Drug release in a cancer cell

Credit: PNAS

Biomedical engineers have reported that daisy-shaped, nanoscale structures can deliver a cocktail of drugs directly to cancer cells.

The “nanodaisies” effectively delivered a 2-drug combination in a range of cell lines, including the leukemia cell line HL-60.

The drug-delivery vehicles also proved effective in a mouse model of lung cancer.

Zhen Gu, PhD, of North Carolina State University and the University of North Carolina at Chapel Hill, and his colleagues detailed these results in Biomaterials.

“We found that this technique was much better than conventional drug-delivery techniques at inhibiting the growth of lung cancer tumors in mice,” Dr Gu said.

“And based on in vitro tests in 9 different cell lines, the technique is also promising for use against leukemia, breast, prostate, liver, ovarian, and brain cancers.”

To make the “nanodaisies,” the researchers begin with a solution that contains a polymer called polyethylene glycol (PEG). The PEG forms long strands that have much shorter strands branching off to either side.

The researchers directly link the anticancer drug camptothecin (CPT) onto the shorter strands and introduce the anticancer drug doxorubicin (Dox) into the solution.

PEG is hydrophilic, but CPT and Dox are hydrophobic. As a result, the CPT and Dox cluster together in the solution, wrapping the PEG around themselves. This results in a daisy-shaped drug cocktail, only 50 nanometers in diameter, that can (in theory) be injected into a cancer patient.

Once injected, the nanodaisies float through the bloodstream until they are absorbed by cancer cells. In fact, one of the reasons the researchers chose to use PEG is because it has chemical properties that prolong the life of the drugs in the bloodstream. Once in a cancer cell, the drugs are released.

“Both drugs attack the cell’s nucleus but via different mechanisms,” said study author Wanyi Tai, PhD, who was previously a researcher in Dr Gu’s lab but is now at the University of Washington in Seattle.

“Combined, the drugs are more effective than either drug is by itself,” Dr Gu added. “We are very optimistic about this technique and are hoping to begin preclinical testing in the near future.”

Drug release in a cancer cell

Credit: PNAS

Biomedical engineers have reported that daisy-shaped, nanoscale structures can deliver a cocktail of drugs directly to cancer cells.

The “nanodaisies” effectively delivered a 2-drug combination in a range of cell lines, including the leukemia cell line HL-60.

The drug-delivery vehicles also proved effective in a mouse model of lung cancer.

Zhen Gu, PhD, of North Carolina State University and the University of North Carolina at Chapel Hill, and his colleagues detailed these results in Biomaterials.

“We found that this technique was much better than conventional drug-delivery techniques at inhibiting the growth of lung cancer tumors in mice,” Dr Gu said.

“And based on in vitro tests in 9 different cell lines, the technique is also promising for use against leukemia, breast, prostate, liver, ovarian, and brain cancers.”

To make the “nanodaisies,” the researchers begin with a solution that contains a polymer called polyethylene glycol (PEG). The PEG forms long strands that have much shorter strands branching off to either side.

The researchers directly link the anticancer drug camptothecin (CPT) onto the shorter strands and introduce the anticancer drug doxorubicin (Dox) into the solution.

PEG is hydrophilic, but CPT and Dox are hydrophobic. As a result, the CPT and Dox cluster together in the solution, wrapping the PEG around themselves. This results in a daisy-shaped drug cocktail, only 50 nanometers in diameter, that can (in theory) be injected into a cancer patient.

Once injected, the nanodaisies float through the bloodstream until they are absorbed by cancer cells. In fact, one of the reasons the researchers chose to use PEG is because it has chemical properties that prolong the life of the drugs in the bloodstream. Once in a cancer cell, the drugs are released.

“Both drugs attack the cell’s nucleus but via different mechanisms,” said study author Wanyi Tai, PhD, who was previously a researcher in Dr Gu’s lab but is now at the University of Washington in Seattle.

“Combined, the drugs are more effective than either drug is by itself,” Dr Gu added. “We are very optimistic about this technique and are hoping to begin preclinical testing in the near future.”

Drug release in a cancer cell

Credit: PNAS

Biomedical engineers have reported that daisy-shaped, nanoscale structures can deliver a cocktail of drugs directly to cancer cells.

The “nanodaisies” effectively delivered a 2-drug combination in a range of cell lines, including the leukemia cell line HL-60.

The drug-delivery vehicles also proved effective in a mouse model of lung cancer.

Zhen Gu, PhD, of North Carolina State University and the University of North Carolina at Chapel Hill, and his colleagues detailed these results in Biomaterials.

“We found that this technique was much better than conventional drug-delivery techniques at inhibiting the growth of lung cancer tumors in mice,” Dr Gu said.

“And based on in vitro tests in 9 different cell lines, the technique is also promising for use against leukemia, breast, prostate, liver, ovarian, and brain cancers.”

To make the “nanodaisies,” the researchers begin with a solution that contains a polymer called polyethylene glycol (PEG). The PEG forms long strands that have much shorter strands branching off to either side.

The researchers directly link the anticancer drug camptothecin (CPT) onto the shorter strands and introduce the anticancer drug doxorubicin (Dox) into the solution.

PEG is hydrophilic, but CPT and Dox are hydrophobic. As a result, the CPT and Dox cluster together in the solution, wrapping the PEG around themselves. This results in a daisy-shaped drug cocktail, only 50 nanometers in diameter, that can (in theory) be injected into a cancer patient.

Once injected, the nanodaisies float through the bloodstream until they are absorbed by cancer cells. In fact, one of the reasons the researchers chose to use PEG is because it has chemical properties that prolong the life of the drugs in the bloodstream. Once in a cancer cell, the drugs are released.

“Both drugs attack the cell’s nucleus but via different mechanisms,” said study author Wanyi Tai, PhD, who was previously a researcher in Dr Gu’s lab but is now at the University of Washington in Seattle.

“Combined, the drugs are more effective than either drug is by itself,” Dr Gu added. “We are very optimistic about this technique and are hoping to begin preclinical testing in the near future.”

Apoptosis in cancer cells

Credit: Egelberg

Investigators say they have solved the mystery of an enzyme’s role in cell survival, thereby offering clues as to how the immune system fights infection and pointing to possible strategies for treating cancers.

The enzyme, receptor-interacting protein kinase 1 (RIPK1), is known to play a pivotal role in survival after birth.

But the new research, published in Cell, reveals that RIPK1 inhibits the pathways that control apoptosis and necroptosis.

By removing different components of each pathway in different combinations, the investigators demonstrated that, after birth, RIPK1 helps cells maintain a balanced response to signals that promote either pathway.

“We are learning that, in disease, this balancing act can be perturbed to produce damage and cell death,” said study author Douglas Green, PhD, of the St Jude Children’s Research Hospital in Memphis, Tennessee.

