PMC8222507_01
PET/CT imaging and histological finding. (A) PET/CT imaging on 2018/03/19 revealed an enlarged nodule measuring 2.0 x 1.6 cm on right lower lobe (RLL) with SUVmax 8.4, bilateral supraclavicular lymph nodes (0.5 cm and 0.6 cm on the right and left sides respectively) with SUVmax 2.8, enlarged mediastinal lymphadenectases including station 2R, 4R, 4L, 3A, 3P, 5, 6, 7, and right hilar lymphadenectasis with SUVmax 26.4 of the largest diameter of 4.2 cm, multiple bony metastases including right humerus, right scapula, T5 and T8 vertebral body, multiple sacrum, right acetabulum, right sciatic bone with a SUVmax 7.8. (B) Histological examination on the metastatic subcarinal lymphadenectasis tissue of pre-ICPi (first-biopsy), pericardial effusion of post-ICPi/pre-BRAFi (second-biopsy), and left supraclavicular lymphadenectasis of post-BRAFi (third biopsy) (hematoxylin and eosin stain, magnification x100) and programmed death ligand-1 (PD-L1) expression in pre-ICPi (immunohistochemical stain, magnification x100; E1L3N, Cell Signaling Technology, Danvers, MA); poorly differentiated lung adenocarcinoma positive for CK, TTF1, and NapsinA, negative for CD56 and P40 by immunohistochemistry stain in pre-ICPi (03/28/2018), post-ICPi/pre-BRAFi (12/20/2019), and post-BRAFi (06/04/2020). ICPi, immune check-point inhibitor; BRAFi, BRAF inhibitor.
fonc-11-634920-g001.jpg
PMC8222507_01_fonc-11-634920-g001.jpg
f1
A 62-year-old female non-smoker experienced a month-lasting fatigue, and PET/CT demonstrated an enlarged lung nodule on right lower lobe, bilateral supraclavicular and mediastinal lymphadenectases and multiple bony metastases confirming stage IV-T1bN3M1c ( Figure 1A ). Endobronchial ultrasound-guided transbronchial biopsy on subcarinal lymph node on 2018/03/28 revealed poorly differentiated lung adenocarcinoma with co-expressing tumors of BRAF V600E and PD-L1 >=50% ( Figure 1B ).
Course of the disease, treatment history, and response evaluation. 1st surveillance CT (SCT): baseline, atezolizumab/cisplatin/pemetrexed induction (Cyc1, 2018/04/11); 2nd SCT: post-induction two cycles (Cyc3, 2018/05/28), PR; 3rd SCT: post-induction four cycles, atezolizumab/pemetrexed maintenance (Cyc5, 2018/07/12), PR; 4th SCT: post-atezolizumab/pemetrexed maintenance 12 cycles (Cyc17, 2019/03/25), PR; 5th SCT: post-atezolizumab maintenance one cycle (Cyc20, 2019/05/27), PR. NOTE: Atezolizumab maintenance on C19V1. Tumor assessment every 9 weeks (three cycles) after the completion of the week 48 tumor assessment per protocol (Cyc20, 2019/05/27); 6th SCT: post-atezolizumab maintenance eight cycles (Cyc27, 2019/12/17), PD; 7th SCT: post-Vemurafenib two cycles (Cyc3, 2020/02/03), SD; 8th SCT: post-Vemurafenib six cycles (Cyc7, 2020/06/04), PD. Red circles: metastatic mediastinal lymphadenectases; Red short arrows: right hilar lymphadenectasis; Red long arrows: primary lung tumor; Blue dotted cycle: new lesion; lesion 1: pericardial effusion (progression on ICPi); lesion 2: left supraclavicular lymph node (progression on BRAFi). PR, partial response; SD, stable disease; PD, progressive disease; ICPi, immune check-point inhibitor; BRAFi, BRAF inhibitor.
fonc-11-634920-g002.jpg
PMC8222507_01_fonc-11-634920-g002.jpg
f2
Unfortunately, disease progressed with the new pericardial effusion on 2019/12/17 after eighth cycles of atezolizumab maintenance, with a total of 20-months PFS of first-line treatment ( Figure 2 ).
Somatic mutation profiles of pre-ICPi, post-ICPi/pre-BRAFi, and post-BRAFi. (A) The heatmap shows an overview of mutations in pre-ICPi, post-ICPi/pre-BRAFi, and post-BRAFi within liquid biopsy, pericardial effusion biopsy, and left supraclavicular lymph node. (B) Clonal evolution in liquid biopsy dynamic monitoring (Upper) and mean variant allele frequency (VAF) change (Lower) during immunotherapy and BRAF inhibitor Vemurafenib treatment. Variants from cfDNA using Bayesian cluster with PyClone. CCF, cancer cell fraction; ICPi, immune check-point inhibitor; BRAFi, BRAF inhibitor.
fonc-11-634920-g003.jpg
PMC8222507_01_fonc-11-634920-g003.jpg
f3
Table 1 ). The variant allele fraction (VAF) of mutation clusters in liquid biopsy was dropped at post-ICPi-progression compared with pre-ICPi; conversely, it drastically increased (excluding cluster 4) and new mutations occurred at post-BRAFi-progression compared with pre-/post-ICPi ( Figure 3B ).