Renal Cell Carcinoma

In patients with renal cell carcinoma, trough concentrations of pazopanib in a specific target range were associated with better safety and comparable efficacy, versus higher concentrations of the drug, authors of an exploratory investigation have reported.

Fewer serious toxicities were seen in patients with pazopanib concentrations in the 20- to 50-mcg/mL range, yet overall response rate was similar compared to patients with concentrations over 50 mcg/mL, according to results of the retrospective study.

The findings suggest therapeutic drug monitoring to achieve a specific trough concentration may be useful to optimize pazopanib dosing, according to investigator Tomohiro Terada, PhD, of Shiga University of Medical Science Hospital, Japan, and coinvestigators.

Therapeutic drug monitoring for sunitinib in RCC patients was recently covered by medical insurance in Japan, Dr. Terada and colleagues wrote in Clinical Genitourinary Cancer.

The strategy may be especially suited to adjusting the dose of pazopanib, which is often associated with severe toxicities and has pharmacokinetics that suggest a wide variation between individuals, they added.

The retrospective study by Dr. Terada and colleagues included 27 renal cell carcinoma patients who received pazopanib at doses of 400, 600, or 800 mg daily based on the recommendation of the treating physician, with doses reduced or discontinued based on adverse events or progression.

Trough concentrations of pazopanib 3 months after starting the treatment ranged from a low of 10.6 mcg/mL to a high of 106 mcg/mL, with a median of 49.1 mcg/mL, according to the report.

One-third of patients experienced grade 3 or greater toxicities, including anorexia, hypertension, anemia, and thrombocytopenia, among others. The median pazopanib concentration for those nine patients was 69.3 mcg/mL, compared with 41.2 mcg/mL for those not experiencing serious toxicities (P less than .05).

A concentration over 50.3 mcg/mL predicted grade 3 or greater toxicity, statistical analysis showed, with 8 out of 13 patients with concentrations above that threshold experiencing serious toxicities. By contrast, 1 of 14 patients below that threshold experienced grade 3 or greater toxicities.

No responses were observed in three patients with pazopanib concentrations below 20.5 mcg/mL, a concentration level considered to be subtherapeutic based on previous investigations.

Overall response rates were similar for patients with concentrations in the “optimal” 20.5- and 50.3-mcg/mL range and those with concentrations over 50.3 mcg/mL, according to the investigators.

Among 11 patients in that “optimal” range, partial responses were seen in 5, they reported, while for the 13 patients with high concentrations of the drug, partial responses were seen in 4 patients and a complete response was seen in 1 patient.

Trough concentrations may not predict all types of toxicities, according to the investigators, who said that the results of their small, retrospective analysis should be validated in a large, prospective study.

In particular, there was no significant relationship between trough concentration of pazopanib and development of grade 2 or greater hepatotoxicity, a common and specific side effect of the drug.

“Based on these findings, pazopanib-induced hepatotoxicity may not be related to the pharmacokinetics of pazopanib,” they wrote. “Therefore, pharmacogenomics testing is needed to predict pazopanib-induced hepatotoxicity.”

Dr. Terada and coauthors said they had no conflicts of interest to report.
 

SOURCE: Noda S et al. Clin Genitourin Cancer. 2018 Dec 7. doi: 10.1016/j.clgc.2018.12.001.

In patients with renal cell carcinoma, trough concentrations of pazopanib in a specific target range were associated with better safety and comparable efficacy, versus higher concentrations of the drug, authors of an exploratory investigation have reported.

Fewer serious toxicities were seen in patients with pazopanib concentrations in the 20- to 50-mcg/mL range, yet overall response rate was similar compared to patients with concentrations over 50 mcg/mL, according to results of the retrospective study.

The findings suggest therapeutic drug monitoring to achieve a specific trough concentration may be useful to optimize pazopanib dosing, according to investigator Tomohiro Terada, PhD, of Shiga University of Medical Science Hospital, Japan, and coinvestigators.

Therapeutic drug monitoring for sunitinib in RCC patients was recently covered by medical insurance in Japan, Dr. Terada and colleagues wrote in Clinical Genitourinary Cancer.

The strategy may be especially suited to adjusting the dose of pazopanib, which is often associated with severe toxicities and has pharmacokinetics that suggest a wide variation between individuals, they added.

The retrospective study by Dr. Terada and colleagues included 27 renal cell carcinoma patients who received pazopanib at doses of 400, 600, or 800 mg daily based on the recommendation of the treating physician, with doses reduced or discontinued based on adverse events or progression.

Trough concentrations of pazopanib 3 months after starting the treatment ranged from a low of 10.6 mcg/mL to a high of 106 mcg/mL, with a median of 49.1 mcg/mL, according to the report.

One-third of patients experienced grade 3 or greater toxicities, including anorexia, hypertension, anemia, and thrombocytopenia, among others. The median pazopanib concentration for those nine patients was 69.3 mcg/mL, compared with 41.2 mcg/mL for those not experiencing serious toxicities (P less than .05).

A concentration over 50.3 mcg/mL predicted grade 3 or greater toxicity, statistical analysis showed, with 8 out of 13 patients with concentrations above that threshold experiencing serious toxicities. By contrast, 1 of 14 patients below that threshold experienced grade 3 or greater toxicities.

No responses were observed in three patients with pazopanib concentrations below 20.5 mcg/mL, a concentration level considered to be subtherapeutic based on previous investigations.

Overall response rates were similar for patients with concentrations in the “optimal” 20.5- and 50.3-mcg/mL range and those with concentrations over 50.3 mcg/mL, according to the investigators.

Among 11 patients in that “optimal” range, partial responses were seen in 5, they reported, while for the 13 patients with high concentrations of the drug, partial responses were seen in 4 patients and a complete response was seen in 1 patient.

Trough concentrations may not predict all types of toxicities, according to the investigators, who said that the results of their small, retrospective analysis should be validated in a large, prospective study.

In particular, there was no significant relationship between trough concentration of pazopanib and development of grade 2 or greater hepatotoxicity, a common and specific side effect of the drug.

“Based on these findings, pazopanib-induced hepatotoxicity may not be related to the pharmacokinetics of pazopanib,” they wrote. “Therefore, pharmacogenomics testing is needed to predict pazopanib-induced hepatotoxicity.”

Dr. Terada and coauthors said they had no conflicts of interest to report.
 

SOURCE: Noda S et al. Clin Genitourin Cancer. 2018 Dec 7. doi: 10.1016/j.clgc.2018.12.001.

In patients with renal cell carcinoma, trough concentrations of pazopanib in a specific target range were associated with better safety and comparable efficacy, versus higher concentrations of the drug, authors of an exploratory investigation have reported.

Fewer serious toxicities were seen in patients with pazopanib concentrations in the 20- to 50-mcg/mL range, yet overall response rate was similar compared to patients with concentrations over 50 mcg/mL, according to results of the retrospective study.

The findings suggest therapeutic drug monitoring to achieve a specific trough concentration may be useful to optimize pazopanib dosing, according to investigator Tomohiro Terada, PhD, of Shiga University of Medical Science Hospital, Japan, and coinvestigators.

Therapeutic drug monitoring for sunitinib in RCC patients was recently covered by medical insurance in Japan, Dr. Terada and colleagues wrote in Clinical Genitourinary Cancer.

The strategy may be especially suited to adjusting the dose of pazopanib, which is often associated with severe toxicities and has pharmacokinetics that suggest a wide variation between individuals, they added.

The retrospective study by Dr. Terada and colleagues included 27 renal cell carcinoma patients who received pazopanib at doses of 400, 600, or 800 mg daily based on the recommendation of the treating physician, with doses reduced or discontinued based on adverse events or progression.

Trough concentrations of pazopanib 3 months after starting the treatment ranged from a low of 10.6 mcg/mL to a high of 106 mcg/mL, with a median of 49.1 mcg/mL, according to the report.

One-third of patients experienced grade 3 or greater toxicities, including anorexia, hypertension, anemia, and thrombocytopenia, among others. The median pazopanib concentration for those nine patients was 69.3 mcg/mL, compared with 41.2 mcg/mL for those not experiencing serious toxicities (P less than .05).

