Versha Pleasant, MD, MPH

Breast cancer represents the most commonly diagnosed cancer in the nation.¹ However, unlike other cancers, most breast cancers are identified at stage I and have a 90% survival rate 5-year prognosis.² These outcomes are attributable to various factors, one of the most significant being screening mammography—a largely accessible, highly sensitive and specific screening tool.³ Data demonstrate that malignant tumors detected on screening mammography have more favorable profiles in tumor size and nodal status compared with symptomatic breast cancers,⁴ which make it critical for early diagnosis. Most importantly, the research overwhelmingly demonstrates that screening mammography decreases breast cancer–related mortality.^5-7

The USPSTF big change: Mammography starting at age 40 for all recommended

Despite the general accessibility and mortality benefits of screening mammography (in light of the high lifetime 12% prevalence of breast cancer in the United States⁸), recommendations still conflict across medical societies regarding optimal timing and frequency.^9-12 Previously, the US Preventive Services Task Force (USPSTF) recommended that screening mammography should occur at age 50 biennially and that screening between ages 40 and 49 should be an individualized decision.^13,14 In the draft recommendation statement issued on May 9, 2023, however, the USPSTF now recommends screening every other year starting at age 40 to decrease the risk of dying from breast cancer.¹⁵

This change represents a critically important shift. The new guidance:

• acknowledges the increasing incidence of early-onset breast cancer
• reinforces a national consciousness toward screening mammography in decreasing mortality,17 even among a younger age group for whom the perception of risk may be lower.

The USPSTF statement represents a significant change in how patients should be counseled. Practitioners now have more direct guidance that is concordant with what other national medical organizations offer or recommend, including the American College of Obstetricians and Gynecologists (ACOG), the American College of Radiology (ACR), and the National Comprehensive Cancer Network (NCCN).

However, while the USPSTF statement can and should encourage health care practitioners to initiate mammography earlier than prior recommendations, ongoing discussion regarding the optimal screening interval is warranted. The USPSTF recommendations state that mammography should be performed biennially. While the age at initiation represents a step in the right direction, this recommended screening interval should be reevaluated.

Annual vs biennial screening?

The debate between annual and biennial screening mammography is not new. While many randomized trials on screening mammography have evaluated such factors as breast cancer mortality by age or rate of false positives,¹⁸ fewer trials have evaluated the optimal screening interval.

One randomized trial from the United Kingdom evaluated 99,389 people aged 50 to 62 from 1989 to 1996 who underwent annual screening (study arm) versus 3 years later (control).¹⁹ Findings demonstrated a significantly smaller tumor size in the study arm (P=.05) as well as an increased total cancer detection rate. However, the authors concluded that shortening the screening interval (from 3 years) would not yield a statistically significant decrease in mortality.¹⁹

In a randomized trial from Finland, researchers screened those aged older than 50 at biennial intervals and those aged younger than 50 at either annual or triennial intervals.²⁰ Results demonstrated that, among those aged 40 to 49, the frequency of stage I cancers was not significantly different from screen-detected cancers, interval cancers, or cancers detected outside of screening (50%, 42%, and 44%, respectively; P=.73). Furthermore, there was a greater likelihood of interval cancers among those aged 40 to 49 at 1-year (27%) and 3-year (39%) screening intervals compared with those aged older than 50 screened biennially (18%; P=.08 and P=.0009, respectively).²⁰

These randomized trials, however, have been scrutinized because of factors such as discrepancies in screening intervals by country as well as substantial improvements made in screening mammography since the time these trials were conducted.⁵ Due to the dearth of more contemporary randomized controlled trials accounting for more up-to-date training and technology, most of the more recent data has been largely observational, retrospective, or used modeling.²¹ The TABLE outlines some of the major studies on this topic.

obgm03512043_pleasant_table.jpg

False-positive results, biopsy rates. The arguments against more frequent screening include the possibility of false positives that require callbacks and biopsies, which may be more frequent among those who undergo annual mammography.²² A systematic review from the Breast Cancer Surveillance Consortium demonstrated a 61.3% annual (confidence interval [CI], 59.4%–63.1%) versus 41.6% biennial (CI, 40.6%–42.5%) false-positive rate, resulting in a 7% (CI, 6.1%–7.8%) versus 4.8% (CI, 4.4–5.2%) rate of biopsy, respectively.²³ This false-positive rate, however, also may be increased in younger patients aged 40 to 49 and in those with dense breasts.^22,24 These callbacks and biopsies could induce significant patient stress, pain, and anxiety, as well as carry financial implications related to subsequent diagnostic imaging.

Overdiagnosis. There is also the risk of overdiagnosis, in which an indolent breast cancer that otherwise would not grow or progress to become symptomatic is identified. This could lead to overtreatment. While the exact incidence of overdiagnosis is unclear (due to recommendations for universal treatment of ductal carcinoma in situ), some data suggest that overdiagnosis could be decreased with biennial screening.²⁵

While discomfort could also be a barrier, it may not necessarily be prohibitive for some to continue with future screening mammograms.²² Further, increased radiation with annual mammography is a concern. However, modeling studies have shown that the mortality benefit for annual mammography starting at age 40 outweighs (by 60-fold) the mortality risk from a radiation-induced breast cancer.²⁶

Benefit from biennial screening

Some research suggests overall benefit from biennial screening. One study that used Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer microsimulation was adapted to measure the incidence, mortality, and life-years gained for Canadian patients.²⁷ This model demonstrated that mortality reduction was linked to greater lifetime screens for breast cancer, but this applied primarily to patients aged 50 and older. Overall, a larger impact was observed by initiating screening at age 40 than by decreasing screening intervals.²⁷

Using modeling, Mandelblatt and colleagues demonstrated that biennial screening could capture most of the benefit of annual screening with less harm.²⁸ In another study in 2016, Mandelblatt and colleagues used updated and revised versions of these simulation models and maintained that biennial screening upheld 79.8% to 81.3% of the benefits of annual screening mammography but with fewer overdiagnoses and false-positive results.²⁵ The authors concluded that while biennial screening is equally effective for average-risk populations, there should be an evaluation of benefits and harms based on the clinical scenario (suggesting that annual screening for those at age 40 who carried elevated risk was similar to biennial screening for average-risk patients starting at age 50).²⁵

Another study that served to inform the European Commission Initiative on Breast Cancer recommendations evaluated randomized controlled trials and observational and modeling studies that assessed breast screening intervals.²⁹ The authors concluded that each screening interval has risks and benefits, with data suggesting more benefit with biennial screening for people aged 50 to 69 years and more possible harm with annual screening in younger people (aged 45–49).²⁹

Continue to: Benefit from annual screening...

However, these data conflict with other studies that demonstrate the benefit of annual compared with biennial screening mammography. One large retrospective review of prospectively collected data evaluated outcome differences based on mammography frequency.³⁰ For those undergoing annual versus biennial screening, the median tumor size was 11 mm (versus 15 mm), the percentage of lymph node metastasis was 14% (versus 24%), and cancer stage II or higher was 17% (versus 29%). The study overall demonstrated that annual screening resulted in lower recall rates (P<.0001) and detection of smaller tumors that carried a more favorable prognosis (P<.04).³⁰

Another observational study from 2004 that assessed data from 7 different mammography registries nationwide noted that, among those aged 40 to 49, patients who underwent biennial screening had an increased likelihood of late-stage disease compared with those with annual screening (28% vs 21%, respectively; odds ratio [OR], 1.35; 95% CI, 1.01–1.81), although this discrepancy was not observed in people aged 50 or older.³¹

A study that critiqued the previous 2012 version of the USPSTF guidelines used CISNET modeling, which demonstrated a 39.6% mortality reduction with annual screening for those aged 40 to 84 versus 23.2% for biennial screening for those aged 50 to 74.⁵

More recent data also reflect these findings. A retrospective cohort study that evaluated patients aged 40 to 84 diagnosed with breast cancer found that those who previously underwent annual versus biennial screening mammography had lower incidences of late-stage diagnoses (24.0% vs 43.8%, respectively; P=.02), fewer interval cancers (10.5% vs 37.5%; P<.001), and smaller mean (SD) tumor diameter (1.4 [1.2] cm vs 1.8 [1.6] cm; P=.04).²¹ Postmenopausal patients in this cohort also demonstrated similar findings when comparing mammogram frequency. Although not significant, biennial (or greater) frequency of screening mammography also resulted in an increased likelihood of axillary lymph node dissection and chemotherapy.

