Susan London

Routine use of the Oncotype DX recurrence score to personalize treatment of early breast cancer could reduce the first-year costs of care, according to results of a population-based cohort study.

“Practice changes based on evidence from the TAILORx trial on using tumor genomic profiles to personalize care could result in small decreases in U.S. national cancer care costs in the initial 12 months post breast cancer diagnosis,” Angela Mariotto, PhD, and colleagues concluded in a study published in JNCI: Journal of the National Cancer Institute. “Longer-term studies will be needed to evaluate the true long-term economic impact and nonmonetary benefits of personalized breast cancer care.”

Findings of the landmark TAILORx trial showed that, with use of the 21-gene score, the majority of women who have node-negative, hormone receptor–positive, HER2-negative breast cancers could safely skip adjuvant chemotherapy (N Engl J Med. 2018;379:111-21). But cost impact of its uptake into routine practice is unclear.

Dr. Mariotto, of the National Cancer Institute and her colleagues used data from the Surveillance, Epidemiology and End Results (SEER), SEER-Medicare, and SEER–Genomic Health datasets to assess how expected changes in practice after the trial might affect costs. They estimated Oncotype DX testing and chemotherapy rates and mean initial costs in 2018 dollars in the pre-TAILORx period (2010-2015) and post-TAILORx period (2018), assuming all women in the latter period received the test and score-suggested therapy.

Going from the pretrial period to the posttrial period, Oncotype DX testing costs were projected to increase from $115 million to $231 million, but chemotherapy use was projected to decrease from 25% to 17%. Mean total initial costs of care fell from $2.816 billion in the pretrial period to $2.766 billion in the posttrial period, for a net savings of $49 million (a 1.8% decrease).

Findings were similar in a variety of sensitivity scenarios entailing alternative compliance with testing, score-suggested treatment, and estimation methods. The only exception was the scenario in which all women aged 50 years or younger having a recurrence score of 16-25 opted to receive chemotherapy, wherein initial care costs could increase by $105 million (a 4% increase).

The investigators reported that they had no relevant conflicts of interest. The study was supported by the National Cancer Institute and its Coordinating Center For Clinical Trials; a Lombardi Comprehensive Cancer Center American Cancer Society Young Investigator Award; and the Cancer Prevention Research Fellowship, sponsored by the American Society of Preventive Oncology and Breast Cancer Research Foundation.

SOURCE: Mariotto A et al. J Natl Cancer Inst. 2019 Apr 24. doi: 10.1093/jnci/djz068.

Routine use of the Oncotype DX recurrence score to personalize treatment of early breast cancer could reduce the first-year costs of care, according to results of a population-based cohort study.

“Practice changes based on evidence from the TAILORx trial on using tumor genomic profiles to personalize care could result in small decreases in U.S. national cancer care costs in the initial 12 months post breast cancer diagnosis,” Angela Mariotto, PhD, and colleagues concluded in a study published in JNCI: Journal of the National Cancer Institute. “Longer-term studies will be needed to evaluate the true long-term economic impact and nonmonetary benefits of personalized breast cancer care.”

Findings of the landmark TAILORx trial showed that, with use of the 21-gene score, the majority of women who have node-negative, hormone receptor–positive, HER2-negative breast cancers could safely skip adjuvant chemotherapy (N Engl J Med. 2018;379:111-21). But cost impact of its uptake into routine practice is unclear.

Dr. Mariotto, of the National Cancer Institute and her colleagues used data from the Surveillance, Epidemiology and End Results (SEER), SEER-Medicare, and SEER–Genomic Health datasets to assess how expected changes in practice after the trial might affect costs. They estimated Oncotype DX testing and chemotherapy rates and mean initial costs in 2018 dollars in the pre-TAILORx period (2010-2015) and post-TAILORx period (2018), assuming all women in the latter period received the test and score-suggested therapy.

Going from the pretrial period to the posttrial period, Oncotype DX testing costs were projected to increase from $115 million to $231 million, but chemotherapy use was projected to decrease from 25% to 17%. Mean total initial costs of care fell from $2.816 billion in the pretrial period to $2.766 billion in the posttrial period, for a net savings of $49 million (a 1.8% decrease).

Findings were similar in a variety of sensitivity scenarios entailing alternative compliance with testing, score-suggested treatment, and estimation methods. The only exception was the scenario in which all women aged 50 years or younger having a recurrence score of 16-25 opted to receive chemotherapy, wherein initial care costs could increase by $105 million (a 4% increase).

The investigators reported that they had no relevant conflicts of interest. The study was supported by the National Cancer Institute and its Coordinating Center For Clinical Trials; a Lombardi Comprehensive Cancer Center American Cancer Society Young Investigator Award; and the Cancer Prevention Research Fellowship, sponsored by the American Society of Preventive Oncology and Breast Cancer Research Foundation.

SOURCE: Mariotto A et al. J Natl Cancer Inst. 2019 Apr 24. doi: 10.1093/jnci/djz068.

Routine use of the Oncotype DX recurrence score to personalize treatment of early breast cancer could reduce the first-year costs of care, according to results of a population-based cohort study.

“Practice changes based on evidence from the TAILORx trial on using tumor genomic profiles to personalize care could result in small decreases in U.S. national cancer care costs in the initial 12 months post breast cancer diagnosis,” Angela Mariotto, PhD, and colleagues concluded in a study published in JNCI: Journal of the National Cancer Institute. “Longer-term studies will be needed to evaluate the true long-term economic impact and nonmonetary benefits of personalized breast cancer care.”

Findings of the landmark TAILORx trial showed that, with use of the 21-gene score, the majority of women who have node-negative, hormone receptor–positive, HER2-negative breast cancers could safely skip adjuvant chemotherapy (N Engl J Med. 2018;379:111-21). But cost impact of its uptake into routine practice is unclear.

Dr. Mariotto, of the National Cancer Institute and her colleagues used data from the Surveillance, Epidemiology and End Results (SEER), SEER-Medicare, and SEER–Genomic Health datasets to assess how expected changes in practice after the trial might affect costs. They estimated Oncotype DX testing and chemotherapy rates and mean initial costs in 2018 dollars in the pre-TAILORx period (2010-2015) and post-TAILORx period (2018), assuming all women in the latter period received the test and score-suggested therapy.

Going from the pretrial period to the posttrial period, Oncotype DX testing costs were projected to increase from $115 million to $231 million, but chemotherapy use was projected to decrease from 25% to 17%. Mean total initial costs of care fell from $2.816 billion in the pretrial period to $2.766 billion in the posttrial period, for a net savings of $49 million (a 1.8% decrease).

Findings were similar in a variety of sensitivity scenarios entailing alternative compliance with testing, score-suggested treatment, and estimation methods. The only exception was the scenario in which all women aged 50 years or younger having a recurrence score of 16-25 opted to receive chemotherapy, wherein initial care costs could increase by $105 million (a 4% increase).

The investigators reported that they had no relevant conflicts of interest. The study was supported by the National Cancer Institute and its Coordinating Center For Clinical Trials; a Lombardi Comprehensive Cancer Center American Cancer Society Young Investigator Award; and the Cancer Prevention Research Fellowship, sponsored by the American Society of Preventive Oncology and Breast Cancer Research Foundation.

SOURCE: Mariotto A et al. J Natl Cancer Inst. 2019 Apr 24. doi: 10.1093/jnci/djz068.

Persistence of oral human papillomavirus (HPV) DNA after primary treatment of HPV-positive oral cavity or oropharyngeal head and neck squamous cell carcinoma (HNSCC) is a strong risk factor for poor outcomes, finds a prospective cohort study.

Investigators working under senior author Maura L. Gillison, MD, PhD, of the department of thoracic head and neck medical oncology at the University of Texas MD Anderson Cancer Center, Houston, collected serial oral rinses from 396 patients with HNSCC (217 with oropharyngeal cancer, 170 with oral cavity cancer, 9 with unknown primary cancer) treated at two institutions. Overall, 51% had HPV-positive tumors.

Patients with HPV-positive tumors were much more likely to have detectable oral HPV at diagnosis than their counterparts with HPV-negative tumors (84.2% vs 12.4%; P less than .001). Detection of oral HPV-16 DNA had good sensitivity (81%) and excellent specificity (100%) for HPV-16-positive tumors, Dr. Gillison and colleagues reported in JAMA Oncology.

Patients’ odds of having detectable tumor-type HPV fell during primary therapy (odds ratio per each postdiagnosis month, 0.41; P less than .001); in contrast, their odds of having of having detectable nontumor types did not. Current smokers were about half as likely to achieve clearing of tumor-type HPV DNA (hazard ratio, 0.49; P = .01).

Compared with counterparts who no longer had detectable tumor-type DNA after therapy, HPV-positive patients who did had dramatically poorer recurrence-free survival (55% vs. 88%; adjusted hazard ratio, 3.72; P  less than .001) and overall survival (68% vs. 95%; adjusted hazard ratio, 6.61; P = .003).

In contrast, persistence of nontumor-type HPV DNA did not predict these outcomes among either patients with HPV-positive tumors or patients with HPV-negative tumors.

“Analysis of tumor type HPV DNA has considerable promise as a biomarker for treatment response and risk of progression,” Dr. Gillison and coinvestigators maintain.

“Our data suggest that a subset of patients with HPV-positive HNSCC at high-risk for locoregional recurrence can be identified by detection of persistent, oral HPV after treatment. However, the clinical utility may be constrained by a need to identify the tumor-type infection, a low-moderate positive predictive value for recurrence, and weak associations with risk of distant metastases,” they conclude. “Ongoing studies will evaluate whether multiplexed detection of plasma HPV DNA can improve these limitations.”

Dr. Gillison disclosed consulting for Roche Holding AG, Bristol-Myers Squibb, Merck & Co Inc., Celgene Corporation, Amgen, AstraZeneca, Rakuten Aspyrian Inc. (now known as Rakuten Medical), EMD Serono Inc., NewLink Genetics Corporation, and Genocea Biosciences. The study was supported by the Oral Cancer Foundation and The Ohio State University Comprehensive Cancer Center. Dr. Gillison is a Cancer Prevention and Research Institute of Texas Scholar.

SOURCE: Fakhry C et al. JAMA Oncol. 2019 May 2. doi: 10.1001/jamaoncol.2019.0439.

Persistence of oral human papillomavirus (HPV) DNA after primary treatment of HPV-positive oral cavity or oropharyngeal head and neck squamous cell carcinoma (HNSCC) is a strong risk factor for poor outcomes, finds a prospective cohort study.

Investigators working under senior author Maura L. Gillison, MD, PhD, of the department of thoracic head and neck medical oncology at the University of Texas MD Anderson Cancer Center, Houston, collected serial oral rinses from 396 patients with HNSCC (217 with oropharyngeal cancer, 170 with oral cavity cancer, 9 with unknown primary cancer) treated at two institutions. Overall, 51% had HPV-positive tumors.

Patients with HPV-positive tumors were much more likely to have detectable oral HPV at diagnosis than their counterparts with HPV-negative tumors (84.2% vs 12.4%; P less than .001). Detection of oral HPV-16 DNA had good sensitivity (81%) and excellent specificity (100%) for HPV-16-positive tumors, Dr. Gillison and colleagues reported in JAMA Oncology.

