In this post, replete with many links within - Circulating tumor DNA to monitor and predict response in melanoma patients - yes - AGAIN!!!! - from earlier this year, I wrote: "I first posted articles related to blood analysis to evaluate circulating tumor DNA in 2014. It is a fairly non-invasive and relatively painless way to diagnose melanoma, measure tumor burden, and evaluate progression or response in melanoma patients. It may even indicate those who are more likely to respond to a particular therapy. Unfortunately, it is not commonly utilized." Now there are these reports:
Circulating tumour DNA in patients with advanced
melanoma treated with dabrafenib or dabrafenib plus trametinib: a clinical
validation study. Syeda,
Wiggins, Corless, et al. Lancet
Oncol. Feb 2021.
Background: Melanoma lacks validated blood-based biomarkers
for monitoring and predicting treatment efficacy. Cell-free circulating tumour
DNA (ctDNA) is a promising biomarker; however, various detection methods have
been used, and, to date, no large studies have examined the association between
serial changes in ctDNA and survival after BRAF, MEK, or BRAF plus MEK
inhibitor therapy. We aimed to evaluate whether baseline ctDNA concentrations
and kinetics could predict survival outcomes.
Methods: In this clinical validation study, we used
analytically validated droplet digital PCR assays to measure BRAFV600-mutant
ctDNA in pretreatment and on-treatment plasma samples from patients aged 18
years or older enrolled in two clinical trials. COMBI-d (NCT01584648) was a
double-blind, randomised phase 3 study of dabrafenib plus trametinib versus
dabrafenib plus placebo in previously untreated patients with BRAFV600
mutation-positive unresectable or metastatic melanoma. Patients had an Eastern
Cooperative Oncology Group (ECOG) performance status of 0 or 1. COMBI-MB
(NCT02039947) was an open-label, non-randomised, phase 2 study evaluating
dabrafenib plus trametinib in patients with BRAFV600 mutation-positive
metastatic melanoma and brain metastases. Patients in cohort A of COMBI-MB had
asymptomatic brain metastases, no previous local brain-directed therapy, and an
ECOG performance status of 0 or 1. Biomarker analysis was a prespecified
exploratory endpoint in both trials and performed in the intention-to-treat
populations in COMBI-d and COMBI-MB. We investigated the association between
mutant copy number (baseline or week 4 or zero conversion status) and efficacy
endpoints (progression-free survival, overall survival, and best overall
response). We used Cox models, Kaplan-Meier plots, and log-rank tests to
explore the association of pretreatment ctDNA concentrations with
progression-free survival and overall survival. The effect of additional
prognostic variables such as lactate dehydrogenase was also investigated in
addition to the mutant copy number.
Findings: In COMBI-d, pretreatment plasma samples were
available from 345 (82%) of 423 patients and on-treatment (week 4) plasma
samples were available from 224 (53%) of 423 patients. In cohort A of COMBI-MB,
pretreatment and on-treatment samples were available from 38 (50%) of 76
patients with intracranial and extracranial metastatic melanoma. ctDNA was
detected in pretreatment samples from 320 (93%) of 345 patients (COMBI-d) and
34 (89%) of 38 patients (COMBI-MB). When assessed as a continuous variable,
elevated baseline BRAFV600 mutation-positive ctDNA concentration was associated
with worse overall survival outcome, independent of treatment group and
baseline lactate dehydrogenase concentration, in COMBI-d. A ctDNA cutoff point
of 64 copies per mL of plasma stratified patients enrolled in COMBI-d as high
risk or low risk with respect to survival outcomes and was validated in the
COMBI-MB cohort. In COMBI-d, undetectable ctDNA at week 4 was significantly
associated with extended progression-free and overall survival, particularly in
patients with elevated lactate dehydrogenase concentrations.
Interpretation: Pretreatment and on-treatment
BRAFV600-mutant ctDNA measurements could serve as independent, predictive
biomarkers of clinical outcome with targeted therapy.
Circulating tumour DNA and melanoma survival: A
systematic literature review and meta-analysis. Gandini, Zanna, De Angelis, et al. Crit Rev Oncol Hematol. Jan 2021.
We reviewed and meta-analysed the available evidence (until
December 2019) about circulating tumour DNA (ctDNA) levels and melanoma
patients survival. We included twenty-six studies (more than 2000 patients overall),
which included mostly stage III-IV cutaneous melanoma patients and differed
widely in terms of systemic therapy received and somatic mutations that were
searched. Patients with detectable ctDNA before treatment had worse
progression-free survival (PFS) and overall survival (OS), with no difference
by tumour stage. ctDNA detectability during follow-up was associated with
poorer PFS and OS; in the latter case, the association was stronger for stage
IV vs. III melanomas. Between-estimates heterogeneity was low for all pooled
estimates. ctDNA is a strong prognostic biomarker for advanced-stage melanoma
patients, robust across tumour (e.g. genomic profile) and patients (e.g.
systemic therapy) characteristics.
