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Prevent Melanoma Progression in tumor-free patients

Actinic keratosis and field cancerisation

Prof. Olivier Dereure

Dermatologist, Montpellier, France

How to prevent Melanoma Progression in tumor-free patients of…

Stage II

Prof. Jean-Jacques Grob (Dermatologist, France)

Melanoma is dominating debates once again, in its advanced stages, naturally, but also increasingly when it comes to its early stages as part of a relapse prevention strategy for “at risk” stages.

But what is an “at risk” patient with regard to stages I and II?

Jean Jacques Grob states that, according to the AJCC staging system, a stage is only a “statistical” element of early-stage relapse risk assessment and that an identical Breslow index can actually be associated with tumours with very different dynamics and aggressiveness, which justifies the dramatic evolution of some very thin tumours. Diagnostic markers, including biological ones that are more relevant than “simply” thickness, are clearly needed to identify high-risk patients who would benefit from adjuvant therapy that has its own adverse effects. A positive sentinel node also appears to be a very flawed aggressiveness index, since the relapse-free survival curves unambiguously indicate a higher risk for the early thick and/or ulceration stages vs. IIIa micrometastatic stages identified in the sentinel lymph node. Therefore, adjuvant therapy seems perfectly justified for early aggressive stages (currently identified according to the AJCC staging system, for lack of better term...) even in the absence of invasion of the sentinel lymph node, ...

But which one?

Jean Jacques Grob also mentions that the 1-year duration chosen for all adjuvant treatments without exception is, in fact, completely arbitrary and that it is quite possible that a shorter duration, especially in early stages, is more appropriate, which seems to be indicated by the results obtained in the few published neoadjuvant studies. It should be noted that current early-stage trials continue to select patients with negative sentinel lymph nodes, whereas it would actually be interesting to stratify the results according to the sentinel status.

Stage III

Prof. Axel Hauschild (Dermatologist, Germany)

With regard to stage III, Axel Hauschild mentioned the results of the 4 main studies and it seems that the results are maintained over time with regard to progression-free survival (at least in the case of targeted dabrafenib/trametinib combination therapy with an estimated cure rate of 54%) but, naturally, overall survival data are not yet mature.

How to treat patients with BRAF-mutant melanoma? It all depends on the patient’s profile and the anticipated toxicity in particular.

When it comes to advanced melanoma, debates are currently focused on optimising the response to available treatments, particularly by overcoming secondary resistance and by manipulating tumour microenvironment, once again based on predictive or early markers of efficacy and toxicity of such treatments as immunotherapy.

Can the immune toxicities of immunotherapy be predicted? The question is really interesting considering the toxicity of the combinations (55 to 60% of IE of grade 3 and 4 for the ipilimumab/nivolumab combination); a score based on a panel of 11 pro- and anti-inflammatory cytokines measured in peripheral blood could be used for detecting low-risk or high-risk patients with respect to these sometimes dangerous or even prolonged adverse effects, and thus selecting those who could benefit from combination immunotherapy with a better risk-to-benefit ratio.

At this time, can we define predictive markers of efficacy, specifically in immunotherapy? Such criteria as Tumour Mutational Burden (TMB) and PD-L1 expression are clearly not associated with a negative predictive value that is sufficient to rely on in order to NOT start treatment and research continues in this direction simultaneously with clinical trials. A very interesting and promising element is currently represented by the connection between the intestinal microbiome (both in terms of diversity and bacterial species composition), which could be both a predictive marker for the efficacy of anti-PD-1, and a potentially manipulable element, either ahead of the treatment or in case of secondary failure.

