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LETTER TO THE EDITOR
Ahead of print publication
 

Denosumab in breast cancer patients receiving aromatase inhibitors: A single-center observational study of effectiveness in adjuvant setting


1 Medical Oncology Unit, Department of Oncology, AUSL 04 Teramo, Italy
2 Allergy and Clinical Immunology Unit, Center for the Diagnosis and Treatment of Osteoporosis, AUSL 04 Teramo; Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy

Date of Submission07-Jan-2020
Date of Decision08-Jan-2020
Date of Acceptance08-Jun-2020
Date of Web Publication17-Oct-2020

Correspondence Address:
Massimo De Martinis,
Allergy and Clinical Immunology Unit, Center for the Diagnosis and Treatment of Osteoporosis, AUSL 04 Teramo; Department of Life, Health and Environmental Sciences, University of L'Aquila
Italy
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_16_20




How to cite this URL:
Irelli A, Sirufo MM, Scipioni T, Pietro FD, Pancotti A, Ginaldi L, Martinis MD. Denosumab in breast cancer patients receiving aromatase inhibitors: A single-center observational study of effectiveness in adjuvant setting. Indian J Cancer [Epub ahead of print] [cited 2020 Oct 20]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=298285




Successes obtained in the treatment of women with breast cancer have also taught us the importance of simultaneously taking care of their bone health. Women with early breast cancer develop skeletal weakening due to cancer treatment-induced bone loss (CTIBL) and postmenopausal osteoporosis with a reduction of health status, quality of life, and the potential subsequent increased risk of pathological fracture. For these reasons, in patients receiving aromatase inhibitors (AI), it should be taken into account the need to add the most effective antiresorptive treatment other than the lifestyle and other modifiable risk factors changes.

A retrospective observational study on adjuvant treatment with AI and denosumab in patients with breast cancer, was conducted in our institution, according to the Helsinki Declaration, after approval by the local ethics committee and after obtaining written informed consent from each participant.

Patients received 60 mg subcutaneous denosumab every 6 months. All patients received calcium (1 g/day) and vitamin D (≥400 IU/day).

From the enrollment of the first patient (June 2015) to the cutoff date (December 2018), the duration of the study was 42 months.

The primary aim of this study was to evaluate the effectiveness of denosumab as variation of bone mineral density (BMD) and C-terminal telopeptide of type 1 collagen (CTx), at 12 months after the beginning of the therapy. Secondary objectives were the assessment of safety and tolerability of the treatment.

In all subjects, BMD measurements were performed at the time of enrollment and then each year, by using dual energy X-ray absorptiometry (DXA) (Hologic QDR 4500 W machine) at the lumbar spine and hip. BMD values were expressed as T-score, the difference (number of standard deviations) between the BMD value of the examined subject and the mean value in the healthy reference population. T-score values lower than -2.5 define osteoporosis, between -1.5 and -2.5 define osteopenia and higher than -1.5 indicates a normal BMD. Diagnosis was made according to the current criteria of the World Health Organization.[1] The CTx was dosed by blood sampling at the time of enrollment and to follow each year.

Subgroup analysis was performed among patients according to the following variables: age, type of aromatase inhibitor (steroid versus non-steroid), prior chemotherapy (yes or not), and basal T-score (≤-1.0 vs. >-1.0).

Criteria for inclusion were: age ≥18 years, histological diagnosis of breast cancer, absence of secondary disease localizations ascertained after performing clinical-instrumental tests such as chest X-ray, complete abdomen ultrasound, bone scintigraphy, total body computed tomography (CT) scan and positron emission tomography (PET) scan, hormone receptors status, adjuvant treatment with aromatase inhibitors, serum calcium corrected for albuminemia ≥8.1 mg/dL and ≤10.4 mg/dL. Previous treatment with chemotherapy and/or bisphosphonates was allowed.

Few studies have been done in a “real life setting” where patients may switch from bisphosphonates to denosumab so we have a paucity of informations in this context. Fraser et al.,[2] reported that the presence of secondary clinical risk factors and previous exposure to bisphosphonate do not affect the BMD response to denosumab. A greater increase in BMD and reduction in bone turnover in subjects transitioning from bisphosphonates to denosumab[3] is possible.

Exclusion criteria were: risk factors for osteonecrosis of the jaw in the oral cavity that necessitated dental intervention (avulsion, sanitation, scaling or curettage, denture reline, conservative or endodontic therapy), osteopenizing drugs intake (except AI).

A t-test was used to compare the groups of patients; a P- value <0.05 was considered statistically significant. The analysis has been carried out using the statistical software GraphPad Prism version 5.01.

A total of 68 patients were evaluated in this study.

