PURPOSE: The role of circulating tumor DNA (ctDNA) monitoring in predicting treatment response and survival outcomes in early-stage and metastatic solid tumors has shown promising results. The value of early ctDNA dynamics in solid tumors treated with immune checkpoint inhibitors (ICIs) merits further investigation. Our study aims to assess the role of early ctDNA changes, measured 3-4 weeks after initiating ICI therapy, in predicting clinical outcomes in patients with advanced-stage melanoma. METHODS: We performed a multi-institutional analysis of real-world data from testing patients with unresectable stage III/IV melanoma using a personalized, tumor-informed ctDNA assay (Signatera) during the course of treatment with anti–PD-1-based therapy. ctDNA levels were assessed before the start of treatment and at 3-4 weeks before the second treatment dose. The change in ctDNA (decrease v increase) between the two points was assessed to evaluate the odds of objective response and disease control and to evaluate the risk of progression-free survival (PFS) and overall survival (OS). RESULTS: One hundred seventeen patients were evaluated. Regression analysis revealed that a decrease in ctDNA was associated with increased odds of disease control (odds ratio [OR], 30.56 [95% CI, 10.64 to 87.84], P < .001) and objective response (OR, 23.54 [95% CI, 8.58 to 64.57], P < .001). Patients with a decrease in ctDNA had an increased PFS (hazard ratio [HR], 0.18 [95% CI, 0.11 to 0.31], P < .001) and OS (HR, 0.28 [95% CI, 0.13 to 0.56], P < .001) probability. CONCLUSION: We found that early ctDNA dynamics after only 3-4 weeks of ICI initiation in patients with advanced-stage melanoma appears to be a candidate strategy to predict overall treatment response, risk of progression, and long-term survival. Larger prospective studies are warranted to validate the utility of early ctDNA changes in treatment monitoring.

Pseudoprogression is known to occur in patients with metastatic melanoma treated with immune checkpoint inhibitors and complicates clinical decision-making. Better methods of distinguishing pseudoprogression from true progression are necessary. In this case report, we show how circulating tumor DNA (ctDNA) plays a role in identifying pseudoprogression on early interval radiologic response assessment in a patient with metastatic melanoma treated with combination anti-programmed cell death protein 1 (anti-PD-1) and anti-lymphocyte activation gene 3 (anti-LAG-3). Circulating tumor DNA is a promising biomarker that has potential to reliably assess response to immune checkpoint inhibitors in melanoma, even when the radiologic findings are misleading or indeterminate. Further research is warranted to identify rates of pseudoprogression across various immune checkpoint inhibitor regimens and to identify the role of ctDNA dynamics to identify this phenomenon.

Targeting PIK3CA-mutant colorectal cancers with precision medicine strategies is of great clinical interest. However, resistance to single-agent PI3K pathway inhibitors has been observed across multiple clinical trials, necessitating the identification of combination therapies that overcome or prevent resistance to precision medicine strategies. Previously, our group identified that inhibition of mTORC1/2 is necessary to induce a response in PIK3CA-mutant colorectal cancers. The PI3K/mTORC1/2 inhibitor copanlisib has demonstrated some clinical activity in PIK3CA-mutant solid tumors as part of the NCI-MATCH trial. In this study, we evaluate potential combination therapies that could enhance the efficacy of copanlisib and other similar inhibitors in PIK3CA-mutant colorectal cancers. Using a novel high-throughput drug screen method in Apc- and Pik3ca-mutant mouse-derived cancer organoids, we identify navitoclax, a BCL-2 family inhibitor, as a drug that could potentially enhance the response to copanlisib. Across multiple in vitro and in vivo colorectal cancer models, navitoclax enhanced PI3K/mTOR inhibition (copanlisib, sapanisertib, and dactolisib) and induced apoptosis. Furthermore, we examine these combination therapies across a panel of patient-derived cancer organoids with a range of mutation profiles. These studies indicate that KRAS mutations could confer resistance. Furthermore, we identify BCL-xL as the major BCL-2 family target important for the response to this combination in this setting. This provides a strong rationale for mTORC1/2 and BCL-2 family inhibition as a potential treatment strategy for PIK3CA-mutant colorectal cancers.

