 Noreen Fraser at The Today Show studio in New York, NY, where she appeared to discuss National Cancer Survivors Day.

	Noreen Fraser clearly recalls the day in 2003 when her doctor informed her that the breast cancer she had been diagnosed with 2 years earlier had metastasized to her bones. She also remembers her reaction. “Hysteria,” she said. “Days of crying. Days of trying to digest what it really mean[t].”

	What it meant was that Fraser’s cancer was now at stage IV—incurable, her doctor told her. “Am I going to die?” she asked him. Her physician told her he had patients who survived for 5 years with stage IV breast cancer. “Then I got really hysterical,” Fraser recalled. “To him, that was good news. To me, it was the death sentence. I cried even harder.”

	Fraser needed time to digest and understand the news she had been given. After telling her husband she needed a couple of days alone, Fraser jumped in her car and drove to the Ojai Valley, approximately 2 hours north of Los Angeles, California. She said she sat in a hotel room, ordered room service, and thought about how she was “ going to beat this,” she recalled. “I had to organize things in my mind, because I’m a television producer, so I was going to lay out everything I was going to do.”

	Her thoughts turned to her 10-year-old daughter Madelyn. Then she became angry. “She is not going to get this, and she is not going to die from this,” Fraser decided at the time. “And all those darling fourth-grade girls who come to our home for sleepover—I will not allow this to happen to them.” But she was stumped on what she could do to keep it from happening. “I switched back to crying. I didn’t know anything about science or cancer. What was I going to do?”

	Then a light bulb went on. She decided to organize a telethon to raise money for cancer research. After some Internet research, she discovered that some of the biggest grants awarded were for a mere $250,000. “I thought, ‘How can anyone make any headway?’” She decided it was time to create a new model for doling out research funds and scheduled a conversation with her doctor, John Glaspy, MD, at University of California, Los Angeles.

	“I told him that from what I could see on the Internet, no one is sharing any of the information,” Fraser recalled. “Everyone is hiding in their lab because they represent a university where they have to make sure that they get the Nobel Prize and that their university gets the accolades that come with that and the money that would eventually come with that.” Fraser felt that the researchers were “hiding” in their labs and failing to share potentially important finds. She pointed out that when research funds are doled out, the amounts are small. As a result, little was accomplished. Exasperated, she told Glaspy, “It’s a vicious cycle of trying to raise money and get something done.” He agreed. So, she decided to do something about it.

 Noreen Fraser with Robert Redford at The Women’s Conference in Long Beach, CA. Fraser produced a segment of the conference called “Once-in-a-Lifetime Conversation With a Legendary Architect of Change,” a discussion with Redford hosted by Linda Ellerbee.

	Fraser developed a concept for her television program, deciding it would focus solely on breast cancer, and she sold the idea to Lifetime and the Oxygen Network. She then formed the Noreen Fraser Foundation, set a goal of raising between $5 million and $10 million, and decided that all the funds raised by the telethon would go to the “one person who has the best idea: the low-hanging fruit that is going to make a difference.”

	She set up a meeting with film producer Laura Ziskin, who, in 2002, became the first woman to produce the Academy Awards telecast alone. “She knows all the Hollywood celebrities, and I need[ed] her to help me book talent for the show,” Fraser explained. She said her philosophy was, “The bigger the names, the more money we’ll make.” Subsequent meetings followed, including one with Sherry Lansing, a film studio executive. The decision was made to target the telethon’s message to all cancers. Lansing felt this would enable her to convince all the major networks to broadcast the telethon. “I agreed [to the change] because I know that whatever advances are made in one cancer will help all cancers. And I knew that if the viewership was quadrupled, the more money we would make and the more we could put into fighting cancer.”

	Fraser’s thoughts proved prophetic. The telethon was called Stand Up to Cancer. It aired simultaneously on ABC, CBS, and NBC, and featured more than 50 of the most renowned personalities in the television, film, sports, and music industries. It also raised more than $100 million for cancer research. “I look back and I’m proud,” Fraser said. “But I don’t sit on that. I think, ‘I’m not done yet. Now what am I going to do?’”

	Fraser decided that she needed to refocus her efforts on breast cancer—until she saw the statistics for ovarian cancer. “Seventeen-thousand women die each year from [ovarian cancer],” she said. “It’s caught so late, and no one is really helping these women.” She decided to shift her focus to all women’s cancers. “It’s all hormonal,” she observed.

“Physically, you wouldn’t know I have cancer by looking at me. You wouldn’t know I was sick.”

	Fraser wanted to distinguish her foundation from the many other breast cancer organizations. Then one of her board members suggested recruiting men to support the cause. “I said, ‘My God, that’s it. No one is using men,’” Fraser recalled. “All these walks, they marginalize men. They have brainwashed women into thinking that only another woman can understand how you feel, so you’d better get another woman to walk with you. No one walks with her husband. No one walks with her brother. It’s all women, and that’s nonsense. Men care. Men are there and support their women. I think men would love the chance to stand up for their women, the women they love: their wife, their sister, their mother, their grandmother.”

	Fraser’s foundation started the Men for Women Now campaign. Her first recruit was the actor Jack Black. As momentum grew, many other luminaries followed, including Kevin Connolly, Zach Galifianakis, Neil Patrick Harris, Bob Saget, and California Governor Arnold Schwarzenegger.

	On December 4, 2010, Variety will host Variety’s Power of Comedy, an evening of comedic performances at the Palladium in Hollywood, California, to benefit the foundation’s Men for Women Now campaign. “I think we’re on the cusp of doing something big,” Fraser said. “It’s going to be fabulous, and [it’s] something we’ll do every year.”

Noreen Fraser with actor Jason Segel, who has teamed with many other celebrities to support the Noreen Fraser Foundation. Segel’s Men for Women Now t-shirt can be purchased at 

	Fraser said her children are very proud of what she has accomplished, but she notes that neither one is interested in volunteering time to the women’s cancer cause. Her philanthropic activities have not gone unnoticed, however. Her daughter Madelyn, now 19, has become active with Educate Girls Globally, an organization that promotes the education of girls in developing countries. It began with a trip to India several years ago and blossomed thereafter.

	“She has the girls [in India] make necklaces and other items,” Fraser explained. “Then she brings them back and every year she has a booth at a fundraiser, with all the money going back to India. It only costs $85 to buy a uniform and educate a girl for an entire year in India. Her efforts have educated more than 100 girls. I think that’s the influence I’ve had on her.”

