Breast cancer natural history: Difference between revisions

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==Overview==
==Overview==
If left untreated, 22% of patients with breast cancer may regress. Common complications of breast cancer include [[metastasis]]. [[Prognosis]] is generally good with treatment.
If left untreated, 22% of patients with breast cancer may regress. Common complications of breast cancer include [[metastasis]]. [[Prognosis]] is generally good with treatment.
Breast cancer used to be [[Cancer staging|staged]] according to the TNM system. Recently, the American Joint Committee on Cancer (AJCC) Staging Manual (8th edition, last updated 1/25/2018) extensively revised their staging system. The 8th edition of the AJCC TNM breast cancer staging system delivers a flexible platform for prognostic classification based on traditional anatomic factors, which may be modified and enhanced with respect to patient biomarkers and other prognostic panel data. Nevertheless, in order to maintain worldwide value, AJCC tumor staging system remained based on classic TNM anatomic factors. Prognosis is closely linked to results of staging, and staging is also used to allocate patients to treatments both in clinical trials and clinical practice.
Bone is the most common site of [[breast cancer]] distant spread. Bone [[metastases]] due to the breast cancer cause major morbidity, decrease survival and reduce the quality of life of many patients. Rather than systemic chemotherapy, bisphosphonates like [[Pamidronate]], [[Alendronate]], [[Ibandronate]], [[Risedronate]], and [[Zoledronic acid]] , RANKL-RANK inhibitors like [[Denosumab|Denosumab, also has been recommended and studied for the treatment of bone metastases.]].Additionally, [[External beam radiotherapy]] (EBRT) has been, and continues to be, the mainstay for the treatment of painful, uncomplicated bone metastases.
==Natural History==
==Natural History==
*There is a theory that up to 22% of small (radiographically detected) breast tumors regress, based on an analysis in a large population.<ref name="pmid19029493">{{cite journal| author=Zahl PH, Maehlen J, Welch HG| title=The natural history of invasive breast cancers detected by screening mammography. | journal=Arch Intern Med | year= 2008 | volume= 168 | issue= 21 | pages= 2311-6 | pmid=19029493 | doi=10.1001/archinte.168.21.2311 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19029493  }} </ref> The study is supported by NCI's SEER data.<ref name="pmid19468099">{{cite journal| author=Jatoi I, Anderson WF| title=Breast cancer overdiagnosis with screening mammography. | journal=Arch Intern Med | year= 2009 | volume= 169 | issue= 10 | pages= 999-1000, author reply 1000-1 | pmid=19468099 | doi=10.1001/archinternmed.2009.95 | pmc=PMC2768420 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19468099  }} </ref>
*There is a theory that up to 22% of small (radiographically detected) breast tumors regress, based on an analysis in a large population.<ref name="pmid19029493">{{cite journal| author=Zahl PH, Maehlen J, Welch HG| title=The natural history of invasive breast cancers detected by screening mammography. | journal=Arch Intern Med | year= 2008 | volume= 168 | issue= 21 | pages= 2311-6 | pmid=19029493 | doi=10.1001/archinte.168.21.2311 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19029493  }} </ref> The study is supported by NCI's SEER data.<ref name="pmid19468099">{{cite journal| author=Jatoi I, Anderson WF| title=Breast cancer overdiagnosis with screening mammography. | journal=Arch Intern Med | year= 2009 | volume= 169 | issue= 10 | pages= 999-1000, author reply 1000-1 | pmid=19468099 | doi=10.1001/archinternmed.2009.95 | pmc=PMC2768420 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19468099  }} </ref>
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:*The relevant cutoff is ≥1 cell.
:*The relevant cutoff is ≥1 cell.


==Staging2==
=Staging=
Breast cancer used to be [[Cancer staging|staged]] according to the TNM system. Recently, the American Joint Committee on Cancer (AJCC) Staging Manual (8th edition, last updated 1/25/2018) extensively revised their staging system. The 8th edition of the AJCC TNM breast cancer staging system delivers a flexible platform for prognostic classification based on traditional anatomic factors, which may be modified and enhanced with respect to patient biomarkers and other prognostic panel data. Nevertheless, in order to maintain worldwide value, AJCC tumor staging system remained based on classic TNM anatomic factors. Prognosis is closely linked to results of staging, and staging is also used to allocate patients to treatments both in clinical trials and clinical practice.
===The 8th edition of the AJCC [[TNM]] breast cancer staging system===
*The 8th edition of the AJCC [[TNM]] breast cancer staging system delivers a flexible platform for prognostic classification based on traditional anatomic factors, which may be modified and enhanced with respect to patient biomarkers and other prognostic panel data.<ref name="pmid29671136">Giuliano AE, Edge SB, Hortobagyi GN (2018) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=29671136 Eighth Edition of the AJCC Cancer Staging Manual: Breast Cancer.] ''Ann Surg Oncol'' 25 (7):1783-1785. [http://dx.doi.org/10.1245/s10434-018-6486-6 DOI:10.1245/s10434-018-6486-6] PMID: [https://pubmed.gov/29671136 29671136]</ref>
*Nevertheless, in order to maintain worldwide value, AJCC tumor staging system remained based on the classic [[TNM]] anatomic factors.
*Major changes in the 8th edition of AJCC TNM staging system were discussed below.<ref name="pmid28294295">Giuliano AE, Connolly JL, Edge SB, Mittendorf EA, Rugo HS, Solin LJ et al. (2017) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=28294295 Breast Cancer-Major changes in the American Joint Committee on Cancer eighth edition cancer staging manual.] ''CA Cancer J Clin'' 67 (4):290-303. [http://dx.doi.org/10.3322/caac.21393 DOI:10.3322/caac.21393] PMID: [https://pubmed.gov/28294295 28294295]</ref>
*AJCC panel incorporated biologic factors into the staging system as follows:
:*Tumor grade
:*Proliferation rate
:* Estrogen and progesterone receptor expression
:*Human epidermal growth factor 2 ([[HER2|HER2)]] expression
:*Gene expression prognostic panels
*Hence components of recent breast cancer staging system are as follows:
:* The extent (size) of the [[Tumor|'''t'''umor]] '''(T)'''
:* The spread to nearby [[Lymph node|lymph '''n'''odes]] '''(N)'''
:* The spread ([[Metastasis|'''m'''etastasis]]) to distant sites '''(M)'''
:* [[Estrogen|Estrogen receptor]] '''(ER)''' presence
:* [[Progesterone receptor]] '''(PR)''' presence
:* Her2/neu '''([[HER2]])''' presence
:* Histopathologic grade of the cancer '''(G):'''
:* In certain circumstances, [[gene expression]] panels might also be used such as The '''Oncotype DX®''' and the '''MammaPrint® .'''
===Gene expression panels===
*  '''Oncotype DX'''®''':'''
:* For small hormone receptor-positive tumors that have not spread to more than 3 lymph nodes
:* Also may be used for more advanced tumors
:* Might be used for DCIS (ductal carcinoma in situ or stage 0 breast cancer). as well looks at a set of 21 genes in tumor biopsy samples to get a “recurrence score,” which is a number between 0 and 100.
:* The score reflects the risk of breast cancer coming back (recurring) in the next 10 years and how likely you will benefit from getting chemo after surgery.
:* '''The lower the score (usually 0-10) the lower the risk of recurrence'''.
:* Benefit from chemotherapy is in doubt in most women with low scores
:* '''An intermediate score (usually 11-25)''': '''intermediate risk of recurrence'''.
:* Benefit from chemotherapy is in doubt in most women with intermediate-recurrence scores,
:* Nevertheless chemotherapy is believed to be beneficial for women younger than 50 with a higher intermediate score (16-25)
:* The possible risks and benefits of chemo should be weighted and discussed prior to decision making.
:* '''A high score (usually 26-100): higher risk of recurrence'''.Chemotherapy is recommended for women with high scores in order to help lower the chance of cancer *recurrence.
:* '''OncotypeDx is the only multigene panel with level I of evidence, and hence has been incorporated in the AJCC staging system'''
*'''MammaPrint'''®''':'''
:*To determine the likelihood of cancer recurrence in a distant part of the body after treatment.
:*May be used in any type of breast cancer with stage 1 or 2 that has spread to no more than 3 lymph nodes.
:*Hormone and HER2 status are also evaluated in this test.  Seventy different genes are examined in this test to determine the 10 years cancer recurrence
:*The test results are reported as either “low risk” or “high risk.”
:*'''Unlike OncotypeDx has not  been incorporated in the AJCC staging system''' '''yet.'''
==[[Cancer staging|TNM Staging]]==
 
