Author: RR

Oncoprescribe Blog Personalized medicine for prostate cancer patients

RR

Prolaris is a molecular diagnostic tool developed by Myriad Genetics, Inc. This 46 gene panel is capable of predicting  aggressiveness of prostate cancer and can be used in conjunction with Gleason score and PSA. By measuring the  expression level of genes involved with cell cycle progression, this test is able to differentiate indolent from aggressive prostate cancers and therefore predict disease outcome.

In a retrospective analysis of 366 patients who had undergone radical prostatectomy and 337 patients with clinically localized prostate cancer, this gene panel was able to give a favorable and unfavorable score to patient subsets and thus predict clinical outcomes. This prognostic information will allow clinicians to recommend appropriate therapy at the time of diagnosis of prostate cancer.

So we have gene signature assays for breast cancer, colon cancer, lung cancer (oncoprescribe blog) and now for prostate cancer as well. In the end, patients benefit.

Oncoprescribe Blog Abiraterone – another promising agent in CRPC

RR

Abiraterone is a steroidal agent and inhibits CYP17A, an enzyme necessary for the production of androgen precursors and subsequently testosterone. It is capable of inhibiting testosterone production both in the adrenals as well as the testes.

Data from a recent phase III trial was presented at the ESMO meeting and in this International trial involving 1,195 patients, Abiraterone plus a steroid was compared with placebo plus steroid in patients with CRPC (Castrate-Resistant Prostate Cancer) who had failed chemotherapy with Docetaxel. Following an interim analysis and upon recommendation from the Independent Data Monitoring Committeee, the study had to be unblinded, as there was a significant improvement in overall survival in the group receiving Abiraterone. With the availability of several new agents for the treatment of CRPC, it may be important to properly sequence these available drugs to get the best of each treatment intervention and thus improve long term survival with limited toxicity.

Oncoprescribe Blog Cabazitaxel – Another new agent for CRPC

RR

Cabazitaxel is a microtubule inhibitor approved for the treatment of patients with CRPC (Castrate-Resistant Prostate Cancer) who have progressed on Docetaxel. This agent in a randomized phase III trial (TROPIC) demonstrated a significant improvement in Overall Survival (OS) compared with Mitoxantrone, with a 30% reduction in the risk of death. We now have another option for the treatment of CRPC which until not too long back was considered as a disease for which chemotherapy was not effective.

Oncoprescribe Blog CRPC – A wave of new agents, but first Sipuleucel-T

RR

This year 2 new agents have been approved for the treatment of Castrate-Resistant Prostate Cancer – Sipuleucel-T and Cabazitaxel. Sipuleucel-T is composed of autologous antigen-presenting cells (APC’s) from the patient, cultured with a fusion protein PA2024 (Prostate Acid Phosphatase-PAP linked to granulocyte/macrophage colony-stimulating factor). Prostatic Acid Phosphatase (PAP) is an antigen expressed in most prostate cancers. When administered, Sipuleucel-T an autologous active cellular immunotherapy stimulates T cell immunity against PAP and thus the prostate cancer cells. This agent demonstrated improvement in median survival and is best suited for those patients who are asymptomatic or have minimal symptoms with CRPC. It is important to note that this agent is given as three infusions 2 weeks apart and one may not see a drop in the PSA or improvement in the bone scan findings until after three months following treatment. For this reason it is best to consider this agent well before chemotherapy with docetaxel is planned. The number of patients who can be treated with this agent presently is limited due to various barriers associated with the processing of autologous Antigen Presenting Cells. It is important to realize that steroids may counter the T cell response associated with this agent and therefore should be avoided.

Oncoprescribe Blog Predicting Chemotherapy Benefit Using Tumor Gene Expression Signature In NSCLC

RR

A recently published article in JCO is a boost to personalized treatment in Non Small Cell Lung Cancer (NSCLC). A 15-gene expression signature derived from NSCLC tumor was able to predict survival after adjuvant chemotherapy with cisplatin and vinorelbine in patients with stage IB to II NSCLC. This study was done on tumors derived from cohort of patients in the JBR.10 trial where patients received adjuvant cisplatin and vinorelbine. Even though the survival predictability was specific for cisplatin and vinorelbine chemotherapy regimen with this 15-gene signature, one could anticipate the discovery of other tumor mRNA expression signatures for different chemotherapy regimens in the very near future. The ability to predict who will most likely benefit from adjuvant chemotherapy in NSCLC is reminiscent of the developments seen breast and colon cancer.

Oncoprescribe Blog Remember Homoharringtonine? It may soon be in the limelight

RR

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.

Oncoprescribe Blog MammaPrint Multigene Assays – On the cutting edge of Personalized Medicine

RR

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

RR

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

RR

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

RR

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