Take-Home Points

• Fractures of the greater tuberosity are often mismanaged.
• Comprehension of greater tuberosity fractures involves classification into nonoperative and operative treatment, displacement >5mm or <5 mm, and open vs arthroscopic surgery.
• Nearly a third of patients may suffer concomitant anterior glenohumeral instability.
• Stiffness is the most common postoperative complication.
• Surgery is associated with high patient satisfaction and low rates of complications and reoperations.

Although proximal humerus fractures are common in the elderly, isolated fractures of the greater tuberosity occur less often. Management depends on several factors, including fracture pattern and displacement.^1,2 Nondisplaced fractures are often successfully managed with sling immobilization and early range of motion.^3,4 Although surgical intervention improves outcomes in displaced greater tuberosity fractures, the ideal surgical treatment is less clear.⁵

Displaced greater tuberosity fractures may require surgery for prevention of subacromial impingement and range-of-motion deficits.² Superior fracture displacement results in decreased shoulder abduction, and posterior displacement can limit external rotation.⁶ Although the greater tuberosity can displace in any direction, posterosuperior displacement has the worst outcomes.¹ The exact surgery-warranting displacement amount ranges from 3 mm to 10 mm but is yet to be clearly elucidated.^5,6 Less displacement is tolerated by young overhead athletes, and more displacement by older less active patients.^5,7,8 Surgical options for isolated greater tuberosity fractures include fragment excision, open reduction and internal fixation (ORIF), closed reduction with percutaneous fixation, and arthroscopically assisted reduction with internal fixation.^3,9,10

We conducted a study to determine the management patterns for isolated greater tuberosity fractures. We hypothesized that greater tuberosity fractures displaced <5 mm may be managed nonoperatively and that greater tuberosity fractures displaced >5 mm require surgical fixation.

Methods

Search Strategy

We performed this systematic review according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist¹¹ and registered it (CRD42014010691) with the PROSPERO international prospective register of systematic reviews. Literature searches using the PubMed/Medline database and the Cochrane Central Register of Clinical Trials were completed in August 2014. There were no date or year restrictions. Key words were used to capture all English- language studies with level I to IV evidence (Oxford Centre for Evidence-Based Medicine) and reported clinical or radiographic outcomes. Initial exclusion criteria were cadaveric, biomechanical, histologic, and kinematic results. An electronic search algorithm with key words and a series of NOT phrases was designed to match our exclusion criteria: 

((((((((((((((((((((((((((((((((((((((((((((((((((greater[Title/Abstract]) AND tuberosity [Title/Abstract] OR tubercle [Title/Abstract]) AND fracture[Title/Abstract]) AND proximal[Title/Abstract] AND (English[lang]))) NOT intramedullary[Title] AND (English[lang]))) NOT nonunion[Title] AND (English[lang]))) NOT malunion[Title] AND (English[lang]))) NOT biomechanical[Title/Abstract] AND (English[lang]))) NOT cadaveric[Title/Abstract] AND (English[lang]))) NOT cadaver[Title/Abstract] AND (English[lang]))) NOT ((basic[Title/Abstract]) AND science[Title/Abstract] AND (English[lang])) AND (English[lang]))) NOT revision[Title] AND (English[lang]))) NOT pediatric[Title] AND (English[lang]))) NOT physeal[Title] AND (English[lang]))) NOT children[Title] AND (English[lang]))) NOT instability[Title] AND (English[lang]))) NOT imaging[Title])) NOT salter[Title])) NOT physis[Title])) NOT shaft[Title])) NOT distal[Title])) NOT clavicle[Title])) NOT scapula[Title])) NOT ((diaphysis[Title]) AND diaphyseal[Title]))) NOT infection[Title])) NOT laboratory[Title/Abstract])) NOT metastatic[Title/Abstract])) NOT (((((((malignancy[Title/Abstract]) OR malignant[Title/Abstract]) OR tumor[Title/Abstract]) OR oncologic[Title/Abstract]) OR cyst[Title/Abstract]) OR aneurysmal[Title/Abstract]) OR unicameral[Title/Abstract]).

Study Selection

We extracted data from the 13 studies that met the eligibility criteria. Details of study design, sample size, and patient demographics, including age, sex, and hand dominance, were recorded, as were mechanism of injury and concomitant anterior shoulder instability. To capture the most patients, we noted radiographic fracture displacement categorically rather than continuously; patients were divided into 2 displacement groups (<5 mm, >5 mm). Most studies did not define degree of comminution or specific direction of displacement per fracture, so these variables were not included in the data analysis. Nonoperative management and operative management were studied. We abstracted surgical factors, such as approach, method, fixation type (screws or sutures), and technique (suture anchors or transosseous tunnels). Clinical outcomes included physical examination findings, functional assessment results (patient satisfaction; Constant and University of California Los Angeles [UCLA] shoulder scores), and the number of revisions. Radiologic outcomes, retrieved from radiographs or computed tomography scans, focused on loss of reduction (as determined by the respective authors), malunion, nonunion, and heterotopic ossification. Each study’s methodologic quality and bias were evaluated with the 15-item Modified Coleman Methodology Score (MCMS), which was described by Cowan and colleagues.²³ The MCMS has been used to assess randomized and nonrandomized patient trials.^24,25 Its scaled potential score ranges from 0 to 100 (85-100, excellent; 70-84, good; 55-69, fair; <55, poor).

Statistical Analysis

We report our data as weighted means (SDs). A mean was calculated for each study that reported a respective data point, and each mean was then weighed according to its study sample size. This calculation was performed by multiplying a study’s individual mean by the number of patients enrolled in that study and dividing the sum of these weighted data points by the number of eligible patients in all relevant studies. The result was that the nonweighted means from studies with smaller sample sizes did not carry as much weight as the nonweighted means from larger studies. We compared 3 paired groups: treatment type (nonoperative vs operative), fracture displacement amount (<5 mm vs >5 mm), and surgery type (open vs arthroscopic). Regarding all patient, surgery, and outcomes data, unpaired Student t tests were used for continuous variables and 2-tailed Fisher exact tests for categorical variables with α = 0.05 (SPSS Version 18; IBM).

Results

Postoperative physical examination findings were underreported so that surgical groups could be compared. Of all the surgical studies, 4 reported postoperative forward elevation (mean, 160°; SD, 9.8°) and external rotation (mean, 46.4°; SD 26.3°).^14,15,18,22 No malunions and only 1 nonunion were reported in all 13 studies. No deaths or other serious medical complications were reported. Patients with anterior instability more often underwent surgery than were treated nonoperatively (39.2% vs 12.0%; P < .01) and more often had fractures displaced >5 mm than <5 mm (44.3% vs 14.5%; P < .01).

Fisher exact tests were used to perform isolated comparisons of screws and sutures as well as suture anchors and transosseous tunnels. Patients with screw fixation were significantly (P = .051) less likely to require reoperation (0/56; 0%) than patients with suture fixation (8/100; 8.0%). Screw fixation also led to significantly less stiffness (0% vs 12.0%; P < .01) but trended toward a higher rate of superficial infection (3.6% vs 0%; P = .13). There was no statistical difference in nerve injury rates between screws and sutures (1.8% vs 3.0%; P = 1.0). There were no significant differences in reoperations, stiffness, superficial infections, or nerve injuries between suture anchor and transosseous tunnel constructs.

For all 13 studies, mean (SD) MCMS was 41.1 (8.6).

Discussion

Five percent of all fractures involve the proximal humerus, and 20% of proximal humerus fractures are isolated greater tuberosity fractures.^26,27 In his classic 1970 article, Neer⁶ formulated the 4-part proximal humerus fracture classification and defined greater tuberosity fracture “parts” using the same criteria as for other fracture “parts.” Neer⁶ recommended nonoperative management for isolated greater tuberosity fractures displaced <1 cm but did not present evidence corroborating his recommendation. More recent cutoffs for nonoperative management include 5 mm (general population) and 3 mm (athletes).^7,17

In the present systematic review of greater tuberosity fractures, 3 separate comparisons were made: treatment type (nonoperative vs operative), fracture displacement amount (<5 mm vs >5 mm), and surgery type (open vs arthroscopic).

Treatment Type. Only 4 studies reported data on nonoperative treatment outcomes.^5,12,16,17 Of these 4 studies, 2 found successful outcomes for fractures displaced <5 mm.^12,17 Platzer and colleagues¹⁷ found good or excellent results in 97% of 135 shoulders after 4 years. Good results were defined with shoulder scores of ≥80 (Constant), <8 (Vienna), and >28 (UCLA), and excellent results were defined with maximum scores on 2 of the 3 systems. Platzer and colleagues¹⁷ also found nonsignificantly worse shoulder scores with superior displacement of 3 mm to 5 mm and recommended surgery for overhead athletes in this group. Rath and colleagues¹² described a successful 3-phase rehabilitation protocol of sling immobilization for 3 weeks, pendulum exercises for 3 weeks, and active exercises thereafter. By an average of 31 months, patient satisfaction scores improved to 9.5 from 4.2 (10-point scale), though the authors cautioned that pain and decreased motion lasted 8 months on average. Conservative treatment was far less successful in the 2 studies of fractures displaced >5 mm.^5,16 Keene and colleagues¹⁶ reported unsatisfactory results in all 4 patients with fractures displaced >1.5 cm. In a study separate from their 2005 analysis,¹⁷ Platzer and colleagues⁵ in 2008 evaluated displaced fractures and found function and patient satisfaction were inferior after nonoperative treatment than after surgery. The studies by Keene and colleagues¹⁶ and Platzer and colleagues⁵ support the finding of an overall lower patient satisfaction rate in nonoperative patients.

Fracture Displacement Amount. Only 2 arthroscopic studies and no open studies addressed surgery for fractures displaced <5 mm. Fewer than 16% of these fractures were managed operatively, and <1% required reoperation. By contrast, almost all fractures displaced >5 mm were managed operatively, and 3.6% required reoperation. Radiographic loss of reduction was more common in fractures displaced <5 mm, primarily because they were managed without fixation. Radiographic loss of reduction was reported in only 9 operatively treated patients, none of whom was symptomatic enough to require another surgery.⁵ Reoperations were most commonly performed for stiffness, which itself was significantly more common in fractures displaced >5 mm. Bhatia and colleagues¹⁴ reported the highest reoperation rate (14.3%; 3/21), but they studied more complex, comminuted fractures of the greater tuberosity. Two of their 3 reoperations were biceps tenodeses for inflamed, stiff tenosynovitis, and the third patient had a foreign body giant cell reaction to suture material. Fewer than 1% of patients with operatively managed displaced fractures required revision ORIF, and <2% developed a superficial infection or postoperative nerve palsy.^19,22 For displaced greater tuberosity fractures, surgery is highly successful overall, complication rates are very low, and 90% of patients report being satisfied.

Surgery Type. Patients were divided into 2 groups. In the nonarthroscopic group, open and percutaneous approaches were used. All studies that described a percutaneous approach used screw fixation^5,21; in addition, 32 patients were treated with screws through an open approach.^2,5 The other open and arthroscopic studies used suture fixation. Interestingly, no studies reported on clinical outcomes of fragment excision. There were no statistically significant differences in rates of reoperation, stiffness, infection, or neurologic injury between the arthroscopic and nonarthroscopic groups. Patient satisfaction scores were slightly higher in the nonarthroscopic group (91.0% vs 87.8%), but the difference was not statistically significant.

With surgical techniques isolated, there were no significant differences between suture anchors and transosseous tunnel constructs, but screws performed significantly better than suture techniques. Compared with suture fixation, screw fixation led to significantly fewer cases of stiffness and reoperation, which suggests surgeons need to give screws more consideration in the operative management of these fractures. However, the number of patients treated with screws was smaller than the number treated with suture fixation; it is possible the differences between these cohorts would be eliminated if there were more patients in the screw cohort. In addition, screw fixation was universally performed with an open or percutaneous approach and trended toward a higher infection rate. As screw and suture techniques have low rates of complications and reoperations, we recommend leaving fixation choice to the surgeon.

Anterior shoulder instability has been associated with greater tuberosity fractures.^1,8,19 The supraspinatus, infraspinatus, and teres minor muscles all insert into the greater tuberosity and resist anterior translation of the proximal humerus. Loss of this dynamic muscle stabilization is amplified by tuberosity fracture displacement: Anterior shoulder instability was significantly more common in fractures displaced >5 mm (44.3%) vs <5 mm (14.5%). In turn, glenohumeral instability was more common in patients treated with surgery, specifically open surgery, because displaced fractures may not be as easily accessed with arthroscopic techniques. No studies reported concomitant labral repair or capsular plication techniques.

