Does focal heterogeneity affect survival in postoperative ipsilateral multifocal and multicentric breast cancers?

Dal, Fatih; Ökmen, Hasan; Ulusan, Kivilcim; Çolak, Şükrü; Havare, Semiha Battal; Trabulus, Fadime Didem Can; Ferlengez, Ekrem; Sari, Serkan

doi:10.1590/1806-9282.20211168

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Revista da Associação Médica Brasileira

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Original Article • Rev. Assoc. Med. Bras. 68 (3) • Mar 2022 • https://doi.org/10.1590/1806-9282.20211168 copy

Does focal heterogeneity affect survival in postoperative ipsilateral multifocal and multicentric breast cancers?

Authorship SCIMAGO INSTITUTIONS RANKINGS

SUMMARY

OBJECTIVE:

In multicentric/multifocal breast tumors, there may be immunological and histological differences between foci that may affect survival and treatment choice. We aimed to evaluate the effect of focal heterogeneity seen in multicentric/multifocal breast tumors on survival.

METHODS:

We retrospectively collected and analyzed the clinicopathological data of 89 female patients with multifocal/multicentric breast cancer, whose surgical and medical treatment was completed and who were followed up for 5 years.

RESULTS:

Of all patients, 29.2% (26/89) were heterogeneous. Heterogeneity of these foci was as follows: histologic heterogeneity of index foci (mix type): 15.7% (14/89), histologic heterogeneity of inter-foci: 7.9% (7/89), and immunohistochemical heterogeneity of inter-foci: 10.1% (9/89). When additional foci were evaluated, oncological therapy was changed for 3 (3.3%) of 89 patients. Heterogeneity does not have a significant (p>0.05) effect on recurrence and survival in multicentric/multifocal breast cancers. Pathological N stage is an independent risk factor for disease-free survival (hazard ratio=2.29, 95% confidence interval=1.39–3.76, p=0.001).

CONCLUSIONS:

In multifocal/multicentric breast cancers, less than 4% of patients may experience heterogeneity requiring change in the therapeutic decision. However, heterogeneity does not have a significant effect on recurrence and survival in multifocal/multicentric breast cancers. The pathological N stage is an independent risk factor for disease-free survival.

