FEATURE ONCOLOGY
At the same time, survival rates are
improving. Since the 1970s, survival rates for cancer overall and for certain site-specific cancers have improved significantly, due in part to both earlier detection and treatment advances. Marked increases in survival rates have been seen in cancers of the breast, prostate, rectum, and blood.
PERSONALISED CHEMOTHERAPY Pharmacologic agents play a major role in the treatment of neoplastic disorders. Historically, chemotherapy regimen selection has always been ‘personalised’ with selection directed primarily by oncologic disease state. Patient-specific parameters also come into play in determining not only dosage adjustments but also drug selection. Patient parameters such as age and organ function; height and weight; performance status; medical, allergy, and chemotherapy histories; therapeutic goals may all be used to clarify the chemotherapy regimen for a specific patient. For example, a patient with reduced renal function may need carboplatin dosage adjustment via the Calvert formula in order to reduce hematologic toxicity. Another patient with non-Hodgkin’s disease may be given a non-anthracycline based regimen to accommodate for his underlying cardiac comorbid condition. A patient with ovarian carcinoma may have to undergo docetaxel alternative therapy due to paclitaxel neurotoxicity. Since 1949, when the FDA approved
the first antineoplastic agent, N-mustard, a number of developments has occurred to further personalise cancer care. Among these developments are technological improvements, advances in supportive care, and drug research. Pharmaceutical research has resulted in more and better drugs, many of which are targeted against specific molecular abnormalities in cancer. It is primarily these targeted agents which will be discussed in more detail in this review.
A GROWING MARKET Pharmacologic agents account for a large number of the healthcare dollars spent. There is a growing market for targeted pharmacologic agents as well. Since 1998, the United States Food and Drug Administration (FDA) has approved 25 targeted agents; an estimated 40 more
“Triple-negative breast tumours account for approximately 15- 20% of all breast cancers and are associated with a poor prognosis”
could be on the market by 2015. Targeted oncology drugs, in 2009, accounted for approximately one-third (or $4 billion) of the top ten drug expenditures for clinics in the United States. Oral targeted oncology drugs taken chronically may cost as much as $9500 per month (see Table 1). Targeted agents are drugs, which are
directed at a specific molecule or object. It is hoped that by using these agents (usually monoclonal antibodies or small molecules) with their higher degree of specificity, drug toxicity is reduced. To individualize therapy, target status must be evaluated as well as the target’s downstream effector pathways in each patient. Thus, by considering molecular staging, patient prognosis, and empirical chemotherapy selection, a patient- specific treatment can be determined. In the United States, approximately one out of every 10 FDA-approved drugs carry labels containing pharmacogenomic information. With an estimated 25% of all outpatients receiving one or more drugs carrying a label with pharmacogenomic information for that drug, targeted drug therapy is poised to have a significant impact in healthcare. We will now look at a few examples of personalised therapy within the oncology setting.
LOOKING AT BREAST CANCER Breast cancer, the most common cancer in American women, has been studied at length and provides two examples of personalised chemotherapy to be reviewed here. In the first example, the oncogene Her2, also known as neu and c-erb-B2, is a member of the epidermal growth factor family of receptors (EGFR). Her2 encodes for a 185-kilodalton transmembrane glycoprotein receptor that has intracellular tyrosine kinase (TK) activity. This receptor is a signal transducer
involved in angiogenesis and epithelial cell growth and differentiation. Her2 amplification, which is found in up to 30% of breast cancer tumours, is correlated to overall patient survival and time to disease progression. Trastuzumab is a humanized monoclonal antibody that binds to the extracellular domain of Her2. In 2001, Slamon and colleagues published a landmark study of trastuzumab in patients with Her2- positive metastatic breast cancer. The group demonstrated that usage of trastuzumab in patients with this uncommon genetic error could now experience a longer time to disease progression, an increased response rate, improved survival. Current standard of care now dictates that patients who exhibit Her2 gene amplification or overexpression via immunohistochemical (IHC) analysis or fluorescence in situ hybridization (FISH) receive trastuzumab with or following chemotherapy. Another example of personalised
chemotherapy in breast cancer is PARP inhibitors. Poly adenosine diphosphate-ribose polymerase is an enzyme involved in DNA base-excision repair. High PARP expression has been found in DNA-unstable breast cancers, including BRCA1-mutated tumours and triple-negative breast tumours. Triple-negative breast tumours (also known as ER-, PR-, Her2- tumours) account for approximately 15-20% of all breast cancers and are associated with a poor prognosis. Cytoplasmic PARP expression also appears to
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