Renal Cell Carcinoma

Stereotactic radiosurgery (SRS) is being used increasingly for brain metastases to prevent central nervous system (CNS) toxicity, and new findings published in Clinical Genitourinary Cancer demonstrate that it is a highly effective procedure for brain metastases from renal cell carcinoma (RCC).

In this study, the 1-year local control rate was more than 90% and durability of control was up to 2 years. SRS appears to be the most efficacious for smaller metastases, while escalated dosing or fractionation are needed to effectively treat larger lesions.

In metastatic RCC, the incidence of brain metastases is as high as 15%, and while surgical resection is associated with an improved survival compared with whole brain radiotherapy alone, for patients who are not candidates for resection, SRS is an alternative option. For this study, the authors sought to determine outcomes after treatment with SRS for brain metastases in 268 patients with metastatic RCC who were treated between 2006 and 2015 at a single institution.

Of this group, 38 patients were identified with brain metastases and a total of 243 lesions were treated with SRS, reported Zabi Wardak, MD, and his associates.

The median lesion size was 0.6 cm (0.2-3.1) and patients received a median SRS treatment dose of 18 Gy (12-24). The median age of patients was 65 years and the most common histology was clear cell RCC. Three quarters (74%) of patients received only one GammaKnife session, with a median number of two lesions treated at each session. The most common intracranial location for metastases was the frontal lobe (39% of lesions) followed by the parietal and temporal lobes (15% of lesions). The median size of treated metastases was 0.6 cm (0.2-3.1), reported Dr. Wardak, of the University of Texas UT Southwestern Medical Center, Dallas, and his associates.

At 1 year, local control rates were 91.8% (95% confidence interval, 85.7-95.4) and at 2 years, 86.1% (77.1-91.7). The median overall survival after a diagnosis of brain metastases was 13.8 months (95% CI, 8.1-28.0), with a 1-year survival of 57.5% (95% CI, 40.2-71.4). For patients with a single brain metastasis, 1-year overall survival was 56.3% (95% CI, 29.5-76.2) and for those with multiple lesions, 59.1% (95% CI, 36.1-76.2).

“Patients with multiple brain metastases (greater than five lesions) from RCC did not have a worse survival and should be considered for SRS to achieve intracranial tumor control while avoiding neurological decline,” wrote Dr. Wardak and his associates.

Coauthor James Brugarolas is supported by a grant from the National Institutes of Health. No other study funding was disclosed. The other authors have no disclosures.

SOURCE: Wardak Z et al. Clin Genitourin Cancer. 2018 Nov 20. doi: 10.1016/j.clgc.2018.11.006.

Stereotactic radiosurgery (SRS) is being used increasingly for brain metastases to prevent central nervous system (CNS) toxicity, and new findings published in Clinical Genitourinary Cancer demonstrate that it is a highly effective procedure for brain metastases from renal cell carcinoma (RCC).

In this study, the 1-year local control rate was more than 90% and durability of control was up to 2 years. SRS appears to be the most efficacious for smaller metastases, while escalated dosing or fractionation are needed to effectively treat larger lesions.

In metastatic RCC, the incidence of brain metastases is as high as 15%, and while surgical resection is associated with an improved survival compared with whole brain radiotherapy alone, for patients who are not candidates for resection, SRS is an alternative option. For this study, the authors sought to determine outcomes after treatment with SRS for brain metastases in 268 patients with metastatic RCC who were treated between 2006 and 2015 at a single institution.

Of this group, 38 patients were identified with brain metastases and a total of 243 lesions were treated with SRS, reported Zabi Wardak, MD, and his associates.

The median lesion size was 0.6 cm (0.2-3.1) and patients received a median SRS treatment dose of 18 Gy (12-24). The median age of patients was 65 years and the most common histology was clear cell RCC. Three quarters (74%) of patients received only one GammaKnife session, with a median number of two lesions treated at each session. The most common intracranial location for metastases was the frontal lobe (39% of lesions) followed by the parietal and temporal lobes (15% of lesions). The median size of treated metastases was 0.6 cm (0.2-3.1), reported Dr. Wardak, of the University of Texas UT Southwestern Medical Center, Dallas, and his associates.

At 1 year, local control rates were 91.8% (95% confidence interval, 85.7-95.4) and at 2 years, 86.1% (77.1-91.7). The median overall survival after a diagnosis of brain metastases was 13.8 months (95% CI, 8.1-28.0), with a 1-year survival of 57.5% (95% CI, 40.2-71.4). For patients with a single brain metastasis, 1-year overall survival was 56.3% (95% CI, 29.5-76.2) and for those with multiple lesions, 59.1% (95% CI, 36.1-76.2).

“Patients with multiple brain metastases (greater than five lesions) from RCC did not have a worse survival and should be considered for SRS to achieve intracranial tumor control while avoiding neurological decline,” wrote Dr. Wardak and his associates.

Coauthor James Brugarolas is supported by a grant from the National Institutes of Health. No other study funding was disclosed. The other authors have no disclosures.

SOURCE: Wardak Z et al. Clin Genitourin Cancer. 2018 Nov 20. doi: 10.1016/j.clgc.2018.11.006.

Stereotactic radiosurgery (SRS) is being used increasingly for brain metastases to prevent central nervous system (CNS) toxicity, and new findings published in Clinical Genitourinary Cancer demonstrate that it is a highly effective procedure for brain metastases from renal cell carcinoma (RCC).

In this study, the 1-year local control rate was more than 90% and durability of control was up to 2 years. SRS appears to be the most efficacious for smaller metastases, while escalated dosing or fractionation are needed to effectively treat larger lesions.

In metastatic RCC, the incidence of brain metastases is as high as 15%, and while surgical resection is associated with an improved survival compared with whole brain radiotherapy alone, for patients who are not candidates for resection, SRS is an alternative option. For this study, the authors sought to determine outcomes after treatment with SRS for brain metastases in 268 patients with metastatic RCC who were treated between 2006 and 2015 at a single institution.

Of this group, 38 patients were identified with brain metastases and a total of 243 lesions were treated with SRS, reported Zabi Wardak, MD, and his associates.

The median lesion size was 0.6 cm (0.2-3.1) and patients received a median SRS treatment dose of 18 Gy (12-24). The median age of patients was 65 years and the most common histology was clear cell RCC. Three quarters (74%) of patients received only one GammaKnife session, with a median number of two lesions treated at each session. The most common intracranial location for metastases was the frontal lobe (39% of lesions) followed by the parietal and temporal lobes (15% of lesions). The median size of treated metastases was 0.6 cm (0.2-3.1), reported Dr. Wardak, of the University of Texas UT Southwestern Medical Center, Dallas, and his associates.

At 1 year, local control rates were 91.8% (95% confidence interval, 85.7-95.4) and at 2 years, 86.1% (77.1-91.7). The median overall survival after a diagnosis of brain metastases was 13.8 months (95% CI, 8.1-28.0), with a 1-year survival of 57.5% (95% CI, 40.2-71.4). For patients with a single brain metastasis, 1-year overall survival was 56.3% (95% CI, 29.5-76.2) and for those with multiple lesions, 59.1% (95% CI, 36.1-76.2).

“Patients with multiple brain metastases (greater than five lesions) from RCC did not have a worse survival and should be considered for SRS to achieve intracranial tumor control while avoiding neurological decline,” wrote Dr. Wardak and his associates.

Coauthor James Brugarolas is supported by a grant from the National Institutes of Health. No other study funding was disclosed. The other authors have no disclosures.

SOURCE: Wardak Z et al. Clin Genitourin Cancer. 2018 Nov 20. doi: 10.1016/j.clgc.2018.11.006.

Expression in metastatic tissues of BAP1, a gene encoding for a tumor suppressor protein, is a significant marker for progression-free and overall survival in patients with metastatic clear cell renal cell carcinoma (ccRCC), investigators contended.

An analysis of tissue samples from 124 patients with metastatic ccRCC showed that patients with metastatic tissues expressing BAP1 had a 5-year overall survival (OS) rate of 53.2%, compared with 35.1% for patients whose tissues did not express the gene (P = .004), reported Walter Henriques da Costa, MD, PhD, and colleagues from the A.C. Camargo Cancer Center in Sao Paulo.

BAP1 expression was also associated with significantly better progression-free survival (PFS), but expression of a different gene thought to be associated with prognosis in metastatic ccRCC, PBRM1, was not a significant predictor of either overall survival (OS) or PFS.

“The pattern of immunohistochemical expression of both PBRM1 and BAP1 was shown to be significantly discordant when comparing the expression of primary tumor and metastatic tumor tissue. The use of prognostic biomarkers identified in the primary tumor tissue might be not reliable in the metastatic disease scenario. Patients with metastatic ccRCC that present loss of BAP1 expression in metastatic tissue demonstrated poor survival rates and represent a relevant risk group for tumor recurrence and death,” the investigators wrote in Urologic Oncology.

Both BAP1 and PBRM1 have been shown to be frequently mutated in ccRCC. These and other mutated genes recently identified through next-generation sequencing encode proteins that are involved in chromatin regulation and act as gene suppressors.

To see whether expression of the genes had prognostic value, they performed immunohistochemical studies of tissues from 124 consecutive patients in their center who underwent metastasectomy or biopsy of metastases and from 38 paired cases with tissues from the primary tumors of patients who underwent partial or radical nephrectomies.

They found that 98 of the metastatic samples (79%) stained negative for PBRM1 and 26 (21%) stained positive for expression of the gene; 62.1% of samples were negative for BAP1 expression and 37.9% were positive.

There were discordant expression patterns between primary tumors and metastases for BAP1 in 17 of the 38 (44.7%) samples from patients with both primary and metastatic tissues and for PBRM1 in 19 of 38 (50%) samples.

As noted before, the 5-year OS rate was 53.2% for patients with BAP1-positive metastases, compared with 35.1% for patients with BAP1-negative tissues (P = .004). The respective 5-year PFS rates for BAP1 expression were 14.9% and 3.9% (P = .003).

There were no significant differences associated with PBRM1 expression for either PFS or OS, however.

Negative expression of BAP1 in metastases was associated in multivariate analysis with both higher risk of death (hazard ratio, 2.017; P = .045) and with disease progression (HR, 1.586; P = .012).

The finding of discordance in expression between the primary tumor and metastases shows that the “strategy of using tissue markers of the primary tumor in the prediction of response of metastatic disease is not reliable. Such fact reinforces the imminent need for identification and validation of tumor markers in metastatic tissue,” the authors wrote.

No funding source or author disclosures were reported.

SOURCE: da Costa WH et al. Urol Oncol. 2018 Nov 13. doi: 10.1016/j.urolonc.2018.10.017.

