Cancer

CHICAGO – Pembrolizumab has shown promise as adjuvant therapy for stage IIB and IIC melanoma, shows the first interim analysis of the phase 3 KEYNOTE-716 study recently published in The Lancet.

The findings meet an unmet need as the recurrence risk in stage IIB and IIC melanoma is “underrecognized,” said author Georgina Long, MD, comedical director of the Melanoma Institute Australia, University of Sydney.

In fact, their risk of recurrence is similar to patients with stage IIIB disease, wrote David Killock, PhD, in a related commentary published in Nature Reviews.

The adjuvant treatment resulted in an 89% recurrence-free survival in patients who received pembrolizumab, compared with 83% of patients in the placebo group (hazard ratio, 0.65; P = .0066). These findings were used as the basis for Food and Drug Administration approval of pembrolizumab (Keytruda, Merck) for this patient population in December 2021.

Despite the positive findings, Dr. Killock called for more research on distant metastasis-free survival, overall survival, and quality of life data to “establish the true clinical benefit of adjuvant pembrolizumab.”

At the annual meeting of the American Society of Clinical Oncology, Dr. Long presented the third interim analysis which showed pembrolizumab reduced recurrence and distant metastases at 24 months, although the clinical benefit was relatively small at an approximately 8% improvement in recurrence-free survival and about a 6% improvement in distant metastasis-free survival. About 83% in the pembrolizumab group had treatment-related toxicities versus 64% in the placebo group. There were no deaths caused by treatment. About 90% of pembrolizumab-related endocrinopathies led to long-term hormone replacement.

In a discussion that followed the presentation at ASCO, Charlotte Eielson Ariyan, MD, PhD, said the results are bittersweet. Higher-risk stage IIC patients have a risk of recurrence of about 40%. “It’s high, but the absolute risk reduction is about 8%. This is a very personalized discussion with the patient and the physician in understanding their risk of toxicity is about 17% and higher than their absolute risk reduction with the treatment. For me, this is a bitter pill to swallow because you’re treating people longer and you’re not sure if you’re really helping them. Until we can further define who the highest-risk patients are, I think it’s hard to give it to everyone,” said Dr. Ariyan, who is a surgeon with Memorial Sloan Kettering Cancer Center, New York.

In addition to weighing short-term benefits and toxicity, there are longer-term concerns. Toxicity experienced from PD-1 inhibitors in the adjuvant setting could impact future treatment decisions. “We’re very lucky here in melanoma to know that systemic therapies are effective and we can cure people who recur. I would argue this is why we probably will never really see a difference in the survival benefit in this group because people who cross over will probably do well,” Dr. Ariyan said.

During the Q&A session, Vernon Sondek, MD, Moffitt Cancer Center, Tampa, encouraged physician colleagues to have an open mind about treatments. “Beware of dogma. We thought that adjuvant immunotherapy works much better in patients with ulcerated primary tumors. That’s a dogma in some parts of the world. Yet the T4a patients in KEYNOTE-716 dramatically outperformed the ulcerated T3b and T4b [patients]. We still don’t know what we don’t know.”
 

The study details

KEYNOTE-716 included 976 patients 12 years or older with newly diagnosed completely resected stage IIB or IIC melanoma with a negative sentinel lymph node. Patients were randomized to placebo or 200 mg pembrolizumab every 3 weeks, or 2 mg/kg in pediatric patients, over 17 cycles. Almost 40% of patients were age 65 or older. T3b and T4b were the most common melanoma subcategories at 41% and 35%, respectively.

The planned third interim analysis occurred after the occurrence of 146 distant metastases. After a median follow-up of 27.4 months, distant metastasis-free survival favored the pembrolizumab group (HR, 0.64; P = .0029). At 24 months, the pembrolizumab group had a higher distant metastasis-free survival at 88.1% versus 82.2% and a lower recurrence rate at 81.2% versus 72.8% (HR, 0.64; 95% confidence interval, 0.50-0.84).

At 24 months, only the T4a patients had a statistically significant reduction in distant metastases at 58% (HR, 0.42; 95% CI, 0.19-0.96), although there were numerical reductions in T3a (HR, 0.71; 95% CI, 0.41-1.22) and T4b (HR, 0.70; 95% CI, 0.44-1.33) patients. Of patients experiencing a distant metastasis, 73% of the placebo group had a first distant metastasis to the lung compared with 49% of the pembrolizumab group.

Dr. Long has held consulting or advisory roles for Merck Sharpe & Dohme, which funded this study.

CHICAGO – Pembrolizumab has shown promise as adjuvant therapy for stage IIB and IIC melanoma, shows the first interim analysis of the phase 3 KEYNOTE-716 study recently published in The Lancet.

The findings meet an unmet need as the recurrence risk in stage IIB and IIC melanoma is “underrecognized,” said author Georgina Long, MD, comedical director of the Melanoma Institute Australia, University of Sydney.

In fact, their risk of recurrence is similar to patients with stage IIIB disease, wrote David Killock, PhD, in a related commentary published in Nature Reviews.

The adjuvant treatment resulted in an 89% recurrence-free survival in patients who received pembrolizumab, compared with 83% of patients in the placebo group (hazard ratio, 0.65; P = .0066). These findings were used as the basis for Food and Drug Administration approval of pembrolizumab (Keytruda, Merck) for this patient population in December 2021.

Despite the positive findings, Dr. Killock called for more research on distant metastasis-free survival, overall survival, and quality of life data to “establish the true clinical benefit of adjuvant pembrolizumab.”

At the annual meeting of the American Society of Clinical Oncology, Dr. Long presented the third interim analysis which showed pembrolizumab reduced recurrence and distant metastases at 24 months, although the clinical benefit was relatively small at an approximately 8% improvement in recurrence-free survival and about a 6% improvement in distant metastasis-free survival. About 83% in the pembrolizumab group had treatment-related toxicities versus 64% in the placebo group. There were no deaths caused by treatment. About 90% of pembrolizumab-related endocrinopathies led to long-term hormone replacement.

In a discussion that followed the presentation at ASCO, Charlotte Eielson Ariyan, MD, PhD, said the results are bittersweet. Higher-risk stage IIC patients have a risk of recurrence of about 40%. “It’s high, but the absolute risk reduction is about 8%. This is a very personalized discussion with the patient and the physician in understanding their risk of toxicity is about 17% and higher than their absolute risk reduction with the treatment. For me, this is a bitter pill to swallow because you’re treating people longer and you’re not sure if you’re really helping them. Until we can further define who the highest-risk patients are, I think it’s hard to give it to everyone,” said Dr. Ariyan, who is a surgeon with Memorial Sloan Kettering Cancer Center, New York.

In addition to weighing short-term benefits and toxicity, there are longer-term concerns. Toxicity experienced from PD-1 inhibitors in the adjuvant setting could impact future treatment decisions. “We’re very lucky here in melanoma to know that systemic therapies are effective and we can cure people who recur. I would argue this is why we probably will never really see a difference in the survival benefit in this group because people who cross over will probably do well,” Dr. Ariyan said.

During the Q&A session, Vernon Sondek, MD, Moffitt Cancer Center, Tampa, encouraged physician colleagues to have an open mind about treatments. “Beware of dogma. We thought that adjuvant immunotherapy works much better in patients with ulcerated primary tumors. That’s a dogma in some parts of the world. Yet the T4a patients in KEYNOTE-716 dramatically outperformed the ulcerated T3b and T4b [patients]. We still don’t know what we don’t know.”
 

The study details

KEYNOTE-716 included 976 patients 12 years or older with newly diagnosed completely resected stage IIB or IIC melanoma with a negative sentinel lymph node. Patients were randomized to placebo or 200 mg pembrolizumab every 3 weeks, or 2 mg/kg in pediatric patients, over 17 cycles. Almost 40% of patients were age 65 or older. T3b and T4b were the most common melanoma subcategories at 41% and 35%, respectively.

The planned third interim analysis occurred after the occurrence of 146 distant metastases. After a median follow-up of 27.4 months, distant metastasis-free survival favored the pembrolizumab group (HR, 0.64; P = .0029). At 24 months, the pembrolizumab group had a higher distant metastasis-free survival at 88.1% versus 82.2% and a lower recurrence rate at 81.2% versus 72.8% (HR, 0.64; 95% confidence interval, 0.50-0.84).

At 24 months, only the T4a patients had a statistically significant reduction in distant metastases at 58% (HR, 0.42; 95% CI, 0.19-0.96), although there were numerical reductions in T3a (HR, 0.71; 95% CI, 0.41-1.22) and T4b (HR, 0.70; 95% CI, 0.44-1.33) patients. Of patients experiencing a distant metastasis, 73% of the placebo group had a first distant metastasis to the lung compared with 49% of the pembrolizumab group.

Dr. Long has held consulting or advisory roles for Merck Sharpe & Dohme, which funded this study.

CHICAGO – Pembrolizumab has shown promise as adjuvant therapy for stage IIB and IIC melanoma, shows the first interim analysis of the phase 3 KEYNOTE-716 study recently published in The Lancet.

The findings meet an unmet need as the recurrence risk in stage IIB and IIC melanoma is “underrecognized,” said author Georgina Long, MD, comedical director of the Melanoma Institute Australia, University of Sydney.

In fact, their risk of recurrence is similar to patients with stage IIIB disease, wrote David Killock, PhD, in a related commentary published in Nature Reviews.

The adjuvant treatment resulted in an 89% recurrence-free survival in patients who received pembrolizumab, compared with 83% of patients in the placebo group (hazard ratio, 0.65; P = .0066). These findings were used as the basis for Food and Drug Administration approval of pembrolizumab (Keytruda, Merck) for this patient population in December 2021.

Despite the positive findings, Dr. Killock called for more research on distant metastasis-free survival, overall survival, and quality of life data to “establish the true clinical benefit of adjuvant pembrolizumab.”

At the annual meeting of the American Society of Clinical Oncology, Dr. Long presented the third interim analysis which showed pembrolizumab reduced recurrence and distant metastases at 24 months, although the clinical benefit was relatively small at an approximately 8% improvement in recurrence-free survival and about a 6% improvement in distant metastasis-free survival. About 83% in the pembrolizumab group had treatment-related toxicities versus 64% in the placebo group. There were no deaths caused by treatment. About 90% of pembrolizumab-related endocrinopathies led to long-term hormone replacement.

In a discussion that followed the presentation at ASCO, Charlotte Eielson Ariyan, MD, PhD, said the results are bittersweet. Higher-risk stage IIC patients have a risk of recurrence of about 40%. “It’s high, but the absolute risk reduction is about 8%. This is a very personalized discussion with the patient and the physician in understanding their risk of toxicity is about 17% and higher than their absolute risk reduction with the treatment. For me, this is a bitter pill to swallow because you’re treating people longer and you’re not sure if you’re really helping them. Until we can further define who the highest-risk patients are, I think it’s hard to give it to everyone,” said Dr. Ariyan, who is a surgeon with Memorial Sloan Kettering Cancer Center, New York.

In addition to weighing short-term benefits and toxicity, there are longer-term concerns. Toxicity experienced from PD-1 inhibitors in the adjuvant setting could impact future treatment decisions. “We’re very lucky here in melanoma to know that systemic therapies are effective and we can cure people who recur. I would argue this is why we probably will never really see a difference in the survival benefit in this group because people who cross over will probably do well,” Dr. Ariyan said.

During the Q&A session, Vernon Sondek, MD, Moffitt Cancer Center, Tampa, encouraged physician colleagues to have an open mind about treatments. “Beware of dogma. We thought that adjuvant immunotherapy works much better in patients with ulcerated primary tumors. That’s a dogma in some parts of the world. Yet the T4a patients in KEYNOTE-716 dramatically outperformed the ulcerated T3b and T4b [patients]. We still don’t know what we don’t know.”
 

The study details

KEYNOTE-716 included 976 patients 12 years or older with newly diagnosed completely resected stage IIB or IIC melanoma with a negative sentinel lymph node. Patients were randomized to placebo or 200 mg pembrolizumab every 3 weeks, or 2 mg/kg in pediatric patients, over 17 cycles. Almost 40% of patients were age 65 or older. T3b and T4b were the most common melanoma subcategories at 41% and 35%, respectively.

The planned third interim analysis occurred after the occurrence of 146 distant metastases. After a median follow-up of 27.4 months, distant metastasis-free survival favored the pembrolizumab group (HR, 0.64; P = .0029). At 24 months, the pembrolizumab group had a higher distant metastasis-free survival at 88.1% versus 82.2% and a lower recurrence rate at 81.2% versus 72.8% (HR, 0.64; 95% confidence interval, 0.50-0.84).

At 24 months, only the T4a patients had a statistically significant reduction in distant metastases at 58% (HR, 0.42; 95% CI, 0.19-0.96), although there were numerical reductions in T3a (HR, 0.71; 95% CI, 0.41-1.22) and T4b (HR, 0.70; 95% CI, 0.44-1.33) patients. Of patients experiencing a distant metastasis, 73% of the placebo group had a first distant metastasis to the lung compared with 49% of the pembrolizumab group.

Dr. Long has held consulting or advisory roles for Merck Sharpe & Dohme, which funded this study.

Estrogen exposure helps protect against colorectal cancer (CRC), and in some instances, the protection is site specific, a new analysis finds.

In a 17-year study involving almost 5,000 women, researchers from Germany found that hormone replacement therapy, oral contraceptive use, pregnancy, breastfeeding, and menopause at age 50 or older were all significantly associated with reductions in CRC risk.

Interestingly, the reduced risk of CRC observed for pregnancy and breastfeeding only applied to proximal colon cancer, while the association with oral contraceptive use was confined to the distal colon and rectum.

The results were published online in JNCI Cancer Spectrum.

CRC is the second most common cause of cancer death. It is responsible for more than one million deaths globally, according to the latest figures from the Global Burden of Disease 2019 Cancer Collaboration.

And sex seems to make a difference. The Global Burden analysis, echoing previous data, found that CRC is less common among women and that fewer women die from the disease.

Little, however, is known about the mechanisms of estrogen signaling in CRC or the impact of reproductive factors on CRC, despite a large amount of literature linking CRC risk to exogenous estrogens, such as hormone replacement therapy and oral contraceptives.

In the current analysis, the team recruited 2,650 patients with CRC from 20 German cancer centers between 2003 and 2020. Researchers used standardized questionnaires to garner the women’s reproductive histories.

A matched control group of 2,175 participants who did not have a history of CRC was randomly selected from population registries. All analyses were adjusted for known CRC risk factors, such as age; body mass index; education level; family history; having previously undergone large-bowel endoscopy; diabetes; and smoking status.

The researchers found that each pregnancy was associated with a small but significant 9% reduction in CRC risk (odds ratio, 0.91), specifically in the proximal colon (OR, 0.86).

Overall, breastfeeding for a year or longer was associated with a significantly lower CRC risk, compared with never breastfeeding (OR, 0.74), but the results were only significant for the proximal colon (OR, 0.58).

Oral contraceptive use for 9 years or longer was associated with a lower CRC risk (OR, 0.75) but was only significant for the distal colon (OR, 0.63). Hormone replacement therapy was associated with a lower risk of CRC irrespective of tumor location (OR, 0.76). And using both was linked to a 42% CRC risk reduction (OR, 0.58).

Although age at menarche was not associated with CRC risk, menopause at age 50 or older was associated with a significant 17% lower risk of CRC.

In an email interview, lead author Tobias Niedermaier, PhD, expressed surprise at two of the findings. The first was the small association between pregnancies and CRC risk, “despite the strong increase in estrogen levels during pregnancy,” he said. He speculated that pregnancy-related increases in insulin levels may have “largely offset the protection effects of estrogen exposure during pregnancy.”

The second surprise was that the age at menarche did not have a bearing on CRC risk, which could be because “exposure to estrogen levels in younger ages [is] less relevant with respect to CRC risk, because CRC typically develops at comparably old age.”