According to the AJCC statement ''<u>"Content is available for user's personal use. It can not be sold, published or incorporated into any software, product or publication with a written license agreement with ACS."</u>'' Hence, we may not provide the details of their recent staging system here.
 
You may find more information for your personal use [https://cancerstaging.org/references-tools/deskreferences/Documents/AJCC%20Breast%20Cancer%20Staging%20System.pdf here].
 
===Breast carcinoma TNM anatomic stage group===
*This system is solely recommended for countries with no/limited access to the other mentioned biochemical and genetic tests.
*This system is the classic Tumor(T) Lymph Node(N), Metastasis (M) system.
 
===Prognostic stage groupings===
:* Patients has been assigned to clinical prognosis stages with respect to the above-mentioned criteria.
:* The clinical prognostic stage applies to all patients with breast cancer.
:* It is the primary prognostic staging system for '''patients who receive neoadjuvant treatment or for those who do not receive surgery.''' 
:* It is based on clinical T, N, and M; grade; and HER2 and hormone receptor status and does not include genomic profile information.
 
===Pathologic prognostic stage===
*For patients who receive surgical resection as initial treatment,
*Based on:
:*Pathologic T, N, and M;
:*Pathologic grade;
:*HER2
:*Hormone receptor status
:*and for T1 to T2 N0, ER-positive, HER2-negative disease:
::*Genomic testing.  
 
=Bone metastasis=
==Overview==
* Bone is the most common site of [[breast cancer]] distant spread. Bone [[metastases]] due to the breast cancer cause major morbidity, decrease survival and reduce the quality of life of many patients. Rather than systemic chemotherapy, bisphosphonates like [[Pamidronate]], [[Alendronate]], [[Ibandronate]], [[Risedronate]], and [[Zoledronic acid]] , RANKL-RANK inhibitors like [[Denosumab|Denosumab, also has been recommended and studied for the treatment of bone metastases.]].Additionally, [[External beam radiotherapy]] (EBRT) has been, and continues to be, the mainstay for the treatment of painful, uncomplicated bone metastases.
 