This systematic review was limited by the studies analyzed. All but 1 study⁵ had level IV evidence. Mean (SD) MCMS was 41.8 (8.6). Any MCMS score <54 indicates a poor methodology level, but this scoring system is designed for randomized controlled trials,²³ and there were none in this study. Physical examination findings, such as range of motion, were underreported. In addition, radiographic parameters were not consistently described but rather were determined by the respective authors’ subjective interpretations of malunion, nonunion, and loss of reduction. Publication bias is present in that we excluded non- English language studies and medical conference abstracts and may have omitted potentially eligible studies not discoverable with our search methodology. Performance bias is a factor in any systematic review with multiple surgeons and wide variation in surgical technique.

Conclusion

Greater tuberosity fractures displaced <5 mm may be safely managed nonoperatively, as there are no reports of nonoperatively managed fractures that subsequently required surgery. Nonoperative treatment was initially associated with low patient satisfaction, but only because displaced fractures were conservatively managed in early studies.^5,16 Fractures displaced >5 mm respond well to operative fixation with screws, suture anchors, or transosseous suture tunnels. Stiffness is the most common postoperative complication (<6%), followed by heterotopic ossification, transient neurapraxias, and superficial infection. There are no discernible differences in outcome between open and arthroscopic techniques, but screw fixation may lead to significantly fewer cases of stiffness and reoperation in comparison with suture constructs.

Take-Home Points

• Fractures of the greater tuberosity are often mismanaged.
• Comprehension of greater tuberosity fractures involves classification into nonoperative and operative treatment, displacement >5mm or <5 mm, and open vs arthroscopic surgery.
• Nearly a third of patients may suffer concomitant anterior glenohumeral instability.
• Stiffness is the most common postoperative complication.
• Surgery is associated with high patient satisfaction and low rates of complications and reoperations.

Although proximal humerus fractures are common in the elderly, isolated fractures of the greater tuberosity occur less often. Management depends on several factors, including fracture pattern and displacement.^1,2 Nondisplaced fractures are often successfully managed with sling immobilization and early range of motion.^3,4 Although surgical intervention improves outcomes in displaced greater tuberosity fractures, the ideal surgical treatment is less clear.⁵

Displaced greater tuberosity fractures may require surgery for prevention of subacromial impingement and range-of-motion deficits.² Superior fracture displacement results in decreased shoulder abduction, and posterior displacement can limit external rotation.⁶ Although the greater tuberosity can displace in any direction, posterosuperior displacement has the worst outcomes.¹ The exact surgery-warranting displacement amount ranges from 3 mm to 10 mm but is yet to be clearly elucidated.^5,6 Less displacement is tolerated by young overhead athletes, and more displacement by older less active patients.^5,7,8 Surgical options for isolated greater tuberosity fractures include fragment excision, open reduction and internal fixation (ORIF), closed reduction with percutaneous fixation, and arthroscopically assisted reduction with internal fixation.^3,9,10

We conducted a study to determine the management patterns for isolated greater tuberosity fractures. We hypothesized that greater tuberosity fractures displaced <5 mm may be managed nonoperatively and that greater tuberosity fractures displaced >5 mm require surgical fixation.

Methods

Search Strategy

We performed this systematic review according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist¹¹ and registered it (CRD42014010691) with the PROSPERO international prospective register of systematic reviews. Literature searches using the PubMed/Medline database and the Cochrane Central Register of Clinical Trials were completed in August 2014. There were no date or year restrictions. Key words were used to capture all English- language studies with level I to IV evidence (Oxford Centre for Evidence-Based Medicine) and reported clinical or radiographic outcomes. Initial exclusion criteria were cadaveric, biomechanical, histologic, and kinematic results. An electronic search algorithm with key words and a series of NOT phrases was designed to match our exclusion criteria: 

((((((((((((((((((((((((((((((((((((((((((((((((((greater[Title/Abstract]) AND tuberosity [Title/Abstract] OR tubercle [Title/Abstract]) AND fracture[Title/Abstract]) AND proximal[Title/Abstract] AND (English[lang]))) NOT intramedullary[Title] AND (English[lang]))) NOT nonunion[Title] AND (English[lang]))) NOT malunion[Title] AND (English[lang]))) NOT biomechanical[Title/Abstract] AND (English[lang]))) NOT cadaveric[Title/Abstract] AND (English[lang]))) NOT cadaver[Title/Abstract] AND (English[lang]))) NOT ((basic[Title/Abstract]) AND science[Title/Abstract] AND (English[lang])) AND (English[lang]))) NOT revision[Title] AND (English[lang]))) NOT pediatric[Title] AND (English[lang]))) NOT physeal[Title] AND (English[lang]))) NOT children[Title] AND (English[lang]))) NOT instability[Title] AND (English[lang]))) NOT imaging[Title])) NOT salter[Title])) NOT physis[Title])) NOT shaft[Title])) NOT distal[Title])) NOT clavicle[Title])) NOT scapula[Title])) NOT ((diaphysis[Title]) AND diaphyseal[Title]))) NOT infection[Title])) NOT laboratory[Title/Abstract])) NOT metastatic[Title/Abstract])) NOT (((((((malignancy[Title/Abstract]) OR malignant[Title/Abstract]) OR tumor[Title/Abstract]) OR oncologic[Title/Abstract]) OR cyst[Title/Abstract]) OR aneurysmal[Title/Abstract]) OR unicameral[Title/Abstract]).

Study Selection

We extracted data from the 13 studies that met the eligibility criteria. Details of study design, sample size, and patient demographics, including age, sex, and hand dominance, were recorded, as were mechanism of injury and concomitant anterior shoulder instability. To capture the most patients, we noted radiographic fracture displacement categorically rather than continuously; patients were divided into 2 displacement groups (<5 mm, >5 mm). Most studies did not define degree of comminution or specific direction of displacement per fracture, so these variables were not included in the data analysis. Nonoperative management and operative management were studied. We abstracted surgical factors, such as approach, method, fixation type (screws or sutures), and technique (suture anchors or transosseous tunnels). Clinical outcomes included physical examination findings, functional assessment results (patient satisfaction; Constant and University of California Los Angeles [UCLA] shoulder scores), and the number of revisions. Radiologic outcomes, retrieved from radiographs or computed tomography scans, focused on loss of reduction (as determined by the respective authors), malunion, nonunion, and heterotopic ossification. Each study’s methodologic quality and bias were evaluated with the 15-item Modified Coleman Methodology Score (MCMS), which was described by Cowan and colleagues.²³ The MCMS has been used to assess randomized and nonrandomized patient trials.^24,25 Its scaled potential score ranges from 0 to 100 (85-100, excellent; 70-84, good; 55-69, fair; <55, poor).

Statistical Analysis

We report our data as weighted means (SDs). A mean was calculated for each study that reported a respective data point, and each mean was then weighed according to its study sample size. This calculation was performed by multiplying a study’s individual mean by the number of patients enrolled in that study and dividing the sum of these weighted data points by the number of eligible patients in all relevant studies. The result was that the nonweighted means from studies with smaller sample sizes did not carry as much weight as the nonweighted means from larger studies. We compared 3 paired groups: treatment type (nonoperative vs operative), fracture displacement amount (<5 mm vs >5 mm), and surgery type (open vs arthroscopic). Regarding all patient, surgery, and outcomes data, unpaired Student t tests were used for continuous variables and 2-tailed Fisher exact tests for categorical variables with α = 0.05 (SPSS Version 18; IBM).

Results

Postoperative physical examination findings were underreported so that surgical groups could be compared. Of all the surgical studies, 4 reported postoperative forward elevation (mean, 160°; SD, 9.8°) and external rotation (mean, 46.4°; SD 26.3°).^14,15,18,22 No malunions and only 1 nonunion were reported in all 13 studies. No deaths or other serious medical complications were reported. Patients with anterior instability more often underwent surgery than were treated nonoperatively (39.2% vs 12.0%; P < .01) and more often had fractures displaced >5 mm than <5 mm (44.3% vs 14.5%; P < .01).

Fisher exact tests were used to perform isolated comparisons of screws and sutures as well as suture anchors and transosseous tunnels. Patients with screw fixation were significantly (P = .051) less likely to require reoperation (0/56; 0%) than patients with suture fixation (8/100; 8.0%). Screw fixation also led to significantly less stiffness (0% vs 12.0%; P < .01) but trended toward a higher rate of superficial infection (3.6% vs 0%; P = .13). There was no statistical difference in nerve injury rates between screws and sutures (1.8% vs 3.0%; P = 1.0). There were no significant differences in reoperations, stiffness, superficial infections, or nerve injuries between suture anchor and transosseous tunnel constructs.

For all 13 studies, mean (SD) MCMS was 41.1 (8.6).

Discussion

Five percent of all fractures involve the proximal humerus, and 20% of proximal humerus fractures are isolated greater tuberosity fractures.^26,27 In his classic 1970 article, Neer⁶ formulated the 4-part proximal humerus fracture classification and defined greater tuberosity fracture “parts” using the same criteria as for other fracture “parts.” Neer⁶ recommended nonoperative management for isolated greater tuberosity fractures displaced <1 cm but did not present evidence corroborating his recommendation. More recent cutoffs for nonoperative management include 5 mm (general population) and 3 mm (athletes).^7,17

In the present systematic review of greater tuberosity fractures, 3 separate comparisons were made: treatment type (nonoperative vs operative), fracture displacement amount (<5 mm vs >5 mm), and surgery type (open vs arthroscopic).

Treatment Type. Only 4 studies reported data on nonoperative treatment outcomes.^5,12,16,17 Of these 4 studies, 2 found successful outcomes for fractures displaced <5 mm.^12,17 Platzer and colleagues¹⁷ found good or excellent results in 97% of 135 shoulders after 4 years. Good results were defined with shoulder scores of ≥80 (Constant), <8 (Vienna), and >28 (UCLA), and excellent results were defined with maximum scores on 2 of the 3 systems. Platzer and colleagues¹⁷ also found nonsignificantly worse shoulder scores with superior displacement of 3 mm to 5 mm and recommended surgery for overhead athletes in this group. Rath and colleagues¹² described a successful 3-phase rehabilitation protocol of sling immobilization for 3 weeks, pendulum exercises for 3 weeks, and active exercises thereafter. By an average of 31 months, patient satisfaction scores improved to 9.5 from 4.2 (10-point scale), though the authors cautioned that pain and decreased motion lasted 8 months on average. Conservative treatment was far less successful in the 2 studies of fractures displaced >5 mm.^5,16 Keene and colleagues¹⁶ reported unsatisfactory results in all 4 patients with fractures displaced >1.5 cm. In a study separate from their 2005 analysis,¹⁷ Platzer and colleagues⁵ in 2008 evaluated displaced fractures and found function and patient satisfaction were inferior after nonoperative treatment than after surgery. The studies by Keene and colleagues¹⁶ and Platzer and colleagues⁵ support the finding of an overall lower patient satisfaction rate in nonoperative patients.

Fracture Displacement Amount. Only 2 arthroscopic studies and no open studies addressed surgery for fractures displaced <5 mm. Fewer than 16% of these fractures were managed operatively, and <1% required reoperation. By contrast, almost all fractures displaced >5 mm were managed operatively, and 3.6% required reoperation. Radiographic loss of reduction was more common in fractures displaced <5 mm, primarily because they were managed without fixation. Radiographic loss of reduction was reported in only 9 operatively treated patients, none of whom was symptomatic enough to require another surgery.⁵ Reoperations were most commonly performed for stiffness, which itself was significantly more common in fractures displaced >5 mm. Bhatia and colleagues¹⁴ reported the highest reoperation rate (14.3%; 3/21), but they studied more complex, comminuted fractures of the greater tuberosity. Two of their 3 reoperations were biceps tenodeses for inflamed, stiff tenosynovitis, and the third patient had a foreign body giant cell reaction to suture material. Fewer than 1% of patients with operatively managed displaced fractures required revision ORIF, and <2% developed a superficial infection or postoperative nerve palsy.^19,22 For displaced greater tuberosity fractures, surgery is highly successful overall, complication rates are very low, and 90% of patients report being satisfied.