John Marshall, MD, who was not involved in the research, commented that such studies “put a lot of pressure on people to perform in a certain way to modify their personal risk of something.” However, “we would not recommend people alter their life choices for reproduction for this,” said Dr. Marshall, chief of the Division of Hematology/Oncology at Georgetown University, Washington, D.C.

Dr. Niedermaier agreed that “while this knowledge will certainly not change a woman’s decision on family planning,” he noted that the findings “could influence current CRC screening strategies, for example, by risk-adapted screening intervals [and] start and stop ages of screening.”

Dr. Niedermaier and colleagues’ work was funded by the German Research Council, the German Federal Ministry of Education and Research, and the Interdisciplinary Research Program of the National Center for Tumor Diseases. Dr. Niedermaier has disclosed no relevant financial relationships. Dr. Marshall writes a column that appears regularly on Medscape: Marshall on Oncology. He has served as speaker or member of a speakers’ bureau for Genentech, Amgen, Bayer, Celgene Corporation, and Caris Life Sciences.

A version of this article first appeared on Medscape.com.

Estrogen exposure helps protect against colorectal cancer (CRC), and in some instances, the protection is site specific, a new analysis finds.

In a 17-year study involving almost 5,000 women, researchers from Germany found that hormone replacement therapy, oral contraceptive use, pregnancy, breastfeeding, and menopause at age 50 or older were all significantly associated with reductions in CRC risk.

Interestingly, the reduced risk of CRC observed for pregnancy and breastfeeding only applied to proximal colon cancer, while the association with oral contraceptive use was confined to the distal colon and rectum.

The results were published online in JNCI Cancer Spectrum.

CRC is the second most common cause of cancer death. It is responsible for more than one million deaths globally, according to the latest figures from the Global Burden of Disease 2019 Cancer Collaboration.

And sex seems to make a difference. The Global Burden analysis, echoing previous data, found that CRC is less common among women and that fewer women die from the disease.

Little, however, is known about the mechanisms of estrogen signaling in CRC or the impact of reproductive factors on CRC, despite a large amount of literature linking CRC risk to exogenous estrogens, such as hormone replacement therapy and oral contraceptives.

In the current analysis, the team recruited 2,650 patients with CRC from 20 German cancer centers between 2003 and 2020. Researchers used standardized questionnaires to garner the women’s reproductive histories.

A matched control group of 2,175 participants who did not have a history of CRC was randomly selected from population registries. All analyses were adjusted for known CRC risk factors, such as age; body mass index; education level; family history; having previously undergone large-bowel endoscopy; diabetes; and smoking status.

The researchers found that each pregnancy was associated with a small but significant 9% reduction in CRC risk (odds ratio, 0.91), specifically in the proximal colon (OR, 0.86).

Overall, breastfeeding for a year or longer was associated with a significantly lower CRC risk, compared with never breastfeeding (OR, 0.74), but the results were only significant for the proximal colon (OR, 0.58).

Oral contraceptive use for 9 years or longer was associated with a lower CRC risk (OR, 0.75) but was only significant for the distal colon (OR, 0.63). Hormone replacement therapy was associated with a lower risk of CRC irrespective of tumor location (OR, 0.76). And using both was linked to a 42% CRC risk reduction (OR, 0.58).

Although age at menarche was not associated with CRC risk, menopause at age 50 or older was associated with a significant 17% lower risk of CRC.

In an email interview, lead author Tobias Niedermaier, PhD, expressed surprise at two of the findings. The first was the small association between pregnancies and CRC risk, “despite the strong increase in estrogen levels during pregnancy,” he said. He speculated that pregnancy-related increases in insulin levels may have “largely offset the protection effects of estrogen exposure during pregnancy.”

The second surprise was that the age at menarche did not have a bearing on CRC risk, which could be because “exposure to estrogen levels in younger ages [is] less relevant with respect to CRC risk, because CRC typically develops at comparably old age.”

John Marshall, MD, who was not involved in the research, commented that such studies “put a lot of pressure on people to perform in a certain way to modify their personal risk of something.” However, “we would not recommend people alter their life choices for reproduction for this,” said Dr. Marshall, chief of the Division of Hematology/Oncology at Georgetown University, Washington, D.C.

Dr. Niedermaier agreed that “while this knowledge will certainly not change a woman’s decision on family planning,” he noted that the findings “could influence current CRC screening strategies, for example, by risk-adapted screening intervals [and] start and stop ages of screening.”

Dr. Niedermaier and colleagues’ work was funded by the German Research Council, the German Federal Ministry of Education and Research, and the Interdisciplinary Research Program of the National Center for Tumor Diseases. Dr. Niedermaier has disclosed no relevant financial relationships. Dr. Marshall writes a column that appears regularly on Medscape: Marshall on Oncology. He has served as speaker or member of a speakers’ bureau for Genentech, Amgen, Bayer, Celgene Corporation, and Caris Life Sciences.

A version of this article first appeared on Medscape.com.

Estrogen exposure helps protect against colorectal cancer (CRC), and in some instances, the protection is site specific, a new analysis finds.

In a 17-year study involving almost 5,000 women, researchers from Germany found that hormone replacement therapy, oral contraceptive use, pregnancy, breastfeeding, and menopause at age 50 or older were all significantly associated with reductions in CRC risk.

Interestingly, the reduced risk of CRC observed for pregnancy and breastfeeding only applied to proximal colon cancer, while the association with oral contraceptive use was confined to the distal colon and rectum.

The results were published online in JNCI Cancer Spectrum.

CRC is the second most common cause of cancer death. It is responsible for more than one million deaths globally, according to the latest figures from the Global Burden of Disease 2019 Cancer Collaboration.

And sex seems to make a difference. The Global Burden analysis, echoing previous data, found that CRC is less common among women and that fewer women die from the disease.

Little, however, is known about the mechanisms of estrogen signaling in CRC or the impact of reproductive factors on CRC, despite a large amount of literature linking CRC risk to exogenous estrogens, such as hormone replacement therapy and oral contraceptives.

In the current analysis, the team recruited 2,650 patients with CRC from 20 German cancer centers between 2003 and 2020. Researchers used standardized questionnaires to garner the women’s reproductive histories.

A matched control group of 2,175 participants who did not have a history of CRC was randomly selected from population registries. All analyses were adjusted for known CRC risk factors, such as age; body mass index; education level; family history; having previously undergone large-bowel endoscopy; diabetes; and smoking status.

The researchers found that each pregnancy was associated with a small but significant 9% reduction in CRC risk (odds ratio, 0.91), specifically in the proximal colon (OR, 0.86).

Overall, breastfeeding for a year or longer was associated with a significantly lower CRC risk, compared with never breastfeeding (OR, 0.74), but the results were only significant for the proximal colon (OR, 0.58).

Oral contraceptive use for 9 years or longer was associated with a lower CRC risk (OR, 0.75) but was only significant for the distal colon (OR, 0.63). Hormone replacement therapy was associated with a lower risk of CRC irrespective of tumor location (OR, 0.76). And using both was linked to a 42% CRC risk reduction (OR, 0.58).

Although age at menarche was not associated with CRC risk, menopause at age 50 or older was associated with a significant 17% lower risk of CRC.

In an email interview, lead author Tobias Niedermaier, PhD, expressed surprise at two of the findings. The first was the small association between pregnancies and CRC risk, “despite the strong increase in estrogen levels during pregnancy,” he said. He speculated that pregnancy-related increases in insulin levels may have “largely offset the protection effects of estrogen exposure during pregnancy.”

The second surprise was that the age at menarche did not have a bearing on CRC risk, which could be because “exposure to estrogen levels in younger ages [is] less relevant with respect to CRC risk, because CRC typically develops at comparably old age.”

John Marshall, MD, who was not involved in the research, commented that such studies “put a lot of pressure on people to perform in a certain way to modify their personal risk of something.” However, “we would not recommend people alter their life choices for reproduction for this,” said Dr. Marshall, chief of the Division of Hematology/Oncology at Georgetown University, Washington, D.C.

Dr. Niedermaier agreed that “while this knowledge will certainly not change a woman’s decision on family planning,” he noted that the findings “could influence current CRC screening strategies, for example, by risk-adapted screening intervals [and] start and stop ages of screening.”

Dr. Niedermaier and colleagues’ work was funded by the German Research Council, the German Federal Ministry of Education and Research, and the Interdisciplinary Research Program of the National Center for Tumor Diseases. Dr. Niedermaier has disclosed no relevant financial relationships. Dr. Marshall writes a column that appears regularly on Medscape: Marshall on Oncology. He has served as speaker or member of a speakers’ bureau for Genentech, Amgen, Bayer, Celgene Corporation, and Caris Life Sciences.

A version of this article first appeared on Medscape.com.

In a phase 2 cohort study, the KRAS (G12C) inhibitor adagrasib induced an objective response in about one out of three patients with KRAS (G12C)–mutated non–small cell lung cancer (NSCLC) who had previously been treated with platinum-based chemotherapy and immune therapy.

Adagrasib targets KRAS (G12C), which had long been thought undruggable until research published in 2013 revealed a new binding pocket that did not compete directly against the protein’s natural binding partner. The new trial further validates the approach. “It supports that clinically effective targeted therapies can be developed for patients with KRAS (G12C)–mutant NSCLC,” said Pasi Jänne, MD, PhD, who is the lead author of the study describing the new results published online in the New England Journal of Medicine.

KRAS is the most frequently mutated oncogene in human cancers. A mutated form is found in about 25% of NSCLCs. KRAS plays a key role in cell signaling governing growth, maturation, and cell death. The mutated form is linked to cancer growth and spread. Patients with mutated KRAS have few effective treatment options.

Adagrasib is currently under study and not yet approved by the Food and Drug Administration. However, sotorasib (Lumakras, Amgen), which also inhibits KRAS (G12C), was approved in May 2021 by the FDA for KRAS (G12C)–mutated NSCLC. There are some key differences between the drugs. Adagrasib has a half-life of 23 hours versus 5 hours for sotorasib, and the newer drug has the potential to penetrate the central nervous system. That could be an important consideration in NSCLC since it often metastasizes to the brain. “Having pharmacological approaches to treat brain metastases is a wonderful new therapeutic option for lung cancer patients,” said Dr. Jänne, who is director of the Lowe Center for Thoracic Oncology at Dana Farber Cancer Institute, Boston.

Adagrasib is being investigated as part of the KRYSTAL-1 study, alone and as part of combinations in various solid tumors. Previously treated NSCLC KRAS (G12C) patients are also being enrolled in a phase 3 study of adagrasib combined with docetaxel, as well as another phase 2 study of adagrasib combined with pembrolizumab as first-line therapy for NSCLC KRAS (G12C).

Adagrasib is likely to remain a second-line therapy following chemotherapy and immunotherapy. “The activity by itself at the moment is not sufficient to be a first-line treatment. That may change in the future in combination with a standard of care agent or in a subset of patients with KRAS (G12C)–mutant NSCLC, although no subset with higher efficacy has been identified to date. Identification of predictive biomarkers for patients likely to benefit from single agent or an adagrasib combination treatment remains a high priority,” Dr. Jänne said.

The study included 116 patients who had previously been treated with platinum-based chemotherapy and anti–programmed death 1 or programmed death–ligand 1 therapy. They received 600 mg oral adagrasib twice per day over a median follow-up period of 12.9 months. About 42.9% (95% confidence interval, 33.5%-52.6%) experienced a confirmed objective response with a median duration of 8.5 months (95% CI, 6.2-13.8 months). The median progression-free survival was 6.5 months (95% CI, 4.7-8.4 months). After a median follow-up of 15.6 months, the median overall survival was 12.6 months (95% CI, 9.2-19.2 months). The estimated overall survival at 1 year was 50.8% (95% CI, 40.9%-60.0%).

33 patients had stable central nervous system metastases that had been previously treated. About 33.3% had an intracranial confirmed objective response (95% CI, 18.0-51.8%) with a median duration of response of 11.2 months (95% CI, 2.99 months to not available).

Adverse events are similar to what is seen with other targeted therapies, according to Dr. Jänne. 97.4% of patient reported a treatment-related adverse event; 52.6% had grade 1-2 adverse events, and 44.8% had grade 3 adverse events. 6.9% discontinued the drug as a result.

Dr. Jänne has consulted for Mirati Therapeutics and is a member of its scientific advisory board. The study was funded by Mirati Therapeutics.

In a phase 2 cohort study, the KRAS (G12C) inhibitor adagrasib induced an objective response in about one out of three patients with KRAS (G12C)–mutated non–small cell lung cancer (NSCLC) who had previously been treated with platinum-based chemotherapy and immune therapy.

Adagrasib targets KRAS (G12C), which had long been thought undruggable until research published in 2013 revealed a new binding pocket that did not compete directly against the protein’s natural binding partner. The new trial further validates the approach. “It supports that clinically effective targeted therapies can be developed for patients with KRAS (G12C)–mutant NSCLC,” said Pasi Jänne, MD, PhD, who is the lead author of the study describing the new results published online in the New England Journal of Medicine.

KRAS is the most frequently mutated oncogene in human cancers. A mutated form is found in about 25% of NSCLCs. KRAS plays a key role in cell signaling governing growth, maturation, and cell death. The mutated form is linked to cancer growth and spread. Patients with mutated KRAS have few effective treatment options.

Adagrasib is currently under study and not yet approved by the Food and Drug Administration. However, sotorasib (Lumakras, Amgen), which also inhibits KRAS (G12C), was approved in May 2021 by the FDA for KRAS (G12C)–mutated NSCLC. There are some key differences between the drugs. Adagrasib has a half-life of 23 hours versus 5 hours for sotorasib, and the newer drug has the potential to penetrate the central nervous system. That could be an important consideration in NSCLC since it often metastasizes to the brain. “Having pharmacological approaches to treat brain metastases is a wonderful new therapeutic option for lung cancer patients,” said Dr. Jänne, who is director of the Lowe Center for Thoracic Oncology at Dana Farber Cancer Institute, Boston.

Adagrasib is being investigated as part of the KRYSTAL-1 study, alone and as part of combinations in various solid tumors. Previously treated NSCLC KRAS (G12C) patients are also being enrolled in a phase 3 study of adagrasib combined with docetaxel, as well as another phase 2 study of adagrasib combined with pembrolizumab as first-line therapy for NSCLC KRAS (G12C).

Adagrasib is likely to remain a second-line therapy following chemotherapy and immunotherapy. “The activity by itself at the moment is not sufficient to be a first-line treatment. That may change in the future in combination with a standard of care agent or in a subset of patients with KRAS (G12C)–mutant NSCLC, although no subset with higher efficacy has been identified to date. Identification of predictive biomarkers for patients likely to benefit from single agent or an adagrasib combination treatment remains a high priority,” Dr. Jänne said.

The study included 116 patients who had previously been treated with platinum-based chemotherapy and anti–programmed death 1 or programmed death–ligand 1 therapy. They received 600 mg oral adagrasib twice per day over a median follow-up period of 12.9 months. About 42.9% (95% confidence interval, 33.5%-52.6%) experienced a confirmed objective response with a median duration of 8.5 months (95% CI, 6.2-13.8 months). The median progression-free survival was 6.5 months (95% CI, 4.7-8.4 months). After a median follow-up of 15.6 months, the median overall survival was 12.6 months (95% CI, 9.2-19.2 months). The estimated overall survival at 1 year was 50.8% (95% CI, 40.9%-60.0%).

33 patients had stable central nervous system metastases that had been previously treated. About 33.3% had an intracranial confirmed objective response (95% CI, 18.0-51.8%) with a median duration of response of 11.2 months (95% CI, 2.99 months to not available).

Adverse events are similar to what is seen with other targeted therapies, according to Dr. Jänne. 97.4% of patient reported a treatment-related adverse event; 52.6% had grade 1-2 adverse events, and 44.8% had grade 3 adverse events. 6.9% discontinued the drug as a result.

