The Journal of Family Practice

ILLUSTRATIVE CASE

A 35-year-old woman with no significant past medical history presents for follow-up of migraine. At the previous visit, she was prescribed sumatriptan for abortive therapy. However, she has been having significant adverse effect intolerance from the oral formulation, and the nasal formulation is cost prohibitive. What can you recommend as an alternative abortive therapy for this patient’s migraine?

Migraine is among the most common causes of disability worldwide, affecting more than 10% of the global population.² The prevalence of migraine is between 2.6% and 21.7% across multiple countries.³ On a scale of 0% to 100%, disability caused by migraine is 43.3%, comparable to the first 2 days after an acute myocardial infarction (42.2%) and severe dementia (43.8%).⁴

Abortive therapy for acute migraine includes nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, ergots, and antiemetics. However, these options are predominantly administered by mouth; non-oral formulations tend to be cost prohibitive and difficult to obtain.

Nausea and vomiting, common components of migraine (that are included in International Classification of Headache Disorders, 3rd edition [ICHD-3] criteria for migraine⁵) present obstacles to effective oral administration if experienced by the patient. In addition, for migraine refractory to first-line treatments, abortive options—including the recently approved calcitonin gene-related peptide (CGRP) receptor antagonists ubrogepant and rimegepant—are also cost prohibitive, potentially costing more than $1000 for 10 tablets (100 mg), depending on insurance coverage.⁶

Two oral beta-blockers, propranolol and timolol, are approved by the US Food and Drug Administration for migraine prophylaxis. Unfortunately, oral beta-blockers are ineffective for abortive treatment.⁷ Ophthalmic timolol is typically used in the treatment of glaucoma, but there have been case reports describing its benefits in acute migraine treatment.^8,9 In addition, ophthalmic timolol is far cheaper than medications such as ubrogepant.¹⁰ A 2014 case series of 7 patients discussed ophthalmic beta-blockers as an effective and possibly cheaper option for acute migraine treatment.⁸ A randomized, crossover, placebo-controlled pilot study of 198 migraine attacks in 10 participants using timolol eyedrops for abortive therapy found timolol was not significantly more effective than placebo.⁹ However, it was an underpowered pilot study, with a lack of masking and an imperfect placebo. The trial discussed here was a controlled, prospective study investigating topical beta-blockers for acute migraine treatment.

STUDY SUMMARY

Crossover study achieved primary endpoint in pain reduction

This randomized, single-center, double-masked, crossover trial compared timolol maleate ophthalmic solution 0.5% with placebo among 43 patients ages 12 or older presenting with a diagnosis of migraine based on ICHD-3 (beta) criteria. Patients were eligible if they had not taken any antimigraine medications for at least 1 month prior to the study and were excluded if they had taken systemic beta-blockers at baseline, or had asthma, bradyarrhythmias, or cardiac dysfunction.

Patients were randomized 1:1 to treatment with timolol maleate 0.5% eyedrops or placebo. At the earliest onset of migraine, patients used 1 drop of timolol maleate 0.5% or placebo in each eye; if they experienced no relief after 10 minutes, they used a second drop or matching placebo. Patients were instructed to score their headache pain on a 10-point scale prior to using the eyedrops and then again 20 minutes after treatment. If a patient had migraine with aura, they were asked to use the eyedrops at the onset of the aura but measure their score at headache onset. If no headaches developed within 20 minutes of the aura, the episode was not included for analysis. All patients were permitted to use their standard oral rescue medication if no relief occurred after 20 minutes of pain onset.

Continue to: The groups were observed...

The groups were observed for 3 months and then followed for a 1-month washout period, during which they received no study medications. The groups were then crossed over to the other treatment and were observed for another 3 months. The primary outcome was a reduction in pain score by 4 or more points, or to 0 on a 10-point pain scale, 20 minutes after treatment. The secondary outcome was nonuse of oral rescue medication.

The primary outcome was achieved in 233 of 284 (82%) timolol-treated migraines, compared to 38 of 271 (14%) placebo-treated migraines.

Forty-three patients were included in a modified intention-to-treat analysis. The primary outcome was achieved in 233 of 284 (82%) timolol-treated migraines, compared to 38 of 271 (14%) placebo-treated migraines (percentage difference = 68 percentage points; 95% CI, 62-74 percentage points; P < .001). The mean pain score at the onset of migraine attacks was 6.01 for those treated with timolol and 5.93 for those treated with placebo. Patients treated with timolol had a reduction in pain of 5.98 points, compared with 0.93 points after using placebo (difference = 5.05; 95% CI, 4.19-5.91). No attacks included in the data required oral rescue medications, and there were no systemic adverse effects from the timolol eyedrops.

WHAT’S NEW

Evidence of benefit as abortive therapy for acute migraine

This randomized controlled trial (RCT) showed evidence to support timolol maleate ophthalmic solution 0.5% vs placebo for treatment of acute migraine by significantly reducing pain when taken at the onset of an acute migraine attack.

CAVEATS

Single-center trial, measuring limited response time

The generalizability of this RCT is limited because it was a single-center trial with a study population from a single region in India. It is unknown whether pain relief, adverse effects, or adherence would differ for the global population. Additionally, only migraines with headache were included in the analysis, limiting non-headache migraine subgroup-directed treatment. Also, this trial evaluated only the response to treatment at 20 minutes, and it is unknown if pain response continued for several hours. Headaches that began more than 20 minutes after the onset of aura were not evaluated.

CHALLENGES TO IMPLEMENTATION

Timolol’s systemic adverse effects require caution

Systemic beta-blocker effects (eg, bradycardia, hypotension, drowsiness, and bronchospasm) from topical timolol have been reported. Caution should be used when prescribing timolol for patients with current cardiovascular and pulmonary conditions. 

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 35-year-old woman with no significant past medical history presents for follow-up of migraine. At the previous visit, she was prescribed sumatriptan for abortive therapy. However, she has been having significant adverse effect intolerance from the oral formulation, and the nasal formulation is cost prohibitive. What can you recommend as an alternative abortive therapy for this patient’s migraine?

Migraine is among the most common causes of disability worldwide, affecting more than 10% of the global population.² The prevalence of migraine is between 2.6% and 21.7% across multiple countries.³ On a scale of 0% to 100%, disability caused by migraine is 43.3%, comparable to the first 2 days after an acute myocardial infarction (42.2%) and severe dementia (43.8%).⁴

Abortive therapy for acute migraine includes nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, ergots, and antiemetics. However, these options are predominantly administered by mouth; non-oral formulations tend to be cost prohibitive and difficult to obtain.

Nausea and vomiting, common components of migraine (that are included in International Classification of Headache Disorders, 3rd edition [ICHD-3] criteria for migraine⁵) present obstacles to effective oral administration if experienced by the patient. In addition, for migraine refractory to first-line treatments, abortive options—including the recently approved calcitonin gene-related peptide (CGRP) receptor antagonists ubrogepant and rimegepant—are also cost prohibitive, potentially costing more than $1000 for 10 tablets (100 mg), depending on insurance coverage.⁶

Two oral beta-blockers, propranolol and timolol, are approved by the US Food and Drug Administration for migraine prophylaxis. Unfortunately, oral beta-blockers are ineffective for abortive treatment.⁷ Ophthalmic timolol is typically used in the treatment of glaucoma, but there have been case reports describing its benefits in acute migraine treatment.^8,9 In addition, ophthalmic timolol is far cheaper than medications such as ubrogepant.¹⁰ A 2014 case series of 7 patients discussed ophthalmic beta-blockers as an effective and possibly cheaper option for acute migraine treatment.⁸ A randomized, crossover, placebo-controlled pilot study of 198 migraine attacks in 10 participants using timolol eyedrops for abortive therapy found timolol was not significantly more effective than placebo.⁹ However, it was an underpowered pilot study, with a lack of masking and an imperfect placebo. The trial discussed here was a controlled, prospective study investigating topical beta-blockers for acute migraine treatment.

STUDY SUMMARY

Crossover study achieved primary endpoint in pain reduction

This randomized, single-center, double-masked, crossover trial compared timolol maleate ophthalmic solution 0.5% with placebo among 43 patients ages 12 or older presenting with a diagnosis of migraine based on ICHD-3 (beta) criteria. Patients were eligible if they had not taken any antimigraine medications for at least 1 month prior to the study and were excluded if they had taken systemic beta-blockers at baseline, or had asthma, bradyarrhythmias, or cardiac dysfunction.

Patients were randomized 1:1 to treatment with timolol maleate 0.5% eyedrops or placebo. At the earliest onset of migraine, patients used 1 drop of timolol maleate 0.5% or placebo in each eye; if they experienced no relief after 10 minutes, they used a second drop or matching placebo. Patients were instructed to score their headache pain on a 10-point scale prior to using the eyedrops and then again 20 minutes after treatment. If a patient had migraine with aura, they were asked to use the eyedrops at the onset of the aura but measure their score at headache onset. If no headaches developed within 20 minutes of the aura, the episode was not included for analysis. All patients were permitted to use their standard oral rescue medication if no relief occurred after 20 minutes of pain onset.

Continue to: The groups were observed...

The groups were observed for 3 months and then followed for a 1-month washout period, during which they received no study medications. The groups were then crossed over to the other treatment and were observed for another 3 months. The primary outcome was a reduction in pain score by 4 or more points, or to 0 on a 10-point pain scale, 20 minutes after treatment. The secondary outcome was nonuse of oral rescue medication.

The primary outcome was achieved in 233 of 284 (82%) timolol-treated migraines, compared to 38 of 271 (14%) placebo-treated migraines.

Forty-three patients were included in a modified intention-to-treat analysis. The primary outcome was achieved in 233 of 284 (82%) timolol-treated migraines, compared to 38 of 271 (14%) placebo-treated migraines (percentage difference = 68 percentage points; 95% CI, 62-74 percentage points; P < .001). The mean pain score at the onset of migraine attacks was 6.01 for those treated with timolol and 5.93 for those treated with placebo. Patients treated with timolol had a reduction in pain of 5.98 points, compared with 0.93 points after using placebo (difference = 5.05; 95% CI, 4.19-5.91). No attacks included in the data required oral rescue medications, and there were no systemic adverse effects from the timolol eyedrops.

