الفهرس 
Traditional histopathological prognostic and predictive factorsOnly 14 pages are availabe for public view
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Abstract
Breast cancer is the most frequent cancer in women and the second most frequent cause of cancer death. In Egypt, it accounts for as high as 37.6% of all reported tumors in females.
Many guidelines have been issued to categorize patients into prognostic groups, according to histopathologic assessment and extension of the disease, and to assign the best treatment to each of this groups.
This essay aims to emphasize that in the era of personalized medicine, and due to the potential curability of early breast cancer, it became mandatory to develop new markers that could better predict clinical behavior, the response to a certain treatment and the risk of developing adverse reactions.
Many studies evaluated individual molecular markers and found interesting results:
Proliferation is a key hallmark of cancer, and the nuclear protein Ki67 is a simple and reproducible biomarker for this process. Studies in the neoadjuvant setting supports that changes of this protein level along the course of treatment has a more prognostic value rather than it’s absolute pretreatment levels.
The IMPACT trial demonstrated that, low recurrence-free survival was significantly was associated with higher Ki67 expression after 2 weeks of endocrine therapy. On the other hand, baseline high Ki67 expression did not show such an association.
In assessment of angiogenesis, studies showed an association between VEGF genotype and median OS as well as grade 3 or 4 hypertension when using bevacizumab. bFGF overexpression was associated longer RFS and OS.
High tumor levels of VEGF led to breast tumors resisting chemotherapy with FAC or CMF and hormonal therapy with tamoxifen.
The hormonal status is one of the most important factors. Patients with ER+/PR+ tumors have the best survival and worsening cumulative cancer-specific survival is seen from ER+/PR+ to ER+/PR- to ER-/PR+ to ER-/PR- tumors.
ER and PR status are not always stable phenotypes and they can, in fact, change over the natural history of the disease or as a consequence of endocrine treatment.
ERα possesses several phosphorylation sites which may modulate ERα action and activate functions through a ligand-independent mechanism. Phosphorylation at Ser167-ERαhas been shown to be a good prognostic factor in primary breast cancer. Ser118-ERα phosphorylation is a feature of normal ERα function but an increase in levels of phosphorylation at this site may play a key role in the emergence of endocrine resistance in breast cancer.
Some studies seemed to prove that elevated ERβ levels correlated with tamoxifen resistance. Other studies about its predictive value were contradictory.
The ER coregulators were able to regulate the relative agonist/antagonist activity of the SERM tamoxifen, and it has been suggested that the coactivator:corepressor ratio may be important both in endocrine therapy responsiveness and the development of resistance. The most relevant findings have been obtained with the two coactivators AIB1 and SRC-1, and the corepressor NCOR1.
Studies on PR indicate that it may be a better indicator than ER for predicting response to SERM therapy since levels of PR reflect the combined and integrated effects of ER and growth factor activity. The ratio between PR-A and PR-B is also of importance. In poor prognostic tumors, the ratio between PR-A and PR-B is altered, with PR-A predominating and loss of PR-B.
The activation of growth factor regulated signaling pathways is also implicated in breast cancer cells behavior. Elevated activation of ERK1/2 MAP kinase, p38 and PI3K/Akt and mTOR signaling pathway have been associated with the more aggressive growth and de novo or acquired endocrine resistant cells.
HER2 overexpression is associated with worse prognosis and predicts response to anthracyclines, taxanes and targeted therapy (trastuzumab, lapatinib). However, in terminally truncated receptors containing the kinase domain, there is a poor response to trastuzumab but are inhibited by lapatinib.
The role of TOP2A as a predictive factor for anthracycline activity is still unclear and in women with HER2/TOPO2A co-amplified tumors, trastuzumab may not be required in addition to an anthracycline-containing regimen.
BRCA1-associated tumors usually are of the basal type, and are sensitive to chemotherapies that induce DNA inter-strand cross-links such as platinum salts, to EGFR inhibitors and PARP1 inhibitors.
There are a large number of molecular markers, which have different prognostic and predictive values. Evaluation of the wide variety of markers sometimes shows contradictory results and is often difficult to interpret. This has let to the implementation of a single test that can categorize patients, using a scoring system which take into consideration these different markers.
Studies using complementary DNA (cDNA) microarrays were able to identify 5 different molecular subtypes of breast cancer: luminal-like A and B, basal-like, HER2-positive, and normal breast like, associated with different prognosis.
cDNA microarrays were found to be significant predictors of distant recurrence and overall survival. Recent data shows a predictive value of these tests to chemotherapy and hormonal treatment. Actually, 2 large randomized control trials (TAILORx and MINDACT) are evaluating the prognostic and predictive value of this test.