Surgery Type. Patients were divided into 2 groups. In the nonarthroscopic group, open and percutaneous approaches were used. All studies that described a percutaneous approach used screw fixation^5,21; in addition, 32 patients were treated with screws through an open approach.^2,5 The other open and arthroscopic studies used suture fixation. Interestingly, no studies reported on clinical outcomes of fragment excision. There were no statistically significant differences in rates of reoperation, stiffness, infection, or neurologic injury between the arthroscopic and nonarthroscopic groups. Patient satisfaction scores were slightly higher in the nonarthroscopic group (91.0% vs 87.8%), but the difference was not statistically significant.

With surgical techniques isolated, there were no significant differences between suture anchors and transosseous tunnel constructs, but screws performed significantly better than suture techniques. Compared with suture fixation, screw fixation led to significantly fewer cases of stiffness and reoperation, which suggests surgeons need to give screws more consideration in the operative management of these fractures. However, the number of patients treated with screws was smaller than the number treated with suture fixation; it is possible the differences between these cohorts would be eliminated if there were more patients in the screw cohort. In addition, screw fixation was universally performed with an open or percutaneous approach and trended toward a higher infection rate. As screw and suture techniques have low rates of complications and reoperations, we recommend leaving fixation choice to the surgeon.

Anterior shoulder instability has been associated with greater tuberosity fractures.^1,8,19 The supraspinatus, infraspinatus, and teres minor muscles all insert into the greater tuberosity and resist anterior translation of the proximal humerus. Loss of this dynamic muscle stabilization is amplified by tuberosity fracture displacement: Anterior shoulder instability was significantly more common in fractures displaced >5 mm (44.3%) vs <5 mm (14.5%). In turn, glenohumeral instability was more common in patients treated with surgery, specifically open surgery, because displaced fractures may not be as easily accessed with arthroscopic techniques. No studies reported concomitant labral repair or capsular plication techniques.

This systematic review was limited by the studies analyzed. All but 1 study⁵ had level IV evidence. Mean (SD) MCMS was 41.8 (8.6). Any MCMS score <54 indicates a poor methodology level, but this scoring system is designed for randomized controlled trials,²³ and there were none in this study. Physical examination findings, such as range of motion, were underreported. In addition, radiographic parameters were not consistently described but rather were determined by the respective authors’ subjective interpretations of malunion, nonunion, and loss of reduction. Publication bias is present in that we excluded non- English language studies and medical conference abstracts and may have omitted potentially eligible studies not discoverable with our search methodology. Performance bias is a factor in any systematic review with multiple surgeons and wide variation in surgical technique.

Conclusion

Greater tuberosity fractures displaced <5 mm may be safely managed nonoperatively, as there are no reports of nonoperatively managed fractures that subsequently required surgery. Nonoperative treatment was initially associated with low patient satisfaction, but only because displaced fractures were conservatively managed in early studies.^5,16 Fractures displaced >5 mm respond well to operative fixation with screws, suture anchors, or transosseous suture tunnels. Stiffness is the most common postoperative complication (<6%), followed by heterotopic ossification, transient neurapraxias, and superficial infection. There are no discernible differences in outcome between open and arthroscopic techniques, but screw fixation may lead to significantly fewer cases of stiffness and reoperation in comparison with suture constructs.

Take-Home Points

• Fractures of the greater tuberosity are often mismanaged.
• Comprehension of greater tuberosity fractures involves classification into nonoperative and operative treatment, displacement >5mm or <5 mm, and open vs arthroscopic surgery.
• Nearly a third of patients may suffer concomitant anterior glenohumeral instability.
• Stiffness is the most common postoperative complication.
• Surgery is associated with high patient satisfaction and low rates of complications and reoperations.

Although proximal humerus fractures are common in the elderly, isolated fractures of the greater tuberosity occur less often. Management depends on several factors, including fracture pattern and displacement.^1,2 Nondisplaced fractures are often successfully managed with sling immobilization and early range of motion.^3,4 Although surgical intervention improves outcomes in displaced greater tuberosity fractures, the ideal surgical treatment is less clear.⁵

Displaced greater tuberosity fractures may require surgery for prevention of subacromial impingement and range-of-motion deficits.² Superior fracture displacement results in decreased shoulder abduction, and posterior displacement can limit external rotation.⁶ Although the greater tuberosity can displace in any direction, posterosuperior displacement has the worst outcomes.¹ The exact surgery-warranting displacement amount ranges from 3 mm to 10 mm but is yet to be clearly elucidated.^5,6 Less displacement is tolerated by young overhead athletes, and more displacement by older less active patients.^5,7,8 Surgical options for isolated greater tuberosity fractures include fragment excision, open reduction and internal fixation (ORIF), closed reduction with percutaneous fixation, and arthroscopically assisted reduction with internal fixation.^3,9,10

We conducted a study to determine the management patterns for isolated greater tuberosity fractures. We hypothesized that greater tuberosity fractures displaced <5 mm may be managed nonoperatively and that greater tuberosity fractures displaced >5 mm require surgical fixation.

Methods

Search Strategy

We performed this systematic review according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist¹¹ and registered it (CRD42014010691) with the PROSPERO international prospective register of systematic reviews. Literature searches using the PubMed/Medline database and the Cochrane Central Register of Clinical Trials were completed in August 2014. There were no date or year restrictions. Key words were used to capture all English- language studies with level I to IV evidence (Oxford Centre for Evidence-Based Medicine) and reported clinical or radiographic outcomes. Initial exclusion criteria were cadaveric, biomechanical, histologic, and kinematic results. An electronic search algorithm with key words and a series of NOT phrases was designed to match our exclusion criteria: 

((((((((((((((((((((((((((((((((((((((((((((((((((greater[Title/Abstract]) AND tuberosity [Title/Abstract] OR tubercle [Title/Abstract]) AND fracture[Title/Abstract]) AND proximal[Title/Abstract] AND (English[lang]))) NOT intramedullary[Title] AND (English[lang]))) NOT nonunion[Title] AND (English[lang]))) NOT malunion[Title] AND (English[lang]))) NOT biomechanical[Title/Abstract] AND (English[lang]))) NOT cadaveric[Title/Abstract] AND (English[lang]))) NOT cadaver[Title/Abstract] AND (English[lang]))) NOT ((basic[Title/Abstract]) AND science[Title/Abstract] AND (English[lang])) AND (English[lang]))) NOT revision[Title] AND (English[lang]))) NOT pediatric[Title] AND (English[lang]))) NOT physeal[Title] AND (English[lang]))) NOT children[Title] AND (English[lang]))) NOT instability[Title] AND (English[lang]))) NOT imaging[Title])) NOT salter[Title])) NOT physis[Title])) NOT shaft[Title])) NOT distal[Title])) NOT clavicle[Title])) NOT scapula[Title])) NOT ((diaphysis[Title]) AND diaphyseal[Title]))) NOT infection[Title])) NOT laboratory[Title/Abstract])) NOT metastatic[Title/Abstract])) NOT (((((((malignancy[Title/Abstract]) OR malignant[Title/Abstract]) OR tumor[Title/Abstract]) OR oncologic[Title/Abstract]) OR cyst[Title/Abstract]) OR aneurysmal[Title/Abstract]) OR unicameral[Title/Abstract]).

Study Selection

We extracted data from the 13 studies that met the eligibility criteria. Details of study design, sample size, and patient demographics, including age, sex, and hand dominance, were recorded, as were mechanism of injury and concomitant anterior shoulder instability. To capture the most patients, we noted radiographic fracture displacement categorically rather than continuously; patients were divided into 2 displacement groups (<5 mm, >5 mm). Most studies did not define degree of comminution or specific direction of displacement per fracture, so these variables were not included in the data analysis. Nonoperative management and operative management were studied. We abstracted surgical factors, such as approach, method, fixation type (screws or sutures), and technique (suture anchors or transosseous tunnels). Clinical outcomes included physical examination findings, functional assessment results (patient satisfaction; Constant and University of California Los Angeles [UCLA] shoulder scores), and the number of revisions. Radiologic outcomes, retrieved from radiographs or computed tomography scans, focused on loss of reduction (as determined by the respective authors), malunion, nonunion, and heterotopic ossification. Each study’s methodologic quality and bias were evaluated with the 15-item Modified Coleman Methodology Score (MCMS), which was described by Cowan and colleagues.²³ The MCMS has been used to assess randomized and nonrandomized patient trials.^24,25 Its scaled potential score ranges from 0 to 100 (85-100, excellent; 70-84, good; 55-69, fair; <55, poor).

Statistical Analysis

We report our data as weighted means (SDs). A mean was calculated for each study that reported a respective data point, and each mean was then weighed according to its study sample size. This calculation was performed by multiplying a study’s individual mean by the number of patients enrolled in that study and dividing the sum of these weighted data points by the number of eligible patients in all relevant studies. The result was that the nonweighted means from studies with smaller sample sizes did not carry as much weight as the nonweighted means from larger studies. We compared 3 paired groups: treatment type (nonoperative vs operative), fracture displacement amount (<5 mm vs >5 mm), and surgery type (open vs arthroscopic). Regarding all patient, surgery, and outcomes data, unpaired Student t tests were used for continuous variables and 2-tailed Fisher exact tests for categorical variables with α = 0.05 (SPSS Version 18; IBM).

Results

Postoperative physical examination findings were underreported so that surgical groups could be compared. Of all the surgical studies, 4 reported postoperative forward elevation (mean, 160°; SD, 9.8°) and external rotation (mean, 46.4°; SD 26.3°).^14,15,18,22 No malunions and only 1 nonunion were reported in all 13 studies. No deaths or other serious medical complications were reported. Patients with anterior instability more often underwent surgery than were treated nonoperatively (39.2% vs 12.0%; P < .01) and more often had fractures displaced >5 mm than <5 mm (44.3% vs 14.5%; P < .01).

Fisher exact tests were used to perform isolated comparisons of screws and sutures as well as suture anchors and transosseous tunnels. Patients with screw fixation were significantly (P = .051) less likely to require reoperation (0/56; 0%) than patients with suture fixation (8/100; 8.0%). Screw fixation also led to significantly less stiffness (0% vs 12.0%; P < .01) but trended toward a higher rate of superficial infection (3.6% vs 0%; P = .13). There was no statistical difference in nerve injury rates between screws and sutures (1.8% vs 3.0%; P = 1.0). There were no significant differences in reoperations, stiffness, superficial infections, or nerve injuries between suture anchor and transosseous tunnel constructs.

For all 13 studies, mean (SD) MCMS was 41.1 (8.6).

Discussion

Five percent of all fractures involve the proximal humerus, and 20% of proximal humerus fractures are isolated greater tuberosity fractures.^26,27 In his classic 1970 article, Neer⁶ formulated the 4-part proximal humerus fracture classification and defined greater tuberosity fracture “parts” using the same criteria as for other fracture “parts.” Neer⁶ recommended nonoperative management for isolated greater tuberosity fractures displaced <1 cm but did not present evidence corroborating his recommendation. More recent cutoffs for nonoperative management include 5 mm (general population) and 3 mm (athletes).^7,17

In the present systematic review of greater tuberosity fractures, 3 separate comparisons were made: treatment type (nonoperative vs operative), fracture displacement amount (<5 mm vs >5 mm), and surgery type (open vs arthroscopic).

Treatment Type. Only 4 studies reported data on nonoperative treatment outcomes.^5,12,16,17 Of these 4 studies, 2 found successful outcomes for fractures displaced <5 mm.^12,17 Platzer and colleagues¹⁷ found good or excellent results in 97% of 135 shoulders after 4 years. Good results were defined with shoulder scores of ≥80 (Constant), <8 (Vienna), and >28 (UCLA), and excellent results were defined with maximum scores on 2 of the 3 systems. Platzer and colleagues¹⁷ also found nonsignificantly worse shoulder scores with superior displacement of 3 mm to 5 mm and recommended surgery for overhead athletes in this group. Rath and colleagues¹² described a successful 3-phase rehabilitation protocol of sling immobilization for 3 weeks, pendulum exercises for 3 weeks, and active exercises thereafter. By an average of 31 months, patient satisfaction scores improved to 9.5 from 4.2 (10-point scale), though the authors cautioned that pain and decreased motion lasted 8 months on average. Conservative treatment was far less successful in the 2 studies of fractures displaced >5 mm.^5,16 Keene and colleagues¹⁶ reported unsatisfactory results in all 4 patients with fractures displaced >1.5 cm. In a study separate from their 2005 analysis,¹⁷ Platzer and colleagues⁵ in 2008 evaluated displaced fractures and found function and patient satisfaction were inferior after nonoperative treatment than after surgery. The studies by Keene and colleagues¹⁶ and Platzer and colleagues⁵ support the finding of an overall lower patient satisfaction rate in nonoperative patients.

