Case Report

Evidence of PSMA Uptake in Brain Metastases in a Patient with Breast Cancer Her2/Neu Positive

Medina-Ornelas SS1*, García-Pérez FO1, Paredes-Amoroto E2 and Medel-Gamez C3
1Departament of Nuclear Medicine and Molecular Imaging, Ciudad de México, México
2Departament of Nuclear Medicine, HNERM, Perú
3Departament of Nuclear Medicine, Ciudad de México, México


*Corresponding author: Medina-Ornelas SS, Department of Nuclear Medicine and Molecular Imaging, Ciudad de México, México


Published: 20 Oct, 2016
Cite this article as: Medina-Ornelas SS, García-Pérez FO, Paredes-Amoroto E, Medel-Gamez C. Evidence of PSMA Uptake in Brain Metastases in a Patient with Breast Cancer Her2/Neu Positive. Clin Oncol. 2016; 1: 1122.

Abstract

Breast cancer is one of the most common causes of brain metastases resulting in a poor survival. The blood-brain barrier is an obstacle to the delivery of chemotherapeutics to the brain; treatment includes whole brain irradiation, stereotactic radio surgery or neurosurgery with whole brain radiation.
The angiogenesis may be associated with metastasis independent of either invasion of normal tissue or intra vacation into normal blood or lymph node.
Prostate Specific Membrane Antigen (PSMA) expression is seen in the neovasculature of many types of tumors, such as prostate, renal, lung and recently breast cancer.
Positron Emission Tomography (PET) imaging with 68Ga-PSMA is very useful in the diagnosis of recurrent prostate cancer, mainly retrospective studies describe the value of 68Ga-PSMA ligand PET/CT in recurrent prostate cancer and most recently as the ragnostic agent, if required provide therapy with 177Lu-PSMA.
These case report suggest that PSMA expression in tumor associated neovasculature may be related to the degree and nature of neoangiogenesis. In addition the present case is the first evidence in which tumor viability is demonstrated in brain metastasis in patients live corroborated by PET-CT with 68Ga-PSMA.
Keywords: Breast cancer; Neoangiogenesis; Neovasculature; Intra vassation


Introduction

The breast cancer in Mexico is the first place in incidence with 20,444 and mortality of 5,680 per year [1].The HER2/neu (c-erbB2), located on chromosome 17q, which encodes a transmembrane protein of 185 kDa (p185), is part of the family of tyrosine kinase receptors including the epidermal growth factor receptor c-erbB11, this proto-oncogene present in 10%-30% of invasive breast carcinomas and serves as a biological target for trastuzumab therapy. Nevertheless, 15-30 % of patients with metastatic breast cancer HER2/neu positive will develop brain metastases. Treatment includes whole brain irradiation, stereotactic radio surgery or neurosurgery with whole brain radiation, resulting in a poor survival. The blood-brain barrier is an obstacle to the delivery of chemotherapeutics to the brain [2-4].
A potentially effective therapeutic strategy may derive from the finding that the transmembrane Prostate Specific Membrane Antigen (PSMA) expression is seen in the neovasculature of many types of tumors, such as prostate, renal, lung and recently breast cancer [5,6].
PSMA is heavily expressed by the tumor vascular endothelium in a variety of solid cancers, including prostate cancer, glioblastoma and primary adenocarcinoma of the breast, but is not evident in normal vascular endothelium and to only very low levels in normal prostate. Molecular imaging has become an indispensable tool in cancer research, clinical trials and medical practice. Imaging is attractive because most imaging techniques are either non- or minimally invasive, nondestructive, provide dynamic, real-time data and permit repeated measurements. Positron Emission Tomography (PET) imaging with 68Ga-PSMA is very useful in the diagnosis of recurrent prostate cancer, mainly retrospective studies describe the value of 68Ga-PSMA ligand PET/CT in different clinical scenarios in prostate cancer; however, there is insufficient evidence of the usefulness in breast cancer [7-8].
These case report suggest that PSMA expression in tumor associated neovasculature may be related to the degree and nature of neoangiogenesis. In addition the present case is the first evidence in which tumor viability is demonstrated in brain metastasis in patients live corroborated by PET-CT with 68Ga-PSMA.


