Clinical Review

In 2009, a question of proper practices was brought before the Arizona Regulatory Board of Physician Assistants. The patient in question was seen in an emergency department by a PA/physician health care team for complaints of cough and fever at home. In question was the team’s decision to discharge the patient, who had a history of immunosuppression with an anti–tumor necrosis factor (anti-TNF) medication for a chronic joint disorder, without ordering laboratory tests or blood cultures. Although there is textbook instruction for evaluation of patients with infection who use agents in this drug class,¹ many clinicians may be unaware that blood cultures should be drawn as part of a proper workup.

In the United States, medications that have anti-TNF-alpha ­(anti-TNF-a) properties, including adalimumab, etanercept, and infliximab, are approved by the FDA to treat rheumatoid arthritis (RA).² Many patients take a second medication; others, a combination of medications. Options ­include methotrexate, cyclo­sporine, prednisone, and hydroxychloroquine. Typically, anti-TNF medications represent second- or third-line therapy after unsatisfactory response to disease-modifying antirheumatic drugs (DMARDs).

Although anti-TNF medications are effective for treatment of autoimmune diseases like RA, it should be noted that TNF-a is an important component in the proper functioning of the immune system. Accordingly, it is recognized that patients who use anti-TNF medications are at increased risk for infection.³ Indeed, patients with RA are already at greater risk for contracting infectious illnesses, even before immunosuppressive medications are administered.⁴

TNF is one cytokine that is responsible for humoral activation and subsequent inflammation.⁵ In RA and certain other diseases (eg, Crohn’s disease, lupus), TNF-a’s interaction with other cytokines is at least partially responsible for the inflammation that leads to RA-associated joint damage.⁵ In­fliximab and adalimumab are monoclonal antibodies developed specifically to bind with TNF-a, thereby neutralizing a pathway for further release of inflammatory cytokines. 

In contrast to recombinant soluble receptors, such as etanercept, the site-specific monoclonal antibodies for TNF-a (ie, infliximab, adalimumab) may play a greater role in suppressing macrophages, which contribute significantly to cellular immunity. Macrophage inhibition may further increase the body’s vulnerability to opportunistic infection.⁶

Anti-TNF Agents: Clinical Trials

The relationship between treatment with immunosuppressive agents (including infliximab and other anti-TNF medications) and serious infection is evident in the literature. In a 2005 study, Listing et al⁴ followed patients for 12 months after they were started on etanercept, infliximab, anakinra (another cytokine inhibitor), or DMARDs (controls). Ninety-two (26.5%) of the 346 patients who were given infliximab, compared with 6% of 601 controls, developed infection; of these, 20 patients (21.7%) had a determinable serious infection (ie, that was considered life-threatening or resulted in inpatient treatment, significant disability, or death). Thus, serious infection affected 5.8% of the patient population studied who had received infliximab.

Five of the 512 patients who used etanercept were diagnosed with sepsis, but no episodes of bacteremia were recorded among the infliximab patients. The most prevalent serious infections observed were pneumonia, infective arthritis, and various skin and subcutaneous infections (see table⁴). Less prevalent respiratory tract ailments included bronchitis, lung abscess, and pleural infection. Overall, small numbers of cases of sepsis were reported, making it difficult for the study authors to comment on the disparity of sepsis rates among treatment groups.⁴

Another prospective study followed 28 patients (median age, 53) who were treated with infliximab between 1999 and 2002.⁷ Dosages administered ranged from the standard 3 mg/kg every 8 weeks to 10 mg/kg every 4 weeks, with variation in duration of treatment. A 13% higher rate of infection was ­reported among these patients, compared with patients who received conventional therapy (DMARDs) over a two-year ­period.

Six patients were determined to have serious, life-threatening infections (ie, requiring hospitalization or IV antibiotic therapy). Of these, two were given a diagnosis of bacteremia via blood cultures. The cultures grew Streptococcus pneumoniae in one patient, who was also diagnosed incidentally with Pneumocystis carinii through bronchial washings, and the other patient had blood cultures positive for Staphylococcus aureus and bilateral necrotizing pulmonary abscesses.

Case Studies

Individual case studies of infection in patients taking infliximab or other anti-TNF agents for RA reveal specific illnesses, their time lines, and relevant patient management. Crum et al2 reported an example of the common pathogen S pneumoniae in a 47-year-old patient who developed a left lower lobe pneumonia. Three of four blood cultures were positive, CBC with differential showed abnormal results, and the patient’s temperature on presentation was 39.5°C.

In a report of two cases of severe abdominal infection during administration of anti-TNF medication, one 40-year-old woman using infliximab for severe RA presented with a temperature of 39.2°C and a three-day history of abdominal pain. Escherichia coli was identified from blood cultures, although urine cultures were negative. CT led to a diagnosis of pyelonephritis. The patient had become septic but improved after 48 hours’ therapy with IV cefuroxime and gentamicin.⁸

The second patient was a man, age 60, with a two-week history of abdominal pain and a six-month history of effective etanercept use for persistent psoriatic arthritis. Contrast-­enhanced CT revealed a large splenic abscess, and blood cultures identified infection with S aureus. Management began with unsuccessful high-dose IV antibiotics, followed by laparotomy and splenectomy, postsurgical sepsis, and finally, high-dose inotropic therapy that proved effective.⁸

Infection With Listeria monocytogenes

Listeria monocytogenes, a pathogen sometimes identified in patients who receive anti-TNF-a therapy, has been the focus of several case reports. For example, Gluck et al⁹ describe a 60-year-old woman with a history of RA and previous treatment with multiple therapies who had recently completed a five-month regimen with infliximab (10 mg/kg every 4 weeks). Fourteen days after receiving her last dose, she presented to a hospital with anemia, fever (measurement undisclosed), and abdominal pain. She was given multiple diagnoses, including a gastric ulcer without hemorrhage, a pulmonary infiltrate, and acute cholecystitis. After she underwent cholecystectomy, her condition deteriorated, and head CT revealed several small subarachnoid hemorrhages and severe brain edema.

The patient experienced multi–organ system failure and died after a brain-stem herniation. What should be noted is that a blood culture taken one day after her surgery was positive for L monocytogenes, as was an intraoperative gallbladder swab-culture for the same organism—this, despite presumed antibiotic therapy.

A second patient described by Gluck et al⁹ was a 62-year-old woman with RA who developed cholecystitis after her second dose of infliximab, administered over a two-week period (200 mg IV/dose). As in the previous case, the patient manifested cerebral edema and had a fever after undergoing cholecystectomy. Blood cultures performed after the surgery were positive for L monocytogenes. The patient recovered slowly with proper antibiotic therapy, including ampicillin and gentamicin.

A third example of listeriosis involved a 52-year-old patient with RA who presented with symptoms including fever and abdominal pain. CT led to a diagnosis of terminal ileitis. One of two blood cultures taken was positive for L monocytogenes.⁶

Finally, a 79-year-old patient with a long-standing diagnosis of RA and prosthetic hips reported a fever of three weeks’ duration and left leg pain. As the patient had no fever on initial presentation, blood cultures were not drawn until five days after he was admitted. Three of four blood cultures were positive for L monocytogenes.⁶

Less Common Infections

Other less common bacterial etiologies have also been reported in the literature, including a fatal case of Salmonella enteritidis septicemia with a pleural empyema after treatment with infliximab.¹⁰ Another fatality was reported in a 54-year-old man who had necrotizing fasciitis, with a group A hemolytic streptococcus that grew in blood cultures. The patient, who had been taking in­fliximab, had no report of fever before or during his hospitalization.¹¹

Discussion

Although infliximab is effective for controlling the symptoms of RA, clinicians must be attentive to fever in patients who use it—even a patient-­reported fever that may not be present on physical exam. Due to the potential blunting of the immune response associated with infliximab use, a serious underlying infection can occur without fever. General malaise may be the only symptom a patient reports.

Infliximab and other anti-TNF medications are included in a textbook list of immunosuppressive medications whose use warrants special attention for patients who are evaluated for infection in an emergency setting. According to Burns,¹ “Rapid diagnosis and early initiation of therapy are essential in preventing serious morbidity and mortality in immunocompromised patients who often have subtle or unusual presentations and are difficult to ­diagnose.”¹

Active tuberculosis (ATB) is another serious illness that has been reported with infliximab use.^12,13 Patients should be screened for TB before taking infliximab, but clinicians must also be aware that ATB can develop as an unwanted result of infliximab therapy. Standard blood cultures may not be an effective means of identifying ATB.

Several types of infection may occur, with or without confirmation by positive blood cultures, including viral and fungal infections. Even bacterial infections, such as a urinary tract infection or bacterial pneumonia, may not yield positive blood cultures immediately, if ever. Each of these has been included among serious illnesses associated with use of anti-TNF medications.⁴ Nevertheless, blood cultures—Gram-stain, anaerobic, and aerobic blood cultures with sensitivities—should be considered an important component of any comprehensive infectious disease evaluation.

Although the purpose of this article has been to emphasize the importance of blood cultures in the timely diagnosis and treatment of patients taking ­anti-TNF medications who present with symptoms of infectious disease, it is important to remember that blood cultures are only part of a full infectious disease workup.

Conclusion

The clinical studies and case presentations discussed here serve to remind clinicians that timely acquisition and evaluation of blood cultures are essential to the identification of serious bacteriologic pathogens, and to the chances of recovery in the RA patient with a systemic infection who is immunosuppressed as a result of treatment with infliximab or other anti-TNF agent. Rapid identification of pathogenic organisms will facilitate the implementation of appropriate therapy, thus avoiding the often-deadly outcomes of severe infection and sepsis. Gram-stain, anaerobic, and aerobic blood cultures with sensitivities should be considered the standard of care in any infliximab-treated patient who presents with fever, a patient report of a fever, or any other signs, symptoms, or patient history that could suggest infection.

While this article focuses for the most part on infections associated with infliximab use, the same strategy in standard of practice should apply to all patients who use anti-TNF therapy for treatment of RA.

In 2009, a question of proper practices was brought before the Arizona Regulatory Board of Physician Assistants. The patient in question was seen in an emergency department by a PA/physician health care team for complaints of cough and fever at home. In question was the team’s decision to discharge the patient, who had a history of immunosuppression with an anti–tumor necrosis factor (anti-TNF) medication for a chronic joint disorder, without ordering laboratory tests or blood cultures. Although there is textbook instruction for evaluation of patients with infection who use agents in this drug class,¹ many clinicians may be unaware that blood cultures should be drawn as part of a proper workup.

In the United States, medications that have anti-TNF-alpha ­(anti-TNF-a) properties, including adalimumab, etanercept, and infliximab, are approved by the FDA to treat rheumatoid arthritis (RA).² Many patients take a second medication; others, a combination of medications. Options ­include methotrexate, cyclo­sporine, prednisone, and hydroxychloroquine. Typically, anti-TNF medications represent second- or third-line therapy after unsatisfactory response to disease-modifying antirheumatic drugs (DMARDs).

Although anti-TNF medications are effective for treatment of autoimmune diseases like RA, it should be noted that TNF-a is an important component in the proper functioning of the immune system. Accordingly, it is recognized that patients who use anti-TNF medications are at increased risk for infection.³ Indeed, patients with RA are already at greater risk for contracting infectious illnesses, even before immunosuppressive medications are administered.⁴

TNF is one cytokine that is responsible for humoral activation and subsequent inflammation.⁵ In RA and certain other diseases (eg, Crohn’s disease, lupus), TNF-a’s interaction with other cytokines is at least partially responsible for the inflammation that leads to RA-associated joint damage.⁵ In­fliximab and adalimumab are monoclonal antibodies developed specifically to bind with TNF-a, thereby neutralizing a pathway for further release of inflammatory cytokines. 

In contrast to recombinant soluble receptors, such as etanercept, the site-specific monoclonal antibodies for TNF-a (ie, infliximab, adalimumab) may play a greater role in suppressing macrophages, which contribute significantly to cellular immunity. Macrophage inhibition may further increase the body’s vulnerability to opportunistic infection.⁶

Anti-TNF Agents: Clinical Trials

The relationship between treatment with immunosuppressive agents (including infliximab and other anti-TNF medications) and serious infection is evident in the literature. In a 2005 study, Listing et al⁴ followed patients for 12 months after they were started on etanercept, infliximab, anakinra (another cytokine inhibitor), or DMARDs (controls). Ninety-two (26.5%) of the 346 patients who were given infliximab, compared with 6% of 601 controls, developed infection; of these, 20 patients (21.7%) had a determinable serious infection (ie, that was considered life-threatening or resulted in inpatient treatment, significant disability, or death). Thus, serious infection affected 5.8% of the patient population studied who had received infliximab.

Five of the 512 patients who used etanercept were diagnosed with sepsis, but no episodes of bacteremia were recorded among the infliximab patients. The most prevalent serious infections observed were pneumonia, infective arthritis, and various skin and subcutaneous infections (see table⁴). Less prevalent respiratory tract ailments included bronchitis, lung abscess, and pleural infection. Overall, small numbers of cases of sepsis were reported, making it difficult for the study authors to comment on the disparity of sepsis rates among treatment groups.⁴

Another prospective study followed 28 patients (median age, 53) who were treated with infliximab between 1999 and 2002.⁷ Dosages administered ranged from the standard 3 mg/kg every 8 weeks to 10 mg/kg every 4 weeks, with variation in duration of treatment. A 13% higher rate of infection was ­reported among these patients, compared with patients who received conventional therapy (DMARDs) over a two-year ­period.

Six patients were determined to have serious, life-threatening infections (ie, requiring hospitalization or IV antibiotic therapy). Of these, two were given a diagnosis of bacteremia via blood cultures. The cultures grew Streptococcus pneumoniae in one patient, who was also diagnosed incidentally with Pneumocystis carinii through bronchial washings, and the other patient had blood cultures positive for Staphylococcus aureus and bilateral necrotizing pulmonary abscesses.

Case Studies

Individual case studies of infection in patients taking infliximab or other anti-TNF agents for RA reveal specific illnesses, their time lines, and relevant patient management. Crum et al2 reported an example of the common pathogen S pneumoniae in a 47-year-old patient who developed a left lower lobe pneumonia. Three of four blood cultures were positive, CBC with differential showed abnormal results, and the patient’s temperature on presentation was 39.5°C.

In a report of two cases of severe abdominal infection during administration of anti-TNF medication, one 40-year-old woman using infliximab for severe RA presented with a temperature of 39.2°C and a three-day history of abdominal pain. Escherichia coli was identified from blood cultures, although urine cultures were negative. CT led to a diagnosis of pyelonephritis. The patient had become septic but improved after 48 hours’ therapy with IV cefuroxime and gentamicin.⁸

The second patient was a man, age 60, with a two-week history of abdominal pain and a six-month history of effective etanercept use for persistent psoriatic arthritis. Contrast-­enhanced CT revealed a large splenic abscess, and blood cultures identified infection with S aureus. Management began with unsuccessful high-dose IV antibiotics, followed by laparotomy and splenectomy, postsurgical sepsis, and finally, high-dose inotropic therapy that proved effective.⁸

Infection With Listeria monocytogenes

Listeria monocytogenes, a pathogen sometimes identified in patients who receive anti-TNF-a therapy, has been the focus of several case reports. For example, Gluck et al⁹ describe a 60-year-old woman with a history of RA and previous treatment with multiple therapies who had recently completed a five-month regimen with infliximab (10 mg/kg every 4 weeks). Fourteen days after receiving her last dose, she presented to a hospital with anemia, fever (measurement undisclosed), and abdominal pain. She was given multiple diagnoses, including a gastric ulcer without hemorrhage, a pulmonary infiltrate, and acute cholecystitis. After she underwent cholecystectomy, her condition deteriorated, and head CT revealed several small subarachnoid hemorrhages and severe brain edema.

The patient experienced multi–organ system failure and died after a brain-stem herniation. What should be noted is that a blood culture taken one day after her surgery was positive for L monocytogenes, as was an intraoperative gallbladder swab-culture for the same organism—this, despite presumed antibiotic therapy.

A second patient described by Gluck et al⁹ was a 62-year-old woman with RA who developed cholecystitis after her second dose of infliximab, administered over a two-week period (200 mg IV/dose). As in the previous case, the patient manifested cerebral edema and had a fever after undergoing cholecystectomy. Blood cultures performed after the surgery were positive for L monocytogenes. The patient recovered slowly with proper antibiotic therapy, including ampicillin and gentamicin.

A third example of listeriosis involved a 52-year-old patient with RA who presented with symptoms including fever and abdominal pain. CT led to a diagnosis of terminal ileitis. One of two blood cultures taken was positive for L monocytogenes.⁶

Finally, a 79-year-old patient with a long-standing diagnosis of RA and prosthetic hips reported a fever of three weeks’ duration and left leg pain. As the patient had no fever on initial presentation, blood cultures were not drawn until five days after he was admitted. Three of four blood cultures were positive for L monocytogenes.⁶

Less Common Infections

Other less common bacterial etiologies have also been reported in the literature, including a fatal case of Salmonella enteritidis septicemia with a pleural empyema after treatment with infliximab.¹⁰ Another fatality was reported in a 54-year-old man who had necrotizing fasciitis, with a group A hemolytic streptococcus that grew in blood cultures. The patient, who had been taking in­fliximab, had no report of fever before or during his hospitalization.¹¹

Discussion

Although infliximab is effective for controlling the symptoms of RA, clinicians must be attentive to fever in patients who use it—even a patient-­reported fever that may not be present on physical exam. Due to the potential blunting of the immune response associated with infliximab use, a serious underlying infection can occur without fever. General malaise may be the only symptom a patient reports.

Infliximab and other anti-TNF medications are included in a textbook list of immunosuppressive medications whose use warrants special attention for patients who are evaluated for infection in an emergency setting. According to Burns,¹ “Rapid diagnosis and early initiation of therapy are essential in preventing serious morbidity and mortality in immunocompromised patients who often have subtle or unusual presentations and are difficult to ­diagnose.”¹

Active tuberculosis (ATB) is another serious illness that has been reported with infliximab use.^12,13 Patients should be screened for TB before taking infliximab, but clinicians must also be aware that ATB can develop as an unwanted result of infliximab therapy. Standard blood cultures may not be an effective means of identifying ATB.

Several types of infection may occur, with or without confirmation by positive blood cultures, including viral and fungal infections. Even bacterial infections, such as a urinary tract infection or bacterial pneumonia, may not yield positive blood cultures immediately, if ever. Each of these has been included among serious illnesses associated with use of anti-TNF medications.⁴ Nevertheless, blood cultures—Gram-stain, anaerobic, and aerobic blood cultures with sensitivities—should be considered an important component of any comprehensive infectious disease evaluation.

Although the purpose of this article has been to emphasize the importance of blood cultures in the timely diagnosis and treatment of patients taking ­anti-TNF medications who present with symptoms of infectious disease, it is important to remember that blood cultures are only part of a full infectious disease workup.