Expression in metastatic tissues of BAP1, a gene encoding for a tumor suppressor protein, is a significant marker for progression-free and overall survival in patients with metastatic clear cell renal cell carcinoma (ccRCC), investigators contended.

An analysis of tissue samples from 124 patients with metastatic ccRCC showed that patients with metastatic tissues expressing BAP1 had a 5-year overall survival (OS) rate of 53.2%, compared with 35.1% for patients whose tissues did not express the gene (P = .004), reported Walter Henriques da Costa, MD, PhD, and colleagues from the A.C. Camargo Cancer Center in Sao Paulo.

BAP1 expression was also associated with significantly better progression-free survival (PFS), but expression of a different gene thought to be associated with prognosis in metastatic ccRCC, PBRM1, was not a significant predictor of either overall survival (OS) or PFS.

“The pattern of immunohistochemical expression of both PBRM1 and BAP1 was shown to be significantly discordant when comparing the expression of primary tumor and metastatic tumor tissue. The use of prognostic biomarkers identified in the primary tumor tissue might be not reliable in the metastatic disease scenario. Patients with metastatic ccRCC that present loss of BAP1 expression in metastatic tissue demonstrated poor survival rates and represent a relevant risk group for tumor recurrence and death,” the investigators wrote in Urologic Oncology.

Both BAP1 and PBRM1 have been shown to be frequently mutated in ccRCC. These and other mutated genes recently identified through next-generation sequencing encode proteins that are involved in chromatin regulation and act as gene suppressors.

To see whether expression of the genes had prognostic value, they performed immunohistochemical studies of tissues from 124 consecutive patients in their center who underwent metastasectomy or biopsy of metastases and from 38 paired cases with tissues from the primary tumors of patients who underwent partial or radical nephrectomies.

They found that 98 of the metastatic samples (79%) stained negative for PBRM1 and 26 (21%) stained positive for expression of the gene; 62.1% of samples were negative for BAP1 expression and 37.9% were positive.

There were discordant expression patterns between primary tumors and metastases for BAP1 in 17 of the 38 (44.7%) samples from patients with both primary and metastatic tissues and for PBRM1 in 19 of 38 (50%) samples.

As noted before, the 5-year OS rate was 53.2% for patients with BAP1-positive metastases, compared with 35.1% for patients with BAP1-negative tissues (P = .004). The respective 5-year PFS rates for BAP1 expression were 14.9% and 3.9% (P = .003).

There were no significant differences associated with PBRM1 expression for either PFS or OS, however.

Negative expression of BAP1 in metastases was associated in multivariate analysis with both higher risk of death (hazard ratio, 2.017; P = .045) and with disease progression (HR, 1.586; P = .012).

The finding of discordance in expression between the primary tumor and metastases shows that the “strategy of using tissue markers of the primary tumor in the prediction of response of metastatic disease is not reliable. Such fact reinforces the imminent need for identification and validation of tumor markers in metastatic tissue,” the authors wrote.

No funding source or author disclosures were reported.

SOURCE: da Costa WH et al. Urol Oncol. 2018 Nov 13. doi: 10.1016/j.urolonc.2018.10.017.

Expression in metastatic tissues of BAP1, a gene encoding for a tumor suppressor protein, is a significant marker for progression-free and overall survival in patients with metastatic clear cell renal cell carcinoma (ccRCC), investigators contended.

An analysis of tissue samples from 124 patients with metastatic ccRCC showed that patients with metastatic tissues expressing BAP1 had a 5-year overall survival (OS) rate of 53.2%, compared with 35.1% for patients whose tissues did not express the gene (P = .004), reported Walter Henriques da Costa, MD, PhD, and colleagues from the A.C. Camargo Cancer Center in Sao Paulo.

BAP1 expression was also associated with significantly better progression-free survival (PFS), but expression of a different gene thought to be associated with prognosis in metastatic ccRCC, PBRM1, was not a significant predictor of either overall survival (OS) or PFS.

“The pattern of immunohistochemical expression of both PBRM1 and BAP1 was shown to be significantly discordant when comparing the expression of primary tumor and metastatic tumor tissue. The use of prognostic biomarkers identified in the primary tumor tissue might be not reliable in the metastatic disease scenario. Patients with metastatic ccRCC that present loss of BAP1 expression in metastatic tissue demonstrated poor survival rates and represent a relevant risk group for tumor recurrence and death,” the investigators wrote in Urologic Oncology.

Both BAP1 and PBRM1 have been shown to be frequently mutated in ccRCC. These and other mutated genes recently identified through next-generation sequencing encode proteins that are involved in chromatin regulation and act as gene suppressors.

To see whether expression of the genes had prognostic value, they performed immunohistochemical studies of tissues from 124 consecutive patients in their center who underwent metastasectomy or biopsy of metastases and from 38 paired cases with tissues from the primary tumors of patients who underwent partial or radical nephrectomies.

They found that 98 of the metastatic samples (79%) stained negative for PBRM1 and 26 (21%) stained positive for expression of the gene; 62.1% of samples were negative for BAP1 expression and 37.9% were positive.

There were discordant expression patterns between primary tumors and metastases for BAP1 in 17 of the 38 (44.7%) samples from patients with both primary and metastatic tissues and for PBRM1 in 19 of 38 (50%) samples.

As noted before, the 5-year OS rate was 53.2% for patients with BAP1-positive metastases, compared with 35.1% for patients with BAP1-negative tissues (P = .004). The respective 5-year PFS rates for BAP1 expression were 14.9% and 3.9% (P = .003).

There were no significant differences associated with PBRM1 expression for either PFS or OS, however.

Negative expression of BAP1 in metastases was associated in multivariate analysis with both higher risk of death (hazard ratio, 2.017; P = .045) and with disease progression (HR, 1.586; P = .012).

The finding of discordance in expression between the primary tumor and metastases shows that the “strategy of using tissue markers of the primary tumor in the prediction of response of metastatic disease is not reliable. Such fact reinforces the imminent need for identification and validation of tumor markers in metastatic tissue,” the authors wrote.

No funding source or author disclosures were reported.

SOURCE: da Costa WH et al. Urol Oncol. 2018 Nov 13. doi: 10.1016/j.urolonc.2018.10.017.

In patients with either sporadic or hereditary clear cell renal cell carcinoma, tumor expression of programmed death–ligand 1 (PD-L1) is associated with aggressive disease, investigators have found.

Analysis of tumor samples from patients with sporadic clear cell renal cell carcinoma (ccRCC) and others with Von Hippel-Lindau (VHL)–associated hereditary ccRCC showed that positive PD-L1 correlated with aggressive clinicopathologic features, reported Baoan Hong, MD, from Peking University First Hospital in Beijing, and colleagues.

“PD-L1 is a promising predictive biomarker for the utilization of PD-1/PD-L1 checkpoint inhibitors in ccRCC patients,” they wrote in Genitourinary Cancer.

The investigators conducted a retrospective analysis of PD-L1 expression and its potential correlation with disease features using samples from 129 patients with sporadic ccRCC and 26 patients with VHL disease who underwent partial or radical nephrectomy at their center from 2010 to 2017.

Sporadic ccRCC

The median age of patients with sporadic ccRCC was 61 years and the median tumor size was 4.3 cm. Of the 129 patients, 56 had pathological stage T1a at diagnosis, 44 had stage T1b, 8 had stage T2, and 21 had stage T3. In all, 25 patients had Fuhrman nuclear grade 3 tumors and 104 had grade 1 or 2 tumors. A total of 7 patients had metastases to lymph nodes, 41 had microvascular invasion, and 16 had tumor necrosis.

In all, 61 of these patients had PD-L1-positive tumors and 68 were PD-L1 negative. Positive PD-L1 was significantly associated with male gender (P = .025) and worse disease features, including higher T stage (P = .0011) and higher Fuhrman nuclear grade (P = .022).

After a median follow-up of 68 months, 9 patients in this group died and 17 others developed distant metastases or recurrent disease. Patients whose tumors were PD-L1 negative had significantly longer disease-free survival than patients with PD-L1-positive tumors, at a median 36 versus 28 months (P = .037).

VHL-associated ccRCC

Of the 26 patients with VHL-associated hereditary ccRCC (13 men and 13 women; median age, 42 years), 13 had pathological stage T1a disease, 7 had T1b, and 2 each has stage T2a, T3a, and T3b tumors. A total of 18 patients had Fuhrman nuclear grade 1 tumors and 8 had grade 2 tumors.

In this cohort, 17 patients had PD-L1-negative tumors, and 9 had PD-L1-positive tumors. PD-L1 expression was more common in patients with Fuhrman nuclear grade 2 tumors (six of eight cases). Patients with Fuhrman nuclear grade 1 tumors were more likely to be PD-L1 negative (15 of 18, P = .008). PD-L1 expression was not significantly correlated with either gender or tumor stage in this cohort.

There were no associations in this population between PD-L1 status and either age, tumor size, microvascular invasion, tumor necrosis, or lymph node metastases.

The investigators also compared the age of onset of all VHL-associated tumors in this cohort in PD-L1-positive versus PD-L1-negative patients, but found no statistically significant differences.

The authors acknowledged that the cohort sizes were small and that follow-up was relatively short, which could have a bearing on the analysis of associations between PD-L1 expression and disease features.

“Whether PD-L1 expression level in ccRCC is related to the effectiveness of PD-1/PD-L1 checkpoint inhibitor immunotherapy needs to be further investigated,” they wrote.

The study was supported by the National Natural Science Foundation of China and Special Health Development Research Project of Capital. The authors reported having no relevant disclosures.

SOURCE: Hong B et al. Clin Genitourin Cancer. 2018 Nov 13. doi: 10.1016/j.clgc.2018.11.001.

In patients with either sporadic or hereditary clear cell renal cell carcinoma, tumor expression of programmed death–ligand 1 (PD-L1) is associated with aggressive disease, investigators have found.

Analysis of tumor samples from patients with sporadic clear cell renal cell carcinoma (ccRCC) and others with Von Hippel-Lindau (VHL)–associated hereditary ccRCC showed that positive PD-L1 correlated with aggressive clinicopathologic features, reported Baoan Hong, MD, from Peking University First Hospital in Beijing, and colleagues.

“PD-L1 is a promising predictive biomarker for the utilization of PD-1/PD-L1 checkpoint inhibitors in ccRCC patients,” they wrote in Genitourinary Cancer.

The investigators conducted a retrospective analysis of PD-L1 expression and its potential correlation with disease features using samples from 129 patients with sporadic ccRCC and 26 patients with VHL disease who underwent partial or radical nephrectomy at their center from 2010 to 2017.

