Doctor with a clipboard

TORONTO—A survey of adult hemophilia patients suggests there is room for improvement in assessing and managing disease-related pain.

Roughly 85% of patients surveyed for this study, known as P-FiQ, said they had experienced acute and/or chronic pain in the past 6 months.

Although most patients had no trouble caring for themselves, the pain often had an impact on their daily lives, especially with regard to physical activity and overall mobility.

“Pain and discomfort are significant challenges for people with hemophilia,” said study investigator Michael Recht, MD, PhD, of Oregon Health Sciences University in Portland.

“These results emphasize the importance of providing comprehensive care and support beyond traditional therapy to people living with bleeding disorders.”

Dr Recht and his colleagues presented results of the P-FiQ study in 3 posters at the ISTH 2015 Congress (abstracts PO277-MON, PO297-WED, and PO298-WED).

The study included adult males with mild to severe hemophilia who had a history of joint pain or bleeding. Subjects were asked to assess pain and functional impairment using patient-reported outcome instruments.

During routine visits over the course of a year, 164 participants completed a pain history and 5 questionnaires: the EQ-5D-5L; Brief Pain Inventory Short Form, version 2; International Physical Activity Questionnaire; SF-36v2; and Hemophilia Activities List.

The patients had a median age of 34. More patients had hemophilia A (n=122) than hemophilia B (n=42), and few (n=10) had inhibitors. Sixty-one percent of patients had self-reported arthritis, bone, or joint problems.

Current patient-reported treatment regimens (n=163) were prophylaxis (42%), on-demand treatment (39%), or mostly on-demand treatment (19%). Twenty-five of the 31 patients using on-demand treatment reported using infusions ahead of activity.

Pain prevalence and management

Most participants (85.2%) said they had experienced acute and/or chronic pain over the past 6 months. Twenty-nine percent said they had experienced acute and chronic pain, 32.7% had chronic pain only, 23.5% had acute pain only, and 14.8% reported no pain.

Acute pain was most frequently described as sharp, aching, shooting, and throbbing. Chronic pain was often described as aching, nagging, throbbing, and sharp.

The most common analgesics used for acute or chronic pain were acetaminophen (69.4% and 58%, respectively), NSAIDs (40% and 52%, respectively), and hydrocodone-acetaminophen (29.4% and 33%, respectively).

The most common nonanalgesic strategies used for acute or chronic pain were ice (72.9% and 37%, respectively), rest (48.2% and 34%, respectively), factor VIII/IX or bypassing agent (48.2% and 24%, respectively), elevation (34.1% and 28%, respectively), relaxation (30.6% and 23.0%, respectively), compression (27.1% and 21%, respectively), and heat (24.7% and 15%, respectively).

Impact of pain on daily life

When completing the EQ-5D-5L questionnaire, most patients reported problems with mobility, performing usual activities, and pain or discomfort. However, most patients said they had no problems with self-care (78%) or anxiety/depression (58.5%).

A similar proportion of patients reported slight and moderate pain and discomfort (29.9% and 31.1%, respectively). Pain and discomfort was severe for 11% of patients and extreme for 1.2%, but 26.8% of patients reported no pain or discomfort.

When it came to mobility, patients reported slight (32.3%), moderate (19.5%), and severe (8.5%) problems, and 1.2% of patients said they were unable to get around. However, 38.4% of patients reported having no such problems.

About 44% of patients reported no problems performing usual activities, but 37.2% had slight problems, 14.6% had moderate problems, and 1.8% of patients each had severe problems or were unable to perform usual activities.

For the Brief Pain Inventory, pain severity and interference with daily activities were rated on a scale of 0 to 10, with 0 being no pain/no interference and 10 being pain as bad as you can imagine/pain that completely interferes with daily life.

The overall median pain severity and pain interference were 3.0 (range, 1.3-4.8) and 2.9 (range, 0.7-5.2), respectively. The median worst pain was 6.0, least pain 2.0, average pain 3.0, and current pain 2.0. Ankles were the most frequently reported site of pain.

When completing the International Physical Activity Questionnaire, 49.3% of patients (73/148) reported no activity in the prior week.

The median SF-36v2 scores were lower for physical health domains than mental health domains, and the overall median health score was 3.0 (range, 2.0-3.0).

The median score on the Hemophilia Activities List was 76.1 (range, 59.2-95.1). And patients said hemophilia had a greater impact on their lower extremities than upper extremities.

Dr Recht and his colleagues said these results substantiate the high prevalence of pain in adults with hemophilia. And the study highlights opportunities to improve the assessment and management of pain in these patients.

Study investigators have received funding/consulting fees from—or are employees/shareholders of—Novo Nordisk, Baxter, Biogen, Bayer, OctaPharma, Pfizer, CSL Behring, Kendrion, Alexion, Grifols, OPKO Health, Sanofi, Merck, and ProMeticLife Sciences.

Doctor with a clipboard

TORONTO—A survey of adult hemophilia patients suggests there is room for improvement in assessing and managing disease-related pain.

Roughly 85% of patients surveyed for this study, known as P-FiQ, said they had experienced acute and/or chronic pain in the past 6 months.

Although most patients had no trouble caring for themselves, the pain often had an impact on their daily lives, especially with regard to physical activity and overall mobility.

“Pain and discomfort are significant challenges for people with hemophilia,” said study investigator Michael Recht, MD, PhD, of Oregon Health Sciences University in Portland.

“These results emphasize the importance of providing comprehensive care and support beyond traditional therapy to people living with bleeding disorders.”

Dr Recht and his colleagues presented results of the P-FiQ study in 3 posters at the ISTH 2015 Congress (abstracts PO277-MON, PO297-WED, and PO298-WED).

The study included adult males with mild to severe hemophilia who had a history of joint pain or bleeding. Subjects were asked to assess pain and functional impairment using patient-reported outcome instruments.

During routine visits over the course of a year, 164 participants completed a pain history and 5 questionnaires: the EQ-5D-5L; Brief Pain Inventory Short Form, version 2; International Physical Activity Questionnaire; SF-36v2; and Hemophilia Activities List.

The patients had a median age of 34. More patients had hemophilia A (n=122) than hemophilia B (n=42), and few (n=10) had inhibitors. Sixty-one percent of patients had self-reported arthritis, bone, or joint problems.

Current patient-reported treatment regimens (n=163) were prophylaxis (42%), on-demand treatment (39%), or mostly on-demand treatment (19%). Twenty-five of the 31 patients using on-demand treatment reported using infusions ahead of activity.

Pain prevalence and management

Most participants (85.2%) said they had experienced acute and/or chronic pain over the past 6 months. Twenty-nine percent said they had experienced acute and chronic pain, 32.7% had chronic pain only, 23.5% had acute pain only, and 14.8% reported no pain.

Acute pain was most frequently described as sharp, aching, shooting, and throbbing. Chronic pain was often described as aching, nagging, throbbing, and sharp.

The most common analgesics used for acute or chronic pain were acetaminophen (69.4% and 58%, respectively), NSAIDs (40% and 52%, respectively), and hydrocodone-acetaminophen (29.4% and 33%, respectively).

The most common nonanalgesic strategies used for acute or chronic pain were ice (72.9% and 37%, respectively), rest (48.2% and 34%, respectively), factor VIII/IX or bypassing agent (48.2% and 24%, respectively), elevation (34.1% and 28%, respectively), relaxation (30.6% and 23.0%, respectively), compression (27.1% and 21%, respectively), and heat (24.7% and 15%, respectively).

Impact of pain on daily life

When completing the EQ-5D-5L questionnaire, most patients reported problems with mobility, performing usual activities, and pain or discomfort. However, most patients said they had no problems with self-care (78%) or anxiety/depression (58.5%).

A similar proportion of patients reported slight and moderate pain and discomfort (29.9% and 31.1%, respectively). Pain and discomfort was severe for 11% of patients and extreme for 1.2%, but 26.8% of patients reported no pain or discomfort.

When it came to mobility, patients reported slight (32.3%), moderate (19.5%), and severe (8.5%) problems, and 1.2% of patients said they were unable to get around. However, 38.4% of patients reported having no such problems.

About 44% of patients reported no problems performing usual activities, but 37.2% had slight problems, 14.6% had moderate problems, and 1.8% of patients each had severe problems or were unable to perform usual activities.

For the Brief Pain Inventory, pain severity and interference with daily activities were rated on a scale of 0 to 10, with 0 being no pain/no interference and 10 being pain as bad as you can imagine/pain that completely interferes with daily life.

The overall median pain severity and pain interference were 3.0 (range, 1.3-4.8) and 2.9 (range, 0.7-5.2), respectively. The median worst pain was 6.0, least pain 2.0, average pain 3.0, and current pain 2.0. Ankles were the most frequently reported site of pain.

When completing the International Physical Activity Questionnaire, 49.3% of patients (73/148) reported no activity in the prior week.

The median SF-36v2 scores were lower for physical health domains than mental health domains, and the overall median health score was 3.0 (range, 2.0-3.0).

The median score on the Hemophilia Activities List was 76.1 (range, 59.2-95.1). And patients said hemophilia had a greater impact on their lower extremities than upper extremities.

Dr Recht and his colleagues said these results substantiate the high prevalence of pain in adults with hemophilia. And the study highlights opportunities to improve the assessment and management of pain in these patients.

Study investigators have received funding/consulting fees from—or are employees/shareholders of—Novo Nordisk, Baxter, Biogen, Bayer, OctaPharma, Pfizer, CSL Behring, Kendrion, Alexion, Grifols, OPKO Health, Sanofi, Merck, and ProMeticLife Sciences.

Doctor with a clipboard

TORONTO—A survey of adult hemophilia patients suggests there is room for improvement in assessing and managing disease-related pain.