Dr. Jänne has consulted for Mirati Therapeutics and is a member of its scientific advisory board. The study was funded by Mirati Therapeutics.

In a phase 2 cohort study, the KRAS (G12C) inhibitor adagrasib induced an objective response in about one out of three patients with KRAS (G12C)–mutated non–small cell lung cancer (NSCLC) who had previously been treated with platinum-based chemotherapy and immune therapy.

Adagrasib targets KRAS (G12C), which had long been thought undruggable until research published in 2013 revealed a new binding pocket that did not compete directly against the protein’s natural binding partner. The new trial further validates the approach. “It supports that clinically effective targeted therapies can be developed for patients with KRAS (G12C)–mutant NSCLC,” said Pasi Jänne, MD, PhD, who is the lead author of the study describing the new results published online in the New England Journal of Medicine.

KRAS is the most frequently mutated oncogene in human cancers. A mutated form is found in about 25% of NSCLCs. KRAS plays a key role in cell signaling governing growth, maturation, and cell death. The mutated form is linked to cancer growth and spread. Patients with mutated KRAS have few effective treatment options.

Adagrasib is currently under study and not yet approved by the Food and Drug Administration. However, sotorasib (Lumakras, Amgen), which also inhibits KRAS (G12C), was approved in May 2021 by the FDA for KRAS (G12C)–mutated NSCLC. There are some key differences between the drugs. Adagrasib has a half-life of 23 hours versus 5 hours for sotorasib, and the newer drug has the potential to penetrate the central nervous system. That could be an important consideration in NSCLC since it often metastasizes to the brain. “Having pharmacological approaches to treat brain metastases is a wonderful new therapeutic option for lung cancer patients,” said Dr. Jänne, who is director of the Lowe Center for Thoracic Oncology at Dana Farber Cancer Institute, Boston.

Adagrasib is being investigated as part of the KRYSTAL-1 study, alone and as part of combinations in various solid tumors. Previously treated NSCLC KRAS (G12C) patients are also being enrolled in a phase 3 study of adagrasib combined with docetaxel, as well as another phase 2 study of adagrasib combined with pembrolizumab as first-line therapy for NSCLC KRAS (G12C).

Adagrasib is likely to remain a second-line therapy following chemotherapy and immunotherapy. “The activity by itself at the moment is not sufficient to be a first-line treatment. That may change in the future in combination with a standard of care agent or in a subset of patients with KRAS (G12C)–mutant NSCLC, although no subset with higher efficacy has been identified to date. Identification of predictive biomarkers for patients likely to benefit from single agent or an adagrasib combination treatment remains a high priority,” Dr. Jänne said.

The study included 116 patients who had previously been treated with platinum-based chemotherapy and anti–programmed death 1 or programmed death–ligand 1 therapy. They received 600 mg oral adagrasib twice per day over a median follow-up period of 12.9 months. About 42.9% (95% confidence interval, 33.5%-52.6%) experienced a confirmed objective response with a median duration of 8.5 months (95% CI, 6.2-13.8 months). The median progression-free survival was 6.5 months (95% CI, 4.7-8.4 months). After a median follow-up of 15.6 months, the median overall survival was 12.6 months (95% CI, 9.2-19.2 months). The estimated overall survival at 1 year was 50.8% (95% CI, 40.9%-60.0%).

33 patients had stable central nervous system metastases that had been previously treated. About 33.3% had an intracranial confirmed objective response (95% CI, 18.0-51.8%) with a median duration of response of 11.2 months (95% CI, 2.99 months to not available).

Adverse events are similar to what is seen with other targeted therapies, according to Dr. Jänne. 97.4% of patient reported a treatment-related adverse event; 52.6% had grade 1-2 adverse events, and 44.8% had grade 3 adverse events. 6.9% discontinued the drug as a result.

Dr. Jänne has consulted for Mirati Therapeutics and is a member of its scientific advisory board. The study was funded by Mirati Therapeutics.

Long thought to be untreatable, KRAS is one of the most difficult to treat oncogenic drivers responsible for approximately 25% of all tumors, including 68% of pancreatic tumors and 20% of all non–small cell lung cancers (NSCLC).

We now have a treatment – sotorasib – for patients with locally advanced or metastatic NSCLC that is driven by a KRAS mutation (G12C). And, now, there is a second treatment – adagrasib – under study, which, according to a presentation recently made at the annual meeting of the American Society of Clinical Oncology, looks promising.

Ras is a membrane-bound regulatory protein (G protein) belonging to the family of guanosine triphosphatases (GTPases). Ras functions as a guanosine diphosphate/triphosphate binary switch by cycling between the active GTP-bound and the inactive GDP-bound states in response to extracellular stimuli. The KRAS (G12C) mutation affects the active form of KRAS and results in abnormally high concentrations of GTP-bound KRAS leading to hyperactivation of downstream oncogenic pathways and uncontrolled cell growth, specifically of ERK and MEK signaling pathways.

At the ASCO annual meeting in June, Spira and colleagues reported the results of cohort A of the KRYSTAL-1 study evaluating adagrasib as second-line therapy patients with advanced solid tumors harboring a KRAS (G12C) mutation. Like sotorasib, adagrasib is a KRAS (G12C) inhibitor that irreversibly and selectively binds KRAS (G12C), locking it in its inactive state. In this study, patients had to have failed first-line chemotherapy and immunotherapy with 43% of lung cancer patients responding. The 12-month overall survival (OS) was 51%, median overall survival was 12.6 and median progression-free survival (PFS) was 6.5 months. Twenty-five patients with KRAS (G12C)–mutant NSCLC and active, untreated central nervous system metastases received adagrasib in a phase 1b cohort. The intracranial overall response rate was 31.6% and median intracranial PFS was 4.2 months. Systemic ORR was 35.0% (7/20), the disease control rate was 80.0% (16/20) and median duration of response was 9.6 months. Based on these data, a phase 3 trial evaluating adagrasib monotherapy versus docetaxel in previously treated patients with KRAS (G12C) mutant NSCLC is ongoing.

The Food and Drug Administration approval of sotorasib in 2021 was, in part, based on the results of a single-arm, phase 2, second-line study of patients who had previously received platinum-based chemotherapy and/or immunotherapy. An ORR rate of 37.1% was reported with a median PFS of 6.8 months and median OS of 12.5 months leading to the FDA approval. Responses were observed across the range of baseline PD-L1 expression levels: 48% of PD-L1 negative, 39% with PD-L1 between 1%-49%, and 22% of patients with a PD-L1 of greater than 50% having a response.

The major toxicities observed in these studies were gastrointestinal (diarrhea, nausea, vomiting) and hepatic (elevated liver enzymes). About 97% of patients on adagrasib experienced any treatment-related adverse events, and 43% experienced a grade 3 or 4 treatment-related adverse event leading to dose reduction in 52% of patients, a dose interruption in 61% of patients, and a 7% discontinuation rate. About 70% of patients treated with sotorasib had a treatment-related adverse event of any grade, and 21% reported grade 3 or 4 treatment-related adverse events.

A subgroup in the KRYSTAL-1 trial reported an intracranial ORR of 32% in patients with active, untreated CNS metastases. Median overall survival has not yet reached concordance between systemic and intracranial disease control was 88%. In addition, preliminary data from two patients with untreated CNS metastases from a phase 1b cohort found cerebrospinal fluid concentrations of adagrasib with a mean ratio of unbound brain-to-plasma concentration of 0.47, which is comparable or exceeds values for known CNS-penetrant tyrosine kinase inhibitors.

Unfortunately, KRAS (G12C) is not the only KRAS mutation out there. There are a myriad of others, such as G12V and G12D. Hopefully, we will be seeing more drugs aimed at this set of important mutations. Another question, of course, is when and if these drugs will move to the first-line setting.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Long thought to be untreatable, KRAS is one of the most difficult to treat oncogenic drivers responsible for approximately 25% of all tumors, including 68% of pancreatic tumors and 20% of all non–small cell lung cancers (NSCLC).

We now have a treatment – sotorasib – for patients with locally advanced or metastatic NSCLC that is driven by a KRAS mutation (G12C). And, now, there is a second treatment – adagrasib – under study, which, according to a presentation recently made at the annual meeting of the American Society of Clinical Oncology, looks promising.

Ras is a membrane-bound regulatory protein (G protein) belonging to the family of guanosine triphosphatases (GTPases). Ras functions as a guanosine diphosphate/triphosphate binary switch by cycling between the active GTP-bound and the inactive GDP-bound states in response to extracellular stimuli. The KRAS (G12C) mutation affects the active form of KRAS and results in abnormally high concentrations of GTP-bound KRAS leading to hyperactivation of downstream oncogenic pathways and uncontrolled cell growth, specifically of ERK and MEK signaling pathways.

At the ASCO annual meeting in June, Spira and colleagues reported the results of cohort A of the KRYSTAL-1 study evaluating adagrasib as second-line therapy patients with advanced solid tumors harboring a KRAS (G12C) mutation. Like sotorasib, adagrasib is a KRAS (G12C) inhibitor that irreversibly and selectively binds KRAS (G12C), locking it in its inactive state. In this study, patients had to have failed first-line chemotherapy and immunotherapy with 43% of lung cancer patients responding. The 12-month overall survival (OS) was 51%, median overall survival was 12.6 and median progression-free survival (PFS) was 6.5 months. Twenty-five patients with KRAS (G12C)–mutant NSCLC and active, untreated central nervous system metastases received adagrasib in a phase 1b cohort. The intracranial overall response rate was 31.6% and median intracranial PFS was 4.2 months. Systemic ORR was 35.0% (7/20), the disease control rate was 80.0% (16/20) and median duration of response was 9.6 months. Based on these data, a phase 3 trial evaluating adagrasib monotherapy versus docetaxel in previously treated patients with KRAS (G12C) mutant NSCLC is ongoing.

The Food and Drug Administration approval of sotorasib in 2021 was, in part, based on the results of a single-arm, phase 2, second-line study of patients who had previously received platinum-based chemotherapy and/or immunotherapy. An ORR rate of 37.1% was reported with a median PFS of 6.8 months and median OS of 12.5 months leading to the FDA approval. Responses were observed across the range of baseline PD-L1 expression levels: 48% of PD-L1 negative, 39% with PD-L1 between 1%-49%, and 22% of patients with a PD-L1 of greater than 50% having a response.

The major toxicities observed in these studies were gastrointestinal (diarrhea, nausea, vomiting) and hepatic (elevated liver enzymes). About 97% of patients on adagrasib experienced any treatment-related adverse events, and 43% experienced a grade 3 or 4 treatment-related adverse event leading to dose reduction in 52% of patients, a dose interruption in 61% of patients, and a 7% discontinuation rate. About 70% of patients treated with sotorasib had a treatment-related adverse event of any grade, and 21% reported grade 3 or 4 treatment-related adverse events.

A subgroup in the KRYSTAL-1 trial reported an intracranial ORR of 32% in patients with active, untreated CNS metastases. Median overall survival has not yet reached concordance between systemic and intracranial disease control was 88%. In addition, preliminary data from two patients with untreated CNS metastases from a phase 1b cohort found cerebrospinal fluid concentrations of adagrasib with a mean ratio of unbound brain-to-plasma concentration of 0.47, which is comparable or exceeds values for known CNS-penetrant tyrosine kinase inhibitors.

Unfortunately, KRAS (G12C) is not the only KRAS mutation out there. There are a myriad of others, such as G12V and G12D. Hopefully, we will be seeing more drugs aimed at this set of important mutations. Another question, of course, is when and if these drugs will move to the first-line setting.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Long thought to be untreatable, KRAS is one of the most difficult to treat oncogenic drivers responsible for approximately 25% of all tumors, including 68% of pancreatic tumors and 20% of all non–small cell lung cancers (NSCLC).

We now have a treatment – sotorasib – for patients with locally advanced or metastatic NSCLC that is driven by a KRAS mutation (G12C). And, now, there is a second treatment – adagrasib – under study, which, according to a presentation recently made at the annual meeting of the American Society of Clinical Oncology, looks promising.

Ras is a membrane-bound regulatory protein (G protein) belonging to the family of guanosine triphosphatases (GTPases). Ras functions as a guanosine diphosphate/triphosphate binary switch by cycling between the active GTP-bound and the inactive GDP-bound states in response to extracellular stimuli. The KRAS (G12C) mutation affects the active form of KRAS and results in abnormally high concentrations of GTP-bound KRAS leading to hyperactivation of downstream oncogenic pathways and uncontrolled cell growth, specifically of ERK and MEK signaling pathways.

At the ASCO annual meeting in June, Spira and colleagues reported the results of cohort A of the KRYSTAL-1 study evaluating adagrasib as second-line therapy patients with advanced solid tumors harboring a KRAS (G12C) mutation. Like sotorasib, adagrasib is a KRAS (G12C) inhibitor that irreversibly and selectively binds KRAS (G12C), locking it in its inactive state. In this study, patients had to have failed first-line chemotherapy and immunotherapy with 43% of lung cancer patients responding. The 12-month overall survival (OS) was 51%, median overall survival was 12.6 and median progression-free survival (PFS) was 6.5 months. Twenty-five patients with KRAS (G12C)–mutant NSCLC and active, untreated central nervous system metastases received adagrasib in a phase 1b cohort. The intracranial overall response rate was 31.6% and median intracranial PFS was 4.2 months. Systemic ORR was 35.0% (7/20), the disease control rate was 80.0% (16/20) and median duration of response was 9.6 months. Based on these data, a phase 3 trial evaluating adagrasib monotherapy versus docetaxel in previously treated patients with KRAS (G12C) mutant NSCLC is ongoing.

The Food and Drug Administration approval of sotorasib in 2021 was, in part, based on the results of a single-arm, phase 2, second-line study of patients who had previously received platinum-based chemotherapy and/or immunotherapy. An ORR rate of 37.1% was reported with a median PFS of 6.8 months and median OS of 12.5 months leading to the FDA approval. Responses were observed across the range of baseline PD-L1 expression levels: 48% of PD-L1 negative, 39% with PD-L1 between 1%-49%, and 22% of patients with a PD-L1 of greater than 50% having a response.

The major toxicities observed in these studies were gastrointestinal (diarrhea, nausea, vomiting) and hepatic (elevated liver enzymes). About 97% of patients on adagrasib experienced any treatment-related adverse events, and 43% experienced a grade 3 or 4 treatment-related adverse event leading to dose reduction in 52% of patients, a dose interruption in 61% of patients, and a 7% discontinuation rate. About 70% of patients treated with sotorasib had a treatment-related adverse event of any grade, and 21% reported grade 3 or 4 treatment-related adverse events.

A subgroup in the KRYSTAL-1 trial reported an intracranial ORR of 32% in patients with active, untreated CNS metastases. Median overall survival has not yet reached concordance between systemic and intracranial disease control was 88%. In addition, preliminary data from two patients with untreated CNS metastases from a phase 1b cohort found cerebrospinal fluid concentrations of adagrasib with a mean ratio of unbound brain-to-plasma concentration of 0.47, which is comparable or exceeds values for known CNS-penetrant tyrosine kinase inhibitors.

Unfortunately, KRAS (G12C) is not the only KRAS mutation out there. There are a myriad of others, such as G12V and G12D. Hopefully, we will be seeing more drugs aimed at this set of important mutations. Another question, of course, is when and if these drugs will move to the first-line setting.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Racial differences in cancer outcomes are widespread. Studies indicate that Black people face higher rates of mortality for most cancers than their White counterparts. To bridge this racial gap, researchers need to investigate the biological effects of structural racism and discrimination on cancer outcomes, experts say.

