Adolescent and young adult (AYA) patients with cancer are a unique category of patients who, depending on age at time of diagnosis, might receive treatment from oncologists specialising either in the treatment of children or adults. AYA patients with cancer typically present with diseases that span the spectrum from paediatric cancers (such as acute lymphoblastic leukaemia – ALL and brain tumours) to adult tumours (such as breast cancer and melanoma), as well as cancers that are largely unique to their age group (such as testicular cancer and bone tumours).
In addition to the potential biological and cancer-specific differences, AYA patients also often have disparate access to clinical trials and suffer from a lack of age-appropriate psychosocial support services and health services, which might influence survival as well as overall quality of life.
In the review article published in the Nature Reviews Clinical Oncology, these issues are discussed, with a focus on two types of AYA cancer, ALL and melanoma. At first glance, these two diseases seem to have little in common; however, they provide key examples of how the molecular profile of a disease can be used to improve understanding of the treatment of cancers using targeted therapies. In this news, we focus on melanoma in AYA patients. It should be noted that a focus is on patients who were diagnosed with cancer as AYAs rather than on AYA survivors of paediatric cancer.
Melanoma in AYAs
Compared with rates of carcinoma development in older adults, melanoma remains a relatively rare disease. Of great concern, however, is the fact that the incidence of this largely preventable disease in AYAs is increasing, urging to do more to protect skin health and reduce the rate of melanoma diagnoses.
Risk factors, prevention and awareness
Risk factors for non-congenital melanoma include exposure to natural and artificial ultraviolet (UV) light, as well as diet. An estimated 75% of melanoma cases diagnosed in people younger than 30 years of age correlate with exposure to natural or artificial sunlight; evidence indicates that the risk of melanoma doubles if a person sustains five or more sunburns before the age of 18 and that each session of indoor tanning increases the odds of developing melanoma by 1.8%.
Interventions focused on sun safety, including regular sunscreen use, have achieved up to a 50% reduction in melanoma risk, but, despite the efforts of public health officials to develop effective health messaging campaigns and legislative efforts to limit the use of indoor tanning facilities by minors, the incidence of melanoma continues to rise.
UV exposure is now considered by the WHO to be a class I carcinogen, placing it alongside risk factors such as arsenic, formaldehyde and plutonium. In addition to concerted efforts to encourage AYAs into adopting key health behaviours that are known to reduce the risk of melanoma, efforts to educate have also been undertaken. Although the conveyed long-term risks do not always outweigh the immediate benefits of tanning for many members of the AYA population, evidence exists that the tide is starting to slowly turn, with increasingly more AYAs practicing primary prevention of melanoma.
In light of the knowledge that AYA health behaviours are difficult to change, practitioners must remain aware of the risk of melanoma in this patient population. During routine examinations, AYA patients should be queried about any lesions observed during skin self-examination and assessed for any skin lesions using the ABCDEs of melanoma: asymmetry, border, colour, diameter, and evolutionary changes.
Although melanoma risk can be lowered by coupling self-examination with professional examination, the current mnemonic of ABCDE does not apply to nodular melanoma owing to its propensity for being small, symmetrical with regular borders and homogeneous in colour. This subtype of melanoma, which is often difficult to treat, accounts for 6.1% of cases of melanoma in male AYAs and 4.2% in female AYAs when a histologic type is reported.
Furthermore, adolescents (aged <19 years) might present with symptoms that are inconsistent with the ABCDE criteria and, instead, show amelanosis, bleeding, and de novo development with no pre-existing nevi from which the malignant lesion developed.
BRAF mutations in melanoma
Emerging knowledge of the biology and genetics of melanoma should enable clinicians to stratify their patients to a medication that is most likely to be effective according to not only morphology and histology, but also to the genomic landscape of the disease.
Interestingly, patients with melanoma who are under 40 years of age have a greater incidence of the BRAF V600E mutation than older patients.
Mutations in BRAF result in constitutive activation of the protein, subsequently promoting overactive signalling and cell proliferation. By binding to the ATP-binding site of BRAF V600E, vemurafenib, an oral agent, inhibits the oncogenic properties of this kinase, and inhibition of the downstream proliferation signal ultimately leads to apoptosis and tumour regression. However, many patients develop resistance to this agent after less than 6 months of treatment.
Combination therapy, such as vemurafenib plus cobimetinib, which inhibits the RAF effector MEK, has demonstrated promising results, as has the use of trametinib, another MEK inhibitor, with dabrafenib, another BRAF inhibitor.
As knowledge of the molecular landscape of malignant melanoma as well as its adaptive resistance to targeted therapies increases, we will probably see trends away from single-agent therapy towards combination therapies that affect multiple components of the molecular pathway including BRAF, MEK, and NRAS.
Metastatic disease is rare among AYAs with newly diagnosed melanoma. However, if present, the prognosis is particularly poor and tumours are often not responsive to first-line or second-line treatments using cytotoxic agents.
Prior to 2011, patients with metastatic disease had limited therapeutic options: dacarbazine as a single-agent therapy yielded overall response rates of 15–25%, and the use of interferon-α-2b, which became the mainstay treatment of metastatic melanoma, remains highly controversial as an adjuvant therapy owing to varying reports of its effectiveness in prolonging overall survival.
In early 2011, however, the FDA approved the use of ipilimumab, a monoclonal antibody that blocks immune-checkpoint protein cytotoxic T-lymphocyte antigen 4 (CTLA-4), and vemurafenib for the treatment of metastatic melanoma. Favourable efficacy was reported for pembrolizumab and nivolumab, which are monoclonal antibodies that target programmed cell death protein 1 (PD-1).
Although ipilimumab use often results in substantial toxicity (including grade 3–4 immune-related adverse events, such as rash, colitis, endocrine dysfunction, and hepatitis), patients have demonstrated durable responses after only a few doses of this agent with improved median overall survival reported in patients with unresectable stage III or IV melanoma.
Similar results have been seen with use of nivolumab. Results using a combination of nivolumab and ipilimumab are also promising, but offset by the higher incidence of adverse events and overall cost of treatment. Furthermore, patients treated with pembrolizumab achieve a durable treatment response, with a high overall response rate in patients with measurable disease and 1-year overall survival; anti-tumour activity was seen even in patients who had low baseline PD-1 expression.
In light of these findings, it is anticipated that the new anti-PD-1 agents, used either as single-agent therapy or in combination with other therapies, will continue to provide both higher response rates and decreased toxicity when used to treat patients with melanoma compared with standard therapy. Finally, studies are now underway looking at the safety and efficacy of agents targeting PD-1 and its principal ligand (PD-L1).
Improving the outcomes of AYA patients with cancer
At the end of their review article, the authors remind the oncology community that, whereas overall survival of AYA patients has improved over the past 30 years, this statement does not apply to all cancers seen in AYA patients. Many of these cancers have a terribly poor prognosis, including high-grade brain tumours, oesophageal cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, primitive neuroectodermal tumours and stomach cancer.
Academic rigour, energy and, importantly, funding need to be directed at improving the outcomes of AYA patients with cancer, not just for the purpose of improving overall survival, but also to improve the QoL, with fewer long-term adverse effects of administered therapeutic interventions. The challenge raised for the medical and scientific communities is to use the knowledge gained over the past ≥20 years and continue to strive for greater scientific understanding of the biological underpinnings of the diseases seen in the AYA-patient population. Private donors, governmental agencies and others have acknowledged the potential of genomic medicine and the formation of new consortia and networks devoted to improving cancer research. However, in the excitement of achieving rapid advances, we must ensure that AYA patients are represented in each and every ‘big ideas’ initiative.