Circulating tumor DNA to monitor and predict response in melanoma patients - yes - AGAIN!!!!

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.  Here are zillions of articles:  Circulating Tumor DNA for melanoma

Now, there are these:

The use of circulating cell-free tumor DNA in routine diagnostics of metastatic melanoma patients.  Knuever, Weiss, Persa, et al. Sci Rep. 2020 Mar 18.

Modern advances in technology such as next-generation sequencing and digital PCR make detection of minor circulating cell-free tumor DNA amounts in blood from cancer patients possible. Samples can be obtained minimal-invasively, tested for treatment-determining genetic alterations and are considered to reflect the genetic constitution of the whole tumor mass. Furthermore, tumor development can be determined by a time course of the quantified circulating cell-free tumor DNA. However, systematic studies which prove the clinical relevance of monitoring patients using liquid biopsies are still lacking. In this study, we collected 115 samples from 47 late stage melanoma patients over 1.5 years alongside therapy-associated clinical routine monitoring. Mutation status was confirmed by molecular analysis of primary tumor material. We can show that detectable levels of circulating cell-free tumor DNA correlate with clinical development over time. Increasing levels of circulating cell-free tumor DNA during melanoma treatment with either targeted therapy (BRAF/MEK inhibitors) or immunotherapy, during recovery time or the intervals between last treatment cycle and second-line treatment point towards clinical progression before the progression becomes obvious in imaging. Therefore, this is a further possibility to closely screen our patients for tumor progression during therapy, in therapy-free phases and in earlier stages before therapy initiation.

YEP!

Longitudinal monitoring of ctDNA in patients with melanoma and brain metastases treated with immune checkpoint inhibitors.  Lee, Menziew, Carlino, et al.  Clin Cancer Res.  2020 April 22.

PURPOSE: Brain involvement occurs in majority of patients with metastatic melanoma. The potential of circulating tumor DNA (ctDNA) for surveillance and monitoring systemic therapy response in patients with melanoma brain metastases merits investigation. 

EXPERIMENTAL DESIGN: This study examined circulating BRAF, NRAS and c-KIT mutations in melanoma patients with active brain metastases receiving PD-1 inhibitor-based therapy. Intracranial and extracranial disease volumes were measured using the sum of product of diameters, and response assessment performed using RECIST. Longitudinal plasma samples were analysed for ctDNA over the first 12 weeks of treatment (threshold 2.5 copies/ml plasma). 

RESULTS: Of a total of 72 patients; 13 patients had intracranial metastases only and 59 patients had concurrent intracranial and extracranial metastases. ctDNA detectability was 0% and 64%, respectively, and detectability was associated with extracranial disease volume. Undetectable ctDNA on-therapy was associated with extracranial response but not intracranial response. The median overall survival in patients with undetectable (n = 34) versus detectable (n = 38) ctDNA at baseline was 39.2 versus 10.6 months and on-therapy was 39.2 versus 9.2 months. 

CONCLUSIONS: ctDNA remains a strong prognostic biomarker in melanoma patients with brain metastases, especially in patients with concurrent extracranial disease. However, ctDNA was not able to detect or monitor intracranial disease activity, and we recommend against using ctDNA as a sole test during surveillance and therapeutic monitoring in patients with melanoma.

In this study of 72 patients, circulating tumor DNA was a useful biomarker in patients who had melanoma in both their body and brain.  The ability to monitor the status of patients with melanoma ONLY in their brain was not found.  It should be noted that this is one study and there were only 13 patients in the "brain met only" arm.

Circulating Tumor DNA Predicts Outcome from First-, but not Second-line Treatment and Identifies Melanoma Patients Who May Benefit from Combination Immunotherapy.   Marsavela, Lee, Calapre, et al.  Clin Cancer Res.  2020 Nov.

Purpose: We evaluated the predictive value of pretreatment ctDNA to inform therapeutic outcomes in patients with metastatic melanoma relative to type and line of treatment.

Experimental design: Plasma circulating tumor DNA (ctDNA) was quantified in 125 samples collected from 110 patients prior to commencing treatment with immune checkpoint inhibitors (ICIs), as first- (n = 32) or second-line (n = 27) regimens, or prior to commencing first-line BRAF/MEK inhibitor therapy (n = 66). An external validation cohort included 128 patients commencing ICI therapies in the first- (N = 77) or second-line (N = 51) settings.

Results: In the discovery cohort, low ctDNA (less than or equal to 20 copies/mL) prior to commencing therapy predicted longer progression-free survival (PFS) in patients treated with first-line ICIs, but not in the second-line setting. An independent cohort validated that ctDNA is predictive of PFS in the first-line setting, but not in the second-line ICI setting. Moreover, ctDNA prior to commencing ICI treatment was not predictive of PFS for patients pretreated with BRAF/MEK inhibitors in either the discovery or validation cohorts. Reduced PFS and overall survival were observed in patients with high ctDNA receiving anti-PD-1 monotherapy, relative to those treated with combination anti-CTLA-4/anti-PD-1 inhibitors.

