I got a phone call recently from a friend north of me. “Gosh, did you hear about the State of Ohio Board of Pharmacy ransacking a dermatologist’s office?” he asked. Yes, I had heard about it, and explained that the office compounding rule in Ohio, the reason behind this surprise search and practice, was the subject of an active struggle going on at the state and federal level (see “Beware the state pharmacy board,” Dermatology News, June 3, 2016). I also told him that the pharmacy board swooped into that location because the office had registered for a license to mix drugs (defined by the board as altering a prescription drug by mixing, diluting, or combining), and agreed to unannounced inspections – and that while the dermatologist was not fined, there was a list of compliance issues to be met, including recording the lot number of all samples, keeping separate paper records of each time he mixed medications, and the promise of a return visit soon.

I went on to explain that representatives – past presidents and board members – of the Ohio Dermatological Association (accompanied by Lisa Albany, director of state policy at the American Academy of Dermatology’s Washington office) had met with the state pharmacy board and explained how ridiculous these regulations were. It was a frustrating meeting.

Alicia Ault/MDedge News

I got a phone call recently from a friend north of me. “Gosh, did you hear about the State of Ohio Board of Pharmacy ransacking a dermatologist’s office?” he asked. Yes, I had heard about it, and explained that the office compounding rule in Ohio, the reason behind this surprise search and practice, was the subject of an active struggle going on at the state and federal level (see “Beware the state pharmacy board,” Dermatology News, June 3, 2016). I also told him that the pharmacy board swooped into that location because the office had registered for a license to mix drugs (defined by the board as altering a prescription drug by mixing, diluting, or combining), and agreed to unannounced inspections – and that while the dermatologist was not fined, there was a list of compliance issues to be met, including recording the lot number of all samples, keeping separate paper records of each time he mixed medications, and the promise of a return visit soon.

I went on to explain that representatives – past presidents and board members – of the Ohio Dermatological Association (accompanied by Lisa Albany, director of state policy at the American Academy of Dermatology’s Washington office) had met with the state pharmacy board and explained how ridiculous these regulations were. It was a frustrating meeting.

Alicia Ault/MDedge News

I got a phone call recently from a friend north of me. “Gosh, did you hear about the State of Ohio Board of Pharmacy ransacking a dermatologist’s office?” he asked. Yes, I had heard about it, and explained that the office compounding rule in Ohio, the reason behind this surprise search and practice, was the subject of an active struggle going on at the state and federal level (see “Beware the state pharmacy board,” Dermatology News, June 3, 2016). I also told him that the pharmacy board swooped into that location because the office had registered for a license to mix drugs (defined by the board as altering a prescription drug by mixing, diluting, or combining), and agreed to unannounced inspections – and that while the dermatologist was not fined, there was a list of compliance issues to be met, including recording the lot number of all samples, keeping separate paper records of each time he mixed medications, and the promise of a return visit soon.

I went on to explain that representatives – past presidents and board members – of the Ohio Dermatological Association (accompanied by Lisa Albany, director of state policy at the American Academy of Dermatology’s Washington office) had met with the state pharmacy board and explained how ridiculous these regulations were. It was a frustrating meeting.

Alicia Ault/MDedge News

Physicians may finally have some clarity on payment for inpatient administration of 2 chimeric antigen receptor (CAR) T-cell therapies if a proposed rule from the Centers of Medicare & Medicaid Services becomes final.

The agency is seeking to assign ICD-10-PCS codes XW033C3 and XW043C3 to the use of axicabtagene ciloleucel (Yescarta; Kite Pharma, acquired by Gilead in October 2017) and tisagenlecleucel (Kymriah; Novartis) in the inpatient setting for fiscal year 2019. It is also considering the creation of a new Medicare Severity-Diagnosis Related Group (MS-DRG) code for procedures involving the use of CAR T-cell therapy drugs.

Stephanie Farnia, director of health policy and strategic relations for the American Society for Blood and Marrow Transplantation, said the proposal demonstrates that CMS is listening to physicians’ concerns about CAR T payments and working to provide a more reasonable framework. “The primary point of significance is that CAR-T care episodes should be assigned to a specific MS-DRG in FY2019, which will give physicians a clearer sense of inpatient reimbursement in advance,” she said in an interview.

Uncertainty about inpatient payment for administration of the 2 approved CAR T therapies (see p. e126) have been a lingering concern of specialists who use, or are interested in using, the therapies. In April 2018, CMS announced payment rates for outpatient administration of the 2 drugs, settling on $395,380 for axicabtagene ciloleucel and $500,839 for tisagenlecleucel. The two medications have list prices of $373,000 and $475,000, respectively.

However, physicians noted at the time that even if the drugs were first administered in the outpatient setting, inpatient care is likely to occur with CAR T-cell therapies because some patients will need to be admitted for monitoring for serious side effects. In such cases, all payments would then become part of the inpatient stay as per CMS’s 3-day payment window rule.

In the most recent payment proposal, CMS stated that its clinical advisers believe that patients receiving treatment with CAR T-cell therapy would have similar clinical characteristics and comorbidities as patients treated with autologous bone marrow transplant therapy, who are currently assigned to MS-DRG 016 Autologous Bone Marrow Transplant with CC/MCC. Therefore, CMS officials said they would suggest ICD-10-PCS procedure codes XW033C3 and XW043C3 to pre-MDC MS-DRG 016. In addition, the agency is proposing to revise the title of MS-DRG 016 to Autologous Bone Marrow Transplant with CC/MCC or T-cell Immunotherapy.

The agency emphasized that it invites public comment on alternative payment approaches for CAR T-cell therapies in the context of the pending, new technology add-on payment applications by the CAR-T drugmakers Novartis and Kite Pharma/Gilead. If approved, the technology add-on payments would provide an additional and separate payment equivalent to up to 50% of the product cost plus the MS-DRG payment received for the episode of care.
 