Similarly, authors of another large prospective cohort study concluded that breast cancers diagnosed in premenopausal patients were more likely to be larger with less favorable prognostic characteristics (tumor size >15 mm, relative risk [RR], 1.21 [95% CI, 1.07–1.37]; P=.002); any less favorable prognostic characteristics (RR, 1.11 [95% CI, 1.00–1.22]; P=.047), and higher stage (stage IIB or higher, RR, 1.28 [95% CI, 1.01–1.63]; P=.04) for those who underwent biennial screening compared with breast cancers diagnosed by annual screening.³² However, this trend was not observed in postmenopausal patients not taking hormone therapy.³²

Some international studies also show more favorable outcomes with annual screening mammography. A Swedish study evaluated mammography screening intervals of 21 months compared with 18 or 12 months in patients aged 40 to 49.³³ Data showed an improved effectiveness of 1.6% to 9.8% for interval cancers and 2.9% to 17.4% for both interval and screening-detected cancers by reducing the screening frequency to 12 months, with authors suggesting a further reduction in breast cancer–related mortality rates for this age group.³³

Results from another descriptive study from Europe also showed increasing interval breast cancer rates with increasing screening intervals.³⁴ After a negative screen, the interval cancer rates and regional ranges for 0 to less than 12 months, 12 to less than 24 months, and 24 to less than 36 months per 1,000 screened were 0.55 (0.43–0.76), 1.13 (0.92–1.47), and 1.22 (0.93–1.57), respectively.³⁴

Finally, a study conducted in Canada evaluated interval breast cancers among people with dense breasts screened between 2008 and 2010.³⁵ Those with screening programs with policies that offered annual screening reported fewer interval cancers (interval cancer rate, 0.89 per 1,000; 95% CI, 0.67–1.11) compared with those who had policies that used biennial screening (interval cancer rate, 1.45 per 1,000 [annualized]; 95% CI, 1.19–1.72), which was 63% higher (P=.002). For those for whom radiologists recommended screening, interval cancer was lower for annual (0.93 per 1,000; 95% CI, 0.71–1.16) versus biennial screening (1.70 per 1,000 [annualized]; 95% CI, 0.70–2.71) (P=.061).³⁵

Continue to: Black patients have a worse breast cancer prognosis...

Black patients have a worse breast cancer prognosis

Additional consideration should be given to populations with worse survival outcomes at baseline for whom screening mammography could play a significant role. In particular, Black people have similar rates of breast cancer compared with White people (127.8 cases per 100,000 vs 133.7 cases per 100,000, respectively) but have a 40% increased breast cancer–related mortality.⁸ The USPSTF recognizes this disparity and mentions it in their recommendations, encouraging health care clinicians to engage in shared decision making with Black patients and asserting that more research is needed on screening mammography in Black communities.¹⁵

While the age modification to the new guidelines better addresses the disparities that impact the Black community (such as increased likelihood of early-onset breast cancer³⁶ and increased rate of breast cancer diagnosis at first mammogram³⁷), the next obvious question is: Can groups with higher breast cancer mortality such as Black communities afford to undergo mammography every 2 years (as opposed to every year)?

Although some data specifically have evaluated the age of initiation and frequency of screening mammography among Black patients,^38,39 little data have specifically assessed outcomes for annual versus biennial screening among Black people. Despite these research gaps, risk factors among the Black community should be considered. There is an increased risk of triple-negative breast cancer that can contribute to higher mortality among Black communities.⁴⁰ Black people also tend to be diagnosed with more aggressive subtypes overall,^41,42 are more likely to have dense breasts,^43,44 have a higher likelihood of advanced stages at the time of diagnosis compared with White people,^8,45 and have a greater chance of diagnosis of a second primary or contralateral breast cancer^46-48—all risk factors that support the importance of regular and early-screening mammography.

How I counsel my patients

As Director of the Cancer Genetics and Breast Health Clinic, I am a gynecologist who primarily evaluates patients at increased risk for breast cancer (and other cancers). As an initial step, I strongly encourage all patients (especially Black patients and those of Ashkenazi Jewish ancestry as per the American College of Radiology recommendations⁹) to undergo risk assessment at age 25 to determine if they may be at increased risk for breast cancer. This first step may include genetic testing if the patient meets NCCN testing criteria based on personal or family history. If results are positive for a germline pathogenic variant, the timing and nature of breast screening would be based on NCCN recommendations for that particular variant (with possible modification of age of initiation based on family history). If testing is negative, lifetime risk assessment would then be performed using risk calculators—such as Tyrer-Cuzick—to determine if the patient meets criteria for intensive surveillance with supplemental breast magnetic resonance imaging. If the patient is subsequently determined to be at average risk after these assessments, I recommend they undergo screening mammography annually starting at age 40. However, it must be recognized that risk may change over time. A patient’s risk can continue to be assessed over a lifetime—with changing family history, personal risk factors, and new discoveries in genetics.

Summary

Ultimately, it is reassuring that the USPSTF guidelines have been updated to be concordant with other national medical society recommendations. They reflect the increasing nationwide trends that clearly demonstrate the high overall prevalence of breast cancer as well as the increasing incidence of early-onset breast cancer.

The updated guidelines, however, do not reflect the entirety of breast cancer trends in this country. With breast cancer being the most commonly diagnosed cancer in the United States, it is imperative to consider the data that demonstrate improved prognostics with annual compared with biennial mammography. Furthermore, the guidelines only begin to explore the disparities that Black patients face regarding breast cancer–related mortality. The risks of younger age at diagnosis, greater likelihood of aggressive subtypes, increased risk of second primary and contralateral breast cancer, and later stage at diagnosis must be seriously evaluated when counseling this patient population.

While the USPSTF recommendations for age at initiation reflect national statistics, recommendations by the ACR and NCCN more appropriately recognize that the benefits of annual screening outweigh the potential risks. Annual screening frequency should be adopted when counseling patients, particularly for the Black community. ●

Breast cancer represents the most commonly diagnosed cancer in the nation.¹ However, unlike other cancers, most breast cancers are identified at stage I and have a 90% survival rate 5-year prognosis.² These outcomes are attributable to various factors, one of the most significant being screening mammography—a largely accessible, highly sensitive and specific screening tool.³ Data demonstrate that malignant tumors detected on screening mammography have more favorable profiles in tumor size and nodal status compared with symptomatic breast cancers,⁴ which make it critical for early diagnosis. Most importantly, the research overwhelmingly demonstrates that screening mammography decreases breast cancer–related mortality.^5-7

The USPSTF big change: Mammography starting at age 40 for all recommended

Despite the general accessibility and mortality benefits of screening mammography (in light of the high lifetime 12% prevalence of breast cancer in the United States⁸), recommendations still conflict across medical societies regarding optimal timing and frequency.^9-12 Previously, the US Preventive Services Task Force (USPSTF) recommended that screening mammography should occur at age 50 biennially and that screening between ages 40 and 49 should be an individualized decision.^13,14 In the draft recommendation statement issued on May 9, 2023, however, the USPSTF now recommends screening every other year starting at age 40 to decrease the risk of dying from breast cancer.¹⁵

This change represents a critically important shift. The new guidance:

• acknowledges the increasing incidence of early-onset breast cancer
• reinforces a national consciousness toward screening mammography in decreasing mortality,17 even among a younger age group for whom the perception of risk may be lower.

The USPSTF statement represents a significant change in how patients should be counseled. Practitioners now have more direct guidance that is concordant with what other national medical organizations offer or recommend, including the American College of Obstetricians and Gynecologists (ACOG), the American College of Radiology (ACR), and the National Comprehensive Cancer Network (NCCN).

However, while the USPSTF statement can and should encourage health care practitioners to initiate mammography earlier than prior recommendations, ongoing discussion regarding the optimal screening interval is warranted. The USPSTF recommendations state that mammography should be performed biennially. While the age at initiation represents a step in the right direction, this recommended screening interval should be reevaluated.

Annual vs biennial screening?

The debate between annual and biennial screening mammography is not new. While many randomized trials on screening mammography have evaluated such factors as breast cancer mortality by age or rate of false positives,¹⁸ fewer trials have evaluated the optimal screening interval.

