Women's Health

ILLUSTRATIVE CASE

A 32-year-old woman with a history of migraine with aura presents to your office for contraception management. She works full-time, has 2 children, and has transportation barriers. She previously used injectable DMPA (administered every 3 months at a health care facility) and would like to restart it. However, because she had to reschedule her last appointment due to a lack of transportation, she missed her injection window and subsequently became pregnant with her second child. She would still prefer injectable DMPA over the other contraceptive options ­offered—etonogestrel implant, oral contraceptive, or intrauterine device (IUD)—given her migraine history. However, she’s concerned she may have difficulty coming to the office every 3 months for her injection. What alternative injectable option can you offer?

When not pregnant or seeking to become pregnant, women may spend a significant amount of their lives trying to avoid pregnancy, and almost all women use contraception at some point.² During the childbearing years of 15 to 49, 65% of women report using contraception.² Although DMPA is a safe and effective option, only 2% of women report using it for contraception.²

For patients who have migraine with aura, there are fewer contraception options because their risk for ischemic stroke is increased 2- to 4-fold if they use combined hormonal contraceptives in pill, patch, or vaginal ring form.³ Safe options for these patients include the copper IUD, levonorgestrel­-releasing intrauterine system, progestin implant, and DMPA injection.³

DMPA is a progestogen-only contraceptive approved by the US Food and Drug Administration to prevent pregnancy. It is available in an intramuscular formulation (DMPA-IM; 150 mg/mL every 13 weeks) and a subcutaneous formulation (DMPA-SC; 104 mg/0.65 mL every 12-14 weeks). DMPA-IM is administered by a health care provider and thus requires patients to present every 3 months for an injection. About 6% of ­DMPA-IM users have an unintended pregnancy in the first year due to inconsistent or incorrect use or late receipt of injection.⁴ DMPA-SC is produced as a prefilled needle that can be self-injected by patients.

Barriers to access are a growing concern. During the COVID-19 pandemic, one-third of women surveyed by the Guttmacher Institute (n = 2009) reported delaying or canceling a health care visit or having difficulty obtaining their contraception. Barriers to health care and contraception access were more common among Black and Hispanic women (vs White women), queer women (vs straight women), and low-income women (vs higher-income women).⁵

Following the overturning of Roe v Wade in June 2022, abortion access is now limited in parts of the United States. Given this significant policy change, physicians have an increasingly important role in providing contraception care and reducing barriers to contraception access. Since the SC forms of injectable contraception can be administered at home rather than in the health care setting, both the World Health Organization and the Centers for Disease Control and Prevention have recommended that self-administered injectable contraception be made widely available to expand access to contraception.^6,7

STUDY SUMMARY

Higher contraceptive continuation rates with comparable safety and efficacy

This 2019 systematic review and meta-­analysis evaluated the outcomes associated with use of self-administered DMPA-SC vs provider-administered DMPA in 5 countries.¹ The authors searched several electronic databases for peer-reviewed studies of women who chose the option to self-administer DMPA-SC vs those who received DMPA injections from a health care provider.

Continue to: Outcomes included pregnancy

Outcomes included pregnancy; adverse effects or events (bleeding, injection site reactions, mental health concerns); initial use of injectable contraception (contraception uptake); and continuation rate of injectable contraception. Two reviewers extracted the data and assessed trials for bias. The authors used random-effects models to calculate pooled relative risk (RR) for studies with the same outcomes.

For patients who prefer an injectable contraceptive, a self-administered formulation of DMPA appears to balance access with convenience without an increase in adverse outcomes.

The analysis included a total of 6 trials (N = 3851): 3 RCTs (n = 1263) and 3 controlled cohort studies (n = 2588), conducted in the United States (2 trials), Malawi, Scotland, Uganda, and Senegal. All studies compared 12-month continuation rates of self-injected DMPA-SC vs provider-administered DMPA­-SC or DMPA-IM every 3 months (12-13 weeks, with a window for early and late injections). Participants were at least 15 years of age (mean range, 26 to 29 years). In some studies, reminders (eg, texts, emails, calendar notifications) were provided to either the self-injection cohort only or to both cohorts of the trial. The RCTs were generally graded as having a low risk for bias, except for nonblinding of participants and personnel, given the nature of the interventions. The authors reported no evidence of significant heterogeneity in the studies.

The meta-analysis found higher continuation rates at 12 months with self-­administrated DMPA compared with provider administration in the RCTs (RR = 1.27; 95% CI, 1.16-1.39) and in the observational cohort studies (RR = 1.18; 95% CI, 1.10-1.26). Pregnancy outcomes were reported in 4 studies, with the meta-analysis finding no significant difference in pregnancy rates in 2 RCTs (RR = 0.58; 95% CI, 0.15-2.22) or 2 observational cohort studies (RR = 1.1; 95% CI, 0.23-5.26).

Adverse effects or events were reported in 4 studies: 2 cohort studies reported increased injection site reactions with self-administration, and 1 RCT reported increased injection site pain or irritation with self-administration at 3 and 9 months. No other reported adverse effects occurred at higher rates with self-administration vs provider administration.

WHAT’S NEW

Demonstrated effectiveness of self-administered formulation

This systematic review and meta-analysis demonstrated that self-administration of DMPA-SC leads to higher contraception continuation rates at 12 months, without notable increased pregnancy rates or adverse effects, when compared with provider-administered DMPA.

Continue to: CAVEATS

Outcome data limited to 12 months

Although self-administered DMPA-SC has the theoretical risk for user error and incorrect administration, this study did not find increased rates of pregnancy despite administration outside a health care center. However, the total number of pregnancies in each of the 4 studies measuring this outcome was low (< 5), and thus the authors noted that the effect size estimates may not be accurate.

Currently, there are no data on long-term outcomes beyond 12 months. Additionally, the health care visits for provider-administered DMPA every 3 months may afford other benefits, such as regular discussion of reproductive health concerns or testing for sexually transmitted infections, which must be weighed against the benefit of increased contraception access with self-administration. However, using the DMPA-SC self-administered formulation at home would not inhibit women from making separate health care visits as needed.

CHALLENGES TO IMPLEMENTATION

Limited resources to teach patients how to self-inject

Barriers to implementation include limited experience with prescribing DMPA-SC and changing practice culture to offer it to patients. Additionally, successful implementation of self-administered DMPA-SC is reliant on providing patients with appropriate information and training on self-injection, which requires knowledge, time, and other resources­ that may be limited in practices. Another potential barrier is product access, as not all insurers cover DMPA-SC and some pharmacies do not carry it.

ILLUSTRATIVE CASE

A 32-year-old woman with a history of migraine with aura presents to your office for contraception management. She works full-time, has 2 children, and has transportation barriers. She previously used injectable DMPA (administered every 3 months at a health care facility) and would like to restart it. However, because she had to reschedule her last appointment due to a lack of transportation, she missed her injection window and subsequently became pregnant with her second child. She would still prefer injectable DMPA over the other contraceptive options ­offered—etonogestrel implant, oral contraceptive, or intrauterine device (IUD)—given her migraine history. However, she’s concerned she may have difficulty coming to the office every 3 months for her injection. What alternative injectable option can you offer?

When not pregnant or seeking to become pregnant, women may spend a significant amount of their lives trying to avoid pregnancy, and almost all women use contraception at some point.² During the childbearing years of 15 to 49, 65% of women report using contraception.² Although DMPA is a safe and effective option, only 2% of women report using it for contraception.²

For patients who have migraine with aura, there are fewer contraception options because their risk for ischemic stroke is increased 2- to 4-fold if they use combined hormonal contraceptives in pill, patch, or vaginal ring form.³ Safe options for these patients include the copper IUD, levonorgestrel­-releasing intrauterine system, progestin implant, and DMPA injection.³

DMPA is a progestogen-only contraceptive approved by the US Food and Drug Administration to prevent pregnancy. It is available in an intramuscular formulation (DMPA-IM; 150 mg/mL every 13 weeks) and a subcutaneous formulation (DMPA-SC; 104 mg/0.65 mL every 12-14 weeks). DMPA-IM is administered by a health care provider and thus requires patients to present every 3 months for an injection. About 6% of ­DMPA-IM users have an unintended pregnancy in the first year due to inconsistent or incorrect use or late receipt of injection.⁴ DMPA-SC is produced as a prefilled needle that can be self-injected by patients.

Barriers to access are a growing concern. During the COVID-19 pandemic, one-third of women surveyed by the Guttmacher Institute (n = 2009) reported delaying or canceling a health care visit or having difficulty obtaining their contraception. Barriers to health care and contraception access were more common among Black and Hispanic women (vs White women), queer women (vs straight women), and low-income women (vs higher-income women).⁵

Following the overturning of Roe v Wade in June 2022, abortion access is now limited in parts of the United States. Given this significant policy change, physicians have an increasingly important role in providing contraception care and reducing barriers to contraception access. Since the SC forms of injectable contraception can be administered at home rather than in the health care setting, both the World Health Organization and the Centers for Disease Control and Prevention have recommended that self-administered injectable contraception be made widely available to expand access to contraception.^6,7

STUDY SUMMARY

Higher contraceptive continuation rates with comparable safety and efficacy

This 2019 systematic review and meta-­analysis evaluated the outcomes associated with use of self-administered DMPA-SC vs provider-administered DMPA in 5 countries.¹ The authors searched several electronic databases for peer-reviewed studies of women who chose the option to self-administer DMPA-SC vs those who received DMPA injections from a health care provider.

Continue to: Outcomes included pregnancy

Outcomes included pregnancy; adverse effects or events (bleeding, injection site reactions, mental health concerns); initial use of injectable contraception (contraception uptake); and continuation rate of injectable contraception. Two reviewers extracted the data and assessed trials for bias. The authors used random-effects models to calculate pooled relative risk (RR) for studies with the same outcomes.

For patients who prefer an injectable contraceptive, a self-administered formulation of DMPA appears to balance access with convenience without an increase in adverse outcomes.

The analysis included a total of 6 trials (N = 3851): 3 RCTs (n = 1263) and 3 controlled cohort studies (n = 2588), conducted in the United States (2 trials), Malawi, Scotland, Uganda, and Senegal. All studies compared 12-month continuation rates of self-injected DMPA-SC vs provider-administered DMPA­-SC or DMPA-IM every 3 months (12-13 weeks, with a window for early and late injections). Participants were at least 15 years of age (mean range, 26 to 29 years). In some studies, reminders (eg, texts, emails, calendar notifications) were provided to either the self-injection cohort only or to both cohorts of the trial. The RCTs were generally graded as having a low risk for bias, except for nonblinding of participants and personnel, given the nature of the interventions. The authors reported no evidence of significant heterogeneity in the studies.

The meta-analysis found higher continuation rates at 12 months with self-­administrated DMPA compared with provider administration in the RCTs (RR = 1.27; 95% CI, 1.16-1.39) and in the observational cohort studies (RR = 1.18; 95% CI, 1.10-1.26). Pregnancy outcomes were reported in 4 studies, with the meta-analysis finding no significant difference in pregnancy rates in 2 RCTs (RR = 0.58; 95% CI, 0.15-2.22) or 2 observational cohort studies (RR = 1.1; 95% CI, 0.23-5.26).

Adverse effects or events were reported in 4 studies: 2 cohort studies reported increased injection site reactions with self-administration, and 1 RCT reported increased injection site pain or irritation with self-administration at 3 and 9 months. No other reported adverse effects occurred at higher rates with self-administration vs provider administration.

WHAT’S NEW

Demonstrated effectiveness of self-administered formulation

This systematic review and meta-analysis demonstrated that self-administration of DMPA-SC leads to higher contraception continuation rates at 12 months, without notable increased pregnancy rates or adverse effects, when compared with provider-administered DMPA.

Continue to: CAVEATS

Outcome data limited to 12 months

Although self-administered DMPA-SC has the theoretical risk for user error and incorrect administration, this study did not find increased rates of pregnancy despite administration outside a health care center. However, the total number of pregnancies in each of the 4 studies measuring this outcome was low (< 5), and thus the authors noted that the effect size estimates may not be accurate.

Currently, there are no data on long-term outcomes beyond 12 months. Additionally, the health care visits for provider-administered DMPA every 3 months may afford other benefits, such as regular discussion of reproductive health concerns or testing for sexually transmitted infections, which must be weighed against the benefit of increased contraception access with self-administration. However, using the DMPA-SC self-administered formulation at home would not inhibit women from making separate health care visits as needed.

CHALLENGES TO IMPLEMENTATION

Limited resources to teach patients how to self-inject

Barriers to implementation include limited experience with prescribing DMPA-SC and changing practice culture to offer it to patients. Additionally, successful implementation of self-administered DMPA-SC is reliant on providing patients with appropriate information and training on self-injection, which requires knowledge, time, and other resources­ that may be limited in practices. Another potential barrier is product access, as not all insurers cover DMPA-SC and some pharmacies do not carry it.

ILLUSTRATIVE CASE

A 32-year-old woman with a history of migraine with aura presents to your office for contraception management. She works full-time, has 2 children, and has transportation barriers. She previously used injectable DMPA (administered every 3 months at a health care facility) and would like to restart it. However, because she had to reschedule her last appointment due to a lack of transportation, she missed her injection window and subsequently became pregnant with her second child. She would still prefer injectable DMPA over the other contraceptive options ­offered—etonogestrel implant, oral contraceptive, or intrauterine device (IUD)—given her migraine history. However, she’s concerned she may have difficulty coming to the office every 3 months for her injection. What alternative injectable option can you offer?

When not pregnant or seeking to become pregnant, women may spend a significant amount of their lives trying to avoid pregnancy, and almost all women use contraception at some point.² During the childbearing years of 15 to 49, 65% of women report using contraception.² Although DMPA is a safe and effective option, only 2% of women report using it for contraception.²

For patients who have migraine with aura, there are fewer contraception options because their risk for ischemic stroke is increased 2- to 4-fold if they use combined hormonal contraceptives in pill, patch, or vaginal ring form.³ Safe options for these patients include the copper IUD, levonorgestrel­-releasing intrauterine system, progestin implant, and DMPA injection.³

DMPA is a progestogen-only contraceptive approved by the US Food and Drug Administration to prevent pregnancy. It is available in an intramuscular formulation (DMPA-IM; 150 mg/mL every 13 weeks) and a subcutaneous formulation (DMPA-SC; 104 mg/0.65 mL every 12-14 weeks). DMPA-IM is administered by a health care provider and thus requires patients to present every 3 months for an injection. About 6% of ­DMPA-IM users have an unintended pregnancy in the first year due to inconsistent or incorrect use or late receipt of injection.⁴ DMPA-SC is produced as a prefilled needle that can be self-injected by patients.

Barriers to access are a growing concern. During the COVID-19 pandemic, one-third of women surveyed by the Guttmacher Institute (n = 2009) reported delaying or canceling a health care visit or having difficulty obtaining their contraception. Barriers to health care and contraception access were more common among Black and Hispanic women (vs White women), queer women (vs straight women), and low-income women (vs higher-income women).⁵

Following the overturning of Roe v Wade in June 2022, abortion access is now limited in parts of the United States. Given this significant policy change, physicians have an increasingly important role in providing contraception care and reducing barriers to contraception access. Since the SC forms of injectable contraception can be administered at home rather than in the health care setting, both the World Health Organization and the Centers for Disease Control and Prevention have recommended that self-administered injectable contraception be made widely available to expand access to contraception.^6,7

STUDY SUMMARY

Higher contraceptive continuation rates with comparable safety and efficacy

This 2019 systematic review and meta-­analysis evaluated the outcomes associated with use of self-administered DMPA-SC vs provider-administered DMPA in 5 countries.¹ The authors searched several electronic databases for peer-reviewed studies of women who chose the option to self-administer DMPA-SC vs those who received DMPA injections from a health care provider.

Continue to: Outcomes included pregnancy

Outcomes included pregnancy; adverse effects or events (bleeding, injection site reactions, mental health concerns); initial use of injectable contraception (contraception uptake); and continuation rate of injectable contraception. Two reviewers extracted the data and assessed trials for bias. The authors used random-effects models to calculate pooled relative risk (RR) for studies with the same outcomes.

For patients who prefer an injectable contraceptive, a self-administered formulation of DMPA appears to balance access with convenience without an increase in adverse outcomes.

The analysis included a total of 6 trials (N = 3851): 3 RCTs (n = 1263) and 3 controlled cohort studies (n = 2588), conducted in the United States (2 trials), Malawi, Scotland, Uganda, and Senegal. All studies compared 12-month continuation rates of self-injected DMPA-SC vs provider-administered DMPA­-SC or DMPA-IM every 3 months (12-13 weeks, with a window for early and late injections). Participants were at least 15 years of age (mean range, 26 to 29 years). In some studies, reminders (eg, texts, emails, calendar notifications) were provided to either the self-injection cohort only or to both cohorts of the trial. The RCTs were generally graded as having a low risk for bias, except for nonblinding of participants and personnel, given the nature of the interventions. The authors reported no evidence of significant heterogeneity in the studies.

The meta-analysis found higher continuation rates at 12 months with self-­administrated DMPA compared with provider administration in the RCTs (RR = 1.27; 95% CI, 1.16-1.39) and in the observational cohort studies (RR = 1.18; 95% CI, 1.10-1.26). Pregnancy outcomes were reported in 4 studies, with the meta-analysis finding no significant difference in pregnancy rates in 2 RCTs (RR = 0.58; 95% CI, 0.15-2.22) or 2 observational cohort studies (RR = 1.1; 95% CI, 0.23-5.26).

Adverse effects or events were reported in 4 studies: 2 cohort studies reported increased injection site reactions with self-administration, and 1 RCT reported increased injection site pain or irritation with self-administration at 3 and 9 months. No other reported adverse effects occurred at higher rates with self-administration vs provider administration.

WHAT’S NEW

Demonstrated effectiveness of self-administered formulation

This systematic review and meta-analysis demonstrated that self-administration of DMPA-SC leads to higher contraception continuation rates at 12 months, without notable increased pregnancy rates or adverse effects, when compared with provider-administered DMPA.

Continue to: CAVEATS

Outcome data limited to 12 months

Although self-administered DMPA-SC has the theoretical risk for user error and incorrect administration, this study did not find increased rates of pregnancy despite administration outside a health care center. However, the total number of pregnancies in each of the 4 studies measuring this outcome was low (< 5), and thus the authors noted that the effect size estimates may not be accurate.

Currently, there are no data on long-term outcomes beyond 12 months. Additionally, the health care visits for provider-administered DMPA every 3 months may afford other benefits, such as regular discussion of reproductive health concerns or testing for sexually transmitted infections, which must be weighed against the benefit of increased contraception access with self-administration. However, using the DMPA-SC self-administered formulation at home would not inhibit women from making separate health care visits as needed.

CHALLENGES TO IMPLEMENTATION

Limited resources to teach patients how to self-inject

Barriers to implementation include limited experience with prescribing DMPA-SC and changing practice culture to offer it to patients. Additionally, successful implementation of self-administered DMPA-SC is reliant on providing patients with appropriate information and training on self-injection, which requires knowledge, time, and other resources­ that may be limited in practices. Another potential barrier is product access, as not all insurers cover DMPA-SC and some pharmacies do not carry it.

Midwives provide safe primary care for pregnant women who are at various levels of medical risk in British Columbia, Canada, new data suggest.

In most cases, for midwifery clients, birth outcomes were similar to or were better than birth outcomes of patients who had physician-led or obstetrician-led care.

In addition, midwifery clients were less likely to experience preterm births or have low-birth-weight babies and to experience cesarean deliveries or births involving instruments.

“Based on previous research, we know that midwives provide safe care for healthy childbearing people or those with no or few risk factors that might complicate the pregnancy or birth,” lead author Kathrin Stoll, PhD, a research associate in the University of British Columbia’s department of family practice, told this news organization.

“What we didn’t know until now is whether midwives provide safe care to people with moderate and high medical risks and what proportion of B.C. [British Columbia] midwifery clients are low, moderate, and high risk,” she said. “This is important to know because of the misperception that midwives only look after low-risk people. This misperception is sometimes used against midwives to justify giving them fewer resources and supports.”

The study was published  in the Canadian Medical Association Journal.
 

Increasing demand

Registered midwives have been part of the health care system in British Columbia since 1998, according to the study authors. The number of pregnant people who are attended by midwives during birth has steadily increased from 4.8% in 2004-2005 to 15.6% in 2019-2020.

The investigators analyzed 2008-2018 data from the British Columbia Perinatal Data Registry, which contains data for 99% of births, including home births. Their analysis included 425,056 births for which a family physician, an obstetrician, or a midwife was listed as the most responsible provider (MRP). The investigators assessed pregnancy risk status (low, moderate, or high), which was determined on the basis of an adapted perinatal risk scoring system used by the Alberta Perinatal Health Program. They estimated the differences in neonatal and maternal outcomes between MRP groups by calculating adjusted absolute and relative risks.