KEYWORDS:
Breas cancer; Multifocal; Multicentric; Tumor heterogeneity; Survival

		Clinicopathological data				Recurrence (-)			Recurrence (+)			p
		Min.–Max.	Median	Mean±SD/n-%		Mean±SD/n-%		Median	Mean±SD/n-%		Median	p
		28.0–79.0	48.0	50.4±12.5		50.0±12.5		48.0	53.8±12.9		55.5	0.498^m m Mann–Whitney U test/
Age	≤50			50	56.2%	39	57.4%		11	52.4%		0.688^m m Mann–Whitney U test/
Age	>50			39	43.8%	29	42.6%		10	47.6%		0.688^m m Mann–Whitney U test/
İndex focus T size (cm)		0.3–9.0	2.5	2.9±1.8		2.8±1.8		2.5	3.8±2.2		3.3	0.186^m m Mann–Whitney U test/
Surgery type	Breast conserving			17	19.1%	16	23.5%		1	4.8%		0.056^x2 x2 Chi-square test (Fischer's exact); T: tumor size, N: lymph node; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epithelial growth factor receptor-2; SİSH: Silver-enhanced in situ hybridization; Ki67: proliferation index. Bold indicates statistically significant values.
Surgery type	Mastectomy			72	80.9%	52	76.5%		20	95.2%
Histologic types of index foci	Ductal carcinoma			63	70.8%	51	75.0%		12	57.1%		0.194^x2 x2 Chi-square test (Fischer's exact); T: tumor size, N: lymph node; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epithelial growth factor receptor-2; SİSH: Silver-enhanced in situ hybridization; Ki67: proliferation index. Bold indicates statistically significant values.
	Lobular carcinoma			3	3.4%	2	2.9%		1	4.8%		0.558^x2 x2 Chi-square test (Fischer's exact); T: tumor size, N: lymph node; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epithelial growth factor receptor-2; SİSH: Silver-enhanced in situ hybridization; Ki67: proliferation index. Bold indicates statistically significant values.
	Mix types			14	15.7%	8	11.8%		6	28.6%		0.132^x2 x2 Chi-square test (Fischer's exact); T: tumor size, N: lymph node; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epithelial growth factor receptor-2; SİSH: Silver-enhanced in situ hybridization; Ki67: proliferation index. Bold indicates statistically significant values.
	Special types			9	10.1%	7	10.3%		2	9.5%		0.755^x2 x2 Chi-square test (Fischer's exact); T: tumor size, N: lymph node; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epithelial growth factor receptor-2; SİSH: Silver-enhanced in situ hybridization; Ki67: proliferation index. Bold indicates statistically significant values.
Pathological T category	pT1≤2 cm			29	32.6%	24	35.3%		5	23.8%		0.148^x2 x2 Chi-square test (Fischer's exact); T: tumor size, N: lymph node; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epithelial growth factor receptor-2; SİSH: Silver-enhanced in situ hybridization; Ki67: proliferation index. Bold indicates statistically significant values.
	2 cm<pT2≤5 cm			35	39.3%	28	41.2%		7	33.3%
	pT3			5	5.6%	4	5.9%		1	4.8%
	pT4			20	22.5%	12	17.6%		8	38.1%
Pathological N category	pN0			20	22.5%	20	29.4%		0	0.0%		0.003×2
	pN1			25	28.1%	19	27.9%		6	28.6%
	pN2			23	25.8%	18	26.5%		5	23.8%
	pN3			20	22.5%	10	14.7%		10	47.6%
	Missing			1	1.1%
Grade of index foci	I			5	5.6%	5	7.5%		0	0.0%		0.258^x2 x2 Chi-square test (Fischer's exact); T: tumor size, N: lymph node; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epithelial growth factor receptor-2; SİSH: Silver-enhanced in situ hybridization; Ki67: proliferation index. Bold indicates statistically significant values.
	II			58	65.2%	46	68.7%		12	60.0%
	III			24	27.0%	16	23.9%		8	40.0%
	Missing			2	2.2%
Number of foci	II			66	74.2%	52	76.5%		14	66.7%		0.540^x2 x2 Chi-square test (Fischer's exact); T: tumor size, N: lymph node; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epithelial growth factor receptor-2; SİSH: Silver-enhanced in situ hybridization; Ki67: proliferation index. Bold indicates statistically significant values.
	III			18	20.2%	12	17.6%		6	28.6%
	IV			4	4.5%	4	5.9%		0	0.0%
	V			1	1.1%	0	0.0%		1	4.8%
İndex focus ER status	≥1%			70	78.7%	55	80.9%		15	71.4%		0.355^x2 x2 Chi-square test (Fischer's exact); T: tumor size, N: lymph node; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epithelial growth factor receptor-2; SİSH: Silver-enhanced in situ hybridization; Ki67: proliferation index. Bold indicates statistically significant values.
İndex focus ER status	<1%			19	21.3%	13	19.1%		6	28.6%
İndex focus PR status	≥1%			65	73.0%	53	77.9%		12	57.1%		0.060^x2 x2 Chi-square test (Fischer's exact); T: tumor size, N: lymph node; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epithelial growth factor receptor-2; SİSH: Silver-enhanced in situ hybridization; Ki67: proliferation index. Bold indicates statistically significant values.
İndex focus PR status	<1%			24	27.0%	15	22.1%		9	42.9%
İndex focus HER2 (SİSH) status	Positive			22	24.7%	18	26.5%		4	19.0%		0.491^x2 x2 Chi-square test (Fischer's exact); T: tumor size, N: lymph node; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epithelial growth factor receptor-2; SİSH: Silver-enhanced in situ hybridization; Ki67: proliferation index. Bold indicates statistically significant values.
İndex focus HER2 (SİSH) status	Negative			67	75.3%	50	73.5%		17	81,0%
Index focus Ki67 status	≥ 20%			46	51.7%	33	48.5%		13	61.9%		0.284^x2 x2 Chi-square test (Fischer's exact); T: tumor size, N: lymph node; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epithelial growth factor receptor-2; SİSH: Silver-enhanced in situ hybridization; Ki67: proliferation index. Bold indicates statistically significant values.
Index focus Ki67 status	< 20%			43	48.3%	35	51.5%		8	38.1%
Lymphovascular invasion	Yes			55	61.8%	39	58.2%		16	76.2%		0.137^x2 x2 Chi-square test (Fischer's exact); T: tumor size, N: lymph node; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epithelial growth factor receptor-2; SİSH: Silver-enhanced in situ hybridization; Ki67: proliferation index. Bold indicates statistically significant values.
	No			33	37.1%	28	41.8%		5	23.8%
	Missing			1	1.1%
Perineural invasion	Yes			18	20.2%	14	21.9%		4	20.0%		0.252^x2 x2 Chi-square test (Fischer's exact); T: tumor size, N: lymph node; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epithelial growth factor receptor-2; SİSH: Silver-enhanced in situ hybridization; Ki67: proliferation index. Bold indicates statistically significant values.
	No			66	74.2%	50	78.1%		16	80.0%
	Missing			5	5.6%
Perinodal invasion	Yes			39	43.8%	27	40.3%		12	57.1%		0.1752
	No			49	55.1%	40	%59.7%		9	42.9%		0.1752
	Missing			1	1.1%
Histologic heterogeneity of index foci	Homogeneity			75	84.4%	59	86.8%		15	71.4%		0.101^x2 x2 Chi-square test (Fischer's exact); T: tumor size, N: lymph node; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epithelial growth factor receptor-2; SİSH: Silver-enhanced in situ hybridization; Ki67: proliferation index. Bold indicates statistically significant values.
Histologic heterogeneity of index foci	Heterogeneity			14	15.7%	8	11.8%		6	28.6%
Histologic heterogeneity inter-foci	Homogeneity			82	92.1%	63	92.6%		19	90.5%		0.888^x2 x2 Chi-square test (Fischer's exact); T: tumor size, N: lymph node; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epithelial growth factor receptor-2; SİSH: Silver-enhanced in situ hybridization; Ki67: proliferation index. Bold indicates statistically significant values.
Histologic heterogeneity inter-foci	Heterogeneity			7	7.9%	5	7.4%		2	9.5%
Immunohistochemical heterogeneity inter-foci	Homogeneity			80	89.9%	60	88.2%		20	95.2%		0.352^x2 x2 Chi-square test (Fischer's exact); T: tumor size, N: lymph node; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epithelial growth factor receptor-2; SİSH: Silver-enhanced in situ hybridization; Ki67: proliferation index. Bold indicates statistically significant values.
Immunohistochemical heterogeneity inter-foci	Heterogeneity			9	10.1%	8	11.8%		1	4.8%
Follow-up time						84.9±20.6		89.0	45.0±27.7		38.0	0.106^m m Mann–Whitney U test/
Disease-related mortality	No					68	100%		13	61.9%		0.000^x2 x2 Chi-square test (Fischer's exact); T: tumor size, N: lymph node; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epithelial growth factor receptor-2; SİSH: Silver-enhanced in situ hybridization; Ki67: proliferation index. Bold indicates statistically significant values.
Disease-related mortality	Yes					0	0.0%		8	38.1%
Recurrence	No			68	76.6%
Recurrence	Yes			21	23.6%
Recurrence location	Local			4	4.5%
	Visceral			5	5.6%
	Bone			11	12.4%
	Bone+visceral			1	1.1%

