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cancersReviewDiagnosis and Treatment of Bone Metastases in BreastCancer: Radiotherapy, Local Approach and SystemicTherapy in a Guide for CliniciansFabio Marazzi 1 , Armando Orlandi 2 , Stefania Manfrida 1 , Valeria Masiello 1, * ,Alba Di Leone 3 , Mariangela Massaccesi 1 , Francesca Moschella 3 , Gianluca Franceschini 3,4 ,Emilio Bria 2,4 , Maria Antonietta Gambacorta 1,4 , Riccardo Masetti 3,4 , Giampaolo Tortora 2,4 andVincenzo Valentini 1,41234*“A. Gemelli” IRCCS, UOC di Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini,Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario, 00168 Roma, Italy;[email protected] (F.M.); [email protected] (S.M.);[email protected] li.it (M.A.G.); [email protected] (V.V.)“A. Gemelli” IRCCS, UOC di Oncologia Medica, Dipartimento di Scienze Mediche e Chirurgiche,Fondazione Policlinico Universitario, 00168 Roma, Italy; [email protected] (A.O.);[email protected] (E.B.); [email protected] (G.T.)“A. Gemelli” IRCCS, UOC di Chirurgia Senologica, Dipartimento di Scienze della Salute della Donna e delBambino e di Sanità Pubblica, Fondazione Policlinico Universitario, 00168 Roma, Italy;[email protected] (A.D.L.); [email protected] (F.M.);[email protected] (G.F.); [email protected] (R.M.)Istituto di Radiologia, Università Cattolica del Sacro Cuore, 00168 Roma, ItalyCorrespondence: ed: 1 May 2020; Accepted: 20 August 2020; Published: 24 August 2020 Abstract: The standard care for metastatic breast cancer (MBC) is systemic therapies with imbricationof focal treatment for symptoms. Recently, thanks to implementation of radiological and metabolicexams and development of new target therapies, oligometastatic and oligoprogressive settings areeven more common—paving the way to a paradigm change of focal treatments role. In fact, accordingto immunophenotype, radiotherapy can be considered with radical intent in these settings of patients.The aim of this literature review is to analyze available clinical data on prognosis of bone metastasesfrom breast cancer and benefits of available treatments for developing a practical guide for clinicians.Keywords: bone metastasis; breast cancer; radiotherapy; diagnostic imaging; systemic therapies1. IntroductionThanks to treatment implementations [1], metastatic breast cancer (MBC) has shown animprovement of outcomes in the last years. However, prognosis is still critical [2], with reported 27%5-year survival rates [3]. Incidence of MBC interests 25–28% as de novo metastatic, while the rate ofmetastatic recurrence is reported in 20–30% of patients in western countries—and can be even higherin low- to medium-income countries [4]. Over time, the risk of becoming metastatic increases, and thedata describe a cumulative risk of 4.8% (4.7–4.8) at one year, 5.6% (5.5–5.6) at two years, 6.9% (6.8–7.0)at five years and 8.4% (8.3–8.5) at ten years [5].Bone metastasis commonly occurs in solid tumors; 36% of the incidence is from breast cancer [5],with a tendency of incidence in luminal subtypes [6]. In the surveillance epidemiology end result(SEER) database, a retrospective analysis based on subtype and incidence of distant metastasis, data onCancers 2020, 12, 2390; ncers

Cancers 2020, 12, 23902 of 20the first site of relapse show that bone metastases commonly involve luminal subtypes (ER /HER2 58.52% and in ER /HER2 subtype 47.28% of incidence) [6]. The ER /HER2 subtype has a higherproportion of liver metastases (31.72%), while the triple negative (TN) subtype is more affected by lunginvolvement (32.09%), with an incidence of bone metastases of 34.49% and 36.39%, respectively [6]. In aretrospective study by Molnar IA et al., the luminal A subtype presented a tendency of isolated bonemetastases in 59% of cases [7]. In breast cancer, bone metastasis can occur in a de novo or recurrentsetting, with a