Fracture Displacement Amount. Only 2 arthroscopic studies and no open studies addressed surgery for fractures displaced <5 mm. Fewer than 16% of these fractures were managed operatively, and <1% required reoperation. By contrast, almost all fractures displaced >5 mm were managed operatively, and 3.6% required reoperation. Radiographic loss of reduction was more common in fractures displaced <5 mm, primarily because they were managed without fixation. Radiographic loss of reduction was reported in only 9 operatively treated patients, none of whom was symptomatic enough to require another surgery.⁵ Reoperations were most commonly performed for stiffness, which itself was significantly more common in fractures displaced >5 mm. Bhatia and colleagues¹⁴ reported the highest reoperation rate (14.3%; 3/21), but they studied more complex, comminuted fractures of the greater tuberosity. Two of their 3 reoperations were biceps tenodeses for inflamed, stiff tenosynovitis, and the third patient had a foreign body giant cell reaction to suture material. Fewer than 1% of patients with operatively managed displaced fractures required revision ORIF, and <2% developed a superficial infection or postoperative nerve palsy.^19,22 For displaced greater tuberosity fractures, surgery is highly successful overall, complication rates are very low, and 90% of patients report being satisfied.

Surgery Type. Patients were divided into 2 groups. In the nonarthroscopic group, open and percutaneous approaches were used. All studies that described a percutaneous approach used screw fixation^5,21; in addition, 32 patients were treated with screws through an open approach.^2,5 The other open and arthroscopic studies used suture fixation. Interestingly, no studies reported on clinical outcomes of fragment excision. There were no statistically significant differences in rates of reoperation, stiffness, infection, or neurologic injury between the arthroscopic and nonarthroscopic groups. Patient satisfaction scores were slightly higher in the nonarthroscopic group (91.0% vs 87.8%), but the difference was not statistically significant.

With surgical techniques isolated, there were no significant differences between suture anchors and transosseous tunnel constructs, but screws performed significantly better than suture techniques. Compared with suture fixation, screw fixation led to significantly fewer cases of stiffness and reoperation, which suggests surgeons need to give screws more consideration in the operative management of these fractures. However, the number of patients treated with screws was smaller than the number treated with suture fixation; it is possible the differences between these cohorts would be eliminated if there were more patients in the screw cohort. In addition, screw fixation was universally performed with an open or percutaneous approach and trended toward a higher infection rate. As screw and suture techniques have low rates of complications and reoperations, we recommend leaving fixation choice to the surgeon.

Anterior shoulder instability has been associated with greater tuberosity fractures.^1,8,19 The supraspinatus, infraspinatus, and teres minor muscles all insert into the greater tuberosity and resist anterior translation of the proximal humerus. Loss of this dynamic muscle stabilization is amplified by tuberosity fracture displacement: Anterior shoulder instability was significantly more common in fractures displaced >5 mm (44.3%) vs <5 mm (14.5%). In turn, glenohumeral instability was more common in patients treated with surgery, specifically open surgery, because displaced fractures may not be as easily accessed with arthroscopic techniques. No studies reported concomitant labral repair or capsular plication techniques.

This systematic review was limited by the studies analyzed. All but 1 study⁵ had level IV evidence. Mean (SD) MCMS was 41.8 (8.6). Any MCMS score <54 indicates a poor methodology level, but this scoring system is designed for randomized controlled trials,²³ and there were none in this study. Physical examination findings, such as range of motion, were underreported. In addition, radiographic parameters were not consistently described but rather were determined by the respective authors’ subjective interpretations of malunion, nonunion, and loss of reduction. Publication bias is present in that we excluded non- English language studies and medical conference abstracts and may have omitted potentially eligible studies not discoverable with our search methodology. Performance bias is a factor in any systematic review with multiple surgeons and wide variation in surgical technique.

Conclusion

Greater tuberosity fractures displaced <5 mm may be safely managed nonoperatively, as there are no reports of nonoperatively managed fractures that subsequently required surgery. Nonoperative treatment was initially associated with low patient satisfaction, but only because displaced fractures were conservatively managed in early studies.^5,16 Fractures displaced >5 mm respond well to operative fixation with screws, suture anchors, or transosseous suture tunnels. Stiffness is the most common postoperative complication (<6%), followed by heterotopic ossification, transient neurapraxias, and superficial infection. There are no discernible differences in outcome between open and arthroscopic techniques, but screw fixation may lead to significantly fewer cases of stiffness and reoperation in comparison with suture constructs.

The belief that corneas that have been preserved for > 7 days are not viable for transplantation is not based on evidence, says Jonathan Lass, MD. In fact, he led a study that found corneas can be preserved safely for 11 days without negative impact on the success of transplantation. In the Cornea Preservation Time Study, funded by the National Eye Institute, Lass and other researchers looked at 3-year graft success rates among 1,090 participants (1,330 eyes) who underwent transplantation via Descemet’s stripping automated endothelial keratoplasty by 70 surgeons at 40 surgical sites. Most of the patients had Fuchs’ endothelial corneal dystrophy, a progressive disease.

The researchers were “unable to conclude” that the success rates were the same for corneas preserved for 8 to 14 days, versus up to 7 days (92% vs 95%). However, they found that much of the difference between the groups was accounted for by patients receiving corneas preserved for 12 to 14 days.

In a separate analysis, the researchers looked to see if differences in corneal preservation time affected endothelial cell loss after 3 years. They found that corneas preserved for up to 7 days had a 37% loss of cells versus 40% in those preserved for 8 to 14 days. A closer look at the data showed that the effect of corneal preservation time on the loss of endothelial cells was comparable from 4 to 13 days.

Dr. Lass emphasizes that while patients who received the older corneas had lower success rates, even those success rates were “impressively high” at 89%.

Donor corneas are not in short supply in the U.S. Outside the U.S., however, corneal disease is the third leading cause of blindness and corneal donor tissue is scarce.

The belief that corneas that have been preserved for > 7 days are not viable for transplantation is not based on evidence, says Jonathan Lass, MD. In fact, he led a study that found corneas can be preserved safely for 11 days without negative impact on the success of transplantation. In the Cornea Preservation Time Study, funded by the National Eye Institute, Lass and other researchers looked at 3-year graft success rates among 1,090 participants (1,330 eyes) who underwent transplantation via Descemet’s stripping automated endothelial keratoplasty by 70 surgeons at 40 surgical sites. Most of the patients had Fuchs’ endothelial corneal dystrophy, a progressive disease.

The researchers were “unable to conclude” that the success rates were the same for corneas preserved for 8 to 14 days, versus up to 7 days (92% vs 95%). However, they found that much of the difference between the groups was accounted for by patients receiving corneas preserved for 12 to 14 days.

In a separate analysis, the researchers looked to see if differences in corneal preservation time affected endothelial cell loss after 3 years. They found that corneas preserved for up to 7 days had a 37% loss of cells versus 40% in those preserved for 8 to 14 days. A closer look at the data showed that the effect of corneal preservation time on the loss of endothelial cells was comparable from 4 to 13 days.

Dr. Lass emphasizes that while patients who received the older corneas had lower success rates, even those success rates were “impressively high” at 89%.

Donor corneas are not in short supply in the U.S. Outside the U.S., however, corneal disease is the third leading cause of blindness and corneal donor tissue is scarce.

The belief that corneas that have been preserved for > 7 days are not viable for transplantation is not based on evidence, says Jonathan Lass, MD. In fact, he led a study that found corneas can be preserved safely for 11 days without negative impact on the success of transplantation. In the Cornea Preservation Time Study, funded by the National Eye Institute, Lass and other researchers looked at 3-year graft success rates among 1,090 participants (1,330 eyes) who underwent transplantation via Descemet’s stripping automated endothelial keratoplasty by 70 surgeons at 40 surgical sites. Most of the patients had Fuchs’ endothelial corneal dystrophy, a progressive disease.

The researchers were “unable to conclude” that the success rates were the same for corneas preserved for 8 to 14 days, versus up to 7 days (92% vs 95%). However, they found that much of the difference between the groups was accounted for by patients receiving corneas preserved for 12 to 14 days.

In a separate analysis, the researchers looked to see if differences in corneal preservation time affected endothelial cell loss after 3 years. They found that corneas preserved for up to 7 days had a 37% loss of cells versus 40% in those preserved for 8 to 14 days. A closer look at the data showed that the effect of corneal preservation time on the loss of endothelial cells was comparable from 4 to 13 days.

Dr. Lass emphasizes that while patients who received the older corneas had lower success rates, even those success rates were “impressively high” at 89%.

Donor corneas are not in short supply in the U.S. Outside the U.S., however, corneal disease is the third leading cause of blindness and corneal donor tissue is scarce.

Take-Home Points

• Gorham disease is a rare condition that manifests as an acute, spontaneous osteolysis.
• There is no clear hereditary pattern of transmission. Bones of any type or location can be affected.
• Imaging studies are nonspecific, but show permeative osteolysis involving the subcortical and intramedullary regions and typically affect regional, contiguous bones, without adjacent sclerosis, somewhat resembling osteoporosis.
• Tissue biopsy is indicated to rule out other potential etiologies of osteolysis, and the histologic findings help confirm a diagnosis of Gorham disease.
• There is no single or combined treatment modality that is considered as the gold standard. Surgical treatment includes resection of the lesion and reconstruction. Also, antiosteoclastic medication can be used.

Gorham disease, a rare condition of unknown etiology, manifests as acute, spontaneous osteolysis associated with benign hemangiomatosis or lymphangiomatosis, which presents as skeletal lucency on radiographs, prompting the classic eponym of vanishing bone disease.^1-6 There is no evidence supporting the idea that osteoclasts are present in any meaningful amount in the resorption areas or that local reparative osteogenesis occurs.^4,6

Jackson and colleagues first described idiopathic osteolysis in 1838,^1,2 and Gorham and Stout³ introduced the syndrome to the orthopedic community in 1955. Since then, few strides have been made in identifying the disease origin.^1,2,4 Diagnosis is possible only after meticulous work-up has excluded neoplastic and infectious etiologies.^7,8

Clinical Presentation

Gorham disease affects patients ranging widely in age, from 2 months to 78 years, but typically presents in those under 40 years. There is a questionable predilection for males but no correlation with ethnicity or geographic region. There is no clear hereditary pattern of transmission.⁷ Although the bones of the head, neck, and upper extremities are involved in most cases, bone of any type or location can be affected.⁶ Pelvic bones seem to be involved least often.^6,7

Initial clinical presentation varies considerably but typically involves prolonged soreness in the affected region and, rarely, acute pathologic fracture.^1,2,4 The nonspecific nature of complaints, lack of markers of systemic illness, and rarity of the disease contribute to delayed diagnosis.^1,2

Imaging

Computed tomography (CT) better defines the severity and extent of these changes.

Diagnosis

There have been 8 histologic and clinical criteria described to diagnose Gorham disease: (1) biopsy positive for presence of angiomatous tissue, (2) complete absence of any cellular atypia, (3) lack of osteoclastic response and lack of dystrophic calcifications, (4) evidence of progressive resorption of native bone, (5) no evidence of expansive or ulcerative lesion, (6) lack of visceral involvement, (7) osteolytic radiographic pattern, and (8) no concrete diagnosis after hereditary, metabolic, neoplastic, immunologic, and infectious work-up.^4-6 These criteria confirm that the diagnosis can be rendered only after exclusion of neoplastic and infectious etiologies through clinical and laboratory work-up, imaging studies, and tissue sampling.

Tissue biopsy is indicated to rule out other potential etiologies of osteolysis, and the histologic findings help confirm a diagnosis of Gorham disease.

