Treating Bone Metastases with Local Therapy in a Breast Cancer Patient Resulted in Decreased Pain and Prevented Fracture

Abstract

Lytic lesions from bone metastases from breast, lung and prostate carcinomas, are associated with a poor prognosis and significant morbidities that include fracture and debilitating pain. Chemotherapeutics, palliative radiation therapy and surgical intervention are routinely used to treat these lesions. The ZetaMet™ Bone Graft is a novel antitumorigenic and osteoinductive graft that offers a potential alternative treatment option. ZetaMet is composed of calcium phosphate salts, type-I collagen and the small molecule N-allyl noroxymorphone dihydrate. Here, we report the case of a stage IV breast cancer patient with multiple lytic metastatic lesions to the spine that were successfully treated, which led to a significant reduction in pain and increased quality of life. This outcome demonstrates that a locally administered therapeutic intervention may represent an important alternative for patients with bone metastases that warrants further study.

Plain language summary

What questions did we seek to answer?

Pain from bone cancer is debilitating, uncurable and often treated with opioid drugs that reduce a person’s quality of life. A recently discovered drug might help patients by preventing bone pain by making new bone while stopping bone destruction caused by the tumor. A patient with stage IV breast cancer, who was in immense pain and could no longer be active, underwent treatment. She had widely distributed metastases from the breast cancer in her liver, lungs, brain and bones. The tumors had traveled to her spine causing immense pain, and she requested treatment with the experimental drug/device ZetaMet™. Via special permission from the US FDA, the patient received the experimental treatment, which has not been approved for use. After FDA approval for the experimental use of ZetaMet, tumors in three bones of the patient’s spine were treated.

What were the results?

2 years after treatments with ZetaMet for the tumors located in three different spinal bones, the patient is alive, and her pain has become manageable, leading to quality-of-life improvements and resumption of many routine daily activities, such as walking and spending time with family, despite the typical prognosis for this type of cancer (survival <6 months). Further, the treatment led the patient to electively reduce pain medication use by over fourfold, which decreases the serious risks and many complications posed by overuse.

What do the results suggest?

The experimental treatment, ZetaMet, has a great deal of promise in treating very sick patients with breast cancer that has spread to bone, improving quality of life and reducing pain medication.

Keywords::

• breast cancer
• lytic tumor
• spinal metastasis

Practice points

• Breast cancer preferentially metastasizes to bone, particularly the spine.

• Debilitating pain and fracture result from bone metastases.

• A patient with ER+/PR-/HER2- breast cancer metastases in the spine was treated via the Expanded Access/Compassionate Use program approved by the US FDA.

• Initially, the T7 and L1 vertebral bodies were treated.

• 1 month later, the patient returned with a bone metastases in the S1 vertebral body.

• A novel bone graft material that releases a small molecule was implanted directly into the tumor lesion using a minimally invasive percutaneous procedure.

• After 22 months, there was no evidence of tumor in the T7 and L1 lesions.

• After 19 months, there was no evidence of tumor in the S1 vertebral bone and the defect had completely healed.

• Importantly, the patient has not experienced a fracture, pain decreased substantially and the patient’s quality of life increased.

In the USA, the all-cancer incidence of bone metastases is approximately 280,000 patients per year [1]. Bone is the third most common site for metastases, and bone metastases are associated with poor prognosis and significant morbidities that include pain and pathologic fracture [2]. Breast, lung and prostate carcinomas are among the most prevalent cancers that metastasize to bone, amounting to approximately 70% of bone metastases in these patients [3–5]. Cancers that metastasize to bone produce a defect in the bone due the destructive nature of the cancer cells, which weaken the bone and increase the risk of fracture through lytic processes mediated by the tumor cells [6]. Bone metastases are also a major cause for morbidity in patients with advanced stage cancer [7].