Shifts and realignments in the face of new developments

The CMS announcement is the latest development in the rapidly growing landscape of CAR T-cell therapies. In 2017, the Food and Drug Administration approved tisagenlecleucel for pediatric acute lymphoblastic leukemia and axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma in adults, and in May 2018, the agency expanded the indication for tisagenlecleucel to include adults with relapsed/refractory large B-cell lymphoma.

Further advancements are expected for CAR T-cell therapies in 2018, said Cai Xuan, PhD, senior analyst in oncology and hematology for GlobalData, a data analytics and commercial intelligence firm.

For starters, pharmaceutical companies are now working toward next-generation CAR T-cell therapies that can be mass produced, Dr Xuan noted. At a recent American Association for Cancer Research meeting, for example, the biopharmaceutical company Cellectis presented early clinical data in pediatric B-cell acute lymphoblastic leukemia for its off-the-shelf CAR T-cell candidate UCART19. In addition, CRISPR Therapeutics presented preclinical data for one of its off-the-shelf CAR T-cell candidates for multiple myeloma, and the company announced it would apply for approval to start human trials by the end of 2018.

“The trend for 2018 is focused on how to eliminate some of the profitability issues with first-generation CAR Ts because companies realize that manufacturing individualized treatments for each patient is not an ideal business model,” Dr Xuan said in an interview.

More market competition is also in the forecast, particularly from smaller companies, Dr Xuan said. “We are likely to see larger companies acquiring smaller ones once their CAR T technology has matured to a certain point. We have seen it with the Gilead-Kite acquisition and Celgene’s acquisition of Juno Therapeutics. This trend will continue as long as smaller companies are able to develop proprietary next-generation CAR T technologies.”
 

Cost, accessibility, and real-world side effects

The key concerns about the therapies are cost and accessibility, especially for the Medicare population. Cost estimates have put the cost of CAR T-cell therapies as high as $1.5 million per patient and that could make them inaccessible for many.

“There remain unanswered questions about value and cost in older adults,” said Walid F Gellad, MD, codirector for the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh. “There are many life-saving treatments in the medical system that cost much less than this therapy. Presumably, its cost will go down as the indications expand and the experience with creating the CAR T cells improves. At least, one would hope.”

The creation of off-the-shelf, third-party products would help improve accessibility for CAR T-cell therapies and lower cost, said Helen Heslop, MD, director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston. “In the longer term, there’re obviously a lot of people looking at how [the treatments] can be made more accessible. These are the first-generation CAR T [products], and I think there’ll be lots of refinements both to make them more effective and safer and also to use a third-party product to bring the cost of goods down.”

Other lingering unknowns about CAR T-cell therapies include how many patients in real-world clinical practice will have serious side effects, compared with those in trials, and the long-term recurrence rates after therapy use, Dr Gellad noted. He recently proposed in an article that government payers reimburse only the cost of manufacturing and some predetermined mark-up for such therapies until confirmatory trials demonstrate clinical benefit (N Engl J Med. 2017;376[21]:2001-4).

The current CAR T-cell therapies are only the beginning, said Dr Richard T Maziarz, MD, a bone marrow transplantation and blood cancer specialist at the Oregon Health and Science University Knight Cancer Institute in Portland. “Genetically engineered cell products are going to explode over the course of the next decade. This is not the end of the line, this is the starting point.”

Disclosures. Dr Maziarz has received consulting fees from Novartis, Juno Therapeutics, and Kite Pharma. Dr Heslop has received consulting fees from Novartis, has conducted research for Cell Medica and holds intellectual property rights/patents from Cell Medica, and has ownership interest in ViraCyte and Marker Therapeutics. Dr Gellad reports grants from Express Scripts.

Physicians may finally have some clarity on payment for inpatient administration of 2 chimeric antigen receptor (CAR) T-cell therapies if a proposed rule from the Centers of Medicare & Medicaid Services becomes final.

The agency is seeking to assign ICD-10-PCS codes XW033C3 and XW043C3 to the use of axicabtagene ciloleucel (Yescarta; Kite Pharma, acquired by Gilead in October 2017) and tisagenlecleucel (Kymriah; Novartis) in the inpatient setting for fiscal year 2019. It is also considering the creation of a new Medicare Severity-Diagnosis Related Group (MS-DRG) code for procedures involving the use of CAR T-cell therapy drugs.

Stephanie Farnia, director of health policy and strategic relations for the American Society for Blood and Marrow Transplantation, said the proposal demonstrates that CMS is listening to physicians’ concerns about CAR T payments and working to provide a more reasonable framework. “The primary point of significance is that CAR-T care episodes should be assigned to a specific MS-DRG in FY2019, which will give physicians a clearer sense of inpatient reimbursement in advance,” she said in an interview.

Uncertainty about inpatient payment for administration of the 2 approved CAR T therapies (see p. e126) have been a lingering concern of specialists who use, or are interested in using, the therapies. In April 2018, CMS announced payment rates for outpatient administration of the 2 drugs, settling on $395,380 for axicabtagene ciloleucel and $500,839 for tisagenlecleucel. The two medications have list prices of $373,000 and $475,000, respectively.

However, physicians noted at the time that even if the drugs were first administered in the outpatient setting, inpatient care is likely to occur with CAR T-cell therapies because some patients will need to be admitted for monitoring for serious side effects. In such cases, all payments would then become part of the inpatient stay as per CMS’s 3-day payment window rule.

In the most recent payment proposal, CMS stated that its clinical advisers believe that patients receiving treatment with CAR T-cell therapy would have similar clinical characteristics and comorbidities as patients treated with autologous bone marrow transplant therapy, who are currently assigned to MS-DRG 016 Autologous Bone Marrow Transplant with CC/MCC. Therefore, CMS officials said they would suggest ICD-10-PCS procedure codes XW033C3 and XW043C3 to pre-MDC MS-DRG 016. In addition, the agency is proposing to revise the title of MS-DRG 016 to Autologous Bone Marrow Transplant with CC/MCC or T-cell Immunotherapy.