The results resolve long-standing questions about RIPK1’s role in cell survival and provide clues about how the immune system might use these pathways to contain infections.

The findings have also prompted the researchers to launch an investigation into whether RIPK1 could be harnessed to kill cancer cells or provide insight into tumor development.

“This study fundamentally changes the way we think about RIPK1, a molecule that we care about because it is required for life,” Dr Green said. “The results helped us identify new pathways involved in regulating programmed cell death and suggest that we might be able to develop cancer therapies that target these pathways or engage them in other ways to advance treatment of a range of diseases.”

The report builds on previous research from Dr Green’s lab regarding regulation of the pathways that control apoptosis and necroptosis. The investigators knew that apoptosis is driven by the enzyme caspase-8, which forms a complex with FADD and other proteins.

And necroptosis involves a pathway orchestrated by the enzyme receptor-interacting protein kinase 3 (RIPK3). Before birth, RIPK1 works through RIPK3 to trigger cell death by necroptosis, but, until now, the enzyme’s primary role after birth was uncertain.

So the investigators bred mice lacking different combinations of genes for RIPK1, RIPK3, caspase-8, FADD and other components of both the apoptotic and necroptotic pathways.

Mice lacking RIPK1 died. Mice missing 2 genes—RIPK1 plus RIPK3 or RIPK1 plus caspase-8 or FADD—also died soon after birth.

However, mice survived and developed normally when the investigators removed 3 genes—RIPK1, RIPK3, and either caspase-8 or FADD.

“The fact that the mice survived was totally unexpected and made us rethink how these pathways work,” Dr Green said.

The results also demonstrated that other pathways must exist in cells to maintain a balanced response to signals pushing for cell death via apoptosis or necroptosis.

Evidence in this study, for example, suggested one possible new pathway that triggered necroptosis using interferon and other elements of the immune response to infections.

Apoptosis in cancer cells

Credit: Egelberg

Investigators say they have solved the mystery of an enzyme’s role in cell survival, thereby offering clues as to how the immune system fights infection and pointing to possible strategies for treating cancers.

The enzyme, receptor-interacting protein kinase 1 (RIPK1), is known to play a pivotal role in survival after birth.

But the new research, published in Cell, reveals that RIPK1 inhibits the pathways that control apoptosis and necroptosis.

By removing different components of each pathway in different combinations, the investigators demonstrated that, after birth, RIPK1 helps cells maintain a balanced response to signals that promote either pathway.

“We are learning that, in disease, this balancing act can be perturbed to produce damage and cell death,” said study author Douglas Green, PhD, of the St Jude Children’s Research Hospital in Memphis, Tennessee.

The results resolve long-standing questions about RIPK1’s role in cell survival and provide clues about how the immune system might use these pathways to contain infections.

The findings have also prompted the researchers to launch an investigation into whether RIPK1 could be harnessed to kill cancer cells or provide insight into tumor development.

“This study fundamentally changes the way we think about RIPK1, a molecule that we care about because it is required for life,” Dr Green said. “The results helped us identify new pathways involved in regulating programmed cell death and suggest that we might be able to develop cancer therapies that target these pathways or engage them in other ways to advance treatment of a range of diseases.”

The report builds on previous research from Dr Green’s lab regarding regulation of the pathways that control apoptosis and necroptosis. The investigators knew that apoptosis is driven by the enzyme caspase-8, which forms a complex with FADD and other proteins.

And necroptosis involves a pathway orchestrated by the enzyme receptor-interacting protein kinase 3 (RIPK3). Before birth, RIPK1 works through RIPK3 to trigger cell death by necroptosis, but, until now, the enzyme’s primary role after birth was uncertain.

So the investigators bred mice lacking different combinations of genes for RIPK1, RIPK3, caspase-8, FADD and other components of both the apoptotic and necroptotic pathways.

Mice lacking RIPK1 died. Mice missing 2 genes—RIPK1 plus RIPK3 or RIPK1 plus caspase-8 or FADD—also died soon after birth.

However, mice survived and developed normally when the investigators removed 3 genes—RIPK1, RIPK3, and either caspase-8 or FADD.

“The fact that the mice survived was totally unexpected and made us rethink how these pathways work,” Dr Green said.

The results also demonstrated that other pathways must exist in cells to maintain a balanced response to signals pushing for cell death via apoptosis or necroptosis.

Evidence in this study, for example, suggested one possible new pathway that triggered necroptosis using interferon and other elements of the immune response to infections.

Apoptosis in cancer cells

Credit: Egelberg

Investigators say they have solved the mystery of an enzyme’s role in cell survival, thereby offering clues as to how the immune system fights infection and pointing to possible strategies for treating cancers.

The enzyme, receptor-interacting protein kinase 1 (RIPK1), is known to play a pivotal role in survival after birth.

But the new research, published in Cell, reveals that RIPK1 inhibits the pathways that control apoptosis and necroptosis.

By removing different components of each pathway in different combinations, the investigators demonstrated that, after birth, RIPK1 helps cells maintain a balanced response to signals that promote either pathway.

“We are learning that, in disease, this balancing act can be perturbed to produce damage and cell death,” said study author Douglas Green, PhD, of the St Jude Children’s Research Hospital in Memphis, Tennessee.

The results resolve long-standing questions about RIPK1’s role in cell survival and provide clues about how the immune system might use these pathways to contain infections.

The findings have also prompted the researchers to launch an investigation into whether RIPK1 could be harnessed to kill cancer cells or provide insight into tumor development.

“This study fundamentally changes the way we think about RIPK1, a molecule that we care about because it is required for life,” Dr Green said. “The results helped us identify new pathways involved in regulating programmed cell death and suggest that we might be able to develop cancer therapies that target these pathways or engage them in other ways to advance treatment of a range of diseases.”

The report builds on previous research from Dr Green’s lab regarding regulation of the pathways that control apoptosis and necroptosis. The investigators knew that apoptosis is driven by the enzyme caspase-8, which forms a complex with FADD and other proteins.

And necroptosis involves a pathway orchestrated by the enzyme receptor-interacting protein kinase 3 (RIPK3). Before birth, RIPK1 works through RIPK3 to trigger cell death by necroptosis, but, until now, the enzyme’s primary role after birth was uncertain.

So the investigators bred mice lacking different combinations of genes for RIPK1, RIPK3, caspase-8, FADD and other components of both the apoptotic and necroptotic pathways.

Mice lacking RIPK1 died. Mice missing 2 genes—RIPK1 plus RIPK3 or RIPK1 plus caspase-8 or FADD—also died soon after birth.

However, mice survived and developed normally when the investigators removed 3 genes—RIPK1, RIPK3, and either caspase-8 or FADD.

“The fact that the mice survived was totally unexpected and made us rethink how these pathways work,” Dr Green said.