Conclusion

The clinical studies and case presentations discussed here serve to remind clinicians that timely acquisition and evaluation of blood cultures are essential to the identification of serious bacteriologic pathogens, and to the chances of recovery in the RA patient with a systemic infection who is immunosuppressed as a result of treatment with infliximab or other anti-TNF agent. Rapid identification of pathogenic organisms will facilitate the implementation of appropriate therapy, thus avoiding the often-deadly outcomes of severe infection and sepsis. Gram-stain, anaerobic, and aerobic blood cultures with sensitivities should be considered the standard of care in any infliximab-treated patient who presents with fever, a patient report of a fever, or any other signs, symptoms, or patient history that could suggest infection.

While this article focuses for the most part on infections associated with infliximab use, the same strategy in standard of practice should apply to all patients who use anti-TNF therapy for treatment of RA.

In 2009, a question of proper practices was brought before the Arizona Regulatory Board of Physician Assistants. The patient in question was seen in an emergency department by a PA/physician health care team for complaints of cough and fever at home. In question was the team’s decision to discharge the patient, who had a history of immunosuppression with an anti–tumor necrosis factor (anti-TNF) medication for a chronic joint disorder, without ordering laboratory tests or blood cultures. Although there is textbook instruction for evaluation of patients with infection who use agents in this drug class,¹ many clinicians may be unaware that blood cultures should be drawn as part of a proper workup.

In the United States, medications that have anti-TNF-alpha ­(anti-TNF-a) properties, including adalimumab, etanercept, and infliximab, are approved by the FDA to treat rheumatoid arthritis (RA).² Many patients take a second medication; others, a combination of medications. Options ­include methotrexate, cyclo­sporine, prednisone, and hydroxychloroquine. Typically, anti-TNF medications represent second- or third-line therapy after unsatisfactory response to disease-modifying antirheumatic drugs (DMARDs).

Although anti-TNF medications are effective for treatment of autoimmune diseases like RA, it should be noted that TNF-a is an important component in the proper functioning of the immune system. Accordingly, it is recognized that patients who use anti-TNF medications are at increased risk for infection.³ Indeed, patients with RA are already at greater risk for contracting infectious illnesses, even before immunosuppressive medications are administered.⁴

TNF is one cytokine that is responsible for humoral activation and subsequent inflammation.⁵ In RA and certain other diseases (eg, Crohn’s disease, lupus), TNF-a’s interaction with other cytokines is at least partially responsible for the inflammation that leads to RA-associated joint damage.⁵ In­fliximab and adalimumab are monoclonal antibodies developed specifically to bind with TNF-a, thereby neutralizing a pathway for further release of inflammatory cytokines. 

In contrast to recombinant soluble receptors, such as etanercept, the site-specific monoclonal antibodies for TNF-a (ie, infliximab, adalimumab) may play a greater role in suppressing macrophages, which contribute significantly to cellular immunity. Macrophage inhibition may further increase the body’s vulnerability to opportunistic infection.⁶

Anti-TNF Agents: Clinical Trials

The relationship between treatment with immunosuppressive agents (including infliximab and other anti-TNF medications) and serious infection is evident in the literature. In a 2005 study, Listing et al⁴ followed patients for 12 months after they were started on etanercept, infliximab, anakinra (another cytokine inhibitor), or DMARDs (controls). Ninety-two (26.5%) of the 346 patients who were given infliximab, compared with 6% of 601 controls, developed infection; of these, 20 patients (21.7%) had a determinable serious infection (ie, that was considered life-threatening or resulted in inpatient treatment, significant disability, or death). Thus, serious infection affected 5.8% of the patient population studied who had received infliximab.

Five of the 512 patients who used etanercept were diagnosed with sepsis, but no episodes of bacteremia were recorded among the infliximab patients. The most prevalent serious infections observed were pneumonia, infective arthritis, and various skin and subcutaneous infections (see table⁴). Less prevalent respiratory tract ailments included bronchitis, lung abscess, and pleural infection. Overall, small numbers of cases of sepsis were reported, making it difficult for the study authors to comment on the disparity of sepsis rates among treatment groups.⁴

Another prospective study followed 28 patients (median age, 53) who were treated with infliximab between 1999 and 2002.⁷ Dosages administered ranged from the standard 3 mg/kg every 8 weeks to 10 mg/kg every 4 weeks, with variation in duration of treatment. A 13% higher rate of infection was ­reported among these patients, compared with patients who received conventional therapy (DMARDs) over a two-year ­period.

Six patients were determined to have serious, life-threatening infections (ie, requiring hospitalization or IV antibiotic therapy). Of these, two were given a diagnosis of bacteremia via blood cultures. The cultures grew Streptococcus pneumoniae in one patient, who was also diagnosed incidentally with Pneumocystis carinii through bronchial washings, and the other patient had blood cultures positive for Staphylococcus aureus and bilateral necrotizing pulmonary abscesses.

Case Studies

Individual case studies of infection in patients taking infliximab or other anti-TNF agents for RA reveal specific illnesses, their time lines, and relevant patient management. Crum et al2 reported an example of the common pathogen S pneumoniae in a 47-year-old patient who developed a left lower lobe pneumonia. Three of four blood cultures were positive, CBC with differential showed abnormal results, and the patient’s temperature on presentation was 39.5°C.

In a report of two cases of severe abdominal infection during administration of anti-TNF medication, one 40-year-old woman using infliximab for severe RA presented with a temperature of 39.2°C and a three-day history of abdominal pain. Escherichia coli was identified from blood cultures, although urine cultures were negative. CT led to a diagnosis of pyelonephritis. The patient had become septic but improved after 48 hours’ therapy with IV cefuroxime and gentamicin.⁸

The second patient was a man, age 60, with a two-week history of abdominal pain and a six-month history of effective etanercept use for persistent psoriatic arthritis. Contrast-­enhanced CT revealed a large splenic abscess, and blood cultures identified infection with S aureus. Management began with unsuccessful high-dose IV antibiotics, followed by laparotomy and splenectomy, postsurgical sepsis, and finally, high-dose inotropic therapy that proved effective.⁸

Infection With Listeria monocytogenes

Listeria monocytogenes, a pathogen sometimes identified in patients who receive anti-TNF-a therapy, has been the focus of several case reports. For example, Gluck et al⁹ describe a 60-year-old woman with a history of RA and previous treatment with multiple therapies who had recently completed a five-month regimen with infliximab (10 mg/kg every 4 weeks). Fourteen days after receiving her last dose, she presented to a hospital with anemia, fever (measurement undisclosed), and abdominal pain. She was given multiple diagnoses, including a gastric ulcer without hemorrhage, a pulmonary infiltrate, and acute cholecystitis. After she underwent cholecystectomy, her condition deteriorated, and head CT revealed several small subarachnoid hemorrhages and severe brain edema.

The patient experienced multi–organ system failure and died after a brain-stem herniation. What should be noted is that a blood culture taken one day after her surgery was positive for L monocytogenes, as was an intraoperative gallbladder swab-culture for the same organism—this, despite presumed antibiotic therapy.

A second patient described by Gluck et al⁹ was a 62-year-old woman with RA who developed cholecystitis after her second dose of infliximab, administered over a two-week period (200 mg IV/dose). As in the previous case, the patient manifested cerebral edema and had a fever after undergoing cholecystectomy. Blood cultures performed after the surgery were positive for L monocytogenes. The patient recovered slowly with proper antibiotic therapy, including ampicillin and gentamicin.

A third example of listeriosis involved a 52-year-old patient with RA who presented with symptoms including fever and abdominal pain. CT led to a diagnosis of terminal ileitis. One of two blood cultures taken was positive for L monocytogenes.⁶

Finally, a 79-year-old patient with a long-standing diagnosis of RA and prosthetic hips reported a fever of three weeks’ duration and left leg pain. As the patient had no fever on initial presentation, blood cultures were not drawn until five days after he was admitted. Three of four blood cultures were positive for L monocytogenes.⁶

Less Common Infections

Other less common bacterial etiologies have also been reported in the literature, including a fatal case of Salmonella enteritidis septicemia with a pleural empyema after treatment with infliximab.¹⁰ Another fatality was reported in a 54-year-old man who had necrotizing fasciitis, with a group A hemolytic streptococcus that grew in blood cultures. The patient, who had been taking in­fliximab, had no report of fever before or during his hospitalization.¹¹

Discussion

Although infliximab is effective for controlling the symptoms of RA, clinicians must be attentive to fever in patients who use it—even a patient-­reported fever that may not be present on physical exam. Due to the potential blunting of the immune response associated with infliximab use, a serious underlying infection can occur without fever. General malaise may be the only symptom a patient reports.

Infliximab and other anti-TNF medications are included in a textbook list of immunosuppressive medications whose use warrants special attention for patients who are evaluated for infection in an emergency setting. According to Burns,¹ “Rapid diagnosis and early initiation of therapy are essential in preventing serious morbidity and mortality in immunocompromised patients who often have subtle or unusual presentations and are difficult to ­diagnose.”¹

Active tuberculosis (ATB) is another serious illness that has been reported with infliximab use.^12,13 Patients should be screened for TB before taking infliximab, but clinicians must also be aware that ATB can develop as an unwanted result of infliximab therapy. Standard blood cultures may not be an effective means of identifying ATB.

Several types of infection may occur, with or without confirmation by positive blood cultures, including viral and fungal infections. Even bacterial infections, such as a urinary tract infection or bacterial pneumonia, may not yield positive blood cultures immediately, if ever. Each of these has been included among serious illnesses associated with use of anti-TNF medications.⁴ Nevertheless, blood cultures—Gram-stain, anaerobic, and aerobic blood cultures with sensitivities—should be considered an important component of any comprehensive infectious disease evaluation.

Although the purpose of this article has been to emphasize the importance of blood cultures in the timely diagnosis and treatment of patients taking ­anti-TNF medications who present with symptoms of infectious disease, it is important to remember that blood cultures are only part of a full infectious disease workup.

Conclusion

The clinical studies and case presentations discussed here serve to remind clinicians that timely acquisition and evaluation of blood cultures are essential to the identification of serious bacteriologic pathogens, and to the chances of recovery in the RA patient with a systemic infection who is immunosuppressed as a result of treatment with infliximab or other anti-TNF agent. Rapid identification of pathogenic organisms will facilitate the implementation of appropriate therapy, thus avoiding the often-deadly outcomes of severe infection and sepsis. Gram-stain, anaerobic, and aerobic blood cultures with sensitivities should be considered the standard of care in any infliximab-treated patient who presents with fever, a patient report of a fever, or any other signs, symptoms, or patient history that could suggest infection.

While this article focuses for the most part on infections associated with infliximab use, the same strategy in standard of practice should apply to all patients who use anti-TNF therapy for treatment of RA.

Scanning the ovaries is no simple task. As we mentioned in Part 1 of this four-part series, the practitioner must use the right equipment, take basic preparatory steps, be watchful for clues in the history, and reach a conclusion about what he or she sees. Not only that: The ultrasonographer must be extraordinarily vigilant, paying close attention to multiple characteristics of any mass, from thickness of the wall to the presence of papillations or a blood supply—signs of potential malignancy.

In this article, we detail the traits of various types of non-neoplastic ovarian masses, including:

• functional cysts—follicles, the corpus luteum, and theca lutein cysts
• nonfunctional cysts—serous masses and endometriomas
• cystadenofibromas. Although these masses are usually categorized histo-logically as neoplasms, we include them here due to their almost daily appearance in a busy gynecologic ultrasonographic (US) facility.

In Part 3, we will cover ovarian neoplasms, and in Part 4, our focus will be tubal entities such as ectopic pregnancy and torsion.

FIGURE 1 What is a mass made of? 6 morphologic building blocks

Take an inventory of the mass

Any adnexal mass should be assessed in light of its essential characteristics (Figure 1).

Wall structure. Pay attention to thickness. We use an arbitrary cutoff of 4 mm, giving extra scrutiny to thicknesses exceeding that measurement. In our experience, the thicker the wall, the more likely the mass is to be malignant.

Septation and loculation. A mass is typically unilocular or multilocular. Multilocularity is more common in tumors of low malignant potential and malignant neoplasms.

Papillation. Any internal or external papillae or excrescences should draw your attention. Papillarity in an ovarian mass renders that mass suspicious for malignancy.

Measure (height and width) any papillae that are identified, and document them. Because papillae are associated with ovarian malignancy, further assessment is warranted immediately. The first step is determining whether the papillations contain blood vessels—a task for which color and power Doppler are helpful. We prefer power Doppler because it is more sensitive, detecting blood-flow velocity in the lowest detectable range of 2 cm/s, and because it is not directionally influenced.

Papillae that contain blood vessels with detectable flow are suspicious for malignancy.

Exacoustos and colleagues found that papillae as large as 15 mm in height and 10 mm in width (base) were present in 48% of borderline ovarian tumors but in only 4% of benign and 4% of malignant tumors. However, when the intracystic solid tissue exceeded those dimensions, the lesions were present in 48% of invasive ovarian tumors, 18% of borderline ovarian tumors, and 7% of benign masses.¹

Internal echo-structure. A mass can be anechoic, a finding that usually indicates the presence of clear fluid. Mostly solid masses are echogenic. And masses that contain particulate matter, such as blood, cellular matter, or even mucous material, usually have echogenicity of a low level, often described as a “ground-glass” appearance. A mass can also have mixed echo-genicity, a finding usually found in cases involving teratoma or malignancy.

Shadowing. If it is present, it may signify the presence of an extremely dense, solid tissue, such as bone or calcification. The diagnosis of a benign teratoma (i.e., dermoid cyst) should be entertained if shadowing is present in a hyperechoic nodule or mass. Malignant masses very rarely, if ever, display frank shadowing.

Overall appearance. On rare occasions, a bizarre shape or “complex” appearance (as it is termed in most radiology reports) may indicate a malignant mass. More likely it indicates the presence of a teratoma, cystadenoma, or even an atypical corpus luteum. In some reports generated by US laboratories, the term “complex” is applied to all structures other than simple cysts.

Size. The size of a mass can be misleading, as small ovarian lesions with the appropriate sonographic characteristics may be malignant and some larger ones without those characteristics may not be. However, it is understood that the larger an ovarian lesion, the more likely it is a tumor. One important distinction: The amount of fluid in a cystic structure or the amount of old blood in an endometrioma is not the disease process…it is the byproduct of the process. So an 8-cm endometrioma may create fewer pain or fertility issues than a 2- or 3-cm endometrioma. Similarly, the amount of “chocolate” fluid is not automatically indicative of the amount of active endometriotic glands or their sequelae!²

Ascites. If it is present, it should be recorded and investigated further because it may be caused by a malignant intra-abdominal tumor.

Motion tenderness. If the to-and-fro movement of the vaginal probe elicits any motion tenderness, it, too, should be documented. It may be a sign of pelvic peritonitis. In such cases, an “ominous appearing” adnexal finding may represent an inflammatory, rather than malignant, mass.

When to use Doppler

One of the components of extensive evaluation of the adnexae in general and ovaries in particular is color or power Doppler interrogation—or both.

Tumors contain a relatively large number of pathologic blood vessels that lack the muscular layer found in normal blood vessels and, as a result, demonstrate lower resistance to flow. Diastolic flow is high in these vessels, and resistance and pulsatility indices are low.

We also pay attention when these blood vessels have a tortuous appearance, changes in caliber, anastomoses, and vascular lakes.³ The more tortuous the vessels, with multiple inter-vessel connections and dilatations with changing calibers, the greater the risk of malignancy.⁴ No less important is the presence of a vessel within a “complex” ovarian mass. A centrally located vessel (also called a “lead vessel”) is suspicious for malignancy.⁵

A gallery of non-neoplastic ovarian masses

Non-neoplastic cysts are, by far, the most common structures of the ovary. They may be functional, as in the case of the follicles, corpus luteum, and theca lutein cysts, or they may be nonfunctional, as in serous cysts and endometriomas. (As we noted in Part 1, do not call the follicles and corpus luteum “cysts” because this designation suggests pathology.)⁶

FIGURE 2 Simple cyst

This cyst is anechoic and unilocular with thin walls and no papillae.

Functional cysts

Functional cysts, also known as “simple” cysts, may grow as large as 4 to 5 cm in diameter (Figure 2). They are typically unilocular, anechoic, and thin-walled, with no papillae, and almost never malignant. They usually resolve and require no treatment unless rupture or torsion occurs. Except for the corpus luteum, they have no increased blood flow, and need be viewed only by transvaginal ultrasonography (TVS).

The corpus luteum also can be recognized by TVS. It can exhibit any of a variety of internal structures and echo patterns, due to the multitude of shapes of the blood or clot that can be seen within it (Figure 3).

FIGURE 3 Corpus luteum

A–C. Gray-scale, color Doppler, and power Doppler images, respectively, of a typical corpus luteum. B and C show the enveloping vessels, or “ring of fire.” D. A rather typical gray-scale appearance with a mesh-like, linear internal texture. E. A common feature of the corpus luteum is a linear interphase (arrow) between the clot (c) and the liquified serum (s).

The corpus luteum is typically enveloped by blood vessels, visible on color Doppler as what is called a “ring of fire.” It regresses without intervention. In hyperstimulated ovaries, however, more than one may be present; this poses a real diagnostic challenge when ectopic pregnancy is suspected because it is difficult to differentiate the two entities.

Because the corpus luteum can sometimes resemble some types of ovarian tumors on TVS, imaging during the secretory phase of the cycle in a woman of reproductive age is not ideal. Instead, she should be scanned (or rescanned) between days 5 and 9 of the cycle.

FIGURE 4 Hormonally stimulated ovaries

A, B. The right and left ovaries stimulated by follicle-stimulating hormone preparation (arrow points to hilus). C. An ovary stimulated by clomiphene.

Lutein cysts may reach 5 to 10 cm in diameter. They generally have a thick wall, are multilocular, and typically occur after hormonal induction of ovulation (Figure 4). They also can occur in diabetes, molar pregnancy, and hydrops fetalis. We have seen a unilateral theca lutein cyst in a normal pregnancy (Figure 5). No treatment is necessary unless rupture or torsion occurs.

FIGURE 5 Lutein cysts

A–C. The typical “stained glass” appearance of three lutein cysts of the right ovary in a pregnant patient. D. Color Doppler image of the ovary demonstrating high-velocity flow (peak systolic velocity of 20.4 cm/s).

Serous cysts

These cysts can reach 4 cm in diameter, have smooth walls with no papillae, are unilocular, and occur most often during menopause. No pathological blood flow is visible in their walls. Most gynecologists follow them (Figure 6).^1,7

FIGURE 6 Serous cyst

A. Right ovary containing the cyst. B. Normal left ovary. C. Power Doppler interrogation showing no particular flow in the walls of a serous cyst.

Endometriomas

After the simple cyst, the endometrioma is the most prevalent ovarian or adnexal cyst (Figure 7). It usually has a thick wall and is filled with homogeneous fluid with low-level echo-genicity. It can reach 10 cm in size, and many are bilateral. It is sometimes called a “chocolate” cyst because of its dark blood content.