A concentration over 50.3 mcg/mL predicted grade 3 or greater toxicity, statistical analysis showed, with 8 out of 13 patients with concentrations above that threshold experiencing serious toxicities. By contrast, 1 of 14 patients below that threshold experienced grade 3 or greater toxicities.

No responses were observed in three patients with pazopanib concentrations below 20.5 mcg/mL, a concentration level considered to be subtherapeutic based on previous investigations.

Overall response rates were similar for patients with concentrations in the “optimal” 20.5- and 50.3-mcg/mL range and those with concentrations over 50.3 mcg/mL, according to the investigators.

Among 11 patients in that “optimal” range, partial responses were seen in 5, they reported, while for the 13 patients with high concentrations of the drug, partial responses were seen in 4 patients and a complete response was seen in 1 patient.

Trough concentrations may not predict all types of toxicities, according to the investigators, who said that the results of their small, retrospective analysis should be validated in a large, prospective study.

In particular, there was no significant relationship between trough concentration of pazopanib and development of grade 2 or greater hepatotoxicity, a common and specific side effect of the drug.

“Based on these findings, pazopanib-induced hepatotoxicity may not be related to the pharmacokinetics of pazopanib,” they wrote. “Therefore, pharmacogenomics testing is needed to predict pazopanib-induced hepatotoxicity.”

Dr. Terada and coauthors said they had no conflicts of interest to report.
 

SOURCE: Noda S et al. Clin Genitourin Cancer. 2018 Dec 7. doi: 10.1016/j.clgc.2018.12.001.

While patients with renal cell carcinoma (RCC) brain metastases are traditionally thought of as having a grim prognosis, a subset of patients may experience durable long-term survival with cytoreductive nephrectomy, authors of a retrospective study have reported.

Specifically, patients with brain lesions and no additional metastatic disease sites who underwent cytoreduction had a 2-year survival rate of 52%, according to the researchers’ analysis of data from the Surveillance, Epidemiology, and End Results (SEER) Program. 

By contrast, these patients with brain-only metastases who did not undergo the procedure had a 2-year survival of 14%, reported Gennady Bratslavsky, MD, of State University of New York, Syracuse, and his associates.

The findings are at odds with “previously accepted dogma” that surgery is inadvisable in patients with RCC with brain metastases, which is traditionally thought of as a poor-risk feature, according to Dr. Bratslavsky and his colleagues.

“These patients seem to benefit from cytoreductive nephrectomy and may potentially be excellent candidates for clinical trials,” they wrote in Urologic Oncology.

However, patient selection likely drove survival outcomes in this retrospective cohort, the authors acknowledged, adding that they did not intend to argue “for or against” the role of cytoreductive nephrectomy.

In their analysis, they identified 6,403 patients with metastatic RCC and complete information on sites of metastasis; of these, 775 (12.1%) had brain metastases.

Patients with brain metastases generally fared worse than did patients with other, non-brain metastases, with 2-year survival rates of 14.9% and 28.6%, respectively (P less than .0001); however, patients with brain-only metastases had a 2-year survival of 31% overall in this analysis.

Cytoreductive nephrectomy was performed in 40.8% of patients with brain-only metastases, versus 20.8% of patients with synchronous metastases (P less than .0001).

Brain-only metastases patients who underwent cytoreductive nephrectomy had 1-year survival of 67%, 2-year survival of 52%, and median survival of 33 months, the data show. In contrast, brain-only metastases patients who did not undergo the procedure had 1-year survival of 26%, 2-year survival of 14%, and median survival of just 5 months.

Even when the researchers included patients with brain metastases in addition to other sites, cytoreduction was associated with superior outcomes, compared with patients with non-brain metastases who did not undergo cytoreduction, the investigators said. The reported 2-year survival rates in that analysis were 34.1% for brain metastasis and cytoreduction versus 14.4% for non-brain metastasis and no cytoreduction.

While this study was retrospective and was based on limited patient data, these findings nevertheless suggest that patients with RCC and isolated brain metastases might benefit from the procedure, Dr. Bratslavsky and his coauthors said.

“We anticipate that this work will be helpful for patient counseling and for modifying future exclusion criteria in clinical trials,” they concluded.

Dr. Bratslavsky and his coauthors listed no disclosures related to their research.

SOURCE: Daugherty M et al. Urol Oncol. 2018 Dec 5. doi: 10.1016/j.urolonc.2018.10.021.

While patients with renal cell carcinoma (RCC) brain metastases are traditionally thought of as having a grim prognosis, a subset of patients may experience durable long-term survival with cytoreductive nephrectomy, authors of a retrospective study have reported.

Specifically, patients with brain lesions and no additional metastatic disease sites who underwent cytoreduction had a 2-year survival rate of 52%, according to the researchers’ analysis of data from the Surveillance, Epidemiology, and End Results (SEER) Program. 

By contrast, these patients with brain-only metastases who did not undergo the procedure had a 2-year survival of 14%, reported Gennady Bratslavsky, MD, of State University of New York, Syracuse, and his associates.

The findings are at odds with “previously accepted dogma” that surgery is inadvisable in patients with RCC with brain metastases, which is traditionally thought of as a poor-risk feature, according to Dr. Bratslavsky and his colleagues.

“These patients seem to benefit from cytoreductive nephrectomy and may potentially be excellent candidates for clinical trials,” they wrote in Urologic Oncology.

However, patient selection likely drove survival outcomes in this retrospective cohort, the authors acknowledged, adding that they did not intend to argue “for or against” the role of cytoreductive nephrectomy.

In their analysis, they identified 6,403 patients with metastatic RCC and complete information on sites of metastasis; of these, 775 (12.1%) had brain metastases.

Patients with brain metastases generally fared worse than did patients with other, non-brain metastases, with 2-year survival rates of 14.9% and 28.6%, respectively (P less than .0001); however, patients with brain-only metastases had a 2-year survival of 31% overall in this analysis.

Cytoreductive nephrectomy was performed in 40.8% of patients with brain-only metastases, versus 20.8% of patients with synchronous metastases (P less than .0001).

Brain-only metastases patients who underwent cytoreductive nephrectomy had 1-year survival of 67%, 2-year survival of 52%, and median survival of 33 months, the data show. In contrast, brain-only metastases patients who did not undergo the procedure had 1-year survival of 26%, 2-year survival of 14%, and median survival of just 5 months.

Even when the researchers included patients with brain metastases in addition to other sites, cytoreduction was associated with superior outcomes, compared with patients with non-brain metastases who did not undergo cytoreduction, the investigators said. The reported 2-year survival rates in that analysis were 34.1% for brain metastasis and cytoreduction versus 14.4% for non-brain metastasis and no cytoreduction.

While this study was retrospective and was based on limited patient data, these findings nevertheless suggest that patients with RCC and isolated brain metastases might benefit from the procedure, Dr. Bratslavsky and his coauthors said.

“We anticipate that this work will be helpful for patient counseling and for modifying future exclusion criteria in clinical trials,” they concluded.

Dr. Bratslavsky and his coauthors listed no disclosures related to their research.

SOURCE: Daugherty M et al. Urol Oncol. 2018 Dec 5. doi: 10.1016/j.urolonc.2018.10.021.

While patients with renal cell carcinoma (RCC) brain metastases are traditionally thought of as having a grim prognosis, a subset of patients may experience durable long-term survival with cytoreductive nephrectomy, authors of a retrospective study have reported.

Specifically, patients with brain lesions and no additional metastatic disease sites who underwent cytoreduction had a 2-year survival rate of 52%, according to the researchers’ analysis of data from the Surveillance, Epidemiology, and End Results (SEER) Program. 

By contrast, these patients with brain-only metastases who did not undergo the procedure had a 2-year survival of 14%, reported Gennady Bratslavsky, MD, of State University of New York, Syracuse, and his associates.

The findings are at odds with “previously accepted dogma” that surgery is inadvisable in patients with RCC with brain metastases, which is traditionally thought of as a poor-risk feature, according to Dr. Bratslavsky and his colleagues.

“These patients seem to benefit from cytoreductive nephrectomy and may potentially be excellent candidates for clinical trials,” they wrote in Urologic Oncology.