“As a physician, I always like to think that I can influence care in that if I just find the right drugs, help patients understand what their options are, it will help them,” said Ruth Carlos, MD, a radiologist with the University of Michigan Hospital, Ann Arbor. But these things alone are often not enough, because a large proportion of the variation in cancer outcomes is attributable to neighborhood social conditions and the physical environment. “It is incredibly important for us to start to understand just how the neighborhood exerts this effect.”

In a commentary published in the Journal of Clinical Oncology, Dr. Carlos and colleagues highlighted the limitations of previous studies aimed at identifying the causes of racial differences in cancer outcomes. They call upon researchers to turn instead to the long-underexamined biological effects of structural racism and discrimination that contribute to these differences.

In the past, studies on the role of race in health outcomes largely looked at race as a proxy for genetic predisposition. But such an interpretation is flawed, because no genes are specific for a racial or ethnic group, Dr. Carlos and coauthors wrote. Researchers have shown that the vast majority of genetic variation occurs within, rather than between groups.

In an analysis published in Science, researchers reported that within-group differences account for more than 90% of genetic variation.

“Using race in these analyses was not necessarily wrong, but the inferences may have been flawed or incomplete,” Dr. Carlos said. On one hand, looking at genetic predisposition has led to important insights, such as the link between mutations in the BRCA gene and increased risk for breast and ovarian cancer.

However, genetic variation alone is not enough to explain the disparities in cancer outcomes between racial and ethnic groups. The fact that breast cancer can be more aggressive in Black women raises several questions, Dr. Carlos said. Is the cancer worse because Black women have a specific genetic predisposition? Is it worse because Black women exist in a society that marginalizes them and exposes them to increased stress, which in turn produces bad outcomes? Or, could it be both?

Despite progress in the screening, diagnosis and treatment of breast cancer, Black women are 40% more likely to die from the disease than White women. At the time of diagnosis, Black women are more likely to have high-grade, more aggressive breast cancer molecular subtypes, and to have had their cancer spread to the lymph nodes. They also tend to be diagnosed at more advanced stages of breast cancer while at the same time, experience higher rates of false-positive screening results.

Although researchers have hypothesized that genetic differences related to African or European ancestry might contribute, studies have not turned up any differences in cancer susceptibility genes by race. Other factors, such as racial differences in the stage of presentation, molecular subtypes, and disparities in treatment, have also emerged as potential culprits.

In her commentary, Dr. Carlos and colleagues wrote that disparities in breast cancer outcomes previously attributed to race need to be examined from multiple angles. This means looking at both the complex interactions between social conditions and policies, which encompass racism both at the individual and structural level, and stressors such as the experience of discrimination in addition to potential biological and genetic contributions.

Many studies now provide evidence for the harmful effects of racism on health. For breast cancer, specifically, studies also suggest that factors such as racial segregation can influence the stage at which Black women get diagnosed and their likelihood of dying from the disease.

However, an important question that remains is what biological changes occur in women exposed to the kind of persistent low-level stress that is associated with structural racism and discrimination, Dr. Carlos said. “We don’t know what stress pathways actually manifest in the body and how they eventually produce the disease.” Studies to address this issue are important, “especially if you would like to develop interventions to prevent or mitigate disease.”

To address this issue, Dr. Carlos and colleagues called upon the research community to conduct both studies that delineate the underlying biology as well as those that test potential interventions – particularly those associated with breast cancer screening outcomes – to try to shed light on why Black women receive more false positives and diagnoses of more aggressive cancer.

Interventions that can target these specific biological pathways could potentially reduce the negative effects of structural racism and discrimination as well as the effects of other social factors that contribute to breast cancer outcomes, “to ultimately help enhance clinical outcomes and close persistent disparities gaps,” the authors wrote.

Racial differences in cancer outcomes are widespread. Studies indicate that Black people face higher rates of mortality for most cancers than their White counterparts. To bridge this racial gap, researchers need to investigate the biological effects of structural racism and discrimination on cancer outcomes, experts say.

“As a physician, I always like to think that I can influence care in that if I just find the right drugs, help patients understand what their options are, it will help them,” said Ruth Carlos, MD, a radiologist with the University of Michigan Hospital, Ann Arbor. But these things alone are often not enough, because a large proportion of the variation in cancer outcomes is attributable to neighborhood social conditions and the physical environment. “It is incredibly important for us to start to understand just how the neighborhood exerts this effect.”

In a commentary published in the Journal of Clinical Oncology, Dr. Carlos and colleagues highlighted the limitations of previous studies aimed at identifying the causes of racial differences in cancer outcomes. They call upon researchers to turn instead to the long-underexamined biological effects of structural racism and discrimination that contribute to these differences.

In the past, studies on the role of race in health outcomes largely looked at race as a proxy for genetic predisposition. But such an interpretation is flawed, because no genes are specific for a racial or ethnic group, Dr. Carlos and coauthors wrote. Researchers have shown that the vast majority of genetic variation occurs within, rather than between groups.

In an analysis published in Science, researchers reported that within-group differences account for more than 90% of genetic variation.

“Using race in these analyses was not necessarily wrong, but the inferences may have been flawed or incomplete,” Dr. Carlos said. On one hand, looking at genetic predisposition has led to important insights, such as the link between mutations in the BRCA gene and increased risk for breast and ovarian cancer.

However, genetic variation alone is not enough to explain the disparities in cancer outcomes between racial and ethnic groups. The fact that breast cancer can be more aggressive in Black women raises several questions, Dr. Carlos said. Is the cancer worse because Black women have a specific genetic predisposition? Is it worse because Black women exist in a society that marginalizes them and exposes them to increased stress, which in turn produces bad outcomes? Or, could it be both?

Despite progress in the screening, diagnosis and treatment of breast cancer, Black women are 40% more likely to die from the disease than White women. At the time of diagnosis, Black women are more likely to have high-grade, more aggressive breast cancer molecular subtypes, and to have had their cancer spread to the lymph nodes. They also tend to be diagnosed at more advanced stages of breast cancer while at the same time, experience higher rates of false-positive screening results.

Although researchers have hypothesized that genetic differences related to African or European ancestry might contribute, studies have not turned up any differences in cancer susceptibility genes by race. Other factors, such as racial differences in the stage of presentation, molecular subtypes, and disparities in treatment, have also emerged as potential culprits.

In her commentary, Dr. Carlos and colleagues wrote that disparities in breast cancer outcomes previously attributed to race need to be examined from multiple angles. This means looking at both the complex interactions between social conditions and policies, which encompass racism both at the individual and structural level, and stressors such as the experience of discrimination in addition to potential biological and genetic contributions.

Many studies now provide evidence for the harmful effects of racism on health. For breast cancer, specifically, studies also suggest that factors such as racial segregation can influence the stage at which Black women get diagnosed and their likelihood of dying from the disease.

However, an important question that remains is what biological changes occur in women exposed to the kind of persistent low-level stress that is associated with structural racism and discrimination, Dr. Carlos said. “We don’t know what stress pathways actually manifest in the body and how they eventually produce the disease.” Studies to address this issue are important, “especially if you would like to develop interventions to prevent or mitigate disease.”

To address this issue, Dr. Carlos and colleagues called upon the research community to conduct both studies that delineate the underlying biology as well as those that test potential interventions – particularly those associated with breast cancer screening outcomes – to try to shed light on why Black women receive more false positives and diagnoses of more aggressive cancer.

Interventions that can target these specific biological pathways could potentially reduce the negative effects of structural racism and discrimination as well as the effects of other social factors that contribute to breast cancer outcomes, “to ultimately help enhance clinical outcomes and close persistent disparities gaps,” the authors wrote.

Racial differences in cancer outcomes are widespread. Studies indicate that Black people face higher rates of mortality for most cancers than their White counterparts. To bridge this racial gap, researchers need to investigate the biological effects of structural racism and discrimination on cancer outcomes, experts say.

“As a physician, I always like to think that I can influence care in that if I just find the right drugs, help patients understand what their options are, it will help them,” said Ruth Carlos, MD, a radiologist with the University of Michigan Hospital, Ann Arbor. But these things alone are often not enough, because a large proportion of the variation in cancer outcomes is attributable to neighborhood social conditions and the physical environment. “It is incredibly important for us to start to understand just how the neighborhood exerts this effect.”

In a commentary published in the Journal of Clinical Oncology, Dr. Carlos and colleagues highlighted the limitations of previous studies aimed at identifying the causes of racial differences in cancer outcomes. They call upon researchers to turn instead to the long-underexamined biological effects of structural racism and discrimination that contribute to these differences.

In the past, studies on the role of race in health outcomes largely looked at race as a proxy for genetic predisposition. But such an interpretation is flawed, because no genes are specific for a racial or ethnic group, Dr. Carlos and coauthors wrote. Researchers have shown that the vast majority of genetic variation occurs within, rather than between groups.

In an analysis published in Science, researchers reported that within-group differences account for more than 90% of genetic variation.

“Using race in these analyses was not necessarily wrong, but the inferences may have been flawed or incomplete,” Dr. Carlos said. On one hand, looking at genetic predisposition has led to important insights, such as the link between mutations in the BRCA gene and increased risk for breast and ovarian cancer.

However, genetic variation alone is not enough to explain the disparities in cancer outcomes between racial and ethnic groups. The fact that breast cancer can be more aggressive in Black women raises several questions, Dr. Carlos said. Is the cancer worse because Black women have a specific genetic predisposition? Is it worse because Black women exist in a society that marginalizes them and exposes them to increased stress, which in turn produces bad outcomes? Or, could it be both?

Despite progress in the screening, diagnosis and treatment of breast cancer, Black women are 40% more likely to die from the disease than White women. At the time of diagnosis, Black women are more likely to have high-grade, more aggressive breast cancer molecular subtypes, and to have had their cancer spread to the lymph nodes. They also tend to be diagnosed at more advanced stages of breast cancer while at the same time, experience higher rates of false-positive screening results.

Although researchers have hypothesized that genetic differences related to African or European ancestry might contribute, studies have not turned up any differences in cancer susceptibility genes by race. Other factors, such as racial differences in the stage of presentation, molecular subtypes, and disparities in treatment, have also emerged as potential culprits.

In her commentary, Dr. Carlos and colleagues wrote that disparities in breast cancer outcomes previously attributed to race need to be examined from multiple angles. This means looking at both the complex interactions between social conditions and policies, which encompass racism both at the individual and structural level, and stressors such as the experience of discrimination in addition to potential biological and genetic contributions.

Many studies now provide evidence for the harmful effects of racism on health. For breast cancer, specifically, studies also suggest that factors such as racial segregation can influence the stage at which Black women get diagnosed and their likelihood of dying from the disease.

However, an important question that remains is what biological changes occur in women exposed to the kind of persistent low-level stress that is associated with structural racism and discrimination, Dr. Carlos said. “We don’t know what stress pathways actually manifest in the body and how they eventually produce the disease.” Studies to address this issue are important, “especially if you would like to develop interventions to prevent or mitigate disease.”

To address this issue, Dr. Carlos and colleagues called upon the research community to conduct both studies that delineate the underlying biology as well as those that test potential interventions – particularly those associated with breast cancer screening outcomes – to try to shed light on why Black women receive more false positives and diagnoses of more aggressive cancer.

Interventions that can target these specific biological pathways could potentially reduce the negative effects of structural racism and discrimination as well as the effects of other social factors that contribute to breast cancer outcomes, “to ultimately help enhance clinical outcomes and close persistent disparities gaps,” the authors wrote.

Findings from a cohort study highlight a potential role of tumor grade for predicting mucosal head and neck squamous cell carcinoma response to immunotherapy, researchers report in JAMA Otolaryngology–Head & Neck Surgery.

The analysis, which was among patients with either high-grade or low-grade recurrent or metastatic mucosal head and neck squamous cell carcinoma (HNSCC) tumors, revealed that tumor grade was independently associated with immunotherapy response.

“Generally, one would expect high-grade tumors to do worse because they are more aggressive,” said Rajarsi Mandal, MD, the study’s lead author. “But it’s thought that high-grade tumors have higher degrees of chromosomal instability with a lot more mutations generated throughout the genome of these tumors ... and we know that higher mutation rates correlate with higher responses to immunotherapy.”

Researchers found that the proportion of patients having a beneficial response to immunotherapy was larger for patients with high grade tumors (12 of 35; 34.3%) than those with low grade tumors (2 of 25, 8.0%) (difference, 26.3%; 95% confidence interval, 7.3%-45.3%). The odds of having a clinically beneficial response to immunotherapy was increased 5.35-fold (95% CI, 1.04-27.37) in patients with high-grade tumors. Among four patients with low-grade tumors and eight patients with high-grade tumors with available tumor mutational burden data, the mean tumor mutational burden was greater for patients with high-grade tumors (mean [standard deviation], 8.6 [5.4] mut/Mb; n = 8) than for patients with low grade tumors (mean [SD], 3.6 [1.1] mut/Mb; n = 4) (difference, 5.0 mut/Mb; 95% CI, −1.4 to 11.4 mut/Mb; Cohen d, 1.2).

“High tumor grade is not a guarantee but it possibly provides an easy biomarker and a good rationale to say that there’s a better chance the patient will respond to immune checkpoint inhibition,” said Dr. Mandal who is a head and neck cancer surgeon with the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore.

Previous studies of HNSCC tumors that are refractory to traditional therapies, including surgery, chemotherapy, and radiation therapy, have demonstrated a clinically beneficial response to immune checkpoint inhibitors (ICIs). An association between increased tumor mutational burden and beneficial response to ICIs has been shown in other cancers.

Researchers hypothesized that tumor histological grade may be associated with responses to immune checkpoint blockade, and designed their study to examine the association between tumor grade and immunotherapy response in patients treated with ICIs for recurrent or metastatic mucosal HNSCC.

In a single-center retrospective cohort study, investigators reviewed the medical records of 60 adult patients (mean age, 64.6 years; 85% male) with a primary mucosal HNSCC tumor treated with an immune checkpoint inhibitor (pembrolizumab, nivolumab, ipilimumab, or durvalumab) treated between July 1, 2015, and Jan. 22, 2020. They stratified them into those with low grade tumors (well differentiated and moderately differentiated) and those with high grade tumors (poorly differentiated). A clinically beneficial immunotherapy response, defined as complete response or partial response was the primary outcome.

Thirty-eight patients in the study cohort were current or former smokers. The most common primary tumor sight was at the oropharynx. Outcomes among those with high-grade tumors were improved, compared with those with low-grade tumors, for median progression-free survival (5.9 months vs. 3.3 months), median overall survival (16.6 months vs. 15.0 months, and risk of death (hazard ratio, 0.94).

The study’s main limitation was its small sample size and small number of patients who had a clinically beneficial immunotherapy response.

Dr. Mandal had no conflicts of interest to disclose.

Findings from a cohort study highlight a potential role of tumor grade for predicting mucosal head and neck squamous cell carcinoma response to immunotherapy, researchers report in JAMA Otolaryngology–Head & Neck Surgery.

The analysis, which was among patients with either high-grade or low-grade recurrent or metastatic mucosal head and neck squamous cell carcinoma (HNSCC) tumors, revealed that tumor grade was independently associated with immunotherapy response.

“Generally, one would expect high-grade tumors to do worse because they are more aggressive,” said Rajarsi Mandal, MD, the study’s lead author. “But it’s thought that high-grade tumors have higher degrees of chromosomal instability with a lot more mutations generated throughout the genome of these tumors ... and we know that higher mutation rates correlate with higher responses to immunotherapy.”

Researchers found that the proportion of patients having a beneficial response to immunotherapy was larger for patients with high grade tumors (12 of 35; 34.3%) than those with low grade tumors (2 of 25, 8.0%) (difference, 26.3%; 95% confidence interval, 7.3%-45.3%). The odds of having a clinically beneficial response to immunotherapy was increased 5.35-fold (95% CI, 1.04-27.37) in patients with high-grade tumors. Among four patients with low-grade tumors and eight patients with high-grade tumors with available tumor mutational burden data, the mean tumor mutational burden was greater for patients with high-grade tumors (mean [standard deviation], 8.6 [5.4] mut/Mb; n = 8) than for patients with low grade tumors (mean [SD], 3.6 [1.1] mut/Mb; n = 4) (difference, 5.0 mut/Mb; 95% CI, −1.4 to 11.4 mut/Mb; Cohen d, 1.2).

