Association between MMR protein expression and efficacy of neoadjuvant chemotherapy in breast cancer

doi:10.3877/cma.j.issn.1674-0785.2020.12.006

Abstract

Abstract:

Objective

To investigate the association between the efficacy of neoadjuvant chemotherapy (NACT) and the expression of mismatch repair (MMR) proteins in breast cancer.

Methods

The clinicopathological data of 53 breast cancer patients treated with NACT from January 1, 2016 to October 31, 2018 in Weifang People's Hospital were collected, and MMR (MSH2, MSH6, PMS2, and MLH1) in pretreatment biopsies of these patients were assessed by immunohistochemistry (IHC) in tissue microarrays (TMAs). Responses to NACT were classified as pathological complete response (pCR; grade 5), partial response (PR; grades 2-4), and stable disease (SD; grade 1) according to the Miller/Payne system. The results were analyzed using SPSS 22.0 statistical software.

Results

Of the 53 breast cancer patients included, 10 (18.9%) achieved pCR (G5), 36 (67.9%) achieved PR (G2-4), and 7 (13.2%) achieved SD (G1). IHC analysis revealed that MSH2, MSH6, PMS2, and MLH1 proteins were all expressed positively in the 53 breast cancer patients and none of them were MMR-deficient. In terms of the relationship with tumor stage, the expression of MSH6 showed a statistical difference among different clinical stages (χ²=6.09, P=0.04). Age, menstrual status, clinical tumor stage, nodal status, ER, PR, HER2, Ki-67, and molecular subtypes had no significant association with the expression of MSH2, PMS2, and MLH1 (P＞0.05). The efficacy of NACT was positively associated with MLH1 (r=0.40, P=0.00) or MSH6 (r=0.37, P=0.01) expression. There was no correlation between the efficacy of NACT and MSH2 or PMS2 (P＞0.05) expression.

Conclusion

Increased expression of MSH6 and MLH1 in pretreatment biopsies of breast cancer patients suggests better efficacy of NACT.

Key words: Breast cancer, Neoadjuvant chemotherapy, Tissue microarrays, Mismatch repair, Miller and Payne system

Cheng Li, Yuanyuan Cai, Guiyan Han, Nan Wang, Hui Wang, Yuping Zhang, Mingchen Wang, Furong Hao, Yunxiang Zhang. Association between MMR protein expression and efficacy of neoadjuvant chemotherapy in breast cancer[J]. Chinese Journal of Clinicians(Electronic Edition), 2020, 14(12): 981-987.