 
===Bone Metastasis===
* Bone is the most common site of [[breast cancer]] distant spread. Bone [[metastases]] due to the breast cancer cause major morbidity, decrease survival and reduce the quality of life of many patients.
Cancer influence on the skeleton results in two main negative consequences: pain and Skeletal-Related events (SREs), defined as any of the following:
:*Pathologic [[fracture]],
:*A requirement for surgical intervention and palliative [[radiotherapy]] to bone lesions,
:*[[spinal cord compression]],
:*[[hypercalcemia]] of malignancy <ref name="pmid3814476">{{cite journal| author=Coleman RE, Rubens RD| title=The clinical course of bone metastases from breast cancer. | journal=Br J Cancer | year= 1987 | volume= 55 | issue= 1 | pages= 61-6 | pmid=3814476 | doi= | pmc=PMC2001575 | url= }} </ref>.
In fact, SREs constitute readily measured clinical parameters that are employed in clinics and clinical trials.
* Many disciplines should be involved in the management of breast cancer bone metastases, including [[medical oncology]], pain and palliative care, [[radiation oncology]], [[orthopedic surgery]] and [[neurosurgery]]. Systemic therapy delays the progression of bone metastases and provides palliation; it includes endocrine therapy, biologic agents, [[chemotherapy]], [[bisphosphonate]] therapy and the new osteoclast inhibitors.
* A thorough knowledge of the molecular basis of bone metastasis caused by breast cancer is essential for the understanding of the therapeutic approach. In fact, The normal balance between bone resorption and deposition is significantly affected by cancer. Bone metastases due to breast cancer are mostly osteolytic lesions, though the predominant osteoblastic disease can occur <ref name="pmid11346860">{{cite journal| author=Coleman RE, Seaman JJ| title=The role of zoledronic acid in cancer: clinical studies in the treatment and prevention of bone metastases. | journal=Semin Oncol | year= 2001 | volume= 28 | issue= 2 Suppl 6 | pages= 11-6 | pmid=11346860 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11346860  }} </ref>.
The breast cancer cells and the bone microenvironment interact extensively through many chemical mediators resulting in bone destruction and tumor growth. These molecular mediators (pimarily Osteopontin, CXCR4, CTGF and Interleukin-11) exert their effect on [[osteoclasts]] which in turn cause bone resorption. This osteoclast-mediated bone resorption is  thought to be the product of the action of numerous molecules including:
:*[[PTHrP]] (Parathyroid Hormone–related Peptide),
:*Tumor Necrosis Factor α (TNF-α),
:*[[Cytokines]] such as [[Interleukin-1]], [[Interleukin-6]], [[Interleukin-8]], and [[interleukin-11]]
* These factors signal [[osteoblasts]] (the bone-building cells) to induce osteoclast differentiation through the [[RANKL]] (the ligand for the receptor activator of nuclearfactor-κB [RANK])- [[RANK]] signaling. When Osteoclasts lyse bone, they cause the release of growth factors such as [[bone morphogenetic proteins]] (BMPs), [[IGF-I]] and [[TGF-β]] from the bone matrix which stimulate and maintain tumor cell proliferation and induce further release of PTHrP <ref name="pmid19109576">{{cite journal| author=Chiang AC, Massagué J| title=Molecular basis of metastasis. | journal=N Engl J Med | year= 2008 | volume= 359 | issue= 26 | pages= 2814-23 | pmid=19109576 | doi=10.1056/NEJMra0805239 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19109576  }} </ref>.
[[Image:SoroushSeifirad, Breast Cancer.png|thumb|center|1000px|<big>'''Pathophysiology of bone metastasis in breast cancer. The diagram is the authors' ([[User:Soroush Seifirad|Soroush Seifirad]]) own work.'''</big>]]
 
==Osteoclast Inhibitors==
===Bisphosphonates===
 
====Indication====
Bisphosphonates constitute a mainstay therapy for patients with bone metastases, they can prevent skeletal complications and palliate bone pain. It should be noted that there is no proven survival benefit. Therapy with high dose bisphosphonates should be initiated after a documented diagnosis of osseous metastases because it has been shown that they do not decrease the incidence of skeletal events in women without metastatic disease.
 
====Pharamacology====
Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption through multiple mechanisms, including downregulation of osteoclast activity, promotion of osteoclast [[apoptosis]] and inhibition of osteoclast maturation and differentiation  <ref name="pmid17183355">Dunstan CR, Felsenberg D, Seibel MJ (2007) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=17183355 Therapy insight: the risks and benefits of bisphosphonates for the treatment of tumor-induced bone disease.] ''Nat Clin Pract Oncol'' 4 (1):42-55. [http://dx.doi.org/10.1038/ncponc0688 DOI:10.1038/ncponc0688] PMID: [http://pubmed.gov/17183355 17183355]</ref>. Furthermore, they may trigger the apoptosis of cancer cells, inhibit [[matrix metalloproteinase]] 1 (an enzyme that degrades extracellular matrix proteins), reduce [[angiogenesis]] and disturb the adhesion of tumour cells to bone <ref name="pmid15802276">Coleman RE (2005) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15802276 Bisphosphonates in breast cancer.] ''Ann Oncol'' 16 (5):687-95. [http://dx.doi.org/10.1093/annonc/mdi162 DOI:10.1093/annonc/mdi162] PMID: [http://pubmed.gov/15802276 15802276]</ref>. The bisphosphonates are analogs of [[pyrophosphate]], with carbon replacing the central oxygen. Their affinity for hydroxyapatite, the main bone mineral, is made possible by the side chains (R1 and R2) from the central carbon <ref name="pmid9494781">Fleisch H (1998) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=9494781 Bisphosphonates: mechanisms of action.] ''Endocr Rev'' 19 (1):80-100. PMID: [http://pubmed.gov/9494781 9494781]</ref>.
 
There are two classes of bisphosphonates, non-nitrogen containing and nitrogen containing, that are different in their action on the osteoclasts. The nitrogen containing bisphosphonates ([[Pamidronate]], [[Alendronate]], [[Ibandronate]], [[Risedronate]], and [[Zoledronic acid]]) are more potent osteoclast inhibitors than the non-nitrogen containing bisphosphonates which include [[Etidronate]], [[Clodronate]], and [[Tiludronate]].
 
====Treatment Guidelines====
 
In the United States, only the intravenous pamidronate and zoledronic acid are approved by the FDA for treatment of osseous metastases. '''The American Society of Clinical Oncology (ASCO)''' recommends that:
*Osteoclast inhibitors including bisphosphonates be initiated in the management of patients with metastatic breast cancer and evidence of bone destruction on plain [[radiograph]]s, [[CT]], or [[MRI]] (but not [[bone scan]]s) even if asymptomatic
*Bisphosphonates administration: Intravenous [[Pamidronic acid|pamidronate]] 90 mg over no less than 2 hours, or zoledronic acid 4 mg over no less than 15 minutes every 3 to 4 weeks
*There is no clear difference between oral or intravenous formulations of bisphosphonates and no clear superiority of either zoledronic acid or pamidronate <ref name="pmid21343561">Van Poznak CH, Temin S, Yee GC, Janjan NA, Barlow WE, Biermann JS et al. (2011) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=21343561 American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer.] ''J Clin Oncol'' 29 (9):1221-7. [http://dx.doi.org/10.1200/JCO.2010.32.5209 DOI:10.1200/JCO.2010.32.5209] PMID: [http://pubmed.gov/21343561 21343561]</ref>.
Another important concept is that bone modifying agents including bisphosphonates should be adjunctive for bone pain control and not a replacement for analgesics, radiotherapy, or surgery <ref name="pmid17393190">Diel IJ (2007) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=17393190 Effectiveness of bisphosphonates on bone pain and quality of life in breast cancer patients with metastatic bone disease: a review.] ''Support Care Cancer'' 15 (11):1243-9. [http://dx.doi.org/10.1007/s00520-007-0244-9 DOI:10.1007/s00520-007-0244-9] PMID: [http://pubmed.gov/17393190 17393190]</ref> <ref name="pmid19190592">Costa L, Major PP (2009) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19190592 Effect of bisphosphonates on pain and quality of life in patients with bone metastases.] ''Nat Clin Pract Oncol'' 6 (3):163-74. [http://dx.doi.org/10.1038/ncponc1323 DOI:10.1038/ncponc1323] PMID: [http://pubmed.gov/19190592 19190592]</ref>. There is no recommended duration of treatment; '''the ASCO guidelines''' suggest that bone modifying agents be continued until evidence of substantial decline in a patient’s general performance status <ref name="pmid21343561">Van Poznak CH, Temin S, Yee GC, Janjan NA, Barlow WE, Biermann JS et al. (2011) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=21343561 American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer.] ''J Clin Oncol'' 29 (9):1221-7. [http://dx.doi.org/10.1200/JCO.2010.32.5209 DOI:10.1200/JCO.2010.32.5209] PMID: [http://pubmed.gov/21343561 21343561]</ref>.
 