One randomized trial from the United Kingdom evaluated 99,389 people aged 50 to 62 from 1989 to 1996 who underwent annual screening (study arm) versus 3 years later (control).¹⁹ Findings demonstrated a significantly smaller tumor size in the study arm (P=.05) as well as an increased total cancer detection rate. However, the authors concluded that shortening the screening interval (from 3 years) would not yield a statistically significant decrease in mortality.¹⁹

In a randomized trial from Finland, researchers screened those aged older than 50 at biennial intervals and those aged younger than 50 at either annual or triennial intervals.²⁰ Results demonstrated that, among those aged 40 to 49, the frequency of stage I cancers was not significantly different from screen-detected cancers, interval cancers, or cancers detected outside of screening (50%, 42%, and 44%, respectively; P=.73). Furthermore, there was a greater likelihood of interval cancers among those aged 40 to 49 at 1-year (27%) and 3-year (39%) screening intervals compared with those aged older than 50 screened biennially (18%; P=.08 and P=.0009, respectively).²⁰

These randomized trials, however, have been scrutinized because of factors such as discrepancies in screening intervals by country as well as substantial improvements made in screening mammography since the time these trials were conducted.⁵ Due to the dearth of more contemporary randomized controlled trials accounting for more up-to-date training and technology, most of the more recent data has been largely observational, retrospective, or used modeling.²¹ The TABLE outlines some of the major studies on this topic.

obgm03512043_pleasant_table.jpg

False-positive results, biopsy rates. The arguments against more frequent screening include the possibility of false positives that require callbacks and biopsies, which may be more frequent among those who undergo annual mammography.²² A systematic review from the Breast Cancer Surveillance Consortium demonstrated a 61.3% annual (confidence interval [CI], 59.4%–63.1%) versus 41.6% biennial (CI, 40.6%–42.5%) false-positive rate, resulting in a 7% (CI, 6.1%–7.8%) versus 4.8% (CI, 4.4–5.2%) rate of biopsy, respectively.²³ This false-positive rate, however, also may be increased in younger patients aged 40 to 49 and in those with dense breasts.^22,24 These callbacks and biopsies could induce significant patient stress, pain, and anxiety, as well as carry financial implications related to subsequent diagnostic imaging.

Overdiagnosis. There is also the risk of overdiagnosis, in which an indolent breast cancer that otherwise would not grow or progress to become symptomatic is identified. This could lead to overtreatment. While the exact incidence of overdiagnosis is unclear (due to recommendations for universal treatment of ductal carcinoma in situ), some data suggest that overdiagnosis could be decreased with biennial screening.²⁵

While discomfort could also be a barrier, it may not necessarily be prohibitive for some to continue with future screening mammograms.²² Further, increased radiation with annual mammography is a concern. However, modeling studies have shown that the mortality benefit for annual mammography starting at age 40 outweighs (by 60-fold) the mortality risk from a radiation-induced breast cancer.²⁶

Benefit from biennial screening

Some research suggests overall benefit from biennial screening. One study that used Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer microsimulation was adapted to measure the incidence, mortality, and life-years gained for Canadian patients.²⁷ This model demonstrated that mortality reduction was linked to greater lifetime screens for breast cancer, but this applied primarily to patients aged 50 and older. Overall, a larger impact was observed by initiating screening at age 40 than by decreasing screening intervals.²⁷

Using modeling, Mandelblatt and colleagues demonstrated that biennial screening could capture most of the benefit of annual screening with less harm.²⁸ In another study in 2016, Mandelblatt and colleagues used updated and revised versions of these simulation models and maintained that biennial screening upheld 79.8% to 81.3% of the benefits of annual screening mammography but with fewer overdiagnoses and false-positive results.²⁵ The authors concluded that while biennial screening is equally effective for average-risk populations, there should be an evaluation of benefits and harms based on the clinical scenario (suggesting that annual screening for those at age 40 who carried elevated risk was similar to biennial screening for average-risk patients starting at age 50).²⁵

Another study that served to inform the European Commission Initiative on Breast Cancer recommendations evaluated randomized controlled trials and observational and modeling studies that assessed breast screening intervals.²⁹ The authors concluded that each screening interval has risks and benefits, with data suggesting more benefit with biennial screening for people aged 50 to 69 years and more possible harm with annual screening in younger people (aged 45–49).²⁹

Continue to: Benefit from annual screening...

However, these data conflict with other studies that demonstrate the benefit of annual compared with biennial screening mammography. One large retrospective review of prospectively collected data evaluated outcome differences based on mammography frequency.³⁰ For those undergoing annual versus biennial screening, the median tumor size was 11 mm (versus 15 mm), the percentage of lymph node metastasis was 14% (versus 24%), and cancer stage II or higher was 17% (versus 29%). The study overall demonstrated that annual screening resulted in lower recall rates (P<.0001) and detection of smaller tumors that carried a more favorable prognosis (P<.04).³⁰

Another observational study from 2004 that assessed data from 7 different mammography registries nationwide noted that, among those aged 40 to 49, patients who underwent biennial screening had an increased likelihood of late-stage disease compared with those with annual screening (28% vs 21%, respectively; odds ratio [OR], 1.35; 95% CI, 1.01–1.81), although this discrepancy was not observed in people aged 50 or older.³¹

A study that critiqued the previous 2012 version of the USPSTF guidelines used CISNET modeling, which demonstrated a 39.6% mortality reduction with annual screening for those aged 40 to 84 versus 23.2% for biennial screening for those aged 50 to 74.⁵

More recent data also reflect these findings. A retrospective cohort study that evaluated patients aged 40 to 84 diagnosed with breast cancer found that those who previously underwent annual versus biennial screening mammography had lower incidences of late-stage diagnoses (24.0% vs 43.8%, respectively; P=.02), fewer interval cancers (10.5% vs 37.5%; P<.001), and smaller mean (SD) tumor diameter (1.4 [1.2] cm vs 1.8 [1.6] cm; P=.04).²¹ Postmenopausal patients in this cohort also demonstrated similar findings when comparing mammogram frequency. Although not significant, biennial (or greater) frequency of screening mammography also resulted in an increased likelihood of axillary lymph node dissection and chemotherapy.

Similarly, authors of another large prospective cohort study concluded that breast cancers diagnosed in premenopausal patients were more likely to be larger with less favorable prognostic characteristics (tumor size >15 mm, relative risk [RR], 1.21 [95% CI, 1.07–1.37]; P=.002); any less favorable prognostic characteristics (RR, 1.11 [95% CI, 1.00–1.22]; P=.047), and higher stage (stage IIB or higher, RR, 1.28 [95% CI, 1.01–1.63]; P=.04) for those who underwent biennial screening compared with breast cancers diagnosed by annual screening.³² However, this trend was not observed in postmenopausal patients not taking hormone therapy.³²

Some international studies also show more favorable outcomes with annual screening mammography. A Swedish study evaluated mammography screening intervals of 21 months compared with 18 or 12 months in patients aged 40 to 49.³³ Data showed an improved effectiveness of 1.6% to 9.8% for interval cancers and 2.9% to 17.4% for both interval and screening-detected cancers by reducing the screening frequency to 12 months, with authors suggesting a further reduction in breast cancer–related mortality rates for this age group.³³

Results from another descriptive study from Europe also showed increasing interval breast cancer rates with increasing screening intervals.³⁴ After a negative screen, the interval cancer rates and regional ranges for 0 to less than 12 months, 12 to less than 24 months, and 24 to less than 36 months per 1,000 screened were 0.55 (0.43–0.76), 1.13 (0.92–1.47), and 1.22 (0.93–1.57), respectively.³⁴

Finally, a study conducted in Canada evaluated interval breast cancers among people with dense breasts screened between 2008 and 2010.³⁵ Those with screening programs with policies that offered annual screening reported fewer interval cancers (interval cancer rate, 0.89 per 1,000; 95% CI, 0.67–1.11) compared with those who had policies that used biennial screening (interval cancer rate, 1.45 per 1,000 [annualized]; 95% CI, 1.19–1.72), which was 63% higher (P=.002). For those for whom radiologists recommended screening, interval cancer was lower for annual (0.93 per 1,000; 95% CI, 0.71–1.16) versus biennial screening (1.70 per 1,000 [annualized]; 95% CI, 0.70–2.71) (P=.061).³⁵

Continue to: Black patients have a worse breast cancer prognosis...