Roughly 85% of patients surveyed for this study, known as P-FiQ, said they had experienced acute and/or chronic pain in the past 6 months.

Although most patients had no trouble caring for themselves, the pain often had an impact on their daily lives, especially with regard to physical activity and overall mobility.

“Pain and discomfort are significant challenges for people with hemophilia,” said study investigator Michael Recht, MD, PhD, of Oregon Health Sciences University in Portland.

“These results emphasize the importance of providing comprehensive care and support beyond traditional therapy to people living with bleeding disorders.”

Dr Recht and his colleagues presented results of the P-FiQ study in 3 posters at the ISTH 2015 Congress (abstracts PO277-MON, PO297-WED, and PO298-WED).

The study included adult males with mild to severe hemophilia who had a history of joint pain or bleeding. Subjects were asked to assess pain and functional impairment using patient-reported outcome instruments.

During routine visits over the course of a year, 164 participants completed a pain history and 5 questionnaires: the EQ-5D-5L; Brief Pain Inventory Short Form, version 2; International Physical Activity Questionnaire; SF-36v2; and Hemophilia Activities List.

The patients had a median age of 34. More patients had hemophilia A (n=122) than hemophilia B (n=42), and few (n=10) had inhibitors. Sixty-one percent of patients had self-reported arthritis, bone, or joint problems.

Current patient-reported treatment regimens (n=163) were prophylaxis (42%), on-demand treatment (39%), or mostly on-demand treatment (19%). Twenty-five of the 31 patients using on-demand treatment reported using infusions ahead of activity.

Pain prevalence and management

Most participants (85.2%) said they had experienced acute and/or chronic pain over the past 6 months. Twenty-nine percent said they had experienced acute and chronic pain, 32.7% had chronic pain only, 23.5% had acute pain only, and 14.8% reported no pain.

Acute pain was most frequently described as sharp, aching, shooting, and throbbing. Chronic pain was often described as aching, nagging, throbbing, and sharp.

The most common analgesics used for acute or chronic pain were acetaminophen (69.4% and 58%, respectively), NSAIDs (40% and 52%, respectively), and hydrocodone-acetaminophen (29.4% and 33%, respectively).

The most common nonanalgesic strategies used for acute or chronic pain were ice (72.9% and 37%, respectively), rest (48.2% and 34%, respectively), factor VIII/IX or bypassing agent (48.2% and 24%, respectively), elevation (34.1% and 28%, respectively), relaxation (30.6% and 23.0%, respectively), compression (27.1% and 21%, respectively), and heat (24.7% and 15%, respectively).

Impact of pain on daily life

When completing the EQ-5D-5L questionnaire, most patients reported problems with mobility, performing usual activities, and pain or discomfort. However, most patients said they had no problems with self-care (78%) or anxiety/depression (58.5%).

A similar proportion of patients reported slight and moderate pain and discomfort (29.9% and 31.1%, respectively). Pain and discomfort was severe for 11% of patients and extreme for 1.2%, but 26.8% of patients reported no pain or discomfort.

When it came to mobility, patients reported slight (32.3%), moderate (19.5%), and severe (8.5%) problems, and 1.2% of patients said they were unable to get around. However, 38.4% of patients reported having no such problems.

About 44% of patients reported no problems performing usual activities, but 37.2% had slight problems, 14.6% had moderate problems, and 1.8% of patients each had severe problems or were unable to perform usual activities.

For the Brief Pain Inventory, pain severity and interference with daily activities were rated on a scale of 0 to 10, with 0 being no pain/no interference and 10 being pain as bad as you can imagine/pain that completely interferes with daily life.

The overall median pain severity and pain interference were 3.0 (range, 1.3-4.8) and 2.9 (range, 0.7-5.2), respectively. The median worst pain was 6.0, least pain 2.0, average pain 3.0, and current pain 2.0. Ankles were the most frequently reported site of pain.

When completing the International Physical Activity Questionnaire, 49.3% of patients (73/148) reported no activity in the prior week.

The median SF-36v2 scores were lower for physical health domains than mental health domains, and the overall median health score was 3.0 (range, 2.0-3.0).

The median score on the Hemophilia Activities List was 76.1 (range, 59.2-95.1). And patients said hemophilia had a greater impact on their lower extremities than upper extremities.

Dr Recht and his colleagues said these results substantiate the high prevalence of pain in adults with hemophilia. And the study highlights opportunities to improve the assessment and management of pain in these patients.

Study investigators have received funding/consulting fees from—or are employees/shareholders of—Novo Nordisk, Baxter, Biogen, Bayer, OctaPharma, Pfizer, CSL Behring, Kendrion, Alexion, Grifols, OPKO Health, Sanofi, Merck, and ProMeticLife Sciences.

Micrograph showing CLL

VIENNA—New research indicates that duvelisib, a dual inhibitor of PI3Kδ and PI3Kγ, can generate rapid partial responses in treatment-naïve patients with chronic lymphocytic leukemia (CLL).

The 18 patients in the expansion cohort of a phase 1 study of duvelisib had a median time to response of 3.7 months, according to iwCLL response criteria.

And 47% of the responses occurred by the first assessment on day 1 of cycle 3.

“One thing that does seem to be different with this drug is that you’re getting your [partial responses] a bit faster than you see with some of the other drugs,” said Susan O’Brien, MD, of UC Irvine Health in Orange, California.

“[W]hat that means in the long run is not completely clear, but there’s no question that the responses are very rapid.”

Dr O’Brien presented these findings at the 20th Congress of the European Hematology Association (abstract S434*). The research was funded by Infinity Pharmaceuticals, Inc., the company developing duvelisib.

Older CLL patients with comorbidities and patients with high-risk genomic alterations, such as 17p deletion and TP53 mutations, often don’t fare well on the standard chemoimmunotherapy. Duvelisib is being developed as a potential alternative for these patients and others with hematologic malignancies.

In the dose-escalation portion of this phase 1 study, duvelisib at 25 mg twice daily was well-tolerated and exhibited clinical activity in relapsed/refractory CLL, even in those patients with TP53 mutations and 17p deletion.

So investigators conducted the expansion cohort with 18 patients who received duvelisib at the same dose in 28-day cycles. Duvelisib is given continuously until patients have an adverse event or lose their response.

Patient demographics

Dr O’Brien said there was nothing unusual about the demographics of the study population, except the risk factors: 83% of the patients were over 65, “which is very different from what you would see in a chemoimmunotherapy trial.”

She noted that the patients’ median age was 74, and 56% of patients had either a 17p deletion or TP53 mutation.

“And that’s very unusual because . . . the percentage of patients with that abnormality in frontline CLL is about 5% to 10%,” she added.

Patients were a median of 3 years (range, 0–9) from their initial diagnosis, 47% had Rai stage 3 or greater disease, 44% had splenomegaly, and 11% had grade 4 cytopenia.

Response

Patients stayed on treatment for a median of 14 months (range, 1–20). Eight (44%) discontinued treatment—6 (33%) due to an adverse event, 1 withdrew consent, and 1 discontinued for other reasons.

The best overall response rate was 88%, which consisted of 15 partial responses. Two patients (12%) had stable disease, and there were no complete responses or cases of progressive disease.

One patient with a TP53 mutation/17p deletion withdrew consent prior to the first efficacy assessment.

“There’s no upfront progression,” Dr O’Brien said, “and the response rate was identical for patients with high-risk disease or 17p deletion.”

The median progression-free survival was not yet reached, and the rate was 92% at 18 months. One patient progressed at cycle 13.

The median overall survival was also not reached, with a 94% survival rate at 18 months. One patient died of progressive disease approximately 5 months after the last dose.

Adverse events

The most frequent adverse events (AEs) occurring in more than 25% of patients were, in order of frequency, diarrhea, rash, cough, neutropenia, peripheral edema, fatigue, nausea, pyrexia, ALT/AST increase, anemia, and dizziness.

Grade 3 AEs included diarrhea (22%), ALT/AST increase (17%), rash (11%), neutropenia (6%), fatigue (6%), and anemia (6%). The only grade 4 AE was neutropenia (28%).

Serious AEs in more than 1 patient included diarrhea (n=3), colitis (n=2), dehydration (n=2), pneumonia (n=2), and pneumonitis (n=2).

The AEs leading to treatment discontinuation were increased ALT/AST, dehydration, and spinal stenosis (all in 1 patient), as well as arthritis, pneumonitis, colitis, diarrhea, and stomatitis.

“We tend to see the transaminitis and the pneumonitis earlier, and then the late toxicity tends to be the diarrhea and colitis,” Dr O’ Brien said. “The one toxicity where I would not be inclined to try and re-treat a patient is pneumonitis, but I do think colitis can be successfully re-treated.”

Pharmacodynamic studies show very rapid inhibition of phosphorylated AKT following treatment, which is sustained throughout the whole first cycle. And following 1 cycle of duvelisib, there is near-complete inhibition of CLL proliferation, as evidenced by the reduction in Ki67.

Given these data, the investigators recommended further development of duvelisib in treatment-naïve CLL.

*Information in the abstract differs from that presented at the meeting.

Micrograph showing CLL

VIENNA—New research indicates that duvelisib, a dual inhibitor of PI3Kδ and PI3Kγ, can generate rapid partial responses in treatment-naïve patients with chronic lymphocytic leukemia (CLL).

The 18 patients in the expansion cohort of a phase 1 study of duvelisib had a median time to response of 3.7 months, according to iwCLL response criteria.

And 47% of the responses occurred by the first assessment on day 1 of cycle 3.

“One thing that does seem to be different with this drug is that you’re getting your [partial responses] a bit faster than you see with some of the other drugs,” said Susan O’Brien, MD, of UC Irvine Health in Orange, California.

“[W]hat that means in the long run is not completely clear, but there’s no question that the responses are very rapid.”