====Side Effects====
 
*Phase III studies have shown that less than 2 percent of patients experience serious toxicity from bisphosphonates <ref name="pmid16547070">Tanvetyanon T, Stiff PJ (2006) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16547070 Management of the adverse effects associated with intravenous bisphosphonates.] ''Ann Oncol'' 17 (6):897-907. [http://dx.doi.org/10.1093/annonc/mdj105 DOI:10.1093/annonc/mdj105] PMID: [http://pubmed.gov/16547070 16547070]</ref>.
 
*Side effects include inflammatory reactions including the [[acute phase reaction]], phlebitis and ocular inflammation ([[conjunctivitis]], [[uveitis]], [[scleritis]]). The acute phase reaction is a flu-like syndrome with [[fever]], [[chills]], [[myalgias]] and [[arthralgias]] occuring in approximately half of the patients; it is more common in non-Japanese Asians, younger subjects, and [[nonsteroidal antiinflammatory drug]] users and less common in smokers, patients with [[diabetes]], previous users of oral bisphosphonates, and Latin Americans <ref name="pmid20554708">Reid IR, Gamble GD, Mesenbrink P, Lakatos P, Black DM (2010) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=20554708 Characterization of and risk factors for the acute-phase response after zoledronic acid.] ''J Clin Endocrinol Metab'' 95 (9):4380-7. [http://dx.doi.org/10.1210/jc.2010-0597 DOI:10.1210/jc.2010-0597] PMID: [http://pubmed.gov/20554708 20554708]</ref>. It is classically seen within 3 days after infusion and is self limiting within 1 to 3 days. Acetaminophen or non-steroidal antiinflammatory drugs intake prior to infusion may decrease symptom severity <ref name="pmid16547070">Tanvetyanon T, Stiff PJ (2006) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16547070 Management of the adverse effects associated with intravenous bisphosphonates.] ''Ann Oncol'' 17 (6):897-907. [http://dx.doi.org/10.1093/annonc/mdj105 DOI:10.1093/annonc/mdj105] PMID: [http://pubmed.gov/16547070 16547070]</ref>. The occurence of the acute phase reaction and its intensity tends to lessen after subsequent infusions.
 
*[[Renal insufficiency]] is another complication of bisphosphonate therapy and it is both dose- and infusion time-dependent. Nephrotoxicity can be reduced by slow infusion durations, providing adequate hydration prior to bisphosphonate infusion and withholding concomitant nephrotoxic medications. '''The ASCO''' recommends no change in dose, infusion time, or interval if creatinine clearance is superior to 60 mL/min. For patients receiving IV bisphosphonates, the creatinine level should be monitored before each infusion <ref name="pmid21343561">Van Poznak CH, Temin S, Yee GC, Janjan NA, Barlow WE, Biermann JS et al. (2011) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=21343561 American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer.] ''J Clin Oncol'' 29 (9):1221-7. [http://dx.doi.org/10.1200/JCO.2010.32.5209 DOI:10.1200/JCO.2010.32.5209] PMID: [http://pubmed.gov/21343561 21343561]</ref>.
 
*[[Electrolyte disturbances]] can occur in patients on bisphosphonates which necessitates regular monitoring of serum [[calcium]], [[magnesium]], and [[phosphate]] during therapy.
 
=====[[Osteonecrosis of the Jaw]]=====
Osteonecrosis (avascular necrosis) of the jaw (ONJ) is a more common complication with zoledronic acid compared with pamidronate. It is defined as an area of exposed bone in the [[maxillofacial]] or [[mandibular]] region that does not heal within 8 weeks of identification by a healthcare provider, in a patient who has been exposed to a bone-modifying agent administered either IV or orally, and has not had radiation therapy to the craniofacial region <ref name="pmid19371809">Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B et al. (2009) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19371809 American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws--2009 update.] ''J Oral Maxillofac Surg'' 67 (5 Suppl):2-12. [http://dx.doi.org/10.1016/j.joms.2009.01.009 DOI:10.1016/j.joms.2009.01.009] PMID: [http://pubmed.gov/19371809 19371809]</ref>.
The pathophysiology is unclear. The most common complaints are pain and/or numbness in the affected region, tooth mobility, and soft tissue swelling.  Conservative management with debridement, mouth rinses and [[antibiotics]] could result in healing <ref name="pmid19304045">Lazarovici TS, Yahalom R, Taicher S, Elad S, Hardan I, Yarom N (2009) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19304045 Bisphosphonate-related osteonecrosis of the jaws: a single-center study of 101 patients.] ''J Oral Maxillofac Surg'' 67 (4):850-5. [http://dx.doi.org/10.1016/j.joms.2008.11.015 DOI:10.1016/j.joms.2008.11.015] PMID: [http://pubmed.gov/19304045 19304045]</ref>.
 