However, patient selection likely drove survival outcomes in this retrospective cohort, the authors acknowledged, adding that they did not intend to argue “for or against” the role of cytoreductive nephrectomy.

In their analysis, they identified 6,403 patients with metastatic RCC and complete information on sites of metastasis; of these, 775 (12.1%) had brain metastases.

Patients with brain metastases generally fared worse than did patients with other, non-brain metastases, with 2-year survival rates of 14.9% and 28.6%, respectively (P less than .0001); however, patients with brain-only metastases had a 2-year survival of 31% overall in this analysis.

Cytoreductive nephrectomy was performed in 40.8% of patients with brain-only metastases, versus 20.8% of patients with synchronous metastases (P less than .0001).

Brain-only metastases patients who underwent cytoreductive nephrectomy had 1-year survival of 67%, 2-year survival of 52%, and median survival of 33 months, the data show. In contrast, brain-only metastases patients who did not undergo the procedure had 1-year survival of 26%, 2-year survival of 14%, and median survival of just 5 months.

Even when the researchers included patients with brain metastases in addition to other sites, cytoreduction was associated with superior outcomes, compared with patients with non-brain metastases who did not undergo cytoreduction, the investigators said. The reported 2-year survival rates in that analysis were 34.1% for brain metastasis and cytoreduction versus 14.4% for non-brain metastasis and no cytoreduction.

While this study was retrospective and was based on limited patient data, these findings nevertheless suggest that patients with RCC and isolated brain metastases might benefit from the procedure, Dr. Bratslavsky and his coauthors said.

“We anticipate that this work will be helpful for patient counseling and for modifying future exclusion criteria in clinical trials,” they concluded.

Dr. Bratslavsky and his coauthors listed no disclosures related to their research.

SOURCE: Daugherty M et al. Urol Oncol. 2018 Dec 5. doi: 10.1016/j.urolonc.2018.10.021.

The ratio of apolipoproteins B and A1 (apo B/A1) is an independent prognostic factor in patients with metastatic renal cell carcinoma, according to authors of a recent retrospective study.

The apo B/A1 ratio, evaluated prior to cytoreductive nephrectomy, was significantly linked with poor progression-free survival and overall survival, according to Fan Zhang, MD, of the Chinese PLA General Hospital in Beijing and coauthors.

Those findings suggest that patients with metastatic RCC should receive “consistent follow-up” that includes evaluation of that ratio, Dr. Zhang and colleagues said.

“As a novel prognostic factor, the preoperative apo B/A1 ratio can be utilized as a supplement to improve the current prognostic evaluation and treatment decision for patients with metastatic RCC,” they wrote in Urologic Oncology.

Apo B and A1, which are predominant components of low-density lipoprotein (LDL) and high-density lipoprotein (HDL), respectively, have “extensive connections” with cardiovascular disease, diabetes, and Alzheimer disease, the authors said.

The apo B/A1 ratio is a known risk index for cardiovascular disease, and in recent studies, it appeared to have some value in prognosis and prediction of gastric and colorectal cancer, among other neoplasms, they added.

In their retrospective study, Dr. Zhang and colleagues analyzed data on 287 metastatic RCC patients who underwent cytoreductive nephrectomy at the Chinese PLA General Hospital. The median age of the patients was 56 years, and the median apo B/A1 ratio was 0.859.

Significantly poorer progression-free survival was seen in the group of patients with a preoperative apo B/A1 ratio over the cutoff of 0.977 (P less than .0001) compared with those under the cutoff, the investigators reported. Likewise, overall survival was poorer for patients with an apo B/A1 ratio over a cutoff of 0.847 (P = .0005).

The apo B/A1 ratio was higher in patients with Fuhrman grade 3-4 versus grade 1-2 patients (P = .010), though the investigators said no significant differences in the ratio were seen in patients stratified by age, body mass index, fatty liver, number of metastases, among other subgroup analyses.

Multivariate analysis revealed that the two independent prognostic factors for progression-free survival were preoperative apo B/A1 ratio and Fuhrman grade, with hazard ratios of 3.131 and 1.906, respectively (P less than .001 for both), while independent prognostic factors for overall survival also included the apo B/A1 ratio (hazard ratio, 2.173; P less than .001) and Fuhrman grade, along with tumor necrosis and receiving targeted therapy.

This retrospective study was limited by relatively small samples from a single center, and the prognostic value of the apo B/A1 ratio needs to be verified in other studies, investigators said.

“Peripheral blood biomarkers only provide a supplement to the traditional prognostic factors in the prediction of the prognosis for patients with metastatic RCC, and are still unable to replace it,” Dr. Zhang and associates said.

The Beijing Natural Science Foundation supported the study. Dr. Zhang and coauthors had no disclosed conflicts of interest related to the work.

SOURCE: Zhang F et al. Urol Oncol. 2018 Nov 30. doi: 10.1016/j.urolonc.2018.11.010.

The ratio of apolipoproteins B and A1 (apo B/A1) is an independent prognostic factor in patients with metastatic renal cell carcinoma, according to authors of a recent retrospective study.

The apo B/A1 ratio, evaluated prior to cytoreductive nephrectomy, was significantly linked with poor progression-free survival and overall survival, according to Fan Zhang, MD, of the Chinese PLA General Hospital in Beijing and coauthors.

Those findings suggest that patients with metastatic RCC should receive “consistent follow-up” that includes evaluation of that ratio, Dr. Zhang and colleagues said.

“As a novel prognostic factor, the preoperative apo B/A1 ratio can be utilized as a supplement to improve the current prognostic evaluation and treatment decision for patients with metastatic RCC,” they wrote in Urologic Oncology.

Apo B and A1, which are predominant components of low-density lipoprotein (LDL) and high-density lipoprotein (HDL), respectively, have “extensive connections” with cardiovascular disease, diabetes, and Alzheimer disease, the authors said.

The apo B/A1 ratio is a known risk index for cardiovascular disease, and in recent studies, it appeared to have some value in prognosis and prediction of gastric and colorectal cancer, among other neoplasms, they added.

In their retrospective study, Dr. Zhang and colleagues analyzed data on 287 metastatic RCC patients who underwent cytoreductive nephrectomy at the Chinese PLA General Hospital. The median age of the patients was 56 years, and the median apo B/A1 ratio was 0.859.

Significantly poorer progression-free survival was seen in the group of patients with a preoperative apo B/A1 ratio over the cutoff of 0.977 (P less than .0001) compared with those under the cutoff, the investigators reported. Likewise, overall survival was poorer for patients with an apo B/A1 ratio over a cutoff of 0.847 (P = .0005).

The apo B/A1 ratio was higher in patients with Fuhrman grade 3-4 versus grade 1-2 patients (P = .010), though the investigators said no significant differences in the ratio were seen in patients stratified by age, body mass index, fatty liver, number of metastases, among other subgroup analyses.

Multivariate analysis revealed that the two independent prognostic factors for progression-free survival were preoperative apo B/A1 ratio and Fuhrman grade, with hazard ratios of 3.131 and 1.906, respectively (P less than .001 for both), while independent prognostic factors for overall survival also included the apo B/A1 ratio (hazard ratio, 2.173; P less than .001) and Fuhrman grade, along with tumor necrosis and receiving targeted therapy.

This retrospective study was limited by relatively small samples from a single center, and the prognostic value of the apo B/A1 ratio needs to be verified in other studies, investigators said.

“Peripheral blood biomarkers only provide a supplement to the traditional prognostic factors in the prediction of the prognosis for patients with metastatic RCC, and are still unable to replace it,” Dr. Zhang and associates said.

The Beijing Natural Science Foundation supported the study. Dr. Zhang and coauthors had no disclosed conflicts of interest related to the work.

SOURCE: Zhang F et al. Urol Oncol. 2018 Nov 30. doi: 10.1016/j.urolonc.2018.11.010.

The ratio of apolipoproteins B and A1 (apo B/A1) is an independent prognostic factor in patients with metastatic renal cell carcinoma, according to authors of a recent retrospective study.

The apo B/A1 ratio, evaluated prior to cytoreductive nephrectomy, was significantly linked with poor progression-free survival and overall survival, according to Fan Zhang, MD, of the Chinese PLA General Hospital in Beijing and coauthors.