	And what about Fraser? “For 6 years, everything was cool,” she said. “Then about a year ago, my tumor markers, which had never moved, began climbing upward, which means there’s activity.” In the last year, Fraser said she has had to undergo bone scans and CT scans every 3 months and has been receiving Faslodex injections every month. None of this has slowed Fraser down. “That’s the crazy thing,” she said. “How can you have stage IV  incurable cancer and not really look that much different than before anything happened? I have more wrinkles because I’m older, and I feel for the first time ever I have to make more lists,” she added, but said she does not know whether that is the result of natural aging or the cancer medication. “Physically, you wouldn’t know I have cancer by looking at me. You wouldn’t know I was sick,” she said.

Articles

Noreen Fraser clearly recalls the day in 2003 when her doctor informed her that the breast cancer she had been diagnosed with 2 years earlier had metastasized to her bones

Breast Cancer Survivor Noreen Fraser Turns Anger into Action

The management of venous thromboembolism (VTE) disorders is well described in the literature,

 and comprehensive guidelines are available from the American College of Chest Physicians.

 In addition, guidelines are available that specifically address management of VTE for the individual with cancer.

 Despite published guidelines, there are many challenges when providing care to those individuals with VTE and cancer. Unfortunately, not all clinical situations can be addressed in even the most comprehensive guidelines. Anticoagulation treatment is dynamic and should take into consideration the unique and often changing clinical aspects of the individual throughout the course of their disease and treatment(s). There is an important role for the pharmacist in anticoagulation therapy, and this role may be even more critical in the patient with cancer and VTE. Pharmacist collaboration with the health care team may better optimize care for the individual with cancer and VTE.

The individual with cancer receiving anticoagulation therapy requires initial and frequent education, counseling, and monitoring to assure that both coagulation and bleeding risks are minimized. Anticoagulation treatment may need to be modified based on the evolving clinical status of the patient, and the anticoagulation treatment plan should be adapted to best meet the treatment goals for the individual. The clinician must consider the cancer diagnosis, extent of disease, and planned treatment(s) for the malignancy as well as the potential impact of disease- and treatment-related complications.

Although the diagnosis of cancer has been associated with an increased risk of developing VTE, all cancers do not have the same risks of thrombosis.

 Similarly, the issues important in providing optimal anticoagulation therapy for a patient vary depending on both the type and extent of malignancy. This article will address some of the unique treatment considerations for the individual with cancer and VTE. Case examples will be used to highlight the role of the pharmacist in working with patients and patient families and/or caregivers as well as the health care team to provide safe and efficacious management of VTE.

PATHOPHYSIOLOGY OF CANCER-RELATED THROMBOSIS

The definition of VTE includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). Unfortunately, VTE is common in individuals with cancer.

 In fact, in the absence of known risk factors in an individual with a new VTE, the presence of an underlying undiagnosed malignancy is often considered.

 The prevalence of VTE in the individual with cancer varies depending on the malignancy and treatment as well as patient-related factors.

The pathophysiology of the cancer-related VTE is thought to be due in part to hypercoagulability associated with procoagulant factors produced from cancer cells. In addition, vascular injury and stasis of blood secondary to tumor compression on vessel walls contribute to the coagulation activation seen with thrombosis in malignancy.

 Cancer treatment(s), including surgery, may increase the risk of VTE. Drug therapy for cancer treatment

 and for management of the cancer- and treatment-related complications (eg, erythropoietin-stimulating agents for management of anemia

) may also increase the risk of VTE.  The use of devices such as central venous catheters (CVC) also place some individuals with cancer at risk for thrombosis.

 A model has been developed to help discriminate the risk of VTE in ambulatory patients with cancer receiving chemotherapy.

 provides a list to help the pharmacist identify those individuals with cancer who are most at risk for VTE.

Ms. Williams is a 56-year-old woman recently diagnosed with colon cancer. She has had resection of the cancer. She is scheduled to start adjuvant chemotherapy with oxaliplatin, fluorouracil, and leucovorin. Last week, a CVC was placed to facilitate the administration of the intravenous fluorouracil. She now reports some swelling in her arm on the same side as the CVC. She has read some of the literature she was given and is concerned about the risk of a blood clot.

What is/are risk factor(s) for VTE in Ms. Williams? What is appropriate counseling for the pharmacist?

• Although it is difficult to identify all of the risk factors in Ms. Williams with such a brief history, one of the seemingly obvious risks includes the diagnosis of colon cancer. It is important to realize that she has received a curative surgery for the treatment of colon cancer, and does not have active disease at this time.

• Surgery also increases risk of thrombosis.

• While she has not yet started chemotherapy, it will pose a risk once therapy is initiated.

• Recommend that Ms. Williams seek medical advice immediately to have the situation evaluated with appropriate imaging. This is not a diagnosis that should be made based on clinical symptoms alone.

• Encourage the patient to contact her oncology team, as most oncology teams have on-call numbers available for this type of issue.

• Encourage the patient to seek medical evaluation immediately, and not to wait until her next appointment.

PREVENTION OF VTE IN THE INDIVIDUAL WITH CANCER

The role of prophylactic anticoagulation therapy for individuals with cancer is well defined in select situations. For those individuals with cancer undergoing a major surgery, prophylaxis with low molecular weight heparin (LMWH), unfractionated heparin (UFH), or fondaparinux is recommended.

 If there are known contraindications for pharmacologic prophylaxis in those individuals considered at high risk for thrombosis, mechanical methods such as pneumatic calf compression should be considered.

 A question remains concerning the duration for prophylaxis following surgery. The criterion often used is the mobility of patients, although there is evidence with some types of surgery (eg, abdominal surgery) that there is benefit for anticoagulation prophylaxis to continue postsurgery.

 This does not mean that anticoagulation prophylaxis is not needed in other patient populations postsurgery, but that the studies have not been done to demonstrate benefit. At a minimum, individuals should be counseled to use complementary nonpharmacologic techniques as appropriate (eg, mobility) after discussion with their health care team.

Prophylactic anticoagulation is also recommended for hospitalized cancer patients with a diagnosis of active cancer who do not have a contraindication to therapy aimed at lowering VTE incidence.

STRATEGIES FOR MANAGEMENT OF VTE IN THE INDIVIDUAL WITH CANCER

Historically, the management of VTE includes the use of anticoagulation with UFH followed by a vitamin K antagonist such as warfarin. These treatment options remain an appropriate choice in the majority of individuals with VTE associated with cancer, but other options now exist. The appropriate treatment strategy is determined after evaluation and consideration of many patient and cancer treatment—related factors. Treatment strategies may include pharmacotherapy such as UFH, LMWH, warfarin, and fondaparinux. Importantly, if the patient has a history or evidence of heparin-induced thrombocytopenia (HIT), other drug therapies may be used and are reviewed more extensively in published guidelines.

