The Prognostic Impact of Hormonal Receptor and HER-2 Expression Discordance in Metastatic Breast Cancer Patients

Figures & data

Table 1 Clinical Characteristics and Therapy (n=270)

Clinicopathological Factors		Mean (Range)	Frequency (%)
Age (years)		46.5 (24–76)
T-stage	pT1	59	21.85%
	pT2	109	40.37%
	pT3	27	10.00%
	pT4	12	4.45%
	pTx	63	23.33%
N-stage	pN0	77	28.52%
	pN1	51	18.89%
	pN2	56	20.74%
	pN3	72	26.67%
	pNx	14	5.18%
M-stage	pM0	257	95.19%
	pM1	11	4.07%
	pMx	2	0.74%
Pathology	Intraductal carcinoma	7	2.59%
	Invasive Duct carcinoma	218	80.74%
	Invasive lobular carcinoma	18	6.67%
	Medullary carcinoma	3	1.11%
	Rare types carcinoma	24	8.89%
Surgery	No	12	4.44%
	Modified radical operation	250	92.59%
	Breast-conserving surgery	6	2.22%
	Not sure	2	0.74%
Chemotherapy	No	34	12.59%
	Yes	236	87.41%
Radiotherapy	No	160	59.25%
	Yes	110	40.74%
Endocrine therapy	No	131	54.13%
	Tamoxifen	91	33.70%
	Aromatase inhibitor ± GnRH	34	12.59%
	Tamoxifen + GnRH	5	1.85%
	Aromatase inhibitor +tamoxifen ± GnRH	8	2.96%
	GnRH mono	1	0.37%
Trastuzumab therapy	No	259	95.93%
	Yes	11	4.07%
Metastasis	Lymph nodes, soft tissue, and bone	136	50.37%
	Viscus	127	47.04%
	Brain	7	2.59%

Abbreviations: T, primary tumor size; N, regional lymph node; M, distant metastasis, pT, pathological tumor; pN, pathological node; pM, pathological metastasis; GnRH, Gonadotropin-Releasing Hormone.

Table 2 ER, PR and HER2 Expression Conversion During Metastasis

	Receptor Status	Cases	Percentage
ER	+ to −	40	14.81%
	− to +	16	5.93%
	+	143	52.96%
	−	71	21.3%
	Concordance	214	79.25%
	Discordance	56	20.70%
PR	+ to −	72	26.67%
	− to +	30	11.11%
	+	87	32.22%
	−	81	30.00%
	Concordance	168	62.22%
	Discordance	102	37.78%
HER2	+ to −	11	4.07%
	− to +	20	7.41%
	+	63	23.33%
	-	126	46.67%
	Concordance	189	70.00%
	Discordance	31	11.48%
	− to not sure	28	10.37%
	+ to not sure	22	8.15%

Notes: Frequencies of receptor changes between primary diagnosis and recurrent disease are shown for estrogen receptor (ER), progesterone receptor (PgR) and HER2 receptor. + to −, loss in expression; − to +, gains in expression; +, Persistent positivity; −, Persistent negativity.

Table 3 Comparison of Tumor Subtype Between Primary and Recurrent Tumors

	HR, HER2 Status in Metastasis Sites						Total
	HR+/HER2-	HR+/HER2+	HR−/HER2+	HR−/HER2-	HR−/HER2 Not Sure	HR+/HER2 Not Sure
HR, HER2 status in primary sites
HR+/HER2−	77(28.5)	11(4.1)	2(0.7)	15(5.6)	5(1.9)	21(7.8)	131(48.5)
HR+/HER2+	5(1.9)	32(11.9)	10(3.7)	2(2.9)	2(2.9)	10(3.7)	61(22.6)
HR-/HER2+	0(0)	5(1.9)	16(6)	5(1.9)	4(1.5)	6(2.2)	36(13.3)
HR-/HER2−	13(4.8)	3(1.1)	4(1.5)	20(7.4)	2(0.7)	0(0)	42(15.5)
Total	95(35.2)	51(18.9)	32(11.9)	42(15.6)	13(4.8)	37(13.7)	270

Note: −, Means receptor expression negative; +, Means receptor expression positive.

Abbreviations: HER2, human epidermal growth factor receptor 2; HR, hormone receptor.