Among the 425,056 births, 63,151 (14.9%) had a midwife as the MRP, 189,679 (44.6%) had a family physician, and 172,226 (40.5%) had an obstetrician. The antenatal risk score ranged from 0 to 23 (median score, 2).

The proportion of births with midwife-led care increased from 9.2% to 19.8% from 2008-2018. In 2018, midwives were listed as the MRP for 24.3% of low-risk, 14.3% of moderate-risk, and 7.9% of high-risk births in the province. This represented an absolute increase of 9.1% for low-risk, 7.7% for moderate-risk, and 5.7% for high-risk births during the study period.

Among the 12,169 at-home births that took place during the study period, 9,776 (80.3%) were low-risk, 2,329 (19.1%) were moderate-risk, and 64 (0.5%) were high-risk births. As the risk score increased, so did the proportion of midwifery and family physician clients who were delivered by obstetricians. Across all risk strata, more family physician clients than midwifery clients underwent deliveries by obstetricians.

Overall, the risk of perinatal death for midwifery clients was similar to the risk for those under the care of family physicians across all risk levels. Low- and moderate-risk clients with midwife-led care were significantly less likely to experience a perinatal death, compared with those with obstetrician-led care, although the adjusted absolute risk differences were small. In the high-risk group, there was no significant difference in the rate of perinatal deaths between midwife-led and physician-led care.

In addition, clients with midwife-led care were significantly less likely to experience preterm birth and have a low-birth-weight baby regardless of medical risk level. The adjusted relative risk of an Apgar score of less than 7 at 5 minutes was significantly lower for midwife-led care than for physician-led care for nearly all comparisons.

The cesarean delivery rate among midwifery clients in the low-risk group was 7.2%, compared with 12.2% for family physicians and 42.3% for obstetrician clients. Cesarean delivery rates increased for midwifery clients as medical risk increased but were significantly lower than the physician rates across all medical risk levels.

Among low-risk clients, the absolute risk reduction for cesarean delivery was 34.4% with midwife-led care, compared with obstetrician-led care. The absolute risk difference increased to 55.3% for moderate-risk clients and to 42.2% for high-risk clients.
 

Labor induction varied

Although low-risk midwifery clients were significantly less likely to experience labor induction with oxytocin, high-risk midwifery clients were more than twice as likely to undergo induction with oxytocin than obstetrician clients (adjusted absolute difference, 11.3%).

For most risk levels, midwifery clients were less likely to have an assisted vaginal birth than physician clients, and they were significantly more likely to have a spontaneous vaginal birth. Low-risk clients who had a midwife as the MRP were nearly twice as likely to have a spontaneous vaginal birth than obstetricians’ clients, and moderate-risk clients were nearly four times as likely to have a spontaneous vaginal birth.

The rates of vaginal birth after cesarean delivery (VBAC) were significantly higher when a midwife was the MRP. In comparing midwifery clients with family physician clients, the relative and absolute differences were small, but they were larger when comparing midwifery clients with obstetrician clients. Among low-risk clients, the VBAC rate was 85.3% among midwifery clients, compared with 78.6% among family physician clients and 51.5% among obstetrician clients.

In general, the prevalence rates of adverse maternal outcomes (including blood transfusion, intensive care admissions, uterine rupture, and postpartum wound infection) were low for midwifery clients across all risk levels.

Breast- or chest-feeding at birth was significantly more common among midwifery clients across all risk levels as well.

Today, nearly 1 in 4 childbearing people in British Columbia receive care from a midwife at some point during pregnancy, birth, or the postpartum period, the study authors write. During the past 20 years, the profile of clients has evolved to include more moderate- and high-risk patients.

“Clients with more complex medical needs take more time and need more support,” said Dr. Stoll. “This means that midwives continue to stay on call, responding to pages and urgent medical concerns for their clients with no pay for being on call, no days off even for sick days, and unsafe working hours, often working more than 24 hours at a time. If we want to expand midwifery to communities where they are needed most, we need to provide an enabling environment.”

Additional studies are needed as to how different practice and remuneration models affect clinical outcomes, health care costs, and client and provider experiences, the study authors write. At the same time, there are several barriers to obtaining funding, conducting studies, and publishing research by and about midwives in Canada, Dr. Stoll said – barriers that she and her co-authors faced.
 

Seeking broader access

Alixandra Bacon, a registered midwife and president of the Canadian Association of Midwives, said, “These findings demonstrate that pregnant people at any level of medical risk can benefit from midwifery care. This is a testament both to the benefits of the Canadian midwifery model of care and to the seamless integration of midwifery into collaborative teams and the health system.” Ms. Bacon wasn’t involved with this study.

“If we can realize our goal of equitable access to midwifery care for all families in Canada, we can help to decrease rates of unnecessary medical intervention, preterm labor, and stillbirth,” she added.

“Midwifery is well established across most of Canada. This is yet one more piece of evidence that shows the clinical benefits of midwifery care,” Jasmin Tecson, a registered midwife and president of the Association of Ontario Midwives, said in an interview.

Ms. Tecson, who wasn’t involved with this study, noted the increasing number of clients with more complex health and social needs in Ontario. “It is time to think about how the skills and knowledge of midwives can be used with clients of different risk profiles and how the current scope of practice of midwives can be optimized and expanded,” she said. “For example, Ontario midwives are still required to prescribe medications from a limited list, despite the potential additional clinical risks and health system costs that this creates.”

The study received financial support from the University of British Columbia Stollery Fund and the University of British Columbia Work Learn Program. Dr. Stoll has an unpaid role with the Midwives Association Contract Negotiation Advisory Council. Ms. Bacon and Ms. Tecson disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Midwives provide safe primary care for pregnant women who are at various levels of medical risk in British Columbia, Canada, new data suggest.

In most cases, for midwifery clients, birth outcomes were similar to or were better than birth outcomes of patients who had physician-led or obstetrician-led care.

In addition, midwifery clients were less likely to experience preterm births or have low-birth-weight babies and to experience cesarean deliveries or births involving instruments.

“Based on previous research, we know that midwives provide safe care for healthy childbearing people or those with no or few risk factors that might complicate the pregnancy or birth,” lead author Kathrin Stoll, PhD, a research associate in the University of British Columbia’s department of family practice, told this news organization.

“What we didn’t know until now is whether midwives provide safe care to people with moderate and high medical risks and what proportion of B.C. [British Columbia] midwifery clients are low, moderate, and high risk,” she said. “This is important to know because of the misperception that midwives only look after low-risk people. This misperception is sometimes used against midwives to justify giving them fewer resources and supports.”

The study was published  in the Canadian Medical Association Journal.
 

Increasing demand

Registered midwives have been part of the health care system in British Columbia since 1998, according to the study authors. The number of pregnant people who are attended by midwives during birth has steadily increased from 4.8% in 2004-2005 to 15.6% in 2019-2020.

The investigators analyzed 2008-2018 data from the British Columbia Perinatal Data Registry, which contains data for 99% of births, including home births. Their analysis included 425,056 births for which a family physician, an obstetrician, or a midwife was listed as the most responsible provider (MRP). The investigators assessed pregnancy risk status (low, moderate, or high), which was determined on the basis of an adapted perinatal risk scoring system used by the Alberta Perinatal Health Program. They estimated the differences in neonatal and maternal outcomes between MRP groups by calculating adjusted absolute and relative risks.

Among the 425,056 births, 63,151 (14.9%) had a midwife as the MRP, 189,679 (44.6%) had a family physician, and 172,226 (40.5%) had an obstetrician. The antenatal risk score ranged from 0 to 23 (median score, 2).

The proportion of births with midwife-led care increased from 9.2% to 19.8% from 2008-2018. In 2018, midwives were listed as the MRP for 24.3% of low-risk, 14.3% of moderate-risk, and 7.9% of high-risk births in the province. This represented an absolute increase of 9.1% for low-risk, 7.7% for moderate-risk, and 5.7% for high-risk births during the study period.

Among the 12,169 at-home births that took place during the study period, 9,776 (80.3%) were low-risk, 2,329 (19.1%) were moderate-risk, and 64 (0.5%) were high-risk births. As the risk score increased, so did the proportion of midwifery and family physician clients who were delivered by obstetricians. Across all risk strata, more family physician clients than midwifery clients underwent deliveries by obstetricians.

Overall, the risk of perinatal death for midwifery clients was similar to the risk for those under the care of family physicians across all risk levels. Low- and moderate-risk clients with midwife-led care were significantly less likely to experience a perinatal death, compared with those with obstetrician-led care, although the adjusted absolute risk differences were small. In the high-risk group, there was no significant difference in the rate of perinatal deaths between midwife-led and physician-led care.

In addition, clients with midwife-led care were significantly less likely to experience preterm birth and have a low-birth-weight baby regardless of medical risk level. The adjusted relative risk of an Apgar score of less than 7 at 5 minutes was significantly lower for midwife-led care than for physician-led care for nearly all comparisons.

The cesarean delivery rate among midwifery clients in the low-risk group was 7.2%, compared with 12.2% for family physicians and 42.3% for obstetrician clients. Cesarean delivery rates increased for midwifery clients as medical risk increased but were significantly lower than the physician rates across all medical risk levels.

Among low-risk clients, the absolute risk reduction for cesarean delivery was 34.4% with midwife-led care, compared with obstetrician-led care. The absolute risk difference increased to 55.3% for moderate-risk clients and to 42.2% for high-risk clients.
 

Labor induction varied

Although low-risk midwifery clients were significantly less likely to experience labor induction with oxytocin, high-risk midwifery clients were more than twice as likely to undergo induction with oxytocin than obstetrician clients (adjusted absolute difference, 11.3%).

For most risk levels, midwifery clients were less likely to have an assisted vaginal birth than physician clients, and they were significantly more likely to have a spontaneous vaginal birth. Low-risk clients who had a midwife as the MRP were nearly twice as likely to have a spontaneous vaginal birth than obstetricians’ clients, and moderate-risk clients were nearly four times as likely to have a spontaneous vaginal birth.

The rates of vaginal birth after cesarean delivery (VBAC) were significantly higher when a midwife was the MRP. In comparing midwifery clients with family physician clients, the relative and absolute differences were small, but they were larger when comparing midwifery clients with obstetrician clients. Among low-risk clients, the VBAC rate was 85.3% among midwifery clients, compared with 78.6% among family physician clients and 51.5% among obstetrician clients.

In general, the prevalence rates of adverse maternal outcomes (including blood transfusion, intensive care admissions, uterine rupture, and postpartum wound infection) were low for midwifery clients across all risk levels.

Breast- or chest-feeding at birth was significantly more common among midwifery clients across all risk levels as well.

Today, nearly 1 in 4 childbearing people in British Columbia receive care from a midwife at some point during pregnancy, birth, or the postpartum period, the study authors write. During the past 20 years, the profile of clients has evolved to include more moderate- and high-risk patients.

“Clients with more complex medical needs take more time and need more support,” said Dr. Stoll. “This means that midwives continue to stay on call, responding to pages and urgent medical concerns for their clients with no pay for being on call, no days off even for sick days, and unsafe working hours, often working more than 24 hours at a time. If we want to expand midwifery to communities where they are needed most, we need to provide an enabling environment.”

Additional studies are needed as to how different practice and remuneration models affect clinical outcomes, health care costs, and client and provider experiences, the study authors write. At the same time, there are several barriers to obtaining funding, conducting studies, and publishing research by and about midwives in Canada, Dr. Stoll said – barriers that she and her co-authors faced.
 

Seeking broader access

Alixandra Bacon, a registered midwife and president of the Canadian Association of Midwives, said, “These findings demonstrate that pregnant people at any level of medical risk can benefit from midwifery care. This is a testament both to the benefits of the Canadian midwifery model of care and to the seamless integration of midwifery into collaborative teams and the health system.” Ms. Bacon wasn’t involved with this study.

“If we can realize our goal of equitable access to midwifery care for all families in Canada, we can help to decrease rates of unnecessary medical intervention, preterm labor, and stillbirth,” she added.

“Midwifery is well established across most of Canada. This is yet one more piece of evidence that shows the clinical benefits of midwifery care,” Jasmin Tecson, a registered midwife and president of the Association of Ontario Midwives, said in an interview.

Ms. Tecson, who wasn’t involved with this study, noted the increasing number of clients with more complex health and social needs in Ontario. “It is time to think about how the skills and knowledge of midwives can be used with clients of different risk profiles and how the current scope of practice of midwives can be optimized and expanded,” she said. “For example, Ontario midwives are still required to prescribe medications from a limited list, despite the potential additional clinical risks and health system costs that this creates.”

The study received financial support from the University of British Columbia Stollery Fund and the University of British Columbia Work Learn Program. Dr. Stoll has an unpaid role with the Midwives Association Contract Negotiation Advisory Council. Ms. Bacon and Ms. Tecson disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Midwives provide safe primary care for pregnant women who are at various levels of medical risk in British Columbia, Canada, new data suggest.

In most cases, for midwifery clients, birth outcomes were similar to or were better than birth outcomes of patients who had physician-led or obstetrician-led care.

In addition, midwifery clients were less likely to experience preterm births or have low-birth-weight babies and to experience cesarean deliveries or births involving instruments.

“Based on previous research, we know that midwives provide safe care for healthy childbearing people or those with no or few risk factors that might complicate the pregnancy or birth,” lead author Kathrin Stoll, PhD, a research associate in the University of British Columbia’s department of family practice, told this news organization.

“What we didn’t know until now is whether midwives provide safe care to people with moderate and high medical risks and what proportion of B.C. [British Columbia] midwifery clients are low, moderate, and high risk,” she said. “This is important to know because of the misperception that midwives only look after low-risk people. This misperception is sometimes used against midwives to justify giving them fewer resources and supports.”

The study was published  in the Canadian Medical Association Journal.
 

Increasing demand

Registered midwives have been part of the health care system in British Columbia since 1998, according to the study authors. The number of pregnant people who are attended by midwives during birth has steadily increased from 4.8% in 2004-2005 to 15.6% in 2019-2020.

The investigators analyzed 2008-2018 data from the British Columbia Perinatal Data Registry, which contains data for 99% of births, including home births. Their analysis included 425,056 births for which a family physician, an obstetrician, or a midwife was listed as the most responsible provider (MRP). The investigators assessed pregnancy risk status (low, moderate, or high), which was determined on the basis of an adapted perinatal risk scoring system used by the Alberta Perinatal Health Program. They estimated the differences in neonatal and maternal outcomes between MRP groups by calculating adjusted absolute and relative risks.

Among the 425,056 births, 63,151 (14.9%) had a midwife as the MRP, 189,679 (44.6%) had a family physician, and 172,226 (40.5%) had an obstetrician. The antenatal risk score ranged from 0 to 23 (median score, 2).

The proportion of births with midwife-led care increased from 9.2% to 19.8% from 2008-2018. In 2018, midwives were listed as the MRP for 24.3% of low-risk, 14.3% of moderate-risk, and 7.9% of high-risk births in the province. This represented an absolute increase of 9.1% for low-risk, 7.7% for moderate-risk, and 5.7% for high-risk births during the study period.

Among the 12,169 at-home births that took place during the study period, 9,776 (80.3%) were low-risk, 2,329 (19.1%) were moderate-risk, and 64 (0.5%) were high-risk births. As the risk score increased, so did the proportion of midwifery and family physician clients who were delivered by obstetricians. Across all risk strata, more family physician clients than midwifery clients underwent deliveries by obstetricians.

Overall, the risk of perinatal death for midwifery clients was similar to the risk for those under the care of family physicians across all risk levels. Low- and moderate-risk clients with midwife-led care were significantly less likely to experience a perinatal death, compared with those with obstetrician-led care, although the adjusted absolute risk differences were small. In the high-risk group, there was no significant difference in the rate of perinatal deaths between midwife-led and physician-led care.

In addition, clients with midwife-led care were significantly less likely to experience preterm birth and have a low-birth-weight baby regardless of medical risk level. The adjusted relative risk of an Apgar score of less than 7 at 5 minutes was significantly lower for midwife-led care than for physician-led care for nearly all comparisons.

The cesarean delivery rate among midwifery clients in the low-risk group was 7.2%, compared with 12.2% for family physicians and 42.3% for obstetrician clients. Cesarean delivery rates increased for midwifery clients as medical risk increased but were significantly lower than the physician rates across all medical risk levels.

Among low-risk clients, the absolute risk reduction for cesarean delivery was 34.4% with midwife-led care, compared with obstetrician-led care. The absolute risk difference increased to 55.3% for moderate-risk clients and to 42.2% for high-risk clients.
 

Labor induction varied

Although low-risk midwifery clients were significantly less likely to experience labor induction with oxytocin, high-risk midwifery clients were more than twice as likely to undergo induction with oxytocin than obstetrician clients (adjusted absolute difference, 11.3%).

For most risk levels, midwifery clients were less likely to have an assisted vaginal birth than physician clients, and they were significantly more likely to have a spontaneous vaginal birth. Low-risk clients who had a midwife as the MRP were nearly twice as likely to have a spontaneous vaginal birth than obstetricians’ clients, and moderate-risk clients were nearly four times as likely to have a spontaneous vaginal birth.

The rates of vaginal birth after cesarean delivery (VBAC) were significantly higher when a midwife was the MRP. In comparing midwifery clients with family physician clients, the relative and absolute differences were small, but they were larger when comparing midwifery clients with obstetrician clients. Among low-risk clients, the VBAC rate was 85.3% among midwifery clients, compared with 78.6% among family physician clients and 51.5% among obstetrician clients.

In general, the prevalence rates of adverse maternal outcomes (including blood transfusion, intensive care admissions, uterine rupture, and postpartum wound infection) were low for midwifery clients across all risk levels.

Breast- or chest-feeding at birth was significantly more common among midwifery clients across all risk levels as well.

Today, nearly 1 in 4 childbearing people in British Columbia receive care from a midwife at some point during pregnancy, birth, or the postpartum period, the study authors write. During the past 20 years, the profile of clients has evolved to include more moderate- and high-risk patients.

“Clients with more complex medical needs take more time and need more support,” said Dr. Stoll. “This means that midwives continue to stay on call, responding to pages and urgent medical concerns for their clients with no pay for being on call, no days off even for sick days, and unsafe working hours, often working more than 24 hours at a time. If we want to expand midwifery to communities where they are needed most, we need to provide an enabling environment.”

Additional studies are needed as to how different practice and remuneration models affect clinical outcomes, health care costs, and client and provider experiences, the study authors write. At the same time, there are several barriers to obtaining funding, conducting studies, and publishing research by and about midwives in Canada, Dr. Stoll said – barriers that she and her co-authors faced.
 

Seeking broader access

Alixandra Bacon, a registered midwife and president of the Canadian Association of Midwives, said, “These findings demonstrate that pregnant people at any level of medical risk can benefit from midwifery care. This is a testament both to the benefits of the Canadian midwifery model of care and to the seamless integration of midwifery into collaborative teams and the health system.” Ms. Bacon wasn’t involved with this study.

“If we can realize our goal of equitable access to midwifery care for all families in Canada, we can help to decrease rates of unnecessary medical intervention, preterm labor, and stillbirth,” she added.

“Midwifery is well established across most of Canada. This is yet one more piece of evidence that shows the clinical benefits of midwifery care,” Jasmin Tecson, a registered midwife and president of the Association of Ontario Midwives, said in an interview.

Ms. Tecson, who wasn’t involved with this study, noted the increasing number of clients with more complex health and social needs in Ontario. “It is time to think about how the skills and knowledge of midwives can be used with clients of different risk profiles and how the current scope of practice of midwives can be optimized and expanded,” she said. “For example, Ontario midwives are still required to prescribe medications from a limited list, despite the potential additional clinical risks and health system costs that this creates.”

The study received financial support from the University of British Columbia Stollery Fund and the University of British Columbia Work Learn Program. Dr. Stoll has an unpaid role with the Midwives Association Contract Negotiation Advisory Council. Ms. Bacon and Ms. Tecson disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

New national data on the occurrence of triple-negative breast cancer (TNBC) among different racial groups confirms that the disease is more common among Black women nationwide. A state-by-state analysis in the study, published online  in JAMA Oncology, shows that these trends persist at the state level.

The analysis revealed that incidence rate ratios of TNBC were significantly higher among Black women, compared with White women, in all states with data on this population. Rates ranged from a low of 1.38 in Colorado to a high of 2.32 in Delaware.

The state-level disparities highlight gaps in physicians’ understanding of how social factors contribute to disparities in TNBC risk and the need “to develop effective preventative measures,” the study authors explain.

“We’ve realized for a long time that Black women have a higher incidence of TNBC. This is related to the genetic signature of the cancer. So that is not at all surprising,” said Arnold M. Baskies, MD, past chairman of the national board of directors of the American Cancer Society, Atlanta, who was not involved in the research. However, “the variance of TNBC among women from state to state is somewhat surprising.”

Existing research shows that TNBC is diagnosed more frequently among non-Hispanic Black women than among other populations in the United States, but it’s unclear whether these racial and ethnic disparities differ at the state level.