Those findings suggest that patients with metastatic RCC should receive “consistent follow-up” that includes evaluation of that ratio, Dr. Zhang and colleagues said.

“As a novel prognostic factor, the preoperative apo B/A1 ratio can be utilized as a supplement to improve the current prognostic evaluation and treatment decision for patients with metastatic RCC,” they wrote in Urologic Oncology.

Apo B and A1, which are predominant components of low-density lipoprotein (LDL) and high-density lipoprotein (HDL), respectively, have “extensive connections” with cardiovascular disease, diabetes, and Alzheimer disease, the authors said.

The apo B/A1 ratio is a known risk index for cardiovascular disease, and in recent studies, it appeared to have some value in prognosis and prediction of gastric and colorectal cancer, among other neoplasms, they added.

In their retrospective study, Dr. Zhang and colleagues analyzed data on 287 metastatic RCC patients who underwent cytoreductive nephrectomy at the Chinese PLA General Hospital. The median age of the patients was 56 years, and the median apo B/A1 ratio was 0.859.

Significantly poorer progression-free survival was seen in the group of patients with a preoperative apo B/A1 ratio over the cutoff of 0.977 (P less than .0001) compared with those under the cutoff, the investigators reported. Likewise, overall survival was poorer for patients with an apo B/A1 ratio over a cutoff of 0.847 (P = .0005).

The apo B/A1 ratio was higher in patients with Fuhrman grade 3-4 versus grade 1-2 patients (P = .010), though the investigators said no significant differences in the ratio were seen in patients stratified by age, body mass index, fatty liver, number of metastases, among other subgroup analyses.

Multivariate analysis revealed that the two independent prognostic factors for progression-free survival were preoperative apo B/A1 ratio and Fuhrman grade, with hazard ratios of 3.131 and 1.906, respectively (P less than .001 for both), while independent prognostic factors for overall survival also included the apo B/A1 ratio (hazard ratio, 2.173; P less than .001) and Fuhrman grade, along with tumor necrosis and receiving targeted therapy.

This retrospective study was limited by relatively small samples from a single center, and the prognostic value of the apo B/A1 ratio needs to be verified in other studies, investigators said.

“Peripheral blood biomarkers only provide a supplement to the traditional prognostic factors in the prediction of the prognosis for patients with metastatic RCC, and are still unable to replace it,” Dr. Zhang and associates said.

The Beijing Natural Science Foundation supported the study. Dr. Zhang and coauthors had no disclosed conflicts of interest related to the work.

SOURCE: Zhang F et al. Urol Oncol. 2018 Nov 30. doi: 10.1016/j.urolonc.2018.11.010.

A review of registry data from a major cancer center revealed a strong, bidirectional association between renal cell carcinoma (RCC) and melanoma.

A greater than twofold risk of melanoma in patients with RCC, and a nearly threefold risk of RCC in melanoma patients, were found in the review of the International Tumor Registry Database at The University of Texas MD Anderson Cancer Center.

The incidence of subsequent melanomas or RCCs in this study was in line with other recent reports from cancer registry analyses, reported Kevin B. Kim, MD, and his coinvestigators.

“Clinicians should be more watchful for these secondary cancers in patients with a history of melanoma or RCC,” they wrote. The report is in Cancer Epidemiology.

They found a total of 13,879 patients with melanoma and 7,597 patients with RCC in their review. Of those patients, 89 had both a melanoma and an RCC diagnosis. About 30% were first diagnosed with RCC, 61% were first diagnosed with melanoma, and 9% had both diagnoses around the same time.

Among the RCC-first patients, the standardized incidence ratio for developing a second primary melanoma was 2.31 (95% confidence interval, 1.52-3.37; P less than .001), while for melanoma-first patients, for developing a second primary RCC, it was 2.87 (95% CI, 2.16-3.74; P less than .001).

Those statistics were consistent with other registry reports, according to Dr. Kim and his colleagues, who wrote that the standardized incidence ratios in those studies ranged from 1.28 to 2.5.

In the MD Anderson registry study, nearly one-third of patients with secondary primary melanoma or RCC had a history of additional secondary cancers, according to the researchers. Those diagnoses included nonmelanoma skin cancers, leukemias, prostate cancer, breast cancer, and colon cancer, among others.

That suggested the presence of possible common risk factors that may have included abnormal genetics, though the database lacked the genetic sequencing and family history data to explore that hypothesis further.

“It would be highly desirable to assess germline genetic information on patients and their families, and also somatic gene aberrations in the tumor lesions, in a more systematic way in order to better elucidate the contribution of the genetics in the association between melanoma and RCC,” Dr. Kim and his colleagues said.

They reported that they had no conflicts of interest.

SOURCE: Kim KB et al. Cancer Epidemiol. 2018 Oct 19;57:80-4.

A review of registry data from a major cancer center revealed a strong, bidirectional association between renal cell carcinoma (RCC) and melanoma.

A greater than twofold risk of melanoma in patients with RCC, and a nearly threefold risk of RCC in melanoma patients, were found in the review of the International Tumor Registry Database at The University of Texas MD Anderson Cancer Center.

The incidence of subsequent melanomas or RCCs in this study was in line with other recent reports from cancer registry analyses, reported Kevin B. Kim, MD, and his coinvestigators.

“Clinicians should be more watchful for these secondary cancers in patients with a history of melanoma or RCC,” they wrote. The report is in Cancer Epidemiology.

They found a total of 13,879 patients with melanoma and 7,597 patients with RCC in their review. Of those patients, 89 had both a melanoma and an RCC diagnosis. About 30% were first diagnosed with RCC, 61% were first diagnosed with melanoma, and 9% had both diagnoses around the same time.

Among the RCC-first patients, the standardized incidence ratio for developing a second primary melanoma was 2.31 (95% confidence interval, 1.52-3.37; P less than .001), while for melanoma-first patients, for developing a second primary RCC, it was 2.87 (95% CI, 2.16-3.74; P less than .001).

Those statistics were consistent with other registry reports, according to Dr. Kim and his colleagues, who wrote that the standardized incidence ratios in those studies ranged from 1.28 to 2.5.

In the MD Anderson registry study, nearly one-third of patients with secondary primary melanoma or RCC had a history of additional secondary cancers, according to the researchers. Those diagnoses included nonmelanoma skin cancers, leukemias, prostate cancer, breast cancer, and colon cancer, among others.

That suggested the presence of possible common risk factors that may have included abnormal genetics, though the database lacked the genetic sequencing and family history data to explore that hypothesis further.

“It would be highly desirable to assess germline genetic information on patients and their families, and also somatic gene aberrations in the tumor lesions, in a more systematic way in order to better elucidate the contribution of the genetics in the association between melanoma and RCC,” Dr. Kim and his colleagues said.

They reported that they had no conflicts of interest.

SOURCE: Kim KB et al. Cancer Epidemiol. 2018 Oct 19;57:80-4.

A review of registry data from a major cancer center revealed a strong, bidirectional association between renal cell carcinoma (RCC) and melanoma.

A greater than twofold risk of melanoma in patients with RCC, and a nearly threefold risk of RCC in melanoma patients, were found in the review of the International Tumor Registry Database at The University of Texas MD Anderson Cancer Center.

The incidence of subsequent melanomas or RCCs in this study was in line with other recent reports from cancer registry analyses, reported Kevin B. Kim, MD, and his coinvestigators.

“Clinicians should be more watchful for these secondary cancers in patients with a history of melanoma or RCC,” they wrote. The report is in Cancer Epidemiology.

They found a total of 13,879 patients with melanoma and 7,597 patients with RCC in their review. Of those patients, 89 had both a melanoma and an RCC diagnosis. About 30% were first diagnosed with RCC, 61% were first diagnosed with melanoma, and 9% had both diagnoses around the same time.

Among the RCC-first patients, the standardized incidence ratio for developing a second primary melanoma was 2.31 (95% confidence interval, 1.52-3.37; P less than .001), while for melanoma-first patients, for developing a second primary RCC, it was 2.87 (95% CI, 2.16-3.74; P less than .001).