Dr O’Brien presented these findings at the 20th Congress of the European Hematology Association (abstract S434*). The research was funded by Infinity Pharmaceuticals, Inc., the company developing duvelisib.

Older CLL patients with comorbidities and patients with high-risk genomic alterations, such as 17p deletion and TP53 mutations, often don’t fare well on the standard chemoimmunotherapy. Duvelisib is being developed as a potential alternative for these patients and others with hematologic malignancies.

In the dose-escalation portion of this phase 1 study, duvelisib at 25 mg twice daily was well-tolerated and exhibited clinical activity in relapsed/refractory CLL, even in those patients with TP53 mutations and 17p deletion.

So investigators conducted the expansion cohort with 18 patients who received duvelisib at the same dose in 28-day cycles. Duvelisib is given continuously until patients have an adverse event or lose their response.

Patient demographics

Dr O’Brien said there was nothing unusual about the demographics of the study population, except the risk factors: 83% of the patients were over 65, “which is very different from what you would see in a chemoimmunotherapy trial.”

She noted that the patients’ median age was 74, and 56% of patients had either a 17p deletion or TP53 mutation.

“And that’s very unusual because . . . the percentage of patients with that abnormality in frontline CLL is about 5% to 10%,” she added.

Patients were a median of 3 years (range, 0–9) from their initial diagnosis, 47% had Rai stage 3 or greater disease, 44% had splenomegaly, and 11% had grade 4 cytopenia.

Response

Patients stayed on treatment for a median of 14 months (range, 1–20). Eight (44%) discontinued treatment—6 (33%) due to an adverse event, 1 withdrew consent, and 1 discontinued for other reasons.

The best overall response rate was 88%, which consisted of 15 partial responses. Two patients (12%) had stable disease, and there were no complete responses or cases of progressive disease.

One patient with a TP53 mutation/17p deletion withdrew consent prior to the first efficacy assessment.

“There’s no upfront progression,” Dr O’Brien said, “and the response rate was identical for patients with high-risk disease or 17p deletion.”

The median progression-free survival was not yet reached, and the rate was 92% at 18 months. One patient progressed at cycle 13.

The median overall survival was also not reached, with a 94% survival rate at 18 months. One patient died of progressive disease approximately 5 months after the last dose.

Adverse events

The most frequent adverse events (AEs) occurring in more than 25% of patients were, in order of frequency, diarrhea, rash, cough, neutropenia, peripheral edema, fatigue, nausea, pyrexia, ALT/AST increase, anemia, and dizziness.

Grade 3 AEs included diarrhea (22%), ALT/AST increase (17%), rash (11%), neutropenia (6%), fatigue (6%), and anemia (6%). The only grade 4 AE was neutropenia (28%).

Serious AEs in more than 1 patient included diarrhea (n=3), colitis (n=2), dehydration (n=2), pneumonia (n=2), and pneumonitis (n=2).

The AEs leading to treatment discontinuation were increased ALT/AST, dehydration, and spinal stenosis (all in 1 patient), as well as arthritis, pneumonitis, colitis, diarrhea, and stomatitis.

“We tend to see the transaminitis and the pneumonitis earlier, and then the late toxicity tends to be the diarrhea and colitis,” Dr O’ Brien said. “The one toxicity where I would not be inclined to try and re-treat a patient is pneumonitis, but I do think colitis can be successfully re-treated.”

Pharmacodynamic studies show very rapid inhibition of phosphorylated AKT following treatment, which is sustained throughout the whole first cycle. And following 1 cycle of duvelisib, there is near-complete inhibition of CLL proliferation, as evidenced by the reduction in Ki67.

Given these data, the investigators recommended further development of duvelisib in treatment-naïve CLL.

*Information in the abstract differs from that presented at the meeting.

Micrograph showing CLL

VIENNA—New research indicates that duvelisib, a dual inhibitor of PI3Kδ and PI3Kγ, can generate rapid partial responses in treatment-naïve patients with chronic lymphocytic leukemia (CLL).

The 18 patients in the expansion cohort of a phase 1 study of duvelisib had a median time to response of 3.7 months, according to iwCLL response criteria.

And 47% of the responses occurred by the first assessment on day 1 of cycle 3.

“One thing that does seem to be different with this drug is that you’re getting your [partial responses] a bit faster than you see with some of the other drugs,” said Susan O’Brien, MD, of UC Irvine Health in Orange, California.

“[W]hat that means in the long run is not completely clear, but there’s no question that the responses are very rapid.”

Dr O’Brien presented these findings at the 20th Congress of the European Hematology Association (abstract S434*). The research was funded by Infinity Pharmaceuticals, Inc., the company developing duvelisib.

Older CLL patients with comorbidities and patients with high-risk genomic alterations, such as 17p deletion and TP53 mutations, often don’t fare well on the standard chemoimmunotherapy. Duvelisib is being developed as a potential alternative for these patients and others with hematologic malignancies.

In the dose-escalation portion of this phase 1 study, duvelisib at 25 mg twice daily was well-tolerated and exhibited clinical activity in relapsed/refractory CLL, even in those patients with TP53 mutations and 17p deletion.

So investigators conducted the expansion cohort with 18 patients who received duvelisib at the same dose in 28-day cycles. Duvelisib is given continuously until patients have an adverse event or lose their response.

Patient demographics

Dr O’Brien said there was nothing unusual about the demographics of the study population, except the risk factors: 83% of the patients were over 65, “which is very different from what you would see in a chemoimmunotherapy trial.”

She noted that the patients’ median age was 74, and 56% of patients had either a 17p deletion or TP53 mutation.

“And that’s very unusual because . . . the percentage of patients with that abnormality in frontline CLL is about 5% to 10%,” she added.

Patients were a median of 3 years (range, 0–9) from their initial diagnosis, 47% had Rai stage 3 or greater disease, 44% had splenomegaly, and 11% had grade 4 cytopenia.

Response

Patients stayed on treatment for a median of 14 months (range, 1–20). Eight (44%) discontinued treatment—6 (33%) due to an adverse event, 1 withdrew consent, and 1 discontinued for other reasons.

The best overall response rate was 88%, which consisted of 15 partial responses. Two patients (12%) had stable disease, and there were no complete responses or cases of progressive disease.

One patient with a TP53 mutation/17p deletion withdrew consent prior to the first efficacy assessment.

“There’s no upfront progression,” Dr O’Brien said, “and the response rate was identical for patients with high-risk disease or 17p deletion.”

The median progression-free survival was not yet reached, and the rate was 92% at 18 months. One patient progressed at cycle 13.

The median overall survival was also not reached, with a 94% survival rate at 18 months. One patient died of progressive disease approximately 5 months after the last dose.

Adverse events

The most frequent adverse events (AEs) occurring in more than 25% of patients were, in order of frequency, diarrhea, rash, cough, neutropenia, peripheral edema, fatigue, nausea, pyrexia, ALT/AST increase, anemia, and dizziness.

Grade 3 AEs included diarrhea (22%), ALT/AST increase (17%), rash (11%), neutropenia (6%), fatigue (6%), and anemia (6%). The only grade 4 AE was neutropenia (28%).

Serious AEs in more than 1 patient included diarrhea (n=3), colitis (n=2), dehydration (n=2), pneumonia (n=2), and pneumonitis (n=2).

The AEs leading to treatment discontinuation were increased ALT/AST, dehydration, and spinal stenosis (all in 1 patient), as well as arthritis, pneumonitis, colitis, diarrhea, and stomatitis.

“We tend to see the transaminitis and the pneumonitis earlier, and then the late toxicity tends to be the diarrhea and colitis,” Dr O’ Brien said. “The one toxicity where I would not be inclined to try and re-treat a patient is pneumonitis, but I do think colitis can be successfully re-treated.”

Pharmacodynamic studies show very rapid inhibition of phosphorylated AKT following treatment, which is sustained throughout the whole first cycle. And following 1 cycle of duvelisib, there is near-complete inhibition of CLL proliferation, as evidenced by the reduction in Ki67.

Given these data, the investigators recommended further development of duvelisib in treatment-naïve CLL.

*Information in the abstract differs from that presented at the meeting.

Blood samples

Photo by Graham Colm

Scientists have identified genetic mutations that appear to be associated with treatment outcomes in patients with aplastic anemia.

When compared to unmutated patients, individuals with mutations in PIGA, BCOR, and BCORL1 tended to have better responses to immunosuppressive therapy and superior survival rates.

Other mutations—such as DNMT3A, ASXL1, and RUNX1—were associated with inferior response and survival rates.

Still, the investigators noted that clonal dynamics were “highly variable” in the patient samples they analyzed and might not necessarily have predicted outcomes.

Neal S. Young, MD, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland, and his colleagues described this research in NEJM.

The team used next-generation DNA sequencing and array-based karyotyping to analyze 668 blood samples from 439 patients, including serial samples from 82 patients.

The investigators identified 249 somatic mutations in 156 patients (36%). The most common mutations occurred in the BCOR (9.3%), BCORL1 (9.3%), DNMT3A (8.4%), PIGA (7.5%), and ASXL1 (6.2%) genes.

Thirty-six percent of patients had multiple mutations. And some patients had multiple mutations in

the same genes, including PIGA, BCOR, DNMT3A, ASXL1, RUNX1, and ZRSR2.

The investigators identified clonal hematopoiesis in 47% of patients, most frequently as acquired mutations.

The team also found that, largely, the presence and number of mutations a patient had was positively correlated with the patient’s age. The exceptions were PIGA, BCOR, and BCORL1 mutations.

Patients with mutations in PIGA, BCOR, or BCORL1 had better responses to immunosuppressive therapy and better overall and progression-free survival than unmutated patients.

Other mutations were associated with worse outcomes. Patients with mutations in ASXL1, DNMT3A, TP53, RUNX1, JAK2, JAK3, or CSMD1 did not respond as well as unmutated patients to immunosuppressive therapy.

