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.

Oncoprescribe Blog Bevacizumab and CNS metastases

The role of Bevacizumab in combination with chemotherapy for patients with advanced Non Small Cell Lung Cancer is well established. However the safety of Bevacizumab in this patient population with brain metastases has been unclear with the potential risk of CNS bleed. This issue was addressed in the PASSPORT trial which enrolled nonsquamous histology Non Small Cell Lung Cancer patients with treated brain metastases. The addition of bevacizumab to conventional chemotherapy or erlotinib in this trial was associated with a low incidence of CNS bleed suggesting that bevacizumab could be safely given for patients with Non Small Cell Lung Cancer with treated brain metastases.