Lytic lesions that occur when a tumor metastasizes to bone, can also cause severe, debilitating pain [8,9]. These lesions are routinely treated with chemotherapeutics, palliative radiation therapy and surgical intervention [5]. Patients with lytic lesions often experience a reduced quality of life with multiple skeletal-related events (SREs), which includes clinical outcomes such as fractures, spinal cord compression, elevated levels of calcium in the blood (i.e., hypercalcemia) and bone pain [10].

Estrogen receptor (ER) and progesterone receptor (PR) expression in breast cancer tumor cells (i.e., hormone receptor status) is highly correlated with survival [11,12]. The patient in this study was ER+/PR-. Patients with ER+/PR+ breast cancer comprise 62.9% of the affected population, whereas 13.9% are ER+/PR- [13]. The loss of either ER or PR status results in significantly worse prognosis for patients [11,12,14,15]. HER2 is a tyrosine kinase receptor that dimerizes with other EGFRs that mediate cell proliferation [16]. The patient in this case report had a tumor identified as ER+/PR-/HER2-. Patients who are PR-/HER2- have tumors that are more aggressive, do not respond to tamoxifen, and have survival and relapse rates similar to patients with triple-negative breast cancers [17,18].

Here we share a case report of a patient with three metastatic breast cancer lesions to the spine. The patient was treated with an experimental, novel implant, the ZetaMet™ Bone Graft, via the Expanded Access/Compassionate Use program, with approval granted by the US FDA. ZetaMet is a novel graft material composed of calcium phosphate salts with type-I collagen, in which the small molecule N-allyl noroxymorphone dihydrate has been incorporated. The calcium phosphate/type-I collagen carrier promotes new bone formation, while the small molecule prevents tumor-mediated bone destruction and concurrently stimulates stem cells to become bone cells [19]. Bone destruction by the tumor produces pain, and ZetaMet’s inhibition of bone destruction and promotion of bone formation are the means through which pain is inhibited [9]. The implant was delivered percutaneously in two procedures using a minimally invasive approach into the bony lesion via the pedicles on the dorsal aspect of the vertebral bone. The treatment reduced debilitating pain, reduced the dose of opioids administered 4.2-fold, prevented fractures and assisted in the patient’s return to an active daily lifestyle. Importantly, no active tumor was identified through imaging in the treated lesions. This case report demonstrates that ZetaMet provided significant local tumor control, prevented vertebral fracture, reduced pain and opioid use, and allowed the patient to return to an active daily lifestyle. To our knowledge, this is the first synthetic bone graft that is both antitumorigenic and osteoinductive.

Results

Case presentation

A 56 year-old female patient with stage IV metastatic breast cancer ER+/PR-/HER2- presented with multiple lytic metastatic lesions in T7 and L1. In 2012, following the initial diagnosis of invasive breast carcinoma of the left breast – that was found to be ER+/PR-/HER2- and BRCA1+ – she underwent bilateral mastectomy followed by conventional chemotherapy. Treatment included 5 mg/day of exemestane and 7.5 mg/day of everolimus with no improvement. She was followed by her oncologist until 2017, at which point she was considered in remission. In December 2020, the patient was involved in a car accident that resulted in low back and neck pain with headaches. In February 2021, after the car accident, MRI showed metastatic lesions at T7 and L1. In addition, these imaging studies showed that the patient had disseminated metastatic disease, with lesions in her liver, lungs and brain. She was treated with chemotherapy, and the bone metastases were treated with localized X-radiation therapy. X-radiation therapy and chemotherapy failed to treat the patient’s pain.

The patient continued to experience debilitating back pain despite being treated with external beam X-radiation therapy, and her continued pain was treated with 250 mg/day of morphine and 30 mg of oxycodone on an as-needed basis. 7 months after the bone metastases were discovered, the patient had limited mobility due to the pain and the opioid analgesia. As a result, she spent most of her day in bed, which limited her ability to ambulate, as well as her ability to perform normal daily activities. The patient requested consideration for Expanded Access treatment to treat the painful metastatic lesions in her T7 and L1 vertebral bones. An Expanded Access application via the Compassionate Use program was submitted to the FDA, which was granted on 9 September 2021 (#U210381/S001).