FIGURE 7 Endometriomas

Endometriomas have low echogenicity. A. Unilateral, unilocular cyst with thin walls. B. Bilateral endometriomas. C. Blood flow in a solid or papillary component of the endometrioma is an occasional finding. It should be investigated further because of the risk that it represents endometrioid cancer.

Endometriomas do not resolve; they usually require surgical excision, although very small ones wholly contained within an ovary are often managed medically or expectantly.

These masses rarely (<1%) give rise to endometrioid carcinoma. Should an endometrioma contain papillae with blood vessels, it is extremely suspicious for endometrioid cancer.

FIGURE 8 Cystic fibromas

A. Sonographic image shows a thin wall and hyperechoic, small mural nodules. B. Macroscopic appearance of an area of internal papillary excrescences. C. Measurement of the small, mural nodules. D. Lack of blood flow in the small papillae, a typical finding on color or power Doppler. E, F. Blood flow in the wall of the cyst and in the mural nodules.

Ovarian fibromas

A fibroma is a slow-growing, benign, solid ovarian tumor. It usually has a cystic component and then is called a cystadenofibroma.

The cystic variety is filled with anechoic fluid and has a thin wall. However, its pathognomonic feature is the small (2–3 mm), extremely hyperechoic mural nodules (papillae) it contains (Figure 8A–C). In the overwhelming majority of cases, no blood vessels are detectable, and the mass is unilocular (Figure 8D–E). It can be recognized in the ovary by the semilunar shape of the tissue surrounding it (crescent sign). The differential diagnosis includes the simple (serous) cyst.

The solid fibroma has a myometrium-like texture, with few or no detectable blood vessels in the stroma. The differential diagnosis includes the Brenner tumor and the Krukenberg tumor.

Stay tuned!

Next issue, in Part 3 of this series, we will review the use of imaging in the investigation of ovarian neoplasms, both benign and malignant, with an abundance of US images to accompany our discussion.

We want to hear from you! Tell us what you think.

Scanning the ovaries is no simple task. As we mentioned in Part 1 of this four-part series, the practitioner must use the right equipment, take basic preparatory steps, be watchful for clues in the history, and reach a conclusion about what he or she sees. Not only that: The ultrasonographer must be extraordinarily vigilant, paying close attention to multiple characteristics of any mass, from thickness of the wall to the presence of papillations or a blood supply—signs of potential malignancy.

In this article, we detail the traits of various types of non-neoplastic ovarian masses, including:

• functional cysts—follicles, the corpus luteum, and theca lutein cysts
• nonfunctional cysts—serous masses and endometriomas
• cystadenofibromas. Although these masses are usually categorized histo-logically as neoplasms, we include them here due to their almost daily appearance in a busy gynecologic ultrasonographic (US) facility.

In Part 3, we will cover ovarian neoplasms, and in Part 4, our focus will be tubal entities such as ectopic pregnancy and torsion.

FIGURE 1 What is a mass made of? 6 morphologic building blocks

Take an inventory of the mass

Any adnexal mass should be assessed in light of its essential characteristics (Figure 1).

Wall structure. Pay attention to thickness. We use an arbitrary cutoff of 4 mm, giving extra scrutiny to thicknesses exceeding that measurement. In our experience, the thicker the wall, the more likely the mass is to be malignant.

Septation and loculation. A mass is typically unilocular or multilocular. Multilocularity is more common in tumors of low malignant potential and malignant neoplasms.

Papillation. Any internal or external papillae or excrescences should draw your attention. Papillarity in an ovarian mass renders that mass suspicious for malignancy.

Measure (height and width) any papillae that are identified, and document them. Because papillae are associated with ovarian malignancy, further assessment is warranted immediately. The first step is determining whether the papillations contain blood vessels—a task for which color and power Doppler are helpful. We prefer power Doppler because it is more sensitive, detecting blood-flow velocity in the lowest detectable range of 2 cm/s, and because it is not directionally influenced.

Papillae that contain blood vessels with detectable flow are suspicious for malignancy.

Exacoustos and colleagues found that papillae as large as 15 mm in height and 10 mm in width (base) were present in 48% of borderline ovarian tumors but in only 4% of benign and 4% of malignant tumors. However, when the intracystic solid tissue exceeded those dimensions, the lesions were present in 48% of invasive ovarian tumors, 18% of borderline ovarian tumors, and 7% of benign masses.¹

Internal echo-structure. A mass can be anechoic, a finding that usually indicates the presence of clear fluid. Mostly solid masses are echogenic. And masses that contain particulate matter, such as blood, cellular matter, or even mucous material, usually have echogenicity of a low level, often described as a “ground-glass” appearance. A mass can also have mixed echo-genicity, a finding usually found in cases involving teratoma or malignancy.

Shadowing. If it is present, it may signify the presence of an extremely dense, solid tissue, such as bone or calcification. The diagnosis of a benign teratoma (i.e., dermoid cyst) should be entertained if shadowing is present in a hyperechoic nodule or mass. Malignant masses very rarely, if ever, display frank shadowing.

Overall appearance. On rare occasions, a bizarre shape or “complex” appearance (as it is termed in most radiology reports) may indicate a malignant mass. More likely it indicates the presence of a teratoma, cystadenoma, or even an atypical corpus luteum. In some reports generated by US laboratories, the term “complex” is applied to all structures other than simple cysts.

Size. The size of a mass can be misleading, as small ovarian lesions with the appropriate sonographic characteristics may be malignant and some larger ones without those characteristics may not be. However, it is understood that the larger an ovarian lesion, the more likely it is a tumor. One important distinction: The amount of fluid in a cystic structure or the amount of old blood in an endometrioma is not the disease process…it is the byproduct of the process. So an 8-cm endometrioma may create fewer pain or fertility issues than a 2- or 3-cm endometrioma. Similarly, the amount of “chocolate” fluid is not automatically indicative of the amount of active endometriotic glands or their sequelae!²

Ascites. If it is present, it should be recorded and investigated further because it may be caused by a malignant intra-abdominal tumor.

Motion tenderness. If the to-and-fro movement of the vaginal probe elicits any motion tenderness, it, too, should be documented. It may be a sign of pelvic peritonitis. In such cases, an “ominous appearing” adnexal finding may represent an inflammatory, rather than malignant, mass.

When to use Doppler

One of the components of extensive evaluation of the adnexae in general and ovaries in particular is color or power Doppler interrogation—or both.

Tumors contain a relatively large number of pathologic blood vessels that lack the muscular layer found in normal blood vessels and, as a result, demonstrate lower resistance to flow. Diastolic flow is high in these vessels, and resistance and pulsatility indices are low.

We also pay attention when these blood vessels have a tortuous appearance, changes in caliber, anastomoses, and vascular lakes.³ The more tortuous the vessels, with multiple inter-vessel connections and dilatations with changing calibers, the greater the risk of malignancy.⁴ No less important is the presence of a vessel within a “complex” ovarian mass. A centrally located vessel (also called a “lead vessel”) is suspicious for malignancy.⁵

A gallery of non-neoplastic ovarian masses

Non-neoplastic cysts are, by far, the most common structures of the ovary. They may be functional, as in the case of the follicles, corpus luteum, and theca lutein cysts, or they may be nonfunctional, as in serous cysts and endometriomas. (As we noted in Part 1, do not call the follicles and corpus luteum “cysts” because this designation suggests pathology.)⁶

FIGURE 2 Simple cyst

This cyst is anechoic and unilocular with thin walls and no papillae.

Functional cysts

Functional cysts, also known as “simple” cysts, may grow as large as 4 to 5 cm in diameter (Figure 2). They are typically unilocular, anechoic, and thin-walled, with no papillae, and almost never malignant. They usually resolve and require no treatment unless rupture or torsion occurs. Except for the corpus luteum, they have no increased blood flow, and need be viewed only by transvaginal ultrasonography (TVS).

The corpus luteum also can be recognized by TVS. It can exhibit any of a variety of internal structures and echo patterns, due to the multitude of shapes of the blood or clot that can be seen within it (Figure 3).

FIGURE 3 Corpus luteum

A–C. Gray-scale, color Doppler, and power Doppler images, respectively, of a typical corpus luteum. B and C show the enveloping vessels, or “ring of fire.” D. A rather typical gray-scale appearance with a mesh-like, linear internal texture. E. A common feature of the corpus luteum is a linear interphase (arrow) between the clot (c) and the liquified serum (s).

The corpus luteum is typically enveloped by blood vessels, visible on color Doppler as what is called a “ring of fire.” It regresses without intervention. In hyperstimulated ovaries, however, more than one may be present; this poses a real diagnostic challenge when ectopic pregnancy is suspected because it is difficult to differentiate the two entities.

Because the corpus luteum can sometimes resemble some types of ovarian tumors on TVS, imaging during the secretory phase of the cycle in a woman of reproductive age is not ideal. Instead, she should be scanned (or rescanned) between days 5 and 9 of the cycle.

FIGURE 4 Hormonally stimulated ovaries

A, B. The right and left ovaries stimulated by follicle-stimulating hormone preparation (arrow points to hilus). C. An ovary stimulated by clomiphene.

Lutein cysts may reach 5 to 10 cm in diameter. They generally have a thick wall, are multilocular, and typically occur after hormonal induction of ovulation (Figure 4). They also can occur in diabetes, molar pregnancy, and hydrops fetalis. We have seen a unilateral theca lutein cyst in a normal pregnancy (Figure 5). No treatment is necessary unless rupture or torsion occurs.

FIGURE 5 Lutein cysts

A–C. The typical “stained glass” appearance of three lutein cysts of the right ovary in a pregnant patient. D. Color Doppler image of the ovary demonstrating high-velocity flow (peak systolic velocity of 20.4 cm/s).

Serous cysts

These cysts can reach 4 cm in diameter, have smooth walls with no papillae, are unilocular, and occur most often during menopause. No pathological blood flow is visible in their walls. Most gynecologists follow them (Figure 6).^1,7

FIGURE 6 Serous cyst

A. Right ovary containing the cyst. B. Normal left ovary. C. Power Doppler interrogation showing no particular flow in the walls of a serous cyst.

Endometriomas

After the simple cyst, the endometrioma is the most prevalent ovarian or adnexal cyst (Figure 7). It usually has a thick wall and is filled with homogeneous fluid with low-level echo-genicity. It can reach 10 cm in size, and many are bilateral. It is sometimes called a “chocolate” cyst because of its dark blood content.

FIGURE 7 Endometriomas

Endometriomas have low echogenicity. A. Unilateral, unilocular cyst with thin walls. B. Bilateral endometriomas. C. Blood flow in a solid or papillary component of the endometrioma is an occasional finding. It should be investigated further because of the risk that it represents endometrioid cancer.

Endometriomas do not resolve; they usually require surgical excision, although very small ones wholly contained within an ovary are often managed medically or expectantly.

These masses rarely (<1%) give rise to endometrioid carcinoma. Should an endometrioma contain papillae with blood vessels, it is extremely suspicious for endometrioid cancer.

FIGURE 8 Cystic fibromas

A. Sonographic image shows a thin wall and hyperechoic, small mural nodules. B. Macroscopic appearance of an area of internal papillary excrescences. C. Measurement of the small, mural nodules. D. Lack of blood flow in the small papillae, a typical finding on color or power Doppler. E, F. Blood flow in the wall of the cyst and in the mural nodules.

Ovarian fibromas

A fibroma is a slow-growing, benign, solid ovarian tumor. It usually has a cystic component and then is called a cystadenofibroma.

The cystic variety is filled with anechoic fluid and has a thin wall. However, its pathognomonic feature is the small (2–3 mm), extremely hyperechoic mural nodules (papillae) it contains (Figure 8A–C). In the overwhelming majority of cases, no blood vessels are detectable, and the mass is unilocular (Figure 8D–E). It can be recognized in the ovary by the semilunar shape of the tissue surrounding it (crescent sign). The differential diagnosis includes the simple (serous) cyst.

The solid fibroma has a myometrium-like texture, with few or no detectable blood vessels in the stroma. The differential diagnosis includes the Brenner tumor and the Krukenberg tumor.

Stay tuned!

Next issue, in Part 3 of this series, we will review the use of imaging in the investigation of ovarian neoplasms, both benign and malignant, with an abundance of US images to accompany our discussion.

We want to hear from you! Tell us what you think.

Scanning the ovaries is no simple task. As we mentioned in Part 1 of this four-part series, the practitioner must use the right equipment, take basic preparatory steps, be watchful for clues in the history, and reach a conclusion about what he or she sees. Not only that: The ultrasonographer must be extraordinarily vigilant, paying close attention to multiple characteristics of any mass, from thickness of the wall to the presence of papillations or a blood supply—signs of potential malignancy.

In this article, we detail the traits of various types of non-neoplastic ovarian masses, including:

• functional cysts—follicles, the corpus luteum, and theca lutein cysts
• nonfunctional cysts—serous masses and endometriomas
• cystadenofibromas. Although these masses are usually categorized histo-logically as neoplasms, we include them here due to their almost daily appearance in a busy gynecologic ultrasonographic (US) facility.

In Part 3, we will cover ovarian neoplasms, and in Part 4, our focus will be tubal entities such as ectopic pregnancy and torsion.

FIGURE 1 What is a mass made of? 6 morphologic building blocks

Take an inventory of the mass

Any adnexal mass should be assessed in light of its essential characteristics (Figure 1).

Wall structure. Pay attention to thickness. We use an arbitrary cutoff of 4 mm, giving extra scrutiny to thicknesses exceeding that measurement. In our experience, the thicker the wall, the more likely the mass is to be malignant.

Septation and loculation. A mass is typically unilocular or multilocular. Multilocularity is more common in tumors of low malignant potential and malignant neoplasms.

Papillation. Any internal or external papillae or excrescences should draw your attention. Papillarity in an ovarian mass renders that mass suspicious for malignancy.

Measure (height and width) any papillae that are identified, and document them. Because papillae are associated with ovarian malignancy, further assessment is warranted immediately. The first step is determining whether the papillations contain blood vessels—a task for which color and power Doppler are helpful. We prefer power Doppler because it is more sensitive, detecting blood-flow velocity in the lowest detectable range of 2 cm/s, and because it is not directionally influenced.

Papillae that contain blood vessels with detectable flow are suspicious for malignancy.

Exacoustos and colleagues found that papillae as large as 15 mm in height and 10 mm in width (base) were present in 48% of borderline ovarian tumors but in only 4% of benign and 4% of malignant tumors. However, when the intracystic solid tissue exceeded those dimensions, the lesions were present in 48% of invasive ovarian tumors, 18% of borderline ovarian tumors, and 7% of benign masses.¹

Internal echo-structure. A mass can be anechoic, a finding that usually indicates the presence of clear fluid. Mostly solid masses are echogenic. And masses that contain particulate matter, such as blood, cellular matter, or even mucous material, usually have echogenicity of a low level, often described as a “ground-glass” appearance. A mass can also have mixed echo-genicity, a finding usually found in cases involving teratoma or malignancy.

Shadowing. If it is present, it may signify the presence of an extremely dense, solid tissue, such as bone or calcification. The diagnosis of a benign teratoma (i.e., dermoid cyst) should be entertained if shadowing is present in a hyperechoic nodule or mass. Malignant masses very rarely, if ever, display frank shadowing.

Overall appearance. On rare occasions, a bizarre shape or “complex” appearance (as it is termed in most radiology reports) may indicate a malignant mass. More likely it indicates the presence of a teratoma, cystadenoma, or even an atypical corpus luteum. In some reports generated by US laboratories, the term “complex” is applied to all structures other than simple cysts.

Size. The size of a mass can be misleading, as small ovarian lesions with the appropriate sonographic characteristics may be malignant and some larger ones without those characteristics may not be. However, it is understood that the larger an ovarian lesion, the more likely it is a tumor. One important distinction: The amount of fluid in a cystic structure or the amount of old blood in an endometrioma is not the disease process…it is the byproduct of the process. So an 8-cm endometrioma may create fewer pain or fertility issues than a 2- or 3-cm endometrioma. Similarly, the amount of “chocolate” fluid is not automatically indicative of the amount of active endometriotic glands or their sequelae!²

Ascites. If it is present, it should be recorded and investigated further because it may be caused by a malignant intra-abdominal tumor.

Motion tenderness. If the to-and-fro movement of the vaginal probe elicits any motion tenderness, it, too, should be documented. It may be a sign of pelvic peritonitis. In such cases, an “ominous appearing” adnexal finding may represent an inflammatory, rather than malignant, mass.

When to use Doppler

One of the components of extensive evaluation of the adnexae in general and ovaries in particular is color or power Doppler interrogation—or both.

Tumors contain a relatively large number of pathologic blood vessels that lack the muscular layer found in normal blood vessels and, as a result, demonstrate lower resistance to flow. Diastolic flow is high in these vessels, and resistance and pulsatility indices are low.

We also pay attention when these blood vessels have a tortuous appearance, changes in caliber, anastomoses, and vascular lakes.³ The more tortuous the vessels, with multiple inter-vessel connections and dilatations with changing calibers, the greater the risk of malignancy.⁴ No less important is the presence of a vessel within a “complex” ovarian mass. A centrally located vessel (also called a “lead vessel”) is suspicious for malignancy.⁵

A gallery of non-neoplastic ovarian masses

Non-neoplastic cysts are, by far, the most common structures of the ovary. They may be functional, as in the case of the follicles, corpus luteum, and theca lutein cysts, or they may be nonfunctional, as in serous cysts and endometriomas. (As we noted in Part 1, do not call the follicles and corpus luteum “cysts” because this designation suggests pathology.)⁶

FIGURE 2 Simple cyst

This cyst is anechoic and unilocular with thin walls and no papillae.

Functional cysts

Functional cysts, also known as “simple” cysts, may grow as large as 4 to 5 cm in diameter (Figure 2). They are typically unilocular, anechoic, and thin-walled, with no papillae, and almost never malignant. They usually resolve and require no treatment unless rupture or torsion occurs. Except for the corpus luteum, they have no increased blood flow, and need be viewed only by transvaginal ultrasonography (TVS).

The corpus luteum also can be recognized by TVS. It can exhibit any of a variety of internal structures and echo patterns, due to the multitude of shapes of the blood or clot that can be seen within it (Figure 3).

FIGURE 3 Corpus luteum

A–C. Gray-scale, color Doppler, and power Doppler images, respectively, of a typical corpus luteum. B and C show the enveloping vessels, or “ring of fire.” D. A rather typical gray-scale appearance with a mesh-like, linear internal texture. E. A common feature of the corpus luteum is a linear interphase (arrow) between the clot (c) and the liquified serum (s).

The corpus luteum is typically enveloped by blood vessels, visible on color Doppler as what is called a “ring of fire.” It regresses without intervention. In hyperstimulated ovaries, however, more than one may be present; this poses a real diagnostic challenge when ectopic pregnancy is suspected because it is difficult to differentiate the two entities.

