This plant alkaloid originally isolated from the evergreen tree Cephalotaxus and in use for acute and chronic leukemias for over 25 years in China, will soon become available in a semisynthetic formulation (omacetaxine). This agent has now been proven to be safe and effective in patients with Chronic Myeloid Leukemia (CML) with T315I mutation. It should be noted that approximately 15% of the patients resistant to imatinib and 30% resistant to dasatinib and nilotinib harbor T315I mutation. The mechanism of action of this compound is independent of tyrosine kinase inhibiton. This drug is administered as a subcutaneous injection and is a giant leap in overcoming resistance to Tyrosine Kinase Inhibitors (TKI) in CML patients.
Author: RR
Oncoprescribe Blog MammaPrint Multigene Assays – On the cutting edge of Personalized Medicine
This MammaPrint technology is capable of predicting the risk of recurrence of breast cancer, in patients with node negative, stage I and II invasive breast cancer whose tumors are 5cm or less in size regardless of the hormone receptor and menopausal status. This FDA approved test uses microarray analysis and looks at 70 critical genes capable of predicting prognosis and classifies patients into low risk (10% chance of recurrence in 10 years without any adjuvant therapy) or high risk (29% chance of recurrence in 10 years without any adjuvant therapy). It can further subclassify breast cancer using molecular subtyping into Luminal type, Basal type and ERBB2 (HER-2) subtypes.
This technology differs from Oncotype DX assay in that fresh tissue specimen is required for testing, hormone receptor status and menopausal state are not relevant and patients are classified into low risk and high risk categories without an intermediate risk group. Decisive treatment recommendations can therefore be made.
This testing methodology has been extensively validated and will help us decide who would and who would not benefit from chemotherapy. With the ability to sub type breast cancer based on molecular profiling and the benefits demonstrated with PARP (Poly (ADP-ribose) polymerase inhibitors in the triple negative (Basal type) breast cancer patients, the era of personalized medicine is welcome news for patients with breast cancer. There is also promising data demonstrating the benefit of this test in predicting disease outcome in patients with 1-3 positive lymph nodes as well as its ability to predict response following neoadjuvant chemotherapy in breast cancer.
Oncoprescribe Blog Improving Survival in Advanced Malignant Melanoma
Advanced malignant melanoma has been an elusive disease with very few treatment options. There has been no treatment available to improve survival. That changed in June 2010 following the presentation of results from a landmark study.
Ipilimumab is an antibody that targets an antigen called CTLA-4 (Cytotoxic T- Lymphocyte-associated Antigen 4) present on the surface of T cells. T cells or T lymphocytes play a key role in cell mediated immunity. CTLA-4 which is present on the surface of T cells has a negative effect on T cell activation. By blocking CTLA-4, T cells are activated to attack and kill melanoma cells.
Ipilimumab in a randomized phase III trial doubled the survival rates compared to the control group. Studies are underway combining this agent with BRAF inhibitors. Stay tuned.
Oncoprescribe Blog ALK inhibitors in NSCLC – Refining individualized therapy
The therapeutic target of interest is an aberrant fusion gene, EML4-ALK. EML4 (echinoderm microtubule-associated protein-like4) – ALK (anaplastic lymphoma kinase) is a fusion-type oncoprotein and is tyrosine kinase. This oncoprotein/tyrosine kinase is found in 2-7% of all Non Small Cell Lung Cancers (NSCLC) and is generated due to an inversion in the short arm of chromosome 2. This oncoprotein is more prevalent in patients with adenocarcinoma who have little or no exposure to tobacco. Tyrosine kinases normally play an important role in cellular proliferation and differentiation. However with point mutations, translocation/rearrangement and amplifications of their respective genes, these tyrosine kinases can potentially cause malignancy. Such is the case with mutations or translocations of the Anaplastic Lymphoma Kinase gene (ALK). In an article published in the October 28, 2010 issue of the NEJM, Crizotinib an oral small molecule tyrosine kinase inhibitor of ALK tyrosine kinase resulted in an overall response rate of 57% in patients who had progressed on prior therapies. Stable disease was noted in 33% of the patients. This is remarkable considering that the response rates in this patient population treated with second line chemotherapy is around 10-15%.
As we move forward, it is very likely that genotyping patients and tailoring therapy accordingly, will become standard practice.
