Then there's melanoma, GCC and me - Study shows increased secondary cancer risk after immunotherapy!!!!! Adjuvant treatment of Stage II GCC = no improvement in OS!!! Well! Isn't that nice???

As most of you reading these pages know, I was diagnosed with Stage IIIb melanoma in 2003, advanced to Stage IV in 2010 with brain and lung mets, subsequently enrolled in a Phase 1 Nivolumab (Opdivo) trial, taking nivo for 2 1/2 years.  On what was to be my last follow-up scan in 2018, something was found in my appendix.  Removal and biopsy indicated Stage II Ex-goblet cell adenocarcinoma of the appendix.  Appendiceal cancer is very rare - found in only 1-2 people per million in the US.  Of those, my type of appendiceal cancer is rarer still!  I completed (almost) a three month, 4 dose regimen of adjuvant CAPOX (Capecitabine and Oxaliplatin).

Currently, that means I am ~

219 months (18 YEARS!!!!) post my original melanoma diagnosis in 2003 at the age of 39
139 months Stage IV (11 and 1/2 years!!!)
133 months NED (well....for melanoma at least)
131 months after starting nivo (Opdivo)
101 months (more than 8 years) AFTER my last nivo infusion in June 2013.

I am also:  
39 months post my diagnosis of adenocarcinoma ex-goblet cell carcinoid (GCC) and the removal of my appendix with its 10.5 cm tumor, my ascending colon including ileocecal valve, gall bladder and ovaries
36 months (3 years!) post completion of 3 months adjuvant CAPOX chemo for same

Then there's this:

Assessment of Trends in Second Primary Cancers in Patients With Metastatic Melanoma From 2005 to 2016.  Deng, Wang, Liu, et al.  JAMA Dec 2020.

Importance: To date, the risk of developing second primary cancers (SPCs) after the first primary melanoma has not been studied in the era of immune checkpoint inhibitors (ICIs).

Objective: To assess differences in the risk of SPCs in patients with primary melanoma before (2005-2010) and after (2011-2016) the introduction and approval of ICIs.

Design, setting, and participants: Population-based cohort study using the Surveillance, Epidemiology, and End Results database from January 2005 to December 2016 of patients diagnosed with metastatic melanoma. Data were analyzed from January 4 to June 30, 2020.

Exposures: Receipt of immunotherapy or other anticancer agents.

Main outcomes and measures: The primary outcome was the development of second primary cancers in patients with melanoma. Standardized incidence ratios (SIRs) were calculated for the development of SPCs before and after the introduction of ICIs.

Results: Among 5016 patients with diagnosed metastatic melanoma, 2888 (58%) were younger than 65 years at the time of diagnosis, and 3441 (69%) were male. From 2005 to 2010, SIRs were 3.24 for small intestine cancer, 1.93 for lung and bronchus cancer, 2.77 for kidney cancer, and 7.29 for myeloma. From 2011 to 2016, SIRs were 9.23 for small intestine cancer, 1.54 for lung and bronchus cancer, 2.66 for kidney cancer, and 5.90 for myeloma. The overall risk of developing SPCs in individuals who survived the first primary melanoma was 65% higher in the pre-ICIs period and 98% higher in the post-ICIs period than the overall cancer incidence rate in the general population.

Conclusions and relevance: In this study, an increase in the overall risk of second primary cancers after melanoma after the introduction of immune checkpoint inhibitors was observed. The pattern of SPCs has been altered in the era of systemic therapy. Close monitoring and screening for SPCs may be warranted in patients with metastatic melanoma.

Well damn!  I think of you so often, my sweet Julie!!!!  And that last sentence - "Close monitoring and screening for Second Primary Cancers may be warranted in patients with metastatic melanoma."  Tell that to oncs and more importantly to insurance companies!!!!!!!!!!!!!!!!!!!!!  Though - before anyone panics I will add these thoughts:

1.  This study is not the end all be all.

2.  When you are dealing with melanoma - especially Stage IV as I was - you are facing death or treatment.  So, what choice is there, really?  Besides, despite Stage IV melanoma, despite immunotherapy side effects, despite a second cancer and the side effects from that treatment - I'm Still Here!!!!!!!!

