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INVESTIGATIVE REPORT
Early Circulating Tumour DNA Variations Predict Tumour Response
in Melanoma Patients Treated with Immunotherapy
Laura KELLER 1–3 , Nicolas GUIBERT 1–4 , Anne CASANOVA 1,2 , Stephanie BRAYER 5 , Magali FARELLA 1,2 , Myriam DELAUNAY 1–4 ,
Julia GILHODES 6 , Elodie MARTIN 6 , Gisèle BALAGUÉ 7 , Gilles FAVRE 1–3 , Anne PRADINES 1,2 and Nicolas MEYER 2,3,5
1
Medical Biology Laboratory, 6 Biostatistics Department and 7 Medical Imaging Department, Claudius Regaud Institute, Toulouse University
Cancer Institute (IUCT-O), 2 CRCT, Inserm, University of Toulouse III - Paul Sabatier, CNRS, 3 University of Toulouse III - Paul Sabatier,
4
Thoracic Oncology Department, Larrey Hospital, University Hospital of Toulouse, and 5 Dermatology Department, University Hospital of
Toulouse, Toulouse University Cancer Institute (IUCT-O), Toulouse, France
Antibodies targeting immune checkpoints were re-
cently approved for metastatic melanoma. However,
not all patients will respond to the treatment and
some will experience grade III–IV immune-related
adverse events. Therefore, early identification of non-
responder patients would greatly aid clinical practice.
Detection of circulating tumour DNA (ctDNA) is a non-
invasive approach to monitor tumour response. Digital
droplet PCR was used to quantify BRAF and NRAS mu-
tations in the plasma of patients with metastatic mela-
noma treated with immunotherapy. In 16 patients, ct-
DNA variations mirrored tumour response (p = 0.034)
and ctDNA augmentation during follow-up detected
tumour progression with 100% specificity. In 13 pa-
tients, early ctDNA variation was associated with clini-
cian decision at first evaluation (p = 0.0046), and early
ctDNA increase with shorter progression-free survival
(median 21 vs. 145 days; p = 0.001). Monitoring ctDNA
variations early during immunotherapy may help clini-
cians rapidly to discriminate non-responder patients,
allow early adaptation of therapeutic strategies, and
reduce exposure to ineffective, expensive treatment.
Key words: ctDNA; melanoma; immunotherapy; biomarker;
therapeutic response.
Accepted Nov 1, 2018; E-published Nov 5, 2018
Acta Derm Venereol 2019; 99: 206–210.
Corr: Dr Anne Pradines, Medical Biology Laboratory, Claudius Regaud In-
stitute, Toulouse University Cancer Institute (IUCT-O), FR-31059 Toulou-
se Cedex 9, and Pr. Nicolas Meyer, CRCT, Inserm, University of Toulouse
III - Paul Sabatier, CNRS, FR-31000 Toulouse Cedex 9, France. E-mail:
[email protected]; [email protected]
I
mmune checkpoint inhibitors (anti-CTLA-4, anti-PD1
or combination of both) have revolutionized the treat
ment of metastatic melanoma (1) with striking results
on overall survival (OS) in advanced-stage metastatic
melanoma (the 3-year OS were, respectively, 34%, 52%
and 58%) (2). However, this mode of treatment is effec-
tive only in a subset of patients as 40–65% have shown
minimal or no RECIST (Response Evaluation Criteria in
Solid Tumours) response and 43% of responders develop
acquired resistance by 3 years (2). In addition, up to 55%
of patients may experience grade 3–4 immune-related
adverse events (2–5). Today, none of predictive biomar-
kers appear sufficiently robust and easily transferable
doi: 10.2340/00015555-3080
Acta Derm Venereol 2019; 99: 206–210
SIGNIFICANCE
Immunotherapy has yielded a dramatic improvement in
the prognosis and survival of patients with unresectable
melanoma. However, not all patients respond to treatment
and some experience severe adverse events. The detec-
tion of mutations in peripheral blood (i.e. ctDNA) is a new,
non-invasive approach to monitor tumour response. Using
a sensitive method, this study showed that early assess-
ment of ctDNA variation during the course of therapy could
predict the tumour response to treatment. These results
may help clinicians to rapidly discriminate non-responders,
allowing early adaptation of therapeutic strategies and re-
ducing their exposure to ineffective and costly treatment.
into clinical practice to guide treatment choices. Indeed,
intratumoural lymphoid infiltrates and tumoural PD-L1
expression at baseline both have a lack of discriminative
capacity between responders and non-responders (6, 7).
The interpretation of PD-L1 immunostaining on pri-
mary tumour biopsies is currently limited by spatiotem-
poral intratumoural heterogeneity. As a consequence, the
choice of treatment and evaluation of its efficacy is based
on clinical–radiological criteria 12 weeks after induction,
since contrary to chemotherapies, immunotherapy (IT)
demonstrates a delayed response to treatment. Thus,
development of new, early prognostic and predictive
biomarkers to enable fine monitoring of tumour response
is critical, as it may: (i) reduce exposure to potentially
toxic and expensive treatments in non-responders; (ii)
allow for early adaptation of therapeutic strategies in
non-responders; and (iii) provide useful information for
the management of adverse events in responders.
Detection of mutations in circulating cell-free tumour
DNA (i.e. ctDNA) is a useful, non-invasive and repea-
table approach that can be used to assess the mutational
status of tumours in different cancers (8). ctDNA has
been correlated with baseline tumour burden (9–11) and
with tumour-size evolution (12). Moreover, it overcomes
tumour heterogeneity. Our team has recently shown the
utility of detection of BRAFV600E and KRAS mutations
in plasma to monitor non-small-cell lung cancer evolu-
tion (13, 14) and to discriminate pseudo-progression
cases (15).
This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta
Journal Compilation © 2019 Acta Dermato-Venereologica.