Approximately 1 month after the first procedure and during the follow-up period, the patient complained of additional back pain, which led to the discovery of three new metastatic lesions, via an MRI and PET imaging study, in T1 and T2, as well as the right sacrum. The T1 and T2 lesions were not painful and were not surgically accessible, and as such, they could not be treated. The third lesion in the right sacrum, however, was the source of the patient’s pain, and this lesion was surgically accessible. A second Expanded Access application was submitted to the FDA, which was granted Compassionate Use on 22 October 2021 (#U210381/S002). Unlike the T7 and L1 lesions, the lesion in the right sacrum was not treated with X-radiation prior to the surgical administration of ZetaMet. The surgical interventions at T7 and L1 (e.g., the first procedure) were performed on 10 September 2021, and the intervention at the sacrum was performed on 10 December 2021 (e.g., the second procedure), respectively.

The percutaneous implantation procedure

On 10 September 2021, the patient underwent percutaneous implantation of the graft material under fluoroscopic guidance to treat the T7 and L1 lesions (e.g., the first procedure). Briefly, one of the vertebral bone pedicles was identified with palpation, a sterile field was created, and a small incision (e.g., ≤1 cm) was made over the pedicle. A Jamshidi bone biopsy needle was placed on the pedicle and was used to carefully drill into the vertebral body using a twisting motion. The needle component of the Jamshidi was removed leaving a hollow metal canula that could hold approximately 1 cc of graft material. ZetaMet was then inserted into the canula using a 10 ml syringe and then carefully pushed into the defect using a metal plunger. This process was repeated until approximately 3 cc of material was inserted into the defects. The patient was under local anesthetic and tolerated the procedure well. On 10 December 2021, the patient underwent a similar percutaneous procedure (e.g., the second procedure); however, for this procedure, the patient was administered general anesthesia. The patient was given the short-form 12 (SF12) and the numeric rating again at 3 months, 9 months and 1 year after the first procedure. The patient’s opioid analgesic use was also monitored during the postoperative period. Imaging studies were conducted using computed tomography (CT), MRI and PET.

Postoperative follow-up

The patient reported a significant reduction in pain 1 month after the first procedure based on a 50% reduction in the numerical rating scale (NRS) scale score (4/10 at 1 month and 8/10 before the procedure). The patient also reported a reduction in her use of opioid pain medication from 250 mg daily down to 60 mg, which is a 4.2-fold decrease. The patient did not accurately report as-needed oxycodone use, and it was assumed to have remained unchanged. CT and MRI imaging demonstrated a resolution of the T7 and L1 lesions (Figure 1) when compared with the preoperative CT image. Subsequent CT and MRI images taken 12 months after the first procedure show that there was no recurrence and or active tumor.

Figure 1. CT, MRI and PET imaging studies of T7 and L1.

(A) CT image, without contrast, showing bone defects (blue arrows) caused by the metastatic breast tumor. Lysis due to bone destruction and loss is black while sclerotic bone due to pathologic bone formation is white. (B) T2 short tau inversion recovery (STIR) MRI image showing the lytic bone defects (blue arrows) due to the tumor. (C) PET/CT image showing the presence of tumor in the vertebral bodies (red-yellow color; blue arrows). (D) CT image, without contrast, 12 months after treatment. Radio dense bone (yellow arrows) is shown in the space treated using ZetaMet™. (E) T2 STIR MRI image of the treated defects (yellow arrows). Images show that the tumor was replaced with radio dense bone. (F) PET/CT image showing that there is no signal due to tumor in the treated defects (yellow arrows).

CT: Computed tomography.