Mutations in ASXL1, DNMT3A, TP53, RUNX1, and CSMD1 were associated with worse overall survival, and mutations in ASXL1, DNMT3A, RUNX1, JAK2, and JAK3 were associated with worse progression-free survival.

The investigators also observed an increase in the size of clones with DNMT3A, ASXL1, RUNX1, or U2AF1 mutations. But the size of clones with PIGA, BCOR, or BCORL1 mutations remained stable or decreased with time.

Blood samples

Photo by Graham Colm

Scientists have identified genetic mutations that appear to be associated with treatment outcomes in patients with aplastic anemia.

When compared to unmutated patients, individuals with mutations in PIGA, BCOR, and BCORL1 tended to have better responses to immunosuppressive therapy and superior survival rates.

Other mutations—such as DNMT3A, ASXL1, and RUNX1—were associated with inferior response and survival rates.

Still, the investigators noted that clonal dynamics were “highly variable” in the patient samples they analyzed and might not necessarily have predicted outcomes.

Neal S. Young, MD, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland, and his colleagues described this research in NEJM.

The team used next-generation DNA sequencing and array-based karyotyping to analyze 668 blood samples from 439 patients, including serial samples from 82 patients.

The investigators identified 249 somatic mutations in 156 patients (36%). The most common mutations occurred in the BCOR (9.3%), BCORL1 (9.3%), DNMT3A (8.4%), PIGA (7.5%), and ASXL1 (6.2%) genes.

Thirty-six percent of patients had multiple mutations. And some patients had multiple mutations in

the same genes, including PIGA, BCOR, DNMT3A, ASXL1, RUNX1, and ZRSR2.

The investigators identified clonal hematopoiesis in 47% of patients, most frequently as acquired mutations.

The team also found that, largely, the presence and number of mutations a patient had was positively correlated with the patient’s age. The exceptions were PIGA, BCOR, and BCORL1 mutations.

Patients with mutations in PIGA, BCOR, or BCORL1 had better responses to immunosuppressive therapy and better overall and progression-free survival than unmutated patients.

Other mutations were associated with worse outcomes. Patients with mutations in ASXL1, DNMT3A, TP53, RUNX1, JAK2, JAK3, or CSMD1 did not respond as well as unmutated patients to immunosuppressive therapy.

Mutations in ASXL1, DNMT3A, TP53, RUNX1, and CSMD1 were associated with worse overall survival, and mutations in ASXL1, DNMT3A, RUNX1, JAK2, and JAK3 were associated with worse progression-free survival.

The investigators also observed an increase in the size of clones with DNMT3A, ASXL1, RUNX1, or U2AF1 mutations. But the size of clones with PIGA, BCOR, or BCORL1 mutations remained stable or decreased with time.

Blood samples

Photo by Graham Colm

Scientists have identified genetic mutations that appear to be associated with treatment outcomes in patients with aplastic anemia.

When compared to unmutated patients, individuals with mutations in PIGA, BCOR, and BCORL1 tended to have better responses to immunosuppressive therapy and superior survival rates.

Other mutations—such as DNMT3A, ASXL1, and RUNX1—were associated with inferior response and survival rates.

Still, the investigators noted that clonal dynamics were “highly variable” in the patient samples they analyzed and might not necessarily have predicted outcomes.

Neal S. Young, MD, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland, and his colleagues described this research in NEJM.

The team used next-generation DNA sequencing and array-based karyotyping to analyze 668 blood samples from 439 patients, including serial samples from 82 patients.

The investigators identified 249 somatic mutations in 156 patients (36%). The most common mutations occurred in the BCOR (9.3%), BCORL1 (9.3%), DNMT3A (8.4%), PIGA (7.5%), and ASXL1 (6.2%) genes.

Thirty-six percent of patients had multiple mutations. And some patients had multiple mutations in

the same genes, including PIGA, BCOR, DNMT3A, ASXL1, RUNX1, and ZRSR2.

The investigators identified clonal hematopoiesis in 47% of patients, most frequently as acquired mutations.

The team also found that, largely, the presence and number of mutations a patient had was positively correlated with the patient’s age. The exceptions were PIGA, BCOR, and BCORL1 mutations.

Patients with mutations in PIGA, BCOR, or BCORL1 had better responses to immunosuppressive therapy and better overall and progression-free survival than unmutated patients.

Other mutations were associated with worse outcomes. Patients with mutations in ASXL1, DNMT3A, TP53, RUNX1, JAK2, JAK3, or CSMD1 did not respond as well as unmutated patients to immunosuppressive therapy.

Mutations in ASXL1, DNMT3A, TP53, RUNX1, and CSMD1 were associated with worse overall survival, and mutations in ASXL1, DNMT3A, RUNX1, JAK2, and JAK3 were associated with worse progression-free survival.

The investigators also observed an increase in the size of clones with DNMT3A, ASXL1, RUNX1, or U2AF1 mutations. But the size of clones with PIGA, BCOR, or BCORL1 mutations remained stable or decreased with time.

John Pandolfino, MD, chief of gastroenterology and hepatology at Northwestern University’s Feinberg School of Medicine in Chicago, talks about best practices for colonoscopies and treating C. diff infections.

John Pandolfino, MD, chief of gastroenterology and hepatology at Northwestern University’s Feinberg School of Medicine in Chicago, talks about best practices for colonoscopies and treating C. diff infections.

John Pandolfino, MD, chief of gastroenterology and hepatology at Northwestern University’s Feinberg School of Medicine in Chicago, talks about best practices for colonoscopies and treating C. diff infections.

Excerpt of our interviews with Choosing Wisely, Lisa Shieh, MD, PhD, of Stanford University School of Medicine, discusses an example of a Choosing Wisely program.

Excerpt of our interviews with Choosing Wisely, Lisa Shieh, MD, PhD, of Stanford University School of Medicine, discusses an example of a Choosing Wisely program.

Excerpt of our interviews with Choosing Wisely, Lisa Shieh, MD, PhD, of Stanford University School of Medicine, discusses an example of a Choosing Wisely program.

Gregory Seymann, MD, discusses a Choosing Wisely program.

Gregory Seymann, MD, discusses a Choosing Wisely program.

Gregory Seymann, MD, discusses a Choosing Wisely program.

Clonal hematopoiesis was detected in DNA samples from approximately half of 439 patients with aplastic anemia, and a third of the study population carried mutations in candidate genes that correlated with clinical outcomes, according to a report published online July 2 in the New England Journal of Medicine.

Most patients with aplastic anemia respond to immunosuppressive therapy or bone marrow transplantation, but about 15% later develop myelodysplastic syndromes, acute myeloid leukemia (AML), or both. Historically, this has been attributed to “clonal evolution,” but a more accurate term is clonal hematopoiesis. However, not all patients with clonal hematopoiesis go on to develop late myelodysplastic syndromes or AML, said Dr. Tetsuichi Yoshizato of the department of pathology and tumor biology at Kyoto (Japan) University and associates.

To clarify the role of clonal hematopoiesis in aplastic anemia, the investigators analyzed DNA in blood, bone marrow, and buccal samples from 439 patients with bone marrow failure who were treated at three specialized centers in the United States and Japan.

Targeted sequencing of a panel of genes that are recurrently mutated in myeloid cancers was performed; 249 mutations were detected in candidate genes for myelodysplastic syndromes/AML in 36% of the study population. And about one-third of patients whose DNA harbored mutations had multiple (as many as 7) mutations. The most frequently mutated genes were BCOR and BCORL1 (in 9.3% of patients), PIGA (7.5%), DNMT3A (8.4%), and ASXL1 (6.2%), which together accounted for 77% of all mutation-positive patients, the investigators reported.

In addition, 47% of patients had expanded hematopoietic cell clones. Clones carrying certain mutations were associated with a better response to immunosuppressive treatment, while clones carrying several other mutations were associated with a poor treatment response, lower survival, and progression to myelodysplastic syndromes/AML. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and better overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes.

The pattern of mutations in individual patients, however, varied markedly over time and was often unpredictable. “It should be underscored that the complex dynamics of clonal hematopoiesis are highly variable and not necessarily determinative,” Dr. Yoshizato and associates said (N. Engl. J. Med. 2015 July 2 [doi:10.1056/NEJMoa1414799]).

Although further genetic research is needed before these findings can be applied clinically to guide prognosis and treatment, they already “have implications for bone marrow failure, for early events in leukemogenesis, and for normal aging,” the investigators added.

Clonal hematopoiesis was detected in DNA samples from approximately half of 439 patients with aplastic anemia, and a third of the study population carried mutations in candidate genes that correlated with clinical outcomes, according to a report published online July 2 in the New England Journal of Medicine.

Most patients with aplastic anemia respond to immunosuppressive therapy or bone marrow transplantation, but about 15% later develop myelodysplastic syndromes, acute myeloid leukemia (AML), or both. Historically, this has been attributed to “clonal evolution,” but a more accurate term is clonal hematopoiesis. However, not all patients with clonal hematopoiesis go on to develop late myelodysplastic syndromes or AML, said Dr. Tetsuichi Yoshizato of the department of pathology and tumor biology at Kyoto (Japan) University and associates.

To clarify the role of clonal hematopoiesis in aplastic anemia, the investigators analyzed DNA in blood, bone marrow, and buccal samples from 439 patients with bone marrow failure who were treated at three specialized centers in the United States and Japan.

Targeted sequencing of a panel of genes that are recurrently mutated in myeloid cancers was performed; 249 mutations were detected in candidate genes for myelodysplastic syndromes/AML in 36% of the study population. And about one-third of patients whose DNA harbored mutations had multiple (as many as 7) mutations. The most frequently mutated genes were BCOR and BCORL1 (in 9.3% of patients), PIGA (7.5%), DNMT3A (8.4%), and ASXL1 (6.2%), which together accounted for 77% of all mutation-positive patients, the investigators reported.

