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Nazário ACP et al.
544 Rev Assoc Med Bras 2015; 61(6):543-552
cancer. BRCA2 is located on chromosome 13 and is associ-
ated with high susceptibility to breast (45%) and ovarian
(11%) cancer, as well as male breast cancer (RR=15).
In most cases, however, the genetic changes are not in-
herited but acquired during life, being a sporadic breast
cancer (70% of cases). This is defined as a cancer in which
no case is observed in two entire generations of 1st and 2nd
degrees. The genetic defect usually results from activation
of one or more proto-oncogenes present in healthy cells.
Most oncogenes encode growth factors and their receptors.
Familial breast cancer accounts for 20% of cases and, al-
though there is a history in 1st or 2nd degree relatives, the
autosomal dominant pedigree is not characterized. Through
the activation of a proto-oncogene or the inactivation of
suppressor genes, the modified cell transmits the error to
next generation cells and so on. The genetic error can be
repaired or the cell is induced to undergo apoptosis. When
this does not occur, the genetic error can be perpetuated;
the neoplastic cell is stimulated to divide forming mutat-
ed cell clones, which characterizes the promotion stage.
Among the factors that promote breast cancer, the
most important are those that maintain the lobe in con-
stant process of cell division, which hinders the physio-
logical repair processes. External (exogenous) or internal
(endogenous) stimuli favor the multiplication of cells
containing genetic changes. The mutated cell clones, how-
ever, do not have the capacity to invade adjacent tissues,
being restricted to the basal membrane (carcinoma in situ).
Sex steroids and growth factors are very important for
promotion. Thus, the main driving factors for breast can-
cer are of reproductive nature, such as early menarche,
late menopause, nulliparity or oligoparity, and late first
pregnancy. The common denominator is the continued
cyclical estrogen-progestogen stimulation (ovulation)
without the restorative break of pregnancy and lactation;
in fact, the sex steroids act synergistically to keep the
breast lobules in constant proliferation.
The pre-clinical stage, that is, the time interval be-
tween the first mutated cell and the formation of a ma-
lignant nodule measuring 1.0 cm (containing 109 cells)
is relatively long, approximately 8 years. However, once
this volume is reached, the nodule’s size doubles every
100 days. From a clinical point of view, at initiation and
the primary stages of promotion, diagnosis using the
available screening methods is not possible. But in the
later stages of neoplastic promotion, with precursor le-
sions (atypical hyperplasia and ductal carcinoma in situ)
already established, early detection through mammogra-
phy is possible. It is believed that, between the normal ep-
ithelium and the invading carcinoma, intermediate
stages of typical and atypical hyperplasia and in situ car-
cinoma can be seen, although not necessarily.
In the stage of progression, the already consolidated
carcinoma breaks the basal membrane, invades blood and
lymphatic vessels, and is capable of reaching tissues and
proliferating at distance (metastasis). Angiogenesis and
proteolytic enzymes, such as cathepsin D, have an impor-
tant role at this stage. The carcinoma begins to form pal-
pable nodules that can be detected on physical and self-
examination. Inexorably, the disease progresses, produces
distant metastases, the main sites being the bones, lungs
and pleura, liver and brain.
Diagnosis
The diagnosis of breast cancer these days, very often, is
done in its subclinical form, through routine mammog-
raphy or population screening programs. In the US, mor-
tality fell by 30% in women over 50 years old and 19% be-
tween 40 and 49 years on the account of earlier diagnosis.
The BI-RADS™ (Breast Imaging Reporting And Data Sys-
tem) was implemented as a screening method, and con-
stitutes a report and terminology standardization system
that ranks the abnormalities seen on imaging studies into
categories, as recommended by the American College of
Radiology (Table 1).
TABLE 1BI-RADS™ classification.
Category Definition Risk of cancer (%)
0 Inconclusive result Additional imaging
Investigation required
I Negative findings 0
II Benign findings 0
III Probably benign findings < 2
IV Suspicious findings 3-94
V Highly suspicious findings ≥ 95
VI Known biopsy-proven
malignant lesion
100
Breast exam has moderate sensitivity and good specifici-
ty for the detection of cancer, and the predictive value
varies according to age. Sensitivity is from 57 and 83% be-
tween 50 and 59 years, and 71% between 40 and 49 years.
Specificity, in turn, is greater, 88 to 96% between 50 and
59 years and 71 to 84% among women aged 40 to 49 years.
It is particularly useful in younger women, due to the lim-
itation of mammography in this age group (dense breasts).
Mammography is the standard method for screening
and diagnosis of breast cancer. Even in cases where the clin-
ical picture is suggestive, a mammogram should be indi-