The results also demonstrated that other pathways must exist in cells to maintain a balanced response to signals pushing for cell death via apoptosis or necroptosis.

Evidence in this study, for example, suggested one possible new pathway that triggered necroptosis using interferon and other elements of the immune response to infections.

Tumor cells producing p53

Credit: A.T. Tikhonenko

A novel sequencing technique has allowed researchers to identify direct targets of p53, providing new insight into this gene’s anticancer activity.

The research, published in eLife, revealed nearly 200 genes that were directly regulated by p53, and many of these had never been identified before.

The study’s authors said this work lays the foundation for investigations into which of these genes are necessary for p53’s cancer-killing effects and how cancer cells evade these genes.

The researchers noted that all cancers must deal with p53’s antitumor effects. Generally, there are 2 ways they do this: by mutating p53 directly or by producing the protein MDM2, which inhibits p53 function. With the current study, the team explored the second strategy.

“MDM2 inhibitors, which are through phase 1 human trials, effectively activate p53 but manage to kill only about 1 in 20 tumors,” said study author Joaquín Espinosa, PhD, of the University of Colorado in Boulder.

“The question is why. What else is happening in these cancer cells that allow them to evade p53?”

According to the researchers, the answer is in the downstream effects of p53. The gene sets in motion a cascade of events that lead to cancer cell destruction. But it has been unclear exactly which other genes are directly activated by p53.

To identify genetic targets of p53, Dr Espinosa and his colleagues used a technique called Global Run-On Sequencing (GRO-Seq). Unlike other methods, GRO-Seq measures new RNA being created, not overall RNA levels.

“Many teams around the world have been getting cancer cells, treating them with MDM2 inhibitors, and waiting hours and hours to see what genes turn on, and then, only imprecisely,” Dr Espinosa said. “GRO-Seq lets us do it in minutes, and the discoveries are massive.”

The technique generates a large quantity of data because it requires counting tens of thousands of RNA molecules before and after p53 activation. So this research required designing algorithms to sort through the data, as well as a computational biologist driving a supercomputer.

But the researchers were able to pinpoint new genes directly regulated by p53. And they believe this could aid the future development of cancer-fighting strategies.

Tumor cells producing p53

Credit: A.T. Tikhonenko

A novel sequencing technique has allowed researchers to identify direct targets of p53, providing new insight into this gene’s anticancer activity.

The research, published in eLife, revealed nearly 200 genes that were directly regulated by p53, and many of these had never been identified before.

The study’s authors said this work lays the foundation for investigations into which of these genes are necessary for p53’s cancer-killing effects and how cancer cells evade these genes.

The researchers noted that all cancers must deal with p53’s antitumor effects. Generally, there are 2 ways they do this: by mutating p53 directly or by producing the protein MDM2, which inhibits p53 function. With the current study, the team explored the second strategy.

“MDM2 inhibitors, which are through phase 1 human trials, effectively activate p53 but manage to kill only about 1 in 20 tumors,” said study author Joaquín Espinosa, PhD, of the University of Colorado in Boulder.

“The question is why. What else is happening in these cancer cells that allow them to evade p53?”

According to the researchers, the answer is in the downstream effects of p53. The gene sets in motion a cascade of events that lead to cancer cell destruction. But it has been unclear exactly which other genes are directly activated by p53.

To identify genetic targets of p53, Dr Espinosa and his colleagues used a technique called Global Run-On Sequencing (GRO-Seq). Unlike other methods, GRO-Seq measures new RNA being created, not overall RNA levels.

“Many teams around the world have been getting cancer cells, treating them with MDM2 inhibitors, and waiting hours and hours to see what genes turn on, and then, only imprecisely,” Dr Espinosa said. “GRO-Seq lets us do it in minutes, and the discoveries are massive.”

The technique generates a large quantity of data because it requires counting tens of thousands of RNA molecules before and after p53 activation. So this research required designing algorithms to sort through the data, as well as a computational biologist driving a supercomputer.

But the researchers were able to pinpoint new genes directly regulated by p53. And they believe this could aid the future development of cancer-fighting strategies.

Tumor cells producing p53

Credit: A.T. Tikhonenko

A novel sequencing technique has allowed researchers to identify direct targets of p53, providing new insight into this gene’s anticancer activity.

The research, published in eLife, revealed nearly 200 genes that were directly regulated by p53, and many of these had never been identified before.

The study’s authors said this work lays the foundation for investigations into which of these genes are necessary for p53’s cancer-killing effects and how cancer cells evade these genes.

The researchers noted that all cancers must deal with p53’s antitumor effects. Generally, there are 2 ways they do this: by mutating p53 directly or by producing the protein MDM2, which inhibits p53 function. With the current study, the team explored the second strategy.

“MDM2 inhibitors, which are through phase 1 human trials, effectively activate p53 but manage to kill only about 1 in 20 tumors,” said study author Joaquín Espinosa, PhD, of the University of Colorado in Boulder.

“The question is why. What else is happening in these cancer cells that allow them to evade p53?”

According to the researchers, the answer is in the downstream effects of p53. The gene sets in motion a cascade of events that lead to cancer cell destruction. But it has been unclear exactly which other genes are directly activated by p53.

To identify genetic targets of p53, Dr Espinosa and his colleagues used a technique called Global Run-On Sequencing (GRO-Seq). Unlike other methods, GRO-Seq measures new RNA being created, not overall RNA levels.

“Many teams around the world have been getting cancer cells, treating them with MDM2 inhibitors, and waiting hours and hours to see what genes turn on, and then, only imprecisely,” Dr Espinosa said. “GRO-Seq lets us do it in minutes, and the discoveries are massive.”

The technique generates a large quantity of data because it requires counting tens of thousands of RNA molecules before and after p53 activation. So this research required designing algorithms to sort through the data, as well as a computational biologist driving a supercomputer.

But the researchers were able to pinpoint new genes directly regulated by p53. And they believe this could aid the future development of cancer-fighting strategies.

CHICAGO – More than 10 years on, nearly one-fourth of patients with gastrointestinal stromal tumors treated initially with imatinib are still alive, according to results from a collaborative trial reported at the annual meeting of the American Society of Clinical Oncology.

"A significant fraction of patients can survive for more than 10 years with imatinib [Gleevec] as their initial therapy for advanced GIST; and for almost half as their only systemic therapy for advanced GIST, understanding the pathobiology of these exceptional outcomes will be important to understanding the disease better," said Dr. George Demetri, director of the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston.

In the 14 years that have ensued since the first patient with GIST received imatinib and had an "extraordinary" response, new drugs in the tyrosine kinase inhibitor (TKI) class have become available for patients whose disease has progressed on the TKI imatinib. The evolution in the treatment of GIST emphasizes the fact that overall survival as a trial endpoint is really "a composite endpoint of on-study and poststudy interventions," Dr. Demetri said at meeting.

