May Reads

Hamnet - Maggie O'Farrell.  Historical fiction, telling Shakespeare's story leading up to the writing of Hamlet.  The following passages hit incredibly close to the bone...

"...He carried with him, always, the sensation of his father's calloused hand enclosing the soft skin of his upper arm, the inescapable grip that kept him there so his father could rain down blows with his other, stronger hand.  The shock of a slap landing, sudden and sharp, from above; the flensing sting of a wooden instrument on the back of the legs.  How hard were the bones in the hand of an adult, how tender and soft the flesh of a child, how easy to bend and strain those young unfinished bones.  The doused, drenched feeling of fury, of impotent humiliation, in the long minutes of a beating.

His father's rages arrived from nowhere, like a gale, then blew quickly on.  There was no pattern, no warning, no rationale; it was never the same thing twice that tipped him over.  The son learnt, at a young age, to sense the onset of these eruptions and a series of feints and dodges to avoid his father's fists.  As an astronomer reads the minuscule shifts and alterations in the alignment of the planets and spheres, to see what lies in store, this eldest son became an expert in reading his father's moods and expressions.  He could tell, from the sound the front door made when his father entered from the street, from the rhythm of his footsteps on the flagstones, whether or not he was in for a beating."

"...He is, he prides himself, adept at dissembling, at reading the thoughts of others, at guessing which way they will jump, what they will do next.  Life with a quick tempered parent will hone these skills at an early age...."

Very few changes would be needed to make that story one I experienced and observed.  Damn.  At any rate - while Shakespeare's life and experiences are the bones of the story - the heart is built on the history, daily life and experiences as a mother, of his wife, Anne Hathaway.  I was incredibly touched by her strength, free spirit and depth of maternal love.  Highly, highly recommend.

Bark - Lorrie Moore.  This volume of short stories had been recommended by multiple sources.  Chose to try it as Hamnet was so powerful that I wanted something rather small and light.   Sorry.  Not a fan.  I didn't like a single character in this collection; always a problem for me.  Almost didn't finish it - but I did!  

INTRO to Marie Benedict's (aka Heather Terrell) work:   First and foremost, though her books tend to be a bit contrived and juvenile in presentation, wordy with a penchant to use "frisson" far too often, I have been most pleased to find them.  The women she writes of have certainly not been given their due in so many ways.  It was interesting to do a bit a of research on each woman and her life independent of these books - which - in one interview - was exactly what Ms. Benedict said she most wanted her writing to achieve.

The Mystery of Mrs. Christie - Marie Benedict.  Having read several biographies of Agatha Christie, there were no astonishing revelations in this one, though the premise of a letter left to her husband, found by him after she vanished, and the unraveling of both her mysterious disappearance and her husband's affair told through his eyes was fun to entertain.

Lady Clementine - Marie Benedict. Perhaps the best written of the lot, I learned a great deal about Churchill and his wife, Clemmie, that I did not know or had never really thought through.  Most impressive were her efforts on behalf of women in particular and Britons generally, during the war.  Their relationship. at least in this telling, was more mutually respectful and appreciative than some of the others of which she wrote.  In addition to reading about Churchill and his wife, I was led to watch Darkest Hour.  While good, it was disappointing how little light it shed on Clementine especially given who she was, the role she played in Churchill's life, and the fact that Kristin Scott Thomas was playing her!!!  Oh well.  You can't have everything.

Carnegie's Maid - Marie Benedict.  Despite the Carnegie name being associated with everything from innumerable libraries, colleges, the discovery of insulin, the dismantling of nuclear weapons and even Sesame Street - I knew little about the man.  An immigrant from Scotland, Andrew Carnegie, was one impressive dude. Brilliant and at times ruthless in his business ventures (telegraph, railroads, steel, bridges) he was an incredible and dedicated philanthropist.  Often directed toward education and libraries. he gave away 90% of his incredible wealth in his lifetime and at his death additional funds were dispersed to individuals, charities and various foundations.  At the age of 33 he wrote, 

"... The amassing of wealth is one of the worst species of idolatry. No idol more debasing than the worship of money."  In order to avoid degrading himself, he wrote in the same memo he would retire at age 35 to pursue the practice of philanthropic giving for "... the man who dies thus rich dies disgraced." 

The book is based on a premise that a relationship and unrequited love for his mother's maid led to this mantra; a possible but unlikely scenario?  Either way, it was used to good effect as a vehicle to tell the story of this complicated and generous man and is the only book that does not feature a woman known to actually exist.

The Other Einstein - Marie Benedict.  The story of Einstein's first wife and brilliant physicist, Mitza Maric.  Soooo - spoiler alert ~  Einstein was an ASSHOLE!!!!!!!!!!  Damn!  They had a daughter together - prior to their marriage - who was either put up for adoption or lost to scarlet fever.  (Further reading seems to favor the later.)  An entire experience that Albert was insensitive to at best.  Marriage did eventually follow along with the birth of two sons.  Despite her assistance with a great deal of his work, through his direct manipulation, Mitza's name was never credited on any of Albert's publications or in connection with any of his other recognitions.  I guess you could say she got the last laugh as his Nobel Prize money was placed in trust, and later in property, to provide income for her and their sons, one of whom required institutionalized care due to schizophrenia, after he left her for his cousin.  That would be his first cousin on his mother's side and second cousin on his father's!  Yes, one of the equations Mitza helped him develop is required to figure that one out! What the tub???!!!!

