Scientific highlights: Day 3
Neoadjuvant immunotherapy in melanoma | Christian BLANK (Netherlands)
Neoadjuvant treatments are a very promising future as pre-surgical anti-cancer treatments. As presented by Prof. Christian BLANK, a neoadjuvant treatment has the advantage of reducing the tumor load before surgery. The other major benefit is to stimulate the immune system to induce a stronger and broader response to tumor-specific T cell production. Neoadjuvant therapy can also identify basic biomarkers by studying homogeneous patient populations, which can then be extrapolated.
On the other hand, the toxicity of the treatment and in particular the auto-immune side effects could dissuade patients from continuing the treatments of their pathology and performing the surgery. In addition, the efficacy of neoadjuvant treatments has not previously shown better results than adjuvant treatments, raising the question of their relevance. However, pseudoprogression is to be considered. Finally, the neoadjuvant treatments are an additional treatment, necessarily implying support and costs extra.
In a second step, Prof. Christian BLANK presented study results showing a significant response rate of 78% (pathologic response rate) with neoadjuvant treatment ipilimumab + nivolumab. He states that the pathological response is potentially underestimated due to radiological responses and independent of mutational tumor burden. However, this treatment remains toxic at standard dose. In addition, anti-PD1 neoadjuvant monotherapy was insufficient. Nivolumab or pembrolizumab were less toxic, but the low pRR was around 30%.
Therefore, it seems important in the near future to identify an association allowing a high response while observing a lower toxicity.
Neoadjuvant targeted therapy in melanoma | Peter MOHR (Germany)
Dr. Peter MOHR presented this morning the first conference of the session on neoadjuvant therapies. He synthesized the excellent results of this therapy more and more in the limelight. He found an ideal response with a treatment of 4 to 6 weeks to get 75% to 100% response. This means that people who are inoperable because of over-extended pathologies become operable. Of these operated patients, 50% have a complete response, while the morbidity rate remains low. In addition, the toxicity of the Dabra / Tram treatment remains entirely correct.
There is still a need for new research to identify biomarkers that will select patients who still need adjuvant therapy after the operation, for example for patients without complete histological remission.
Dr. MOHR assumes that neoadjuvant treatments are so promising that they could replace surgery in the future. The future will tell…
Neoadjuvant therapy and lessons from other tumor types and lessons to learn from former neoadjuvant trials in melanoma | James LARKIN (United Kingdom)
Dr. James LARKIN spoke at the session this morning on neoadjuvant treatments. After echoing Dr. MOHR's lecture in the same session, he presented a fairly comprehensive view of neoadjuvant treatments.
Her purpose was to argue that a 6-week neoadjuvant treatment was an ideal model for biomarker studies and patient selection for adjuvant therapy.
In addition, Dr. James LARKIN raised many questions from this type of treatment:
- Is medication better before surgery than after?
- Are there differences in side effects?
- Can we replace neoadjuvant treatment by others in case of failure for patients who fail to improve overall effectiveness?
- Can we identify molecular predictors of drug resistance / response?
Like Dr. MOHR, Dr.LARKIN wonders if neoadjuvant treatments could not replace surgery. Before reaching this point, many trials will be needed to test these questions.
In addition to the treatment identified, the speaker emphasizes that breast cancer is an excellent model. Strategies and protocols established for neoadjuvant treatments for breast cancers should be re-used for skin cancers.
Finally, for Dr. LARKIN, neoadjuvant trials can be a quick way to move forward in areas where medical needs are not being met. In order to progress more quickly, transversal collaboration appears essential between oncology / surgery / pathology / radiology / scientist / universities / industry.
New technologies for the diagnosis of skin cancer: from computer vision (automatized diagnosis) to innovation in photonics
LC OCT : A new definition for Optical coherence tomography to diagnose skin cancer | Mariano SUPPA (Belgium)
Dr. SUPPA presented the principles of LC-OCT (Line-field Confocal Optical Coherene Tomography), a new imaging technology. In a non-invasive way, LC-OCT obtains verticals similar to what one obtains in histopathology- two dimensions with a deep penetration. This is compatible with the study of cells in vivo.
The LC-OCT technique has the significant advantage of associating the technical principles of the confocal microscope with those of the OCT. Indeed, a specific, supercontinuum laser with an ultra broadband allows high axial resolution. Moreover, the high numeric aperture of the objective microscope (similar to those of CM) and the continuous dynamic readjustment of the interferometer allow high lateral resolution. Finally, the line illumination and the allowable acquisition (so-in-vivo imaging).
A new prototype under construction will make it possible to see both the vertical and the horizontal planes simultaneously. We will soon be able, by a very fast acquisition, to have 3D images.
Early skin cancer detection and follow up using polarized dynamic speckle | Xavier ORLIK (France)
As part of the session dedicated to technologies, Dr. Xavier ORLIK held a conference to present the technique of the Micro-Vasculoscope Imager (MV1 Imager). It is based on a successful coupling between polarimetry and dynamic speckle to go deeper through the skin.
In order to allow earlier diagnosis, this technique makes it possible to detect localized changes in microvascular activity.
A classical nevus completely disappears in the microvascular activity signal because the activity is the same as the activity of the microenvironment. A non-classical element (nevus, angioma) can be detected with this technique because of the difference in microvascular activity. The same goes for melanomas where specific microvascular activity can be identified.