Conclusions: Pretreatment ctDNA is a reliable indicator of patient outcome in the first-line ICI treatment setting, but not in the second-line ICI setting, especially in patients pretreated with BRAF/MEK inhibitors. Preliminary evidence indicated that treatment-naïve patients with high ctDNA may preferentially benefit from combined ICIs.

We already know that progression free survival and overall survival is better in those with the lowest tumor burden (no matter how you attain that information) and better in those who respond to treatment on the first go.  This study confirms that using ctDNA.  We don't fully understand why melanoma peeps respond less well on their second round of therapy and this report indicates that ctDNA is less useful in that setting as well - though they looked at small numbers here with 32 patients in the first line immunotherapy treatment cohort and only 27 peeps were using it for the second time.  There were 66 patients using targeted therapy for the first time.

Circulating tumour DNA and melanoma survival: A systematic literature review and meta-analysis.  Gandini, Zanna, De Angelis, et al.  Crit Rev Oncol Hematol.  2020 Nov.

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.

Detectable ctDNA  before treatment correlated in a decreased progression free survival and overall survival for both Stage III and Stage IV peeps.  When ctDNA was detectable during follow-up after treatment, associated PFS and OS was worse, but the decreased OS was even more significant in Stage IV patients.

Circulating Tumour DNA in Advanced Melanoma Patients Ceasing PD1 Inhibition in the Absence of Disease Progression.  Warbutron, Calapre, Pereira, et al.  Cancers. 2020 Nov.

Immunotherapy is an important and established treatment option for patients with advanced melanoma. Initial anti-PD1 trials arbitrarily defined a two-year treatment duration, but a shorter treatment duration may be appropriate. In this study, we retrospectively assessed 70 patients who stopped anti-PD1 therapy in the absence of progressive disease (PD) to determine clinical outcomes. In our cohort, the median time on treatment was 11.8 months. Complete response was attained at time of anti-PD1 discontinuation in 61 (87%). After a median follow up of 34.2 months (range: 2-70.8) post discontinuation, 81% remained disease free. Using ddPCR, we determine the utility of circulating tumour DNA (ctDNA) to predict progressive disease after cessation (n = 38). There was a significant association between presence of ctDNA at cessation and disease progression and this conferred a negative and positive predictive value of 0.82 and 0.80, respectively. Additionally, dichotomised treatment-free survival in patients with or without ctDNA at cessation was significantly longer in the latter group. Overall, our study confirms that durable disease control can be achieved with cessation of therapy in the absence of disease progression and undetectable ctDNA at cessation was associated with longer treatment-free survival.

In this study, looking at melanoma patients who stopped immunotherapy after about a year, researchers found that disease progression was strongly associated with those who had detectable ctDNA when they stopped treatment.  Not a surprise.  SO - if you are thinking of stopping treatment due to side effects or a complete response per scans, getting ctDNA analyzed may be an important factor in that decision making process!

Stopping targeted therapy for complete responders in advanced BRAF mutant melanoma. Warbutron, Menjawy, Calapre, et al.  Sci Rep.  2020 Nov 2.

BRAF inhibitors revolutionised the management of melanoma patients and although resistance occurs, there is a subgroup of patients who maintain durable disease control. For those cases with durable complete response (CR) it is not clear whether it is safe to cease therapy. Here we identified 13 patients treated with BRAF +/- MEK inhibitors, who cease therapy after prolonged CR (median = 34 months, range 20-74). Recurrence was observed in 3/13 (23%) patients. In the remaining 10 patients with sustained CR off therapy, the median follow up after discontinuation was 19 months (range 8-36). We retrospectively measured ctDNA levels using droplet digital PCR (ddPCR) in longitudinal plasma samples. CtDNA levels were undetectable in 11/13 cases after cessation and remained undetectable in patients in CR (10/13). CtDNA eventually became detectable in 2/3 cases with disease recurrence, but remained undetectable in 1 patient with brain only progression. Our study suggests that consideration could be given to ceasing targeted therapy in the context of prolonged treatment, durable response and no evidence of residual disease as measured by ctDNA.

Same song, second verse in regard to two points here.  Folks going off targeted therapy did better if they had no detectable ctDNA.  And ctDNA was not detectable in one brain met only patient despite the obvious brain met.

We STILL have much to learn about melanoma and ctDNA.  However, it is CLEAR (after more than 7 years!!!) that analyzing ctDNA can be a helpful tool and should be routinely used in combination with other methods to monitor and evaluate melanoma patients - before and after therapy.  Thanks, ratties.  Demand the healthcare you deserve!!! - c