Predictors of response to neoadjuvant treatment and changes to HER2 status in HER2-positive invasive breast cancer

doi:10.19401/j.cnki.1007-3639.2022.05.007

Abstract

Abstract:

Background and purpose: The response of human epidermal growth factor receptor 2 (HER2)-positive invasive breast cancer to HER2 targeted neoadjuvant therapy is significant. However, the response is not uniform, and a proportion of patients respond poorly. This study aimed to identify predictors of response in the neoadjuvant treatment and to assess the discordance rate of HER2 status between pre- and post-treatment specimens in HER2-positive breast cancer. Methods: The study group included 110 HER2-positive breast cancer patients treated with neoadjuvant therapy and surgery who were diagnosed from 2019 to 2021 in Shenzhen People’s Hospital. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were used to detect the expression of HER2 in core needle biopsy specimens. Pathological complete response (pCR) and residual cancer burden (RCB) of surgically resected specimens after neoadjuvant therapy were used to assess the therapy response of patients. HER2, estrogen receptor (ER) and progesterone receptor (PR) status were further assessed in the residual invasive carcinoma present after neoadjuvant therapy. Results: One hundred and ten breast cancer patients were divided into IHC diffuse 3+ group (n=81), heterogeneous 3+ group (n=20), IHC 2+ and FISH amplified (2+FISH+) group (n=9). The pCR rate of HER2 diffuse 3+ group was 54.3%, which was significantly higher compared with heterogeneous 3+ group (5.0%) and 2+FISH+ group (11.1%), and the difference was statistically significant (P<0.05). RCB categories were higher in heterogeneous 3+ and 2+FISH+ groups. Multivariate analysis showed that HER2 diffuse 3+ was an independent predictor of pCR. Seven cases (11.9%) became HER2-negative, the majority (85.7%) from heterogeneous 3+ and 2+FISH+ groups. Conclusion: HER2 heterogeneity predicts the neoadjuvant therapy response of HER2-positive breast cancer. Evaluation of the heterogeneity of HER2 IHC in biopsy specimens and repeating HER2, ER and PR testing after neoadjuvant treatment should therefore be considered, which will facilitate further management decisions. The patients with HER2 heterogeneity may potentially benefit from the novel antibody-drug conjugate (ADC).

Key words: Human epidermal growth factor receptor 2 heterogeneity, Breast cancer, Neoadjuvant therapy

CLC Number:

R737.9

LIU Jianlan, CHEN Daishi, HU Hong, ZHOU Dongxian, HU Jintao. Predictors of response to neoadjuvant treatment and changes to HER2 status in HER2-positive invasive breast cancer[J]. China Oncology, 2022, 32(5): 417-426.

Figures/Tables 6

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Characteristic	HER2			χ²	P value
Characteristic	Diffuse 3+	Heterogeneous 3+	2+FISH+	χ²	P value
Age/year				0.226	0.893
≤50	53 (65.4)	12 (60.0)	6 (66.7)
>50	28 (34.6)	8 (40.0)	3 (33.3)
ER				4.628	0.099
Positive	45 (55.6)	14 (70.0)	8 (88.9)
Negative	36 (44.4)	6 (30.0)	1 (11.1)
PR				0.868	0.648
Positive	54 (66.7)	15 (75.0)	7 (77.8)
Negative	27 (33.3)	5 (25.0)	2 (22.2)
Ki-67 proliferation index				4.319	0.115
≥30%	54 (66.7)	18 (90.0)	6 (66.7)
<30%	27 (33.3)	2 (10.0)	3 (33.3)
Tumor size D/cm				3.717	0.446
>5	12 (14.8)	6 (30.0)	1 (11.1)
2-5	59 (72.8)	11 (55.0)	6 (66.7)
≤2	10 (12.3)	3 (15.0)	2 (22.2)
Lymph node metastasis				2.703	0.259
+	41 (50.6)	12 (60.0)	7 (77.8)
-	40 (49.4)	8 (40.0)	2 (22.2)
Histology type				0.361	0.835
NST	80 (98.8)	20 (100.0)	9 (100.0)
ILC	1 (1.2)	0 (0.0)	0 (0.0)
Neoadjuvant treatments				0.192	0.908
Chemotherapy+dual anti-HER2	59 (72.8)	14 (70.0)	6 (66.7)
Chemotherapy+single anti-HER2	22 (27.2)	6 (30.0)	3 (22.2)