The Prognostic Impact of Circulating Tumour DNA in
Melanoma Patients Treated with Systemic Therapies-Beyond BRAF Mutant Detection. Marsavela, Johansson, Pereira, et al. Cancers (Basel). Dec 2020.
In this study, we evaluated the predictive value of
circulating tumour DNA (ctDNA) to inform therapeutic outcomes in metastatic
melanoma patients receiving systemic therapies. We analyzed 142 plasma samples
from metastatic melanoma patients prior to commencement of systemic therapy: 70
were treated with BRAF/MEK inhibitors and 72 with immunotherapies.
Patient-specific droplet digital polymerase chain reaction assays were designed
for ctDNA detection. Plasma ctDNA was detected in 56% of patients prior to
first-line anti-PD1 and/or anti-CTLA-4 treatment. The detection rate in the
immunotherapy cohort was comparably lower than those with BRAF inhibitors
(76%). Decreasing ctDNA levels within 12 weeks of treatment was strongly
concordant with treatment response and predictive of longer progression free
survival. Notably, a slower kinetic of ctDNA decline was observed in patients
treated with immunotherapy compared to those on BRAF/MEK inhibitors. Whole
exome sequencing of ctDNA was also conducted in 9 patients commencing anti-PD-1
therapy to derive tumour mutational burden (TMB) and neoepitope load
measurements. The results showed a trend of high TMB and neoepitope load in responders
compared to non-responders. Overall, our data suggest that changes in ctDNA can
serve as an early indicator of outcomes in metastatic melanoma patients treated
with systemic therapies and therefore may serve as a tool to guide treatment
decisions.
Yep! THAT LAST SENTENCE!!!
Prognostic Value of ctDNA Mutation in Melanoma: A Meta-Analysis. Zheng, Sun, Cong, et al. J Oncol.. May 2021.
Purpose: Melanoma is the most aggressive form of skin
cancer. Circulating tumor DNA (ctDNA) is a diagnostic and prognostic marker of
melanoma. However, whether ctDNA mutations can independently predict survival
remains controversial. This meta-analysis assessed the prognostic value of the
presence or change in ctDNA mutations in melanoma patients.
Methods: We identified studies from the PubMed, EMBASE, Web
of Science, and Cochrane databases. We estimated the combined hazard ratios
(HRs) for overall survival (OS) and progression-free survival (PFS) using
either fixed-effect or random-effect models based on heterogeneity.
Results: Sixteen studies including 1,781 patients were
included. Both baseline and posttreatment detectable ctDNA were associated with
poor OS. For PFS, baseline detectable ctDNA may be associated with adverse PFS and
baseline high ctDNA and increased ctDNA were significantly associated with
adverse PFS. The baseline BRAFV600 ctDNA mutation-positive group was
significantly associated with adverse OS compared with the baseline
ctDNA-negative group. There were no significant differences in PFS between the
baseline BRAFV600 ctDNA mutation-detectable group and the undetectable group.
Conclusion: The presence or elevation of ctDNA mutation or
BRAFV600 ctDNA mutation was significantly associated with worse prognosis in
melanoma patients.
Liquid biopsy and radiological response predict outcomes following discontinuation of targeted therapy in patients with BRAF mutated melanoma. Di Guardo, Randon, Corti, et al. Oncologist. August 2021.
Background: Outcomes of patients with metastatic melanoma
discontinuing BRAF-targeted therapy for cumulative toxicity after sustained
response are unknown.
Patients and methods: This retrospective case series analysis
conducted at a single Cancer Center in Italy included patients with BRAF
mutated metastatic melanoma treated with a BRAF inhibitor as a single agent or
in combination with a MEK inhibitor between June 1, 2011 and January 1, 2020
and interrupting treatment after achieving complete response (CR) or
long-lasting partial response (PR - i.e. greater than 12 months) due to
cumulative toxicity.
Results: We included 24 patients with a median treatment
duration of 59.4 months. CR and PR were achieved in 71% and 29% of patients,
respectively. At a median follow-up after treatment discontinuation of 37.8
months, 12-months progression free survival after discontinuation (dPFS) rate
was 70.8% and 24-months dPFS rate was 58.3%. Baseline patients and tumor
characteristics as well as treatment duration and best response did not
significantly impact on dPFS. Patients with CR and negative circulating tumor
DNA (ctDNA) at time of discontinuation had a significantly improved dPFS
compared to patients with either radiological residual disease or ctDNA
positivity. No patient in CR with undetectable ctDNA experienced progression.