Black patients have a worse breast cancer prognosis

Additional consideration should be given to populations with worse survival outcomes at baseline for whom screening mammography could play a significant role. In particular, Black people have similar rates of breast cancer compared with White people (127.8 cases per 100,000 vs 133.7 cases per 100,000, respectively) but have a 40% increased breast cancer–related mortality.⁸ The USPSTF recognizes this disparity and mentions it in their recommendations, encouraging health care clinicians to engage in shared decision making with Black patients and asserting that more research is needed on screening mammography in Black communities.¹⁵

While the age modification to the new guidelines better addresses the disparities that impact the Black community (such as increased likelihood of early-onset breast cancer³⁶ and increased rate of breast cancer diagnosis at first mammogram³⁷), the next obvious question is: Can groups with higher breast cancer mortality such as Black communities afford to undergo mammography every 2 years (as opposed to every year)?

Although some data specifically have evaluated the age of initiation and frequency of screening mammography among Black patients,^38,39 little data have specifically assessed outcomes for annual versus biennial screening among Black people. Despite these research gaps, risk factors among the Black community should be considered. There is an increased risk of triple-negative breast cancer that can contribute to higher mortality among Black communities.⁴⁰ Black people also tend to be diagnosed with more aggressive subtypes overall,^41,42 are more likely to have dense breasts,^43,44 have a higher likelihood of advanced stages at the time of diagnosis compared with White people,^8,45 and have a greater chance of diagnosis of a second primary or contralateral breast cancer^46-48—all risk factors that support the importance of regular and early-screening mammography.

How I counsel my patients

As Director of the Cancer Genetics and Breast Health Clinic, I am a gynecologist who primarily evaluates patients at increased risk for breast cancer (and other cancers). As an initial step, I strongly encourage all patients (especially Black patients and those of Ashkenazi Jewish ancestry as per the American College of Radiology recommendations⁹) to undergo risk assessment at age 25 to determine if they may be at increased risk for breast cancer. This first step may include genetic testing if the patient meets NCCN testing criteria based on personal or family history. If results are positive for a germline pathogenic variant, the timing and nature of breast screening would be based on NCCN recommendations for that particular variant (with possible modification of age of initiation based on family history). If testing is negative, lifetime risk assessment would then be performed using risk calculators—such as Tyrer-Cuzick—to determine if the patient meets criteria for intensive surveillance with supplemental breast magnetic resonance imaging. If the patient is subsequently determined to be at average risk after these assessments, I recommend they undergo screening mammography annually starting at age 40. However, it must be recognized that risk may change over time. A patient’s risk can continue to be assessed over a lifetime—with changing family history, personal risk factors, and new discoveries in genetics.

Summary

Ultimately, it is reassuring that the USPSTF guidelines have been updated to be concordant with other national medical society recommendations. They reflect the increasing nationwide trends that clearly demonstrate the high overall prevalence of breast cancer as well as the increasing incidence of early-onset breast cancer.

The updated guidelines, however, do not reflect the entirety of breast cancer trends in this country. With breast cancer being the most commonly diagnosed cancer in the United States, it is imperative to consider the data that demonstrate improved prognostics with annual compared with biennial mammography. Furthermore, the guidelines only begin to explore the disparities that Black patients face regarding breast cancer–related mortality. The risks of younger age at diagnosis, greater likelihood of aggressive subtypes, increased risk of second primary and contralateral breast cancer, and later stage at diagnosis must be seriously evaluated when counseling this patient population.

While the USPSTF recommendations for age at initiation reflect national statistics, recommendations by the ACR and NCCN more appropriately recognize that the benefits of annual screening outweigh the potential risks. Annual screening frequency should be adopted when counseling patients, particularly for the Black community. ●

Breast cancer represents the most commonly diagnosed cancer in the nation.¹ However, unlike other cancers, most breast cancers are identified at stage I and have a 90% survival rate 5-year prognosis.² These outcomes are attributable to various factors, one of the most significant being screening mammography—a largely accessible, highly sensitive and specific screening tool.³ Data demonstrate that malignant tumors detected on screening mammography have more favorable profiles in tumor size and nodal status compared with symptomatic breast cancers,⁴ which make it critical for early diagnosis. Most importantly, the research overwhelmingly demonstrates that screening mammography decreases breast cancer–related mortality.^5-7

The USPSTF big change: Mammography starting at age 40 for all recommended

Despite the general accessibility and mortality benefits of screening mammography (in light of the high lifetime 12% prevalence of breast cancer in the United States⁸), recommendations still conflict across medical societies regarding optimal timing and frequency.^9-12 Previously, the US Preventive Services Task Force (USPSTF) recommended that screening mammography should occur at age 50 biennially and that screening between ages 40 and 49 should be an individualized decision.^13,14 In the draft recommendation statement issued on May 9, 2023, however, the USPSTF now recommends screening every other year starting at age 40 to decrease the risk of dying from breast cancer.¹⁵

This change represents a critically important shift. The new guidance:

• acknowledges the increasing incidence of early-onset breast cancer
• reinforces a national consciousness toward screening mammography in decreasing mortality,17 even among a younger age group for whom the perception of risk may be lower.

The USPSTF statement represents a significant change in how patients should be counseled. Practitioners now have more direct guidance that is concordant with what other national medical organizations offer or recommend, including the American College of Obstetricians and Gynecologists (ACOG), the American College of Radiology (ACR), and the National Comprehensive Cancer Network (NCCN).

However, while the USPSTF statement can and should encourage health care practitioners to initiate mammography earlier than prior recommendations, ongoing discussion regarding the optimal screening interval is warranted. The USPSTF recommendations state that mammography should be performed biennially. While the age at initiation represents a step in the right direction, this recommended screening interval should be reevaluated.

Annual vs biennial screening?

The debate between annual and biennial screening mammography is not new. While many randomized trials on screening mammography have evaluated such factors as breast cancer mortality by age or rate of false positives,¹⁸ fewer trials have evaluated the optimal screening interval.

One randomized trial from the United Kingdom evaluated 99,389 people aged 50 to 62 from 1989 to 1996 who underwent annual screening (study arm) versus 3 years later (control).¹⁹ Findings demonstrated a significantly smaller tumor size in the study arm (P=.05) as well as an increased total cancer detection rate. However, the authors concluded that shortening the screening interval (from 3 years) would not yield a statistically significant decrease in mortality.¹⁹

In a randomized trial from Finland, researchers screened those aged older than 50 at biennial intervals and those aged younger than 50 at either annual or triennial intervals.²⁰ Results demonstrated that, among those aged 40 to 49, the frequency of stage I cancers was not significantly different from screen-detected cancers, interval cancers, or cancers detected outside of screening (50%, 42%, and 44%, respectively; P=.73). Furthermore, there was a greater likelihood of interval cancers among those aged 40 to 49 at 1-year (27%) and 3-year (39%) screening intervals compared with those aged older than 50 screened biennially (18%; P=.08 and P=.0009, respectively).²⁰

These randomized trials, however, have been scrutinized because of factors such as discrepancies in screening intervals by country as well as substantial improvements made in screening mammography since the time these trials were conducted.⁵ Due to the dearth of more contemporary randomized controlled trials accounting for more up-to-date training and technology, most of the more recent data has been largely observational, retrospective, or used modeling.²¹ The TABLE outlines some of the major studies on this topic.

obgm03512043_pleasant_table.jpg

False-positive results, biopsy rates. The arguments against more frequent screening include the possibility of false positives that require callbacks and biopsies, which may be more frequent among those who undergo annual mammography.²² A systematic review from the Breast Cancer Surveillance Consortium demonstrated a 61.3% annual (confidence interval [CI], 59.4%–63.1%) versus 41.6% biennial (CI, 40.6%–42.5%) false-positive rate, resulting in a 7% (CI, 6.1%–7.8%) versus 4.8% (CI, 4.4–5.2%) rate of biopsy, respectively.²³ This false-positive rate, however, also may be increased in younger patients aged 40 to 49 and in those with dense breasts.^22,24 These callbacks and biopsies could induce significant patient stress, pain, and anxiety, as well as carry financial implications related to subsequent diagnostic imaging.