Table 4 Association Between the Change of ER, PR, and Her-2 Status and Clinicopathological Variables

Feature	No Change	Change	Change in Any Receptor		ER Discordance P value	PR Discordance P value	HER2 Discordance P value
			Chi-Square p value
T-stage(n=242)			5.778	0.216	0.728	0.106	0.746
pT1	25(10.3)	29(12.9)			12(5.0)	19(7.8)	5(2.1)
pT2	39(16.1)	60(24.8)			27(11.2)	44(18.2)	15(6.2)
pT3	6(2.5)	18(7.4)			4(1.6)	13(5.4)	4(1.6)
pT4	6(2.5)	3(1.2)			2(0.8)	1(0.4)	0(0)
pTx	24(9.9)	32(13.2)			11(4.5)	25(10.3)	6(2.5)
N-stage(n=242)			4.325	0.363	0.170	0.922	0.974
pN1	24(9.9)	23(9.5)			7(2.9)	18(7.4)	7(2.9)
pN2	17(7.0)	32(13.2)			17(7.0)	22(9.1)	7(2.9)
pN3	22(9.1)	41(16.9)			16(6.6)	30(12.4)	7(2.9)
pN4	6(2.5)	6(2.5)			1(0.4)	5(2.1)	1(0.4)
pNx	31(12.8)	40(16.5)			15(6.2)	27(11.2)	9(3.7)
M-stage(n=242)			2.213	0.331	0.749	0.720	0.912
pM0	95(39.3)	138(57.0)			54(22.3)	98(40.5)	30(12.4)
pM1	5(2.1)	3(1.2)			2(0.8)	3(1.2)	1(0.4)
pMx	0(0)	1(0.4)			0(0)	1(0.4)	0(0)
Surgery(n=242)			0.324	0.569	0.278	0.776	0.806
Yes	95(39.3)	137(56.6)			55(22.7)	97(40.1)	28(11.6)
Not	5(2.1)	5(2.1)			1(0.4)	5(2.1)	3(1.2)
Radiotherapy(n=242)			0.248	0.618	0.331	0.164	0.886
Yes	66(27.3)	39(16.1)			26(10.7)	47(19.4)	13(5.4)
No	91(37.6)	47(19.4)			30(12.4)	55(22.7)	18(7.4)
Chemotherapy(n=242)			5.481	0.0192	0.031	0.259	0.258
Yes	125(51.6)	90(37.2)			51(21.1)	88(36.4)	29(12.0)
No	22(9.1)	5(2.1)			4(1.6)	14(5.8)	2(0.8)
Endocrine therapy(n=242)			3.9	0.048	0.877	0.002	0.850
Yes	55(22.7)	61(25.2)			30(12.4)	65(26.9)	16(6.6)
No	44(18.2)	82(33.9)			27(11.2)	36(14.9)	15(6.2)
Trastuzumab therapy(n=242)			3.212	0.073	0.331	0.171	0.366
Yes	7(2.9)	3(1.2)			1(0.4)	2(0.8)	2(0.8)
No	96(39.7)	136(56.2)			55(22.7)	100(41.3)	29(12.0)
Auxiliary endocrine therapy(n=242)			4.55	0.336	0.624	0.071	0.776
Untreated	55(22.7)	60(24.8)			27(11.2)	36(14.9)	15(6.2)
Tamoxifen	29(12.0)	53(21.9)			21(8.7)	43(17.8)	10(4.1)
AI ± GnRH	11(4.5)	21(8.7)			8(3.3)	15(6.2)	2(0.8)
TAM + GnRH	3(1.2)	4(1.6)			0(0)	4(1.7)	1(0.4)
AI + TAM ± GnRH	1(0.4)	4(1.6)			0(0)	3(1.2)	1(0.4)
GnRH mono	1(0.4)	0(0)			0(0)	0(0)	0(0)
Metastasis			0.853	0.653	0.189	0.136	0.390
Lymph nodes and bone	49(20.2)	74(30.6)			31(12.8)	53(21.9)	14(5.8)
Viscus	49(20.2)	63(26.0)			22(9.1)	44(18.2)	17(7.0)
Brain	2(0.83)	5(2.1)			3(1.2)	4(1.7)	1(0.4)
Different lines of ET(n=86)			51.76	0.0001
0	80(93.0)	6(7.0)
1	42(17.3)	44(18.1)
2	70(28.9)	16(6.6)
3	77(31.8)	9(3.7)
4	80(33.0)	6(2.5)
5	85(35.1)	1(0.4)
6	84(34.7)	2(0.8)
7	84(34.7)	2(0.8)

Notes: Correlations between several diagnostic factors or adjuvant therapies and the occurrence of receptor changes were analyzed. Data was not fully (n = 270 = 100%) available for each factor but percentage according to n=242 = 100% is displayed in brackets (Twenty-eight patients were unable to determine whether hormonal receptor changes occurred because of the uncertain state of Her2 at metastasis sites, so exclude).