Those statistics were consistent with other registry reports, according to Dr. Kim and his colleagues, who wrote that the standardized incidence ratios in those studies ranged from 1.28 to 2.5.

In the MD Anderson registry study, nearly one-third of patients with secondary primary melanoma or RCC had a history of additional secondary cancers, according to the researchers. Those diagnoses included nonmelanoma skin cancers, leukemias, prostate cancer, breast cancer, and colon cancer, among others.

That suggested the presence of possible common risk factors that may have included abnormal genetics, though the database lacked the genetic sequencing and family history data to explore that hypothesis further.

“It would be highly desirable to assess germline genetic information on patients and their families, and also somatic gene aberrations in the tumor lesions, in a more systematic way in order to better elucidate the contribution of the genetics in the association between melanoma and RCC,” Dr. Kim and his colleagues said.

They reported that they had no conflicts of interest.

SOURCE: Kim KB et al. Cancer Epidemiol. 2018 Oct 19;57:80-4.

Recent research on the genetic basis of renal cell carcinoma has expanded and improved treatment options; however, personalized medicine is still largely unavailable, so future efforts should aim to link genetic knowledge with prognosis and treatment selection, according to the authors of a recent review article.

The article, written by Christopher D’Avella, MD, of the Fox Chase Cancer Center in Philadelphia, and his colleagues provides an overview of renal cell carcinoma (RCC) mutations and associated therapies, with updates of ongoing trials and a look at future directions.

“The expansion of treatment options for patients with advanced RCC over the past 15 years is a testament to enhanced understanding of the genetics and genomics of RCC and the ability to apply this knowledge to drug development,” the authors wrote in Urologic Oncology. “However, much work remains to be done as there are still no validated biomarkers to select patient treatment, and in only rare cases, the knowledge of particular mutations in RCC can lead to rational treatment selection.”

RCC accounts for approximately 80%-85% of renal tumors. About three out of four RCC patients have clear cell disease, of which about 30% develop metastases and need systemic therapy. The authors pointed out that vascular endothelial growth factor tyrosine kinase inhibitors (TKIs) have been standard first-line care for these patients since the mid-2000s, based on improved molecular understanding. Still, responses to TKIs are limited and patients eventually develop resistance. Several agents are in development to overcome this obstacle, including inhibitors of hypoxia inducible factor, which have recently shown promise. Among biomarkers for ccRCC, PBRM1 mutations may be associated with susceptibility to checkpoint inhibitors, and TSC1 could predict response to mTOR (mammalian target of rapamycin) inhibition.

Along with clear cell RCC, the review article addressed topics in papillary and sarcomatoid subtypes.

Patients with papillary RCC often have MET mutations, and ongoing research is focused on associated targeted therapies. For example, savolitinib is a highly selective MET inhibitor that has shown promise in this patient subgroup.

Sarcomatoid features remain characteristic of large and aggressive tumors. Unfortunately, treatment options are currently limited in this area. Recent studies suggest that TP53 and NF2 mutations are associated with sarcomatoid differentiation.

“Future studies should explore linking genetics to prognosis, resistance to targeted therapies, and the identification of future therapeutic targets,” the authors concluded.

SOURCE: D’Avella C et al. Urol Oncol. 2018 Nov 23. doi: 10.1016/j.urolonc.2018.10.027.

Recent research on the genetic basis of renal cell carcinoma has expanded and improved treatment options; however, personalized medicine is still largely unavailable, so future efforts should aim to link genetic knowledge with prognosis and treatment selection, according to the authors of a recent review article.

The article, written by Christopher D’Avella, MD, of the Fox Chase Cancer Center in Philadelphia, and his colleagues provides an overview of renal cell carcinoma (RCC) mutations and associated therapies, with updates of ongoing trials and a look at future directions.

“The expansion of treatment options for patients with advanced RCC over the past 15 years is a testament to enhanced understanding of the genetics and genomics of RCC and the ability to apply this knowledge to drug development,” the authors wrote in Urologic Oncology. “However, much work remains to be done as there are still no validated biomarkers to select patient treatment, and in only rare cases, the knowledge of particular mutations in RCC can lead to rational treatment selection.”

RCC accounts for approximately 80%-85% of renal tumors. About three out of four RCC patients have clear cell disease, of which about 30% develop metastases and need systemic therapy. The authors pointed out that vascular endothelial growth factor tyrosine kinase inhibitors (TKIs) have been standard first-line care for these patients since the mid-2000s, based on improved molecular understanding. Still, responses to TKIs are limited and patients eventually develop resistance. Several agents are in development to overcome this obstacle, including inhibitors of hypoxia inducible factor, which have recently shown promise. Among biomarkers for ccRCC, PBRM1 mutations may be associated with susceptibility to checkpoint inhibitors, and TSC1 could predict response to mTOR (mammalian target of rapamycin) inhibition.

Along with clear cell RCC, the review article addressed topics in papillary and sarcomatoid subtypes.

Patients with papillary RCC often have MET mutations, and ongoing research is focused on associated targeted therapies. For example, savolitinib is a highly selective MET inhibitor that has shown promise in this patient subgroup.

Sarcomatoid features remain characteristic of large and aggressive tumors. Unfortunately, treatment options are currently limited in this area. Recent studies suggest that TP53 and NF2 mutations are associated with sarcomatoid differentiation.

“Future studies should explore linking genetics to prognosis, resistance to targeted therapies, and the identification of future therapeutic targets,” the authors concluded.

SOURCE: D’Avella C et al. Urol Oncol. 2018 Nov 23. doi: 10.1016/j.urolonc.2018.10.027.

Recent research on the genetic basis of renal cell carcinoma has expanded and improved treatment options; however, personalized medicine is still largely unavailable, so future efforts should aim to link genetic knowledge with prognosis and treatment selection, according to the authors of a recent review article.

The article, written by Christopher D’Avella, MD, of the Fox Chase Cancer Center in Philadelphia, and his colleagues provides an overview of renal cell carcinoma (RCC) mutations and associated therapies, with updates of ongoing trials and a look at future directions.

“The expansion of treatment options for patients with advanced RCC over the past 15 years is a testament to enhanced understanding of the genetics and genomics of RCC and the ability to apply this knowledge to drug development,” the authors wrote in Urologic Oncology. “However, much work remains to be done as there are still no validated biomarkers to select patient treatment, and in only rare cases, the knowledge of particular mutations in RCC can lead to rational treatment selection.”

RCC accounts for approximately 80%-85% of renal tumors. About three out of four RCC patients have clear cell disease, of which about 30% develop metastases and need systemic therapy. The authors pointed out that vascular endothelial growth factor tyrosine kinase inhibitors (TKIs) have been standard first-line care for these patients since the mid-2000s, based on improved molecular understanding. Still, responses to TKIs are limited and patients eventually develop resistance. Several agents are in development to overcome this obstacle, including inhibitors of hypoxia inducible factor, which have recently shown promise. Among biomarkers for ccRCC, PBRM1 mutations may be associated with susceptibility to checkpoint inhibitors, and TSC1 could predict response to mTOR (mammalian target of rapamycin) inhibition.

Along with clear cell RCC, the review article addressed topics in papillary and sarcomatoid subtypes.

Patients with papillary RCC often have MET mutations, and ongoing research is focused on associated targeted therapies. For example, savolitinib is a highly selective MET inhibitor that has shown promise in this patient subgroup.

Sarcomatoid features remain characteristic of large and aggressive tumors. Unfortunately, treatment options are currently limited in this area. Recent studies suggest that TP53 and NF2 mutations are associated with sarcomatoid differentiation.

“Future studies should explore linking genetics to prognosis, resistance to targeted therapies, and the identification of future therapeutic targets,” the authors concluded.

SOURCE: D’Avella C et al. Urol Oncol. 2018 Nov 23. doi: 10.1016/j.urolonc.2018.10.027.

Human telomerase reverse transcriptase (hTERT) protein expression is associated with clear cell renal carcinoma (ccRCC) tumor aggressiveness and disease-specific survival (DSS), according to investigators.