In the phase III Southwest Oncology Group (SWOG) Intergroup S0033 trial, initiated in 2000, 746 patients with metastatic or unresectable GIST were randomly assigned to receive daily imatinib at a dose of either 400 mg or 800 mg (400 mg twice daily). Patients in the 400-mg qd group had the option of crossing over to the 800-mg dose at the time of disease progression, and 130 patients chose to do so.

The trial was sparked by the discovery by Japanese investigators in 1998 of gain-of-function mutations in the gene encoding for KIT kinase.

As the SWOG S0033 investigators reported in 2008, median progression-free survival at a median follow-up of 4.5 years was 18 months for patients on the 400-mg dose and 20 months for those receiving 800 mg. The median overall survival was 55 months for patients in the 400-mg arm and 51 months for those in the 800-mg arm.

"A question we ask ourselves is, what accounts for this 33-month survival median difference after objective disease progression? It seems like a long time, which is why we wanted to know what happened to these patients after progression," Dr. Demetri said.

The investigators looked at survival by mutational status. Data on the GIST genotype were available on 395 patients, 282 of whom (71%) had KIT exon 11 mutations, 32 of whom (8%) had KIT exon 9 mutations, and 14 (4%) had other KIT or PDGFRA (platelet-derived growth factor receptor–alpha) mutations. Another 67 patients (17%) had no detectable KIT or PDGFRA mutations.

An analysis of data on these patients at 4.5 months’ median follow-up showed that patients with KIT exon 11 mutations had significantly better overall survival than patients with either wild-type (no mutation) KIT (P = .0011) or exon 9 mutations (P = .049).

Updated data with follow-up out to 10 years shows that patients with the KIT exon 9 mutation had significantly worse overall survival than patients with either exon 11 mutations (P = .0001) or no mutations (P = .047). There was no significant difference between patients with exon 11 mutations and no KIT or PDGFRA mutations.

Other factors significantly associated with overall survival in multivariate analysis included age by decade, male sex, performance status, maximum tumor diameter, and serum albumin (3.5 g/dL or less vs. more than 3.5 g/dL).

An analysis of on-study and postprogression therapies among 137 of 180 long-term survivors (8 years and longer) showed that 67 of the 137 (49%) had taken imatinib continuously as the only long-term therapy.

The remaining 70 patients (51%) had some additional therapy, including systemic therapies such as sunitinib (Sutent; 30% of the 137 patients), sorafenib (Nexavar; 12%), and other agents (31%).

In addition, 41 patients (30%) had metastasectomy or other type of surgery, 10 (7%) had radiofrequency ablation of tumors, and 6 (4%) had radiation therapy.

"We know that the landscape of therapeutic options for GIST has evolved greatly since this early large-scale study. We have new TKI therapies like sunitinib, sorafenib, and regorafenib [Stivarga], which has been approved for patients following progression of first-line imatinib, and we now accept the fact that multidisciplinary management of GIST, with resection of limited sites of oligoclonal resistant disease, is a standard option, with continuation of TKI therapy to control residual, unresectable disease," he said.

"Nonetheless , what the survival curves show us is that new options for management of KIT exon 9 mutant and other resistant genotypes are still needed," he concluded.

Dr. Jon Trent, director of the bone and soft-tissue program at the University of Miami Sylvester Cancer Center, the invited discussant, commented that "molecular subtyping should be required for all GIST patients."

"Most of all, I think we really need a tool other than the current version of RECIST [Response Evaluation Criteria in Solid Tumors], in order to really identify early makers of response and early markers of progression in our GIST patients," he said.

RECIST criteria often fail to provide useful information about early responses to therapy in GIST, he said.

The study was supported by the National Cancer Institute. Dr. Demetri disclosed serving as a consultant or adviser to ARIAD, Bayer, Novartis, and Pfizer; receiving research funding from Bayer, Novartis, and Pfizer; and receiving other remuneration from Novartis. Dr. Trent disclosed consulting/advising for Ariad, Bayer/Onyx, Novartis, and Pfizer, and receiving honoraria from Pfizer.

CHICAGO – More than 10 years on, nearly one-fourth of patients with gastrointestinal stromal tumors treated initially with imatinib are still alive, according to results from a collaborative trial reported at the annual meeting of the American Society of Clinical Oncology.

"A significant fraction of patients can survive for more than 10 years with imatinib [Gleevec] as their initial therapy for advanced GIST; and for almost half as their only systemic therapy for advanced GIST, understanding the pathobiology of these exceptional outcomes will be important to understanding the disease better," said Dr. George Demetri, director of the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston.

In the 14 years that have ensued since the first patient with GIST received imatinib and had an "extraordinary" response, new drugs in the tyrosine kinase inhibitor (TKI) class have become available for patients whose disease has progressed on the TKI imatinib. The evolution in the treatment of GIST emphasizes the fact that overall survival as a trial endpoint is really "a composite endpoint of on-study and poststudy interventions," Dr. Demetri said at meeting.

In the phase III Southwest Oncology Group (SWOG) Intergroup S0033 trial, initiated in 2000, 746 patients with metastatic or unresectable GIST were randomly assigned to receive daily imatinib at a dose of either 400 mg or 800 mg (400 mg twice daily). Patients in the 400-mg qd group had the option of crossing over to the 800-mg dose at the time of disease progression, and 130 patients chose to do so.

The trial was sparked by the discovery by Japanese investigators in 1998 of gain-of-function mutations in the gene encoding for KIT kinase.

As the SWOG S0033 investigators reported in 2008, median progression-free survival at a median follow-up of 4.5 years was 18 months for patients on the 400-mg dose and 20 months for those receiving 800 mg. The median overall survival was 55 months for patients in the 400-mg arm and 51 months for those in the 800-mg arm.

"A question we ask ourselves is, what accounts for this 33-month survival median difference after objective disease progression? It seems like a long time, which is why we wanted to know what happened to these patients after progression," Dr. Demetri said.

The investigators looked at survival by mutational status. Data on the GIST genotype were available on 395 patients, 282 of whom (71%) had KIT exon 11 mutations, 32 of whom (8%) had KIT exon 9 mutations, and 14 (4%) had other KIT or PDGFRA (platelet-derived growth factor receptor–alpha) mutations. Another 67 patients (17%) had no detectable KIT or PDGFRA mutations.

An analysis of data on these patients at 4.5 months’ median follow-up showed that patients with KIT exon 11 mutations had significantly better overall survival than patients with either wild-type (no mutation) KIT (P = .0011) or exon 9 mutations (P = .049).