The agency emphasized that it invites public comment on alternative payment approaches for CAR T-cell therapies in the context of the pending, new technology add-on payment applications by the CAR-T drugmakers Novartis and Kite Pharma/Gilead. If approved, the technology add-on payments would provide an additional and separate payment equivalent to up to 50% of the product cost plus the MS-DRG payment received for the episode of care.
 

Shifts and realignments in the face of new developments

The CMS announcement is the latest development in the rapidly growing landscape of CAR T-cell therapies. In 2017, the Food and Drug Administration approved tisagenlecleucel for pediatric acute lymphoblastic leukemia and axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma in adults, and in May 2018, the agency expanded the indication for tisagenlecleucel to include adults with relapsed/refractory large B-cell lymphoma.

Further advancements are expected for CAR T-cell therapies in 2018, said Cai Xuan, PhD, senior analyst in oncology and hematology for GlobalData, a data analytics and commercial intelligence firm.

For starters, pharmaceutical companies are now working toward next-generation CAR T-cell therapies that can be mass produced, Dr Xuan noted. At a recent American Association for Cancer Research meeting, for example, the biopharmaceutical company Cellectis presented early clinical data in pediatric B-cell acute lymphoblastic leukemia for its off-the-shelf CAR T-cell candidate UCART19. In addition, CRISPR Therapeutics presented preclinical data for one of its off-the-shelf CAR T-cell candidates for multiple myeloma, and the company announced it would apply for approval to start human trials by the end of 2018.

“The trend for 2018 is focused on how to eliminate some of the profitability issues with first-generation CAR Ts because companies realize that manufacturing individualized treatments for each patient is not an ideal business model,” Dr Xuan said in an interview.

More market competition is also in the forecast, particularly from smaller companies, Dr Xuan said. “We are likely to see larger companies acquiring smaller ones once their CAR T technology has matured to a certain point. We have seen it with the Gilead-Kite acquisition and Celgene’s acquisition of Juno Therapeutics. This trend will continue as long as smaller companies are able to develop proprietary next-generation CAR T technologies.”
 

Cost, accessibility, and real-world side effects

The key concerns about the therapies are cost and accessibility, especially for the Medicare population. Cost estimates have put the cost of CAR T-cell therapies as high as $1.5 million per patient and that could make them inaccessible for many.

“There remain unanswered questions about value and cost in older adults,” said Walid F Gellad, MD, codirector for the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh. “There are many life-saving treatments in the medical system that cost much less than this therapy. Presumably, its cost will go down as the indications expand and the experience with creating the CAR T cells improves. At least, one would hope.”

The creation of off-the-shelf, third-party products would help improve accessibility for CAR T-cell therapies and lower cost, said Helen Heslop, MD, director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston. “In the longer term, there’re obviously a lot of people looking at how [the treatments] can be made more accessible. These are the first-generation CAR T [products], and I think there’ll be lots of refinements both to make them more effective and safer and also to use a third-party product to bring the cost of goods down.”

Other lingering unknowns about CAR T-cell therapies include how many patients in real-world clinical practice will have serious side effects, compared with those in trials, and the long-term recurrence rates after therapy use, Dr Gellad noted. He recently proposed in an article that government payers reimburse only the cost of manufacturing and some predetermined mark-up for such therapies until confirmatory trials demonstrate clinical benefit (N Engl J Med. 2017;376[21]:2001-4).

The current CAR T-cell therapies are only the beginning, said Dr Richard T Maziarz, MD, a bone marrow transplantation and blood cancer specialist at the Oregon Health and Science University Knight Cancer Institute in Portland. “Genetically engineered cell products are going to explode over the course of the next decade. This is not the end of the line, this is the starting point.”

Disclosures. Dr Maziarz has received consulting fees from Novartis, Juno Therapeutics, and Kite Pharma. Dr Heslop has received consulting fees from Novartis, has conducted research for Cell Medica and holds intellectual property rights/patents from Cell Medica, and has ownership interest in ViraCyte and Marker Therapeutics. Dr Gellad reports grants from Express Scripts.

Physicians may finally have some clarity on payment for inpatient administration of 2 chimeric antigen receptor (CAR) T-cell therapies if a proposed rule from the Centers of Medicare & Medicaid Services becomes final.

The agency is seeking to assign ICD-10-PCS codes XW033C3 and XW043C3 to the use of axicabtagene ciloleucel (Yescarta; Kite Pharma, acquired by Gilead in October 2017) and tisagenlecleucel (Kymriah; Novartis) in the inpatient setting for fiscal year 2019. It is also considering the creation of a new Medicare Severity-Diagnosis Related Group (MS-DRG) code for procedures involving the use of CAR T-cell therapy drugs.

Stephanie Farnia, director of health policy and strategic relations for the American Society for Blood and Marrow Transplantation, said the proposal demonstrates that CMS is listening to physicians’ concerns about CAR T payments and working to provide a more reasonable framework. “The primary point of significance is that CAR-T care episodes should be assigned to a specific MS-DRG in FY2019, which will give physicians a clearer sense of inpatient reimbursement in advance,” she said in an interview.

Uncertainty about inpatient payment for administration of the 2 approved CAR T therapies (see p. e126) have been a lingering concern of specialists who use, or are interested in using, the therapies. In April 2018, CMS announced payment rates for outpatient administration of the 2 drugs, settling on $395,380 for axicabtagene ciloleucel and $500,839 for tisagenlecleucel. The two medications have list prices of $373,000 and $475,000, respectively.