The Personal Librarian - Marie Benedict and Victoria Christopher Murray.  Perhaps the most tediously written of the group, describes the life of Bella da Costa Greene, who was JP Morgan's personal librarian from 1905, continuing even after his death in that role, working for his son until 1948.  She was a black woman 'passing' for white in a man's world.  I can't even imagine how it felt to face the challenges or the choices she made.  As glad as I am to know of Ms. Greene, the book itself is a bland shadow compared to Passing by Nella Larsen.  Then again, I don't think its authors were trying to reach those heights.  

Her Hidden Genius - Marie Benedict.  The story of Rosalind Franklin who, through her use of crystalline X-ray techniques, led to the understanding of the helix formation of DNA.  Sexism, underhanded stealing, and her death from ovarian cancer, likely caused or at least exacerbated by her excessive exposure to radiation at the age of 38, precluded her being awarded the Nobel Prize for that discovery, which was instead awarded to Watson and Crick in 1962.  She also worked on unraveling the mystery of RNA, learning things that enabled Doudna and Charpentier to attain the Nobel prize in 2020 for their work on CRISPR genome editing technology - paving their way as a researcher on the subject and woman in the field.  Sadly, this book may have been the most poorly written of the series, standing in sad relief when compared to The Code Breaker by Walter Isaacson.

The Aviator's Wife - Melanie Benjamin.  Another spoiler alert!  Ready?  Charles Lindberg was an ASSHOLE!!!  Much like, Einstein, he never gave ample credit to his wife Anne Morrow Lindberg who, though they met and married after his historic transatlantic flight, was his copilot and cowriter for many years.  He was a cold man who never seemed to really appreciate his children or wife, or the toll exacted on Anne after the abduction and murder of their first child, and was a Nazi sympathizer to boot!  If that wasn't enough, turns out he had three additional families through three women in Germany (two of whom were sisters!!!!) and a total of 7 children with those women from 1958 to 1967 in addition to the 6 he had with Anne.  Additional reading indicates that DNA testing demonstrated that those 7 were indeed his.  The children he had with Anne became aware of their existence after his and her death.  The book presumes that Anne learned of those "families" through letters he did actually write to the women imploring them to keep his secret even after his death, upon his death bed.  My reading indicates that finding the letters led to the aforementioned DNA testing and those children reaching out to their American siblings.  Hmmm....  Benjamin has written her story in a style and manner similar to those by Benedict - but it is worth reading.

When Crickets Cry - Charles Martin.  Though utterly predictable and more than a little romanticized (from someone who is a pediatric medical person) and not as good as Unwritten - Martin has a way of holding your attention.

Little Fires Everywhere - Celeste Ng.  I couldn't have read this at a more pivotal time.  Abortion, adoption (from both sides - those who wish to adopt and those who for myriad reasons are compelled to give their baby up), socioeconomic/class distinctions, race, cultural issues, raising children who are and aren't of your ethnicity, surrogacy -  motherhood in all its forms - it's here. Heart rending issues. Fairly well addressed - making one think.  Not sure the book lived up to all its hype - but that's not really the fault of the book nor the author.  If these issues of motherhood interest you - one of the more recent pod casts by Haptic and Hue - Fabric and Foundlings is definitely worth a listen as it addresses babies left, most often, by mothers who could not afford to feed and care for them, but were not lacking in love.  Because the foundling hospital - begun by a sea captain who wanted to improve the lives of those women and the children they could not keep, as a safe place, with accommodations to care for feed the children who previously were being left on the streets of 1720's London, required anonymity - most babies were left with bits of cloth attached to their blankets, which the mother could later describe and often had a matching piece of, so that should her plight improve, she could return and reclaim her child.  Records of these bits of cloth as well as the clothing the children were left in were meticulously kept.  This anonymous poem was left with one child ~

Hard is my Lot in Deep Distress

To Have No Help where most should find.

Sure nature meant her sacred laws

Should men as strong as women bind.

Regardless he, Unable I,

To keep this image of my heart.

‘Tis Vile to Murder! Hard to Starve,

And death almost to me to part.

If fortune should her favours give

That I in better plight might live

I’d try to have my boy again

And train him up the best of men.

I didn't plan to read predominantly of women and motherhood this month - but it seems I did and it was good.  "Sure nature meant her sacred laws should men as strong as women bind."  That says so much as we face determinations by the Supreme Court regarding women's health - having been placed in circumstances women did not - could not - attain alone.

Read chaotically!  - les

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

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 

August Reads ~

I Alone Can Fix It - Carol Leonnig and Philip Rucker   My third in a somewhat dispiriting series reporting what can happen when those who are undeserving of office attain it.  On the other hand, there are those who rise to the occasion when much needed and perhaps more than we can even comprehend at this moment may be at stake.

East of Eden - John Steinbeck  Speaking of rising - Thou Mayest.  My fourth reading over the years of my life.  Each one has revealed new perspectives.  This round reminded me of the import surrounding the lives of the lesser characters.  So very much to think about.  

