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Evidence on skin cancer
screening is limited
Comment by Thomas Stasko, MD
I
t is difficult to disagree with the US Pre-
ventive Services Task Force statement
that “the current evidence is insufficient
to assess the balance of benefits and harms
of visual skin examination by a clinician to
screen for skin cancer in adults.” High-level
studies addressing this topic are sadly lack-
ing. The absence of these studies does not
negate the potential and intuitive benefits of
skin cancer screening, and certainly should
not imply that there are no benefits or that
theorised harms outweigh benefits.
Unfortunately, because of the tone of the
discussion of the Task Force’s examination
of the unresolved questions concerning skin
cancer screening, most readers with only a su-
perficial understanding of the issues will jump
to the unwarranted conclusion that screening
is of no or negative value and should not be
encouraged.
The New York Times headline was the
mildly pejorative “Should you get screened for
skin cancer?” Worse was the American Can-
cer Society’s blog entry entitled “US panel
says no to skin cancer exams by clinicians”.
Let us not get distracted by what we don’t
know. A careful reading of the Task Force
publications will reveal that there was actually
one clear finding, “All studies demonstrated a
consistent linear increase in risk of melanoma
mortality with increasing tumour thickness or
stage, regardless of categorisation.” Without
contradicting evidence, the most reasonable
extrapolation is that the earlier melanoma is
detected, by screening or otherwise, the more
likely there will be a favourable outcome.
Yes, we would like to base our practices
and the use of resources on the evidence
supplied by large-scale, carefully designed,
controlled studies; however, the lack of such
studies should not keep us from utilising a
low cost, low risk, readily available technique
to save lives and prevent morbidity. Patients
and practitioners should be encouraged to
engage in such potentially life-saving visits.
Dr Stasko is Professor and Chair,
Department of Dermatology, The
University of Oklahoma Health Sciences
Center, Oklahoma. He is a Mohs
surgeon and the current president of the
American College of Mohs Surgery.
Mutations linked with acquired resistance to anti-PD-1 in melanoma
Comment by Lee S. Schwartzberg, MD, FACP
T
he immune system is locked in a delicate struggle with
established cancers, with the body trying to eradicate the
cancer with cytotoxic T-cells, which infiltrate the tumour.
A tumour protective mechanism of blocking the effector cells
by expressing PD-L1 causes checkpoint blockade through
interaction with the receptor PD-1 on T cells. Checkpoint
inhibition with the PD-1 antibody pembrolizumab releasing
the brake, and allowing cancer cell kill, leads to, in some cases,
extraordinary tumour responses in metastatic melanoma. Most
patients eventually progress, however, for reasons that have
previously been obscure.
This elegant study in
NEJM
reveals the putative
molecular mechanism of resistance to pembrolizum-
ab in some patients: clonal evolution of tumours to
silence effector signalling pathways involved gamma
interferon activation by mutations in the JAK1 and
JAK2 genes, or by affecting antigen presentation
through the B2M gene.
This study lends proof of principle that, by
combining precision medicine techniques using
whole-exome sequencing with immunotherapy, the
field can be advanced. We may be able to use these
methods in a clinical fashion in the future to avoid
emergence of clinically relevant clones.
This research also tells us that residual cancer cells
continue to struggle for survival, even after prolonged
inhibition by immunotherapy, through evolution to
engender resistance, suggesting that we need new
approaches to determining and evaluating residual
disease.
Dr Schwartzberg is a senior
partner and Medical Director of
the West Clinic, a 30-physician
practice specialising in oncology,
haematology and radiology
located in Memphis, Tennessee.
Screening for skin cancer in adults: updated evidence report and
systematic review for the US Preventive Services Task Force
The Journal of the American Medical Association
Take-home message
•
A systemic review was conducted to determine the benefits of skin cancer screening for reducing
disease frommelanoma. Limited evidence was found. The number of excisions needed to detect
1 skin cancer patient varied by age and gender. The sensitivity and specificity for identifying
melanoma via visual skin examination were higher when performed by a dermatologist (n =
7436) than by a primary care physician (n = 16,383). Tumours >4.0 mm and late-stage disease at
diagnosis were both associated with increased mortality.
•
There are limited studies evaluating the benefits of skin cancer screening. Future research
needs to evaluate screening of persons at high risk for skin cancer and the effect of screening
on melanoma-specific mortality rates.
Abstract
IMPORTANCE
Skin cancer, primarily melanoma, is
a leading cause of morbidity and mortality in the
United States.
OBJECTIVE
To provide an updated systematic review
for the US Preventive Services Task Force regard-
ing clinical skin cancer screening among adults.
DATA SOURCES
MEDLINE, PubMed, and the
Cochrane Central Register of Controlled Trials were
searched for relevant studies published from Janu-
ary 1, 1995, through June 1, 2015, with surveillance
through February 16, 2016.
