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Korean Cancer Study Group 
Webzine Vol.26  DEC 2022 
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KCSG ์—ฐ๊ตฌ ๋…ผ๋ฌธ ์†Œ๊ฐœ
โ–ถ KCSG BR13-11
Potential role of CMPK1, SLC29A1, and TLE4 polymorphisms in gemcitabine-based chemotherapy in HER2-negative metastatic breast cancer patients: pharmacogenetic study results from the prospective randomized phase II study of eribulin plus gemcitabine versus paclitaxel plus gemcitabine (KCSG-BR-13-11)

์ €๋„: ESMO Open. 2021 Oct;6(5):100236. Epub 2021 Aug 23.

 

์ œ1์ €์ž ๊น€์ง€์—ฐ (์‚ผ์„ฑ์„œ์šธ๋ณ‘์›)

 

Q. ์—ฐ๊ตฌ์˜ ๋ฐฐ๊ฒฝ์€?

์ ฌ์‹œํƒ€๋นˆ(Gemcitabine, 2',2'-difluorodeoxycytidine; dFdC)์€ deoxycytidine์˜ ์ƒˆ๋กœ์šด S phase specific cytidine nucleoside analogue๋กœ์„œ ์œ ๋ฐฉ์•”์—์„œ ๋‹จ์ผ ์š”๋ฒ•์œผ๋กœ ํšจ๊ณผ๋ฅผ ๋‚˜ํƒ€๋‚ด๋Š” ์•ฝ์ œ์ž…๋‹ˆ๋‹ค. ์œ ์ „์  ๋‹คํ˜•์„ฑ(genetic polymorphism)์€ ์ ฌ์‹œํƒ€๋นˆ ๋Œ€์‚ฌ์— ๊ด€์—ฌํ•˜๋Š” ์ˆ˜์†ก์ฒด ๋ฐ ํšจ์†Œ์˜ ํ™œ์„ฑ์— ์˜ํ–ฅ์„ ๋ฏธ์น˜๋Š” ์ค‘์š”ํ•œ ์š”์ธ์ด๋ฉฐ, ์ ฌ์‹œํƒ€๋นˆ ํšจ๋Šฅ์˜ ๊ฐœ์ธ๊ฐ„ ์ฐจ์ด๋ฅผ ์„ค๋ช…ํ•  ์ˆ˜ ์žˆ์Šต๋‹ˆ๋‹ค. ์ด๋Ÿฌํ•œ ์œ ์ „์  ๋‹คํ˜•์„ฑ๊ณผ ์ ฌ์‹œํƒ€๋นˆ์˜ ์ž„์ƒ์  ํšจ๋Šฅ ์‚ฌ์ด์˜ ์—ฐ๊ด€์„ฑ์€ ํ์•”, ์ทŒ์žฅ์•” ๋ฐ ์œ ๋ฐฉ์•” ํ™˜์ž์—์„œ ์—ฐ๊ตฌ๋˜์—ˆ์Šต๋‹ˆ๋‹ค. ์ ฌ์‹œํƒ€๋นˆ์˜ ์œ ์ „์  ๋‹คํ˜•์„ฑ์— ๋Œ€ํ•œ ์ด์ „ ์—ฐ๊ตฌ์—์„œ๋Š” SLC28A3, SLC29A1 ๋ฐ RRM1 ์œ ์ „์  ๋‹คํ˜•์„ฑ์ด ํŒŒํด๋ฆฌํƒ์…€๊ณผ ์ ฌ์‹œํƒ€๋นˆ์„ ๋ณ‘์šฉํ•œ MBC ํ™˜์ž์˜ ์ž„์ƒ ๊ฒฐ๊ณผ๋ฅผ ์˜ˆ์ธกํ–ˆ์Šต๋‹ˆ๋‹ค. ํ•˜์ง€๋งŒ, ๋Œ€๋ถ€๋ถ„์˜ ์—ฐ๊ตฌ๋Š” ์œ ์ „์  ๋‹คํ˜•์„ฑ๊ณผ ์ ฌ์‹œํƒ€๋นˆ์˜ ์ž„์ƒ์  ํšจ๋Šฅ ์‚ฌ์ด์˜ ์—ฐ๊ด€์„ฑ์„ ํ‰๊ฐ€ํ•˜๊ธฐ์— ์ถฉ๋ถ„ํ•˜์ง€ ์•Š์„ ์ˆ˜ ์žˆ๋Š” ์†Œ์ˆ˜์˜ ์œ ์ „์  ๋‹คํ˜•์„ฑ์— ์ดˆ์ ์„ ๋งž์ท„์Šต๋‹ˆ๋‹ค. ๋”ฐ๋ผ์„œ, ์—ฌ๋Ÿฌ ์œ ์ „์ž๊ฐ€ ์ ฌ์‹œํƒ€๋นˆ ์ˆ˜์†ก ๋ฐ ๋Œ€์‚ฌ์— ๊ด€์—ฌํ•˜๊ธฐ ๋•Œ๋ฌธ์— ๊ฐ€๋Šฅํ•œ ํ•œ ๋งŽ์€ ์œ ์ „์ž๋ฅผ ๋™์‹œ์— ๋ถ„์„ํ•˜๋Š” ๊ฒƒ์ด ํ•„์š”ํ•ฉ๋‹ˆ๋‹ค.