Characteristic	RCB			χ²	P value
Characteristic	0	Ⅰ	Ⅱ+Ⅲ	χ²	P value
Age/year				0.753	0.686
≤50	31 (67.4)	15 (68.2)	25 (59.5)
>50	15 (32.6)	7 (31.8)	17 (40.5)
ER				7.74	0.021
Positive	21 (45.7)	16 (72.7)	30 (71.4)
Negative	25 (54.3)	6 (27.3)	12 (28.6)
PR				6.063	0.048
Positive	26 (56.5)	18 (81.8)	32 (76.2)
Negative	20 (43.5)	4 (18.2)	10 (23.8)
Ki-67 proliferation index				1.233	0.540
≥30%	35 (76.1)	14 (63.6)	29 (69.0)
<30%	11 (23.9)	8 (36.4)	13 (31.0)
tumor size D/cm				6.296	0.178
>5	4 (8.7)	4 (18.2)	11 (26.2)
2-5	34 (73.9)	14 (63.6)	28 (66.7)
≤2	8 (17.4)	4 (18.2)	3 (7.1)
Lymph node metastasis				1.484	0.476
+	23 (50.0)	11 (50.0)	26 (61.9)
-	23 (50.0)	11 (50.0)	16 (38.1)
Histology type				1.404	0.496
NST	45 (97.8)	22 (100.0)	42 (100.0)
ILC	1 (2.2)	0 (0.0)	0 (0.0)
Neoadjuvant treatments				0.483	0.786
Chemotherapy+dual anti-HER2	33 (71.7)	17 (77.3)	29 (69.0)
Chemotherapy+single anti-HER2	13 (28.3)	5 (22.7)	13 (28.6)

Parameter	Risk/reference	pCR/non-pCR n/n (%)			Univariant analysis			Multivariant analysis
Parameter	Risk/reference	pCR/non-pCR n/n (%)			OR	95% CI	P value	OR	95% CI	P value
HER2	Diffuse 3+/heterogeneous 3+/2+FISH+	44/37 (54.3)	1/19 (5)	1/8 (11.1)	7.501	2.268-24.802	0.001	6.912	2.048-23.329	0.002
Age/year	>50/≤50	15/24 (38.5)	31/40 (43.7)		0.806	0.363-1.790	0.597	-	-	-
ER	-/+	25/18 (58.1)	21/46 (31.3)		3.042	1.373-6.743	0.006	1.711	0.574-5.100	0.335
PR	-/+	20/14 (58.8)	26/50 (34.2)		2.747	1.196-6.308	0.017	1.784	0.555-5.734	0.331
Ki-67 proliferation index	≥30%/<30%	35/43 (44.9)	11/21 (34.4)		1.554	0.661-3.654	0.312	-	-	-
Tumor size D/mm	>5/≤5	4/15 (21.1)	42/49 (46.2)		0.311	0.096-1.010	0.052	0.371	0.104-1.323	0.126
Lymph node metastasis	-/+	23/27 (46)	23/37 (38.3)		1.370	0.640-2.935	0.417	-	-	-

Parameter	Risk/reference	pCR/non-pCR n/n (%)		Univariant analysis			Multivariant analysis
Parameter	Risk/reference	pCR/non-pCR n/n (%)		OR	95% CI	P value	OR	95% CI	P value
Age/year	>50/≤50	13/15 (46.4)	31/22 (58.5)	0.615	0.245-1.546	0.302	-	-	-
ER	-/+	23/13 (63.9)	21/24 (46.7)	2.022	0.824-4.961	0.124	1.474	0.449-4.840	0.523
PR	-/+	18/9 (66.7)	26/28 (48.1)	2.154	0.823-5.636	0.118	1.457	0.408-5.196	0.562
Ki-67 proliferation index	≥30%/<30%	34/20 (63.0)	10/17 (37.0)	2.890	1.110-7.523	0.03	2.479	0.920-6.676	0.073
Tumor size D/mm	>5/≤5	4/8 (33.3)	40/29 (58.0)	0.363	0.100-1.319	0.124	0.506	0.130-1.963	0.324
Lymph node metastasis	-/+	21/19 (52.5)	23/18 (56.1)	0.865	0.361-2.075	0.865	-	-	-

Pre-treatment	Total	Post-treatment		P value
Pre-treatment	Total	Positive	Negative	P value
HER2				<0.001
Diffuse 3+	34 (57.6)	33 (97.1)	1 (2.9)
Heterogeneous 3+	18 (30.5)	15 (83.3)	3 (16.7)
2+FISH+	7 (11.9)	4 (57.1)	3 (42.9)
ER				>0.05
Positive	43 (71.7)	41 (95.3)	2 (4.7)
Negative	17 (28.3)	2 (11.8)	15 (88.2)
PR				0.267
Positive	46 (78.0)	37 (80.4)	9 (19.6)
Negative	13 (22.0)	4 (30.8)	9 (69.2)