Patients’ odds of having detectable tumor-type HPV fell during primary therapy (odds ratio per each postdiagnosis month, 0.41; P less than .001); in contrast, their odds of having of having detectable nontumor types did not. Current smokers were about half as likely to achieve clearing of tumor-type HPV DNA (hazard ratio, 0.49; P = .01).

Compared with counterparts who no longer had detectable tumor-type DNA after therapy, HPV-positive patients who did had dramatically poorer recurrence-free survival (55% vs. 88%; adjusted hazard ratio, 3.72; P  less than .001) and overall survival (68% vs. 95%; adjusted hazard ratio, 6.61; P = .003).

In contrast, persistence of nontumor-type HPV DNA did not predict these outcomes among either patients with HPV-positive tumors or patients with HPV-negative tumors.

“Analysis of tumor type HPV DNA has considerable promise as a biomarker for treatment response and risk of progression,” Dr. Gillison and coinvestigators maintain.

“Our data suggest that a subset of patients with HPV-positive HNSCC at high-risk for locoregional recurrence can be identified by detection of persistent, oral HPV after treatment. However, the clinical utility may be constrained by a need to identify the tumor-type infection, a low-moderate positive predictive value for recurrence, and weak associations with risk of distant metastases,” they conclude. “Ongoing studies will evaluate whether multiplexed detection of plasma HPV DNA can improve these limitations.”

Dr. Gillison disclosed consulting for Roche Holding AG, Bristol-Myers Squibb, Merck & Co Inc., Celgene Corporation, Amgen, AstraZeneca, Rakuten Aspyrian Inc. (now known as Rakuten Medical), EMD Serono Inc., NewLink Genetics Corporation, and Genocea Biosciences. The study was supported by the Oral Cancer Foundation and The Ohio State University Comprehensive Cancer Center. Dr. Gillison is a Cancer Prevention and Research Institute of Texas Scholar.

SOURCE: Fakhry C et al. JAMA Oncol. 2019 May 2. doi: 10.1001/jamaoncol.2019.0439.

Persistence of oral human papillomavirus (HPV) DNA after primary treatment of HPV-positive oral cavity or oropharyngeal head and neck squamous cell carcinoma (HNSCC) is a strong risk factor for poor outcomes, finds a prospective cohort study.

Investigators working under senior author Maura L. Gillison, MD, PhD, of the department of thoracic head and neck medical oncology at the University of Texas MD Anderson Cancer Center, Houston, collected serial oral rinses from 396 patients with HNSCC (217 with oropharyngeal cancer, 170 with oral cavity cancer, 9 with unknown primary cancer) treated at two institutions. Overall, 51% had HPV-positive tumors.

Patients with HPV-positive tumors were much more likely to have detectable oral HPV at diagnosis than their counterparts with HPV-negative tumors (84.2% vs 12.4%; P less than .001). Detection of oral HPV-16 DNA had good sensitivity (81%) and excellent specificity (100%) for HPV-16-positive tumors, Dr. Gillison and colleagues reported in JAMA Oncology.

Patients’ odds of having detectable tumor-type HPV fell during primary therapy (odds ratio per each postdiagnosis month, 0.41; P less than .001); in contrast, their odds of having of having detectable nontumor types did not. Current smokers were about half as likely to achieve clearing of tumor-type HPV DNA (hazard ratio, 0.49; P = .01).

Compared with counterparts who no longer had detectable tumor-type DNA after therapy, HPV-positive patients who did had dramatically poorer recurrence-free survival (55% vs. 88%; adjusted hazard ratio, 3.72; P  less than .001) and overall survival (68% vs. 95%; adjusted hazard ratio, 6.61; P = .003).

In contrast, persistence of nontumor-type HPV DNA did not predict these outcomes among either patients with HPV-positive tumors or patients with HPV-negative tumors.

“Analysis of tumor type HPV DNA has considerable promise as a biomarker for treatment response and risk of progression,” Dr. Gillison and coinvestigators maintain.

“Our data suggest that a subset of patients with HPV-positive HNSCC at high-risk for locoregional recurrence can be identified by detection of persistent, oral HPV after treatment. However, the clinical utility may be constrained by a need to identify the tumor-type infection, a low-moderate positive predictive value for recurrence, and weak associations with risk of distant metastases,” they conclude. “Ongoing studies will evaluate whether multiplexed detection of plasma HPV DNA can improve these limitations.”

Dr. Gillison disclosed consulting for Roche Holding AG, Bristol-Myers Squibb, Merck & Co Inc., Celgene Corporation, Amgen, AstraZeneca, Rakuten Aspyrian Inc. (now known as Rakuten Medical), EMD Serono Inc., NewLink Genetics Corporation, and Genocea Biosciences. The study was supported by the Oral Cancer Foundation and The Ohio State University Comprehensive Cancer Center. Dr. Gillison is a Cancer Prevention and Research Institute of Texas Scholar.

SOURCE: Fakhry C et al. JAMA Oncol. 2019 May 2. doi: 10.1001/jamaoncol.2019.0439.

The burden of the U.S. oropharynx cancer epidemic is shifting toward older adults, finds a population-based cohort study spanning 23 years. As a result, the disease will likely become one predominantly affecting elderly white men over the next decade. In addition, projections suggest that the annual number of new cases will likely rise exponentially.

Historically, the incidence of oropharynx cancer rose rapidly among white men aged younger than 60 years because of human papillomavirus (HPV) infections (J Clin Oncol. 2011;29:4294-301). But given factors such as aging, possible changes in behavior, and vaccination, the current trajectory is unknown.

Investigators led by Joseph E. Tota, PhD, of the division of cancer epidemiology and genetics at the National Cancer Institute analyzed Surveillance, Epidemiology, and End Results registry data for 1992-2015 to ascertain whether the increases in oropharynx cancer have continued into recent birth cohorts and to forecast future burden across subgroups.

Results published in the Journal of Clinical Oncology showed that, among white men, oropharynx cancer incidence accelerated among those born during 1927-1939 (by 3.5% per 2-year birth cohort) and during 1939-1955 (by 5.3% per 2-year birth cohort), whereas the pace of increase moderated among those born during 1955-1969 (by 1.7% per 2-year birth cohort).

Given these trends, the investigators forecast that incidence will increase sharply between 2016 and 2029 among older white men aged 65-74 years (from 40.7 to 71.2 per 100,000) and 75-84 years (from 25.7 to 50.1 per 100,000), increase moderately among white men aged 55-64 years (from 40.3 to 52.0 per 100,000), and remain stable among white men aged 45-54 years (at roughly 18 per 100,000).

Taking population growth into account, Dr. Tota and colleagues project a 52% increase in annual number of cases in the United States (from 20,124 to 30,629 between 2016 and 2029), mainly driven by a 127% increase among older adults aged at least 65 years (from 7,976 to 18,072) and a 54% increase among white men (from 14,453 to 22,241). As of 2029, white men older than 65 years will account for approximately 44% of all cases.

“Our results suggest an ebbing of the oropharynx cancer epidemic in younger individuals, exaggeration of the epidemic in older individuals, and a continued exponential increase in the annual number of oropharynx cancers over the next decade,” Dr. Tota and coinvestigators summarized.

The findings have important implications regarding treatment of older patients with oropharynx cancer, they noted. “It is likely that the biology of HPV-positive tumors is similar in younger versus older patients; nonetheless, older patients have poorer survival outcomes because of competing comorbidities, treatment-associated acute and chronic toxicity with chemoradiation, or an inability to receive maximally effective therapies. … Thus, older patients with oropharynx cancer may have different risks and benefits when receiving deintensified regimens than younger patients. The emergence of immunotherapies, whose efficacy may be more age invariant than cytotoxic chemotherapies, could provide a promising treatment avenue for older patients with oropharynx cancer.”

Dr. Tota reported receiving travel, accommodations, and expenses from Merck. The study was supported by the Intramural Research Program of the National Institutes of Health/NCI.

SOURCE: Tota JE et al. J Clin Oncol. 2019 Apr 26. doi: 10.1200/JCO.19.00370.

The burden of the U.S. oropharynx cancer epidemic is shifting toward older adults, finds a population-based cohort study spanning 23 years. As a result, the disease will likely become one predominantly affecting elderly white men over the next decade. In addition, projections suggest that the annual number of new cases will likely rise exponentially.

Historically, the incidence of oropharynx cancer rose rapidly among white men aged younger than 60 years because of human papillomavirus (HPV) infections (J Clin Oncol. 2011;29:4294-301). But given factors such as aging, possible changes in behavior, and vaccination, the current trajectory is unknown.

Investigators led by Joseph E. Tota, PhD, of the division of cancer epidemiology and genetics at the National Cancer Institute analyzed Surveillance, Epidemiology, and End Results registry data for 1992-2015 to ascertain whether the increases in oropharynx cancer have continued into recent birth cohorts and to forecast future burden across subgroups.

Results published in the Journal of Clinical Oncology showed that, among white men, oropharynx cancer incidence accelerated among those born during 1927-1939 (by 3.5% per 2-year birth cohort) and during 1939-1955 (by 5.3% per 2-year birth cohort), whereas the pace of increase moderated among those born during 1955-1969 (by 1.7% per 2-year birth cohort).

Given these trends, the investigators forecast that incidence will increase sharply between 2016 and 2029 among older white men aged 65-74 years (from 40.7 to 71.2 per 100,000) and 75-84 years (from 25.7 to 50.1 per 100,000), increase moderately among white men aged 55-64 years (from 40.3 to 52.0 per 100,000), and remain stable among white men aged 45-54 years (at roughly 18 per 100,000).

Taking population growth into account, Dr. Tota and colleagues project a 52% increase in annual number of cases in the United States (from 20,124 to 30,629 between 2016 and 2029), mainly driven by a 127% increase among older adults aged at least 65 years (from 7,976 to 18,072) and a 54% increase among white men (from 14,453 to 22,241). As of 2029, white men older than 65 years will account for approximately 44% of all cases.

“Our results suggest an ebbing of the oropharynx cancer epidemic in younger individuals, exaggeration of the epidemic in older individuals, and a continued exponential increase in the annual number of oropharynx cancers over the next decade,” Dr. Tota and coinvestigators summarized.

The findings have important implications regarding treatment of older patients with oropharynx cancer, they noted. “It is likely that the biology of HPV-positive tumors is similar in younger versus older patients; nonetheless, older patients have poorer survival outcomes because of competing comorbidities, treatment-associated acute and chronic toxicity with chemoradiation, or an inability to receive maximally effective therapies. … Thus, older patients with oropharynx cancer may have different risks and benefits when receiving deintensified regimens than younger patients. The emergence of immunotherapies, whose efficacy may be more age invariant than cytotoxic chemotherapies, could provide a promising treatment avenue for older patients with oropharynx cancer.”

Dr. Tota reported receiving travel, accommodations, and expenses from Merck. The study was supported by the Intramural Research Program of the National Institutes of Health/NCI.