Figure 1

Another alt text

Figure 1
(a) Mastectomy specimen. Showed a high grade ductal carcinoma with necrosis of 10%, and infiltration papillary dermis and nipple, lymphovascular and perineural permeation (Hematoxylin and Eosin stain, original magnification x200. (b) Nuclear staining of ER was negative. (c) Nuclear staining of PR was negative. (d) Membrane staining of HER-2/neu was positive. Ki-67 positive in 90%.

Case Presentation

A forty-five-year-old woman, having nodule in the right breast with 2 years of evolution. Biopsy was performed fine needle aspiration whose histopathologic report was fibro adenoma; the injury progresses after a year with increased size. Ultrasound and mammography was performed, where a radiopaque mass of high density is evident in Upper Outer Quadrant (UOQ) right breast, with the presence of pleomorphic calcifications grouped. Right axillary adenopathy suspicious looking Birads 5. Trucut biopsy was performed reporting infiltrating ductal carcinoma SBR9 (Figure 1a and b). She was undergoing to neoadjuvant chemotherapy, receiving 12 cycles of paclitaxel / trastuzumab (with previous ventriculography normal, up 60%), and then four cycles of colony stimulating factor plus trastuzumab scheme; and continues with trastuzumab each three cycles per week. Once completed chemotherapy she was underwent modified radical mastectomy more right pectoralis major impeller. Pathology report infiltrating ductal carcinoma with 75% of necrosis. The patient fails to radiation oncology, and loses track for 6 months for unknown reasons. She was return after 4 months with history of progressive headache, dizziness and respiratory symptoms treated out our institute high at the time of valuation refers moderate headache and dizziness that limit progress. For this reason, brain MRI was performed, evidence lesion supratentorial and intra-axial (Figure 2), concluded as known primary reservoir and central nervous system progression is established.
Holocraneal patient initiates radiotherapy 30Gy in 10 fractions plustemozolomide, and restart trastuzumab plus capecitabine. It documented disease progression despite treatment.
It was decided to perform PET-CT 68Ga-PSMA with reflected normal distribution without abnormal uptake in body, but increased uptake of radiotracer in brain, corresponding to brain metastases (Figure 3 and 4).


Figure 2

Another alt text

Figure 2
Brain MRI with contrast. Showed in the occipital region of the left side and ipsilateral wedge a ring enhancement after the intravenous contrast observing vasogenic edema which clears the parietal-occipital sulcus ipsilateral with maximum axis of 45 millimeters.

Figure 3

Another alt text

Figure 3
MIP of 68Ga-PSMA PET. Note the normal biodistribution of 68Ga- PSMA 1 h after injection. Accumulation is seen in salivary glands, nasal mucosa, liver, spleen, bowel, kidneys and bladder, and no focal abnormal uptake.