Because the corpus luteum can sometimes resemble some types of ovarian tumors on TVS, imaging during the secretory phase of the cycle in a woman of reproductive age is not ideal. Instead, she should be scanned (or rescanned) between days 5 and 9 of the cycle.

FIGURE 4 Hormonally stimulated ovaries

A, B. The right and left ovaries stimulated by follicle-stimulating hormone preparation (arrow points to hilus). C. An ovary stimulated by clomiphene.

Lutein cysts may reach 5 to 10 cm in diameter. They generally have a thick wall, are multilocular, and typically occur after hormonal induction of ovulation (Figure 4). They also can occur in diabetes, molar pregnancy, and hydrops fetalis. We have seen a unilateral theca lutein cyst in a normal pregnancy (Figure 5). No treatment is necessary unless rupture or torsion occurs.

FIGURE 5 Lutein cysts

A–C. The typical “stained glass” appearance of three lutein cysts of the right ovary in a pregnant patient. D. Color Doppler image of the ovary demonstrating high-velocity flow (peak systolic velocity of 20.4 cm/s).

Serous cysts

These cysts can reach 4 cm in diameter, have smooth walls with no papillae, are unilocular, and occur most often during menopause. No pathological blood flow is visible in their walls. Most gynecologists follow them (Figure 6).^1,7

FIGURE 6 Serous cyst

A. Right ovary containing the cyst. B. Normal left ovary. C. Power Doppler interrogation showing no particular flow in the walls of a serous cyst.

Endometriomas

After the simple cyst, the endometrioma is the most prevalent ovarian or adnexal cyst (Figure 7). It usually has a thick wall and is filled with homogeneous fluid with low-level echo-genicity. It can reach 10 cm in size, and many are bilateral. It is sometimes called a “chocolate” cyst because of its dark blood content.

FIGURE 7 Endometriomas

Endometriomas have low echogenicity. A. Unilateral, unilocular cyst with thin walls. B. Bilateral endometriomas. C. Blood flow in a solid or papillary component of the endometrioma is an occasional finding. It should be investigated further because of the risk that it represents endometrioid cancer.

Endometriomas do not resolve; they usually require surgical excision, although very small ones wholly contained within an ovary are often managed medically or expectantly.

These masses rarely (<1%) give rise to endometrioid carcinoma. Should an endometrioma contain papillae with blood vessels, it is extremely suspicious for endometrioid cancer.

FIGURE 8 Cystic fibromas

A. Sonographic image shows a thin wall and hyperechoic, small mural nodules. B. Macroscopic appearance of an area of internal papillary excrescences. C. Measurement of the small, mural nodules. D. Lack of blood flow in the small papillae, a typical finding on color or power Doppler. E, F. Blood flow in the wall of the cyst and in the mural nodules.

Ovarian fibromas

A fibroma is a slow-growing, benign, solid ovarian tumor. It usually has a cystic component and then is called a cystadenofibroma.

The cystic variety is filled with anechoic fluid and has a thin wall. However, its pathognomonic feature is the small (2–3 mm), extremely hyperechoic mural nodules (papillae) it contains (Figure 8A–C). In the overwhelming majority of cases, no blood vessels are detectable, and the mass is unilocular (Figure 8D–E). It can be recognized in the ovary by the semilunar shape of the tissue surrounding it (crescent sign). The differential diagnosis includes the simple (serous) cyst.

The solid fibroma has a myometrium-like texture, with few or no detectable blood vessels in the stroma. The differential diagnosis includes the Brenner tumor and the Krukenberg tumor.

Stay tuned!

Next issue, in Part 3 of this series, we will review the use of imaging in the investigation of ovarian neoplasms, both benign and malignant, with an abundance of US images to accompany our discussion.

We want to hear from you! Tell us what you think.

Think breast cancer survivors are unlikely to show up in your practice? You should think again.

At last official count, 2.5 million women in the United States had a history of breast cancer.¹ Most of them are now free of malignancy, but others are still grappling with the disease in some form or fashion.² All need continuing health care.

Roughly two thirds of women who have breast cancer have disease that is hormone-receptor–positive.^2,3 Recently updated guidelines from the American Society of Clinical Oncology (ASCO) recommend that adjuvant therapy for postmenopausal women who have hormone-positive breast cancer include an aromatase inhibitor (AI) (see a summary of these guidelines on page 36). That makes it likely that a good number of breast cancer survivors who visit your practice are taking one of these medications: anastrozole (Arimidex), letrozole (Femara), or exemestane (Aromasin). These drugs are antiestrogens, given to postmenopausal women to reduce the likelihood of disease recurrence and progression.

The antiestrogenic properties of these drugs are what make them lifesavers. But the same qualities can create a range of health issues, from increased risk of osteoporosis and fracture to vasomotor and joint symptoms. And although ObGyns are not the physicians who prescribe these drugs, you may be the provider one of these women consults about their side effects and related issues.

To find out the latest on the management of women who are taking one of these agents, we inserted ourselves into the busy schedule of Andrew M. Kaunitz, MD, who agreed to address some fundamental—and some not so basic—questions about the drugs. In this extended Q&A, Dr. Kaunitz touches on mechanism of action, benefits versus risks, common side effects, compliance with therapy, and the ill effects of early discontinuation.

Aromatase inhibitors are better than tamoxifen at reducing the risk of breast cancer recurrence in postmenopausal women who have hormone-receptor–positive disease. But, they increase the risk of osteoporosis and fracture and often cause arthralgias and other complaints that ObGyn practitioners may be called upon to manage.

OBG Management: What is the overall aim of adjuvant endocrine therapy in the setting of breast cancer?

Dr. Kaunitz: Endocrine therapy—specifically, use of an AI—prevents the stimulation of breast cancer cells by endogenous estrogen. In other words, aromatase inhibitors suppress the growth of cancer cells that have estrogen receptors. These drugs also inhibit aromatase near any breast tumor and reduce estrogen levels in breast tissue.

OBG Management: What is the mechanism of action of adjuvant endocrine therapy?

Dr. Kaunitz: In postmenopausal women, androgens are converted to estrogens via the aromatase enzyme, which is present in adipose tissue and other sites. By blocking this enzyme, AIs reduce endogenous estrogen levels by as much as 95%.⁴

OBG Management: How does that differ from the mechanism of action of tamoxifen, another drug used in breast cancer patients?

Dr. Kaunitz: Tamoxifen is a selective estrogen receptor modulator (SERM). It blocks estrogen in breast tissue selectively, by competitively binding to estrogen receptors.⁵ However, tamoxifen has estrogenic effects in the uterus, bone, and liver, as well as other tissues.

The efficacy of AIs in preventing breast cancer recurrence in the first 2 years after breast cancer surgery is higher than that of tamoxifen. And unlike tamoxifen, the AIs do not increase the risk of venous thromboembolism or cause endometrial disease.

OBG Management: What effects do aromatase inhibitors have in premenopausal women?

Dr. Kaunitz: These agents are not recommended for use in premenopausal women because, in that population, the lion’s share of estrogen production takes place in the ovary rather than in adipose tissue and muscle. If you were to administer an AI to a premenopausal woman, the reduced hypothalamic and pituitary estrogen feedback could lead to ovarian stimulation—which could increase ovarian steroid production.

OBG Management: What about women who become amenorrheic as a result of chemotherapy or other cancer treatment? Do most oncologists assume that they are postmenopausal and prescribe an aromatase inhibitor?

Dr. Kaunitz: Clinicians should not assume that chemotherapy-induced amenorrhea signals permanent cessation of ovarian function. It is common for ovarian function to return in this setting. Accordingly, follicle-stimulating hormone (FSH) and estradiol levels should be assessed before an AI is considered as adjuvant therapy. Some investigators have suggested that the use of an AI in women who have chemotherapy-induced amenorrhea may actually increase the likelihood that ovarian function will return.⁶

OBG Management: Do all AIs produce the same effects?

Dr. Kaunitz: The AIs used in women with breast cancer are third-generation drugs. These AIs are classified as steroidal (type 1; exemestane) or nonsteroidal (type 2; anastrozole, letrozole). Exemestane, a steroid derived from androstenedione, inhibits the aromatase enzyme irreversibly. The nonsteroidal AIs are reversible.

Although all three AIs have numerous similarities, there are other distinctions between them in pharmacokinetics, mechanism of action, and toxicity—so they are not completely interchangeable.⁷ However, from our perspective as ObGyns caring for breast cancer survivors, we can assume that all three AIs will have similar effects on skeletal health and produce similar side effects in postmenopausal women.

How much do we know about these drugs?

OBG Management: How long does a woman typically take an AI?

Dr. Kaunitz: At present, in women treated for early-stage, hormone-positive breast cancer, the optimal duration of treatment is unknown. Most oncologists prescribe an AI for 5 years, the length of treatment in a prominent trial of the drugs.⁸

OBG Management: Is that duration likely to increase as more data come in?

Dr. Kaunitz: The optimal duration of adjuvant AI therapy will be determined by the findings of long-term clinical trials. The National Surgical Adjuvant Breast and Bowel Project B-42 trial may provide new insights into optimal duration of AI treatment after initial tamoxifen therapy.⁹

OBG Management: How thoroughly have AIs been studied in regard to their use in breast cancer survivors and women who have early-stage disease? How would you characterize the quantity and quality of data that we have so far?

Dr. Kaunitz: AIs have been extensively studied. The most important clinical trials of AIs in this setting, including the Anastrozole, Tamoxifen Alone or in Combination (ATAC) trial (over 6,000 participants, median follow-up of 100 months) and the Breast International Group (BIG) trial (almost 5,000 participants, median follow-up of 76 months) have been detailed in the recent ASCO report.¹⁰ These two large landmark trials, in particular, formed the basis for ASCO’s recommendations to routinely incorporate AIs into the therapy of postmenopausal women who have hormone-receptor–positive breast cancer.

OBG Management: In treating breast cancer, what other applications are AIs used for?

Dr. Kaunitz: AIs appear to be slightly more effective than tamoxifen in treating postmenopausal women who have metastatic breast cancer.¹¹

They are approved as first-line therapy for breast cancer in:

• postmenopausal women who have hormone-receptor–positive disease
• postmenopausal women who have locally advanced disease when the hormone receptor is unknown
• postmenopausal women who have metastatic disease.

In addition, they are approved as second-line treatment of advanced breast cancer in postmenopausal women who have disease progression following tamoxifen therapy.¹²

How effective is AI therapy?

OBG Management: What do we know about the efficacy of these drugs?

Dr. Kaunitz: Most of the studies that have explored efficacy compare an AI with tamoxifen rather than with placebo. In the ATAC trial, after a median follow-up of 33 months, women who were taking anastrozole for early-stage breast cancer had longer disease-free survival and time to recurrence and a lower incidence of contralateral breast cancer than did women taking tamoxifen.⁸

After 4 years of follow-up in the ATAC trial, women taking anastrozole continued to have more favorable disease-free survival (86.9% vs 84.5% for anastrozole and tamoxifen, respectively; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.76–0.99; P =.03).¹³ They also had a more favorable time to recurrence than did women taking tamoxifen (HR, 0.83; 95% CI, 0.71–0.96; P =.015). And women taking anastrozole had a lower incidence of contralateral breast cancer, as well, although this different did not achieve statistical significance (HR, 0.62; 95% CI, 0.38–1.02; P =.062).¹³

In the BIG study, women taking letrozole had a 5-year disease-free survival estimate of 84.0%, compared with 81.4% for women taking tamoxifen.¹⁴ In addition, women taking letrozole were significantly less likely than those taking tamoxifen to experience an event that ended a period of disease-free survival (HR, 0.81; 95% CI, 0.70–0.93; P =.003), especially the event of distant recurrence (HR, 0.73; 95% CI, 0.60–0.88; P =.001).¹⁴

And a phase-3 study of exemestane versus tamoxifen in women who had metastatic breast cancer found that the AI produced a superior response rate (46% vs 31% for exemestane and tamoxifen, respectively; odds ratio [OR], 1.85; 95% CI, 1.21–2.82; P =.005). In addition, median progression-free survival was greater with exemestane (9.9 months; 95% CI, 8.7–11.8 months) than with tamoxifen (5.8 months; 95% CI, 5.3–8.1 months). However, there was no difference between arms in progression-free survival or overall survival.

How well tolerated are AIs?

OBG Management: What adverse effects are associated with AIs?

Dr. Kaunitz: Although AIs, overall, are safe medications, their use is associated with a number of adverse events. The most prominent side effects include arthralgias and hot flushes, while the most serious health impact appears to be a decrease in bone mineral density (BMD).

However, the drugs are generally perceived as being easier to tolerate than tamoxifen. That’s because endometrial cancer, vaginal bleeding and discharge, cerebrovascular events, venous thromboembolic events, and hot flushes all are less common among women taking an AI than among those taking tamoxifen.^8,13

For overweight women, who face an elevated baseline risk of thromboembolism, the availability of AIs represents a major advantage over tamoxifen. Similarly, AIs offer advantages over tamoxifen for women who have an intact uterus. In addition, postmenopausal women who are taking a selective serotonin reuptake inhibitor (SSRI) such as paroxetine should take an AI rather than tamoxifen, because the concomitant use of SSRIs attenuates the efficacy of tamoxifen.¹⁵

What can be done about the most prominent risks?

OBG Management: Let’s focus on what’s probably the best-known adverse effect of AIs—the heightened risk of osteoporosis and fracture. How significant is this effect?

Dr. Kaunitz: Because use of an AI is associated with a profound reduction in endogenous estrogen levels, it also decreases BMD and can lead to osteoporotic fractures. All major phase-3 trials of adjuvant use of AIs in women who have early breast cancer found an increased risk of fracture, with no significant differences between AIs.¹⁶

Fortunately, bisphosphonate therapy (oral or intravenous) has been found to reduce bone loss associated with AI therapy.^17,18

Assessing baseline BMD is important as women initiate AI therapy. Although no consensus exists regarding follow-up BMD assessment in the setting of AI use, an interval of 2 years is prudent, with the follow-up study preferably performed at the same imaging center and by the same technician as the first. If baseline osteoporosis is observed at the lumbar spine or hip, bisphosphonate therapy is appropriate. If a woman taking an AI has low bone mass (osteopenia) but not osteoporosis, bisphosphonate therapy should be considered if any of the following risk factors are present:

• advanced age
• history of fracture
• glucocorticoid therapy
• parental history of hip fracture
• low body weight
• current smoking status
• excess alcohol consumption
• rheumatoid arthritis
• known risk factors for secondary osteoporosis.¹⁹

In breast cancer survivors initiating or continuing AI therapy, it is also appropriate to check a serum vitamin D level and ensure that intake of this nutrient is adequate.

Bisphosphonates may offer oncologic benefits, as well; preliminary evidence suggests that the drugs may prevent recurrence of the cancer and prolong survival.²⁰

OBG Management: What can an ObGyn offer to a woman who complains of significant AI-related arthralgia?

Dr. Kaunitz: Bone and joint symptoms, including aches, pain, and stiffness that is bilateral and not associated with other evidence of rheumatologic disorders, are among the most common side effects of AI therapy. On the plus side of the equation, these symptoms are more likely to be mild to moderate than severe. On the negative side, no specific treatment has been found to be effective in relieving these symptoms, which usually resolve within 2 months or so after discontinuing AI therapy.¹⁰

OBG Management: Do AIs have a negative impact on cardiovascular health?

Dr. Kaunitz: Unlike tamoxifen, AIs do not increase the risk of thromboembolic disease. Although the use of an AI may modestly increase the risk of ischemic cardiovascular disease (and lipid changes), compared with tamoxifen, AIs do not appear to increase cardiovascular risk compared with placebo.^21,22

OBG Management: Do the antiestrogenic effects of AIs have a significant impact on vaginal health and sexual desire?

Dr. Kaunitz: A review of published reports did not find that the use of AIs has a predictable impact on vaginal dryness or sexual desire.¹⁰ However, symptomatic genital atrophy is common in postmenopausal breast cancer survivors, whether or not they use adjuvant therapy.

Although the FDA considers the use of any estrogen (systemic or vaginal) following a diagnosis of breast cancer to be contraindicated, some breast cancer survivors who have symptomatic genital atrophy express an interest in the use of vaginal estrogen. Use of 25-μg estradiol tablets (Vagifem) is associated with a short-term increase in serum estradiol levels.²³ This finding has reinforced caution among medical oncologists about the safety of vaginal estrogen in breast cancer survivors. (The 25-μg tablets are no longer marketed.) The lowest dosage of vaginal estrogen available for the treatment of genital atrophy is found in 10-μg estradiol tablets (Vagifem) and the estradiol (2-mg) 3-month vaginal ring (Estring). Nonetheless, in the absence of data, oncologists will likely continue to be concerned that even the lowest dosage of vaginal estrogen could attenuate the favorable impact of AIs on breast cancer. Accordingly, use of vaginal lubricants and moisturizers are the mainstay strategy for symptomatic genital atrophy.

OBG Management: What about the ubiquitous hot flush? Vasomotor symptoms may be more common in women who take tamoxifen, but women on AIs are also bothered by flushes. What are the alternatives to estrogen therapy?

Dr. Kaunitz: Both nonprescription and prescription alternatives are available. Nonprescription options include soy extract and red clover isoflavones, black cohosh, and Chinese herbs. However, none of these over-the-counter approaches has been found to be more effective than placebo in the treatment of menopausal hot flushes.^24-26

As for prescription nonhormonal options, ObGyns should recognize that all such treatments are off-label and that none attain the efficacy of hormone therapy in the treatment of vasomotor symptoms. The best-studied and most effective medications include gabapentin, SSRIs (especially paroxetine), and serotonin-norepinephrine reuptake inhibitors (venlafaxine and desvenlafaxine).^24,27

OBG Management: Is there any evidence that AIs impair cognitive function in postmenopausal women?

Dr. Kaunitz: Because estrogen is important for cognition, one might anticipate that the profound reduction in background estrogen associated with AI use would impair cognition. Fortunately, the evidence to date is reassuring. Substudies of the BIG trial and the Tamoxifen and Exemestane Adjuvant Multinational Trial indicate that, compared with tamoxifen (which is associated with declines in cognitive function in postmenopausal women), letrozole and exemestane do not diminish cognitive function.^28,29

OBG Management: Overall, what is the typical impact of an AI on a woman’s quality of life?

Dr. Kaunitz: Most women do very well on an AI, finding it easier to tolerate than tamoxifen, as we have discussed. However, a significant minority of women is seriously bothered by the adverse effects, with arthralgias usually leading the pack of complaints.^30,31

OBG Management: Do some women discontinue adjuvant endocrine therapy because of adverse effects?

Dr. Kaunitz: Regrettably, the answer is “Yes.” A recent study from Kaiser Permanente of northern California found that roughly 50% of women who are prescribed adjuvant endocrine therapy with tamoxifen or an AI discontinue the drug early.³²

OBG Management: What can an ObGyn do to encourage compliance with and completion of AI therapy?