Oncoprescribe Blog Triple Negative Breast Cancers – A different breed
Using DNA microarray analysis breast tumors can be divided into 5 subtypes:
1) Luminal A: Tumor cells originate from luminal epithelium and have high levels of ER expression, express cytokeratin (CK) 8 and 18, are low grade, are less responsive to chemotherapy and have a good prognosis
2) Luminal B: Similar to Luminal A with a different gene expression profile. Prognosis in this subtype is slightly worse than in Luminal A.
3) Basal-like: Express markers of basal or myoepithelial cells CK 5/6, CK 8/18, vimentin, smooth muscle actin and EGFR. Tumors are ER, PR and HER negative (Triple negative). P53 mutations are common in this subtype. Tumors tend to be aggressive and this subtype includes BRCA-1 mutant tumors. This is a heterogenous group and only 70% of triple negative breast tumors fall into this subtype.
4) HER-2 amplified: Tumors have amplificated HER gene located on the long arm of chromosome 17 and are usually ER and PR negative but have upregulation of vascular endothelial growth factor (VEGF). The aggressive behavior of these tumors has been tempered with the availability of trastuzumab.
5) Normal breast-like: Tumors have gene expression profile similar to normal breast epithelium and prognosis is similar to Luminal B subtype
This molecular classification may help us better understand the biology of breast tumors and thus develop and plan therapy accordingly
Oncoprescribe Blog To treat or not to treat Stage II colon cancer? – Molecular Markers to the rescue
As we understand the molecular biology of colon cancer, it is becoming clear that tumors with MisMatch Repair Deficiency (MMR-D) and high MicroSatellite Instability (MSI) tend to have a favorable prognosis and do not benefit from chemotherapy and on the contrary, 5-FU based chemotherapy may potentially result in a detrimental effect. The Oncotype DX colon cancer 12 gene assay is a valuable tool that can provide additional information in the decision making process.
Oncoprescribe Blog Malignant Melanoma – An Elusive Disease?
Not anymore. A point mutation in the BRAF proto-oncogene has now been identified. This is detected in approximately 60% of the patients with metastatic melanoma. This mutation appears to be one of the key genetic drivers responsible of the initiation and progression of malignant melanoma. Several selective BRAF inhibitors are in development and these agents have demonstrated significantly high overall response rates. In addition to the anti-CTLA-4 monoclonal antibodies we may soon have a new player with a different mechanism of action to combat this deadly disease.
Oncoprescribe Blog Fulvestrant in Metastatic Breast cancer- New Dosing Schedule
Fulvestrant is a selective estrogen receptor downregulator administered as an injection once a month. Approved in April 2002 by the FDA for the treatment of hormone receptor positive metastatic breast cancer, the recommended dose was Faslodex 250 mg given intramuscularly once a month. FDA has now recommended a new dosing schedule based on the CONFIRM (Comparison of Faslodex in Recurrent or Metastatic Breast Cancer) trial, in which the new dosing schedule significantly prolonged progression free survival compared to the originally recommended dose. The new dosing schedule is as follows – Faslodex 500 mg given intramuscularly on days 1,15 and 29 and monthly thereafter.
Oncoprescribe Blog More progress in Chronic Myeloid Leukemia
Imatinib, a breakthru development in the treatment of CML has been the standard first line treatment for the past several years. This is about to change following presentations at the ASH 2009 and ASCO 2010 meetings.
In the first study Dasatinib was compared head to head with Imatinib in newly diagnosed patients with CML. The complete cytogenetic responses and major molecular responses were higher in the Dasatinib group and these responses were acheived sooner than in the Imatinib group.
In the second study Nilotinib compared to Imatinib in newly diagnosed CML patients resulted in superior complete cytogenetic and major molecular responses.
These second generation BCR-ABL tyrosine kinase inhibitors may take over as first line treatment of CML although economics could play a major role.
Oncoprescribe Blog Another shot at postmenomausal hormone therapy and Breast Cancer
The results of the Women’s Health Initiative (WHI) trial which began in 1993, was updated after a 11 year followup. The outcomes from this study should give us pause as we consider postmenopausal hormonal therapy. The conclusions of this study published in JAMA are clear. Estrogen plus Progestin in postmenopausal women not only increases the risk of breast cancer but also results in more advanced cancer at the time of diagnosis. Further there is an increased rate of breast cancer death in this population. Whether short term use of hormonal treatment in postmenopausal individuals to alleviate symptoms is safe, remains unknown and it may be wise not to consider hormonal treatment in these individuals.