, findings from pre-clinical and large observational studies strongly suggest that the 14 micronutrients identified in this review likely play a protective role against breast cancer. Therefore, maintaining adequate intake and plasma levels of these nutrients could potentially alleviate the global burden of breast cancer. In the context of scarcity of evidence from randomized controlled trials, it’s essential to consider findings from other research methodologies.
Acknowledgements
The Authors extend their gratitude to Jocelyn Rosenberg and her late husband, Michael Rosenberg, for their support of their research program.
Footnotes
Authors’ Contributions
Kinan Mokbel and Kefah Mokbel conceptualized the study and designed the research. Kefah Mokbel supervised the study.
Conflicts of Interest
The senior Author (Kefah Mokbel) is the director of OncoBotanica Limited, which is involved in the commercialization of the OncoMute supplement.
Funding
The Authors have not received any formal funding to support this work.
- Received March 8, 2024.
- Revision received April 23, 2024.
- Accepted April 24, 2024.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