Associations between hTERT expression and clinicopathologic features and outcomes were less robust or nonexistent in papillary and chromophobe subtypes, reported Leili Saeednejad Zanjani, MD, of the Oncopathology Research Center at Iran University of Medical Sciences in Tehran, and colleagues.

“Evidence shows that telomerase is expressed in 85% of malignancies, and the level of its activity is higher in advanced and metastatic tumors,” the authors wrote in Pathology.

“A number of clinical studies have been performed to evaluate the association between telomerase activity and clinicopathological parameters in renal cancer showing that telomerase activity level correlates with progression of RCC,” Dr. Zanjani and associates wrote. As none of these specifically evaluated hTERT protein expression, the investigators conducted a study to learn more.

The investigators analyzed hTERT expression level in 176 cases of RCC, requiring that each tumor had three core biopsies because of concerns of heterogeneity. The population consisted of 113 clear cell, 12 type I papillary, 20 type II papillary, and 31 chromophobe subtypes. Patient and clinicopathologic features were compared with survival and hTERT expression. Median follow-up time was 42 months.

Correlations between hTERT expression and disease characteristics were pronounced in cases of ccRCC, compared with other subtypes. In ccRCC, hTERT expression was significantly associated with tumor stage, nucleolar grade, tumor size, microvascular invasion, lymph node invasion, renal pelvis involvement, renal sinus fat involvement, Gerota fascia invasion, and distant metastasis. Survival analysis showed that DSS of ccRCC patients with high hTERT expression was 58 months, compared with 68 months for those with low hTERT expression (P =.012). Other parameters associated with survival were nucleolar grade, tumor stage, and tumor size.

For type I and II papillary subtypes, associations were found between hTERT expression and tumor stage and distant metastasis. In contrast, chromophobe RCC revealed no such relationships. No associations were found between hTERT expression and survival in any of these three latter subtypes, for slightly different reasons; no patients with type I disease died of renal cancer, disallowing creation of a Kaplan-Meier survival curve, whereas type II and chromophobe survival curves revealed insignificant relationships with hTERT expression. Along the same lines, no clinicopathologic characteristics of these subtypes were tied with survival.

“From these findings we are able to conclude that hTERT protein expression may be a novel prognostic indicator of worse outcome in tumor biopsies of patients with ccRCC, if follow up time is more prolonged,” the authors wrote. They noted that “telomerase is an attractive and ideal target for therapy due to overexpression in the majority of malignancies and low or nonexpression in most somatic cells.”

The study was funded by the Iran National Science Foundation. The authors declared no conflicts of interest.
 

SOURCE: Zanjani LS et al. Pathology. 2018 Nov 19. doi: 10.1016/j.pathol.2018.08.019.

Human telomerase reverse transcriptase (hTERT) protein expression is associated with clear cell renal carcinoma (ccRCC) tumor aggressiveness and disease-specific survival (DSS), according to investigators.

Associations between hTERT expression and clinicopathologic features and outcomes were less robust or nonexistent in papillary and chromophobe subtypes, reported Leili Saeednejad Zanjani, MD, of the Oncopathology Research Center at Iran University of Medical Sciences in Tehran, and colleagues.

“Evidence shows that telomerase is expressed in 85% of malignancies, and the level of its activity is higher in advanced and metastatic tumors,” the authors wrote in Pathology.

“A number of clinical studies have been performed to evaluate the association between telomerase activity and clinicopathological parameters in renal cancer showing that telomerase activity level correlates with progression of RCC,” Dr. Zanjani and associates wrote. As none of these specifically evaluated hTERT protein expression, the investigators conducted a study to learn more.

The investigators analyzed hTERT expression level in 176 cases of RCC, requiring that each tumor had three core biopsies because of concerns of heterogeneity. The population consisted of 113 clear cell, 12 type I papillary, 20 type II papillary, and 31 chromophobe subtypes. Patient and clinicopathologic features were compared with survival and hTERT expression. Median follow-up time was 42 months.

Correlations between hTERT expression and disease characteristics were pronounced in cases of ccRCC, compared with other subtypes. In ccRCC, hTERT expression was significantly associated with tumor stage, nucleolar grade, tumor size, microvascular invasion, lymph node invasion, renal pelvis involvement, renal sinus fat involvement, Gerota fascia invasion, and distant metastasis. Survival analysis showed that DSS of ccRCC patients with high hTERT expression was 58 months, compared with 68 months for those with low hTERT expression (P =.012). Other parameters associated with survival were nucleolar grade, tumor stage, and tumor size.

For type I and II papillary subtypes, associations were found between hTERT expression and tumor stage and distant metastasis. In contrast, chromophobe RCC revealed no such relationships. No associations were found between hTERT expression and survival in any of these three latter subtypes, for slightly different reasons; no patients with type I disease died of renal cancer, disallowing creation of a Kaplan-Meier survival curve, whereas type II and chromophobe survival curves revealed insignificant relationships with hTERT expression. Along the same lines, no clinicopathologic characteristics of these subtypes were tied with survival.

“From these findings we are able to conclude that hTERT protein expression may be a novel prognostic indicator of worse outcome in tumor biopsies of patients with ccRCC, if follow up time is more prolonged,” the authors wrote. They noted that “telomerase is an attractive and ideal target for therapy due to overexpression in the majority of malignancies and low or nonexpression in most somatic cells.”

The study was funded by the Iran National Science Foundation. The authors declared no conflicts of interest.
 

SOURCE: Zanjani LS et al. Pathology. 2018 Nov 19. doi: 10.1016/j.pathol.2018.08.019.

Human telomerase reverse transcriptase (hTERT) protein expression is associated with clear cell renal carcinoma (ccRCC) tumor aggressiveness and disease-specific survival (DSS), according to investigators.

Associations between hTERT expression and clinicopathologic features and outcomes were less robust or nonexistent in papillary and chromophobe subtypes, reported Leili Saeednejad Zanjani, MD, of the Oncopathology Research Center at Iran University of Medical Sciences in Tehran, and colleagues.

“Evidence shows that telomerase is expressed in 85% of malignancies, and the level of its activity is higher in advanced and metastatic tumors,” the authors wrote in Pathology.

“A number of clinical studies have been performed to evaluate the association between telomerase activity and clinicopathological parameters in renal cancer showing that telomerase activity level correlates with progression of RCC,” Dr. Zanjani and associates wrote. As none of these specifically evaluated hTERT protein expression, the investigators conducted a study to learn more.

The investigators analyzed hTERT expression level in 176 cases of RCC, requiring that each tumor had three core biopsies because of concerns of heterogeneity. The population consisted of 113 clear cell, 12 type I papillary, 20 type II papillary, and 31 chromophobe subtypes. Patient and clinicopathologic features were compared with survival and hTERT expression. Median follow-up time was 42 months.

Correlations between hTERT expression and disease characteristics were pronounced in cases of ccRCC, compared with other subtypes. In ccRCC, hTERT expression was significantly associated with tumor stage, nucleolar grade, tumor size, microvascular invasion, lymph node invasion, renal pelvis involvement, renal sinus fat involvement, Gerota fascia invasion, and distant metastasis. Survival analysis showed that DSS of ccRCC patients with high hTERT expression was 58 months, compared with 68 months for those with low hTERT expression (P =.012). Other parameters associated with survival were nucleolar grade, tumor stage, and tumor size.

For type I and II papillary subtypes, associations were found between hTERT expression and tumor stage and distant metastasis. In contrast, chromophobe RCC revealed no such relationships. No associations were found between hTERT expression and survival in any of these three latter subtypes, for slightly different reasons; no patients with type I disease died of renal cancer, disallowing creation of a Kaplan-Meier survival curve, whereas type II and chromophobe survival curves revealed insignificant relationships with hTERT expression. Along the same lines, no clinicopathologic characteristics of these subtypes were tied with survival.

“From these findings we are able to conclude that hTERT protein expression may be a novel prognostic indicator of worse outcome in tumor biopsies of patients with ccRCC, if follow up time is more prolonged,” the authors wrote. They noted that “telomerase is an attractive and ideal target for therapy due to overexpression in the majority of malignancies and low or nonexpression in most somatic cells.”

The study was funded by the Iran National Science Foundation. The authors declared no conflicts of interest.
 