'''US [[FDA]] labeling and ASCO guidelines''' for bone-modifying agents (including Bisphosphonates and [[Denosumab]]) suggest dental examination and necessary preventive [[dentistry]] for cancer patients before initiating therapy with these agents <ref name="pmid21343561">Van Poznak CH, Temin S, Yee GC, Janjan NA, Barlow WE, Biermann JS et al. (2011) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=21343561 American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer.] ''J Clin Oncol'' 29 (9):1221-7. [http://dx.doi.org/10.1200/JCO.2010.32.5209 DOI:10.1200/JCO.2010.32.5209] PMID: [http://pubmed.gov/21343561 21343561]</ref>. Maintaining oral hygiene and avoiding dental procedures of the [[mandible]], [[maxilla]] or [[periosteum]] should be advised.
Patients receiving therapy with bisphosphonates should get calcium and [[vitamin D]] supplementation to reduce the risk of bisphosphonate-induced [[hypocalcemia]]. Also, it should be noted that vitamin D deficiency increases the risk for bisphosphonate-induced hypocalcemia.
 
===Denosumab===
As mentioned in the pathogenesis section, the RANKL-RANK signaling pathway is a main molecular tool used by osteoclasts to resorb bone. Denosumab is a monoclonal [[antibody]] to the [[RANKL]] that inhibits it from binding to RANK leading to osteoclast inhibition. Denosumab is '''FDA''' approved to prevent SREs in patients with bone metastases from solid tumors at a dose of 120 mg subcutaneously every four weeks. In a randomized double-blind phase III trial comparing the efficacy of Denosumab to zoledronic acid in delaying time to first SRE, [[Denosumab]] was superior to zoledronic acid in delaying time to first on-study SRE ''(hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .01 superiority) and time to first and subsequent (multiple) on-study SREs (rate ratio, 0.77; 95% CI, 0.66 to 0.89; P = .001)'' <ref name="pmid21060033">Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH et al. (2010) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=21060033 Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study.] ''J Clin Oncol'' 28 (35):5132-9. [http://dx.doi.org/10.1200/JCO.2010.29.7101 DOI:10.1200/JCO.2010.29.7101] PMID: [http://pubmed.gov/21060033 21060033]</ref>. This trial also showed that overall survival, disease progression, and rates of adverse events (AEs) and serious AEs were similar between groups. Renal toxicity and acute-phase reactions occurred more frequently with zoledronic acid but hypocalcemia occurred more frequently with denosumab <ref name="pmid21060033">Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH et al. (2010) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=21060033 Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study.] ''J Clin Oncol'' 28 (35):5132-9. [http://dx.doi.org/10.1200/JCO.2010.29.7101 DOI:10.1200/JCO.2010.29.7101] PMID: [http://pubmed.gov/21060033 21060033]</ref>. The most common side effects of denosumab are [[fatigue]], [[nausea]] and [[hypophosphatemia]]; [[dyspnea]] is the most common serious side effect. The Combination of denosumab with an IV bisphosphonate for the treatment of bone metastases is not recommended. Calcium and vitamin D supplementation is recommended during therapy with denosumab to prevent hypocalcemia.
 
==Palliative Radiation Therapy==
 
According to '''the American Society of therapeutic Radiation Oncology (ASTRO)''':<ref name="pmid21277118">Lutz S, Berk L, Chang E, Chow E, Hahn C, Hoskin P et al. (2011) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=21277118 Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline.] ''Int J Radiat Oncol Biol Phys'' 79 (4):965-76. [http://dx.doi.org/10.1016/j.ijrobp.2010.11.026 DOI:10.1016/j.ijrobp.2010.11.026] PMID: [http://pubmed.gov/21277118 21277118]</ref>
*[[External beam radiotherapy]] (EBRT) has been, and continues to be, the mainstay for the treatment of painful, uncomplicated bone metastases
 
*Although various fractionation schemes can provide good rates of [[palliation]], numerous prospective randomized trials have shown that 30 Gy in 10 fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions, or 8 Gy in a single fraction can provide excellent pain control and minimal side effects. The longer course has the advantage of a lower incidence of repeat treatment to the same site, and the single fraction has proved more convenient for patients and caregivers
 
*Repeat irradiation with EBRT might be safe, effective, and less commonly necessary in patients with a short life expectancy
 
*Bisphosphonates do not obviate the need for EBRT for painful sites of metastases and might, indeed, act effectively when combined with EBRT
 
*Surgical decompression and stabilization plus postoperative RT should be considered for selected patients with single-level spinal cord compression or spinal instability unless the patients have an anticipated life expectancy that is too short. Kyphoplasty and [[vertebroplasty]] might be useful for the treatment of lytic osteoclastic spinal metastases or in cases of spinal instability for which surgery is not feasible or indicated. They do not obviate the need for EBRT, and no data are available to suggest that the addition of vertebroplasty or kyphoplasty further improve [[symptoms]] or has a greater effect on clinically significant endpoints than EBRT alone. Additional prospective trials are needed to better define whether a patient population exists that would benefit from treatment with kyphoplasty or vertebroplasty, and, if so, how those procedures should best be sequenced with EBRT.
 
 


==References==
==References==

Latest revision as of 15:13, 15 October 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2] Mirdula Sharma, MBBS [3]

Overview

If left untreated, 22% of patients with breast cancer may regress. Common complications of breast cancer include metastasis. Prognosis is generally good with treatment. Breast cancer used to be staged according to the TNM system. Recently, the American Joint Committee on Cancer (AJCC) Staging Manual (8th edition, last updated 1/25/2018) extensively revised their staging system. The 8th edition of the AJCC TNM breast cancer staging system delivers a flexible platform for prognostic classification based on traditional anatomic factors, which may be modified and enhanced with respect to patient biomarkers and other prognostic panel data. Nevertheless, in order to maintain worldwide value, AJCC tumor staging system remained based on classic TNM anatomic factors. Prognosis is closely linked to results of staging, and staging is also used to allocate patients to treatments both in clinical trials and clinical practice. Bone is the most common site of breast cancer distant spread. Bone metastases due to the breast cancer cause major morbidity, decrease survival and reduce the quality of life of many patients. Rather than systemic chemotherapy, bisphosphonates like Pamidronate, Alendronate, Ibandronate, Risedronate, and Zoledronic acid , RANKL-RANK inhibitors like Denosumab, also has been recommended and studied for the treatment of bone metastases..Additionally, External beam radiotherapy (EBRT) has been, and continues to be, the mainstay for the treatment of painful, uncomplicated bone metastases.