Optimisation of the response to already used treatments is certainly a major challenge in advanced melanoma, either from the outset or in case of secondary resistance, and can be based on various strategies:

Combination therapy, including combining different types of immunotherapy and targeted therapy + immunotherapy, however it is not guaranteed that the overall survival would improve in comparison with the same products used sequentially in the context of relatively conventional first- and second-line treatments while toxicity is visibly higher. The use of predefined therapeutic sequences or intermittent combinations is also useful, but the appropriate sequence remains to be defined (it may also be variable depending on the patient); trials are underway, for instance, comparing immunotherapy with initial targeted therapy, which after 12 weeks, is relayed by immunotherapy for patients with mutated melanoma.
Manipulation of gut flora with fecal microbiota transplants
Manipulation of tumour metabolism via oxidative phosphorylation
Association of targeted combination therapy with an anti-CDK4 treatment that acts downstream of the MAPK pathway
Reprogramming protein translation and in particular selective translation of the so-called “metabolic” mRNAs
Especially by manipulating tumour microenvironment by making it more immunologically active, rich in CD8+ T-cells with an inflammatory “signature” notably marked by the expression of the g interferon; this can be achieved with various means, for example by stimulating innate immunity through the use of STING agonists, intratumoral injections of oncolytic viruses or TLR ligands, use of TIL, radiotherapy, local recruitment of Batf3-driven dendritic cells or inhibition of the beta-catenin pathway.

Actinic keratosis and field cancerisation

Biology of actinic keratoses (AK)

Prof. Eggert Stockfleth (Dermatologist, Germany)

But there is more to an onco-dermatologist’s life than melanoma.

A session has been devoted to actinic keratosis which, granted, does not make the covers of top medical journals, and yet affects a very large number of patients.

A number of elements concerning the biology of actinic keratoses was brought up, stating in particular that the mutations in the p53 gene are not the only ones responsible. In addition, the natural history of actinic keratoses developing sequentially and “normally” through stages I to III until invasive cutaneous squamous cell carcinoma has recently been questioned with a significant possibility of direct transition from type 1 actinic keratosis (dysplasia of only the lower part of the epidermis) to genuine invasive carcinoma without going through the intermediate stages II and III. In fact, this evolution also depends (perhaps above all) on the proliferation profile in the basal layer and cutaneous squamous-cell carcinoma (cSCC) would rather be associated with a high proliferation profile at this level, probably more than with the importance of epithelial dysplasia related to the thickness of the epidermis.

Diagnosis of actinic keratoses (AK)

Prof. Caterina Longo (Dermatologist, Italy)

The following presentation is devoted to the diagnosis of actinic keratoses with an overview of the gradation of lesions according to their thickness.

Attention is drawn to the presence of white areas, ring-shaped or not, which can be significant indicators of SCC. Confocal microscopy and optical coherence tomography are noticeably more effective than simple dermoscopy in identifying the lesions of “simple” actinic keratosis vs. genuine SCC, otherwise these techniques are complementary but require experience and the equipment is relatively expensive.

Field directed treatments

Dr. Nicole W.J. Kelleners-Smeets (Dermatologist, Netherlands)

An interesting novelty is the definition of lesion scores, particularly useful in field cancerisation with the definition of two essential scores, AKASI and AKFAS, taking into account various parameters, that are also rather complementary. These scores have shown a strong correlation with the risk of SCC and also allow to conduct more standardised clinical trials with respect to evaluation criteria. The concept of cancer field effect continues to be clinically promising as it refers to the global risk of SCC in areas modified by UV-induced mutations but which are not necessarily most clinically relevant.

A recent study has shown that among the four topical field treatments that are 5-FU, imiquimod, dynamic phototherapy and ingenol mebutate gel, 5-FU has the highest success rate as well as the highest satisfaction rate among patients. Moreover, it is also the cheapest product. There is also a preventive effect on the occurrence of SCC, whether 5-FU is used alone (twice a day for four weeks with a reduction of the risk of SCC within the following year) or associated with topical calcipotriol where the preventive effect on the onset of SCC can be prolonged for three years following the treatment.

Actinic keratoses (AK) treatment in organ transplant recipients

Prof. Ketty Peris (Dermatologist, Italy)

Finally, the treatment of actinic keratoses and cancer fields in organ transplant patients (i.e. immunosuppressed patients) is not yet well established with little specific data and recommendations that vary from country to country. A recent systematic review published in the British Journal of Dermatology has shown that dynamic phototherapy (conventional or daylight) is the best-documented treatment in this situation. No topical treatment of immune-mediated conditions has been associated with an increased risk of graft dysfunction or even rejection. The role of oral retinoid or nicotinamide treatments has yet to be demonstrated in this particular population, as well as the reduction in the incidence of invasive SCC by systematic treatment of actinic keratoses or even cancer fields.