When a patient develops a VTE, anticoagulation should be initiated as soon as possible. Anticoagulation therapy is initiated for management of VTE to prevent thrombus extension. Long-term treatment involves continuation of anticoagulation to both minimize the extension of thrombosis and reduce VTE recurrence. Anticoagulation therapy does not break down the thrombus; however, this is an area of confusion for many patients. It is helpful to patients and caregivers to review the intent of anticoagulation therapy. For example, an individual with a diagnosis of cancer and VTE may have multiple imaging scans to assess the management of cancer therapy. If the thrombus is still present after treatment, the patient may believe the anticoagulation therapy is not working. Conversely, if the thrombosis is resolved on subsequent imaging scans, the patient may feel it is not important to continue anticoagulation therapy. It is important to reinforce that the body is slowly dissolving the thrombus, and anticoagulation therapy is used to prevent extension and recurrence of thrombosis.

The risk of VTE recurrence is of major concern in an individual with active cancer because of the inherent thrombogenic risk associated with malignancy as described above. Patients with advanced disease or high tumor burden appear to have the highest risk of recurrence. The duration of anticoagulation for the individual with cancer is determined based on the type of VTE and the presence of active disease. For example, the patient with a diagnosis of VTE associated with malignancy may remain on anticoagulation therapy until they are considered disease free.

CASE: DURATION OF ANTICOAGULATION THERAPY IN THE INDIVIDUAL WITH CANCER AND VTE

Mr. Jones is an elderly man with a long history of prostate cancer. Until recently, his prostate cancer was managed with antiandrogen therapy. There is evidence of disease progression, and he now has metastatic prostate cancer. The plan was to start chemotherapy. He was recently discharged from the hospital after it was discovered he had spinal cord compression, and he has severely limited mobility. Additionally, he was found to have a lower extremity DVT. His family has a number of questions about his medications, and is very concerned that he will be on a “blood thinner.” They have done some research, and their understanding is that he will continue on anticoagulation therapy for 3 months.

What is the duration of therapy for anticoagulation in the patient with VTE and cancer?

There is not one correct answer for this question. The duration of anticoagulation therapy is determined on an individual case basis. The decision will need to include consideration of risk versus benefit issues. At any time, if the risk of anticoagulation therapy outweighs its perceived benefit, the therapy should be discontinued. Therefore, in counseling Mr. Jones and his family, it is important to discuss that a definitive answer may not be appropriate. Some guiding points include:

• Patients with active disease, such as Mr. Jones, require anticoagulation therapy while they have evidence of cancer. Although Mr. Jones will be receiving chemotherapy, the intent of the therapy is to decrease disease progression and not to cure the cancer. It is likely that Mr. Jones will remain on anticoagulation therapy for the rest of his life, unless there is a change in status that makes the risk of anticoagulation outweigh the benefit.

• Patients with curable cancers may not require anticoagulation therapy longer than the time recommended for individuals without cancer. Unfortunately, this is not the situation with Mr. Jones.

• Patients with VTE associated with a CVC will require anticoagulation therapy for the duration of the time they have the device in place. Again, this is considered on an individual basis.

The role of mechanical devices such as inferior vena cava (IVC) filters in the individual with cancer is less clear in the literature, but is addressed in clinical guidelines.

 IVC filters are percutaneously placed devices that prevent PE. However, the risk of DVT is increased in patients with permanent filters.

 IVC filters may be used in patients where anticoagulation is not considered appropriate (eg, active bleeding, severe thrombocytopenia) or in patients with recurrent VTE despite “adequate” anticoagulation. In recent years, IVC filters that can be retrieved have been developed so that the filters may be left in place during the high-risk period, but subsequently removed when appropriate. For example, a patient with a history of VTE who is receiving myelosuppressive therapy associated with severe thrombocytopenia may benefit from placement of an IVC filter, and the filter can be removed when myelosuppressive therapy is complete and the risk of thrombocytopenia and associated bleeding resolves. Unfortunately, the filter itself is thrombogenic and associated with an increased risk of DVT and IVC thrombosis. Anticoagulation therapy is often used concurrently in individuals with an IVC filter if not contraindicated.

The decision to hold or discontinue anticoagulation therapy may be considered in a patient when the perceived risk of bleeding outweighs the perceived benefit. For example, the risk of significant bleeding, unmanageable thrombocytopenia, or platelet dysfunction may outweigh the risk of VTE. 

 gives examples of when the risk of anticoagulation therapy should be carefully considered. Contraindications to anticoagulation may be temporary, and should be reevaluated periodically to determine if initiation of anticoagulation therapy is appropriate.

LMWH potentiates the inhibitory activity of antithrombin against factor Xa and thrombin. These agents are used for the acute management of VTE, chronic management of VTE in the individual with cancer, and as a strategy to convert patients from long-acting oral anticoagulants to shorter-acting anticoagulation prior to a planned procedure associated with a bleeding risk. 

 lists LMWH products and the standard doses used in the management of VTE. These doses are often individualized based on patient factors (eg, renal dysfunction) and less commonly on monitoring of anticoagulant effect discussed later.

 The role of LMWH for acute management of VTE is well established. The rapid onset of action of these agents allows the initiation of effective anticoagulation to be done quickly. The availability of a product given subcutaneously allows for administration to be done by patients, caregivers, and the health care team in the ambulatory setting, including home. In the individual with cancer, VTE is not infrequently discovered incidentally on a routine imaging scan performed to evaluate disease. The individual is often asymptomatic. When dispensing LMWH to a patient for this initial dose, it is essential that the pharmacist ensures that the patient and/or caregiver has received and understands appropriate education. Counseling should include information on the proper storage, handling, and administration of the specific LMWH product. Pharmacists should also communicate risks and monitoring parameters associated with bleeding, signs and symptoms of VTE, and the impact that other prescription and OTC medications may have on anticoagulant therapy. For example, patients should be counseled to avoid use of aspirin and nonsteroidal anti-inflammatory agents for pain management due to the increased risk of bleeding while on anticoagulation therapy. The pharmacist may suggest the benefit of having a wallet card or identification bracelet that indicates the individual is on anticoagulation therapy. Although this type of counseling may be routine with oral anticoagulation such as warfarin, it may have been overlooked with LMWH when the first doses are given in the hospital or physician’s office.

There is clinical evidence that LMWH monotherapy is appropriate for the chronic management of patients with proximal DVT and/or PE to prevent recurrent VTE in individuals with advanced or metastatic cancer.

 One trial compared the LMWH dalteparin versus a coumarin anticoagulant for the prevention of recurrence of VTE in individuals with cancer. This study, often referred to as the CLOT trial, demonstrated that 6 months of dalteparin therapy was more effective than 6 months of therapy with an oral coumarin in reduction of recurrent VTE without increased risk of bleeding. Although the study evaluated the use of LMWH for only a 6-month treatment period, in practice, some patients may continue therapy beyond 6 months. Also, as LMWHs provide a relatively predictable anticoagulation response, routine laboratory monitoring to guide dosing is not required.