Natural History

  • There is a theory that up to 22% of small (radiographically detected) breast tumors regress, based on an analysis in a large population.[1] The study is supported by NCI's SEER data.[2]
  • The natural history of breast cancer is extremely variable ranging from indolent cancers to aggressive cancers that can metastasize with fatal consequences.[3]

Prognosis

The prognosis and treatment options depend on the following:

Nottingham Prognostic Index

The Nottingham prognostic index (NPI) is used to determine prognosis following surgery for breast cancer. Its value is calculated using three pathological criteria: the size of the lesion; the number of involved lymph nodes; and the grade of the tumor.[4]

Calculation

The index is calculated using the formula:

NPI = [0.2 x S] + N + G

Where:

  • S is the size of the index lesion in centimetres
  • N is the node status: 0 nodes = 1, 1-4 nodes = 2, >4 nodes = 3
  • G is the grade of tumour: Grade I =1, Grade II =2, Grade III =3

Interpretation

Score 5-year survival
2.0 to 2.4 93%
2.5 to 3.4 85%
3.5 to 5.4 70%
> 5.4 50%

Estimated five year survival rates:[5]

stage I: ~87%
stage II: ~75%
stage III: ~46%
stage IV: ~13%

AJCC clinical prognosis categorization

  • The 8th revision of AJCC staging system for breast cancer has been extensively modified.
  • Rather than classic TNM system, other characteristics of tumors such as pathologic grade, the presence of ER, PR, hormone receptors as well as presence of certain genetic mutations such as HER2 has been integrated into the latest revision. Among multi gene panels only RS score (Oncotype DX) has been integrated into AJCC 8th edition of breast cancer staging system. It is recommended solely for the pathologic groupings of the patients whom surgery is the initial treatment for them. For more information please refer to the staging section of this chapter.
  • Patients has been assigned to clinical prognosis stages with respect to the above-mentioned criteria.

Approach to determine the prognostic stage group of the patients according to the AJCC staging recommendations for breast cancer (8th edition)

Approach to determine the clinical prognostic stage group of the patients according to the AJCC staging recommendations for breast cancer (8th edition). The diagram is the authors' (Soroush Seifirad) own work.

Adopted and modified from AJCC 8th Edition staging system.

Other prognostic factors

In a nutshell, rather than classic TNM staging system, the following biological factors were incorporated into the prognostic staging system of the eighth edition of the AJCC staging manual:

  • Estrogen receptor (ER) and progesterone receptor (PR) expression
  • Human epidermal growth factor receptor 2 (HER2)
  • Histologic grade
  • Recurrence Score (RS):Oncotype DX

In addition to the above-mentioned factors, the AJCC mentioned several other factors that might help to determine the prognosis in patients with breast cancer, although the followings were not formally included in the current staging system:

  • Ki-67 :
  • Cellular proliferation and tumor balk marker
  • Multigene expression assays other than RS:
  • Mammaprint, EndoPredict, PAM50 Risk of Recurrence (ROR), and the Breast Cancer Index (level II evidence)
  • Risk assessment models:
  • Adjuvant! Online
  • PREDICT-Plus
  • Circulating tumor cells (CTCs):
  • Cancer cells that separate from solid tumors and enter the bloodstream
  • The cutoff for an unfavorable prognosis is ≥5 cells/7.5 mL
  • Disseminated tumor cells (DTCs):
  • Disseminated tumor cells in the bone marrow
  • Might predict the likelihood of relapse at the time of initial tumor resection
  • The relevant cutoff is ≥1 cell.

Staging

Breast cancer used to be staged according to the TNM system. Recently, the American Joint Committee on Cancer (AJCC) Staging Manual (8th edition, last updated 1/25/2018) extensively revised their staging system. The 8th edition of the AJCC TNM breast cancer staging system delivers a flexible platform for prognostic classification based on traditional anatomic factors, which may be modified and enhanced with respect to patient biomarkers and other prognostic panel data. Nevertheless, in order to maintain worldwide value, AJCC tumor staging system remained based on classic TNM anatomic factors. Prognosis is closely linked to results of staging, and staging is also used to allocate patients to treatments both in clinical trials and clinical practice.

The 8th edition of the AJCC TNM breast cancer staging system

  • The 8th edition of the AJCC TNM breast cancer staging system delivers a flexible platform for prognostic classification based on traditional anatomic factors, which may be modified and enhanced with respect to patient biomarkers and other prognostic panel data.[6]
  • Nevertheless, in order to maintain worldwide value, AJCC tumor staging system remained based on the classic TNM anatomic factors.
  • Major changes in the 8th edition of AJCC TNM staging system were discussed below.[7]
  • AJCC panel incorporated biologic factors into the staging system as follows:
  • Tumor grade
  • Proliferation rate
  • Estrogen and progesterone receptor expression
  • Human epidermal growth factor 2 (HER2) expression
  • Gene expression prognostic panels
  • Hence components of recent breast cancer staging system are as follows:

Gene expression panels

  • Oncotype DX®:
  • For small hormone receptor-positive tumors that have not spread to more than 3 lymph nodes
  • Also may be used for more advanced tumors
  • Might be used for DCIS (ductal carcinoma in situ or stage 0 breast cancer). as well looks at a set of 21 genes in tumor biopsy samples to get a “recurrence score,” which is a number between 0 and 100.
  • The score reflects the risk of breast cancer coming back (recurring) in the next 10 years and how likely you will benefit from getting chemo after surgery.
  • The lower the score (usually 0-10) the lower the risk of recurrence.
  • Benefit from chemotherapy is in doubt in most women with low scores
  • An intermediate score (usually 11-25): intermediate risk of recurrence.
  • Benefit from chemotherapy is in doubt in most women with intermediate-recurrence scores,
  • Nevertheless chemotherapy is believed to be beneficial for women younger than 50 with a higher intermediate score (16-25)
  • The possible risks and benefits of chemo should be weighted and discussed prior to decision making.
  • A high score (usually 26-100): higher risk of recurrence.Chemotherapy is recommended for women with high scores in order to help lower the chance of cancer *recurrence.
  • OncotypeDx is the only multigene panel with level I of evidence, and hence has been incorporated in the AJCC staging system
  • MammaPrint®:
  • To determine the likelihood of cancer recurrence in a distant part of the body after treatment.
  • May be used in any type of breast cancer with stage 1 or 2 that has spread to no more than 3 lymph nodes.
  • Hormone and HER2 status are also evaluated in this test. Seventy different genes are examined in this test to determine the 10 years cancer recurrence
  • The test results are reported as either “low risk” or “high risk.”
  • Unlike OncotypeDx has not been incorporated in the AJCC staging system yet.