Treatment

Surgical treatment usually includes lesion resection and subsequent reconstruction using combinations of bone grafts (allogenic) and prostheses. Bone graft alone is quickly resorbed and has not been found to be beneficial.^1,2,4,20

Take-Home Points

• Gorham disease is a rare condition that manifests as an acute, spontaneous osteolysis.
• There is no clear hereditary pattern of transmission. Bones of any type or location can be affected.
• Imaging studies are nonspecific, but show permeative osteolysis involving the subcortical and intramedullary regions and typically affect regional, contiguous bones, without adjacent sclerosis, somewhat resembling osteoporosis.
• Tissue biopsy is indicated to rule out other potential etiologies of osteolysis, and the histologic findings help confirm a diagnosis of Gorham disease.
• There is no single or combined treatment modality that is considered as the gold standard. Surgical treatment includes resection of the lesion and reconstruction. Also, antiosteoclastic medication can be used.

Gorham disease, a rare condition of unknown etiology, manifests as acute, spontaneous osteolysis associated with benign hemangiomatosis or lymphangiomatosis, which presents as skeletal lucency on radiographs, prompting the classic eponym of vanishing bone disease.^1-6 There is no evidence supporting the idea that osteoclasts are present in any meaningful amount in the resorption areas or that local reparative osteogenesis occurs.^4,6

Jackson and colleagues first described idiopathic osteolysis in 1838,^1,2 and Gorham and Stout³ introduced the syndrome to the orthopedic community in 1955. Since then, few strides have been made in identifying the disease origin.^1,2,4 Diagnosis is possible only after meticulous work-up has excluded neoplastic and infectious etiologies.^7,8

Clinical Presentation

Gorham disease affects patients ranging widely in age, from 2 months to 78 years, but typically presents in those under 40 years. There is a questionable predilection for males but no correlation with ethnicity or geographic region. There is no clear hereditary pattern of transmission.⁷ Although the bones of the head, neck, and upper extremities are involved in most cases, bone of any type or location can be affected.⁶ Pelvic bones seem to be involved least often.^6,7

Initial clinical presentation varies considerably but typically involves prolonged soreness in the affected region and, rarely, acute pathologic fracture.^1,2,4 The nonspecific nature of complaints, lack of markers of systemic illness, and rarity of the disease contribute to delayed diagnosis.^1,2

Imaging

Computed tomography (CT) better defines the severity and extent of these changes.

Diagnosis

There have been 8 histologic and clinical criteria described to diagnose Gorham disease: (1) biopsy positive for presence of angiomatous tissue, (2) complete absence of any cellular atypia, (3) lack of osteoclastic response and lack of dystrophic calcifications, (4) evidence of progressive resorption of native bone, (5) no evidence of expansive or ulcerative lesion, (6) lack of visceral involvement, (7) osteolytic radiographic pattern, and (8) no concrete diagnosis after hereditary, metabolic, neoplastic, immunologic, and infectious work-up.^4-6 These criteria confirm that the diagnosis can be rendered only after exclusion of neoplastic and infectious etiologies through clinical and laboratory work-up, imaging studies, and tissue sampling.

Tissue biopsy is indicated to rule out other potential etiologies of osteolysis, and the histologic findings help confirm a diagnosis of Gorham disease.

Treatment

Surgical treatment usually includes lesion resection and subsequent reconstruction using combinations of bone grafts (allogenic) and prostheses. Bone graft alone is quickly resorbed and has not been found to be beneficial.^1,2,4,20

Take-Home Points

• Gorham disease is a rare condition that manifests as an acute, spontaneous osteolysis.
• There is no clear hereditary pattern of transmission. Bones of any type or location can be affected.
• Imaging studies are nonspecific, but show permeative osteolysis involving the subcortical and intramedullary regions and typically affect regional, contiguous bones, without adjacent sclerosis, somewhat resembling osteoporosis.
• Tissue biopsy is indicated to rule out other potential etiologies of osteolysis, and the histologic findings help confirm a diagnosis of Gorham disease.
• There is no single or combined treatment modality that is considered as the gold standard. Surgical treatment includes resection of the lesion and reconstruction. Also, antiosteoclastic medication can be used.

Gorham disease, a rare condition of unknown etiology, manifests as acute, spontaneous osteolysis associated with benign hemangiomatosis or lymphangiomatosis, which presents as skeletal lucency on radiographs, prompting the classic eponym of vanishing bone disease.^1-6 There is no evidence supporting the idea that osteoclasts are present in any meaningful amount in the resorption areas or that local reparative osteogenesis occurs.^4,6

Jackson and colleagues first described idiopathic osteolysis in 1838,^1,2 and Gorham and Stout³ introduced the syndrome to the orthopedic community in 1955. Since then, few strides have been made in identifying the disease origin.^1,2,4 Diagnosis is possible only after meticulous work-up has excluded neoplastic and infectious etiologies.^7,8

Clinical Presentation

Gorham disease affects patients ranging widely in age, from 2 months to 78 years, but typically presents in those under 40 years. There is a questionable predilection for males but no correlation with ethnicity or geographic region. There is no clear hereditary pattern of transmission.⁷ Although the bones of the head, neck, and upper extremities are involved in most cases, bone of any type or location can be affected.⁶ Pelvic bones seem to be involved least often.^6,7

Initial clinical presentation varies considerably but typically involves prolonged soreness in the affected region and, rarely, acute pathologic fracture.^1,2,4 The nonspecific nature of complaints, lack of markers of systemic illness, and rarity of the disease contribute to delayed diagnosis.^1,2

Imaging

Computed tomography (CT) better defines the severity and extent of these changes.

Diagnosis

There have been 8 histologic and clinical criteria described to diagnose Gorham disease: (1) biopsy positive for presence of angiomatous tissue, (2) complete absence of any cellular atypia, (3) lack of osteoclastic response and lack of dystrophic calcifications, (4) evidence of progressive resorption of native bone, (5) no evidence of expansive or ulcerative lesion, (6) lack of visceral involvement, (7) osteolytic radiographic pattern, and (8) no concrete diagnosis after hereditary, metabolic, neoplastic, immunologic, and infectious work-up.^4-6 These criteria confirm that the diagnosis can be rendered only after exclusion of neoplastic and infectious etiologies through clinical and laboratory work-up, imaging studies, and tissue sampling.

Tissue biopsy is indicated to rule out other potential etiologies of osteolysis, and the histologic findings help confirm a diagnosis of Gorham disease.

Treatment

Surgical treatment usually includes lesion resection and subsequent reconstruction using combinations of bone grafts (allogenic) and prostheses. Bone graft alone is quickly resorbed and has not been found to be beneficial.^1,2,4,20

Photo courtesy of ASH

ATLANTA—Two novel prognostic scoring systems can help clinicians decide how to treat certain patients with primary myelofibrosis (PMF), according to a new study.

The scoring systems, which build upon the International Prognostic Scoring System (IPSS), were developed for use in PMF patients age 70 and younger who are potential candidates for hematopoietic stem cell transplant (HSCT).

One of the scoring systems—MIPSS70—integrates clinical, histologic, and molecular information. The other—MIPSS70-plus—also includes cytogenetic information.

Alessandro M. Vannucchi, MD, of the University of Florence in Italy, presented details on these prognostic scoring systems at the 2017 ASH Annual Meeting (abstract 200*).

The information was published simultaneously in the Journal of Clinical Oncology.

Dr Vannucchi noted that, in PMF, survival is currently predicted by the IPSS, the dynamic IPSS, and the dynamic IPSS-plus.

“The IPSS score is used at the time of diagnosis, while the dynamic IPSS or dynamic IPSS-plus are used to provide survival estimates at the time of patient referral,” he explained. “In clinical practice, these prognostic risk scores are mainly used for [HSCT] decision-making in younger patients.”

Driver mutations and other myeloid neoplasm-associated mutations provide prognostic information that is independent of the IPSS/dynamic IPSS/dynamic IPSS-plus scoring systems.

The degree of bone marrow fibrosis and cytogenetic abnormalities configuring an unfavorable category also contribute prognostic information that is independent of these scoring systems.

With this in mind, Dr Vannucchi and his colleagues set out to develop an updated prognostic score that included molecular information (MIPSS70) and, if possible, cytogenetic information (MIPSS70-plus) for PMF patients age 70 and younger who are potential candidates for HSCT.

The researchers developed 2 prognostic models using a training/validation cohort approach.

For MIPSS70, the training cohort included 490 patients from 6 Italian institutions associated with the Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative project (AGIMM group), and the validation cohort included 211 patients from the Mayo Clinic in Rochester, Minnesota.

For MIPSS70-plus, the training cohort included 315 patients from the Mayo Clinic, and the validation cohort included 261 patients from the AGIMM group.

Using the MIPSS70 risk score in the validation cohort, the 5-year overall survival rate was 96% in low-risk, 67% in intermediate-risk, and 34% in high-risk patients.

“MIPSS70 performed better than IPSS in predicting survival,” Dr Vannucchi said. “About 30% of patients who were high-risk with MIPPS70 were missed by IPSS.”

Using the MIPSS70-plus risk score in the validation cohort, the 5-year overall survival rate was 100% in low-risk, 90% in intermediate-risk, 76% in high-risk, and 46.5% in very high-risk patients.

The MIPSS70-plus risk score also identified patients at very high risk for leukemic transformation, Dr Vannucchi said.

Furthermore, both MIPSS70 and MIPSS70-plus remained predictive of survival when the researchers evaluated patients older than 70 years of age.

“The new MIPSS70 and MIPSS70-plus scores include modern disease-associated risk variables pertinent to both pre-PMF and overt-PMF according to the 2016 WHO classification,” Dr Vannucchi said. “They integrate prognostically relevant clinical, cytogenetic, and mutation data and provide complementary systems of improved risk stratification for transplantation-age patients with PMF.”

Dr Vannucchi disclosed membership in speaker’s bureaus with Gilead, Shire, and Novartis, and research funding and membership on Board of Directors or advisory committees with Novartis.

*Data in the presentation differ from the abstract. 

Photo courtesy of ASH

ATLANTA—Two novel prognostic scoring systems can help clinicians decide how to treat certain patients with primary myelofibrosis (PMF), according to a new study.

The scoring systems, which build upon the International Prognostic Scoring System (IPSS), were developed for use in PMF patients age 70 and younger who are potential candidates for hematopoietic stem cell transplant (HSCT).

One of the scoring systems—MIPSS70—integrates clinical, histologic, and molecular information. The other—MIPSS70-plus—also includes cytogenetic information.

Alessandro M. Vannucchi, MD, of the University of Florence in Italy, presented details on these prognostic scoring systems at the 2017 ASH Annual Meeting (abstract 200*).

The information was published simultaneously in the Journal of Clinical Oncology.

Dr Vannucchi noted that, in PMF, survival is currently predicted by the IPSS, the dynamic IPSS, and the dynamic IPSS-plus.

“The IPSS score is used at the time of diagnosis, while the dynamic IPSS or dynamic IPSS-plus are used to provide survival estimates at the time of patient referral,” he explained. “In clinical practice, these prognostic risk scores are mainly used for [HSCT] decision-making in younger patients.”

Driver mutations and other myeloid neoplasm-associated mutations provide prognostic information that is independent of the IPSS/dynamic IPSS/dynamic IPSS-plus scoring systems.

The degree of bone marrow fibrosis and cytogenetic abnormalities configuring an unfavorable category also contribute prognostic information that is independent of these scoring systems.

With this in mind, Dr Vannucchi and his colleagues set out to develop an updated prognostic score that included molecular information (MIPSS70) and, if possible, cytogenetic information (MIPSS70-plus) for PMF patients age 70 and younger who are potential candidates for HSCT.

The researchers developed 2 prognostic models using a training/validation cohort approach.

For MIPSS70, the training cohort included 490 patients from 6 Italian institutions associated with the Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative project (AGIMM group), and the validation cohort included 211 patients from the Mayo Clinic in Rochester, Minnesota.

For MIPSS70-plus, the training cohort included 315 patients from the Mayo Clinic, and the validation cohort included 261 patients from the AGIMM group.

Using the MIPSS70 risk score in the validation cohort, the 5-year overall survival rate was 96% in low-risk, 67% in intermediate-risk, and 34% in high-risk patients.

“MIPSS70 performed better than IPSS in predicting survival,” Dr Vannucchi said. “About 30% of patients who were high-risk with MIPPS70 were missed by IPSS.”

Using the MIPSS70-plus risk score in the validation cohort, the 5-year overall survival rate was 100% in low-risk, 90% in intermediate-risk, 76% in high-risk, and 46.5% in very high-risk patients.

The MIPSS70-plus risk score also identified patients at very high risk for leukemic transformation, Dr Vannucchi said.

Furthermore, both MIPSS70 and MIPSS70-plus remained predictive of survival when the researchers evaluated patients older than 70 years of age.