์ด์ „์— HER2 ์Œ์„ฑ ์ „์ด์„ฑ ์œ ๋ฐฉ์•” ํ™˜์ž๋ฅผ ๋Œ€์ƒ์œผ๋กœ 1์ฐจ ์น˜๋ฃŒ๋กœ์„œ ์ ฌ์‹œํƒ€๋นˆ ๊ธฐ๋ฐ˜ ํ™”ํ•™ ์š”๋ฒ•์˜ 2์ƒ ์ž„์ƒ ์‹œํ—˜์„ ์ˆ˜ํ–‰ํ–ˆ์Šต๋‹ˆ๋‹ค. ๋ณธ ์—ฐ๊ตฌ์—์„œ, ์—ฐ๊ตฌ์— ์ฐธ์—ฌํ•œ ํ™˜์ž๋ฅผ ๋Œ€์ƒ์œผ๋กœ, 23๊ฐœ ์œ ์ „์ž์˜ 103๊ฐœ ์œ ์ „์ž ๋‹คํ˜•์„ฑ๊ณผ ์ ฌ์‹œํƒ€๋นˆ์˜ ์ž„์ƒ์  ํšจ๋Šฅ์„ ๋น„๊ตํ•˜๋Š” phamacogenomic study๋ฅผ ์ง„ํ–‰ํ•˜์˜€์Šต๋‹ˆ๋‹ค.



Q. ์—ฐ๊ตฌ์˜ ๋ชฉ์ ์€?

KCSG-BR-13-11 ์—ฐ๊ตฌ๋กœ ์ง„ํ–‰๋œ HER2 ์Œ์„ฑ ์œ ๋ฐฉ์•”์—์„œ eribulin/gemcitabine vs. paclitaxel/gemcitabine ์˜ ํšจ๊ณผ๋ฅผ ๋น„๊ตํ•˜๋Š” 2์ƒ ์ž„์ƒ์—ฐ๊ตฌ์—์„œ ํ™˜์ž์˜ ํ˜ˆ์•ก์„ ํ†ตํ•ด, genetic polymorphism๊ณผ gemcitabine based chemotherapy์˜ ํšจ๊ณผ์™€์˜ ์—ฐ๊ด€๊ด€๊ณ„๋ฅผ ๋ณธ pharmacogenetic study ์ž…๋‹ˆ๋‹ค.


Q. ์—ฐ๊ตฌ ๋ฐฉ๋ฒ•?

์ „ํ–ฅ์  ์ž„์ƒ์—ฐ๊ตฌ(KCSG-BR-13-11)์˜ parallel pharmacogenetic study๋กœ์„œ, ์ ฌ์‹œํƒ€๋นˆ์˜ ์ˆ˜์†ก(transport) ๊ณผ ๋Œ€์‚ฌ(metabolism)์— ์—ฐ๊ด€๋œ 23๊ฐœ ์œ ์ „์ž์˜ 103๊ฐœ์˜ ์œ ์ „์  ๋‹คํ˜•์„ฑ์„ ํ™•์ธํ•˜์˜€์Šต๋‹ˆ๋‹ค. ์ด ์œ ์ „์  ๋‹คํ˜•์„ฑ๊ณผ ์งˆ๋ณ‘ ๋ฌด์ง„ํ–‰ ์ƒ์กด์œจ(progression free survival [PFS]) ๋ฐ 6๊ฐœ์›” ๋ฌด์ง„ํ–‰ ์ƒ์กด์œจ (6 month PFS) ์˜ ์—ฐ๊ด€์„ฑ์„ ๋ถ„์„ํ•˜์˜€์Šต๋‹ˆ๋‹ค.


