Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways.

Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma. SIGNIFICANCE: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA. See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275.

Oral beclomethasone dipropionate is an effective treatment for immune checkpoint inhibitor induced colitis.

INTRODUCTION: Systemic corticosteroids are the mainstay of treatment for immune checkpoint inhibitor induced (CPI) colitis but are associated with complications including life-threatening infection. The topically acting oral corticosteroid beclomethasone dipropionate (BD) is an effective treatment for mild to moderate flares of ulcerative colitis, and has fewer side effects than systemic corticosteroids. We hypothesized that BD would be an effective treatment for CPI-induced colitis. METHODS: We performed a retrospective analysis of all patients who started BD for CPI-induced colitis at three UK cancer centers between November 2017 and October 2020. All patients underwent endoscopic assessment and biopsy. The initial regimen of BD was 5 mg once daily for 28 days. Data were collected from electronic patient records. Clinical outcomes were assessed at 28 days after initiation of treatment. RESULTS: Twenty-two patients (14 male) with a median age of 64 (range 45-84) with CPI-induced colitis were treated with BD. At baseline, the median number of loose stools in a 24-hour period was six (common terminology criteria for adverse events, CTCAE grade diarrhea=2). Thirteen patients (59%) were dependent on systemic corticosteroids prior to starting BD. Baseline sigmoidoscopy showed moderate inflammation (Mayo Endoscopic Score (MES) = 2) in two patients (9%), mild inflammation (MES=1) in nine patients (41%) and normal findings (MES=0) in eleven patients (50%). Twenty patients (91%) had histopathological features of inflammation. All 22 patients (100%) had a clinical response to BD and 21 (95%) achieved clinical remission with a return to baseline stool frequency (CTCAE diarrhea=0). Ten patients (45%) had symptomatic relapse on cessation of BD, half within 7 days of stopping. All patients recaptured response on restarting BD. No adverse events were reported in patients treated with BD. CONCLUSIONS: Topical BD represents an appealing alternative option to systemic immunosuppressive treatments to treat colonic inflammation. In this study, BD was effective and safe at inducing remission in CPI-induced colitis, which was refractory to systemic corticosteroids. Further randomized studies are needed to confirm these findings and determine the optimum dosing regimen.

Clinical outcomes of patients with corticosteroid refractory immune checkpoint inhibitor-induced enterocolitis treated with infliximab.

INTRODUCTION: Immune checkpoint inhibitors (CPIs) have changed the treatment landscape for many cancers, but also cause severe inflammatory side effects including enterocolitis. CPI-induced enterocolitis is treated empirically with corticosteroids, and infliximab (IFX) is used in corticosteroid-refractory cases. However, robust outcome data for these patients are scarce. METHODS: We conducted a multicenter (six cancer centers), cohort study of outcomes in patients treated with IFX for corticosteroid-refractory CPI-induced enterocolitis between 2007 and 2020. The primary outcome was corticosteroid-free clinical remission (CFCR) with Common Terminology Criteria for Adverse Events (CTCAE) grade 0 for diarrhea at 12 weeks after IFX initiation. We also assessed cancer outcomes at 1 year using RECIST V1.1 criteria. RESULTS: 127 patients (73 male; median age 59 years) were treated with IFX for corticosteroid-refractory CPI-induced enterocolitis. Ninety-six (75.6%) patients had diarrhea CTCAE grade >2 and 115 (90.6%) required hospitalization for colitis. CFCR was 41.2% at 12 weeks and 50.9% at 26 weeks. In multivariable logistic regression, IFX-resistant enterocolitis was associated with rectal bleeding (OR 0.19; 95% CI 0.04 to 0.80; p=0.03) and absence of colonic crypt abscesses (OR 2.16; 95% CI 1.13 to 8.05; p=0.03). Cancer non-progression was significantly more common in patients with IFX-resistant enterocolitis (64.4%) as compared with patients with IFX-responsive enterocolitis (37.5%; p=0.013). CONCLUSION: This is the largest study to date reporting outcomes of IFX therapy in patients with corticosteroid-refractory CPI-induced enterocolitis. Using predefined robust endpoints, we have demonstrated that fewer than half of patients achieved CFCR. Our data also indicate that cancer outcomes may be better in patients developing prolonged and severe inflammatory side effects of CPI therapy.

'This is not part of my life plan': A qualitative study on the psychosocial experiences and practical challenges in young adults with cancer age 25 to 39 years at diagnosis.

OBJECTIVE: Adolescents and young adults with cancer face unique psychosocial and practical issues. However, patients across this group encounter different life experiences, cancer diagnoses and treatment settings given the tailored services for patients ages 15 to 24. Here, we qualitatively explore the psychosocial experiences and practical challenges of young adults (YAs) with cancer diagnosed between ages 25 and 39 in the United Kingdom. METHODS: We invited YAs diagnosed with cancer in the 5 years prior to enrolment at participating sites to take part in semi-structured interviews or focus groups. Transcripts were analysed using inductive thematic analysis. Two YA patients reviewed the results to ensure robustness. RESULTS: Sixty-five YAs with varied diagnoses participated. Participants struggled to balance work, childcare and financial solvency with treatment. The halt in family and work life as well as changes in image and ability threatened participants' identity and perceived 'normality' as a YA, however, these also stimulated positive changes. YAs experienced social isolation from friends and family, including children. Many struggled to cope with uncertainty around treatment outcomes and disease recurrence. CONCLUSION: The disruption of family and work life can lead to age-specific issues in YAs diagnosed with cancer. Age-tailored psychological and practical services must be considered.

British Society of Gastroenterology endorsed guidance for the management of immune checkpoint inhibitor-induced enterocolitis.

Immune checkpoint inhibitors are a novel class of cancer treatment that have improved outcomes for a subset of cancer patients. They work by antagonising inhibitory immune pathways, thereby augmenting immune-mediated antitumour responses. However, immune activation is not cancer-specific and often results in the activation of immune cells in non-cancer tissues, resulting in off-target immune-mediated injury and organ dysfunction. Diarrhoea and gastrointestinal tract inflammation are common and sometimes serious side-effects of this type of therapy. Prompt recognition of gastrointestinal toxicity and, in many cases, rapid institution of anti-inflammatory or biologic therapy (or both) is required to reverse these complications. Management of organ-specific complications benefits from multidisciplinary input, including engagement with gastroenterologists for optimal management of immune checkpoint inhibitor-induced enterocolitis. In this British Society of Gastroenterology endorsed guidance document, we have developed a consensus framework for the investigation and management of immune checkpoint inhibitor-induced enterocolitis.