“The new MIPSS70 and MIPSS70-plus scores include modern disease-associated risk variables pertinent to both pre-PMF and overt-PMF according to the 2016 WHO classification,” Dr Vannucchi said. “They integrate prognostically relevant clinical, cytogenetic, and mutation data and provide complementary systems of improved risk stratification for transplantation-age patients with PMF.”

Dr Vannucchi disclosed membership in speaker’s bureaus with Gilead, Shire, and Novartis, and research funding and membership on Board of Directors or advisory committees with Novartis.

*Data in the presentation differ from the abstract. 

Photo courtesy of ASH

ATLANTA—Two novel prognostic scoring systems can help clinicians decide how to treat certain patients with primary myelofibrosis (PMF), according to a new study.

The scoring systems, which build upon the International Prognostic Scoring System (IPSS), were developed for use in PMF patients age 70 and younger who are potential candidates for hematopoietic stem cell transplant (HSCT).

One of the scoring systems—MIPSS70—integrates clinical, histologic, and molecular information. The other—MIPSS70-plus—also includes cytogenetic information.

Alessandro M. Vannucchi, MD, of the University of Florence in Italy, presented details on these prognostic scoring systems at the 2017 ASH Annual Meeting (abstract 200*).

The information was published simultaneously in the Journal of Clinical Oncology.

Dr Vannucchi noted that, in PMF, survival is currently predicted by the IPSS, the dynamic IPSS, and the dynamic IPSS-plus.

“The IPSS score is used at the time of diagnosis, while the dynamic IPSS or dynamic IPSS-plus are used to provide survival estimates at the time of patient referral,” he explained. “In clinical practice, these prognostic risk scores are mainly used for [HSCT] decision-making in younger patients.”

Driver mutations and other myeloid neoplasm-associated mutations provide prognostic information that is independent of the IPSS/dynamic IPSS/dynamic IPSS-plus scoring systems.

The degree of bone marrow fibrosis and cytogenetic abnormalities configuring an unfavorable category also contribute prognostic information that is independent of these scoring systems.

With this in mind, Dr Vannucchi and his colleagues set out to develop an updated prognostic score that included molecular information (MIPSS70) and, if possible, cytogenetic information (MIPSS70-plus) for PMF patients age 70 and younger who are potential candidates for HSCT.

The researchers developed 2 prognostic models using a training/validation cohort approach.

For MIPSS70, the training cohort included 490 patients from 6 Italian institutions associated with the Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative project (AGIMM group), and the validation cohort included 211 patients from the Mayo Clinic in Rochester, Minnesota.

For MIPSS70-plus, the training cohort included 315 patients from the Mayo Clinic, and the validation cohort included 261 patients from the AGIMM group.

Using the MIPSS70 risk score in the validation cohort, the 5-year overall survival rate was 96% in low-risk, 67% in intermediate-risk, and 34% in high-risk patients.

“MIPSS70 performed better than IPSS in predicting survival,” Dr Vannucchi said. “About 30% of patients who were high-risk with MIPPS70 were missed by IPSS.”

Using the MIPSS70-plus risk score in the validation cohort, the 5-year overall survival rate was 100% in low-risk, 90% in intermediate-risk, 76% in high-risk, and 46.5% in very high-risk patients.

The MIPSS70-plus risk score also identified patients at very high risk for leukemic transformation, Dr Vannucchi said.

Furthermore, both MIPSS70 and MIPSS70-plus remained predictive of survival when the researchers evaluated patients older than 70 years of age.

“The new MIPSS70 and MIPSS70-plus scores include modern disease-associated risk variables pertinent to both pre-PMF and overt-PMF according to the 2016 WHO classification,” Dr Vannucchi said. “They integrate prognostically relevant clinical, cytogenetic, and mutation data and provide complementary systems of improved risk stratification for transplantation-age patients with PMF.”

Dr Vannucchi disclosed membership in speaker’s bureaus with Gilead, Shire, and Novartis, and research funding and membership on Board of Directors or advisory committees with Novartis.

*Data in the presentation differ from the abstract. 

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has granted orphan drug and fast track designations to tenalisib (RP6530) for the treatment of peripheral T-cell lymphoma (PTCL).

Tenalisib is a dual PI3K delta/gamma inhibitor being developed by Rhizen Pharmaceuticals.

Research has shown that tenalisib inhibits the growth of immortalized cancerous cell lines and primary leukemia/lymphoma cells.

In preclinical studies, tenalisib reprogrammed macrophages from an immunosuppressive M2-like phenotype (pro-tumor) to an inflammatory M1-like state (anti-tumor).

Researchers are currently conducting a phase 1 study of tenalisib in patients with relapsed/refractory PTCL. Results from this study were presented at the 2017 ASH Annual Meeting (abstract 2791*).

The presentation included data on 50 patients—24 with PTCL and 26 with cutaneous T-cell lymphoma (CTCL).

For the PTCL patients, the median age was 63 (range, 40-89), and 67% were male. The median number of prior therapies was 3 (range, 1-7). All patients had an ECOG status of 0 (n=14) or 1 (n=10). More patients had relapsed disease (n=17, 58%) than refractory disease (n=10, 42%).

For the CTCL patients, the median age was 67 (range, 37-84), and 46% were male. The median number of prior therapies was 5.5 (range, 2-15). All patients had an ECOG status of 0 (n=23) or 1 (n=3). More patients had refractory disease (n=15, 58%) than relapsed disease (n=11, 42%).

In the dose-escalation portion of the study, patients received tenalisib at 200 mg twice daily (BID), 400 mg BID, 800 mg BID fasting, or 800 mg BID fed. The maximum tolerated dose was 800 mg BID fasting, so this dose is being used in the expansion cohort.

Twelve PTCL patients were evaluable for efficacy. The overall response rate in these patients was 58% (7/12), with a 25% complete response rate (3/12).

Sixteen CTCL patients were evaluable for efficacy. The overall response rate was 56% (9/16). All responders had partial responses.

In both PTCL and CTCL patients, treatment-related grade 3 or higher adverse events (AEs) included transaminitis (22%), rash (6%), neutropenia (6%), hypophosphatemia (2%), increased international normalized ratio (2%), diplopia secondary to neuropathy (2%), and sepsis (2%).

Treatment-related serious AEs included sepsis, increased international normalized ratio, diplopia secondary to neuropathy, and pyrexia. Five patients discontinued treatment due to AEs.

About orphan and fast track designations

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

The FDA’s fast track drug development program is designed to expedite clinical development and submission of new drug applications for medicines with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss all aspects of development to support a drug’s approval, and also provides the opportunity to submit sections of a new drug application on a rolling basis as data become available.

*Data in the abstract differ from the presentation.

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has granted orphan drug and fast track designations to tenalisib (RP6530) for the treatment of peripheral T-cell lymphoma (PTCL).

Tenalisib is a dual PI3K delta/gamma inhibitor being developed by Rhizen Pharmaceuticals.

Research has shown that tenalisib inhibits the growth of immortalized cancerous cell lines and primary leukemia/lymphoma cells.

In preclinical studies, tenalisib reprogrammed macrophages from an immunosuppressive M2-like phenotype (pro-tumor) to an inflammatory M1-like state (anti-tumor).

Researchers are currently conducting a phase 1 study of tenalisib in patients with relapsed/refractory PTCL. Results from this study were presented at the 2017 ASH Annual Meeting (abstract 2791*).

The presentation included data on 50 patients—24 with PTCL and 26 with cutaneous T-cell lymphoma (CTCL).

For the PTCL patients, the median age was 63 (range, 40-89), and 67% were male. The median number of prior therapies was 3 (range, 1-7). All patients had an ECOG status of 0 (n=14) or 1 (n=10). More patients had relapsed disease (n=17, 58%) than refractory disease (n=10, 42%).

For the CTCL patients, the median age was 67 (range, 37-84), and 46% were male. The median number of prior therapies was 5.5 (range, 2-15). All patients had an ECOG status of 0 (n=23) or 1 (n=3). More patients had refractory disease (n=15, 58%) than relapsed disease (n=11, 42%).

In the dose-escalation portion of the study, patients received tenalisib at 200 mg twice daily (BID), 400 mg BID, 800 mg BID fasting, or 800 mg BID fed. The maximum tolerated dose was 800 mg BID fasting, so this dose is being used in the expansion cohort.

Twelve PTCL patients were evaluable for efficacy. The overall response rate in these patients was 58% (7/12), with a 25% complete response rate (3/12).

Sixteen CTCL patients were evaluable for efficacy. The overall response rate was 56% (9/16). All responders had partial responses.

In both PTCL and CTCL patients, treatment-related grade 3 or higher adverse events (AEs) included transaminitis (22%), rash (6%), neutropenia (6%), hypophosphatemia (2%), increased international normalized ratio (2%), diplopia secondary to neuropathy (2%), and sepsis (2%).

Treatment-related serious AEs included sepsis, increased international normalized ratio, diplopia secondary to neuropathy, and pyrexia. Five patients discontinued treatment due to AEs.

About orphan and fast track designations

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

The FDA’s fast track drug development program is designed to expedite clinical development and submission of new drug applications for medicines with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss all aspects of development to support a drug’s approval, and also provides the opportunity to submit sections of a new drug application on a rolling basis as data become available.

*Data in the abstract differ from the presentation.

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has granted orphan drug and fast track designations to tenalisib (RP6530) for the treatment of peripheral T-cell lymphoma (PTCL).

Tenalisib is a dual PI3K delta/gamma inhibitor being developed by Rhizen Pharmaceuticals.

Research has shown that tenalisib inhibits the growth of immortalized cancerous cell lines and primary leukemia/lymphoma cells.

In preclinical studies, tenalisib reprogrammed macrophages from an immunosuppressive M2-like phenotype (pro-tumor) to an inflammatory M1-like state (anti-tumor).

Researchers are currently conducting a phase 1 study of tenalisib in patients with relapsed/refractory PTCL. Results from this study were presented at the 2017 ASH Annual Meeting (abstract 2791*).

The presentation included data on 50 patients—24 with PTCL and 26 with cutaneous T-cell lymphoma (CTCL).

For the PTCL patients, the median age was 63 (range, 40-89), and 67% were male. The median number of prior therapies was 3 (range, 1-7). All patients had an ECOG status of 0 (n=14) or 1 (n=10). More patients had relapsed disease (n=17, 58%) than refractory disease (n=10, 42%).

For the CTCL patients, the median age was 67 (range, 37-84), and 46% were male. The median number of prior therapies was 5.5 (range, 2-15). All patients had an ECOG status of 0 (n=23) or 1 (n=3). More patients had refractory disease (n=15, 58%) than relapsed disease (n=11, 42%).

In the dose-escalation portion of the study, patients received tenalisib at 200 mg twice daily (BID), 400 mg BID, 800 mg BID fasting, or 800 mg BID fed. The maximum tolerated dose was 800 mg BID fasting, so this dose is being used in the expansion cohort.

Twelve PTCL patients were evaluable for efficacy. The overall response rate in these patients was 58% (7/12), with a 25% complete response rate (3/12).

Sixteen CTCL patients were evaluable for efficacy. The overall response rate was 56% (9/16). All responders had partial responses.

In both PTCL and CTCL patients, treatment-related grade 3 or higher adverse events (AEs) included transaminitis (22%), rash (6%), neutropenia (6%), hypophosphatemia (2%), increased international normalized ratio (2%), diplopia secondary to neuropathy (2%), and sepsis (2%).

Treatment-related serious AEs included sepsis, increased international normalized ratio, diplopia secondary to neuropathy, and pyrexia. Five patients discontinued treatment due to AEs.

About orphan and fast track designations

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

The FDA’s fast track drug development program is designed to expedite clinical development and submission of new drug applications for medicines with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss all aspects of development to support a drug’s approval, and also provides the opportunity to submit sections of a new drug application on a rolling basis as data become available.

*Data in the abstract differ from the presentation.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted orphan drug designation to CG’806 for the treatment of patients with acute myeloid leukemia (AML).

CG’806 is an oral, first-in-class pan-FLT3/pan-BTK inhibitor being developed by Aptose Biosciences Inc.

In preclinical studies, CG’806 inhibited all wild-type and mutant forms of FLT3 tested, suppressed multiple oncogenic pathways operative in AML, and eliminated AML tumors (without toxicity) in murine xenograft models.