The median follow-up of patients' population was 38 months.

The clinical features of the patients are described in [Table 1].
Table 1: Clinical characteristics of patients

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The evaluation of changes in BMD (T-score), lumbar spine and femoral neck, and in CTx (ng/ml) from time 0 (i.e., at the beginning of treatment with AI therapy and concomitant denosumab) at the 12 month, showed that median BMD values improved, both at the lumbar spine (+2.3%, P = 0.0005) and at the femoral neck (+ <1%, P = 0.0193); as well as median CTx levels were reduced (-41.6%, P < 0.0001).

Subgroup analyses of the patients' population at 12 months are shown in [Table 2].
Table 2: Subgroup analyses of the patients' population at 12 months

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No non-traumatic fractures, osteonecrosis of the jaw, G (grade) ≥2 hypocalcemia, G3 osteoarticular pain have been reported.

No patients discontinued treatment with AI therapy and/or denosumab.

Early breast cancer patients develop bone damage secondary to cancer treatment (chemotherapy and/or hormone therapy), characterized by reduced bone mass and qualitative changes in bone structure such as the interruption of bone trabeculae, increasing the risk of fractures.[4]

The rate of bone loss depends on the fall of estrogen levels. Estrogens exert their action directly on osteoblasts increasing their number and activity, while attenuating osteoclastogenesis and stimulating osteoclast apoptosis.[5] They increase osteoblast lifespan, inhibit osteoblast apoptosis, suppress RANKL-induced osteoclast differentiation thus reducing bone remodeling, decreasing bone resorption, and maintaining bone formation.[6],[7],[8],[9] Dysregulated autophagy is involved in several pathological processes including cancer and bone diseases[10] and inhibition of authophagy in osteoclasts preserve bone mass.[11] Other individual risk factors for bone loss should be considered, such as: age, low body mass index (BMI), previous fragility fracture, familiarity with fracture of the femur/vertebrae, smoking, alcohol habit, vitamin D deficiency, menopause before 45 years, reduced physical activity, prolonged immobilization, reduced calcium or excessive sodium intake, several diseases (chronic inflammatory, autoimmune, cirrosis, etc.) organ transplantation and related immunosuppressive therapy, use of osteopenizing drugs such as corticosteroids and several others like antiepileptics, hormonal therapy, GnRH antagonists, calcineurin inhibitors, antiretroviral drugs, selective inhibitors of serotonin reuptake, loop diuretics, heparins, oral anticoagulants, high doses of thyroxine and proton pump inhibitors, should be considered.[12],[13]

Denosumab is a fully human monoclonal antibody with a high affinity and specificity for RANKL; this binding inhibits the activity of RANKL.[14]

In the study by Ellis et al., early breast cancer patients with reduced bone mass (excluding osteoporosis) and on AI treatment were assigned to receive placebo versus denosumab, subcutaneously at the 60 mg dose every 6 months. At 12 and 24 months, BMD of the lumbar spine increased by 5.5% and 7.6%, respectively, in the denosumab group compared to placebo (P < 0.0001, in both time points). In addition, BMD increases were observed at the pelvis and femoral neck as well as the reduction of bone turnover markers in denosumab.[15]

In the phase 3 ABCSG-18 trial, post-menopausal women, treated with AI, were assigned to receive denosumab 60 mg or placebo, subcutaneously, every 6 months. Compared to the placebo group, patients treated with denosumab showed significantly delayed time to the first clinical fracture regardless of baseline BMD (Hazard Ratio = 0.50, P < 0.0001).[16]

This retrospective observational study confirms ability of denosumab to improve the BMD values of the lumbar spine and the femur in just 12 months of treatment. The decrease in CTx that we demonstrated during denosumab therapy confirms the latter's ability to interfere with bone loss.

The safety analysis showed that treatment with denosumab during therapy with AI is well tolerated; no patient discontinued the treatment for limiting toxicity, in particular no musculoskeletal symptoms associated with aromatase inhibitors of degree ≥3 were recorded.

A limitation of our study is that it was designed as a retrospective, observational analysis, which cannot produce the high level of evidence associated with randomized, controlled trials. Its observational nature, on the other hand, allowed confirmation of safety and effectiveness of denosumab outside the selected and controlled conditions of randomized studies and the retrospective design ensures that the physician's behavior is not affected by the ongoing study.

The bone health objective gains more meaning in light of the literature data,[17],[18] denosumab reduces fractures in postmenopausal breast cancer receiving aromatase inhibitors.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

This work was supported by Department of Life, Health & Environmental Sciences, University of L'Aquila (fondi RIA 2017).