Updated data with follow-up out to 10 years shows that patients with the KIT exon 9 mutation had significantly worse overall survival than patients with either exon 11 mutations (P = .0001) or no mutations (P = .047). There was no significant difference between patients with exon 11 mutations and no KIT or PDGFRA mutations.

Other factors significantly associated with overall survival in multivariate analysis included age by decade, male sex, performance status, maximum tumor diameter, and serum albumin (3.5 g/dL or less vs. more than 3.5 g/dL).

An analysis of on-study and postprogression therapies among 137 of 180 long-term survivors (8 years and longer) showed that 67 of the 137 (49%) had taken imatinib continuously as the only long-term therapy.

The remaining 70 patients (51%) had some additional therapy, including systemic therapies such as sunitinib (Sutent; 30% of the 137 patients), sorafenib (Nexavar; 12%), and other agents (31%).

In addition, 41 patients (30%) had metastasectomy or other type of surgery, 10 (7%) had radiofrequency ablation of tumors, and 6 (4%) had radiation therapy.

"We know that the landscape of therapeutic options for GIST has evolved greatly since this early large-scale study. We have new TKI therapies like sunitinib, sorafenib, and regorafenib [Stivarga], which has been approved for patients following progression of first-line imatinib, and we now accept the fact that multidisciplinary management of GIST, with resection of limited sites of oligoclonal resistant disease, is a standard option, with continuation of TKI therapy to control residual, unresectable disease," he said.

"Nonetheless , what the survival curves show us is that new options for management of KIT exon 9 mutant and other resistant genotypes are still needed," he concluded.

Dr. Jon Trent, director of the bone and soft-tissue program at the University of Miami Sylvester Cancer Center, the invited discussant, commented that "molecular subtyping should be required for all GIST patients."

"Most of all, I think we really need a tool other than the current version of RECIST [Response Evaluation Criteria in Solid Tumors], in order to really identify early makers of response and early markers of progression in our GIST patients," he said.

RECIST criteria often fail to provide useful information about early responses to therapy in GIST, he said.

The study was supported by the National Cancer Institute. Dr. Demetri disclosed serving as a consultant or adviser to ARIAD, Bayer, Novartis, and Pfizer; receiving research funding from Bayer, Novartis, and Pfizer; and receiving other remuneration from Novartis. Dr. Trent disclosed consulting/advising for Ariad, Bayer/Onyx, Novartis, and Pfizer, and receiving honoraria from Pfizer.

CHICAGO – More than 10 years on, nearly one-fourth of patients with gastrointestinal stromal tumors treated initially with imatinib are still alive, according to results from a collaborative trial reported at the annual meeting of the American Society of Clinical Oncology.

"A significant fraction of patients can survive for more than 10 years with imatinib [Gleevec] as their initial therapy for advanced GIST; and for almost half as their only systemic therapy for advanced GIST, understanding the pathobiology of these exceptional outcomes will be important to understanding the disease better," said Dr. George Demetri, director of the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston.

In the 14 years that have ensued since the first patient with GIST received imatinib and had an "extraordinary" response, new drugs in the tyrosine kinase inhibitor (TKI) class have become available for patients whose disease has progressed on the TKI imatinib. The evolution in the treatment of GIST emphasizes the fact that overall survival as a trial endpoint is really "a composite endpoint of on-study and poststudy interventions," Dr. Demetri said at meeting.

In the phase III Southwest Oncology Group (SWOG) Intergroup S0033 trial, initiated in 2000, 746 patients with metastatic or unresectable GIST were randomly assigned to receive daily imatinib at a dose of either 400 mg or 800 mg (400 mg twice daily). Patients in the 400-mg qd group had the option of crossing over to the 800-mg dose at the time of disease progression, and 130 patients chose to do so.

The trial was sparked by the discovery by Japanese investigators in 1998 of gain-of-function mutations in the gene encoding for KIT kinase.

As the SWOG S0033 investigators reported in 2008, median progression-free survival at a median follow-up of 4.5 years was 18 months for patients on the 400-mg dose and 20 months for those receiving 800 mg. The median overall survival was 55 months for patients in the 400-mg arm and 51 months for those in the 800-mg arm.

"A question we ask ourselves is, what accounts for this 33-month survival median difference after objective disease progression? It seems like a long time, which is why we wanted to know what happened to these patients after progression," Dr. Demetri said.

The investigators looked at survival by mutational status. Data on the GIST genotype were available on 395 patients, 282 of whom (71%) had KIT exon 11 mutations, 32 of whom (8%) had KIT exon 9 mutations, and 14 (4%) had other KIT or PDGFRA (platelet-derived growth factor receptor–alpha) mutations. Another 67 patients (17%) had no detectable KIT or PDGFRA mutations.

An analysis of data on these patients at 4.5 months’ median follow-up showed that patients with KIT exon 11 mutations had significantly better overall survival than patients with either wild-type (no mutation) KIT (P = .0011) or exon 9 mutations (P = .049).

Updated data with follow-up out to 10 years shows that patients with the KIT exon 9 mutation had significantly worse overall survival than patients with either exon 11 mutations (P = .0001) or no mutations (P = .047). There was no significant difference between patients with exon 11 mutations and no KIT or PDGFRA mutations.

Other factors significantly associated with overall survival in multivariate analysis included age by decade, male sex, performance status, maximum tumor diameter, and serum albumin (3.5 g/dL or less vs. more than 3.5 g/dL).

An analysis of on-study and postprogression therapies among 137 of 180 long-term survivors (8 years and longer) showed that 67 of the 137 (49%) had taken imatinib continuously as the only long-term therapy.

The remaining 70 patients (51%) had some additional therapy, including systemic therapies such as sunitinib (Sutent; 30% of the 137 patients), sorafenib (Nexavar; 12%), and other agents (31%).

In addition, 41 patients (30%) had metastasectomy or other type of surgery, 10 (7%) had radiofrequency ablation of tumors, and 6 (4%) had radiation therapy.

"We know that the landscape of therapeutic options for GIST has evolved greatly since this early large-scale study. We have new TKI therapies like sunitinib, sorafenib, and regorafenib [Stivarga], which has been approved for patients following progression of first-line imatinib, and we now accept the fact that multidisciplinary management of GIST, with resection of limited sites of oligoclonal resistant disease, is a standard option, with continuation of TKI therapy to control residual, unresectable disease," he said.

"Nonetheless , what the survival curves show us is that new options for management of KIT exon 9 mutant and other resistant genotypes are still needed," he concluded.

Dr. Jon Trent, director of the bone and soft-tissue program at the University of Miami Sylvester Cancer Center, the invited discussant, commented that "molecular subtyping should be required for all GIST patients."

"Most of all, I think we really need a tool other than the current version of RECIST [Response Evaluation Criteria in Solid Tumors], in order to really identify early makers of response and early markers of progression in our GIST patients," he said.

