Circulating tumor DNA predicting resistance to endocrine therapy in hormone receptor positive advanced breast cancer

doi:10.3877/cma.j.issn.1674-0807.2017.03.002

Abstract

Abstract:

Objective

To evaluate the feasibility of serial gene-panel circulating tumor DNA(ctDNA) sequencing in predicting resistance to endocrine therapy of hormone receptor (HR) positive advanced breast cancer.

Methods

We retrospectively analyzed the clinical data of 30 patients with HR positive advanced breast cancer in the Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College from January 2015 to August 2016. Blood sample of 10 ml was collected from these patients before endocrine therapy. ctDNA mutation was assayed by gene-panel target-capture next-generation sequencing. Based on the existence of drug resistance-related gene mutation (TP53, PIK3CA, mTOR,ERBB2, ESR1 and FGFR1), all samples were further subdivided into two groups: mutant group and nonmutant group. The relationship between resistance to endocrine therapy and gene mutation was analyzed.Survival curves of progression-free survival (PFS) were estimated using the Kaplan-Meier method and comparison of these estimates was performed using log-rank test. χ² test was used to compare the primary drug resistance rates between mutant group and non-mutant group.

Results

In all 30 patients, there were 20 patients in mutant group and 10 patients in non-mutant group respectively. The median follow-up was 3 months (range 1-19 months). The median PFS was 3.0 months in the mutant group and 5.0 months in nonmutant group respectively. The 6-month PFS in mutant group was significantly lower than that in non-mutant group (10% vs 50%, χ² =8.328, P=0.004). In mutant group (20 patients), 18 patients had primary resistance to endocrine therapy and 2 patients had secondary resistance. In non-mutant group (10 patients),5 patients had primary resistance to endocrine therapy and 5 patients had secondary resistance. The primary resistance rate in mutant group was significantly higher than that in non-mutant group (χ² = 5.963, P =0.026).

Conclusion

The combined detection of ctDNA in multiple drug resistance-related genes can predict the resistance to endocrine therapy in HR positive advanced breast cancer patients.

Key words: Breast neoplasms, Receptors, estrogen, Drug response, Circulating tumor DNA

Zongbi Yi, Fei Ma, Lifang Yuan, Chunxiao Li, Yanfang Guan, Xiuwen Guan, Lixi Li, Jiayu Wang, Binghe Xu. Circulating tumor DNA predicting resistance to endocrine therapy in hormone receptor positive advanced breast cancer[J]. Chinese Journal of Breast Disease(Electronic Edition), 2017, 11(03): 132-137.

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https://zhrxbzz.cma-cmc.com.cn/EN/Y2017/V11/I03/132

Figures/Tables 4

References 19

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编号	发病年龄(岁)	HER-2	Ki67(%)	转移器官(个)	是否手术	既往内分泌治疗(次)	既往化疗(次)	既往靶向治疗(次)	DFS(月)	药物	PFS(月)
P1	52	阳性	5	3	是	2	3	1	14	托瑞米芬	7
P2	47	阴性	0	4	是	2	4	3	44	阿那曲唑	2
P3	31	阴性	5	3	是	2	5	3	9	托瑞米芬	3
P4	41	阳性	20	3	是	3	5	3	19	来曲唑	12
P5^a	58	阳性	40	3	否	3	4	4		来曲唑	2
P6	46	阴性	40	4	是	1	2	0	39	来曲唑	4
P7	45	阴性	20	4	是	1	3	1	50	来曲唑	1
P8	46	阴性	10	3	是	2	6	0	29	托瑞米芬	18
P9	44	阳性	25	1	是	1	1	0	64	来曲唑	19
P10	34	阳性	2	3	是	1	2	1	23	来曲唑	5
P11	34	阳性	30	2	是	1	1	0	50	依西美坦	3
P12	24	阳性	30	2	是	2	7	1	29	来曲唑	8
P13	26	阳性	5	4	是	1	6	6	8	氟维司群	5
P14^a	55	阳性	18	2	否	1	0	1		来曲唑	3
P15	32	阳性	25	3	是	2	4	3	62	托瑞米芬	2
P16^a	47	阳性	35	3	否	2	2	0		来曲唑	1
P17	46	阴性	25	4	是	2	4	0	49	来曲唑	1
P18^a	68	阳性	35	2	否	0	2	1		依西美坦	2
P19^a	34	阴性	60	4	否	1	2	0		托瑞米芬	3
P20	55	阴性	25	2	是	1	0	0	74	氟维斯群	5
P21^a	68	阴性	10	3	否	3	1	0		阿那曲唑	3
P22	39	阴性	50	2	是	1	0	1	57	来曲唑	4
P23	42	阴性	30	1	是	2	2	0	83	托瑞米芬	4
P24	47	阴性	50	2	是	2	6	1	13	托瑞米芬	1
P25	64	阴性	NA	2	是	2	NA	NA	21	托瑞米芬	11
P26^a	42	阴性	25	4	否	1	0	0		托瑞米芬	3
P27	48	阴性	30	4	是	1	0	1	31	来曲唑	2
P28	30	阳性	70	3	是	1	0	2	21	依西美坦	7
P29	45	阴性	50	3	是	2	NA	0	37	托瑞米芬	2
P30	51	阴性	NA	4	是	2	NA	1	132	托瑞米芬	5