The authors identified 133,579 women with TNBC from the U.S. Cancer Statistics Public Use Research Database whose conditions were diagnosed from January 2015 through the end of December 2019. Most patients (64.5%) were White, 21.5% were Black, nearly 10% were Hispanic, 3.7% were Asian or Pacific Islander, and 0.6% were American Indian or Alaska Native. States with fewer than 30 cases were excluded, as was Nevada, owing to concerns regarding data quality. That left eight states for American Indian or Alaska Natives, 22 for Asian or Pacific Islanders, 35 for Hispanic women, 38 for Black women, and 50 for White women.

Overall, the incidence ratios of TNBC were highest among Black women (IR, 25.2 per 100,000), followed by White women (IR, 12.9 per 100,000), American Indian or Alaska Native women (IR, 11.2 per 100,000), Hispanic women (IR, 11.1 per 100,000 women), and Asian or Pacific Islander (IR, 9.0 per 100,000) women.

The authors also uncovered significant state-by-state variations in TNBC incidence by racial and ethnic groups. The lowest IR rates occurred among Asian or Pacific Islander women in Oregon and Pennsylvania – fewer than 7 per 100,000 women – and the highest occurred among Black women in Delaware, Missouri, Louisiana, and Mississippi – more than 29 per 100,000 women.

In the 38 states for which data on Black women were available, IR rates were significantly higher among Black women in all 38, compared with White women. The IR rates ranged from a low of 1.38 (IR, 17.4 per 100 000 women) in Colorado to a high of 2.32 (IR, 32.0 per 100 000 women) in Delaware.

While genetics play a role in TNBC risk, “the substantial geographic variation we found within each racial and ethnic group is highly suggestive that there are structural, environmental, and social factors at play in determining women’s risk of TNBC,” said lead study author Hyuna Sung, PhD, senior principal scientist and cancer epidemiologist at the American Cancer Society, Atlanta.

Existing evidence indicates that Black and White women living in socioeconomically disadvantaged neighborhoods are at higher risk of developing more aggressive subtypes of breast cancer, Dr. Sung said. Another factor, Dr. Sung and co-authors note, is breastfeeding. Across races, women who breastfeed have lower rates of TNBC.

Getting more definitive answers as to what causes differences in TNBC rates across states and what strategies can help reduce these disparities will be difficult and requires more research. “We really need to do a better job at researching and treating TNBC to improve health care equality for all women,” Dr. Baskies said. “The mortality rates from this cancer are high, and we rely heavily on surgery and toxic chemotherapy to treat it.”

Dr. Sung agreed, noting that “the observed state variation in TNBC rates merits further studies with risk factor data at multiple levels to better understand the associations of social exposures with the risk of TNBC.”

In states such as Louisiana and Mississippi, which are known to have a disproportionately higher burden of many types of cancers, “addressing barriers to access to preventive care and empowering public health efforts to promote a healthy living environment are the best policy prescription that could be deduced from our results,” Dr. Sung concluded.

Dr. Baskies is on the board of directors of Anixa Biosciences, which is currently conducting a clinical trial of a TNBC vaccine at the Cleveland Clinic. Dr. Sung has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

New national data on the occurrence of triple-negative breast cancer (TNBC) among different racial groups confirms that the disease is more common among Black women nationwide. A state-by-state analysis in the study, published online  in JAMA Oncology, shows that these trends persist at the state level.

The analysis revealed that incidence rate ratios of TNBC were significantly higher among Black women, compared with White women, in all states with data on this population. Rates ranged from a low of 1.38 in Colorado to a high of 2.32 in Delaware.

The state-level disparities highlight gaps in physicians’ understanding of how social factors contribute to disparities in TNBC risk and the need “to develop effective preventative measures,” the study authors explain.

“We’ve realized for a long time that Black women have a higher incidence of TNBC. This is related to the genetic signature of the cancer. So that is not at all surprising,” said Arnold M. Baskies, MD, past chairman of the national board of directors of the American Cancer Society, Atlanta, who was not involved in the research. However, “the variance of TNBC among women from state to state is somewhat surprising.”

Existing research shows that TNBC is diagnosed more frequently among non-Hispanic Black women than among other populations in the United States, but it’s unclear whether these racial and ethnic disparities differ at the state level.

The authors identified 133,579 women with TNBC from the U.S. Cancer Statistics Public Use Research Database whose conditions were diagnosed from January 2015 through the end of December 2019. Most patients (64.5%) were White, 21.5% were Black, nearly 10% were Hispanic, 3.7% were Asian or Pacific Islander, and 0.6% were American Indian or Alaska Native. States with fewer than 30 cases were excluded, as was Nevada, owing to concerns regarding data quality. That left eight states for American Indian or Alaska Natives, 22 for Asian or Pacific Islanders, 35 for Hispanic women, 38 for Black women, and 50 for White women.

Overall, the incidence ratios of TNBC were highest among Black women (IR, 25.2 per 100,000), followed by White women (IR, 12.9 per 100,000), American Indian or Alaska Native women (IR, 11.2 per 100,000), Hispanic women (IR, 11.1 per 100,000 women), and Asian or Pacific Islander (IR, 9.0 per 100,000) women.

The authors also uncovered significant state-by-state variations in TNBC incidence by racial and ethnic groups. The lowest IR rates occurred among Asian or Pacific Islander women in Oregon and Pennsylvania – fewer than 7 per 100,000 women – and the highest occurred among Black women in Delaware, Missouri, Louisiana, and Mississippi – more than 29 per 100,000 women.

In the 38 states for which data on Black women were available, IR rates were significantly higher among Black women in all 38, compared with White women. The IR rates ranged from a low of 1.38 (IR, 17.4 per 100 000 women) in Colorado to a high of 2.32 (IR, 32.0 per 100 000 women) in Delaware.

While genetics play a role in TNBC risk, “the substantial geographic variation we found within each racial and ethnic group is highly suggestive that there are structural, environmental, and social factors at play in determining women’s risk of TNBC,” said lead study author Hyuna Sung, PhD, senior principal scientist and cancer epidemiologist at the American Cancer Society, Atlanta.

Existing evidence indicates that Black and White women living in socioeconomically disadvantaged neighborhoods are at higher risk of developing more aggressive subtypes of breast cancer, Dr. Sung said. Another factor, Dr. Sung and co-authors note, is breastfeeding. Across races, women who breastfeed have lower rates of TNBC.

Getting more definitive answers as to what causes differences in TNBC rates across states and what strategies can help reduce these disparities will be difficult and requires more research. “We really need to do a better job at researching and treating TNBC to improve health care equality for all women,” Dr. Baskies said. “The mortality rates from this cancer are high, and we rely heavily on surgery and toxic chemotherapy to treat it.”

Dr. Sung agreed, noting that “the observed state variation in TNBC rates merits further studies with risk factor data at multiple levels to better understand the associations of social exposures with the risk of TNBC.”

In states such as Louisiana and Mississippi, which are known to have a disproportionately higher burden of many types of cancers, “addressing barriers to access to preventive care and empowering public health efforts to promote a healthy living environment are the best policy prescription that could be deduced from our results,” Dr. Sung concluded.

Dr. Baskies is on the board of directors of Anixa Biosciences, which is currently conducting a clinical trial of a TNBC vaccine at the Cleveland Clinic. Dr. Sung has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

New national data on the occurrence of triple-negative breast cancer (TNBC) among different racial groups confirms that the disease is more common among Black women nationwide. A state-by-state analysis in the study, published online  in JAMA Oncology, shows that these trends persist at the state level.

The analysis revealed that incidence rate ratios of TNBC were significantly higher among Black women, compared with White women, in all states with data on this population. Rates ranged from a low of 1.38 in Colorado to a high of 2.32 in Delaware.

The state-level disparities highlight gaps in physicians’ understanding of how social factors contribute to disparities in TNBC risk and the need “to develop effective preventative measures,” the study authors explain.

“We’ve realized for a long time that Black women have a higher incidence of TNBC. This is related to the genetic signature of the cancer. So that is not at all surprising,” said Arnold M. Baskies, MD, past chairman of the national board of directors of the American Cancer Society, Atlanta, who was not involved in the research. However, “the variance of TNBC among women from state to state is somewhat surprising.”

Existing research shows that TNBC is diagnosed more frequently among non-Hispanic Black women than among other populations in the United States, but it’s unclear whether these racial and ethnic disparities differ at the state level.

The authors identified 133,579 women with TNBC from the U.S. Cancer Statistics Public Use Research Database whose conditions were diagnosed from January 2015 through the end of December 2019. Most patients (64.5%) were White, 21.5% were Black, nearly 10% were Hispanic, 3.7% were Asian or Pacific Islander, and 0.6% were American Indian or Alaska Native. States with fewer than 30 cases were excluded, as was Nevada, owing to concerns regarding data quality. That left eight states for American Indian or Alaska Natives, 22 for Asian or Pacific Islanders, 35 for Hispanic women, 38 for Black women, and 50 for White women.

Overall, the incidence ratios of TNBC were highest among Black women (IR, 25.2 per 100,000), followed by White women (IR, 12.9 per 100,000), American Indian or Alaska Native women (IR, 11.2 per 100,000), Hispanic women (IR, 11.1 per 100,000 women), and Asian or Pacific Islander (IR, 9.0 per 100,000) women.

The authors also uncovered significant state-by-state variations in TNBC incidence by racial and ethnic groups. The lowest IR rates occurred among Asian or Pacific Islander women in Oregon and Pennsylvania – fewer than 7 per 100,000 women – and the highest occurred among Black women in Delaware, Missouri, Louisiana, and Mississippi – more than 29 per 100,000 women.

In the 38 states for which data on Black women were available, IR rates were significantly higher among Black women in all 38, compared with White women. The IR rates ranged from a low of 1.38 (IR, 17.4 per 100 000 women) in Colorado to a high of 2.32 (IR, 32.0 per 100 000 women) in Delaware.

While genetics play a role in TNBC risk, “the substantial geographic variation we found within each racial and ethnic group is highly suggestive that there are structural, environmental, and social factors at play in determining women’s risk of TNBC,” said lead study author Hyuna Sung, PhD, senior principal scientist and cancer epidemiologist at the American Cancer Society, Atlanta.

Existing evidence indicates that Black and White women living in socioeconomically disadvantaged neighborhoods are at higher risk of developing more aggressive subtypes of breast cancer, Dr. Sung said. Another factor, Dr. Sung and co-authors note, is breastfeeding. Across races, women who breastfeed have lower rates of TNBC.

Getting more definitive answers as to what causes differences in TNBC rates across states and what strategies can help reduce these disparities will be difficult and requires more research. “We really need to do a better job at researching and treating TNBC to improve health care equality for all women,” Dr. Baskies said. “The mortality rates from this cancer are high, and we rely heavily on surgery and toxic chemotherapy to treat it.”

Dr. Sung agreed, noting that “the observed state variation in TNBC rates merits further studies with risk factor data at multiple levels to better understand the associations of social exposures with the risk of TNBC.”

In states such as Louisiana and Mississippi, which are known to have a disproportionately higher burden of many types of cancers, “addressing barriers to access to preventive care and empowering public health efforts to promote a healthy living environment are the best policy prescription that could be deduced from our results,” Dr. Sung concluded.

Dr. Baskies is on the board of directors of Anixa Biosciences, which is currently conducting a clinical trial of a TNBC vaccine at the Cleveland Clinic. Dr. Sung has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Sam Chavarría said her doctor was clear about the birth defects her medication could cause if she became pregnant but agreed to keep her on it as long as she had an IUD.

As she was waiting to get her contraceptive intrauterine device replaced at her local clinic, however, the billing nurse told her that her insurance wouldn’t cover the removal – or a new IUD. Chavarría didn’t understand why not.

“Then she said very delicately, ‘Well, people on this insurance typically tend to be older,’ ” Chavarría recalled.

Although Chavarría is 34, she is enrolled in Medicare, the government insurance program designed for those 65 and older. Chavarría, who lives in Houston, is disabled by fibromyalgia, rheumatoid arthritis, and mental health issues. Medicare automatically enrolls anyone who has received Social Security disability benefits for two years and this was her first time getting an IUD while in the government program.

Without insurance, just removing her expired IUD would cost Chavarría $350 out of pocket; exchanging it for a new one would be $2,000. She left the clinic in tears.

Chavarría’s experience is not rare. Medicare was originally intended for people of retirement age. Over the years, the program has evolved to include new populations, such as those who have disabilities or are critically ill, said Jennifer Lea Huer, a public health expert at Yale University, New Haven, Conn. In 2020, 1.7 million people ages 18-44 were enrolled in Medicare.

An estimated 70% of childbearing-age women on Medicare are also eligible for Medicaid, a state and federal program for those with low incomes, which should fill the gap for contraception. It’s not clear how many transgender or nonbinary people – who also might need contraception – are on Medicare or are eligible for Medicaid.

Medicaid, like the plans offered via the federal Affordable Care Act, mandates coverage of birth control. But those who aren’t eligible for Medicaid are left in the lurch – Medicare’s origins mean it does not require access to birth control.

Traditional Medicare includes two parts: Part A covers hospital costs, while Part B covers physicians’ care and certain other services, such as ambulance rides. Neither ordinarily includes contraception.

People can get contraception through a Medicare Advantage plan or Part D of Medicare, which covers prescription drugs, but those come at a cost. And even people who pay for Part D often aren’t covered for some types of birth control, such as IUDs.

“So, if you are disabled, if you are locked outside of the labor market, if you do not have the means or any other way to financially support yourself, you were likely still on traditional Medicare, which is Part A and Part B,” Huer said. “In which case, your access to contraception is incredibly difficult.”

Contraception for those with traditional Medicare is given on a case-by-case basis, Huer said. It can be covered only if a doctor can make a credible case that the patient needs it for medical reasons – because their body cannot sustain a pregnancy – as opposed to merely wanting to avoid one.

“You have to have a champion physician who’s willing to partner with you and make those arguments,” Huer said.

That’s what Chavarría’s doctor tried to do. Before she left the clinic, staffers there told her they would try to make the case she needed the IUD for medical reasons. The IUD exchange was scheduled almost 10 weeks later, but during those weeks, she got pregnant. Her body couldn’t sustain a pregnancy, so she and her partner rushed to get an abortion just before Texas tightened its rules Sept. 1, 2021.

“If Medicare had just covered the IUD removal or exchange to begin with, none of this would have happened,” Chavarría said. “It would have saved me having to make a really tough decision that I never thought I’d have to make.”

Women with disabilities often face a stigma from health care practitioners, especially when it comes to birth control, said Willi Horner-Johnson, a public health researcher specializing in disabilities at Oregon Health & Science University, Portland. In her research, women with disabilities have described being treated like children or having to go to multiple doctors to find someone with whom they felt comfortable.

“We don’t want to acknowledge that disabled people have sex,” said Miriam Garber, a 36-year-old sex worker who lives in Rhode Island and is also on Medicare because of her disabilities. Garber got an IUD from Planned Parenthood because her insurance wouldn’t cover it.

Even those who pay for Part D to have their prescription drugs covered and have a “champion physician” face difficulties. Liz Moore, a nonbinary person in their 30s who lives in the Washington, D.C., area, could not get Medicare to pay for the Mirena IUD their doctor prescribed for their polycystic ovary syndrome. Moore is disabled with fibromyalgia and dysautonomia, a condition of the autonomic nervous system, which regulates breathing, heart rate, and more.

“After literally months of phone calls, it seemed like my Medicare Part D and original Medicare could not agree on who should pay for my IUD,” they wrote in a direct message. “Was it a prescription or durable medical equipment?”

When Moore finally learned it would cost $800 upfront, they said, they decided to get a hysterectomy – which Medicare would pay for – instead.

Chavarría’s doctor told her a tubal ligation also was more likely to be approved by Medicare than an IUD, because older people have that procedure more often. Like all surgeries, both come with risks of complications and recovery.

Even for those on both Medicare and Medicaid, getting contraception also isn’t always easy, as in Katie Elizabeth Walsh’s case.

Walsh, 34, who lives in northeastern Connecticut, is disabled by a traumatic brain injury, depression, and chronic fatigue syndrome. She got an IUD at an ob.gyn. clinic and was told there her insurance would cover it.

Then she got a bill for nearly $2,000.

Medicaid should cover contraceptive devices for dual-eligibility people, according to Centers for Medicare & Medicaid Services policy guidance, but when Walsh tried to get her bill covered, Medicare and Medicaid could not agree on which of them should pay.

“Every single time I have called one of the insurance offices, they are like, ‘Oh, no, you have to talk to the other one, and we don’t really talk to each other,’ ” Walsh said.

Walsh said the hassle to get her contraception covered feels like a kick in the stomach: “Like truly you do not have a place in this world, and your insurance is telling you that.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Sam Chavarría said her doctor was clear about the birth defects her medication could cause if she became pregnant but agreed to keep her on it as long as she had an IUD.

As she was waiting to get her contraceptive intrauterine device replaced at her local clinic, however, the billing nurse told her that her insurance wouldn’t cover the removal – or a new IUD. Chavarría didn’t understand why not.

“Then she said very delicately, ‘Well, people on this insurance typically tend to be older,’ ” Chavarría recalled.

Although Chavarría is 34, she is enrolled in Medicare, the government insurance program designed for those 65 and older. Chavarría, who lives in Houston, is disabled by fibromyalgia, rheumatoid arthritis, and mental health issues. Medicare automatically enrolls anyone who has received Social Security disability benefits for two years and this was her first time getting an IUD while in the government program.

Without insurance, just removing her expired IUD would cost Chavarría $350 out of pocket; exchanging it for a new one would be $2,000. She left the clinic in tears.

Chavarría’s experience is not rare. Medicare was originally intended for people of retirement age. Over the years, the program has evolved to include new populations, such as those who have disabilities or are critically ill, said Jennifer Lea Huer, a public health expert at Yale University, New Haven, Conn. In 2020, 1.7 million people ages 18-44 were enrolled in Medicare.

An estimated 70% of childbearing-age women on Medicare are also eligible for Medicaid, a state and federal program for those with low incomes, which should fill the gap for contraception. It’s not clear how many transgender or nonbinary people – who also might need contraception – are on Medicare or are eligible for Medicaid.

Medicaid, like the plans offered via the federal Affordable Care Act, mandates coverage of birth control. But those who aren’t eligible for Medicaid are left in the lurch – Medicare’s origins mean it does not require access to birth control.

Traditional Medicare includes two parts: Part A covers hospital costs, while Part B covers physicians’ care and certain other services, such as ambulance rides. Neither ordinarily includes contraception.

People can get contraception through a Medicare Advantage plan or Part D of Medicare, which covers prescription drugs, but those come at a cost. And even people who pay for Part D often aren’t covered for some types of birth control, such as IUDs.

“So, if you are disabled, if you are locked outside of the labor market, if you do not have the means or any other way to financially support yourself, you were likely still on traditional Medicare, which is Part A and Part B,” Huer said. “In which case, your access to contraception is incredibly difficult.”

Contraception for those with traditional Medicare is given on a case-by-case basis, Huer said. It can be covered only if a doctor can make a credible case that the patient needs it for medical reasons – because their body cannot sustain a pregnancy – as opposed to merely wanting to avoid one.

“You have to have a champion physician who’s willing to partner with you and make those arguments,” Huer said.

That’s what Chavarría’s doctor tried to do. Before she left the clinic, staffers there told her they would try to make the case she needed the IUD for medical reasons. The IUD exchange was scheduled almost 10 weeks later, but during those weeks, she got pregnant. Her body couldn’t sustain a pregnancy, so she and her partner rushed to get an abortion just before Texas tightened its rules Sept. 1, 2021.

“If Medicare had just covered the IUD removal or exchange to begin with, none of this would have happened,” Chavarría said. “It would have saved me having to make a really tough decision that I never thought I’d have to make.”

Women with disabilities often face a stigma from health care practitioners, especially when it comes to birth control, said Willi Horner-Johnson, a public health researcher specializing in disabilities at Oregon Health & Science University, Portland. In her research, women with disabilities have described being treated like children or having to go to multiple doctors to find someone with whom they felt comfortable.

“We don’t want to acknowledge that disabled people have sex,” said Miriam Garber, a 36-year-old sex worker who lives in Rhode Island and is also on Medicare because of her disabilities. Garber got an IUD from Planned Parenthood because her insurance wouldn’t cover it.

Even those who pay for Part D to have their prescription drugs covered and have a “champion physician” face difficulties. Liz Moore, a nonbinary person in their 30s who lives in the Washington, D.C., area, could not get Medicare to pay for the Mirena IUD their doctor prescribed for their polycystic ovary syndrome. Moore is disabled with fibromyalgia and dysautonomia, a condition of the autonomic nervous system, which regulates breathing, heart rate, and more.

“After literally months of phone calls, it seemed like my Medicare Part D and original Medicare could not agree on who should pay for my IUD,” they wrote in a direct message. “Was it a prescription or durable medical equipment?”