3.  There are variables besides immunotherapy that have to be considered here as well - 

    a) The propensity of these patients to develop cancer - for whatever reason.

    b) The 9 gazillion scans used as follow-up/treatment management in these patients.

    c) The use of radiation in these patients as part of their treatment.

There may well be more, but those come to me at the moment.  In cancer world, we know that treatment, though necessary, is not benign.

Next up -

Gotta say, I thought I was a beast when I got through my 2 1/2 year nivo trial.  Working roughly 10-12 hours Mon, Tue, Wed as a pediatric NP in a busy office.  Driving the two hours to Atlanta on Thursday morning to catch the flight down to Tampa that afternoon.  Spending the night in the good ol La Quinta.  Treatment at the butt crack of dawn on Friday.  A mad dash back to the airport for the flight back to Atlanta.  Two hour drive home.  Usually arriving back in Chattown around midnight.  Rinse and repeat every 2 weeks for 6 months, then every 3 months for 2 years, missing only 3 days of work during that time.  Perhaps I was just insane.  Check out this post-it note sent home to B from a dear coworker during that time:  Friends in need are friends indeed! Here's to the caregivers!!!  Still, for all the fatigue, wheezing, arthralgias, rashes and oral lesions - immunotherapy was a walk in the park compared to CAPOX.  That shit kicked my ass - literally and figuratively!  Now, there's this.... 

Is adjuvant chemotherapy beneficial for stage II-III goblet cell carcinoid/goblet cell adenocarcinoma of the appendix?  Zakka, Williamson, Jiang, et al.  Surg Oncol.  2020 Dec.

Background: Goblet cell carcinoma (GCC), formerly known as goblet cell carcinoid, of the appendix constitutes less than 14% of all primary appendiceal neoplasms. Surgical resection is the main treatment and the role of adjuvant chemotherapy (AC) is not established. This study aims to evaluate the impact of AC in stage II-III appendiceal GCC.

Methods: Patients with pathological stage II and III GCC who underwent surgical resection between 2006 and 2015 were identified from the National Cancer Database (NCDB) using ICD-O-3 morphology and topography codes: 8243/3 (goblet cell carcinoid) and C18.1. Patients treated with neoadjuvant systemic and/or radiation therapy and adjuvant radiation were excluded. Univariate and multivariable analyses were conducted, and Kaplan-Meier Curves were used to compare overall survival (OS) based on treatment received with Log-rank test.

Results: A total of 619 patients [over 9 years!!!] were identified. 54.4% males and 89.0% Caucasian; median age 56 (range, 23-90) years. Distribution across pathological stages II-III was 82.7% (N = 512) and 17.3% (N = 107) respectively. AC was administered in 9.4% (N = 48) of stage II and 47.7% (N = 51) of stage III patients. For stage II patients, AC was not associated with better OS. By contrast, in stage III patients, AC was associated with better OS. In the entire cohort 5-year OS for patients that received AC was 85.5% (74.0%, 92.1%) versus 82.7% (77.5%, 86.8%) with no AC. For stage II patients, 5-year OS was 96.9% with AC vs. 89.1% with no AC. For stage III patients, 5-year OS was 77.1% with AC vs. 42.8% with no AC.

Conclusion: AC was associated with improved OS in patients with pathological stage III GCC of the appendix, but not with pathological stage II.

Well, ain't that a bitch??!!!  Now this - 

Outcomes in Peritoneal Carcinomatosis from Appendiceal Goblet Cell Carcinoma Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS/HIPEC).  Zambrano-Vera, Sardi, Munoz-Zuluaga, et al.  Ann Surg Oncol.  2020 Jan 27.

Background: Appendiceal goblet cell adenocarcinoma (GCA) is often misclassified and mistreated due to mixed histologic features. In general, cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is standard of care for peritoneal carcinomatosis (PC) from mucinous appendiceal tumors; however, in PC from GCA, data are limited and the role of CRS/HIPEC is controversial. We report outcomes in PC from appendiceal GCA treated with CRS/HIPEC.

Patients and methods: A prospective institutional database of 391 CRS/HIPEC patients with appendiceal carcinomatosis from 1998 to 2018 was reviewed. Twenty-seven patients with GCA were identified. Perioperative variables were described. Survival was estimated using the Kaplan-Meier method.