RECIST criteria often fail to provide useful information about early responses to therapy in GIST, he said.

The study was supported by the National Cancer Institute. Dr. Demetri disclosed serving as a consultant or adviser to ARIAD, Bayer, Novartis, and Pfizer; receiving research funding from Bayer, Novartis, and Pfizer; and receiving other remuneration from Novartis. Dr. Trent disclosed consulting/advising for Ariad, Bayer/Onyx, Novartis, and Pfizer, and receiving honoraria from Pfizer.

Nonforensic psychiatrists in private practice rarely expect to be dealing with patients involved in the correctional system, but unexpected things happen even with the most carefully chosen patients. I’m writing this column to offer guidance to clinicians facing this situation for the first time, based upon the most common questions I get asked.

The most common situation I hear about is that a patient has missed an appointment, and the clinician hears from a family member that the patient has been arrested. The conscientious doctor wants to make sure that his seriously mentally ill client doesn’t experience an interruption in treatment, and that an appointment will be ready after release. The first challenge is to locate the patient.

In small communities, or when a family member was present at the time of arrest, it’s relatively easy to figure out which detention center or jail the patient was taken to. If the patient was arrested in a large urban area, or even out of state, this can be more of a challenge. Fortunately, many states and even now some local county or city jurisdictions have inmate locator web pages. The website will provide search capabilities to identify anyone currently in custody, and will generally provide a unique booking or inmate number that should be used in any facility communication, along with a date of birth and the address of the facility. Be aware that a large jail with high turnover may not have real-time data capability, meaning that new arrests may not show up on the website for 24 hours.

For psychiatrists who spend a lot of time tracking down their patients in custody, there is even an iPhone- and Android-compatible app called MobilePatrol, which provides a convenient interface to many inmate locator databases nationwide. MobilePatrol does not provide information about charges or date of birth, so it’s mainly useful if the patient can be identified by age and has a unique name.

The next step is to ensure that the patient has been identified as needing psychiatric care within the facility. Almost all jails and prisons now have routine multilevel screens to identify arrestees with chronic medical or mental health needs, and to assess suicide risk at intake. This is required by any jail or prison accredited by the National Commission on Correctional Health Care. Nevertheless, some patients are reluctant to self-identify out of fear they might be inappropriately or precipitously thrown into a suicide observation cell.

When it comes to transmitting information to a correctional facility, don’t rely on custody staff. They aren’t clinicians, they change with every shift, and they won’t know what questions to ask about the patient. This includes the warden’s office. The best thing to do is call the psychology department to transmit the patient’s name, date of birth, jail or prison number, and any pertinent clinical information. Don’t rely on an administrative assistant or nonmedical therapist to do this for you – I can’t tell you the number of times I’ve gotten a message that "...John Doe is in your jail and he needs to be seen..." with absolutely no information about medication names, dosage, and frequency, or even a diagnosis! An initial phone call will ensure that the patient is found within the facility and scheduled to see the institutional psychiatrist.

Follow the phone call up with a letter. This will ensure that the clinical information is still available on the day the psychiatrist comes in, and for the next institutional physician if the patient is transferred to another facility. The letter should summarize pertinent symptoms, violence or suicide risk factors, and previous medication trials. The past med trial information is particularly important for correctional psychiatrists, given that many jails and prisons require "fail-first" prescribing policies. Outside documentation that supports a current nonformulary medication regimen can be crucial to ensuring a smooth transition of care. But please, resist the temptation to reprimand the correctional psychiatrist in advance for making a medication change – there are many valid clinical reasons for a correctional psychiatrist to alter a treatment regimen upon arrest that have nothing to do with formulary issues.

Finally, encourage the patient’s family members to maintain contact with their incarcerated loved one if that relationship is healthy and supportive. No one knows a patient better than those in his own household, and a family member can be particularly sensitive to early signs of relapse sometimes through nothing more than a patient’s tone of voice during a phone call. Give the primary caregivers contact information for the institutional psychology department and encourage them to call if they observe anything concerning during a visit or court appearance. Court dates are particularly stressful times and may serve as a crisis point for a suicidal inmate. Having an extra pair of eyes on the scene could be lifesaving.

Once the patient has been identified and referred, and treatment started, your job is done until release. For misdemeanor offenders in local detention, this could take place within days or a few weeks, or even the day of arrest if the patient is able to make bail. Following the steps I’ve recommended to ensure continuity of care will help your patient return to you in at least as good a condition as when he came in.

Dr. Hanson is a forensic psychiatrist and coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: The Johns Hopkins University Press, 2011). The opinions expressed are those of the author only, and do not represent those of any of Dr. Hanson’s employers or consultees, including the Maryland Department of Health and Mental Hygiene or the Maryland Division of Correction.

Nonforensic psychiatrists in private practice rarely expect to be dealing with patients involved in the correctional system, but unexpected things happen even with the most carefully chosen patients. I’m writing this column to offer guidance to clinicians facing this situation for the first time, based upon the most common questions I get asked.

The most common situation I hear about is that a patient has missed an appointment, and the clinician hears from a family member that the patient has been arrested. The conscientious doctor wants to make sure that his seriously mentally ill client doesn’t experience an interruption in treatment, and that an appointment will be ready after release. The first challenge is to locate the patient.

In small communities, or when a family member was present at the time of arrest, it’s relatively easy to figure out which detention center or jail the patient was taken to. If the patient was arrested in a large urban area, or even out of state, this can be more of a challenge. Fortunately, many states and even now some local county or city jurisdictions have inmate locator web pages. The website will provide search capabilities to identify anyone currently in custody, and will generally provide a unique booking or inmate number that should be used in any facility communication, along with a date of birth and the address of the facility. Be aware that a large jail with high turnover may not have real-time data capability, meaning that new arrests may not show up on the website for 24 hours.

For psychiatrists who spend a lot of time tracking down their patients in custody, there is even an iPhone- and Android-compatible app called MobilePatrol, which provides a convenient interface to many inmate locator databases nationwide. MobilePatrol does not provide information about charges or date of birth, so it’s mainly useful if the patient can be identified by age and has a unique name.

The next step is to ensure that the patient has been identified as needing psychiatric care within the facility. Almost all jails and prisons now have routine multilevel screens to identify arrestees with chronic medical or mental health needs, and to assess suicide risk at intake. This is required by any jail or prison accredited by the National Commission on Correctional Health Care. Nevertheless, some patients are reluctant to self-identify out of fear they might be inappropriately or precipitously thrown into a suicide observation cell.

