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Several methods have been used to estimate the probability of carrying a BRCA mutation, based on the number of breast and ovarian cancer among 1st and 2nd degree relatives, the age of occurrence, the presence of bilateral breast cancers and, when relevant, ethnicity. Most methods, however, do not take into account the size of the family (in particular the number and ages of healthy relatives), the lifespan of each family member that has actually been observed, the structure of the pedigree, or the change of cancer risk over subsequent generations. G. Parmigiani developed a method that properly incorporates the whole information available from each family member.
The probability that a given family member is a carrier is obtained comparing the probabilities of observing his/her family history assuming either the incidence of the general population or the gene penetrance. The computation is based on Bayes�s theorem, using the mutation prevalence in the population as the prior distribution and the family history as the evidence. The method takes fully into account mendelian transmission pathways. The weight of the maternal grandmother or of a aunt with breast cancer, for instance, will be higher if the mother had breast cancer too (or if she died when still too young to have breast cancer) than if the mother reached adult or old age without developing the disease.
The results of the Parmigiani method are quite sensitive to varying assumptions about the age specific incidence function of breast and ovarian cancer in mutation carriers and in the general population. In the C.O.S. project the method has been improved using generation specific incidence functions estimated from age-period-cohort models, i.e. a different function for each family member. As a consequence it provides more accurate estimates of the breast and ovarian cancer cases that one would expect in the family, either if the family harbour a mutation or not. The lifetime cumulative breast cancer risk of a European woman born in the fifties, in fact, is about three times higher than the risk of her grandmother born at the beginning of the 20th century. A similar cohort effect has also been shown for mutation carriers.
The specific software developed for the C.O.S. project provides an estimate of the probability that a breast cancer patient carry an high penetrance BRCA 1 or 2 mutation on the basis of her family history.
It requires the following assumptions:
- The prevalence of mutation in the population (more specifically the software incorporates the allele frequency),
- Birth cohort specific incidence curves of breast and ovarian cancer in the general population, and
- Birth cohort specific incidence curves in carriers of BRCA mutation, i.e. the penetrance. It requires entering dates of birth, death and diagnosis of breast and ovarian cancer for all members of the family. Country and cohort specific incidence estimates have been computed on the basis of mathematical modelling of mortality and survival trends.
The validity of the estimates has been checked plotting estimated incidence trends against the trends observed by cancer registries operating since several decades. Country specific estimates have been used for Estonia, France, Germany, Italy, Scotland and Slovenia.
The same C.O.S. software has been used to estimate the penetance function of BRCA1 and BRCA2 mutations. Instead of estimating the probability of mutation given the family history, in fact, it can estimate the best penetrance curves to explain the observed incidence in a series of families with proven mutation. Based on a numerical maximisation method, the model identifies the curves that maximise the probability of observing the clinical history of the families.
Several authors have estimated BRCA allelic frequencies in western populations. We have used the following estimates:0.00120 for BRCA1 and 0.00044 for BRCA2 for all countries except Israel, for which we have used the allelic frequencies estimated for the Ashkenazi population, the most prevalent ethnic group in Israel: 0.0100 for BRCA1 and 0.0036 for BRCA2.
The main hypotheses of the COS project were:
- That a diet rich in fruit and vegetable, and in antioxidant micronutrients, is more protective in women with genetic predisposition than in women with wild type BRCA genes, because such a diet may protect DNA from oxidative damage. This hypothesis is largely falsified by the C.O.S. results on total and specific fruits and on antioxidant vitamins. A possible limitation of our results is that the widespread recommendation of increasing the consumption of fruit and vegetables to prevent cancer may have induced patients belonging to families with several cancer cases to change their diet and increase fruit and vegetables by a greater extent than patients belonging to families without cancer cases.
- That cruciferous vegetables are more protective in presence of BRCA mutations, because of their high content in indolyl glucosinolates, which upon hydrolysis yield indole-3-carbinol and its dimer diindolylmetane. These substances reduce estrogenic activity by favouring the 2-hydroxilation pathway with respect to the more estrogenic 16-hydroxilation act as androgen antagonists, help detoxifying carcinogenic xenobiotics through the activation of phase-1 and phase-2 enzymes, and upregulate BRCA1 expression. This hypothesis has been fairly strongly corroborated by our results.
- That phytoestrogens are more protective in BRCA mutation carriers. Phytoestrogens are plant polyphenols with week estrogenic activity that may reduce estrogenic stimuli by preventing the link of endogenous estrogens to estrogen receptors (Magee and Rowland, 2002). They are present in soy products (mainly isoflavonoids) and in several other seeds (mainly lignans). Another possible preventive mechanism is that soy isoflavonoids may upregulate BRCA1 expression Upregulation of BRCA expression in women with a germline mutation is important because one functional allele is still present in every cell. We observed a lower interaction OR for soy products consumption, but the proportion of consumers was too low for any firm conclusion.. The hypothesis, therefore, is neither corroborated nor falsified.
- That elevated waist to hip ratio, a marker of insulin resistance, is associated with increasing risk in mutation carriers. This observation was not confirmed by the C.O.S. study, but there was a suggestion that adult obesity, contrary to the general observations in premenopausal women, may be associated with increasing risk in carriers of mutated BRCA genes.
- That foods that increase insulin and IGF-I levels increase breast cancer risk by a greater extent in presence of mutated BRCA genes. Highly refined carbohydrates may stimulate insulin production by causing rapid increases in glycaemia, and saturated fat by increasing insulin resistance. Milk, on the contrary, despite its low glicemic index, directly stimulate insulin production or release. There is evidence that it is the whey fraction of milk protein, which is the fraction that remains in milk serum after cheese production, that contains the predominating insulin secretagogue, and that fermented milk may reduce the insulinemic index of refined cereals. These observations may explain why C.O.S. did not show any interaction with butter, cream, cheese, and even suggested a protective effect of yogurt. Milk consumption, on the other hand, has been consistently found associated with higher plasma levels of IGF-I. High levels of IGF-I may actually be a major determinant of the early occurrence of breast cancer in BRCA mutation carriers, and studies to evaluate this biomarker are urgently needed. C.O.S. results strongly corroborated the hypothesis of an interaction with milk. Results were also consistent, without reaching statistical significance, with an interaction with simple sugars and with the food group including cakes, pies, cookies and biscuits. The latter interaction, however, might be due to the presence of milk in the recipes.
- That tobacco smoking might be protective in mutation carriers, because tobacco may reduce estrogenic stimulation by shifting oestrogen metabolism from 16 to 2-hydroxilation (Bradlow 1996). Our study definitely falsified this hypothesis.
The cloning of two breast cancer susceptibility genes (BRCA1 and 2), along with the introduction of predictive genetic testing, has allowed for the identification of high-risk women. Options currently available for these women include surveillance programs aimed at early detection, prophylactic bilateral mastectomy, and prophylactic oophorectomy, while non-surgical primary prevention options (e.g. chemopreventive options for interrupting the oestrogen-signalling pathway) are not yet firmly established.
The present C.O.S. study is the first study addressing the interaction of dietary habits with BRCA gene mutations. Results indicate that susceptible women have further options for reducing their breast cancer risk. These are sustainable dietary modification as simple as avoiding the consumption of cow milk and increasing the consumption of cruciferous vegetables, suck as broccoli, cabbage, cauliflower and Brussels sprouts. This is the base for implementing dietary recommendations in family clinics for the prevention of heritable breast cancer.
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