WHAT’S NEW

Evidence of benefit as abortive therapy for acute migraine

This randomized controlled trial (RCT) showed evidence to support timolol maleate ophthalmic solution 0.5% vs placebo for treatment of acute migraine by significantly reducing pain when taken at the onset of an acute migraine attack.

CAVEATS

Single-center trial, measuring limited response time

The generalizability of this RCT is limited because it was a single-center trial with a study population from a single region in India. It is unknown whether pain relief, adverse effects, or adherence would differ for the global population. Additionally, only migraines with headache were included in the analysis, limiting non-headache migraine subgroup-directed treatment. Also, this trial evaluated only the response to treatment at 20 minutes, and it is unknown if pain response continued for several hours. Headaches that began more than 20 minutes after the onset of aura were not evaluated.

CHALLENGES TO IMPLEMENTATION

Timolol’s systemic adverse effects require caution

Systemic beta-blocker effects (eg, bradycardia, hypotension, drowsiness, and bronchospasm) from topical timolol have been reported. Caution should be used when prescribing timolol for patients with current cardiovascular and pulmonary conditions. 

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 35-year-old woman with no significant past medical history presents for follow-up of migraine. At the previous visit, she was prescribed sumatriptan for abortive therapy. However, she has been having significant adverse effect intolerance from the oral formulation, and the nasal formulation is cost prohibitive. What can you recommend as an alternative abortive therapy for this patient’s migraine?

Migraine is among the most common causes of disability worldwide, affecting more than 10% of the global population.² The prevalence of migraine is between 2.6% and 21.7% across multiple countries.³ On a scale of 0% to 100%, disability caused by migraine is 43.3%, comparable to the first 2 days after an acute myocardial infarction (42.2%) and severe dementia (43.8%).⁴

Abortive therapy for acute migraine includes nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, ergots, and antiemetics. However, these options are predominantly administered by mouth; non-oral formulations tend to be cost prohibitive and difficult to obtain.

Nausea and vomiting, common components of migraine (that are included in International Classification of Headache Disorders, 3rd edition [ICHD-3] criteria for migraine⁵) present obstacles to effective oral administration if experienced by the patient. In addition, for migraine refractory to first-line treatments, abortive options—including the recently approved calcitonin gene-related peptide (CGRP) receptor antagonists ubrogepant and rimegepant—are also cost prohibitive, potentially costing more than $1000 for 10 tablets (100 mg), depending on insurance coverage.⁶

Two oral beta-blockers, propranolol and timolol, are approved by the US Food and Drug Administration for migraine prophylaxis. Unfortunately, oral beta-blockers are ineffective for abortive treatment.⁷ Ophthalmic timolol is typically used in the treatment of glaucoma, but there have been case reports describing its benefits in acute migraine treatment.^8,9 In addition, ophthalmic timolol is far cheaper than medications such as ubrogepant.¹⁰ A 2014 case series of 7 patients discussed ophthalmic beta-blockers as an effective and possibly cheaper option for acute migraine treatment.⁸ A randomized, crossover, placebo-controlled pilot study of 198 migraine attacks in 10 participants using timolol eyedrops for abortive therapy found timolol was not significantly more effective than placebo.⁹ However, it was an underpowered pilot study, with a lack of masking and an imperfect placebo. The trial discussed here was a controlled, prospective study investigating topical beta-blockers for acute migraine treatment.

STUDY SUMMARY

Crossover study achieved primary endpoint in pain reduction

This randomized, single-center, double-masked, crossover trial compared timolol maleate ophthalmic solution 0.5% with placebo among 43 patients ages 12 or older presenting with a diagnosis of migraine based on ICHD-3 (beta) criteria. Patients were eligible if they had not taken any antimigraine medications for at least 1 month prior to the study and were excluded if they had taken systemic beta-blockers at baseline, or had asthma, bradyarrhythmias, or cardiac dysfunction.

Patients were randomized 1:1 to treatment with timolol maleate 0.5% eyedrops or placebo. At the earliest onset of migraine, patients used 1 drop of timolol maleate 0.5% or placebo in each eye; if they experienced no relief after 10 minutes, they used a second drop or matching placebo. Patients were instructed to score their headache pain on a 10-point scale prior to using the eyedrops and then again 20 minutes after treatment. If a patient had migraine with aura, they were asked to use the eyedrops at the onset of the aura but measure their score at headache onset. If no headaches developed within 20 minutes of the aura, the episode was not included for analysis. All patients were permitted to use their standard oral rescue medication if no relief occurred after 20 minutes of pain onset.

Continue to: The groups were observed...

The groups were observed for 3 months and then followed for a 1-month washout period, during which they received no study medications. The groups were then crossed over to the other treatment and were observed for another 3 months. The primary outcome was a reduction in pain score by 4 or more points, or to 0 on a 10-point pain scale, 20 minutes after treatment. The secondary outcome was nonuse of oral rescue medication.

The primary outcome was achieved in 233 of 284 (82%) timolol-treated migraines, compared to 38 of 271 (14%) placebo-treated migraines.

Forty-three patients were included in a modified intention-to-treat analysis. The primary outcome was achieved in 233 of 284 (82%) timolol-treated migraines, compared to 38 of 271 (14%) placebo-treated migraines (percentage difference = 68 percentage points; 95% CI, 62-74 percentage points; P < .001). The mean pain score at the onset of migraine attacks was 6.01 for those treated with timolol and 5.93 for those treated with placebo. Patients treated with timolol had a reduction in pain of 5.98 points, compared with 0.93 points after using placebo (difference = 5.05; 95% CI, 4.19-5.91). No attacks included in the data required oral rescue medications, and there were no systemic adverse effects from the timolol eyedrops.

WHAT’S NEW

Evidence of benefit as abortive therapy for acute migraine

This randomized controlled trial (RCT) showed evidence to support timolol maleate ophthalmic solution 0.5% vs placebo for treatment of acute migraine by significantly reducing pain when taken at the onset of an acute migraine attack.

CAVEATS

Single-center trial, measuring limited response time

The generalizability of this RCT is limited because it was a single-center trial with a study population from a single region in India. It is unknown whether pain relief, adverse effects, or adherence would differ for the global population. Additionally, only migraines with headache were included in the analysis, limiting non-headache migraine subgroup-directed treatment. Also, this trial evaluated only the response to treatment at 20 minutes, and it is unknown if pain response continued for several hours. Headaches that began more than 20 minutes after the onset of aura were not evaluated.

CHALLENGES TO IMPLEMENTATION

Timolol’s systemic adverse effects require caution

Systemic beta-blocker effects (eg, bradycardia, hypotension, drowsiness, and bronchospasm) from topical timolol have been reported. Caution should be used when prescribing timolol for patients with current cardiovascular and pulmonary conditions. 

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

THE CASE

A 62-year-old postmenopausal woman presented to the clinic as a new patient for her annual physical examination. She reported a 9-year history of symptoms including dysuria, post-void dribbling, dyspareunia, and urinary incontinence on review of systems. Her physical examination revealed an anterior vaginal wall bulge (FIGURE). Results of a urinalysis were negative. The patient was referred to Urology for further evaluation.

THE DIAGNOSIS

A pelvic magnetic resonance imaging (MRI) scan revealed a large periurethral diverticulum with a horseshoe shape.

DISCUSSION

Urethral diverticulum is a permanent sac-like cavity projecting into the periurethral fascia arising from the posterior urethral lumen.¹ It is a rare condition that affects fewer than 20 per 1 million women per year.² Urethral diverticulum can range from 1 cm to 8 cm in diameter and is located in the mid or distal urethra.^1,3

Women are more likely than men to develop urethral diverticulum, and it can manifest at any age, usually in the third through seventh decade.^4,5 It was once thought to be more common in Black women, although the literature does not support this.⁶ Black women are 3 times more likely to be operated on than White women to treat urethral diverticula.⁷

Unknown origin. Most cases of urethral diverticulum are acquired; the etiology is uncertain.^8,9 The assumption is that urethral diverticulum occurs as a result of repeated infection of the periurethral glands with subsequent obstruction, abscess formation, and chronic inflammation.^1,2,4 Childbirth trauma, iatrogenic causes, and urethral instrumentation have also been implicated.^3,4 In rare cases of congenital urethral diverticula, the diverticula are thought to be remnants of Gartner duct cysts, and yet, incidence in the pediatric population is low.⁸

Diagnosis is confirmed through physical exam and imaging

The urethral diverticulum manifests anteriorly and palpation of the anterior vaginal wall may reveal a painful mass.¹⁰ A split-speculum is used for careful inspection and palpation of the anterior vaginal wall.⁹ If the diverticulum is found to be firm on palpation, or there is bloody urethral drainage, malignancy (although rare) must be ruled out.^4,5 Refer such patients to a urologist or urogynecologist.

The MRI, with or without endoluminal coil, is considered the gold standard in diagnosing urethral diverticulum.

Radiologic imaging (eg, ultrasound, voiding cystourethrography [VCUG], and MRI) is useful in detecting the size, location, and extent of the diverticulum, revealing the relationship to surrounding tissues, and providing insights for appropriate surgical management.^3,4,9 Ultrasound, which is usually readily available, noninvasive, and less expensive, can be considered for initial screening of suspected urethral diverticulum.^3,11 A postvoid MRI is recommended when a urethral diverticulum is highly suspected.^11,12 The MRI, with or without endoluminal coil, is considered the gold standard; it is a favorable complement to the work-up and offers the most diagnostic value.^3,4 According to a single-institution study, the MRI was 100% sensitive and specific in diagnosing urethral diverticulum.¹² However, the limitation of the MRI lies in its cost and lack of availability in some countries.¹³

Continue to: Nonspecific symptoms may lead to misdiagnosis

Nonspecific symptoms may lead to misdiagnosis. The symptoms associated with urethral diverticulum are diverse and linked to several differential diagnoses (TABLE).^3,4,12 The most common signs and symptoms are pelvic pain, urethral mass, dyspareunia, dysuria, urinary incontinence, and post-void dribbling—all of which are considered nonspecific.^3,10,11 These nonspecific symptoms (or even an absence of symptoms), along with a physician’s lack of familiarity with urethral diverticulum, can result in a misdiagnosis or even a delayed diagnosis (up to 5.2 years).^3,10

Managing symptoms vs preventing recurrence

Conservative management with antibiotics, anticholinergics, and/or observation is acceptable for patients with mild symptoms and those who are pregnant or who have a current infection or serious comorbidities that preclude surgery.^3,9 Complete excision of the urethral diverticulum with reconstruction is considered the most effective surgical management for symptom relief and recurrence prevention.^3,4,11,14

Our patient underwent a successful transvaginal suburethral diverticulectomy.