Sporadic ccRCC

The median age of patients with sporadic ccRCC was 61 years and the median tumor size was 4.3 cm. Of the 129 patients, 56 had pathological stage T1a at diagnosis, 44 had stage T1b, 8 had stage T2, and 21 had stage T3. In all, 25 patients had Fuhrman nuclear grade 3 tumors and 104 had grade 1 or 2 tumors. A total of 7 patients had metastases to lymph nodes, 41 had microvascular invasion, and 16 had tumor necrosis.

In all, 61 of these patients had PD-L1-positive tumors and 68 were PD-L1 negative. Positive PD-L1 was significantly associated with male gender (P = .025) and worse disease features, including higher T stage (P = .0011) and higher Fuhrman nuclear grade (P = .022).

After a median follow-up of 68 months, 9 patients in this group died and 17 others developed distant metastases or recurrent disease. Patients whose tumors were PD-L1 negative had significantly longer disease-free survival than patients with PD-L1-positive tumors, at a median 36 versus 28 months (P = .037).

VHL-associated ccRCC

Of the 26 patients with VHL-associated hereditary ccRCC (13 men and 13 women; median age, 42 years), 13 had pathological stage T1a disease, 7 had T1b, and 2 each has stage T2a, T3a, and T3b tumors. A total of 18 patients had Fuhrman nuclear grade 1 tumors and 8 had grade 2 tumors.

In this cohort, 17 patients had PD-L1-negative tumors, and 9 had PD-L1-positive tumors. PD-L1 expression was more common in patients with Fuhrman nuclear grade 2 tumors (six of eight cases). Patients with Fuhrman nuclear grade 1 tumors were more likely to be PD-L1 negative (15 of 18, P = .008). PD-L1 expression was not significantly correlated with either gender or tumor stage in this cohort.

There were no associations in this population between PD-L1 status and either age, tumor size, microvascular invasion, tumor necrosis, or lymph node metastases.

The investigators also compared the age of onset of all VHL-associated tumors in this cohort in PD-L1-positive versus PD-L1-negative patients, but found no statistically significant differences.

The authors acknowledged that the cohort sizes were small and that follow-up was relatively short, which could have a bearing on the analysis of associations between PD-L1 expression and disease features.

“Whether PD-L1 expression level in ccRCC is related to the effectiveness of PD-1/PD-L1 checkpoint inhibitor immunotherapy needs to be further investigated,” they wrote.

The study was supported by the National Natural Science Foundation of China and Special Health Development Research Project of Capital. The authors reported having no relevant disclosures.

SOURCE: Hong B et al. Clin Genitourin Cancer. 2018 Nov 13. doi: 10.1016/j.clgc.2018.11.001.

In patients with either sporadic or hereditary clear cell renal cell carcinoma, tumor expression of programmed death–ligand 1 (PD-L1) is associated with aggressive disease, investigators have found.

Analysis of tumor samples from patients with sporadic clear cell renal cell carcinoma (ccRCC) and others with Von Hippel-Lindau (VHL)–associated hereditary ccRCC showed that positive PD-L1 correlated with aggressive clinicopathologic features, reported Baoan Hong, MD, from Peking University First Hospital in Beijing, and colleagues.

“PD-L1 is a promising predictive biomarker for the utilization of PD-1/PD-L1 checkpoint inhibitors in ccRCC patients,” they wrote in Genitourinary Cancer.

The investigators conducted a retrospective analysis of PD-L1 expression and its potential correlation with disease features using samples from 129 patients with sporadic ccRCC and 26 patients with VHL disease who underwent partial or radical nephrectomy at their center from 2010 to 2017.

Sporadic ccRCC

The median age of patients with sporadic ccRCC was 61 years and the median tumor size was 4.3 cm. Of the 129 patients, 56 had pathological stage T1a at diagnosis, 44 had stage T1b, 8 had stage T2, and 21 had stage T3. In all, 25 patients had Fuhrman nuclear grade 3 tumors and 104 had grade 1 or 2 tumors. A total of 7 patients had metastases to lymph nodes, 41 had microvascular invasion, and 16 had tumor necrosis.

In all, 61 of these patients had PD-L1-positive tumors and 68 were PD-L1 negative. Positive PD-L1 was significantly associated with male gender (P = .025) and worse disease features, including higher T stage (P = .0011) and higher Fuhrman nuclear grade (P = .022).

After a median follow-up of 68 months, 9 patients in this group died and 17 others developed distant metastases or recurrent disease. Patients whose tumors were PD-L1 negative had significantly longer disease-free survival than patients with PD-L1-positive tumors, at a median 36 versus 28 months (P = .037).

VHL-associated ccRCC

Of the 26 patients with VHL-associated hereditary ccRCC (13 men and 13 women; median age, 42 years), 13 had pathological stage T1a disease, 7 had T1b, and 2 each has stage T2a, T3a, and T3b tumors. A total of 18 patients had Fuhrman nuclear grade 1 tumors and 8 had grade 2 tumors.

In this cohort, 17 patients had PD-L1-negative tumors, and 9 had PD-L1-positive tumors. PD-L1 expression was more common in patients with Fuhrman nuclear grade 2 tumors (six of eight cases). Patients with Fuhrman nuclear grade 1 tumors were more likely to be PD-L1 negative (15 of 18, P = .008). PD-L1 expression was not significantly correlated with either gender or tumor stage in this cohort.

There were no associations in this population between PD-L1 status and either age, tumor size, microvascular invasion, tumor necrosis, or lymph node metastases.

The investigators also compared the age of onset of all VHL-associated tumors in this cohort in PD-L1-positive versus PD-L1-negative patients, but found no statistically significant differences.

The authors acknowledged that the cohort sizes were small and that follow-up was relatively short, which could have a bearing on the analysis of associations between PD-L1 expression and disease features.

“Whether PD-L1 expression level in ccRCC is related to the effectiveness of PD-1/PD-L1 checkpoint inhibitor immunotherapy needs to be further investigated,” they wrote.

The study was supported by the National Natural Science Foundation of China and Special Health Development Research Project of Capital. The authors reported having no relevant disclosures.

SOURCE: Hong B et al. Clin Genitourin Cancer. 2018 Nov 13. doi: 10.1016/j.clgc.2018.11.001.

WASHINGTON – Fecal microbiota transplantation (FMT) shows promise for the treatment of refractory immune checkpoint inhibitor–associated colitis, according to Yinghong Wang, MD.

In two patients who developed severe, refractory, immune-mediated colitis (IMC), FMT led to recovery, Dr. Wang of M.D. Anderson Cancer Center, Houston, reported at the annual meeting of the Society for Immunotherapy of Cancer.

Patient 1 was a woman with renal cell cancer who developed grade 2+ IMC within 1 month of initiation of treatment with combined ipilimumab and nivolumab. Infectious etiology was ruled out, and her symptoms and ulcers persisted despite 3 months of treatment with corticosteroids, two doses of infliximab, and one dose of vedolizumab.

A single FMT delivered via colonoscopy led to complete symptom resolution within 10 days, and a repeat colonoscopy showed “very nice healing of inflammation and ulcers,” Dr. Wang said.

Patient 2 was a man with prostate cancer who developed grade 2+ IMC 3 months after receiving two doses of ipilimumab. Infectious etiologies were ruled out, and like patient 1, his symptoms and mucosal ulcerations persisted despite 5 months of immunosuppression with corticosteroids, two doses of infliximab, and three doses of vedolizumab. He underwent two FMTs via colonoscopy.

“The first fecal transplant achieved partial response, and the second fecal transplant achieved complete clinical response, and this remission was sustained for a total of 8 months,” Dr. Wang said.

Immune checkpoint inhibitor–related IMC is typically treated with immunosuppressive therapy that is associated with significant morbidity, including a possible adverse impact on the antitumor effects of checkpoint inhibitors, Dr. Wang said.

However, studies have suggested that “the microbiome in healthy people potentially plays a very important and synergistic role for tumor regression in combination with immunotherapy,” and animal models also suggest that patients who develop IMC have differential bacterial signatures in their gut microbiome, she said.

“Based on that preliminary information, we performed fecal transplant as a compassionate treatment for cases refractory to all immunosuppression in June 2017 at M.D. Anderson,” she said.

Stool microbiome analyses showed successful engraftment of donor microbiome in recipient stool samples, and microbiome taxonomy showed increases in specific Escherichia species that “we think potentially play a role in this colitis recovery,” she said.

“Fecal transplant is safe and effective based on our preliminary study,” she said, adding that restoration of a healthy microbiome seems to reverse IMC. “Future large-scale studies are needed to evaluate this finding.”

Dr. Wang reported having no disclosures.

SOURCE: Wang Y et al. SITC 2018, Abstract P194.

WASHINGTON – Fecal microbiota transplantation (FMT) shows promise for the treatment of refractory immune checkpoint inhibitor–associated colitis, according to Yinghong Wang, MD.

In two patients who developed severe, refractory, immune-mediated colitis (IMC), FMT led to recovery, Dr. Wang of M.D. Anderson Cancer Center, Houston, reported at the annual meeting of the Society for Immunotherapy of Cancer.

Patient 1 was a woman with renal cell cancer who developed grade 2+ IMC within 1 month of initiation of treatment with combined ipilimumab and nivolumab. Infectious etiology was ruled out, and her symptoms and ulcers persisted despite 3 months of treatment with corticosteroids, two doses of infliximab, and one dose of vedolizumab.

A single FMT delivered via colonoscopy led to complete symptom resolution within 10 days, and a repeat colonoscopy showed “very nice healing of inflammation and ulcers,” Dr. Wang said.

Patient 2 was a man with prostate cancer who developed grade 2+ IMC 3 months after receiving two doses of ipilimumab. Infectious etiologies were ruled out, and like patient 1, his symptoms and mucosal ulcerations persisted despite 5 months of immunosuppression with corticosteroids, two doses of infliximab, and three doses of vedolizumab. He underwent two FMTs via colonoscopy.

“The first fecal transplant achieved partial response, and the second fecal transplant achieved complete clinical response, and this remission was sustained for a total of 8 months,” Dr. Wang said.

Immune checkpoint inhibitor–related IMC is typically treated with immunosuppressive therapy that is associated with significant morbidity, including a possible adverse impact on the antitumor effects of checkpoint inhibitors, Dr. Wang said.

However, studies have suggested that “the microbiome in healthy people potentially plays a very important and synergistic role for tumor regression in combination with immunotherapy,” and animal models also suggest that patients who develop IMC have differential bacterial signatures in their gut microbiome, she said.

“Based on that preliminary information, we performed fecal transplant as a compassionate treatment for cases refractory to all immunosuppression in June 2017 at M.D. Anderson,” she said.

Stool microbiome analyses showed successful engraftment of donor microbiome in recipient stool samples, and microbiome taxonomy showed increases in specific Escherichia species that “we think potentially play a role in this colitis recovery,” she said.