Conclusion: The risk of progression is high even in patients
with sustained sensitivity to BRAF/MEK inhibitors. Integration of liquid biopsy
in clinical trials investigating optimal management of patients with sustained
sensitivity to BRAF/MEK inhibitors is warranted.
Implications for practice: Outcomes of patients with
metastatic melanoma discontinuing BRAF-targeted therapy for cumulative toxicity
are unknown. We analyzed patients with sustained responses (median treatment
duration 59.4 months). Twelve and 24-months progression free survival following
discontinuation were 70.8% and 58.3% respectively. Complete response and
negative ctDNA at time of discontinuation are promising prognostic biomarkers
in this setting.
Detection of clinical progression through plasma ctDNA in metastatic melanoma patients: a comparison to radiological progression. Marsavela, McEvoy, Pereira, et al. Br J Cancer. August 2021.
Background: The validity of circulating tumour DNA (ctDNA)
as an indicator of disease progression compared to medical imaging in patients
with metastatic melanoma requires detailed evaluation.
Methods: Here, we carried out a retrospective ctDNA analysis
of 108 plasma samples collected at the time of disease progression. We also
analysed a validation cohort of 66 metastatic melanoma patients monitored
prospectively after response to systemic therapy.
Results: ctDNA was detected in 62% of patients at the time
of disease progression. For 67 patients that responded to treatment, the mean
ctDNA level at progressive disease was significantly higher than at the time of
response. However, only 30 of these 67 (45%) patients had a statistically
significant increase in ctDNA by Poisson test. A validation cohort of 66
metastatic melanoma patients monitored prospectively indicated a 56% detection
rate of ctDNA at progression, with only two cases showing increased ctDNA prior
to radiological progression. Finally, a correlation between ctDNA levels and
metabolic tumour burden was only observed in treatment naïve patients but not
at the time of progression in a subgroup of patients failing BRAF inhibition (N
= 15).
Conclusions: These results highlight the low efficacy of
ctDNA to detect disease progression in melanoma when compared mainly to
standard positron emission tomography imaging.
I think the vast preponderance of the evidence shows that knowing the presence of and/or quantity of bits of melanoma floating in your blood stream gives the patient and their physician important information that can impact treatment choice. That same data can help make decisions about whether or not to stop or change treatments. Many studies have demonstrated that this simple blood draw can tell you your status weeks to months sooner than tumors can be seen on radiographic studies. The last study above stands in contrast to that but I try to be complete. I will say that it is important to note that the study above was a retrospective review of 108 blood samples collected at the time of disease progression vs 66 patients monitored after response to systemic therapy. I don't think that is the best way to collect and compare data - maybe that's just me. I leave you with this ~
The prognostic value of circulating tumor DNA in
patients with melanoma: A systematic review and meta-analysis. Feng, Cen, Tan, et al. Transl Oncol.
June 2021.
Background: Circulating tumor DNA (ctDNA) has been
investigated as a potential prognostic biomarker to evaluate the therapeutic
efficacy and disease progression in melanoma patients, yet results remain
inconclusive. The purpose of this study was to illustrate the prognostic value
of ctDNA in melanoma.
Objectives: To describe the clinical prognostic value of
ctDNA for melanoma patients.
Methods: Searched for eligible articles from Pubmed, Web of
Science and Embase. Pooled hazard ratios (HRs) and 95% confidence intervals
(CIs) were calculated to evaluate the association between ctDNA at baseline or
during treatment and overall survival (OS) and progression-free survival (PFS).
Results: A total of 9 articles were obtained, involving 617
melanoma patients. The pooled HRs revealed that compared with baseline
undetectable ctDNA patients, detectable ctDNA was highly correlated with poor
OS and PFS. A meta-analysis of these adjusted HRs was performed
and confirmed that ctDNA collected at baseline was associated with poorer
OS/PFS. During treatment, a significant association was shown
between ctDNA and poorer OS/PFS.
Conclusion: Investigation and application of ctDNA will
improve "liquid biopsy" and play a role in early prediction,
monitoring disease progression and precise adjusting treatment strategies in
melanoma patients.
For me, I think ctDNA can provide valuable information that we can use when having to make the incredibly difficult decisions faced by cancer patients. Coming soon - putting my money and my blood - where my mouth is. Hang tough. - c
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