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TEs, such as deep venous thrombosis and PE, are uncommon but serious potential consequences related to all malignancies, breast cancer being no exception.384 Cancers are prothrombotic states, and the association of malignancies and the development of hypercoagulability have been well recognized for more than 150 years. Initially described by Rudolf Virchow,385 this association has come to be known as the triad of Virchow or Virchow’s triad: damage to endothelial cells, hypercoagulability (elaboration of procoagulants), and stasis (alteration in blood flow)12,386,387 (Figure 1).

The risk of TE in cancer-affected patients is estimated to range from 15% to 20% and is the second-leading cause of death in those with cancer, although it is often seen in conjunction with multiple additional comorbidities.384,388 The incidence of TE appears to be on the rise because of improved diagnostic imaging technologies, advanced and more effective therapeutic interventions, and, most importantly, increased long-term survival (DFS rates, measured in years after diagnosis and treatment).389 Multiple risk factors for TE in patients with cancer have been identified as significantly affecting morbidity and mortality. It has been estimated that patients in whom a malignancy was diagnosed have a 4- to 7-fold higher risk of TE compared with individuals without a cancer diagnosis.390,391

In addition to the diagnosis of cancer, which itself is a thrombogenic and prothrombotic state,392-394 other risk factors for TE have been identified. As with all diseases, age older than 40 years remains a primary risk factor for TE.395 Stage of disease at the time of diagnosis has also been associated with an increased risk of TE. The more aggressive the disease, the higher the chance of experiencing an episode of TE.390,391,396,397 Stage of disease dictates, in large part, further and more aggressive therapeutic interventions, including the more frequent use of invasive technologies and advanced chemotherapeutic regimens, which further increase the risk of TE.390,398-400 Chemotherapy increases TE risk through multiple pathways and mechanisms involving multifactorial issues, which are beyond the scope of this article. Several excellent reviews on the complex interactions of the association between chemotherapy and the increased risk of TE are available in the references provided.13,292,392 Again, it is important to mention that advanced and/or metastatic disease places patients at an increased risk of TE.400

Most patients with breast cancer (upwards of 70%) have ER+ status, meaning their tumors are being fueled by endogenous estrogen.99-103,401,402 Having an ER+ tumor is important for 2 reasons. First, ER+ tumors tend to be less aggressive, and second, such tumors can be treated with an array of AETs. Tamoxifen has long been considered the primary antiestrogenic drug of choice for ER+ breast cancers. A major side effect, recognized early after its implementation, has been the increased incidence of TE.104-107 The risk of TEs in patients receiving tamoxifen as adjuvant therapy is 1% to 2%105,403 and appears to be highest in the initial 2 years of treatment, although the risk remains throughout all years of therapy.390,404

The recognition of the extremely effective role of AET in the treatment of most breast cancers has resulted in the so-called “third generation” of AETs, the AIs (letrozole, anastrazole, and exemestane).188-190,405 As previously stated, the effects of AIs on the circulatory system remain controversial.106-108,121-126 What seems to have been resolved is the incidence of AIs and TEs. Multiple studies have now documented the decreased incidence of TEs with the use of AIs in direct comparison to tamoxifen.127,406,407Thus, it now appears that AIs do not increase the risk of TE in patients with breast cancer. What remains controversial are the long-term effects of AIs on lipid levels, which may affect cardiovascular profiles, and subsequent risk factors, which may contribute to CVD. 106-108,121-126 Clearly, for those women with a history of TE, AIs are the drug of choice for adjuvant AET in the postmenopausal patient with an ER+ breast cancer.

Additional risk factors for TE exist in patients with breast cancer. Many contemporary patients receive long-term intravenous therapies, which extend beyond the short-term chemotherapy regimen. These include a one-year cycle of trastuzumab and/or pertuzumab as well as bisphosphonates for bone metastasis and protection against fractures. For the comfort of the patients, indwelling catheters are often placed for administration of such medications as well as to provide easy vascular access to monitor whole blood cell counts. Indwelling catheters may lead to thrombotic complications, the incidence of which is poorly documented in the literature.384,400,408,409 Additional risk factors for TE are not unique to patients with breast cancer but are often identified along with their comorbidities. These include any history of cardiac disease (myocardial infarction, CHF) and a history of TE.395,410Obesity and its impact on breast cancer is described in the section, Lifestyle Management and Breast Cancer. Relating to the development of TE, obesity is a well-recognized risk factor.395,411,412 Overweight and obesity are often associated with a sedentary lifestyle and general immobility (lack of exercise). It is a modifiable lifestyle risk factor in most patients. Exceptions include increased immobilization caused by hemiplegia after nonfatal cerebral vascular events and fractures of the lower extremities and hips.164,384,392,413

The mechanism by which malignant tumors cause a hypercoagulative state is incompletely understood and is likely multifactorial in nature. Numerous abnormalities in blood composition have been identified, including increased levels of clotting factors, excessive tumor production of inflammatory proteins (cytokines, tumor necrosis factor-a, interleukin-1b), C-reactive protein, and tissue factor from vascular endothelial cells, which all interfere with the normal hemostatic mechanism.387-389,393,414,415

Angiogenesis (the formation of new blood vessels) has been identified recently as a process that may also interfere with the coagulation cascade because both tissue factor and vascular endothelial growth factor are produced by tumorous cells that acquire their own vascular supply.13,388,416,417 In fact, detection of tissue factor in breast cancer vascular endothelium has been shown to be proportionally related to the initiation of new blood vessel formation.418 Further linking angiogenesis and TE are the well-described role of platelet aggregation and the production of platelet dermal growth factor. As such, these also contribute to the risk of TE development.56,392,418 Angiogenesis may also result in the formation of blood vessel structures that are abnormal in their basic anatomic scaffolds and appearance and that display aberrant blood flow patterns.384 Such flow discrepancies may have a role in the development of TE.

p60A TE significantly decreases long-term survival rates in patients with cancer.384,400 Patients with a malignancy who experience a TE have a fourfold to eightfold higher risk of dying of TE than those who do not have a concurrent malignancy.419-422 Without doubt, patients with malignancies and an episode of TE have a poor prognosis. Furthermore, the risk of a recurrence of TE after an initial episode of TE is higher in patients who have a diagnosis of malignancy. The development of TE is well documented to lead to significantly decreased long-term survival in patients with breast cancer,405,423 and malignancies resulting in death often involve a thrombotic component.

Surprisingly, as high as the incidence of TE is, nearly three-fourths of Americans surveyed were unaware of the condition and its long-term sequelae.413,424 Because TE is a lifetime risk factor after breast cancer,391 it is incumbent on the survivorship care team to educate patients with breast cancer on the signs and symptoms of TE. Usually DVT is heralded by the sudden onset of pain, swelling, tenderness, and occasionally redness and/or warmth in an extremity. A PE, sometimes the sequela of untreated DVT, is heralded by the sudden onset of shortness of breath, chest pain exaggerated by deep breathing, a rapid or irregular pulse, lightheadedness, and occasionally hemoptysis. Education of patients regarding these symptoms can be lifesaving.425,426(See Sidebar: Risk Factors for Thromboembolic Events.)



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