Dr. Kaunitz: First, it is critical that patients understand that AIs are lifesaving drugs. As a recent paper points out, early discontinuation or noncompliance with AI therapy is associated with higher mortality.³³

Clinicians should also help breast cancer patients understand what common side effects to anticipate with these medications.

Finally, clinicians who understand the financial toll a breast cancer diagnosis and treatment can take are better positioned to help women overcome challenges that may interfere with long-term compliance with AI therapy.

OBG Management: Do you expect the use of AIs in breast cancer survivors to become more commonplace?

Dr. Kaunitz: Given how common breast cancer is, and given the new ASCO guidelines and the extensive literature upon which they are based, ObGyns will be seeing more women using AIs. Although we are not the physicians who prescribe AIs, we need to remain up to date on their benefits and side effects. This important class of drugs is positioned to improve outcomes for postmenopausal women with breast cancer.

We want to hear from you! Tell us what you think.

Think breast cancer survivors are unlikely to show up in your practice? You should think again.

At last official count, 2.5 million women in the United States had a history of breast cancer.¹ Most of them are now free of malignancy, but others are still grappling with the disease in some form or fashion.² All need continuing health care.

Roughly two thirds of women who have breast cancer have disease that is hormone-receptor–positive.^2,3 Recently updated guidelines from the American Society of Clinical Oncology (ASCO) recommend that adjuvant therapy for postmenopausal women who have hormone-positive breast cancer include an aromatase inhibitor (AI) (see a summary of these guidelines on page 36). That makes it likely that a good number of breast cancer survivors who visit your practice are taking one of these medications: anastrozole (Arimidex), letrozole (Femara), or exemestane (Aromasin). These drugs are antiestrogens, given to postmenopausal women to reduce the likelihood of disease recurrence and progression.

The antiestrogenic properties of these drugs are what make them lifesavers. But the same qualities can create a range of health issues, from increased risk of osteoporosis and fracture to vasomotor and joint symptoms. And although ObGyns are not the physicians who prescribe these drugs, you may be the provider one of these women consults about their side effects and related issues.

To find out the latest on the management of women who are taking one of these agents, we inserted ourselves into the busy schedule of Andrew M. Kaunitz, MD, who agreed to address some fundamental—and some not so basic—questions about the drugs. In this extended Q&A, Dr. Kaunitz touches on mechanism of action, benefits versus risks, common side effects, compliance with therapy, and the ill effects of early discontinuation.

Aromatase inhibitors are better than tamoxifen at reducing the risk of breast cancer recurrence in postmenopausal women who have hormone-receptor–positive disease. But, they increase the risk of osteoporosis and fracture and often cause arthralgias and other complaints that ObGyn practitioners may be called upon to manage.

OBG Management: What is the overall aim of adjuvant endocrine therapy in the setting of breast cancer?

Dr. Kaunitz: Endocrine therapy—specifically, use of an AI—prevents the stimulation of breast cancer cells by endogenous estrogen. In other words, aromatase inhibitors suppress the growth of cancer cells that have estrogen receptors. These drugs also inhibit aromatase near any breast tumor and reduce estrogen levels in breast tissue.

OBG Management: What is the mechanism of action of adjuvant endocrine therapy?

Dr. Kaunitz: In postmenopausal women, androgens are converted to estrogens via the aromatase enzyme, which is present in adipose tissue and other sites. By blocking this enzyme, AIs reduce endogenous estrogen levels by as much as 95%.⁴

OBG Management: How does that differ from the mechanism of action of tamoxifen, another drug used in breast cancer patients?

Dr. Kaunitz: Tamoxifen is a selective estrogen receptor modulator (SERM). It blocks estrogen in breast tissue selectively, by competitively binding to estrogen receptors.⁵ However, tamoxifen has estrogenic effects in the uterus, bone, and liver, as well as other tissues.

The efficacy of AIs in preventing breast cancer recurrence in the first 2 years after breast cancer surgery is higher than that of tamoxifen. And unlike tamoxifen, the AIs do not increase the risk of venous thromboembolism or cause endometrial disease.

OBG Management: What effects do aromatase inhibitors have in premenopausal women?

Dr. Kaunitz: These agents are not recommended for use in premenopausal women because, in that population, the lion’s share of estrogen production takes place in the ovary rather than in adipose tissue and muscle. If you were to administer an AI to a premenopausal woman, the reduced hypothalamic and pituitary estrogen feedback could lead to ovarian stimulation—which could increase ovarian steroid production.

OBG Management: What about women who become amenorrheic as a result of chemotherapy or other cancer treatment? Do most oncologists assume that they are postmenopausal and prescribe an aromatase inhibitor?

Dr. Kaunitz: Clinicians should not assume that chemotherapy-induced amenorrhea signals permanent cessation of ovarian function. It is common for ovarian function to return in this setting. Accordingly, follicle-stimulating hormone (FSH) and estradiol levels should be assessed before an AI is considered as adjuvant therapy. Some investigators have suggested that the use of an AI in women who have chemotherapy-induced amenorrhea may actually increase the likelihood that ovarian function will return.⁶

OBG Management: Do all AIs produce the same effects?

Dr. Kaunitz: The AIs used in women with breast cancer are third-generation drugs. These AIs are classified as steroidal (type 1; exemestane) or nonsteroidal (type 2; anastrozole, letrozole). Exemestane, a steroid derived from androstenedione, inhibits the aromatase enzyme irreversibly. The nonsteroidal AIs are reversible.

Although all three AIs have numerous similarities, there are other distinctions between them in pharmacokinetics, mechanism of action, and toxicity—so they are not completely interchangeable.⁷ However, from our perspective as ObGyns caring for breast cancer survivors, we can assume that all three AIs will have similar effects on skeletal health and produce similar side effects in postmenopausal women.

How much do we know about these drugs?

OBG Management: How long does a woman typically take an AI?

Dr. Kaunitz: At present, in women treated for early-stage, hormone-positive breast cancer, the optimal duration of treatment is unknown. Most oncologists prescribe an AI for 5 years, the length of treatment in a prominent trial of the drugs.⁸

OBG Management: Is that duration likely to increase as more data come in?

Dr. Kaunitz: The optimal duration of adjuvant AI therapy will be determined by the findings of long-term clinical trials. The National Surgical Adjuvant Breast and Bowel Project B-42 trial may provide new insights into optimal duration of AI treatment after initial tamoxifen therapy.⁹

OBG Management: How thoroughly have AIs been studied in regard to their use in breast cancer survivors and women who have early-stage disease? How would you characterize the quantity and quality of data that we have so far?

Dr. Kaunitz: AIs have been extensively studied. The most important clinical trials of AIs in this setting, including the Anastrozole, Tamoxifen Alone or in Combination (ATAC) trial (over 6,000 participants, median follow-up of 100 months) and the Breast International Group (BIG) trial (almost 5,000 participants, median follow-up of 76 months) have been detailed in the recent ASCO report.¹⁰ These two large landmark trials, in particular, formed the basis for ASCO’s recommendations to routinely incorporate AIs into the therapy of postmenopausal women who have hormone-receptor–positive breast cancer.

OBG Management: In treating breast cancer, what other applications are AIs used for?

Dr. Kaunitz: AIs appear to be slightly more effective than tamoxifen in treating postmenopausal women who have metastatic breast cancer.¹¹

They are approved as first-line therapy for breast cancer in:

• postmenopausal women who have hormone-receptor–positive disease
• postmenopausal women who have locally advanced disease when the hormone receptor is unknown
• postmenopausal women who have metastatic disease.

In addition, they are approved as second-line treatment of advanced breast cancer in postmenopausal women who have disease progression following tamoxifen therapy.¹²

How effective is AI therapy?

OBG Management: What do we know about the efficacy of these drugs?

Dr. Kaunitz: Most of the studies that have explored efficacy compare an AI with tamoxifen rather than with placebo. In the ATAC trial, after a median follow-up of 33 months, women who were taking anastrozole for early-stage breast cancer had longer disease-free survival and time to recurrence and a lower incidence of contralateral breast cancer than did women taking tamoxifen.⁸

After 4 years of follow-up in the ATAC trial, women taking anastrozole continued to have more favorable disease-free survival (86.9% vs 84.5% for anastrozole and tamoxifen, respectively; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.76–0.99; P =.03).¹³ They also had a more favorable time to recurrence than did women taking tamoxifen (HR, 0.83; 95% CI, 0.71–0.96; P =.015). And women taking anastrozole had a lower incidence of contralateral breast cancer, as well, although this different did not achieve statistical significance (HR, 0.62; 95% CI, 0.38–1.02; P =.062).¹³

In the BIG study, women taking letrozole had a 5-year disease-free survival estimate of 84.0%, compared with 81.4% for women taking tamoxifen.¹⁴ In addition, women taking letrozole were significantly less likely than those taking tamoxifen to experience an event that ended a period of disease-free survival (HR, 0.81; 95% CI, 0.70–0.93; P =.003), especially the event of distant recurrence (HR, 0.73; 95% CI, 0.60–0.88; P =.001).¹⁴

And a phase-3 study of exemestane versus tamoxifen in women who had metastatic breast cancer found that the AI produced a superior response rate (46% vs 31% for exemestane and tamoxifen, respectively; odds ratio [OR], 1.85; 95% CI, 1.21–2.82; P =.005). In addition, median progression-free survival was greater with exemestane (9.9 months; 95% CI, 8.7–11.8 months) than with tamoxifen (5.8 months; 95% CI, 5.3–8.1 months). However, there was no difference between arms in progression-free survival or overall survival.

How well tolerated are AIs?

OBG Management: What adverse effects are associated with AIs?

Dr. Kaunitz: Although AIs, overall, are safe medications, their use is associated with a number of adverse events. The most prominent side effects include arthralgias and hot flushes, while the most serious health impact appears to be a decrease in bone mineral density (BMD).

However, the drugs are generally perceived as being easier to tolerate than tamoxifen. That’s because endometrial cancer, vaginal bleeding and discharge, cerebrovascular events, venous thromboembolic events, and hot flushes all are less common among women taking an AI than among those taking tamoxifen.^8,13

For overweight women, who face an elevated baseline risk of thromboembolism, the availability of AIs represents a major advantage over tamoxifen. Similarly, AIs offer advantages over tamoxifen for women who have an intact uterus. In addition, postmenopausal women who are taking a selective serotonin reuptake inhibitor (SSRI) such as paroxetine should take an AI rather than tamoxifen, because the concomitant use of SSRIs attenuates the efficacy of tamoxifen.¹⁵

What can be done about the most prominent risks?

OBG Management: Let’s focus on what’s probably the best-known adverse effect of AIs—the heightened risk of osteoporosis and fracture. How significant is this effect?

Dr. Kaunitz: Because use of an AI is associated with a profound reduction in endogenous estrogen levels, it also decreases BMD and can lead to osteoporotic fractures. All major phase-3 trials of adjuvant use of AIs in women who have early breast cancer found an increased risk of fracture, with no significant differences between AIs.¹⁶

Fortunately, bisphosphonate therapy (oral or intravenous) has been found to reduce bone loss associated with AI therapy.^17,18

Assessing baseline BMD is important as women initiate AI therapy. Although no consensus exists regarding follow-up BMD assessment in the setting of AI use, an interval of 2 years is prudent, with the follow-up study preferably performed at the same imaging center and by the same technician as the first. If baseline osteoporosis is observed at the lumbar spine or hip, bisphosphonate therapy is appropriate. If a woman taking an AI has low bone mass (osteopenia) but not osteoporosis, bisphosphonate therapy should be considered if any of the following risk factors are present:

• advanced age
• history of fracture
• glucocorticoid therapy
• parental history of hip fracture
• low body weight
• current smoking status
• excess alcohol consumption
• rheumatoid arthritis
• known risk factors for secondary osteoporosis.¹⁹

In breast cancer survivors initiating or continuing AI therapy, it is also appropriate to check a serum vitamin D level and ensure that intake of this nutrient is adequate.

Bisphosphonates may offer oncologic benefits, as well; preliminary evidence suggests that the drugs may prevent recurrence of the cancer and prolong survival.²⁰

OBG Management: What can an ObGyn offer to a woman who complains of significant AI-related arthralgia?

Dr. Kaunitz: Bone and joint symptoms, including aches, pain, and stiffness that is bilateral and not associated with other evidence of rheumatologic disorders, are among the most common side effects of AI therapy. On the plus side of the equation, these symptoms are more likely to be mild to moderate than severe. On the negative side, no specific treatment has been found to be effective in relieving these symptoms, which usually resolve within 2 months or so after discontinuing AI therapy.¹⁰

OBG Management: Do AIs have a negative impact on cardiovascular health?

Dr. Kaunitz: Unlike tamoxifen, AIs do not increase the risk of thromboembolic disease. Although the use of an AI may modestly increase the risk of ischemic cardiovascular disease (and lipid changes), compared with tamoxifen, AIs do not appear to increase cardiovascular risk compared with placebo.^21,22

OBG Management: Do the antiestrogenic effects of AIs have a significant impact on vaginal health and sexual desire?

Dr. Kaunitz: A review of published reports did not find that the use of AIs has a predictable impact on vaginal dryness or sexual desire.¹⁰ However, symptomatic genital atrophy is common in postmenopausal breast cancer survivors, whether or not they use adjuvant therapy.

Although the FDA considers the use of any estrogen (systemic or vaginal) following a diagnosis of breast cancer to be contraindicated, some breast cancer survivors who have symptomatic genital atrophy express an interest in the use of vaginal estrogen. Use of 25-μg estradiol tablets (Vagifem) is associated with a short-term increase in serum estradiol levels.²³ This finding has reinforced caution among medical oncologists about the safety of vaginal estrogen in breast cancer survivors. (The 25-μg tablets are no longer marketed.) The lowest dosage of vaginal estrogen available for the treatment of genital atrophy is found in 10-μg estradiol tablets (Vagifem) and the estradiol (2-mg) 3-month vaginal ring (Estring). Nonetheless, in the absence of data, oncologists will likely continue to be concerned that even the lowest dosage of vaginal estrogen could attenuate the favorable impact of AIs on breast cancer. Accordingly, use of vaginal lubricants and moisturizers are the mainstay strategy for symptomatic genital atrophy.

OBG Management: What about the ubiquitous hot flush? Vasomotor symptoms may be more common in women who take tamoxifen, but women on AIs are also bothered by flushes. What are the alternatives to estrogen therapy?

Dr. Kaunitz: Both nonprescription and prescription alternatives are available. Nonprescription options include soy extract and red clover isoflavones, black cohosh, and Chinese herbs. However, none of these over-the-counter approaches has been found to be more effective than placebo in the treatment of menopausal hot flushes.^24-26

As for prescription nonhormonal options, ObGyns should recognize that all such treatments are off-label and that none attain the efficacy of hormone therapy in the treatment of vasomotor symptoms. The best-studied and most effective medications include gabapentin, SSRIs (especially paroxetine), and serotonin-norepinephrine reuptake inhibitors (venlafaxine and desvenlafaxine).^24,27

OBG Management: Is there any evidence that AIs impair cognitive function in postmenopausal women?

Dr. Kaunitz: Because estrogen is important for cognition, one might anticipate that the profound reduction in background estrogen associated with AI use would impair cognition. Fortunately, the evidence to date is reassuring. Substudies of the BIG trial and the Tamoxifen and Exemestane Adjuvant Multinational Trial indicate that, compared with tamoxifen (which is associated with declines in cognitive function in postmenopausal women), letrozole and exemestane do not diminish cognitive function.^28,29

OBG Management: Overall, what is the typical impact of an AI on a woman’s quality of life?

Dr. Kaunitz: Most women do very well on an AI, finding it easier to tolerate than tamoxifen, as we have discussed. However, a significant minority of women is seriously bothered by the adverse effects, with arthralgias usually leading the pack of complaints.^30,31

OBG Management: Do some women discontinue adjuvant endocrine therapy because of adverse effects?

Dr. Kaunitz: Regrettably, the answer is “Yes.” A recent study from Kaiser Permanente of northern California found that roughly 50% of women who are prescribed adjuvant endocrine therapy with tamoxifen or an AI discontinue the drug early.³²

OBG Management: What can an ObGyn do to encourage compliance with and completion of AI therapy?

Dr. Kaunitz: First, it is critical that patients understand that AIs are lifesaving drugs. As a recent paper points out, early discontinuation or noncompliance with AI therapy is associated with higher mortality.³³

Clinicians should also help breast cancer patients understand what common side effects to anticipate with these medications.

Finally, clinicians who understand the financial toll a breast cancer diagnosis and treatment can take are better positioned to help women overcome challenges that may interfere with long-term compliance with AI therapy.

OBG Management: Do you expect the use of AIs in breast cancer survivors to become more commonplace?

Dr. Kaunitz: Given how common breast cancer is, and given the new ASCO guidelines and the extensive literature upon which they are based, ObGyns will be seeing more women using AIs. Although we are not the physicians who prescribe AIs, we need to remain up to date on their benefits and side effects. This important class of drugs is positioned to improve outcomes for postmenopausal women with breast cancer.

We want to hear from you! Tell us what you think.

Think breast cancer survivors are unlikely to show up in your practice? You should think again.

At last official count, 2.5 million women in the United States had a history of breast cancer.¹ Most of them are now free of malignancy, but others are still grappling with the disease in some form or fashion.² All need continuing health care.

Roughly two thirds of women who have breast cancer have disease that is hormone-receptor–positive.^2,3 Recently updated guidelines from the American Society of Clinical Oncology (ASCO) recommend that adjuvant therapy for postmenopausal women who have hormone-positive breast cancer include an aromatase inhibitor (AI) (see a summary of these guidelines on page 36). That makes it likely that a good number of breast cancer survivors who visit your practice are taking one of these medications: anastrozole (Arimidex), letrozole (Femara), or exemestane (Aromasin). These drugs are antiestrogens, given to postmenopausal women to reduce the likelihood of disease recurrence and progression.

The antiestrogenic properties of these drugs are what make them lifesavers. But the same qualities can create a range of health issues, from increased risk of osteoporosis and fracture to vasomotor and joint symptoms. And although ObGyns are not the physicians who prescribe these drugs, you may be the provider one of these women consults about their side effects and related issues.

To find out the latest on the management of women who are taking one of these agents, we inserted ourselves into the busy schedule of Andrew M. Kaunitz, MD, who agreed to address some fundamental—and some not so basic—questions about the drugs. In this extended Q&A, Dr. Kaunitz touches on mechanism of action, benefits versus risks, common side effects, compliance with therapy, and the ill effects of early discontinuation.

Aromatase inhibitors are better than tamoxifen at reducing the risk of breast cancer recurrence in postmenopausal women who have hormone-receptor–positive disease. But, they increase the risk of osteoporosis and fracture and often cause arthralgias and other complaints that ObGyn practitioners may be called upon to manage.

OBG Management: What is the overall aim of adjuvant endocrine therapy in the setting of breast cancer?

