Research associates post-menopausal breast density with mutation
Karina Toledo/AGÊNCIA FAPESP/DICYT As women age, the firm glandular tissue of the breasts is slowly replaced by fat. In medical terms, the breast loses density and becomes “liposubstituted.” However, in certain cases, the breasts remain dense, even after menopause. What may seem to be an esthetic advantage is a factor that, according to the scientific literature, may increase the risk of breast cancer by nearly four to six times.
A recently conducted study that involved 463 patients at the Hospital das Clínicas (HC) of the School of Medicine at the University of São Paulo (FMUSP) showed that the group of women who had dense breasts were 75% more likely to carry a mutation known as Pvull, which affects the estrogen receptor gene in the breasts and increases hormonal action in this tissue. The findings were published in the December 2013 issue of The Journal of Cancer Science & Therapy.
The study was conducted during the doctoral work of Marilene Alicia de Souza, under the mentorship of FMUSP professor Angela Maggio da Fonseca, coordinator of the FAPESP-funded project “The obesity with and without metabolic syndrome as a risk factor for the breast cancer.”
“Our hypothesis was that this mutation in the estrogen gene receptor, which is hereditary, could lead to post-menopausal high breast density, which is an important risk factor for cancer. The data confirmed our hypothesis,” said Souza.
The study participants – between the ages of 45 and 65, all of whom had not menstruated for at least one year – were divided into two groups: 308 women with dense breasts and 155 women (controls) with low breast density.
“More than 4,000 women were initially evaluated, but we excluded those on hormone therapy and those with suspected or previous breast cancer,” explained Souza.
All of the volunteers who were considered to be eligible underwent genetic sequencing to determine the presence of the mutation; mammography; and an examination of weight, height and body mass index (BMI) and answered a questionnaire regarding family history and daily habits.
The results revealed that cases of breast cancer were more frequently observed in the families of women in the group that had dense breasts. Whereas only 4% of the general population of women have first-degree relatives (mothers and daughters) with cancer, the frequency was 19% in the population studied.
“What worried us most is that we noted a higher frequency of other behavioral risk factors, unrelated to this genetic characteristic, in this group of women. Generally speaking, they had fewer pregnancies, and we know that with every pregnancy, the chance of being classified as having high breast density diminishes by 17%. We also noted a higher frequency of late pregnancies (above the age of 28). Cancer risk increases by 5.3% for every year of delay in the first full-term pregnancy. In addition, there were more smokers and regular users of alcohol. That amounts to several risk factors for breast cancer beginning to add up,” cautioned Souza.
Several previous studies have shown that pregnancy – especially before the age of 28 – and breastfeeding have a protective effect against breast cancer because they induce the full differentiation of the cells of the mammary glands.
Breast density in post-menopausal women is an indicator of a greater presence of non-differentiated cells, which are more susceptible to mutations that lead to cancer. In addition, estrogen induces increased cell proliferation in the tissue, further elevating the risk of mutations.
“These findings alert us to the need to treat these higher-risk women differently. Genetic sequencing is easy and should be performed on everyone with a family history of cancer and post-menopausal high breast density. Once the presence of the Pvull genetic polymorphism is confirmed, stringent monitoring will need to be performed, including examinations every six months,” said Souza.
The physician also defended the possibility of using preventive therapy in these cases. “One of the options that could be studied is use of the drug tamoxifen, which is capable of reducing hormonal action in the breasts. Many women who suffer from mastalgia (breast pain) already use this drug,” she said.
Although the group of women with dense breasts, on average, had a lower BMI than did the control group, the obesity rate – another known risk factor for breast cancer – was high: 40.7%. “These data are disturbing because they constitute two important risk factors that begin to add up,” said Souza.
The group of researchers also investigated another mutation, known as XbaI, that affects the estrogen receptor gene in the breast. “Unlike Pvull, XbaI did not have a strong correlation with post-menopausal high breast density. Instead, the XbaI mutation seems to unleash hormonal action that favors obesity. Nearly 69% of those who carried the mutation had a BMI over 25, compared with 30% of women without the XbaI mutation. The data are in line with the literature,” said Souza.
Other findings from the study were published in three articles in the journal Gynecological Endocrinology, in February 2013, August 2013 and January 2014.