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
De Martinis M, Sirufo MM, Ginaldi L. Osteoporosis: Current and emerging therapies targeted to immunological checkpoints. Curr Med Chem 2019. doi: 10.2174/0929867326666190730113123.  Back to cited text no. 1
    
2.
Fraser TR, Flogaitis I, Moore AE, Hampson G. The effect of previous treatment with bisphosphonate and renal impairment on the response to denosumab in osteoporosis: A 'real-life' study. J Endocrinol Invest 2020;43:469-75.  Back to cited text no. 2
    
3.
Miller PD, Pannacciulli N, Malouf-Sierra J, Singer A, Czerwiński E, Bone HG, et al. Efficacy and safety of denosumab vs. bisphosphonates in postmenopausal women previously treated with oral bisphosphonates. Osteoporos Int 2020;31:181-91.  Back to cited text no. 3
    
4.
Bauer M, Bryce J, Hadji P. Aromatase inhibitor-associated bone loss and its management with bisphosphonates in patients with breast cancer. Breast Cancer (Dove Med Press) 2012;20:91-101.  Back to cited text no. 4
    
5.
Martin-Millan M, Almeida M, Ambrogini E, Han L, Zhao H, Weinstein RS, et al. The estrogen receptor-alpha in osteoclasts mediates the protective effects of estrogens on cancellous but not cortical bone. Mol Endocrinol 2010;24:323-34.  Back to cited text no. 5
    
6.
Ginaldi L, De Martinis M. Osteoimmunology and beyond. Curr Med Chem 2016;23:3754-74.  Back to cited text no. 6
    
7.
De Martinis M, Sirufo MM, Suppa M, Ginaldi L. IL-33/IL-31 axis in osteoporosis. Int J Mol Sci 2020;21:1239.  Back to cited text no. 7
    
8.
Sirufo MM, Suppa M, Ginaldi, De Martinis M. Does allergy break bones? Osteoporosis and its connection to allergy. Int J Mol Sci 2020;21:712.  Back to cited text no. 8
    
9.
De Martinis M, Ginaldi L, Sirufo MM, Pioggia G, Calapai G, Gangemi S, et al. Alarmins in osteoporosis, RAGE and IL-33 pathways: A literature review. Medicina 2020;56:138.  Back to cited text no. 9
    
10.
Massimini M, Palmieri C, De Maria R, Romanucci M, Malatesta D, De Martinis M, et al. 17-AAG and apoptosis, autophagy and mitophagy in 142 canine osteosarcoma cell lines. Vet Pathol 2017,54:405-12.  Back to cited text no. 10
    
11.
Irelli A, Sirufo MM, Scipioni T, De Pietro F, Pancotti A, Ginaldi L, et al. mTOR links tumor immunity and bone metabolism: What clinical implications? Int J Mol Sci 2019;20:5841.  Back to cited text no. 11
    
12.
Ciccarelli F, De Martinis M, Ginaldi L. Glucocorticoids in patients with rheumatic diseases: Friends or enemies of bone? Curr Med Chem 2015;22:596-603.  Back to cited text no. 12
    
13.
Rossini M, Adami S, Bertoldo F, Diacinti D, Gatti D, Giannini S, et al. Guidelines for the diagnosis, prevention and management of osteoporosis. Reumatismo 2016;68:1-39.  Back to cited text no. 13
    
14.
Cortellini A, Cocciolone V, Irelli A, Pavese F, Sidoni T, Parisi A, et al. The possible different roles of denosumab in prevention and cure breast cancer bone metastases: A 'hypothesis-generator' study from clinical practice. Oncol Lett 2018;16:7195-203.  Back to cited text no. 14
    
15.
Ellis GK, Bone HG, Chlebowski R, Paul D, Spadafora S, Smith J, et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol 2008;26:4875-82.  Back to cited text no. 15
    
16.
Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, et al. Adjuvant denosumab in breast cancer (ABCSG-18): A multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2015;386:433-43.  Back to cited text no. 16
    
17.
Irelli A, Sirufo MM, Scipioni T, De Pietro F, Pancotti A, Ginaldi L, et al. Breast cancer patients receiving denosumab during adjuvant aromatase inhibitors treatment: Who are the “inadequate responders” patients to denosumab? J BUON 2020;25:648-54.  Back to cited text no. 17
    
18.
Gralow J, Barlow WE, Paterson AHG, Lew D, Stopeck A, Hayes DF, et al. SWOG S0307 phase III trial of bisphosphonates as adjuvant therapy in primary breast cancer: Comparison of toxicities and patient-stated preference for oral versus intravenous delivery. J Clin Oncol 2014;32;(Suppl 15):558-8.  Back to cited text no. 18
    



 
 
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