THE TAKEAWAY

The diagnosis of female urethral diverticulum is often delayed or misdiagnosed because symptoms are diverse and nonspecific. One should have a high degree of suspicion for urethral diverticulum in patients with dysuria, dyspareunia, pelvic pain, urinary incontinence, and irritative voiding symptoms who are not responding to conservative management. Ultrasound is an appropriate first-line imaging modality. However, a pelvic MRI is the most sensitive and specific in diagnosing urethral diverticulum.¹²

CORRESPONDENCE
Folashade Omole, MD, FAAFP, 720 Westview Drive, Atlanta, GA 30310; [email protected]

THE CASE

A 62-year-old postmenopausal woman presented to the clinic as a new patient for her annual physical examination. She reported a 9-year history of symptoms including dysuria, post-void dribbling, dyspareunia, and urinary incontinence on review of systems. Her physical examination revealed an anterior vaginal wall bulge (FIGURE). Results of a urinalysis were negative. The patient was referred to Urology for further evaluation.

THE DIAGNOSIS

A pelvic magnetic resonance imaging (MRI) scan revealed a large periurethral diverticulum with a horseshoe shape.

DISCUSSION

Urethral diverticulum is a permanent sac-like cavity projecting into the periurethral fascia arising from the posterior urethral lumen.¹ It is a rare condition that affects fewer than 20 per 1 million women per year.² Urethral diverticulum can range from 1 cm to 8 cm in diameter and is located in the mid or distal urethra.^1,3

Women are more likely than men to develop urethral diverticulum, and it can manifest at any age, usually in the third through seventh decade.^4,5 It was once thought to be more common in Black women, although the literature does not support this.⁶ Black women are 3 times more likely to be operated on than White women to treat urethral diverticula.⁷

Unknown origin. Most cases of urethral diverticulum are acquired; the etiology is uncertain.^8,9 The assumption is that urethral diverticulum occurs as a result of repeated infection of the periurethral glands with subsequent obstruction, abscess formation, and chronic inflammation.^1,2,4 Childbirth trauma, iatrogenic causes, and urethral instrumentation have also been implicated.^3,4 In rare cases of congenital urethral diverticula, the diverticula are thought to be remnants of Gartner duct cysts, and yet, incidence in the pediatric population is low.⁸

Diagnosis is confirmed through physical exam and imaging

The urethral diverticulum manifests anteriorly and palpation of the anterior vaginal wall may reveal a painful mass.¹⁰ A split-speculum is used for careful inspection and palpation of the anterior vaginal wall.⁹ If the diverticulum is found to be firm on palpation, or there is bloody urethral drainage, malignancy (although rare) must be ruled out.^4,5 Refer such patients to a urologist or urogynecologist.

The MRI, with or without endoluminal coil, is considered the gold standard in diagnosing urethral diverticulum.

Radiologic imaging (eg, ultrasound, voiding cystourethrography [VCUG], and MRI) is useful in detecting the size, location, and extent of the diverticulum, revealing the relationship to surrounding tissues, and providing insights for appropriate surgical management.^3,4,9 Ultrasound, which is usually readily available, noninvasive, and less expensive, can be considered for initial screening of suspected urethral diverticulum.^3,11 A postvoid MRI is recommended when a urethral diverticulum is highly suspected.^11,12 The MRI, with or without endoluminal coil, is considered the gold standard; it is a favorable complement to the work-up and offers the most diagnostic value.^3,4 According to a single-institution study, the MRI was 100% sensitive and specific in diagnosing urethral diverticulum.¹² However, the limitation of the MRI lies in its cost and lack of availability in some countries.¹³

Continue to: Nonspecific symptoms may lead to misdiagnosis

Nonspecific symptoms may lead to misdiagnosis. The symptoms associated with urethral diverticulum are diverse and linked to several differential diagnoses (TABLE).^3,4,12 The most common signs and symptoms are pelvic pain, urethral mass, dyspareunia, dysuria, urinary incontinence, and post-void dribbling—all of which are considered nonspecific.^3,10,11 These nonspecific symptoms (or even an absence of symptoms), along with a physician’s lack of familiarity with urethral diverticulum, can result in a misdiagnosis or even a delayed diagnosis (up to 5.2 years).^3,10

Managing symptoms vs preventing recurrence

Conservative management with antibiotics, anticholinergics, and/or observation is acceptable for patients with mild symptoms and those who are pregnant or who have a current infection or serious comorbidities that preclude surgery.^3,9 Complete excision of the urethral diverticulum with reconstruction is considered the most effective surgical management for symptom relief and recurrence prevention.^3,4,11,14

Our patient underwent a successful transvaginal suburethral diverticulectomy.

THE TAKEAWAY

The diagnosis of female urethral diverticulum is often delayed or misdiagnosed because symptoms are diverse and nonspecific. One should have a high degree of suspicion for urethral diverticulum in patients with dysuria, dyspareunia, pelvic pain, urinary incontinence, and irritative voiding symptoms who are not responding to conservative management. Ultrasound is an appropriate first-line imaging modality. However, a pelvic MRI is the most sensitive and specific in diagnosing urethral diverticulum.¹²

CORRESPONDENCE
Folashade Omole, MD, FAAFP, 720 Westview Drive, Atlanta, GA 30310; [email protected]

THE CASE

A 62-year-old postmenopausal woman presented to the clinic as a new patient for her annual physical examination. She reported a 9-year history of symptoms including dysuria, post-void dribbling, dyspareunia, and urinary incontinence on review of systems. Her physical examination revealed an anterior vaginal wall bulge (FIGURE). Results of a urinalysis were negative. The patient was referred to Urology for further evaluation.

THE DIAGNOSIS

A pelvic magnetic resonance imaging (MRI) scan revealed a large periurethral diverticulum with a horseshoe shape.

DISCUSSION

Urethral diverticulum is a permanent sac-like cavity projecting into the periurethral fascia arising from the posterior urethral lumen.¹ It is a rare condition that affects fewer than 20 per 1 million women per year.² Urethral diverticulum can range from 1 cm to 8 cm in diameter and is located in the mid or distal urethra.^1,3

Women are more likely than men to develop urethral diverticulum, and it can manifest at any age, usually in the third through seventh decade.^4,5 It was once thought to be more common in Black women, although the literature does not support this.⁶ Black women are 3 times more likely to be operated on than White women to treat urethral diverticula.⁷

Unknown origin. Most cases of urethral diverticulum are acquired; the etiology is uncertain.^8,9 The assumption is that urethral diverticulum occurs as a result of repeated infection of the periurethral glands with subsequent obstruction, abscess formation, and chronic inflammation.^1,2,4 Childbirth trauma, iatrogenic causes, and urethral instrumentation have also been implicated.^3,4 In rare cases of congenital urethral diverticula, the diverticula are thought to be remnants of Gartner duct cysts, and yet, incidence in the pediatric population is low.⁸

Diagnosis is confirmed through physical exam and imaging

The urethral diverticulum manifests anteriorly and palpation of the anterior vaginal wall may reveal a painful mass.¹⁰ A split-speculum is used for careful inspection and palpation of the anterior vaginal wall.⁹ If the diverticulum is found to be firm on palpation, or there is bloody urethral drainage, malignancy (although rare) must be ruled out.^4,5 Refer such patients to a urologist or urogynecologist.

The MRI, with or without endoluminal coil, is considered the gold standard in diagnosing urethral diverticulum.

Radiologic imaging (eg, ultrasound, voiding cystourethrography [VCUG], and MRI) is useful in detecting the size, location, and extent of the diverticulum, revealing the relationship to surrounding tissues, and providing insights for appropriate surgical management.^3,4,9 Ultrasound, which is usually readily available, noninvasive, and less expensive, can be considered for initial screening of suspected urethral diverticulum.^3,11 A postvoid MRI is recommended when a urethral diverticulum is highly suspected.^11,12 The MRI, with or without endoluminal coil, is considered the gold standard; it is a favorable complement to the work-up and offers the most diagnostic value.^3,4 According to a single-institution study, the MRI was 100% sensitive and specific in diagnosing urethral diverticulum.¹² However, the limitation of the MRI lies in its cost and lack of availability in some countries.¹³

Continue to: Nonspecific symptoms may lead to misdiagnosis

Nonspecific symptoms may lead to misdiagnosis. The symptoms associated with urethral diverticulum are diverse and linked to several differential diagnoses (TABLE).^3,4,12 The most common signs and symptoms are pelvic pain, urethral mass, dyspareunia, dysuria, urinary incontinence, and post-void dribbling—all of which are considered nonspecific.^3,10,11 These nonspecific symptoms (or even an absence of symptoms), along with a physician’s lack of familiarity with urethral diverticulum, can result in a misdiagnosis or even a delayed diagnosis (up to 5.2 years).^3,10

Managing symptoms vs preventing recurrence

Conservative management with antibiotics, anticholinergics, and/or observation is acceptable for patients with mild symptoms and those who are pregnant or who have a current infection or serious comorbidities that preclude surgery.^3,9 Complete excision of the urethral diverticulum with reconstruction is considered the most effective surgical management for symptom relief and recurrence prevention.^3,4,11,14

Our patient underwent a successful transvaginal suburethral diverticulectomy.