SOURCE: Tota JE et al. J Clin Oncol. 2019 Apr 26. doi: 10.1200/JCO.19.00370.

The burden of the U.S. oropharynx cancer epidemic is shifting toward older adults, finds a population-based cohort study spanning 23 years. As a result, the disease will likely become one predominantly affecting elderly white men over the next decade. In addition, projections suggest that the annual number of new cases will likely rise exponentially.

Historically, the incidence of oropharynx cancer rose rapidly among white men aged younger than 60 years because of human papillomavirus (HPV) infections (J Clin Oncol. 2011;29:4294-301). But given factors such as aging, possible changes in behavior, and vaccination, the current trajectory is unknown.

Investigators led by Joseph E. Tota, PhD, of the division of cancer epidemiology and genetics at the National Cancer Institute analyzed Surveillance, Epidemiology, and End Results registry data for 1992-2015 to ascertain whether the increases in oropharynx cancer have continued into recent birth cohorts and to forecast future burden across subgroups.

Results published in the Journal of Clinical Oncology showed that, among white men, oropharynx cancer incidence accelerated among those born during 1927-1939 (by 3.5% per 2-year birth cohort) and during 1939-1955 (by 5.3% per 2-year birth cohort), whereas the pace of increase moderated among those born during 1955-1969 (by 1.7% per 2-year birth cohort).

Given these trends, the investigators forecast that incidence will increase sharply between 2016 and 2029 among older white men aged 65-74 years (from 40.7 to 71.2 per 100,000) and 75-84 years (from 25.7 to 50.1 per 100,000), increase moderately among white men aged 55-64 years (from 40.3 to 52.0 per 100,000), and remain stable among white men aged 45-54 years (at roughly 18 per 100,000).

Taking population growth into account, Dr. Tota and colleagues project a 52% increase in annual number of cases in the United States (from 20,124 to 30,629 between 2016 and 2029), mainly driven by a 127% increase among older adults aged at least 65 years (from 7,976 to 18,072) and a 54% increase among white men (from 14,453 to 22,241). As of 2029, white men older than 65 years will account for approximately 44% of all cases.

“Our results suggest an ebbing of the oropharynx cancer epidemic in younger individuals, exaggeration of the epidemic in older individuals, and a continued exponential increase in the annual number of oropharynx cancers over the next decade,” Dr. Tota and coinvestigators summarized.

The findings have important implications regarding treatment of older patients with oropharynx cancer, they noted. “It is likely that the biology of HPV-positive tumors is similar in younger versus older patients; nonetheless, older patients have poorer survival outcomes because of competing comorbidities, treatment-associated acute and chronic toxicity with chemoradiation, or an inability to receive maximally effective therapies. … Thus, older patients with oropharynx cancer may have different risks and benefits when receiving deintensified regimens than younger patients. The emergence of immunotherapies, whose efficacy may be more age invariant than cytotoxic chemotherapies, could provide a promising treatment avenue for older patients with oropharynx cancer.”

Dr. Tota reported receiving travel, accommodations, and expenses from Merck. The study was supported by the Intramural Research Program of the National Institutes of Health/NCI.

SOURCE: Tota JE et al. J Clin Oncol. 2019 Apr 26. doi: 10.1200/JCO.19.00370.

The prognostic influence of estrogen receptor-beta (ESR2) expression in breast cancer – favorable versus unfavorable – appears to hinge on tumor TP53 mutational status, an interaction that may have therapeutic implications for triple-negative disease, a new study suggests.

Up to 80% of triple-negative breast cancers (TNBCs) express ESR2, but its role has been hard to pin down because of conflicting data, according to the investigators, who were led by senior author Gokul M. Das, PhD, of the department of pharmacology and therapeutics, Center for Genetics and Pharmacology, Roswell Park Comprehensive Cancer Center, Buffalo, N.Y. Expression has been found to have both antiproliferative activity and proproliferative activity, depending on the experimental conditions.

Dr. Das and colleagues performed a series of in vitro assays in breast cancer cell lines and a clinical study of patients with basal-like TNBC from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort (308 patients with TP53 mutational status determined by sequencing) and a Roswell cohort (46 patients with TP53 mutational status determined by immunohistochemistry).

Results showed that in vitro, ESR2 interaction with wild-type TP53 had proproliferative effects, whereas interaction of ESR2 with mutant TP53 had antiproliferative effects. The report is in the Journal of the National Cancer Institute.

In luminal breast cancer cell lines with wild-type TP53, compared with control, depleting ESR2 increased expression of the TP53 target genes CDKN1A and BBC3 (P = .003 and P = .003, respectively); in contrast, in those with mutant TP53, depleting ESR2 decreased their expression (P = .02 and P = .008). Opposite results were seen when ESR2 was instead overexpressed.

In cells with mutant TP53, tamoxifen treatment increased interaction of ESR2 with the mutant protein, ultimately leading to reactivation of TP73 and apoptosis.

Finally, among women with basal-like TNBC in the METABRIC cohort, high ESR2 expression was associated with better overall survival for those with mutant TP53 tumors (hazard ratio for death, 0.26) but a trend toward poorer overall survival for those with wild-type TP53 tumors (P = .05). Results were similar in the Roswell cohort.

SOURCE: Mukhopadhyay UK et al. J Natl Cancer Inst. 2019 Apr 16. doi: 10.1093/jnci/djz051.

The prognostic influence of estrogen receptor-beta (ESR2) expression in breast cancer – favorable versus unfavorable – appears to hinge on tumor TP53 mutational status, an interaction that may have therapeutic implications for triple-negative disease, a new study suggests.

Up to 80% of triple-negative breast cancers (TNBCs) express ESR2, but its role has been hard to pin down because of conflicting data, according to the investigators, who were led by senior author Gokul M. Das, PhD, of the department of pharmacology and therapeutics, Center for Genetics and Pharmacology, Roswell Park Comprehensive Cancer Center, Buffalo, N.Y. Expression has been found to have both antiproliferative activity and proproliferative activity, depending on the experimental conditions.

Dr. Das and colleagues performed a series of in vitro assays in breast cancer cell lines and a clinical study of patients with basal-like TNBC from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort (308 patients with TP53 mutational status determined by sequencing) and a Roswell cohort (46 patients with TP53 mutational status determined by immunohistochemistry).

Results showed that in vitro, ESR2 interaction with wild-type TP53 had proproliferative effects, whereas interaction of ESR2 with mutant TP53 had antiproliferative effects. The report is in the Journal of the National Cancer Institute.

In luminal breast cancer cell lines with wild-type TP53, compared with control, depleting ESR2 increased expression of the TP53 target genes CDKN1A and BBC3 (P = .003 and P = .003, respectively); in contrast, in those with mutant TP53, depleting ESR2 decreased their expression (P = .02 and P = .008). Opposite results were seen when ESR2 was instead overexpressed.

In cells with mutant TP53, tamoxifen treatment increased interaction of ESR2 with the mutant protein, ultimately leading to reactivation of TP73 and apoptosis.

Finally, among women with basal-like TNBC in the METABRIC cohort, high ESR2 expression was associated with better overall survival for those with mutant TP53 tumors (hazard ratio for death, 0.26) but a trend toward poorer overall survival for those with wild-type TP53 tumors (P = .05). Results were similar in the Roswell cohort.

SOURCE: Mukhopadhyay UK et al. J Natl Cancer Inst. 2019 Apr 16. doi: 10.1093/jnci/djz051.

The prognostic influence of estrogen receptor-beta (ESR2) expression in breast cancer – favorable versus unfavorable – appears to hinge on tumor TP53 mutational status, an interaction that may have therapeutic implications for triple-negative disease, a new study suggests.

Up to 80% of triple-negative breast cancers (TNBCs) express ESR2, but its role has been hard to pin down because of conflicting data, according to the investigators, who were led by senior author Gokul M. Das, PhD, of the department of pharmacology and therapeutics, Center for Genetics and Pharmacology, Roswell Park Comprehensive Cancer Center, Buffalo, N.Y. Expression has been found to have both antiproliferative activity and proproliferative activity, depending on the experimental conditions.

Dr. Das and colleagues performed a series of in vitro assays in breast cancer cell lines and a clinical study of patients with basal-like TNBC from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort (308 patients with TP53 mutational status determined by sequencing) and a Roswell cohort (46 patients with TP53 mutational status determined by immunohistochemistry).

Results showed that in vitro, ESR2 interaction with wild-type TP53 had proproliferative effects, whereas interaction of ESR2 with mutant TP53 had antiproliferative effects. The report is in the Journal of the National Cancer Institute.

In luminal breast cancer cell lines with wild-type TP53, compared with control, depleting ESR2 increased expression of the TP53 target genes CDKN1A and BBC3 (P = .003 and P = .003, respectively); in contrast, in those with mutant TP53, depleting ESR2 decreased their expression (P = .02 and P = .008). Opposite results were seen when ESR2 was instead overexpressed.

In cells with mutant TP53, tamoxifen treatment increased interaction of ESR2 with the mutant protein, ultimately leading to reactivation of TP73 and apoptosis.

Finally, among women with basal-like TNBC in the METABRIC cohort, high ESR2 expression was associated with better overall survival for those with mutant TP53 tumors (hazard ratio for death, 0.26) but a trend toward poorer overall survival for those with wild-type TP53 tumors (P = .05). Results were similar in the Roswell cohort.

SOURCE: Mukhopadhyay UK et al. J Natl Cancer Inst. 2019 Apr 16. doi: 10.1093/jnci/djz051.

Patient navigation programs improve outcomes across the cancer care continuum and have financial benefits, finds a systematic review.

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The study, which was published in Cancer (2019 Apr 29. doi: 10.1002/cncr.32147) also found methodologic limitations and gaps in the research regarding cancer sites and steps in care, highlighting areas needing more focus.

The patient navigation model, introduced in 1990 to address poverty-related disparities in cancer care (Cancer. 2011;117(15 Suppl):3539-42), is now widely used in chronic illness management and has support from legislation as well as public and private funding. However, a 2011 review of patient navigation programs used in cancer care identified only 33 articles assessing impact and yielded mixed results, suggesting improvement in some out-comes but not others (CA Cancer J Clin. 2011;61:237-49), and there has been scant research on their cost-effectiveness.

Investigators led by Brittany M. Bernardo, MPH, Division of Population Sciences, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, searched PubMed and EMBASE databases for studies investigating the efficacy and cost-effectiveness of patient navigation across the cancer continuum, with aims of summarizing their results, assessing quality, determining gaps, and identifying avenues for future research.

Ultimately, the investigators included 113 articles published between August 1, 2010, and February 1, 2018. A total of 14 reported on the cost-effectiveness of patient navigation programs.

Results reported in Cancer showed that the largest share of the articles focused on the effectiveness of patient navigation in screening (50%) and diagnosis (27%), while few focused on treatment (15%), survivorship (9%), clinical trial enrollment (2 articles), and prevention (1 article). With respect to cancer site, the majority of programs pertained to breast cancer (52%) and colorectal cancer (51%).

Overall, studies reported patient navigation programs had positive outcomes. For example, they improved uptake of and adherence to cancer screenings, timely diagnostic resolution and follow-up, completion rates for cancer therapy, and rates of attending medical appointments.

