case_images: PMC11216098_01
case_images: (a) Duration of study participation and efficacy assessment for the per-protocol BRAF-mutant population (experimental group (E), n = 3; control group (C), n = 6). Dynamics of plasma BRAF V600E DNA over the study treatment in (b) two experimental-group subjects and (c) three control-group subjects.
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case_images: One patient (Figure 1(a), second from the top; baseline plasma BRAF V600E VAF 3.9%), presenting with multiple peritoneal and para-aortal lymph node metastases, responded with CR in the first treatment break, which lasted almost a year before a new treatment sequence caused an immediate second CR. One patient (Figure 1(a), fourth from the top; baseline plasma BRAF V600E VAF 100%) presented with metastases in most liver segments and several lymph node stations below and above the diaphragm (Figure 2, right panel).
case_images: Left framed panel: The primary tumor site; baseline endoscopy and biopsy (top), endoscopy and biopsy at radiologic complete response (bottom). Right framed panel: The metastatic disease; the primary tumor (encircled) and multiple liver metastases at baseline (top), the ascending colon and liver at radiologic complete response (bottom). Further details are displayed in Supplementary Figures S3 and S5.
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case_images: The T4b subject had the CR status confirmed by endoscopy showing slight mucosal edema and scarring, from where biopsies proved restored mucosa with crypt branching and slight inflammation without residual tumor (Figure 2, left panel). One patient (Figure 1(a), fourth from the top; baseline plasma BRAF V600E VAF 100%) presented with metastases in most liver segments and several lymph node stations below and above the diaphragm (Figure 2, right panel).
case_images: T-cell receptor (TCR) repertoire in sequential liver metastases. TCR sequencing was done on a baseline biopsy sample from one of multiple liver metastases, three samples from the two resected liver metastases that relapsed after the radiologic complete response, and two samples from the resected end-stage liver metastases. (a) T-cell fractions in the repertoire of each sample, stratified by sampling time. The mean number of TCR sequences detected was 22,185 at baseline, 82,263 at the first liver resection, and 7,252 at the second. (b) Repertoire clonality of each sample, stratified by sampling time. The clonality index is defined as 10 minus the area under the curve of the evenness profile, with higher values signifying more monoclonal repertoires. (c) Hill diversity profile and (d) Hill evenness profile for each repertoire, presented by mean (solid line) with 95% confidence interval (shaded area). The left part of the diversity curve (alpha = 0) represents the number of unique clones present in the repertoire. The further and more rapidly each curve declines at increasing alpha values, the more uneven is the clonal frequency distribution (more monoclonal repertoires). The evenness profiles represent the diversity profiles normalized by clonal richness in the repertoire.
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case_images: The patients were >=70-year-old females presenting with ascending colon adenocarcinomas (Supplementary Figures S3-4) with TMB 6.2-11.8 mutations per megabase and no POLD1/POLE mutations (Supplementary Tables S2-3). T-cell fraction of 3.2% at baseline had increased to 8.2% at the first resection but fallen to 0.07% at the second (Figure 3(a)). The corresponding mean clonality indices (higher values implying more monoclonal repertoires) were 2.9, 5.5, and 2.9 (Figure 3(b)). Specifically, the Hill diversity profiles (Figure 3(c)) revealed an absolute clonal diversity, averaging 27,423 clones, peaking in the primarily relapsed metastases, compared to 5,768 clones at baseline and 2,340 clones at end-stage (alpha = 0). As illustrated by the Hill evenness profiles (Figure 3(d)), which are diversity profiles normalized against the number of unique clones, the clonal frequency distribution was more uneven (the most rapid decline at increasing alpha values) for the primarily relapsed liver metastases than at baseline and end-stage.