Aggressive treatment may be warranted in patients with a high burden of keratinocytes, says a leading dermatologist.
Doctors are facing a paradigm shift in understanding and preventing skin cancer, particularly keratinocyte cancers, with more aggressive and targeted strategies needed, according to a leading dermatologist.
The traditional focus on primary prevention and early detection wasn’t enough to manage the growing burden of field cancerisation, delegates heard at the Australasian College of Dermatologists scientific meeting in Brisbane last month.
“A very small fraction of the population has almost half of the keratinocyte cancer burden,” said Professor Kiarash Khosrotehrani, director of the department of dermatology at Princess Alexandra Hospital, and co-director of the Australian Skin and Skin Cancer Research Centre in Brisbane.
For that group, a more aggressive approach may be better to manage their high cancer load, he argued. This included strategies such as laser abrasion to remove mutated skin cells, topical mTOR inhibitors to slow cell proliferation and immune checkpoint inhibitors to reduce immunogenic mutations.
A new view of skin cancer
Professor Khosrotehrani said the past decade had brought a paradigm shift in how skin cancers were understood.
“[Previously, it was believed] you have your normal skin and then at some point you start getting mutations, then you get the pre-cancerous stage and then it evolves by accumulating mutations all the way to the SCC,” he said.
“However, what we know now is that there is no such thing as normal skin, and even your normal-looking skin is actually riddled with mutations,” said Professor Khosrotehrani.
Even areas like the eyelids had many of the mutations found in fully grown SCCs and, to some extent, BCCs, he said.
“The mutational burden that you find in normal-looking skin is actually quite high – it’s higher than what you’d find in an ovarian or breast cancer.”
Research also suggested people with a higher burden of keratinocyte cancers carried a greater mutational load, particularly the CC to TT mutations linked to UV exposure.
While primary prevention remained essential, it won’t solve the problem for patients with a high burden of keratinocyte cancers. “We have at our disposal a number of really effective agents,” Professor Khosrotehrani said.
Topical 5-fluorouracil chemotherapy, for instance, could cut SCCs by 75% in a year, but patient was a major barrier.
“Very few patients want to do it – or they do it once and they don’t want to do it the second time,” he said.
What to do instead
One alternative approach is laser abrasion or dermabrasion of the damaged epidermis, allowing skin to heal from the deeper, relatively UV-protected, bottom of the hair follicle.
Mouse studies show dermabrasion significantly reduces the size of the clones, and appears to reduce in the mutational load, although Professor Khosrotehrani said that didn’t reach statistical significance.
A pilot study in humans by Professor Khosrotehrani’s team found reductions in the mutational burden in all biopsies taken one month after laser ablation, with a greater benefit at deeper levels.
Mouse studies also suggest dermabrasion can cut the number of small BCCs by sevenfold, and human studies found fractional laser cleared BCCs and SCCs from participants’ arms.
“Scraping mutations can work,” Professor Khosrotehrani said. “Reducing the mutations by ablations reduces the risk of cancer.”
The role of the immune system
Another promising avenue is immunotherapy.
At last year’s scientific meeting, Professor Khosrotehrani presented findings showing immune checkpoint inhibitors, such as anti-PD-1 therapy, appeared to reduce field cancerisation.
In patients receiving these therapies for other cancers, the number of actinic keratosis on sun-damaged forearms was tracked over 12 months. There was a significant reduction in the number of actinic keratosis and a “really clear” trend of fewer SCCs and BCCs compared to before treatment, he said.
Moreover, new unpublished data from these participants showed immune checkpoint inhibitors reduced the size of the clones that were carrying immunogenic mutations after 12 weeks of treatment, but not non-immunogenic ones.
“Immunotherapy essentially reduced the size of mutant clones, not the number of mutations, and immunotherapy only acted on immunogenic clones,” Professor Khosrotehrani said.
“That really gives us confidence about the specificity of these treatments,” he said.
“We can harness the PD-1 blockade to reduce immunogenic mutations and, as a result, to reduce actinic keratosis and SCCs.”
Not all agents showed this specificity though. Efudix, for example, didn’t seem to affect clone size.
Targeting proliferation
Preventing cells from proliferating is another strategy.
Professor Khosrotehrani said that mutated cells that proliferate faster than the surrounding skin will increase the mutation load, without further sun exposure.
Mouse studies suggest UV light accelerates the growth of mutant clones, but that process is reversible when sun exposure is removed.
Oneway to interrupt this proliferation is by targeting the mTOR pathway.
While sirolimus is used orally in organ transplant patients to reduce cancer risk, it’s poorly tolerated long-term. So Professor Khosrotehrani and his team trialled a topical version.
In a double-blind, placebo-controlled pilot study, 28 patients were randomly assigned to apply 1% sirolimus cream to one forearm and placebo to the other for three months. Only 18 completed the trial.
“People don’t like to put a lot of creams on themselves for three months,” he said.
But among those who did, the sirolimus-treated arms had fewer actinic keratoses.
While the trial didn’t find a difference in invasive SCC rates, an unpublished spatial transcriptomics analysis of biopsies showed reduced proliferation in the epidermis of sirolimus arms.
“I think clonal proliferation is the major element in this carcinogenesis journey,” Professor Khosrotehrani said.
Beyond UV exposure, ageing also contributes to clone growth.
“Ageing results in a lot of epigenetic changes that actually affect clone size,” he said, adding that his team is now investigating how ageing influences proliferation.
Field cancerisation remained a major burden that demanded new strategies, Professor Khosrotehrani said.
“We have to, as always, combine all the tools that we have – and probably be a bit more aggressive with the patients who have a lot of keratinocyte cancers,” he said.