The 14 studies focusing on cost-effectiveness suggested that patient navigation programs had financial benefits as well. Two found that the programs generated net revenue for clinics and hospitals. Programs additionally reduced medical treatment costs, improved life expectancy and quality-adjusted life-years, and decreased health care use.

When the quality of studies was assessed with the Quality Assessment Tool for Quantitative Studies, just 5% had strong methodology (having no weak components) and 30% had moderate methodology (having 1 weak component), while 65% had weak methodology (greater than or equal to 2 weak components).

“[Patient navigation] continues to be an effective method for overcoming barriers to care and should be integrated into more health care systems,” Ms. Bernardo and coinvestigators concluded. “With the encouraging results of this review and past reviews, it is hoped that new research will be conducted to fill in the remaining gaps and further elucidate the benefits of [patient navigation] in health care.”

One investigator disclosed having grant funding from the Merck Foundation and being a stockholder in Pfizer and a member of the American Cancer Society Patient Navigation Round Table; the other investigators made no disclosures. The study was supported by the Susan G. Komen Foundation and the Bradley Charles Cooper Foundation.

SOURCE: Bernardo BM et al. Cancer. 2019 Apr 29. doi: 10.1002/cncr.32147.

Patient navigation programs improve outcomes across the cancer care continuum and have financial benefits, finds a systematic review.

Thinkstock

The study, which was published in Cancer (2019 Apr 29. doi: 10.1002/cncr.32147) also found methodologic limitations and gaps in the research regarding cancer sites and steps in care, highlighting areas needing more focus.

The patient navigation model, introduced in 1990 to address poverty-related disparities in cancer care (Cancer. 2011;117(15 Suppl):3539-42), is now widely used in chronic illness management and has support from legislation as well as public and private funding. However, a 2011 review of patient navigation programs used in cancer care identified only 33 articles assessing impact and yielded mixed results, suggesting improvement in some out-comes but not others (CA Cancer J Clin. 2011;61:237-49), and there has been scant research on their cost-effectiveness.

Investigators led by Brittany M. Bernardo, MPH, Division of Population Sciences, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, searched PubMed and EMBASE databases for studies investigating the efficacy and cost-effectiveness of patient navigation across the cancer continuum, with aims of summarizing their results, assessing quality, determining gaps, and identifying avenues for future research.

Ultimately, the investigators included 113 articles published between August 1, 2010, and February 1, 2018. A total of 14 reported on the cost-effectiveness of patient navigation programs.

Results reported in Cancer showed that the largest share of the articles focused on the effectiveness of patient navigation in screening (50%) and diagnosis (27%), while few focused on treatment (15%), survivorship (9%), clinical trial enrollment (2 articles), and prevention (1 article). With respect to cancer site, the majority of programs pertained to breast cancer (52%) and colorectal cancer (51%).

Overall, studies reported patient navigation programs had positive outcomes. For example, they improved uptake of and adherence to cancer screenings, timely diagnostic resolution and follow-up, completion rates for cancer therapy, and rates of attending medical appointments.

The 14 studies focusing on cost-effectiveness suggested that patient navigation programs had financial benefits as well. Two found that the programs generated net revenue for clinics and hospitals. Programs additionally reduced medical treatment costs, improved life expectancy and quality-adjusted life-years, and decreased health care use.

When the quality of studies was assessed with the Quality Assessment Tool for Quantitative Studies, just 5% had strong methodology (having no weak components) and 30% had moderate methodology (having 1 weak component), while 65% had weak methodology (greater than or equal to 2 weak components).

“[Patient navigation] continues to be an effective method for overcoming barriers to care and should be integrated into more health care systems,” Ms. Bernardo and coinvestigators concluded. “With the encouraging results of this review and past reviews, it is hoped that new research will be conducted to fill in the remaining gaps and further elucidate the benefits of [patient navigation] in health care.”

One investigator disclosed having grant funding from the Merck Foundation and being a stockholder in Pfizer and a member of the American Cancer Society Patient Navigation Round Table; the other investigators made no disclosures. The study was supported by the Susan G. Komen Foundation and the Bradley Charles Cooper Foundation.

SOURCE: Bernardo BM et al. Cancer. 2019 Apr 29. doi: 10.1002/cncr.32147.

Patient navigation programs improve outcomes across the cancer care continuum and have financial benefits, finds a systematic review.

Thinkstock

The study, which was published in Cancer (2019 Apr 29. doi: 10.1002/cncr.32147) also found methodologic limitations and gaps in the research regarding cancer sites and steps in care, highlighting areas needing more focus.

The patient navigation model, introduced in 1990 to address poverty-related disparities in cancer care (Cancer. 2011;117(15 Suppl):3539-42), is now widely used in chronic illness management and has support from legislation as well as public and private funding. However, a 2011 review of patient navigation programs used in cancer care identified only 33 articles assessing impact and yielded mixed results, suggesting improvement in some out-comes but not others (CA Cancer J Clin. 2011;61:237-49), and there has been scant research on their cost-effectiveness.

Investigators led by Brittany M. Bernardo, MPH, Division of Population Sciences, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, searched PubMed and EMBASE databases for studies investigating the efficacy and cost-effectiveness of patient navigation across the cancer continuum, with aims of summarizing their results, assessing quality, determining gaps, and identifying avenues for future research.

Ultimately, the investigators included 113 articles published between August 1, 2010, and February 1, 2018. A total of 14 reported on the cost-effectiveness of patient navigation programs.

Results reported in Cancer showed that the largest share of the articles focused on the effectiveness of patient navigation in screening (50%) and diagnosis (27%), while few focused on treatment (15%), survivorship (9%), clinical trial enrollment (2 articles), and prevention (1 article). With respect to cancer site, the majority of programs pertained to breast cancer (52%) and colorectal cancer (51%).

Overall, studies reported patient navigation programs had positive outcomes. For example, they improved uptake of and adherence to cancer screenings, timely diagnostic resolution and follow-up, completion rates for cancer therapy, and rates of attending medical appointments.

The 14 studies focusing on cost-effectiveness suggested that patient navigation programs had financial benefits as well. Two found that the programs generated net revenue for clinics and hospitals. Programs additionally reduced medical treatment costs, improved life expectancy and quality-adjusted life-years, and decreased health care use.

When the quality of studies was assessed with the Quality Assessment Tool for Quantitative Studies, just 5% had strong methodology (having no weak components) and 30% had moderate methodology (having 1 weak component), while 65% had weak methodology (greater than or equal to 2 weak components).

“[Patient navigation] continues to be an effective method for overcoming barriers to care and should be integrated into more health care systems,” Ms. Bernardo and coinvestigators concluded. “With the encouraging results of this review and past reviews, it is hoped that new research will be conducted to fill in the remaining gaps and further elucidate the benefits of [patient navigation] in health care.”

One investigator disclosed having grant funding from the Merck Foundation and being a stockholder in Pfizer and a member of the American Cancer Society Patient Navigation Round Table; the other investigators made no disclosures. The study was supported by the Susan G. Komen Foundation and the Bradley Charles Cooper Foundation.

SOURCE: Bernardo BM et al. Cancer. 2019 Apr 29. doi: 10.1002/cncr.32147.

Stress disorders triggered by life events or trauma have a marked deleterious impact on the cardiovascular system, especially in the short term, suggests a Swedish population-based cohort study of more than 1.6 million people.

Previous studies have had limited power to detect associations and have seldom explored conditions other than PTSD, noted the investigators, led by Huan Song, PhD. In addition, little is known about how genetic predisposition to cardiovascular disease may influence the association.

Results of the new study, reported online in the BMJ, showed that with a median follow-up of about 6.5 years, relative to unaffected siblings, patients who had PTSD, acute stress reaction, adjustment disorder, or another stress reaction had a 64% higher risk of developing a cardiovascular disease during the first year post diagnosis, and a 29% higher risk thereafter.

In the first year, risk was most elevated for heart failure – nearly seven times higher for the patients than for their siblings. In addition, overall risk was increased to a significantly greater extent for cardiovascular diseases with early onset, starting before age 50 years, than for those with later onset, according to Dr. Song of the Center of Public Health Sciences at the University of Iceland, Reykjavík, and the Karolinska Institutet in Stockholm. Findings were essentially the same when patients were instead compared with age- and sex-matched individuals from the general population.

“Stress-related disorders are robustly associated with multiple types of cardiovascular disease, independently of familial background, history of somatic/psychiatric diseases, and psychiatric comorbidity,” Dr. Song and her coinvestigators wrote. “These findings call for enhanced clinical awareness and, if verified, monitoring or early intervention among patients with recently diagnosed stress related disorders.”

Study details

In their population-based cohort study of the Swedish National Patient Register, the investigators identified 136,637 patients with new-onset, stress-related disorders diagnosed between 1987 and 2013. They compared these patients with 171,314 unaffected full siblings and with 1,366,370 unaffected matched people from the general population. Median follow-up was 6.2 years, 6.9 years, and 6.5 years, respectively.

Results showed that the crude incidence rate of any cardiovascular disease was 10.5 per 1,000 person years among the patients with stress-related disorders, 8.4 per 1,000 person years among their unaffected siblings, and 6.9 per 1,000 person years among the matched unaffected individuals from the general population.

Compared with unaffected siblings, patients with stress-related disorders had a 60% elevated risk for developing any cardiovascular disease during the first year after diagnosis. Risk in this window was most elevated for heart failure (hazard ratio, 6.95); cerebrovascular disease other than ischemic and hemorrhagic stroke and arachnoidal bleeding (HR, 5.64), conduction disorders (HR, 5.00), and cardiac arrest (HR, 3.37).

Risk of any cardiovascular disease associated with stress-related disorders was still elevated but to a lesser extent after the first year post diagnosis (HR, 1.29). During this period, risk was most elevated for arterial thrombosis/embolus (HR, 2.02), hemorrhagic stroke (HR, 1.56), and fatal cerebrovascular events (HR, 1.56).

In analyses looking at age of onset of the cardiovascular disease, stress-related disorders showed stronger association with early-onset disease (occurring before age 50 years) than with later-onset disease (HR, 1.40 vs. 1.24; P = .002).

Fatal cardiovascular disease was the only category for which the associations were modified by presence of psychiatric comorbidity. Here, presence of such comorbidity amplified the risk conferred by the stress-related disorder.

Findings were much the same when patients were compared with matched individuals from the general population. Risk for any cardiovascular disease was again elevated substantially in the first year post diagnosis by 71%, and to 36% thereafter.

The authors reported that they had no relevant conflicts of interest. The study was supported by the Icelandic Research Fund, an ERC Consolidator Grant, the Karolinska Institutet, and the Swedish Research Council.

SOURCE: Song H et al. BMJ. 2019 Apr 10. doi: 10.1136/bmj.l1255.

Stress disorders triggered by life events or trauma have a marked deleterious impact on the cardiovascular system, especially in the short term, suggests a Swedish population-based cohort study of more than 1.6 million people.