Results: GCA occurred in 7% (27/391) of appendiceal CRS/HIPEC patients. Seven (26%) cases were aborted. Two patients underwent a second CRS/HIPEC for peritoneal recurrence. Median age at diagnosis was 53 years (range 39-72 years), and 12 (60%) were female. All underwent previous surgery. Seven (35%) had prior chemotherapy and received a median of 5 cycles (range 3-8). Median PCI was 6 (range 1-39). Complete cytoreduction was achieved in 95% (19/20). Grade III complications occurred in three (15%) patients, and no perioperative deaths occurred. Median follow-up was 97 months. Overall survival at 1, 3 and 5 years was 100%, 74% and 67%, respectively. Progression-free survival at 1, 3, and 5 years was 94%, 67% and 59%, respectively.

Conclusion: CRS/HIPEC should be considered as the main treatment option for patients with PC from appendiceal GCA. When performed at a CRS/HIPEC specialty center, 5-year OS of 67% can be achieved.

Poor peeps!  I hope I never have to undergo that shit!!!!  Man!  Don't you love how researchers state things like "When performed at a CRS/HIPEC specialty center, 5-year OS of 67% can be achieved." - as though 33% of patients dying within 5 years is a good thing?  Sigh.....

Y'all know I've been yelling for YEARS, as recently as earlier this month, about ctDNA use in melanoma - rather - how it SHOULD be used in melanoma!!! - A Zillion Posts  Now, there's this -

Analysis of Plasma Cell-Free DNA by Ultradeep Sequencing in Patients With Stages I to III Colorectal Cancer.  Reinert, Henriksen, Christensen, et al.  JAMA Oncol.  2019, May.

Importance:  Novel sensitive methods for detection and monitoring of residual disease can improve postoperative risk stratification with implications for patient selection for adjuvant chemotherapy (ACT), ACT duration, intensity of radiologic surveillance, and, ultimately, outcome for patients with colorectal cancer (CRC).

Objective:  To investigate the association of circulating tumor DNA (ctDNA) with recurrence using longitudinal data from ultradeep sequencing of plasma cell-free DNA in patients with CRC before and after surgery, during and after ACT, and during surveillance.

Design, Setting, and Participants:  In this prospective, multicenter cohort study, ctDNA was quantified in the preoperative and postoperative settings of stages I to III CRC by personalized multiplex, polymerase chain reaction–based, next-generation sequencing. The study enrolled 130 patients at the surgical departments of Aarhus University Hospital, Randers Hospital, and Herning Hospital in Denmark from May 1, 2014, to January 31, 2017. Plasma samples (n = 829) were collected before surgery, postoperatively at day 30, and every third month for up to 3 years.

Results:  A total of 130 patients with stages I to III CRC (mean age, 67.9 years; 74 male) were enrolled in the study; 5 patients discontinued participation, leaving 125 patients for analysis. Preoperatively, ctDNA was detectable in 108 of 122 patients. After definitive treatment, longitudinal ctDNA analysis identified 14 of 16 relapses (87.5%). At postoperative day 30, ctDNA-positive patients were 7 times more likely to relapse than ctDNA-negative patients. Similarly, shortly after ACT ctDNA-positive patients were 17 times  more likely to relapse. All 7 patients who were ctDNA positive after ACT experienced relapse. Monitoring during and after ACT indicated that 3 of the 10 ctDNA-positive patients (30.0%) were cleared by ACT. During surveillance after definitive therapy, ctDNA-positive patients were more than 40 times more likely to experience disease recurrence than ctDNA-negative patients. In all multivariate analyses, ctDNA status was independently associated with relapse after adjusting for known clinicopathologic risk factors. Serial ctDNA analyses revealed disease recurrence up to 16.5 months ahead of standard-of-care radiologic imaging (mean, 8.7 months; range, 0.8-16.5 months). Actionable mutations were identified in 81.8% of the ctDNA-positive relapse samples.

Conclusions and Relevance:  Circulating tumor DNA analysis can potentially change the postoperative management of CRC by enabling risk stratification, ACT monitoring, and early relapse detection.