PURPOSE: Circulating tumor DNA (ctDNA) has emerged as a noninvasive biomarker for minimal residual disease (MRD) detection in many solid tumors. However, the role of ctDNA in MRD monitoring for melanoma remains unexplored. In this retrospective study, we aim to assess the sensitivity of a commercially available, tumor-informed, exome-based, ctDNA assay to detect recurrence or relapse of melanoma. METHODS: Fifty-six patients with a history of stage II to IV melanoma with no evidence of disease and a seronegative (0 MTM/mL) ctDNA result that preceded histologic or radiologic confirmation of melanoma recurrence were identified. The overall sensitivity of ctDNA detection at recurrence or relapse was evaluated and further stratified based on anatomic sites of relapse. RESULTS: The ctDNA assay demonstrated an overall sensitivity of 53.6%. The odds of detecting ctDNA at relapse or recurrence were significant among patients with lymph node metastases (odds ratios [ORs], 12.0 [95% CI, 2.40 to 60.05]; P = .001) and patients with multiple anatomic sites (2+) of metastases (OR, 9.52 [95% CI, 1.10 to 82.44]; P = .027). Sensitivity for ctDNA detection of recurrence was 33.3% in the brain ( P = .248), 37.5% in skin or muscle ( P = .317), 61.5% in lung metastases ( P = .405), 75% in bone ( P = .625), 87.5% in liver was ( P = .034), and 87.5% in lymph node metastases ( P = .003). CONCLUSION: ctDNA monitoring shows potential for detecting relapse in patients with melanoma. The location of melanoma recurrence or relapse may affect shedding of ctDNA and its detection. Larger studies are needed to refine the role of ctDNA in recurrence detection and to improve its diagnostic performance to optimize oncologic surveillance.

Background: Although squamous cell carcinoma of the anus (SCCA) is a relatively uncommon malignancy in the United States, it continues to increase in incidence. Treatment for locoregional disease includes mitomycin and 5-fluorouracil with radiation. This combination is associated with significant toxicity, limiting its use in patients who are older or have certain comorbidities. Carboplatin and paclitaxel (C/P) is an accepted treatment regimen for metastatic SCCA. We aim to evaluate the efficacy and toxicity of weekly C/P given with radiation for patients unable to receive standard chemoradiation for SCCA. Methods: From our cancer registry, adult patients who received weekly intravenous C/P concurrent with standard-dose radiation for localized SCCA were included in this study. Clinical response was determined based on the evidence of disease on imaging and/or anoscopy. Toxicities were graded according to the CTCAE v5. Results: Ten patients were included; eight were female, and the median age was 75.5 years (54–87). Six had T2 disease, and four had T3 tumors. Four had node-positive disease. The majority (70%) of patients were dosed at standard C (AUC 2) and P (50 mg/m²), with a limited subset requiring dose reduction for baseline performance status. Patients completed a mean of 78.3% (40–100%) of the intended treatments. A total of 89% of the patients achieved a complete clinical response. With a median follow-up of 25.8 months (3.4–50.4 months), 67% of the patients are alive and without recurrence. Two patients have had local recurrence, and one patient had metastatic progression. The most common toxicities of any grade included leukopenia (100%), anemia (100%), radiation dermatitis (100%), diarrhea (100%), and fatigue (100%). Grade 3 or higher toxicities included neutropenic fever (20%), neutropenia (30%), and anemia (30%). Conclusions: This study demonstrates promising tolerability and efficacy for weekly C/P chemoradiation for patients with anal cancer unable to receive mitomycin and 5-fluorouracil. This regimen merits further investigation in prospective clinical trials.

Circulating tumor DNA (ctDNA) has rapidly emerged over the last several years as a sensitive biomarker for minimal residual disease (MRD), cancer that remains in the body but is undetectable by conventional imaging. Studies have shown its clinical utility across several cancer types, including colorectal cancer. However, its role in MRD detection and treatment monitoring for melanoma remains an evolving area of research. While multiple commercially available ctDNA assays exist, none have been clinically validated specifically for melanoma as of 2025. This chapter will explore the emerging landscape of blood-based biomarkers, such as ctDNA, for patients with melanoma and its role in clinical practice.