When Moore finally learned it would cost $800 upfront, they said, they decided to get a hysterectomy – which Medicare would pay for – instead.

Chavarría’s doctor told her a tubal ligation also was more likely to be approved by Medicare than an IUD, because older people have that procedure more often. Like all surgeries, both come with risks of complications and recovery.

Even for those on both Medicare and Medicaid, getting contraception also isn’t always easy, as in Katie Elizabeth Walsh’s case.

Walsh, 34, who lives in northeastern Connecticut, is disabled by a traumatic brain injury, depression, and chronic fatigue syndrome. She got an IUD at an ob.gyn. clinic and was told there her insurance would cover it.

Then she got a bill for nearly $2,000.

Medicaid should cover contraceptive devices for dual-eligibility people, according to Centers for Medicare & Medicaid Services policy guidance, but when Walsh tried to get her bill covered, Medicare and Medicaid could not agree on which of them should pay.

“Every single time I have called one of the insurance offices, they are like, ‘Oh, no, you have to talk to the other one, and we don’t really talk to each other,’ ” Walsh said.

Walsh said the hassle to get her contraception covered feels like a kick in the stomach: “Like truly you do not have a place in this world, and your insurance is telling you that.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Sam Chavarría said her doctor was clear about the birth defects her medication could cause if she became pregnant but agreed to keep her on it as long as she had an IUD.

As she was waiting to get her contraceptive intrauterine device replaced at her local clinic, however, the billing nurse told her that her insurance wouldn’t cover the removal – or a new IUD. Chavarría didn’t understand why not.

“Then she said very delicately, ‘Well, people on this insurance typically tend to be older,’ ” Chavarría recalled.

Although Chavarría is 34, she is enrolled in Medicare, the government insurance program designed for those 65 and older. Chavarría, who lives in Houston, is disabled by fibromyalgia, rheumatoid arthritis, and mental health issues. Medicare automatically enrolls anyone who has received Social Security disability benefits for two years and this was her first time getting an IUD while in the government program.

Without insurance, just removing her expired IUD would cost Chavarría $350 out of pocket; exchanging it for a new one would be $2,000. She left the clinic in tears.

Chavarría’s experience is not rare. Medicare was originally intended for people of retirement age. Over the years, the program has evolved to include new populations, such as those who have disabilities or are critically ill, said Jennifer Lea Huer, a public health expert at Yale University, New Haven, Conn. In 2020, 1.7 million people ages 18-44 were enrolled in Medicare.

An estimated 70% of childbearing-age women on Medicare are also eligible for Medicaid, a state and federal program for those with low incomes, which should fill the gap for contraception. It’s not clear how many transgender or nonbinary people – who also might need contraception – are on Medicare or are eligible for Medicaid.

Medicaid, like the plans offered via the federal Affordable Care Act, mandates coverage of birth control. But those who aren’t eligible for Medicaid are left in the lurch – Medicare’s origins mean it does not require access to birth control.

Traditional Medicare includes two parts: Part A covers hospital costs, while Part B covers physicians’ care and certain other services, such as ambulance rides. Neither ordinarily includes contraception.

People can get contraception through a Medicare Advantage plan or Part D of Medicare, which covers prescription drugs, but those come at a cost. And even people who pay for Part D often aren’t covered for some types of birth control, such as IUDs.

“So, if you are disabled, if you are locked outside of the labor market, if you do not have the means or any other way to financially support yourself, you were likely still on traditional Medicare, which is Part A and Part B,” Huer said. “In which case, your access to contraception is incredibly difficult.”

Contraception for those with traditional Medicare is given on a case-by-case basis, Huer said. It can be covered only if a doctor can make a credible case that the patient needs it for medical reasons – because their body cannot sustain a pregnancy – as opposed to merely wanting to avoid one.

“You have to have a champion physician who’s willing to partner with you and make those arguments,” Huer said.

That’s what Chavarría’s doctor tried to do. Before she left the clinic, staffers there told her they would try to make the case she needed the IUD for medical reasons. The IUD exchange was scheduled almost 10 weeks later, but during those weeks, she got pregnant. Her body couldn’t sustain a pregnancy, so she and her partner rushed to get an abortion just before Texas tightened its rules Sept. 1, 2021.

“If Medicare had just covered the IUD removal or exchange to begin with, none of this would have happened,” Chavarría said. “It would have saved me having to make a really tough decision that I never thought I’d have to make.”

Women with disabilities often face a stigma from health care practitioners, especially when it comes to birth control, said Willi Horner-Johnson, a public health researcher specializing in disabilities at Oregon Health & Science University, Portland. In her research, women with disabilities have described being treated like children or having to go to multiple doctors to find someone with whom they felt comfortable.

“We don’t want to acknowledge that disabled people have sex,” said Miriam Garber, a 36-year-old sex worker who lives in Rhode Island and is also on Medicare because of her disabilities. Garber got an IUD from Planned Parenthood because her insurance wouldn’t cover it.

Even those who pay for Part D to have their prescription drugs covered and have a “champion physician” face difficulties. Liz Moore, a nonbinary person in their 30s who lives in the Washington, D.C., area, could not get Medicare to pay for the Mirena IUD their doctor prescribed for their polycystic ovary syndrome. Moore is disabled with fibromyalgia and dysautonomia, a condition of the autonomic nervous system, which regulates breathing, heart rate, and more.

“After literally months of phone calls, it seemed like my Medicare Part D and original Medicare could not agree on who should pay for my IUD,” they wrote in a direct message. “Was it a prescription or durable medical equipment?”

When Moore finally learned it would cost $800 upfront, they said, they decided to get a hysterectomy – which Medicare would pay for – instead.

Chavarría’s doctor told her a tubal ligation also was more likely to be approved by Medicare than an IUD, because older people have that procedure more often. Like all surgeries, both come with risks of complications and recovery.

Even for those on both Medicare and Medicaid, getting contraception also isn’t always easy, as in Katie Elizabeth Walsh’s case.

Walsh, 34, who lives in northeastern Connecticut, is disabled by a traumatic brain injury, depression, and chronic fatigue syndrome. She got an IUD at an ob.gyn. clinic and was told there her insurance would cover it.

Then she got a bill for nearly $2,000.

Medicaid should cover contraceptive devices for dual-eligibility people, according to Centers for Medicare & Medicaid Services policy guidance, but when Walsh tried to get her bill covered, Medicare and Medicaid could not agree on which of them should pay.

“Every single time I have called one of the insurance offices, they are like, ‘Oh, no, you have to talk to the other one, and we don’t really talk to each other,’ ” Walsh said.

Walsh said the hassle to get her contraception covered feels like a kick in the stomach: “Like truly you do not have a place in this world, and your insurance is telling you that.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Most women with breast cancer undergo primary surgery within 8 weeks of diagnosis and any later may be associated with worse overall survival, according to findings from a case series.

With no national quality metrics delineating optimal breast cancer surgery timing, the researchers recommend surgery before 8 weeks from breast cancer diagnosis.

“This time interval does not appear to have a detrimental association with cancer outcomes and allows for multidisciplinary care,” the researchers, led by Alyssa A. Wiener, MD, from University of Wisconsin–Madison, said.

But, in an accompanying editorial, two surgical oncologists questioned whether faster surgery is always better.

“Efficiency might associate with quality, but doesn’t always ensure it,” Rita Mukhtar, MD, and Laura Esserman, MD, with the division of surgical oncology, University of California, San Francisco, said.

The study and editorial were published online in JAMA Surgery.


 

Optimal timing for surgery?

Some studies have found worse survival outcomes for women who experience delays between breast cancer diagnosis and surgical treatment, but the optimal window for surgery and the point at which surgery becomes less advantageous remain unknown.

Using the National Cancer Database, Dr. Wiener and colleagues identified 373,334 women (median age, 61) who were diagnosed with stage I to stage III ductal or lobular breast cancer from 2010 to 2014 and followed up through 2019.

All women underwent surgery as their first course of treatment. Patients with prior breast cancer, those who had neoadjuvant or experimental therapy or missing receptor information, and those who were diagnosed with breast cancer on the date of their primary surgery were excluded.

Most patients had timely surgery. The median time to surgery was 30 days, and 88% of patients underwent surgery before the 57-day time point.

Only 12% of patients had surgery more than 8 weeks after their diagnosis. Factors associated with longer times to surgery included age younger than 45, having Medicaid or no insurance, and lower household income.

The overall 5-year survival for the cohort was high at 90%. On multivariable analysis, the researchers found no statistically significant association between time to surgery and overall survival when surgery was performed between 0 and 8 weeks.

However, women who had surgery 9 or more weeks after diagnosis had a significantly higher rate of death within 5 years, compared with those who had surgery performed between 0 and 4 weeks (hazard ratio, 1.15; P < .001). Performing surgery up to 9 weeks (57-63 days) post diagnosis also did not appear to be negatively associated with survival.

This study “highlights that time to treatment of breast cancer is important,” said Sarah P. Cate, MD, director, Breast Surgery Quality Program, Mount Sinai Health System, New York, who wasn’t involved in the study. “Surgery is only one-third of the treatment of breast cancer, so these patients who had longer delays to the OR may have also not started their postsurgery treatments in time.”

In addition, the study found that socioeconomic status – Medicaid or uninsured status and lower household incomes – was associated with longer times to surgery.

“Socioeconomic factors like these may be independently associated with worse outcomes and may contribute to some of the disparities in cancer outcomes observed for resource-limited patients due to delayed care,” the authors said.

Identifying 8 weeks as a goal for time to surgery can help uncover delays associated with socioeconomic factors and provide adequate time for decision-making, the researchers noted.
 

Is faster always better?

Dr. Wiener and colleagues cautioned, however, that their findings should be considered “hypothesis generating,” given that decision-making surrounding breast cancer surgery is complex.

Importantly, the authors noted, tumor characteristics, such as tumor size, nodal status, and receptor subtype, appeared to have a pronounced impact on overall survival, compared with timing of surgery. For instance, compared with a tumor size of 2 cm or fewer, larger tumors – those > 2 cm to ≤ 5 cm and > 5 cm – were associated with worse survival (HR, 1.80 and 2.62, respectively).

“This highlights that tumor biology is the primary driver of patients’ breast cancer outcomes,” the authors noted.

In an accompanying editorial, two surgical oncologists highlighted that faster may not always be better.

For instance, Dr. Mukhtar and Dr. Esserman explained, if a patient with a large node-positive, triple-negative breast cancer receives surgery within a week of diagnosis, “one must question whether this timely care represents quality care, as the opportunity to understand tumor response and affect breast cancer survival has been lost.”

The editorialists noted that time to surgery might also matter very little for indolent, screen-detected cancers, and time to treatment start might matter a lot for fast-growing, interval cancers.

In addition, they questioned whether including the socioeconomic factors highlighted in the overall model would “mitigate the association between time to surgery and survival seen in this study.”

Overall, “operating too soon could indicate lack of quality, while operating too late perhaps reflects lack of access to care,” the editorialists said.

This study was supported by grants from the National Cancer Institute and the National Institutes of Health. Dr. Wiener and Dr. Cate report no relevant financial relationships. Dr. Esserman is a member of the Blue Cross Medical advisory panel, is a board member of the Quantum Leap Healthcare Collaborative, and leads an investigator-initiated vaccine trial for high-risk ductal carcinoma in situ, which is funded by Merck.

A version of this article first appeared on Medscape.com.

Most women with breast cancer undergo primary surgery within 8 weeks of diagnosis and any later may be associated with worse overall survival, according to findings from a case series.

With no national quality metrics delineating optimal breast cancer surgery timing, the researchers recommend surgery before 8 weeks from breast cancer diagnosis.

“This time interval does not appear to have a detrimental association with cancer outcomes and allows for multidisciplinary care,” the researchers, led by Alyssa A. Wiener, MD, from University of Wisconsin–Madison, said.

But, in an accompanying editorial, two surgical oncologists questioned whether faster surgery is always better.

“Efficiency might associate with quality, but doesn’t always ensure it,” Rita Mukhtar, MD, and Laura Esserman, MD, with the division of surgical oncology, University of California, San Francisco, said.

The study and editorial were published online in JAMA Surgery.


 

Optimal timing for surgery?

Some studies have found worse survival outcomes for women who experience delays between breast cancer diagnosis and surgical treatment, but the optimal window for surgery and the point at which surgery becomes less advantageous remain unknown.

Using the National Cancer Database, Dr. Wiener and colleagues identified 373,334 women (median age, 61) who were diagnosed with stage I to stage III ductal or lobular breast cancer from 2010 to 2014 and followed up through 2019.

All women underwent surgery as their first course of treatment. Patients with prior breast cancer, those who had neoadjuvant or experimental therapy or missing receptor information, and those who were diagnosed with breast cancer on the date of their primary surgery were excluded.

Most patients had timely surgery. The median time to surgery was 30 days, and 88% of patients underwent surgery before the 57-day time point.

Only 12% of patients had surgery more than 8 weeks after their diagnosis. Factors associated with longer times to surgery included age younger than 45, having Medicaid or no insurance, and lower household income.

The overall 5-year survival for the cohort was high at 90%. On multivariable analysis, the researchers found no statistically significant association between time to surgery and overall survival when surgery was performed between 0 and 8 weeks.

However, women who had surgery 9 or more weeks after diagnosis had a significantly higher rate of death within 5 years, compared with those who had surgery performed between 0 and 4 weeks (hazard ratio, 1.15; P < .001). Performing surgery up to 9 weeks (57-63 days) post diagnosis also did not appear to be negatively associated with survival.

This study “highlights that time to treatment of breast cancer is important,” said Sarah P. Cate, MD, director, Breast Surgery Quality Program, Mount Sinai Health System, New York, who wasn’t involved in the study. “Surgery is only one-third of the treatment of breast cancer, so these patients who had longer delays to the OR may have also not started their postsurgery treatments in time.”

In addition, the study found that socioeconomic status – Medicaid or uninsured status and lower household incomes – was associated with longer times to surgery.

“Socioeconomic factors like these may be independently associated with worse outcomes and may contribute to some of the disparities in cancer outcomes observed for resource-limited patients due to delayed care,” the authors said.

Identifying 8 weeks as a goal for time to surgery can help uncover delays associated with socioeconomic factors and provide adequate time for decision-making, the researchers noted.
 

Is faster always better?

Dr. Wiener and colleagues cautioned, however, that their findings should be considered “hypothesis generating,” given that decision-making surrounding breast cancer surgery is complex.

Importantly, the authors noted, tumor characteristics, such as tumor size, nodal status, and receptor subtype, appeared to have a pronounced impact on overall survival, compared with timing of surgery. For instance, compared with a tumor size of 2 cm or fewer, larger tumors – those > 2 cm to ≤ 5 cm and > 5 cm – were associated with worse survival (HR, 1.80 and 2.62, respectively).

“This highlights that tumor biology is the primary driver of patients’ breast cancer outcomes,” the authors noted.

In an accompanying editorial, two surgical oncologists highlighted that faster may not always be better.

For instance, Dr. Mukhtar and Dr. Esserman explained, if a patient with a large node-positive, triple-negative breast cancer receives surgery within a week of diagnosis, “one must question whether this timely care represents quality care, as the opportunity to understand tumor response and affect breast cancer survival has been lost.”

The editorialists noted that time to surgery might also matter very little for indolent, screen-detected cancers, and time to treatment start might matter a lot for fast-growing, interval cancers.

In addition, they questioned whether including the socioeconomic factors highlighted in the overall model would “mitigate the association between time to surgery and survival seen in this study.”

Overall, “operating too soon could indicate lack of quality, while operating too late perhaps reflects lack of access to care,” the editorialists said.

This study was supported by grants from the National Cancer Institute and the National Institutes of Health. Dr. Wiener and Dr. Cate report no relevant financial relationships. Dr. Esserman is a member of the Blue Cross Medical advisory panel, is a board member of the Quantum Leap Healthcare Collaborative, and leads an investigator-initiated vaccine trial for high-risk ductal carcinoma in situ, which is funded by Merck.

A version of this article first appeared on Medscape.com.

Most women with breast cancer undergo primary surgery within 8 weeks of diagnosis and any later may be associated with worse overall survival, according to findings from a case series.

With no national quality metrics delineating optimal breast cancer surgery timing, the researchers recommend surgery before 8 weeks from breast cancer diagnosis.

“This time interval does not appear to have a detrimental association with cancer outcomes and allows for multidisciplinary care,” the researchers, led by Alyssa A. Wiener, MD, from University of Wisconsin–Madison, said.

But, in an accompanying editorial, two surgical oncologists questioned whether faster surgery is always better.

“Efficiency might associate with quality, but doesn’t always ensure it,” Rita Mukhtar, MD, and Laura Esserman, MD, with the division of surgical oncology, University of California, San Francisco, said.

The study and editorial were published online in JAMA Surgery.


 

Optimal timing for surgery?

Some studies have found worse survival outcomes for women who experience delays between breast cancer diagnosis and surgical treatment, but the optimal window for surgery and the point at which surgery becomes less advantageous remain unknown.

Using the National Cancer Database, Dr. Wiener and colleagues identified 373,334 women (median age, 61) who were diagnosed with stage I to stage III ductal or lobular breast cancer from 2010 to 2014 and followed up through 2019.

All women underwent surgery as their first course of treatment. Patients with prior breast cancer, those who had neoadjuvant or experimental therapy or missing receptor information, and those who were diagnosed with breast cancer on the date of their primary surgery were excluded.

Most patients had timely surgery. The median time to surgery was 30 days, and 88% of patients underwent surgery before the 57-day time point.

Only 12% of patients had surgery more than 8 weeks after their diagnosis. Factors associated with longer times to surgery included age younger than 45, having Medicaid or no insurance, and lower household income.

The overall 5-year survival for the cohort was high at 90%. On multivariable analysis, the researchers found no statistically significant association between time to surgery and overall survival when surgery was performed between 0 and 8 weeks.

However, women who had surgery 9 or more weeks after diagnosis had a significantly higher rate of death within 5 years, compared with those who had surgery performed between 0 and 4 weeks (hazard ratio, 1.15; P < .001). Performing surgery up to 9 weeks (57-63 days) post diagnosis also did not appear to be negatively associated with survival.

This study “highlights that time to treatment of breast cancer is important,” said Sarah P. Cate, MD, director, Breast Surgery Quality Program, Mount Sinai Health System, New York, who wasn’t involved in the study. “Surgery is only one-third of the treatment of breast cancer, so these patients who had longer delays to the OR may have also not started their postsurgery treatments in time.”

In addition, the study found that socioeconomic status – Medicaid or uninsured status and lower household incomes – was associated with longer times to surgery.

“Socioeconomic factors like these may be independently associated with worse outcomes and may contribute to some of the disparities in cancer outcomes observed for resource-limited patients due to delayed care,” the authors said.

Identifying 8 weeks as a goal for time to surgery can help uncover delays associated with socioeconomic factors and provide adequate time for decision-making, the researchers noted.
 

Is faster always better?

Dr. Wiener and colleagues cautioned, however, that their findings should be considered “hypothesis generating,” given that decision-making surrounding breast cancer surgery is complex.

Importantly, the authors noted, tumor characteristics, such as tumor size, nodal status, and receptor subtype, appeared to have a pronounced impact on overall survival, compared with timing of surgery. For instance, compared with a tumor size of 2 cm or fewer, larger tumors – those > 2 cm to ≤ 5 cm and > 5 cm – were associated with worse survival (HR, 1.80 and 2.62, respectively).

“This highlights that tumor biology is the primary driver of patients’ breast cancer outcomes,” the authors noted.

In an accompanying editorial, two surgical oncologists highlighted that faster may not always be better.

For instance, Dr. Mukhtar and Dr. Esserman explained, if a patient with a large node-positive, triple-negative breast cancer receives surgery within a week of diagnosis, “one must question whether this timely care represents quality care, as the opportunity to understand tumor response and affect breast cancer survival has been lost.”

The editorialists noted that time to surgery might also matter very little for indolent, screen-detected cancers, and time to treatment start might matter a lot for fast-growing, interval cancers.

In addition, they questioned whether including the socioeconomic factors highlighted in the overall model would “mitigate the association between time to surgery and survival seen in this study.”

Overall, “operating too soon could indicate lack of quality, while operating too late perhaps reflects lack of access to care,” the editorialists said.

This study was supported by grants from the National Cancer Institute and the National Institutes of Health. Dr. Wiener and Dr. Cate report no relevant financial relationships. Dr. Esserman is a member of the Blue Cross Medical advisory panel, is a board member of the Quantum Leap Healthcare Collaborative, and leads an investigator-initiated vaccine trial for high-risk ductal carcinoma in situ, which is funded by Merck.

A version of this article first appeared on Medscape.com.

Much attention has been focused recently on the idea that breast cancer with a low expression of HER2 can be treated with HER2-targeted agents. Not surprisingly, manufacturers of these drugs have pounced on this idea, as it opens up a whole new patient population: previously these drugs were only for tumors with a high HER2 expression.