Discussion

The PSMA is a type II membrane glycoprotein consisting of 750 amino acids (100-120 kDa), with a 19 amino acid intracellular component, a 24 amino acid intramembrane segment, and a large 707 amino acid extracellular component. PSMA gene is located on chromosome 11, and exhibits folate hydrolase/glutamate carboxypeptidase II enzymatic activity [9,10].
Instead, PSMA regulates tumor cell invasion and tumor angiogenesis by modulating integrin signal transduction in endothelial cells. The transcription of PSMA can be selectively activated through a transcriptional enhancer region in endothelial cells of the tumor neovasculature, but this region is absent in normal blood vessels [11-13].
PSMA PET/CT imaging seems to be a valuable imaging modality for evaluation of primary prostate cancer and it seems to have potential for the detection of lymph node and bone metastases, meanwhile this demonstrated that other tumors have overexpression of this glycoprotein in vitro, and the PET technique can be demonstrated in vivo [7-9].
Chang et al. [14] were perhaps the first to demonstrate by immunohistochemistry the presence of PSMA in 5 of 6 cases of breast cancer, characterized by the monoclonal antibody 7E11 and those of four recently developed anti-PSMA mAbs (J591, J415, and Hybritech PEQ226.5 and PM2J004.5), each of which binds a distinct epitope of PSMA; this study confirm PSMA expression in the neovasculature of a wide spectrum of malignant neoplasms.; rather than a PSMA-like molecule, is expressed in tumor-associated neovasculature.
More over Liuet al. [15] studied four external domain-binding anti-PSMA mAbs (J591, J415, J533, and E99) and showed that each bound the tumor-associated neovasculature in several variety of carcinomas (including lung, colon, breast, and others).
Wernicke et al. [16] they have the largest study in patients with breast cancer. Ninety-two patients had primary breast cancer (invasive breast carcinoma with or without co-existing ductal carcinoma in situ (DCIS) or DCIS alone). In addition, 14 patients with breast cancer metastases to the brain. Tumor-associated vasculature was PSMApositive in 68/92 (74%) of primary breast cancers and in 14/14 (100%) of breast cancers metastatic to brain. PSMA was not detected in normal breast tissue or carcinoma cells.
Vascular Endothelial Growth Factor (VEGF) is one of several agents promoting angiogenesis. Some members of the VEGF family promote lymphogenesis as well. These newly formed blood and lymph vessels may be more susceptible to tumor cell invasion than normal vessels. A recent experimental model suggests that angiogenesis may be associated with metastasis independent of either invasion of normal tissue or intravasation into normal blood or lymph node.
These and other observations are remarkable given presence of PSMA expression in tumor-associated neovasculature of other cancer types [17].
Once tumor cells have infiltrated the brain, they require an adequate blood supply to grow and develop a metastatic lesion. The mechanisms that are involved in blood vessel recruitment by brain metastases cells appear to be strongly dependent on tumor origin as well as the metastatic microenvironment [18].
The importance of angiogenesis in breast cancer is well documented, and endothelial cell expression of PSMA appears highly restricted to tumor-associated neovasculature and may represent a novel target therapy with 177Lu-PSMA.
Further analyses are required to confirm our findings and to further evaluate the characteristics of different types of metastases in different hormonal status, where it is demonstrated by PET-CT 68Ga-PSMA tool, with the aim of administer therapeutic doses with 177Lu-PSMA.


Figure 4

Another alt text

Figure 4
(upper left) MIP of skull showed abnormal uptake in brain. (rest of pictures) encephalomalacia area front temporo-occipito parietal left and area poorly defined irregular administration of contrast enhancement in parietaloccipital region ipsilateral surrounded by edema in the white matter of the ipsilateral hemisphere diversion line middle right associated with increased concentration of radiopharmaceutical.

Conclusion

Understanding the molecular changes that breast tumor cells is crucial in obtaining novel targeting brain metastases therapeutics.68Ga- PSMA PET/CT is a recent modality of molecular imaging especially for the diagnosis of recurrence in treated prostate cancer patients, meanwhile the heterogeneity of breast cancer requires a thorough analysis to identify those potential patients to receive therapy with the 177Lu-PSMA may represent a promising approach. This case report further highlights to improve the value of PET-CT in this scenario.


Acknowledgements

We thank Dr. Enrique Estrada, for their support and interest in conducting this work, and Dr. Alexander España, pathologist for their support of images.