At the 1 month postoperative follow-up, the patient complained of new lower back pain that she experienced when sitting, which was found to be the result of a metastatic lesion in the right sacrum. Metastatic lesions were also discovered in T1 and T2 that were nonpainful and not surgically accessible. The patient wished to forgo X-radiation therapy for the lesion in the right sacrum and requested treatment using ZetaMet via percutaneous implantation under fluoroscopic guidance as an alternative. At the 1-year follow-up for the first procedure (i.e., 9 months after the second procedure in the sacrum), the patient reported complete pain resolution via the NRS, while CT and PET imaging showed complete resolution of the lesion in the right sacrum. Furthermore, there was no activity observed on an MRI image 9 months after the second procedure (Figure 2). At 12 months after the first procedure (i.e., 9 months after the second procedure), the patient had reduced her morphine use from 250 to 60 mg, which is a 4.2-fold decrease in chronic opioid use.

Figure 2. CT and MRI imaging study of the right sacrum.

(A) CT imaging showing the defect created by the tumor (blue arrows). The scalloped appearance of bone is associated with bone lysis/destruction adjacent to regions of sclerotic bone. (B) T2 STIR MRI image with gadolinium contrast showing the tumor located in the sacrum defect (blue arrow and dashed line). (C) CT image showing the resolution of the defect (yellow arrow). (D) T2 STIR MRI with gadolinium contrast showing that there is no tumor in the treated defect (yellow arrow). STIR: Short tau inversion recovery.

CT: Computed tomography.

Currently, 22 months after the first procedure and 19 months following the second procedure, the patient is doing well, and there have been no fractures, no signs of local metastatic tumor recurrence, and the appearance of significant healing via new bone formation in the right sacrum and the L1 vertebral body. Further, the patient has not experienced any adverse events through the posttreatment period.

Methods

Written, informed consent was obtained from the patient for this Expanded Access/Compassionate Use therapeutic intervention, which included consent to publish the results. The patient history and the MRI, CT and PET imaging data were acquired from the electronic medical record. The ZetaMet Bone Graft samples (N = 2 implants per procedure; 10 cc/implant; total of N = 4 implants) were provided as a kit, which was re-constituted from a supplied powder and diluent immediately prior to the procedure. ZetaMet is a novel graft material composed of calcium phosphate salts with type-I collagen, in which the small molecule N-allyl noroxymorphone dihydrate – C₁₉H₂₁NO₄ · HCl · 2H₂O (Mallinckrodt Pharmaceuticals, Staines-upon-Thames, UK; CAS# 51481-60-8) – has been added.

Discussion

Three metastatic breast cancer lesions were treated in a patient with recurrent stage IV ER+/PR-/HER2- breast cancer with disseminated metastatic disease. We employed a novel investigational implant, the ZetaMet Bone Graft, to locally treat these tumors. In lesions at T7 and L1, the intervention ceased tumor activity and progression, which was confirmed via imaging through 22 months. In the right sacrum lesion, the therapeutic intervention resolved the tumor lesion, and bone healing was observed within the defect through 19 months. Opioid pain medication use decreased 4.2-fold overall, no active tumor was identified, and there were no SREs, which allowed the patient to return to a more active lifestyle and an overall improved quality of life.

ZetaMet is a calcium phosphate/type-I collagen graft material designed to deliver the small molecule, N-allyl noroxymorphone dihydrate, at a controlled rate. The small molecule modulates the opioid growth factor receptor (OGFR), a nuclear pore receptor. In our previous work [19], the small molecule N-allyl noroxymorphone dihydrate was shown to antagonize the OGFR and increase p21 expression that led to decreased cell proliferation and a corresponding increase in mesenchymal stem cell differentiation into osteoblasts. Increased nuclear localization of p21 due to OGFR antagonism led to an increase in two of the pro-osteogenic SMAD expression (SMAD1 and SMAD8/9), as well as SMAD target gene, ID1, and the osteoblast-specific phenotypic gene, osteocalcin [19].