With an MV1, it is possible to take one image each second and immediately detect abnormal microvascular activity. The data is automatically acquired by a computer, and the use is easy with a sufficient acquisition of five minutes. The scanned area is 25mm in diameter, with a transversal resolution of more than 0.1mm, while the penetration is estimated at about 3mm. In addition, the technique poses no risk to the skin nor to the eyes.
However, until clinical trials are complete, the technique should not influence the medical diagnosis or discourage the removal of a suspected area.
Ex vivo confocal microscopy a new approach for skin cancer margins | Josep MALVEHY (Spain)
Pathology needs are very important, and there is often a lack of technical staff to respond to them. Dr. Josep MALVEHY presented a new technology allowing to take the relay of the anatomopathologists in an automated way.
Ex vivo confocal microscopy is capable of visualizing freshly excised tissue in real-time with cellular resolution without routine processing in record time.
Beyond the black and white version, which already allows a good resolution, this new technique allows to obtain three colors. AO targets the epidermis and dermis with green fluorescence. Ethidium bromide binds specifically to DNA. Finally, the blue color corresponds to auto-fluorescence. Fluorophores are used to improve contrasts. The tissue is analyzed concomitantly by different lasers at different wavelengths to detect the cell elements targeted by the dyes.
All fluorescence is then collected by the microscope, displaying the final images in a 3-color scale format to obtain a final image corresponding to a mosaic.
Management of advanced BCC and SCC
General principles of management of NMSC | Alexander STRATIGOS (Greece)
Prof. Alexander STRATIGOS exposed general principles of management in NMSC.
Whether the applied treatment is surgical, destructive, topical or systemic, the goal is to eradicate a tumor while preserving the functions of the tissues where the tumor is located.
When a BCC is identified, it is essential to check the whole skin because it often happens that there are others and to proceed to a systematic biopsy.
According to the NCCN 2019 guidelines, low-risk tumors can also be treated destructively or with superficial therapy. On the contrary, high-risk tumors require surgery with large margins of excision, for example.
A major issue concerns the recurrence of BCC after stopping the treatment that could come from cells insensitive to inhibition among others. A clinical case of medulloblastoma also raised another important issue: resistance was observed in one patient with all targeted therapies. There was an acquired mutation disrupting the link of vismodegib with its target. This situation has never been described for patients with BCC.
In general, BCC are treated as outpatients, unlike other cancers, and present a significant lifetime risk. Despite rare metastases, a group of BCC appears particularly aggressive.
For SCC, despite high overall survival, this type of tumor remains at the origin of 20% of all skin cancer deaths. New criteria are taken into account to establish the profile of these tumors:
- the degree of histological differentiation,
- the depth of the tumor,
- the histological type,
- the perineural or perivascular invasion,
- the factors related to the patient,
For thick melanomas, they are aggressive tumors that have a phase of vertical growth. They do not meet the ABCD criteria with an atypical dermoscopic profile. They are found mainly in men over fifty years.
Surgery in advanced tumors (SCC and BCC) | David MORENO-RAMIREZ (Spain)
Dr. David MORENO-RAMIREZ presented a conference on the management of surgeries in the case of advanced tumors.
The skin cancers correspond to tumors sometimes very different from each others, but they also have some points in common : if they are not resectable, it is because the major vascular and neuronal structures are invaded, if they are resectable, sometimes the complete removal of the tumor can not be performed. In addition, ablation can cause an aesthetic anatomical defect or functional impairment. For patients who cannot be candidates for surgery, radiotherapy or systemic therapy is implemented.
In cases of advanced basal cell carcinoma, 50-66% overall response is achieved with a single treatment with of vismodegib and complete responses in 20-30% of cases with a response of less than 2 years only, with probably suppressive action more than curative. This suppressive action facilitates the surgical removal. Trials were initiated with this treatment as a neoadjuvant, all showed a significant reduction in tumors and the treatment allowed less aggressive surgeries. The speaker warned anyway non-centripetal narrowing of tumors and clinical and histological correlation.
More generally, Dr. MORENO-RAMIREZ believes that neoadjuvancy can become a routine for advanced cSCC, and more generally for many surgeries.
New therapeutic targets in melanoma
Targeted therapies in NRAS mutated melanoma, what can we expect ? | Amelie BOESPFLUG
As Dr. Amélie BOESPFLUG pointed out in her lecture on targeted therapies for NRAS mutated metastatic melanoma, no treatment has been approved yet. However, BRAF mutant melanomas can, for their part, be treated with three combinations of BRAF and MEK inhibitors.
Dr. BOESPFLUG has listed a number of tested treatments and overall unsatisfactoring results. Among others, one strategy was to modify the post-translationally NRAS via a farnesyltransferase inhibitor, but this inhibition was compensated by the parallel activation of a prenylation, while the double inhibition posed a toxicity problem.
The inhibition of a mutated NRAS being particularly complex, research groups turned to the inhibition of upstream and downstream effectors, but again the results were disappointing, among others because NRAS takes part in several paths of signaling. Nevertheless, one study showed that immunotherapeutic treatment followed by MEK inhibition treatment gave better results.
Autophagy is the most promising approach. Induced by inhibition of MAPK in SRA-induced tumors, this approach induced a mechanism of primary resistance to MAPK inhibitors. Further studies need to be undertaken to identify the mechanisms by which inhibition of MAPK induces autophagy.