References

  1. Ferlay J, Soerjomataram I, Ervik M, et al. “GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 11 [Internet]”, Lyon, France: International Agency for Research on Cancer. 2013.
  2. Mamani-Cancino A, Veloz-Martínez M, Casasola-Busteros I, Christian Moctezuma-Meza, Juan Manuel García-Cebada. Frecuencia de sobrexpresión del factor Her-2/neu en pacientes con cáncer de mama. Ginecol Obstet Mex. 2014; 82: 369-376.
  3. Artufel M, Valero A, Lladó R, Sagalés NE , Llorca MC , Carazo AM, et al. Molecular protocol for HER2/neu analysis in breast carcinoma. Clin Transl Oncol. 2005; 7: 504-511.
  4. Tabouret E, Chinot O, Metellus P, Tallet A, Viens P, Gonçalves A. Recent trends in epidemiology of brain metastases: an overview. Anticancer Res. 2012; 32: 4655-4662.
  5. Demirci E, Ocak M, Kabasakal L, Decristoforo C, Talat Z, Halaç M, et al. (68)Ga-PSMA PET/CT imaging of metastatic clear cell renal cell carcinoma. Eur J Nucl Med Mol Imaging. 2014; 41: 1461-1462.
  6. Wernicke AG, Varma S, Greenwood EA, Christos PJ, Chao KS, Liu H, et al. Prostate-specific membrane antigen expression in tumor-associated vasculature of breast cancers. APMIS. 2014; 122: 482-489.
  7. Afshar-Oromieh A, Avtzi E, Giesel F, Holland-Letz T, Linhart HG, Eder M, et al. The diagnostic value of PET/CT imaging with the 68Ga-labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2015; 42: 197-209.
  8. Afshar-Oromieh A, Malcher A, Eder M, Eisenhut M, Linhart HG, Hadaschik BA, et al. PET imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions. Eur J Nucl Med Mol Imaging. 2013; 40: 486-495.
  9. Mease RC, Foss CA, Pomper MG. PET imaging in prostate cancer: Focus on prostate-specific membrane antigen. Curr Top Med Chem. 2013; 13: 951-962.
  10. Rinker-Schaeffer C, Hawkins A, Su S, Israeli RS, Griffin CA, Isaacs JT, et al. Localization and physical mapping of the prostate-specific membrane antigen (PSMA) gene to human chromosome 11. Genomics. 1995; 30: 105-108.
  11. Mhawech-Fauceglia P, Smiraglia DJ, Bshara W, Andrews C, Schwaller J, South S, et al. Prostate-specific membrane antigen expression is a potential prognostic marker in endometrial adenocarcinoma. Cancer Epid Biomark Prevention. 2008; 17: 571-577.
  12. KR Noss, SA Wolfe, SR Grimes, Upregulation of prostate specific membrane antigen/folate hydrolase transcription by an enhancer. Gene. 2002; 285: 247-256.
  13. Conway R, Petrovic N, Li Z, Heston W, Wu D, Shapiro LH, et al. Prostate-specific membrane antigen regulates angiogenesis by modulating integrin signal transduction. Mol Cell Biol. 2006; 26: 5310-5324.
  14. Chang S, Reuter V, Heston W, Bander NH, Grauer LS, Gaudin PB. Five Different Anti-Prostate-specific Membrane Antigen (PSMA) Antibodies Confirm PSMA Expression in Tumor-associated Neovasculature. Cancer Res. 1999; 59: 3192-3198.
  15. Liu H, Moy P, Kim S, Xia Y, Rajasekaran A, Navarro V, et al. Monoclonal antibodies to the extracellular domain of prostate-specific membrane antigen also react with tumor vascular endothelium. Cancer Res. 1997; 57: 3629-3634.
  16. Nomura N, Pastorino S, Jiang P, Lambert G, Crawford JR, Gymnopoulos M, et al. Prostate specific membrane antigen (PSMA) expression in primary gliomas and breast cancer brain metastases. Cancer Cell Int. 2014; 14-26.
  17. Haffner M, Kronberger I, Ross J, Sheehan CE, Zitt M, Mühlmann G, et al. Prostate-specific membrane antigen expression in the neovasculature of gastric and colorectal cancers. Hum Pathol. 2009; 40: 1754-1761.
  18. Kerbel R, Guerin E, Francia G, Xu P, Lee CR, Ebos JM, et al. Preclinical recapitulation of antiangiogenic drug clinical efficacies using models of early or late stage breast cancer metastatis. Breast. 2013; 22: 57-65.