Overdiagnosis. There is also the risk of overdiagnosis, in which an indolent breast cancer that otherwise would not grow or progress to become symptomatic is identified. This could lead to overtreatment. While the exact incidence of overdiagnosis is unclear (due to recommendations for universal treatment of ductal carcinoma in situ), some data suggest that overdiagnosis could be decreased with biennial screening.²⁵

While discomfort could also be a barrier, it may not necessarily be prohibitive for some to continue with future screening mammograms.²² Further, increased radiation with annual mammography is a concern. However, modeling studies have shown that the mortality benefit for annual mammography starting at age 40 outweighs (by 60-fold) the mortality risk from a radiation-induced breast cancer.²⁶

Benefit from biennial screening

Some research suggests overall benefit from biennial screening. One study that used Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer microsimulation was adapted to measure the incidence, mortality, and life-years gained for Canadian patients.²⁷ This model demonstrated that mortality reduction was linked to greater lifetime screens for breast cancer, but this applied primarily to patients aged 50 and older. Overall, a larger impact was observed by initiating screening at age 40 than by decreasing screening intervals.²⁷

Using modeling, Mandelblatt and colleagues demonstrated that biennial screening could capture most of the benefit of annual screening with less harm.²⁸ In another study in 2016, Mandelblatt and colleagues used updated and revised versions of these simulation models and maintained that biennial screening upheld 79.8% to 81.3% of the benefits of annual screening mammography but with fewer overdiagnoses and false-positive results.²⁵ The authors concluded that while biennial screening is equally effective for average-risk populations, there should be an evaluation of benefits and harms based on the clinical scenario (suggesting that annual screening for those at age 40 who carried elevated risk was similar to biennial screening for average-risk patients starting at age 50).²⁵

Another study that served to inform the European Commission Initiative on Breast Cancer recommendations evaluated randomized controlled trials and observational and modeling studies that assessed breast screening intervals.²⁹ The authors concluded that each screening interval has risks and benefits, with data suggesting more benefit with biennial screening for people aged 50 to 69 years and more possible harm with annual screening in younger people (aged 45–49).²⁹

Continue to: Benefit from annual screening...

However, these data conflict with other studies that demonstrate the benefit of annual compared with biennial screening mammography. One large retrospective review of prospectively collected data evaluated outcome differences based on mammography frequency.³⁰ For those undergoing annual versus biennial screening, the median tumor size was 11 mm (versus 15 mm), the percentage of lymph node metastasis was 14% (versus 24%), and cancer stage II or higher was 17% (versus 29%). The study overall demonstrated that annual screening resulted in lower recall rates (P<.0001) and detection of smaller tumors that carried a more favorable prognosis (P<.04).³⁰

Another observational study from 2004 that assessed data from 7 different mammography registries nationwide noted that, among those aged 40 to 49, patients who underwent biennial screening had an increased likelihood of late-stage disease compared with those with annual screening (28% vs 21%, respectively; odds ratio [OR], 1.35; 95% CI, 1.01–1.81), although this discrepancy was not observed in people aged 50 or older.³¹

A study that critiqued the previous 2012 version of the USPSTF guidelines used CISNET modeling, which demonstrated a 39.6% mortality reduction with annual screening for those aged 40 to 84 versus 23.2% for biennial screening for those aged 50 to 74.⁵

More recent data also reflect these findings. A retrospective cohort study that evaluated patients aged 40 to 84 diagnosed with breast cancer found that those who previously underwent annual versus biennial screening mammography had lower incidences of late-stage diagnoses (24.0% vs 43.8%, respectively; P=.02), fewer interval cancers (10.5% vs 37.5%; P<.001), and smaller mean (SD) tumor diameter (1.4 [1.2] cm vs 1.8 [1.6] cm; P=.04).²¹ Postmenopausal patients in this cohort also demonstrated similar findings when comparing mammogram frequency. Although not significant, biennial (or greater) frequency of screening mammography also resulted in an increased likelihood of axillary lymph node dissection and chemotherapy.

Similarly, authors of another large prospective cohort study concluded that breast cancers diagnosed in premenopausal patients were more likely to be larger with less favorable prognostic characteristics (tumor size >15 mm, relative risk [RR], 1.21 [95% CI, 1.07–1.37]; P=.002); any less favorable prognostic characteristics (RR, 1.11 [95% CI, 1.00–1.22]; P=.047), and higher stage (stage IIB or higher, RR, 1.28 [95% CI, 1.01–1.63]; P=.04) for those who underwent biennial screening compared with breast cancers diagnosed by annual screening.³² However, this trend was not observed in postmenopausal patients not taking hormone therapy.³²

Some international studies also show more favorable outcomes with annual screening mammography. A Swedish study evaluated mammography screening intervals of 21 months compared with 18 or 12 months in patients aged 40 to 49.³³ Data showed an improved effectiveness of 1.6% to 9.8% for interval cancers and 2.9% to 17.4% for both interval and screening-detected cancers by reducing the screening frequency to 12 months, with authors suggesting a further reduction in breast cancer–related mortality rates for this age group.³³

Results from another descriptive study from Europe also showed increasing interval breast cancer rates with increasing screening intervals.³⁴ After a negative screen, the interval cancer rates and regional ranges for 0 to less than 12 months, 12 to less than 24 months, and 24 to less than 36 months per 1,000 screened were 0.55 (0.43–0.76), 1.13 (0.92–1.47), and 1.22 (0.93–1.57), respectively.³⁴

Finally, a study conducted in Canada evaluated interval breast cancers among people with dense breasts screened between 2008 and 2010.³⁵ Those with screening programs with policies that offered annual screening reported fewer interval cancers (interval cancer rate, 0.89 per 1,000; 95% CI, 0.67–1.11) compared with those who had policies that used biennial screening (interval cancer rate, 1.45 per 1,000 [annualized]; 95% CI, 1.19–1.72), which was 63% higher (P=.002). For those for whom radiologists recommended screening, interval cancer was lower for annual (0.93 per 1,000; 95% CI, 0.71–1.16) versus biennial screening (1.70 per 1,000 [annualized]; 95% CI, 0.70–2.71) (P=.061).³⁵

Continue to: Black patients have a worse breast cancer prognosis...

Black patients have a worse breast cancer prognosis

Additional consideration should be given to populations with worse survival outcomes at baseline for whom screening mammography could play a significant role. In particular, Black people have similar rates of breast cancer compared with White people (127.8 cases per 100,000 vs 133.7 cases per 100,000, respectively) but have a 40% increased breast cancer–related mortality.⁸ The USPSTF recognizes this disparity and mentions it in their recommendations, encouraging health care clinicians to engage in shared decision making with Black patients and asserting that more research is needed on screening mammography in Black communities.¹⁵

While the age modification to the new guidelines better addresses the disparities that impact the Black community (such as increased likelihood of early-onset breast cancer³⁶ and increased rate of breast cancer diagnosis at first mammogram³⁷), the next obvious question is: Can groups with higher breast cancer mortality such as Black communities afford to undergo mammography every 2 years (as opposed to every year)?

Although some data specifically have evaluated the age of initiation and frequency of screening mammography among Black patients,^38,39 little data have specifically assessed outcomes for annual versus biennial screening among Black people. Despite these research gaps, risk factors among the Black community should be considered. There is an increased risk of triple-negative breast cancer that can contribute to higher mortality among Black communities.⁴⁰ Black people also tend to be diagnosed with more aggressive subtypes overall,^41,42 are more likely to have dense breasts,^43,44 have a higher likelihood of advanced stages at the time of diagnosis compared with White people,^8,45 and have a greater chance of diagnosis of a second primary or contralateral breast cancer^46-48—all risk factors that support the importance of regular and early-screening mammography.

How I counsel my patients

As Director of the Cancer Genetics and Breast Health Clinic, I am a gynecologist who primarily evaluates patients at increased risk for breast cancer (and other cancers). As an initial step, I strongly encourage all patients (especially Black patients and those of Ashkenazi Jewish ancestry as per the American College of Radiology recommendations⁹) to undergo risk assessment at age 25 to determine if they may be at increased risk for breast cancer. This first step may include genetic testing if the patient meets NCCN testing criteria based on personal or family history. If results are positive for a germline pathogenic variant, the timing and nature of breast screening would be based on NCCN recommendations for that particular variant (with possible modification of age of initiation based on family history). If testing is negative, lifetime risk assessment would then be performed using risk calculators—such as Tyrer-Cuzick—to determine if the patient meets criteria for intensive surveillance with supplemental breast magnetic resonance imaging. If the patient is subsequently determined to be at average risk after these assessments, I recommend they undergo screening mammography annually starting at age 40. However, it must be recognized that risk may change over time. A patient’s risk can continue to be assessed over a lifetime—with changing family history, personal risk factors, and new discoveries in genetics.