However, physicians noted at the time that even if the drugs were first administered in the outpatient setting, inpatient care is likely to occur with CAR T-cell therapies because some patients will need to be admitted for monitoring for serious side effects. In such cases, all payments would then become part of the inpatient stay as per CMS’s 3-day payment window rule.

In the most recent payment proposal, CMS stated that its clinical advisers believe that patients receiving treatment with CAR T-cell therapy would have similar clinical characteristics and comorbidities as patients treated with autologous bone marrow transplant therapy, who are currently assigned to MS-DRG 016 Autologous Bone Marrow Transplant with CC/MCC. Therefore, CMS officials said they would suggest ICD-10-PCS procedure codes XW033C3 and XW043C3 to pre-MDC MS-DRG 016. In addition, the agency is proposing to revise the title of MS-DRG 016 to Autologous Bone Marrow Transplant with CC/MCC or T-cell Immunotherapy.

The agency emphasized that it invites public comment on alternative payment approaches for CAR T-cell therapies in the context of the pending, new technology add-on payment applications by the CAR-T drugmakers Novartis and Kite Pharma/Gilead. If approved, the technology add-on payments would provide an additional and separate payment equivalent to up to 50% of the product cost plus the MS-DRG payment received for the episode of care.
 

Shifts and realignments in the face of new developments

The CMS announcement is the latest development in the rapidly growing landscape of CAR T-cell therapies. In 2017, the Food and Drug Administration approved tisagenlecleucel for pediatric acute lymphoblastic leukemia and axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma in adults, and in May 2018, the agency expanded the indication for tisagenlecleucel to include adults with relapsed/refractory large B-cell lymphoma.

Further advancements are expected for CAR T-cell therapies in 2018, said Cai Xuan, PhD, senior analyst in oncology and hematology for GlobalData, a data analytics and commercial intelligence firm.

For starters, pharmaceutical companies are now working toward next-generation CAR T-cell therapies that can be mass produced, Dr Xuan noted. At a recent American Association for Cancer Research meeting, for example, the biopharmaceutical company Cellectis presented early clinical data in pediatric B-cell acute lymphoblastic leukemia for its off-the-shelf CAR T-cell candidate UCART19. In addition, CRISPR Therapeutics presented preclinical data for one of its off-the-shelf CAR T-cell candidates for multiple myeloma, and the company announced it would apply for approval to start human trials by the end of 2018.

“The trend for 2018 is focused on how to eliminate some of the profitability issues with first-generation CAR Ts because companies realize that manufacturing individualized treatments for each patient is not an ideal business model,” Dr Xuan said in an interview.

More market competition is also in the forecast, particularly from smaller companies, Dr Xuan said. “We are likely to see larger companies acquiring smaller ones once their CAR T technology has matured to a certain point. We have seen it with the Gilead-Kite acquisition and Celgene’s acquisition of Juno Therapeutics. This trend will continue as long as smaller companies are able to develop proprietary next-generation CAR T technologies.”
 

Cost, accessibility, and real-world side effects

The key concerns about the therapies are cost and accessibility, especially for the Medicare population. Cost estimates have put the cost of CAR T-cell therapies as high as $1.5 million per patient and that could make them inaccessible for many.

“There remain unanswered questions about value and cost in older adults,” said Walid F Gellad, MD, codirector for the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh. “There are many life-saving treatments in the medical system that cost much less than this therapy. Presumably, its cost will go down as the indications expand and the experience with creating the CAR T cells improves. At least, one would hope.”

The creation of off-the-shelf, third-party products would help improve accessibility for CAR T-cell therapies and lower cost, said Helen Heslop, MD, director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston. “In the longer term, there’re obviously a lot of people looking at how [the treatments] can be made more accessible. These are the first-generation CAR T [products], and I think there’ll be lots of refinements both to make them more effective and safer and also to use a third-party product to bring the cost of goods down.”

Other lingering unknowns about CAR T-cell therapies include how many patients in real-world clinical practice will have serious side effects, compared with those in trials, and the long-term recurrence rates after therapy use, Dr Gellad noted. He recently proposed in an article that government payers reimburse only the cost of manufacturing and some predetermined mark-up for such therapies until confirmatory trials demonstrate clinical benefit (N Engl J Med. 2017;376[21]:2001-4).

The current CAR T-cell therapies are only the beginning, said Dr Richard T Maziarz, MD, a bone marrow transplantation and blood cancer specialist at the Oregon Health and Science University Knight Cancer Institute in Portland. “Genetically engineered cell products are going to explode over the course of the next decade. This is not the end of the line, this is the starting point.”

Disclosures. Dr Maziarz has received consulting fees from Novartis, Juno Therapeutics, and Kite Pharma. Dr Heslop has received consulting fees from Novartis, has conducted research for Cell Medica and holds intellectual property rights/patents from Cell Medica, and has ownership interest in ViraCyte and Marker Therapeutics. Dr Gellad reports grants from Express Scripts.

The next major approval in the chimeric antigen receptor (CAR) T-cell therapy arena will target multiple myeloma, according to Carl June, MD, the Richard W Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia. That approval is anticipated sometime in 2019, and will “completely transform oncology,” Dr June said in a recent interview. “Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells.”

Researcher-turned-patient

The first treated patient in a trial of a novel anti–B-cell maturation antigen (BCMA)–specific CAR T-cell therapy (CART-BCMA)¹ developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset. Earlier this year, Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas (UT) Southwestern Medical Center in Dallas, outed himself as that first patient when he announced that CART-BCMA saved his life.²

Dr Wright had been diagnosed with multiple myeloma about 12 years ago and had failed 11 previous chemotherapies before he was enrolled in the CART-BCMA trial. He remains cancer free more than 2 years after receiving CART-BCMA and he’s now conducting CAR T-cell–related research in his UT Southwestern laboratory to broaden the effectiveness of current CAR T-cell therapies. In particular, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, because most patients who fail CAR T-cell therapy are elderly and might have terminally short telomeres. ²

Pharma lines up the trials

An ongoing University of Pennsylvania trial led by Adam D Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the 2016 annual meeting of the American Society of Hematology (ASH).³ In addition, multiple companies are pursuing registration trials for CAR T-cell therapies in myeloma, Dr June said.