When it comes to transmitting information to a correctional facility, don’t rely on custody staff. They aren’t clinicians, they change with every shift, and they won’t know what questions to ask about the patient. This includes the warden’s office. The best thing to do is call the psychology department to transmit the patient’s name, date of birth, jail or prison number, and any pertinent clinical information. Don’t rely on an administrative assistant or nonmedical therapist to do this for you – I can’t tell you the number of times I’ve gotten a message that "...John Doe is in your jail and he needs to be seen..." with absolutely no information about medication names, dosage, and frequency, or even a diagnosis! An initial phone call will ensure that the patient is found within the facility and scheduled to see the institutional psychiatrist.

Follow the phone call up with a letter. This will ensure that the clinical information is still available on the day the psychiatrist comes in, and for the next institutional physician if the patient is transferred to another facility. The letter should summarize pertinent symptoms, violence or suicide risk factors, and previous medication trials. The past med trial information is particularly important for correctional psychiatrists, given that many jails and prisons require "fail-first" prescribing policies. Outside documentation that supports a current nonformulary medication regimen can be crucial to ensuring a smooth transition of care. But please, resist the temptation to reprimand the correctional psychiatrist in advance for making a medication change – there are many valid clinical reasons for a correctional psychiatrist to alter a treatment regimen upon arrest that have nothing to do with formulary issues.

Finally, encourage the patient’s family members to maintain contact with their incarcerated loved one if that relationship is healthy and supportive. No one knows a patient better than those in his own household, and a family member can be particularly sensitive to early signs of relapse sometimes through nothing more than a patient’s tone of voice during a phone call. Give the primary caregivers contact information for the institutional psychology department and encourage them to call if they observe anything concerning during a visit or court appearance. Court dates are particularly stressful times and may serve as a crisis point for a suicidal inmate. Having an extra pair of eyes on the scene could be lifesaving.

Once the patient has been identified and referred, and treatment started, your job is done until release. For misdemeanor offenders in local detention, this could take place within days or a few weeks, or even the day of arrest if the patient is able to make bail. Following the steps I’ve recommended to ensure continuity of care will help your patient return to you in at least as good a condition as when he came in.

Dr. Hanson is a forensic psychiatrist and coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: The Johns Hopkins University Press, 2011). The opinions expressed are those of the author only, and do not represent those of any of Dr. Hanson’s employers or consultees, including the Maryland Department of Health and Mental Hygiene or the Maryland Division of Correction.

Nonforensic psychiatrists in private practice rarely expect to be dealing with patients involved in the correctional system, but unexpected things happen even with the most carefully chosen patients. I’m writing this column to offer guidance to clinicians facing this situation for the first time, based upon the most common questions I get asked.

The most common situation I hear about is that a patient has missed an appointment, and the clinician hears from a family member that the patient has been arrested. The conscientious doctor wants to make sure that his seriously mentally ill client doesn’t experience an interruption in treatment, and that an appointment will be ready after release. The first challenge is to locate the patient.

In small communities, or when a family member was present at the time of arrest, it’s relatively easy to figure out which detention center or jail the patient was taken to. If the patient was arrested in a large urban area, or even out of state, this can be more of a challenge. Fortunately, many states and even now some local county or city jurisdictions have inmate locator web pages. The website will provide search capabilities to identify anyone currently in custody, and will generally provide a unique booking or inmate number that should be used in any facility communication, along with a date of birth and the address of the facility. Be aware that a large jail with high turnover may not have real-time data capability, meaning that new arrests may not show up on the website for 24 hours.

For psychiatrists who spend a lot of time tracking down their patients in custody, there is even an iPhone- and Android-compatible app called MobilePatrol, which provides a convenient interface to many inmate locator databases nationwide. MobilePatrol does not provide information about charges or date of birth, so it’s mainly useful if the patient can be identified by age and has a unique name.

The next step is to ensure that the patient has been identified as needing psychiatric care within the facility. Almost all jails and prisons now have routine multilevel screens to identify arrestees with chronic medical or mental health needs, and to assess suicide risk at intake. This is required by any jail or prison accredited by the National Commission on Correctional Health Care. Nevertheless, some patients are reluctant to self-identify out of fear they might be inappropriately or precipitously thrown into a suicide observation cell.

When it comes to transmitting information to a correctional facility, don’t rely on custody staff. They aren’t clinicians, they change with every shift, and they won’t know what questions to ask about the patient. This includes the warden’s office. The best thing to do is call the psychology department to transmit the patient’s name, date of birth, jail or prison number, and any pertinent clinical information. Don’t rely on an administrative assistant or nonmedical therapist to do this for you – I can’t tell you the number of times I’ve gotten a message that "...John Doe is in your jail and he needs to be seen..." with absolutely no information about medication names, dosage, and frequency, or even a diagnosis! An initial phone call will ensure that the patient is found within the facility and scheduled to see the institutional psychiatrist.

Follow the phone call up with a letter. This will ensure that the clinical information is still available on the day the psychiatrist comes in, and for the next institutional physician if the patient is transferred to another facility. The letter should summarize pertinent symptoms, violence or suicide risk factors, and previous medication trials. The past med trial information is particularly important for correctional psychiatrists, given that many jails and prisons require "fail-first" prescribing policies. Outside documentation that supports a current nonformulary medication regimen can be crucial to ensuring a smooth transition of care. But please, resist the temptation to reprimand the correctional psychiatrist in advance for making a medication change – there are many valid clinical reasons for a correctional psychiatrist to alter a treatment regimen upon arrest that have nothing to do with formulary issues.

Finally, encourage the patient’s family members to maintain contact with their incarcerated loved one if that relationship is healthy and supportive. No one knows a patient better than those in his own household, and a family member can be particularly sensitive to early signs of relapse sometimes through nothing more than a patient’s tone of voice during a phone call. Give the primary caregivers contact information for the institutional psychology department and encourage them to call if they observe anything concerning during a visit or court appearance. Court dates are particularly stressful times and may serve as a crisis point for a suicidal inmate. Having an extra pair of eyes on the scene could be lifesaving.

Once the patient has been identified and referred, and treatment started, your job is done until release. For misdemeanor offenders in local detention, this could take place within days or a few weeks, or even the day of arrest if the patient is able to make bail. Following the steps I’ve recommended to ensure continuity of care will help your patient return to you in at least as good a condition as when he came in.

Dr. Hanson is a forensic psychiatrist and coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: The Johns Hopkins University Press, 2011). The opinions expressed are those of the author only, and do not represent those of any of Dr. Hanson’s employers or consultees, including the Maryland Department of Health and Mental Hygiene or the Maryland Division of Correction.

MRI scanner

Results of a new study indicate that MRI and mammography can detect invasive breast tumors at very early stages in female survivors of Hodgkin lymphoma (HL).

Researchers said the findings underscore the need for at-risk childhood HL survivors and their physicians to be aware of screening guidelines.

The guidelines recommend survivors undergo breast MRI screening beginning at age 25 or 8 years after they received chest radiation, whichever is later.

