Predicting Cancer Behaviour: The Role of Prognostic Markers for Treatment Planning
For a variety of cancer types, it is evident that it is the biologic behaviour of the cancer that is the primary determinant of patient outcome, rather than the extent or aggressiveness of any treatment applied. It follows that being able to elucidate the innate 'behaviour' of a cancer would enable better determination of which treatment, or indeed a combination of treatments, would be best for that individual.
The current buzzword in human oncology is "individualised" therapy. The goal of this strategy is to evolve from the conventional approach - where every patient is treated with the same, relatively nonspecific cyto-destructive methods (for example, surgery, radiotherapy, chemotherapy) - to a more elegant solution in which patients are given treatments "aimed" explicitly at the unique characteristics of their tumour.
The severity of a particular cancer is currently classified according to various morphological criteria visible under a microscope. By convention, cancers are graded on a spectrum from well-differentiated to anaplastic based on several visible criteria, with the expectation that "poorly differentiated" cancers will demonstrate a more aggressive biologic behaviour. Although this method of grouping is a reliable predictor of outcome for many tumours, there are instances where the behaviour of the cancer appears to defy these expectations. Because of these limitations, it can be difficult to accurately identify those tumours that are likely to show more aggressive behaviour. The clinician is then forced to treat all cases based on generic advice. The ability to predict the "good" from the "bad" would greatly assist clinical management of patients, influencing decisions about the extent of surgical margins required, the need for adjuvant chemotherapy or follow-up monitoring.
In humans, genetic variations within a single tumour population are now recognised for a wide variety of tumour types including colon, lung, breast and many others. These genetic variations may confer significant differences in tumour behaviour, patient survival or treatment response. Recognising the markers that help define these different sub-groups of tumour is becoming important in human oncology, because it enables an individual patient to receive the most appropriate treatment based on the likely biological behaviour of their tumour.
Developments in the recognition of different prognostic markers are also beginning to make an impact in veterinary oncology, though our efforts lag well behind those of our human colleagues. This lecture will review the current status of some common cancer conditions, and discuss which prognostic markers are available - or are showing promise - and how these markers may be used to influence treatment decisions. Some of these markers may not be readily offered at all pathology services, but this situation may change as more knowledge of their clinical utility is gained.
Mast Cell Tumours
Currently, prediction of MCT behaviour can be difficult on histological criteria alone. Some tumours will behave in an almost benign fashion and adequate local control should provide a cure. However, a subset of tumours will display more aggressive tendencies, demanding wider local resections and systemic chemotherapy to control potential metastatic disease. Conventional histologic methods lack the precision to accurately identify tumours with more aggressive potential. The mitotic index (MI = number of mitoses/10 high-power fields) has been shown to be predictive of more aggressive behaviour for many tumours, including MCTs. Romansik et al. (2007) showed a significant association between MI and overall survival, especially for Grade II tumours. Dogs with Grade II tumours possessing an MI > 5 had an extremely short median survival time (3 months) compared with those with an MI < 5 (80 months). Moreover, for dogs with Grade III MCTs possessing an MI < 5, the median survival time was not reached, suggesting that MI could also be used to identify a subset of Grade III tumours likely to have a good prognosis.
Other studies have assessed surrogate markers of cellular proliferation by detecting increased intracellular levels of proteins expressed during cell division. Ki67 is an antigen that is expressed during the cell cycle and can be detected on histopathology slides by immunohistochemistry. Expression of Ki67 has been shown to be highly associated with MCT prognosis, and is independent of histologic grade. For tumours with low expression levels (< 1.8%), the 1-year, 2-year and 3-year survival probabilities were 95% (at all times) whereas for higher expression levels (> 1.8%), the survival proportions were 54%, 45% and 33%, respectively. Thus, Ki67 is a quantitative prognostic marker that could be used to identify those tumours that should be treated with chemotherapy following local therapy.
Other markers that are showing prognostic significance for mast cell tumours include KIT, E-Cadherin and VEGF although as the expression of these markers correlate with histologic grade, the clinical utility of these markers is as yet unclear.
Mammary gland tumours are one of the most common neoplastic conditions affecting the female dog. Using conventional histological criteria, mammary tumours can display considerable heterogeneity. Whilst successful local control is usually possible, approximately 50% of tumours are malignant. Reliable prognostic factors would therefore greatly assist patient management. The age of the patient, tumour size, type, histologic differentiation, and grade have all been found to have prognostic importance, but current treatment recommendations remain very generic. Specific genetic markers that may have clinical utility include oestrogen (ER), her2/neu and CK-19. There is an inverse relationship between ER expression and histologic differentiation. Benign tumours and well-differentiated tumours tend to be ER-positive, whereas undifferentiated, anaplastic tumors are more likely to be ER-negative. In humans, patients with ER-positive tumors are likely to respond to estrogen ablation or ER blockage, and the decision whether to use hormonal therapy in women with breast cancer is influenced by the tumour's receptor status. Similar evidence is available for canine patients, but more evidence is required to demonstrate a survival advantage. In humans, overexpression of the HER2/neu receptor has been associated with resistance to endocrine therapy, shorter time to relapse, and a low survival rate. Although HER2/neu expression is recognized in both canine and feline mammary tumours, correlation with survival and metastasis is not as yet clear and further research is required.
Soft-tissue sarcomas (STS) are common mesenchymal tumours in the dog. Although aggressive surgical resection (3-cm margins and a deep fascial plane) is typically recommended, there is increasing evidence that not every tumour demands such extensive intervention. Several retrospective studies have failed to demonstrate a survival advantage when patients are stratified by the extent of surgical excision performed. Currently, the best predictor we have of tumour behaviour is histological grade, and this information may help guide the surgical dose required for adequate local control. However, local recurrence remains a concern. Molecular markers that may help predict local tumour behaviour include Vascular Endothelial Growth Factor (VEGF) and Decorin. In one study, soft-tissue sarcomas that expressed high levels of VEGF were 2.6 times more likely to recur following marginal excision and patients had a significantly shorter survival time. Decorin expression correlated with VEGF levels, and the combined expression levels of both cytokines may improve prediction of tumour behaviour. With further research it is hoped such markers will assist surgical planning to determine optimal surgical margins for patients.
Other tumours where prognostic markers are also being investigated include osteosarcoma and melanoma, but the clinical utility of these markers remains unclear. In OSA, the expression of epidermal growth factor was not found to correlate with differences in patient outcome. However, a subset of OSA with high EGFR expression had a significantly shorter disease-free interval and overall survival, suggesting this proportion of patients may benefit from specific anti-EGFR therapy in their adjuvant protocols. For melanoma, a variety of molecular parameters have been examined for their ability to predict the prognosis of canine melanocytic neoplasms including proliferative markers (Ki67, cell-cycle phase index [PI], proliferating cell nuclear antigen [PCNA] labeling), and other genetic markers (Melan A/MART-1, S-100, vimentin, neuron-specific enolase (NSE), p53, PTEN, Rb, p21 (waf-1), and p16 (ink-4a), and vascular endothelial growth factor (VEGF). Apart from Ki67, the other markers have not demonstrated convincing evidence for effective prognostication so far.
When discussing survival or outcome expectations with owners, the veterinary oncologist has to rely on generic median values that have been previously reported for a heterogenous group of similar tumours. In actuality, what owners (and oncologists) want to know is: "where does my dog's tumour fit on this survival curve...?" Prognostic markers potentially provide the ability to identify subsets of tumours - either those that will do well, or those that will do poorly, or those that would benefit from additional therapy. The ability to differentiate individual tumour behaviour in this manner would greatly assist decision making and treatment options for clients and veterinarians.
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