“Fecal transplant is safe and effective based on our preliminary study,” she said, adding that restoration of a healthy microbiome seems to reverse IMC. “Future large-scale studies are needed to evaluate this finding.”

Dr. Wang reported having no disclosures.

SOURCE: Wang Y et al. SITC 2018, Abstract P194.

WASHINGTON – Fecal microbiota transplantation (FMT) shows promise for the treatment of refractory immune checkpoint inhibitor–associated colitis, according to Yinghong Wang, MD.

In two patients who developed severe, refractory, immune-mediated colitis (IMC), FMT led to recovery, Dr. Wang of M.D. Anderson Cancer Center, Houston, reported at the annual meeting of the Society for Immunotherapy of Cancer.

Patient 1 was a woman with renal cell cancer who developed grade 2+ IMC within 1 month of initiation of treatment with combined ipilimumab and nivolumab. Infectious etiology was ruled out, and her symptoms and ulcers persisted despite 3 months of treatment with corticosteroids, two doses of infliximab, and one dose of vedolizumab.

A single FMT delivered via colonoscopy led to complete symptom resolution within 10 days, and a repeat colonoscopy showed “very nice healing of inflammation and ulcers,” Dr. Wang said.

Patient 2 was a man with prostate cancer who developed grade 2+ IMC 3 months after receiving two doses of ipilimumab. Infectious etiologies were ruled out, and like patient 1, his symptoms and mucosal ulcerations persisted despite 5 months of immunosuppression with corticosteroids, two doses of infliximab, and three doses of vedolizumab. He underwent two FMTs via colonoscopy.

“The first fecal transplant achieved partial response, and the second fecal transplant achieved complete clinical response, and this remission was sustained for a total of 8 months,” Dr. Wang said.

Immune checkpoint inhibitor–related IMC is typically treated with immunosuppressive therapy that is associated with significant morbidity, including a possible adverse impact on the antitumor effects of checkpoint inhibitors, Dr. Wang said.

However, studies have suggested that “the microbiome in healthy people potentially plays a very important and synergistic role for tumor regression in combination with immunotherapy,” and animal models also suggest that patients who develop IMC have differential bacterial signatures in their gut microbiome, she said.

“Based on that preliminary information, we performed fecal transplant as a compassionate treatment for cases refractory to all immunosuppression in June 2017 at M.D. Anderson,” she said.

Stool microbiome analyses showed successful engraftment of donor microbiome in recipient stool samples, and microbiome taxonomy showed increases in specific Escherichia species that “we think potentially play a role in this colitis recovery,” she said.

“Fecal transplant is safe and effective based on our preliminary study,” she said, adding that restoration of a healthy microbiome seems to reverse IMC. “Future large-scale studies are needed to evaluate this finding.”

Dr. Wang reported having no disclosures.

SOURCE: Wang Y et al. SITC 2018, Abstract P194.

Stereotactic radiosurgery (SRS) provides better early local control of brain metastases than complete surgical resection, but this advantage fades with time, according to investigators.

By 6 months, lower risks associated with SRS shifted in favor of those who had surgical resection, reported lead author Thomas Churilla, MD, of Fox Chase Cancer Center in Philadelphia and his colleagues.

“Outside recognized indications for surgery such as establishing diagnosis or relieving mass effect, little evidence is available to guide the therapeutic choice of SRS vs. surgical resection in the treatment of patients with limited brain metastases,” the investigators wrote in JAMA Oncology.

The investigators performed an exploratory analysis of data from the European Organization for the Research and Treatment of Cancer (EORTC) 22952-26001 phase 3 trial, which was designed to evaluate whole-brain radiotherapy for patients with one to three brain metastases who had undergone SRS or complete surgical resection. The present analysis involved 268 patients, of whom 154 had SRS and 114 had complete surgical resection.

Primary tumors included lung, breast, colorectum, kidney, and melanoma. Initial analysis showed that patients undergoing surgical resection, compared with those who had SRS, typically had larger brain metastases (median, 28 mm vs. 20 mm) and more often had 1 brain metastasis (98.2% vs. 74.0%). Mass locality also differed between groups; compared with patients receiving SRS, surgical patients more often had metastases in the posterior fossa (26.3% vs. 7.8%) and less often in the parietal lobe (18.4% vs. 39.6%).

After median follow-up of 39.9 months, risks of local recurrence were similar between surgical and SRS groups (hazard ratio, 1.15). Stratifying by interval, however, showed that surgical patients were at much higher risk of local recurrence in the first 3 months following treatment (HR for 0-3 months, 5.94). Of note, this risk faded with time (HR for 3-6 months, 1.37; HR for 6-9 months, 0.75; HR for 9 months or longer, 0.36). From the 6-9 months interval onward, surgical patients had lower risk of recurrence, compared with SRS patients, and the risk even decreased after the 6-9 month interval.

“Prospective controlled trials are warranted to direct the optimal local approach for patients with brain metastases and to define whether any population may benefit from escalation in local therapy,” the investigators concluded.

The study was funded by the National Cancer Institute, National Institutes of Health, and Fonds Cancer in Belgium. One author reported receiving financial compensation from Pfizer via her institution.

SOURCE: Churilla T et al. JAMA Onc. 2018. doi: 10.1001/jamaoncol.2018.4610.
 

Stereotactic radiosurgery (SRS) provides better early local control of brain metastases than complete surgical resection, but this advantage fades with time, according to investigators.

By 6 months, lower risks associated with SRS shifted in favor of those who had surgical resection, reported lead author Thomas Churilla, MD, of Fox Chase Cancer Center in Philadelphia and his colleagues.

“Outside recognized indications for surgery such as establishing diagnosis or relieving mass effect, little evidence is available to guide the therapeutic choice of SRS vs. surgical resection in the treatment of patients with limited brain metastases,” the investigators wrote in JAMA Oncology.

The investigators performed an exploratory analysis of data from the European Organization for the Research and Treatment of Cancer (EORTC) 22952-26001 phase 3 trial, which was designed to evaluate whole-brain radiotherapy for patients with one to three brain metastases who had undergone SRS or complete surgical resection. The present analysis involved 268 patients, of whom 154 had SRS and 114 had complete surgical resection.

Primary tumors included lung, breast, colorectum, kidney, and melanoma. Initial analysis showed that patients undergoing surgical resection, compared with those who had SRS, typically had larger brain metastases (median, 28 mm vs. 20 mm) and more often had 1 brain metastasis (98.2% vs. 74.0%). Mass locality also differed between groups; compared with patients receiving SRS, surgical patients more often had metastases in the posterior fossa (26.3% vs. 7.8%) and less often in the parietal lobe (18.4% vs. 39.6%).

After median follow-up of 39.9 months, risks of local recurrence were similar between surgical and SRS groups (hazard ratio, 1.15). Stratifying by interval, however, showed that surgical patients were at much higher risk of local recurrence in the first 3 months following treatment (HR for 0-3 months, 5.94). Of note, this risk faded with time (HR for 3-6 months, 1.37; HR for 6-9 months, 0.75; HR for 9 months or longer, 0.36). From the 6-9 months interval onward, surgical patients had lower risk of recurrence, compared with SRS patients, and the risk even decreased after the 6-9 month interval.

“Prospective controlled trials are warranted to direct the optimal local approach for patients with brain metastases and to define whether any population may benefit from escalation in local therapy,” the investigators concluded.

The study was funded by the National Cancer Institute, National Institutes of Health, and Fonds Cancer in Belgium. One author reported receiving financial compensation from Pfizer via her institution.

SOURCE: Churilla T et al. JAMA Onc. 2018. doi: 10.1001/jamaoncol.2018.4610.
 

Stereotactic radiosurgery (SRS) provides better early local control of brain metastases than complete surgical resection, but this advantage fades with time, according to investigators.

By 6 months, lower risks associated with SRS shifted in favor of those who had surgical resection, reported lead author Thomas Churilla, MD, of Fox Chase Cancer Center in Philadelphia and his colleagues.

“Outside recognized indications for surgery such as establishing diagnosis or relieving mass effect, little evidence is available to guide the therapeutic choice of SRS vs. surgical resection in the treatment of patients with limited brain metastases,” the investigators wrote in JAMA Oncology.

The investigators performed an exploratory analysis of data from the European Organization for the Research and Treatment of Cancer (EORTC) 22952-26001 phase 3 trial, which was designed to evaluate whole-brain radiotherapy for patients with one to three brain metastases who had undergone SRS or complete surgical resection. The present analysis involved 268 patients, of whom 154 had SRS and 114 had complete surgical resection.

Primary tumors included lung, breast, colorectum, kidney, and melanoma. Initial analysis showed that patients undergoing surgical resection, compared with those who had SRS, typically had larger brain metastases (median, 28 mm vs. 20 mm) and more often had 1 brain metastasis (98.2% vs. 74.0%). Mass locality also differed between groups; compared with patients receiving SRS, surgical patients more often had metastases in the posterior fossa (26.3% vs. 7.8%) and less often in the parietal lobe (18.4% vs. 39.6%).

After median follow-up of 39.9 months, risks of local recurrence were similar between surgical and SRS groups (hazard ratio, 1.15). Stratifying by interval, however, showed that surgical patients were at much higher risk of local recurrence in the first 3 months following treatment (HR for 0-3 months, 5.94). Of note, this risk faded with time (HR for 3-6 months, 1.37; HR for 6-9 months, 0.75; HR for 9 months or longer, 0.36). From the 6-9 months interval onward, surgical patients had lower risk of recurrence, compared with SRS patients, and the risk even decreased after the 6-9 month interval.

“Prospective controlled trials are warranted to direct the optimal local approach for patients with brain metastases and to define whether any population may benefit from escalation in local therapy,” the investigators concluded.

The study was funded by the National Cancer Institute, National Institutes of Health, and Fonds Cancer in Belgium. One author reported receiving financial compensation from Pfizer via her institution.

SOURCE: Churilla T et al. JAMA Onc. 2018. doi: 10.1001/jamaoncol.2018.4610.
 

Circulating tumor DNA could be effectively isolated from plasma by focusing on a particular range of fragment sizes, which paves the way for noninvasive genomic analysis of tumor DNA, new research suggests.

In a study of 344 plasma samples from 200 patients with 18 cancer types and 65 samples from healthy controls, DNA fragment length could be used to distinguish circulating tumor DNA (ctDNA) from other cell-free DNA (cfDNA), investigators reported in Science Translational Medicine.

“We hypothesized that we could improve the sensitivity for noninvasive cancer genomics by selective sequencing of ctDNA fragments and by leveraging differences in the biology that determine DNA fragmentation,” wrote Florent Mouliere, PhD, from the Cancer Research UK Cambridge Institute, and coauthors.