In addition, 47% of patients had expanded hematopoietic cell clones. Clones carrying certain mutations were associated with a better response to immunosuppressive treatment, while clones carrying several other mutations were associated with a poor treatment response, lower survival, and progression to myelodysplastic syndromes/AML. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and better overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes.

The pattern of mutations in individual patients, however, varied markedly over time and was often unpredictable. “It should be underscored that the complex dynamics of clonal hematopoiesis are highly variable and not necessarily determinative,” Dr. Yoshizato and associates said (N. Engl. J. Med. 2015 July 2 [doi:10.1056/NEJMoa1414799]).

Although further genetic research is needed before these findings can be applied clinically to guide prognosis and treatment, they already “have implications for bone marrow failure, for early events in leukemogenesis, and for normal aging,” the investigators added.

Clonal hematopoiesis was detected in DNA samples from approximately half of 439 patients with aplastic anemia, and a third of the study population carried mutations in candidate genes that correlated with clinical outcomes, according to a report published online July 2 in the New England Journal of Medicine.

Most patients with aplastic anemia respond to immunosuppressive therapy or bone marrow transplantation, but about 15% later develop myelodysplastic syndromes, acute myeloid leukemia (AML), or both. Historically, this has been attributed to “clonal evolution,” but a more accurate term is clonal hematopoiesis. However, not all patients with clonal hematopoiesis go on to develop late myelodysplastic syndromes or AML, said Dr. Tetsuichi Yoshizato of the department of pathology and tumor biology at Kyoto (Japan) University and associates.

To clarify the role of clonal hematopoiesis in aplastic anemia, the investigators analyzed DNA in blood, bone marrow, and buccal samples from 439 patients with bone marrow failure who were treated at three specialized centers in the United States and Japan.

Targeted sequencing of a panel of genes that are recurrently mutated in myeloid cancers was performed; 249 mutations were detected in candidate genes for myelodysplastic syndromes/AML in 36% of the study population. And about one-third of patients whose DNA harbored mutations had multiple (as many as 7) mutations. The most frequently mutated genes were BCOR and BCORL1 (in 9.3% of patients), PIGA (7.5%), DNMT3A (8.4%), and ASXL1 (6.2%), which together accounted for 77% of all mutation-positive patients, the investigators reported.

In addition, 47% of patients had expanded hematopoietic cell clones. Clones carrying certain mutations were associated with a better response to immunosuppressive treatment, while clones carrying several other mutations were associated with a poor treatment response, lower survival, and progression to myelodysplastic syndromes/AML. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and better overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes.

The pattern of mutations in individual patients, however, varied markedly over time and was often unpredictable. “It should be underscored that the complex dynamics of clonal hematopoiesis are highly variable and not necessarily determinative,” Dr. Yoshizato and associates said (N. Engl. J. Med. 2015 July 2 [doi:10.1056/NEJMoa1414799]).

Although further genetic research is needed before these findings can be applied clinically to guide prognosis and treatment, they already “have implications for bone marrow failure, for early events in leukemogenesis, and for normal aging,” the investigators added.

Illustrative case

It’s noon, you are finishing up a visit with a 62-year-old man with erectile dysfunction (ED), and you want to evaluate for androgen deficiency. Should you ask him to return for an early-morning visit so you can test his testosterone level?

Increasing public awareness of androgen deficiency has led to more men being tested for testosterone levels. Current Endocrine Society guidelines recommend against routine screening for androgen deficiency in men who do not have symptoms.² However, for men with classic symptoms of androgen deficiency—such as decreased libido, ED, infertility, depression, osteoporosis, loss of secondary sexual characteristics, or reduced muscle bulk or strength—measurement of total testosterone level is recommended.²

Due to the natural diurnal variation in serum testosterone levels, the guidelines recommend collecting the sample in the early morning.² This recommendation is based on small observational studies that included men mostly younger than 45 years of age that found a significant difference in testosterone levels between samples drawn early in the morning and in the afternoon.^3-5

In recent years, several studies have indicated that this variation declines as men age.^4-6 Recently, researchers evaluated the effects of age and time of testing on men’s total testosterone levels.

STUDY SUMMARY: Differences in testosterone levels are significant only in younger men

Welliver et al¹ performed a retrospective chart review of 2569 men seen at a Minneapolis Veterans Affairs hospital for ED who had total testosterone levels measured between 7 am and 2 pm over a 15-year period. Men whose total testosterone levels were outside the normal range (>1000 or <50 ng/dL) or who had total testosterone drawn after 2 pm were excluded. The authors analyzed the results based on age, creating one group for men ages <40 years and 5-year age groups for all other men. Using scatterplot techniques, they separated each age group into 2 subgroups based on draw times—7 am to 9 am, or 9 am to 2 pm—and compared the mean total testosterone level for each age and time.

The participants’ mean age was 63 years. Younger men (<45 years) had the largest variation in serum total testosterone, with a large and significant decrease after 9 am. Only the youngest 2 groups (ages <40 and 40-44 years) showed a large decrease in total testosterone in specimens collected after 9 am compared to those drawn between 7 am and 9 am (mean difference 207 and 149 ng/dL, respectively). This variation was not observed in patients over age 45. Although there was a statistically significant difference between early and later testosterone levels in men ages 70 to 74 years, the absolute difference—34 ng/dL (452 vs 418 ng/dL)—was unlikely to be clinically significant.

WHAT'S NEW: For older men, later testing will not affect results

This study confirms previous research showing that the diurnal effect on testosterone levels becomes blunted with increasing age, at least in this group of men with ED. Allowing older men to have total testosterone levels drawn until 2 pm would allow for greater patient flexibility in draw times with little change in results.

CAVEATS: Study's methodology cannot account for several potential confounders

This retrospective study analyzed only a single random testosterone level measurement from each participant, rather than repeat testosterone levels over the course of a day. However, the study was large (2569 men) and it used mean values, which should at least partially mitigate the effect of having only a single level from each participant.

Only the youngest 2 groups (ages <40 and 40-44 years) showed a large decrease in total testosterone in specimens collected after 9 am compared to those drawn between 7 am and 9 am.

The study measured total testosterone and did not account for potential confounding factors—such as obesity or use of testosterone replacement therapy or androgen deprivation therapy—that could affect sexhormone binding globulin, thus potentially altering total testosterone level. However, the authors estimated that less than 2% of the entire cohort were likely to have unrecognized hormonal manipulation with exogenous gonadotropins.

All of the men in the study were seen for ED, and it could be that men with ED have more flattening of the diurnal variation than men without ED; however, we are unaware of other data that support this.

Up to 30% of men who have an early-morning testosterone level that is low may have a normal result when testing is repeated.^2,5 Therefore, for all men who have low testosterone level test results, draw a repeat total testosterone level before 9 am to confirm the diagnosis. Also, this study did not evaluate the course of testosterone levels throughout the later afternoon and evening, and it remains unclear whether levels can be drawn even later in the day.

CHALLENGES TO IMPLEMENTATION: Your lab's policies might require early-morning draws

There will probably be few barriers to implementing this change, unless local laboratory policies are inflexible regarding the timing of testosterone draws.

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

Illustrative case

It’s noon, you are finishing up a visit with a 62-year-old man with erectile dysfunction (ED), and you want to evaluate for androgen deficiency. Should you ask him to return for an early-morning visit so you can test his testosterone level?

Increasing public awareness of androgen deficiency has led to more men being tested for testosterone levels. Current Endocrine Society guidelines recommend against routine screening for androgen deficiency in men who do not have symptoms.² However, for men with classic symptoms of androgen deficiency—such as decreased libido, ED, infertility, depression, osteoporosis, loss of secondary sexual characteristics, or reduced muscle bulk or strength—measurement of total testosterone level is recommended.²

Due to the natural diurnal variation in serum testosterone levels, the guidelines recommend collecting the sample in the early morning.² This recommendation is based on small observational studies that included men mostly younger than 45 years of age that found a significant difference in testosterone levels between samples drawn early in the morning and in the afternoon.^3-5

In recent years, several studies have indicated that this variation declines as men age.^4-6 Recently, researchers evaluated the effects of age and time of testing on men’s total testosterone levels.

STUDY SUMMARY: Differences in testosterone levels are significant only in younger men

Welliver et al¹ performed a retrospective chart review of 2569 men seen at a Minneapolis Veterans Affairs hospital for ED who had total testosterone levels measured between 7 am and 2 pm over a 15-year period. Men whose total testosterone levels were outside the normal range (>1000 or <50 ng/dL) or who had total testosterone drawn after 2 pm were excluded. The authors analyzed the results based on age, creating one group for men ages <40 years and 5-year age groups for all other men. Using scatterplot techniques, they separated each age group into 2 subgroups based on draw times—7 am to 9 am, or 9 am to 2 pm—and compared the mean total testosterone level for each age and time.

The participants’ mean age was 63 years. Younger men (<45 years) had the largest variation in serum total testosterone, with a large and significant decrease after 9 am. Only the youngest 2 groups (ages <40 and 40-44 years) showed a large decrease in total testosterone in specimens collected after 9 am compared to those drawn between 7 am and 9 am (mean difference 207 and 149 ng/dL, respectively). This variation was not observed in patients over age 45. Although there was a statistically significant difference between early and later testosterone levels in men ages 70 to 74 years, the absolute difference—34 ng/dL (452 vs 418 ng/dL)—was unlikely to be clinically significant.

WHAT'S NEW: For older men, later testing will not affect results

This study confirms previous research showing that the diurnal effect on testosterone levels becomes blunted with increasing age, at least in this group of men with ED. Allowing older men to have total testosterone levels drawn until 2 pm would allow for greater patient flexibility in draw times with little change in results.

