Adherence to the low carbohydrate diet and the risk of breast Cancer in Iran

Low- carbohydrate diets (LCD) are popular diets, and studies have reported beneficial effects on several chronic diseases, including obesity [1], diabetes [2], epilepsy [3, 4], cardiovascular diseases [5] and some cancers [6, 7]. High dietary intake of carbohydrates is associated with low levels of total- and LDL cholesterol, as well as low concentrations of HDL-cholesterol and high levels of triglycerides [8]. On the other hand, consumption of low carbohydrate diets has been linked with elevated concentrations of inflammatory biomarkers [9‐11], which could be underlying factors for cancer [12].

An inverse association was reported between adherence to LCD and risk of mortality from all causes, and also from cancer and cardiovascular disease [13‐17]. Despite huge evidence on the protective role of low-carbohydrate diets in several cancers, some investigations have linked such diets with restricted tumor growth [16, 18]. Findings from other studies have provided null results with regards to the relation of LCD and incidence of cancers [19]. Data on the association between adherence to LCD and risk of breast cancer are scarce. In a published study from the Nurses’ Health Study, consumption of a low carbohydrate diet was associated with reduced risk of breast cancer in postmenopausal women who were estrogen receptor-negative [17].

The dietary intake of people in the Middle-East, due to its heterogeneity as well as other general characteristics, provides a unique opportunity to examine the relation between diet and disease. Most people in this region consume refined grains (refined bread and white rice) as their staple food [20]. In addition, due to the nutritional transition that is occurring in these countries, dietary fat intake, and in particular, detrimental fats, are increasing [21]. Such dietary characteristics make it reasonable to examine the contribution of different macronutrients to human health. Although the role of individual macronutrients in different cancers has been examined before [22, 23], no study is available linking breast cancer and a combination of macronutrients. Assessment of LCD in relation to chronic conditions is of great importance in Middle-Eastern countries since carbohydrates are the main source of energy in these countries and protein is expensive [24]. Dietary fat intake in this region is consumed at the level of DRI, however, type of dietary fat is a problem [25]. Given the aforementioned points, this study was done to assess the association between adherence to LCD and the odds of breast cancer in a case-control study in Iran.

Patients with BC were slightly older (46.3 νs. 44.2 years, P = 0.003), had lower BMI (28.1 νs. 28.8 kg/m², P < 0.01), and were more likely to have a family history of breast cancer (10.1 νs. 1.54, P < 0.001) compared to controls (Table 1). They were less likely to be physically active (20.1 νs. 26.4 MET h/wk., P = 0.001), married (81.1 ν. 84.4%, P < 0.001), use oral contraceptives (52.8 vs. 61.3%, P = 0.02), use postmenopausal hormones (0.49 vs. 1.97%, P = 0.05) and drink alcohol (2.43 vs. 5.83%, P = 0.01) than controls (Table 1). Patients also had a lower intake of red meat and protein. The mean LCD score of participants was 8.9 ± 2.5 (8.9 ± 2.6 in cases and 9.0 ± 2.5 in controls).

Demographic, reproductive, and lifestyle characteristics of study participants (pre-and postmenopausal women) across quartile categories of LCD score are provided in Table 2. Mean (±SD) low-carbohydrate-diet score was 8.9 ± 2.5 for premenopausal and 9.0 ± 2.6 for postmenopausal women. Postmenopausal women in the top quartile of LCD score tended to be alcohol users, with a slightly lower age at menarche and lower family history of breast cancer compared to those in the bottom quartile.

Table 3 shows the mean daily dietary intake of food groups and nutrients across the quartiles of LCD score in pre-and postmenopausal women. Pre- and postmenopausal women in the top quartile of LCD score had a higher intake of red meat, full-fat dairy, protein, fat, saturated fat, and vitamin E and lower intake of whole grains, refined grains, fruits, and carbohydrate than those in the lowest quartile. In postmenopausal women, being in the top quartile of LCD score was associated with a lower intake of energy. Greater adherence to LCD in premenopausal women was associated with higher intake of vitamin A and lower intake of iron.

Multivariable-adjusted odds ratios and 95% CIs for breast cancer across categories of LCD score are provided in Table 4. Although no significant association was observed between adherence to LCD and odds of breast cancer in the whole study population, a trend toward significant positive association was seen between consumption of LCD and odds of breast cancer in postmenopausal women; after controlling for several potential confounders, individuals in the third quartile of LCD score were 1.94 times more likely to have breast cancer than those in the lowest quartile (95% CI: 1.00, 3.76). This association was strengthened after controlling for dietary variables (2.50; 1.18–5.32). Even after further adjustment for BMI, this association remained significant (2.64; 1.23–5.67). No such significant relationship was observed in premenopausal women, either before or after controlling for confounders.

In this case-control study, we found that adherence to a low-carbohydrate diet was not significantly associated with increased odds of breast cancer in the study population, a trend toward significant positive association was seen between consumption of LCD and odds of breast cancer in postmenopausal women. To our knowledge, this is the first study examining the relationship between low-carbohydrate diet score and risk of breast cancer in a Middle- Eastern country.