Q. ์—ฐ๊ตฌ ๊ฒฐ๊ณผ?

์ด 118๋ช…์˜ ํ™˜์ž ์ค‘ 91๋ช…์˜ ํ™˜์ž๊ฐ€ ์ด ์—ฐ๊ตฌ์— ๋“ฑ๋ก๋˜์—ˆ์Šต๋‹ˆ๋‹ค. CMPK1์˜ rs1044457์˜ ์œ ์ „์  ๋‹คํ˜•์„ฑ์ด 6๊ฐœ์›” ๋ฌด์ง„ํ–‰ ์ƒ์กด์œจ์—์„œ ๊ฐ€์žฅ ์˜ํ–ฅ์„ ๋งŽ์ด ๋ผ์น˜๋Š” SNP์œผ๋กœ ํ™•์ธ๋˜์—ˆ์Šต๋‹ˆ๋‹ค. (55.9% for CT and TT and 78.9% for CC, P < 0.001, hazard ratio [HR]: 4.444, 95% confidence interval [CI]: 1.905-10.363). SLC29A1 ์œ ์ „์ž์˜ rs693955 ์œ„์น˜์˜ AA ์œ ์ „์  ๋‹คํ˜•์„ฑ์„ ๊ฐ€์ง„ ์œ ๋ฐฉ์•” ํ™˜์ž์˜ ์ค‘์•™ ๋ฌด์ง„ํ–‰ ์ƒ์กด๊ธฐ๊ฐ„(median duration of PFS)์ด 5.4๊ฐœ์›”์ด๋ฉฐ, CA์™€ CC ์œ ์ „์  ๋‹คํ˜•์„ฑ์„ ๊ฐ€์ง„ ์œ ๋ฐฉ์•” ํ™˜์ž๋Š” 10.5 ๊ฐœ์›”์˜ ์ค‘์•™ ๋ฌด์ง„ํ–‰ ์ƒ์กด๊ธฐ๊ฐ„์„ ๋ณด๊ณ ํ•˜์˜€์Šต๋‹ˆ๋‹ค. (P = 0.002, HR: 3.704, 95% CI: 1.615-8.497). TLE4์˜ rs2807312 ์œ„์น˜์˜ TT ์œ ์ „์  ๋‹คํ˜•์„ฑ์„ ๊ฐ€์ง„ ํ™˜์ž์˜ ์ค‘์•™ ๋ฌด์ง„ํ–‰ ์ƒ์กด๊ธฐ๊ฐ„์€ 5.7๊ฐœ์›”์ด์—ˆ๊ณ , CT ๋ฐ CC ์œ ์ „์  ๋‹คํ˜•์„ฑ์˜ ๊ฒฝ์šฐ 10.4๊ฐœ์›”์˜ ๋ฌด์ง„ํ–‰ ์ƒ์กด๊ธฐ๊ฐ„์„ ๋ณด๊ณ ํ•˜์˜€์Šต๋‹ˆ๋‹ค.  (P = 0.005, HR: 4.948, 95% CI: 1.612-15.190).


Multi-gene ๋ชจ๋ธ์—์„œ rs2807312์˜ TT genotype์€ ๋‹ค๋ฅธ ์œ ์ „์  ๋‹คํ˜•์„ฑ์— ๊ด€๊ณ„ ์—†์ด, ์•„์ฃผ ์ข‹์ง€์•Š์€ ์˜ˆํ›„๋ฅผ ๋ณด๊ณ ํ•˜์˜€์Šต๋‹ˆ๋‹ค. ๋ฐ˜๋ฉด์—, rs693955 ์˜ CA genotype ํ˜น์€ rs2807312์˜ CT genotype ์ด๋‚˜, rs693955์˜ AA genotype์ด ์•„๋‹Œ ๊ฒฝ์šฐ ๋งค์šฐ ์ข‹์€ ์˜ˆํ›„๋ฅผ ์˜ˆ์ธกํ•˜์˜€์Šต๋‹ˆ๋‹ค (P < 0.001).




Q. ๋งˆ์ง€๋ง‰์œผ๋กœ ํ•˜๊ณ  ์‹ถ์€ ๋ง์€?

์ž„์ƒ์—ฐ๊ตฌ์˜ phamacogenetic study๋ฅผ ํ†ตํ•ด, SNP์™€ ์•ฝ๋ฌผ์˜ ํšจ๊ณผ์— ๋Œ€ํ•ด ํ™•์ธํ•  ์ˆ˜ ์žˆ์—ˆ๋˜ ์—ฐ๊ตฌ์˜€์Šต๋‹ˆ๋‹ค. ๋งŽ์€ ์—ฐ๊ตฌ์ž๋ถ„์˜ ๋…ธ๋ ฅ๊ณผ ํ™˜์ž๋ถ„์˜ ์ฐธ์—ฌ๊ฐ€ ์žˆ์–ด ์ด๋Ÿฌํ•œ ์—ฐ๊ตฌ๊ฒฐ๊ณผ๋ฅผ ๋„์ถœ ํ•  ์ˆ˜ ์žˆ์—ˆ์Šต๋‹ˆ๋‹ค. ์ฐธ์—ฌํ•ด ์ฃผ์‹  ๋ชจ๋“  ํ™˜์ž๋ถ„๊ณผ, KCSG-BR-13-11์ž„์ƒ์—ฐ๊ตฌ๋ฅผ ์ง„ํ–‰ํ•ด ์ฃผ์‹  ๋ชจ๋“  ์—ฐ๊ตฌ์ž ๋ถ„๋“ค๊ป˜ ์ง„์‹ฌ์œผ๋กœ ๊ฐ์‚ฌ๋“œ๋ฆฝ๋‹ˆ๋‹ค.