Cell-free plasma fragments are often cleaved at around 167 base pairs in length and differences in length between circulating fetal and maternal DNA are already used for noninvasive prenatal diagnosis. However, the authors said that only a few studies, with conflicting results, have looked at the size distribution of tumor-derived cfDNA.

The study used two approaches to determining the size profile of mutant ctDNA. The first looked at tumor and nontumor cfDNA in mice with human ovarian cancer xenografts and the second approach used deep sequencing in 19 cancer patients. This revealed that tumor-derived cfDNA was most commonly found in fragments between 90-150 base pairs or 250-320 base pairs in size.

The researchers also noted that mutant circulating tumor DNA was generally more fragmented than nonmutant cfDNA and that patients with untreated advanced cancer showed consistently shorter lengths of mutant DNA.

The next question was whether size selection and other biological properties – such as somatic alterations – of the cfDNA could be used to enhance detection of ctDNA via machine learning technology.

Two models, designed to distinguish between healthy and cancerous samples, were developed using 153 samples, then validated on two datasets of 94 and 83 samples.

One of these models correctly classified cancerous samples in 94% of samples from patients with cancers known to have high levels of ctDNA – colorectal, cholangiocarcinoma, ovarian, breast, and melanoma – and in 65% of samples from low-ctDNA cancers – pancreatic, renal, and glioma.

Another model focused just on fragmentation patterns and was still able to distinguish cancer samples from those of healthy controls, although with slightly reduced area under the curve.

“Our results indicate that exploiting fundamental properties of cfDNA with fragment-specific analyses can allow more sensitive evaluation of ctDNA,” the authors wrote. “We identified features that could determine the presence and amount of ctDNA in plasma samples, without a prior knowledge of somatic aberrations.”

The authors pointed out that size selection of DNA fragments was relatively simple and cheap, and was also compatible with other genome-wide and targeted genomic analyses, “greatly increasing the potential value and utility of liquid biopsies as well as the cost-effectiveness of cfDNA sequencing.”

However, they cautioned that their catalogue had focused solely on double-stranded DNA and was subject to potential biases from the DNA extraction and sequencing methods they used in the study. They also commented that other biological effects could help refine the analysis of ctDNA.

“Other bodily fluids [urine, cerebrospinal fluid, and saliva], different nucleic acids and structures, altered mechanisms of release into circulation, or sample processing methods could exhibit varying fragment size signatures and could offer additional exploitable biological patterns for selective sequencing,” they wrote.

The study was supported by the University of Cambridge, Cancer Research UK, and the Engineering and Physical Sciences Research Council. Research supporting the study was also funded by the European Research Council, the National Institute for Health Research Cambridge, National Cancer Research Network, Cambridge Experimental Cancer Medicine Centre, Hutchison Whampoa, Target Ovarian Cancer, the Medical Research Council, and AstraZeneca. Three authors are cofounders, shareholders, and officers/consultants in a company specializing in ctDNA analysis. One author declared research funding and advisory board fees from private industry. Seven authors are listed on related patents.

SOURCE: Mouliere F et al. Sci Transl Med. 2018 Nov 7. doi: 10.1126/scitranslmed.aat4921.
 

Circulating tumor DNA could be effectively isolated from plasma by focusing on a particular range of fragment sizes, which paves the way for noninvasive genomic analysis of tumor DNA, new research suggests.

In a study of 344 plasma samples from 200 patients with 18 cancer types and 65 samples from healthy controls, DNA fragment length could be used to distinguish circulating tumor DNA (ctDNA) from other cell-free DNA (cfDNA), investigators reported in Science Translational Medicine.

“We hypothesized that we could improve the sensitivity for noninvasive cancer genomics by selective sequencing of ctDNA fragments and by leveraging differences in the biology that determine DNA fragmentation,” wrote Florent Mouliere, PhD, from the Cancer Research UK Cambridge Institute, and coauthors.

Cell-free plasma fragments are often cleaved at around 167 base pairs in length and differences in length between circulating fetal and maternal DNA are already used for noninvasive prenatal diagnosis. However, the authors said that only a few studies, with conflicting results, have looked at the size distribution of tumor-derived cfDNA.

The study used two approaches to determining the size profile of mutant ctDNA. The first looked at tumor and nontumor cfDNA in mice with human ovarian cancer xenografts and the second approach used deep sequencing in 19 cancer patients. This revealed that tumor-derived cfDNA was most commonly found in fragments between 90-150 base pairs or 250-320 base pairs in size.

The researchers also noted that mutant circulating tumor DNA was generally more fragmented than nonmutant cfDNA and that patients with untreated advanced cancer showed consistently shorter lengths of mutant DNA.

The next question was whether size selection and other biological properties – such as somatic alterations – of the cfDNA could be used to enhance detection of ctDNA via machine learning technology.

Two models, designed to distinguish between healthy and cancerous samples, were developed using 153 samples, then validated on two datasets of 94 and 83 samples.

One of these models correctly classified cancerous samples in 94% of samples from patients with cancers known to have high levels of ctDNA – colorectal, cholangiocarcinoma, ovarian, breast, and melanoma – and in 65% of samples from low-ctDNA cancers – pancreatic, renal, and glioma.

Another model focused just on fragmentation patterns and was still able to distinguish cancer samples from those of healthy controls, although with slightly reduced area under the curve.

“Our results indicate that exploiting fundamental properties of cfDNA with fragment-specific analyses can allow more sensitive evaluation of ctDNA,” the authors wrote. “We identified features that could determine the presence and amount of ctDNA in plasma samples, without a prior knowledge of somatic aberrations.”

The authors pointed out that size selection of DNA fragments was relatively simple and cheap, and was also compatible with other genome-wide and targeted genomic analyses, “greatly increasing the potential value and utility of liquid biopsies as well as the cost-effectiveness of cfDNA sequencing.”

However, they cautioned that their catalogue had focused solely on double-stranded DNA and was subject to potential biases from the DNA extraction and sequencing methods they used in the study. They also commented that other biological effects could help refine the analysis of ctDNA.

“Other bodily fluids [urine, cerebrospinal fluid, and saliva], different nucleic acids and structures, altered mechanisms of release into circulation, or sample processing methods could exhibit varying fragment size signatures and could offer additional exploitable biological patterns for selective sequencing,” they wrote.

The study was supported by the University of Cambridge, Cancer Research UK, and the Engineering and Physical Sciences Research Council. Research supporting the study was also funded by the European Research Council, the National Institute for Health Research Cambridge, National Cancer Research Network, Cambridge Experimental Cancer Medicine Centre, Hutchison Whampoa, Target Ovarian Cancer, the Medical Research Council, and AstraZeneca. Three authors are cofounders, shareholders, and officers/consultants in a company specializing in ctDNA analysis. One author declared research funding and advisory board fees from private industry. Seven authors are listed on related patents.

SOURCE: Mouliere F et al. Sci Transl Med. 2018 Nov 7. doi: 10.1126/scitranslmed.aat4921.
 

Circulating tumor DNA could be effectively isolated from plasma by focusing on a particular range of fragment sizes, which paves the way for noninvasive genomic analysis of tumor DNA, new research suggests.

In a study of 344 plasma samples from 200 patients with 18 cancer types and 65 samples from healthy controls, DNA fragment length could be used to distinguish circulating tumor DNA (ctDNA) from other cell-free DNA (cfDNA), investigators reported in Science Translational Medicine.

“We hypothesized that we could improve the sensitivity for noninvasive cancer genomics by selective sequencing of ctDNA fragments and by leveraging differences in the biology that determine DNA fragmentation,” wrote Florent Mouliere, PhD, from the Cancer Research UK Cambridge Institute, and coauthors.

Cell-free plasma fragments are often cleaved at around 167 base pairs in length and differences in length between circulating fetal and maternal DNA are already used for noninvasive prenatal diagnosis. However, the authors said that only a few studies, with conflicting results, have looked at the size distribution of tumor-derived cfDNA.

The study used two approaches to determining the size profile of mutant ctDNA. The first looked at tumor and nontumor cfDNA in mice with human ovarian cancer xenografts and the second approach used deep sequencing in 19 cancer patients. This revealed that tumor-derived cfDNA was most commonly found in fragments between 90-150 base pairs or 250-320 base pairs in size.

The researchers also noted that mutant circulating tumor DNA was generally more fragmented than nonmutant cfDNA and that patients with untreated advanced cancer showed consistently shorter lengths of mutant DNA.

The next question was whether size selection and other biological properties – such as somatic alterations – of the cfDNA could be used to enhance detection of ctDNA via machine learning technology.

Two models, designed to distinguish between healthy and cancerous samples, were developed using 153 samples, then validated on two datasets of 94 and 83 samples.

One of these models correctly classified cancerous samples in 94% of samples from patients with cancers known to have high levels of ctDNA – colorectal, cholangiocarcinoma, ovarian, breast, and melanoma – and in 65% of samples from low-ctDNA cancers – pancreatic, renal, and glioma.

Another model focused just on fragmentation patterns and was still able to distinguish cancer samples from those of healthy controls, although with slightly reduced area under the curve.

“Our results indicate that exploiting fundamental properties of cfDNA with fragment-specific analyses can allow more sensitive evaluation of ctDNA,” the authors wrote. “We identified features that could determine the presence and amount of ctDNA in plasma samples, without a prior knowledge of somatic aberrations.”

The authors pointed out that size selection of DNA fragments was relatively simple and cheap, and was also compatible with other genome-wide and targeted genomic analyses, “greatly increasing the potential value and utility of liquid biopsies as well as the cost-effectiveness of cfDNA sequencing.”

However, they cautioned that their catalogue had focused solely on double-stranded DNA and was subject to potential biases from the DNA extraction and sequencing methods they used in the study. They also commented that other biological effects could help refine the analysis of ctDNA.

“Other bodily fluids [urine, cerebrospinal fluid, and saliva], different nucleic acids and structures, altered mechanisms of release into circulation, or sample processing methods could exhibit varying fragment size signatures and could offer additional exploitable biological patterns for selective sequencing,” they wrote.

The study was supported by the University of Cambridge, Cancer Research UK, and the Engineering and Physical Sciences Research Council. Research supporting the study was also funded by the European Research Council, the National Institute for Health Research Cambridge, National Cancer Research Network, Cambridge Experimental Cancer Medicine Centre, Hutchison Whampoa, Target Ovarian Cancer, the Medical Research Council, and AstraZeneca. Three authors are cofounders, shareholders, and officers/consultants in a company specializing in ctDNA analysis. One author declared research funding and advisory board fees from private industry. Seven authors are listed on related patents.

SOURCE: Mouliere F et al. Sci Transl Med. 2018 Nov 7. doi: 10.1126/scitranslmed.aat4921.
 