Summary

Ultimately, it is reassuring that the USPSTF guidelines have been updated to be concordant with other national medical society recommendations. They reflect the increasing nationwide trends that clearly demonstrate the high overall prevalence of breast cancer as well as the increasing incidence of early-onset breast cancer.

The updated guidelines, however, do not reflect the entirety of breast cancer trends in this country. With breast cancer being the most commonly diagnosed cancer in the United States, it is imperative to consider the data that demonstrate improved prognostics with annual compared with biennial mammography. Furthermore, the guidelines only begin to explore the disparities that Black patients face regarding breast cancer–related mortality. The risks of younger age at diagnosis, greater likelihood of aggressive subtypes, increased risk of second primary and contralateral breast cancer, and later stage at diagnosis must be seriously evaluated when counseling this patient population.

While the USPSTF recommendations for age at initiation reflect national statistics, recommendations by the ACR and NCCN more appropriately recognize that the benefits of annual screening outweigh the potential risks. Annual screening frequency should be adopted when counseling patients, particularly for the Black community. ●

Ryu KJ, Kim MS, Lee JY, et al. Risk of endometrial polyps, hyperplasia, carcinoma, and uterine cancer after tamoxifen treatment in premenopausal women with breast cancer. JAMA Netw Open. 2022;5:e2243951.

EXPERT COMMENTARY

Tamoxifen is a selective estrogen receptor modulator (SERM) approved by the US Food and Drug Administration (FDA) for both adjuvant treatment of invasive or metastatic breast cancer with hormone receptor (HR)–positive tumors (duration, 5 to 10 years) and for reduction of future breast cancers in certain high-risk individuals (duration, 5 years). It is also occasionally used for non-FDA approved indications, such as cyclic mastodynia.

Because breast cancer is among the most frequently diagnosed cancers in the United States (297,790 new cases expected in 2023) and approximately 80% are HR-positive tumors that will require hormonal adjuvant therapy,¹ physicians and other gynecologic clinicians should have a working understanding of tamoxifen, including the risks and benefits associated with its use. Among the recognized serious adverse effects of tamoxifen is the increased risk of endometrial cancer in menopausal patients. This adverse effect creates a potential conundrum for clinicians who may be managing patients with tamoxifen to treat or prevent breast cancer, while also increasing the risk of another cancer. Prior prospective studies of tamoxifen have demonstrated a statistically and clinically significant increased risk of endometrial cancer in menopausal patients but not in premenopausal patients.

A recent study challenged those previous findings, suggesting that the risk of endometrial cancer is similar in both premenopausal and postmenopausal patients taking tamoxifen for treatment of breast cancer.²

Details of the study

The study by Ryu and colleagues used data from the Korean National Health Insurance Service, which covers 97% of the Korean population.² The authors selected patients being treated for invasive breast cancer from January 1, 2003, through December 31, 2018, who were between the ages of 20 and 50 years when the breast cancer diagnosis was first made. Patients with a diagnostic code entered into their electronic health record that was consistent with menopausal status were excluded, along with any patients with a current or prior history of aromatase inhibitor use (for which one must be naturally, medically, or surgically menopausal to use). Based on these exclusions, the study cohort was then assumed to be premenopausal.

The study group included patients diagnosed with invasive breast cancer who were treated with adjuvant hormonal therapy with tamoxifen (n = 34,637), and the control group included patients with invasive breast cancer who were not treated with adjuvant hormonal therapy (n = 43,683). The primary study end point was the finding of endometrial or uterine pathology, including endometrial polyps, endometrial hyperplasia, endometrial cancer, and other uterine malignant neoplasms not originating in the endometrium (for example, uterine sarcomas).

Because this was a retrospective cohort study that included all eligible patients, the 2 groups were not matched. The treatment group was statistically older, had a higher body mass index (BMI) and a larger waist circumference, were more likely to be hypertensive, and included more patients with diabetes than the control group—all known risk factors for endometrial cancer. However, after adjusting for these 4 factors, an increased risk of endometrial cancer remained in the tamoxifen group compared with the control group (hazard ratio [HR], 3.77; 95% confidence interval [CI], 3.04–4.66). In addition, tamoxifen use was independently associated with an increased risk of endometrial polyps (HR, 3.90; 95% CI, 3.65–4.16), endometrial hyperplasia (HR, 5.56; 95% CI, 5.06–6.12), and other uterine cancers (HR, 2.27; 95% CI, 1.54–3.33). In a subgroup analysis, the risk for endometrial cancer was not higher in patients treated for more than 5 years of tamoxifen compared with those treated for 5 years or less.

Study strengths and limitations

A major strength of this study was the large number of study participants (n = 34,637 tamoxifen; n = 43,683 control), the long duration of follow-up (up to 15 years), and use of a single source of data with coverage of nearly the entire population of Korea. While the 2 study populations (tamoxifen vs no tamoxifen) were initially unbalanced in terms of endometrial cancer risk (age, BMI, concurrent diagnoses of hypertension and diabetes), the authors corrected for this with a multivariate analysis.

Furthermore, while the likely homogeneity of the study population may not make the results generalizable, the authors noted that Korean patients have a higher tendency toward early-onset breast cancer. This observation could make this cohort better suited for a study on premenopausal effects of tamoxifen.

Limitations. These data are provocative as they conflict with level 1 evidence based on multiple well-designed, double-blind, placebo-controlled randomized trials in which tamoxifen use for 5 years did not demonstrate a statistically increased risk of endometrial cancer in patients younger than age 50.^3-5 Because of the importance of the question and the implications for many premenopausal women being treated with tamoxifen, we carefully evaluated the study methodology to better understand this discrepancy.

Continue to: Methodological concerns...

In the study by Ryu and colleagues, we found the definition of premenopausal to be problematic. Ultimately, if patients did not have a diagnosis of menopause in the problem summary list, they were assumed to be premenopausal if they were between the ages of 20 and 50 and not taking an aromatase inhibitor. However, important considerations in this population include the cancer stage and treatment regimens that can and do directly impact menopausal status.

Data demonstrate that early-onset breast cancer tends to be associated with more biologically aggressive characteristics that frequently require adjuvant or neoadjuvant chemotherapy.^6,7 This chemotherapy regimen is comprised most commonly of Adriamycin (doxorubicin), paclitaxel, and cyclophosphamide. Cyclophosphamide is an alkylating agent that is a known gonadotoxin, and it often renders patients either temporarily or permanently menopausal due to chemotherapy-induced ovarian failure. Prior studies have demonstrated that for patients in their 40s, approximately 90% of those treated with cyclophosphamide-containing chemo-therapy for breast cancer will experience chemotherapy-induced amenorrhea (CIA).⁸ Although some patients in their 40s with CIA will resume ovarian function, the majority will not.^8,9

Due to the lack of reliability in diagnosing CIA, blood levels of estradiol and follicle stimulating hormone are often necessary for confirmation and, even so, may be only temporary. One prospective analysis of 4 randomized neoadjuvant/adjuvant breast cancer trials used this approach and demonstrated that 85.1% of the study cohort experienced chemotherapy-induced ovarian failure at the end of their treatment, with some fluctuating back to premenopausal hormonal levels at 6 and 12 months.¹⁰

Furthermore, in the study by Ryu and colleagues, there is no description or confirmation of menstrual patterns in the study group to support the diagnosis of ongoing premenopausal status. Data on CIA and loss of ovarian function, therefore, are critical to the accurate categorization of patients as premenopausal or menopausal in this study. The study also relied on consistent and accurate recording of appropriate medical codes to capture a patient’s menopausal status, which is unclear for this particular population and health system.