Previous studies have had limited power to detect associations and have seldom explored conditions other than PTSD, noted the investigators, led by Huan Song, PhD. In addition, little is known about how genetic predisposition to cardiovascular disease may influence the association.

Results of the new study, reported online in the BMJ, showed that with a median follow-up of about 6.5 years, relative to unaffected siblings, patients who had PTSD, acute stress reaction, adjustment disorder, or another stress reaction had a 64% higher risk of developing a cardiovascular disease during the first year post diagnosis, and a 29% higher risk thereafter.

In the first year, risk was most elevated for heart failure – nearly seven times higher for the patients than for their siblings. In addition, overall risk was increased to a significantly greater extent for cardiovascular diseases with early onset, starting before age 50 years, than for those with later onset, according to Dr. Song of the Center of Public Health Sciences at the University of Iceland, Reykjavík, and the Karolinska Institutet in Stockholm. Findings were essentially the same when patients were instead compared with age- and sex-matched individuals from the general population.

“Stress-related disorders are robustly associated with multiple types of cardiovascular disease, independently of familial background, history of somatic/psychiatric diseases, and psychiatric comorbidity,” Dr. Song and her coinvestigators wrote. “These findings call for enhanced clinical awareness and, if verified, monitoring or early intervention among patients with recently diagnosed stress related disorders.”

Study details

In their population-based cohort study of the Swedish National Patient Register, the investigators identified 136,637 patients with new-onset, stress-related disorders diagnosed between 1987 and 2013. They compared these patients with 171,314 unaffected full siblings and with 1,366,370 unaffected matched people from the general population. Median follow-up was 6.2 years, 6.9 years, and 6.5 years, respectively.

Results showed that the crude incidence rate of any cardiovascular disease was 10.5 per 1,000 person years among the patients with stress-related disorders, 8.4 per 1,000 person years among their unaffected siblings, and 6.9 per 1,000 person years among the matched unaffected individuals from the general population.

Compared with unaffected siblings, patients with stress-related disorders had a 60% elevated risk for developing any cardiovascular disease during the first year after diagnosis. Risk in this window was most elevated for heart failure (hazard ratio, 6.95); cerebrovascular disease other than ischemic and hemorrhagic stroke and arachnoidal bleeding (HR, 5.64), conduction disorders (HR, 5.00), and cardiac arrest (HR, 3.37).

Risk of any cardiovascular disease associated with stress-related disorders was still elevated but to a lesser extent after the first year post diagnosis (HR, 1.29). During this period, risk was most elevated for arterial thrombosis/embolus (HR, 2.02), hemorrhagic stroke (HR, 1.56), and fatal cerebrovascular events (HR, 1.56).

In analyses looking at age of onset of the cardiovascular disease, stress-related disorders showed stronger association with early-onset disease (occurring before age 50 years) than with later-onset disease (HR, 1.40 vs. 1.24; P = .002).

Fatal cardiovascular disease was the only category for which the associations were modified by presence of psychiatric comorbidity. Here, presence of such comorbidity amplified the risk conferred by the stress-related disorder.

Findings were much the same when patients were compared with matched individuals from the general population. Risk for any cardiovascular disease was again elevated substantially in the first year post diagnosis by 71%, and to 36% thereafter.

The authors reported that they had no relevant conflicts of interest. The study was supported by the Icelandic Research Fund, an ERC Consolidator Grant, the Karolinska Institutet, and the Swedish Research Council.

SOURCE: Song H et al. BMJ. 2019 Apr 10. doi: 10.1136/bmj.l1255.

Stress disorders triggered by life events or trauma have a marked deleterious impact on the cardiovascular system, especially in the short term, suggests a Swedish population-based cohort study of more than 1.6 million people.

Previous studies have had limited power to detect associations and have seldom explored conditions other than PTSD, noted the investigators, led by Huan Song, PhD. In addition, little is known about how genetic predisposition to cardiovascular disease may influence the association.

Results of the new study, reported online in the BMJ, showed that with a median follow-up of about 6.5 years, relative to unaffected siblings, patients who had PTSD, acute stress reaction, adjustment disorder, or another stress reaction had a 64% higher risk of developing a cardiovascular disease during the first year post diagnosis, and a 29% higher risk thereafter.

In the first year, risk was most elevated for heart failure – nearly seven times higher for the patients than for their siblings. In addition, overall risk was increased to a significantly greater extent for cardiovascular diseases with early onset, starting before age 50 years, than for those with later onset, according to Dr. Song of the Center of Public Health Sciences at the University of Iceland, Reykjavík, and the Karolinska Institutet in Stockholm. Findings were essentially the same when patients were instead compared with age- and sex-matched individuals from the general population.

“Stress-related disorders are robustly associated with multiple types of cardiovascular disease, independently of familial background, history of somatic/psychiatric diseases, and psychiatric comorbidity,” Dr. Song and her coinvestigators wrote. “These findings call for enhanced clinical awareness and, if verified, monitoring or early intervention among patients with recently diagnosed stress related disorders.”

Study details

In their population-based cohort study of the Swedish National Patient Register, the investigators identified 136,637 patients with new-onset, stress-related disorders diagnosed between 1987 and 2013. They compared these patients with 171,314 unaffected full siblings and with 1,366,370 unaffected matched people from the general population. Median follow-up was 6.2 years, 6.9 years, and 6.5 years, respectively.

Results showed that the crude incidence rate of any cardiovascular disease was 10.5 per 1,000 person years among the patients with stress-related disorders, 8.4 per 1,000 person years among their unaffected siblings, and 6.9 per 1,000 person years among the matched unaffected individuals from the general population.

Compared with unaffected siblings, patients with stress-related disorders had a 60% elevated risk for developing any cardiovascular disease during the first year after diagnosis. Risk in this window was most elevated for heart failure (hazard ratio, 6.95); cerebrovascular disease other than ischemic and hemorrhagic stroke and arachnoidal bleeding (HR, 5.64), conduction disorders (HR, 5.00), and cardiac arrest (HR, 3.37).

Risk of any cardiovascular disease associated with stress-related disorders was still elevated but to a lesser extent after the first year post diagnosis (HR, 1.29). During this period, risk was most elevated for arterial thrombosis/embolus (HR, 2.02), hemorrhagic stroke (HR, 1.56), and fatal cerebrovascular events (HR, 1.56).

In analyses looking at age of onset of the cardiovascular disease, stress-related disorders showed stronger association with early-onset disease (occurring before age 50 years) than with later-onset disease (HR, 1.40 vs. 1.24; P = .002).

Fatal cardiovascular disease was the only category for which the associations were modified by presence of psychiatric comorbidity. Here, presence of such comorbidity amplified the risk conferred by the stress-related disorder.

Findings were much the same when patients were compared with matched individuals from the general population. Risk for any cardiovascular disease was again elevated substantially in the first year post diagnosis by 71%, and to 36% thereafter.

The authors reported that they had no relevant conflicts of interest. The study was supported by the Icelandic Research Fund, an ERC Consolidator Grant, the Karolinska Institutet, and the Swedish Research Council.

SOURCE: Song H et al. BMJ. 2019 Apr 10. doi: 10.1136/bmj.l1255.

SAN FRANCISCO – Dual targeting of the androgen signaling axis in metastatic hormone-sensitive prostate cancer improves outcomes and is well tolerated, according to results of the phase 3 ARCHES trial reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

“Androgen-deprivation therapy [ADT] has been the mainstay of therapy for men who present with metastatic disease for many years. But generally, progression to castration-resistant diseases is observed within approximately 3 years,” said lead investigator Andrew J. Armstrong, MD, a professor of medicine in medical oncology at Duke University, Durham, N.C.

“Thus the advent of improving outcomes with the [additional] use of early docetaxel, abiraterone, and now radiation to the primary in the face of oligometastatic disease has been shown to improve survival,” he added. “However, the most recent studies have really not studied the sequential use of docetaxel and have largely excluded patients who had had prior docetaxel chemotherapy in the hormone-sensitive setting.”

The investigators in the ARCHES trial (NCT02677896) randomized 1,150 men with metastatic hormone-sensitive prostate cancer to enzalutamide (Xtandi) plus ADT or placebo plus ADT.

With a median follow-up of 14.4 months, radiographic progression-free survival – the trial’s primary endpoint – was prolonged in the enzalutamide arm. Risk of progression or death was reduced by a relative 61% with enzalutamide versus placebo. There were also significant relative reductions in risks of other important outcomes such as time to prostate-specific antigen (PSA) progression (81% reduction), time to new antineoplastic therapy (72% reduction), and time to castration resistance (72% reduction).

Meanwhile, the enzalutamide group had somewhat more fatigue, hot flashes, and hypertension, but most of these events were grade 1 or 2. Rates of adverse events leading to treatment withdrawal were similar and low.

“Following the success of this study, all patients in the placebo group will be offered participation in an open-label extension protocol where they’ll be offered enzalutamide and the opportunity to receive a clinically beneficial treatment,” Dr. Armstrong reported.
 

Ready for prime time?

The ARCHES findings are probably not yet sufficient to be implemented in real-world practice, according to invited discussant Ian D. Davis, MBBS, PhD, a professor at Monash University, Melbourne.

The condition studied in the trial – metastatic hormone-sensitive prostate cancer – certainly needs treatment, but it is unclear whether radiographic progression-free survival is a meaningful endpoint, he said. “We know in the CRPC [castration-resistant prostate cancer] setting for enzalutamide in the PREVAIL study, radiographic progression-free survival was correlated with overall survival, but we haven’t actually proven that yet in the CSPC [castration-sensitive prostate cancer] setting.”

Toxicity was acceptable, but information about the efficacy of subsequent treatment is lacking. “This is where progression-free survival 2 [PFS2] information would be useful if we had it,” Dr. Davis noted. Cost-effectiveness in terms of overall survival is likewise still unknown.

“Cautiously, and I’m conscious of my conflict of interest here because I’m doing a similar trial, I’d say that the ARCHES trial should probably not yet change practice,” he said. However, he qualified that statement by pointing to recently announced results from the phase 3 TITAN trial (NCT02489318) of apalutamide (Erleada), showing significant radiographic progression-free survival and overall survival benefit in this patient population. “So we await those data with interest.”

The first interim analysis of the enzalutamide trial he is cochairing, ANZUP ENZAMET (NCT02446405), is imminent, according to Dr. Davis. “The differences here are the primary endpoint of ENZAMET is overall survival and there was an early amendment to allow concurrent docetaxel, so a significant proportion of patients on this study will have received concurrent docetaxel with enzalutamide or ADT,” he noted.

Men enrolled in ARCHES were allowed to have received prior ADT for up to 3 months or, if they had received docetaxel, for up to 6 months, Dr. Armstrong noted at the symposium.

About two-thirds each had high disease volume and had distant metastasis at their initial diagnosis. Overall, median duration of prior ADT was 1.6 months.

Radiographic progression-free survival was not reached with enzalutamide versus 19.45 months with placebo (hazard ratio, 0.39; P less than .0001). Corresponding 12-month rates were 84% and 64%. Findings were essentially the same across diverse subgroups, including among the 18% of patients who had received prior docetaxel (HR, 0.53).