CAVEATS: Study's methodology cannot account for several potential confounders

This retrospective study analyzed only a single random testosterone level measurement from each participant, rather than repeat testosterone levels over the course of a day. However, the study was large (2569 men) and it used mean values, which should at least partially mitigate the effect of having only a single level from each participant.

Only the youngest 2 groups (ages <40 and 40-44 years) showed a large decrease in total testosterone in specimens collected after 9 am compared to those drawn between 7 am and 9 am.

The study measured total testosterone and did not account for potential confounding factors—such as obesity or use of testosterone replacement therapy or androgen deprivation therapy—that could affect sexhormone binding globulin, thus potentially altering total testosterone level. However, the authors estimated that less than 2% of the entire cohort were likely to have unrecognized hormonal manipulation with exogenous gonadotropins.

All of the men in the study were seen for ED, and it could be that men with ED have more flattening of the diurnal variation than men without ED; however, we are unaware of other data that support this.

Up to 30% of men who have an early-morning testosterone level that is low may have a normal result when testing is repeated.^2,5 Therefore, for all men who have low testosterone level test results, draw a repeat total testosterone level before 9 am to confirm the diagnosis. Also, this study did not evaluate the course of testosterone levels throughout the later afternoon and evening, and it remains unclear whether levels can be drawn even later in the day.

CHALLENGES TO IMPLEMENTATION: Your lab's policies might require early-morning draws

There will probably be few barriers to implementing this change, unless local laboratory policies are inflexible regarding the timing of testosterone draws.

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

Illustrative case

It’s noon, you are finishing up a visit with a 62-year-old man with erectile dysfunction (ED), and you want to evaluate for androgen deficiency. Should you ask him to return for an early-morning visit so you can test his testosterone level?

Increasing public awareness of androgen deficiency has led to more men being tested for testosterone levels. Current Endocrine Society guidelines recommend against routine screening for androgen deficiency in men who do not have symptoms.² However, for men with classic symptoms of androgen deficiency—such as decreased libido, ED, infertility, depression, osteoporosis, loss of secondary sexual characteristics, or reduced muscle bulk or strength—measurement of total testosterone level is recommended.²

Due to the natural diurnal variation in serum testosterone levels, the guidelines recommend collecting the sample in the early morning.² This recommendation is based on small observational studies that included men mostly younger than 45 years of age that found a significant difference in testosterone levels between samples drawn early in the morning and in the afternoon.^3-5

In recent years, several studies have indicated that this variation declines as men age.^4-6 Recently, researchers evaluated the effects of age and time of testing on men’s total testosterone levels.

STUDY SUMMARY: Differences in testosterone levels are significant only in younger men

Welliver et al¹ performed a retrospective chart review of 2569 men seen at a Minneapolis Veterans Affairs hospital for ED who had total testosterone levels measured between 7 am and 2 pm over a 15-year period. Men whose total testosterone levels were outside the normal range (>1000 or <50 ng/dL) or who had total testosterone drawn after 2 pm were excluded. The authors analyzed the results based on age, creating one group for men ages <40 years and 5-year age groups for all other men. Using scatterplot techniques, they separated each age group into 2 subgroups based on draw times—7 am to 9 am, or 9 am to 2 pm—and compared the mean total testosterone level for each age and time.

The participants’ mean age was 63 years. Younger men (<45 years) had the largest variation in serum total testosterone, with a large and significant decrease after 9 am. Only the youngest 2 groups (ages <40 and 40-44 years) showed a large decrease in total testosterone in specimens collected after 9 am compared to those drawn between 7 am and 9 am (mean difference 207 and 149 ng/dL, respectively). This variation was not observed in patients over age 45. Although there was a statistically significant difference between early and later testosterone levels in men ages 70 to 74 years, the absolute difference—34 ng/dL (452 vs 418 ng/dL)—was unlikely to be clinically significant.

WHAT'S NEW: For older men, later testing will not affect results

This study confirms previous research showing that the diurnal effect on testosterone levels becomes blunted with increasing age, at least in this group of men with ED. Allowing older men to have total testosterone levels drawn until 2 pm would allow for greater patient flexibility in draw times with little change in results.

CAVEATS: Study's methodology cannot account for several potential confounders

This retrospective study analyzed only a single random testosterone level measurement from each participant, rather than repeat testosterone levels over the course of a day. However, the study was large (2569 men) and it used mean values, which should at least partially mitigate the effect of having only a single level from each participant.

Only the youngest 2 groups (ages <40 and 40-44 years) showed a large decrease in total testosterone in specimens collected after 9 am compared to those drawn between 7 am and 9 am.

The study measured total testosterone and did not account for potential confounding factors—such as obesity or use of testosterone replacement therapy or androgen deprivation therapy—that could affect sexhormone binding globulin, thus potentially altering total testosterone level. However, the authors estimated that less than 2% of the entire cohort were likely to have unrecognized hormonal manipulation with exogenous gonadotropins.

All of the men in the study were seen for ED, and it could be that men with ED have more flattening of the diurnal variation than men without ED; however, we are unaware of other data that support this.

Up to 30% of men who have an early-morning testosterone level that is low may have a normal result when testing is repeated.^2,5 Therefore, for all men who have low testosterone level test results, draw a repeat total testosterone level before 9 am to confirm the diagnosis. Also, this study did not evaluate the course of testosterone levels throughout the later afternoon and evening, and it remains unclear whether levels can be drawn even later in the day.

CHALLENGES TO IMPLEMENTATION: Your lab's policies might require early-morning draws

There will probably be few barriers to implementing this change, unless local laboratory policies are inflexible regarding the timing of testosterone draws.

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

The United States Preventive Services Task Force (USPSTF) recently released draft recommendations on breast cancer screening, which could be finalized within the next few months.¹ The last time the Task Force (TF) weighed in on this topic was in 2009, just as the Affordable Care Act (ACA) was being debated. At that time, the TF recommendations were so controversial that Congress specified in the ACA that they should not be used to determine insurance coverage (more on this later).

The draft recommendations (TABLE 1)¹ carry a C grade for women ages 40 to 49 years (ie, offer or provide screening mammography for selected patients depending on individual circumstances) and a B grade for biennial screening of women ages 50 to 74. The proposed recommendations are basically the same as the ones made in 2009, with more detailed wording to explain the rationale for the C recommendation, and to address 2 new issues: tomosynthesis (3-D mammography) and adjunctive screening for women with dense breasts. The previous D recommendation against self breast examination was left unchanged.

Benefit of mammography screening varies by decade of life

Breast cancer is the leading cause of non-skin cancers in women and, after lung cancer, the second leading cause of cancer deaths in women. In 2014 there were 233,000 new cases diagnosed and 40,000 breast cancer deaths.^1,2 While the TF found that mammography reduces deaths from breast cancer in women between the ages of 40 and 74, women ages 40 to 49 benefit the least; those ages 60 to 69 benefit the most.^1,3

If 10,000 women are screened routinely for 10 years, 4 breast cancer deaths will be prevented in those ages 40 to 49, 8 in those 50 to 59, and 21 in those 60 to 69.¹ And harms appear to be higher in the younger age group. TABLE 2^1,3 shows some of the harms resulting from one-time mammography screening of 10,000 women in each age group. Notice the benefits listed previously are from repeated screenings over a 10-year period and the harms in TABLE 2^1,3 are from a single mammogram.

The total benefits and harms of biennial screening in 1000 women starting at age 40 (vs age 50) include 8 cancer deaths prevented (vs 7) with a cost of 1529 false positive tests (vs 953); 204 unnecessary breast biopsies (vs 146); and 20 overdiagnoses (vs 18). However, the confidence intervals on these estimates are wide, and in each case, they overlap between the 2 groups.¹

The TF recommended biennial screening for women between the ages of 50 and 74 because observational studies and modeling show no clear benefit with annual screening vs every 2 years, while annual screening results in more false positives and biopsies.

Overdiagnosis may occur in nearly 20% of cases

The potential for overdiagnosis and overtreatment is increasingly recognized as a harm of cancer screening. Overdiagnosis results from detecting a tumor during screening that would not have been detected otherwise and that would not have caused death or disease but is treated anyway. This sometimes occurs with the detection of early tumors that would not have progressed or would have progressed slowly, not causing health problems before the woman dies of other causes.

The TF is one of the only organizations that considers the potential harmful effects of this problem. While it is not possible to know for certain the rate of overdiagnosis that occurs with cancer screening, high-quality studies indicate it is close to 20% for breast cancer.³

Guidance regarding women ages 40 to 49

The new draft recommendations carefully point out that, while the overall benefit of screening women ages 40 to 49 is small, the decision to begin screening before age 50 should be an individual one, and an informed one. They state that women who value the small potential benefit over the potential for harm may choose to be screened, as might women who have a family history of breast cancer. And the recommendations do not apply to women who have a genotype that places them at increased risk for breast cancer.

Tomosynthesis: Evidence of benefit is insufficient

Tomosynthesis as a primary breast cancer screening tool was studied in a separate evidence report commissioned by the TF.⁴ While tomosynthesis, compared with routine mammography, appears to have increased sensitivity and specificity in detecting breast cancer, no studies looked at this technology as a primary screening tool and its effect on breast cancer mortality, overall mortality, and quality of life. Sticking to its nationally-recognized methodological rigor, the TF states that information at this time is insufficient to make a recommendation on the use of tomosynthesis.

