EURURO Vol. 72 No. 3

Letter to the Editor

Re: James J

[1_TD$DIFF]

. Hsieh, David Chen, Patricia

[6_TD$DIFF]

I. Wang,

[7_TD$DIFF]

[8_TD$DIFF]

al.

Genomic Biomarkers of a Randomized Trial Comparing

First-line Everolimus and Sunitinib in Patients with

Metastatic Renal Cell Carcinoma. Eur Urol 2017;71:

405–14

A recent publicationwith a total of 220metastatic clear cell

renal cell carcinoma (ccRCC) patients from RECORD-3, a

randomized phase 2 trial, showed that mutation events

were enriched in metastatic ccRCC patients and

PBRM1

BAP1

, and

KDM5C

mutation status impacted outcomes of

targeted therapies. This deep sequencing assay would be

very exciting and clinically meaningful to know the gene

mutation affect response efficacy of vascular endothelial

growth factor and

[9_TD$DIFF]

mammalian target of rapamycin

inhibitors in metastatic ccRCC which could be potential

biomarkers in targeted therapy selection and medication

sequence for patients with metastatic ccRCC. However,

although the findings of this advanced technique seemed to

be promising and encouraging, we hold some questions for

the scientific rigor and practicality of this study, hoping to

offer more useful references for this theory’s clinical

practice.

Firstly, we noticed the authors

[1]

conducted the deep

sequencing at the beginning of the targeted treatment

and drew the conclusions that with everolimus/sunitinib,

PBRM1

and

BAP1

mutations contributed to a longer and

shorter median first-line progression free survival,

relatively, and with sunitinib/everolimus, the

KDM5C

mutation resulted in a longer median first-line progres-

sion free survival. However, it seemed to ignore the

dynamic process of the interaction between tumor status

and targeted treatment. Because the tumor adaptability

and microenvironment change, quantities of acquired

mutations are produced during the targeted therapy and

it is the root cause of almost all patients’ acquisition of

resistance who are initially sensitive to targeted therapy

[2]

. This indicates the mutation status before crossover

is not the same as the initial first-line treatment.

For second-line treatment, besides vascular endothelial

growth factor and

[9_TD$DIFF]

mammalian target of rapamycin

inhibitor, cabozatinibas, a new multitarget inhibitor,

has been confirmed that it could significantly

increase overall survival and also decrease disease

progression risks

[3]

. In the meantime, it is well known

that specific targeted therapy has a different clinical

efficacy to different mutations. Hence, faced with a

variety of second-line drugs, we have good reasons to

believe patients may obtain the maximum survival

benefits when urologists dynamically monitor mutation

changes and select the most appropriate second-line

therapy.

Furthermore, the great heterogeneity of RCC should be

noted and genotypic variation exists not only among

individuals, but also intratumor, even the individual

tumors and their metastasis

[4]

. Thereby, it is very likely

that the efficacy of the same targeted drug is different

from primary and metastatic lesions. In addition, smok-

ing, as the most important risk factor of RCC tumorigen-

esis, is deemed to affect the clinical effects of sunitinib, as

well as increase the somatic mutation load

[5,6] ;

therefore, it is not correct to infer smoking may be a

confounding factor in gene mutations predicting out-

comes of targeted therapy. Hence, we wonder how many

smoking patients are enrolled in this study and whether

there would have been the same results when taking

smoking as a stratified factor.

In conclusion, we strongly recommend to monitor gene

mutations in real-time sequencing during targeted thera-

pies, together with other clinical data, simultaneously

using multi-disciplinary mode to ultimately provide a

comprehensive precision medicine evidence of the indi-

vidual targeted treatment for advanced metastatic ccRCC

patients.

Conflicts of interest:

[4_TD$DIFF]

The authors have nothing to disclose.

References

[1]

Hsieh JJ, Chen D, Wang PI, et al. Genomic biomarkers of a random- ized trial comparing first-line everolimus and sunitinib in patients with metastatic renal cell carcinoma. Eur Urol 2017;71:405–14.

[2]

Asic´ K. Dominant mechanisms of primary resistance differ from dominant mechanisms of secondary resistance to targeted thera- pies. Crit Rev Oncol Hematol 2016;97:178–96. E U R O P E A N U R O L O G Y 7 2 ( 2 0 1 7 ) e 7 2 – e 7 3

available at

www.scienced irect.com

journal homepage:

www.europeanurology.com

DOI of original article:

http://dx.doi.org/10.1016/j.eururo.2016.10.007

http://dx.doi.org/10.1016/j.eururo.2017.01.012

0302-2838/