Various disease parameters can help clinicians make treatment decisions for patients with metastatic renal cell carcinoma (mRCC) undergoing active surveillance, but the change in tumor burden may be the best, suggests an Italian cohort study.

Investigators led by Davide Bimbatti, MD, of Azienda Ospedaliera Universitaria Integrata in Verona, Italy, retrospectively studied 52 patients with mRCC who started active surveillance as their initial strategy for disease management. They assessed three predictors of outcomes: International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk class, number of metastatic sites, and tumor burden.

Patients remained on active surveillance for a median of 18.3 months and had a median total overall survival of 80.1 months, according to study results published in Urologic Oncology. Fully 69.2% started first-line systemic therapy during a median follow-up of 38.5 months.

The only baseline factor predicting time on active surveillance was IMDC class (hazard ratio, 2.15; P = .011).

An increasing number of metastatic sites during active surveillance was associated with poorer total overall survival (HR, 2.86; P = .010) and a trend toward poorer postsurveillance overall survival (HR, 2.37; P = .060).

Increasing tumor burden, measured as the sum in millimeters of the longest tumor diameter of each measurable lesion, during active surveillance was associated with both poorer total overall survival (HR, 1.16; P = .024) and poorer postsurveillance overall survival (HR, 1.21; P = .004).

Finally, an IMDC class of good or intermediate versus poor at the start of systemic therapy was a favorable predictor (HR, 0.07; P = .010; and HR, 0.12; P = .044, respectively) and an increase in tumor burden was an unfavorable predictor (HR, 1.26; P = .005) of postsurveillance overall survival.

“Our study confirms that active surveillance is a safe option for certain patients, with a median time on surveillance of 1.5 years delaying the beginning of systemic therapies and avoiding drug-related toxicities, with a median overall survival greater than 6.5 years,” wrote Dr. Bimbatti and coinvestigators.

“During active surveillance, patients rarely show any deterioration of the IMDC prognostic class. Meanwhile, the tumor burden changes, more than the increase of metastatic sites, account for the heterogeneity of the disease and may help physicians to make decisions about the early termination of active surveillance and the start of systemic therapy,” they concluded.

SOURCE: Bimbatti D et al. Urol Oncol. 2018 Oct 6. doi: 10.1016/j.urolonc.2018.08.018.

Various disease parameters can help clinicians make treatment decisions for patients with metastatic renal cell carcinoma (mRCC) undergoing active surveillance, but the change in tumor burden may be the best, suggests an Italian cohort study.

Investigators led by Davide Bimbatti, MD, of Azienda Ospedaliera Universitaria Integrata in Verona, Italy, retrospectively studied 52 patients with mRCC who started active surveillance as their initial strategy for disease management. They assessed three predictors of outcomes: International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk class, number of metastatic sites, and tumor burden.

Patients remained on active surveillance for a median of 18.3 months and had a median total overall survival of 80.1 months, according to study results published in Urologic Oncology. Fully 69.2% started first-line systemic therapy during a median follow-up of 38.5 months.

The only baseline factor predicting time on active surveillance was IMDC class (hazard ratio, 2.15; P = .011).

An increasing number of metastatic sites during active surveillance was associated with poorer total overall survival (HR, 2.86; P = .010) and a trend toward poorer postsurveillance overall survival (HR, 2.37; P = .060).

Increasing tumor burden, measured as the sum in millimeters of the longest tumor diameter of each measurable lesion, during active surveillance was associated with both poorer total overall survival (HR, 1.16; P = .024) and poorer postsurveillance overall survival (HR, 1.21; P = .004).

Finally, an IMDC class of good or intermediate versus poor at the start of systemic therapy was a favorable predictor (HR, 0.07; P = .010; and HR, 0.12; P = .044, respectively) and an increase in tumor burden was an unfavorable predictor (HR, 1.26; P = .005) of postsurveillance overall survival.

“Our study confirms that active surveillance is a safe option for certain patients, with a median time on surveillance of 1.5 years delaying the beginning of systemic therapies and avoiding drug-related toxicities, with a median overall survival greater than 6.5 years,” wrote Dr. Bimbatti and coinvestigators.

“During active surveillance, patients rarely show any deterioration of the IMDC prognostic class. Meanwhile, the tumor burden changes, more than the increase of metastatic sites, account for the heterogeneity of the disease and may help physicians to make decisions about the early termination of active surveillance and the start of systemic therapy,” they concluded.

SOURCE: Bimbatti D et al. Urol Oncol. 2018 Oct 6. doi: 10.1016/j.urolonc.2018.08.018.

Various disease parameters can help clinicians make treatment decisions for patients with metastatic renal cell carcinoma (mRCC) undergoing active surveillance, but the change in tumor burden may be the best, suggests an Italian cohort study.

Investigators led by Davide Bimbatti, MD, of Azienda Ospedaliera Universitaria Integrata in Verona, Italy, retrospectively studied 52 patients with mRCC who started active surveillance as their initial strategy for disease management. They assessed three predictors of outcomes: International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk class, number of metastatic sites, and tumor burden.

Patients remained on active surveillance for a median of 18.3 months and had a median total overall survival of 80.1 months, according to study results published in Urologic Oncology. Fully 69.2% started first-line systemic therapy during a median follow-up of 38.5 months.

The only baseline factor predicting time on active surveillance was IMDC class (hazard ratio, 2.15; P = .011).

An increasing number of metastatic sites during active surveillance was associated with poorer total overall survival (HR, 2.86; P = .010) and a trend toward poorer postsurveillance overall survival (HR, 2.37; P = .060).

Increasing tumor burden, measured as the sum in millimeters of the longest tumor diameter of each measurable lesion, during active surveillance was associated with both poorer total overall survival (HR, 1.16; P = .024) and poorer postsurveillance overall survival (HR, 1.21; P = .004).

Finally, an IMDC class of good or intermediate versus poor at the start of systemic therapy was a favorable predictor (HR, 0.07; P = .010; and HR, 0.12; P = .044, respectively) and an increase in tumor burden was an unfavorable predictor (HR, 1.26; P = .005) of postsurveillance overall survival.

“Our study confirms that active surveillance is a safe option for certain patients, with a median time on surveillance of 1.5 years delaying the beginning of systemic therapies and avoiding drug-related toxicities, with a median overall survival greater than 6.5 years,” wrote Dr. Bimbatti and coinvestigators.

“During active surveillance, patients rarely show any deterioration of the IMDC prognostic class. Meanwhile, the tumor burden changes, more than the increase of metastatic sites, account for the heterogeneity of the disease and may help physicians to make decisions about the early termination of active surveillance and the start of systemic therapy,” they concluded.

SOURCE: Bimbatti D et al. Urol Oncol. 2018 Oct 6. doi: 10.1016/j.urolonc.2018.08.018.

In a southwestern U.S. population having renal cell carcinoma (RCC), patient and disease characteristics differ by race/ethnicity in ways that may have implications for prevention, diagnosis, prognosis, and treatment, finds a single-center cohort study.

Investigators led by Ken Batai, PhD, of University of Arizona, Tucson, retrospectively reviewed the medical records of 294 patients with RCC as their first cancer who underwent partial or radical nephrectomy: 151 European Americans, 95 Hispanic Americans, 22 Native Americans, 9 African Americans, and 17 other race/ethnicity. About 12% overall had metastases at presentation.

On average, compared with European Americans, Hispanic Americans were about 5 years younger at diagnosis (55.8 vs. 60.5) and had higher odds of diagnosis before the age of 50 (odds ratio, 2.77), according to results published in Clinical Genitourinary Cancer.

Native Americans were even younger (49.7) and had dramatically elevated odds of diagnosis before that age (odds ratio, 6.23).

Relative to their European American counterparts, Hispanic Americans less commonly smoked (30.5% vs 48.6%) and African Americans more commonly had chronic kidney disease (37.5% vs. 5.8%). Both groups had higher prevalence of diabetes (45.6% and 54.5% vs. 21.7%). In addition, Native Americans had higher body mass index (35.2 vs. 30.7).

Clear cell histology was seen in 78.8% of European Americans, but in 92.6% of Hispanic Americans (odds ratio, 2.79) and 86.4% of Native Americans. African Americans more commonly had stage III or IV disease at diagnosis (77.8% vs. 35.3%; odds ratio, 6.51), but the racial/ethnic groups did not differ significantly on grade, tumor size, or presence of necrosis.

Among the Hispanic American patients undergoing radical nephrectomy, disease was more commonly of stage III or IV at diagnosis in those who were aged 65 or older (odds ratio, 10.48) and those who spoke Spanish as their primary language (odds ratios, 4.61).

The reasons for the observed racial/ethnic disparities remain unclear, according to Dr. Batai and his coinvestigators. Nonetheless, “it is necessary to better understand the clinical characteristics of these underserved Hispanic American and Native American populations with high kidney cancer burden,” they wrote.

“Our findings can direct future research toward elucidating the difference in tumor behavior among the different ethnic groups and health care issues causing poor outcomes,” they concluded. The findings also “bring ... awareness to practitioners treating patients from these racial/ethnic minority groups regarding the clinical characteristics and underlying issues in these patient populations.”

The study was supported by the American Cancer Society and the Partnership for Native American Cancer Prevention.

SOURCE: Batai K et al. Clin Genitourin Cancer. 2018 Oct 26. doi: 10.1016/j.clgc.2018.10.012.

In a southwestern U.S. population having renal cell carcinoma (RCC), patient and disease characteristics differ by race/ethnicity in ways that may have implications for prevention, diagnosis, prognosis, and treatment, finds a single-center cohort study.

Investigators led by Ken Batai, PhD, of University of Arizona, Tucson, retrospectively reviewed the medical records of 294 patients with RCC as their first cancer who underwent partial or radical nephrectomy: 151 European Americans, 95 Hispanic Americans, 22 Native Americans, 9 African Americans, and 17 other race/ethnicity. About 12% overall had metastases at presentation.

On average, compared with European Americans, Hispanic Americans were about 5 years younger at diagnosis (55.8 vs. 60.5) and had higher odds of diagnosis before the age of 50 (odds ratio, 2.77), according to results published in Clinical Genitourinary Cancer.

Native Americans were even younger (49.7) and had dramatically elevated odds of diagnosis before that age (odds ratio, 6.23).

Relative to their European American counterparts, Hispanic Americans less commonly smoked (30.5% vs 48.6%) and African Americans more commonly had chronic kidney disease (37.5% vs. 5.8%). Both groups had higher prevalence of diabetes (45.6% and 54.5% vs. 21.7%). In addition, Native Americans had higher body mass index (35.2 vs. 30.7).

