- large tumors (> 3 cm) will shrink and allow breast-conserving surgery, with low rate of recurrence
- neoadjuvant hormone therapy vs. neoadjuvant chemotherapy vs. ovarian ablation
- CMF vs. ovarian +/- prednisolone 7.5 mg for 5 yrs compared and no difference in survival was detected
- ovarian ablation may have adverse effect on bone mineralization and protection against coronary artery disease and libido (Scottish Cancer Trials Breast Group 1993)
- lots of T4 in chemotherapy group vs. letrozole group (Thomas, Julian, et al. Histopathology 2007)
- Compared with CMF-type regimen, anthracycline-containing chemotherapy achieves higher response rates and slightly improves survival(A'Hern et al 1993), however increased toxicity needs to be considered.
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Cyclophosphamide Methotrexate Fluorouracil (CMF) is a commonly used regimen of chemotherapy, and is one of the more toxic regimens used. It is named for the three medicines that comprise the therapy: cyclophosphamide, methotrexate, and 5-fluorouracil.
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Anthracyclines are a class of chemotherapeutic agents based upon samine and tetra-hydro-naphthacene-dione. These compounds are used to treat a wide range of cancers, including (but not limited to) leukemias, lymphomas, and breast, uterine, ovarian, and lung cancers.Available agents include:
- Daunorubicin
- Daunorubicin (liposomal)
- Doxorubicin
- Doxorubicin (liposomal)
- Epirubicin
- Idarubicin
- Mitoxantrone
Anthracyclines technically are also antibiotics, although their high toxicity precludes their use as such.
[edit] Mechanism of action
Anthracyclines inhibit DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells.
They also create iron-mediated free oxygen radicals that damage the DNA and cell membranes.
[edit] Cardiotoxicity
As well as many of the expected adverse reactions of chemotherapeutic agents, anthracyclines are notorious for causing cardiotoxicity. This cardiotoxicity may be caused by many factors, which may include interference with the ryanodine receptors of the sarcoplasmic reticulum in the heart muscle cells, free radical formation in the heart or from buildup of metabolic products of the anthracycline in the heart. The cardioxicity often presents as EKG changes and arrhythmias, or as a cardiomyopathy leading to congestive heart failure (sometimes presenting many years after treatment). This cardiotoxicity is related to a patient's cumulative lifetime dose. A patient's lifetime dose is calculated during treatment, and anthracycline treatment is usually stopped (or at least re-evaluated by the oncologist) upon reaching the maximum cumulative dose of the particular anthracycline.
There exists evidence that the affect of cardiotoxicity increases in long term survivors, from 2% after 2 years to 5% after 15 years. [1]
Dexrazoxane is a cardioprotectant agent that is sometimes used to reduce the risk of cardiotoxicity. Liposomal formulations of daunorubicin and doxorubicin have been approved that appear to be somewhat less toxic to cardiac tissue.
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Letrozole (INN, trade name Femara®) is an oral non-steroidal aromatase inhibitor that has been introduced for the adjuvant treatment of hormonally-responsive breast cancer
Estrogens are produced by the conversion of androgens through the activity of the aromatase enzyme. Letrozole blocks production of estrogens in this way by competitive, reversible binding to the heme of its cytochrome P450 unit. The action is specific, and letrozole does not reduce production of mineralo- or corticosteroids. In contrast, the antiestrogenic action of tamoxifen, the major medical therapy prior to the arrival of aromatase inhibitors, is due to its interfering with the estrogen receptor, rather than inhibiting estrogen production.
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Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2/neu (erbB2) receptor. Trastuzumab's principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over express (produce more than the usual amount of) this receptor. Trastuzumab is administered either once a week or once every three weeks intravenously for 30 to 90 minutes.
Mechanism of action
Amplification of ErbB2 occurs in 25-30% of early-stage breast cancers.[1] It encodes the transmembrane tyrosine kinase p185-erbB2 glycoprotein. Although the signaling pathways induced by the erbB2 receptor are incompletely characterized, it is thought that activation of the PI3K/Akt pathway is important. This pathway is normally associated with mitogenic signaling involving the MAPK pathway. However in cancer the growth promoting signals from erbB2 are constitutively transmitted — promoting invasion, survival and angiogenesis of cells.[2] Furthermore overexpression can also confer therapeutic resistance to cancer therapies. The prime mechanism that causes increase in proliferation speed is due to induction of p27Kip1, an inhibitor of cdk2 and of cell proliferation, to remain in the cytoplasm instead of translocation in to the nucleus.[3] This is caused by phosphorylation by Akt.
Trastuzumab is a humanized monoclonal antibody which binds to the extracellular segment of the erbB2 receptor. Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferation. It has been suggested that trastuzumab induces some of its effect by downregulation of erbB2 leading to disruption of receptor dimerization and signaling through the downstream PI3K cascade. P27Kip1 is then not phosphorylated and is able to enter the nucleus and inhibit cdk2 activity, causing cell cycle arrest.[3] Also, trastuzumab suppresses angiogenesis by both induction of antiangiogenic factors and repression of proangiogenic factors. It is thought that a contribution to the unregulated growth observed in cancer could be due to proteolytic cleavage of erbB2 that results in the release of the extracellular domain. Trastuzumab has been shown to inhibit erbB2 ectodomain cleavage in breast cancer cells.[4] There may be other undiscovered mechanisms by which trastuzumab induces regression in cancer.
[edit] Predicting response to therapy
The initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression. Various methodologies have been developed to identify overexpression of HER-2. In the routine clinical laboratory, the most commonly employed methods are immunohistochemistry (IHC) and either chromogenic or fluorescent in situ hybridisation (CISH/FISH). In addition numerous PCR-based methodologies have also been described.
Routine HER-2 status is performed by IHC, and there are currently two FDA-approved commercial kits available; Dako Herceptest tm and the Ventana Pathway tm. These are highly standardised, semi-quantitative assays which stratify expression levels into; 0 (<20,000> 10% of cells overexpressing HER-2), and 3+ (~2,000,000 receptors per cell, strong complete membrane staining, > 10% of cells overexpressing HER-2). The presence of cytoplasmic expression is disregarded. Treatment with trastuzumab is indicated in cases where HER-2 expression has a score of 3+. However, IHC has been shown to have numerous limitations, both technical and interpretative, which have been found to impact on the reproducibility and accuracy of results, especially when compared with ISH methodologies. It is also true, however, that some reports have stated that IHC provides excellent correlation between gene copy number and protein expression.
Fluorescent in situ hybridization (FISH) is viewed as being the “gold standard” technique in identifying patients who would benefit from trastuzumab. It is, however expensive, and requires a fluorescent microscope and an image capture system. The main expense involved with CISH is in the purchase of FDA-approved kits, and as it is not a fluorescent technique it does not require specialist microscopy and slides may be kept permanently. Comparative studies between CISH and FISH have shown that these two techniques show excellent correlation. The lack of a separate chromosome 17 probe on the same section is an issue with regards to acceptance of CISH.
Currently the recommended assays are a combination of IHC and FISH, whereby IHC scores of 0 and 1+ are negative, scores of 3+ are positive, and scores of 2+ and 2+/3+ are refereed to FISH for definitive diagnosis.