The Code Breaker:  Jennifer Doudna, Gene Editing, and the Future of the Human Race -Walter Isaacson  For anyone who thinks that the current, effective mRNA vaccines against COVID appeared over night, this tale should clarify and reassure you.  Ms. Doudna is definitely in a league with Marie Curie, not only in her incredible contributions to human knowledge and understanding, but in the egalitarian leadership she demonstrated at the onset of our ongoing pandemic.  A well told, readable story that made complex scientific mysteries of DNA, RNA, and CRISPR technology comprehensible.

Not the lightest fare this month.  The last two being very different, but brilliant examples of the triumph of human intelligence and spirit over our lesser selves.   Much needed in this time.

Read well.  Seek peace. - les

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

Strategies for treating melanoma subtypes - Acral, Mucosal, Uveal, Nodular, Lentigo

 

While melanoma, despite the huge improvements made when targeted and immunotherapies gained FDA approved in 2011 remains a very difficult cancer to treat and survive, the subtypes noted in the title make cutaneous melanoma look like a walk in the park.  This LINK takes you to reports on those subtypes that I have previously posted.  The link below takes you to a pretty thorough report addressing these particular forms of melanoma as well as a good history regarding BRAF status.  I have included much of the report below.  Words are from the authors - not me.  However, checking out the link is valuable, as it includes tables and references not reported here.

Emerging strategies to treat rare and intractable subtypes of melanoma. Gretchen and Vito. Pigment Cell Melanoma Res. Jan 2021.

Melanoma is the deadliest form of skin cancer, possessing a diverse landscape of subtypes with distinct molecular signatures and levels of aggressiveness. Although immense progress has been achieved therapeutically for patients with the most common forms of this disease, little is known of how to effectively treat patients with rarer subtypes of melanoma. These subtypes include acral lentiginous (the rarest form of cutaneous melanoma; AL), uveal, and mucosal melanomas, which display variations in distribution across (a) the world, (b) patient age-groups, and (c) anatomic sites. Unfortunately, patients with these relatively rare subtypes of melanoma typically respond worse to therapies approved for the more common, non-AL cutaneous melanoma and do not have effective alternatives, and thus consequently have worse overall survival rates. Achieving durable therapeutic responses in these high-risk melanoma subtypes represents one of the greatest challenges of the field. This review aims to collate and highlight effective preclinical and/or clinical strategies against these rare forms of melanoma.

INTRO - 

The melanoma field represents a paradigm for preclinical and clinical advancements in targeted and immune therapy modalities, with 13 new FDA-approved therapies since 2011. The catalyst for the development of targeted therapy modalities was the identification of activating NRAS mutations and BRAF mutations in 1984 and 2002... which paved the way for molecular stratification of the melanoma patient population. Approximately 45%–50% of non-acral lentiginous (AL) cutaneous melanoma patients have tumors that harbor activating BRAF mutations, with a single amino acid substitution of valine for glutamic acid at codon 600 (V600E) occurring in 90% of cases. Activating NRAS mutations at codon 12, 13, or 61 are detectable in 15%–20% of non-AL cutaneous melanoma patients and serve as an independent predictor of worse patient overall survival. Mutations of BRAF and NRAS are considered mutually exclusive; however, there are rare reports where both mutations exist in different regions of the same tumor or at different metastatic sites of the same patient. To date, it remains unclear whether the same melanoma cell can harbor both a BRAF and an NRAS mutation, or at the single-cell level, these mutations are indeed mutually exclusive.

With discoveries revealing that ~70% of non-AL cutaneous melanomas contain mutations constitutively activating the mitogen-activated protein kinase (MAPK) pathway came intense development of inhibitors capable of targeting various nodes of the mitogen-activated protein kinase (MAPK) pathway (i.e., BRAF, MEK, and ERK inhibitors) that continues to date. The first targeted therapy approved for the treatment of patients with BRAFV600E/K mutant melanoma was the small molecule inhibitor vemurafenib, an agent designed to have high specificity against the mutant V600E, V600K, V600D, and V600R forms of BRAF. Vemurafenib had response rates of ~48% in phase II and III clinical trials leading to the 2011 Food Drug and Agriculture (FDA) approval. A few years later, the combination of a BRAF inhibitor and a MEK inhibitor was observed to further increase the response rate to ~76% leading to the 2014 FDA approval of dabrafenib and trametinib. There are now three BRAF inhibitor plus MEK inhibitor combinations FDA approved for melanoma patients with BRAFV600E/K mutations (dabrafenib/trametinib, vemurafenib/cobimetinib, and encorafenib/binimetinib.

