Somatostatin Radioligand Therapy of Breast Cancer: A Target of Opportunity

See also the article by Ulaner et al in this issue.

Dr Frank Lin is board-certified in medical oncology and nuclear medicine. He is head of the Targeted Radionuclide Therapy Section of the Molecular Imaging Branch at the National Cancer Institute (NCI). Dr Lin leads several preclinical and clinical investigations of radionuclide therapy agents. He is particularly interested in the clinical translation of alpha particle and Auger electron–emitting radionuclides as targeted therapy for cancer.

Dr Peter Choyke is the chief of the Molecular Imaging Branch at NCI. His work has focused on the diagnosis and image-guided treatment of cancer, with a special interest in malignancies of the genitourinary tract. Dr Choyke is currently developing radiopharmaceutical agents that target tumors and their immune microenvironment for diagnosis and treatment.

Tumor heterogeneity is a key feature of malignancy, explaining its resistance to therapy and its proclivity to recur. Immunohistochemistry of most solid cancers reflects this heterogeneity at a microscopic level, resulting in a patchwork of competing cellular phenotypes with differing molecular expression patterns. Breast cancer is an excellent example of tumor heterogeneity, which is reflected in its naming convention. Estrogen receptor (ER)– and progesterone receptor (PR)–positive cells are denoted as ER-positive and PR-positive breast cancers, whereas human epidermal growth factor receptor 2 (HER2)–expressing cells are denoted as HER2-positive. All variants are possible, and especially feared is triple-negative breast cancer, which expresses none of these receptors and is denoted as ER-, PR-, and HER2-negative. However, this nomenclature just begins to describe the diversity of receptors in breast cancer cells, each of which is a potential target for therapy. ER-positive breast cancers also tend to coexpress somatostatin receptor 2 (SSTR2) (1). Because SSTR2 radioligand therapy is already established for SSTR2-positive neuroendocrine cancer, it is logical to investigate the potential of SSTR2-directed radioligand therapy to treat selected cases of breast cancer.

In this issue of Radiology, Ulaner et al (2) describe the prevalence of SSTR2-positive tissue in ER-positive breast cancer with use of tissue arrays and immunohistochemistry. They found that 51% of ER-positive breast cancers coexpressed SSTR2. However, positivity at immunohistochemistry does not necessarily confer responsiveness to receptor-targeted therapy. This is because the target must be expressed on the cell surface, present in sufficient abundance at the molecular level, and accessible to exogenously administered drugs; immunohistochemistry cannot reliably predict these critical factors. Experience with breast cancer has shown that ER-positive, PR-positive tumors are generally responsive to hormonal therapies, and HER2-positive tumors are responsive to anti-HER2 therapies such as trastuzumab. Would ER-positive, SSTR2-positive tumors also be responsive to SSTR2-directed radioligand therapy? To address this, Ulaner et al (2) conducted a study of gallium 68 (⁶⁸Ga) or copper 64 (⁶⁴Cu) tetraazacyclododecane tetraacetic acid octreotate (Dotatate) PET examinations in participants with metastatic ER-positive breast cancer, using fluorine 18 fluorodeoxyglucose PET/CT imaging for comparison. These agents are diagnostic and bind to either SSTR2 receptors or glucose transporters. In the 30 participants who underwent scanning with ⁶⁸Ga- or ⁶⁴Cu-Dotatate, 30% of participants had lesions that met the criteria of Krenning 3 (tumor uptake greater than liver activity) or Krenning 4 (tumor uptake greater than splenic activity), indicating uptake potentially sufficient for targeted radioligand therapy (3).

One of the participants with an ER-positive, SSTR2-positive tumor was subsequently administered actinium 225 (²²⁵Ac) Dotatate therapy. This participant had undergone multiple previous treatments for breast cancer, but it had recurred at multiple sites, including pleural disease with effusions. It is unclear why ²²⁵Ac-Dotatate was selected over the more widely available and U.S. Food and Drug Administration (FDA)–approved lutetium 177 (¹⁷⁷Lu) Dotatate. It may be relevant that the study was in part supported by a company that is currently developing the agent. Nonetheless, after undergoing two cycles of treatment with ²²⁵Ac-Dotatate, the participant responded well, with a near-complete response that included symptomatic improvement of dyspnea. However, the participant later experienced recurrence with ascites that proved to be SSTR2-negative, which indicated that the treatment may have eliminated most, if not all, of the SSTR2-positive clones, but SSTR2-negative clones had emerged.