Dense breasts: Usefulness of adjunctive screening modalities

Breast density is categorized into 4 groups, from category a (breasts are almost all fatty with little fibro nodular tissue) to category d (breasts are extremely dense).¹ About 43% of women ages 40 to 74 are in categories c and d.¹ Dense breasts adversely affect the accuracy of mammography, decreasing sensitivity and specificity. In one study, sensitivity was 87% in category a and 63% in category d; specificities were 97% and 89%, respectively.⁵

Tomosynthesis, magnetic resonance imaging, and ultrasound, when used in addition to mammography, all appear to detect more cancers, but they also yield more false-positive results.⁶ The long-term outcome of detecting more tumors is not known. For an individual, there are 3 possibilities when a tumor is detected earlier: a better outcome, no difference in outcome, or a worse outcome resulting from overdiagnosis and overtreatment. The TF felt that the available data are insufficient to judge benefits and harms of an increased frequency of screening or the use of adjunctive screening methods in women with dense breasts.

Benefit for women ≥75 years is inconclusive

There are limited data on the impact of mammography on outcomes for women older than 70. The TF feels that, since women ages 60 to 69 benefit the most from mammography, this benefit is likely to carry over into the next decade. Modeling also predicts this.

While mammography helps reduce breast cancer deaths, women ages 40 to 49 benefit the least; women ages 60 to 69 benefit the most.

However, women ages 70 to 74 who have chronic illnesses are unlikely to benefit from mammography. The conditions specifically mentioned are cardiovascular disease, diabetes, lung disease, liver disease, renal failure, acquired immunodeficiency syndrome, and dementia.

For all women ages 75 and older, the TF feels the evidence is insufficient to make a recommendation.

Insurance coverage

The ACA mandates that 4 sets of preventive services be included in commercial health insurance plans with no out-of-pocket expenses to the patient: immunizations recommended by the Advisory Committee on Immunization Practices; children’s preventive services recommended by the Health Resources and Services Administration (HRSA); women’s preventive services recommended by HRSA; and recommendations with an A or B rating from the USPSTF.⁷

For children, HRSA opted to use those preventive services listed by the American Academy of Pediatrics in Bright Futures, the society’s national initiative providing recommendations on prevention screenings and well-child visits.⁸ For women, HRSA asked the Institute of Medicine to form a panel to construct a list of recommended preventive services.

At the time the ACA was passed, the TF had just made new recommendations on breast cancer screening, which were very similar to the current draft recommendations. Due to the resulting controversy, Congress mandated that the new recommendations not be used to determine first-dollar insurance coverage, and it cited the TF’s pre-2009 recommendations as the applicable standard.

Those earlier recommendations included annual mammography starting at age 40. The wording of the law, however, was not clear as to future mammography recommendations. One interpretation is that the TF recommendations in place before 2009 are the basis for first-dollar coverage until changed by Congress. Another interpretation is that the ACA special provision trumped only the 2009 recommendations and the 2015 recommendations will become the standard. If the latter turns out to be true, it is not clear if commercial insurance plans will begin to charge co-payments for mammography before age 50 or for mammograms ordered more frequently than every 2 years for women ages 50 to 74.

Annual mammography screening has shown no clear benefit over screening every 2 years, and it results in more false positives and biopsies.

The issue of insurance coverage is important because of the lack of uniformity in recommendations regarding mammography. The American Congress of Obstetricians and Gynecologists,⁹ the American Cancer Society,¹⁰ and the American College of Radiology¹¹ all recommend annual mammography starting at age 40. The American Academy of Family Physicians recommendations¹² mirror those of the USPSTF, and the Canadian Task Force on Preventive Health Care recommends against routine screening for women ages 40 to 49 and recommends mammography every 2 to 3 years for women ages 50 to 74.¹³

USPSTF rationale is informed and accessible for review

Breast cancer screening remains a highly controversial and emotional topic. The USPSTF has made a set of recommendations based on extensive and rigorous evidence reports that consider both benefits and harms. There will be those who vigorously disagree. The evidence reports, recommendations, and rationale behind them are easily accessible on the TF Web site (www.uspreventiveservicestaskforce.org) for those who want to read them.¹

The United States Preventive Services Task Force (USPSTF) recently released draft recommendations on breast cancer screening, which could be finalized within the next few months.¹ The last time the Task Force (TF) weighed in on this topic was in 2009, just as the Affordable Care Act (ACA) was being debated. At that time, the TF recommendations were so controversial that Congress specified in the ACA that they should not be used to determine insurance coverage (more on this later).

The draft recommendations (TABLE 1)¹ carry a C grade for women ages 40 to 49 years (ie, offer or provide screening mammography for selected patients depending on individual circumstances) and a B grade for biennial screening of women ages 50 to 74. The proposed recommendations are basically the same as the ones made in 2009, with more detailed wording to explain the rationale for the C recommendation, and to address 2 new issues: tomosynthesis (3-D mammography) and adjunctive screening for women with dense breasts. The previous D recommendation against self breast examination was left unchanged.

Benefit of mammography screening varies by decade of life

Breast cancer is the leading cause of non-skin cancers in women and, after lung cancer, the second leading cause of cancer deaths in women. In 2014 there were 233,000 new cases diagnosed and 40,000 breast cancer deaths.^1,2 While the TF found that mammography reduces deaths from breast cancer in women between the ages of 40 and 74, women ages 40 to 49 benefit the least; those ages 60 to 69 benefit the most.^1,3

If 10,000 women are screened routinely for 10 years, 4 breast cancer deaths will be prevented in those ages 40 to 49, 8 in those 50 to 59, and 21 in those 60 to 69.¹ And harms appear to be higher in the younger age group. TABLE 2^1,3 shows some of the harms resulting from one-time mammography screening of 10,000 women in each age group. Notice the benefits listed previously are from repeated screenings over a 10-year period and the harms in TABLE 2^1,3 are from a single mammogram.

The total benefits and harms of biennial screening in 1000 women starting at age 40 (vs age 50) include 8 cancer deaths prevented (vs 7) with a cost of 1529 false positive tests (vs 953); 204 unnecessary breast biopsies (vs 146); and 20 overdiagnoses (vs 18). However, the confidence intervals on these estimates are wide, and in each case, they overlap between the 2 groups.¹

The TF recommended biennial screening for women between the ages of 50 and 74 because observational studies and modeling show no clear benefit with annual screening vs every 2 years, while annual screening results in more false positives and biopsies.

Overdiagnosis may occur in nearly 20% of cases

The potential for overdiagnosis and overtreatment is increasingly recognized as a harm of cancer screening. Overdiagnosis results from detecting a tumor during screening that would not have been detected otherwise and that would not have caused death or disease but is treated anyway. This sometimes occurs with the detection of early tumors that would not have progressed or would have progressed slowly, not causing health problems before the woman dies of other causes.

The TF is one of the only organizations that considers the potential harmful effects of this problem. While it is not possible to know for certain the rate of overdiagnosis that occurs with cancer screening, high-quality studies indicate it is close to 20% for breast cancer.³

Guidance regarding women ages 40 to 49

The new draft recommendations carefully point out that, while the overall benefit of screening women ages 40 to 49 is small, the decision to begin screening before age 50 should be an individual one, and an informed one. They state that women who value the small potential benefit over the potential for harm may choose to be screened, as might women who have a family history of breast cancer. And the recommendations do not apply to women who have a genotype that places them at increased risk for breast cancer.

Tomosynthesis: Evidence of benefit is insufficient

Tomosynthesis as a primary breast cancer screening tool was studied in a separate evidence report commissioned by the TF.⁴ While tomosynthesis, compared with routine mammography, appears to have increased sensitivity and specificity in detecting breast cancer, no studies looked at this technology as a primary screening tool and its effect on breast cancer mortality, overall mortality, and quality of life. Sticking to its nationally-recognized methodological rigor, the TF states that information at this time is insufficient to make a recommendation on the use of tomosynthesis.

Dense breasts: Usefulness of adjunctive screening modalities

Breast density is categorized into 4 groups, from category a (breasts are almost all fatty with little fibro nodular tissue) to category d (breasts are extremely dense).¹ About 43% of women ages 40 to 74 are in categories c and d.¹ Dense breasts adversely affect the accuracy of mammography, decreasing sensitivity and specificity. In one study, sensitivity was 87% in category a and 63% in category d; specificities were 97% and 89%, respectively.⁵

Tomosynthesis, magnetic resonance imaging, and ultrasound, when used in addition to mammography, all appear to detect more cancers, but they also yield more false-positive results.⁶ The long-term outcome of detecting more tumors is not known. For an individual, there are 3 possibilities when a tumor is detected earlier: a better outcome, no difference in outcome, or a worse outcome resulting from overdiagnosis and overtreatment. The TF felt that the available data are insufficient to judge benefits and harms of an increased frequency of screening or the use of adjunctive screening methods in women with dense breasts.

Benefit for women ≥75 years is inconclusive

There are limited data on the impact of mammography on outcomes for women older than 70. The TF feels that, since women ages 60 to 69 benefit the most from mammography, this benefit is likely to carry over into the next decade. Modeling also predicts this.

While mammography helps reduce breast cancer deaths, women ages 40 to 49 benefit the least; women ages 60 to 69 benefit the most.

However, women ages 70 to 74 who have chronic illnesses are unlikely to benefit from mammography. The conditions specifically mentioned are cardiovascular disease, diabetes, lung disease, liver disease, renal failure, acquired immunodeficiency syndrome, and dementia.

For all women ages 75 and older, the TF feels the evidence is insufficient to make a recommendation.

Insurance coverage

The ACA mandates that 4 sets of preventive services be included in commercial health insurance plans with no out-of-pocket expenses to the patient: immunizations recommended by the Advisory Committee on Immunization Practices; children’s preventive services recommended by the Health Resources and Services Administration (HRSA); women’s preventive services recommended by HRSA; and recommendations with an A or B rating from the USPSTF.⁷

For children, HRSA opted to use those preventive services listed by the American Academy of Pediatrics in Bright Futures, the society’s national initiative providing recommendations on prevention screenings and well-child visits.⁸ For women, HRSA asked the Institute of Medicine to form a panel to construct a list of recommended preventive services.