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References 26

1	郑荣寿, 孙可欣, 张思维, 等. 2015年中国恶性肿瘤流行情况分析 [J]. 中华肿瘤杂志, 2019, 41(1): 19-28.
2	Puig CA, Hoskin TL, Day CN, et al. National trends in the use of neoadjuvant chemotherapy for hormone receptor-negative breast cancer: a national cancer data base study [J]. Ann Surg Oncol, 2017, 24(5): 1242-1250.
3	Spring L, Greenup R, Niemierko A, et al. Pathologic complete response after neoadjuvant chemotherapy and long-term outcomes among young women with breast cancer [J]. J Natl Compr Canc Netw, 2017, 15(10): 1216-1223.
4	LeVasseur N, Sun J, Gondara L, et al. Impact of pathologic complete response on survival after neoadjuvant chemotherapy in early-stage breast cancer: a population-based analysis [J]. J Cancer Res Clin Oncol, 2020, 146(2): 529-536.
5	Gupta D,Heinen CD. The mismatch repair-dependent DNA damage response: Mechanisms and implications [J]. DNA Repair (Amst), 2019, 78: 60-69.
6	Zaanan A, Shi Q, Taieb J, et al. Role of deficient DNA mismatch repair status in patients with stage III colon cancer treated with FOLFOX adjuvant chemotherapy: a pooled analysis from 2 randomized clinical trials [J]. JAMA Oncol, 2018, 4(3): 379-383.
7	邱春华, 张志宏, 董丹丹, 等. 错配修复基因蛋白在结直肠癌诊治中的临床应用 [J]. 中国肿瘤临床, 2018, 45(19): 39-42.
8	Roberts ME, Jackson SA, Susswein LR, et al. MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer [J]. Genet Med, 2018, 20(10): 1167-1174.
9	Cheng AS, Leung SCY, Gao D, et al. Mismatch repair protein loss in breast cancer: clinicopathological associations in a large British Columbia cohort [J]. Breast Cancer Res Treat, 2020, 179(1): 3-10.
10	Davies H, Morganella S, Purdie CA, et al. Whole-genome sequencing reveals breast cancers with mismatch repair deficiency [J]. Cancer Res, 2017, 77(18): 4755-4762.
11	Fusco N, Lopez G, Corti C, et al. Mismatch repair protein loss as a prognostic and predictive biomarker in breast cancers regardless of microsatellite instability [J]. JNCI Cancer Spectr, 2018, 2(4): pky056.
12	王敬华, 郑美珠,李永清. 乳腺癌免疫组化分子分型与新辅助化疗疗效相关性分析 [J]. 中华肿瘤防治杂志, 2018, 25(10): 704-708.
13	徐乘骏, 张朝蓬, 邱恒, 等. 分子分型对乳腺癌新辅助化疗后肿瘤退缩模式的影响 [J]. 中国肿瘤临床, 2018, 45(17): 894-897.
14	Kheirelseid EA, Miller N, Chang KH, et al. Mismatch repair protein expression in colorectal cancer [J]. J Gastrointest Oncol, 2013, 4(4): 397-408.
15	Malik SS, Masood N, Asif M, et al. Expressional analysis of MLH1 and MSH2 in breast cancer [J]. Curr Probl Cancer, 2019, 43(2): 97-105.
16	Goldhirsch A, Wood WC, Coates AS, et al. Strategies for subtypes-dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the primary therapy of early breast cancer 2011 [J]. Ann Oncol, 2011, 22(8): 1736-1747.
17	Ogston KN, Miller ID, Payne S, et al. A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival [J]. Breast, 2003, 12(5): 320-327.
18	晋龙, 眭玉霞, 王丽萍, 等. 结直肠癌错配修复蛋白MLH1、MSH2、MSH6及PMS2表达与临床病理特征的关系 [J]. 诊断病理学杂志, 2017, 24(11): 813-817.
19	Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade [J]. Science, 2017, 357(6349): 409-413.
20	Mills AM, Dill EA, Moskaluk CA, et al. The relationship between mismatch repair deficiency and PD-L1 expression in breast carcinoma [J]. Am J Surg Pathol, 2018, 42(2): 183-191.
21	计骏, 陈国庭, 于颖彦, 等. 错配修复基因hMSH2在乳腺癌中的表达及意义 [J]. 中国癌症杂志, 2002, 12(6): 101-102.
22	徐玲玉, 江勇. hMSH2、hMLH1和p53在乳腺癌的表达及临床意义 [J]. 江苏医药, 2015, 41(24): 2972-2974+3083.
23	Li XB, Krishnamurti U, Bhattarai S, et al. Biomarkers predicting pathologic complete response to neoadjuvant chemotherapy in breast cancer [J]. Am J Clin Pathol, 2016, 145(6): 871-878.
24	Wu Z, Zhang L, Peng J, et al. Predictive and prognostic value of PDL1 protein expression in breast cancer patients in neoadjuvant setting [J]. Cancer Biol Ther, 2019, 20(6): 941-947.
25	Santarpia L, Iwamoto T, Di Leo A, et al. DNA repair gene patterns as prognostic and predictive factors in molecular breast cancer subtypes [J]. The Oncologist, 2013, 18(10): 1063-1073.
26	Fedier A, Schwarz VA, Walt H, et al. Resistance to topoisomerase poisons due to loss of DNA mismatch repair [J]. Int J Cancer, 2001, 93(4): 571-576.

项目	MSH2		χ²值	P值	MSH6			χ²值	P值	PMS2			χ²值	P值	MLH1			χ²值	P值
项目	中	强	χ²值	P值	弱	中	强	χ²值	P值	弱	中	强	χ²值	P值	弱	中	强	χ²值	P值
年龄			2.11	0.27				1.55	0.53				1.36	0.69				2.33	0.44
＜50	2	21			2	7	14			1	21	1			0	22	1
≥50	7	23			2	14	14			1	25	4			3	25	2
月经			0.30	0.59				0.18	1.00				3.21	0.20				0.69	1.00
绝经前	3	22			2	10	13			0	24	1			1	23	1
绝经后	6	22			2	11	15			2	22	4			2	24	2
T分期			2.47	0.18				6.09	0.04				0.45	1.00				1.86	0.32
cT_1~2	9	34			4	20	19			2	37	4			2	39	2
cT_3~4	0	10			0	1	9			0	9	1			1	8	1
淋巴结			0.04	1.00				0.33	1.00				3.34	0.23				1.71	0.60
cN-	1	6			0	3	4			0	5	2			0	6	1
cN+	8	38			4	18	24			2	41	3			3	41	2
ER状态			0.03	1.00				1.28	0.64				1.73	0.67				0.69	1.00
阴性	4	21			2	8	15			1	23	1			1	23	1
阳性	5	23			2	13	13			1	23	4			2	24	2
PR状态			0.18	0.67				0.86	0.77				0.83	0.82				0.57	1.00
阴性	3	21			2	8	14			1	20	3			1	22	1
阳性	6	23			2	13	14			1	26	2			2	25	2
HER-2			0.00	1.00				0.44	0.90				1.03	0.53				1.23	0.80
阴性	6	30			3	15	18			1	32	3			3	31	2
阳性	3	14			1	6	10			1	14	2			0	16	1
Ki-67			0.00	1.00				0.31	1.00				3.43	0.24				2.53	0.47
＜14%	1	4			0	2	3			1	4	0			0	4	1
≥14%	8	40			4	19	25			1	42	5			3	43	2
分子分型			0.33	1.00				2.53	0.62				2.47	0.74				2.19	0.73
Luminal	6	29			2	16	17			1	30	4			2	30	3
HER-2	2	8			1	3	6			1	8	1			0	10	0
三阴性	1	7			1	2	5			0	8	0			1	7	0