Although there are obvious limitations to reports consisting of one patient, known as n = 1 studies, the case is instructive in several ways. First, it draws attention to the expression of SSTR2 in breast cancer, especially in ER-positive tumors. Only 18% of ER-negative tumors expressed SSTR2. Second, it demonstrates that SSTR2-targeted imaging can help guide decisions to use SSTR2 radioligand therapy, and, finally, it shows that α-based ²²⁵Ac-Dotatate, although not yet approved by the FDA, has potential for dramatic responses in at least some selected patients. Of course, n = 1 studies are designed to be provocative, and the results will hopefully encourage clinician-scientists who treat metastatic breast cancer to consider studying SSTR2-targeted therapies in prospective clinical trials.

These data appear at an opportune time. The NETTER (Neuroendocrine Tumors Therapy) trial documented the value of ¹⁷⁷Lu-Dotatate (and its derivative agents) in treating grade 1 and 2 neuroendocrine tumors (4). Carrasquillo et al (5) also applied ¹⁷⁷Lu-Dotatate to metastatic pheochromocytomas. The treatment is effective in staving off progression and in prolonging life, with relatively modest adverse effects. However, the revolution in radioligand therapy began with the FDA’s approval, in 2022, of ¹⁷⁷Lu prostate-specific membrane antigen (PSMA) 617 (Pluvicto; Novartis) in patients with metastatic prostate cancer expressing PSMA. Metastatic prostate cancer is more common than neuroendocrine cancer, with expected remunerative benefits for industry. Medical oncologists have embraced ¹⁷⁷Lu-PSMA to reduce the symptoms of metastatic prostate cancer, particularly skeletal-related events, as well as prolong survival, again with only modest adverse effects (6). These changes in diagnosis of prostate cancer and in its treatment have resulted in a flood of interest in other targets for other tumors, as well as other β and α emitters. Indeed, it has stimulated an entire supply chain of manufacturers to produce therapeutic radioisotopes. Pharmaceutical companies that until recently did not have a single radioligand therapy project in their portfolio are now aggressively pursuing products in this field.

Part of the allure of radioligand therapy is that it appears to yield meaningful responses with relatively few adverse effects. Like any therapy, radioligand therapy can have severe adverse effects if administered at high enough doses. Currently, the field is using a one-dose-fits-all model. In an era where precision medicine is the byword, this seems to be anachronistic. However, adjusting doses is complicated, not only on the part of suppliers, who would have to customize doses for each patient, but also on the part of the treating physician, who would have to perform dosimetry studies to calculate the proper dose. There are some data to suggest that dosimetry-based approaches can improve clinical outcomes over a fixed-dose approach in localized radioligand therapy, such as yttrium 90 microspheres (7). However, to our knowledge, no good prospective studies have demonstrated the same benefit in systemically administered radioligands, which makes adoption of the dosimetry-based approach difficult in this setting. Whereas α-based therapy seems to be an obvious next direction because it is many times more potent that β therapies, clinical experience with α therapy in prostate cancer has emphasized the need for caution.

In the case of ²²⁵Ac-PSMA therapy, severe xerostomia resulted from ablation of the salivary glands due to α irradiation (8). In the case of SSTR2-Dotatate, which is taken up normally in the adrenal glands, pituitary gland, kidney, and thyroid, adverse effects might be expected from damage to these organs with α therapy, especially if the targeted tumor was not particularly avid for the agent. Thus, it is important to be cautious about how and when to use α radioligand therapy as an adjuvant.

The biggest limitation of this study is that although it points to an opportunity, it does not address the potential challenges of this treatment. More than 160 000 women in the United States alone currently have metastatic breast cancer, and 80% are ER-positive (9). If 30% of these patients’ cancers express SSTR2 sufficient for SSTR2-based radioligand therapy, then this report could be transformational for many women with metastatic breast cancer. However, these potential benefits must be weighed against the potential adverse effects and survival benefits. Hopefully, this study will draw the attention of physicians specializing in the treatment of breast cancer and make them aware of the potential of SSTR2-directed therapy. Perhaps ⁶⁸Ga- or ⁶⁴Cu-Dotatate imaging will become routine in patients with ER-positive breast cancers, and positive cases could be followed by α or β (or both) radioligand therapy as an adjunct to other standard-of-care treatments available for metastatic breast cancer. It is enticing to think that other radioligands targeting receptors other than SSTR2 might also be used to treat metastatic breast cancer (10). A lot of work remains to be done.

Therefore, the study by Ulaner et al (2) is just the first step. Confirming the effectiveness of this therapy will require hard work to document treatment efficacy and outcomes prospectively in trials with adequate control groups and extensive documentation of adverse events so that a true risk-benefit analysis can take place. Until then, the study is an important reminder of the opportunities that the burgeoning field of radioligand therapy is making possible.