pluri- or oligometastatic presentation and may or may not be associated with other sitesof involvement, so the spectrum of prognoses can differ greatly [6,8,9].Etiopathology of bone metastasis is based on multicellular unit (osteoblasts, osteoclasts, bone liningcells, osteocytes) disruption with release of growing factors (TGF-B, FGF, PDGF, IGF) that promotesincrease of tumor cell growth and compromise of secondary bone architecture [5,10]. In particular,biologic theory hypnotizes that, in sclerotic lesions, the tumor produces growth factors and inducesosteoblast differentiation with the inhibition of bone resorption, while, in lytic lesions, tumor-derivedfactors enhance pro-osteoclastogenic differentiation and activity with consequently bone resorption [11].Due to the release of chemical mediators, bone metastases are a common cause of cancer pain,with increasing of pressure in the bone, microfractures, stretching of the periosteum, reactive musclespasm, nerve root infiltration, compression of the nerve due to collapse of the bone [12].Skeletal-related events (SRE) are complications of bone metastasis growth and consist of pathologicfractures, spinal cord compressions and the necessity of radiotherapy for pain/impending fracture orsurgery to bone. SRE can compromise performance status, with a reduction of quality of life, poorsurvival outcomes and also limited access to systemic therapies [13].Thanks to new emerging diagnostic imaging and systemic therapies [14], alongside the mostcompromised presentations of bone metastases in breast cancer, we are assisting even more witholigometastatic presentations (de novo or inducted) [8]. Early detection of metastases—andpossibly using targeting agents—can enhance disease control over time [2,15,16]. Associated withsystemic therapeutic options, local treatments such as radiotherapy (RT), are possible optionsfor the implementation of local controls—with both palliative and eradication intents [17,18].The radiobiological aim of radiotherapy is to cause an interruption of the vicious biomolecularpain cycle with not only pain relief, but also decreasing the local tumor burden in more radiosensitivetumor subtypes [19]. It has been clinically demonstrated that patients obtain an immediate reliefof symptoms in 2–4 weeks [11,20,21], and radiologically demonstrated that, for intent-to-eradicatetreatments, local controls at 1 and 2 years can achieve 90.3% and 82.4% success with excellentsafety [22]. For this reason, oligometastatic/oligoprogressive patients are even more challengingbecause physicians can imbricate local treatments such as radiotherapy with new systemic drugs toachieve higher progression-free survival—and in general, improve overall survival. In these settings,radiotherapy can also promote eradication of subclones resistant to systemic therapy.Here we propose a review of diagnostic imaging for the early detection of bone metastasis in breastcancer, their use for radiotherapy targeting and local therapy options with a focus on radiotherapypossibilities in terms of dose and volumes and integration of chemoradiotherapy to improve clinicaloutcomes. The final purpose is to offer a practical guide for multidisciplinary management of patientswith bone metastases from breast cancer.2. Diagnostic Imaging for Bone Metastasis from Breast CancerThe metastatic spread from a primary breast tumor can occur at an early, pre-symptomaticstage. Disseminated cells can lie dormant for years before becoming clinically evident [23]. In somestudies [24,25], it has been shown that during the metastatic process of breast tumors, disseminatedcancer cells at early stages of tumor evolution successfully establish themselves in the bone marrow [23].Based on this theory, adjuvant systemic therapy (chemotherapy, target therapy and/or hormonetherapy), is always administered when indicated.