Median time to PSA progression – typically one of the first indications of castration resistance – was not reached in either group, but the 12-month rate was 91% with enzalutamide versus 63% with placebo (HR, 0.19; P less than .0001), Dr. Armstrong reported. Median time to castration resistance was not reached with enzalutamide versus 13.9 months with placebo (HR, 0.28; P less than .0001).

There also were significant differences in favor of enzalutamide on the rate of achievement of undetectable PSA (68.1% vs. 17.6%; P less than .0001), the objective response rate (83.1% vs. 63.7%; P less than .0001), and the time to initiation of new antineoplastic therapy (not reached vs. 30.19 months; HR, 0.28; P less than .0001).

Quality of life was very high in both groups at study baseline and remained similarly so during follow-up. An interim analysis showed overall survival had not been reached in either group, although there was a nonsignificant trend favoring enzalutamide.

Safety was much the same, with the enzalutamide and placebo groups having similar rates of grade 3 or worse adverse events (24.3% vs. 25.6%), as well as similar rates of adverse events leading to treatment withdrawal (7.2% vs. 5.2%) and death (2.4% vs. 1.7%).

In terms of adverse events of special interest, the groups were comparable on rates of grade 3 or 4 convulsion, ischemic heart disease, falls, and fractures.

Dr. Armstrong disclosed that he has a consulting or advisory role with, receives research funding (institutional) from, and receives travel, accommodations, and/or expenses from Astellas – among other disclosures. The trial was sponsored by Astellas.

SOURCE: Armstrong AJ et al. GUCS 2019, Abstract 687.

SAN FRANCISCO – Dual targeting of the androgen signaling axis in metastatic hormone-sensitive prostate cancer improves outcomes and is well tolerated, according to results of the phase 3 ARCHES trial reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

“Androgen-deprivation therapy [ADT] has been the mainstay of therapy for men who present with metastatic disease for many years. But generally, progression to castration-resistant diseases is observed within approximately 3 years,” said lead investigator Andrew J. Armstrong, MD, a professor of medicine in medical oncology at Duke University, Durham, N.C.

“Thus the advent of improving outcomes with the [additional] use of early docetaxel, abiraterone, and now radiation to the primary in the face of oligometastatic disease has been shown to improve survival,” he added. “However, the most recent studies have really not studied the sequential use of docetaxel and have largely excluded patients who had had prior docetaxel chemotherapy in the hormone-sensitive setting.”

The investigators in the ARCHES trial (NCT02677896) randomized 1,150 men with metastatic hormone-sensitive prostate cancer to enzalutamide (Xtandi) plus ADT or placebo plus ADT.

With a median follow-up of 14.4 months, radiographic progression-free survival – the trial’s primary endpoint – was prolonged in the enzalutamide arm. Risk of progression or death was reduced by a relative 61% with enzalutamide versus placebo. There were also significant relative reductions in risks of other important outcomes such as time to prostate-specific antigen (PSA) progression (81% reduction), time to new antineoplastic therapy (72% reduction), and time to castration resistance (72% reduction).

Meanwhile, the enzalutamide group had somewhat more fatigue, hot flashes, and hypertension, but most of these events were grade 1 or 2. Rates of adverse events leading to treatment withdrawal were similar and low.

“Following the success of this study, all patients in the placebo group will be offered participation in an open-label extension protocol where they’ll be offered enzalutamide and the opportunity to receive a clinically beneficial treatment,” Dr. Armstrong reported.
 

Ready for prime time?

The ARCHES findings are probably not yet sufficient to be implemented in real-world practice, according to invited discussant Ian D. Davis, MBBS, PhD, a professor at Monash University, Melbourne.

The condition studied in the trial – metastatic hormone-sensitive prostate cancer – certainly needs treatment, but it is unclear whether radiographic progression-free survival is a meaningful endpoint, he said. “We know in the CRPC [castration-resistant prostate cancer] setting for enzalutamide in the PREVAIL study, radiographic progression-free survival was correlated with overall survival, but we haven’t actually proven that yet in the CSPC [castration-sensitive prostate cancer] setting.”

Toxicity was acceptable, but information about the efficacy of subsequent treatment is lacking. “This is where progression-free survival 2 [PFS2] information would be useful if we had it,” Dr. Davis noted. Cost-effectiveness in terms of overall survival is likewise still unknown.

“Cautiously, and I’m conscious of my conflict of interest here because I’m doing a similar trial, I’d say that the ARCHES trial should probably not yet change practice,” he said. However, he qualified that statement by pointing to recently announced results from the phase 3 TITAN trial (NCT02489318) of apalutamide (Erleada), showing significant radiographic progression-free survival and overall survival benefit in this patient population. “So we await those data with interest.”

The first interim analysis of the enzalutamide trial he is cochairing, ANZUP ENZAMET (NCT02446405), is imminent, according to Dr. Davis. “The differences here are the primary endpoint of ENZAMET is overall survival and there was an early amendment to allow concurrent docetaxel, so a significant proportion of patients on this study will have received concurrent docetaxel with enzalutamide or ADT,” he noted.

Men enrolled in ARCHES were allowed to have received prior ADT for up to 3 months or, if they had received docetaxel, for up to 6 months, Dr. Armstrong noted at the symposium.

About two-thirds each had high disease volume and had distant metastasis at their initial diagnosis. Overall, median duration of prior ADT was 1.6 months.

Radiographic progression-free survival was not reached with enzalutamide versus 19.45 months with placebo (hazard ratio, 0.39; P less than .0001). Corresponding 12-month rates were 84% and 64%. Findings were essentially the same across diverse subgroups, including among the 18% of patients who had received prior docetaxel (HR, 0.53).

Median time to PSA progression – typically one of the first indications of castration resistance – was not reached in either group, but the 12-month rate was 91% with enzalutamide versus 63% with placebo (HR, 0.19; P less than .0001), Dr. Armstrong reported. Median time to castration resistance was not reached with enzalutamide versus 13.9 months with placebo (HR, 0.28; P less than .0001).

There also were significant differences in favor of enzalutamide on the rate of achievement of undetectable PSA (68.1% vs. 17.6%; P less than .0001), the objective response rate (83.1% vs. 63.7%; P less than .0001), and the time to initiation of new antineoplastic therapy (not reached vs. 30.19 months; HR, 0.28; P less than .0001).

Quality of life was very high in both groups at study baseline and remained similarly so during follow-up. An interim analysis showed overall survival had not been reached in either group, although there was a nonsignificant trend favoring enzalutamide.

Safety was much the same, with the enzalutamide and placebo groups having similar rates of grade 3 or worse adverse events (24.3% vs. 25.6%), as well as similar rates of adverse events leading to treatment withdrawal (7.2% vs. 5.2%) and death (2.4% vs. 1.7%).

In terms of adverse events of special interest, the groups were comparable on rates of grade 3 or 4 convulsion, ischemic heart disease, falls, and fractures.

Dr. Armstrong disclosed that he has a consulting or advisory role with, receives research funding (institutional) from, and receives travel, accommodations, and/or expenses from Astellas – among other disclosures. The trial was sponsored by Astellas.

SOURCE: Armstrong AJ et al. GUCS 2019, Abstract 687.

SAN FRANCISCO – Dual targeting of the androgen signaling axis in metastatic hormone-sensitive prostate cancer improves outcomes and is well tolerated, according to results of the phase 3 ARCHES trial reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

“Androgen-deprivation therapy [ADT] has been the mainstay of therapy for men who present with metastatic disease for many years. But generally, progression to castration-resistant diseases is observed within approximately 3 years,” said lead investigator Andrew J. Armstrong, MD, a professor of medicine in medical oncology at Duke University, Durham, N.C.

“Thus the advent of improving outcomes with the [additional] use of early docetaxel, abiraterone, and now radiation to the primary in the face of oligometastatic disease has been shown to improve survival,” he added. “However, the most recent studies have really not studied the sequential use of docetaxel and have largely excluded patients who had had prior docetaxel chemotherapy in the hormone-sensitive setting.”

The investigators in the ARCHES trial (NCT02677896) randomized 1,150 men with metastatic hormone-sensitive prostate cancer to enzalutamide (Xtandi) plus ADT or placebo plus ADT.

With a median follow-up of 14.4 months, radiographic progression-free survival – the trial’s primary endpoint – was prolonged in the enzalutamide arm. Risk of progression or death was reduced by a relative 61% with enzalutamide versus placebo. There were also significant relative reductions in risks of other important outcomes such as time to prostate-specific antigen (PSA) progression (81% reduction), time to new antineoplastic therapy (72% reduction), and time to castration resistance (72% reduction).

Meanwhile, the enzalutamide group had somewhat more fatigue, hot flashes, and hypertension, but most of these events were grade 1 or 2. Rates of adverse events leading to treatment withdrawal were similar and low.

“Following the success of this study, all patients in the placebo group will be offered participation in an open-label extension protocol where they’ll be offered enzalutamide and the opportunity to receive a clinically beneficial treatment,” Dr. Armstrong reported.
 

Ready for prime time?

The ARCHES findings are probably not yet sufficient to be implemented in real-world practice, according to invited discussant Ian D. Davis, MBBS, PhD, a professor at Monash University, Melbourne.

The condition studied in the trial – metastatic hormone-sensitive prostate cancer – certainly needs treatment, but it is unclear whether radiographic progression-free survival is a meaningful endpoint, he said. “We know in the CRPC [castration-resistant prostate cancer] setting for enzalutamide in the PREVAIL study, radiographic progression-free survival was correlated with overall survival, but we haven’t actually proven that yet in the CSPC [castration-sensitive prostate cancer] setting.”

Toxicity was acceptable, but information about the efficacy of subsequent treatment is lacking. “This is where progression-free survival 2 [PFS2] information would be useful if we had it,” Dr. Davis noted. Cost-effectiveness in terms of overall survival is likewise still unknown.

“Cautiously, and I’m conscious of my conflict of interest here because I’m doing a similar trial, I’d say that the ARCHES trial should probably not yet change practice,” he said. However, he qualified that statement by pointing to recently announced results from the phase 3 TITAN trial (NCT02489318) of apalutamide (Erleada), showing significant radiographic progression-free survival and overall survival benefit in this patient population. “So we await those data with interest.”

The first interim analysis of the enzalutamide trial he is cochairing, ANZUP ENZAMET (NCT02446405), is imminent, according to Dr. Davis. “The differences here are the primary endpoint of ENZAMET is overall survival and there was an early amendment to allow concurrent docetaxel, so a significant proportion of patients on this study will have received concurrent docetaxel with enzalutamide or ADT,” he noted.

Men enrolled in ARCHES were allowed to have received prior ADT for up to 3 months or, if they had received docetaxel, for up to 6 months, Dr. Armstrong noted at the symposium.

About two-thirds each had high disease volume and had distant metastasis at their initial diagnosis. Overall, median duration of prior ADT was 1.6 months.

Radiographic progression-free survival was not reached with enzalutamide versus 19.45 months with placebo (hazard ratio, 0.39; P less than .0001). Corresponding 12-month rates were 84% and 64%. Findings were essentially the same across diverse subgroups, including among the 18% of patients who had received prior docetaxel (HR, 0.53).