In evaluating prior research, multiple studies demonstrated no increased risk of endometrial cancer in premenopausal women taking tamoxifen for breast cancer prevention (TABLE).^3,5 These breast cancer prevention trials have several major advantages in assessing tamoxifen-associated endometrial cancer risk for premenopausal patients compared with the current study:

• Both studies were prospective double-blind, placebo-controlled randomized clinical breast cancer prevention trials with carefully designed and measured outcomes.
• Since these were breast cancer prevention trials, administration of gonadotoxic chemotherapy was not a concern. As a result, miscategorizing patients with chemotherapy-induced menopause as premenopausal would not be expected, and premature menopause would not be expected at a higher rate than the general population.
• Careful histories were required prior to study entry and throughout the study, including data on menopausal status and menstrual and uterine bleeding histories.¹¹

obgm03508017_pearlman_evidence_t.jpg

In these prevention trials, the effect of tamoxifen on uterine pathology demonstratedrepeatable evidence that there was a statistically significant increased risk of endometrial cancer in postmenopausal women, but there was no similar increased risk of endometrial cancer in premenopausal women (TABLE).^3,5 Interestingly, the magnitude of the endometrial cancer risk found in the premenopausal patients in the study by Ryu and colleagues (RR, 3.77) is comparable to that of the menopausal group in the prevention trials, raising concern that many or most of the patients in the treatment group assumed to be premenopausal may have indeed been “menopausal” for some or all the time they were taking tamoxifen due to the possible aforementioned reasons. ●

Ryu KJ, Kim MS, Lee JY, et al. Risk of endometrial polyps, hyperplasia, carcinoma, and uterine cancer after tamoxifen treatment in premenopausal women with breast cancer. JAMA Netw Open. 2022;5:e2243951.

EXPERT COMMENTARY

Tamoxifen is a selective estrogen receptor modulator (SERM) approved by the US Food and Drug Administration (FDA) for both adjuvant treatment of invasive or metastatic breast cancer with hormone receptor (HR)–positive tumors (duration, 5 to 10 years) and for reduction of future breast cancers in certain high-risk individuals (duration, 5 years). It is also occasionally used for non-FDA approved indications, such as cyclic mastodynia.

Because breast cancer is among the most frequently diagnosed cancers in the United States (297,790 new cases expected in 2023) and approximately 80% are HR-positive tumors that will require hormonal adjuvant therapy,¹ physicians and other gynecologic clinicians should have a working understanding of tamoxifen, including the risks and benefits associated with its use. Among the recognized serious adverse effects of tamoxifen is the increased risk of endometrial cancer in menopausal patients. This adverse effect creates a potential conundrum for clinicians who may be managing patients with tamoxifen to treat or prevent breast cancer, while also increasing the risk of another cancer. Prior prospective studies of tamoxifen have demonstrated a statistically and clinically significant increased risk of endometrial cancer in menopausal patients but not in premenopausal patients.

A recent study challenged those previous findings, suggesting that the risk of endometrial cancer is similar in both premenopausal and postmenopausal patients taking tamoxifen for treatment of breast cancer.²

Details of the study

The study by Ryu and colleagues used data from the Korean National Health Insurance Service, which covers 97% of the Korean population.² The authors selected patients being treated for invasive breast cancer from January 1, 2003, through December 31, 2018, who were between the ages of 20 and 50 years when the breast cancer diagnosis was first made. Patients with a diagnostic code entered into their electronic health record that was consistent with menopausal status were excluded, along with any patients with a current or prior history of aromatase inhibitor use (for which one must be naturally, medically, or surgically menopausal to use). Based on these exclusions, the study cohort was then assumed to be premenopausal.

The study group included patients diagnosed with invasive breast cancer who were treated with adjuvant hormonal therapy with tamoxifen (n = 34,637), and the control group included patients with invasive breast cancer who were not treated with adjuvant hormonal therapy (n = 43,683). The primary study end point was the finding of endometrial or uterine pathology, including endometrial polyps, endometrial hyperplasia, endometrial cancer, and other uterine malignant neoplasms not originating in the endometrium (for example, uterine sarcomas).

Because this was a retrospective cohort study that included all eligible patients, the 2 groups were not matched. The treatment group was statistically older, had a higher body mass index (BMI) and a larger waist circumference, were more likely to be hypertensive, and included more patients with diabetes than the control group—all known risk factors for endometrial cancer. However, after adjusting for these 4 factors, an increased risk of endometrial cancer remained in the tamoxifen group compared with the control group (hazard ratio [HR], 3.77; 95% confidence interval [CI], 3.04–4.66). In addition, tamoxifen use was independently associated with an increased risk of endometrial polyps (HR, 3.90; 95% CI, 3.65–4.16), endometrial hyperplasia (HR, 5.56; 95% CI, 5.06–6.12), and other uterine cancers (HR, 2.27; 95% CI, 1.54–3.33). In a subgroup analysis, the risk for endometrial cancer was not higher in patients treated for more than 5 years of tamoxifen compared with those treated for 5 years or less.

Study strengths and limitations

A major strength of this study was the large number of study participants (n = 34,637 tamoxifen; n = 43,683 control), the long duration of follow-up (up to 15 years), and use of a single source of data with coverage of nearly the entire population of Korea. While the 2 study populations (tamoxifen vs no tamoxifen) were initially unbalanced in terms of endometrial cancer risk (age, BMI, concurrent diagnoses of hypertension and diabetes), the authors corrected for this with a multivariate analysis.

Furthermore, while the likely homogeneity of the study population may not make the results generalizable, the authors noted that Korean patients have a higher tendency toward early-onset breast cancer. This observation could make this cohort better suited for a study on premenopausal effects of tamoxifen.

Limitations. These data are provocative as they conflict with level 1 evidence based on multiple well-designed, double-blind, placebo-controlled randomized trials in which tamoxifen use for 5 years did not demonstrate a statistically increased risk of endometrial cancer in patients younger than age 50.^3-5 Because of the importance of the question and the implications for many premenopausal women being treated with tamoxifen, we carefully evaluated the study methodology to better understand this discrepancy.

Continue to: Methodological concerns...

In the study by Ryu and colleagues, we found the definition of premenopausal to be problematic. Ultimately, if patients did not have a diagnosis of menopause in the problem summary list, they were assumed to be premenopausal if they were between the ages of 20 and 50 and not taking an aromatase inhibitor. However, important considerations in this population include the cancer stage and treatment regimens that can and do directly impact menopausal status.

Data demonstrate that early-onset breast cancer tends to be associated with more biologically aggressive characteristics that frequently require adjuvant or neoadjuvant chemotherapy.^6,7 This chemotherapy regimen is comprised most commonly of Adriamycin (doxorubicin), paclitaxel, and cyclophosphamide. Cyclophosphamide is an alkylating agent that is a known gonadotoxin, and it often renders patients either temporarily or permanently menopausal due to chemotherapy-induced ovarian failure. Prior studies have demonstrated that for patients in their 40s, approximately 90% of those treated with cyclophosphamide-containing chemo-therapy for breast cancer will experience chemotherapy-induced amenorrhea (CIA).⁸ Although some patients in their 40s with CIA will resume ovarian function, the majority will not.^8,9

Due to the lack of reliability in diagnosing CIA, blood levels of estradiol and follicle stimulating hormone are often necessary for confirmation and, even so, may be only temporary. One prospective analysis of 4 randomized neoadjuvant/adjuvant breast cancer trials used this approach and demonstrated that 85.1% of the study cohort experienced chemotherapy-induced ovarian failure at the end of their treatment, with some fluctuating back to premenopausal hormonal levels at 6 and 12 months.¹⁰

Furthermore, in the study by Ryu and colleagues, there is no description or confirmation of menstrual patterns in the study group to support the diagnosis of ongoing premenopausal status. Data on CIA and loss of ovarian function, therefore, are critical to the accurate categorization of patients as premenopausal or menopausal in this study. The study also relied on consistent and accurate recording of appropriate medical codes to capture a patient’s menopausal status, which is unclear for this particular population and health system.

In evaluating prior research, multiple studies demonstrated no increased risk of endometrial cancer in premenopausal women taking tamoxifen for breast cancer prevention (TABLE).^3,5 These breast cancer prevention trials have several major advantages in assessing tamoxifen-associated endometrial cancer risk for premenopausal patients compared with the current study:

• Both studies were prospective double-blind, placebo-controlled randomized clinical breast cancer prevention trials with carefully designed and measured outcomes.
• Since these were breast cancer prevention trials, administration of gonadotoxic chemotherapy was not a concern. As a result, miscategorizing patients with chemotherapy-induced menopause as premenopausal would not be expected, and premature menopause would not be expected at a higher rate than the general population.
• Careful histories were required prior to study entry and throughout the study, including data on menopausal status and menstrual and uterine bleeding histories.¹¹

obgm03508017_pearlman_evidence_t.jpg

In these prevention trials, the effect of tamoxifen on uterine pathology demonstratedrepeatable evidence that there was a statistically significant increased risk of endometrial cancer in postmenopausal women, but there was no similar increased risk of endometrial cancer in premenopausal women (TABLE).^3,5 Interestingly, the magnitude of the endometrial cancer risk found in the premenopausal patients in the study by Ryu and colleagues (RR, 3.77) is comparable to that of the menopausal group in the prevention trials, raising concern that many or most of the patients in the treatment group assumed to be premenopausal may have indeed been “menopausal” for some or all the time they were taking tamoxifen due to the possible aforementioned reasons. ●

Ryu KJ, Kim MS, Lee JY, et al. Risk of endometrial polyps, hyperplasia, carcinoma, and uterine cancer after tamoxifen treatment in premenopausal women with breast cancer. JAMA Netw Open. 2022;5:e2243951.