There is a large potential market at stake: HER2-low (also referred to as ERBB2-low), as defined by a score of 0 to 3+ on immunohistochemistry (IHC), is seen in approximately 50%-60% of all breast cancers

However, there is still much debate over whether low-HER2 breast cancer is, in fact, a separate clinical entity.

A new large-scale analysis concludes that it is not. The authors argued that it actually it represents a series of biological differences from HER2-negative disease that do not have a strong bearing on outcomes.

The analysis was published online in JAMA Oncology.

For the study, researchers from the University of Chicago examined data on more than 1.1 million breast cancer patients recorded as HER2-negative in the U.S. National Cancer Database, and re-classified almost two thirds as HER2-low on further analysis.

They found that HER2-low status was associated with higher estrogen receptor (ER) expression, as well as a lower rate of pathologic complete response, compared with HER2-negative disease. It was also linked to an improvement in overall survival on multivariate analysis of up to 9% in advance stage triple negative tumors.

“However, the clinical significance of these differences is questionable,” the researchers commented.

HER2-low status alone “should not influence neoadjuvant treatment decisions with currently approved regimens,” they added.

These results “do not support classification of HER2-low breast cancer as a distinct clinical subtype,” the team concluded.

Not necessarily, according to Giuseppe Curigliano, MD, PhD, director of the new drugs and early drug development for innovative therapies division at the European Institute of Oncology, Milan. He argued the opposite case, that HER2-low is a separate clinical entity, in a recent debate on the topic held at the 2022 San Antonio Breast Cancer Symposium.

In a comment, Dr. Curigliano said that a “major strength” of the current study is its large patient cohort, which reflects the majority of cancer diagnoses in the United States, but that it nevertheless has “important limitations that should be considered when interpreting the results.”

The inclusion of only overall survival in the dataset limits the ability to make associations between HER2-low status and cancer-specific prognosis, as “survival may lag years behind recurrence.”

The lack of centralized assessment of IHC results is also an issue, as “some of the results may be associated with regional variation in practice of classifying cases as HER2 0 versus HER2 1+.”

“In my opinion, this is a great limitation,” he said, in being able to conclude that there is “no prognostic difference between ERBB2-low and -negative patients.”

He also noted that, from a molecular point of view, “the key determinant of the gene expression profile is the expression of hormone receptors, [and] if we perform a correction for hormone receptor expression, only marginal differences in gene expression are found” between HER2-low and HER2-negative tumors.

“Similarly, large genomic studies have identified no specific and consistent difference in genomic profiles,” Dr. Curigliano said, and so, HER2-low disease, “as currently defined, should not be considered a distinct molecular entity, but rather a heterogeneous group of tumors, with biology primarily driven by hormone receptor expression.”
 

Analysis quoted by both sides

Senior author of the new analysis, Frederick M. Howard, MD, from the section of hematology-oncology in the department of medicine at the University of Chicago, said that his team’s work was quoted by both sides of the debate at SABCS 2022.

This reflects the fact that, while differences between ERBB2-low and -negative are present, it is “questionable how clinically significant those differences are,” he said in an interview. It’s a matter of “the eye of the beholder.”

Dr. Howard does not think that clinicians are going to modify standard treatment regimens based solely on HER2-low status, and that low expression of the protein “is probably just a reflection of some underlying biologic processes.”

Dr. Howard agreed with Dr. Curigliano that a “caveat” of their study is that the IHC analyses were performed locally, especially as it has shown that there can be discordance between pathologists in around 40% of cases, and that the associations they found might therefore be “strengthened” by more precise quantification of HER2 expression.

“But, even then,” Dr. Howard continued, “I doubt that [ERBB2-low status] is going to be that strong a prognostic factor.”

He believes that advances in analytic techniques will, in the future, allow tumors to be characterized more precisely, and it may be that HER2-low tumors end up being called something else in 5 years.
 

Renewed interest in this subgroup

In their paper, Dr. Howard and colleagues pointed out that, as a group, HER2-low tumors are heterogeneous, with HER2-low found in both hormone receptor–positive and triple-negative breast cancers. Also, various studies have come to different conclusions about what HER2 low means prognostically, with conclusions ranging from negative to neutral and to positive prognoses.

However, new research has shown that patients with HER2-low tumors can benefit from HER2-targeted drugs. In particular, the recent report that the antibody-drug conjugate trastuzumab deruxtecan doubled progression-free survival versus chemotherapy in ERBB2-low tumors led to “renewed interest in the subgroup,” the researchers noted.

To examine this subgroup further, they embarked on their analysis. Examining the National Cancer Database, they gathered information on more than 1.1 million U.S. patients diagnosed with HER2-negative invasive breast cancer in the 10-year period 2010-2019, and for whom IHC results were available.

The patients were reclassified as having HER2-low disease if they had an IHC score of 1+, or 2+ with a negative in situ hybridization test, while those with an IHC score of 0 were deemed to be HER2-negative. They were followed up until Nov. 30, 2022.

These patients had a mean age of 62.4 years, and 99.1% were female. The majority (78.6%) were non-Hispanic white. HER2-low was identified in 65.5% of the cohort, while 34.5% were HER2-negative.

The proportion of HER2-low disease was lower in non-Hispanic black (62.8%) and Hispanic (61%) patients than in non-Hispanic White patients, at 66.1%.

HER2-low disease was also more common in hormone receptor–positive than triple-negative tumors, at just 51.5%, rising to 58.6% for progesterone receptor–positive, ER-negative, and 69.1% for PR-positive, ER-positive tumors.

Multivariate logistic regression analysis taking into account age, sex, race and ethnicity, comorbidity score, and treatment facility type, among other factors, revealed that the likelihood of HER2-low disease was significantly with increased ER expression, at an adjusted odds ratio of 1.15 for each 10% increase (P < .001).

Non-Hispanic Black, Asian, and Pacific Islander patients had similar rates of HER2-low disease as non-Hispanic White patients after adjustment, whereas Native American patients had an increased rate, at an aOR of 1.22 (P < .001), and Hispanic patients had a lower rate, at an aOR of 0.85 (P < .001).

HER2-low status was associated with a slightly reduced likelihood of having a pathologic complete response (aOR, 0.89; P < .001), with similar results when restricting the analysis to patients with triple negative or hormone receptor-positive tumors.

After a median follow-up of 54 months, HER2-low disease was associated with a minor improvement in survival on multivariate analysis, at an adjusted hazard ratio for death of 0.98 (P < .001).

The greatest improvement in survival was seen in patients with stage III and IV triple-negative breast cancer, at HRs of 0.92 and 0.91, respectively, although the researchers noted that this represented only a 2% and 0.4% improvement in 5-year overall survival, respectively.

The study was supported by the Breast Cancer Research Foundation, the American Society of Clinical Oncology/Conquer Cancer Foundation, the Department of Defense, the National Institutes of Health/National Cancer Institute, Susan G. Komen, the Breast Cancer Research Foundation, and the University of Chicago Elwood V. Jensen Scholars Program. Dr. Howard reported no relevant financial relationships. Dr. Curigliano has relationships with Pfizer, Novartis, Lilly, Roche, Seattle Genetics, Celltrion, Veracyte, Daiichi Sankyo, AstraZeneca, Merck, Seagen, Exact Sciences, Gilead, Bristol-Myers Squibb, Scientific Affairs Group, and Ellipsis.

A version of this article first appeared on Medscape.com.

Much attention has been focused recently on the idea that breast cancer with a low expression of HER2 can be treated with HER2-targeted agents. Not surprisingly, manufacturers of these drugs have pounced on this idea, as it opens up a whole new patient population: previously these drugs were only for tumors with a high HER2 expression.

There is a large potential market at stake: HER2-low (also referred to as ERBB2-low), as defined by a score of 0 to 3+ on immunohistochemistry (IHC), is seen in approximately 50%-60% of all breast cancers

However, there is still much debate over whether low-HER2 breast cancer is, in fact, a separate clinical entity.

A new large-scale analysis concludes that it is not. The authors argued that it actually it represents a series of biological differences from HER2-negative disease that do not have a strong bearing on outcomes.

The analysis was published online in JAMA Oncology.

For the study, researchers from the University of Chicago examined data on more than 1.1 million breast cancer patients recorded as HER2-negative in the U.S. National Cancer Database, and re-classified almost two thirds as HER2-low on further analysis.

They found that HER2-low status was associated with higher estrogen receptor (ER) expression, as well as a lower rate of pathologic complete response, compared with HER2-negative disease. It was also linked to an improvement in overall survival on multivariate analysis of up to 9% in advance stage triple negative tumors.

“However, the clinical significance of these differences is questionable,” the researchers commented.

HER2-low status alone “should not influence neoadjuvant treatment decisions with currently approved regimens,” they added.

These results “do not support classification of HER2-low breast cancer as a distinct clinical subtype,” the team concluded.

Not necessarily, according to Giuseppe Curigliano, MD, PhD, director of the new drugs and early drug development for innovative therapies division at the European Institute of Oncology, Milan. He argued the opposite case, that HER2-low is a separate clinical entity, in a recent debate on the topic held at the 2022 San Antonio Breast Cancer Symposium.

In a comment, Dr. Curigliano said that a “major strength” of the current study is its large patient cohort, which reflects the majority of cancer diagnoses in the United States, but that it nevertheless has “important limitations that should be considered when interpreting the results.”

The inclusion of only overall survival in the dataset limits the ability to make associations between HER2-low status and cancer-specific prognosis, as “survival may lag years behind recurrence.”

The lack of centralized assessment of IHC results is also an issue, as “some of the results may be associated with regional variation in practice of classifying cases as HER2 0 versus HER2 1+.”

“In my opinion, this is a great limitation,” he said, in being able to conclude that there is “no prognostic difference between ERBB2-low and -negative patients.”

He also noted that, from a molecular point of view, “the key determinant of the gene expression profile is the expression of hormone receptors, [and] if we perform a correction for hormone receptor expression, only marginal differences in gene expression are found” between HER2-low and HER2-negative tumors.

“Similarly, large genomic studies have identified no specific and consistent difference in genomic profiles,” Dr. Curigliano said, and so, HER2-low disease, “as currently defined, should not be considered a distinct molecular entity, but rather a heterogeneous group of tumors, with biology primarily driven by hormone receptor expression.”
 

Analysis quoted by both sides

Senior author of the new analysis, Frederick M. Howard, MD, from the section of hematology-oncology in the department of medicine at the University of Chicago, said that his team’s work was quoted by both sides of the debate at SABCS 2022.

This reflects the fact that, while differences between ERBB2-low and -negative are present, it is “questionable how clinically significant those differences are,” he said in an interview. It’s a matter of “the eye of the beholder.”

Dr. Howard does not think that clinicians are going to modify standard treatment regimens based solely on HER2-low status, and that low expression of the protein “is probably just a reflection of some underlying biologic processes.”

Dr. Howard agreed with Dr. Curigliano that a “caveat” of their study is that the IHC analyses were performed locally, especially as it has shown that there can be discordance between pathologists in around 40% of cases, and that the associations they found might therefore be “strengthened” by more precise quantification of HER2 expression.

“But, even then,” Dr. Howard continued, “I doubt that [ERBB2-low status] is going to be that strong a prognostic factor.”

He believes that advances in analytic techniques will, in the future, allow tumors to be characterized more precisely, and it may be that HER2-low tumors end up being called something else in 5 years.
 

Renewed interest in this subgroup

In their paper, Dr. Howard and colleagues pointed out that, as a group, HER2-low tumors are heterogeneous, with HER2-low found in both hormone receptor–positive and triple-negative breast cancers. Also, various studies have come to different conclusions about what HER2 low means prognostically, with conclusions ranging from negative to neutral and to positive prognoses.

However, new research has shown that patients with HER2-low tumors can benefit from HER2-targeted drugs. In particular, the recent report that the antibody-drug conjugate trastuzumab deruxtecan doubled progression-free survival versus chemotherapy in ERBB2-low tumors led to “renewed interest in the subgroup,” the researchers noted.

To examine this subgroup further, they embarked on their analysis. Examining the National Cancer Database, they gathered information on more than 1.1 million U.S. patients diagnosed with HER2-negative invasive breast cancer in the 10-year period 2010-2019, and for whom IHC results were available.

The patients were reclassified as having HER2-low disease if they had an IHC score of 1+, or 2+ with a negative in situ hybridization test, while those with an IHC score of 0 were deemed to be HER2-negative. They were followed up until Nov. 30, 2022.

These patients had a mean age of 62.4 years, and 99.1% were female. The majority (78.6%) were non-Hispanic white. HER2-low was identified in 65.5% of the cohort, while 34.5% were HER2-negative.

The proportion of HER2-low disease was lower in non-Hispanic black (62.8%) and Hispanic (61%) patients than in non-Hispanic White patients, at 66.1%.

HER2-low disease was also more common in hormone receptor–positive than triple-negative tumors, at just 51.5%, rising to 58.6% for progesterone receptor–positive, ER-negative, and 69.1% for PR-positive, ER-positive tumors.

Multivariate logistic regression analysis taking into account age, sex, race and ethnicity, comorbidity score, and treatment facility type, among other factors, revealed that the likelihood of HER2-low disease was significantly with increased ER expression, at an adjusted odds ratio of 1.15 for each 10% increase (P < .001).

Non-Hispanic Black, Asian, and Pacific Islander patients had similar rates of HER2-low disease as non-Hispanic White patients after adjustment, whereas Native American patients had an increased rate, at an aOR of 1.22 (P < .001), and Hispanic patients had a lower rate, at an aOR of 0.85 (P < .001).

HER2-low status was associated with a slightly reduced likelihood of having a pathologic complete response (aOR, 0.89; P < .001), with similar results when restricting the analysis to patients with triple negative or hormone receptor-positive tumors.

After a median follow-up of 54 months, HER2-low disease was associated with a minor improvement in survival on multivariate analysis, at an adjusted hazard ratio for death of 0.98 (P < .001).

The greatest improvement in survival was seen in patients with stage III and IV triple-negative breast cancer, at HRs of 0.92 and 0.91, respectively, although the researchers noted that this represented only a 2% and 0.4% improvement in 5-year overall survival, respectively.

The study was supported by the Breast Cancer Research Foundation, the American Society of Clinical Oncology/Conquer Cancer Foundation, the Department of Defense, the National Institutes of Health/National Cancer Institute, Susan G. Komen, the Breast Cancer Research Foundation, and the University of Chicago Elwood V. Jensen Scholars Program. Dr. Howard reported no relevant financial relationships. Dr. Curigliano has relationships with Pfizer, Novartis, Lilly, Roche, Seattle Genetics, Celltrion, Veracyte, Daiichi Sankyo, AstraZeneca, Merck, Seagen, Exact Sciences, Gilead, Bristol-Myers Squibb, Scientific Affairs Group, and Ellipsis.

A version of this article first appeared on Medscape.com.

Much attention has been focused recently on the idea that breast cancer with a low expression of HER2 can be treated with HER2-targeted agents. Not surprisingly, manufacturers of these drugs have pounced on this idea, as it opens up a whole new patient population: previously these drugs were only for tumors with a high HER2 expression.

There is a large potential market at stake: HER2-low (also referred to as ERBB2-low), as defined by a score of 0 to 3+ on immunohistochemistry (IHC), is seen in approximately 50%-60% of all breast cancers

However, there is still much debate over whether low-HER2 breast cancer is, in fact, a separate clinical entity.

A new large-scale analysis concludes that it is not. The authors argued that it actually it represents a series of biological differences from HER2-negative disease that do not have a strong bearing on outcomes.

The analysis was published online in JAMA Oncology.

For the study, researchers from the University of Chicago examined data on more than 1.1 million breast cancer patients recorded as HER2-negative in the U.S. National Cancer Database, and re-classified almost two thirds as HER2-low on further analysis.

They found that HER2-low status was associated with higher estrogen receptor (ER) expression, as well as a lower rate of pathologic complete response, compared with HER2-negative disease. It was also linked to an improvement in overall survival on multivariate analysis of up to 9% in advance stage triple negative tumors.

“However, the clinical significance of these differences is questionable,” the researchers commented.

HER2-low status alone “should not influence neoadjuvant treatment decisions with currently approved regimens,” they added.

These results “do not support classification of HER2-low breast cancer as a distinct clinical subtype,” the team concluded.

Not necessarily, according to Giuseppe Curigliano, MD, PhD, director of the new drugs and early drug development for innovative therapies division at the European Institute of Oncology, Milan. He argued the opposite case, that HER2-low is a separate clinical entity, in a recent debate on the topic held at the 2022 San Antonio Breast Cancer Symposium.

In a comment, Dr. Curigliano said that a “major strength” of the current study is its large patient cohort, which reflects the majority of cancer diagnoses in the United States, but that it nevertheless has “important limitations that should be considered when interpreting the results.”

The inclusion of only overall survival in the dataset limits the ability to make associations between HER2-low status and cancer-specific prognosis, as “survival may lag years behind recurrence.”

The lack of centralized assessment of IHC results is also an issue, as “some of the results may be associated with regional variation in practice of classifying cases as HER2 0 versus HER2 1+.”

“In my opinion, this is a great limitation,” he said, in being able to conclude that there is “no prognostic difference between ERBB2-low and -negative patients.”

He also noted that, from a molecular point of view, “the key determinant of the gene expression profile is the expression of hormone receptors, [and] if we perform a correction for hormone receptor expression, only marginal differences in gene expression are found” between HER2-low and HER2-negative tumors.

“Similarly, large genomic studies have identified no specific and consistent difference in genomic profiles,” Dr. Curigliano said, and so, HER2-low disease, “as currently defined, should not be considered a distinct molecular entity, but rather a heterogeneous group of tumors, with biology primarily driven by hormone receptor expression.”
 

Analysis quoted by both sides

Senior author of the new analysis, Frederick M. Howard, MD, from the section of hematology-oncology in the department of medicine at the University of Chicago, said that his team’s work was quoted by both sides of the debate at SABCS 2022.

This reflects the fact that, while differences between ERBB2-low and -negative are present, it is “questionable how clinically significant those differences are,” he said in an interview. It’s a matter of “the eye of the beholder.”

Dr. Howard does not think that clinicians are going to modify standard treatment regimens based solely on HER2-low status, and that low expression of the protein “is probably just a reflection of some underlying biologic processes.”

Dr. Howard agreed with Dr. Curigliano that a “caveat” of their study is that the IHC analyses were performed locally, especially as it has shown that there can be discordance between pathologists in around 40% of cases, and that the associations they found might therefore be “strengthened” by more precise quantification of HER2 expression.

“But, even then,” Dr. Howard continued, “I doubt that [ERBB2-low status] is going to be that strong a prognostic factor.”

He believes that advances in analytic techniques will, in the future, allow tumors to be characterized more precisely, and it may be that HER2-low tumors end up being called something else in 5 years.
 

Renewed interest in this subgroup

In their paper, Dr. Howard and colleagues pointed out that, as a group, HER2-low tumors are heterogeneous, with HER2-low found in both hormone receptor–positive and triple-negative breast cancers. Also, various studies have come to different conclusions about what HER2 low means prognostically, with conclusions ranging from negative to neutral and to positive prognoses.

However, new research has shown that patients with HER2-low tumors can benefit from HER2-targeted drugs. In particular, the recent report that the antibody-drug conjugate trastuzumab deruxtecan doubled progression-free survival versus chemotherapy in ERBB2-low tumors led to “renewed interest in the subgroup,” the researchers noted.

To examine this subgroup further, they embarked on their analysis. Examining the National Cancer Database, they gathered information on more than 1.1 million U.S. patients diagnosed with HER2-negative invasive breast cancer in the 10-year period 2010-2019, and for whom IHC results were available.

The patients were reclassified as having HER2-low disease if they had an IHC score of 1+, or 2+ with a negative in situ hybridization test, while those with an IHC score of 0 were deemed to be HER2-negative. They were followed up until Nov. 30, 2022.

These patients had a mean age of 62.4 years, and 99.1% were female. The majority (78.6%) were non-Hispanic white. HER2-low was identified in 65.5% of the cohort, while 34.5% were HER2-negative.

The proportion of HER2-low disease was lower in non-Hispanic black (62.8%) and Hispanic (61%) patients than in non-Hispanic White patients, at 66.1%.

HER2-low disease was also more common in hormone receptor–positive than triple-negative tumors, at just 51.5%, rising to 58.6% for progesterone receptor–positive, ER-negative, and 69.1% for PR-positive, ER-positive tumors.

Multivariate logistic regression analysis taking into account age, sex, race and ethnicity, comorbidity score, and treatment facility type, among other factors, revealed that the likelihood of HER2-low disease was significantly with increased ER expression, at an adjusted odds ratio of 1.15 for each 10% increase (P < .001).