“Female survivors of childhood HL who had chest radiation should speak with their family doctor about after-care assessment and breast cancer screening,” said David Hodgson, MD, of Princess Margaret Cancer Centre in Toronto, Canada.

“We estimate that 75% of women who are at high risk because of prior radiotherapy to the chest are not being screened. So my hope is that this new evidence will encourage these survivors to discuss early screening with their doctors.”

Dr Hodgson and his colleagues reported this evidence in Cancer.

The researchers evaluated the results of breast MRI and mammography screening among 96 female survivors of childhood HL who had been treated with chest radiotherapy.

The median patient age at first screening was 30 years, and the median number of MRI screening rounds was 3. Ten breast cancers—half of them invasive tumors—were diagnosed in 9 women during 363 person-years follow up.

The median age at breast cancer diagnosis was 39 years (range, 24 to 43 years), and the median latency period between HL diagnosis and age at breast cancer diagnoses was 21 years (range, 12 to 27 years).

“This illustrates the young age at which these cancers can occur,” Dr Hodgson said. “For some of these women, if they had been screened starting at age 40 or 50, like average-risk women, it would have been too late.”

MRI alone detected tumors with 80% sensitivity and 93.5% specificity. Mammography alone detected tumors with 70% sensitivity and 95% specificity. And both modalities combined detected tumors with 100% sensitivity and 88.6% specificity. All invasive tumors were detected by MRI.

In other words, of the 10 breast tumors, 5 were visible on both MRI and mammogram, 3 were visible only on MRI, and 2 were detected via mammogram alone (but were non-invasive). The median size of invasive tumors size was 8 mm (range, 3-15 mm), and none had spread to the lymph nodes.

The researchers noted that these results are substantially better than prior studies using only mammographic screening in young patients.

Dr Hodgson also pointed out that, because MRI screening is so much more sensitive to small changes in the appearance of the breast tissue than mammography, up to a third of patients may be called back for further testing of suspicious findings. But many of these are benign or not clinically significant and, therefore, require no treatment.

MRI scanner

Results of a new study indicate that MRI and mammography can detect invasive breast tumors at very early stages in female survivors of Hodgkin lymphoma (HL).

Researchers said the findings underscore the need for at-risk childhood HL survivors and their physicians to be aware of screening guidelines.

The guidelines recommend survivors undergo breast MRI screening beginning at age 25 or 8 years after they received chest radiation, whichever is later.

“Female survivors of childhood HL who had chest radiation should speak with their family doctor about after-care assessment and breast cancer screening,” said David Hodgson, MD, of Princess Margaret Cancer Centre in Toronto, Canada.

“We estimate that 75% of women who are at high risk because of prior radiotherapy to the chest are not being screened. So my hope is that this new evidence will encourage these survivors to discuss early screening with their doctors.”

Dr Hodgson and his colleagues reported this evidence in Cancer.

The researchers evaluated the results of breast MRI and mammography screening among 96 female survivors of childhood HL who had been treated with chest radiotherapy.

The median patient age at first screening was 30 years, and the median number of MRI screening rounds was 3. Ten breast cancers—half of them invasive tumors—were diagnosed in 9 women during 363 person-years follow up.

The median age at breast cancer diagnosis was 39 years (range, 24 to 43 years), and the median latency period between HL diagnosis and age at breast cancer diagnoses was 21 years (range, 12 to 27 years).

“This illustrates the young age at which these cancers can occur,” Dr Hodgson said. “For some of these women, if they had been screened starting at age 40 or 50, like average-risk women, it would have been too late.”

MRI alone detected tumors with 80% sensitivity and 93.5% specificity. Mammography alone detected tumors with 70% sensitivity and 95% specificity. And both modalities combined detected tumors with 100% sensitivity and 88.6% specificity. All invasive tumors were detected by MRI.

In other words, of the 10 breast tumors, 5 were visible on both MRI and mammogram, 3 were visible only on MRI, and 2 were detected via mammogram alone (but were non-invasive). The median size of invasive tumors size was 8 mm (range, 3-15 mm), and none had spread to the lymph nodes.

The researchers noted that these results are substantially better than prior studies using only mammographic screening in young patients.

Dr Hodgson also pointed out that, because MRI screening is so much more sensitive to small changes in the appearance of the breast tissue than mammography, up to a third of patients may be called back for further testing of suspicious findings. But many of these are benign or not clinically significant and, therefore, require no treatment.

MRI scanner

Results of a new study indicate that MRI and mammography can detect invasive breast tumors at very early stages in female survivors of Hodgkin lymphoma (HL).

Researchers said the findings underscore the need for at-risk childhood HL survivors and their physicians to be aware of screening guidelines.

The guidelines recommend survivors undergo breast MRI screening beginning at age 25 or 8 years after they received chest radiation, whichever is later.

“Female survivors of childhood HL who had chest radiation should speak with their family doctor about after-care assessment and breast cancer screening,” said David Hodgson, MD, of Princess Margaret Cancer Centre in Toronto, Canada.

“We estimate that 75% of women who are at high risk because of prior radiotherapy to the chest are not being screened. So my hope is that this new evidence will encourage these survivors to discuss early screening with their doctors.”

Dr Hodgson and his colleagues reported this evidence in Cancer.

The researchers evaluated the results of breast MRI and mammography screening among 96 female survivors of childhood HL who had been treated with chest radiotherapy.

The median patient age at first screening was 30 years, and the median number of MRI screening rounds was 3. Ten breast cancers—half of them invasive tumors—were diagnosed in 9 women during 363 person-years follow up.

The median age at breast cancer diagnosis was 39 years (range, 24 to 43 years), and the median latency period between HL diagnosis and age at breast cancer diagnoses was 21 years (range, 12 to 27 years).

“This illustrates the young age at which these cancers can occur,” Dr Hodgson said. “For some of these women, if they had been screened starting at age 40 or 50, like average-risk women, it would have been too late.”

MRI alone detected tumors with 80% sensitivity and 93.5% specificity. Mammography alone detected tumors with 70% sensitivity and 95% specificity. And both modalities combined detected tumors with 100% sensitivity and 88.6% specificity. All invasive tumors were detected by MRI.

In other words, of the 10 breast tumors, 5 were visible on both MRI and mammogram, 3 were visible only on MRI, and 2 were detected via mammogram alone (but were non-invasive). The median size of invasive tumors size was 8 mm (range, 3-15 mm), and none had spread to the lymph nodes.

The researchers noted that these results are substantially better than prior studies using only mammographic screening in young patients.

Dr Hodgson also pointed out that, because MRI screening is so much more sensitive to small changes in the appearance of the breast tissue than mammography, up to a third of patients may be called back for further testing of suspicious findings. But many of these are benign or not clinically significant and, therefore, require no treatment.