编号	发病年龄(岁)	HER-2	Ki67(%)	转移器官(个)	是否手术	既往内分泌治疗(次)	既往化疗(次)	既往靶向治疗(次)	DFS(月)	药物	PFS(月)
P1	52	阳性	5	3	是	2	3	1	14	托瑞米芬	7
P2	47	阴性	0	4	是	2	4	3	44	阿那曲唑	2
P3	31	阴性	5	3	是	2	5	3	9	托瑞米芬	3
P4	41	阳性	20	3	是	3	5	3	19	来曲唑	12
P5^a	58	阳性	40	3	否	3	4	4		来曲唑	2
P6	46	阴性	40	4	是	1	2	0	39	来曲唑	4
P7	45	阴性	20	4	是	1	3	1	50	来曲唑	1
P8	46	阴性	10	3	是	2	6	0	29	托瑞米芬	18
P9	44	阳性	25	1	是	1	1	0	64	来曲唑	19
P10	34	阳性	2	3	是	1	2	1	23	来曲唑	5
P11	34	阳性	30	2	是	1	1	0	50	依西美坦	3
P12	24	阳性	30	2	是	2	7	1	29	来曲唑	8
P13	26	阳性	5	4	是	1	6	6	8	氟维司群	5
P14^a	55	阳性	18	2	否	1	0	1		来曲唑	3
P15	32	阳性	25	3	是	2	4	3	62	托瑞米芬	2
P16^a	47	阳性	35	3	否	2	2	0		来曲唑	1
P17	46	阴性	25	4	是	2	4	0	49	来曲唑	1
P18^a	68	阳性	35	2	否	0	2	1		依西美坦	2
P19^a	34	阴性	60	4	否	1	2	0		托瑞米芬	3
P20	55	阴性	25	2	是	1	0	0	74	氟维斯群	5
P21^a	68	阴性	10	3	否	3	1	0		阿那曲唑	3
P22	39	阴性	50	2	是	1	0	1	57	来曲唑	4
P23	42	阴性	30	1	是	2	2	0	83	托瑞米芬	4
P24	47	阴性	50	2	是	2	6	1	13	托瑞米芬	1
P25	64	阴性	NA	2	是	2	NA	NA	21	托瑞米芬	11
P26^a	42	阴性	25	4	否	1	0	0		托瑞米芬	3
P27	48	阴性	30	4	是	1	0	1	31	来曲唑	2
P28	30	阳性	70	3	是	1	0	2	21	依西美坦	7
P29	45	阴性	50	3	是	2	NA	0	37	托瑞米芬	2
P30	51	阴性	NA	4	是	2	NA	1	132	托瑞米芬	5

临床特征	基因突变组(n=20)	非基因突变组(n=10)	P值
HER-2状态
阳性	9	4	1.000
阴性	11	6	1.000
转移器官数
1～2个	4	6	0.077
3个	8	3
4个	8	1
既往内分泌治疗情况
初治晚期患者	5	2	0.893
原发耐药	6	2
继发耐药	7	5
有效	2	1
既往内分泌治疗次数
0～1	10	4	0.709
≥2	10	6	0.709
内分泌治疗药物
SERMs	10	2	0.256
AI	9	7
SERDs	1	1

临床特征	基因突变组(n=20)	非基因突变组(n=10)	P值
HER-2状态
阳性	9	4	1.000
阴性	11	6	1.000
转移器官数
1～2个	4	6	0.077
3个	8	3
4个	8	1
既往内分泌治疗情况
初治晚期患者	5	2	0.893
原发耐药	6	2
继发耐药	7	5
有效	2	1
既往内分泌治疗次数
0～1	10	4	0.709
≥2	10	6	0.709
内分泌治疗药物
SERMs	10	2	0.256
AI	9	7
SERDs	1	1

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