By Atreyi Mukherji, MD, MPH, FRCPC

Private Practice, Integrative Internal Medicine & Infectious Diseases, Ontario, Canada

Dr. Mukherji reports no financial relationships relevant to this field of study.

SUMMARY POINTS

  • Breast cancer incidence has increased by 20% since 2008.
  • Dietary intervention involving a Mediterranean style diet supplemented with extra-virgin olive oil (1 L/week) may be a useful primary prevention strategy among white postmenopausal women.
  • Longer term and larger studies with this intervention as a primary outcome are needed to confirm these findings.

SYNOPSIS: A Mediterranean diet supplemented with the consumption of one liter of extra-virgin olive oil per week may be beneficial in the primary prevention of breast cancer.

SOURCE: Toledo E, Salas-Salvado J, Donat-Vargas C, et al. Mediterranean diet and invasive breast cancer risk among women at high cardiovascular risk in the PREDIMED trial: A randomized clinical trial. JAMA Intern Med 2015;175:1752-1760.

Breast cancer is the leading cause of cancer among women. World estimates since 2008 have showed a 20% increase in breast cancer incidence and a 14% increase in mortality.1 There is an inconsistent association between diet and breast cancer, with high alcohol consumption being the only convincing risk factor in women.2

The Mediterranean diet (MedDiet) consists of an abundance of plant foods, fish, and olive oil.3 The potential benefits of a MedDiet may be partly explained by reduction in oxidative DNA damage. Olive oil has a high supply of monounsaturated fatty acids, mainly oleic acid and squalene. Additionally, extra-virgin olive oil (EVOO) has various biologically active compounds, such as the polyphenols oleocanthal, oleuropein, hydroxytyrosol, and lignans. In vitro studies have suggested that oleic acid has an antiproliferative effect by affecting the expression of human oncogenes.4 The hydrocarbon squalene has been reported to have intracellular oxidative stress and DNA oxidative damage in mammary epithelia cells.5 Oleocanthol has been associated with inhibition of tumor growth, proliferation, migration, and invasiveness in breast cancer cells in in vivo models.6 Finally, lignans are phytoestrogens whose consumption has been associated with a lower risk of breast cancer in postmenopausal women.7

One secondary outcome of the Lyon Diet Heart Study showed a 61% lower risk of all subtypes of cancer in participants following a MedDiet compared to controls, who followed the American Heart Association diet.8

Toledo et al sought to examine the effects of the MedDiet on breast cancer risk, and specifically, the effects of EVOO or nuts in the randomized intervention of the PREDIMED trial on the incidence of breast cancer.

The study was conducted within the frame of the PREDIMED trial, which was designed as a multicenter, single-blind, randomized, controlled trial to test the effects of MedDiet on the primary prevention of cardiovascular disease. The study was conducted between 2003-2009 at primary care clinics in Spain. The median follow-up was 4.8 years, and the trial was stopped because of early evidence of cardiovascular benefit.

In this study, 4,282 women between 60 and 80 years of age who were at high risk of cardiovascular disease were randomly allocated to MedDiet supplemented with EVOO (1 L/week), a MedDiet supplemented with mixed nuts (30 g/day; 15 walnuts, 7.5 g hazelnuts, and 7.5 g almonds), or a control arm (advice to reduce dietary fat). Energy restriction or physical activity was not specifically promoted in any group. For this study, one woman was excluded due to prior diagnosis of breast cancer and seven others were excluded because of probable (unconfirmed) malignant breast tumors. Outcome was defined as first invasive breast cancer diagnosis using current ICD codes. Results of cytological or histological examination was considered as confirmation. Cancer incidence was defined as a secondary outcome in the original study protocol.

