**7. Conclusion**

80 Breast Cancer – Focusing Tumor Microenvironment, Stem Cells and Metastasis

combinations), doxorubicin (Adriamycin), epirubicin, paclitaxel (Taxol), and docetaxol (Taxotere). Although the benefit and clinical outcome of chemotherapy is dependent on clinical and histopathological parameters, but there are a percentage of cases that behave in an unexpected manner, even if the clinical and pathological parameters indicate the opposite (Gonzalez-Angulo et al., 2007). The introduction of hormonal receptor status to the classical clinical parameters improved the clinical outcome (Goldhirsch et al., 2003). The chemotherapeutic drugs are designed to target the specific molecular markers (molecular targeted therapy) overexpressed in cancer tissues. The presence of ER is correlated with a better prognosis, predicting response to hormonal therapies such as tamoxifen and aromatase inhibitors. But still 15-20% of breast cancer patients with ER+ have recurrent disease. It's the luminal B subgroup of previously classified ER+ tumor that is irresponsive to tamoxifen treatment as they co-express EGFRs and shows poor relapse-free survival (RFS) and over-all survival (OS). Thus over-simplified classification based on ER status required additional molecular makers for sub-classification for optimal treatment. The molecular portraits based on gene profiling divides breast carcinomas into luminal (A and B), basal, HER-2 and normal like. Basal and HER-2 types normally overexpress EGFR and HER-2 respectively. EGFR and HER-2 is overexpressed in 17-30% and 20-30% respectively in breast cancer. Both EGFR and HER-2 is associated with poor prognosis and worse clinical outcome. Basal like subtypes are more aggressive and less responsive to conventional chemotherapy and expected to benefit from EGFR-targeted therapies. Tyrosine kinase inhibitors (TKI) (ZD1839, ZD6474) in combined with anthracyclines (doxorubicin, epirubicin) or taxanes based regimens will improve the clinical outcome of the basal subtypes. HER-2 might serve as a marker for tissue HER-2 status, especially for the prediction of benefit from trastuzumab and/or chemotherapy regimens (anthracyclines) (Sandri et al., 2004). Although the molecular profile of the tumor is a major determinant of disease progression and response to treatment, other factors including chemo- sensitvity or resistivity may be of considerable importance. It is found that for 100 node-negative, premenopausal women receiving chemotherapy according to standard criteria, at 5 years 3 are cured by chemotherapy, 83.50 would have been alive without chemotherapy and 13.50 die despite chemotherapy. With application of molecular profiling to predict the outcome (for the same 100 people), the number treated would be reduced to 39.05 (allowing for a false-positive rate equivalent to that seen in the van 't Veer study (van 't Veer et al., 2002), resulting in an increase in the proportion cured (from 3 out of 100 to 3 out of 39 or 8%). If it were possible to predict chemo-responsiveness, it is possible that the number receiving chemotherapy would reduce further from 39.05 to 29.20 (allowing for a false-positive rate equivalent to that seen in the van't Veer study). In this scenario, the proportion cured by chemotherapy would be 3 out of 29.20 (10.16%) (>3-fold increase in survival rate using chemotherapy), and the number of women treated has been reduced by 70.80%. Thus it is found that molecular profiling will enhance the survival benefit of chemotherapeutic regimens, which will be further improved applying the knowledge of chemo-responsiveness as shown in Fig. 7. If accurate determination of chemo-sensitivity were achieved by observing the set of genes responsible for treatment response, the overall number receiving cytotoxic treatment unnecessarily would decrease, and the overall survival benefit derived, per person treated, increase accordingly, as shown in Fig. 7. However, the absolute survival benefit of patients diagnosed with breast cancer would be unaffected and would be improved with more molecular subtypes along with the development of specific agents

targeting particular biomarkers (molecular targeted therapy).

Adjuvant chemo- and radiotherapy improves survival of patients but it is being increasingly recognized that the benefit is not equal for all patients of breast cancer. Molecular characteristics of the cancer affect sensitivity to chemo- and radiotherapy. In general, ER- (Basal and HER-2) is more sensitive to chemotherapy than ER+ (Luminal A and Luminal B) breast cancer where as ER+ is more sensitive to radiotherapy than ER- breast cancer. The prognostic predictions made by traditional histopathological based models and molecular based models are discordant in about 30% of the cases (van de Vijver et al., 2002), suggesting that one of these methods may be superior to the other or at least that the information they capture is complementary. Corollary to this, it is found that when both the type of classifications are combined (histopathological and molecular), it yield better prognostic values as observed in Fig. 6. It is currently unknown whether genomic tests based on molecular signatures yield a more accurate risk prediction than conventional models. A better prognostic test based on molecular classification with the knowledge of chemoresponsiveness could lead to a reduction in overtreatment of low-risk individuals who are falsely assigned to high-risk category by clinical variables. Such a test could also lead to better overall survival by correctly identifying high-risk individuals who might currently miss out on systemic therapy. Even if molecular classification do not prove to be better than clinical models in prognosis and prediction outcome of breast cancer, inclusion of their results, as additional variables, in current models could improve prognostic predictions.

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