Predictive biomarkers of response and survival following immunotherapy with a PD-L1 inhibitor benmelstobart(TQB2450)and antiangiogenic therapy with a VEGFR inhibitor anlotinib for pretreated advanced triple negative breast cancer

In our phase Ib trial(ClinialTrials.gov Identifier:NCT03855358),benmelstobart(TQB2450),a novel humanized IgG1 antibody against PD-L1,plus antiangiogenic multikinase inhibitor,anlotinib,demonstrated promising antitumor activities in pretreated triple negative breast cancer(TNBC)patients.We conducted explorative analyses of genomic biomarkers to explore the associations with treatment response and survival outcomes.Targeted next generation sequencing(NGS)was undertaken toward circulating tumor DNA(ctDNA)collected from peripheral blood samples prior to the start of treatment and after disease progression.A total of 31 patients received targeted NGS and functional driver mutations in 29 patients were analyzed.The most frequent mutations were TP53(72%),MLL3(28%),and PIK3CA(17%).At a blood-based tumor mutational burden(bTMB)cutoff of 6.7 mutations per megabase,patients with low bTMB showed better response to anlotinib plus TQB2450(50%vs.7%,P=0.015)and gained greater PFS benefits(7.3 vs.4.1 months,P=0.012)than those with high bTMB.At a maximum somatic allele frequency(MSAF)cutoff of 10%,a low MSAF indicated a better objective response(43%vs.20%)as well as a significantly longer median PFS(7.9 vs.2.7 months,P<0.001).Patients with both low MSAF and low bTMB showed a notably better objective response to anlotinib plus TQB2450(70%vs.11%,P<0.001)and a significantly longer median PFS(11.0 vs.2.9 months,P<0.001)than patients with other scenarios.Our findings support future studes and validation of MSAF and the combined bTMB-MSAF classification as predictive biomarkers of immune checkpoint inhibitor-based regimens in advanced TNBC patients.

Rare tumors: a blue ocean of investigation

Advances in novel drugs,therapies,and genetic techniques have revolutionized the diagnosis and treatment of cancers,substantially improving cancer patients’prognosis.Although rare tumors account for a non-negligible number,the practice of precision medicine and development of novel therapies are largely hampered by many obstacles.Their low incidence and drastic regional disparities result in the difficulty of informative evidence-based diagnosis and subtyping.Sample exhaustion due to difficulty in diagnosis also leads to a lack of recommended therapeutic strategies in clinical guidelines,insufficient biomarkers for prognosis/efficacy,and inability to identify potential novel therapies in clinical trials.Herein,by reviewing the epidemiological data of Chinese solid tumors and publications defining rare tumors in other areas,we proposed a definition of rare tumor in China,including 515 tumor types with incidences of less than 2.5/100000 per year.We also summarized the current diagnosis process,treatment recommendations,and global developmental progress of targeted drugs and immunotherapy agents on the status quo.Lastly,we pinpointed the current recommendation chance for patients with rare tumors to be involved in a clinical trial by NCCN.With this informative report,we aimed to raise awareness on the importance of rare tumor investigations and guarantee a bright future for rare tumor patients.

Integrated circulating tumor DNA and T cell repertoire predict radiotherapeutic response and outcome in non-small cell lung cancer patients with brain metastasis

Dear editor,The scarcity of routinemetastatic biopsies or resection limits the finding of biomarkers of diagnosis and prognosis in patients with brain metastases.Derived from necrosis,apoptosis,and secretion of tumor cells,circulating tumor DNA(ctDNA)is widely distributed in various body fluids,including peripheral blood and cerebrospinal fluid(CSF),as an alternative biomarker for tumor-associated analysis[1].Fortunately,genomic alterations of blood ctDNA and CSF ctDNA have been proven as prognostic markers in non-small cell lung cancer(NSCLC)patients with brain metastasis[2,3].

Genomic evolution during locoregional recurrence in colorectal cancer determined by whole-exome sequencing: a retrospective observational study

Objective:The genomic landscapes of metastatic colorectal cancer(mCRC)have been extensively studied;however,the genetic mechanisms underlying the locoregional recurrence(LR)of CRC remain unclear.The objective of our study was to investigate genomic evolution during LR in CRC using high-throughput sequencing.Methods:Twenty-three CRC patients with matched primary and LR tissues were recruited from Nanfang Hospital and Zhejiang Cancer Hospital between January 2011 and December 2018.The last date of follow-up was March 2020.Tissue samples were analyzed by whole-exome sequencing and the genomic profiles were depicted by single nucleotide variation,mutational signature,copy number variation,clonal architecture,and other features.The evolutionary process was speculated with comparison of the genetic variations between primary and LR lesions.The disseminating clusters from primary to LR lesions were identified by variant allele frequency dynamics.Furthermore,the early-recurrent biomarker was explored by comparing the indel signature between early-and late-recurrent patients.The study was approved by the Institutional Review Board of Nanfang Hospital of Southern Medical University(approval No.2020010)on September 11,2020.Results:The results highlighted distinct origins of LR between patients with high microsatellite instability and microsatellite stability.LR lesions evolved independently in patients with high microsatellite instability,while LR lesions were highly clonally related to the primary lesions in patients with microsatellite stability.Late-acquired variations in LR lesions encompassed a wide range of driver genes involved in histone methylation,DNA replication,T cell activation,PDCD1 gain,and LMNA loss.Furthermore,clonal analysis of the disseminating cells identified a dominant polyclonal seeding pattern during LR.The indel signature ID4 was associated with significantly shorter disease-free survival in patients with relapsed CRC according to a public dataset.Conclusion:These findings pose a challenge for the development of new approaches targeting the interactions of multiple clones in the establishment of LR and in terms of optimizing the clinical management of susceptible patients.

Whole-exome sequencing reveals genetic underpinnings of salivary adenoid cystic carcinoma in the Chinese population

Salivary gland carcinomas(SGCs)are rare malignancies that remain poorly understood owing to their low incidence(Matsuba et al.,1986b;Liu et al.,2012).As per GLOBOCAN 2018.52.800 new cancers arising from salivary glands were estimated to be diag-nosed across the world that year.Because of their high propensity to invade local and perineural structures.