Detection of persistent circulating tumor DNA (ctDNA) after curative-intent surgery can identify patients with minimal residual disease (MRD) who will ultimately recur. Most ctDNA MRD assays require ...tumor sequencing to identify tumor-derived mutations to facilitate ctDNA detection, requiring tumor and blood. We evaluated a plasma-only ctDNA assay integrating genomic and epigenomic cancer signatures to enable tumor-uninformed MRD detection.
A total of 252 prospective serial plasma specimens from 103 patients with colorectal cancer undergoing curative-intent surgery were analyzed and correlated with recurrence.
Of 103 patients, 84 stage I (9.5%), II (23.8%), III (47.6%), IV (19%) had evaluable plasma drawn after completion of definitive therapy, defined as surgery only (
= 39) or completion of adjuvant therapy (
= 45). In "landmark" plasma drawn 1-month (median, 31.5 days) after definitive therapy and >1 year follow-up, 15 patients had detectable ctDNA, and all 15 recurred positive predictive value (PPV), 100%; HR, 11.28 (
< 0.0001). Of 49 patients without detectable ctDNA at the landmark timepoint, 12 (24.5%) recurred. Landmark recurrence sensitivity and specificity were 55.6% and 100%. Incorporating serial longitudinal and surveillance (drawn within 4 months of recurrence) samples, sensitivity improved to 69% and 91%. Integrating epigenomic signatures increased sensitivity by 25%-36% versus genomic alterations alone. Notably, standard serum carcinoembryonic antigen levels did not predict recurrence HR, 1.84 (
= 0.18); PPV = 53.9%.
Plasma-only MRD detection demonstrated favorable sensitivity and specificity for recurrence, comparable with tumor-informed approaches. Integrating analysis of epigenomic and genomic alterations enhanced sensitivity. These findings support the potential clinical utility of plasma-only ctDNA MRD detection.
.
ctDNA offers a promising, noninvasive approach to monitor therapeutic efficacy in real-time. We explored whether the quantitative percent change in ctDNA early after therapy initiation can predict ...treatment response and progression-free survival (PFS) in patients with metastatic gastrointestinal cancer.
A total of 138 patients with metastatic gastrointestinal cancers and tumor profiling by next-generation sequencing had serial blood draws pretreatment and at scheduled intervals during therapy. ctDNA was assessed using individualized droplet digital PCR measuring the mutant allele fraction in plasma of mutations identified in tumor biopsies. ctDNA changes were correlated with tumor markers and radiographic response.
A total of 138 patients enrolled. A total of 101 patients were evaluable for ctDNA and 68 for tumor markers at 4 weeks. Percent change of ctDNA by 4 weeks predicted partial response (PR,
< 0.0001) and clinical benefit CB: PR and stable disease (SD),
< 0.0001. ctDNA decreased by 98% (median) and >30% for all PR patients. ctDNA change at 8 weeks, but not 2 weeks, also predicted CB (
< 0.0001). Four-week change in tumor markers also predicted response (
= 0.0026) and CB (
= 0.022). However, at a clinically relevant specificity threshold of 90%, 4-week ctDNA change more effectively predicted CB versus tumor markers, with a sensitivity of 60% versus 24%, respectively (
= 0.0109). Patients whose 4-week ctDNA decreased beyond this threshold (≥30% decrease) had a median PFS of 175 days versus 59.5 days (HR, 3.29; 95% CI, 1.55-7.00;
< 0.0001).
Serial ctDNA monitoring may provide early indication of response to systemic therapy in patients with metastatic gastrointestinal cancer prior to radiographic assessments and may outperform standard tumor markers, warranting further evaluation.
Background
Patient‐reported outcomes (PROs) assessing quality of life (QOL) and symptom burden correlate with clinical outcomes in patients with cancer. However, to the authors' knowledge, data ...regarding associations between PROs and treatment response are lacking.
Methods
The authors prospectively approached consecutive patients with advanced gastrointestinal cancer who were initiating a new treatment. Prior to treatment, patients reported their QOL (Functional Assessment of Cancer Therapy‐General FACT‐G, 4 subscales: Functional, Physical, Emotional, Social; higher scores indicate better QOL) and symptom burden (Edmonton Symptom Assessment System ESAS, Patient Health Questionnaire‐4 PHQ‐4; higher scores represent greater symptoms). Regression models were used to examine associations of baseline PROs with treatment response (clinical benefit or progressive disease PD at time of first scan), healthcare utilization, and survival.
Results
From May 2019 to April 2020, a total of 112 patients with advanced gastrointestinal cancer were enrolled. For treatment response, 64.3% had CB and 35.7% had PD. Higher baseline ESAS‐Physical (odds ratio, 1.04; P = .027) and lower FACT‐G Functional (odds ratio, 0.92; P = .038) scores were associated with PD. Higher ESAS‐Physical (hazard ratio HR, 1.03; P = .044) and lower FACT‐G Total (HR, 0.96; P = .005), FACT‐G Physical (HR, 0.89; P < .001), and FACT‐G Functional (HR, 0.87; P < .001) scores were associated with a greater hospitalization risk. Lower FACT‐G Total (HR, 0.96; P = .009) and FACT‐G Emotional (HR, 0.86; P = .012) scores as well as higher ESAS‐Total (HR, 1.03; P = .014) and ESAS‐Physical (HR, 1.04; P = .032) scores were associated with worse survival.