THE TAKEAWAY

The diagnosis of female urethral diverticulum is often delayed or misdiagnosed because symptoms are diverse and nonspecific. One should have a high degree of suspicion for urethral diverticulum in patients with dysuria, dyspareunia, pelvic pain, urinary incontinence, and irritative voiding symptoms who are not responding to conservative management. Ultrasound is an appropriate first-line imaging modality. However, a pelvic MRI is the most sensitive and specific in diagnosing urethral diverticulum.¹²

CORRESPONDENCE
Folashade Omole, MD, FAAFP, 720 Westview Drive, Atlanta, GA 30310; [email protected]

AN 8-YEAR-OLD BOY was evaluated by his family physician for a widespread rash that had first appeared on his arms 4 months earlier. Physical examination revealed 1- to 2-mm hypopigmented, smooth, and dome-shaped papules in clusters and linear arrays on the child’s back, shoulders, and extensor surfaces of both arms (FIGURE). There was no tenderness to palpation of the affected areas, but the patient complained of pruritus. Otherwise, he was in good health.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

This clinical manifestation of multiple, hypopigmented, pinhead-sized papules is most consistent with the diagnosis of lichen nitidus. The linear appearance of the micropapules at sites of trauma or skin pressure (known as the Koebner phenomenon) is a valuable clue in the diagnosis of this skin disorder. In this case, it was most likely the result of the child scratching his skin.

A rare and chronic inflammatory skin condition, lichen nitidus is characterized by numerous small, skin-colored papules that are often arranged in clusters on the upper extremities, the genitalia, and the anterior trunk.¹ The papules are less likely to occur on the face, lower extremities, palms, and soles. Oral mucosal and nail involvement are rare. The condition is usually asymptomatic but can sometimes be associated with pruritus.

Most patients experience spontaneous resolution of lesions within several years; treatment is primarily for symptomatic or cosmetic purposes.

Lichen nitidus occurs more frequently in children or young adults and has a female predominance.¹ It does not exhibit a predilection of any race.² The etiology and pathogenesis of lichen nitidus remain unclear. Genetic factors have been proposed as a potential cause; it has also been reported to be associated with Down syndrome.³

Making the Dx with dermoscopy, skin biopsy

Dermoscopy is a useful technique for diagnosing lichen nitidus. Dermoscopic features of lichen nitidus include white, well-demarcated circular areas with a brown shadow.⁴ Skin biopsy provides a definitive diagnosis. Lichen nitidus has a distinct histopathologic “ball and claw” appearance of rete ridges clutching a lymphohistiocytic infiltrate.¹

Consider these common conditions in the differential

The differential diagnosis includes lichen spinulosus, papular eczema, lichen planus, keratosis pilaris, and verruca plana (flat warts).

Continue to: Lichen spinulosus

Lichen spinulosus lesions are similar in appearance to lichen nitidus but are grouped in patches on the neck, arms, abdomen, and buttocks.¹ The Koebner phenomenon is not typically present. Lichen spinulosus lesions consist of follicular papules that may exhibit a central keratotic plug.

Papular eczema lesions lack the uniform and discrete appearance observed in lichen nitidus. Pruritus is also more likely to be present in papular eczema.

Lichen planus lesions are typically violaceous, flat, and larger in size than lichen nitidus (measuring 1 mm to 1 cm), and have characteristic Wickham striae. Oral involvement is also more suggestive of lichen planus.

Keratosis pilaris is distinguished by its much more common occurrence and perifollicular erythema.

Verruca plana, in contrast to lichen nitidus, are typically pink, flat-topped lesions. They are also larger in size (2 mm to 5 mm).

Continue to: Topical treatment can help manage the condition

Most patients experience spontaneous resolution of lesions within several years; treatment is primarily for symptomatic or cosmetic purposes. When pruritus is present, topical corticosteroids and oral antihistamines may help (eg, hydrocortisone 2.5% cream and oral hydroxyzine). Topical calcineurin inhibitors, such as pimecrolimus cream, have also been reported as an effective therapy in children with lichen nitidus.¹ In patients with generalized lichen nitidus who have not responded to topical corticosteroids, phototherapy can be used.⁵ There are no randomized controlled trials to assess the effectiveness of different types of treatments.

In this case, the patient was advised to start using an over-the-counter topical steroid, such as 1% hydrocortisone cream, to help control pruritus. He was scheduled for a follow-up appointment in 3 months.

AN 8-YEAR-OLD BOY was evaluated by his family physician for a widespread rash that had first appeared on his arms 4 months earlier. Physical examination revealed 1- to 2-mm hypopigmented, smooth, and dome-shaped papules in clusters and linear arrays on the child’s back, shoulders, and extensor surfaces of both arms (FIGURE). There was no tenderness to palpation of the affected areas, but the patient complained of pruritus. Otherwise, he was in good health.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

This clinical manifestation of multiple, hypopigmented, pinhead-sized papules is most consistent with the diagnosis of lichen nitidus. The linear appearance of the micropapules at sites of trauma or skin pressure (known as the Koebner phenomenon) is a valuable clue in the diagnosis of this skin disorder. In this case, it was most likely the result of the child scratching his skin.

A rare and chronic inflammatory skin condition, lichen nitidus is characterized by numerous small, skin-colored papules that are often arranged in clusters on the upper extremities, the genitalia, and the anterior trunk.¹ The papules are less likely to occur on the face, lower extremities, palms, and soles. Oral mucosal and nail involvement are rare. The condition is usually asymptomatic but can sometimes be associated with pruritus.

Most patients experience spontaneous resolution of lesions within several years; treatment is primarily for symptomatic or cosmetic purposes.

Lichen nitidus occurs more frequently in children or young adults and has a female predominance.¹ It does not exhibit a predilection of any race.² The etiology and pathogenesis of lichen nitidus remain unclear. Genetic factors have been proposed as a potential cause; it has also been reported to be associated with Down syndrome.³

Making the Dx with dermoscopy, skin biopsy

Dermoscopy is a useful technique for diagnosing lichen nitidus. Dermoscopic features of lichen nitidus include white, well-demarcated circular areas with a brown shadow.⁴ Skin biopsy provides a definitive diagnosis. Lichen nitidus has a distinct histopathologic “ball and claw” appearance of rete ridges clutching a lymphohistiocytic infiltrate.¹

Consider these common conditions in the differential

The differential diagnosis includes lichen spinulosus, papular eczema, lichen planus, keratosis pilaris, and verruca plana (flat warts).

Continue to: Lichen spinulosus

Lichen spinulosus lesions are similar in appearance to lichen nitidus but are grouped in patches on the neck, arms, abdomen, and buttocks.¹ The Koebner phenomenon is not typically present. Lichen spinulosus lesions consist of follicular papules that may exhibit a central keratotic plug.

Papular eczema lesions lack the uniform and discrete appearance observed in lichen nitidus. Pruritus is also more likely to be present in papular eczema.

Lichen planus lesions are typically violaceous, flat, and larger in size than lichen nitidus (measuring 1 mm to 1 cm), and have characteristic Wickham striae. Oral involvement is also more suggestive of lichen planus.

Keratosis pilaris is distinguished by its much more common occurrence and perifollicular erythema.

Verruca plana, in contrast to lichen nitidus, are typically pink, flat-topped lesions. They are also larger in size (2 mm to 5 mm).

Continue to: Topical treatment can help manage the condition

Most patients experience spontaneous resolution of lesions within several years; treatment is primarily for symptomatic or cosmetic purposes. When pruritus is present, topical corticosteroids and oral antihistamines may help (eg, hydrocortisone 2.5% cream and oral hydroxyzine). Topical calcineurin inhibitors, such as pimecrolimus cream, have also been reported as an effective therapy in children with lichen nitidus.¹ In patients with generalized lichen nitidus who have not responded to topical corticosteroids, phototherapy can be used.⁵ There are no randomized controlled trials to assess the effectiveness of different types of treatments.

In this case, the patient was advised to start using an over-the-counter topical steroid, such as 1% hydrocortisone cream, to help control pruritus. He was scheduled for a follow-up appointment in 3 months.

AN 8-YEAR-OLD BOY was evaluated by his family physician for a widespread rash that had first appeared on his arms 4 months earlier. Physical examination revealed 1- to 2-mm hypopigmented, smooth, and dome-shaped papules in clusters and linear arrays on the child’s back, shoulders, and extensor surfaces of both arms (FIGURE). There was no tenderness to palpation of the affected areas, but the patient complained of pruritus. Otherwise, he was in good health.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

This clinical manifestation of multiple, hypopigmented, pinhead-sized papules is most consistent with the diagnosis of lichen nitidus. The linear appearance of the micropapules at sites of trauma or skin pressure (known as the Koebner phenomenon) is a valuable clue in the diagnosis of this skin disorder. In this case, it was most likely the result of the child scratching his skin.

A rare and chronic inflammatory skin condition, lichen nitidus is characterized by numerous small, skin-colored papules that are often arranged in clusters on the upper extremities, the genitalia, and the anterior trunk.¹ The papules are less likely to occur on the face, lower extremities, palms, and soles. Oral mucosal and nail involvement are rare. The condition is usually asymptomatic but can sometimes be associated with pruritus.

Most patients experience spontaneous resolution of lesions within several years; treatment is primarily for symptomatic or cosmetic purposes.

Lichen nitidus occurs more frequently in children or young adults and has a female predominance.¹ It does not exhibit a predilection of any race.² The etiology and pathogenesis of lichen nitidus remain unclear. Genetic factors have been proposed as a potential cause; it has also been reported to be associated with Down syndrome.³

Making the Dx with dermoscopy, skin biopsy

Dermoscopy is a useful technique for diagnosing lichen nitidus. Dermoscopic features of lichen nitidus include white, well-demarcated circular areas with a brown shadow.⁴ Skin biopsy provides a definitive diagnosis. Lichen nitidus has a distinct histopathologic “ball and claw” appearance of rete ridges clutching a lymphohistiocytic infiltrate.¹

Consider these common conditions in the differential

The differential diagnosis includes lichen spinulosus, papular eczema, lichen planus, keratosis pilaris, and verruca plana (flat warts).