“High tumor grade is not a guarantee but it possibly provides an easy biomarker and a good rationale to say that there’s a better chance the patient will respond to immune checkpoint inhibition,” said Dr. Mandal who is a head and neck cancer surgeon with the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore.

Previous studies of HNSCC tumors that are refractory to traditional therapies, including surgery, chemotherapy, and radiation therapy, have demonstrated a clinically beneficial response to immune checkpoint inhibitors (ICIs). An association between increased tumor mutational burden and beneficial response to ICIs has been shown in other cancers.

Researchers hypothesized that tumor histological grade may be associated with responses to immune checkpoint blockade, and designed their study to examine the association between tumor grade and immunotherapy response in patients treated with ICIs for recurrent or metastatic mucosal HNSCC.

In a single-center retrospective cohort study, investigators reviewed the medical records of 60 adult patients (mean age, 64.6 years; 85% male) with a primary mucosal HNSCC tumor treated with an immune checkpoint inhibitor (pembrolizumab, nivolumab, ipilimumab, or durvalumab) treated between July 1, 2015, and Jan. 22, 2020. They stratified them into those with low grade tumors (well differentiated and moderately differentiated) and those with high grade tumors (poorly differentiated). A clinically beneficial immunotherapy response, defined as complete response or partial response was the primary outcome.

Thirty-eight patients in the study cohort were current or former smokers. The most common primary tumor sight was at the oropharynx. Outcomes among those with high-grade tumors were improved, compared with those with low-grade tumors, for median progression-free survival (5.9 months vs. 3.3 months), median overall survival (16.6 months vs. 15.0 months, and risk of death (hazard ratio, 0.94).

The study’s main limitation was its small sample size and small number of patients who had a clinically beneficial immunotherapy response.

Dr. Mandal had no conflicts of interest to disclose.

Findings from a cohort study highlight a potential role of tumor grade for predicting mucosal head and neck squamous cell carcinoma response to immunotherapy, researchers report in JAMA Otolaryngology–Head & Neck Surgery.

The analysis, which was among patients with either high-grade or low-grade recurrent or metastatic mucosal head and neck squamous cell carcinoma (HNSCC) tumors, revealed that tumor grade was independently associated with immunotherapy response.

“Generally, one would expect high-grade tumors to do worse because they are more aggressive,” said Rajarsi Mandal, MD, the study’s lead author. “But it’s thought that high-grade tumors have higher degrees of chromosomal instability with a lot more mutations generated throughout the genome of these tumors ... and we know that higher mutation rates correlate with higher responses to immunotherapy.”

Researchers found that the proportion of patients having a beneficial response to immunotherapy was larger for patients with high grade tumors (12 of 35; 34.3%) than those with low grade tumors (2 of 25, 8.0%) (difference, 26.3%; 95% confidence interval, 7.3%-45.3%). The odds of having a clinically beneficial response to immunotherapy was increased 5.35-fold (95% CI, 1.04-27.37) in patients with high-grade tumors. Among four patients with low-grade tumors and eight patients with high-grade tumors with available tumor mutational burden data, the mean tumor mutational burden was greater for patients with high-grade tumors (mean [standard deviation], 8.6 [5.4] mut/Mb; n = 8) than for patients with low grade tumors (mean [SD], 3.6 [1.1] mut/Mb; n = 4) (difference, 5.0 mut/Mb; 95% CI, −1.4 to 11.4 mut/Mb; Cohen d, 1.2).

“High tumor grade is not a guarantee but it possibly provides an easy biomarker and a good rationale to say that there’s a better chance the patient will respond to immune checkpoint inhibition,” said Dr. Mandal who is a head and neck cancer surgeon with the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore.

Previous studies of HNSCC tumors that are refractory to traditional therapies, including surgery, chemotherapy, and radiation therapy, have demonstrated a clinically beneficial response to immune checkpoint inhibitors (ICIs). An association between increased tumor mutational burden and beneficial response to ICIs has been shown in other cancers.

Researchers hypothesized that tumor histological grade may be associated with responses to immune checkpoint blockade, and designed their study to examine the association between tumor grade and immunotherapy response in patients treated with ICIs for recurrent or metastatic mucosal HNSCC.

In a single-center retrospective cohort study, investigators reviewed the medical records of 60 adult patients (mean age, 64.6 years; 85% male) with a primary mucosal HNSCC tumor treated with an immune checkpoint inhibitor (pembrolizumab, nivolumab, ipilimumab, or durvalumab) treated between July 1, 2015, and Jan. 22, 2020. They stratified them into those with low grade tumors (well differentiated and moderately differentiated) and those with high grade tumors (poorly differentiated). A clinically beneficial immunotherapy response, defined as complete response or partial response was the primary outcome.

Thirty-eight patients in the study cohort were current or former smokers. The most common primary tumor sight was at the oropharynx. Outcomes among those with high-grade tumors were improved, compared with those with low-grade tumors, for median progression-free survival (5.9 months vs. 3.3 months), median overall survival (16.6 months vs. 15.0 months, and risk of death (hazard ratio, 0.94).

The study’s main limitation was its small sample size and small number of patients who had a clinically beneficial immunotherapy response.

Dr. Mandal had no conflicts of interest to disclose.

A large Danish study has found that cancer increases the risk of new-onset type 2 diabetes, especially certain types of cancer, most notably pancreatic malignancies.

“Our study demonstrates that there is an elevated risk of developing diabetes if a person is affected by lung, pancreatic, breast, brain, urinary tract, or uterine cancers,” said Lykke Sylow, PhD, associate professor in the Molecular Metabolism in Cancer and Ageing Group at the University of Copenhagen, in a statement.

“It is great to see such a large, well-designed study confirm the findings of previous smaller studies and observations,” said Elias S. Siraj, MD, the David L. Bernd Distinguished Chair for EVMS-Sentara Cardiovascular Diabetes Program at Eastern Virginia Medical School in Norfolk, when asked for comment by this news organization. Dr. Siraj also noted that “in clinical care we do observe that many patients develop diabetes after being diagnosed with cancer although one needs a well-designed study to confirm that observation.”
 

Diabetes risk highest with pancreatic cancer

Type 2 diabetes at the time of cancer diagnosis is known to increase cancer-specific and all-cause mortality, but not much is known about whether cancer is a risk factor for type 2 diabetes, the researchers state in their study, published in Diabetes Care.

Dr. Sylow and colleagues from the Steno Diabetes Center Copenhagen, Rigshospitalet, analyzed a database consisting of 112 million blood samples from 1.3 million Danes from 2000 to 2015. They looked at cancer cases with an incidence of more than 1,000 and excluded individuals with diabetes prior to cancer diagnosis. 

They found an increased risk of new-onset type 2 diabetes for all cancers (hazard ratio, 1.09; 95% confidence interval, 1.03-1.14). For pancreatic cancer, the hazard ratio rose to 5.0 (95% CI, 3.62-6.90), for brain and nervous system cancers the hazard ratio was 1.54 (95% CI, 1.22-1.95), and for uterine cancer the hazard ratio was 1.41 (95% CI, 1.10-1.84).

The link with pancreatic cancer was not surprising, said Dr. Sylow.

Dr. Siraj agreed, noting that a few studies have shown a strong association. “It has also been observed for years that many patients with pancreatic cancer may present with new-onset diabetes,” he said. “The mechanism is not clearly understood but could include a direct damage of the beta cells by the pancreatic cancer or could be due to a paraneoplastic secretion of special factors by the cancer that can affect beta-cell function or insulin resistance,” said Dr. Siraj, who is also professor and chief of endocrinology and director of the Strelitz Diabetes Center at Eastern Virginia Medical School.

The higher diabetes risk associated with brain and nervous system cancers has not been previously described and is “an intriguing finding,” he said.

In their statement, the Danish investigators said there is nothing in their research to suggest why some cancers are associated with a higher risk of new-onset type 2 diabetes, but they offered some theories, including that chemotherapeutics and perhaps the cancer, itself, may contribute.

“We know that cancer cells are able to secrete substances that can affect organs and possibility contribute to an increased incidence of diabetes,” said Dr. Sylow in the statement.
 

Increased mortality risk in those with cancer and type 2 diabetes

Dr. Sylow and colleagues also analyzed mortality in a subset of 28,308 patients with cancer who were still alive 2 years after diagnosis. They documented a 21% higher rate of all-cause mortality in these patients compared with those who did not have new-onset type 2 diabetes.

“We do not know enough about the patients who were diagnosed with type 2 diabetes, but we think our findings illustrate a potential new area of intervention in the cancer clinic,” Dr. Sylow said. However, the findings still require replication before drawing any definite conclusions, she added.

Christoffer Johansen, MD, PhD, DMSc, of Rigshospitalet, said in the statement that it might be prudent to screen patients with lung, breast, brain, uterine, and urinary tract cancers for diabetes. “Early intervention could have an impact on certain cancer patients,” said Dr. Johansen.

Dr. Siraj said he would urge oncologists to routinely monitor blood glucose levels during cancer treatment and as part of long-term surveillance, and to consider the potential risk of new-onset diabetes when choosing a cancer therapy. If diabetes is diagnosed, clinicians should be sure that it’s managed by a primary care physician or endocrinologist, “as proper treatment may contribute to better outcomes of the cancer,” said Dr. Siraj.

Endocrinologists should consider the possibility of pancreatic cancer if someone with few risk factors for type 2 diabetes has a new-onset diagnosis, he said. And they should aim for good glycemic control in those with new-onset type 2 diabetes, as it may lead to better cancer outcomes, he said.

Dr. Sylow has reported grant support from the Novo Nordisk Foundation and Independent Research Fund Denmark. Dr. Johansen has reported serving as an educator for Janssen and Pfizer. Coauthors have received grant support from the Danish Cancer Society and served as consultants, on advisory boards, or as educators for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Incyte, GSK, MSD, Mundipharma, Novartis, Novo Nordisk, Pfizer, and Sanofi.

A version of this article first appeared on Medscape.com.

A large Danish study has found that cancer increases the risk of new-onset type 2 diabetes, especially certain types of cancer, most notably pancreatic malignancies.

“Our study demonstrates that there is an elevated risk of developing diabetes if a person is affected by lung, pancreatic, breast, brain, urinary tract, or uterine cancers,” said Lykke Sylow, PhD, associate professor in the Molecular Metabolism in Cancer and Ageing Group at the University of Copenhagen, in a statement.

“It is great to see such a large, well-designed study confirm the findings of previous smaller studies and observations,” said Elias S. Siraj, MD, the David L. Bernd Distinguished Chair for EVMS-Sentara Cardiovascular Diabetes Program at Eastern Virginia Medical School in Norfolk, when asked for comment by this news organization. Dr. Siraj also noted that “in clinical care we do observe that many patients develop diabetes after being diagnosed with cancer although one needs a well-designed study to confirm that observation.”
 

Diabetes risk highest with pancreatic cancer

Type 2 diabetes at the time of cancer diagnosis is known to increase cancer-specific and all-cause mortality, but not much is known about whether cancer is a risk factor for type 2 diabetes, the researchers state in their study, published in Diabetes Care.

Dr. Sylow and colleagues from the Steno Diabetes Center Copenhagen, Rigshospitalet, analyzed a database consisting of 112 million blood samples from 1.3 million Danes from 2000 to 2015. They looked at cancer cases with an incidence of more than 1,000 and excluded individuals with diabetes prior to cancer diagnosis. 

They found an increased risk of new-onset type 2 diabetes for all cancers (hazard ratio, 1.09; 95% confidence interval, 1.03-1.14). For pancreatic cancer, the hazard ratio rose to 5.0 (95% CI, 3.62-6.90), for brain and nervous system cancers the hazard ratio was 1.54 (95% CI, 1.22-1.95), and for uterine cancer the hazard ratio was 1.41 (95% CI, 1.10-1.84).

The link with pancreatic cancer was not surprising, said Dr. Sylow.

Dr. Siraj agreed, noting that a few studies have shown a strong association. “It has also been observed for years that many patients with pancreatic cancer may present with new-onset diabetes,” he said. “The mechanism is not clearly understood but could include a direct damage of the beta cells by the pancreatic cancer or could be due to a paraneoplastic secretion of special factors by the cancer that can affect beta-cell function or insulin resistance,” said Dr. Siraj, who is also professor and chief of endocrinology and director of the Strelitz Diabetes Center at Eastern Virginia Medical School.

The higher diabetes risk associated with brain and nervous system cancers has not been previously described and is “an intriguing finding,” he said.

In their statement, the Danish investigators said there is nothing in their research to suggest why some cancers are associated with a higher risk of new-onset type 2 diabetes, but they offered some theories, including that chemotherapeutics and perhaps the cancer, itself, may contribute.

“We know that cancer cells are able to secrete substances that can affect organs and possibility contribute to an increased incidence of diabetes,” said Dr. Sylow in the statement.
 

Increased mortality risk in those with cancer and type 2 diabetes

Dr. Sylow and colleagues also analyzed mortality in a subset of 28,308 patients with cancer who were still alive 2 years after diagnosis. They documented a 21% higher rate of all-cause mortality in these patients compared with those who did not have new-onset type 2 diabetes.

“We do not know enough about the patients who were diagnosed with type 2 diabetes, but we think our findings illustrate a potential new area of intervention in the cancer clinic,” Dr. Sylow said. However, the findings still require replication before drawing any definite conclusions, she added.

Christoffer Johansen, MD, PhD, DMSc, of Rigshospitalet, said in the statement that it might be prudent to screen patients with lung, breast, brain, uterine, and urinary tract cancers for diabetes. “Early intervention could have an impact on certain cancer patients,” said Dr. Johansen.

Dr. Siraj said he would urge oncologists to routinely monitor blood glucose levels during cancer treatment and as part of long-term surveillance, and to consider the potential risk of new-onset diabetes when choosing a cancer therapy. If diabetes is diagnosed, clinicians should be sure that it’s managed by a primary care physician or endocrinologist, “as proper treatment may contribute to better outcomes of the cancer,” said Dr. Siraj.

Endocrinologists should consider the possibility of pancreatic cancer if someone with few risk factors for type 2 diabetes has a new-onset diagnosis, he said. And they should aim for good glycemic control in those with new-onset type 2 diabetes, as it may lead to better cancer outcomes, he said.

Dr. Sylow has reported grant support from the Novo Nordisk Foundation and Independent Research Fund Denmark. Dr. Johansen has reported serving as an educator for Janssen and Pfizer. Coauthors have received grant support from the Danish Cancer Society and served as consultants, on advisory boards, or as educators for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Incyte, GSK, MSD, Mundipharma, Novartis, Novo Nordisk, Pfizer, and Sanofi.

A version of this article first appeared on Medscape.com.

A large Danish study has found that cancer increases the risk of new-onset type 2 diabetes, especially certain types of cancer, most notably pancreatic malignancies.

“Our study demonstrates that there is an elevated risk of developing diabetes if a person is affected by lung, pancreatic, breast, brain, urinary tract, or uterine cancers,” said Lykke Sylow, PhD, associate professor in the Molecular Metabolism in Cancer and Ageing Group at the University of Copenhagen, in a statement.

“It is great to see such a large, well-designed study confirm the findings of previous smaller studies and observations,” said Elias S. Siraj, MD, the David L. Bernd Distinguished Chair for EVMS-Sentara Cardiovascular Diabetes Program at Eastern Virginia Medical School in Norfolk, when asked for comment by this news organization. Dr. Siraj also noted that “in clinical care we do observe that many patients develop diabetes after being diagnosed with cancer although one needs a well-designed study to confirm that observation.”
 