Non-Hispanic Black, Asian, and Pacific Islander patients had similar rates of HER2-low disease as non-Hispanic White patients after adjustment, whereas Native American patients had an increased rate, at an aOR of 1.22 (P < .001), and Hispanic patients had a lower rate, at an aOR of 0.85 (P < .001).

HER2-low status was associated with a slightly reduced likelihood of having a pathologic complete response (aOR, 0.89; P < .001), with similar results when restricting the analysis to patients with triple negative or hormone receptor-positive tumors.

After a median follow-up of 54 months, HER2-low disease was associated with a minor improvement in survival on multivariate analysis, at an adjusted hazard ratio for death of 0.98 (P < .001).

The greatest improvement in survival was seen in patients with stage III and IV triple-negative breast cancer, at HRs of 0.92 and 0.91, respectively, although the researchers noted that this represented only a 2% and 0.4% improvement in 5-year overall survival, respectively.

The study was supported by the Breast Cancer Research Foundation, the American Society of Clinical Oncology/Conquer Cancer Foundation, the Department of Defense, the National Institutes of Health/National Cancer Institute, Susan G. Komen, the Breast Cancer Research Foundation, and the University of Chicago Elwood V. Jensen Scholars Program. Dr. Howard reported no relevant financial relationships. Dr. Curigliano has relationships with Pfizer, Novartis, Lilly, Roche, Seattle Genetics, Celltrion, Veracyte, Daiichi Sankyo, AstraZeneca, Merck, Seagen, Exact Sciences, Gilead, Bristol-Myers Squibb, Scientific Affairs Group, and Ellipsis.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has expanded the indication for adjuvant abemaciclib (Verzenio) in combination with endocrine therapy for patients with hormone receptor–positive, HER2-negative, node-positive early breast cancer who are at high risk for recurrence.

Abemaciclib was previously approved for this group of high-risk patients with the requirement that they have a Ki-67 score of at least 20%. The new expansion removes the Ki-67 testing requirement, meaning more patients are now eligible to receive this drug. High-risk patients eligible for the CDK4/6 inhibitor can now be identified solely on the basis of nodal status, tumor size, and tumor grade.

The FDA’s decision to expand the approval was based on 4-year data from the phase 3 monarchE trial of adjuvant abemaciclib, which showed benefit in invasive disease-free survival beyond the 2-year treatment course.

At 4 years, 85.5% of patients remained recurrence free with abemaciclib plus endocrine therapy, compared with 78.6% who received endocrine therapy alone, an absolute difference in invasive disease-free survival of 6.9%.

“The initial Verzenio FDA approval in early breast cancer was practice changing and now, through this indication expansion, we have the potential to reduce the risk of breast cancer recurrence for many more patients, relying solely on commonly utilized clinicopathologic features to identify them,” Erika P. Hamilton, MD, an investigator on the monarchE clinical trial, said in a press release.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has expanded the indication for adjuvant abemaciclib (Verzenio) in combination with endocrine therapy for patients with hormone receptor–positive, HER2-negative, node-positive early breast cancer who are at high risk for recurrence.

Abemaciclib was previously approved for this group of high-risk patients with the requirement that they have a Ki-67 score of at least 20%. The new expansion removes the Ki-67 testing requirement, meaning more patients are now eligible to receive this drug. High-risk patients eligible for the CDK4/6 inhibitor can now be identified solely on the basis of nodal status, tumor size, and tumor grade.

The FDA’s decision to expand the approval was based on 4-year data from the phase 3 monarchE trial of adjuvant abemaciclib, which showed benefit in invasive disease-free survival beyond the 2-year treatment course.

At 4 years, 85.5% of patients remained recurrence free with abemaciclib plus endocrine therapy, compared with 78.6% who received endocrine therapy alone, an absolute difference in invasive disease-free survival of 6.9%.

“The initial Verzenio FDA approval in early breast cancer was practice changing and now, through this indication expansion, we have the potential to reduce the risk of breast cancer recurrence for many more patients, relying solely on commonly utilized clinicopathologic features to identify them,” Erika P. Hamilton, MD, an investigator on the monarchE clinical trial, said in a press release.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has expanded the indication for adjuvant abemaciclib (Verzenio) in combination with endocrine therapy for patients with hormone receptor–positive, HER2-negative, node-positive early breast cancer who are at high risk for recurrence.

Abemaciclib was previously approved for this group of high-risk patients with the requirement that they have a Ki-67 score of at least 20%. The new expansion removes the Ki-67 testing requirement, meaning more patients are now eligible to receive this drug. High-risk patients eligible for the CDK4/6 inhibitor can now be identified solely on the basis of nodal status, tumor size, and tumor grade.

The FDA’s decision to expand the approval was based on 4-year data from the phase 3 monarchE trial of adjuvant abemaciclib, which showed benefit in invasive disease-free survival beyond the 2-year treatment course.

At 4 years, 85.5% of patients remained recurrence free with abemaciclib plus endocrine therapy, compared with 78.6% who received endocrine therapy alone, an absolute difference in invasive disease-free survival of 6.9%.

“The initial Verzenio FDA approval in early breast cancer was practice changing and now, through this indication expansion, we have the potential to reduce the risk of breast cancer recurrence for many more patients, relying solely on commonly utilized clinicopathologic features to identify them,” Erika P. Hamilton, MD, an investigator on the monarchE clinical trial, said in a press release.

A version of this article first appeared on Medscape.com.

I am often asked about the impact of dietary nutrients on bone health, particularly as many patients with low bone density, many with a history of multiple fractures, are referred to me. Many factors affect bone density, an important predictor of fracture risk, including genetics, body weight and muscle mass, bone loading exercise, menstrual status, other hormonal factors, nutritional status, optimal absorption of dietary nutrients, and medication use.

Dietary nutrients include macronutrients (carbohydrates, proteins, fat, and fiber) and micronutrients (such as dietary minerals and vitamins). The importance of micronutrients such as calcium, phosphorus, magnesium, and vitamins C, D, and K in optimizing bone mineralization and bone formation has been well documented.

The impact of protein intake on bone health is slightly more controversial, with some studies suggesting that increased protein intake may be deleterious to bone by increasing acid load, which in turn, increases calcium loss in urine. Overall data analysis from multiple studies support the finding that a higher protein intake is modestly beneficial for bone at certain sites, such as the spine.

Though data regarding the impact of dietary carbohydrates on bone are not as robust, it’s important to understand these effects given the increasing knowledge of the deleterious impact of processed carbohydrates on weight and cardiometabolic outcomes. This leads to the growing recommendations to limit carbohydrates in diet.
 

Quality and quantity of carbs affect bone health

Available studies suggest that both the quality and quantity of carbohydrates that are in a diet as well as the glycemic index of food may affect bone outcomes. Glycemic index refers to the extent of blood glucose elevation that occurs after the intake of any specific food. Foods with a higher glycemic index cause a rapid increase in blood glucose, whereas those with a low glycemic index result in a slower and more gradual increase. Examples of high–glycemic index food include processed and baked foods (such as breakfast cereals [unless whole grain], pretzels, cookies, doughnuts, pastries, cake, white bread, bagels, croissants, and corn chips), sugar-sweetened beverages, white rice, fast food (such as pizza and burgers), and potatoes. Examples of low glycemic index foods include vegetables, fruits, legumes, dairy and dairy products (without added sugar), whole-grain foods (such as oat porridge), and nuts.

A high–glycemic index diet has been associated with a greater risk for obesity and cardiovascular disease, and with lower bone density, an increased risk for fracture. This has been attributed to acute increases in glucose and insulin levels after consumption of high–glycemic index food, which causes increased oxidative stress and secretion of inflammatory cytokines, such as interleukin 6 and tumor necrosis factor alpha, that activate cells in bone that increase bone loss.

Higher blood glucose concentrations induced by a higher dietary glycemic index can have deleterious effects on osteoblasts, the cells important for bone formation, and increase bone loss through production of advanced glycation end products that affect the cross linking of collagen in bone (important for bone strength), as well as calcium loss in urine. This was recently reported in a study by Garcia-Gavilan and others, in which the authors showed that high dietary glycemic index and dietary glucose load are associated with a higher risk for osteoporosis-related fractures in an older Mediterranean population who are at high risk for cardiovascular events. Similar data were reported by Nouri and coauthors in a study from Iran.

The quantity and quality of dietary carbohydrates may also have an impact on bone. The quality of carbohydrates has been assessed using the carbohydrate quality index (CQI) and the low carbohydrate diet score (LCDS). The CQI takes into account dietary fiber intake, glycemic index, intake of processed vs. whole grain, and solid vs. total carbohydrates in diet. A higher CQI diet is associated with reduced cardiovascular risk. Higher LCDS reflects lower carbohydrate and higher fat and protein intake.

Diets that are rich in refined or processed carbohydrates with added sugar are proinflammatory and increase oxidative stress, which may lead to increased bone loss, low bone density, and increased fracture risk. These foods also have a high glycemic index.

In contrast, diets that are rich in whole grains, legumes, fruits, vegetables, nuts, and olive oil have a lower glycemic index and are beneficial to bone. These diets have a higher CQI and LCDS (as reported by Nouri and coauthors) and provide a rich source of antioxidants, vitamins, minerals, and other nutrients (such as calcium, magnesium, and vitamins B, C, and K), which are all beneficial to bone. Gao and others have reported that implementing a low glycemic index pulse-based diet (lentils, peas, beans) is superior to a regular hospital diet in preventing the increase in bone loss that typically occurs during hospitalization with enforced bed rest.

Most reports of the impact of carbohydrates on bone health are from observational studies. In an interventional study, Dalskov and coauthors randomly assigned children aged 5-18 years who had parents with overweight to one of five diets (high protein/low glycemic index, high protein/high glycemic index, low protein/low glycemic index, low protein/high glycemic index, or regular) for 6 months.

Contrasting with our understanding that protein intake is overall good for bone, this study found that among patients receiving a high–glycemic index diet, those who were on a high-protein diet had greater reductions in a bone formation marker than did those on a low-protein diet, with no major changes observed with the other diets. This suggests the influence of associated dietary nutrients on bone outcomes and that protein intake may modify the effects of dietary carbohydrates on bone formation. Similarly, the fat content of food can alter the glycemic index and thus may modify the impact of dietary carbohydrates on bone.

In summary, available data suggest that the quantity and quality of carbohydrates, including the glycemic index of food, may affect bone health and that it is important to exercise moderation in the consumption of such foods. However, there are only a few studies that have examined these associations, and more studies are necessary to further clarify the impact of dietary carbohydrates on bone as well as any modifications of these effects by other associated food groups. These studies will allow us to refine our recommendations to our patients as we advance our understanding of the impact of the combined effects of various dietary nutrients on bone.

Madhusmita Misra, MD, MPH, is chief of the division of pediatric endocrinology, Mass General for Children, Boston, and serves or has served as a director, officer, partner, employee, advisor, consultant, or trustee for AbbVie, Sanofi, and Ipsen.

A version of this article first appeared on Medscape.com.

I am often asked about the impact of dietary nutrients on bone health, particularly as many patients with low bone density, many with a history of multiple fractures, are referred to me. Many factors affect bone density, an important predictor of fracture risk, including genetics, body weight and muscle mass, bone loading exercise, menstrual status, other hormonal factors, nutritional status, optimal absorption of dietary nutrients, and medication use.

Dietary nutrients include macronutrients (carbohydrates, proteins, fat, and fiber) and micronutrients (such as dietary minerals and vitamins). The importance of micronutrients such as calcium, phosphorus, magnesium, and vitamins C, D, and K in optimizing bone mineralization and bone formation has been well documented.

The impact of protein intake on bone health is slightly more controversial, with some studies suggesting that increased protein intake may be deleterious to bone by increasing acid load, which in turn, increases calcium loss in urine. Overall data analysis from multiple studies support the finding that a higher protein intake is modestly beneficial for bone at certain sites, such as the spine.

Though data regarding the impact of dietary carbohydrates on bone are not as robust, it’s important to understand these effects given the increasing knowledge of the deleterious impact of processed carbohydrates on weight and cardiometabolic outcomes. This leads to the growing recommendations to limit carbohydrates in diet.
 

Quality and quantity of carbs affect bone health

Available studies suggest that both the quality and quantity of carbohydrates that are in a diet as well as the glycemic index of food may affect bone outcomes. Glycemic index refers to the extent of blood glucose elevation that occurs after the intake of any specific food. Foods with a higher glycemic index cause a rapid increase in blood glucose, whereas those with a low glycemic index result in a slower and more gradual increase. Examples of high–glycemic index food include processed and baked foods (such as breakfast cereals [unless whole grain], pretzels, cookies, doughnuts, pastries, cake, white bread, bagels, croissants, and corn chips), sugar-sweetened beverages, white rice, fast food (such as pizza and burgers), and potatoes. Examples of low glycemic index foods include vegetables, fruits, legumes, dairy and dairy products (without added sugar), whole-grain foods (such as oat porridge), and nuts.

A high–glycemic index diet has been associated with a greater risk for obesity and cardiovascular disease, and with lower bone density, an increased risk for fracture. This has been attributed to acute increases in glucose and insulin levels after consumption of high–glycemic index food, which causes increased oxidative stress and secretion of inflammatory cytokines, such as interleukin 6 and tumor necrosis factor alpha, that activate cells in bone that increase bone loss.

Higher blood glucose concentrations induced by a higher dietary glycemic index can have deleterious effects on osteoblasts, the cells important for bone formation, and increase bone loss through production of advanced glycation end products that affect the cross linking of collagen in bone (important for bone strength), as well as calcium loss in urine. This was recently reported in a study by Garcia-Gavilan and others, in which the authors showed that high dietary glycemic index and dietary glucose load are associated with a higher risk for osteoporosis-related fractures in an older Mediterranean population who are at high risk for cardiovascular events. Similar data were reported by Nouri and coauthors in a study from Iran.

The quantity and quality of dietary carbohydrates may also have an impact on bone. The quality of carbohydrates has been assessed using the carbohydrate quality index (CQI) and the low carbohydrate diet score (LCDS). The CQI takes into account dietary fiber intake, glycemic index, intake of processed vs. whole grain, and solid vs. total carbohydrates in diet. A higher CQI diet is associated with reduced cardiovascular risk. Higher LCDS reflects lower carbohydrate and higher fat and protein intake.

Diets that are rich in refined or processed carbohydrates with added sugar are proinflammatory and increase oxidative stress, which may lead to increased bone loss, low bone density, and increased fracture risk. These foods also have a high glycemic index.

In contrast, diets that are rich in whole grains, legumes, fruits, vegetables, nuts, and olive oil have a lower glycemic index and are beneficial to bone. These diets have a higher CQI and LCDS (as reported by Nouri and coauthors) and provide a rich source of antioxidants, vitamins, minerals, and other nutrients (such as calcium, magnesium, and vitamins B, C, and K), which are all beneficial to bone. Gao and others have reported that implementing a low glycemic index pulse-based diet (lentils, peas, beans) is superior to a regular hospital diet in preventing the increase in bone loss that typically occurs during hospitalization with enforced bed rest.

Most reports of the impact of carbohydrates on bone health are from observational studies. In an interventional study, Dalskov and coauthors randomly assigned children aged 5-18 years who had parents with overweight to one of five diets (high protein/low glycemic index, high protein/high glycemic index, low protein/low glycemic index, low protein/high glycemic index, or regular) for 6 months.

Contrasting with our understanding that protein intake is overall good for bone, this study found that among patients receiving a high–glycemic index diet, those who were on a high-protein diet had greater reductions in a bone formation marker than did those on a low-protein diet, with no major changes observed with the other diets. This suggests the influence of associated dietary nutrients on bone outcomes and that protein intake may modify the effects of dietary carbohydrates on bone formation. Similarly, the fat content of food can alter the glycemic index and thus may modify the impact of dietary carbohydrates on bone.

In summary, available data suggest that the quantity and quality of carbohydrates, including the glycemic index of food, may affect bone health and that it is important to exercise moderation in the consumption of such foods. However, there are only a few studies that have examined these associations, and more studies are necessary to further clarify the impact of dietary carbohydrates on bone as well as any modifications of these effects by other associated food groups. These studies will allow us to refine our recommendations to our patients as we advance our understanding of the impact of the combined effects of various dietary nutrients on bone.

Madhusmita Misra, MD, MPH, is chief of the division of pediatric endocrinology, Mass General for Children, Boston, and serves or has served as a director, officer, partner, employee, advisor, consultant, or trustee for AbbVie, Sanofi, and Ipsen.

A version of this article first appeared on Medscape.com.

I am often asked about the impact of dietary nutrients on bone health, particularly as many patients with low bone density, many with a history of multiple fractures, are referred to me. Many factors affect bone density, an important predictor of fracture risk, including genetics, body weight and muscle mass, bone loading exercise, menstrual status, other hormonal factors, nutritional status, optimal absorption of dietary nutrients, and medication use.

Dietary nutrients include macronutrients (carbohydrates, proteins, fat, and fiber) and micronutrients (such as dietary minerals and vitamins). The importance of micronutrients such as calcium, phosphorus, magnesium, and vitamins C, D, and K in optimizing bone mineralization and bone formation has been well documented.

The impact of protein intake on bone health is slightly more controversial, with some studies suggesting that increased protein intake may be deleterious to bone by increasing acid load, which in turn, increases calcium loss in urine. Overall data analysis from multiple studies support the finding that a higher protein intake is modestly beneficial for bone at certain sites, such as the spine.

Though data regarding the impact of dietary carbohydrates on bone are not as robust, it’s important to understand these effects given the increasing knowledge of the deleterious impact of processed carbohydrates on weight and cardiometabolic outcomes. This leads to the growing recommendations to limit carbohydrates in diet.
 

Quality and quantity of carbs affect bone health

Available studies suggest that both the quality and quantity of carbohydrates that are in a diet as well as the glycemic index of food may affect bone outcomes. Glycemic index refers to the extent of blood glucose elevation that occurs after the intake of any specific food. Foods with a higher glycemic index cause a rapid increase in blood glucose, whereas those with a low glycemic index result in a slower and more gradual increase. Examples of high–glycemic index food include processed and baked foods (such as breakfast cereals [unless whole grain], pretzels, cookies, doughnuts, pastries, cake, white bread, bagels, croissants, and corn chips), sugar-sweetened beverages, white rice, fast food (such as pizza and burgers), and potatoes. Examples of low glycemic index foods include vegetables, fruits, legumes, dairy and dairy products (without added sugar), whole-grain foods (such as oat porridge), and nuts.

A high–glycemic index diet has been associated with a greater risk for obesity and cardiovascular disease, and with lower bone density, an increased risk for fracture. This has been attributed to acute increases in glucose and insulin levels after consumption of high–glycemic index food, which causes increased oxidative stress and secretion of inflammatory cytokines, such as interleukin 6 and tumor necrosis factor alpha, that activate cells in bone that increase bone loss.

Higher blood glucose concentrations induced by a higher dietary glycemic index can have deleterious effects on osteoblasts, the cells important for bone formation, and increase bone loss through production of advanced glycation end products that affect the cross linking of collagen in bone (important for bone strength), as well as calcium loss in urine. This was recently reported in a study by Garcia-Gavilan and others, in which the authors showed that high dietary glycemic index and dietary glucose load are associated with a higher risk for osteoporosis-related fractures in an older Mediterranean population who are at high risk for cardiovascular events. Similar data were reported by Nouri and coauthors in a study from Iran.

The quantity and quality of dietary carbohydrates may also have an impact on bone. The quality of carbohydrates has been assessed using the carbohydrate quality index (CQI) and the low carbohydrate diet score (LCDS). The CQI takes into account dietary fiber intake, glycemic index, intake of processed vs. whole grain, and solid vs. total carbohydrates in diet. A higher CQI diet is associated with reduced cardiovascular risk. Higher LCDS reflects lower carbohydrate and higher fat and protein intake.

Diets that are rich in refined or processed carbohydrates with added sugar are proinflammatory and increase oxidative stress, which may lead to increased bone loss, low bone density, and increased fracture risk. These foods also have a high glycemic index.

In contrast, diets that are rich in whole grains, legumes, fruits, vegetables, nuts, and olive oil have a lower glycemic index and are beneficial to bone. These diets have a higher CQI and LCDS (as reported by Nouri and coauthors) and provide a rich source of antioxidants, vitamins, minerals, and other nutrients (such as calcium, magnesium, and vitamins B, C, and K), which are all beneficial to bone. Gao and others have reported that implementing a low glycemic index pulse-based diet (lentils, peas, beans) is superior to a regular hospital diet in preventing the increase in bone loss that typically occurs during hospitalization with enforced bed rest.

Most reports of the impact of carbohydrates on bone health are from observational studies. In an interventional study, Dalskov and coauthors randomly assigned children aged 5-18 years who had parents with overweight to one of five diets (high protein/low glycemic index, high protein/high glycemic index, low protein/low glycemic index, low protein/high glycemic index, or regular) for 6 months.