EXPERT COMMENTARY

Tamoxifen is a selective estrogen receptor modulator (SERM) approved by the US Food and Drug Administration (FDA) for both adjuvant treatment of invasive or metastatic breast cancer with hormone receptor (HR)–positive tumors (duration, 5 to 10 years) and for reduction of future breast cancers in certain high-risk individuals (duration, 5 years). It is also occasionally used for non-FDA approved indications, such as cyclic mastodynia.

Because breast cancer is among the most frequently diagnosed cancers in the United States (297,790 new cases expected in 2023) and approximately 80% are HR-positive tumors that will require hormonal adjuvant therapy,¹ physicians and other gynecologic clinicians should have a working understanding of tamoxifen, including the risks and benefits associated with its use. Among the recognized serious adverse effects of tamoxifen is the increased risk of endometrial cancer in menopausal patients. This adverse effect creates a potential conundrum for clinicians who may be managing patients with tamoxifen to treat or prevent breast cancer, while also increasing the risk of another cancer. Prior prospective studies of tamoxifen have demonstrated a statistically and clinically significant increased risk of endometrial cancer in menopausal patients but not in premenopausal patients.

A recent study challenged those previous findings, suggesting that the risk of endometrial cancer is similar in both premenopausal and postmenopausal patients taking tamoxifen for treatment of breast cancer.²

Details of the study

The study by Ryu and colleagues used data from the Korean National Health Insurance Service, which covers 97% of the Korean population.² The authors selected patients being treated for invasive breast cancer from January 1, 2003, through December 31, 2018, who were between the ages of 20 and 50 years when the breast cancer diagnosis was first made. Patients with a diagnostic code entered into their electronic health record that was consistent with menopausal status were excluded, along with any patients with a current or prior history of aromatase inhibitor use (for which one must be naturally, medically, or surgically menopausal to use). Based on these exclusions, the study cohort was then assumed to be premenopausal.

The study group included patients diagnosed with invasive breast cancer who were treated with adjuvant hormonal therapy with tamoxifen (n = 34,637), and the control group included patients with invasive breast cancer who were not treated with adjuvant hormonal therapy (n = 43,683). The primary study end point was the finding of endometrial or uterine pathology, including endometrial polyps, endometrial hyperplasia, endometrial cancer, and other uterine malignant neoplasms not originating in the endometrium (for example, uterine sarcomas).

Because this was a retrospective cohort study that included all eligible patients, the 2 groups were not matched. The treatment group was statistically older, had a higher body mass index (BMI) and a larger waist circumference, were more likely to be hypertensive, and included more patients with diabetes than the control group—all known risk factors for endometrial cancer. However, after adjusting for these 4 factors, an increased risk of endometrial cancer remained in the tamoxifen group compared with the control group (hazard ratio [HR], 3.77; 95% confidence interval [CI], 3.04–4.66). In addition, tamoxifen use was independently associated with an increased risk of endometrial polyps (HR, 3.90; 95% CI, 3.65–4.16), endometrial hyperplasia (HR, 5.56; 95% CI, 5.06–6.12), and other uterine cancers (HR, 2.27; 95% CI, 1.54–3.33). In a subgroup analysis, the risk for endometrial cancer was not higher in patients treated for more than 5 years of tamoxifen compared with those treated for 5 years or less.

Study strengths and limitations

A major strength of this study was the large number of study participants (n = 34,637 tamoxifen; n = 43,683 control), the long duration of follow-up (up to 15 years), and use of a single source of data with coverage of nearly the entire population of Korea. While the 2 study populations (tamoxifen vs no tamoxifen) were initially unbalanced in terms of endometrial cancer risk (age, BMI, concurrent diagnoses of hypertension and diabetes), the authors corrected for this with a multivariate analysis.

Furthermore, while the likely homogeneity of the study population may not make the results generalizable, the authors noted that Korean patients have a higher tendency toward early-onset breast cancer. This observation could make this cohort better suited for a study on premenopausal effects of tamoxifen.

Limitations. These data are provocative as they conflict with level 1 evidence based on multiple well-designed, double-blind, placebo-controlled randomized trials in which tamoxifen use for 5 years did not demonstrate a statistically increased risk of endometrial cancer in patients younger than age 50.^3-5 Because of the importance of the question and the implications for many premenopausal women being treated with tamoxifen, we carefully evaluated the study methodology to better understand this discrepancy.

Continue to: Methodological concerns...

In the study by Ryu and colleagues, we found the definition of premenopausal to be problematic. Ultimately, if patients did not have a diagnosis of menopause in the problem summary list, they were assumed to be premenopausal if they were between the ages of 20 and 50 and not taking an aromatase inhibitor. However, important considerations in this population include the cancer stage and treatment regimens that can and do directly impact menopausal status.

Data demonstrate that early-onset breast cancer tends to be associated with more biologically aggressive characteristics that frequently require adjuvant or neoadjuvant chemotherapy.^6,7 This chemotherapy regimen is comprised most commonly of Adriamycin (doxorubicin), paclitaxel, and cyclophosphamide. Cyclophosphamide is an alkylating agent that is a known gonadotoxin, and it often renders patients either temporarily or permanently menopausal due to chemotherapy-induced ovarian failure. Prior studies have demonstrated that for patients in their 40s, approximately 90% of those treated with cyclophosphamide-containing chemo-therapy for breast cancer will experience chemotherapy-induced amenorrhea (CIA).⁸ Although some patients in their 40s with CIA will resume ovarian function, the majority will not.^8,9

Due to the lack of reliability in diagnosing CIA, blood levels of estradiol and follicle stimulating hormone are often necessary for confirmation and, even so, may be only temporary. One prospective analysis of 4 randomized neoadjuvant/adjuvant breast cancer trials used this approach and demonstrated that 85.1% of the study cohort experienced chemotherapy-induced ovarian failure at the end of their treatment, with some fluctuating back to premenopausal hormonal levels at 6 and 12 months.¹⁰

Furthermore, in the study by Ryu and colleagues, there is no description or confirmation of menstrual patterns in the study group to support the diagnosis of ongoing premenopausal status. Data on CIA and loss of ovarian function, therefore, are critical to the accurate categorization of patients as premenopausal or menopausal in this study. The study also relied on consistent and accurate recording of appropriate medical codes to capture a patient’s menopausal status, which is unclear for this particular population and health system.

In evaluating prior research, multiple studies demonstrated no increased risk of endometrial cancer in premenopausal women taking tamoxifen for breast cancer prevention (TABLE).^3,5 These breast cancer prevention trials have several major advantages in assessing tamoxifen-associated endometrial cancer risk for premenopausal patients compared with the current study:

• Both studies were prospective double-blind, placebo-controlled randomized clinical breast cancer prevention trials with carefully designed and measured outcomes.
• Since these were breast cancer prevention trials, administration of gonadotoxic chemotherapy was not a concern. As a result, miscategorizing patients with chemotherapy-induced menopause as premenopausal would not be expected, and premature menopause would not be expected at a higher rate than the general population.
• Careful histories were required prior to study entry and throughout the study, including data on menopausal status and menstrual and uterine bleeding histories.¹¹

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In these prevention trials, the effect of tamoxifen on uterine pathology demonstratedrepeatable evidence that there was a statistically significant increased risk of endometrial cancer in postmenopausal women, but there was no similar increased risk of endometrial cancer in premenopausal women (TABLE).^3,5 Interestingly, the magnitude of the endometrial cancer risk found in the premenopausal patients in the study by Ryu and colleagues (RR, 3.77) is comparable to that of the menopausal group in the prevention trials, raising concern that many or most of the patients in the treatment group assumed to be premenopausal may have indeed been “menopausal” for some or all the time they were taking tamoxifen due to the possible aforementioned reasons. ●