Conclusions
Baseline PROs are associated with treatment response in patients with advanced gastrointestinal cancer, namely physical symptoms and functional QOL, in addition to health care use and survival. The findings of the current study support the association between PROs and important clinical outcomes, including the novel finding of treatment response.
In the current study, the authors investigate associations between patient‐reported outcomes (PROs), health care use, and clinical outcomes in a prospectively enrolled cohort of patients with advanced gastrointestinal cancer. Baseline PROs are associated with important clinical outcomes, including the novel finding of treatment response, in patients with advanced gastrointestinal cancer.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract only
186
Background: PROs assessing quality of life (QOL) and physical symptoms often correlate with clinical outcomes in patients (pts) with cancer. Yet, data are lacking about the use of ...PROs to predict treatment response. We evaluated associations of baseline PROs with treatment response, healthcare use, and survival among pts with advanced gastrointestinal cancer. Methods: We prospectively enrolled pts with metastatic gastrointestinal cancer prior to initiating chemotherapy at Massachusetts General Hospital. At baseline (start of treatment), pts reported their QOL (Functional Assessment of Cancer Therapy General FACT-G, subscales assess QOL across 4 domains: functional, physical, emotional, social well-being) and symptom burden (Edmonton Symptom Assessment System ESAS). Higher scores on FACT-G indicate better QOL, while higher scores on ESAS represent a greater symptom burden. We used regression models to examine associations of baseline PRO scores with treatment response (clinical benefit CB or progressive disease PD at the time of first scan based on clinical documentation), healthcare use (unplanned hospital admissions), and survival. Results: From 5/2019-3/2020, we enrolled 112 of 131 (85.5% enrollment) consecutive pts (median age = 62.8, 61.6% male, 45.5% pancreatobiliary cancer). For treatment response, 64.3% had CB and 35.7% had PD. Higher ESAS-physical (B = 1.04, p = .027) and lower FACT-G functional (B = 0.92, p = .038) scores at baseline were significant predictors of PD. On the specific ESAS items, pts who experienced PD were more likely to report moderate/severe poor well-being (57.9% vs 29.7%; p = .001), pain (44.7% vs 25.0%; p < .050), drowsiness (42.1% vs 20.3%; p = .024), and diarrhea (23.7% vs 4.7%; p = .008) at baseline. Lower FACT-G total (HR = 0.96, p = .003), FACT-G physical (HR = 0.89, p < .001), FACT-G functional (HR = 0.87, p < .001), and higher ESAS-physical (HR = 1.03, p = .028) scores at baseline were significantly associated with greater risk of hospital admission. Lower FACT-G total (HR = 0.96, p = .009), FACT-G emotional (HR = 0.87, p = .014), as well as higher ESAS-total (HR = 1.03, p = .018) and ESAS-physical (HR = 1.03, p = .040) scores at baseline were significantly associated with greater risk of death. Conclusions: We found that baseline PROs predict treatment response in pts with advanced cancer, namely physical symptoms and functional QOL, in addition to healthcare use and survival outcomes. These findings further support the use of PROs to predict important clinical outcomes, including the novel finding of treatment response.
Abstract only
833
Background: Changes in ctDNA and serum TMs (CEA and CA19-9) can serve as predictors of response to systemic therapy in GI cancer patients (pts). Similarly, PROs correlate with ...survival and treatment response. We present a preliminary analysis of ctDNA, TMs, and PROs in predicting treatment response. Methods: We are enrolling 200 pts in a prospective study with metastatic pancreatic (PDAC), colorectal (CRC), gastroesophageal (GE), and biliary cancers. We are collecting ctDNA, TMs (CEA for all tumor types; CA19-9 for PDAC, GE, biliary), and PROs (FACT-G for QOL higher scores indicate better QOL; ESAS-r and PRO-CTCAE for symptoms; and PHQ-4 consists of GAD-2 and PHQ-2 for anxiety and depression; higher ESAS-r, PRO-CTCAE, and PHQ-4 scores reflect greater symptom burden) at baseline and 4 weeks. ctDNA is benchmarked against somatic tissue alterations, and serially assessed by digital droplet PCR. We correlated median percent change from baseline to 4 weeks for ctDNA, TMs, and PROs with treatment response (clinical benefit CB, progressive disease PD). Results: From April to August 2019, we have enrolled 38/45 (84.4%) eligible pts (median age = 64 years; 36.8% female). Among these 38 pts, tumor types are PDAC (36.8%), CRC (31.6%), GE (28.9%), and biliary (2.6%). 18/38 pts were evaluable for ctDNA. Change in ctDNA was -94.5% in pts with CB (n = 10) and -19.5% in pts with PD (n = 8; p = 0.025). No correlation was observed between CEA and treatment response (p = 0.367). Change in CA19-9 was -1.5% for pts with CB and +47% for pts with PD (p = 0.019). Changes in PRO-CTCAE (p = 0.345), GAD-2 (p = 0.697), and ESAS scores (p = 0.743) did not differ between pts with CB and PD. However, changes in PHQ-2 (CB 0% v. PD +22.5%; p < 0.001), PHQ-4 (CB -8.5% v. PD +5%; p = 0.015), and FACT-G (CB +30% v. PD +5%; p = 0.049) were significant. Conclusions: Preliminary analysis suggests that ctDNA and PROs demonstrate promising utility for early prediction of treatment response, with favorable performance relative to standard TMs. Further analyses of larger pt numbers in this ongoing study may clarify the use and integration of these measures to better predict pt outcomes.
PDF