For patients with wild-type BRAF, treatment with BRAF inhibitors that specifically target V600E/K mutant BRAF may increase melanoma aggressiveness due to the paradoxical activation of wild-type BRAF and downstream MAPK pathway signaling. Preclinically, targeting downstream of BRAF with MEK inhibitors in BRAF-wild-type melanoma cells demonstrates the importance of the MAPK pathway for their survival, with significant anticancer activity. However, clinical trials testing multiple MEK inhibitors (i.e., binimetinib, trametinib) have concluded that although encouraging response rates and small increases in progression-free survival could be achieved in certain trials relative to dacarbazine, no significant increase in overall survival of patients with BRAF-wild-type melanoma was achieved with MEK inhibition. In an effort to increase MEK inhibitor efficacy, combination strategies with other agents (i.e., PI3K inhibitors, CDK4/6 inhibitors) are being clinically tested in the BRAF-wild-type (i.e., patients with or without NRAS-MT melanoma) setting after failure of immunotherapy. ERK inhibitors are also being clinically investigated to see if durable efficacy can be achieved in patients with wild-type BRAF, with reports showing the first-in-class ERK1/2 inhibitor ulixertinib has an acceptable safety profile and early evidence of clinical activity. Preclinical evidence suggests that concurrent inhibition of multiple nodes of the MAPK pathway in NRAS-mutant melanoma (i.e., MEK and ERK) may have synergistic activity on par with the BRAF inhibitor and MEK inhibitor combination in BRAF-mutant melanomas, and further studies evaluating this strategy are under way.

In parallel, large strides have been made in the development of immune checkpoint blockade strategies with the FDA approval of antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA4, ipilimumab) in 2011 and programmed cell death 1 (PD1, pembrolizumab, nivolumab) in 2014  and the combination of ipilimumab and nivolumab in 2015. Immune checkpoint blockade describes the use of therapeutic antibodies that overcome immunosuppressive checkpoints with the goal of unchaining antitumor immune responses. CTLA4 and PD-1 are both receptors that suppress effector T-cell activity. These immunotherapy-based strategies elicit long-lasting responses in a subset of patients and represent a therapeutic strategy suitable for all genotypes of non-AL cutaneous melanoma. However, the majority of patients treated with immunotherapy progress within 5 years due to poorly understood primary resistance mechanisms, and clinicians still cannot reliably discriminate which patients will respond or not respond. Both tumor intrinsic (i.e., insufficient tumor antigenicity, tumor interferon-γ signaling, tumor stemness) and extrinsic (i.e., regulatory T cells, myeloid-derived suppressor cells) resistance mechanisms have been reported, and there are intense efforts focused on overcoming these therapeutic hurdles to further increase the efficacy of immune checkpoint blockade strategies.

The promising efficacy of these new therapeutic strategies has been demonstrated largely in non-AL cutaneous melanoma patients with either superficial spreading melanoma (SSM), nodular melanoma (NM), or lentigo maligna melanoma (LMM). SSM, NM, and LMM represent the most common forms of melanoma in Caucasians (>85% of cases). It is important to appreciate that most of the recent pivotal discoveries in melanoma were performed on SSM cell lines, short-term cultures, animal models, and tumor biopsies taken from patients with SSM largely due to their greater availability. AL melanoma represents the fourth and rarest subtype of cutaneous melanoma. In addition, mucosal melanoma and uveal melanoma are other rare subtypes of melanoma that are non-cutaneous in origin. The efficacy of immune checkpoint blockade is lower in rarer subtypes of melanoma relative to patients with non-AL cutaneous melanoma, which will be discussed later. There is also little information regarding the efficacy of combination BRAF inhibitor and MEK inhibitor therapy in these subtypes. 

Acral - 

Acral lentiginous melanoma is an uncommon yet relatively aggressive subtype of CMM that accounts for 2%–3% of all melanoma cases. AL melanoma arises on sun-protected, glabrous skin of the soles, palms, and nail beds. AL melanoma has been historically associated with worse 10-year survival rates relative to other forms of CMM (67.5% vs. 87.5%). Further, 10-year AL melanoma survival rates are highest in non-Hispanic Whites (69.4%), intermediate in Blacks (71.5%), and lowest in Hispanic Whites (57.3%) and Asian/Pacific Islanders (54.1%), as found by the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute evaluating data from 17 population-based cancer registries from 1986 to 2005. Another analysis of AL melanoma prognostic features in a cohort of German, Swiss, and Austrian patients suggests no significant difference exist relative to other subtypes of cutaneous melanoma; however, this conclusion may stem due to differential ethnicity landscapes between this patient cohort and that in the SEER study. There does not appear to be a gender bias, with a similar frequency between men and women and a comparable median age of diagnosis of 63.1 years for men and 62.2 years for women. The incidence of AL melanoma increases with age, and for reasons poorly understood, men are twice as likely to develop AL melanoma relative to women after the age of 80.

The distribution of AL melanoma varies geographically among populations throughout the world. While AL melanoma represents only ~2%–3% of all melanoma cases in Caucasian populations, AL melanoma makes up 50%–80% of all cases in non-Caucasian individuals in the United States (i.e., those of African, Latin American, and Asian descent). Furthermore, the incidence in Hispanic Whites doubles compared to non-Hispanic Whites after the aged of 70. A 2009 SEER study found the overall incidence rates of AL melanoma were similar between non-Hispanic Whites and Blacks; however, Hispanic Whites have statistically higher incidence rates relative to non-Hispanic Whites . Updated epidemiological studies should be performed to continue understanding the differential incidence trends that may exist across different ethnicities. Of note, the incidence of other subtypes of cutaneous melanoma (i.e., NM, SSM) is much lower in non-Caucasians relative to Caucasians. As this subtype of melanoma is not related to ultraviolet radiation (UV), there are different theories of the cause of AL melanoma. Some reports state that trauma and pressure in the foot (a predilected area of AL) is causal. However, the hand is also exposed to trauma but its location is less favorable. The main sites of AL melanoma metastases are the lungs, distant lymph nodes, scalp, contralateral limb, and liver.