STUDY SELECTION
English-language studies con-
ducted in asymptomatic populations 15 years and
older at general risk for skin cancer.
DATA EXTRACTION AND SYNTHESIS
Relevant data were
abstracted, and study quality was rated.
MAIN OUTCOMES AND MEASURES
Melanoma inci-
dence and mortality, harms from cancer screening,
diagnostic accuracy, and stage distribution.
RESULTS
No randomised clinical trials were identi-
fied. There was limited evidence on the associa-
tion between skin cancer screening and mortality.
A German ecologic study (n = 360,288) found a
decrease of 0.8 per 100,000 melanoma deaths
in a region with population-based skin cancer
screening compared with no change or slight
increases in comparison regions. The number
of excisions needed to detect 1 skin cancer from
clinical visual skin examinations varied by age and
sex; for example, 22 for women 65 years or older
compared with 41 for women aged 20 to 34 years.
In 2 studies of performing visual skin examination,
sensitivity to detect melanoma was 40.2% and
specificity was 86.1% when conducted by primary
care physicians (n= 16,383). Sensitivity was 49.0%
and specificity was 97.6% when skin examinations
were performed by dermatologists (n= 7436). In a
case-control study of melanoma (n= 7586), cases
diagnosed with thicker lesions (>0.75 mm) had an
odds ratio of 0.86 (95% CI, 0.75–0.98) for receipt
of a physician skin examination in the prior 3 years
compared with controls. Eight cohort studies
(n = 236,485) demonstrated a statistically signifi-
cant relationship between the degree of disease
involvement at diagnosis and melanoma mortality,
regardless of the characterization of the stage or
lesion thickness. Tumour thickness greater than
4.0 mm was associated with increased melanoma
mortality compared with thinner lesions, and late
stage at diagnosis was associated with increased
all-cause mortality.
CONCLUSIONS AND RELEVANCE
Only limited evidence
was identified for skin cancer screening, particularly
regarding potential benefit of skin cancer screen-
ing on melanoma mortality. Future research on
skin cancer screening should focus on evaluating
the effectiveness of targeted screening in those
considered to be at higher risk for skin cancer.
JAMA
2016;316:436-447, Wernli KJ, Henrikson NB,
Morrison CC, et al.
Mutations associated with acquired
resistance to PD-1 blockade inmelanoma
The New England Journal of Medicine
Take-home message
•
In 2 of 4 patients with metastatic melanoma, sequencing analysis
of relapsed lesions following PD-1 therapy revealed deletion of
the wild-type alleles of the JAK1 and JAK2 genes and genetic
alterations in the remaining alleles, resulting in deficient responses
to interferon gamma. In a third patient, loss of surface expression
of major histocompatibility complex class I due to a truncating
mutation in the B2M gene was noted.
•
Acquired resistance to PD-1 inhibition in patients with melanoma is
associated with changes in antigen presentation and in signalling
through the interferon receptor.
Abstract
BACKGROUND
Approximately 75% of objective responses to anti-pro-
grammed death 1 (PD-1) therapy in patients with melanoma are durable,
lasting for years, but delayed relapses have been noted long after initial
objective tumour regression despite continuous therapy. Mechanisms of
immune escape in this context are unknown.
METHODS
We analysed biopsy samples from paired baseline and re-
lapsing lesions in four patients with metastatic melanoma who had had
an initial objective tumour regression in response to anti-PD-1 therapy
(pembrolizumab) followed by disease progression months to years later.
RESULTS
Whole-exome sequencing detected clonal selection and out-
growth of the acquired resistant tumours and, in two of the four patients,
revealed resistance-associated loss-of-function mutations in the genes
encoding interferon-receptor-associated Janus kinase 1 (JAK1) or Janus
kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A trun-
cating mutation in the gene encoding the antigen-presenting protein
beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and
JAK2 truncating mutations resulted in a lack of response to interferon
gamma, including insensitivity to its antiproliferative effects on cancer
cells. The B2M truncating mutation led to loss of surface expression of
major histocompatibility complex class I.
CONCLUSIONS
In this study, acquired resistance to PD-1 blockade im-
munotherapy in patients with melanoma was associated with defects in
the pathways involved in interferon-receptor signalling and in antigen
presentation.
N Engl J Med
2016 Jul 13;[Epub ahead of print], Zaretsky JM, Garcia-
Diaz A, Shin DS, et al.
Residual cancer cells continue to struggle
for survival, even after prolonged
inhibition by immunotherapy, through
evolution to engender resistance,
suggesting that we need new approaches
to determining and evaluating
residual disease.
Let us not get distracted by what
we don’t know. Without
contradicting evidence, the most
reasonable extrapolation is that
the earlier melanoma is detected,
by screening or otherwise, the
more likely there will be a
favourable outcome.
SKIN
PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY
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