Among those companies are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. The product was granted breakthrough therapy designation by the US Food and Drug Administration in November 2017 and will thus receive expedited review by the agency. It has also been fast-tracked in Europe.

The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial.⁴ Updated findings from that trial were presented at the 2017 ASH annual meeting and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 10⁶ CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.

Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 10⁶ CAR+ T cells.⁵

Janssen Biotech Inc and Legend Biotech USA Inc/ Legend Biotech Ireland Ltd have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr June said. The companies announced in late 2017 that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate, LCAR-B38M.⁶ It has been accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.
 

Cost, financial toxicity, and a new therapeutic landscape

The rush for the approval of a CAR T-cell therapy for myeloma will lead to a welcome addition to the treatment armamentarium not just because of the clinical benefits, but because of the possibility of reducing disease-related costs (p. e177). Although myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr June noted, and since many patients live with their disease for a long time, that can mean substantial “financial toxicity” being associated with treatment for the disease. “So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added.

Dr June explained that tisagenlecleucel, the first CAR T-cell therapy to be approved (in August 2017; p. e126), was for pediatric acute lymphoblastic leukemia that had relapsed at least twice.⁷ “That’s only about 600 kids a year in the United States, so it’s an ultra-orphan market,” he said. However, with the subsequent October 2017 approval of axicabtagene ciloleucel for certain cases of large B-cell lymphoma⁸ and the anticipated myeloma approval, CAR T-cell therapy will move away from that orphan status.

“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s, when many voiced concern about the new therapy because it was available at only 2 centers in the United states and required a high level of specialized skill. “But over the years, millions of transplants have been done [and] they’re done at many community centers. And it’s the same thing with CARs.” There are now 30 centers offering CAR T-cell therapy and people have to be trained. “It’s a new skill set, and it will take time,” he said.
 

Access to trials: balancing demand and availability

That delay can be particularly frustrating because there are many patients who might benefit “in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr June noted.

“There’s more demand than availability, and it’s going to take a while” for that to change, he said. The solution most likely will involve the complementary use of off-the-shelf CAR T cells in some patients to induce remission and perhaps provide a bridge to another definitive therapy, and ultrapersonalized CAR T-cell therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.

CRISPR-Cas9 gene editing is also being considered as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute-funded NYCE study,⁹ Dr June said. “We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial.”

Disclosures. Dr June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.

The next major approval in the chimeric antigen receptor (CAR) T-cell therapy arena will target multiple myeloma, according to Carl June, MD, the Richard W Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia. That approval is anticipated sometime in 2019, and will “completely transform oncology,” Dr June said in a recent interview. “Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells.”

Researcher-turned-patient

The first treated patient in a trial of a novel anti–B-cell maturation antigen (BCMA)–specific CAR T-cell therapy (CART-BCMA)¹ developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset. Earlier this year, Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas (UT) Southwestern Medical Center in Dallas, outed himself as that first patient when he announced that CART-BCMA saved his life.²

Dr Wright had been diagnosed with multiple myeloma about 12 years ago and had failed 11 previous chemotherapies before he was enrolled in the CART-BCMA trial. He remains cancer free more than 2 years after receiving CART-BCMA and he’s now conducting CAR T-cell–related research in his UT Southwestern laboratory to broaden the effectiveness of current CAR T-cell therapies. In particular, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, because most patients who fail CAR T-cell therapy are elderly and might have terminally short telomeres. ²

Pharma lines up the trials

An ongoing University of Pennsylvania trial led by Adam D Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the 2016 annual meeting of the American Society of Hematology (ASH).³ In addition, multiple companies are pursuing registration trials for CAR T-cell therapies in myeloma, Dr June said.

Among those companies are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. The product was granted breakthrough therapy designation by the US Food and Drug Administration in November 2017 and will thus receive expedited review by the agency. It has also been fast-tracked in Europe.

The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial.⁴ Updated findings from that trial were presented at the 2017 ASH annual meeting and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 10⁶ CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.

Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 10⁶ CAR+ T cells.⁵

Janssen Biotech Inc and Legend Biotech USA Inc/ Legend Biotech Ireland Ltd have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr June said. The companies announced in late 2017 that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate, LCAR-B38M.⁶ It has been accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.
 

Cost, financial toxicity, and a new therapeutic landscape

The rush for the approval of a CAR T-cell therapy for myeloma will lead to a welcome addition to the treatment armamentarium not just because of the clinical benefits, but because of the possibility of reducing disease-related costs (p. e177). Although myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr June noted, and since many patients live with their disease for a long time, that can mean substantial “financial toxicity” being associated with treatment for the disease. “So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added.

Dr June explained that tisagenlecleucel, the first CAR T-cell therapy to be approved (in August 2017; p. e126), was for pediatric acute lymphoblastic leukemia that had relapsed at least twice.⁷ “That’s only about 600 kids a year in the United States, so it’s an ultra-orphan market,” he said. However, with the subsequent October 2017 approval of axicabtagene ciloleucel for certain cases of large B-cell lymphoma⁸ and the anticipated myeloma approval, CAR T-cell therapy will move away from that orphan status.

“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s, when many voiced concern about the new therapy because it was available at only 2 centers in the United states and required a high level of specialized skill. “But over the years, millions of transplants have been done [and] they’re done at many community centers. And it’s the same thing with CARs.” There are now 30 centers offering CAR T-cell therapy and people have to be trained. “It’s a new skill set, and it will take time,” he said.
 