We have hypothesized that the increase in new bone and bone cells produces a less favorable environment for the growth of metastatic breast cancer cells, which is consistent with a hypothesis first proposed by Sasaki et al. [20]. We believe that this change in the local bone environment includes a decrease in the pool of RANK-ligand, which is expressed in osteoblast precursor cells and is required for the differentiation of monocytes, the hematological precursor cells to osteoclasts [21]. Breast cancer tumor cells that have metastasized to bone directly mediate lytic bone destruction by recruiting osteoclasts [21], the cells responsible for inducing pain [9]. Lytic destruction of the local bone tissue promotes tumor growth, by increasing the space in which the tumor can grow and releases growth factors, such as TGF-β, that drive tumor cell proliferation [22]. The increase in tumor size leads, in turn, to recruitment of more osteoclasts, the growth of the lytic lesion, and the increased incidence of SREs [6]. This is the ‘vicious cycle’ of tumor growth in bone [6], and it has been hypothesized that disrupting this cycle might also short circuit tumor progression in bone [23], which would reduce local lytic bone destruction and the likelihood of an SRE. Importantly, we have also shown that the local therapeutic intervention can reduce tumor cell proliferation directly and concurrently increase tumor cell death, likely through the p21 mechanism; however, this remains speculative and is the focus of ongoing studies.

Greater than 50% of metastatic lesions from breast cancer can cause SREs, such as severe pain, decreased mobility and fracture [24,25]. These lesions are often treated with a combination of systemic chemotherapy and local X-radiation when they become painfully symptomatic [8,26]. Confavreux et al. [27] estimated that 50% of bone metastases result in an SRE within 6 months after diagnosis in the absence of a treatment and emphasized, in agreement with Coleman [26], that interventions for spinal metastases should be immediate. Progression to a fracture in the spine typically necessitates an invasive surgical intervention, which includes a cement-based stabilization procedure (kyphoplasty/vertebroplasty in the spine), surgical decompression or an open-instrumented spinal fusion procedure [28,29].

In this clinical case, the patient had severe debilitating pain that had been treated with systemic chemotherapy, X-radiation therapy and pain management using opioid analgesics. Nevertheless, using these mainline therapies resulted in neither resolution of pain nor any decrease in tumor growth. ZetaMet was able to significantly decrease pain that led to a decrease in opioid use and ceased tumor progression, which resulted in an improved quality of life and return to normal functional activity. To our knowledge, this is the first report that has used a locally administered synthetic bone graft with antitumorigenic and osteoinductive properties to achieve a local resolution of the metastatic tumor lesion in bone. Comparable products in this space are inert, such as polymethyl methacrylate (PMMA) bone cement or metallic hardware (e.g., plates or screws), and have no ability to promote bone healing or to reduce tumor burden. As such, these treatments are strictly palliative in nature. In contrast, ZetaMet offers the promise of delaying the onset of an SRE in addition to offering palliation for pain.

Treatment of the T7 and L1 lesions demonstrated tumor control, while there was late evidence of bone healing in the L1 vertebral body at 22 months, and treatment of the sacral lesion demonstrated complete resolution and bone healing, which prevented progression of these lesions to fracture. In a Danish population-based study of 35,912 patients with breast cancer, 43.2% of the 178 patients with bone metastases at time of primary diagnosis developed an SRE that was identified on a follow-up exam; of the 1272 patients who developed bone metastases between diagnosis and follow-up, 46.4% developed an SRE at median follow-up of 8.4 months [30]. Hill et al. [31] found that 47% of symptomatic lesions that progress to fracture results in death within 6.3 months. In a retrospective study of randomized clinical trial with 1130 breast cancer patients, Saad et al. found a similar incidence of 55% for patients who died after pathologic fracture [25].