Acral lentiginous melanomas possess a significantly lower mutational burden relative to the more common cutaneous melanoma subtypes, likely due to the sun-protected locations they arise from. BRAF mutations in are found in 1 in every 5 Al melanoma patients, leaving ~80% ineligible to receive BRAF inhibitor and combination BRAF/MEK inhibitor strategies . Therefore, new targets specific for AL melanoma are needed. 80% of AL melanomas display genetic aberrations of cyclin-dependent kinase 4/6 (CDK4/6) pathway-related genes (i.e., amplification of CDK4 and CCND1, and/or loss of CDK2NA), representing the most frequent copy number alteration detected . Additionally, activating KIT mutations are present in ~6% of cases. AL melanoma displays similar incidence of NRAS mutations as non-AL cutaneous melanoma, detectable in 15%–28% of AL melanoma patients, and NRAS mutations are an independent prognostic factor of worse overall survival.

Considerable barriers exist to treat patients with AL melanoma: (a) a contrasting genomic and genetic landscape relative to non-AL cutaneous melanomas, (b) unclear targetable drivers, and (3) sparse experimental models available for preclinical drug development. Unfortunately, FDA-approved targeted therapy strategies for melanoma are not available for the majority of AL melanoma patients (i.e., BRAF inhibitors since AL melanoma has a low frequency of BRAF mutations), and the efficacy of immune checkpoint blockade strategies is not well known in AL melanoma, with differing overall response rates (ORR) differing by country. For example, the ORR of anti-PD-1 in AL melanoma patients was found to be similar to that in non-AL cutaneous melanoma patients within the United States. In contrast, the ORR was 66.7% for SSM patients and 28.6% of AL melanoma patients in a recent Japanese study, suggesting the efficacy of immune checkpoint blockade may vary with ethnicity. The lower mutational burden observed in AL melanoma cases is thought to drive the reduced efficacy of immune checkpoint inhibitor strategies (e.g., PD-1 blockade) in patients. Although AL melanoma patients with Kit mutations can be treated with a KIT inhibitor per National Comprehensive Cancer Network (NCCN) guidelines, resistance mechanisms that reactivate downstream MAPK and PI3K pathway signaling have been suggested to blunt long-term durability. Due to the high percentage of AL melanoma tumors with CDK4/6-pathway aberrations, CDK4/6 inhibition represents one of the most promising targeted therapy strategies for AL melanomas clinically. However, durable responses are not observed in all patients due to resistance and CDK4/6 inhibitor-based combinations will likely be needed to improve the curative rate for patients with AL melanoma. Preclinical investigation to optimize targeted therapy strategies has not been extensively performed in AL melanoma models, but the rich body of literature that exists from studies in non-AL cutaneous melanoma models strongly suggests that single-agent approaches will not be durable due to the nearly universal onset of resistance. In SSM models, treatment with a MAPK pathway inhibitor plus a CDK4/6 inhibitor has shown synergistic activity in BRAF-MT and BRAF-wild-type settings; however, residual disease persists. Resistance mechanisms to CDK4/6 inhibitors and/or MEK inhibitors must be delineated to develop combination strategies that produce durable responses in AL melanoma patients.

Mucosal Melanoma - 

Mucosal melanoma (MM) is one of the rarest types of melanoma, accounting for only 1% of all cases, and has a significantly worse prognosis relative to the other subtypes. Distinct from cutaneous melanoma, MM arises from melanocytes located in mucosal membranes inside the body (i.e., genitourinary, anorectal, nasopharyngeal). The head and neck (55), vulva (18), and anus (24) are the most common observed sites; however, MM can also occur in the gut, lungs, and urinary track. It is rarely diagnosed at early stages due to difficult visual detection, which is much more tractable for cutaneous subtypes of melanoma. The overall median age of diagnosis is 70 years, with the exception of MMs arising in the mouth that manifest more frequently in younger patients. The incidence of MM has been stable for the last few years with the exception of MM in the genital tract, which is higher in females relative to males for reasons not clearly understood.

Approximately 3%–15% of MMs harbor an activating mutation in BRAF, with ~63% located on the V600 codon and 37% located on a non-V600 codon. This is in contrast to non-AL cutaneous melanomas where <10% of BRAF mutations are outside of the V600 codon, and more closely resembles the high prevalence of non-V600 mutations found in 48% of lung adenocarcinomas. A closer analysis of the most common non-V600 mutations reveals (a) a difference between the frequency of mutations on D594, G469, and K601 between non-AL cutaneous melanomas and MMs, and (b) convergence in the non-V600 mutational landscape between MM and lung cancers where mutations are often associated with genotoxic agents.