The use of LMWH for chronic therapy presents challenges. One potential problem is the patient’s willingness to continue subcutaneous therapy. Some patients are unable or unwilling to administer subcutaneous injections daily; this also must be assessed prior to initiation of therapy. At times, encouragement and education will help persuade a patient to consider this treatment option. The pharmacist can work with the patient, family, and/or caregiver to help alleviate fears. Demonstration of administration techniques and suggestions for strategies to minimize discomfort can be very helpful to optimize care.

Patients and/or their families may be resistant to chronic LMWH therapy due to costs associated with therapy. The out-of-pocket cost, even with insurance coverage, may be prohibitive for some patients. When verifying if an individual has insurance coverage for LMWH products, it is important to determine if there are limits on the duration of the coverage (eg, coverage limited for 7 days). Similar to other high-cost medications, LMWH may be covered by an individual’s insurance plan with a required copayment. Patients may be unable to afford or unwilling to pay the cost of such copayments. If an individual determines that the cost of therapy is prohibitive, then the pharmacist can facilitate discussion with the health care team to ensure that appropriate anticoagulation therapy is continued. In some cases, this may require initiation of another strategy of anticoagulation.

It is important that the health care team discuss the patient’s ability and willingness to continue LMWH when determining if this is the best chronic treatment option. Unfortunately, if this has not been assessed fully, the pharmacist may be the clinician faced with the patient’s reluctance to continue therapy.

As mentioned, the routine use of laboratory monitoring is not required for dosing of these agents. When required, measurement of antifactor Xa activity can be used to help monitor LMWH therapy. The clinical situations where this monitoring may be appropriate include patients with significant renal impairment (eg, creatinine clearance <30 mL/min), malnourished patients (eg, weight <50 kg), morbidly obese patients, and those patients who experience bleeding with standard dosing.

CASE: ACUTE AND CHRONIC LMWH FOR VTE OF CANCER

Mr. Elliot is a 45-year-old man with history of non-Hodgkin’s lymphoma (NHL). He was initially treated with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy with complete response. After 6 cycles, he had no evidence of cancer. Unfortunately, recent follow-up imaging scans show a recurrence of cancer and an incidental finding of a PE. The plan is to begin anticoagulation therapy as well as therapy for recurrent NHL. The oncologist has told Mr. Elliot he will receive 2 cycles of chemotherapy and then proceed with an autologous stem cell transplantation.

What are appropriate options for management of this PE in Mr. Elliot?

—An incidental finding of PE requires treatment, and anticoagulation should be started immediately. Therapy could include UFH, but as this would require hospitalization, LMWH is probably a better option.

—Chronic therapy with LMWH offers many benefits, including the ability to easily hold anticoagulation for a short period of time when needed for procedures (eg, placement of CVC, bone marrow biopsy). Another beneficial effect of chronic therapy with LMWH is a lack of drug—drug interactions.

Fondaparinux is a factor Xa inhibitor that is approved for the prophylaxis and treatment of VTE. Fondaparinux is rapidly and completely absorbed following subcutaneous administration, and therefore may be used in the treatment of DVT and PE. This drug has the advantage of a long halflife (17—21 hours), and it allows for daily dosing. Although there are limited data specifically regarding use in the cancer population, it is a therapeutic option for patients that are unable to use heparin products (eg, patients with history of HIT). Unfortunately, the long half-life of the drug may be a problem in some patients, as the anticoagulation effect of fondaparinux persists for 2 to 4 days in patients with normal renal function. As the drug is primarily cleared via renal excretion, the effect may last longer in patients with renal dysfunction. In fact, the drug is not recommended in patients with renal failure. An example of where the prolonged effect is a problem is in the patient who requires frequent procedures that require reversal of anticoagulation.

Warfarin is the most commonly prescribed of the vitamin K antagonists, and has been extensively reviewed.

 Warfarin produces an anticoagulant effect by interfering with the cyclic interconversion of vitamin K and vitamin K epoxide. This action inhibits the production of functional forms of vitamin K—dependent factors including the coagulation factors II, VII, IX, X, and the endogenous anticoagulation proteins C and S.

The impact of warfarin is dependent, in part, on the individual’s intake of vitamin K. Patients should be educated to maintain a consistent diet of vitamin K, and to notify their health care team if there is any change in diet. Many common foods include vitamin K, and patients should be reassured that they can eat foods with vitamin K. Appetite and nutrition are often a challenge for the individual receiving chemotherapy, and food choices should not be limited whenever possible. Foods high in vitamin K include green leafy vegetables and beef liver, but other sources of vitamin K in this population may include daily vitamins and nutritional supplements. As patients may have frequent changes in diet during the course of disease and/or cancer treatment, it is important to reassess diet routinely to help identify changes that may impact warfarin therapy. Directed questioning regarding diet and use of dietary supplements is an excellent method to help identify potential problems with diet and warfarin therapy.

Warfarin is highly water soluble and is rapidly absorbed from the gastrointestinal tract. The bioavailability is close to 100%. In those individuals with disruption of the gastrointestinal tract secondary to surgery or cancer, the absorption of warfarin may be affected. Additionally, cancer- or treatment-related emesis and/or diarrhea may impact warfarin absorption. It is important for the pharmacist to counsel patients taking warfarin on the necessity of communicating any onset or changes in diarrhea and emesis. This counseling should be reinforced regularly. For those patients receiving chemotherapy, the week following treatment is, at times, difficult due to nausea, vomiting, or taste changes. The pharmacist has an opportunity to help evaluate these symptoms to determine the potential impact on warfarin dosing, and to help manage symptoms with appropriate drug therapy.

Warfarin is highly bound to albumin and is extensively metabolized in the liver by enzymes of the cytochrome P450 (CYP) system. Commercially available warfarin is a racemic mixture of R and S isomers. The S isomer of warfarin is the more potent isomer and is metabolized predominantly by CYP2C9. The R isomer of warfarin is less potent and is metabolized via CYP1A2, CYP2C19, and CYP3A4. There is significant variation in the metabolism of warfarin between patients. As the impact of these individual variations is evaluated, the clinical question is, “How do we use this in practice?” The controversy has not been settled regarding the use of pharmacogenomic evaluation of the genetic variations in CYP2C9 isoenzymes and the vitamin K epoxide reductase to help determine warfarin dosing.

The half-life of warfarin is long and can range over 40 hours. The impact of the drug on the proteins it targets is dependent on the half-life of the protein. For example, the initial increase of the international normalized ratio (INR) is due predominantly to the impact of warfarin on factor VII, which has a relatively short half-life of 6 hours. The full impact of warfarin may not be seen for almost a week because of the long half-life of factor II. Similarly, it may take a few days until the full impact of a dose change may be seen. When the pharmacist evaluates the dose of warfarin, it is important to consider the dose(s) of drug taken over the last week of therapy at a minimum.