Dr. Kaunitz: Endocrine therapy—specifically, use of an AI—prevents the stimulation of breast cancer cells by endogenous estrogen. In other words, aromatase inhibitors suppress the growth of cancer cells that have estrogen receptors. These drugs also inhibit aromatase near any breast tumor and reduce estrogen levels in breast tissue.

OBG Management: What is the mechanism of action of adjuvant endocrine therapy?

Dr. Kaunitz: In postmenopausal women, androgens are converted to estrogens via the aromatase enzyme, which is present in adipose tissue and other sites. By blocking this enzyme, AIs reduce endogenous estrogen levels by as much as 95%.⁴

OBG Management: How does that differ from the mechanism of action of tamoxifen, another drug used in breast cancer patients?

Dr. Kaunitz: Tamoxifen is a selective estrogen receptor modulator (SERM). It blocks estrogen in breast tissue selectively, by competitively binding to estrogen receptors.⁵ However, tamoxifen has estrogenic effects in the uterus, bone, and liver, as well as other tissues.

The efficacy of AIs in preventing breast cancer recurrence in the first 2 years after breast cancer surgery is higher than that of tamoxifen. And unlike tamoxifen, the AIs do not increase the risk of venous thromboembolism or cause endometrial disease.

OBG Management: What effects do aromatase inhibitors have in premenopausal women?

Dr. Kaunitz: These agents are not recommended for use in premenopausal women because, in that population, the lion’s share of estrogen production takes place in the ovary rather than in adipose tissue and muscle. If you were to administer an AI to a premenopausal woman, the reduced hypothalamic and pituitary estrogen feedback could lead to ovarian stimulation—which could increase ovarian steroid production.

OBG Management: What about women who become amenorrheic as a result of chemotherapy or other cancer treatment? Do most oncologists assume that they are postmenopausal and prescribe an aromatase inhibitor?

Dr. Kaunitz: Clinicians should not assume that chemotherapy-induced amenorrhea signals permanent cessation of ovarian function. It is common for ovarian function to return in this setting. Accordingly, follicle-stimulating hormone (FSH) and estradiol levels should be assessed before an AI is considered as adjuvant therapy. Some investigators have suggested that the use of an AI in women who have chemotherapy-induced amenorrhea may actually increase the likelihood that ovarian function will return.⁶

OBG Management: Do all AIs produce the same effects?

Dr. Kaunitz: The AIs used in women with breast cancer are third-generation drugs. These AIs are classified as steroidal (type 1; exemestane) or nonsteroidal (type 2; anastrozole, letrozole). Exemestane, a steroid derived from androstenedione, inhibits the aromatase enzyme irreversibly. The nonsteroidal AIs are reversible.

Although all three AIs have numerous similarities, there are other distinctions between them in pharmacokinetics, mechanism of action, and toxicity—so they are not completely interchangeable.⁷ However, from our perspective as ObGyns caring for breast cancer survivors, we can assume that all three AIs will have similar effects on skeletal health and produce similar side effects in postmenopausal women.

How much do we know about these drugs?

OBG Management: How long does a woman typically take an AI?

Dr. Kaunitz: At present, in women treated for early-stage, hormone-positive breast cancer, the optimal duration of treatment is unknown. Most oncologists prescribe an AI for 5 years, the length of treatment in a prominent trial of the drugs.⁸

OBG Management: Is that duration likely to increase as more data come in?

Dr. Kaunitz: The optimal duration of adjuvant AI therapy will be determined by the findings of long-term clinical trials. The National Surgical Adjuvant Breast and Bowel Project B-42 trial may provide new insights into optimal duration of AI treatment after initial tamoxifen therapy.⁹

OBG Management: How thoroughly have AIs been studied in regard to their use in breast cancer survivors and women who have early-stage disease? How would you characterize the quantity and quality of data that we have so far?

Dr. Kaunitz: AIs have been extensively studied. The most important clinical trials of AIs in this setting, including the Anastrozole, Tamoxifen Alone or in Combination (ATAC) trial (over 6,000 participants, median follow-up of 100 months) and the Breast International Group (BIG) trial (almost 5,000 participants, median follow-up of 76 months) have been detailed in the recent ASCO report.¹⁰ These two large landmark trials, in particular, formed the basis for ASCO’s recommendations to routinely incorporate AIs into the therapy of postmenopausal women who have hormone-receptor–positive breast cancer.

OBG Management: In treating breast cancer, what other applications are AIs used for?

Dr. Kaunitz: AIs appear to be slightly more effective than tamoxifen in treating postmenopausal women who have metastatic breast cancer.¹¹

They are approved as first-line therapy for breast cancer in:

• postmenopausal women who have hormone-receptor–positive disease
• postmenopausal women who have locally advanced disease when the hormone receptor is unknown
• postmenopausal women who have metastatic disease.

In addition, they are approved as second-line treatment of advanced breast cancer in postmenopausal women who have disease progression following tamoxifen therapy.¹²

How effective is AI therapy?

OBG Management: What do we know about the efficacy of these drugs?

Dr. Kaunitz: Most of the studies that have explored efficacy compare an AI with tamoxifen rather than with placebo. In the ATAC trial, after a median follow-up of 33 months, women who were taking anastrozole for early-stage breast cancer had longer disease-free survival and time to recurrence and a lower incidence of contralateral breast cancer than did women taking tamoxifen.⁸

After 4 years of follow-up in the ATAC trial, women taking anastrozole continued to have more favorable disease-free survival (86.9% vs 84.5% for anastrozole and tamoxifen, respectively; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.76–0.99; P =.03).¹³ They also had a more favorable time to recurrence than did women taking tamoxifen (HR, 0.83; 95% CI, 0.71–0.96; P =.015). And women taking anastrozole had a lower incidence of contralateral breast cancer, as well, although this different did not achieve statistical significance (HR, 0.62; 95% CI, 0.38–1.02; P =.062).¹³

In the BIG study, women taking letrozole had a 5-year disease-free survival estimate of 84.0%, compared with 81.4% for women taking tamoxifen.¹⁴ In addition, women taking letrozole were significantly less likely than those taking tamoxifen to experience an event that ended a period of disease-free survival (HR, 0.81; 95% CI, 0.70–0.93; P =.003), especially the event of distant recurrence (HR, 0.73; 95% CI, 0.60–0.88; P =.001).¹⁴

And a phase-3 study of exemestane versus tamoxifen in women who had metastatic breast cancer found that the AI produced a superior response rate (46% vs 31% for exemestane and tamoxifen, respectively; odds ratio [OR], 1.85; 95% CI, 1.21–2.82; P =.005). In addition, median progression-free survival was greater with exemestane (9.9 months; 95% CI, 8.7–11.8 months) than with tamoxifen (5.8 months; 95% CI, 5.3–8.1 months). However, there was no difference between arms in progression-free survival or overall survival.

How well tolerated are AIs?

OBG Management: What adverse effects are associated with AIs?

Dr. Kaunitz: Although AIs, overall, are safe medications, their use is associated with a number of adverse events. The most prominent side effects include arthralgias and hot flushes, while the most serious health impact appears to be a decrease in bone mineral density (BMD).

However, the drugs are generally perceived as being easier to tolerate than tamoxifen. That’s because endometrial cancer, vaginal bleeding and discharge, cerebrovascular events, venous thromboembolic events, and hot flushes all are less common among women taking an AI than among those taking tamoxifen.^8,13

For overweight women, who face an elevated baseline risk of thromboembolism, the availability of AIs represents a major advantage over tamoxifen. Similarly, AIs offer advantages over tamoxifen for women who have an intact uterus. In addition, postmenopausal women who are taking a selective serotonin reuptake inhibitor (SSRI) such as paroxetine should take an AI rather than tamoxifen, because the concomitant use of SSRIs attenuates the efficacy of tamoxifen.¹⁵

What can be done about the most prominent risks?

OBG Management: Let’s focus on what’s probably the best-known adverse effect of AIs—the heightened risk of osteoporosis and fracture. How significant is this effect?

Dr. Kaunitz: Because use of an AI is associated with a profound reduction in endogenous estrogen levels, it also decreases BMD and can lead to osteoporotic fractures. All major phase-3 trials of adjuvant use of AIs in women who have early breast cancer found an increased risk of fracture, with no significant differences between AIs.¹⁶

Fortunately, bisphosphonate therapy (oral or intravenous) has been found to reduce bone loss associated with AI therapy.^17,18

Assessing baseline BMD is important as women initiate AI therapy. Although no consensus exists regarding follow-up BMD assessment in the setting of AI use, an interval of 2 years is prudent, with the follow-up study preferably performed at the same imaging center and by the same technician as the first. If baseline osteoporosis is observed at the lumbar spine or hip, bisphosphonate therapy is appropriate. If a woman taking an AI has low bone mass (osteopenia) but not osteoporosis, bisphosphonate therapy should be considered if any of the following risk factors are present:

• advanced age
• history of fracture
• glucocorticoid therapy
• parental history of hip fracture
• low body weight
• current smoking status
• excess alcohol consumption
• rheumatoid arthritis
• known risk factors for secondary osteoporosis.¹⁹

In breast cancer survivors initiating or continuing AI therapy, it is also appropriate to check a serum vitamin D level and ensure that intake of this nutrient is adequate.

Bisphosphonates may offer oncologic benefits, as well; preliminary evidence suggests that the drugs may prevent recurrence of the cancer and prolong survival.²⁰

OBG Management: What can an ObGyn offer to a woman who complains of significant AI-related arthralgia?

Dr. Kaunitz: Bone and joint symptoms, including aches, pain, and stiffness that is bilateral and not associated with other evidence of rheumatologic disorders, are among the most common side effects of AI therapy. On the plus side of the equation, these symptoms are more likely to be mild to moderate than severe. On the negative side, no specific treatment has been found to be effective in relieving these symptoms, which usually resolve within 2 months or so after discontinuing AI therapy.¹⁰

OBG Management: Do AIs have a negative impact on cardiovascular health?

Dr. Kaunitz: Unlike tamoxifen, AIs do not increase the risk of thromboembolic disease. Although the use of an AI may modestly increase the risk of ischemic cardiovascular disease (and lipid changes), compared with tamoxifen, AIs do not appear to increase cardiovascular risk compared with placebo.^21,22

OBG Management: Do the antiestrogenic effects of AIs have a significant impact on vaginal health and sexual desire?

Dr. Kaunitz: A review of published reports did not find that the use of AIs has a predictable impact on vaginal dryness or sexual desire.¹⁰ However, symptomatic genital atrophy is common in postmenopausal breast cancer survivors, whether or not they use adjuvant therapy.

Although the FDA considers the use of any estrogen (systemic or vaginal) following a diagnosis of breast cancer to be contraindicated, some breast cancer survivors who have symptomatic genital atrophy express an interest in the use of vaginal estrogen. Use of 25-μg estradiol tablets (Vagifem) is associated with a short-term increase in serum estradiol levels.²³ This finding has reinforced caution among medical oncologists about the safety of vaginal estrogen in breast cancer survivors. (The 25-μg tablets are no longer marketed.) The lowest dosage of vaginal estrogen available for the treatment of genital atrophy is found in 10-μg estradiol tablets (Vagifem) and the estradiol (2-mg) 3-month vaginal ring (Estring). Nonetheless, in the absence of data, oncologists will likely continue to be concerned that even the lowest dosage of vaginal estrogen could attenuate the favorable impact of AIs on breast cancer. Accordingly, use of vaginal lubricants and moisturizers are the mainstay strategy for symptomatic genital atrophy.

OBG Management: What about the ubiquitous hot flush? Vasomotor symptoms may be more common in women who take tamoxifen, but women on AIs are also bothered by flushes. What are the alternatives to estrogen therapy?

Dr. Kaunitz: Both nonprescription and prescription alternatives are available. Nonprescription options include soy extract and red clover isoflavones, black cohosh, and Chinese herbs. However, none of these over-the-counter approaches has been found to be more effective than placebo in the treatment of menopausal hot flushes.^24-26

As for prescription nonhormonal options, ObGyns should recognize that all such treatments are off-label and that none attain the efficacy of hormone therapy in the treatment of vasomotor symptoms. The best-studied and most effective medications include gabapentin, SSRIs (especially paroxetine), and serotonin-norepinephrine reuptake inhibitors (venlafaxine and desvenlafaxine).^24,27

OBG Management: Is there any evidence that AIs impair cognitive function in postmenopausal women?

Dr. Kaunitz: Because estrogen is important for cognition, one might anticipate that the profound reduction in background estrogen associated with AI use would impair cognition. Fortunately, the evidence to date is reassuring. Substudies of the BIG trial and the Tamoxifen and Exemestane Adjuvant Multinational Trial indicate that, compared with tamoxifen (which is associated with declines in cognitive function in postmenopausal women), letrozole and exemestane do not diminish cognitive function.^28,29

OBG Management: Overall, what is the typical impact of an AI on a woman’s quality of life?

Dr. Kaunitz: Most women do very well on an AI, finding it easier to tolerate than tamoxifen, as we have discussed. However, a significant minority of women is seriously bothered by the adverse effects, with arthralgias usually leading the pack of complaints.^30,31

OBG Management: Do some women discontinue adjuvant endocrine therapy because of adverse effects?

Dr. Kaunitz: Regrettably, the answer is “Yes.” A recent study from Kaiser Permanente of northern California found that roughly 50% of women who are prescribed adjuvant endocrine therapy with tamoxifen or an AI discontinue the drug early.³²

OBG Management: What can an ObGyn do to encourage compliance with and completion of AI therapy?

Dr. Kaunitz: First, it is critical that patients understand that AIs are lifesaving drugs. As a recent paper points out, early discontinuation or noncompliance with AI therapy is associated with higher mortality.³³

Clinicians should also help breast cancer patients understand what common side effects to anticipate with these medications.

Finally, clinicians who understand the financial toll a breast cancer diagnosis and treatment can take are better positioned to help women overcome challenges that may interfere with long-term compliance with AI therapy.

OBG Management: Do you expect the use of AIs in breast cancer survivors to become more commonplace?

Dr. Kaunitz: Given how common breast cancer is, and given the new ASCO guidelines and the extensive literature upon which they are based, ObGyns will be seeing more women using AIs. Although we are not the physicians who prescribe AIs, we need to remain up to date on their benefits and side effects. This important class of drugs is positioned to improve outcomes for postmenopausal women with breast cancer.

We want to hear from you! Tell us what you think.

Late last year, the US Preventive Services Task Force (USPSTF) sparked a nationwide controversy when it announced that it was recommending against routine screening mammography for women younger than age 50.¹ Indeed, that’s a recommendation that many other organizations, including the American Cancer Society (ACS),² the American College of Obstetricians and Gynecologists (ACOG),³ and the National Comprehensive Cancer Network (NCCN),⁴ disagree with. But the age at which women should begin routine mammography isn’t the only controversial question. Experts disagree on the benefits of breast self-examination, the optimal frequency of clinical breast exams, and the use of digital mammography—among other issues. This evidence-based review can help you cut through the confusion.

CASE Carrie, a 39-year-old woman who has never been pregnant, comes in for an annual Pap smear and gynecologic exam. She has a negative past medical history, but a positive family history for breast cancer—both her mother and 1 of her sisters had the disease. How would you assess Carrie’s risk of breast cancer, and what preventive measures would you recommend?

Use this predictive model to pinpoint your patient’s risk

When making decisions regarding primary prevention of and screening for breast cancer, an accurate assessment of risk is critical. Many predictive models have been developed with that in mind. The most widely studied, the Gail model, incorporates a number of important risk factors (TABLE 1), including age; race; family history; reproductive factors such as age of menarche, menopause, and first childbirth; and previous history of breast biopsy and atypical findings, to calculate a woman’s 5-year risk.⁵

A risk calculator (the Breast Cancer Risk Assessment Tool) based on the Gail model is available on the National Cancer Institute’s Web site, at http://www.cancer.gov/bcrisktool. Generally, a score ≥1.66%,⁵ which indicates that a patient has at least a 1.66% chance of developing breast cancer over the next 5 years, is considered high risk.^6,7

CASE Carrie’s 2 first-degree relatives affected by breast cancer and her nulliparous status place her at increased risk. Further questioning reveals a particularly strong family history, as both relatives were diagnosed before the age of 50 (her mom at 45 years of age and her sister, at 39). Carrie’s 5-year risk is 1.8%.

TABLE 1
Risk factors for breast cancer^5,29

All women can benefit from these preventive measures

As primary care physicians, we have a responsibility to stress lifestyle modification as the mainstay of breast cancer prevention. Whether or not a woman is at high risk, advise her that maintaining a normal weight, exercising vigorously, limiting alcohol consumption, and breastfeeding are evidence-based methods of primary prevention. Diets low in fat and high in fiber may be associated with a lower risk of invasive breast cancer, but there is no conclusive evidence to support specific dietary interventions to reduce the risk.^8-11 Nor has a link between active or passive smoking, antioxidants, or fruit and vegetable intake been firmly established.¹²

There is a clear association between prolonged estrogen exposure and breast cancer, however. Many reproductive factors, such as early menarche, late menopause, later age at time of first full-term pregnancy, and nulliparity, increase a woman’s exposure to endogenous estrogen—and her risk of developing breast cancer.^12,13

Exposure to exogenous estrogen is also linked to the development of breast cancer. In 2002, the Women’s Health Initiative (WHI) was stopped early after a report was released stating that the risks of hormone replacement therapy (HRT)—a higher incidence of cardiovascular events, stroke, and venous thromboembolism, as well as breast cancer—outweighed the benefits.¹⁴ Subsequent analyses have found a relationship between the declining incidence of breast cancer and the marked decrease in HRT use prompted by the WHI report. While causality has not been firmly established, multiple studies strongly suggest it.^15,16

The association between oral contraceptives (OCs) and breast cancer is more controversial. Some studies have found an increased breast cancer risk among OC users, but both the relative risk and absolute risk were found to be very small and to dissipate 10 years after stopping OC use. More recent studies with newer formulations containing lower doses of estrogen have failed to show an increased risk.⁸

Breast cancer screening: The parameters have changed

Various organizations have published guidelines for breast cancer screening (TABLE 2), and all are somewhat different. Here’s what you need to know.

Breast self-examination (BSE), which women were previously advised to perform monthly, has not been shown to improve mortality in any age group, and is no longer routinely recommended.¹⁷ While both the USPSTF and the Canadian Task Force on Preventive Health Care recommend against teaching women BSE, the ACS, ACOG, and NCCN encourage self-examination—particularly among women older than 40 years.^1-4,17,18

Clinical breast examination has an average sensitivity of 50% and detects approximately 5% of mammographically occult cancers.¹⁹ It is still not clear whether clinical breast exams save lives, however—a finding that is reflected in the USPSTF’s “I” (insufficient evidence to assess the benefits and harms) recommendation.¹ Other consensus guidelines still recommend clinical breast examination, albeit at varying frequencies.