In addition, CG’806 demonstrated non-covalent inhibition of the wild-type and Cys481Ser mutant forms of the BTK enzyme, as well as other oncogenic kinases operative in B-cell malignancies.

Preclinical results with CG’806 were presented as posters at the AACR conference “Hematologic Malignancies: Translating Discoveries to Novel Therapies,” which took place last May.

“Results from non-clinical studies that we and our research collaborators have generated are promising and give reason for our eagerness to begin clinical trials in both AML and B-cell malignancies in 2018,” said William G. Rice, PhD, chairman, president, and chief executive officer at Aptose.

“We are pleased that the FDA has recognized the unique potential of CG’806 to address AML and has assigned CG’806 the status of orphan drug designation.”

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted orphan drug designation to CG’806 for the treatment of patients with acute myeloid leukemia (AML).

CG’806 is an oral, first-in-class pan-FLT3/pan-BTK inhibitor being developed by Aptose Biosciences Inc.

In preclinical studies, CG’806 inhibited all wild-type and mutant forms of FLT3 tested, suppressed multiple oncogenic pathways operative in AML, and eliminated AML tumors (without toxicity) in murine xenograft models.

In addition, CG’806 demonstrated non-covalent inhibition of the wild-type and Cys481Ser mutant forms of the BTK enzyme, as well as other oncogenic kinases operative in B-cell malignancies.

Preclinical results with CG’806 were presented as posters at the AACR conference “Hematologic Malignancies: Translating Discoveries to Novel Therapies,” which took place last May.

“Results from non-clinical studies that we and our research collaborators have generated are promising and give reason for our eagerness to begin clinical trials in both AML and B-cell malignancies in 2018,” said William G. Rice, PhD, chairman, president, and chief executive officer at Aptose.

“We are pleased that the FDA has recognized the unique potential of CG’806 to address AML and has assigned CG’806 the status of orphan drug designation.”

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted orphan drug designation to CG’806 for the treatment of patients with acute myeloid leukemia (AML).

CG’806 is an oral, first-in-class pan-FLT3/pan-BTK inhibitor being developed by Aptose Biosciences Inc.

In preclinical studies, CG’806 inhibited all wild-type and mutant forms of FLT3 tested, suppressed multiple oncogenic pathways operative in AML, and eliminated AML tumors (without toxicity) in murine xenograft models.

In addition, CG’806 demonstrated non-covalent inhibition of the wild-type and Cys481Ser mutant forms of the BTK enzyme, as well as other oncogenic kinases operative in B-cell malignancies.

Preclinical results with CG’806 were presented as posters at the AACR conference “Hematologic Malignancies: Translating Discoveries to Novel Therapies,” which took place last May.

“Results from non-clinical studies that we and our research collaborators have generated are promising and give reason for our eagerness to begin clinical trials in both AML and B-cell malignancies in 2018,” said William G. Rice, PhD, chairman, president, and chief executive officer at Aptose.

“We are pleased that the FDA has recognized the unique potential of CG’806 to address AML and has assigned CG’806 the status of orphan drug designation.”

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Clinical question: Does azithromycin decrease the frequency of asthma exacerbations in adults with persistent asthma symptoms despite use of inhaled corticosteroid (ICS) and a long-acting beta-agonist (LABA)?

Background: Asthma is a chronic inflammatory airway disease that is highly prevalent worldwide within a subset of people with asthma who have symptoms that are poorly controlled despite ICS and LABA maintenance therapy. Currently, add-on therapy options include monoclonal antibodies, which are cost prohibitive. The need for additional therapeutic options exists. At the same time, macrolide antibiotics are known to have anti-inflammatory, antiviral, and antibacterial effects and have proven to have beneficial effects on asthma symptoms.

Dr. Farber is a medical instructor, Duke University Health System.

Clinical question: Does azithromycin decrease the frequency of asthma exacerbations in adults with persistent asthma symptoms despite use of inhaled corticosteroid (ICS) and a long-acting beta-agonist (LABA)?

Background: Asthma is a chronic inflammatory airway disease that is highly prevalent worldwide within a subset of people with asthma who have symptoms that are poorly controlled despite ICS and LABA maintenance therapy. Currently, add-on therapy options include monoclonal antibodies, which are cost prohibitive. The need for additional therapeutic options exists. At the same time, macrolide antibiotics are known to have anti-inflammatory, antiviral, and antibacterial effects and have proven to have beneficial effects on asthma symptoms.

Dr. Farber is a medical instructor, Duke University Health System.

Clinical question: Does azithromycin decrease the frequency of asthma exacerbations in adults with persistent asthma symptoms despite use of inhaled corticosteroid (ICS) and a long-acting beta-agonist (LABA)?

Background: Asthma is a chronic inflammatory airway disease that is highly prevalent worldwide within a subset of people with asthma who have symptoms that are poorly controlled despite ICS and LABA maintenance therapy. Currently, add-on therapy options include monoclonal antibodies, which are cost prohibitive. The need for additional therapeutic options exists. At the same time, macrolide antibiotics are known to have anti-inflammatory, antiviral, and antibacterial effects and have proven to have beneficial effects on asthma symptoms.

Dr. Farber is a medical instructor, Duke University Health System.

SAN ANTONIO – Axillary dissection can be avoided in patients with early breast cancer and limited sentinel node involvement, investigators reported at the San Antonio Breast Cancer Symposium.

Both disease-free survival (DFS) and overall survival (OS) were similar in a population of patients with cT1-T2 N0M0 breast cancer and sentinel node micrometastases who underwent axillary dissection (AD), compared with those who did not. Complications associated with axillary surgery can be avoided in this population, without any adverse effect on survival.

“Our findings are fully consistent with those of the Z0011 trial, which after 10 years found no differences between the AD and no-AD groups for any endpoint in patients with moderate disease burden in the axilla undergoing conservative breast surgery,” said study author Viviana Galimberti, MD, of the European Institute of Oncology in Milan.

In the ACOSOG Z0011, trial, the use of sentinel node biopsy alone was not inferior to AD in patients with limited sentinel node metastasis treated with breast conservation and systemic therapy.

“We also suggest that non-AD is acceptable treatment in patients scheduled for mastectomy,” Dr. Galimberti said.

For patients with breast cancer and metastases in the sentinel nodes, AD has been the standard of care, but for those with limited sentinel node involvement, it was hypothesized that AD might not be necessary.

The phase 3 IBCSG 23-01 study was a multicenter, randomized, noninferiority trial that compared DFS in breast cancer patients with one or more micrometastases (greater than or equal to 2 mm) in the sentinel nodes who were randomized to either AD or no axillary dissection (no-AD). The 5-year results, which were published in 2013 in the Lancet Oncology (2013 Jun;14[7]:e251-2) showed no difference in DFS between the two groups.

At the meeting, Dr. Galimberti reported on outcomes after an extended median follow-up of 9.8 years. A cohort of 934 women (931 evaluable) were enrolled from 27 centers from 2001 to 2010 and randomized to either AD or no AD (467 in the no-AD group and 464 in the AD group).

The results were similar to those reported at 5 years. The 10-year DFS rates were similar for both cohorts; 77% for non-AD vs. 75% for AD (hazard ratio [no-AD vs. AD], 0.85; 95% confidence interval, 0.65-1.11; log-rank P = .23; noninferiority P = .002).

The rate of axillary failure in the no-AD group was low, Dr. Galimberti pointed out, at 1.7% and 0.8% among women who underwent breast-conserving surgery. There were nine ipsilateral axillary events in the no-AD group vs. three in the AD group, and 45 deaths in the no-AD group vs. 58 in the AD group. The 10-year OS was 91% (95% CI, 88%-94%) in the no-AD group and 88% (95% CI, 85%-92%) in the AD group (HR [no-AD vs. AD], 0.77; 95% CI, 0.56-1.07; log-rank P = .19).

There was no difference between groups for the main endpoint of DFS or the secondary endpoint of OS, said Dr. Galimberti.

In subgroup analyses, which included tumor size, estrogen-receptor status, progesterone-receptor status, tumor grade, and type of surgery, there were no subgroups identified that benefited from AD over no-AD.

“Our data fully support the change in clinical practice that started after the early published results,” Dr Galimberti concluded. “No AD is now standard treatment in early breast cancer when the sentinel node is only minimally involved.”

The study received no outside funding and the authors had no disclosures.

SOURCE: Galimberti et al. SABCS Abstract GS5-02

SAN ANTONIO – Axillary dissection can be avoided in patients with early breast cancer and limited sentinel node involvement, investigators reported at the San Antonio Breast Cancer Symposium.

Both disease-free survival (DFS) and overall survival (OS) were similar in a population of patients with cT1-T2 N0M0 breast cancer and sentinel node micrometastases who underwent axillary dissection (AD), compared with those who did not. Complications associated with axillary surgery can be avoided in this population, without any adverse effect on survival.

“Our findings are fully consistent with those of the Z0011 trial, which after 10 years found no differences between the AD and no-AD groups for any endpoint in patients with moderate disease burden in the axilla undergoing conservative breast surgery,” said study author Viviana Galimberti, MD, of the European Institute of Oncology in Milan.

In the ACOSOG Z0011, trial, the use of sentinel node biopsy alone was not inferior to AD in patients with limited sentinel node metastasis treated with breast conservation and systemic therapy.

“We also suggest that non-AD is acceptable treatment in patients scheduled for mastectomy,” Dr. Galimberti said.

For patients with breast cancer and metastases in the sentinel nodes, AD has been the standard of care, but for those with limited sentinel node involvement, it was hypothesized that AD might not be necessary.

The phase 3 IBCSG 23-01 study was a multicenter, randomized, noninferiority trial that compared DFS in breast cancer patients with one or more micrometastases (greater than or equal to 2 mm) in the sentinel nodes who were randomized to either AD or no axillary dissection (no-AD). The 5-year results, which were published in 2013 in the Lancet Oncology (2013 Jun;14[7]:e251-2) showed no difference in DFS between the two groups.

At the meeting, Dr. Galimberti reported on outcomes after an extended median follow-up of 9.8 years. A cohort of 934 women (931 evaluable) were enrolled from 27 centers from 2001 to 2010 and randomized to either AD or no AD (467 in the no-AD group and 464 in the AD group).

The results were similar to those reported at 5 years. The 10-year DFS rates were similar for both cohorts; 77% for non-AD vs. 75% for AD (hazard ratio [no-AD vs. AD], 0.85; 95% confidence interval, 0.65-1.11; log-rank P = .23; noninferiority P = .002).

The rate of axillary failure in the no-AD group was low, Dr. Galimberti pointed out, at 1.7% and 0.8% among women who underwent breast-conserving surgery. There were nine ipsilateral axillary events in the no-AD group vs. three in the AD group, and 45 deaths in the no-AD group vs. 58 in the AD group. The 10-year OS was 91% (95% CI, 88%-94%) in the no-AD group and 88% (95% CI, 85%-92%) in the AD group (HR [no-AD vs. AD], 0.77; 95% CI, 0.56-1.07; log-rank P = .19).

There was no difference between groups for the main endpoint of DFS or the secondary endpoint of OS, said Dr. Galimberti.

In subgroup analyses, which included tumor size, estrogen-receptor status, progesterone-receptor status, tumor grade, and type of surgery, there were no subgroups identified that benefited from AD over no-AD.

“Our data fully support the change in clinical practice that started after the early published results,” Dr Galimberti concluded. “No AD is now standard treatment in early breast cancer when the sentinel node is only minimally involved.”

The study received no outside funding and the authors had no disclosures.

SOURCE: Galimberti et al. SABCS Abstract GS5-02

SAN ANTONIO – Axillary dissection can be avoided in patients with early breast cancer and limited sentinel node involvement, investigators reported at the San Antonio Breast Cancer Symposium.

Both disease-free survival (DFS) and overall survival (OS) were similar in a population of patients with cT1-T2 N0M0 breast cancer and sentinel node micrometastases who underwent axillary dissection (AD), compared with those who did not. Complications associated with axillary surgery can be avoided in this population, without any adverse effect on survival.

“Our findings are fully consistent with those of the Z0011 trial, which after 10 years found no differences between the AD and no-AD groups for any endpoint in patients with moderate disease burden in the axilla undergoing conservative breast surgery,” said study author Viviana Galimberti, MD, of the European Institute of Oncology in Milan.

In the ACOSOG Z0011, trial, the use of sentinel node biopsy alone was not inferior to AD in patients with limited sentinel node metastasis treated with breast conservation and systemic therapy.

