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[edit | edit source]

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[edit | edit source]

• 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[edit | edit source]

The prognosis and treatment options depend on the following:

• The stage of the cancer (the size of the tumor and whether it is in the breast only or has spread to lymph nodes or other places in the body)
• The type of breast cancer
• Estrogen receptor and progesterone receptor levels in the tumor tissue
• Human epidermal growth factor type 2 receptor (HER2/neu) levels in the tumor tissue
• Whether the tumor tissue is triple negative (cells that do not have estrogen receptors, progesterone receptors, or high levels of HER2/neu)
• How fast the tumor is growing
• How likely the tumor is to recur (come back)
• A woman’s age, general health, and menopausal status (whether a woman is still having menstrual periods)
• Whether the cancer has just been diagnosed or has recurred (come back)

Nottingham Prognostic Index[edit | edit source]

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[edit | edit source]

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[edit | edit source]

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)

Adopted and modified from AJCC 8th Edition staging system.

Other prognostic factors[edit | edit source]

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[edit | edit source]

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[edit | edit source]

• 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:

• The extent (size) of the tumor (T)
• The spread to nearby lymph nodes (N)
• The spread (metastasis) to distant sites (M)
• 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[edit | edit source]

• 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[edit | edit source]

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[edit | edit source]

• 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[edit | edit source]

• 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[edit | edit source]

• 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[edit | edit source]

Overview[edit | edit source]

• 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.

Bone Metastasis[edit | edit source]

• 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 ^[8].

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:

• 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 ^[10].

Osteoclast Inhibitors[edit | edit source]

Bisphosphonates[edit | edit source]

Indication[edit | edit source]

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[edit | edit source]

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[edit | edit source]

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[edit | edit source]

• 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].

• Electrolyte disturbances can occur in patients on bisphosphonates which necessitates regular monitoring of serum calcium, magnesium, and phosphate during therapy.

Osteonecrosis of the Jaw[edit | edit source]

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[edit | edit source]

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[edit | edit source]

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[edit | edit source]

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