How could this not be a good thing, right???? So, I put my money where my mouth is.  Several months ago, I had the Signatera - Circulating tumor DNA blood test done.  The company analyzed a sample from my appendiceal tumor to create an assay generated by the mutations in my specific tumor to know what to look for in a simple blood draw.  It was negative.  Meaning - no bits or bobs of the tumor DNA they searched for was in my blood sample.  This is in no way an advert for that particular company. (Though medical folks from the company answered ALL B's questions in several phone calls, so that is something!!!)  This is simply a report of what I did, the research behind it, and how it went.  I told B I ought to do a two-fer and have them look for melanoma as well as GCC!!  Surprisingly, he was not amused!  Such a party pooper!  Poor boy.  

So, to finish up 2021 with a bang, a couple of weeks ago, routine follow-up scans were clear - the strange ascites that keep jogging around with me was diminished, so that's good, I guess.  Yesterday, I had a visit with my onc and labs (to follow relative proteins, iron, folate and such) drawn.  An uneventful event, though I had to be stuck twice.  Such is the life of a cancer patient.  And to think - having had bilateral complete lymphadenectomies of both arms in 2003 and 2007 - I was told never to have so much as a blood pressure check in either.  Well!!!  That went out the window YEARS ago!  I am moving to annual scans and doc visits with labs every 6 months.  Clearly, I am to be seen sooner if I have any problems. Though how to ID said 'problems' is a little unclear.  Leaving the visit, I told B I was tired of being a cancer patient.  But, as quickly as I said it I realized that when you ARE a cancer patient, getting to be one for so many years is pretty lucky, no?  Neuropathies to hands and feet continue.  B religiously applies Voltaren to my feet each night.  Again, not an advert.  I'm not really sure it does anything, but he is convinced.  We've tried a variety of things - icy hot type preparations, Blue emu something or other, a hemp oil ta-dah.  These well and truly did nothing at all!!!  I've learned to manage my bowel situation, though some days are better than others.  I still run and sew and work and play.  At the end of the day - especially at the end of THREE /18 crazy years - what more can one ask for?

Wishing each of you peaceful moments, much love, and a zillion small joys in the coming year.   ~ les

And, yes.  The observant among you will note that it took me a year to post the data included here.  Sometimes it takes a minute to face your reality. And, yes.  I am smiling. - c

Sew Chaotically! ~ Jam's Layette

As I made Roo's maternity dresses, if there was extra fabric, I stitched a little something for Jam!  As sweet peeps gifted her and the Jamester with cute little outfits, tops and onesies - she went through my knit remnants and we came up with what he needed to complete his outfits for the coming 6 months.  While he has lots of newborn tops and onesies - the boy needed some bottoms!!!  But, I couldn't resist using a bit of Roo's soft citrus knit (her serious fav!) to stitch up just one more little newborn onesie!

Since we figured the little pants can last several months, I didn't make up any 4 month sizes.

I did use these remnants to make up a few 4 month sized tops.

To go with all of the above, I made the cutest little jacket.  The back is a smidge of grey knit I used for one of Roo's skirts.  The sleeves and front pieces are the super soft flannel I used in one of her last dresses, while the collar and sleeve cuffs are made from a scrap of the softest moleskin.

For the bigger guy - HA! - there are some 6-9 month sized tops and little pants.

If we didn't guesstimate perfectly on the sizes, I can always make more!!!  All the little snap neck t-shirts are a free pattern from Small Dreamfactory.  The lap neck onesies are the Baby Bodysuit, also free from Small Dreamfactory.  The cute joggers and the jacket are both from the McCalls 7827 pattern.  B did a great job applying all the needed snaps.  I think Roo and Jamie put together a cute functional layette that was ever SEW much fun for me to make!!!  There will no doubt be more cute outfits to come!!!!!

As Jeanne says so well ~ "Life is good!"  Sew Chaotically! ~ les

Sew (and decorate) chaotically! ~ Jam's Nursery

 And ~ Voila!  The nursery is ready!!!

Giraffe curtains are hung.  (Fabric detail below).  Sweet gifted giraffes wait patiently.

B's giraffe photos and growth chart he found decorate some of the walls.

The cradle has a perfect sunny spot.

Daybed for Mom and Dad is cute and comfy, with Roo's comforter, Jam's quilt and lots of pillows.  Including some with new cases - giraffe style - of course!

Many thanks to the lady who overheard me and Roo in JoAnns last summer and showed us this fun and colorful giraffe print fabric!  It was perfect for the curtains!

Roo's ROYGBIV childhood comforter.

Didn't she match the giraffe fabric perfectly?