The above results from large population-based studies agree with the following smaller case series reported. Cho et al. [32] found in a cohort of 54 patients with spinal metastases from various cancers that the time from the identification of a spinal metastases and an SRE (e.g., they report only pathologic spinal fractures) was 0.9 ± 2.5 months with a range from 0 to 12 months. Cho et al. also reported that the predicted mean survival for breast cancer patients with spinal metastases was 20.9 months (95% confidence interval, 11.7 and 30.2 months). Given the small sample size (N = 7) of breast cancer patients, this outcome is not inconsistent with the larger population studies or our own results.

Tokuhashi et al. [33] developed the Tokuhashi scoring system, which predicts overall survival in patients with metastatic spine tumors. Retrospectively, the patient in this study was evaluated and found to have a Tokuhashi score of 6, which corresponds to a prognosis of ≤6 months for a patient with a score of between 0 and 8. The median progression-free survival is approximately 4.8 months for women with ER+/PR-/HER2- breast cancer [34], with Xie et al. [35] finding that some ER+/PR-/HER2- (eg, also commonly known as HR+/HER2- in the literature) patients have an immune phenotype that is associated with a worse prognosis. Bae et al. [36] found in a retrospective analysis of 6980 women with ER+/PR-/HER2- to have an equivalent long-term survival to triple-negative breast cancer (TNBC). These observations are particularly significant since the subject of this report has exceeded the average life expectancy of ≤6 months for this patient population based on the data from the studies cited above.

There are several limitations to the reported results. First, this is a single-patient report, which can add significant bias to the interpretation of the results because there is no control group. This is also a limitation for assessing the incidence of adverse events, which could be very different in a fully powered study. Second, patients treated through Expanded Access/Compassionate Use have failed conventional therapy and may have significant comorbidities that could confound the interpretation of the results. Finally, the data reviewed for this report are retrospective, and none of the parameters used to collect data were controlled, e.g., imaging parameters are not the same. Nevertheless, treating a patient using Compassionate Use provided significant insights into where in the treatment continuum ZetaMet would be most effective and clarified several end points that had not been considered as relevant (e.g., the dose of opioid analgesics administered over time).

In conclusion, this case report demonstrates the first successful treatment of multiple bone metastasis due to lytic breast lesions in the spine using a small molecule-eluting bone graft biomaterial. These tumors were previously found to be refractory to chemotherapy as well as local X-radiation therapy. The positive outcomes observed in this study were mediated by a novel antitumorigenic and osteoinductive synthetic bone graft. Moreover, fracture progression was prevented, spinal stability was increased and patient quality of life was improved, which contributed to increased life expectancy. Further testing is currently being planned as part of clinical trials for the same patient population.

Competing interests disclosure

The Authors declare no Competing Non-Financial Interests but declare the following Competing Financial Interests: N.T., J.C.L., and B.S.M. are employed by and have stock options in Zetagen Therapeutics. D.P. declares no competing financial interests. The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing disclosure

Writing assistance was provided by Stephen Bublitz, ELS, of MedValScientific Information services, LLC, and funded by Zetagen therapeutics, Inc.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board (IRB) approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved. Further, studies were conducted consistent with the principles outlined in the National Institutes of Health (NIH) guidelines on the ethical conduct of research.

Data availability

All the data generated or analyzed during this study are included in this published article.

Ethics approval

Both procedures were reviewed and approved by Western IRB (Seattle WA; IRB# 20214825).

Editorial assistance to prepare this manuscript for publication was provided by S Bublitz of MedVal Scientific Information Services, LLC, and was funded by Zetagen Therapeutics, Inc. Research reported in this publication was supported, in part, by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) under awards R43CA221553 (BS Margulies) and R44CA221553 (BS Margulies). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

Editorial assistance to prepare this manuscript for publication was provided by S Bublitz of MedVal Scientific Information Services, LLC, and was funded by Zetagen Therapeutics, Inc. Research reported in this publication was supported, in part, by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) under awards R43CA221553 (BS Margulies) and R44CA221553 (BS Margulies). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.