Contrasting with our understanding that protein intake is overall good for bone, this study found that among patients receiving a high–glycemic index diet, those who were on a high-protein diet had greater reductions in a bone formation marker than did those on a low-protein diet, with no major changes observed with the other diets. This suggests the influence of associated dietary nutrients on bone outcomes and that protein intake may modify the effects of dietary carbohydrates on bone formation. Similarly, the fat content of food can alter the glycemic index and thus may modify the impact of dietary carbohydrates on bone.

In summary, available data suggest that the quantity and quality of carbohydrates, including the glycemic index of food, may affect bone health and that it is important to exercise moderation in the consumption of such foods. However, there are only a few studies that have examined these associations, and more studies are necessary to further clarify the impact of dietary carbohydrates on bone as well as any modifications of these effects by other associated food groups. These studies will allow us to refine our recommendations to our patients as we advance our understanding of the impact of the combined effects of various dietary nutrients on bone.

Madhusmita Misra, MD, MPH, is chief of the division of pediatric endocrinology, Mass General for Children, Boston, and serves or has served as a director, officer, partner, employee, advisor, consultant, or trustee for AbbVie, Sanofi, and Ipsen.

A version of this article first appeared on Medscape.com.

Frequent aspirin intake may reduce a woman’s risk of getting ovarian cancer, regardless of genetic susceptibility, new research suggests.

The study found that daily or almost daily aspirin use was associated with a 13% reduction in ovarian cancer risk, which was not modified by an individual’s polygenic score (PGS).

“Our findings suggest that frequent use of aspirin is associated with reduced ovarian cancer risk, regardless of whether a woman has lower or higher genetic susceptibility to ovarian cancer, as predicted by a set of known, common risk variants,” said lead author Lauren M. Hurwitz, PhD, MHS, division of cancer epidemiology and genetics at the National Cancer Institute, Rockville, Md.

The study was published online in JAMA Network Open.

Patients diagnosed with ovarian cancer face difficult survival odds, which make preventive strategies especially important. Evidence suggests that frequent aspirin use can reduce the risk for ovarian cancer by about 13%, but it’s unclear whether genetic factors change those odds.

Although promising for chemoprevention, aspirin use can also come with downsides, including gastric ulcer and hemorrhagic stroke, which is why identifying and targeting individuals at higher risk for ovarian cancer who may benefit from frequent aspirin use is important.

In the current analysis, Dr. Hurwitz and colleagues used a PGS to determine whether the protective effects of daily or near-daily aspirin use for 6 months or more could be modified by genetics.

The study was a pooled analysis of eight case-controlled studies from the Ovarian Cancer Association Consortium conducted in the United Kingdom, the United States, and Australia over a 14-year period. The researchers looked at genetic data and data on frequent aspirin use among 4,476 case patients with nonmucinous ovarian cancer (average age, 57) and 6,659 control participants (average age, 58). Overall, 575 patients (13%) and 1,030 controls (15%) reported frequent aspirin use.

The authors used a PGS previously developed using 22 single-nucleotide variants. Because this PGS was developed for nonmucinous epithelial ovarian cancer, only these patients were included in the analysis.

Consistent with previous evidence, the authors found that frequent aspirin use was associated with a 13% lower risk for nonmucinous ovarian cancer (odds ratio, 0.87). And, notably, this association did not differ by PGS. Risk reductions were greatest for high-grade serous (OR, 0.83) and endometrioid tumors (OR, 0.73), with no evidence that PGS modified this association.

Overall, “we observed consistent protective associations between frequent aspirin use and nonmucinous ovarian cancer across strata of genetic susceptibility to ovarian cancer,” the authors conclude. “This work expands on the evidence base to suggest that chemoprevention programs could target individuals at higher risk of ovarian cancer.”

However, the authors noted that they were unable to test for effect modifications by specific pathogenic variants, such as BRCA1 or BRCA2.  

“Our study did not address whether aspirin use is associated with reduced ovarian cancer risk among BRCA or other pathogenic variant carriers, and so our findings should not be used to inform discussions around aspirin use for these specific high-risk groups,” Dr. Hurwitz said. “Women with higher genetic susceptibility to ovarian cancer based on these common risk variants should discuss with their doctor the benefits and harms of taking aspirin for disease prevention.”

This study was supported by a grant from the DoD Ovarian Cancer Research Program. Dr. Hurwitz reports no relevant financial relationships, but several coauthors did report funding and support.
 

A version of this article first appeared on Medscape.com.

Frequent aspirin intake may reduce a woman’s risk of getting ovarian cancer, regardless of genetic susceptibility, new research suggests.

The study found that daily or almost daily aspirin use was associated with a 13% reduction in ovarian cancer risk, which was not modified by an individual’s polygenic score (PGS).

“Our findings suggest that frequent use of aspirin is associated with reduced ovarian cancer risk, regardless of whether a woman has lower or higher genetic susceptibility to ovarian cancer, as predicted by a set of known, common risk variants,” said lead author Lauren M. Hurwitz, PhD, MHS, division of cancer epidemiology and genetics at the National Cancer Institute, Rockville, Md.

The study was published online in JAMA Network Open.

Patients diagnosed with ovarian cancer face difficult survival odds, which make preventive strategies especially important. Evidence suggests that frequent aspirin use can reduce the risk for ovarian cancer by about 13%, but it’s unclear whether genetic factors change those odds.

Although promising for chemoprevention, aspirin use can also come with downsides, including gastric ulcer and hemorrhagic stroke, which is why identifying and targeting individuals at higher risk for ovarian cancer who may benefit from frequent aspirin use is important.

In the current analysis, Dr. Hurwitz and colleagues used a PGS to determine whether the protective effects of daily or near-daily aspirin use for 6 months or more could be modified by genetics.

The study was a pooled analysis of eight case-controlled studies from the Ovarian Cancer Association Consortium conducted in the United Kingdom, the United States, and Australia over a 14-year period. The researchers looked at genetic data and data on frequent aspirin use among 4,476 case patients with nonmucinous ovarian cancer (average age, 57) and 6,659 control participants (average age, 58). Overall, 575 patients (13%) and 1,030 controls (15%) reported frequent aspirin use.

The authors used a PGS previously developed using 22 single-nucleotide variants. Because this PGS was developed for nonmucinous epithelial ovarian cancer, only these patients were included in the analysis.

Consistent with previous evidence, the authors found that frequent aspirin use was associated with a 13% lower risk for nonmucinous ovarian cancer (odds ratio, 0.87). And, notably, this association did not differ by PGS. Risk reductions were greatest for high-grade serous (OR, 0.83) and endometrioid tumors (OR, 0.73), with no evidence that PGS modified this association.

Overall, “we observed consistent protective associations between frequent aspirin use and nonmucinous ovarian cancer across strata of genetic susceptibility to ovarian cancer,” the authors conclude. “This work expands on the evidence base to suggest that chemoprevention programs could target individuals at higher risk of ovarian cancer.”

However, the authors noted that they were unable to test for effect modifications by specific pathogenic variants, such as BRCA1 or BRCA2.  

“Our study did not address whether aspirin use is associated with reduced ovarian cancer risk among BRCA or other pathogenic variant carriers, and so our findings should not be used to inform discussions around aspirin use for these specific high-risk groups,” Dr. Hurwitz said. “Women with higher genetic susceptibility to ovarian cancer based on these common risk variants should discuss with their doctor the benefits and harms of taking aspirin for disease prevention.”

This study was supported by a grant from the DoD Ovarian Cancer Research Program. Dr. Hurwitz reports no relevant financial relationships, but several coauthors did report funding and support.
 

A version of this article first appeared on Medscape.com.

Frequent aspirin intake may reduce a woman’s risk of getting ovarian cancer, regardless of genetic susceptibility, new research suggests.

The study found that daily or almost daily aspirin use was associated with a 13% reduction in ovarian cancer risk, which was not modified by an individual’s polygenic score (PGS).

“Our findings suggest that frequent use of aspirin is associated with reduced ovarian cancer risk, regardless of whether a woman has lower or higher genetic susceptibility to ovarian cancer, as predicted by a set of known, common risk variants,” said lead author Lauren M. Hurwitz, PhD, MHS, division of cancer epidemiology and genetics at the National Cancer Institute, Rockville, Md.

The study was published online in JAMA Network Open.

Patients diagnosed with ovarian cancer face difficult survival odds, which make preventive strategies especially important. Evidence suggests that frequent aspirin use can reduce the risk for ovarian cancer by about 13%, but it’s unclear whether genetic factors change those odds.

Although promising for chemoprevention, aspirin use can also come with downsides, including gastric ulcer and hemorrhagic stroke, which is why identifying and targeting individuals at higher risk for ovarian cancer who may benefit from frequent aspirin use is important.

In the current analysis, Dr. Hurwitz and colleagues used a PGS to determine whether the protective effects of daily or near-daily aspirin use for 6 months or more could be modified by genetics.

The study was a pooled analysis of eight case-controlled studies from the Ovarian Cancer Association Consortium conducted in the United Kingdom, the United States, and Australia over a 14-year period. The researchers looked at genetic data and data on frequent aspirin use among 4,476 case patients with nonmucinous ovarian cancer (average age, 57) and 6,659 control participants (average age, 58). Overall, 575 patients (13%) and 1,030 controls (15%) reported frequent aspirin use.

The authors used a PGS previously developed using 22 single-nucleotide variants. Because this PGS was developed for nonmucinous epithelial ovarian cancer, only these patients were included in the analysis.

Consistent with previous evidence, the authors found that frequent aspirin use was associated with a 13% lower risk for nonmucinous ovarian cancer (odds ratio, 0.87). And, notably, this association did not differ by PGS. Risk reductions were greatest for high-grade serous (OR, 0.83) and endometrioid tumors (OR, 0.73), with no evidence that PGS modified this association.

Overall, “we observed consistent protective associations between frequent aspirin use and nonmucinous ovarian cancer across strata of genetic susceptibility to ovarian cancer,” the authors conclude. “This work expands on the evidence base to suggest that chemoprevention programs could target individuals at higher risk of ovarian cancer.”

However, the authors noted that they were unable to test for effect modifications by specific pathogenic variants, such as BRCA1 or BRCA2.  

“Our study did not address whether aspirin use is associated with reduced ovarian cancer risk among BRCA or other pathogenic variant carriers, and so our findings should not be used to inform discussions around aspirin use for these specific high-risk groups,” Dr. Hurwitz said. “Women with higher genetic susceptibility to ovarian cancer based on these common risk variants should discuss with their doctor the benefits and harms of taking aspirin for disease prevention.”

This study was supported by a grant from the DoD Ovarian Cancer Research Program. Dr. Hurwitz reports no relevant financial relationships, but several coauthors did report funding and support.
 

A version of this article first appeared on Medscape.com.

Lille, France – The American College of Physicians has just updated its guidelines for osteoporosis treatment. Bernard Cortet, MD, PhD, chairperson of the Osteoporosis Research and Information Group and head of the rheumatology department at Lille (France) University Hospital, has agreed to compare the new U.S. guidelines to the 2018 French recommendations written under the aegis of the French Society for Rheumatology and GRIO. Dr. Cortet participated in drafting the French recommendations.

Question: The ACP “strongly” recommends initial pharmacologic treatment with bisphosphonate antiresorptive drugs (alendronate, ibandronate, risedronate, zoledronate) in postmenopausal females diagnosed with primary osteoporosis. Isn’t this what the SFR–GRIO have been recommending for many years?

Answer: The ACP reinforces its stance by arguing that in postmenopausal females with primary osteoporosis, bisphosphonates have the most favorable balance between benefits, harms, patient values and preferences, and cost among the drug classes that were evaluated. In addition to net clinical benefits, bisphosphonates are much cheaper than other pharmacologic treatments and are available in generic oral and injectable formulations.

Our French recommendations specify the choice of drug based on the type of fracture in women and on their bone mineral density (BMD). However, bisphosphonates are definitely given pride of place. When treatment for osteoporosis needs to be started, most of the time, a bisphosphonate is the treatment of choice.

Nevertheless, as also highlighted by the ACP, a more “aggressive” approach must be considered for more severe cases.

In the case of a severe fracture, the French recommendations indicate that all treatments can be prescribed. However, zoledronic acid should be favored as first-line treatment for a hip fracture. In other cases – with or without a nonsevere fracture – the therapeutic indication depends on the BMD values, and in difficult cases, on tools such as FRAX [the Fracture Risk Assessment Tool].

Our guidance strongly recommends opting for an injection in other contexts, such as significant decrease in bone density, presence of comorbidities, poor treatment compliance, brain function disorders, and polymedication.

Q. But it’s not really as simple as prescribing a bisphosphonate, is it?

A. You’re right, many people find the idea of taking bisphosphonates worrying because of associated jaw problems – osteonecrosis of the jaw – or atypical femoral fractures, based on what they’ve read on the Internet, where these serious adverse events are on display front and center with no mention of how often they actually happen and, often, failing to mention how effective bisphosphonates truly are.

These complications are real, but fortunately rare, especially during the first 5 years of treatment. To put this into context, for bisphosphonates, there’s one case of osteonecrosis of the jaw for every 10,000. And for denosumab, there are five cases for every 10,000. For atypical fractures, there’s one case for every 30,000 to 50,000.

Q. The U.S. guidelines also recommend that clinicians use a RANK ligand inhibitor – denosumab, also an antiresorptive drug – as second-line medical treatment. This is to reduce the risk of fractures in postmenopausal women diagnosed with primary osteoporosis and presenting with contraindications or side effects of bisphosphonates. Do you support the use of denosumab as second-line treatment?

A. French legislation classifies it as a second-line treatment, after bisphosphonates. However, there are arguments in favor of prescribing it as first-line treatment in some contexts. If denosumab is to be prescribed – via a twice-yearly subcutaneous injection – full compliance must be observed. If a patient is to stop taking denosumab, an opinion from a medical professional is required before treatment can be discontinued, and then treatment with bisphosphonates must be prescribed.

Q. The ACP recommends that clinicians use either a sclerostin inhibitor – romosozumab – or recombinant human parathyroid hormone – teriparatide – two anabolic agents, followed by a bisphosphonate, with the aim of reducing the risk of fractures. This is only used in women with primary osteoporosis who are at a very high risk of fracture. As romosozumab is not available in France, it’s not really worth discussing its use. Does this strategy seem advisable to you, though?

A. The main issue is what is understood by “women at a very high risk of fracture.” There’s no consensus on the definition of what constitutes a woman at a very high risk of fracture, but we can assume that it involves the combination of low BMD and at least one severe fracture.

The role of anabolic bone treatment, as [the ACP] has defined it, seems logical to me, because in cases of severe osteoporosis with fracture, the risk of recurrence is very high in the next 2-3 years. In a study comparing risedronate and teriparatide in cases of severe osteoporosis, teriparatide was more effective in reducing the recurrence of vertebral fractures.

The favorable opinion of the French National Authority for Health in relation to medical coverage for romosozumab in the treatment of severe postmenopausal osteoporosis in women under the age of 75 years with a history of severe fractures, a T-score less than –2.5, and no previous history of coronary artery disease dates to 2021. This is because medical coverage for this specific group was not listed in the marketing authorization (MA) description for this drug.

But the review by the Economic Committee for Health Products failed to reach a consensus regarding the price. Today, in theory, romosozumab can be dispensed in France by hospital pharmacies, because it is approved for use in public hospitals. Romosozumab is a very interesting drug for relatively young women, especially those with multiple vertebral fractures. This injectable treatment is more effective than teriparatide in increasing BMD values and more effective than alendronate in preventing the recurrence of fractures.

Regarding medical coverage, as it stands, in cases where patients have a T-score less than or equal to –3, the 2018 SFR–GRIO recommends starting treatment even if the patient has no fractures. In cases with severe fractures combined with very low BMD (T-score ≤ –3), injectable treatments may be used to reach a bone density target (T-score > –2.5 to –2 for the hip) at the end of the treatment plan. [These treatments include] zoledronic acid, denosumab (in case of bisphosphonate failure or intolerance), or a treatment plan with teriparatide (covered by medical insurance if the patient has at least two vertebral fractures) followed by an antiresorptive drug (bisphosphonate or denosumab).

Romosozumab is a humanized monoclonal antibody (IgG2) that binds to sclerostin and acts as an inhibitor. This increases bone formation because of the activation of [bone lining cells], the production of bone matrix by osteoblasts, and the recruitment of osteochondroprogenitor cells. Moreover, romosozumab causes changes in the expression of osteoclast mediators, which decreases bone resorption. Together, these two effects that increase bone formation and decrease bone resorption lead to the rapid increase of trabecular and cortical bone mass, as well as improvements in bone structure and strength.

Women treated with a bone anabolic agent must take an antiresorptive agent at the end of their treatment so that the benefits from the treatment remain in the long term. The French and U.S. guidelines line up on this point.

In patients with two prevalent vertebral fractures, the U.S. guidelines state that teriparatide can be prescribed as first-line treatment at diagnosis in the absence of any contraindications. We agree on this point as well.

Moreover, in women under the age of 70 years with osteoporosis requiring treatment, French experts recommend prescribing raloxifene, a selective estrogen-receptor modulator. This is if the risk of nonvertebral fracture is low, as defined by the absence of the following criteria: low hip T-score, risk of falling, and history of nonvertebral fracture. Opportunities for its use are limited, and it doesn’t even figure among the U.S. recommendations.

Q. The ACP recommends that clinicians adopt an individualized approach regarding whether to start medical treatment with a bisphosphonate in women over age 65 years with low bone mass (osteopenia) to reduce the risk of fractures. If treatment is started, they›re of the opinion that a bisphosphonate must be used. What are the recommendations in France?

A. It should be noted that this recommendation by the ACP is conditional because of the low-certainty evidence.

Here’s a brief reminder of important things to note: a T-score between –2.5 and –1 indicates osteopenia; a T-score less than or equal to –2.5 indicates osteoporosis; a T-score less than or equal to –2.5 with one or several fractures indicates severe osteoporosis. The French recommendations state that treatment is not justified if a patient’s T-score is higher than –2 and there’s no presence of fractures, even with risk factors (and/or multiple falls). For T-scores less than or equal to –2 and higher than –3, the decision to prescribe depends on the specialist.

Q. The ACP recommends that clinicians use bisphosphonates for the initial medical treatment to reduce the risk of fractures in men diagnosed with primary osteoporosis.

A. The ACP recommends that clinicians use a RANK ligand inhibitor – denosumab – as second-line medical treatment to reduce the risk of fractures in men diagnosed with primary osteoporosis who present with contraindications or who are experiencing side effects of bisphosphonates. This treatment is not covered by health insurance for men in France.

Between 20% and 25% of clinical osteoporotic fractures occur in men. After age 50 years, men are roughly 20% more likely to experience an osteoporotic fracture in their lifetime. The French recommendations regarding the management and treatment of osteoporosis in men were published in 2021.

In the case of severe fractures (vertebrae, pelvis, upper end of the femur, distal femur, proximal humerus) attributable to bone fragility, osteoporosis treatment is recommended if one of the T-scores is less than or equal to –1.

In the case of nonsevere fractures (particularly wrist and ankle) attributable to bone fragility, osteoporosis treatment is recommended if one of the T-scores is less than or equal to –2. If there are no fractures, osteoporosis treatment is recommended in men at risk of bone fragility or of falling and if one of the T-scores is less than or equal to –3. In patients who had a fracture of the upper end of the femur attributable to bone fragility, zoledronic acid is recommended as first-line treatment.

For men with a severe nonvertebral fracture, single vertebral fracture, or nonsevere fracture, two treatments are indicated and covered by health insurance in France: zoledronic acid and risedronate. In men with at least two vertebral fractures, the following treatments are indicated and covered by health insurance in France: teriparatide and risedronate. In this case, teriparatide is prescribed for a period of 18 months. It must be followed by a prescription of oral or intravenous bisphosphonates.

Q. What is your take on the HAS update to the proper use of osteoporosis medication that’s just been published?

A. Like in the 2018 SFR–GRIO guidelines, no update has been made to the section on postmenopausal osteoporosis, except for the HAS introduction to the proper use of romosozumab, even though it’s not covered by health insurance in France.

In accordance with the MA, it doesn’t make sense to include this drug on the list of treatment options available for women with and without fractures, as it’s not included in the HAS-selected list of drugs covered by health insurance in France.

But I’m glad that the HAS has adopted the GRIO and SFR recommendations regarding corticosteroid-induced osteoporosis. Preventive treatment for corticosteroid-induced osteoporosis must be considered as soon as the daily dose of corticosteroids reaches or exceeds the equivalent of 7.5 mg of prednisone and when the estimated duration of corticosteroid therapy exceeds 3 months.

In summary, in women and men over the age of 50 years, the intake of the equivalent of 7.5 mg/day or more of prednisone or a history of a low-trauma fracture or being age 70 years or older, even with a T-score less than or equal to –2.5 for one of the two sites, indicates prescribing a bisphosphonate. Teriparatide is indicated if the patient has two vertebral fractures.

