Molecular Genetic Determinants of Shorter Time on Active Surveillance in a Prospective Phase 2 Clinical Trial in Metastatic Renal Cell Carcinoma

Torras, Oscar Reig; Mishra, Akhilesh; Christie, Alana; McKenzie, Tiffani; Onabolu, Oreoluwa; Singla, Nirmish; Plimack, Elizabeth R.; Suárez, Cristina; Ornstein, Moshe Chaim; Alpaugh, R. Katherine; Elias, Roy; Bowman, I. Alex; McKay, Renée M.; Przybycin, Christopher; Kapur, Payal; Brugarolas, James; Rini, Brian I.

doi:10.1016/j.eururo.2021.12.003

Cited by 11 publications

(8 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A previous study identified VHL mutations as the most common gene mutation (72%), followed by PBRM1 (45%), SETD2 (34%), and BAP1 mutations (17%) in 29 Caucasian patients with advanced ccRCC ( 21 ). It is also suggested that BAP1 , SETD2 , and PBRM1 are prevalent co-drivers of tumor grade and invasion of ccRCC and associated with aggressive progression ( 21 – 23 ). However, PBRM1-mutant patients tended to have a higher TMB and might evoke immunotherapy sensitivity ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

Genomic alteration of MTAP/CDKN2A predicts sarcomatoid differentiation and poor prognosis and modulates response to immune checkpoint blockade in renal cell carcinoma

Anwaier

Liu

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

Sarcomatoid differentiation is a highly aggressive pathological characteristic of renal cell carcinoma (RCC) and is characterized by susceptibility to progression and extremely poor prognosis. In this study, we included all genomic alteration events that led to a loss of protein function of MTAP and CDKN2A, and enrolled 5,307 RCC patients with genomic sequencing data from Western and Chinese cohorts. Notably, MTAP/CDKN2AMUT occurred in the Chinese population ~2 times more frequently than in the Western cohort and showed significant co-mutation trends. We found significantly higher proportions of sarcomatoid-positive patients with MTAPMUT or CDKN2AMUT compared with MTAP/CDKN2A wild-type (WT) patients (P < 0.001). Of the 574 RCC samples from the FUSCC cohort and 3,563 RCC samples from 17 independent cohorts, the MTAP/CDKN2AMUT significantly predicted extremely poor outcomes (P < 0.0001). The Western cohort suggested a concordant relationship between MTAP/CDKN2AMUT and sarcomatoid differentiation in RCC. Moreover, although MTAP/CDKN2AMUT RCC may be insensitive to targeted therapy, the high degree of tumor heterogeneity and higher PD-L1 and CXCL13 expression characterizations reflected that MTAP/CDKN2A-deficient features could benefit from immunotherapy for patients with RCC. This study utilized RCC samples from large-scale, global, multicenter sequencing cohorts and first proved that MTAP/CDKN2A deficiency significantly correlates with sarcomatoid differentiation in RCC and predicts aggressive progression, poor prognosis, and primary resistance to targeted therapy and potential favorable responses to immune checkpoint blockade. Unlike conventional targeted therapies, emerging drugs such as immunotherapies or synthetic lethal PRMT5 inhibitors may become novel therapeutic options for patients with MTAP/CDKN2AMUT RCC.

show abstract

Section: Discussionmentioning

confidence: 99%

Genomic alteration of MTAP/CDKN2A predicts sarcomatoid differentiation and poor prognosis and modulates response to immune checkpoint blockade in renal cell carcinoma

Anwaier

Liu

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…For example, a recently published paper proposed a 2-factor model that predicted time on surveillance in a cohort of patients with mRCC based on genomic alterations in TP53 and SMARCA4. 30 Whether this extrapolates to a large cohort remains to be seen, however such strategies will be important in future lines of work to accurately risk stratify patients. Additionally, we relied on clinician intuition about treatment decisions and thus could not prospectively and/or more precisely define the criteria about starting a patient on surveillance vs initiating focal treatment or systemic therapy.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Factors for Survival in Patients Undergoing Surveillance After Cytoreductive Nephrectomy

et al. 2023

View full text Add to dashboard Cite

show abstract

“…However, so far there is only a small amount of research focusing on the analysis of the p53 status in patients affected by RCC, and therefore there is not enough data to provide a complete picture of the TP53 mutation pattern and function when it comes to this particular cancer. Moreover, it has recently been reported that RCC patients who have mutations in the TP53 gene and in the SMARCA4 (BRG1) gene, which is part of the SWI/SNF remodeling complex, have a poor prognosis [ 64 , 65 ].…”

Section: Wild-type and Mutant P53 In Rccmentioning

confidence: 99%

The Underestimated Role of the p53 Pathway in Renal Cancer

Amendolare

Marzano

Petruzzella

et al. 2022

Cancers

View full text Add to dashboard Cite

The TP53 tumor suppressor gene is known as the guardian of the genome, playing a pivotal role in controlling genome integrity, and its functions are lost in more than 50% of human tumors due to somatic mutations. This percentage rises to 90% if mutations and alterations in the genes that code for regulators of p53 stability and activity are taken into account. Renal cell carcinoma (RCC) is a clear example of cancer that despite having a wild-type p53 shows poor prognosis because of the high rate of resistance to radiotherapy or chemotherapy, which leads to recurrence, metastasis and death. Remarkably, the fact that p53 is poorly mutated does not mean that it is functionally active, and increasing experimental evidences have demonstrated this. Therefore, RCC represents an extraordinary example of the importance of p53 pathway alterations in therapy resistance. The search for novel molecular biomarkers involved in the pathways that regulate altered p53 in RCC is mandatory for improving early diagnosis, evaluating the prognosis and developing novel potential therapeutic targets for better RCC treatment.

show abstract

Molecular Genetic Determinants of Shorter Time on Active Surveillance in a Prospective Phase 2 Clinical Trial in Metastatic Renal Cell Carcinoma

Cited by 11 publications

References 10 publications

Genomic alteration of MTAP/CDKN2A predicts sarcomatoid differentiation and poor prognosis and modulates response to immune checkpoint blockade in renal cell carcinoma

Genomic alteration of MTAP/CDKN2A predicts sarcomatoid differentiation and poor prognosis and modulates response to immune checkpoint blockade in renal cell carcinoma

Prognostic Factors for Survival in Patients Undergoing Surveillance After Cytoreductive Nephrectomy

The Underestimated Role of the p53 Pathway in Renal Cancer

Contact Info

Product

Resources

About