Patient	Number of foci	Size (cm)	Grade of index foci	Histology of intra- index and inter-foci	Histology of inter foci	Immunohistology of inter-foci (St. Galen)	Those whose medical treatment changed
1	2	1.2/0.3	2	D-MP/D-MP	D-MP/D-MP	LuA/LuA	−
2	2	1.9/1.6	3	L-T/L-T	L-T/L-T	LuA/LuA	−
3	2	2.3/2	3	D-MP/D-MP	D-MP/D-MP	LuB/LuB	−
4	2	2.5/1.5	2	M-D/M-D	M-D/M-D	LuB/LuB	−
5	2	3.5/0.2	2	D-M/D-M	D-M/D-M	LuB/LuB	−
6	2	4/2.5	2	D-MP/D-MP	D-MP/D-MP	LuB/LuB	−
7	2	5/0.2	2	N-D/N-D	N-D/N-D	LuB/LuB	−
8	2	2.5/0.3	2	D-MP/D-MP	D-MP/D-MP	HER/HER	−
9	2	5.5/1	2	D-MP/D-MP	D-MP/D-MP	HER/HER	−
10	2	6/0.9	3	M-MP/M-MP	M-MP/M-MP	HER/HER	−
11	3	6/4/1	2	D-L/D-L/D	D-L/D-L/D	LuA/LuA/LuA	−
12	3	3.5/1.9/1.4	3	D-MP/D-MP/D-MP	D-MP/D-MP/D-MP	LuB/LuB/LuB	−
13	2	0.9/0.6	1	C/T	C/T	LuA/LuA	−
14	2	1/0.6	2	D/T	D/T	LuA/LuA	−
15	2	2/0.2	2	C/L	C/L	LuA/LuA	−
16	2	2/1.8	3	D/D-L	D/D-L	Tn/Tn	−
17	3	2.8/2/0.2	2	D/L/L	D/L/L	LuA/LuA/LuA	−
18	2	1.5/1.2	2	D/D	D/D	LuB/LuA	−
19	2	1.8/1.5	2	D-P/D-P	D-P/D-P	LuB/LuA	−
20	2	2.5/2.5	2	D-L/D-L	D-L/D-L	LuB/LuA	−
21	2	4/3	2	D/D	D/D	LuB/LuA	−
22	3	2.4/1.8/1.5	2	D/D/D	D/D/D	LuB/LuB/LuA	−
23	3	2.6/1.1/0.3	2	D/D/D	D/D/D	LuB/LuA/LuA	−
24	2	2.5/2.1	3	D/D	D/D	LuA/LuB	+
25	2	3/1.6	2	D/D	D/D	LuA/LuB	+
26	2	1/1	3	D/D	D/D	Tn/LuB	+

