Clinical Relevance of Targeting the Gastrin-Releasing Peptide Receptor, Somatostatin Receptor 2, or Chemokine C-X-C Motif Receptor 4 in Breast Cancer for Imaging and Therapy

Simone U. Dalm; Anieta M. Sieuwerts; Maxime P. Look; Marleen Melis; Carolien H.M. van Deurzen; John A. Foekens; Marion de Jong; John W.M. Martens

doi:10.2967/jnumed.115.160739

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FIGURE 1.
Study design. mRNA expression levels of GRPR, SSTR2, and CXCR4 of 915 primary breast cancer specimens (684 M0 LNN, 194 M0 LNP, 13 with unknown nodal status, and 24 M1) were analyzed using RT-qPCR. LNN and LNP M0 patient groups were used to study association of GRPR, SSTR2, and CXCR4 expression and clinicopathologic and biologic factors, with focus on M0 LNN patient group. Association of GRPR, SSTR2, and CXCR4 with prognostic factors was studied in M0 LNN patients. mRNA levels of ER-positive primary tumors of patients with recurrent breast cancer who received first-line tamoxifen treatment were used to study association of GRPR, SSTR2, and CXCR4 mRNA expression and PFS.
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FIGURE 2.
(A) In vitro autoradiography of human breast cancer specimens using ¹¹¹In-AMBA (GRP analog) and ¹¹¹In-DOTA-Tyr³-octreotate (SST analog) with and without block, demonstrating specific binding of radiotracers to receptor-positive tumor tissue. H69 (SSTR-positive, GRPR-negative) and PC3 xenografts (SSTR-negative, GRPR-positive) were used as controls. Tumor-containing areas are encircled in hematoxylin and eosin (H&E) stainings. As example, arrows indicate non–tumor-containing tissue in first H&E staining. (B) Significant correlation between GRPR and SSTR2 mRNA levels and quantification of in vitro autoradiography results analyzed in 13 breast cancer specimens with variable receptor expression, demonstrating that mRNA levels of receptors can be used as predictor for radiotracer binding. AD = added dose.
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FIGURE 3.
Distant MFS in 684 LNN patients as function of levels of CXCR4. CI = confidence interval; HR = hazard ratio.
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FIGURE 4.
Association of GRPR expression with PFS on first-line tamoxifen treatment. CI = confidence interval; HR = hazard ratio.

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TABLE 1

Associations of GRPR, SSTR2, and CXCR4 mRNA Levels in LNN M0 Patients

			GRPR mRNA (x10⁻²)		SSTR2 mRNA (x10⁻²)		CXCR4 mRNA (x10⁻²)
Characteristic	No. of patients^*	Percentage of patients	Median	Interquartile range	Median	Interquartile range	Median	Interquartile range
All patients in this cohort	684	100%	0.72	7.07	0.58	1.75	11.78	13.13
Age at surgery (y)
≤40	60	9%	1.17	12.72	0.90	2.99	14.06	13.75
41–55	252	37%	0.97	9.20	0.61	1.64	11.58	13.18
56–70	218	32%	0.52	5.38	0.52	1.68	12.19	11.34
>70	154	23%	0.72	4.44	0.62	1.61	9.99	12.98
P^†			0.52		0.68		0.0403
Menopausal status
Premenopausal	273	40%	1.26	10.95	0.62	1.82	11.81	13.73
Postmenopausal	411	60%	0.60	4.87	0.55	1.57	11.76	12.12
P^†			0.13		0.53		0.39
Surgery
Lumpectomy	378	55%	0.61	7.69	0.57	1.82	11.67	13.15
Ablation	306	45%	0.90	6.79	0.60	1.56	11.90	13.00
P^†			0.69		0.59		0.65
Pathologic tumor size
pT1	307	45%	1.25	8.54	0.69	1.87	12.03	13.40
pT2 + unknown	351	51%	0.41	5.25	0.51	1.65	11.53	12.84
pT3 + pT4	26	4%	0.58	3.05	0.50	1.38	12.19	13.53
P^†			0.0014		0.24		0.92
ESR1 mRNA status^‡
Negative < 0.2	184	27%	0.09	0.13	0.28	0.42	14.74	13.83
Positive ≥ 0.2	500	73%	2.46	10.98	0.81	2.59	10.98	12.16
P^‡			<0.001		<0.001		<0.001
PGR mRNA status^‡
Negative < 0.1	285	42%	0.12	0.32	0.32	0.56	14.36	14.31
Positive ≥ 0.1	399	58%	3.67	12.68	1.02	2.98	10.45	11.09
P^‡			< 0.001		<0.001		<0.001
ERBB2 mRNA status^‡
Negative < 18	574	84%	0.99	8.28	0.61	1.92	11.64	12.96
Positive ≥ 18	107	16%	0.30	1.51	0.49	1.00	13.88	13.32
P^¶			<0.001		0.0344		0.22
Grade (GGI)
1	227	33%	2.42	10.46	0.75	2.11	10.83	11.03
2	229	33%	0.89	6.92	0.63	2.41	11.44	14.59
3	224	33%	0.13	1.42	0.34	0.98	13.83	13.58
P^¶			<0.001		<0.001		<0.001
Percentage invasive tumor cells
≤70%	470	69%	0.81	6.84	0.63	1.88	12.57	13.92
>70%	214	31%	0.64	8.28	0.43	1.28	9.13	10.70
P^†			0.87		0.002		<0.001

↵* Because of missing numbers, not all categories add up to 684.
↵† P for Mann–Whitney U or Kruskal–Wallis test when appropriate.
↵‡ ESR1, PGR, and ERBB2 were determined by real-time PCR; cut points were as follows: ESR1 = 0.2, PGR = 0.1, and ERBB2 = 18.0 (mRNA level relative to reference gene set).
↵¶ P for Spearman rank-correlation test.