“We also suggest that non-AD is acceptable treatment in patients scheduled for mastectomy,” Dr. Galimberti said.

For patients with breast cancer and metastases in the sentinel nodes, AD has been the standard of care, but for those with limited sentinel node involvement, it was hypothesized that AD might not be necessary.

The phase 3 IBCSG 23-01 study was a multicenter, randomized, noninferiority trial that compared DFS in breast cancer patients with one or more micrometastases (greater than or equal to 2 mm) in the sentinel nodes who were randomized to either AD or no axillary dissection (no-AD). The 5-year results, which were published in 2013 in the Lancet Oncology (2013 Jun;14[7]:e251-2) showed no difference in DFS between the two groups.

At the meeting, Dr. Galimberti reported on outcomes after an extended median follow-up of 9.8 years. A cohort of 934 women (931 evaluable) were enrolled from 27 centers from 2001 to 2010 and randomized to either AD or no AD (467 in the no-AD group and 464 in the AD group).

The results were similar to those reported at 5 years. The 10-year DFS rates were similar for both cohorts; 77% for non-AD vs. 75% for AD (hazard ratio [no-AD vs. AD], 0.85; 95% confidence interval, 0.65-1.11; log-rank P = .23; noninferiority P = .002).

The rate of axillary failure in the no-AD group was low, Dr. Galimberti pointed out, at 1.7% and 0.8% among women who underwent breast-conserving surgery. There were nine ipsilateral axillary events in the no-AD group vs. three in the AD group, and 45 deaths in the no-AD group vs. 58 in the AD group. The 10-year OS was 91% (95% CI, 88%-94%) in the no-AD group and 88% (95% CI, 85%-92%) in the AD group (HR [no-AD vs. AD], 0.77; 95% CI, 0.56-1.07; log-rank P = .19).

There was no difference between groups for the main endpoint of DFS or the secondary endpoint of OS, said Dr. Galimberti.

In subgroup analyses, which included tumor size, estrogen-receptor status, progesterone-receptor status, tumor grade, and type of surgery, there were no subgroups identified that benefited from AD over no-AD.

“Our data fully support the change in clinical practice that started after the early published results,” Dr Galimberti concluded. “No AD is now standard treatment in early breast cancer when the sentinel node is only minimally involved.”

The study received no outside funding and the authors had no disclosures.

SOURCE: Galimberti et al. SABCS Abstract GS5-02

ATLANTA – Daratumumab monotherapy led to durable partial responses among intermediate to high-risk patients with smoldering multiple myeloma, according to results from the phase II CENTAURUS trial.

Although less than 5% of patients had complete responses, 27% had at least a very good partial response to long-term therapy (up to 20 treatment cycles lasting 8 weeks each), Craig C. Hofmeister, MD, of the Ohio State University Comprehensive Cancer Center, Columbus, said at the annual meeting of the American Society of Hematology. The coprimary endpoint, median progression-free survival, exceeded 24 months in all dose cohorts, and was the longest when patients were treated longest.

Amy Karon/Frontline Medical News

SOURCE: Hofmeister C et al, ASH 2017, Abstract 510.

ATLANTA – Daratumumab monotherapy led to durable partial responses among intermediate to high-risk patients with smoldering multiple myeloma, according to results from the phase II CENTAURUS trial.

Although less than 5% of patients had complete responses, 27% had at least a very good partial response to long-term therapy (up to 20 treatment cycles lasting 8 weeks each), Craig C. Hofmeister, MD, of the Ohio State University Comprehensive Cancer Center, Columbus, said at the annual meeting of the American Society of Hematology. The coprimary endpoint, median progression-free survival, exceeded 24 months in all dose cohorts, and was the longest when patients were treated longest.

Amy Karon/Frontline Medical News

SOURCE: Hofmeister C et al, ASH 2017, Abstract 510.

ATLANTA – Daratumumab monotherapy led to durable partial responses among intermediate to high-risk patients with smoldering multiple myeloma, according to results from the phase II CENTAURUS trial.

Although less than 5% of patients had complete responses, 27% had at least a very good partial response to long-term therapy (up to 20 treatment cycles lasting 8 weeks each), Craig C. Hofmeister, MD, of the Ohio State University Comprehensive Cancer Center, Columbus, said at the annual meeting of the American Society of Hematology. The coprimary endpoint, median progression-free survival, exceeded 24 months in all dose cohorts, and was the longest when patients were treated longest.

Amy Karon/Frontline Medical News

SOURCE: Hofmeister C et al, ASH 2017, Abstract 510.

SAN ANTONIO – Among patients receiving trastuzumab plus lapatinib neoadjuvant therapy for HER2-positive early breast cancer, amplification of ERBB2 was predictive of a pathologic complete response (pCR), according to findings presented at the San Antonio Breast Cancer Symposium.

However, ERBB2 mRNA expression and PAM50-enriched HER2 better predicted pCR, said lead study author Cristos Sotiriou, MD, of the Breast Cancer Translational Research Laboratory at the Institut Jules Bordet in Belgium

High genomic instability was associated with a higher pCR rate in patients with estrogen receptor–positive tumors, but copy number alterations (CNAs) were not associated with event-free survival (EFS).

In the large phase 3 NeoALTTO trial, lapatinib combined with trastuzumab in the neoadjuvant setting nearly doubled the pCR rate as compared with either agent used alone. The 3-year EFS was also improved with dual HER2 blockage versus single HER2 therapy (84% for the combination, hazard ratio, 0.78; P = .33 vs. 78% for lapatinib alone and 76% for trastuzumab alone, HR, 1.06; P = .81 for both).

The researchers of this trial also found that pCR was a surrogate for long-term outcome.

“Expression of ERBB2, ESR1, and immune signatures were the main drivers of pCR,” said Dr. Sotiriou.

The main goal of the current study was to investigate the relevance of CNAs for pCR and EFS in this population. A total of 455 patients were enrolled in the NeoALTTO study, and of this cohort, 270 had tumor content that was sufficient to assay for CNAs. Tumor-infiltrating lymphocytes and gene expression were also obtained and the genome instability index was calculated, and 184 samples were included in the final analysis.

Of the cancer genes, only ERBB2 was predictive of pCR.

A total of 159 recurrent CNA regions were identified. ERBB2 amplification was associated with high pCR (P = .0007), but less than ERBB2 expression, and it lost its significance after correcting for ERBB2 expression.

The genome instability index (GII) was defined as the “median absolute deviation of the normalized copy number” and independent of ERBB2 amplification, the pCR rate increased with the GII (P = .03.

Amplification of two regions on 6q23-24 was significantly associated with higher pCR (P = .00005 and P = .00087). One of the segments harbored 39 genes, some with an expression level that was also predictive of pCR. The 6q23-24 segment was associated with pCR in estrogen receptor–positive tumors only (interaction test P = .04).

After multiple testing correction, there were no amplified regions or genes found to be predictive of EFS.

“A novel amplified region on 6q23-24 was shown to be predictive of pCR, in particular for estrogen receptor–positive tumors,” said Dr. Sotiriou. “This may warrant further investigation.”

SOURCE: Sotiriou et al. SABCS Abstract GS1-04

SAN ANTONIO – Among patients receiving trastuzumab plus lapatinib neoadjuvant therapy for HER2-positive early breast cancer, amplification of ERBB2 was predictive of a pathologic complete response (pCR), according to findings presented at the San Antonio Breast Cancer Symposium.

However, ERBB2 mRNA expression and PAM50-enriched HER2 better predicted pCR, said lead study author Cristos Sotiriou, MD, of the Breast Cancer Translational Research Laboratory at the Institut Jules Bordet in Belgium

High genomic instability was associated with a higher pCR rate in patients with estrogen receptor–positive tumors, but copy number alterations (CNAs) were not associated with event-free survival (EFS).

In the large phase 3 NeoALTTO trial, lapatinib combined with trastuzumab in the neoadjuvant setting nearly doubled the pCR rate as compared with either agent used alone. The 3-year EFS was also improved with dual HER2 blockage versus single HER2 therapy (84% for the combination, hazard ratio, 0.78; P = .33 vs. 78% for lapatinib alone and 76% for trastuzumab alone, HR, 1.06; P = .81 for both).

The researchers of this trial also found that pCR was a surrogate for long-term outcome.

“Expression of ERBB2, ESR1, and immune signatures were the main drivers of pCR,” said Dr. Sotiriou.

The main goal of the current study was to investigate the relevance of CNAs for pCR and EFS in this population. A total of 455 patients were enrolled in the NeoALTTO study, and of this cohort, 270 had tumor content that was sufficient to assay for CNAs. Tumor-infiltrating lymphocytes and gene expression were also obtained and the genome instability index was calculated, and 184 samples were included in the final analysis.

Of the cancer genes, only ERBB2 was predictive of pCR.

A total of 159 recurrent CNA regions were identified. ERBB2 amplification was associated with high pCR (P = .0007), but less than ERBB2 expression, and it lost its significance after correcting for ERBB2 expression.

The genome instability index (GII) was defined as the “median absolute deviation of the normalized copy number” and independent of ERBB2 amplification, the pCR rate increased with the GII (P = .03.

Amplification of two regions on 6q23-24 was significantly associated with higher pCR (P = .00005 and P = .00087). One of the segments harbored 39 genes, some with an expression level that was also predictive of pCR. The 6q23-24 segment was associated with pCR in estrogen receptor–positive tumors only (interaction test P = .04).

After multiple testing correction, there were no amplified regions or genes found to be predictive of EFS.

“A novel amplified region on 6q23-24 was shown to be predictive of pCR, in particular for estrogen receptor–positive tumors,” said Dr. Sotiriou. “This may warrant further investigation.”

SOURCE: Sotiriou et al. SABCS Abstract GS1-04

SAN ANTONIO – Among patients receiving trastuzumab plus lapatinib neoadjuvant therapy for HER2-positive early breast cancer, amplification of ERBB2 was predictive of a pathologic complete response (pCR), according to findings presented at the San Antonio Breast Cancer Symposium.

However, ERBB2 mRNA expression and PAM50-enriched HER2 better predicted pCR, said lead study author Cristos Sotiriou, MD, of the Breast Cancer Translational Research Laboratory at the Institut Jules Bordet in Belgium

High genomic instability was associated with a higher pCR rate in patients with estrogen receptor–positive tumors, but copy number alterations (CNAs) were not associated with event-free survival (EFS).

In the large phase 3 NeoALTTO trial, lapatinib combined with trastuzumab in the neoadjuvant setting nearly doubled the pCR rate as compared with either agent used alone. The 3-year EFS was also improved with dual HER2 blockage versus single HER2 therapy (84% for the combination, hazard ratio, 0.78; P = .33 vs. 78% for lapatinib alone and 76% for trastuzumab alone, HR, 1.06; P = .81 for both).

The researchers of this trial also found that pCR was a surrogate for long-term outcome.

“Expression of ERBB2, ESR1, and immune signatures were the main drivers of pCR,” said Dr. Sotiriou.

The main goal of the current study was to investigate the relevance of CNAs for pCR and EFS in this population. A total of 455 patients were enrolled in the NeoALTTO study, and of this cohort, 270 had tumor content that was sufficient to assay for CNAs. Tumor-infiltrating lymphocytes and gene expression were also obtained and the genome instability index was calculated, and 184 samples were included in the final analysis.

Of the cancer genes, only ERBB2 was predictive of pCR.

A total of 159 recurrent CNA regions were identified. ERBB2 amplification was associated with high pCR (P = .0007), but less than ERBB2 expression, and it lost its significance after correcting for ERBB2 expression.

The genome instability index (GII) was defined as the “median absolute deviation of the normalized copy number” and independent of ERBB2 amplification, the pCR rate increased with the GII (P = .03.

Amplification of two regions on 6q23-24 was significantly associated with higher pCR (P = .00005 and P = .00087). One of the segments harbored 39 genes, some with an expression level that was also predictive of pCR. The 6q23-24 segment was associated with pCR in estrogen receptor–positive tumors only (interaction test P = .04).

After multiple testing correction, there were no amplified regions or genes found to be predictive of EFS.

“A novel amplified region on 6q23-24 was shown to be predictive of pCR, in particular for estrogen receptor–positive tumors,” said Dr. Sotiriou. “This may warrant further investigation.”

SOURCE: Sotiriou et al. SABCS Abstract GS1-04