TNM Staging

According to the AJCC statement "Content is available for user's personal use. It can not be sold, published or incorporated into any software, product or publication with a written license agreement with ACS." Hence, we may not provide the details of their recent staging system here.

You may find more information for your personal use here.

Breast carcinoma TNM anatomic stage group

  • This system is solely recommended for countries with no/limited access to the other mentioned biochemical and genetic tests.
  • This system is the classic Tumor(T) Lymph Node(N), Metastasis (M) system.

Prognostic stage groupings

  • Patients has been assigned to clinical prognosis stages with respect to the above-mentioned criteria.
  • The clinical prognostic stage applies to all patients with breast cancer.
  • It is the primary prognostic staging system for patients who receive neoadjuvant treatment or for those who do not receive surgery.
  • It is based on clinical T, N, and M; grade; and HER2 and hormone receptor status and does not include genomic profile information.

Pathologic prognostic stage

  • For patients who receive surgical resection as initial treatment,
  • Based on:
  • Pathologic T, N, and M;
  • Pathologic grade;
  • HER2
  • Hormone receptor status
  • and for T1 to T2 N0, ER-positive, HER2-negative disease:
  • Genomic testing.  

Bone metastasis

Overview


Bone Metastasis

  • Bone is the most common site of breast cancer distant spread. Bone metastases due to the breast cancer cause major morbidity, decrease survival and reduce the quality of life of many patients.

Cancer influence on the skeleton results in two main negative consequences: pain and Skeletal-Related events (SREs), defined as any of the following:

In fact, SREs constitute readily measured clinical parameters that are employed in clinics and clinical trials.

  • Many disciplines should be involved in the management of breast cancer bone metastases, including medical oncology, pain and palliative care, radiation oncology, orthopedic surgery and neurosurgery. Systemic therapy delays the progression of bone metastases and provides palliation; it includes endocrine therapy, biologic agents, chemotherapy, bisphosphonate therapy and the new osteoclast inhibitors.
  • A thorough knowledge of the molecular basis of bone metastasis caused by breast cancer is essential for the understanding of the therapeutic approach. In fact, The normal balance between bone resorption and deposition is significantly affected by cancer. Bone metastases due to breast cancer are mostly osteolytic lesions, though the predominant osteoblastic disease can occur [9].

The breast cancer cells and the bone microenvironment interact extensively through many chemical mediators resulting in bone destruction and tumor growth. These molecular mediators (pimarily Osteopontin, CXCR4, CTGF and Interleukin-11) exert their effect on osteoclasts which in turn cause bone resorption. This osteoclast-mediated bone resorption is thought to be the product of the action of numerous molecules including:

  • These factors signal osteoblasts (the bone-building cells) to induce osteoclast differentiation through the RANKL (the ligand for the receptor activator of nuclearfactor-κB [RANK])- RANK signaling. When Osteoclasts lyse bone, they cause the release of growth factors such as bone morphogenetic proteins (BMPs), IGF-I and TGF-β from the bone matrix which stimulate and maintain tumor cell proliferation and induce further release of PTHrP [10].
Pathophysiology of bone metastasis in breast cancer. The diagram is the authors' (Soroush Seifirad) own work.

Osteoclast Inhibitors

Bisphosphonates

Indication

Bisphosphonates constitute a mainstay therapy for patients with bone metastases, they can prevent skeletal complications and palliate bone pain. It should be noted that there is no proven survival benefit. Therapy with high dose bisphosphonates should be initiated after a documented diagnosis of osseous metastases because it has been shown that they do not decrease the incidence of skeletal events in women without metastatic disease.

Pharamacology

Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption through multiple mechanisms, including downregulation of osteoclast activity, promotion of osteoclast apoptosis and inhibition of osteoclast maturation and differentiation [11]. Furthermore, they may trigger the apoptosis of cancer cells, inhibit matrix metalloproteinase 1 (an enzyme that degrades extracellular matrix proteins), reduce angiogenesis and disturb the adhesion of tumour cells to bone [12]. The bisphosphonates are analogs of pyrophosphate, with carbon replacing the central oxygen. Their affinity for hydroxyapatite, the main bone mineral, is made possible by the side chains (R1 and R2) from the central carbon [13].

There are two classes of bisphosphonates, non-nitrogen containing and nitrogen containing, that are different in their action on the osteoclasts. The nitrogen containing bisphosphonates (Pamidronate, Alendronate, Ibandronate, Risedronate, and Zoledronic acid) are more potent osteoclast inhibitors than the non-nitrogen containing bisphosphonates which include Etidronate, Clodronate, and Tiludronate.

Treatment Guidelines

In the United States, only the intravenous pamidronate and zoledronic acid are approved by the FDA for treatment of osseous metastases. The American Society of Clinical Oncology (ASCO) recommends that:

  • Osteoclast inhibitors including bisphosphonates be initiated in the management of patients with metastatic breast cancer and evidence of bone destruction on plain radiographs, CT, or MRI (but not bone scans) even if asymptomatic
  • Bisphosphonates administration: Intravenous pamidronate 90 mg over no less than 2 hours, or zoledronic acid 4 mg over no less than 15 minutes every 3 to 4 weeks
  • There is no clear difference between oral or intravenous formulations of bisphosphonates and no clear superiority of either zoledronic acid or pamidronate [14].