In regard to NRAS mutations, approximately 12% of MMs harbor activating mutations, which is lower relative to cutaneous melanomas where NRAS mutations occur in 15%–20% of cases. There is also a divergence in the location of NRAS mutations between MM and cutaneous melanoma, with 54% located on codon 61 in MM versus 88% in cutaneous melanoma, and 46% located on codons 12 and 13 in MM versus 12% for cutaneous melanomas. Approximately 7%–22% of MMs have v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) somatic mutations or amplifications. MMs located in the genital area appear to be driven by mutations in SF3B1 which encodes the subunit 1 of splicing factor 3b, a component of the spliceosome that processes pre-mRNA into mature transcripts. A recent study analyzing the mutational landscape of MM identified IGF2R mutations in 31.7% of MM samples relative to 6.3% of SSM cases. Interestingly, a lower frequency of UV-induced DNA damage, a lower number of mutations and a link to high tobacco exposure have also been identified in MM.

Unfortunately, MM is typically detected at relatively more advanced states due to difficulty in early detection. The main treatment for MM differs slightly on where the tumor is located; however, like any other subtype of melanoma, patients are initially treated with surgical excision. MMs arising in the head and neck are treated with complete surgical excision of the tumor when the patient is in stages III and IVA. However, this is associated with a high rate of recurrence. MMs that have arisen in the vulvovaginal or anorectal area also receive radiation in addition to surgical tumor excision. Therapeutic efficacy may be improved in select patients when treatment is personalized by tumor mutational status. Clinical trials targeting KIT with imatinib show no clear effect in unselected metastatic melanoma patient populations, but encouraging clinical benefit has been observed with KIT inhibition specifically in patients with melanomas harboring KIT mutations (not in patients whose melanoma harbor KIT amplification only). Nonetheless, disease progression ultimately occurs in the majority of cases. These data support the practice of determining KIT mutational status for MM patients to have a higher chance of receiving additional clinical benefi. Subsequent phase II clinical trials now require a KIT alteration for enrollment. For the relatively small number of MM patients whose tumors harbor BRAF mutations (relative to the ~50% in non-AL cutaneous melanoma patients), treatment with combination BRAF inhibitor and MEK inhibitor therapy is available. However, the efficacy of targeted therapy specifically in the MM patient population is not completely understood due to the low number available for analysis.

The efficacy of immune checkpoint inhibitor therapy also remains unclear in MM patients, with conflicting evidence of whether MM patients respond as well as non-AL cutaneous melanoma patients. In one multi-institutional analysis of clinical trials focusing on all the subtypes of metastatic melanoma, patients with MM had similar responses compared with non-AL cutaneous melanoma patients when treated with anti-PD-1 single-agent therapy, with a progression-free survival of 3.9 months . In another pooled analysis, MM patients treated with nivolumab as monotherapy or nivolumab in combination with ipilimumab experienced reduced clinical benefit relative to non-AL cutaneous melanoma patients. MM patients experienced 50% shorter progression-free survival (3.0 months) relative to patients with non-AL cutaneous melanoma (6.2 months) for monotherapy (nivolumab) and for nivolumab plus ipilimumab (5.9 vs. 11.7 months. Another recent study combining axitinib (small molecule receptor tyrosine kinase inhibitor) with toripalimab (anti-PD-1) found a median progression-free survival of 7.5 months in among 29 patients with chemotherapy-naïve mucosal melanoma. Although these data suggest that MM patients may not achieve as much benefit with immune checkpoint inhibitor therapy as non-AL cutaneous melanoma patients, it should be considered that in each of the pooled analyses, the number of MM cases was only 10% of patients compared to 75% from cutaneous melanoma. Also notable, another prospective study where 44 patients with unresectable MM were treated with immune checkpoint inhibitors concluded that the site of origin for MM (i.e., vaginal, anal) may not have a significant impact on the objective response rate, which was 8.2% for ipilimumab and 35% for pembrolizumab. The lower mutational burden in MM relative to non-AL cutaneous melanoma may explain the decreased efficacy of immune checkpoint blockade in MM.

Uveal Melanoma -

Uveal melanoma (UM) is the most common form of ocular melanoma, as well as the most prevalent form of non-cutaneous melanoma, accounting for 5% of all melanomas . It most commonly arises in non-Hispanic Whites relative to other races (i.e., African and Asian Americans), with a slight predominance for men (52.3%) relative to women (47.7%). The incidence of UM has remained stable over the last few decades and is diagnosed in 4–5 per million individuals in the United States each year. The median age of diagnosis is 62, and the incidence of UM increases with age. Early detection of UM provides a favorable 85% survival rate; however, this survival rate significantly decreases to 15% once UM cells have disseminated. Approximately 50% of UM patients develop metastases, and among patients with metastatic disease, 90% have liver involvement and ~70% have liver-only disease. This is a distinct metastatic pattern relative to cutaneous melanoma or mucosal melanoma.