The relationship between the dose of warfarin and response is modified by both genetic and environmental factors that influence the pharmacokinetics and pharmacodynamics of the drug. Because warfarin has a narrow therapeutic window, its effect can be impacted by diet, drugs, and clinical issues such as diarrhea.

 The dosing of warfarin can be challenging and is guided by assessment of patient-specific factors including diet, drug therapy, liver function, and by monitoring the patient’s INR. The INR is a method to determine the biologic activity of factors II, VII, and X and correlates to warfarin anticoagulation effect. The target or goal INR should be established prior to initiation of therapy, and a common target range is an INR of 2 to 3. The delayed impact of warfarin doses can present a challenge to the monitoring of INR and patient dosing as mentioned previously.

Some of the clinical challenges associated with the use of warfarin in the patient with cancer are highlighted in the following cases. As with any individual on warfarin, it is essential to continually monitor medication changes (eg, new medications, discontinuation of medications, dose modifications of medications) and evaluate the potential and actual effect on warfarin and its anticoagulation effect as measured by INR. During the time of treatment, patients with cancer often have frequent drug therapy changes based on clinical needs (eg, infection, nausea, pain). These changes may affect chronic medications. Additionally, medication changes occur during and between treatment cycles. As drug interactions with warfarin are common, all drug therapy changes must be routinely and frequently assessed. The pharmacist should be cautious in relying on only those published lists of drugs that interact with warfarin, as many agents used to treat cancer or manage cancer-related symptoms may not have been studied.

CASE: INITIATION OF THERAPY WITH WARFARIN

Mr. Glenn is a 35-year-old man with lung cancer. He was recently diagnosed with a thrombosis associated with his infusion port and was started on LMWH. He has limited insurance coverage at this time, and the plan is to start warfarin for chronic anticoagulation.

What is the appropriate starting dose of warfarin for Mr. Glenn?

It is important to continue therapy with LMWH as warfarin is initiated. As it will take a few days to a week to see anticoagulation effects from the warfarin, it is important to continue LMWH until the INR is within the targeted therapeutic range.

The clinical practice guidelines2 recommend the initiation of warfarin at doses between 5 and 10 mg for 1 to 2 days, and subsequent dosing is based on INR response. Lower doses are suggested for patients who are older, debilitated, malnourished, have liver disease and/or dysfunction, or are taking medications known to increase sensitivity to warfarin. Prior to recommending a dose for Mr. Glenn, it is important to assess the following:

• Concurrent dietary intake of vitamin K, including that provided in nutritional supplements, vitamins, and diet

As it is essential to monitor the INR to determine dose modification, it is important to assess when the patient will be able to have an INR monitored to determine “aggressiveness” of dosing.

Mr. Peterson is a 39-year-old man with head and neck cancer receiving radiation therapy. He has had extensive surgery, and his oral intake is limited to nutritional supplements. Other medical problems include history of DVT in his left leg, hypertension, and liver dysfunction secondary to chronic alcohol use. He has been managed with LMWH, but he has requested that he be changed to another therapy. He has continued on LMWH and was started on warfarin 2 mg po daily. Two days after initiation of warfarin, his INR is 2.9 with a target goal of 2 to 3.

What is your recommendation for anticoagulation therapy?

• Anticoagulation therapy should include 4 to 5 days of overlap with both a LMWH and warfarin as well as a therapeutic INR before discontinuation of LMWH.

• It is concerning that the INR is 2.9 after only 2 days of warfarin, and the full effect of these doses has not been seen. It is likely that the INR will continue to rise, and that the dose of warfarin should be decreased even though his INR is in the goal range. It is important to closely monitor INR.

• There is an opportunity to talk with Mr. Peterson to determine what the impact of diet, concomitant drug therapy, and/or other modifiable factors have on the apparent low warfarin dose requirement.

- Assess amount of nutritional supplementation (and vitamin K content in supplementation)

Ms. Green is a 63-year-old woman diagnosed with colon cancer. She has had surgical resection of the cancer and is now scheduled to start adjuvant chemotherapy with oral capecitabine (daily for 14 days every 21 days) and oxaliplatin (intravenous infusion every 21 days). She recently was found to have a DVT in her right lower extremity. She was initially managed with LMWH and bridged to warfarin therapy. She is taking 2.5 mg po daily with an INR of 2.8.

Are there drug interactions with the chemotherapy and warfarin?

There are drug interactions with warfarin and many chemotherapy agents. Some interactions are well described in the literature, but many are not. Additionally, the severity of interaction, onset, and mechanism of interaction are often not described. The pharmacist has the unique opportunity to identify when there is a change in medication for an individual and to monitor the impact of the interaction.

Individuals with cancer may obtain their medications from multiple pharmacies, including specialty pharmacies, community pharmacies, and physicians’ offices or clinics. It is important to educate the patient and family on the importance of keeping a complete list of all medications that the individual is taking, and sharing this with the pharmacist in addition to all health care providers.

In this case, capecitabine has been shown to increase the INR in patients taking warfarin.

 The challenges of managing the interaction are identifying the onset, as the drug interaction may be delayed, and managing warfarin with the episodic dosing of capecitabine (eg, 14 of every 21 days). This requires careful monitoring of therapy or, in some patients, a change in therapy to LMWH.

Mr. Botoni is a 57-year-old man with a history of a neuroendocrine tumor of the pancreas. He has been receiving monthly injections of octreotide with relatively good management of diarrhea. About 1 week ago, he noted new-onset shortness of breath and was found to have a PE. He was started on LMWH for initial treatment, but then bridged to warfarin therapy as he refused to subcutaneously self-administer any medication chronically. His INR has been erratic, and his dose of warfarin has been modified weekly. He is very upset that he is still having his blood work done once weekly.

What questions should the pharmacist ask to help assess potential causes of this fluctuation in INR?

A number of issues should be evaluated to determine potential changes in warfarin requirements:

• Dietary changes, including vitamin K containing vegetables, liver, nutritional supplement, etc.

• Changes in bowel function, especially in relation to monthly octreotide injections, as some patients will have an increase in diarrhea for the days to 1 week prior to scheduled dose of octreotide.

• Adherence to the dosing regimen prescribed.

• Alcohol use (eg, chronic alcohol use may increase warfarin requirements and episodic alcohol use may increase INR for individuals on warfarin).

• Use of OTC medications and complementary medications including acetaminophen and multivitamins.

• Any clinical changes, such as infection and fever.