Access to trials: balancing demand and availability

That delay can be particularly frustrating because there are many patients who might benefit “in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr June noted.

“There’s more demand than availability, and it’s going to take a while” for that to change, he said. The solution most likely will involve the complementary use of off-the-shelf CAR T cells in some patients to induce remission and perhaps provide a bridge to another definitive therapy, and ultrapersonalized CAR T-cell therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.

CRISPR-Cas9 gene editing is also being considered as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute-funded NYCE study,⁹ Dr June said. “We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial.”

Disclosures. Dr June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.

The next major approval in the chimeric antigen receptor (CAR) T-cell therapy arena will target multiple myeloma, according to Carl June, MD, the Richard W Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia. That approval is anticipated sometime in 2019, and will “completely transform oncology,” Dr June said in a recent interview. “Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells.”

Researcher-turned-patient

The first treated patient in a trial of a novel anti–B-cell maturation antigen (BCMA)–specific CAR T-cell therapy (CART-BCMA)¹ developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset. Earlier this year, Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas (UT) Southwestern Medical Center in Dallas, outed himself as that first patient when he announced that CART-BCMA saved his life.²

Dr Wright had been diagnosed with multiple myeloma about 12 years ago and had failed 11 previous chemotherapies before he was enrolled in the CART-BCMA trial. He remains cancer free more than 2 years after receiving CART-BCMA and he’s now conducting CAR T-cell–related research in his UT Southwestern laboratory to broaden the effectiveness of current CAR T-cell therapies. In particular, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, because most patients who fail CAR T-cell therapy are elderly and might have terminally short telomeres. ²

Pharma lines up the trials

An ongoing University of Pennsylvania trial led by Adam D Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the 2016 annual meeting of the American Society of Hematology (ASH).³ In addition, multiple companies are pursuing registration trials for CAR T-cell therapies in myeloma, Dr June said.

Among those companies are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. The product was granted breakthrough therapy designation by the US Food and Drug Administration in November 2017 and will thus receive expedited review by the agency. It has also been fast-tracked in Europe.

The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial.⁴ Updated findings from that trial were presented at the 2017 ASH annual meeting and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 10⁶ CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.

Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 10⁶ CAR+ T cells.⁵

Janssen Biotech Inc and Legend Biotech USA Inc/ Legend Biotech Ireland Ltd have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr June said. The companies announced in late 2017 that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate, LCAR-B38M.⁶ It has been accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.
 

Cost, financial toxicity, and a new therapeutic landscape

The rush for the approval of a CAR T-cell therapy for myeloma will lead to a welcome addition to the treatment armamentarium not just because of the clinical benefits, but because of the possibility of reducing disease-related costs (p. e177). Although myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr June noted, and since many patients live with their disease for a long time, that can mean substantial “financial toxicity” being associated with treatment for the disease. “So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added.

Dr June explained that tisagenlecleucel, the first CAR T-cell therapy to be approved (in August 2017; p. e126), was for pediatric acute lymphoblastic leukemia that had relapsed at least twice.⁷ “That’s only about 600 kids a year in the United States, so it’s an ultra-orphan market,” he said. However, with the subsequent October 2017 approval of axicabtagene ciloleucel for certain cases of large B-cell lymphoma⁸ and the anticipated myeloma approval, CAR T-cell therapy will move away from that orphan status.

“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s, when many voiced concern about the new therapy because it was available at only 2 centers in the United states and required a high level of specialized skill. “But over the years, millions of transplants have been done [and] they’re done at many community centers. And it’s the same thing with CARs.” There are now 30 centers offering CAR T-cell therapy and people have to be trained. “It’s a new skill set, and it will take time,” he said.
 

Access to trials: balancing demand and availability

That delay can be particularly frustrating because there are many patients who might benefit “in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr June noted.

“There’s more demand than availability, and it’s going to take a while” for that to change, he said. The solution most likely will involve the complementary use of off-the-shelf CAR T cells in some patients to induce remission and perhaps provide a bridge to another definitive therapy, and ultrapersonalized CAR T-cell therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.

CRISPR-Cas9 gene editing is also being considered as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute-funded NYCE study,⁹ Dr June said. “We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial.”

Disclosures. Dr June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.

The landmark US Food and Drug Administration approvals last year of tisagenlecleucel and axicabtagene ciloluecel – the first two chimeric antigen receptor (CAR) T-cell therapies for cancer – signified a new era of therapeutic possibilities (p. e126). CAR T-cells are a type of adoptive cell therapy or immunotherapy in which a patient’s immune cells are genetically engineered to target a tumor-associated antigen (in the case of these first two approvals, that target is CD19). In August, tisagenlecleucel got the green light for the treatment of B-cell precursor acute lymphoblastic leukemia in patients up to age 25 years, and in the fall, axicabtagene ciloluecel was approved for the treatment of refractory, aggressive B-cell non-Hodgkin lymphoma. The earlier this year, the agency also approved tisagenlecleucel for adult patients with relapsed or refractory large B-cell lymphoma. As Carl June, MD, a pioneer in CAR T-cell research notes in an interview on page e175, the next approval likely will be for multiple myeloma.

But while the science and the potential of these therapies are exciting, the impact of their cost and toxicities on patients tempers some of the enthusiasm. The Centers of Medicare & Medicaid Services is working on a final rule on payment for the inpatient administration of the two therapies for fiscal year 2019 and is considering the creation of a new Medicare Severity-Diagnosis Related Group code for procedures involving the use of CAR T-cell therapies (p. e177). Walid F Gellad, MD, of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, has said that some estimates for the cost of these therapies as high as $1.5 million per patient, and there is particular concern for the older adults who make up the Medicare population. These high costs would affect access to the therapy for many patients, irrespective of age, but one encouraging development on this front would be the development of lower-priced, off-the-shelf, third-party products. Another unknown with CAR T-cell therapies is the extent of side effects in real-world patients compared with those in trials, and what the long-term posttherapy recurrence rates would be.