Another important concept is that bone modifying agents including bisphosphonates should be adjunctive for bone pain control and not a replacement for analgesics, radiotherapy, or surgery [15] [16]. There is no recommended duration of treatment; the ASCO guidelines suggest that bone modifying agents be continued until evidence of substantial decline in a patient’s general performance status [14].

Side Effects

  • Phase III studies have shown that less than 2 percent of patients experience serious toxicity from bisphosphonates [17].
  • Side effects include inflammatory reactions including the acute phase reaction, phlebitis and ocular inflammation (conjunctivitis, uveitis, scleritis). The acute phase reaction is a flu-like syndrome with fever, chills, myalgias and arthralgias occuring in approximately half of the patients; it is more common in non-Japanese Asians, younger subjects, and nonsteroidal antiinflammatory drug users and less common in smokers, patients with diabetes, previous users of oral bisphosphonates, and Latin Americans [18]. It is classically seen within 3 days after infusion and is self limiting within 1 to 3 days. Acetaminophen or non-steroidal antiinflammatory drugs intake prior to infusion may decrease symptom severity [17]. The occurence of the acute phase reaction and its intensity tends to lessen after subsequent infusions.
  • Renal insufficiency is another complication of bisphosphonate therapy and it is both dose- and infusion time-dependent. Nephrotoxicity can be reduced by slow infusion durations, providing adequate hydration prior to bisphosphonate infusion and withholding concomitant nephrotoxic medications. The ASCO recommends no change in dose, infusion time, or interval if creatinine clearance is superior to 60 mL/min. For patients receiving IV bisphosphonates, the creatinine level should be monitored before each infusion [14].
Osteonecrosis of the Jaw

Osteonecrosis (avascular necrosis) of the jaw (ONJ) is a more common complication with zoledronic acid compared with pamidronate. It is defined as an area of exposed bone in the maxillofacial or mandibular region that does not heal within 8 weeks of identification by a healthcare provider, in a patient who has been exposed to a bone-modifying agent administered either IV or orally, and has not had radiation therapy to the craniofacial region [19]. The pathophysiology is unclear. The most common complaints are pain and/or numbness in the affected region, tooth mobility, and soft tissue swelling. Conservative management with debridement, mouth rinses and antibiotics could result in healing [20].

US FDA labeling and ASCO guidelines for bone-modifying agents (including Bisphosphonates and Denosumab) suggest dental examination and necessary preventive dentistry for cancer patients before initiating therapy with these agents [14]. Maintaining oral hygiene and avoiding dental procedures of the mandible, maxilla or periosteum should be advised. Patients receiving therapy with bisphosphonates should get calcium and vitamin D supplementation to reduce the risk of bisphosphonate-induced hypocalcemia. Also, it should be noted that vitamin D deficiency increases the risk for bisphosphonate-induced hypocalcemia.

Denosumab

As mentioned in the pathogenesis section, the RANKL-RANK signaling pathway is a main molecular tool used by osteoclasts to resorb bone. Denosumab is a monoclonal antibody to the RANKL that inhibits it from binding to RANK leading to osteoclast inhibition. Denosumab is FDA approved to prevent SREs in patients with bone metastases from solid tumors at a dose of 120 mg subcutaneously every four weeks. In a randomized double-blind phase III trial comparing the efficacy of Denosumab to zoledronic acid in delaying time to first SRE, Denosumab was superior to zoledronic acid in delaying time to first on-study SRE (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .01 superiority) and time to first and subsequent (multiple) on-study SREs (rate ratio, 0.77; 95% CI, 0.66 to 0.89; P = .001) [21]. This trial also showed that overall survival, disease progression, and rates of adverse events (AEs) and serious AEs were similar between groups. Renal toxicity and acute-phase reactions occurred more frequently with zoledronic acid but hypocalcemia occurred more frequently with denosumab [21]. The most common side effects of denosumab are fatigue, nausea and hypophosphatemia; dyspnea is the most common serious side effect. The Combination of denosumab with an IV bisphosphonate for the treatment of bone metastases is not recommended. Calcium and vitamin D supplementation is recommended during therapy with denosumab to prevent hypocalcemia.

Palliative Radiation Therapy

According to the American Society of therapeutic Radiation Oncology (ASTRO):[22]

  • External beam radiotherapy (EBRT) has been, and continues to be, the mainstay for the treatment of painful, uncomplicated bone metastases
  • Although various fractionation schemes can provide good rates of palliation, numerous prospective randomized trials have shown that 30 Gy in 10 fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions, or 8 Gy in a single fraction can provide excellent pain control and minimal side effects. The longer course has the advantage of a lower incidence of repeat treatment to the same site, and the single fraction has proved more convenient for patients and caregivers
  • Repeat irradiation with EBRT might be safe, effective, and less commonly necessary in patients with a short life expectancy
  • Bisphosphonates do not obviate the need for EBRT for painful sites of metastases and might, indeed, act effectively when combined with EBRT
  • Surgical decompression and stabilization plus postoperative RT should be considered for selected patients with single-level spinal cord compression or spinal instability unless the patients have an anticipated life expectancy that is too short. Kyphoplasty and vertebroplasty might be useful for the treatment of lytic osteoclastic spinal metastases or in cases of spinal instability for which surgery is not feasible or indicated. They do not obviate the need for EBRT, and no data are available to suggest that the addition of vertebroplasty or kyphoplasty further improve symptoms or has a greater effect on clinically significant endpoints than EBRT alone. Additional prospective trials are needed to better define whether a patient population exists that would benefit from treatment with kyphoplasty or vertebroplasty, and, if so, how those procedures should best be sequenced with EBRT.


References

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  3. Breast Cancer. Cleveland Clinic (2015) http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hematology-oncology/breast-cancer/ Accessed on January 18 2016
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  5. Breast Cancer. RadioPedia (2015) http://radiopaedia.org/articles/breast-cancer-staging Accessed on January 16, 2016
  6. Giuliano AE, Edge SB, Hortobagyi GN (2018) Eighth Edition of the AJCC Cancer Staging Manual: Breast Cancer. Ann Surg Oncol 25 (7):1783-1785. DOI:10.1245/s10434-018-6486-6 PMID: 29671136
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