Continue to: Lichen spinulosus

Lichen spinulosus lesions are similar in appearance to lichen nitidus but are grouped in patches on the neck, arms, abdomen, and buttocks.¹ The Koebner phenomenon is not typically present. Lichen spinulosus lesions consist of follicular papules that may exhibit a central keratotic plug.

Papular eczema lesions lack the uniform and discrete appearance observed in lichen nitidus. Pruritus is also more likely to be present in papular eczema.

Lichen planus lesions are typically violaceous, flat, and larger in size than lichen nitidus (measuring 1 mm to 1 cm), and have characteristic Wickham striae. Oral involvement is also more suggestive of lichen planus.

Keratosis pilaris is distinguished by its much more common occurrence and perifollicular erythema.

Verruca plana, in contrast to lichen nitidus, are typically pink, flat-topped lesions. They are also larger in size (2 mm to 5 mm).

Continue to: Topical treatment can help manage the condition

Most patients experience spontaneous resolution of lesions within several years; treatment is primarily for symptomatic or cosmetic purposes. When pruritus is present, topical corticosteroids and oral antihistamines may help (eg, hydrocortisone 2.5% cream and oral hydroxyzine). Topical calcineurin inhibitors, such as pimecrolimus cream, have also been reported as an effective therapy in children with lichen nitidus.¹ In patients with generalized lichen nitidus who have not responded to topical corticosteroids, phototherapy can be used.⁵ There are no randomized controlled trials to assess the effectiveness of different types of treatments.

In this case, the patient was advised to start using an over-the-counter topical steroid, such as 1% hydrocortisone cream, to help control pruritus. He was scheduled for a follow-up appointment in 3 months.

Migraine headaches pose a challenge for many patients and their physicians, so new, effective approaches are always welcome. Sometimes new treatments come as total surprises. For example, who would have guessed that timolol eyedrops could be effective for acute migraine?¹ Granted, the results (discussed in this issue's PURLs) are from a single randomized trial, but they look very promising.

This is not the only new and innovative treatment for migraine. Everyone knows about the heavily marketed calcium gene-related peptide antagonists, which include monoclonal antibodies and the so-called “gepants.” The monoclonal antibodies and atogepant are approved for migraine prevention, and they do a decent job (although at a high price). In randomized trials, these agents reduced migraine days per month by an average of about 1.5 to 2.5 days compared to placebo.^2-5

Who would have guessed that timolol eyedrops could be effective for acute migraine?

Ubrogepant and rimegepant are approved for acute migraine treatment. In clinical trials, about 20% of patients taking ubrogepant or rimegepant were pain free at 2 hours post dose, compared to 12% to 14% taking placebo.^6,7 Unfortunately, that means 80% of patients still have some pain at 2 hours. By comparison, zolmitriptan performs a bit better, with 34% of patients pain free at 2 hours.⁸ However, for those who can’t tolerate zolmitriptan, these newer options provide an alternative.

We also now have nonpharmacologic options. The caloric vestibular stimulation device is essentially a headset with ear probes that change temperature, alternating warm and cold. In a randomized controlled trial, it reduced monthly migraine days by 1.1 compared to placebo, from a baseline of 7.7 to 3.9 days.⁹ It can also be used to treat acute migraine. There is also a vagus nerve–stimulating device that reduced migraine headache severity by 20% on average in 32.2% of patients in 30 minutes. Sham treatment was as effective for 18.5% of patients, giving a number needed to treat of 6 compared to sham.¹⁰

And finally, there are complementary and alternative medicine options. Two recent randomized trials demonstrated that ≥ 2000 IU/d of vitamin D reduced monthly migraine days an average of 2 days, which is comparable to the effectiveness of the calcium gene-related peptide antagonists at a fraction of the cost.^11,12 In another randomized trial, intranasal 1.5% peppermint oil was as effective as topical 4% lidocaine in providing substantial pain relief for acute migraine; about 42% of patients achieved significant relief with either treatment.¹³

While we may not have a perfect treatment for our patients with migraine headache, we certainly have many options to choose from.

Migraine headaches pose a challenge for many patients and their physicians, so new, effective approaches are always welcome. Sometimes new treatments come as total surprises. For example, who would have guessed that timolol eyedrops could be effective for acute migraine?¹ Granted, the results (discussed in this issue's PURLs) are from a single randomized trial, but they look very promising.

This is not the only new and innovative treatment for migraine. Everyone knows about the heavily marketed calcium gene-related peptide antagonists, which include monoclonal antibodies and the so-called “gepants.” The monoclonal antibodies and atogepant are approved for migraine prevention, and they do a decent job (although at a high price). In randomized trials, these agents reduced migraine days per month by an average of about 1.5 to 2.5 days compared to placebo.^2-5

Who would have guessed that timolol eyedrops could be effective for acute migraine?

Ubrogepant and rimegepant are approved for acute migraine treatment. In clinical trials, about 20% of patients taking ubrogepant or rimegepant were pain free at 2 hours post dose, compared to 12% to 14% taking placebo.^6,7 Unfortunately, that means 80% of patients still have some pain at 2 hours. By comparison, zolmitriptan performs a bit better, with 34% of patients pain free at 2 hours.⁸ However, for those who can’t tolerate zolmitriptan, these newer options provide an alternative.

We also now have nonpharmacologic options. The caloric vestibular stimulation device is essentially a headset with ear probes that change temperature, alternating warm and cold. In a randomized controlled trial, it reduced monthly migraine days by 1.1 compared to placebo, from a baseline of 7.7 to 3.9 days.⁹ It can also be used to treat acute migraine. There is also a vagus nerve–stimulating device that reduced migraine headache severity by 20% on average in 32.2% of patients in 30 minutes. Sham treatment was as effective for 18.5% of patients, giving a number needed to treat of 6 compared to sham.¹⁰

And finally, there are complementary and alternative medicine options. Two recent randomized trials demonstrated that ≥ 2000 IU/d of vitamin D reduced monthly migraine days an average of 2 days, which is comparable to the effectiveness of the calcium gene-related peptide antagonists at a fraction of the cost.^11,12 In another randomized trial, intranasal 1.5% peppermint oil was as effective as topical 4% lidocaine in providing substantial pain relief for acute migraine; about 42% of patients achieved significant relief with either treatment.¹³

While we may not have a perfect treatment for our patients with migraine headache, we certainly have many options to choose from.

Migraine headaches pose a challenge for many patients and their physicians, so new, effective approaches are always welcome. Sometimes new treatments come as total surprises. For example, who would have guessed that timolol eyedrops could be effective for acute migraine?¹ Granted, the results (discussed in this issue's PURLs) are from a single randomized trial, but they look very promising.

This is not the only new and innovative treatment for migraine. Everyone knows about the heavily marketed calcium gene-related peptide antagonists, which include monoclonal antibodies and the so-called “gepants.” The monoclonal antibodies and atogepant are approved for migraine prevention, and they do a decent job (although at a high price). In randomized trials, these agents reduced migraine days per month by an average of about 1.5 to 2.5 days compared to placebo.^2-5

Who would have guessed that timolol eyedrops could be effective for acute migraine?

Ubrogepant and rimegepant are approved for acute migraine treatment. In clinical trials, about 20% of patients taking ubrogepant or rimegepant were pain free at 2 hours post dose, compared to 12% to 14% taking placebo.^6,7 Unfortunately, that means 80% of patients still have some pain at 2 hours. By comparison, zolmitriptan performs a bit better, with 34% of patients pain free at 2 hours.⁸ However, for those who can’t tolerate zolmitriptan, these newer options provide an alternative.

We also now have nonpharmacologic options. The caloric vestibular stimulation device is essentially a headset with ear probes that change temperature, alternating warm and cold. In a randomized controlled trial, it reduced monthly migraine days by 1.1 compared to placebo, from a baseline of 7.7 to 3.9 days.⁹ It can also be used to treat acute migraine. There is also a vagus nerve–stimulating device that reduced migraine headache severity by 20% on average in 32.2% of patients in 30 minutes. Sham treatment was as effective for 18.5% of patients, giving a number needed to treat of 6 compared to sham.¹⁰

And finally, there are complementary and alternative medicine options. Two recent randomized trials demonstrated that ≥ 2000 IU/d of vitamin D reduced monthly migraine days an average of 2 days, which is comparable to the effectiveness of the calcium gene-related peptide antagonists at a fraction of the cost.^11,12 In another randomized trial, intranasal 1.5% peppermint oil was as effective as topical 4% lidocaine in providing substantial pain relief for acute migraine; about 42% of patients achieved significant relief with either treatment.¹³

While we may not have a perfect treatment for our patients with migraine headache, we certainly have many options to choose from.

Breast cancer is the most common invasive cancer in women in the United States; it is estimated that there will be 287,850 new cases of breast cancer in the United States during 2022 with 43,250 deaths.¹ Lives are extended and saved every day because of a robust arsenal of treatments and interventions available to those who have been given a diagnosis of breast cancer. And, of course, lives are also extended and saved when we identify women at risk and provide early interventions. But in busy offices where time is short and there are competing demands on our time, proper assessment of a woman’s risk of breast cancer does not always happen. As a result, women with a higher risk of breast cancer may not be getting appropriate management.^2,3

Familiarizing yourself with several risk-assessment tools and knowing when genetic testing is needed can make a big difference. Knowing the timing of mammograms and magnetic resonance imaging (MRI) for women deemed to be at high risk is also key. The following review employs a case-based approach (with an accompanying ALGORITHM) to illustrate how best to identify women who are at heightened risk of breast cancer and maximize their care. We also discuss the chemoprophylaxis regimens that may be used for those at increased risk.

CASE

Rachel P, age 37, presents to establish care. She has an Ashkenazi Jewish background and wonders if she should start doing breast cancer screening before age 40. She has 2 children, ages 4 years and 2 years. Her maternal aunt had unilateral breast cancer at age 54, and her maternal grandmother died of ovarian cancer at age 65.

