Amaya Viros - Skin Cancer and Ageing

Understanding melanoma biology and microenvironment cues that drive poor outcome in the aged population

Cancer is more common in elderly patients and melanoma incidence in particular continues to rise in this population. Most melanoma deaths occur in older patients, and mortality is specifically increasing in the elderly. Older patients are more likely to suffer from multiple melanocytic and non-melanocytic skin cancers, and they tend more frequently to present with thick primary tumours (Breslow thickness >4mm), placing them in a high-risk primary disease class (Stage IIB-IIC). The overall survival for stage IIB-IIC patients of all ages at 5 years is 60% and 45%, respectively, despite being localised to the skin and non-metastatic at diagnosis. Importantly, there is a gradual decline in 5-yr survival with increasing decades of life, with an almost 20% decrease from ages 60 to 69, to ages greater than 80 years. Additional characteristics of poor prognosis, such as ulceration and elevated mitotic rate are also more common in the elderly, but paradoxically, elderly patients are less likely to have lymph node metastases than younger patients1. The lower likelihood of regional nodal metastasis in patients who are at higher risk of distant recurrence suggests a different biology of metastatic progression, but the precise mechanisms underlying poor survival are not known2. Even after taking the main prognostic factors (Breslow thickness, mitosis and ulceration) into account, there is a survival discrepancy between elderly and young patients, and old age is recognised in multivariate analysis as the strongest independent adverse prognostic factor together with Breslow thickness3.

The aim of this project is to investigate the factors in the aged skin and in the tumour that are responsible for poor outcome of elderly patients. The secondary aim is to develop rationales for adjuvant therapy for the elderly, who are at highest risk of disease progression.

Specifically:

  1. We will characterise accrued genetic damage during ageing of the skin

    The accumulation of UVR-induced DNA damage in different cell types of photoaged skin will be dissected in order to understand the events, which precede and are selected to drive melanoma and other skin cancer initiation and progression to in situ disease in elderly patients.

  2. We will dissect drivers of melanoma progression in elderly patients

    Microenvironmental modifications in the chronically sun-damaged skin of elderly patients will be characterised to understand the role of cutaneous ageing and UVR-exposure during melanoma progression. Specifically, immune cell infiltrates will be studied to determine whether melanoma in elderly patients possesses a distinct immunome which drives metastasis. This information will be used to determine whether elderly patients are viable candidates for adjuvant secondary prevention treatment with anti-inflammatory drugs.3. We will study the molecular profiles of melanoma tumours from patients with good and poor outcome and integrate the molecular profiles with detailed studies of each patient’s microenvironment.