Cancers 2020, 12, 23903 of 20In terms of correctly identifying subsetting and prognosis, it is challenging for physicians toprecociously identify bone metastasis during staging and follow-up. Even more diagnostic andfunctional imaging are moving towards this goal. Today, with innovations in morphologic andfunctional exams, novel technologies offer possibilities to detect early bone metastases. Imaging isconsidered fundamental not only for diagnosis, but also as necessary to identify target lesions inlocal treatments.2.1. Morphologic ImagingMorphologic exams, including radiographs or computed tomography (CT), are based on changesin bone density. Based on metastasis behavior, (lytic, sclerotic or mixed) metastases can present differentpattern at imaging.To be detected at CT exams, bone metastases need to be at least one cm with a loss of densityaround 25–50%. Usually breast cancer bone metastasis are lytic, but during treatments, due to responsewith osteoblastic reaction, they can become peripherally osteosclerotic. CT also allows to definesoft-tissue invasion outside bone. Moreover, morphologic exams are fundamental to define critical siteof bone metastasis which are at risk for SRE.Magnetic resonance imaging. Conventional MRI sequences with T1, T2 and DWI studies, allow todetect breast cancer bone metastases with a sensitivity reported since to 100% [26] and a specificityof 90%, so they are used in case of doubt and are very useful for early detection. The pattern of MRIbehavior of bone metastases usually determines low T1-signal, T2 hyperintensity and DWI signalrestriction [27]. MRI allows visualizing lesions with high precision, and it is also useful to studyintegrity of spinal cord and eventually condition of its compression. For bone study, MRI is performedwithout contrast, but for study of spinal cord or surrounding soft tissue, contrast is required. Recently,whole-body MRI (WB-MRI) has been developed for study of entire bone compartment, but its utility forclinical practice is still under investigation—especially for early detection of bone metastasis [28]. In anycase, its application could be interesting for early detection of oligometastatic patients. In literature,data on WB-MRI also provide a quantitative measure of treatment response in skeletal metastases andits sensitivity and specificity are superior to skeletal scintigraphy [29,30].2.2. Functional ImagingBone scintigraphy. Functional imaging finds a role in staging, restaging and, during follow-up indetecting bone metastasis in breast cancer. The osteotropic agent used for skeletal imaging is metastabletechnetium 99 (99mTc) labeled diphosphonates for bone scintigraphy.99mTc-radiolabeled diphosphonates has been in use since 1970s and thanks to its effectivenessand low cost, it is worldwide dedicated to first-level staging. Reported sensitivity and specificityare 78 and 48%, respectively [27,31]. Bone scintigraphy usually detects bone turnover, so metastasiswith a prevalent lytic behavior can be considered as false negative. An alteration, not exclusivelycancer-related, in 5–10% bone can cause accumulation of agents on bone scans, though this can bealso a confounding factor with a benign pathology such as degenerative disease. For this reason,a second-level exam can be required in borderline cases. Another limitation of bone scan is representedfrom absence of volumetric evaluation and poor spatial resolution ( 1 cm). An implementation of abone scan is represented by single photon emission CT (SPECT/CT), in which the same radionuclideused for conventional skeletal scintigraphy is injected during acquisition of additional axial slices,with the possibility to have volumetric evaluation.Positron emission tomography (PET). PET is superior to the bone scan in terms of spatial resolutionwith acquisition of tomographic images. It also provides information about treatment response andprognosis [32]. Most employed radiopharmaceutical agents for skeletal investigation are 18F labeledsodium fluoride (18F NaF) and 18F labeled fluorodeoxyglucose (18F FDG). Due to fluoride ionscollocation in the remodeling skeletal areas, 18F-NaF PET is particularly sensible to osteoblastic activity.18F-NaF PET presents a high sensibility (100%) and specificity of 97% and it is more efficacy to detect

Cancers 2020, 12, 23904 of 20bone metastases than 18F FDG, though it is still to be defined the setting of patients in which it couldbe useful [27]. About breast cancer, indolent subtypes with bone tropism such as luminal or lobularcancer, could be considered for specific protocols with 18F-NaF PET. Moreover, these subtypes withslower cellular growth and consequent lower uptake of glucose, present a poor sensibility of 18-FDGPET/CT and their spread could be missed.18-FDG PET/CT is instead considered useful in case of locally advanced or metastatic disease forstaging, evaluate treatment response and prognosis [33]. Accumulation of its agent is in high turnoverareas. The sensitivity and specificity of 18F-FDG PET for detection of bone metastasis is 98% and 56%,respectively, even if it can be different according to subtypes [27]. Indication for use in follow-up isstill controversial.Hybrid images. A recent review by Cook G et al. [29] reported that molecular