At the time the ACA was passed, the TF had just made new recommendations on breast cancer screening, which were very similar to the current draft recommendations. Due to the resulting controversy, Congress mandated that the new recommendations not be used to determine first-dollar insurance coverage, and it cited the TF’s pre-2009 recommendations as the applicable standard.

Those earlier recommendations included annual mammography starting at age 40. The wording of the law, however, was not clear as to future mammography recommendations. One interpretation is that the TF recommendations in place before 2009 are the basis for first-dollar coverage until changed by Congress. Another interpretation is that the ACA special provision trumped only the 2009 recommendations and the 2015 recommendations will become the standard. If the latter turns out to be true, it is not clear if commercial insurance plans will begin to charge co-payments for mammography before age 50 or for mammograms ordered more frequently than every 2 years for women ages 50 to 74.

Annual mammography screening has shown no clear benefit over screening every 2 years, and it results in more false positives and biopsies.

The issue of insurance coverage is important because of the lack of uniformity in recommendations regarding mammography. The American Congress of Obstetricians and Gynecologists,⁹ the American Cancer Society,¹⁰ and the American College of Radiology¹¹ all recommend annual mammography starting at age 40. The American Academy of Family Physicians recommendations¹² mirror those of the USPSTF, and the Canadian Task Force on Preventive Health Care recommends against routine screening for women ages 40 to 49 and recommends mammography every 2 to 3 years for women ages 50 to 74.¹³

USPSTF rationale is informed and accessible for review

Breast cancer screening remains a highly controversial and emotional topic. The USPSTF has made a set of recommendations based on extensive and rigorous evidence reports that consider both benefits and harms. There will be those who vigorously disagree. The evidence reports, recommendations, and rationale behind them are easily accessible on the TF Web site (www.uspreventiveservicestaskforce.org) for those who want to read them.¹

The United States Preventive Services Task Force (USPSTF) recently released draft recommendations on breast cancer screening, which could be finalized within the next few months.¹ The last time the Task Force (TF) weighed in on this topic was in 2009, just as the Affordable Care Act (ACA) was being debated. At that time, the TF recommendations were so controversial that Congress specified in the ACA that they should not be used to determine insurance coverage (more on this later).

The draft recommendations (TABLE 1)¹ carry a C grade for women ages 40 to 49 years (ie, offer or provide screening mammography for selected patients depending on individual circumstances) and a B grade for biennial screening of women ages 50 to 74. The proposed recommendations are basically the same as the ones made in 2009, with more detailed wording to explain the rationale for the C recommendation, and to address 2 new issues: tomosynthesis (3-D mammography) and adjunctive screening for women with dense breasts. The previous D recommendation against self breast examination was left unchanged.

Benefit of mammography screening varies by decade of life

Breast cancer is the leading cause of non-skin cancers in women and, after lung cancer, the second leading cause of cancer deaths in women. In 2014 there were 233,000 new cases diagnosed and 40,000 breast cancer deaths.^1,2 While the TF found that mammography reduces deaths from breast cancer in women between the ages of 40 and 74, women ages 40 to 49 benefit the least; those ages 60 to 69 benefit the most.^1,3

If 10,000 women are screened routinely for 10 years, 4 breast cancer deaths will be prevented in those ages 40 to 49, 8 in those 50 to 59, and 21 in those 60 to 69.¹ And harms appear to be higher in the younger age group. TABLE 2^1,3 shows some of the harms resulting from one-time mammography screening of 10,000 women in each age group. Notice the benefits listed previously are from repeated screenings over a 10-year period and the harms in TABLE 2^1,3 are from a single mammogram.

The total benefits and harms of biennial screening in 1000 women starting at age 40 (vs age 50) include 8 cancer deaths prevented (vs 7) with a cost of 1529 false positive tests (vs 953); 204 unnecessary breast biopsies (vs 146); and 20 overdiagnoses (vs 18). However, the confidence intervals on these estimates are wide, and in each case, they overlap between the 2 groups.¹

The TF recommended biennial screening for women between the ages of 50 and 74 because observational studies and modeling show no clear benefit with annual screening vs every 2 years, while annual screening results in more false positives and biopsies.

Overdiagnosis may occur in nearly 20% of cases

The potential for overdiagnosis and overtreatment is increasingly recognized as a harm of cancer screening. Overdiagnosis results from detecting a tumor during screening that would not have been detected otherwise and that would not have caused death or disease but is treated anyway. This sometimes occurs with the detection of early tumors that would not have progressed or would have progressed slowly, not causing health problems before the woman dies of other causes.

The TF is one of the only organizations that considers the potential harmful effects of this problem. While it is not possible to know for certain the rate of overdiagnosis that occurs with cancer screening, high-quality studies indicate it is close to 20% for breast cancer.³

Guidance regarding women ages 40 to 49

The new draft recommendations carefully point out that, while the overall benefit of screening women ages 40 to 49 is small, the decision to begin screening before age 50 should be an individual one, and an informed one. They state that women who value the small potential benefit over the potential for harm may choose to be screened, as might women who have a family history of breast cancer. And the recommendations do not apply to women who have a genotype that places them at increased risk for breast cancer.

Tomosynthesis: Evidence of benefit is insufficient

Tomosynthesis as a primary breast cancer screening tool was studied in a separate evidence report commissioned by the TF.⁴ While tomosynthesis, compared with routine mammography, appears to have increased sensitivity and specificity in detecting breast cancer, no studies looked at this technology as a primary screening tool and its effect on breast cancer mortality, overall mortality, and quality of life. Sticking to its nationally-recognized methodological rigor, the TF states that information at this time is insufficient to make a recommendation on the use of tomosynthesis.

Dense breasts: Usefulness of adjunctive screening modalities

Breast density is categorized into 4 groups, from category a (breasts are almost all fatty with little fibro nodular tissue) to category d (breasts are extremely dense).¹ About 43% of women ages 40 to 74 are in categories c and d.¹ Dense breasts adversely affect the accuracy of mammography, decreasing sensitivity and specificity. In one study, sensitivity was 87% in category a and 63% in category d; specificities were 97% and 89%, respectively.⁵

Tomosynthesis, magnetic resonance imaging, and ultrasound, when used in addition to mammography, all appear to detect more cancers, but they also yield more false-positive results.⁶ The long-term outcome of detecting more tumors is not known. For an individual, there are 3 possibilities when a tumor is detected earlier: a better outcome, no difference in outcome, or a worse outcome resulting from overdiagnosis and overtreatment. The TF felt that the available data are insufficient to judge benefits and harms of an increased frequency of screening or the use of adjunctive screening methods in women with dense breasts.

Benefit for women ≥75 years is inconclusive

There are limited data on the impact of mammography on outcomes for women older than 70. The TF feels that, since women ages 60 to 69 benefit the most from mammography, this benefit is likely to carry over into the next decade. Modeling also predicts this.

While mammography helps reduce breast cancer deaths, women ages 40 to 49 benefit the least; women ages 60 to 69 benefit the most.

However, women ages 70 to 74 who have chronic illnesses are unlikely to benefit from mammography. The conditions specifically mentioned are cardiovascular disease, diabetes, lung disease, liver disease, renal failure, acquired immunodeficiency syndrome, and dementia.

For all women ages 75 and older, the TF feels the evidence is insufficient to make a recommendation.

Insurance coverage

The ACA mandates that 4 sets of preventive services be included in commercial health insurance plans with no out-of-pocket expenses to the patient: immunizations recommended by the Advisory Committee on Immunization Practices; children’s preventive services recommended by the Health Resources and Services Administration (HRSA); women’s preventive services recommended by HRSA; and recommendations with an A or B rating from the USPSTF.⁷

For children, HRSA opted to use those preventive services listed by the American Academy of Pediatrics in Bright Futures, the society’s national initiative providing recommendations on prevention screenings and well-child visits.⁸ For women, HRSA asked the Institute of Medicine to form a panel to construct a list of recommended preventive services.

At the time the ACA was passed, the TF had just made new recommendations on breast cancer screening, which were very similar to the current draft recommendations. Due to the resulting controversy, Congress mandated that the new recommendations not be used to determine first-dollar insurance coverage, and it cited the TF’s pre-2009 recommendations as the applicable standard.

Those earlier recommendations included annual mammography starting at age 40. The wording of the law, however, was not clear as to future mammography recommendations. One interpretation is that the TF recommendations in place before 2009 are the basis for first-dollar coverage until changed by Congress. Another interpretation is that the ACA special provision trumped only the 2009 recommendations and the 2015 recommendations will become the standard. If the latter turns out to be true, it is not clear if commercial insurance plans will begin to charge co-payments for mammography before age 50 or for mammograms ordered more frequently than every 2 years for women ages 50 to 74.

Annual mammography screening has shown no clear benefit over screening every 2 years, and it results in more false positives and biopsies.

The issue of insurance coverage is important because of the lack of uniformity in recommendations regarding mammography. The American Congress of Obstetricians and Gynecologists,⁹ the American Cancer Society,¹⁰ and the American College of Radiology¹¹ all recommend annual mammography starting at age 40. The American Academy of Family Physicians recommendations¹² mirror those of the USPSTF, and the Canadian Task Force on Preventive Health Care recommends against routine screening for women ages 40 to 49 and recommends mammography every 2 to 3 years for women ages 50 to 74.¹³

USPSTF rationale is informed and accessible for review

Breast cancer screening remains a highly controversial and emotional topic. The USPSTF has made a set of recommendations based on extensive and rigorous evidence reports that consider both benefits and harms. There will be those who vigorously disagree. The evidence reports, recommendations, and rationale behind them are easily accessible on the TF Web site (www.uspreventiveservicestaskforce.org) for those who want to read them.¹