SOURCE: Zanjani LS et al. Pathology. 2018 Nov 19. doi: 10.1016/j.pathol.2018.08.019.

Older patients with ccRCC may respond better than younger patients to phosphoinositide 3-kinase (PI3K) or checkpoint inhibition because of age-related changes in gene expression, according to investigators.

This possibility was raised by in silico results from a broader study of gene expression patterns in clear cell renal carcinoma (ccRCC) and normal kidney tissues, reported lead author, Lara Feulner, MD, of the department of human genetics at McGill University and Genome Quebec Innovation Centre in Montreal.

“Several factors could contribute to the interindividual diversity among cancer patients,” the investigators wrote in a report published in Urologic Oncology.

“Their disease course could be affected not only by cell-intrinsic factors, but also by age-related changes impacting the vasculature, immune system and stroma. Little is known in this regard about ccRCC, a disease which affects adults across a wide age spectrum. Whether and how aging and comorbidities such as atherosclerosis may affect the biology and therapy of ccRCC has scarcely been considered,” they wrote.

The investigators explored this territory by analyzing datasets from The Cancer Genome Atlas (TCGA) and the Cancer Genomics of the Kidney (CAGEKID) program of the International Cancer Genome Consortium. Using regression, pathway enrichment, and connectivity mapping analyses, they were able to determine associations between age and gene expression, cellular processes, and drug treatment responses, respectively.

The investigators reported that age-related gene expression patterns occurred commonly in both normal and tumor tissues. Associations were reproducible between TCGA and CAGEKID datasets for both classes of tissue (tumor samples, R equal to 0.416, P less than 2.2 x 10-16; normal samples, R equal to 0.403, P less than 2.2 x 10-16). Out of the top 1,000 age-associated genes in tumor samples from each dataset, 383 were commonly downregulated with age and 294 were commonly upregulated with age in both datasets (P less than 2.2 x 10-16).

Among cellular pathways, the investigators found opposite age-relationship patterns. For example, normal tissues upregulated extracellular matrix and cell adhesion pathways with age, whereas tumor tissues downregulated the same pathways. Similar patterns of opposition were found in metabolism and oxidation pathways. Other age-related patterns were noted in some immune pathways, such as upregulation of toll-like receptor and tumor necrosis factor 2 noncanonical NF-kappa-B signaling in tumors, which became more common with age. A closer look showed that upregulation of tumor necrosis factor signaling was more common in female patients, who also downregulated Notch pathways more often than men.

Analysis of treatment responses showed possible relationships with age-dependent gene expression and immunotherapy. Specifically, of 532 genes tied to programmed cell death protein 1 (PD-1) resistance, 69 were among the 383 genes downregulated in older patients with ccRCC (P less than 2.2 x 10-16; 4.05 fold-enrichment), suggesting that older patients may respond better to anti-PD-1 therapy than younger patients. Similarly, connectivity map analysis showed that age-dependent gene expression may improve candidacy of older ccRCC patients for PI3K inhibition.

“We now have evidence that there are notable differences in tumor-associated pathway regulation between younger and older ccRCC patients, which may be therapeutically actionable,” the authors concluded.

The study was funded by the Cancer Research Society operation grant, a Canadian Cancer Society Research Institute Innovation-to-Impact grant, and a Canadian Institutes of Health Research Foundation grant. The authors reported no conflicts of interest.

SOURCE: Feulner et al. Urol Onc. 2018 Nov 23. doi: 10.1016/j.urolonc.2018.11.006.

Older patients with ccRCC may respond better than younger patients to phosphoinositide 3-kinase (PI3K) or checkpoint inhibition because of age-related changes in gene expression, according to investigators.

This possibility was raised by in silico results from a broader study of gene expression patterns in clear cell renal carcinoma (ccRCC) and normal kidney tissues, reported lead author, Lara Feulner, MD, of the department of human genetics at McGill University and Genome Quebec Innovation Centre in Montreal.

“Several factors could contribute to the interindividual diversity among cancer patients,” the investigators wrote in a report published in Urologic Oncology.

“Their disease course could be affected not only by cell-intrinsic factors, but also by age-related changes impacting the vasculature, immune system and stroma. Little is known in this regard about ccRCC, a disease which affects adults across a wide age spectrum. Whether and how aging and comorbidities such as atherosclerosis may affect the biology and therapy of ccRCC has scarcely been considered,” they wrote.

The investigators explored this territory by analyzing datasets from The Cancer Genome Atlas (TCGA) and the Cancer Genomics of the Kidney (CAGEKID) program of the International Cancer Genome Consortium. Using regression, pathway enrichment, and connectivity mapping analyses, they were able to determine associations between age and gene expression, cellular processes, and drug treatment responses, respectively.

The investigators reported that age-related gene expression patterns occurred commonly in both normal and tumor tissues. Associations were reproducible between TCGA and CAGEKID datasets for both classes of tissue (tumor samples, R equal to 0.416, P less than 2.2 x 10-16; normal samples, R equal to 0.403, P less than 2.2 x 10-16). Out of the top 1,000 age-associated genes in tumor samples from each dataset, 383 were commonly downregulated with age and 294 were commonly upregulated with age in both datasets (P less than 2.2 x 10-16).

Among cellular pathways, the investigators found opposite age-relationship patterns. For example, normal tissues upregulated extracellular matrix and cell adhesion pathways with age, whereas tumor tissues downregulated the same pathways. Similar patterns of opposition were found in metabolism and oxidation pathways. Other age-related patterns were noted in some immune pathways, such as upregulation of toll-like receptor and tumor necrosis factor 2 noncanonical NF-kappa-B signaling in tumors, which became more common with age. A closer look showed that upregulation of tumor necrosis factor signaling was more common in female patients, who also downregulated Notch pathways more often than men.

Analysis of treatment responses showed possible relationships with age-dependent gene expression and immunotherapy. Specifically, of 532 genes tied to programmed cell death protein 1 (PD-1) resistance, 69 were among the 383 genes downregulated in older patients with ccRCC (P less than 2.2 x 10-16; 4.05 fold-enrichment), suggesting that older patients may respond better to anti-PD-1 therapy than younger patients. Similarly, connectivity map analysis showed that age-dependent gene expression may improve candidacy of older ccRCC patients for PI3K inhibition.

“We now have evidence that there are notable differences in tumor-associated pathway regulation between younger and older ccRCC patients, which may be therapeutically actionable,” the authors concluded.

The study was funded by the Cancer Research Society operation grant, a Canadian Cancer Society Research Institute Innovation-to-Impact grant, and a Canadian Institutes of Health Research Foundation grant. The authors reported no conflicts of interest.

SOURCE: Feulner et al. Urol Onc. 2018 Nov 23. doi: 10.1016/j.urolonc.2018.11.006.

Older patients with ccRCC may respond better than younger patients to phosphoinositide 3-kinase (PI3K) or checkpoint inhibition because of age-related changes in gene expression, according to investigators.

This possibility was raised by in silico results from a broader study of gene expression patterns in clear cell renal carcinoma (ccRCC) and normal kidney tissues, reported lead author, Lara Feulner, MD, of the department of human genetics at McGill University and Genome Quebec Innovation Centre in Montreal.

“Several factors could contribute to the interindividual diversity among cancer patients,” the investigators wrote in a report published in Urologic Oncology.

“Their disease course could be affected not only by cell-intrinsic factors, but also by age-related changes impacting the vasculature, immune system and stroma. Little is known in this regard about ccRCC, a disease which affects adults across a wide age spectrum. Whether and how aging and comorbidities such as atherosclerosis may affect the biology and therapy of ccRCC has scarcely been considered,” they wrote.

The investigators explored this territory by analyzing datasets from The Cancer Genome Atlas (TCGA) and the Cancer Genomics of the Kidney (CAGEKID) program of the International Cancer Genome Consortium. Using regression, pathway enrichment, and connectivity mapping analyses, they were able to determine associations between age and gene expression, cellular processes, and drug treatment responses, respectively.