and hybrid imaginghas an increasing role in early detecting of bone metastases and in monitoring response at early timepoints. In this sense, functional imaging as emission computed tomography (SPECT/CT), positronemission tomography/CT (PET/CT) or PET/MRI in breast cancer could find a role in identified earlypatients not responder to systemic therapies for shifting to further line of treatment with a benefiton disease control and cost/effectiveness of health systems. This advantage is based on combinationof morphologic, physiologic and metabolic aspect for skeletal evaluation. Comparing the data inliterature, the advantages of PET/MRI are still few and studies are focused on finding the best settingof patients [34].2.3. Diagnostic Imaging for Treatment Planning of RadiotherapyMorphologic imaging is useful for identify bone lesions and soft tissue invasion. In palliativeradiotherapy treatments of bulky metastases, CT scan simulation allows radiotherapist contouringalso of soft tissue surrounding. In some cases, co-registration with diagnostic CT scan with contrastcan be helpful for distinguish healthy soft tissue from that interested by spread of disease outside bonemetastases. MRI is useful for treatments with radical intent because it allows higher precision in grosstumor volume (GTV) and spinal cord contouring. Increased accuracy is always associated with higherlocal control and less side effects. MRI is usually required for stereotactic body radiotherapy (SBRT),in which target of the treatment is the lesion with a millimetric margin and dose are high. Functionalimaging is less strictly used for contouring of bone metastasis in breast cancer and hold a function ofsupporting detecting of lesion at co-registration.2.4. Biopsy on Bone Metastasis: When Imaging Is Not EnoughMetastatic presentation—especially in case of relapse—usually required a biopsy for prognosticfactors study to confirm nature of disease and setting of systemic therapies. More often, in case of denovo metastatic patients, soft-tissue or primary tumor undergo pathologic study, while in case of relapse,especially for isolated bone presentation, a biopsy of lesion can become mandatory. Other conditionsin which biopsy can be mandatory are necessities of differential diagnosis. The differential diagnosisfor bone metastases includes chondrosarcoma, primary malignant lymphoma of the bone, multiplemyeloma, post-radiation sarcoma and osteomyelitis. A distinction between acute osteoporotic fracturesversus metastatic fractures should be made on radiographic imaging. In osteoporosis, the corticalbone may appear preserved, while in secondary lesions, cortical bone is typically destructed. Anotherpossible differential diagnosis is sarcoidosis, because lesions cannot be reliably distinguished frommetastatic lesions on routine MRI studies [35]. 18F-FDG PET/CT is highly sensitive in detectinggranulomatous bone marrow infiltration, but an increased 18F-FDG uptake can mimic metastaticdisease, reducing the specificity of 18-FDG PET/CT when both sarcoidosis and a tumor which maydevelop bone metastases occur in the same patient [36].

Cancers 2020, 12, 23905 of 203. Radiotherapy Treatments Options and New DrugsRadiotherapy effect on bone metastasis. In-human pathologic data of radiotherapy damage on bonemetastasesIn general, RT effect is mediated by sublethal damage from free radical generatedCancers 2020,are12, few.x5 of 20by water molecules or, in case of high doses, also direct lethal damage on DNA [37]. In fact, effectofRTdamageisdisruption with vascular death [38,39] (Figure 1). On bone metastases, final effect of RT therapywithpalliativeand decrease of tumor burden [40]. Radiotherapy with palliative atorymechanismby earlydepletionof inflammatoryan interruption on neuromodulatoryalgic algicmechanismby earlydepletionof inflammatorycells,cells,thanksto ertrigger ofof pain modulationthanksto inhibitionof ofthetheinflammatorycellsmodulation adykinin,serotonin,adenosinetriphosphate,H ,lipidsmetastases are nerve growth factor (NGF), bradykinin, serotonin, adenosine triphosphate, H , osteolysisosteolysisisis mediatedmediated byby osteoclastsosteoclasts apoptosis,apoptosis, asas inin vitrovitrodatadata showedshowed uredbonebone[12].[12].InIna astasismetastasiswhowhounderwentunderwenta tive SBRT of 18 Gy, a change of tissue in 21 h, as necrosis development, happened in 83%ofofsample.consistentreductionof mitoticactivityactivityand vesselin renal cellinmetastasessample.A Aconsistentreductionof mitoticanddensityvessel (especiallydensity (especiallyrenal cellwhoare enrichedwasreported.On eswho ofarevessels)enrichedofalsovessels)was alsoreported.On therphase,immune-relatedunderlined a persistence of T-cell and natural kill cell density after SBRT. Probably, in a further phase,reactionsstarts againstantigenstumor exposedcell damage.immune-relatedreactionsstartsexposedagainst byantigensby tumor cell da

survival outcomes and also limited access to systemic therapies [13]. Thanks to new emerging diagnostic imaging and systemic therapies [14], alongside the most compromised presentations of bone metastases in breast cancer, we are assisting even more with oligometastatic presentations (de novo or inducted) [8]. Early detection of metastases—and