Diabetes risk highest with pancreatic cancer

Type 2 diabetes at the time of cancer diagnosis is known to increase cancer-specific and all-cause mortality, but not much is known about whether cancer is a risk factor for type 2 diabetes, the researchers state in their study, published in Diabetes Care.

Dr. Sylow and colleagues from the Steno Diabetes Center Copenhagen, Rigshospitalet, analyzed a database consisting of 112 million blood samples from 1.3 million Danes from 2000 to 2015. They looked at cancer cases with an incidence of more than 1,000 and excluded individuals with diabetes prior to cancer diagnosis. 

They found an increased risk of new-onset type 2 diabetes for all cancers (hazard ratio, 1.09; 95% confidence interval, 1.03-1.14). For pancreatic cancer, the hazard ratio rose to 5.0 (95% CI, 3.62-6.90), for brain and nervous system cancers the hazard ratio was 1.54 (95% CI, 1.22-1.95), and for uterine cancer the hazard ratio was 1.41 (95% CI, 1.10-1.84).

The link with pancreatic cancer was not surprising, said Dr. Sylow.

Dr. Siraj agreed, noting that a few studies have shown a strong association. “It has also been observed for years that many patients with pancreatic cancer may present with new-onset diabetes,” he said. “The mechanism is not clearly understood but could include a direct damage of the beta cells by the pancreatic cancer or could be due to a paraneoplastic secretion of special factors by the cancer that can affect beta-cell function or insulin resistance,” said Dr. Siraj, who is also professor and chief of endocrinology and director of the Strelitz Diabetes Center at Eastern Virginia Medical School.

The higher diabetes risk associated with brain and nervous system cancers has not been previously described and is “an intriguing finding,” he said.

In their statement, the Danish investigators said there is nothing in their research to suggest why some cancers are associated with a higher risk of new-onset type 2 diabetes, but they offered some theories, including that chemotherapeutics and perhaps the cancer, itself, may contribute.

“We know that cancer cells are able to secrete substances that can affect organs and possibility contribute to an increased incidence of diabetes,” said Dr. Sylow in the statement.
 

Increased mortality risk in those with cancer and type 2 diabetes

Dr. Sylow and colleagues also analyzed mortality in a subset of 28,308 patients with cancer who were still alive 2 years after diagnosis. They documented a 21% higher rate of all-cause mortality in these patients compared with those who did not have new-onset type 2 diabetes.

“We do not know enough about the patients who were diagnosed with type 2 diabetes, but we think our findings illustrate a potential new area of intervention in the cancer clinic,” Dr. Sylow said. However, the findings still require replication before drawing any definite conclusions, she added.

Christoffer Johansen, MD, PhD, DMSc, of Rigshospitalet, said in the statement that it might be prudent to screen patients with lung, breast, brain, uterine, and urinary tract cancers for diabetes. “Early intervention could have an impact on certain cancer patients,” said Dr. Johansen.

Dr. Siraj said he would urge oncologists to routinely monitor blood glucose levels during cancer treatment and as part of long-term surveillance, and to consider the potential risk of new-onset diabetes when choosing a cancer therapy. If diabetes is diagnosed, clinicians should be sure that it’s managed by a primary care physician or endocrinologist, “as proper treatment may contribute to better outcomes of the cancer,” said Dr. Siraj.

Endocrinologists should consider the possibility of pancreatic cancer if someone with few risk factors for type 2 diabetes has a new-onset diagnosis, he said. And they should aim for good glycemic control in those with new-onset type 2 diabetes, as it may lead to better cancer outcomes, he said.

Dr. Sylow has reported grant support from the Novo Nordisk Foundation and Independent Research Fund Denmark. Dr. Johansen has reported serving as an educator for Janssen and Pfizer. Coauthors have received grant support from the Danish Cancer Society and served as consultants, on advisory boards, or as educators for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Incyte, GSK, MSD, Mundipharma, Novartis, Novo Nordisk, Pfizer, and Sanofi.

A version of this article first appeared on Medscape.com.

Adults younger than 55 years were least likely to get screened for colorectal cancer over the past 2 decades, particularly if they were Hispanic or Asian or had a low income, lower education level, or no health insurance, according to a new study published online in Cancer Epidemiology, Biomarkers & Prevention.

The findings have raised concerns that disparities in screening rates will be even greater in adults aged 45-49 years, prompting the need for increased awareness and outreach to ensure that underserved groups have access to screenings.

“Differences in prevalence of screening by race and ethnicity, educational attainment, household income, and health insurance were most pronounced for those ages 50-54 years, whereas older adults experienced larger increases in prevalence across these groups,” wrote Po-Hong Liu, MD, MPH, a clinical investigator at Harvard University, Boston, and his colleagues. “The persistent and worsening disparities we observed in adults 50-54 years may extend to those ages 45-49 as they become eligible for screening.”

The U.S. Preventive Services Task Force shifted their recommendation for colorectal cancer screening in May 2021 to 5 years earlier, advising people to start screenings at 45 instead of 50, which aligns with the recommendations the American Cancer Society made 3 years earlier.

Both organizations made the change because of increasing rates of colorectal cancer in adults under age 50 and research indicating that beginning screenings at age 45 results in fewer cases, fewer deaths, and more life years gained.

“Across all age groups, colorectal cancer screening participation remains below national goals, and the benefits of screening are not equally realized across populations,” senior author Caitlin Murphy, PhD, MPH, associate professor, UTHealth School of Public Health, Houston, said in a prepared statement. “Extra care must be taken to ensure that expanding screening to younger ages does not negatively impact efforts to eliminate disparities in colorectal screening and outcomes nor jeopardize efforts to increase screening initiation among older adults who remain unscreened.”
 

Data analyzed from 8 years over 2 decades

The researchers analyzed data from the CDC’s cross-sectional National Health Interview Survey during 8 years over the past 2 decades: 2000, 2003, 2005, 2008, 2010, 2013, 2015, and 2018.

The number of participants each year ranged from a low of 21,781 in 2008 to a high of 34,557 in 2013. After excluding participants with a history of colorectal cancer or missing information on screenings, the total population sample included 80,220 participants 50-75 years old.

The researchers considered a person as having been screened if they received at least one recommended screening test within the year covered by the survey, regardless of why they underwent the test.

Recommended tests included sigmoidoscopy, colonoscopy, and stool-based tests for all survey years. In addition, the surveys for 2010, 2015, and 2018 included CT colonography, and the 2018 survey included FIT-DNA.
 

Screening across population groups

Colorectal cancer screening rates have doubled in the past 2 decades, from 36.7% in 2000 to 66.1% in 2018.

Rates are considerably lower, however, for several key groups, including the youngest group. Less than half (47.6%) of those aged 50-54 years received screenings in 2018, though this was still a nearly 20-point improvement over the 28.2% in this age group who were screened in 2000.

Separate from age, several other groups continue to have low screening rates in general, including Hispanics (56.5%, up from 25.9% in 2000), Asians (57.1%, up from 22.6% in 2000), those who have not received a high school degree (53.6%, up from 26.8% in 2000), and those from low income families (56.6%, up from 30.2% in 2000).

The group with the greatest need for more outreach and screenings are people without insurance, only 39.7% of whom were screened in 2018, a modest increase from 30.2% in 2000.

The biggest increase in screenings over time occurred in those aged 70-75 years, from 46.4% in 2000 to 78% in 2018 overall.

Racial/ethnic, economic, education, and insurance-based disparities were particularly evident the younger people were, including in terms of progress made over time.

For example, screenings of non-Hispanic White people aged 50-54 years improved 21 points (30.3% to 51%) between 2000 and 2018, compared with 19 points in Hispanics (16.7% to 35.5%) and 15 points in Asians (17.3% to 32.3%). Fortunately, Black Americans made even greater strides than White Americans with a 27-point increase during that time (23.4% to 50%). 

Similarly, income correlated with expansion in screening rates for 50- to 54-year-olds: Those earning at least 400% over the federal poverty line improved 20 points (from 33.5% to 53.8%), compared with a 16-point improvement in those earning less than 200% above the poverty line (from 19.3% to 35%).

Those with private insurance likewise improved 21 points (from 30.7% to 51.7%), while those in this age group without insurance declined, with just 21.2% getting screened in 2018, compared with 28.2% in 2000. Those on public insurance saw a 15-point improvement, from 27.8% in 2000 to 43.1% in 2018.

“The individual and societal burden of colorectal cancer is especially great among younger adults,” the authors wrote.

The reasons for the much lower prevalence of screening in those under 55, the authors suggested, is likely due to less concern about colorectal cancer, less access to medical care (including being underinsured or uninsured), and the barriers created by competing priorities, such as work schedules, family responsibilities, and caregiving. The latter may be particularly true in underserved populations, the authors noted.

“Screening programs must consider the barriers unique to younger adults, ensuring the benefits of screening are equally realized by all population groups,” the authors concluded.

The research was funded by the National Institutes of Health and the Cancer Prevention and Research Institute of Texas. One author reported grants from Epigenomics and Freenome and personal fees from Guardant Health. Another author reported personal fees from Freenome, and a third author reported personal fees from Exact Sciences. No other authors had industry disclosures.

A version of this article first appeared on Medscape.com.

Adults younger than 55 years were least likely to get screened for colorectal cancer over the past 2 decades, particularly if they were Hispanic or Asian or had a low income, lower education level, or no health insurance, according to a new study published online in Cancer Epidemiology, Biomarkers & Prevention.

The findings have raised concerns that disparities in screening rates will be even greater in adults aged 45-49 years, prompting the need for increased awareness and outreach to ensure that underserved groups have access to screenings.

“Differences in prevalence of screening by race and ethnicity, educational attainment, household income, and health insurance were most pronounced for those ages 50-54 years, whereas older adults experienced larger increases in prevalence across these groups,” wrote Po-Hong Liu, MD, MPH, a clinical investigator at Harvard University, Boston, and his colleagues. “The persistent and worsening disparities we observed in adults 50-54 years may extend to those ages 45-49 as they become eligible for screening.”

The U.S. Preventive Services Task Force shifted their recommendation for colorectal cancer screening in May 2021 to 5 years earlier, advising people to start screenings at 45 instead of 50, which aligns with the recommendations the American Cancer Society made 3 years earlier.

Both organizations made the change because of increasing rates of colorectal cancer in adults under age 50 and research indicating that beginning screenings at age 45 results in fewer cases, fewer deaths, and more life years gained.

“Across all age groups, colorectal cancer screening participation remains below national goals, and the benefits of screening are not equally realized across populations,” senior author Caitlin Murphy, PhD, MPH, associate professor, UTHealth School of Public Health, Houston, said in a prepared statement. “Extra care must be taken to ensure that expanding screening to younger ages does not negatively impact efforts to eliminate disparities in colorectal screening and outcomes nor jeopardize efforts to increase screening initiation among older adults who remain unscreened.”
 

Data analyzed from 8 years over 2 decades

The researchers analyzed data from the CDC’s cross-sectional National Health Interview Survey during 8 years over the past 2 decades: 2000, 2003, 2005, 2008, 2010, 2013, 2015, and 2018.

The number of participants each year ranged from a low of 21,781 in 2008 to a high of 34,557 in 2013. After excluding participants with a history of colorectal cancer or missing information on screenings, the total population sample included 80,220 participants 50-75 years old.

The researchers considered a person as having been screened if they received at least one recommended screening test within the year covered by the survey, regardless of why they underwent the test.

Recommended tests included sigmoidoscopy, colonoscopy, and stool-based tests for all survey years. In addition, the surveys for 2010, 2015, and 2018 included CT colonography, and the 2018 survey included FIT-DNA.
 

Screening across population groups

Colorectal cancer screening rates have doubled in the past 2 decades, from 36.7% in 2000 to 66.1% in 2018.

Rates are considerably lower, however, for several key groups, including the youngest group. Less than half (47.6%) of those aged 50-54 years received screenings in 2018, though this was still a nearly 20-point improvement over the 28.2% in this age group who were screened in 2000.

Separate from age, several other groups continue to have low screening rates in general, including Hispanics (56.5%, up from 25.9% in 2000), Asians (57.1%, up from 22.6% in 2000), those who have not received a high school degree (53.6%, up from 26.8% in 2000), and those from low income families (56.6%, up from 30.2% in 2000).

The group with the greatest need for more outreach and screenings are people without insurance, only 39.7% of whom were screened in 2018, a modest increase from 30.2% in 2000.

The biggest increase in screenings over time occurred in those aged 70-75 years, from 46.4% in 2000 to 78% in 2018 overall.

Racial/ethnic, economic, education, and insurance-based disparities were particularly evident the younger people were, including in terms of progress made over time.

For example, screenings of non-Hispanic White people aged 50-54 years improved 21 points (30.3% to 51%) between 2000 and 2018, compared with 19 points in Hispanics (16.7% to 35.5%) and 15 points in Asians (17.3% to 32.3%). Fortunately, Black Americans made even greater strides than White Americans with a 27-point increase during that time (23.4% to 50%). 

Similarly, income correlated with expansion in screening rates for 50- to 54-year-olds: Those earning at least 400% over the federal poverty line improved 20 points (from 33.5% to 53.8%), compared with a 16-point improvement in those earning less than 200% above the poverty line (from 19.3% to 35%).

Those with private insurance likewise improved 21 points (from 30.7% to 51.7%), while those in this age group without insurance declined, with just 21.2% getting screened in 2018, compared with 28.2% in 2000. Those on public insurance saw a 15-point improvement, from 27.8% in 2000 to 43.1% in 2018.

“The individual and societal burden of colorectal cancer is especially great among younger adults,” the authors wrote.

The reasons for the much lower prevalence of screening in those under 55, the authors suggested, is likely due to less concern about colorectal cancer, less access to medical care (including being underinsured or uninsured), and the barriers created by competing priorities, such as work schedules, family responsibilities, and caregiving. The latter may be particularly true in underserved populations, the authors noted.

“Screening programs must consider the barriers unique to younger adults, ensuring the benefits of screening are equally realized by all population groups,” the authors concluded.

The research was funded by the National Institutes of Health and the Cancer Prevention and Research Institute of Texas. One author reported grants from Epigenomics and Freenome and personal fees from Guardant Health. Another author reported personal fees from Freenome, and a third author reported personal fees from Exact Sciences. No other authors had industry disclosures.

A version of this article first appeared on Medscape.com.

Adults younger than 55 years were least likely to get screened for colorectal cancer over the past 2 decades, particularly if they were Hispanic or Asian or had a low income, lower education level, or no health insurance, according to a new study published online in Cancer Epidemiology, Biomarkers & Prevention.

The findings have raised concerns that disparities in screening rates will be even greater in adults aged 45-49 years, prompting the need for increased awareness and outreach to ensure that underserved groups have access to screenings.

“Differences in prevalence of screening by race and ethnicity, educational attainment, household income, and health insurance were most pronounced for those ages 50-54 years, whereas older adults experienced larger increases in prevalence across these groups,” wrote Po-Hong Liu, MD, MPH, a clinical investigator at Harvard University, Boston, and his colleagues. “The persistent and worsening disparities we observed in adults 50-54 years may extend to those ages 45-49 as they become eligible for screening.”

The U.S. Preventive Services Task Force shifted their recommendation for colorectal cancer screening in May 2021 to 5 years earlier, advising people to start screenings at 45 instead of 50, which aligns with the recommendations the American Cancer Society made 3 years earlier.

Both organizations made the change because of increasing rates of colorectal cancer in adults under age 50 and research indicating that beginning screenings at age 45 results in fewer cases, fewer deaths, and more life years gained.

“Across all age groups, colorectal cancer screening participation remains below national goals, and the benefits of screening are not equally realized across populations,” senior author Caitlin Murphy, PhD, MPH, associate professor, UTHealth School of Public Health, Houston, said in a prepared statement. “Extra care must be taken to ensure that expanding screening to younger ages does not negatively impact efforts to eliminate disparities in colorectal screening and outcomes nor jeopardize efforts to increase screening initiation among older adults who remain unscreened.”
 