The investigators reported that age-related gene expression patterns occurred commonly in both normal and tumor tissues. Associations were reproducible between TCGA and CAGEKID datasets for both classes of tissue (tumor samples, R equal to 0.416, P less than 2.2 x 10-16; normal samples, R equal to 0.403, P less than 2.2 x 10-16). Out of the top 1,000 age-associated genes in tumor samples from each dataset, 383 were commonly downregulated with age and 294 were commonly upregulated with age in both datasets (P less than 2.2 x 10-16).

Among cellular pathways, the investigators found opposite age-relationship patterns. For example, normal tissues upregulated extracellular matrix and cell adhesion pathways with age, whereas tumor tissues downregulated the same pathways. Similar patterns of opposition were found in metabolism and oxidation pathways. Other age-related patterns were noted in some immune pathways, such as upregulation of toll-like receptor and tumor necrosis factor 2 noncanonical NF-kappa-B signaling in tumors, which became more common with age. A closer look showed that upregulation of tumor necrosis factor signaling was more common in female patients, who also downregulated Notch pathways more often than men.

Analysis of treatment responses showed possible relationships with age-dependent gene expression and immunotherapy. Specifically, of 532 genes tied to programmed cell death protein 1 (PD-1) resistance, 69 were among the 383 genes downregulated in older patients with ccRCC (P less than 2.2 x 10-16; 4.05 fold-enrichment), suggesting that older patients may respond better to anti-PD-1 therapy than younger patients. Similarly, connectivity map analysis showed that age-dependent gene expression may improve candidacy of older ccRCC patients for PI3K inhibition.

“We now have evidence that there are notable differences in tumor-associated pathway regulation between younger and older ccRCC patients, which may be therapeutically actionable,” the authors concluded.

The study was funded by the Cancer Research Society operation grant, a Canadian Cancer Society Research Institute Innovation-to-Impact grant, and a Canadian Institutes of Health Research Foundation grant. The authors reported no conflicts of interest.

SOURCE: Feulner et al. Urol Onc. 2018 Nov 23. doi: 10.1016/j.urolonc.2018.11.006.

Clear cell renal cell carcinoma (ccRCC) with predominant papillary features is best classified as a rare morphologic variant of ccRCC, not MiT family translocation or papillary RCC, according to an analysis of 23 tumors.

Areas of papillary pattern made up anywhere from 40% to 100% of the 23 tumors. Even so, cytology and immunohistochemical and genetic testing was most consistent with ccRCC, and tumors were negative for TFE3 protein, which ruled out MiT family translocation RCC, reported Reza Alaghehbandan, MD, and his associates. The report is in Annals of Diagnostic Pathology.

The findings help clarify where ccRCC fits in the diagnostic tree when there’s significant papillary morphology, something that hasn’t been clear until now. The proper classification matters because it carries treatment implications; for instance, ccRCC generally responds well to immunotherapy and targeted therapy, but papillary RCC does not, so doctors often recommend treatment through a clinical trial.

“The presence of mixed morphologic components in renal neoplasms in general and in ccRCCs in particular can be puzzling in routine practice, which can potentially lead to misdiagnosis.” Getting it right is “crucial” to ensure the best treatment, said Dr. Alaghehbandan, of the University of British Columbia, Vancouver, and his associates.

Cytokeratin 7 (CK7) staining was negative in the nonpapillary areas of 20 tumors (87%), and only focally positive in three (13%). In contrast, clear cell papillary RCC is strongly and diffusely positive for CK7.

In papillary areas, Alpha-methyl CoA racemase was positive or focally positive in 17 tumors (73.9%); in nonpapillary areas, it was positive or focally positive in 22 (95.6%). Carbonic anhydrase IX was mainly negative in both nonpapillary and papillary areas, while vimentin and CD10 were positive or focally positive in both.

Patients were a mean of 65.2 years old, and 19 were men. The median tumor size was 6.5 cm. At a median follow-up of 2.5 years, two patients had died of their disease, and two had developed metastasis.

There was no industry funding, and the investigators didn’t have any disclosures.

SOURCE: Alaghehbandan R et al. Ann Diagn Pathol. 2018 Nov 22. doi: 10.1016/j.anndiagpath.2018.11.004.

Clear cell renal cell carcinoma (ccRCC) with predominant papillary features is best classified as a rare morphologic variant of ccRCC, not MiT family translocation or papillary RCC, according to an analysis of 23 tumors.

Areas of papillary pattern made up anywhere from 40% to 100% of the 23 tumors. Even so, cytology and immunohistochemical and genetic testing was most consistent with ccRCC, and tumors were negative for TFE3 protein, which ruled out MiT family translocation RCC, reported Reza Alaghehbandan, MD, and his associates. The report is in Annals of Diagnostic Pathology.

The findings help clarify where ccRCC fits in the diagnostic tree when there’s significant papillary morphology, something that hasn’t been clear until now. The proper classification matters because it carries treatment implications; for instance, ccRCC generally responds well to immunotherapy and targeted therapy, but papillary RCC does not, so doctors often recommend treatment through a clinical trial.

“The presence of mixed morphologic components in renal neoplasms in general and in ccRCCs in particular can be puzzling in routine practice, which can potentially lead to misdiagnosis.” Getting it right is “crucial” to ensure the best treatment, said Dr. Alaghehbandan, of the University of British Columbia, Vancouver, and his associates.

Cytokeratin 7 (CK7) staining was negative in the nonpapillary areas of 20 tumors (87%), and only focally positive in three (13%). In contrast, clear cell papillary RCC is strongly and diffusely positive for CK7.

In papillary areas, Alpha-methyl CoA racemase was positive or focally positive in 17 tumors (73.9%); in nonpapillary areas, it was positive or focally positive in 22 (95.6%). Carbonic anhydrase IX was mainly negative in both nonpapillary and papillary areas, while vimentin and CD10 were positive or focally positive in both.

Patients were a mean of 65.2 years old, and 19 were men. The median tumor size was 6.5 cm. At a median follow-up of 2.5 years, two patients had died of their disease, and two had developed metastasis.

There was no industry funding, and the investigators didn’t have any disclosures.

SOURCE: Alaghehbandan R et al. Ann Diagn Pathol. 2018 Nov 22. doi: 10.1016/j.anndiagpath.2018.11.004.

Clear cell renal cell carcinoma (ccRCC) with predominant papillary features is best classified as a rare morphologic variant of ccRCC, not MiT family translocation or papillary RCC, according to an analysis of 23 tumors.

Areas of papillary pattern made up anywhere from 40% to 100% of the 23 tumors. Even so, cytology and immunohistochemical and genetic testing was most consistent with ccRCC, and tumors were negative for TFE3 protein, which ruled out MiT family translocation RCC, reported Reza Alaghehbandan, MD, and his associates. The report is in Annals of Diagnostic Pathology.

The findings help clarify where ccRCC fits in the diagnostic tree when there’s significant papillary morphology, something that hasn’t been clear until now. The proper classification matters because it carries treatment implications; for instance, ccRCC generally responds well to immunotherapy and targeted therapy, but papillary RCC does not, so doctors often recommend treatment through a clinical trial.

“The presence of mixed morphologic components in renal neoplasms in general and in ccRCCs in particular can be puzzling in routine practice, which can potentially lead to misdiagnosis.” Getting it right is “crucial” to ensure the best treatment, said Dr. Alaghehbandan, of the University of British Columbia, Vancouver, and his associates.

Cytokeratin 7 (CK7) staining was negative in the nonpapillary areas of 20 tumors (87%), and only focally positive in three (13%). In contrast, clear cell papillary RCC is strongly and diffusely positive for CK7.

In papillary areas, Alpha-methyl CoA racemase was positive or focally positive in 17 tumors (73.9%); in nonpapillary areas, it was positive or focally positive in 22 (95.6%). Carbonic anhydrase IX was mainly negative in both nonpapillary and papillary areas, while vimentin and CD10 were positive or focally positive in both.

Patients were a mean of 65.2 years old, and 19 were men. The median tumor size was 6.5 cm. At a median follow-up of 2.5 years, two patients had died of their disease, and two had developed metastasis.

There was no industry funding, and the investigators didn’t have any disclosures.

SOURCE: Alaghehbandan R et al. Ann Diagn Pathol. 2018 Nov 22. doi: 10.1016/j.anndiagpath.2018.11.004.

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.