In addition to highlighting CAR T-cell therapies in this issue, on page e167, Jane de Lartigue takes a look at tumor heterogeneity and the challenges it presents in the ongoing quest for effective cancer treatments. Dr de Lartigue describes the two key models used to explain how tumors develop – the clonal evolution model and the cancer stem cell model. She argues that although evidence suggests the models are not mutually exclusive and contribute to heterogeneity differently in different tumor types, heterogeneity and evolution, fueled by genomic alterations, are “intricately intertwined” in the development of cancer.

With cancer therapies come side effects, psychosocial effects, and sometimes challenges with posttreatment mobility, activities of daily living, and even self-care. Three articles in this issue deal with those posttreatment issues. On page e130, Kundu and colleagues report on a prospective study in which they evaluated physical and psychosocial functioning after diagnosis of prostate cancer and the factors associated with treatment satisfaction after treatment. They found that despite declines in erectile function and sexual domains, treatment satisfaction was more closely related to emotional, psychosocial, and nonsexual effects, underscoring the importance of assessing health-related quality-of-life outcomes beyond physical functioning. Forrest and colleagues (p. e138) set out to report outcomes of patients who received radiation therapy while on an inpatient rehabilitation facility and found that comprehensive care that includes radiation and rehabilitation at the inpatient rehabilitation facility level benefits appropriately selected patients. And on page e145, Ibrahim and colleagues tracked the effectiveness of a 12-week exercise program on long-term levels of upper-limb pain in young survivors of breast cancer and found that although there was some transient improvement in shoulder pain, it did not translate in to long-term benefits.

Our usual line-up of Case Reports on clinical challenges in the practice setting includes the case of a child with carcinoma of the colon (p. e152); two separate reports on patients with therapy-related skin reactions, one with radiation dermatitis (p.e156), the other with a reaction to a checkpoint inhibitor (p. e159); and a patient with recurrence of a small gastric gastrointestinal stromal tumor with high mitotic index (p. e163).

The landmark US Food and Drug Administration approvals last year of tisagenlecleucel and axicabtagene ciloluecel – the first two chimeric antigen receptor (CAR) T-cell therapies for cancer – signified a new era of therapeutic possibilities (p. e126). CAR T-cells are a type of adoptive cell therapy or immunotherapy in which a patient’s immune cells are genetically engineered to target a tumor-associated antigen (in the case of these first two approvals, that target is CD19). In August, tisagenlecleucel got the green light for the treatment of B-cell precursor acute lymphoblastic leukemia in patients up to age 25 years, and in the fall, axicabtagene ciloluecel was approved for the treatment of refractory, aggressive B-cell non-Hodgkin lymphoma. The earlier this year, the agency also approved tisagenlecleucel for adult patients with relapsed or refractory large B-cell lymphoma. As Carl June, MD, a pioneer in CAR T-cell research notes in an interview on page e175, the next approval likely will be for multiple myeloma.

But while the science and the potential of these therapies are exciting, the impact of their cost and toxicities on patients tempers some of the enthusiasm. The Centers of Medicare & Medicaid Services is working on a final rule on payment for the inpatient administration of the two therapies for fiscal year 2019 and is considering the creation of a new Medicare Severity-Diagnosis Related Group code for procedures involving the use of CAR T-cell therapies (p. e177). Walid F Gellad, MD, of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, has said that some estimates for the cost of these therapies as high as $1.5 million per patient, and there is particular concern for the older adults who make up the Medicare population. These high costs would affect access to the therapy for many patients, irrespective of age, but one encouraging development on this front would be the development of lower-priced, off-the-shelf, third-party products. Another unknown with CAR T-cell therapies is the extent of side effects in real-world patients compared with those in trials, and what the long-term posttherapy recurrence rates would be.

In addition to highlighting CAR T-cell therapies in this issue, on page e167, Jane de Lartigue takes a look at tumor heterogeneity and the challenges it presents in the ongoing quest for effective cancer treatments. Dr de Lartigue describes the two key models used to explain how tumors develop – the clonal evolution model and the cancer stem cell model. She argues that although evidence suggests the models are not mutually exclusive and contribute to heterogeneity differently in different tumor types, heterogeneity and evolution, fueled by genomic alterations, are “intricately intertwined” in the development of cancer.

With cancer therapies come side effects, psychosocial effects, and sometimes challenges with posttreatment mobility, activities of daily living, and even self-care. Three articles in this issue deal with those posttreatment issues. On page e130, Kundu and colleagues report on a prospective study in which they evaluated physical and psychosocial functioning after diagnosis of prostate cancer and the factors associated with treatment satisfaction after treatment. They found that despite declines in erectile function and sexual domains, treatment satisfaction was more closely related to emotional, psychosocial, and nonsexual effects, underscoring the importance of assessing health-related quality-of-life outcomes beyond physical functioning. Forrest and colleagues (p. e138) set out to report outcomes of patients who received radiation therapy while on an inpatient rehabilitation facility and found that comprehensive care that includes radiation and rehabilitation at the inpatient rehabilitation facility level benefits appropriately selected patients. And on page e145, Ibrahim and colleagues tracked the effectiveness of a 12-week exercise program on long-term levels of upper-limb pain in young survivors of breast cancer and found that although there was some transient improvement in shoulder pain, it did not translate in to long-term benefits.

Our usual line-up of Case Reports on clinical challenges in the practice setting includes the case of a child with carcinoma of the colon (p. e152); two separate reports on patients with therapy-related skin reactions, one with radiation dermatitis (p.e156), the other with a reaction to a checkpoint inhibitor (p. e159); and a patient with recurrence of a small gastric gastrointestinal stromal tumor with high mitotic index (p. e163).