Unlike non-AL cutaneous melanomas, UMs have a much lower mutational burden due to the sun-protected site they arise from within the ocular cavity. Activating mutations in BRAF or NRAS are not detected (extremely rare) in tumor cells of UM patients. In contrast, the main drivers for UM are activating mutations of guanine nucleotide-binding protein G (GNAQ/11), splicing factor 3B subunit 1 (SF3B1), eukaryotic translation initiation factor (EIF1AX), and inactivating mutations of the tumor suppressor BRCA-associated protein-1 (BAP1). The GNAQ/11 genes encode specific GTP binding proteins that mediate signal transduction from the inner cell surface to the MAPK pathway through activation of the protein kinase C (PKC) enzyme. GNAQ and GNA11 mutations are mutually exclusive, and thus in total are detected in 85%–94% of UM across all stages of disease. Due to their detection in benign uveal nevi, GNAQ/11 mutations are thought to be early mutational events.

BAP1 (located on the short arm of chromosome 3) loss-of-function mutations are posited to serve as a predisposing factor for diverse hereditary cancers including mesothelioma, cutaneous melanoma, renal cell carcinoma, and UM. A recent comprehensive review identified that among 174 patients harboring germline BAP1 mutations, 130 developed tumors that were either UM (31% of cases), cutaneous melanoma (13% of cases), renal cell carcinoma (10% of cases), or MM (22% of cases). In UM, loss of BAP1 returns melanoma cells to a more stem cell-like state as BAP1 is involved in melanocyte differentiation. BAP1 is frequently mutated in metastasizing uveal melanomas, which supports the growing evidence that stem-like melanoma cell states drive elements of the metastatic cascade.

There has been a recent decline in UM patients treated solely with surgery due to micrometastases that develop years before primary tumor detection. The current approach for treatment of metastatic UM is radiation; however, the survival rate is not significantly improved relative to what is possible from surgery. There have been an array of clinical studies trying to identify efficacious therapeutic strategies for patients with metastatic UM. UM patients that possess GNAQ or GNA11 mutations can be treated in clinical trials with targeted therapy approaches specific for the MAPK pathway (i.e., MEK inhibitor, ERK inhibitor) as these tumors display elevated MAPK activity. Preclinical studies have shown that treatment of UM with a combination of a MAPK pathway inhibitor and a PKC inhibitor may provide synergistic efficacy relative to what is achievable by either agent alone. Clinical trials with selumetinib, a MEK inhibitor, reported a higher progression-free survival among UM patients (15.9 vs. 7 weeks); however, no clinically meaningful increase in overall survival was observed in comparison to the chemotherapeutic temozolomide in the metastatic setting (10.8 vs. 9.4 months). Additionally, preclinical studies identified that targeting the PI3K/AKT pathway (in GNAQ and GNA11 mutant xenograft models) in combination with a MEK inhibitor may be an effective treatment strategy for patients with GNAQ or GNA11 mutations; however, clinical trials using this combination have stopped due to low response rates and high toxicity. Inhibitors against bromodomain and extraterminal (BET) proteins have had encouraging activity preclinically in UM, which could be further increased by concurrent inhibition of escape mechanisms mediated by fibroblast growth factor receptors. Similarly, targeting microenvironment-derived factors including HGF can also increase MEK inhibitor efficacy against UM cells, preclinically. For UM with BAP1 mutations, it has been shown preclinically that treatment with a histone deacetylase (HDAC) inhibitor could be beneficial. Because BAP1 mutations are associated with loss of melanocytic differentiation, treatment with HDAC inhibitors (valproic acid) are postulated to inhibit the growth of uveal melanoma in vivo by inducing morphological differentiation.

While immune checkpoint inhibitors are the standard of care for cutaneous melanoma, UM has not yet had a phase III clinical trial for immune therapy. Small studies in UM patients (10 patients) treated with pembrolizumab (anti-PD-1) after treatment with ipilimumab reported a median progression-free survival of 18 weeks; ranging from 3.14 to 49.3 weeks. Of the eight evaluable patients, four rapidly progressed, one had stable disease, two had partial responses, and one had a complete response. Although this small study resulted in comparable results seen in patients with non-AL cutaneous melanoma, other studies suggest far lower response rates to single agent anti-PD-1 and combination anti-PD-1 plus anti-CTLA-4 in UM patients. An analysis of Danish UM patients observed partial responses in 7% of patients to anti-PD-1 and 21% to concurrent anti-PD-1 plus anti-CTLA-4. Metastatic UM patients treated with ipilimumab from two additional clinical studies had a median overall survival of 9 months (in contrast to 19.9 months in non-AL cutaneous melanoma). Despite the reduced efficacy of immune checkpoint blockade in UM patients, this option may represent the most effective strategy to date.

Nodular Melanoma -

Nodular melanoma represents the second most common subtype of melanoma, responsible for 10%–15% of total melanomas in Caucasians. NM is the melanoma subtype most associated with increased thickness at clinical presentation, which is attributed to the relatively poorer prognosis of patients with NM. The median age of diagnosis for NM is 53 years, with thicker tumors more common in older patients. NM is more common in women than men for reasons poorly understood and commonly presents de novo on the head, neck, or trunk of patients.