Survival		Disease-free survival						Overall survival
Survival		Univariate model			Multivariate model			Univariate model			Multivariate model
Disease-free survival		HR	95%CI	p	HR	95%CI	p	HR	95%CI	p	HR	95%CI	p
Age (≤50/>50)		0.99	0.96–1.03	0.628				1.02	0.969–1.08	0.411
Index focus size (cm)		1.13	0.93–1.37	0.230				1.22	0.912–1.64	0.178
Surgery type (breast conserving/mastectomy)		4.38	0.59–32.70	0.149				28.28	0.016–>100	0.383
Histological types of index foci		1.24	0.87–1.79	0.239				1.52	0.891–2.59	0.125
	Pathological T stage	1.58	1.07–2.33	0.021				1.82	0.987–3.34	0.055
	Pathological N stage	2.29	1.39–3.76	0.001	2.29	1.39–3.76	0.001	5.82	1.580–21.43	0.008
Grade of index foci		2.32	1.01–5.32	0.048				1.85	0.500–6.85	0.356
Number of foci		1.52	0.76–3.02	0.236				11.19	0.408–3.47	0.750
Index focus ER status (ER≥1%/ER<1%)		1.64	0.64–4.23	0.306				2.41	0.575–10.09	0.229
Index focus PR status (PR≥1%/PR<1%)		2.71	1.14–6.45	0.024				2.81	0.701–11.24	0.145
Index focus HER-2 (SİSH) status (+/−)		1.15	0.39–3.41	0.805				2.21	0.272–17.98	0.458
Index focus Ki67 status (≥20%/<20%)		0.52	0.21–1.15	0.145				0.61	0.146–2.55	0.499
Lymphovascular invasion (yes/no)		0.46	0.17–1.27	0.133				0.21	0.025–1.70	0.143
Perineural invasion (yes/no)		1.36	0.45–4.07	0.586				1.85	2.223–15.46	0.568
Perinodal invasion (yes/no)		0.67	0.28–1.58	0.356				0.24	0.049–1.21	0.084
Histologic heterogeneity of index foci (homogeneity/heterogeneity)		1.90	0.73–4.89	0.186				3.47	0.823–14.60	0.090
Histologic heterogeneity of inter-foci (homogeneity/heterogeneity)		1.10	0.26–4.74	0.895				1.71	0.210–13.93	0.616
Immunohistochemical heterogeneity of inter-foci (homogeneity/heterogeneity)		0.32	0.04–2.39	0.267				0.04	0.000–984.83	0.537

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[1] *Corresponding author: fatihdal07@gmail.com