Screening mammography decreases mortality rates by anywhere from 28% to 65%, depending on the statistical model used.²⁰ The benefit is greatest in women between the ages of 50 and 69 years, however, and most groups agree that mammography every 1 to 2 years is advisable for this age group. (There is limited data on the value of mammography for women 70 years of age and older, and no consensus on the age at which to stop screening.^1,21) But because the mortality benefit from screening mammography is lower for women aged 40 to 49, guidelines for this age group are more controversial.

Mammography’s sensitivity is affected by a variety of factors, including age and menopausal status, prior breast surgery or radiation, breast density, and the experience of the radiologist. Women in their 40s have denser breast tissue than older women, making mammography less sensitive for this age group. Because of that, and because the overall incidence of breast cancer is lower for women younger than 50, some argue that screening mammography for women between the ages of 40 and 49 years leads to unacceptably high false-positive rates (9.8% annually²²) and that the harm associated with mammography may outweigh the benefit. Others counter that tumors in younger women tend to be more aggressive and faster growing, making early detection even more critical than for older women.

What should you advise women in this age group? You might point out that the USPSTF recommends against routine screening, but indicates that the decision to begin (or defer) routine mammography before age 50 should be individualized, based on the needs and values of each patient.¹

Digital mammography. A recent study of more than 43,000 women demonstrated that digital mammography is more accurate than film—but only for certain groups: These include women <50 years of age, women with dense breasts, and pre- and perimenopausal women. ²³ Because it is still not clear whether the increased accuracy will translate into a mortality benefit, more research is needed before digital mammography is widely adopted. The USPSTF maintains that there is insufficient evidence to assess the benefits and harms of using either digital mammography or magnetic resonance imaging (MRI) rather than film mammography to screen for breast cancer.¹

MRI. In 2007, the ACS published guidelines on the use of MRI as an adjunct to mammography for breast cancer screening in high-risk women.²⁴ According to ACS guidelines, screening MRI should be offered to patients with a known BRCA 1 or 2 mutation (5%-10% of all breast cancers are associated with a mutation in the BRCA 1 or BRCA 2 gene, which is transmitted in an autosomal dominant pattern⁶). It also should be offered to those with a strong family history, or a lifetime risk of developing breast cancer that is >20% to 25%. And finally, MRI should be offered to women who had chest wall radiation when they were between the ages of 10 and 30 years—another significant risk factor for breast cancer—and those with other genetic syndromes that increase their lifetime risk of breast cancer.²⁴

Evidence is insufficient for or against MRI screening for women with a personal history of breast cancer, atypical hyperplasia, or lobular carcinoma in situ, however, and neither breast ultrasound (which is generally used diagnostically, not for screening purposes) nor MRI has been shown to be helpful as a screening tool in women with <15% lifetime risk of developing breast cancer.^24,25

TABLE 2
Guidelines for breast cancer screening for women with average risk

When to consider chemoprevention

For women like Carrie, who are at high risk of developing breast cancer, selective estrogen receptor modulator (SERM) therapy and surgical interventions may be options to consider. The Breast Cancer Prevention Trial demonstrated the efficacy of tamoxifen as a preventive agent. This landmark trial showed that for high-risk women older than 35, 5 years of tamoxifen therapy can reduce the incidence of invasive breast cancer by nearly 50%.²⁶

Women with the BRCA 1 or 2 mutation—all of whom should be offered genetic counseling—were included in the study. Tamoxifen reduced the incidence of breast cancer in BRCA 2 carriers by 62%, the researchers found, but did not reduce risk in carriers of the BRCA 1 gene. This is likely due to the high prevalence of estrogen receptor-negative breast cancers among BRCA 1 carriers.²⁶

More recently, the Study of Tamoxifen and Raloxifene (STAR) trial compared the efficacy of tamoxifen and raloxifene, a second-generation SERM, in high-risk postmenopausal women ages 35 and older. The drugs were found to be equally effective in reducing the risk of invasive breast cancer, but raloxifene had a better side effect profile, with a lower incidence of thromboembolism and cataracts. ²⁷

What the guidelines call for. In 2003, the USPSTF recommended that clinicians discuss chemoprevention with women at high risk for breast cancer and low risk for adverse effects of SERMs.²⁸

The most recent update to the NCCN breast cancer risk reduction guidelines recommends that clinicians offer tamoxifen to premenopausal women with a 5-year projected breast cancer risk ≥1.7% and offer tamoxifen or raloxifene to high-risk postmenopausal women.²⁹ It is worth noting, however, that SERMs can have significant adverse effects, including venous thromboembolism, stroke, cataracts, uterine malignancy, and hot flashes, while lifestyle modifications and the avoidance of HRT have few, if any, negative effects.

CASE After consultation with a genetic counselor, Carrie underwent testing for both the BRCA 1 and BRCA 2 mutations. She tested negative for both. She declined chemoprevention and prophylactic surgery, opting for enhanced screening with yearly mammography and MRI and lifestyle modification instead.

When a mass is found

For women ages 30 or older with palpable masses or solid masses ≥2 cm found on imaging, core needle biopsy is recommended.^30,31 Biopsy is indicated for women younger than 30 as well, if the mass is >2 cm or imaging is suspicious. In general, a needle biopsy read as benign is considered adequate for diagnostic purposes only if the lesion appeared benign on imaging.

For lesions shown to be cystic on imaging, recommendations for follow-up or additional testing are based on the characteristics of the cyst. For simple cysts, 2- to 4-month follow up for stability, followed by routine screening, is adequate.²¹ Additional evaluation of complex cysts is indicated, including aspiration for complicated cysts and biopsy for complex cysts. After aspiration, surgical excision of bloody aspirates or persistent masses is recommended.^30,31

Staging using the TNM system
The TNM (tumor, node, metastases) classification system is used for the staging of breast cancer:

• T refers to the tumor type, size, and extent of local involvement
• N describes regional lymph node involvement
• M refers to distant metastases.

The TNM classifications are also grouped by stage (I through IV).,

Lumpectomy and sentinel node mapping with excision is the preferred method for staging of early-stage breast cancer without palpable lymphadenopathy—provided that the surgical team has documented experience with sentinel node biopsy.³² Sentinel node biopsy is preferred because of its safety, low (<10%) false negative rate, and decreased morbidity compared with full axillary dissection, although dissection is recommended for patients with more advanced cancer or a positive sentinel node.³² The comparative effects of sentinel node biopsy vs axillary node dissection on tumor recurrence and patient survival are not known.³³

Testing for tumor markers such as estrogen and progesterone receptors and human epidermal growth factor receptor 2 (HER2) expression status in biopsy-proven breast cancer is now the standard of care. Seventy percent of breast cancers are estrogen receptor-positive, with increasing frequency associated with older age.³⁴ Estrogen/progesterone receptor positivity is associated with a more favorable outcome, and multiple hormonal therapies can be aimed at these receptors.³⁴ While HER2 overexpression—which occurs in 15% to 30% of newly diagnosed breast cancers³⁵—is associated with more aggressive tumors, women with this type of tumor cell can benefit from trastuzumab, an anti-HER2 drug.³⁶

Key factors that affect prognosis

Important factors affecting prognosis and treatment of localized breast cancer are tumor size, age and menopausal status, tumor expression of hormone receptors and/ or the HER2 protein, as well as the status of the draining axillary nodes. Factors that predict a greater chance of recurrence include the spread of disease to axillary nodes, larger tumor size, invasive histology, inflammatory pathology, lack of estrogen/progesterone receptors, and age <50 years or premenopausal status.

Treatment options include surgical resection, radiation, and systemic adjuvant therapy in the form of chemotherapy, endocrine therapy, or anti-HER2 monoclonal antibodies.³⁷ (For more on treatment, see “Surgery, radiation, and systemic therapy: Making the most of what’s in our arsenal” at jfponline.com.)

Don’t overlook quality-of-life issues
Follow-up of breast cancer patients should go beyond treatment and work-up for recurrence and metastatic disease to focus on health and lifestyle issues, such as stress reduction, mood, smoking cessation, diet and exercise, treatment of hot flashes, sexual dysfunction, and bone health. A recent study found both reduced recurrence and increased survival in women receiving psychological interventions to improve quality-of-life measures after an 11-year follow-up.³⁸

Refer women to targeted Web sites such as the National Breast Cancer Awareness Month organization (http://www.nbcam.org/), the National Breast Cancer Foundation (http://community.nationalbreastcancer.org/), and the Susan G. Komen Breast Cancer Foundation (http://ww5.komen.org/). Offer treatment for bothersome symptoms. Hot flashes and depression, for example, often related to endocrine therapy, can be treated with selective serotonin reuptake inhibitors (SSRIs). That said, some SSRIs decrease the active metabolite of tamoxifen by inhibiting CYP2D6 enzyme and must, therefore, be used with caution. However, venlafaxine and citalopram are less likely to alter tamoxifen metabolism than other SSRIs.³⁹

CASE When Carrie was 47, she had an abnormal MRI of the left breast. Core needle biopsy and pathology of the lesion revealed an estrogen and progesterone receptor-positive tumor that was negative for HER2 overexpression. She underwent lumpectomy, which revealed a 1.5 cm tumor, followed by a negative sentinel node biopsy, and was diagnosed with stage I (T1N0M0) breast cancer. Carrie had radiation after surgery; she did not require chemotherapy, but was told to take tamoxifen for 5 years. This adjuvant endocrine therapy led to hot flashes and depression, both of which were successfully treated with venlafaxine. Carrie is currently cancer-free and participates in a breast cancer survivor program that includes regular visits with her primary physician and her oncologist.

CORRESPONDENCE Denise Sur, MD, 1920 Colorado Avenue, Santa Monica, CA 90404; [email protected] 

Late last year, the US Preventive Services Task Force (USPSTF) sparked a nationwide controversy when it announced that it was recommending against routine screening mammography for women younger than age 50.¹ Indeed, that’s a recommendation that many other organizations, including the American Cancer Society (ACS),² the American College of Obstetricians and Gynecologists (ACOG),³ and the National Comprehensive Cancer Network (NCCN),⁴ disagree with. But the age at which women should begin routine mammography isn’t the only controversial question. Experts disagree on the benefits of breast self-examination, the optimal frequency of clinical breast exams, and the use of digital mammography—among other issues. This evidence-based review can help you cut through the confusion.

CASE Carrie, a 39-year-old woman who has never been pregnant, comes in for an annual Pap smear and gynecologic exam. She has a negative past medical history, but a positive family history for breast cancer—both her mother and 1 of her sisters had the disease. How would you assess Carrie’s risk of breast cancer, and what preventive measures would you recommend?

Use this predictive model to pinpoint your patient’s risk

When making decisions regarding primary prevention of and screening for breast cancer, an accurate assessment of risk is critical. Many predictive models have been developed with that in mind. The most widely studied, the Gail model, incorporates a number of important risk factors (TABLE 1), including age; race; family history; reproductive factors such as age of menarche, menopause, and first childbirth; and previous history of breast biopsy and atypical findings, to calculate a woman’s 5-year risk.⁵

A risk calculator (the Breast Cancer Risk Assessment Tool) based on the Gail model is available on the National Cancer Institute’s Web site, at http://www.cancer.gov/bcrisktool. Generally, a score ≥1.66%,⁵ which indicates that a patient has at least a 1.66% chance of developing breast cancer over the next 5 years, is considered high risk.^6,7

CASE Carrie’s 2 first-degree relatives affected by breast cancer and her nulliparous status place her at increased risk. Further questioning reveals a particularly strong family history, as both relatives were diagnosed before the age of 50 (her mom at 45 years of age and her sister, at 39). Carrie’s 5-year risk is 1.8%.

TABLE 1
Risk factors for breast cancer^5,29

All women can benefit from these preventive measures

As primary care physicians, we have a responsibility to stress lifestyle modification as the mainstay of breast cancer prevention. Whether or not a woman is at high risk, advise her that maintaining a normal weight, exercising vigorously, limiting alcohol consumption, and breastfeeding are evidence-based methods of primary prevention. Diets low in fat and high in fiber may be associated with a lower risk of invasive breast cancer, but there is no conclusive evidence to support specific dietary interventions to reduce the risk.^8-11 Nor has a link between active or passive smoking, antioxidants, or fruit and vegetable intake been firmly established.¹²

There is a clear association between prolonged estrogen exposure and breast cancer, however. Many reproductive factors, such as early menarche, late menopause, later age at time of first full-term pregnancy, and nulliparity, increase a woman’s exposure to endogenous estrogen—and her risk of developing breast cancer.^12,13

Exposure to exogenous estrogen is also linked to the development of breast cancer. In 2002, the Women’s Health Initiative (WHI) was stopped early after a report was released stating that the risks of hormone replacement therapy (HRT)—a higher incidence of cardiovascular events, stroke, and venous thromboembolism, as well as breast cancer—outweighed the benefits.¹⁴ Subsequent analyses have found a relationship between the declining incidence of breast cancer and the marked decrease in HRT use prompted by the WHI report. While causality has not been firmly established, multiple studies strongly suggest it.^15,16

The association between oral contraceptives (OCs) and breast cancer is more controversial. Some studies have found an increased breast cancer risk among OC users, but both the relative risk and absolute risk were found to be very small and to dissipate 10 years after stopping OC use. More recent studies with newer formulations containing lower doses of estrogen have failed to show an increased risk.⁸

Breast cancer screening: The parameters have changed

Various organizations have published guidelines for breast cancer screening (TABLE 2), and all are somewhat different. Here’s what you need to know.

Breast self-examination (BSE), which women were previously advised to perform monthly, has not been shown to improve mortality in any age group, and is no longer routinely recommended.¹⁷ While both the USPSTF and the Canadian Task Force on Preventive Health Care recommend against teaching women BSE, the ACS, ACOG, and NCCN encourage self-examination—particularly among women older than 40 years.^1-4,17,18

Clinical breast examination has an average sensitivity of 50% and detects approximately 5% of mammographically occult cancers.¹⁹ It is still not clear whether clinical breast exams save lives, however—a finding that is reflected in the USPSTF’s “I” (insufficient evidence to assess the benefits and harms) recommendation.¹ Other consensus guidelines still recommend clinical breast examination, albeit at varying frequencies.

Screening mammography decreases mortality rates by anywhere from 28% to 65%, depending on the statistical model used.²⁰ The benefit is greatest in women between the ages of 50 and 69 years, however, and most groups agree that mammography every 1 to 2 years is advisable for this age group. (There is limited data on the value of mammography for women 70 years of age and older, and no consensus on the age at which to stop screening.^1,21) But because the mortality benefit from screening mammography is lower for women aged 40 to 49, guidelines for this age group are more controversial.

Mammography’s sensitivity is affected by a variety of factors, including age and menopausal status, prior breast surgery or radiation, breast density, and the experience of the radiologist. Women in their 40s have denser breast tissue than older women, making mammography less sensitive for this age group. Because of that, and because the overall incidence of breast cancer is lower for women younger than 50, some argue that screening mammography for women between the ages of 40 and 49 years leads to unacceptably high false-positive rates (9.8% annually²²) and that the harm associated with mammography may outweigh the benefit. Others counter that tumors in younger women tend to be more aggressive and faster growing, making early detection even more critical than for older women.

What should you advise women in this age group? You might point out that the USPSTF recommends against routine screening, but indicates that the decision to begin (or defer) routine mammography before age 50 should be individualized, based on the needs and values of each patient.¹

Digital mammography. A recent study of more than 43,000 women demonstrated that digital mammography is more accurate than film—but only for certain groups: These include women <50 years of age, women with dense breasts, and pre- and perimenopausal women. ²³ Because it is still not clear whether the increased accuracy will translate into a mortality benefit, more research is needed before digital mammography is widely adopted. The USPSTF maintains that there is insufficient evidence to assess the benefits and harms of using either digital mammography or magnetic resonance imaging (MRI) rather than film mammography to screen for breast cancer.¹

MRI. In 2007, the ACS published guidelines on the use of MRI as an adjunct to mammography for breast cancer screening in high-risk women.²⁴ According to ACS guidelines, screening MRI should be offered to patients with a known BRCA 1 or 2 mutation (5%-10% of all breast cancers are associated with a mutation in the BRCA 1 or BRCA 2 gene, which is transmitted in an autosomal dominant pattern⁶). It also should be offered to those with a strong family history, or a lifetime risk of developing breast cancer that is >20% to 25%. And finally, MRI should be offered to women who had chest wall radiation when they were between the ages of 10 and 30 years—another significant risk factor for breast cancer—and those with other genetic syndromes that increase their lifetime risk of breast cancer.²⁴

Evidence is insufficient for or against MRI screening for women with a personal history of breast cancer, atypical hyperplasia, or lobular carcinoma in situ, however, and neither breast ultrasound (which is generally used diagnostically, not for screening purposes) nor MRI has been shown to be helpful as a screening tool in women with <15% lifetime risk of developing breast cancer.^24,25

TABLE 2
Guidelines for breast cancer screening for women with average risk

When to consider chemoprevention

For women like Carrie, who are at high risk of developing breast cancer, selective estrogen receptor modulator (SERM) therapy and surgical interventions may be options to consider. The Breast Cancer Prevention Trial demonstrated the efficacy of tamoxifen as a preventive agent. This landmark trial showed that for high-risk women older than 35, 5 years of tamoxifen therapy can reduce the incidence of invasive breast cancer by nearly 50%.²⁶

Women with the BRCA 1 or 2 mutation—all of whom should be offered genetic counseling—were included in the study. Tamoxifen reduced the incidence of breast cancer in BRCA 2 carriers by 62%, the researchers found, but did not reduce risk in carriers of the BRCA 1 gene. This is likely due to the high prevalence of estrogen receptor-negative breast cancers among BRCA 1 carriers.²⁶

More recently, the Study of Tamoxifen and Raloxifene (STAR) trial compared the efficacy of tamoxifen and raloxifene, a second-generation SERM, in high-risk postmenopausal women ages 35 and older. The drugs were found to be equally effective in reducing the risk of invasive breast cancer, but raloxifene had a better side effect profile, with a lower incidence of thromboembolism and cataracts. ²⁷

What the guidelines call for. In 2003, the USPSTF recommended that clinicians discuss chemoprevention with women at high risk for breast cancer and low risk for adverse effects of SERMs.²⁸

The most recent update to the NCCN breast cancer risk reduction guidelines recommends that clinicians offer tamoxifen to premenopausal women with a 5-year projected breast cancer risk ≥1.7% and offer tamoxifen or raloxifene to high-risk postmenopausal women.²⁹ It is worth noting, however, that SERMs can have significant adverse effects, including venous thromboembolism, stroke, cataracts, uterine malignancy, and hot flashes, while lifestyle modifications and the avoidance of HRT have few, if any, negative effects.

CASE After consultation with a genetic counselor, Carrie underwent testing for both the BRCA 1 and BRCA 2 mutations. She tested negative for both. She declined chemoprevention and prophylactic surgery, opting for enhanced screening with yearly mammography and MRI and lifestyle modification instead.