Earlier studies on the association between dietary carbohydrate intake and several outcomes have mostly examined total carbohydrate intake alone or in the context of low-carbohydrate, high-protein (LCHP) or low-carbohydrate, high-fat diets [2, 17, 23, 33‐35]. The low-carbohydrate dietary pattern we focused on here, is usually characterized by low intake of carbohydrates and high intake of proteins and fats [36]. Therefore, this approach considers all macronutrients and can provide better insight into the link between macronutrient intake and risk of breast cancer compared to individual intake of these macronutrients. We found that adherence to a low carbohydrate diet was not significantly associated with increased risk of breast cancer in the study population. Two previous studies have reported association between adherence to LCD and risk of breast cancer [17, 33]. In a cohort study of Swedish women, adherence to LCHP was not associated with increased risk of respiratory tract cancer, even though a significant association was observed in men [33]. Another study was conducted among postmenopausal women of the Nurses’ Health Study and demonstrated an inverse association between consumption of a vegetable-based LCD and estrogen receptor-negative (ER-) breast cancer risk [17]. In addition to these observational studies, the effect of a low carbohydrate ketogenic diet on several cancers has been examined [37]. It has been shown that a low carbohydrate ketogenic diet had beneficial effects on cancer cells [38]. In addition to the carbohydrate content of the diet, other carbohydrate-related indices were also examined in relation to the risk of breast cancer. Farvid et al. within the framework of the Nurses’ Health Study population failed to find any significant association between dietary glycemic index (GI), glycemic load (GL) and insulin load during adolescence, and risk of breast cancer during adulthood [39]. Similarly, two prospective cohort studies on French and Canadian women, revealed no association between dietary GI, GL and carbohydrate intake with overall breast cancer risk [40, 41]. In contrast, in a case-control study on Mexican women, a positive association between carbohydrate intake and risk of breast cancer was found [42]. The quality and quantity of macronutrients in the diet might explain the null association we found. Low-carbohydrate diets have been reported to obtain less than 26% of their energy from carbohydrates [37], whereas the amount of energy from carbohydrates among those with the greatest adherence to the LCD in the current study was 41.5%. This might further help in understanding the difference in findings.

When we analyzed the results by menopausal status, a trend toward significant association was observed between adherence to LCD and risk of breast cancer among post-menopausal women. Despite lack of a significant association between dietary GI and risk of breast cancer in the population, Canadian researchers found a positive association between high GI diets and increased risk of breast cancer among postmenopausal women [41]. In a case-control study among premenopausal Mexican women [43], an increased risk of breast cancer with higher intake of carbohydrate was seen. The relationship between diet and risk of breast cancer has been different in pre- and postmenopausal women. It seems that the contribution of diet to the risk of breast cancer is strong in premenopausal women. However, we failed to find such an association in premenopausal women and further studies are needed to clarify the association between adherence to LCD and odds of breast cancer.

Although there are no clear mechanisms on the link between low carbohydrate dietary patterns and risk of breast cancer, some studies suggest some potential mechanisms. High carbohydrate intake was associated with elevated blood glucose and insulin levels, which can promote glucose intolerance, insulin resistance and hyperinsulinemia. Warburg et al. expressed that cancer cells depend on glucose as a fuel [44]. Insulin resistance results in decreased levels of insulin-like growth factor (IGF) binding proteins 1 and 2, therefore, the availability of IGF-Ι, which can in turn increase tumor cell proliferation, would increase [45, 46]. Elevated levels of insulin and IGF-Ι result in higher levels of free estrogen and androgen via inhibiting the hepatic synthesis of the sex hormone binding globulin [47, 48]. Therefore, adherence to a diet with a low carbohydrate content might suppress tumor cell proliferation and regulate apoptosis via cell signaling pathways, the PI3K/Akt/Mtor and RAS/RAF/MEK/ERK sequences, which are insulin or IGF-Ι-dependent [7, 46, 49]. The significant association between circulating levels of IGF-Ι and increased risk of breast cancer in premenopausal women has previously been shown [50].

The strengths of the current study include considering several potential confounders, recruiting participants from a referral hospital, in which subjects are from all across the country. Stratified analysis by menopausal status is a strength of this study. However, several limitations need to be considered. First, due to the case-control design of the study with its inherent recall and selection bias, one cannot infer causality. Second, as with all epidemiologic studies that apply FFQ, misclassification of participants in terms of dietary intake cannot be excluded. Third, prominence in the third quartile may be due to chance as the sample size is limited in each quartile. Therefore further studies with larger sample sizes are needed to confirm this finding. Fourth, we did not gather information on the hormone receptor status of participants. This may affect our findings.

Based on the present findings, we found no evidence on association between consumption of a low carbohydrate diet (LCD), and odds of breast cancer risk in the study population; however, adherence to LCD might be associated with increased odds of breast cancer in postmenopausal women. Further research, especially cohort studies are needed to confirm these findings.