Data analyzed from 8 years over 2 decades

The researchers analyzed data from the CDC’s cross-sectional National Health Interview Survey during 8 years over the past 2 decades: 2000, 2003, 2005, 2008, 2010, 2013, 2015, and 2018.

The number of participants each year ranged from a low of 21,781 in 2008 to a high of 34,557 in 2013. After excluding participants with a history of colorectal cancer or missing information on screenings, the total population sample included 80,220 participants 50-75 years old.

The researchers considered a person as having been screened if they received at least one recommended screening test within the year covered by the survey, regardless of why they underwent the test.

Recommended tests included sigmoidoscopy, colonoscopy, and stool-based tests for all survey years. In addition, the surveys for 2010, 2015, and 2018 included CT colonography, and the 2018 survey included FIT-DNA.
 

Screening across population groups

Colorectal cancer screening rates have doubled in the past 2 decades, from 36.7% in 2000 to 66.1% in 2018.

Rates are considerably lower, however, for several key groups, including the youngest group. Less than half (47.6%) of those aged 50-54 years received screenings in 2018, though this was still a nearly 20-point improvement over the 28.2% in this age group who were screened in 2000.

Separate from age, several other groups continue to have low screening rates in general, including Hispanics (56.5%, up from 25.9% in 2000), Asians (57.1%, up from 22.6% in 2000), those who have not received a high school degree (53.6%, up from 26.8% in 2000), and those from low income families (56.6%, up from 30.2% in 2000).

The group with the greatest need for more outreach and screenings are people without insurance, only 39.7% of whom were screened in 2018, a modest increase from 30.2% in 2000.

The biggest increase in screenings over time occurred in those aged 70-75 years, from 46.4% in 2000 to 78% in 2018 overall.

Racial/ethnic, economic, education, and insurance-based disparities were particularly evident the younger people were, including in terms of progress made over time.

For example, screenings of non-Hispanic White people aged 50-54 years improved 21 points (30.3% to 51%) between 2000 and 2018, compared with 19 points in Hispanics (16.7% to 35.5%) and 15 points in Asians (17.3% to 32.3%). Fortunately, Black Americans made even greater strides than White Americans with a 27-point increase during that time (23.4% to 50%). 

Similarly, income correlated with expansion in screening rates for 50- to 54-year-olds: Those earning at least 400% over the federal poverty line improved 20 points (from 33.5% to 53.8%), compared with a 16-point improvement in those earning less than 200% above the poverty line (from 19.3% to 35%).

Those with private insurance likewise improved 21 points (from 30.7% to 51.7%), while those in this age group without insurance declined, with just 21.2% getting screened in 2018, compared with 28.2% in 2000. Those on public insurance saw a 15-point improvement, from 27.8% in 2000 to 43.1% in 2018.

“The individual and societal burden of colorectal cancer is especially great among younger adults,” the authors wrote.

The reasons for the much lower prevalence of screening in those under 55, the authors suggested, is likely due to less concern about colorectal cancer, less access to medical care (including being underinsured or uninsured), and the barriers created by competing priorities, such as work schedules, family responsibilities, and caregiving. The latter may be particularly true in underserved populations, the authors noted.

“Screening programs must consider the barriers unique to younger adults, ensuring the benefits of screening are equally realized by all population groups,” the authors concluded.

The research was funded by the National Institutes of Health and the Cancer Prevention and Research Institute of Texas. One author reported grants from Epigenomics and Freenome and personal fees from Guardant Health. Another author reported personal fees from Freenome, and a third author reported personal fees from Exact Sciences. No other authors had industry disclosures.

A version of this article first appeared on Medscape.com.

LONDON – Around the world, nonalcoholic fatty liver disease (NAFLD) has driven an increase in deaths from liver cancer over the past decade, overtaking alcoholic liver disease, hepatitis B, and hepatitis C, according to an analysis of the Global Burden of Disease Study 2019.

A global rise in liver cancer deaths and chronic liver disease reflects changes in underlying health patterns, said Zobair Younossi, MD, MPH, professor and chair, department of medicine, Inova Fairfax Medical Campus, Falls Church, Va., who presented the analysis at the International Liver Congress (ILC) 2022.

“NAFLD and NASH [nonalcoholic steatohepatitis] are rapidly becoming the main causes of cirrhosis and liver cancer in the world,” Dr. Younossi told this news organization. “We have known about the increasing prevalence for some time, but now the outcomes in terms of mortality are catching up,” he said.

“The bottom line of this study is that the burden of this disease [NAFLD] is going up, and it will be the most important disease of the next decade or so,” he said, adding that “the largest annual percentage increase in rates of mortality from liver cancer or chronic liver disease cirrhosis is related to NAFLD.”

Specifically, during the decade of 2009-2019, the annual percent change (APC) of +1.33% in the global liver cancer death rate was driven by the fact that the APC for NAFLD was +2.47%. By comparison, the APC for alcoholic liver disease was +1.91%; for hepatitis B, the APC was +0.21%; and for hepatitis C, the APC was +1.12%.

Aleksander Krag, MD, PhD, professor and senior consultant of hepatology and director of Odense Liver Research Centre at SDU and Odense University Hospital, Denmark, who chaired the session in which this presentation was a part, acknowledged the importance of recognizing the contribution of NAFLD to liver cancer mortality.

“Liver diseases are on the rise. They are the fastest rising cause of death in the United Kingdom, faster than heart disease and other cancers. NAFLD in particular is the fastest growing cause of liver cancer, and the leading cause in France and the United States,” he remarked.

Dr. Krag also highlighted the costs of disease management.

“Managing fatty liver disease in Europe is estimated at €35 billion in direct health care, so we need to do something now,” he stressed.

“The global burden of NAFLD is so high that we need both prevention and treatment tools,” Dr. Krag said. “Change to lifestyle is a ‘no-brainer’ and costs governments very little. For the sake of our young people, we need to take this very seriously. At a political level, we can easily implement this, for example, by banning junk food advertisements, but also educating young people and their families. Good drugs will also help.”
 

NAFLD: The liver manifestation of type 2 diabetes

About 25%-30% of the global population have NAFLD, and 3%-5% have NASH. Dr. Younossi highlighted that the U.S. transplant database shows that NAFLD was the second indication for all liver transplants in the country. NAFLD also was a leading cause of liver transplants for patients with hepatocellular carcinoma.

There are around two billion cases of chronic liver disease globally, he said. He noted that over time, there has been an increase in all kinds of liver diseases, as reflected in the annual percent change.

“The global epidemic of obesity and type 2 diabetes is driving the rise in NAFLD, but even among lean people, the prevalence of NAFLD is around 9%,” Dr. Younossi said. “Alongside the eye and kidney complications of diabetes, this is the liver manifestation of type 2 diabetes.”

To assess global liver disease and death, Dr. Younossi and his colleagues turned to the Global Burden of Disease Study, which gathered data from around 7,000 investigators located across 22 different regions of the world, comprising 156 countries.

They calculated the incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) in relation to liver cancer and chronic liver disease, including the APC. They linked the data to changes in four liver diseases: NAFLD, alcoholic liver disease, hepatitis B infection, and hepatitis C infection.

The cases of NAFLD reported in the study had been diagnosed by ultrasound or other imaging. Importantly, the prevalence of NAFLD was adjusted for alcohol use in the various national populations, explained Dr. Younossi.

In 2019, they reported that globally, the overall prevalence of liver disease reached 1.69 billion (liver cancer, 0.04%; chronic liver disease, 99.96%), with an incidence of 2.59 million (liver cancer, 20.7%; chronic liver disease, 79.3%), mortality of 1.95 million (liver cancer, 24.8%; chronic liver disease, 75.3%), and DALYs of 58.7 million (liver cancer, 21.3%; chronic liver disease, 78.7%).

Between 2009 and 2019, deaths from liver cancer rose by 27.2%, and deaths from chronic liver disease rose by 10.6%. DALYs from liver cancer rose by 21.9%, and DALYs from chronic liver disease were up by 5.1%.

In contrast to the increase in liver cancer deaths, deaths from chronic liver disease decreased (APC, –0.18%). The decrease was driven by a decrease in hepatitis B (APC, –1.83%). APCs for hepatitis C (+0.37%), alcoholic liver disease (+0.45%), and NAFLD (+1.33%) increased.

“The burden of hepatitis B–related mortality has decreased because we have been so good at vaccinating people,” Dr. Younossi remarked.
 

NAFLD ‘exploding’ in Middle East, North Africa, and East Asia

The increase in NAFLD has been seen in all regions of the world, but a breakdown by region shows that NAFLD is primarily “exploding” with highest prevalence and mortality in the Middle East (mostly Egypt, Iran, and Turkey), North Africa, and East Asia, said Dr. Younossi. In addition, there are large increases in the West and South America.

“We knew that the prevalence was high in the Middle East, but we now know that mortality is also high, so we are connecting these data,” said Dr. Younossi.
 

Awareness lacking

Dr. Younossi pressed the fact that awareness among the general population, primary care providers, and policymakers is very low. “From my perspective, raising awareness of NAFLD is the number one priority, and that is the value of this study.”

He added that more people will become aware as testing becomes more manageable.

“There are some noninvasive tests being developed, so in the future, we won’t have to do liver biopsies to diagnose these patients,” he said. “Currently, there are some excellent treatments being developed.”

“The WHO [World Health Organization] does not mention NAFLD as an important noncommunicable disease, and this too has to change,” Dr. Younossi added.

Dr. Younossi has received research funds and/or has consulted for Abbott, Allergan, Bristol-Myers Squibb, Echosens, Genfit, Gilead Sciences, Intercept, Madrigal, Merck, and Novo Nordisk. Dr. Krag has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

LONDON – Around the world, nonalcoholic fatty liver disease (NAFLD) has driven an increase in deaths from liver cancer over the past decade, overtaking alcoholic liver disease, hepatitis B, and hepatitis C, according to an analysis of the Global Burden of Disease Study 2019.

A global rise in liver cancer deaths and chronic liver disease reflects changes in underlying health patterns, said Zobair Younossi, MD, MPH, professor and chair, department of medicine, Inova Fairfax Medical Campus, Falls Church, Va., who presented the analysis at the International Liver Congress (ILC) 2022.

“NAFLD and NASH [nonalcoholic steatohepatitis] are rapidly becoming the main causes of cirrhosis and liver cancer in the world,” Dr. Younossi told this news organization. “We have known about the increasing prevalence for some time, but now the outcomes in terms of mortality are catching up,” he said.

“The bottom line of this study is that the burden of this disease [NAFLD] is going up, and it will be the most important disease of the next decade or so,” he said, adding that “the largest annual percentage increase in rates of mortality from liver cancer or chronic liver disease cirrhosis is related to NAFLD.”

Specifically, during the decade of 2009-2019, the annual percent change (APC) of +1.33% in the global liver cancer death rate was driven by the fact that the APC for NAFLD was +2.47%. By comparison, the APC for alcoholic liver disease was +1.91%; for hepatitis B, the APC was +0.21%; and for hepatitis C, the APC was +1.12%.

Aleksander Krag, MD, PhD, professor and senior consultant of hepatology and director of Odense Liver Research Centre at SDU and Odense University Hospital, Denmark, who chaired the session in which this presentation was a part, acknowledged the importance of recognizing the contribution of NAFLD to liver cancer mortality.

“Liver diseases are on the rise. They are the fastest rising cause of death in the United Kingdom, faster than heart disease and other cancers. NAFLD in particular is the fastest growing cause of liver cancer, and the leading cause in France and the United States,” he remarked.

Dr. Krag also highlighted the costs of disease management.

“Managing fatty liver disease in Europe is estimated at €35 billion in direct health care, so we need to do something now,” he stressed.

“The global burden of NAFLD is so high that we need both prevention and treatment tools,” Dr. Krag said. “Change to lifestyle is a ‘no-brainer’ and costs governments very little. For the sake of our young people, we need to take this very seriously. At a political level, we can easily implement this, for example, by banning junk food advertisements, but also educating young people and their families. Good drugs will also help.”
 

NAFLD: The liver manifestation of type 2 diabetes

About 25%-30% of the global population have NAFLD, and 3%-5% have NASH. Dr. Younossi highlighted that the U.S. transplant database shows that NAFLD was the second indication for all liver transplants in the country. NAFLD also was a leading cause of liver transplants for patients with hepatocellular carcinoma.

There are around two billion cases of chronic liver disease globally, he said. He noted that over time, there has been an increase in all kinds of liver diseases, as reflected in the annual percent change.

“The global epidemic of obesity and type 2 diabetes is driving the rise in NAFLD, but even among lean people, the prevalence of NAFLD is around 9%,” Dr. Younossi said. “Alongside the eye and kidney complications of diabetes, this is the liver manifestation of type 2 diabetes.”

To assess global liver disease and death, Dr. Younossi and his colleagues turned to the Global Burden of Disease Study, which gathered data from around 7,000 investigators located across 22 different regions of the world, comprising 156 countries.

They calculated the incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) in relation to liver cancer and chronic liver disease, including the APC. They linked the data to changes in four liver diseases: NAFLD, alcoholic liver disease, hepatitis B infection, and hepatitis C infection.

The cases of NAFLD reported in the study had been diagnosed by ultrasound or other imaging. Importantly, the prevalence of NAFLD was adjusted for alcohol use in the various national populations, explained Dr. Younossi.

In 2019, they reported that globally, the overall prevalence of liver disease reached 1.69 billion (liver cancer, 0.04%; chronic liver disease, 99.96%), with an incidence of 2.59 million (liver cancer, 20.7%; chronic liver disease, 79.3%), mortality of 1.95 million (liver cancer, 24.8%; chronic liver disease, 75.3%), and DALYs of 58.7 million (liver cancer, 21.3%; chronic liver disease, 78.7%).

Between 2009 and 2019, deaths from liver cancer rose by 27.2%, and deaths from chronic liver disease rose by 10.6%. DALYs from liver cancer rose by 21.9%, and DALYs from chronic liver disease were up by 5.1%.

In contrast to the increase in liver cancer deaths, deaths from chronic liver disease decreased (APC, –0.18%). The decrease was driven by a decrease in hepatitis B (APC, –1.83%). APCs for hepatitis C (+0.37%), alcoholic liver disease (+0.45%), and NAFLD (+1.33%) increased.

“The burden of hepatitis B–related mortality has decreased because we have been so good at vaccinating people,” Dr. Younossi remarked.
 

NAFLD ‘exploding’ in Middle East, North Africa, and East Asia

The increase in NAFLD has been seen in all regions of the world, but a breakdown by region shows that NAFLD is primarily “exploding” with highest prevalence and mortality in the Middle East (mostly Egypt, Iran, and Turkey), North Africa, and East Asia, said Dr. Younossi. In addition, there are large increases in the West and South America.

“We knew that the prevalence was high in the Middle East, but we now know that mortality is also high, so we are connecting these data,” said Dr. Younossi.
 

Awareness lacking

Dr. Younossi pressed the fact that awareness among the general population, primary care providers, and policymakers is very low. “From my perspective, raising awareness of NAFLD is the number one priority, and that is the value of this study.”

He added that more people will become aware as testing becomes more manageable.

“There are some noninvasive tests being developed, so in the future, we won’t have to do liver biopsies to diagnose these patients,” he said. “Currently, there are some excellent treatments being developed.”

“The WHO [World Health Organization] does not mention NAFLD as an important noncommunicable disease, and this too has to change,” Dr. Younossi added.