Couldn't resist this fabric in the clearance section of Wally World when on the look out for all things giraffe, with no idea how I would put it to use.  But, it worked out!

Jamie and Roo found the perfect print to hang over the bed!

Okay, Jammer!  We ret ta go!!!!   - les

Sew Chaotically! ~ Quilt #4 - Jam's Giraffes

When Roo and Jamie decided on a giraffe theme for Jam's nursery, I was super excited to discover this cute quilt pattern - Giraffes in a Row, by Sew Fresh Quilts!  Roo and Jamester loved it too, so it was off to the races.  Roo selected the fabric for the ROYBGIV giraffes to match a quilt from her childhood that she will also be using in the nursery.  

The pattern for the quilt top went together well - once I figured out the heads!  A couple of the giraffes had too many blocks for their necks per the pattern.  Or perhaps the error was mine.  I didn't put in the work to recalculate, as the fix was super simple - just leave them out!

The batting is Quilter's Cream 80/20.  There is a baby blanket sized option, but I made the 60X60 throw as you could include more giraffe cuteness with that size!

I was tempted to quilt it using rainbow colored thread, but feared that would distract from the design.  I ended up using a cream color that matched the background and backing - outlining the giraffes and using parallel and diagonal lines in the negative space.  In the end, I think it was the best decision.  The binding is made from material also used in the yellow giraffe and actually has a giraffe pattern on it!

Here is a sneak peek of it in place in the nursery along the rainbow quilt and pillowcase.  Sew much fun, indeed!!  Sew Chaotically!!! ~ les

Sew Chaotically! ~ Cradle and bedding

Both my sweet babies slept in this cradle, often with silly Thimble - their fearless protector - snoozing underneath.  The somewhat useless 'comforter' - unless they were playing on the floor - and bumpers were theirs too!  Roo and Jamie were excited to use it, so I gave it a little up-grade!  A scrub and oiling got the wood in shape.  I replaced the original ribbons in the comforter with green ones and used the ribbon to add extra ties to the bumpers as well.

I stitched up a case, rather than a sheet, for the new mattress B procured, so you can use both sides.  For fun, I made them of different soft flannels, and made a reversable blanket to match!

Rock a bye and good night!   Sew much fun! - les 

November Reads

Still happily dissolved in le Carre's Smiley series!!

Tinker Tailor Soldier Spy - John le Carre.  From 1974, Smiley is brought back from retirement to ferret out a Soviet mole in the British Intelligence Service.  With many twists and turns, Smiley uncovers the duplicity that has been in place under his, and all the other Circus top dogs, very noses.  Had to make a list of characters and who they were as I got started on this one!  Haven't done that since reading complicated Russian novels.  But as spies go by various names and keep their personal descriptors to a minimum, it was helpful as this one played out

The Honourable School Boy - John le Carre. From 1977, with the complete breakdown of the British Secret Service after the ousting of the double agent, Smiley is tasked with putting the Circus back together.  In the midst of all the crazy that is the Vietnam conflict Smiley traces a lead that may end in the demise of Karla, the Soviet officer and mastermind behind the treachery of the British mole.  Field agent and sometime journalist Jerry Westerby follows the trail of a Russian/Chinese plot through Hong Kong, Vietnam, Cambodia - unfurling a tale of blackmail, drug trafficking, defection, loyalty, political intrigue, power, greed and the ultimate question of who, exactly, are the good guys?

Smiley's People - John le Carre.  From 1979, the story ranges from a sturdy Russian emigree in Paris to double crosses and murder on Hampstead Heath.  Smiley is recruited from yet another "retirement" to deal with the twists and turns that eventually lead him to his nemesis - Karla.

A Legacy of Spies - John le Carre.  From 2017, Peter Guillam, Smiley's longtime protégé, is called in as the new powers-that-be at the Circus investigate the events that led to the death of Alec Leamas and his lover, Liz Gold, at the Berlin Wall years prior.  Told by Peter, the events before and after that fateful night are explained and wrestled with given their effects on the lives left behind.  Not my fav as neither Peter nor Alec are characters that I particularly care for, but even when le Carre's story focuses on characters that I do not particularly appreciate, he still weaves an entrancing tale.

Happy reading! - les

Circulating tumor DNA (ctDNA) the little bits of tumor floating in our blood and how they can impact melanoma patients

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