CASE: MANAGEMENT OF SUPRATHERAPEUTIC INR FOR THE PATIENT ON WARFARIN

Ms. Keith is a 44-year-old woman with metastatic breast cancer who has a relatively recent history of DVT managed with warfarin 7.5 mg po daily. Her INRs have ranged from 1.9 to 2.3 over the last few weeks. She was doing well until recently when she experienced confusion and severe headaches. Subsequent evaluation demonstrated multiple brain lesions consistent with brain metastases. She is scheduled to start radiation therapy and was started on dexamethasone 4 mg po every 8 hours. Her INR today was 5.6 when she had blood work prior to radiation. The INR results were not reported until Ms. Keith left the physician’s office, and she is now at home.

The management of venous thromboembolism (VTE) disorders is well described in the literature, and comprehensive guidelines are available from the American College of Chest Physicians.

Venous Thromboembolism and Cancer: An Opportunity for Pharmacists to Optimize Care

The past 2 to 3 decades saw a palpable therapeutic nihilism associated with the management of patients with advanced renal cell carcinoma (RCC), interrupted briefly by the initial excitement regarding high-dose interleukin-2.

 Over the past several years, phase I/II clinical trials of tyrosine kinase inhibitors (TKIs), vascular endothelial growth factor (VEGF) inhibitors, and mammalian target of rapamycin (mTOR) inhibitors in advanced RCC (primarily of clear cell histology) demonstrated intriguing, paradigm-shifting activity. This led to a series of phase III trials that culminated with the FDA’s approval of 6 new drugs in a 5-year span for the management of advanced RCC.

As we reach the midway point of the first decade of targeted therapeutics in RCC, some high-level observations can be made. Despite unequivocal progress, none of the currently available agents cure patients with metastatic RCC and few complete responses are seen with any of them. Although clinical studies with the mTOR inhibitor temsirolimus (Torisel) provided evidence of an improvement in overall survival (OS) in patients with poor risk (per Memorial Sloan-Kettering criteria) disease, demonstrating improvement in survival with other agents has been problematic. This is likely because studies for most of these drugs allowed crossover by large numbers of patients.

 From a patient management perspective, these agents are generally associated with significant toxicity, negatively affecting the quality of life for many patients. Although published data on sequential therapy are limited, it has become a de facto standard of care. Using these agents in combination is more than a little challenging, pending results from additional studies.

 PROPOSED MECHANISMS OF RESISTANCE IN SEQUENTIAL THERAPY

It was the significant progress in our understanding of the molecular pathogenesis of RCC during the past decade that led to the development of therapies targeting the VEGF and mTOR pathways.

 Results from a series of phase III studies provide compelling evidence that sunitinib (Sutent), pazopanib (Votrient), temsirolimus, and the combination of bevacizumab (Avastin) and interferon-alpha are clinically active in patients with metastatic RCC as initial therapies or following initial cytokine therapy. The objective response rate (ORR) ranged from 7% to 31% with these agents, and progression-free survival (PFS) ranged from 4 to 11 months.

In chronic myeloid leukemia, another malignant disease commonly treated with targeted agents (eg, imatinib [Gleevec] and nilotinib [Tasigna]), the mechanism of drug resistance is presumed to be mutation of a gene that encodes a key tyrosine kinase receptor targeted by the drug. In contrast, investigators exploring resistance mechanisms in RCC note that because the main target for VEGF receptor (VEGFR) inhibitors resides on the surface of endothelial cells,

 a mutation conferring treatment resistance would most likely have to occur in the tumor endothelium, but it is highly improbable that such a mutation would occur simultaneously in the endothelium of each individual tumor metastasis.

 Other proposed mechanisms for acquired resistance include reemergence of VEGF-driven vasculature, upregulation of alternative proteins in the setting of persistent VEGF or mTOR blockade, and novel mechanisms that are not antiangiogenic in nature.

Following FDA approval of sunitinib, many clinicians managing RCC patients with disease progression on sorafenib (Nexavar) empirically used sunitinib as a salvage option. Retrospective series soon appeared in the literature documenting responses to both agents when used in sequence and reporting clinical activity in patients with disease progression following other VEGFtargeting agents, such as bevacizumab.

More recently, prospectively designed phase II trials have addressed the issue of cross-resistance when using VEGFtargeted therapeutics in sequence. Rini and associates conducted a prospective multicenter phase II trial of sunitinib in 61 patients with metastatic clear cell RCC that had evidence of progression following a bevacizumab-based therapy regimen. Patients received 50 mg of sunitinib daily in 6-week cycles, comprising 4 weeks on therapy followed by 2 weeks off therapy. The researchers observed an ORR of 23% with a median PFS of 30 weeks and a median OS of 47 weeks. Observed treatment-related toxicity was typical of sunitinib in other settings.

The investigational drug axitinib is an oral, potent, selective inhibitor of VEGFRs 1, 2, and 3 that demonstrated substantial activity in a phase II trial of patients with cytokine-refractory metastatic RCC.

 In this multicenter trial, Rini and associates administered 5 mg of axitinib twice daily to patients with metastatic RCC (all histologic subtypes) whose disease progressed following therapy with sorafenib. The prior number of therapies a patient had received was not a limiting factor in enrollment. All 62 patients enrolled had received prior sorafenib and 74.2% had received ≥2 prior systemic treatments. The ORR, which was the study’s primary endpoint, was 23%. The median duration of response was 17.5 months and median OS was 7.4 months.

 Although these studies have limitations, including their design and small size, they provide compelling clinical evidence that cross-resistance is not inevitable when patients who fail on one VEGF-targeting drug switch to another.

Motzer and colleagues recently reported the results of an international phase III trial testing the role of mTOR inhibition following disease progression on agents that target VEGF.

 Patients who received prior therapy with bevacizumab, interleukin-2, or interferon-alfa were also permitted to participate. Researchers randomly assigned patients at a 2:1 ratio to 10 mg of the mTOR inhibitor everolimus (Afinitor; n = 272) or placebo (n = 138) daily. The primary endpoint was median PFS, which was documented using Response Evaluation Criteria in Solid Tumors and assessed via a blinded, independent central review. At the time of disease progression, treatment was unblinded and patients receiving placebo were offered open-label everolimus. Objective antitumor activity was observed, with 60% of patients treated with everolimus experiencing tumor shrinkage compared with 10% given placebo. Based on independent review, median PFS in the everolimus arm was 4 months versus 1.9 months in the placebo group, representing significant improvement (hazard ratio [HR], 0.30; 95% confidence interval [CI], 0.22-0.40; 

 <.001). When stratifying patients according to prior VEGF TKI therapy, the PFS advantage for everolimus persisted across all groups (

The current clinical paradigm for the management of advanced RCC is rapidly evolving. Following the FDA approval of sorafenib and sunitinib, and given the scarcity of effective therapies, patients treated with 1 of these agents were typically treated with the alternative agent following progression. Clinical evidence indicating a lack of cross-resistance between these TKIs validated this empiric approach. Subsequent studies provided additional data on sequencing approaches, such as evidence from a phase III study supporting the utility of everolimus following therapy with a VEGF TKI.