Median time to PSA progression – typically one of the first indications of castration resistance – was not reached in either group, but the 12-month rate was 91% with enzalutamide versus 63% with placebo (HR, 0.19; P less than .0001), Dr. Armstrong reported. Median time to castration resistance was not reached with enzalutamide versus 13.9 months with placebo (HR, 0.28; P less than .0001).

There also were significant differences in favor of enzalutamide on the rate of achievement of undetectable PSA (68.1% vs. 17.6%; P less than .0001), the objective response rate (83.1% vs. 63.7%; P less than .0001), and the time to initiation of new antineoplastic therapy (not reached vs. 30.19 months; HR, 0.28; P less than .0001).

Quality of life was very high in both groups at study baseline and remained similarly so during follow-up. An interim analysis showed overall survival had not been reached in either group, although there was a nonsignificant trend favoring enzalutamide.

Safety was much the same, with the enzalutamide and placebo groups having similar rates of grade 3 or worse adverse events (24.3% vs. 25.6%), as well as similar rates of adverse events leading to treatment withdrawal (7.2% vs. 5.2%) and death (2.4% vs. 1.7%).

In terms of adverse events of special interest, the groups were comparable on rates of grade 3 or 4 convulsion, ischemic heart disease, falls, and fractures.

Dr. Armstrong disclosed that he has a consulting or advisory role with, receives research funding (institutional) from, and receives travel, accommodations, and/or expenses from Astellas – among other disclosures. The trial was sponsored by Astellas.

SOURCE: Armstrong AJ et al. GUCS 2019, Abstract 687.

SAN FRANCISCO – The risk-benefit profile of the novel vascular endothelial growth factor (VEGF) inhibitor tivozanib when used as later-line therapy for renal cell carcinoma (RCC) appears to be similar to when it is used earlier, according to eagerly awaited results of the TIVO-3 trial.

Susan London/MDedge News

Study details

About 60% of patients in TIVO-3 had received two prior lines of therapy, Dr. Rini reported at the symposium. The proportion stopping study treatment because of adverse events was 13% in the tivozanib group and 23% in the sorafenib group.

Median progression-free survival according to an independent review committee was 5.6 months and 3.9 months, respectively (hazard ratio, 0.73; P = .0165). Corresponding 1-year rates were 28% and 11%.

Among patients previously treated with an immune checkpoint inhibitor, median progression-free survival according to an independent review committee was 7.3 months with tivozanib and 5.1 months with sorafenib (hazard ratio, 0.55; P = .028). Corresponding 1-year rates were 35% and 4%.

In the entire trial population, the overall response rate was 18% for tivozanib versus 8% for sorafenib (P = .02). Median duration of response was not reached, compared with 5.7 months.

An interim analysis showed a median overall survival of 16.4 months in the tivozanib group and 19.7 months in the sorafenib group.

The rate of any-grade treatment-related adverse events was 84% with tivozanib and 94% with sorafenib. Tivozanib had a higher rate of grade 3 or 4 hypertension (20% vs. 14%), but lower rates of grade 3 or 4 diarrhea (2% vs. 9%), hand-foot syndrome (1% vs. 10%), and rash (0% vs. 8%).

Dr. Rini reported that he has a consulting role with Aveo, which sponsored the trial, and financial relationships with several other companies.

SOURCE: Rini BI et al. GUCS 2019, Abstract 541.

SAN FRANCISCO – The risk-benefit profile of the novel vascular endothelial growth factor (VEGF) inhibitor tivozanib when used as later-line therapy for renal cell carcinoma (RCC) appears to be similar to when it is used earlier, according to eagerly awaited results of the TIVO-3 trial.

Susan London/MDedge News

Study details

About 60% of patients in TIVO-3 had received two prior lines of therapy, Dr. Rini reported at the symposium. The proportion stopping study treatment because of adverse events was 13% in the tivozanib group and 23% in the sorafenib group.

Median progression-free survival according to an independent review committee was 5.6 months and 3.9 months, respectively (hazard ratio, 0.73; P = .0165). Corresponding 1-year rates were 28% and 11%.

Among patients previously treated with an immune checkpoint inhibitor, median progression-free survival according to an independent review committee was 7.3 months with tivozanib and 5.1 months with sorafenib (hazard ratio, 0.55; P = .028). Corresponding 1-year rates were 35% and 4%.

In the entire trial population, the overall response rate was 18% for tivozanib versus 8% for sorafenib (P = .02). Median duration of response was not reached, compared with 5.7 months.

An interim analysis showed a median overall survival of 16.4 months in the tivozanib group and 19.7 months in the sorafenib group.

The rate of any-grade treatment-related adverse events was 84% with tivozanib and 94% with sorafenib. Tivozanib had a higher rate of grade 3 or 4 hypertension (20% vs. 14%), but lower rates of grade 3 or 4 diarrhea (2% vs. 9%), hand-foot syndrome (1% vs. 10%), and rash (0% vs. 8%).

Dr. Rini reported that he has a consulting role with Aveo, which sponsored the trial, and financial relationships with several other companies.

SOURCE: Rini BI et al. GUCS 2019, Abstract 541.

SAN FRANCISCO – The risk-benefit profile of the novel vascular endothelial growth factor (VEGF) inhibitor tivozanib when used as later-line therapy for renal cell carcinoma (RCC) appears to be similar to when it is used earlier, according to eagerly awaited results of the TIVO-3 trial.

Susan London/MDedge News

Study details

About 60% of patients in TIVO-3 had received two prior lines of therapy, Dr. Rini reported at the symposium. The proportion stopping study treatment because of adverse events was 13% in the tivozanib group and 23% in the sorafenib group.

Median progression-free survival according to an independent review committee was 5.6 months and 3.9 months, respectively (hazard ratio, 0.73; P = .0165). Corresponding 1-year rates were 28% and 11%.

Among patients previously treated with an immune checkpoint inhibitor, median progression-free survival according to an independent review committee was 7.3 months with tivozanib and 5.1 months with sorafenib (hazard ratio, 0.55; P = .028). Corresponding 1-year rates were 35% and 4%.

In the entire trial population, the overall response rate was 18% for tivozanib versus 8% for sorafenib (P = .02). Median duration of response was not reached, compared with 5.7 months.

An interim analysis showed a median overall survival of 16.4 months in the tivozanib group and 19.7 months in the sorafenib group.

The rate of any-grade treatment-related adverse events was 84% with tivozanib and 94% with sorafenib. Tivozanib had a higher rate of grade 3 or 4 hypertension (20% vs. 14%), but lower rates of grade 3 or 4 diarrhea (2% vs. 9%), hand-foot syndrome (1% vs. 10%), and rash (0% vs. 8%).

Dr. Rini reported that he has a consulting role with Aveo, which sponsored the trial, and financial relationships with several other companies.

SOURCE: Rini BI et al. GUCS 2019, Abstract 541.

SAN FRANCISCO – When used as first-line therapy for renal cell carcinoma (RCC), the combination of avelumab and axitinib has better efficacy than does single-agent sunitinib, which is the current standard of care, across a wide range of patients, subgroup analyses of the JAVELIN Renal 101 trial have shown. Results were reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Previous research had shown that avelumab (Bavencio), an immune checkpoint inhibitor targeting programmed death-ligand 1 (PD-L1), is active when used alone for advanced RCC, noted lead investigator Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston. And axitinib (Inlyta), a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, is approved for use in the second line. In an early-phase trial among patients being treated in the first line, a combination of the two drugs led to an impressive 58% objective response rate (ORR) and had a favorable safety profile (Lancet Oncol. 2018 Apr;19(4):451-60).

JAVELIN Renal 101 (NCT02684006), a phase 3 randomized, controlled trial, enrolled 886 patients with treatment-naive advanced RCC having a clear cell component regardless of their tumor’s PD-L1 status. They were randomized to the combination of avelumab/axitinib or to the VEGF tyrosine kinase inhibitor sunitinib (Sutent) alone.

Full trial results, published during the symposium in the New England Journal of Medicine (2019 Feb 16. doi: 10.1056/NEJMoa1816047), showed significant progression-free and overall survival benefits of avelumab/axitinib over sunitinib in the 63.2% of patients with PD-L1–positive tumors – the trial’s primary endpoints – as well as a progression-free survival benefit in the entire trial population.

In the subgroup analyses reported at the symposium, the combination reduced risk of progression or death by roughly 20%-50% across patients having different statuses in regard to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group, Memorial Sloan Kettering Cancer Center (MSKCC) risk group, and tumor PD-L1, as well as other characteristics. Findings were similar for ORR, with the combination roughly doubling to quadrupling the odds of response, irrespective of patient and disease characteristics.

“The progression-free survival and response rate benefit was observed in all patients, regardless of PD-L1 status, regardless of prognostic risk group. At this time, the study continues to follow up for overall survival,” Dr. Choueiri commented. Taken together, “the results do support avelumab plus axitinib as a new first-line standard of care for patients with advanced RCC.”

When it comes to selecting among the three combinations above, “I don’t think PD-L1 expression is going to help us at all,” she said. In contrast, IMDC risk category is likely still helpful because, in CheckMate 214, there was no progression-free or overall survival benefit of ipilimumab/nivolumab in patients with favorable-risk disease.

Differences in rates of discontinuation of all treatment because of treatment-related adverse events are hard to assess because CheckMate 214 had restrictions on allowing patients in the combination group to receive single-agent nivolumab, according to Dr. Wood. Financial costs are a major consideration, but so are time and staffing costs: Compared with single-agent sunitinib, the combinations as much as triple physician visits, nurse visits, infusions, and unscheduled visits.

SOURCE: Choueiri TK et al. GUCS 2019, Abstract 544.

SAN FRANCISCO – When used as first-line therapy for renal cell carcinoma (RCC), the combination of avelumab and axitinib has better efficacy than does single-agent sunitinib, which is the current standard of care, across a wide range of patients, subgroup analyses of the JAVELIN Renal 101 trial have shown. Results were reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Previous research had shown that avelumab (Bavencio), an immune checkpoint inhibitor targeting programmed death-ligand 1 (PD-L1), is active when used alone for advanced RCC, noted lead investigator Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston. And axitinib (Inlyta), a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, is approved for use in the second line. In an early-phase trial among patients being treated in the first line, a combination of the two drugs led to an impressive 58% objective response rate (ORR) and had a favorable safety profile (Lancet Oncol. 2018 Apr;19(4):451-60).

JAVELIN Renal 101 (NCT02684006), a phase 3 randomized, controlled trial, enrolled 886 patients with treatment-naive advanced RCC having a clear cell component regardless of their tumor’s PD-L1 status. They were randomized to the combination of avelumab/axitinib or to the VEGF tyrosine kinase inhibitor sunitinib (Sutent) alone.

Full trial results, published during the symposium in the New England Journal of Medicine (2019 Feb 16. doi: 10.1056/NEJMoa1816047), showed significant progression-free and overall survival benefits of avelumab/axitinib over sunitinib in the 63.2% of patients with PD-L1–positive tumors – the trial’s primary endpoints – as well as a progression-free survival benefit in the entire trial population.