Clear cell histology was seen in 78.8% of European Americans, but in 92.6% of Hispanic Americans (odds ratio, 2.79) and 86.4% of Native Americans. African Americans more commonly had stage III or IV disease at diagnosis (77.8% vs. 35.3%; odds ratio, 6.51), but the racial/ethnic groups did not differ significantly on grade, tumor size, or presence of necrosis.

Among the Hispanic American patients undergoing radical nephrectomy, disease was more commonly of stage III or IV at diagnosis in those who were aged 65 or older (odds ratio, 10.48) and those who spoke Spanish as their primary language (odds ratios, 4.61).

The reasons for the observed racial/ethnic disparities remain unclear, according to Dr. Batai and his coinvestigators. Nonetheless, “it is necessary to better understand the clinical characteristics of these underserved Hispanic American and Native American populations with high kidney cancer burden,” they wrote.

“Our findings can direct future research toward elucidating the difference in tumor behavior among the different ethnic groups and health care issues causing poor outcomes,” they concluded. The findings also “bring ... awareness to practitioners treating patients from these racial/ethnic minority groups regarding the clinical characteristics and underlying issues in these patient populations.”

The study was supported by the American Cancer Society and the Partnership for Native American Cancer Prevention.

SOURCE: Batai K et al. Clin Genitourin Cancer. 2018 Oct 26. doi: 10.1016/j.clgc.2018.10.012.

In a southwestern U.S. population having renal cell carcinoma (RCC), patient and disease characteristics differ by race/ethnicity in ways that may have implications for prevention, diagnosis, prognosis, and treatment, finds a single-center cohort study.

Investigators led by Ken Batai, PhD, of University of Arizona, Tucson, retrospectively reviewed the medical records of 294 patients with RCC as their first cancer who underwent partial or radical nephrectomy: 151 European Americans, 95 Hispanic Americans, 22 Native Americans, 9 African Americans, and 17 other race/ethnicity. About 12% overall had metastases at presentation.

On average, compared with European Americans, Hispanic Americans were about 5 years younger at diagnosis (55.8 vs. 60.5) and had higher odds of diagnosis before the age of 50 (odds ratio, 2.77), according to results published in Clinical Genitourinary Cancer.

Native Americans were even younger (49.7) and had dramatically elevated odds of diagnosis before that age (odds ratio, 6.23).

Relative to their European American counterparts, Hispanic Americans less commonly smoked (30.5% vs 48.6%) and African Americans more commonly had chronic kidney disease (37.5% vs. 5.8%). Both groups had higher prevalence of diabetes (45.6% and 54.5% vs. 21.7%). In addition, Native Americans had higher body mass index (35.2 vs. 30.7).

Clear cell histology was seen in 78.8% of European Americans, but in 92.6% of Hispanic Americans (odds ratio, 2.79) and 86.4% of Native Americans. African Americans more commonly had stage III or IV disease at diagnosis (77.8% vs. 35.3%; odds ratio, 6.51), but the racial/ethnic groups did not differ significantly on grade, tumor size, or presence of necrosis.

Among the Hispanic American patients undergoing radical nephrectomy, disease was more commonly of stage III or IV at diagnosis in those who were aged 65 or older (odds ratio, 10.48) and those who spoke Spanish as their primary language (odds ratios, 4.61).

The reasons for the observed racial/ethnic disparities remain unclear, according to Dr. Batai and his coinvestigators. Nonetheless, “it is necessary to better understand the clinical characteristics of these underserved Hispanic American and Native American populations with high kidney cancer burden,” they wrote.

“Our findings can direct future research toward elucidating the difference in tumor behavior among the different ethnic groups and health care issues causing poor outcomes,” they concluded. The findings also “bring ... awareness to practitioners treating patients from these racial/ethnic minority groups regarding the clinical characteristics and underlying issues in these patient populations.”

The study was supported by the American Cancer Society and the Partnership for Native American Cancer Prevention.

SOURCE: Batai K et al. Clin Genitourin Cancer. 2018 Oct 26. doi: 10.1016/j.clgc.2018.10.012.

High expression of karyopherin alpha 2 (KPNA2), a carrier protein that helps shuttle cancer-associated proteins from the nucleus to the cytoplasm, is an adverse prognostic factor in patients with clear cell or papillary renal cell carcinoma (RCC), according to a retrospective cohort study.

Senior author Glen Kristiansen, MD, director of the Institute of Pathology at the University Hospital Bonn (Germany), and his colleagues assessed tumor levels of KPNA2 protein by immunohistochemistry in 240 clinic patients with RCC (217 with clear cell histology, 23 with papillary histology). They also assessed tumor levels of KPNA2 mRNA in 771 patients with RCC (481 with clear cell histology, 290 with papillary cell histology) using publicly available gene expression data from the Cancer Genome Atlas (CGA).

Overall, 19% of the clinic patients’ tumors showed high expression of KPNA2 protein, according to results reported in Clinical Genitourinary Cancer. In addition, 26% of the CGA patients’ tumors showed high expression of KPNA2 mRNA.

Among patients with clear cell RCC, those with high tumor levels of KPNA2 protein survived roughly half as long as counterparts with low levels or none (74 months vs. 171 months); the difference was significant in univariate analysis (P = .012) but not in multivariate analysis that included well-known prognostic factors (HR, 1.491; P = .237). On the other hand, those with high tumor levels of KPNA2 mRNA had an elevated risk of death in both univariate analysis (HR, 2.31; P less than .001) and multivariate analysis (HR, 1.45; P = .035).

Among patients with papillary RCC, tumor levels of KPNA2 protein were not significantly associated with survival. However, those with high tumor levels of KPNA2 mRNA had a sharply elevated risk of death in both univariate analysis (HR, 9.7; P less than .001) and multivariate analysis (HR, 6.2; P = .004).

KPNA2 expression “represents a novel prognostic factor in these subtypes of RCC,” concluded Dr. Kristiansen and his coinvestigators. Therefore, this biomarker “could be used to stratify risk groups within RCC.” Collectively, the study’s findings suggest that KPNA2 is involved in both the pathogenesis and the progression of RCC. Given evidence that it helps transport p53 and fibroblast growth factor 2 at least in tumors with clear cell histology, “investigation of the nucleocytoplasmic transport through KPNA2 in [clear cell] RCC is an important task for future studies to better understand the link between elevated KPNA2 expression and altered biological processes like proliferation, cell growth, migration, invasion and tumor formation in RCC. In addition, examination of other members of [the] karyopherin-alpha family could elucidate the role of the nucleocytoplasmic transport system in pathogenesis of RCC.”

The authors reported that they had no conflict of interests.

SOURCE: Kristiansen G et al. Clin Genitourin Cancer. 2018 Oct 22. doi: 10.1016/j.clgc.2018.10.008.

High expression of karyopherin alpha 2 (KPNA2), a carrier protein that helps shuttle cancer-associated proteins from the nucleus to the cytoplasm, is an adverse prognostic factor in patients with clear cell or papillary renal cell carcinoma (RCC), according to a retrospective cohort study.

Senior author Glen Kristiansen, MD, director of the Institute of Pathology at the University Hospital Bonn (Germany), and his colleagues assessed tumor levels of KPNA2 protein by immunohistochemistry in 240 clinic patients with RCC (217 with clear cell histology, 23 with papillary histology). They also assessed tumor levels of KPNA2 mRNA in 771 patients with RCC (481 with clear cell histology, 290 with papillary cell histology) using publicly available gene expression data from the Cancer Genome Atlas (CGA).

Overall, 19% of the clinic patients’ tumors showed high expression of KPNA2 protein, according to results reported in Clinical Genitourinary Cancer. In addition, 26% of the CGA patients’ tumors showed high expression of KPNA2 mRNA.

Among patients with clear cell RCC, those with high tumor levels of KPNA2 protein survived roughly half as long as counterparts with low levels or none (74 months vs. 171 months); the difference was significant in univariate analysis (P = .012) but not in multivariate analysis that included well-known prognostic factors (HR, 1.491; P = .237). On the other hand, those with high tumor levels of KPNA2 mRNA had an elevated risk of death in both univariate analysis (HR, 2.31; P less than .001) and multivariate analysis (HR, 1.45; P = .035).

Among patients with papillary RCC, tumor levels of KPNA2 protein were not significantly associated with survival. However, those with high tumor levels of KPNA2 mRNA had a sharply elevated risk of death in both univariate analysis (HR, 9.7; P less than .001) and multivariate analysis (HR, 6.2; P = .004).

KPNA2 expression “represents a novel prognostic factor in these subtypes of RCC,” concluded Dr. Kristiansen and his coinvestigators. Therefore, this biomarker “could be used to stratify risk groups within RCC.” Collectively, the study’s findings suggest that KPNA2 is involved in both the pathogenesis and the progression of RCC. Given evidence that it helps transport p53 and fibroblast growth factor 2 at least in tumors with clear cell histology, “investigation of the nucleocytoplasmic transport through KPNA2 in [clear cell] RCC is an important task for future studies to better understand the link between elevated KPNA2 expression and altered biological processes like proliferation, cell growth, migration, invasion and tumor formation in RCC. In addition, examination of other members of [the] karyopherin-alpha family could elucidate the role of the nucleocytoplasmic transport system in pathogenesis of RCC.”

The authors reported that they had no conflict of interests.

SOURCE: Kristiansen G et al. Clin Genitourin Cancer. 2018 Oct 22. doi: 10.1016/j.clgc.2018.10.008.

High expression of karyopherin alpha 2 (KPNA2), a carrier protein that helps shuttle cancer-associated proteins from the nucleus to the cytoplasm, is an adverse prognostic factor in patients with clear cell or papillary renal cell carcinoma (RCC), according to a retrospective cohort study.

Senior author Glen Kristiansen, MD, director of the Institute of Pathology at the University Hospital Bonn (Germany), and his colleagues assessed tumor levels of KPNA2 protein by immunohistochemistry in 240 clinic patients with RCC (217 with clear cell histology, 23 with papillary histology). They also assessed tumor levels of KPNA2 mRNA in 771 patients with RCC (481 with clear cell histology, 290 with papillary cell histology) using publicly available gene expression data from the Cancer Genome Atlas (CGA).

Overall, 19% of the clinic patients’ tumors showed high expression of KPNA2 protein, according to results reported in Clinical Genitourinary Cancer. In addition, 26% of the CGA patients’ tumors showed high expression of KPNA2 mRNA.

Among patients with clear cell RCC, those with high tumor levels of KPNA2 protein survived roughly half as long as counterparts with low levels or none (74 months vs. 171 months); the difference was significant in univariate analysis (P = .012) but not in multivariate analysis that included well-known prognostic factors (HR, 1.491; P = .237). On the other hand, those with high tumor levels of KPNA2 mRNA had an elevated risk of death in both univariate analysis (HR, 2.31; P less than .001) and multivariate analysis (HR, 1.45; P = .035).