项目	MSH2		χ²值	P值	MSH6			χ²值	P值	PMS2			χ²值	P值	MLH1			χ²值	P值
项目	中	强	χ²值	P值	弱	中	强	χ²值	P值	弱	中	强	χ²值	P值	弱	中	强	χ²值	P值
年龄			2.11	0.27				1.55	0.53				1.36	0.69				2.33	0.44
＜50	2	21			2	7	14			1	21	1			0	22	1
≥50	7	23			2	14	14			1	25	4			3	25	2
月经			0.30	0.59				0.18	1.00				3.21	0.20				0.69	1.00
绝经前	3	22			2	10	13			0	24	1			1	23	1
绝经后	6	22			2	11	15			2	22	4			2	24	2
T分期			2.47	0.18				6.09	0.04				0.45	1.00				1.86	0.32
cT_1~2	9	34			4	20	19			2	37	4			2	39	2
cT_3~4	0	10			0	1	9			0	9	1			1	8	1
淋巴结			0.04	1.00				0.33	1.00				3.34	0.23				1.71	0.60
cN-	1	6			0	3	4			0	5	2			0	6	1
cN+	8	38			4	18	24			2	41	3			3	41	2
ER状态			0.03	1.00				1.28	0.64				1.73	0.67				0.69	1.00
阴性	4	21			2	8	15			1	23	1			1	23	1
阳性	5	23			2	13	13			1	23	4			2	24	2
PR状态			0.18	0.67				0.86	0.77				0.83	0.82				0.57	1.00
阴性	3	21			2	8	14			1	20	3			1	22	1
阳性	6	23			2	13	14			1	26	2			2	25	2
HER-2			0.00	1.00				0.44	0.90				1.03	0.53				1.23	0.80
阴性	6	30			3	15	18			1	32	3			3	31	2
阳性	3	14			1	6	10			1	14	2			0	16	1
Ki-67			0.00	1.00				0.31	1.00				3.43	0.24				2.53	0.47
＜14%	1	4			0	2	3			1	4	0			0	4	1
≥14%	8	40			4	19	25			1	42	5			3	43	2
分子分型			0.33	1.00				2.53	0.62				2.47	0.74				2.19	0.73
Luminal	6	29			2	16	17			1	30	4			2	30	3
HER-2	2	8			1	3	6			1	8	1			0	10	0
三阴性	1	7			1	2	5			0	8	0			1	7	0

MMR	NACT疗效			r值	P值
MMR	SD（G1）	PR（G2~4）	pCR（G5）	r值	P值
MSH2				0.05	0.73
中阳	1（11.1）	7（77.8）	1（11.1）
强阳	6（13.6）	29（65.9）	9（20.5）
MSH6				0.37	0.01
弱阳	1（25.0）	3（75.0）	0（0.0）
中阳	4（19.0）	16（76.2）	1（4.8）
强阳	2（7.1）	17（60.7）	9（32.1）
PMS2				0.17	0.23
弱阳	1（50.0）	0（0.0）	1（50.0）
中阳	6（13.0）	33（71.7）	7（15.2）
强阳	0（0.0）	3（60.0）	2（40.0）
MLH1				0.40	0.00
弱阳	2（66.7）	1（33.3）	0（0.0）
中阳	5（10.6）	34（72.3）	8（17.0）
强阳	0（0.0）	1（33.3）	2（66.7）

MMR	NACT疗效			r值	P值
MMR	SD（G1）	PR（G2~4）	pCR（G5）	r值	P值
MSH2				0.05	0.73
中阳	1（11.1）	7（77.8）	1（11.1）
强阳	6（13.6）	29（65.9）	9（20.5）
MSH6				0.37	0.01
弱阳	1（25.0）	3（75.0）	0（0.0）
中阳	4（19.0）	16（76.2）	1（4.8）
强阳	2（7.1）	17（60.7）	9（32.1）
PMS2				0.17	0.23
弱阳	1（50.0）	0（0.0）	1（50.0）
中阳	6（13.0）	33（71.7）	7（15.2）
强阳	0（0.0）	3（60.0）	2（40.0）
MLH1				0.40	0.00
弱阳	2（66.7）	1（33.3）	0（0.0）
中阳	5（10.6）	34（72.3）	8（17.0）
强阳	0（0.0）	1（33.3）	2（66.7）

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