PubMed · 10778164
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E Odagiri. 1999. [CA19-9].. https://pubmed.ncbi.nlm.nih.gov/10778164/
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Next-generation sequencing data is fundamentally changing the clinical management of patients with cancer. The most frequent genomic alterations in malignancy are mutations and amplifications, with a subset of tumors having multiple amplifications - "amplificators". We sought to understand the molecular correlates of high tumor amplification burden in a pan-cancer context. Using both national registries and a single-institution dataset, our results demonstrate that cancers with TP53 mutations (as compared to those with wild-type TP53) exhibited significantly higher tumor amplification burden across all datasets. Amplifications, generally associated with overexpression, may be potentially actionable secondary consequences of TP53 mutations.
BACKGROUND: While 2-4% of lung cancers possess alterations in BRAF, little is known about the immune responsiveness of these tumours. METHODS: Clinical and genomic data were collected from 5945 patients with lung cancers whose tumours underwent next-generation sequencing between 2015 and 2018. Patients were followed through 2020. RESULTS: In total, 127 patients with metastatic BRAF-altered lung cancers were identified: 29 tumours had Class I mutations, 59 had Class II/III alterations, and 39 had variants of unknown significance (VUS). Tumour mutation burden was higher in Class II/III than Class I-altered tumours (8.8 mutations/Mb versus 4.9, P < 0.001), but this difference was diminished when stratified by smoking status. The overall response rate to immune checkpoint inhibitors (ICI) was 9% in Class I-altered tumours and 26% in Class II/III (P = 0.25), with median time on treatment of 1.9 months in both groups. Among patients with Class I-III-altered tumours, 36-month HR for death in those who ever versus never received ICI was 1.82 (1.17-6.11). Nine patients were on ICI for >2 years (two with Class I mutations, two with Class II/III alterations, and five with VUS). CONCLUSIONS: A subset of patients with BRAF-altered lung cancers achieved durable disease control on ICI. However, collectively no significant clinical benefit was seen.
We assessed whether current therapies could lead to hematogenous dissemination of malignant hepatocytes in hepatocellular carcinoma (HCC) patients using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) for alpha-fetoprotein (afp) and albumin (alb) mRNAs. We analyzed 137 peripheral blood samples before, during and after treatment from 84 patients under radiotherapy, surgical resection or chemotherapy. As compared to the upper limit for 53 healthy/non-HCC controls, alb- mRNA levels increased 2-10-fold in 6% of patients pre-treatment and 2-2.6x10(4)-fold in 32% post-treatment. Levels of afp- mRNA increased 3-210-fold in 17% pre-treatment and 4-5x10(5)-fold in 30% post-treatment. During a longitudinal follow-up of eight patients under radiotherapy or radiotherapy/resection, alb-mRNA levels were normal before treatment, whereas afp-mRNA levels increased 10-fold in two patients. During treatment, alb-mRNA and afp-mRNA levels increased 2-61-fold in three patients and 2.5-5-fold in two patients, respectively. After treatment, alb-mRNA levels declined to normal in all three patients within 3.5 months, but afp-mRNA levels increased 127-5x10(5)-fold in three patients within 5 months. We show evidence that HCC cells disseminating mostly post-treatment may be the 'seed' of recurrence/metastasis. In conjunction with the serum alpha-fetoprotein test, sequential afp-mRNA quantification could predict clinical metastasis/recurrence in 56% of patients during a 4-year follow-up.