Among patients with papillary RCC, tumor levels of KPNA2 protein were not significantly associated with survival. However, those with high tumor levels of KPNA2 mRNA had a sharply elevated risk of death in both univariate analysis (HR, 9.7; P less than .001) and multivariate analysis (HR, 6.2; P = .004).

KPNA2 expression “represents a novel prognostic factor in these subtypes of RCC,” concluded Dr. Kristiansen and his coinvestigators. Therefore, this biomarker “could be used to stratify risk groups within RCC.” Collectively, the study’s findings suggest that KPNA2 is involved in both the pathogenesis and the progression of RCC. Given evidence that it helps transport p53 and fibroblast growth factor 2 at least in tumors with clear cell histology, “investigation of the nucleocytoplasmic transport through KPNA2 in [clear cell] RCC is an important task for future studies to better understand the link between elevated KPNA2 expression and altered biological processes like proliferation, cell growth, migration, invasion and tumor formation in RCC. In addition, examination of other members of [the] karyopherin-alpha family could elucidate the role of the nucleocytoplasmic transport system in pathogenesis of RCC.”

The authors reported that they had no conflict of interests.

SOURCE: Kristiansen G et al. Clin Genitourin Cancer. 2018 Oct 22. doi: 10.1016/j.clgc.2018.10.008.

While adjuvant axitinib failed to improve disease-free survival in a recent phase 3 renal cell carcinoma (RCC) trial, the highest-risk subgroup appeared to benefit, according to a report on the study.

The phase 3 ATLAS trial was stopped early because of a lack of benefit for axitinib versus placebo in the study, which included patients with locoregional RCC at risk of recurrence after nephrectomy.

However, a prespecified analysis showed that axitinib reduced risk of disease-free survival events by about one-third in the highest-risk subset of patients, according to investigator David I. Quinn, MD, USC Norris Comprehensive Cancer Center, Los Angeles, and colleagues.

That finding tracks with results of the earlier S-TRAC trial, in which patients at high risk of tumor recurrence after nephrectomy had significantly longer disease-free survival with sunitinib versus placebo, Dr. Quinn and coauthors said.

“Taken together, these results support that patients at highest risk for RCC recurrence benefit from adjuvant treatment,” they wrote in Annals of Oncology.

In the ATLAS trial, Dr. Quinn and coinvestigators at 137 centers in eight countries enrolled 724 adults with newly diagnosed renal cell carcinoma (greater than or equal to pT2 and/or N+, any Fuhrman grade) with Eastern Cooperative Oncology Group status of 0 or 1 and prior nephrectomy.

Patients were randomly assigned to oral, twice-daily axitinib 5 mg or placebo for up to 3 years of treatment, and at least 1 year of treatment provided there was no recurrence, substantial toxicity, or withdrawal of consent.

For the primary endpoint, disease-free survival per independent review committee assessment, the hazard ratio was 0.870 (95% confidence interval, 0.660-1.147; P = .3211), according to the report. Disease-free survival as rated by investigators showed a somewhat larger but still not statistically significant reduction in risk of an event, Dr. Quinn and colleagues said.

However, in the prespecified subgroup analyses, the patients at highest risk (pT3 with Fuhrman grade greater than or equal to 3 or pT4 and/or N+, any T, any Fuhrman grade) had a reduction of risk with hazard ratios of 0.735 per independent review committee (P = .0704) and 0.641 per investigator (P = .0051).

The ATLAS study was designed before results of the S-TRAC study were known, and so patients at lower risk of recurrence were included, said Dr. Quinn and coauthors.

Ongoing trials are looking at sorafenib, everolimus, and immune checkpoint inhibitors in the adjuvant RCC setting, they noted in their discussion of ATLAS, S-TRAC, and other investigations.

Results from these trials may provide clarification on the future of adjuvant treatment for RCC, and whether angiogenesis inhibition is the key mechanism to obtain a reduction in risk of relapse after nephrectomy,” they said.

The study was sponsored by Pfizer and SFJ Pharmaceuticals. Dr. Quinn reported providing advisory board services for Pfizer, Bayer, Novartis, Bristol-Myers Squibb, Merck, Exelixis, Genentech, Roche, AstraZeneca, and Astellas. Coauthors reported disclosures related to Bristol-Myers Squibb, Ipsen, MSD, Novartis, Pfizer, and Roche, among others.

SOURCE: Quinn DI et al. Ann Oncol. 2018 Oct 20. doi: 10.1093/annonc/mdy454.

While adjuvant axitinib failed to improve disease-free survival in a recent phase 3 renal cell carcinoma (RCC) trial, the highest-risk subgroup appeared to benefit, according to a report on the study.

The phase 3 ATLAS trial was stopped early because of a lack of benefit for axitinib versus placebo in the study, which included patients with locoregional RCC at risk of recurrence after nephrectomy.

However, a prespecified analysis showed that axitinib reduced risk of disease-free survival events by about one-third in the highest-risk subset of patients, according to investigator David I. Quinn, MD, USC Norris Comprehensive Cancer Center, Los Angeles, and colleagues.

That finding tracks with results of the earlier S-TRAC trial, in which patients at high risk of tumor recurrence after nephrectomy had significantly longer disease-free survival with sunitinib versus placebo, Dr. Quinn and coauthors said.

“Taken together, these results support that patients at highest risk for RCC recurrence benefit from adjuvant treatment,” they wrote in Annals of Oncology.

In the ATLAS trial, Dr. Quinn and coinvestigators at 137 centers in eight countries enrolled 724 adults with newly diagnosed renal cell carcinoma (greater than or equal to pT2 and/or N+, any Fuhrman grade) with Eastern Cooperative Oncology Group status of 0 or 1 and prior nephrectomy.

Patients were randomly assigned to oral, twice-daily axitinib 5 mg or placebo for up to 3 years of treatment, and at least 1 year of treatment provided there was no recurrence, substantial toxicity, or withdrawal of consent.

For the primary endpoint, disease-free survival per independent review committee assessment, the hazard ratio was 0.870 (95% confidence interval, 0.660-1.147; P = .3211), according to the report. Disease-free survival as rated by investigators showed a somewhat larger but still not statistically significant reduction in risk of an event, Dr. Quinn and colleagues said.

However, in the prespecified subgroup analyses, the patients at highest risk (pT3 with Fuhrman grade greater than or equal to 3 or pT4 and/or N+, any T, any Fuhrman grade) had a reduction of risk with hazard ratios of 0.735 per independent review committee (P = .0704) and 0.641 per investigator (P = .0051).

The ATLAS study was designed before results of the S-TRAC study were known, and so patients at lower risk of recurrence were included, said Dr. Quinn and coauthors.

Ongoing trials are looking at sorafenib, everolimus, and immune checkpoint inhibitors in the adjuvant RCC setting, they noted in their discussion of ATLAS, S-TRAC, and other investigations.

Results from these trials may provide clarification on the future of adjuvant treatment for RCC, and whether angiogenesis inhibition is the key mechanism to obtain a reduction in risk of relapse after nephrectomy,” they said.

The study was sponsored by Pfizer and SFJ Pharmaceuticals. Dr. Quinn reported providing advisory board services for Pfizer, Bayer, Novartis, Bristol-Myers Squibb, Merck, Exelixis, Genentech, Roche, AstraZeneca, and Astellas. Coauthors reported disclosures related to Bristol-Myers Squibb, Ipsen, MSD, Novartis, Pfizer, and Roche, among others.

SOURCE: Quinn DI et al. Ann Oncol. 2018 Oct 20. doi: 10.1093/annonc/mdy454.

While adjuvant axitinib failed to improve disease-free survival in a recent phase 3 renal cell carcinoma (RCC) trial, the highest-risk subgroup appeared to benefit, according to a report on the study.

The phase 3 ATLAS trial was stopped early because of a lack of benefit for axitinib versus placebo in the study, which included patients with locoregional RCC at risk of recurrence after nephrectomy.

However, a prespecified analysis showed that axitinib reduced risk of disease-free survival events by about one-third in the highest-risk subset of patients, according to investigator David I. Quinn, MD, USC Norris Comprehensive Cancer Center, Los Angeles, and colleagues.

That finding tracks with results of the earlier S-TRAC trial, in which patients at high risk of tumor recurrence after nephrectomy had significantly longer disease-free survival with sunitinib versus placebo, Dr. Quinn and coauthors said.

“Taken together, these results support that patients at highest risk for RCC recurrence benefit from adjuvant treatment,” they wrote in Annals of Oncology.

In the ATLAS trial, Dr. Quinn and coinvestigators at 137 centers in eight countries enrolled 724 adults with newly diagnosed renal cell carcinoma (greater than or equal to pT2 and/or N+, any Fuhrman grade) with Eastern Cooperative Oncology Group status of 0 or 1 and prior nephrectomy.

Patients were randomly assigned to oral, twice-daily axitinib 5 mg or placebo for up to 3 years of treatment, and at least 1 year of treatment provided there was no recurrence, substantial toxicity, or withdrawal of consent.

For the primary endpoint, disease-free survival per independent review committee assessment, the hazard ratio was 0.870 (95% confidence interval, 0.660-1.147; P = .3211), according to the report. Disease-free survival as rated by investigators showed a somewhat larger but still not statistically significant reduction in risk of an event, Dr. Quinn and colleagues said.

However, in the prespecified subgroup analyses, the patients at highest risk (pT3 with Fuhrman grade greater than or equal to 3 or pT4 and/or N+, any T, any Fuhrman grade) had a reduction of risk with hazard ratios of 0.735 per independent review committee (P = .0704) and 0.641 per investigator (P = .0051).

The ATLAS study was designed before results of the S-TRAC study were known, and so patients at lower risk of recurrence were included, said Dr. Quinn and coauthors.

Ongoing trials are looking at sorafenib, everolimus, and immune checkpoint inhibitors in the adjuvant RCC setting, they noted in their discussion of ATLAS, S-TRAC, and other investigations.

Results from these trials may provide clarification on the future of adjuvant treatment for RCC, and whether angiogenesis inhibition is the key mechanism to obtain a reduction in risk of relapse after nephrectomy,” they said.

The study was sponsored by Pfizer and SFJ Pharmaceuticals. Dr. Quinn reported providing advisory board services for Pfizer, Bayer, Novartis, Bristol-Myers Squibb, Merck, Exelixis, Genentech, Roche, AstraZeneca, and Astellas. Coauthors reported disclosures related to Bristol-Myers Squibb, Ipsen, MSD, Novartis, Pfizer, and Roche, among others.

SOURCE: Quinn DI et al. Ann Oncol. 2018 Oct 20. doi: 10.1093/annonc/mdy454.