Thirty-five confirmed incident cases of malignant breast cancer were identified. There were no data available for 122 participants. The breast cancer rate per 1,000 person-years for the control group was 2.9. Among the intervention group, the lowest rate was found in the EVOO group (1.1), followed by the EVOO and nuts group (1.4), and then nuts alone (1.8). The multivariate hazard ratio (HR) followed a similar pattern when compared to control, with the EVOO group having the lowest risk 0.32 (95% confidence interval [CI], 0.13-0.79), followed by EVOO and nuts 0.43 (95 % CI, 0.21-0.88), and nuts alone 0.59 (95% CI, 0.26-1.35). Those who had a higher EVOO consumption during follow-up had an HR of 0.18 (95% CI, 0.06-0.57). Consumption of EVOO accounted for 22% of the total caloric intake in the MedDiet-EVOO arm, whereas nuts represented 10% of the total caloric intake in the MedDiet-nuts arm.

COMMENTARY

Toledo et al found that supplementation with EVOO (> 15% of total energy intake) as part of a Mediterranean-style diet that consists of plant foods, fish, and olive oil provided statistically significant decrease in the risk of developing breast cancer. A non-significant trend was also observed with a Mediterranean-style diet supplemented with 30 g of mixed nuts.

The strength of this study was the randomized, controlled design and large sample size, which the authors indicated likely balanced out certain potential residual confounding factors. These residual confounders included: 1) breast cancer not being the primary outcome of the original PREDIMED trial, which resulted in not all women having a documented baseline disease-free mammogram; 2) possible subclinical cases; and 3) data on reproductive factors associated with breast cancer not being available for further adjustment during the analysis.

Other limitations of the study included the small incident number of breast cancer cases. However, the authors argued that if any cases were missed, they would have been in the control group, which comprised the majority of cases lost to follow-up. This would have further increased the incidence rates in the control group and would not have affected the findings of the study. There was a very high rate of adherence to the MedDiet at baseline, which was speculated to be the reason for the small incident cases.

The study population consisted mainly of white postmenopausal women, so it may not be generalizable to other age groups or ethnicities.

This is the first randomized trial on the effect of a long-term dietary intervention on breast cancer incidence. The study found a beneficial effect of a MedDiet supplemented with EVOO in white postmenopausal women. However, the role of nuts in primary prevention of breast cancer remains ambiguous, although there was a non-statistical risk reduction found with consumption of nuts. Longer-term studies are needed with higher number of incident cases to improve the strength of evidence in terms of breast cancer prevention. However, the MedDiet pattern has been shown to have cardioprotective effect. Therefore, it is reasonable for clinicians to recommend it as part of a healthy heart diet, which includes plant foods, fish, and EVOO.

REFERENCES

  1. Ferlay J, et al. Cancer incidence and mortality patterns in Europe: Estimates in 40 countries in 2012. Eur J Cancer 2013;49:1374-1403.
  2. WHO International Agency for Research on Cancer IARC monographs on the evaluation of carcinogenic risks to humans. Vol 96. Alcohol consumption and ethyl carbamate.
  3. Willett WC, et al. Mediterranean diet pyramid: A cultural model for healthy eating. Am J Clin Nutr 1995;6(Suppl):14025-14065.
  4. Menendez JA, et al. A genomic explanation connecting “Mediterranean diet,” olive oil and cancer. Eur J Cancer 2006;42:2425-2432.
  5. Warleta F, et al. Squalene protects against oxidative DNA damage in MCF10A human mammary celsl but not in MCF7 and MDA-MB 231 human breast cancer cells. Food Chem Toxicol 2010;48:1092-1100.
  6. Akl MR, et al. Olive phenolics as c-Met inhibitors: Olecanthol attenuates cell proliferation, invasiveness and tumor growth in breast cancer models. PLoS One 2014;9:e97622.
  7. Buck K, et al. Meta-analysis of lignans and enterolignans in relationship to breast cancer risk. Am J Clin Nutr 2010;92:141-153.
  8. De Lorgeru M, et al. Mediterranean dietary pattern in a randomized trial: Prolonged survival and possible reduced cancer rate. Arch Intern Med 1998;158:1181-1187.