Abbreviations: T, primary tumor size; N, regional lymph node; M, distant metastasis, pT, pathological tumor; pN, pathological node; pM, pathological metastasis. ATM, Tamoxifen; AI, Aromatase inhibitor.

Table 5 Influence of Receptor Conversion on Overall Survival, Disease-Free Survival, Post-Recurrence Survival

		OS Median	DFS Median	PRS Median
ER	+to-	50(24.72–75.28)	40(3.44–76.57)	44(26.11–61.89)
	-to+	56(40.50–71.50)	58(10.53–105.47)	43(20.63–65.37)
	-	39(31.45–46.55)	29(26.17–31.83)	30(23.43–36.57)
	+	60(54.51–65.49)	72(50.24–93.76)	56(50.96–61.04)
PR	+to-	56(48.27–63.73)	56(20.55–91.45)	54(39.77–68.23)
	-to+	39(29.20–48.80)	27(0.00–72.56)	28(18.02–37.98)
	-	44(33.69–54.31)	29(25.72–32.28)	31(16.45–45.55)
	+	77(49.39–104.60)	73(54.09–91.90)	57(43.79–70.21)
HER2	+to-	62(36.34–87.66)	34(18.14–49.86)	40(28.56–51.44)
	-to+	33(12.60–53.40)	95(53.37–90.89)	92(52.34–87.88)
	-	56(48.52–63.48)	55(41.66–68.34)	38(25.04–50.96)
	+	43(24.21–61.79)	54(21.56–86.44)	55(28.16–81.84)

Figure 1 Overall survival. (A) +, ER persistent positivity; + to -, ER loss in expression; -, ER persistent negativity; - to +, ER gains in expression; (B) +, PR persistent positivity; + to -, PR loss in expression; -, PR persistent negativity; - to +, PR gains in expression; (C) Group1, HR⁺/HER2^−/+ to HR⁺/HER2^−/+; Group 2, HR⁺/HER2^−/+ to HR⁻/HER2^−/+; Group 3, HR⁻/HER2⁻to HR⁻/HER2⁻; Group 4, HR⁻/HER2^−/+ to HR⁺/HER2^−/+.

Table 6 Univariate and Multivariate Analysis Between Clinicopathological Characteristics and OS of Breast Cancer Patients

	Univariate Analysis		Multivariate Analysis
	HR (95% CI)	P-value	HR (95% CI)	P-value
Age
≤45	Reference	–	Reference	–
>45	1.52 (1.08–2.13)	0.0151	1.58(1.12–2.23)	0.0096
T stage (0/1/2/3/4)	1.38 (1.17–1.63)	<0.0005	1.21 (1.03–1.42)	0.0244
Axillary lymph node
Negative	Reference		Reference
Positive	1.06 (1.01–1.12)	0.017	–
Molecular subtype
HR+/HER2-	Reference	–	Reference
HR+/HER2+	1.38(0.89–2.15)	0.1483	–	–
HR−/HER2+	1.88(1.13–3.13)	0.0152	–	–
TNBC	3.29(2.04–5.28)	<0.0001	2.671(1.7–4.198)	<0.0001
Distant metastasis
No	Reference		Reference
Yes	4.71 (2.07–11.11)	<0.0005	6.16 (2.54–14.92)	<0.0001
Surgery
No	reference		reference
Yes	0.191 (0.083–0.44)	<0.0001	0.59 (0.50–0.69)	<0.0001
Chemotherapy
No	Reference		Reference
Yes	0.65 (0.42–1.02)	0.0622	–	–
Radiation			–	–
No	Reference		Reference	–
Yes	1.62 (1.13–2.33)	0.0089	1.66 (1.17–2.36)	0.0461
Endocrine therapy
No	Reference		Reference	–
Yes	0.59(0.43–0.83)	<0.0005	–	–
HR change
HR+/HER2−^/+to HR+/HER2−^/+	Reference	–	Reference	–
HR+/HER2−^/+ to HR-/HER2−^/+	1.75(1.01–3.03)	0.047	1.78(1.02–3.1)	0.0409
HR−/HER2− to HR−/HER2−	3.21(1.74–5.90)	0.0002	2.98(1.61–5.55)	0.0005
HR−/HER2−^/+ to HR+/HER2−^/+	2.79(1.62–4.83)	0.0002	2.48(1.41–4.37)	0.0016

Notes: +, Means receptor expression positive; −, Means receptor expression negative.

Abbreviations: HER2, human epidermal growth factor receptor 2; HR, hormone receptor.