This article was translated from Medscape’s French edition.

A version of this article first appeared on Medscape.com.

Lille, France – The American College of Physicians has just updated its guidelines for osteoporosis treatment. Bernard Cortet, MD, PhD, chairperson of the Osteoporosis Research and Information Group and head of the rheumatology department at Lille (France) University Hospital, has agreed to compare the new U.S. guidelines to the 2018 French recommendations written under the aegis of the French Society for Rheumatology and GRIO. Dr. Cortet participated in drafting the French recommendations.

Question: The ACP “strongly” recommends initial pharmacologic treatment with bisphosphonate antiresorptive drugs (alendronate, ibandronate, risedronate, zoledronate) in postmenopausal females diagnosed with primary osteoporosis. Isn’t this what the SFR–GRIO have been recommending for many years?

Answer: The ACP reinforces its stance by arguing that in postmenopausal females with primary osteoporosis, bisphosphonates have the most favorable balance between benefits, harms, patient values and preferences, and cost among the drug classes that were evaluated. In addition to net clinical benefits, bisphosphonates are much cheaper than other pharmacologic treatments and are available in generic oral and injectable formulations.

Our French recommendations specify the choice of drug based on the type of fracture in women and on their bone mineral density (BMD). However, bisphosphonates are definitely given pride of place. When treatment for osteoporosis needs to be started, most of the time, a bisphosphonate is the treatment of choice.

Nevertheless, as also highlighted by the ACP, a more “aggressive” approach must be considered for more severe cases.

In the case of a severe fracture, the French recommendations indicate that all treatments can be prescribed. However, zoledronic acid should be favored as first-line treatment for a hip fracture. In other cases – with or without a nonsevere fracture – the therapeutic indication depends on the BMD values, and in difficult cases, on tools such as FRAX [the Fracture Risk Assessment Tool].

Our guidance strongly recommends opting for an injection in other contexts, such as significant decrease in bone density, presence of comorbidities, poor treatment compliance, brain function disorders, and polymedication.

Q. But it’s not really as simple as prescribing a bisphosphonate, is it?

A. You’re right, many people find the idea of taking bisphosphonates worrying because of associated jaw problems – osteonecrosis of the jaw – or atypical femoral fractures, based on what they’ve read on the Internet, where these serious adverse events are on display front and center with no mention of how often they actually happen and, often, failing to mention how effective bisphosphonates truly are.

These complications are real, but fortunately rare, especially during the first 5 years of treatment. To put this into context, for bisphosphonates, there’s one case of osteonecrosis of the jaw for every 10,000. And for denosumab, there are five cases for every 10,000. For atypical fractures, there’s one case for every 30,000 to 50,000.

Q. The U.S. guidelines also recommend that clinicians use a RANK ligand inhibitor – denosumab, also an antiresorptive drug – as second-line medical treatment. This is to reduce the risk of fractures in postmenopausal women diagnosed with primary osteoporosis and presenting with contraindications or side effects of bisphosphonates. Do you support the use of denosumab as second-line treatment?

A. French legislation classifies it as a second-line treatment, after bisphosphonates. However, there are arguments in favor of prescribing it as first-line treatment in some contexts. If denosumab is to be prescribed – via a twice-yearly subcutaneous injection – full compliance must be observed. If a patient is to stop taking denosumab, an opinion from a medical professional is required before treatment can be discontinued, and then treatment with bisphosphonates must be prescribed.

Q. The ACP recommends that clinicians use either a sclerostin inhibitor – romosozumab – or recombinant human parathyroid hormone – teriparatide – two anabolic agents, followed by a bisphosphonate, with the aim of reducing the risk of fractures. This is only used in women with primary osteoporosis who are at a very high risk of fracture. As romosozumab is not available in France, it’s not really worth discussing its use. Does this strategy seem advisable to you, though?

A. The main issue is what is understood by “women at a very high risk of fracture.” There’s no consensus on the definition of what constitutes a woman at a very high risk of fracture, but we can assume that it involves the combination of low BMD and at least one severe fracture.

The role of anabolic bone treatment, as [the ACP] has defined it, seems logical to me, because in cases of severe osteoporosis with fracture, the risk of recurrence is very high in the next 2-3 years. In a study comparing risedronate and teriparatide in cases of severe osteoporosis, teriparatide was more effective in reducing the recurrence of vertebral fractures.

The favorable opinion of the French National Authority for Health in relation to medical coverage for romosozumab in the treatment of severe postmenopausal osteoporosis in women under the age of 75 years with a history of severe fractures, a T-score less than –2.5, and no previous history of coronary artery disease dates to 2021. This is because medical coverage for this specific group was not listed in the marketing authorization (MA) description for this drug.

But the review by the Economic Committee for Health Products failed to reach a consensus regarding the price. Today, in theory, romosozumab can be dispensed in France by hospital pharmacies, because it is approved for use in public hospitals. Romosozumab is a very interesting drug for relatively young women, especially those with multiple vertebral fractures. This injectable treatment is more effective than teriparatide in increasing BMD values and more effective than alendronate in preventing the recurrence of fractures.

Regarding medical coverage, as it stands, in cases where patients have a T-score less than or equal to –3, the 2018 SFR–GRIO recommends starting treatment even if the patient has no fractures. In cases with severe fractures combined with very low BMD (T-score ≤ –3), injectable treatments may be used to reach a bone density target (T-score > –2.5 to –2 for the hip) at the end of the treatment plan. [These treatments include] zoledronic acid, denosumab (in case of bisphosphonate failure or intolerance), or a treatment plan with teriparatide (covered by medical insurance if the patient has at least two vertebral fractures) followed by an antiresorptive drug (bisphosphonate or denosumab).

Romosozumab is a humanized monoclonal antibody (IgG2) that binds to sclerostin and acts as an inhibitor. This increases bone formation because of the activation of [bone lining cells], the production of bone matrix by osteoblasts, and the recruitment of osteochondroprogenitor cells. Moreover, romosozumab causes changes in the expression of osteoclast mediators, which decreases bone resorption. Together, these two effects that increase bone formation and decrease bone resorption lead to the rapid increase of trabecular and cortical bone mass, as well as improvements in bone structure and strength.

Women treated with a bone anabolic agent must take an antiresorptive agent at the end of their treatment so that the benefits from the treatment remain in the long term. The French and U.S. guidelines line up on this point.

In patients with two prevalent vertebral fractures, the U.S. guidelines state that teriparatide can be prescribed as first-line treatment at diagnosis in the absence of any contraindications. We agree on this point as well.

Moreover, in women under the age of 70 years with osteoporosis requiring treatment, French experts recommend prescribing raloxifene, a selective estrogen-receptor modulator. This is if the risk of nonvertebral fracture is low, as defined by the absence of the following criteria: low hip T-score, risk of falling, and history of nonvertebral fracture. Opportunities for its use are limited, and it doesn’t even figure among the U.S. recommendations.

Q. The ACP recommends that clinicians adopt an individualized approach regarding whether to start medical treatment with a bisphosphonate in women over age 65 years with low bone mass (osteopenia) to reduce the risk of fractures. If treatment is started, they›re of the opinion that a bisphosphonate must be used. What are the recommendations in France?

A. It should be noted that this recommendation by the ACP is conditional because of the low-certainty evidence.

Here’s a brief reminder of important things to note: a T-score between –2.5 and –1 indicates osteopenia; a T-score less than or equal to –2.5 indicates osteoporosis; a T-score less than or equal to –2.5 with one or several fractures indicates severe osteoporosis. The French recommendations state that treatment is not justified if a patient’s T-score is higher than –2 and there’s no presence of fractures, even with risk factors (and/or multiple falls). For T-scores less than or equal to –2 and higher than –3, the decision to prescribe depends on the specialist.

Q. The ACP recommends that clinicians use bisphosphonates for the initial medical treatment to reduce the risk of fractures in men diagnosed with primary osteoporosis.

A. The ACP recommends that clinicians use a RANK ligand inhibitor – denosumab – as second-line medical treatment to reduce the risk of fractures in men diagnosed with primary osteoporosis who present with contraindications or who are experiencing side effects of bisphosphonates. This treatment is not covered by health insurance for men in France.

Between 20% and 25% of clinical osteoporotic fractures occur in men. After age 50 years, men are roughly 20% more likely to experience an osteoporotic fracture in their lifetime. The French recommendations regarding the management and treatment of osteoporosis in men were published in 2021.

In the case of severe fractures (vertebrae, pelvis, upper end of the femur, distal femur, proximal humerus) attributable to bone fragility, osteoporosis treatment is recommended if one of the T-scores is less than or equal to –1.

In the case of nonsevere fractures (particularly wrist and ankle) attributable to bone fragility, osteoporosis treatment is recommended if one of the T-scores is less than or equal to –2. If there are no fractures, osteoporosis treatment is recommended in men at risk of bone fragility or of falling and if one of the T-scores is less than or equal to –3. In patients who had a fracture of the upper end of the femur attributable to bone fragility, zoledronic acid is recommended as first-line treatment.

For men with a severe nonvertebral fracture, single vertebral fracture, or nonsevere fracture, two treatments are indicated and covered by health insurance in France: zoledronic acid and risedronate. In men with at least two vertebral fractures, the following treatments are indicated and covered by health insurance in France: teriparatide and risedronate. In this case, teriparatide is prescribed for a period of 18 months. It must be followed by a prescription of oral or intravenous bisphosphonates.

Q. What is your take on the HAS update to the proper use of osteoporosis medication that’s just been published?

A. Like in the 2018 SFR–GRIO guidelines, no update has been made to the section on postmenopausal osteoporosis, except for the HAS introduction to the proper use of romosozumab, even though it’s not covered by health insurance in France.

In accordance with the MA, it doesn’t make sense to include this drug on the list of treatment options available for women with and without fractures, as it’s not included in the HAS-selected list of drugs covered by health insurance in France.

But I’m glad that the HAS has adopted the GRIO and SFR recommendations regarding corticosteroid-induced osteoporosis. Preventive treatment for corticosteroid-induced osteoporosis must be considered as soon as the daily dose of corticosteroids reaches or exceeds the equivalent of 7.5 mg of prednisone and when the estimated duration of corticosteroid therapy exceeds 3 months.

In summary, in women and men over the age of 50 years, the intake of the equivalent of 7.5 mg/day or more of prednisone or a history of a low-trauma fracture or being age 70 years or older, even with a T-score less than or equal to –2.5 for one of the two sites, indicates prescribing a bisphosphonate. Teriparatide is indicated if the patient has two vertebral fractures.

This article was translated from Medscape’s French edition.

A version of this article first appeared on Medscape.com.

Lille, France – The American College of Physicians has just updated its guidelines for osteoporosis treatment. Bernard Cortet, MD, PhD, chairperson of the Osteoporosis Research and Information Group and head of the rheumatology department at Lille (France) University Hospital, has agreed to compare the new U.S. guidelines to the 2018 French recommendations written under the aegis of the French Society for Rheumatology and GRIO. Dr. Cortet participated in drafting the French recommendations.

Question: The ACP “strongly” recommends initial pharmacologic treatment with bisphosphonate antiresorptive drugs (alendronate, ibandronate, risedronate, zoledronate) in postmenopausal females diagnosed with primary osteoporosis. Isn’t this what the SFR–GRIO have been recommending for many years?

Answer: The ACP reinforces its stance by arguing that in postmenopausal females with primary osteoporosis, bisphosphonates have the most favorable balance between benefits, harms, patient values and preferences, and cost among the drug classes that were evaluated. In addition to net clinical benefits, bisphosphonates are much cheaper than other pharmacologic treatments and are available in generic oral and injectable formulations.

Our French recommendations specify the choice of drug based on the type of fracture in women and on their bone mineral density (BMD). However, bisphosphonates are definitely given pride of place. When treatment for osteoporosis needs to be started, most of the time, a bisphosphonate is the treatment of choice.

Nevertheless, as also highlighted by the ACP, a more “aggressive” approach must be considered for more severe cases.

In the case of a severe fracture, the French recommendations indicate that all treatments can be prescribed. However, zoledronic acid should be favored as first-line treatment for a hip fracture. In other cases – with or without a nonsevere fracture – the therapeutic indication depends on the BMD values, and in difficult cases, on tools such as FRAX [the Fracture Risk Assessment Tool].

Our guidance strongly recommends opting for an injection in other contexts, such as significant decrease in bone density, presence of comorbidities, poor treatment compliance, brain function disorders, and polymedication.

Q. But it’s not really as simple as prescribing a bisphosphonate, is it?

A. You’re right, many people find the idea of taking bisphosphonates worrying because of associated jaw problems – osteonecrosis of the jaw – or atypical femoral fractures, based on what they’ve read on the Internet, where these serious adverse events are on display front and center with no mention of how often they actually happen and, often, failing to mention how effective bisphosphonates truly are.

These complications are real, but fortunately rare, especially during the first 5 years of treatment. To put this into context, for bisphosphonates, there’s one case of osteonecrosis of the jaw for every 10,000. And for denosumab, there are five cases for every 10,000. For atypical fractures, there’s one case for every 30,000 to 50,000.

Q. The U.S. guidelines also recommend that clinicians use a RANK ligand inhibitor – denosumab, also an antiresorptive drug – as second-line medical treatment. This is to reduce the risk of fractures in postmenopausal women diagnosed with primary osteoporosis and presenting with contraindications or side effects of bisphosphonates. Do you support the use of denosumab as second-line treatment?

A. French legislation classifies it as a second-line treatment, after bisphosphonates. However, there are arguments in favor of prescribing it as first-line treatment in some contexts. If denosumab is to be prescribed – via a twice-yearly subcutaneous injection – full compliance must be observed. If a patient is to stop taking denosumab, an opinion from a medical professional is required before treatment can be discontinued, and then treatment with bisphosphonates must be prescribed.

Q. The ACP recommends that clinicians use either a sclerostin inhibitor – romosozumab – or recombinant human parathyroid hormone – teriparatide – two anabolic agents, followed by a bisphosphonate, with the aim of reducing the risk of fractures. This is only used in women with primary osteoporosis who are at a very high risk of fracture. As romosozumab is not available in France, it’s not really worth discussing its use. Does this strategy seem advisable to you, though?

A. The main issue is what is understood by “women at a very high risk of fracture.” There’s no consensus on the definition of what constitutes a woman at a very high risk of fracture, but we can assume that it involves the combination of low BMD and at least one severe fracture.

The role of anabolic bone treatment, as [the ACP] has defined it, seems logical to me, because in cases of severe osteoporosis with fracture, the risk of recurrence is very high in the next 2-3 years. In a study comparing risedronate and teriparatide in cases of severe osteoporosis, teriparatide was more effective in reducing the recurrence of vertebral fractures.

The favorable opinion of the French National Authority for Health in relation to medical coverage for romosozumab in the treatment of severe postmenopausal osteoporosis in women under the age of 75 years with a history of severe fractures, a T-score less than –2.5, and no previous history of coronary artery disease dates to 2021. This is because medical coverage for this specific group was not listed in the marketing authorization (MA) description for this drug.

But the review by the Economic Committee for Health Products failed to reach a consensus regarding the price. Today, in theory, romosozumab can be dispensed in France by hospital pharmacies, because it is approved for use in public hospitals. Romosozumab is a very interesting drug for relatively young women, especially those with multiple vertebral fractures. This injectable treatment is more effective than teriparatide in increasing BMD values and more effective than alendronate in preventing the recurrence of fractures.

Regarding medical coverage, as it stands, in cases where patients have a T-score less than or equal to –3, the 2018 SFR–GRIO recommends starting treatment even if the patient has no fractures. In cases with severe fractures combined with very low BMD (T-score ≤ –3), injectable treatments may be used to reach a bone density target (T-score > –2.5 to –2 for the hip) at the end of the treatment plan. [These treatments include] zoledronic acid, denosumab (in case of bisphosphonate failure or intolerance), or a treatment plan with teriparatide (covered by medical insurance if the patient has at least two vertebral fractures) followed by an antiresorptive drug (bisphosphonate or denosumab).

Romosozumab is a humanized monoclonal antibody (IgG2) that binds to sclerostin and acts as an inhibitor. This increases bone formation because of the activation of [bone lining cells], the production of bone matrix by osteoblasts, and the recruitment of osteochondroprogenitor cells. Moreover, romosozumab causes changes in the expression of osteoclast mediators, which decreases bone resorption. Together, these two effects that increase bone formation and decrease bone resorption lead to the rapid increase of trabecular and cortical bone mass, as well as improvements in bone structure and strength.

Women treated with a bone anabolic agent must take an antiresorptive agent at the end of their treatment so that the benefits from the treatment remain in the long term. The French and U.S. guidelines line up on this point.

In patients with two prevalent vertebral fractures, the U.S. guidelines state that teriparatide can be prescribed as first-line treatment at diagnosis in the absence of any contraindications. We agree on this point as well.

Moreover, in women under the age of 70 years with osteoporosis requiring treatment, French experts recommend prescribing raloxifene, a selective estrogen-receptor modulator. This is if the risk of nonvertebral fracture is low, as defined by the absence of the following criteria: low hip T-score, risk of falling, and history of nonvertebral fracture. Opportunities for its use are limited, and it doesn’t even figure among the U.S. recommendations.

Q. The ACP recommends that clinicians adopt an individualized approach regarding whether to start medical treatment with a bisphosphonate in women over age 65 years with low bone mass (osteopenia) to reduce the risk of fractures. If treatment is started, they›re of the opinion that a bisphosphonate must be used. What are the recommendations in France?

A. It should be noted that this recommendation by the ACP is conditional because of the low-certainty evidence.

Here’s a brief reminder of important things to note: a T-score between –2.5 and –1 indicates osteopenia; a T-score less than or equal to –2.5 indicates osteoporosis; a T-score less than or equal to –2.5 with one or several fractures indicates severe osteoporosis. The French recommendations state that treatment is not justified if a patient’s T-score is higher than –2 and there’s no presence of fractures, even with risk factors (and/or multiple falls). For T-scores less than or equal to –2 and higher than –3, the decision to prescribe depends on the specialist.

Q. The ACP recommends that clinicians use bisphosphonates for the initial medical treatment to reduce the risk of fractures in men diagnosed with primary osteoporosis.

A. The ACP recommends that clinicians use a RANK ligand inhibitor – denosumab – as second-line medical treatment to reduce the risk of fractures in men diagnosed with primary osteoporosis who present with contraindications or who are experiencing side effects of bisphosphonates. This treatment is not covered by health insurance for men in France.

Between 20% and 25% of clinical osteoporotic fractures occur in men. After age 50 years, men are roughly 20% more likely to experience an osteoporotic fracture in their lifetime. The French recommendations regarding the management and treatment of osteoporosis in men were published in 2021.

In the case of severe fractures (vertebrae, pelvis, upper end of the femur, distal femur, proximal humerus) attributable to bone fragility, osteoporosis treatment is recommended if one of the T-scores is less than or equal to –1.

In the case of nonsevere fractures (particularly wrist and ankle) attributable to bone fragility, osteoporosis treatment is recommended if one of the T-scores is less than or equal to –2. If there are no fractures, osteoporosis treatment is recommended in men at risk of bone fragility or of falling and if one of the T-scores is less than or equal to –3. In patients who had a fracture of the upper end of the femur attributable to bone fragility, zoledronic acid is recommended as first-line treatment.

For men with a severe nonvertebral fracture, single vertebral fracture, or nonsevere fracture, two treatments are indicated and covered by health insurance in France: zoledronic acid and risedronate. In men with at least two vertebral fractures, the following treatments are indicated and covered by health insurance in France: teriparatide and risedronate. In this case, teriparatide is prescribed for a period of 18 months. It must be followed by a prescription of oral or intravenous bisphosphonates.

Q. What is your take on the HAS update to the proper use of osteoporosis medication that’s just been published?

A. Like in the 2018 SFR–GRIO guidelines, no update has been made to the section on postmenopausal osteoporosis, except for the HAS introduction to the proper use of romosozumab, even though it’s not covered by health insurance in France.

In accordance with the MA, it doesn’t make sense to include this drug on the list of treatment options available for women with and without fractures, as it’s not included in the HAS-selected list of drugs covered by health insurance in France.

But I’m glad that the HAS has adopted the GRIO and SFR recommendations regarding corticosteroid-induced osteoporosis. Preventive treatment for corticosteroid-induced osteoporosis must be considered as soon as the daily dose of corticosteroids reaches or exceeds the equivalent of 7.5 mg of prednisone and when the estimated duration of corticosteroid therapy exceeds 3 months.

In summary, in women and men over the age of 50 years, the intake of the equivalent of 7.5 mg/day or more of prednisone or a history of a low-trauma fracture or being age 70 years or older, even with a T-score less than or equal to –2.5 for one of the two sites, indicates prescribing a bisphosphonate. Teriparatide is indicated if the patient has two vertebral fractures.

This article was translated from Medscape’s French edition.

A version of this article first appeared on Medscape.com.