Investigators exploring the role of combination therapy have applied the concepts of vertical blockade and horizontal blockade.

 A vertical blockade uses at least 2 agents to target 1 pathway at ≥2 levels; a horizontal blockade uses ≥2 agents to target separate pathways with different functions in parallel.

The initial attempt to test the concept of horizontal blockade was a phase II trial of bevacizumab in combination with the epidermal growth factor receptor inhibitor erlotinib (Tarceva). Patients were treated with 10 mg/kg of bevacizumab every 2 weeks and an oral, 150-mg dose of erlotinib daily. Of 58 evaluable patients, 12 (21%) had objective partial remissions. At a median follow-up of 15 months, median PFS was 11 months; 43% of patients were progression-free at 12 months and 26% were progression-free at 18 months.

 The subsequent addition of the platelet-derived growth factor receptor inhibitor imatinib to the combination was not tolerable.

Bukowski and colleagues attempted to define the role of combination therapy further by conducting a randomized, placebo-controlled phase II trial.

 Eligible patients had metastatic RCC, predominantly of clear cell histology, and they were randomized to receive 10 mg/kg of bevacizumab every 2 weeks combined with 150 mg daily of erlotinib or placebo. For patients treated with bevacizumab plus erlotinib, the ORR was 13% and median PFS was 8.5 months compared with an ORR of 14% and median PFS of 9.9 months for patients treated with bevacizumab alone. The study provided additional data supporting the single-agent activity of bevacizumab.

Recent reports describe attempts to achieve vertical blockade by blocking the VEGF-VEGFR axis and/or hypoxiainducible factor. Feldman and associates conducted a phase I trial evaluating bevacizumab plus sunitinib in patients with metastatic RCC.

 Patients who received ≤2 prior therapy regimens, excluding bevacizumab or sunitinib, were eligible. Bevacizumab was administered at a fixed dose of 10 mg/kg every 2 weeks, combined with an escalating dose of sunitinib.

The study determined that the maximum tolerated dose (MTD) for the regimen consisted of 50 mg of sunitinib and 10 mg/kg of bevacizumab. The authors noted, however, that chronic therapy with the MTD dose frequently resulted in grades 3/4 levels of hypertension and hematologic and vascular toxicities, with approximately half the patients stopping therapy secondary to adverse events.

Although activity was seen, with 1 complete and 12 partial responses, the authors said that they did not recommend pursuing this regimen at the MTD because of the significant therapy-related toxicity.

 While this trial documented the constellation of thrombocytopenia, hemolytic anemia, hypertension, proteinuria, and renal insufficiency with microangiopathy in 5 patients, a similar phase I trial that enrolled patients with RCC and other solid tumors did not observe this constellation of events in any participants.

A phase II study recently reported positive data on the efficacy of everolimus in combination with bevacizumab following VEGFtargeted TKI therapy. Investigators gave this doublet to 59 patients, 29 of whom had been previously treated with sunitinib or sorafenib.

 The median PFS in this patient population was 10 months, suggesting that these agents might act synergistically in patients with TKI—refractory disease.

Fischer and colleagues conducted a phase I study of temsirolimus in combination with sunitinib in patients with advanced RCC.

 Patients were eligible if they had received ≤2 prior systemic regimens for metastatic disease. Investigators administered 15 mg of temsirolimus once weekly by intravenous infusion, and 25 mg of sunitinib was administered orally once daily for 4 weeks; this was followed by a 2-week rest period. In the first cohort of 3 patients, 2 patients experienced dose-limiting toxicities. The study was terminated because of the substantial toxicity observed with even the low starting doses of both agents.

Sosman and colleagues conducted a phase I trial investigating the combination of sorafenib and bevacizumab in patients with advanced RCC who had not received prior VEGF TKI therapy.

 Initial doses consisted of 200 mg of sorafenib twice daily with a 5 mg/kg dose of bevacizumab once every 2 weeks in 28-day cycles, with dose modification based on observed toxicities. Therapy was relatively well tolerated, with only 4 of 48 patients discontinuing because of toxicity. The investigators established the MTD at 200 mg daily of sorafenib plus 15 mg/kg of bevacizumab once every 2 weeks. Of the 46 evaluable patients, 21 (46%) achieved a partial response. The median time to progression was 11 months, and 10 patients (21%) were progression-free at 18 months.

Several ongoing prospective trials are testing the role of combination therapy. The Eastern Cooperative Oncology Group is conducting the randomized phase II BEST (Bevacizumab, Sorafenib, and Temsirolimus) trial, which randomizes patients to bevacizumab monotherapy, bevacizumab combined with temsirolimus or sorafenib, or a doublet of sorafenib and temsirolimus.

Ongoing industry randomized trials include a phase III study comparing the combination of bevacizumab and interferon-alpha versus the combination of bevacizumab and temsirolimus, and a randomized phase II trial comparing the combination of everolimus and bevacizumab with interferon-alpha and bevacizumab (

Following a protracted period in which interleukin-2 was the only FDA-approved drug available for the management of advanced RCC, the last several years have seen the approval of sorafenib, sunitinib, temsirolimus, everolimus, bevacizumab (in combination with interferon), and, most recently, pazopanib. The trials that led to the regulatory approval of these agents support their role as initial therapy, but they offer little guidance regarding the optimal means of selecting therapy for patients with clear cell RCC and essentially no guidance for RCC patients with non-clear cell histologies.

Current evidence supports the role of temsirolimus as initial therapy for patients with advanced RCC who are classified as “poor risk,” based on a trial design that used a modified version of the Memorial Sloan-Kettering Cancer Center definition for poor risk. Clinical trial evidence also supports the use of everolimus in patients with disease progression following therapy with sorafenib, sunitinib, or both.

Following disease progression on a front-line agent, data guiding subsequent therapy selection are limited. None of the available data support 1 sequence of agents over another. Currently, therapy decisions are frequently informed by a patient’s disease status, issues regarding therapy logistics (ie, oral vs parenteral therapy), and an agent’s potential toxicity.

The role of combination therapy in advanced RCC remains the subject of ongoing investigation. Experience to date suggests that many combinations present challenges, secondary to significant toxicity. Prospective, randomized trials are needed to determine whether sequential therapy or combination therapy is the optimal approach.