Risk assessment

The risk assessment process (see ALGORITHM) must start with either the clinician or the patient initiating the discussion about breast cancer risk. The clinician may initiate the discussion with a new patient or at an annual physical examination. The patient may start the discussion because they are experiencing new breast symptoms, have anxiety about developing breast cancer, or have a family member with a new cancer diagnosis.

Risk factors. There are single factors that convey enough risk to automatically designate the patient as high risk (see TABLE 1^4-9). These factors include having a history of chest radiation between the ages of 10 and 30, a history of breast biopsy with either lobular carcinoma in situ (LCIS) or atypical ductal hyperplasia (ADH), past breast and/or ovarian cancer, and either a family or personal history of a high penetrant genetic variant for breast cancer.^4-9

In women with previous chest radiation, breast cancer risk correlates with the total dose of radiation.⁵ For women with a personal history of breast cancer, the younger the age at diagnosis, the higher the risk of contralateral breast cancer.⁵ Precancerous changes such as ADH, LCIS, and ductal carcinoma in situ (DCIS) also confer moderate increases in risk. Women with these diagnoses will commonly have follow-up with specialists.

Risk assessment tools. There are several models available to assess a woman’s breast cancer risk (see TABLE 2^10-12). The Gail model (https://bcrisktool.cancer.gov/) is the oldest, quickest, and most widely known. However, the Gail model only accounts for first-degree relatives diagnosed with breast cancer, may underpredict risk in women with a more extensive family history, and has not been studied in women younger than 35. The International Breast Cancer Intervention Study (IBIS) Risk Evaluation Tool (https://ibis-risk-calculator.magview.com/), commonly referred to as the Tyrer-Cuzick model, incorporates second-degree relatives into the prediction model—although women may not know their full family history. Both the IBIS and the Breast Cancer Surveillance Consortium (BCSC) model (https://tools.bcsc-scc.org/BC5yearRisk/intro.htm) include breast density in the prediction algorithm. The choice of tool depends on clinician comfort and individual patient risk factors. There is no evidence that one model is better than another.^10-12

Continue to: CASE

CASE

Ms. P’s clinician starts with an assessment using the Gail model. However, when the result comes back with average risk, the clinician decides to follow up with the Tyrer-Cuzick model in order to incorporate Ms. P’s multiple ­second-degree relatives with breast and ovarian cancer. (The BCSC model was not used because it only includes first-degree relatives.)

Genetic testing

The National Comprehensive Cancer Network (NCCN) guidelines recommend genetic testing if a woman has a first- or ­second-degree relative with pancreatic cancer, metastatic prostate cancer, male breast cancer, breast cancer at age 45 or younger, 2 or more breast cancers in a single person, 2 or more people on the same side of the family with at least 1 diagnosed at age 50 or younger, or any relative with ovarian cancer (see TABLE 3).⁷ Before ordering genetic testing, it is useful to refer the patient to a genetic counselor for a thorough discussion of options.

Results of genetic testing may include high-risk variants, moderate-risk variants, and variants of unknown significance (VUS), or be negative for any variants. High-risk variants for breast cancer include BRCA1, BRCA2, PALB2, and cancer syndrome variants such as TP53, PTEN, STK11, and CDH1.^5,6,9,13-15 These high-risk variants confer sufficient risk that women with these mutations are automatically categorized in the high-risk group. It is estimated that high-risk variants account for only 25% of the genetic risk for breast cancer.¹⁶

BRCA1/2 and PTEN mutations confer greater than 80% lifetime risk, while other high-risk variants such as TP53, CDH1, and STK11 confer risks between 25% and 40%. These variants are also associated with cancers of other organs, depending on the mutation.¹⁷

Moderate-risk variants—ATM and CHEK2—do not confer sufficient risk to elevate women into the high-risk group. However, they do qualify these intermediate-risk women to participate in a specialized management strategy.^5,9,13,18

VUS are those for which the associated risk is unclear, but more research may be done to categorize the risk.⁹ The clinical management of women with VUS usually entails close monitoring.

In an effort to better characterize breast cancer risk using a combination of pathogenic variants found in broad multi-gene cancer predisposition panels, researchers have developed a method to combine risks in a “polygenic risk score” (PRS) that can be used to counsel women (see “What is a polygenic risk score for breast cancer?” on page 203).^19-21PRS predicts an additional 18% of genetic risk in women of European descent.²¹

Continue to: CASE

CASE

Using the assessment results, the clinician talks to Ms. P about her lifetime risk for breast cancer. The Gail model indicates her lifetime risk is 13.3%, just slightly higher than the average (12.5%), and her 5-year risk is 0.5% (average, 0.4%). The IBIS or Tyrer-­Cuzick model, which takes into account her second-degree relatives with breast and ovarian cancer and her Ashkenazi ethnicity (which confers increased risk due to elevated risk of BRCA mutations), predicts her lifetime risk of breast cancer to be 20.4%. This categorizes Ms. P as high risk.

Enhanced screening recommendations for women at high risk

TABLE 4^8,13,22 summarizes screening recommendations for women deemed to be at high risk for breast cancer. The American Cancer Society (ACS), NCCN, and the American College of Radiology (ACR) recommend that women with at least a 20% lifetime risk have yearly magnetic resonance imaging (MRI) and mammography (staggered so that the patient has 1 test every 6 months) starting 10 years before the age of onset for the youngest affected relative but not before age 30.⁸ For carriers of high-risk (as well as intermediate-risk) genes, NCCN recommends annual MRI screening starting at age 40.¹³BRCA1/2 screening includes annual MRI starting at age 25 and annual mammography every 6 months starting at age 30.²² Clinicians should counsel women with moderate risk factors (elevated breast density; personal history of ADH, LCIS, or DCIS) about the potential risks and benefits of enhanced screening and chemoprophylaxis.

Risk-reduction strategies

Chemoprophylaxis

The US Preventive Services Task Force (USPSTF) recommends that all women at increased risk for breast cancer consider chemoprophylaxis (B recommendation)²³ based on convincing evidence that 5 years of treatment with either a synthetic estrogen reuptake modulator (SERM) or an aromatase inhibitor (AI) decreases the incidence of estrogen receptor positive breast cancers. (See TABLE 5^7,23,24 for absolute risk reduction.) There is no benefit for chemoprophylaxis in women at average risk (D recommendation).²³ It is unclear whether chemoprophylaxis is indicated in women with moderate increased risk (ie, who do not meet the 20% lifetime risk criteria). Chemoprophylaxis may not be effective in women with BRCA1 mutations, as they often develop triple-negative breast cancers.

Accurate risk assessment and shared decision-making enable the clinician and patient to discuss the potential risks and benefits of chemoprophylaxis.^7,24 The USPSTF did not find that any 1 risk prediction tool was better than another to identify women who should be counseled about chemoprophylaxis. Clinicians should counsel all women taking AIs about optimizing bone health with adequate calcium and vitamin D intake and routine bone density tests.

Surgical risk reduction

The NCCN guidelines state that risk-reducing bilateral mastectomy is reserved for individuals with high-risk gene variants and individuals with prior chest radiation between ages 10 and 30.²⁵ NCCN also recommends discussing risk-reducing mastectomy with all women with BRCA mutations.²²

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer.

Bilateral mastectomy is the most effective method to reduce breast cancer risk and should be discussed after age 25 in women with BRCA mutations and at least 8 years after chest radiation is completed.²⁶ There is a reduction in breast cancer incidence of 90%.²⁵ Breast imaging for screening (mammography or MRI) is not indicated after risk-reducing mastectomy. However, clinical breast examinations of the surgical site are important, because there is a small risk of developing breast cancer in that area.²⁶

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer. It can also reduce the risk of breast cancer in women with BRCA mutations.²⁷

Continue to: CASE

CASE

Based on her risk assessment results, family history, and genetic heritage, Ms. P qualifies for referral to a genetic counselor for discussion of BRCA testing. The clinician discusses adding annual MRI to Ms. P’s breast cancer screening regimen, based on ACS, NCCN, and ACR recommendations, due to her 20.4% lifetime risk. Discussion of whether and when to start chemoprophylaxis is typically based on breast cancer risk, projected benefit, and the potential impact of medication adverse effects. A high-risk woman is eligible for 5 years of chemoprophylaxis (tamoxifen if premenopausal) based on her lifetime risk. The clinician discusses timing with Ms. P, and even though she is finished with childbearing, she would like to wait until she is age 45, which is before the age at which her aunt was given a diagnosis of breast cancer.

Conclusion

Primary care clinicians are well positioned to identify women with an elevated risk of breast cancer and refer them for enhanced screening and chemoprophylaxis (see ALGORITHM). Shared decision-making with the inclusion of patient decision aids (https://decisionaid.ohri.ca/AZsearch.php?criteria=breast+cancer) about genetic testing, chemoprophylaxis, and prophylactic mastectomy or oophorectomy may help women at intermediate or high risk of breast cancer feel empowered to make decisions about their breast—and overall—health.

CORRESPONDENCE
Sarina Schrager, MD, MS, Professor, Department of Family Medicine and Community Health, University of Wisconsin, 1100 Delaplaine Court, Madison, WI 53715; [email protected]

Breast cancer is the most common invasive cancer in women in the United States; it is estimated that there will be 287,850 new cases of breast cancer in the United States during 2022 with 43,250 deaths.¹ Lives are extended and saved every day because of a robust arsenal of treatments and interventions available to those who have been given a diagnosis of breast cancer. And, of course, lives are also extended and saved when we identify women at risk and provide early interventions. But in busy offices where time is short and there are competing demands on our time, proper assessment of a woman’s risk of breast cancer does not always happen. As a result, women with a higher risk of breast cancer may not be getting appropriate management.^2,3

Familiarizing yourself with several risk-assessment tools and knowing when genetic testing is needed can make a big difference. Knowing the timing of mammograms and magnetic resonance imaging (MRI) for women deemed to be at high risk is also key. The following review employs a case-based approach (with an accompanying ALGORITHM) to illustrate how best to identify women who are at heightened risk of breast cancer and maximize their care. We also discuss the chemoprophylaxis regimens that may be used for those at increased risk.