When a mass is found

For women ages 30 or older with palpable masses or solid masses ≥2 cm found on imaging, core needle biopsy is recommended.^30,31 Biopsy is indicated for women younger than 30 as well, if the mass is >2 cm or imaging is suspicious. In general, a needle biopsy read as benign is considered adequate for diagnostic purposes only if the lesion appeared benign on imaging.

For lesions shown to be cystic on imaging, recommendations for follow-up or additional testing are based on the characteristics of the cyst. For simple cysts, 2- to 4-month follow up for stability, followed by routine screening, is adequate.²¹ Additional evaluation of complex cysts is indicated, including aspiration for complicated cysts and biopsy for complex cysts. After aspiration, surgical excision of bloody aspirates or persistent masses is recommended.^30,31

Staging using the TNM system
The TNM (tumor, node, metastases) classification system is used for the staging of breast cancer:

• T refers to the tumor type, size, and extent of local involvement
• N describes regional lymph node involvement
• M refers to distant metastases.

The TNM classifications are also grouped by stage (I through IV).,

Lumpectomy and sentinel node mapping with excision is the preferred method for staging of early-stage breast cancer without palpable lymphadenopathy—provided that the surgical team has documented experience with sentinel node biopsy.³² Sentinel node biopsy is preferred because of its safety, low (<10%) false negative rate, and decreased morbidity compared with full axillary dissection, although dissection is recommended for patients with more advanced cancer or a positive sentinel node.³² The comparative effects of sentinel node biopsy vs axillary node dissection on tumor recurrence and patient survival are not known.³³

Testing for tumor markers such as estrogen and progesterone receptors and human epidermal growth factor receptor 2 (HER2) expression status in biopsy-proven breast cancer is now the standard of care. Seventy percent of breast cancers are estrogen receptor-positive, with increasing frequency associated with older age.³⁴ Estrogen/progesterone receptor positivity is associated with a more favorable outcome, and multiple hormonal therapies can be aimed at these receptors.³⁴ While HER2 overexpression—which occurs in 15% to 30% of newly diagnosed breast cancers³⁵—is associated with more aggressive tumors, women with this type of tumor cell can benefit from trastuzumab, an anti-HER2 drug.³⁶

Key factors that affect prognosis

Important factors affecting prognosis and treatment of localized breast cancer are tumor size, age and menopausal status, tumor expression of hormone receptors and/ or the HER2 protein, as well as the status of the draining axillary nodes. Factors that predict a greater chance of recurrence include the spread of disease to axillary nodes, larger tumor size, invasive histology, inflammatory pathology, lack of estrogen/progesterone receptors, and age <50 years or premenopausal status.

Treatment options include surgical resection, radiation, and systemic adjuvant therapy in the form of chemotherapy, endocrine therapy, or anti-HER2 monoclonal antibodies.³⁷ (For more on treatment, see “Surgery, radiation, and systemic therapy: Making the most of what’s in our arsenal” at jfponline.com.)

Don’t overlook quality-of-life issues
Follow-up of breast cancer patients should go beyond treatment and work-up for recurrence and metastatic disease to focus on health and lifestyle issues, such as stress reduction, mood, smoking cessation, diet and exercise, treatment of hot flashes, sexual dysfunction, and bone health. A recent study found both reduced recurrence and increased survival in women receiving psychological interventions to improve quality-of-life measures after an 11-year follow-up.³⁸

Refer women to targeted Web sites such as the National Breast Cancer Awareness Month organization (http://www.nbcam.org/), the National Breast Cancer Foundation (http://community.nationalbreastcancer.org/), and the Susan G. Komen Breast Cancer Foundation (http://ww5.komen.org/). Offer treatment for bothersome symptoms. Hot flashes and depression, for example, often related to endocrine therapy, can be treated with selective serotonin reuptake inhibitors (SSRIs). That said, some SSRIs decrease the active metabolite of tamoxifen by inhibiting CYP2D6 enzyme and must, therefore, be used with caution. However, venlafaxine and citalopram are less likely to alter tamoxifen metabolism than other SSRIs.³⁹

CASE When Carrie was 47, she had an abnormal MRI of the left breast. Core needle biopsy and pathology of the lesion revealed an estrogen and progesterone receptor-positive tumor that was negative for HER2 overexpression. She underwent lumpectomy, which revealed a 1.5 cm tumor, followed by a negative sentinel node biopsy, and was diagnosed with stage I (T1N0M0) breast cancer. Carrie had radiation after surgery; she did not require chemotherapy, but was told to take tamoxifen for 5 years. This adjuvant endocrine therapy led to hot flashes and depression, both of which were successfully treated with venlafaxine. Carrie is currently cancer-free and participates in a breast cancer survivor program that includes regular visits with her primary physician and her oncologist.

CORRESPONDENCE Denise Sur, MD, 1920 Colorado Avenue, Santa Monica, CA 90404; [email protected] 

Late last year, the US Preventive Services Task Force (USPSTF) sparked a nationwide controversy when it announced that it was recommending against routine screening mammography for women younger than age 50.¹ Indeed, that’s a recommendation that many other organizations, including the American Cancer Society (ACS),² the American College of Obstetricians and Gynecologists (ACOG),³ and the National Comprehensive Cancer Network (NCCN),⁴ disagree with. But the age at which women should begin routine mammography isn’t the only controversial question. Experts disagree on the benefits of breast self-examination, the optimal frequency of clinical breast exams, and the use of digital mammography—among other issues. This evidence-based review can help you cut through the confusion.

CASE Carrie, a 39-year-old woman who has never been pregnant, comes in for an annual Pap smear and gynecologic exam. She has a negative past medical history, but a positive family history for breast cancer—both her mother and 1 of her sisters had the disease. How would you assess Carrie’s risk of breast cancer, and what preventive measures would you recommend?

Use this predictive model to pinpoint your patient’s risk

When making decisions regarding primary prevention of and screening for breast cancer, an accurate assessment of risk is critical. Many predictive models have been developed with that in mind. The most widely studied, the Gail model, incorporates a number of important risk factors (TABLE 1), including age; race; family history; reproductive factors such as age of menarche, menopause, and first childbirth; and previous history of breast biopsy and atypical findings, to calculate a woman’s 5-year risk.⁵

A risk calculator (the Breast Cancer Risk Assessment Tool) based on the Gail model is available on the National Cancer Institute’s Web site, at http://www.cancer.gov/bcrisktool. Generally, a score ≥1.66%,⁵ which indicates that a patient has at least a 1.66% chance of developing breast cancer over the next 5 years, is considered high risk.^6,7

CASE Carrie’s 2 first-degree relatives affected by breast cancer and her nulliparous status place her at increased risk. Further questioning reveals a particularly strong family history, as both relatives were diagnosed before the age of 50 (her mom at 45 years of age and her sister, at 39). Carrie’s 5-year risk is 1.8%.

TABLE 1
Risk factors for breast cancer^5,29

All women can benefit from these preventive measures

As primary care physicians, we have a responsibility to stress lifestyle modification as the mainstay of breast cancer prevention. Whether or not a woman is at high risk, advise her that maintaining a normal weight, exercising vigorously, limiting alcohol consumption, and breastfeeding are evidence-based methods of primary prevention. Diets low in fat and high in fiber may be associated with a lower risk of invasive breast cancer, but there is no conclusive evidence to support specific dietary interventions to reduce the risk.^8-11 Nor has a link between active or passive smoking, antioxidants, or fruit and vegetable intake been firmly established.¹²

There is a clear association between prolonged estrogen exposure and breast cancer, however. Many reproductive factors, such as early menarche, late menopause, later age at time of first full-term pregnancy, and nulliparity, increase a woman’s exposure to endogenous estrogen—and her risk of developing breast cancer.^12,13

Exposure to exogenous estrogen is also linked to the development of breast cancer. In 2002, the Women’s Health Initiative (WHI) was stopped early after a report was released stating that the risks of hormone replacement therapy (HRT)—a higher incidence of cardiovascular events, stroke, and venous thromboembolism, as well as breast cancer—outweighed the benefits.¹⁴ Subsequent analyses have found a relationship between the declining incidence of breast cancer and the marked decrease in HRT use prompted by the WHI report. While causality has not been firmly established, multiple studies strongly suggest it.^15,16

The association between oral contraceptives (OCs) and breast cancer is more controversial. Some studies have found an increased breast cancer risk among OC users, but both the relative risk and absolute risk were found to be very small and to dissipate 10 years after stopping OC use. More recent studies with newer formulations containing lower doses of estrogen have failed to show an increased risk.⁸

Breast cancer screening: The parameters have changed

Various organizations have published guidelines for breast cancer screening (TABLE 2), and all are somewhat different. Here’s what you need to know.

Breast self-examination (BSE), which women were previously advised to perform monthly, has not been shown to improve mortality in any age group, and is no longer routinely recommended.¹⁷ While both the USPSTF and the Canadian Task Force on Preventive Health Care recommend against teaching women BSE, the ACS, ACOG, and NCCN encourage self-examination—particularly among women older than 40 years.^1-4,17,18

Clinical breast examination has an average sensitivity of 50% and detects approximately 5% of mammographically occult cancers.¹⁹ It is still not clear whether clinical breast exams save lives, however—a finding that is reflected in the USPSTF’s “I” (insufficient evidence to assess the benefits and harms) recommendation.¹ Other consensus guidelines still recommend clinical breast examination, albeit at varying frequencies.

Screening mammography decreases mortality rates by anywhere from 28% to 65%, depending on the statistical model used.²⁰ The benefit is greatest in women between the ages of 50 and 69 years, however, and most groups agree that mammography every 1 to 2 years is advisable for this age group. (There is limited data on the value of mammography for women 70 years of age and older, and no consensus on the age at which to stop screening.^1,21) But because the mortality benefit from screening mammography is lower for women aged 40 to 49, guidelines for this age group are more controversial.

Mammography’s sensitivity is affected by a variety of factors, including age and menopausal status, prior breast surgery or radiation, breast density, and the experience of the radiologist. Women in their 40s have denser breast tissue than older women, making mammography less sensitive for this age group. Because of that, and because the overall incidence of breast cancer is lower for women younger than 50, some argue that screening mammography for women between the ages of 40 and 49 years leads to unacceptably high false-positive rates (9.8% annually²²) and that the harm associated with mammography may outweigh the benefit. Others counter that tumors in younger women tend to be more aggressive and faster growing, making early detection even more critical than for older women.

What should you advise women in this age group? You might point out that the USPSTF recommends against routine screening, but indicates that the decision to begin (or defer) routine mammography before age 50 should be individualized, based on the needs and values of each patient.¹

Digital mammography. A recent study of more than 43,000 women demonstrated that digital mammography is more accurate than film—but only for certain groups: These include women <50 years of age, women with dense breasts, and pre- and perimenopausal women. ²³ Because it is still not clear whether the increased accuracy will translate into a mortality benefit, more research is needed before digital mammography is widely adopted. The USPSTF maintains that there is insufficient evidence to assess the benefits and harms of using either digital mammography or magnetic resonance imaging (MRI) rather than film mammography to screen for breast cancer.¹

MRI. In 2007, the ACS published guidelines on the use of MRI as an adjunct to mammography for breast cancer screening in high-risk women.²⁴ According to ACS guidelines, screening MRI should be offered to patients with a known BRCA 1 or 2 mutation (5%-10% of all breast cancers are associated with a mutation in the BRCA 1 or BRCA 2 gene, which is transmitted in an autosomal dominant pattern⁶). It also should be offered to those with a strong family history, or a lifetime risk of developing breast cancer that is >20% to 25%. And finally, MRI should be offered to women who had chest wall radiation when they were between the ages of 10 and 30 years—another significant risk factor for breast cancer—and those with other genetic syndromes that increase their lifetime risk of breast cancer.²⁴

Evidence is insufficient for or against MRI screening for women with a personal history of breast cancer, atypical hyperplasia, or lobular carcinoma in situ, however, and neither breast ultrasound (which is generally used diagnostically, not for screening purposes) nor MRI has been shown to be helpful as a screening tool in women with <15% lifetime risk of developing breast cancer.^24,25

TABLE 2
Guidelines for breast cancer screening for women with average risk

When to consider chemoprevention

For women like Carrie, who are at high risk of developing breast cancer, selective estrogen receptor modulator (SERM) therapy and surgical interventions may be options to consider. The Breast Cancer Prevention Trial demonstrated the efficacy of tamoxifen as a preventive agent. This landmark trial showed that for high-risk women older than 35, 5 years of tamoxifen therapy can reduce the incidence of invasive breast cancer by nearly 50%.²⁶

Women with the BRCA 1 or 2 mutation—all of whom should be offered genetic counseling—were included in the study. Tamoxifen reduced the incidence of breast cancer in BRCA 2 carriers by 62%, the researchers found, but did not reduce risk in carriers of the BRCA 1 gene. This is likely due to the high prevalence of estrogen receptor-negative breast cancers among BRCA 1 carriers.²⁶

More recently, the Study of Tamoxifen and Raloxifene (STAR) trial compared the efficacy of tamoxifen and raloxifene, a second-generation SERM, in high-risk postmenopausal women ages 35 and older. The drugs were found to be equally effective in reducing the risk of invasive breast cancer, but raloxifene had a better side effect profile, with a lower incidence of thromboembolism and cataracts. ²⁷

What the guidelines call for. In 2003, the USPSTF recommended that clinicians discuss chemoprevention with women at high risk for breast cancer and low risk for adverse effects of SERMs.²⁸

The most recent update to the NCCN breast cancer risk reduction guidelines recommends that clinicians offer tamoxifen to premenopausal women with a 5-year projected breast cancer risk ≥1.7% and offer tamoxifen or raloxifene to high-risk postmenopausal women.²⁹ It is worth noting, however, that SERMs can have significant adverse effects, including venous thromboembolism, stroke, cataracts, uterine malignancy, and hot flashes, while lifestyle modifications and the avoidance of HRT have few, if any, negative effects.

CASE After consultation with a genetic counselor, Carrie underwent testing for both the BRCA 1 and BRCA 2 mutations. She tested negative for both. She declined chemoprevention and prophylactic surgery, opting for enhanced screening with yearly mammography and MRI and lifestyle modification instead.

When a mass is found

For women ages 30 or older with palpable masses or solid masses ≥2 cm found on imaging, core needle biopsy is recommended.^30,31 Biopsy is indicated for women younger than 30 as well, if the mass is >2 cm or imaging is suspicious. In general, a needle biopsy read as benign is considered adequate for diagnostic purposes only if the lesion appeared benign on imaging.

For lesions shown to be cystic on imaging, recommendations for follow-up or additional testing are based on the characteristics of the cyst. For simple cysts, 2- to 4-month follow up for stability, followed by routine screening, is adequate.²¹ Additional evaluation of complex cysts is indicated, including aspiration for complicated cysts and biopsy for complex cysts. After aspiration, surgical excision of bloody aspirates or persistent masses is recommended.^30,31

Staging using the TNM system
The TNM (tumor, node, metastases) classification system is used for the staging of breast cancer:

• T refers to the tumor type, size, and extent of local involvement
• N describes regional lymph node involvement
• M refers to distant metastases.

The TNM classifications are also grouped by stage (I through IV).,

Lumpectomy and sentinel node mapping with excision is the preferred method for staging of early-stage breast cancer without palpable lymphadenopathy—provided that the surgical team has documented experience with sentinel node biopsy.³² Sentinel node biopsy is preferred because of its safety, low (<10%) false negative rate, and decreased morbidity compared with full axillary dissection, although dissection is recommended for patients with more advanced cancer or a positive sentinel node.³² The comparative effects of sentinel node biopsy vs axillary node dissection on tumor recurrence and patient survival are not known.³³

Testing for tumor markers such as estrogen and progesterone receptors and human epidermal growth factor receptor 2 (HER2) expression status in biopsy-proven breast cancer is now the standard of care. Seventy percent of breast cancers are estrogen receptor-positive, with increasing frequency associated with older age.³⁴ Estrogen/progesterone receptor positivity is associated with a more favorable outcome, and multiple hormonal therapies can be aimed at these receptors.³⁴ While HER2 overexpression—which occurs in 15% to 30% of newly diagnosed breast cancers³⁵—is associated with more aggressive tumors, women with this type of tumor cell can benefit from trastuzumab, an anti-HER2 drug.³⁶

Key factors that affect prognosis

Important factors affecting prognosis and treatment of localized breast cancer are tumor size, age and menopausal status, tumor expression of hormone receptors and/ or the HER2 protein, as well as the status of the draining axillary nodes. Factors that predict a greater chance of recurrence include the spread of disease to axillary nodes, larger tumor size, invasive histology, inflammatory pathology, lack of estrogen/progesterone receptors, and age <50 years or premenopausal status.

Treatment options include surgical resection, radiation, and systemic adjuvant therapy in the form of chemotherapy, endocrine therapy, or anti-HER2 monoclonal antibodies.³⁷ (For more on treatment, see “Surgery, radiation, and systemic therapy: Making the most of what’s in our arsenal” at jfponline.com.)

Don’t overlook quality-of-life issues
Follow-up of breast cancer patients should go beyond treatment and work-up for recurrence and metastatic disease to focus on health and lifestyle issues, such as stress reduction, mood, smoking cessation, diet and exercise, treatment of hot flashes, sexual dysfunction, and bone health. A recent study found both reduced recurrence and increased survival in women receiving psychological interventions to improve quality-of-life measures after an 11-year follow-up.³⁸

Refer women to targeted Web sites such as the National Breast Cancer Awareness Month organization (http://www.nbcam.org/), the National Breast Cancer Foundation (http://community.nationalbreastcancer.org/), and the Susan G. Komen Breast Cancer Foundation (http://ww5.komen.org/). Offer treatment for bothersome symptoms. Hot flashes and depression, for example, often related to endocrine therapy, can be treated with selective serotonin reuptake inhibitors (SSRIs). That said, some SSRIs decrease the active metabolite of tamoxifen by inhibiting CYP2D6 enzyme and must, therefore, be used with caution. However, venlafaxine and citalopram are less likely to alter tamoxifen metabolism than other SSRIs.³⁹

CASE When Carrie was 47, she had an abnormal MRI of the left breast. Core needle biopsy and pathology of the lesion revealed an estrogen and progesterone receptor-positive tumor that was negative for HER2 overexpression. She underwent lumpectomy, which revealed a 1.5 cm tumor, followed by a negative sentinel node biopsy, and was diagnosed with stage I (T1N0M0) breast cancer. Carrie had radiation after surgery; she did not require chemotherapy, but was told to take tamoxifen for 5 years. This adjuvant endocrine therapy led to hot flashes and depression, both of which were successfully treated with venlafaxine. Carrie is currently cancer-free and participates in a breast cancer survivor program that includes regular visits with her primary physician and her oncologist.

CORRESPONDENCE Denise Sur, MD, 1920 Colorado Avenue, Santa Monica, CA 90404; [email protected]