In the subgroup analyses reported at the symposium, the combination reduced risk of progression or death by roughly 20%-50% across patients having different statuses in regard to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group, Memorial Sloan Kettering Cancer Center (MSKCC) risk group, and tumor PD-L1, as well as other characteristics. Findings were similar for ORR, with the combination roughly doubling to quadrupling the odds of response, irrespective of patient and disease characteristics.

“The progression-free survival and response rate benefit was observed in all patients, regardless of PD-L1 status, regardless of prognostic risk group. At this time, the study continues to follow up for overall survival,” Dr. Choueiri commented. Taken together, “the results do support avelumab plus axitinib as a new first-line standard of care for patients with advanced RCC.”

When it comes to selecting among the three combinations above, “I don’t think PD-L1 expression is going to help us at all,” she said. In contrast, IMDC risk category is likely still helpful because, in CheckMate 214, there was no progression-free or overall survival benefit of ipilimumab/nivolumab in patients with favorable-risk disease.

Differences in rates of discontinuation of all treatment because of treatment-related adverse events are hard to assess because CheckMate 214 had restrictions on allowing patients in the combination group to receive single-agent nivolumab, according to Dr. Wood. Financial costs are a major consideration, but so are time and staffing costs: Compared with single-agent sunitinib, the combinations as much as triple physician visits, nurse visits, infusions, and unscheduled visits.

SOURCE: Choueiri TK et al. GUCS 2019, Abstract 544.

SAN FRANCISCO – When used as first-line therapy for renal cell carcinoma (RCC), the combination of avelumab and axitinib has better efficacy than does single-agent sunitinib, which is the current standard of care, across a wide range of patients, subgroup analyses of the JAVELIN Renal 101 trial have shown. Results were reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Previous research had shown that avelumab (Bavencio), an immune checkpoint inhibitor targeting programmed death-ligand 1 (PD-L1), is active when used alone for advanced RCC, noted lead investigator Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston. And axitinib (Inlyta), a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, is approved for use in the second line. In an early-phase trial among patients being treated in the first line, a combination of the two drugs led to an impressive 58% objective response rate (ORR) and had a favorable safety profile (Lancet Oncol. 2018 Apr;19(4):451-60).

JAVELIN Renal 101 (NCT02684006), a phase 3 randomized, controlled trial, enrolled 886 patients with treatment-naive advanced RCC having a clear cell component regardless of their tumor’s PD-L1 status. They were randomized to the combination of avelumab/axitinib or to the VEGF tyrosine kinase inhibitor sunitinib (Sutent) alone.

Full trial results, published during the symposium in the New England Journal of Medicine (2019 Feb 16. doi: 10.1056/NEJMoa1816047), showed significant progression-free and overall survival benefits of avelumab/axitinib over sunitinib in the 63.2% of patients with PD-L1–positive tumors – the trial’s primary endpoints – as well as a progression-free survival benefit in the entire trial population.

In the subgroup analyses reported at the symposium, the combination reduced risk of progression or death by roughly 20%-50% across patients having different statuses in regard to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group, Memorial Sloan Kettering Cancer Center (MSKCC) risk group, and tumor PD-L1, as well as other characteristics. Findings were similar for ORR, with the combination roughly doubling to quadrupling the odds of response, irrespective of patient and disease characteristics.

“The progression-free survival and response rate benefit was observed in all patients, regardless of PD-L1 status, regardless of prognostic risk group. At this time, the study continues to follow up for overall survival,” Dr. Choueiri commented. Taken together, “the results do support avelumab plus axitinib as a new first-line standard of care for patients with advanced RCC.”

When it comes to selecting among the three combinations above, “I don’t think PD-L1 expression is going to help us at all,” she said. In contrast, IMDC risk category is likely still helpful because, in CheckMate 214, there was no progression-free or overall survival benefit of ipilimumab/nivolumab in patients with favorable-risk disease.

Differences in rates of discontinuation of all treatment because of treatment-related adverse events are hard to assess because CheckMate 214 had restrictions on allowing patients in the combination group to receive single-agent nivolumab, according to Dr. Wood. Financial costs are a major consideration, but so are time and staffing costs: Compared with single-agent sunitinib, the combinations as much as triple physician visits, nurse visits, infusions, and unscheduled visits.

SOURCE: Choueiri TK et al. GUCS 2019, Abstract 544.

SAN FRANCISCO – Darolutamide, a novel investigational antiandrogen agent, is efficacious and well tolerated when used to treat nonmetastatic, castration-resistant prostate cancer (nmCRPC), according to results of the phase 3, randomized, controlled ARAMIS trial.

Susan London/MDedge News

“In men with high-risk M0 CRPC, two next-generation androgen receptor inhibitors, namely, enzalutamide (Xtandi) and apalutamide (Erleada), were recently shown to improve metastasis-free survival, although they were associated with increased cognitive impairment, falls, and other side effects,” commented lead investigator Karim Fizazi, MD, PhD, head of the department of cancer medicine at the Institut Gustave Roussy in Paris. “Enzalutamide and apalutamide are chemically very similar, while darolutamide is structurally distinct. Also, darolutamide does not cross the blood-brain barrier, which may result in less CNS-related side effects.”

ARAMIS enrolled 1,509 men with nmCRPC who had a prostate-specific antigen (PSA) doubling time of 10 months or less and were on and continued androgen deprivation therapy. The men were randomized 2:1 to receive darolutamide or placebo.

With a median follow-up of 17.9 months, median metastasis-free survival was almost 2 years longer with darolutamide, corresponding to a 59% reduction in the risk of distant metastases or death, relative to placebo, according to results reported at the symposium and simultaneously published in the New England Journal of Medicine (2019 Feb 14. doi: 10.1056/NEJMoa1815671). There was also a 29% reduction in risk of death (in an interim analysis), a 35% reduction in risk of pain progression, and 57% reductions each in need for chemotherapy and first symptomatic skeletal events. Meanwhile, the drug had a good safety and tolerability profile, with rates and types of events similar to those seen with placebo.

“We believe that darolutamide should become a new standard of care for men with high-risk nmCRPC,” Dr. Fizazi concluded.

Practice-changing results?

The ARAMIS findings meet some – but not all – of a set of criteria that would support a change in current practice to using darolutamide, according to invited discussant Ian D. Davis, MBBS, PhD, a professor at Monash University, Melbourne.

The first criterion, whether the disease is a condition needing treatment, is likely met, as 69% of patients had a PSA doubling time of 6 months or less, and previous research suggests that this subset, at least, has high risk for bone metastases or death.

SOURCE: Fizazi K et al. GUCS 2019, Abstract 140.

SAN FRANCISCO – Darolutamide, a novel investigational antiandrogen agent, is efficacious and well tolerated when used to treat nonmetastatic, castration-resistant prostate cancer (nmCRPC), according to results of the phase 3, randomized, controlled ARAMIS trial.

Susan London/MDedge News

“In men with high-risk M0 CRPC, two next-generation androgen receptor inhibitors, namely, enzalutamide (Xtandi) and apalutamide (Erleada), were recently shown to improve metastasis-free survival, although they were associated with increased cognitive impairment, falls, and other side effects,” commented lead investigator Karim Fizazi, MD, PhD, head of the department of cancer medicine at the Institut Gustave Roussy in Paris. “Enzalutamide and apalutamide are chemically very similar, while darolutamide is structurally distinct. Also, darolutamide does not cross the blood-brain barrier, which may result in less CNS-related side effects.”

ARAMIS enrolled 1,509 men with nmCRPC who had a prostate-specific antigen (PSA) doubling time of 10 months or less and were on and continued androgen deprivation therapy. The men were randomized 2:1 to receive darolutamide or placebo.

With a median follow-up of 17.9 months, median metastasis-free survival was almost 2 years longer with darolutamide, corresponding to a 59% reduction in the risk of distant metastases or death, relative to placebo, according to results reported at the symposium and simultaneously published in the New England Journal of Medicine (2019 Feb 14. doi: 10.1056/NEJMoa1815671). There was also a 29% reduction in risk of death (in an interim analysis), a 35% reduction in risk of pain progression, and 57% reductions each in need for chemotherapy and first symptomatic skeletal events. Meanwhile, the drug had a good safety and tolerability profile, with rates and types of events similar to those seen with placebo.

“We believe that darolutamide should become a new standard of care for men with high-risk nmCRPC,” Dr. Fizazi concluded.

Practice-changing results?

The ARAMIS findings meet some – but not all – of a set of criteria that would support a change in current practice to using darolutamide, according to invited discussant Ian D. Davis, MBBS, PhD, a professor at Monash University, Melbourne.

The first criterion, whether the disease is a condition needing treatment, is likely met, as 69% of patients had a PSA doubling time of 6 months or less, and previous research suggests that this subset, at least, has high risk for bone metastases or death.

SOURCE: Fizazi K et al. GUCS 2019, Abstract 140.

SAN FRANCISCO – Darolutamide, a novel investigational antiandrogen agent, is efficacious and well tolerated when used to treat nonmetastatic, castration-resistant prostate cancer (nmCRPC), according to results of the phase 3, randomized, controlled ARAMIS trial.

Susan London/MDedge News

“In men with high-risk M0 CRPC, two next-generation androgen receptor inhibitors, namely, enzalutamide (Xtandi) and apalutamide (Erleada), were recently shown to improve metastasis-free survival, although they were associated with increased cognitive impairment, falls, and other side effects,” commented lead investigator Karim Fizazi, MD, PhD, head of the department of cancer medicine at the Institut Gustave Roussy in Paris. “Enzalutamide and apalutamide are chemically very similar, while darolutamide is structurally distinct. Also, darolutamide does not cross the blood-brain barrier, which may result in less CNS-related side effects.”

ARAMIS enrolled 1,509 men with nmCRPC who had a prostate-specific antigen (PSA) doubling time of 10 months or less and were on and continued androgen deprivation therapy. The men were randomized 2:1 to receive darolutamide or placebo.

With a median follow-up of 17.9 months, median metastasis-free survival was almost 2 years longer with darolutamide, corresponding to a 59% reduction in the risk of distant metastases or death, relative to placebo, according to results reported at the symposium and simultaneously published in the New England Journal of Medicine (2019 Feb 14. doi: 10.1056/NEJMoa1815671). There was also a 29% reduction in risk of death (in an interim analysis), a 35% reduction in risk of pain progression, and 57% reductions each in need for chemotherapy and first symptomatic skeletal events. Meanwhile, the drug had a good safety and tolerability profile, with rates and types of events similar to those seen with placebo.

“We believe that darolutamide should become a new standard of care for men with high-risk nmCRPC,” Dr. Fizazi concluded.

Practice-changing results?

The ARAMIS findings meet some – but not all – of a set of criteria that would support a change in current practice to using darolutamide, according to invited discussant Ian D. Davis, MBBS, PhD, a professor at Monash University, Melbourne.

The first criterion, whether the disease is a condition needing treatment, is likely met, as 69% of patients had a PSA doubling time of 6 months or less, and previous research suggests that this subset, at least, has high risk for bone metastases or death.

SOURCE: Fizazi K et al. GUCS 2019, Abstract 140.