CASE

Rachel P, age 37, presents to establish care. She has an Ashkenazi Jewish background and wonders if she should start doing breast cancer screening before age 40. She has 2 children, ages 4 years and 2 years. Her maternal aunt had unilateral breast cancer at age 54, and her maternal grandmother died of ovarian cancer at age 65.

Risk assessment

The risk assessment process (see ALGORITHM) must start with either the clinician or the patient initiating the discussion about breast cancer risk. The clinician may initiate the discussion with a new patient or at an annual physical examination. The patient may start the discussion because they are experiencing new breast symptoms, have anxiety about developing breast cancer, or have a family member with a new cancer diagnosis.

Risk factors. There are single factors that convey enough risk to automatically designate the patient as high risk (see TABLE 1^4-9). These factors include having a history of chest radiation between the ages of 10 and 30, a history of breast biopsy with either lobular carcinoma in situ (LCIS) or atypical ductal hyperplasia (ADH), past breast and/or ovarian cancer, and either a family or personal history of a high penetrant genetic variant for breast cancer.^4-9

In women with previous chest radiation, breast cancer risk correlates with the total dose of radiation.⁵ For women with a personal history of breast cancer, the younger the age at diagnosis, the higher the risk of contralateral breast cancer.⁵ Precancerous changes such as ADH, LCIS, and ductal carcinoma in situ (DCIS) also confer moderate increases in risk. Women with these diagnoses will commonly have follow-up with specialists.

Risk assessment tools. There are several models available to assess a woman’s breast cancer risk (see TABLE 2^10-12). The Gail model (https://bcrisktool.cancer.gov/) is the oldest, quickest, and most widely known. However, the Gail model only accounts for first-degree relatives diagnosed with breast cancer, may underpredict risk in women with a more extensive family history, and has not been studied in women younger than 35. The International Breast Cancer Intervention Study (IBIS) Risk Evaluation Tool (https://ibis-risk-calculator.magview.com/), commonly referred to as the Tyrer-Cuzick model, incorporates second-degree relatives into the prediction model—although women may not know their full family history. Both the IBIS and the Breast Cancer Surveillance Consortium (BCSC) model (https://tools.bcsc-scc.org/BC5yearRisk/intro.htm) include breast density in the prediction algorithm. The choice of tool depends on clinician comfort and individual patient risk factors. There is no evidence that one model is better than another.^10-12

Continue to: CASE

CASE

Ms. P’s clinician starts with an assessment using the Gail model. However, when the result comes back with average risk, the clinician decides to follow up with the Tyrer-Cuzick model in order to incorporate Ms. P’s multiple ­second-degree relatives with breast and ovarian cancer. (The BCSC model was not used because it only includes first-degree relatives.)

Genetic testing

The National Comprehensive Cancer Network (NCCN) guidelines recommend genetic testing if a woman has a first- or ­second-degree relative with pancreatic cancer, metastatic prostate cancer, male breast cancer, breast cancer at age 45 or younger, 2 or more breast cancers in a single person, 2 or more people on the same side of the family with at least 1 diagnosed at age 50 or younger, or any relative with ovarian cancer (see TABLE 3).⁷ Before ordering genetic testing, it is useful to refer the patient to a genetic counselor for a thorough discussion of options.

Results of genetic testing may include high-risk variants, moderate-risk variants, and variants of unknown significance (VUS), or be negative for any variants. High-risk variants for breast cancer include BRCA1, BRCA2, PALB2, and cancer syndrome variants such as TP53, PTEN, STK11, and CDH1.^5,6,9,13-15 These high-risk variants confer sufficient risk that women with these mutations are automatically categorized in the high-risk group. It is estimated that high-risk variants account for only 25% of the genetic risk for breast cancer.¹⁶

BRCA1/2 and PTEN mutations confer greater than 80% lifetime risk, while other high-risk variants such as TP53, CDH1, and STK11 confer risks between 25% and 40%. These variants are also associated with cancers of other organs, depending on the mutation.¹⁷

Moderate-risk variants—ATM and CHEK2—do not confer sufficient risk to elevate women into the high-risk group. However, they do qualify these intermediate-risk women to participate in a specialized management strategy.^5,9,13,18

VUS are those for which the associated risk is unclear, but more research may be done to categorize the risk.⁹ The clinical management of women with VUS usually entails close monitoring.

In an effort to better characterize breast cancer risk using a combination of pathogenic variants found in broad multi-gene cancer predisposition panels, researchers have developed a method to combine risks in a “polygenic risk score” (PRS) that can be used to counsel women (see “What is a polygenic risk score for breast cancer?” on page 203).^19-21PRS predicts an additional 18% of genetic risk in women of European descent.²¹

Continue to: CASE

CASE

Using the assessment results, the clinician talks to Ms. P about her lifetime risk for breast cancer. The Gail model indicates her lifetime risk is 13.3%, just slightly higher than the average (12.5%), and her 5-year risk is 0.5% (average, 0.4%). The IBIS or Tyrer-­Cuzick model, which takes into account her second-degree relatives with breast and ovarian cancer and her Ashkenazi ethnicity (which confers increased risk due to elevated risk of BRCA mutations), predicts her lifetime risk of breast cancer to be 20.4%. This categorizes Ms. P as high risk.

Enhanced screening recommendations for women at high risk

TABLE 4^8,13,22 summarizes screening recommendations for women deemed to be at high risk for breast cancer. The American Cancer Society (ACS), NCCN, and the American College of Radiology (ACR) recommend that women with at least a 20% lifetime risk have yearly magnetic resonance imaging (MRI) and mammography (staggered so that the patient has 1 test every 6 months) starting 10 years before the age of onset for the youngest affected relative but not before age 30.⁸ For carriers of high-risk (as well as intermediate-risk) genes, NCCN recommends annual MRI screening starting at age 40.¹³BRCA1/2 screening includes annual MRI starting at age 25 and annual mammography every 6 months starting at age 30.²² Clinicians should counsel women with moderate risk factors (elevated breast density; personal history of ADH, LCIS, or DCIS) about the potential risks and benefits of enhanced screening and chemoprophylaxis.

Risk-reduction strategies

Chemoprophylaxis

The US Preventive Services Task Force (USPSTF) recommends that all women at increased risk for breast cancer consider chemoprophylaxis (B recommendation)²³ based on convincing evidence that 5 years of treatment with either a synthetic estrogen reuptake modulator (SERM) or an aromatase inhibitor (AI) decreases the incidence of estrogen receptor positive breast cancers. (See TABLE 5^7,23,24 for absolute risk reduction.) There is no benefit for chemoprophylaxis in women at average risk (D recommendation).²³ It is unclear whether chemoprophylaxis is indicated in women with moderate increased risk (ie, who do not meet the 20% lifetime risk criteria). Chemoprophylaxis may not be effective in women with BRCA1 mutations, as they often develop triple-negative breast cancers.

Accurate risk assessment and shared decision-making enable the clinician and patient to discuss the potential risks and benefits of chemoprophylaxis.^7,24 The USPSTF did not find that any 1 risk prediction tool was better than another to identify women who should be counseled about chemoprophylaxis. Clinicians should counsel all women taking AIs about optimizing bone health with adequate calcium and vitamin D intake and routine bone density tests.

Surgical risk reduction

The NCCN guidelines state that risk-reducing bilateral mastectomy is reserved for individuals with high-risk gene variants and individuals with prior chest radiation between ages 10 and 30.²⁵ NCCN also recommends discussing risk-reducing mastectomy with all women with BRCA mutations.²²

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer.

Bilateral mastectomy is the most effective method to reduce breast cancer risk and should be discussed after age 25 in women with BRCA mutations and at least 8 years after chest radiation is completed.²⁶ There is a reduction in breast cancer incidence of 90%.²⁵ Breast imaging for screening (mammography or MRI) is not indicated after risk-reducing mastectomy. However, clinical breast examinations of the surgical site are important, because there is a small risk of developing breast cancer in that area.²⁶

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer. It can also reduce the risk of breast cancer in women with BRCA mutations.²⁷

Continue to: CASE

CASE

Based on her risk assessment results, family history, and genetic heritage, Ms. P qualifies for referral to a genetic counselor for discussion of BRCA testing. The clinician discusses adding annual MRI to Ms. P’s breast cancer screening regimen, based on ACS, NCCN, and ACR recommendations, due to her 20.4% lifetime risk. Discussion of whether and when to start chemoprophylaxis is typically based on breast cancer risk, projected benefit, and the potential impact of medication adverse effects. A high-risk woman is eligible for 5 years of chemoprophylaxis (tamoxifen if premenopausal) based on her lifetime risk. The clinician discusses timing with Ms. P, and even though she is finished with childbearing, she would like to wait until she is age 45, which is before the age at which her aunt was given a diagnosis of breast cancer.

Conclusion

Primary care clinicians are well positioned to identify women with an elevated risk of breast cancer and refer them for enhanced screening and chemoprophylaxis (see ALGORITHM). Shared decision-making with the inclusion of patient decision aids (https://decisionaid.ohri.ca/AZsearch.php?criteria=breast+cancer) about genetic testing, chemoprophylaxis, and prophylactic mastectomy or oophorectomy may help women at intermediate or high risk of breast cancer feel empowered to make decisions about their breast—and overall—health.

CORRESPONDENCE
Sarina Schrager, MD, MS, Professor, Department of Family Medicine and Community Health, University of Wisconsin, 1100 Delaplaine Court, Madison, WI 53715; [email protected]

Breast cancer is the most common invasive cancer in women in the United States; it is estimated that there will be 287,850 new cases of breast cancer in the United States during 2022 with 43,250 deaths.¹ Lives are extended and saved every day because of a robust arsenal of treatments and interventions available to those who have been given a diagnosis of breast cancer. And, of course, lives are also extended and saved when we identify women at risk and provide early interventions. But in busy offices where time is short and there are competing demands on our time, proper assessment of a woman’s risk of breast cancer does not always happen. As a result, women with a higher risk of breast cancer may not be getting appropriate management.^2,3

Familiarizing yourself with several risk-assessment tools and knowing when genetic testing is needed can make a big difference. Knowing the timing of mammograms and magnetic resonance imaging (MRI) for women deemed to be at high risk is also key. The following review employs a case-based approach (with an accompanying ALGORITHM) to illustrate how best to identify women who are at heightened risk of breast cancer and maximize their care. We also discuss the chemoprophylaxis regimens that may be used for those at increased risk.