Activating BRAF mutations are detected in patients with NM at a slightly lower frequency relative to SSM, with 43%–47% of patients possessing mutations mostly (88% of cases) in V600E. A recent study identified evidence that BRAFV600E expression may serve as a prognostic marker in primary NM associated with ulceration and reduced survival. Preclinically, it was reported that hyperactivation of the downstream MAPK effector ribosomal protein S6 kinase (RSK1) is detectable in metastatic tumor tissues derived from NM to a higher extent relative to SSM. Activating NRAS mutations are detected at a significantly elevated frequency in NM relative to SSM in 30%–33% vs. 19% of cases, respectively. Interestingly, BRAF and NRAS mutations may not be as mutually exclusive in NM relative to SSM, with the identification of both mutations in the same tumor specimens when assessed by laser capture dissection followed by direct sequencing analysis of exons 11 and 15 of the BRAF gene and exons 1 and 2 of the NRAS gene. Additional high-throughput sequencing of patient-derived samples of single nucleotide variations (SNVs) expected to impact protein coding reveals NOTCH4, RPSKA6, BCL2L12, TERT, ERBB3, ZNF560, SSPO, and SNX31 to be significantly under-mutated in NM relative to SSM.

An analysis of the most recent Surveillance, Epidemiology, and End Results (SEER) cohort and the New York University (NRU) cohort suggests that relative to patients with metastatic SSM treated with BRAF inhibitor (BRAFi) therapy, patients with metastatic NM may respond worse to BRAFi for reasons not completely understood, suggesting the potential existence of distinct clinical and biological properties between NM and SSM. The observation of activated RSK1 via constitutive phosphorylation at the Ser-380 residue may explain the poorer efficacy of BRAFi and/or BRAFi/MEKi in patients with this melanoma subtype. In contrast, no significant difference in response rates and survival was detected in NM versus SSM among a cohort of 154 patients treated with either anti-CTLA-4, anti-PD-1, or the combination of both immune checkpoint inhibitor approaches. Immune checkpoint blockade may serve an ideal first-line therapy for patients with this subtype.

Lentigo Maligna - 

Lentigo maligna (LM) is the third most common subtype of melanoma, comprising roughly 4%–15% of all melanoma cases and its incidence has dramatically increased over the past few decades across the United States, and other regions of the world. LM melanoma typically presents on chronically sun-damaged (CSD) skin of the head and neck, appearing as an irregular brown macule commonly on the head and neck in the elderly. In contrast to the mean age of diagnosis of SSM between 40 and 60 years, the mean age of diagnosis for LM melanoma is 66–72 years. Credit is given to Sir John Hutchinson for the earliest description of LM melanoma in 1890. LM melanoma was initially referred to as “Hutchinson’s melanocytic freckle” due to the prevailing thought that it was benign, non-infectious lesion owing to its slow growing nature. Critical work by Ackerman and Silvers in the late 1970s–1980s finally led to wide acceptance of LM melanoma as a malignant disease worthy of clinical attention and intervention. Chronic ultraviolet radiation is the major risk factor for the development of LM melanoma, which differs from NM and SSM that are associated with intense intermittent ultraviolet radiation exposure. LM melanomas arise most frequently on the face and other sites of chronic sun damage which also differs from NM and SSM that arise most commonly on the trunk in men and legs in women. LM melanoma is thought to occur in older patients due to the increased lifetime sun and ultraviolet radiation exposure.

Lentigo maligna melanomas have a relatively high mutational burden compared to other melanoma subtypes due to chronic ultraviolet exposure. The frequency of activating BRAF mutations in LM is unclear, with reports finding 16.7%–53.4% of LM patients harboring BRAF mutations. The large variation may, in part, be attributed to the regional differences among tested patient tissue cohorts. In a Greek cohort, 16.7% of LM melanoma cases expressed BRAF mutations and 50% of LM cases in a Japanese cohort expressed BRAF mutations. When BRAF mutations are present, the V600K substitution is frequently observed (~77%) relative to the V600E (~23%) as observed in SSM, in this small set of 13 LM patient tumor samples. This finding is consistent with V600K mutations arising on chronically sun-damaged skin. Activating NRAS mutations have been reported to occur in ~8.1%–16% of LM cases .

The treatment of choice for patients with localized LM melanoma consists of surgical excision as first line of therapy, followed by radiation therapy with fractionated superficial radiotherapy, or topical imiquimod cream as an alternative to surgery. Once LM melanoma metastasizes to visceral organs, the five-year survival is similar to SSM. Interestingly, the efficacy of immune checkpoint blockade may be significantly higher in patients with LM melanoma relative to the other subtypes discussed. A study investigating the overall response rate (ORR) of anti-PD-1/PD-L1 in different subtypes of melanoma found patients with melanoma on CSD skin (including LM melanoma, desmoplastic melanoma, and subtype not-specified cases) exhibited an overall response rate of 70%, which fits the theory that cancer cells with high mutational burdens may be more sensitive to immune checkpoint blockade due to the increased presence of immune-stimulatory neoepitopes. Additional investigations on the efficacy of targeted and immune-based therapy are needed specifically for patients with LM melanoma to ensure the optimal treatment(s) is identified for this cohort and further improved through preclinical experimentation and clinical trials.

To date, this is the most comprehensive review of the data and treatments best suited for these melanoma subtypes that I have found.  So hoping that understanding and effective treatment options increase for these patients very soon.  -  c