Dr. Younossi has received research funds and/or has consulted for Abbott, Allergan, Bristol-Myers Squibb, Echosens, Genfit, Gilead Sciences, Intercept, Madrigal, Merck, and Novo Nordisk. Dr. Krag has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

LONDON – Around the world, nonalcoholic fatty liver disease (NAFLD) has driven an increase in deaths from liver cancer over the past decade, overtaking alcoholic liver disease, hepatitis B, and hepatitis C, according to an analysis of the Global Burden of Disease Study 2019.

A global rise in liver cancer deaths and chronic liver disease reflects changes in underlying health patterns, said Zobair Younossi, MD, MPH, professor and chair, department of medicine, Inova Fairfax Medical Campus, Falls Church, Va., who presented the analysis at the International Liver Congress (ILC) 2022.

“NAFLD and NASH [nonalcoholic steatohepatitis] are rapidly becoming the main causes of cirrhosis and liver cancer in the world,” Dr. Younossi told this news organization. “We have known about the increasing prevalence for some time, but now the outcomes in terms of mortality are catching up,” he said.

“The bottom line of this study is that the burden of this disease [NAFLD] is going up, and it will be the most important disease of the next decade or so,” he said, adding that “the largest annual percentage increase in rates of mortality from liver cancer or chronic liver disease cirrhosis is related to NAFLD.”

Specifically, during the decade of 2009-2019, the annual percent change (APC) of +1.33% in the global liver cancer death rate was driven by the fact that the APC for NAFLD was +2.47%. By comparison, the APC for alcoholic liver disease was +1.91%; for hepatitis B, the APC was +0.21%; and for hepatitis C, the APC was +1.12%.

Aleksander Krag, MD, PhD, professor and senior consultant of hepatology and director of Odense Liver Research Centre at SDU and Odense University Hospital, Denmark, who chaired the session in which this presentation was a part, acknowledged the importance of recognizing the contribution of NAFLD to liver cancer mortality.

“Liver diseases are on the rise. They are the fastest rising cause of death in the United Kingdom, faster than heart disease and other cancers. NAFLD in particular is the fastest growing cause of liver cancer, and the leading cause in France and the United States,” he remarked.

Dr. Krag also highlighted the costs of disease management.

“Managing fatty liver disease in Europe is estimated at €35 billion in direct health care, so we need to do something now,” he stressed.

“The global burden of NAFLD is so high that we need both prevention and treatment tools,” Dr. Krag said. “Change to lifestyle is a ‘no-brainer’ and costs governments very little. For the sake of our young people, we need to take this very seriously. At a political level, we can easily implement this, for example, by banning junk food advertisements, but also educating young people and their families. Good drugs will also help.”
 

NAFLD: The liver manifestation of type 2 diabetes

About 25%-30% of the global population have NAFLD, and 3%-5% have NASH. Dr. Younossi highlighted that the U.S. transplant database shows that NAFLD was the second indication for all liver transplants in the country. NAFLD also was a leading cause of liver transplants for patients with hepatocellular carcinoma.

There are around two billion cases of chronic liver disease globally, he said. He noted that over time, there has been an increase in all kinds of liver diseases, as reflected in the annual percent change.

“The global epidemic of obesity and type 2 diabetes is driving the rise in NAFLD, but even among lean people, the prevalence of NAFLD is around 9%,” Dr. Younossi said. “Alongside the eye and kidney complications of diabetes, this is the liver manifestation of type 2 diabetes.”

To assess global liver disease and death, Dr. Younossi and his colleagues turned to the Global Burden of Disease Study, which gathered data from around 7,000 investigators located across 22 different regions of the world, comprising 156 countries.

They calculated the incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) in relation to liver cancer and chronic liver disease, including the APC. They linked the data to changes in four liver diseases: NAFLD, alcoholic liver disease, hepatitis B infection, and hepatitis C infection.

The cases of NAFLD reported in the study had been diagnosed by ultrasound or other imaging. Importantly, the prevalence of NAFLD was adjusted for alcohol use in the various national populations, explained Dr. Younossi.

In 2019, they reported that globally, the overall prevalence of liver disease reached 1.69 billion (liver cancer, 0.04%; chronic liver disease, 99.96%), with an incidence of 2.59 million (liver cancer, 20.7%; chronic liver disease, 79.3%), mortality of 1.95 million (liver cancer, 24.8%; chronic liver disease, 75.3%), and DALYs of 58.7 million (liver cancer, 21.3%; chronic liver disease, 78.7%).

Between 2009 and 2019, deaths from liver cancer rose by 27.2%, and deaths from chronic liver disease rose by 10.6%. DALYs from liver cancer rose by 21.9%, and DALYs from chronic liver disease were up by 5.1%.

In contrast to the increase in liver cancer deaths, deaths from chronic liver disease decreased (APC, –0.18%). The decrease was driven by a decrease in hepatitis B (APC, –1.83%). APCs for hepatitis C (+0.37%), alcoholic liver disease (+0.45%), and NAFLD (+1.33%) increased.

“The burden of hepatitis B–related mortality has decreased because we have been so good at vaccinating people,” Dr. Younossi remarked.
 

NAFLD ‘exploding’ in Middle East, North Africa, and East Asia

The increase in NAFLD has been seen in all regions of the world, but a breakdown by region shows that NAFLD is primarily “exploding” with highest prevalence and mortality in the Middle East (mostly Egypt, Iran, and Turkey), North Africa, and East Asia, said Dr. Younossi. In addition, there are large increases in the West and South America.

“We knew that the prevalence was high in the Middle East, but we now know that mortality is also high, so we are connecting these data,” said Dr. Younossi.
 

Awareness lacking

Dr. Younossi pressed the fact that awareness among the general population, primary care providers, and policymakers is very low. “From my perspective, raising awareness of NAFLD is the number one priority, and that is the value of this study.”

He added that more people will become aware as testing becomes more manageable.

“There are some noninvasive tests being developed, so in the future, we won’t have to do liver biopsies to diagnose these patients,” he said. “Currently, there are some excellent treatments being developed.”

“The WHO [World Health Organization] does not mention NAFLD as an important noncommunicable disease, and this too has to change,” Dr. Younossi added.

Dr. Younossi has received research funds and/or has consulted for Abbott, Allergan, Bristol-Myers Squibb, Echosens, Genfit, Gilead Sciences, Intercept, Madrigal, Merck, and Novo Nordisk. Dr. Krag has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

New research shows that the metastatic spread of breast cancer occurs predominantly during sleep, a discovery the investigators called “striking and unexpected.”

“This has not been shown before [and] we were surprised, indeed,” Nicola Aceto, PhD, professor of molecular oncology, Swiss Federal Institute of Technology Zürich, said in an interview.

The findings carry potential implications for the timing of biopsy and treatment of metastasis-prone cancers, the authors said.

The study was published online in Nature. 

Circulating tumor cells (CTCs) are generally believed to shed constantly or following particular events such as surgery or physical activity; however, the processes that regulate tumor cell metastasis and how circadian rhythms may play into tumorigenesis remain unclear.

To better understand these processes, Dr. Aceto and colleagues collected blood samples from 30 women with breast cancer at 4:00 a.m. and 10:00 a.m. – times representing the body’s resting and active phases, respectively.

The researchers observed that more than 78% of all CTCs obtained were from samples taken during the resting phase.

This finding is astounding, Harrison Ball, a PhD candidate, and Sunitha Nagrath, PhD, with the University of Michigan, Ann Arbor, wrote in Nature News & Views .

Dr. Aceto and colleagues also found that CTCs generated at night divide more quickly and therefore have a higher potential to metastasize, compared with those generated during the day, which “are devoid of metastatic ability,” according to the authors, who obtained similar results in a series of mouse models.

The team also observed that key circadian rhythm hormones (such as melatonin, testosterone, and glucocorticoids) regulate CTC generation, and insulin promotes tumor cell proliferation in a time-dependent manner, suggesting a “need for time-controlled approaches for the characterization and treatment of breast cancer,” the authors wrote.
 

Practice changing?

Dr. Ball and Dr. Nagrath said the time-dependent nature of CTC dynamics could very well transform how cancer patients are assessed and treated.

“The data pointing to CTC proliferation and release during the rest phase suggest that doctors might need to become more conscious of when to administer specific treatments,” they wrote.

Both cautioned, however, that large clinical trials would be needed before any consideration of circadian rhythms is incorporated into standard practice. It’s also unclear whether these results in breast cancer hold true for other tumor types.

Mariana G. Figueiro, PhD, who was not involved in the research, agreed that, if studies confirm more metastatic spread at night, “there is an opportunity to treat patients at strategic times.”

Dr. Figueiro, of the Icahn School of Medicine at Mount Sinai, New York, also saw a potential impact on the timing of blood draws. “I think tightening up on how people do biopsies and bloodwork based on circadian time is important.”

Marleen Meyers, MD, agreed that these findings could have many clinical implications.

“The most obvious is that the time of day [that] treatment is administered may influence efficacy,” said Dr. Meyers, clinical professor of medicine at New York University Langone’s Perlmutter Cancer Center.

But, Dr. Meyers noted, the benefits of treating someone at night would need to be weighed against the downsides of interrupting a person’s normal sleep-wake cycle. “If this finding is clinically important it will be a challenge incorporating this into clinical care,” she said.

The study had no funding reported. Dr. Aceto is a cofounder and member of the board of PAGE Therapeutics, listed as an inventor in patent applications related to circulating tumor cells, a paid consultant for several companies, and a Novartis shareholder. One coauthor is a cofounder of PAGE Therapeutics. All other authors declare no competing interests. Dr. Meyers and Dr. Figueiro reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

New research shows that the metastatic spread of breast cancer occurs predominantly during sleep, a discovery the investigators called “striking and unexpected.”

“This has not been shown before [and] we were surprised, indeed,” Nicola Aceto, PhD, professor of molecular oncology, Swiss Federal Institute of Technology Zürich, said in an interview.

The findings carry potential implications for the timing of biopsy and treatment of metastasis-prone cancers, the authors said.

The study was published online in Nature. 

Circulating tumor cells (CTCs) are generally believed to shed constantly or following particular events such as surgery or physical activity; however, the processes that regulate tumor cell metastasis and how circadian rhythms may play into tumorigenesis remain unclear.

To better understand these processes, Dr. Aceto and colleagues collected blood samples from 30 women with breast cancer at 4:00 a.m. and 10:00 a.m. – times representing the body’s resting and active phases, respectively.

The researchers observed that more than 78% of all CTCs obtained were from samples taken during the resting phase.

This finding is astounding, Harrison Ball, a PhD candidate, and Sunitha Nagrath, PhD, with the University of Michigan, Ann Arbor, wrote in Nature News & Views .

Dr. Aceto and colleagues also found that CTCs generated at night divide more quickly and therefore have a higher potential to metastasize, compared with those generated during the day, which “are devoid of metastatic ability,” according to the authors, who obtained similar results in a series of mouse models.

The team also observed that key circadian rhythm hormones (such as melatonin, testosterone, and glucocorticoids) regulate CTC generation, and insulin promotes tumor cell proliferation in a time-dependent manner, suggesting a “need for time-controlled approaches for the characterization and treatment of breast cancer,” the authors wrote.
 

Practice changing?

Dr. Ball and Dr. Nagrath said the time-dependent nature of CTC dynamics could very well transform how cancer patients are assessed and treated.

“The data pointing to CTC proliferation and release during the rest phase suggest that doctors might need to become more conscious of when to administer specific treatments,” they wrote.

Both cautioned, however, that large clinical trials would be needed before any consideration of circadian rhythms is incorporated into standard practice. It’s also unclear whether these results in breast cancer hold true for other tumor types.

Mariana G. Figueiro, PhD, who was not involved in the research, agreed that, if studies confirm more metastatic spread at night, “there is an opportunity to treat patients at strategic times.”

Dr. Figueiro, of the Icahn School of Medicine at Mount Sinai, New York, also saw a potential impact on the timing of blood draws. “I think tightening up on how people do biopsies and bloodwork based on circadian time is important.”

Marleen Meyers, MD, agreed that these findings could have many clinical implications.

“The most obvious is that the time of day [that] treatment is administered may influence efficacy,” said Dr. Meyers, clinical professor of medicine at New York University Langone’s Perlmutter Cancer Center.

But, Dr. Meyers noted, the benefits of treating someone at night would need to be weighed against the downsides of interrupting a person’s normal sleep-wake cycle. “If this finding is clinically important it will be a challenge incorporating this into clinical care,” she said.

The study had no funding reported. Dr. Aceto is a cofounder and member of the board of PAGE Therapeutics, listed as an inventor in patent applications related to circulating tumor cells, a paid consultant for several companies, and a Novartis shareholder. One coauthor is a cofounder of PAGE Therapeutics. All other authors declare no competing interests. Dr. Meyers and Dr. Figueiro reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

New research shows that the metastatic spread of breast cancer occurs predominantly during sleep, a discovery the investigators called “striking and unexpected.”

“This has not been shown before [and] we were surprised, indeed,” Nicola Aceto, PhD, professor of molecular oncology, Swiss Federal Institute of Technology Zürich, said in an interview.

The findings carry potential implications for the timing of biopsy and treatment of metastasis-prone cancers, the authors said.

The study was published online in Nature. 

Circulating tumor cells (CTCs) are generally believed to shed constantly or following particular events such as surgery or physical activity; however, the processes that regulate tumor cell metastasis and how circadian rhythms may play into tumorigenesis remain unclear.

To better understand these processes, Dr. Aceto and colleagues collected blood samples from 30 women with breast cancer at 4:00 a.m. and 10:00 a.m. – times representing the body’s resting and active phases, respectively.

The researchers observed that more than 78% of all CTCs obtained were from samples taken during the resting phase.

This finding is astounding, Harrison Ball, a PhD candidate, and Sunitha Nagrath, PhD, with the University of Michigan, Ann Arbor, wrote in Nature News & Views .

Dr. Aceto and colleagues also found that CTCs generated at night divide more quickly and therefore have a higher potential to metastasize, compared with those generated during the day, which “are devoid of metastatic ability,” according to the authors, who obtained similar results in a series of mouse models.

The team also observed that key circadian rhythm hormones (such as melatonin, testosterone, and glucocorticoids) regulate CTC generation, and insulin promotes tumor cell proliferation in a time-dependent manner, suggesting a “need for time-controlled approaches for the characterization and treatment of breast cancer,” the authors wrote.
 

Practice changing?

Dr. Ball and Dr. Nagrath said the time-dependent nature of CTC dynamics could very well transform how cancer patients are assessed and treated.

“The data pointing to CTC proliferation and release during the rest phase suggest that doctors might need to become more conscious of when to administer specific treatments,” they wrote.

Both cautioned, however, that large clinical trials would be needed before any consideration of circadian rhythms is incorporated into standard practice. It’s also unclear whether these results in breast cancer hold true for other tumor types.

Mariana G. Figueiro, PhD, who was not involved in the research, agreed that, if studies confirm more metastatic spread at night, “there is an opportunity to treat patients at strategic times.”

Dr. Figueiro, of the Icahn School of Medicine at Mount Sinai, New York, also saw a potential impact on the timing of blood draws. “I think tightening up on how people do biopsies and bloodwork based on circadian time is important.”

Marleen Meyers, MD, agreed that these findings could have many clinical implications.

“The most obvious is that the time of day [that] treatment is administered may influence efficacy,” said Dr. Meyers, clinical professor of medicine at New York University Langone’s Perlmutter Cancer Center.

But, Dr. Meyers noted, the benefits of treating someone at night would need to be weighed against the downsides of interrupting a person’s normal sleep-wake cycle. “If this finding is clinically important it will be a challenge incorporating this into clinical care,” she said.

The study had no funding reported. Dr. Aceto is a cofounder and member of the board of PAGE Therapeutics, listed as an inventor in patent applications related to circulating tumor cells, a paid consultant for several companies, and a Novartis shareholder. One coauthor is a cofounder of PAGE Therapeutics. All other authors declare no competing interests. Dr. Meyers and Dr. Figueiro reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.