CASE

Rachel P, age 37, presents to establish care. She has an Ashkenazi Jewish background and wonders if she should start doing breast cancer screening before age 40. She has 2 children, ages 4 years and 2 years. Her maternal aunt had unilateral breast cancer at age 54, and her maternal grandmother died of ovarian cancer at age 65.

Risk assessment

The risk assessment process (see ALGORITHM) must start with either the clinician or the patient initiating the discussion about breast cancer risk. The clinician may initiate the discussion with a new patient or at an annual physical examination. The patient may start the discussion because they are experiencing new breast symptoms, have anxiety about developing breast cancer, or have a family member with a new cancer diagnosis.

Risk factors. There are single factors that convey enough risk to automatically designate the patient as high risk (see TABLE 1^4-9). These factors include having a history of chest radiation between the ages of 10 and 30, a history of breast biopsy with either lobular carcinoma in situ (LCIS) or atypical ductal hyperplasia (ADH), past breast and/or ovarian cancer, and either a family or personal history of a high penetrant genetic variant for breast cancer.^4-9

In women with previous chest radiation, breast cancer risk correlates with the total dose of radiation.⁵ For women with a personal history of breast cancer, the younger the age at diagnosis, the higher the risk of contralateral breast cancer.⁵ Precancerous changes such as ADH, LCIS, and ductal carcinoma in situ (DCIS) also confer moderate increases in risk. Women with these diagnoses will commonly have follow-up with specialists.

Risk assessment tools. There are several models available to assess a woman’s breast cancer risk (see TABLE 2^10-12). The Gail model (https://bcrisktool.cancer.gov/) is the oldest, quickest, and most widely known. However, the Gail model only accounts for first-degree relatives diagnosed with breast cancer, may underpredict risk in women with a more extensive family history, and has not been studied in women younger than 35. The International Breast Cancer Intervention Study (IBIS) Risk Evaluation Tool (https://ibis-risk-calculator.magview.com/), commonly referred to as the Tyrer-Cuzick model, incorporates second-degree relatives into the prediction model—although women may not know their full family history. Both the IBIS and the Breast Cancer Surveillance Consortium (BCSC) model (https://tools.bcsc-scc.org/BC5yearRisk/intro.htm) include breast density in the prediction algorithm. The choice of tool depends on clinician comfort and individual patient risk factors. There is no evidence that one model is better than another.^10-12

Continue to: CASE

CASE

Ms. P’s clinician starts with an assessment using the Gail model. However, when the result comes back with average risk, the clinician decides to follow up with the Tyrer-Cuzick model in order to incorporate Ms. P’s multiple ­second-degree relatives with breast and ovarian cancer. (The BCSC model was not used because it only includes first-degree relatives.)

Genetic testing

The National Comprehensive Cancer Network (NCCN) guidelines recommend genetic testing if a woman has a first- or ­second-degree relative with pancreatic cancer, metastatic prostate cancer, male breast cancer, breast cancer at age 45 or younger, 2 or more breast cancers in a single person, 2 or more people on the same side of the family with at least 1 diagnosed at age 50 or younger, or any relative with ovarian cancer (see TABLE 3).⁷ Before ordering genetic testing, it is useful to refer the patient to a genetic counselor for a thorough discussion of options.

Results of genetic testing may include high-risk variants, moderate-risk variants, and variants of unknown significance (VUS), or be negative for any variants. High-risk variants for breast cancer include BRCA1, BRCA2, PALB2, and cancer syndrome variants such as TP53, PTEN, STK11, and CDH1.^5,6,9,13-15 These high-risk variants confer sufficient risk that women with these mutations are automatically categorized in the high-risk group. It is estimated that high-risk variants account for only 25% of the genetic risk for breast cancer.¹⁶

BRCA1/2 and PTEN mutations confer greater than 80% lifetime risk, while other high-risk variants such as TP53, CDH1, and STK11 confer risks between 25% and 40%. These variants are also associated with cancers of other organs, depending on the mutation.¹⁷

Moderate-risk variants—ATM and CHEK2—do not confer sufficient risk to elevate women into the high-risk group. However, they do qualify these intermediate-risk women to participate in a specialized management strategy.^5,9,13,18

VUS are those for which the associated risk is unclear, but more research may be done to categorize the risk.⁹ The clinical management of women with VUS usually entails close monitoring.

In an effort to better characterize breast cancer risk using a combination of pathogenic variants found in broad multi-gene cancer predisposition panels, researchers have developed a method to combine risks in a “polygenic risk score” (PRS) that can be used to counsel women (see “What is a polygenic risk score for breast cancer?” on page 203).^19-21PRS predicts an additional 18% of genetic risk in women of European descent.²¹

Continue to: CASE

CASE

Using the assessment results, the clinician talks to Ms. P about her lifetime risk for breast cancer. The Gail model indicates her lifetime risk is 13.3%, just slightly higher than the average (12.5%), and her 5-year risk is 0.5% (average, 0.4%). The IBIS or Tyrer-­Cuzick model, which takes into account her second-degree relatives with breast and ovarian cancer and her Ashkenazi ethnicity (which confers increased risk due to elevated risk of BRCA mutations), predicts her lifetime risk of breast cancer to be 20.4%. This categorizes Ms. P as high risk.

Enhanced screening recommendations for women at high risk

TABLE 4^8,13,22 summarizes screening recommendations for women deemed to be at high risk for breast cancer. The American Cancer Society (ACS), NCCN, and the American College of Radiology (ACR) recommend that women with at least a 20% lifetime risk have yearly magnetic resonance imaging (MRI) and mammography (staggered so that the patient has 1 test every 6 months) starting 10 years before the age of onset for the youngest affected relative but not before age 30.⁸ For carriers of high-risk (as well as intermediate-risk) genes, NCCN recommends annual MRI screening starting at age 40.¹³BRCA1/2 screening includes annual MRI starting at age 25 and annual mammography every 6 months starting at age 30.²² Clinicians should counsel women with moderate risk factors (elevated breast density; personal history of ADH, LCIS, or DCIS) about the potential risks and benefits of enhanced screening and chemoprophylaxis.

Risk-reduction strategies

Chemoprophylaxis

The US Preventive Services Task Force (USPSTF) recommends that all women at increased risk for breast cancer consider chemoprophylaxis (B recommendation)²³ based on convincing evidence that 5 years of treatment with either a synthetic estrogen reuptake modulator (SERM) or an aromatase inhibitor (AI) decreases the incidence of estrogen receptor positive breast cancers. (See TABLE 5^7,23,24 for absolute risk reduction.) There is no benefit for chemoprophylaxis in women at average risk (D recommendation).²³ It is unclear whether chemoprophylaxis is indicated in women with moderate increased risk (ie, who do not meet the 20% lifetime risk criteria). Chemoprophylaxis may not be effective in women with BRCA1 mutations, as they often develop triple-negative breast cancers.

Accurate risk assessment and shared decision-making enable the clinician and patient to discuss the potential risks and benefits of chemoprophylaxis.^7,24 The USPSTF did not find that any 1 risk prediction tool was better than another to identify women who should be counseled about chemoprophylaxis. Clinicians should counsel all women taking AIs about optimizing bone health with adequate calcium and vitamin D intake and routine bone density tests.

Surgical risk reduction

The NCCN guidelines state that risk-reducing bilateral mastectomy is reserved for individuals with high-risk gene variants and individuals with prior chest radiation between ages 10 and 30.²⁵ NCCN also recommends discussing risk-reducing mastectomy with all women with BRCA mutations.²²

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer.

Bilateral mastectomy is the most effective method to reduce breast cancer risk and should be discussed after age 25 in women with BRCA mutations and at least 8 years after chest radiation is completed.²⁶ There is a reduction in breast cancer incidence of 90%.²⁵ Breast imaging for screening (mammography or MRI) is not indicated after risk-reducing mastectomy. However, clinical breast examinations of the surgical site are important, because there is a small risk of developing breast cancer in that area.²⁶

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer. It can also reduce the risk of breast cancer in women with BRCA mutations.²⁷

Continue to: CASE

CASE

Based on her risk assessment results, family history, and genetic heritage, Ms. P qualifies for referral to a genetic counselor for discussion of BRCA testing. The clinician discusses adding annual MRI to Ms. P’s breast cancer screening regimen, based on ACS, NCCN, and ACR recommendations, due to her 20.4% lifetime risk. Discussion of whether and when to start chemoprophylaxis is typically based on breast cancer risk, projected benefit, and the potential impact of medication adverse effects. A high-risk woman is eligible for 5 years of chemoprophylaxis (tamoxifen if premenopausal) based on her lifetime risk. The clinician discusses timing with Ms. P, and even though she is finished with childbearing, she would like to wait until she is age 45, which is before the age at which her aunt was given a diagnosis of breast cancer.

Conclusion

Primary care clinicians are well positioned to identify women with an elevated risk of breast cancer and refer them for enhanced screening and chemoprophylaxis (see ALGORITHM). Shared decision-making with the inclusion of patient decision aids (https://decisionaid.ohri.ca/AZsearch.php?criteria=breast+cancer) about genetic testing, chemoprophylaxis, and prophylactic mastectomy or oophorectomy may help women at intermediate or high risk of breast cancer feel empowered to make decisions about their breast—and overall—health.

CORRESPONDENCE
Sarina Schrager, MD, MS, Professor, Department of Family Medicine and Community Health, University of Wisconsin, 1100 Delaplaine Court, Madison, WI 53715; [email protected]