A Review of Data on Optimal Sequencing and Combinations of Current Therapies in Renal Cell 

	Breast cancer is the most frequently diagnosed malignancy in women in the United States. Triple receptor-negative breast cancer (TNBC) represents a small percentage of all breast cancers, but it constitutes the majority of breast cancers of the basal-like subtype. TNBC is characterized by the lack of expression of estrogen and progesterone receptors and by the lack of overexpression of human epidermal growth factor receptor-2 (HER2). Published studies have shown that TNBC is highly sensitive to chemotherapy in the neoadjuvant, adjuvant, and metastatic settings. Even with TNBC’s high sensitivity to chemotherapy, patients with TNBC have high recurrence and relapse rates. Many of the ongoing clinical trials available for patients with TNBC focus on the safety and/or efficacy of new, targeted agents given alone or in combination with standard or alternative chemotherapy.

	Breast cancer is the number one malignancy diagnosed  in women in the United States. In 2009, it was estimated that more than 190,000 individuals would be diagnosed with breast cancer and approximately 40,000 would die from the disease.

 The incidence of invasive breast cancer has decreased over the years, largely because screening rates have increased, facilitating earlier diagnosis. Even when diagnosed early, however, triple receptor—negative breast cancer (TNBC) has a poor prognosis and represents a major unmet need.

	Breast cancer consists of a group of diseases with many clinical, pathologic, and molecular characteristics that affect prognosis and treatment. There are 4 intrinsic breast cancer subtypes by gene expression: basal-like, HER2, luminal A, and luminal B.

 These 4 subtypes have been shown to have different prognoses and different responses to therapy.

	The majority of cases of breast cancer of the basal-like subtype lack expression of estrogen and progesterone receptors and exhibit normal expression of HER2 receptors. Like the basal-like subtype, the HER2 subtype does not express estrogen receptors (ER) and progesterone receptors (PR), but it is associated with overexpression and/or gene amplification of HER2. The basal-like and HER2 subtypes have high rates of pathologic complete response (pCR) to preoperative chemotherapy. pCR is typically defined as no microscopic evidence of residual invasive cancer in the breast and axillary lymph nodes. Studies show that after preoperative chemotherapy, rates of pCR range from 27% to 45% for the basal-like subtype and from 36% to 45% for the HER2 subtype.

 These subtypes have also been associated with short durations of relapse-free survival (RFS) and overall survival (OS).

	The advent of trastuzumab (Herceptin) for HER2-positive breast cancer, however, has significantly improved outcomes for patients with this subtype.

	The luminal subtypes (luminal A and luminal B), which express ER and PR, have low rates of pCR to preoperative chemotherapy (6%-7%), but they seem to have more favorable clinical outcomes with the use of endocrine therapy.

	Clinical Characteristics of Triple Receptor—Negative Breast Cancer (TNBC)

	TNBC represents about 10% to 15% of all breast cancers and constitutes more than 80% of all basal-like diagnoses.

 TNBC’s classification is established by the lack of ER and PR expression by immunohistochemical (IHC) assay and by the normal expression of HER2 by IHC or fluorescence in situ hybridization.

	TNBC is characterized as an aggressive disease with poor clinical outcomes, including short durations of RFS and OS.

 Today’s patients with TNBC have a worse clinical outcome than patients whose tumors are HER2-positive.

 A TNBC diagnosis is associated with an earlier age of onset compared with other breast cancer subtypes (

 A descriptive analysis by Bauer and colleagues found that TNBC was significantly associated with younger age, non-Hispanic black race, and lower socioeconomic status.

 In a study by Carey and colleagues, African-American women had a higher incidence of TNBC compared with other subtypes.

 Data from this study also showed a higher incidence of TNBC among premenopausal women compared with postmenopausal women.

 In a recent study by Dawood and colleagues, designed to analyze the effect of race on pCR rates and OS in women with TNBC treated with systemic chemotherapy, data showed that 17% of black patients achieved pCR compared with 25.1% of white/other patients (

 The researchers found that after controlling for patient and tumor characteristics, race did not significantly affect pCR, RFS, or OS.

	Data show that a high proportion of patients with TNBC (~34%) experience distant recurrence, with a mean of 2.6 years to distant recurrence.

 This compares with a distant recurrence rate of 20% and a mean of 5 years to distant recurrence in other breast cancer subtypes.

 The 5-year OS rate is also inferior for patients with TNBC compared with the rate of 5-year OS observed with other types of breast cancer. In TNBC, the risk of recurrence peaks 1 to 3 years after diagnosis then decreases.

 Patients with TNBC are most likely to experience recurrence in the visceral organs. A study by Liedtke and colleagues found that 74% of patients with TNBC developed recurrences in visceral organs; for 13% of patients, recurrences developed in the soft tissue, and another 13% had recurrences in bone.

	A retrospective study by Dawood and colleagues of 679 patients with TNBC found that 6.2% had developed brain metastases at a median follow-up of 26.9 months, with a 2-year and 5-year cumulative incidence of 5.6% and 9.6%, respectively.

 When looking at breast cancer overall, including all subtypes, patients have a 10% to 16% risk of developing brain metastases at any point during the metastatic setting.

 The risk of developing brain metastasis is greater in patients who are younger, and in patients with ≥4 positive lymph nodes, high tumor grade, or HER2 overexpression.

	TNBC tumors tend to be grade III and large (>2.0 cm) at diagnosis.

 They have been associated with a higher rate of lymph node positivity than other breast cancer subtypes, but there does not appear to be any correlation between tumor size and nodal status.

	TNBC is closely associated with expression of basal cytokeratins (CKs) 5/6, 14, and 17 and epidermal growth factor receptor (EGFR). Gene expression analysis of the basal-like subtype is similar to that of basal/myoepithelial cells found in normal breast tissue.

 In a panel of 21 basal-like tumors, Nielsen and colleagues observed IHC positivity for basal CKs, EGFR, and c-KIT overexpression.

 Overexpression of basal CKs and EGFR appear to be associated with poor survival in breast cancer patients.

Breast cancer is the number one malignancy diagnosed  in women in the United States. In 2009, it was estimated that more than 190,000 individuals would be diagnosed with breast cancer and approximately 40,000 would die from the disease.

Fall 2010 | Contemporary Oncology®

Breast Cancer Survivor Noreen Fraser Turns Anger into Action

Venous Thromboembolism and Cancer: An Opportunity for Pharmacists to Optimize Care

A Review of Data on Optimal Sequencing and Combinations of Current Therapies in Renal Cell

Triple Receptor-Negative Breast Cancer: Current and Future Treatments

Preventing VTE in Cancer Outpatients: Are We There Yet?

Fall FDA Updates

Abiraterone Praised as a Significant Advance in Metastatic Prostate Cancer

Taking the Bull's-Eye Off the Pharma Companies

Inside the Fall 2010 Issue