The landmark US Food and Drug Administration approvals last year of tisagenlecleucel and axicabtagene ciloluecel – the first two chimeric antigen receptor (CAR) T-cell therapies for cancer – signified a new era of therapeutic possibilities (p. e126). CAR T-cells are a type of adoptive cell therapy or immunotherapy in which a patient’s immune cells are genetically engineered to target a tumor-associated antigen (in the case of these first two approvals, that target is CD19). In August, tisagenlecleucel got the green light for the treatment of B-cell precursor acute lymphoblastic leukemia in patients up to age 25 years, and in the fall, axicabtagene ciloluecel was approved for the treatment of refractory, aggressive B-cell non-Hodgkin lymphoma. The earlier this year, the agency also approved tisagenlecleucel for adult patients with relapsed or refractory large B-cell lymphoma. As Carl June, MD, a pioneer in CAR T-cell research notes in an interview on page e175, the next approval likely will be for multiple myeloma.

But while the science and the potential of these therapies are exciting, the impact of their cost and toxicities on patients tempers some of the enthusiasm. The Centers of Medicare & Medicaid Services is working on a final rule on payment for the inpatient administration of the two therapies for fiscal year 2019 and is considering the creation of a new Medicare Severity-Diagnosis Related Group code for procedures involving the use of CAR T-cell therapies (p. e177). Walid F Gellad, MD, of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, has said that some estimates for the cost of these therapies as high as $1.5 million per patient, and there is particular concern for the older adults who make up the Medicare population. These high costs would affect access to the therapy for many patients, irrespective of age, but one encouraging development on this front would be the development of lower-priced, off-the-shelf, third-party products. Another unknown with CAR T-cell therapies is the extent of side effects in real-world patients compared with those in trials, and what the long-term posttherapy recurrence rates would be.

In addition to highlighting CAR T-cell therapies in this issue, on page e167, Jane de Lartigue takes a look at tumor heterogeneity and the challenges it presents in the ongoing quest for effective cancer treatments. Dr de Lartigue describes the two key models used to explain how tumors develop – the clonal evolution model and the cancer stem cell model. She argues that although evidence suggests the models are not mutually exclusive and contribute to heterogeneity differently in different tumor types, heterogeneity and evolution, fueled by genomic alterations, are “intricately intertwined” in the development of cancer.

With cancer therapies come side effects, psychosocial effects, and sometimes challenges with posttreatment mobility, activities of daily living, and even self-care. Three articles in this issue deal with those posttreatment issues. On page e130, Kundu and colleagues report on a prospective study in which they evaluated physical and psychosocial functioning after diagnosis of prostate cancer and the factors associated with treatment satisfaction after treatment. They found that despite declines in erectile function and sexual domains, treatment satisfaction was more closely related to emotional, psychosocial, and nonsexual effects, underscoring the importance of assessing health-related quality-of-life outcomes beyond physical functioning. Forrest and colleagues (p. e138) set out to report outcomes of patients who received radiation therapy while on an inpatient rehabilitation facility and found that comprehensive care that includes radiation and rehabilitation at the inpatient rehabilitation facility level benefits appropriately selected patients. And on page e145, Ibrahim and colleagues tracked the effectiveness of a 12-week exercise program on long-term levels of upper-limb pain in young survivors of breast cancer and found that although there was some transient improvement in shoulder pain, it did not translate in to long-term benefits.

Our usual line-up of Case Reports on clinical challenges in the practice setting includes the case of a child with carcinoma of the colon (p. e152); two separate reports on patients with therapy-related skin reactions, one with radiation dermatitis (p.e156), the other with a reaction to a checkpoint inhibitor (p. e159); and a patient with recurrence of a small gastric gastrointestinal stromal tumor with high mitotic index (p. e163).

A record-setting 40,000-plus oncology professionals attended this year’s annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago. The outstanding education and scientific program, with the theme of Delivering Discoveries: Expanding the Reach of Precision Medicine, was planned and led by ASCO President Dr Bruce Johnson, professor and director of Thoracic Oncology at the Dana Farber Cancer Institute in Boston, and chaired by Sarah Cannon’s Dr David Spigel and Harvard’s Dr Ann Partridge. A recurring finding throughout the meeting was that “less is more” in several key areas of cancer therapy. From small molecules targeting driver mutations across various tumors to the application of immunotherapy in subsets of common cancers, it is clear that more patients are experiencing dramatic results from novel approaches.

A featured plenary session trial was TAILORx, a study of 10,273 women with hormone-receptor–positive, surgically resected breast cancer that had not spread to the lymph nodes, was less than 5 cm, and was not positive for the HER2 gene amplification. This clinical trial was sponsored by the NCI and initiated in 2006. It used the OncotypeDX genetic test to stratify patients into groups of low, intermediate, or high risk for recurrence. The low-risk patients received only hormonal therapy, and the high-risk patients were treated with hormonal therapy plus chemotherapy.

Dr Joseph Sparano, professor of Medicine and Women’s Health at the Albert Einstein College of Medicine in New York, presented the results from the group of 6,700 intermediate risk women who were randomized to receive hormonal therapy alone or in combination with chemotherapy. After 9 years of follow-up, 83.3% of the volunteers, as Dr Sparano appropriately referred to them, who were treated with hormonal therapy were still cancer free, compared with 84.3% of those who also received chemotherapy, demonstrating no statistical benefit for the addition of chemotherapy. Of note, breast cancer experts discussing the trial, including Dr Lisa Carey, professor of Breast Cancer Research at the UNC Lineberger Cancer Institute in Chapel Hill, urged that younger women, under the age of 50, with recurrence scores (RS) toward the higher end of the intermediate risk group (RS, 16-25) should still discuss and consider chemotherapy with their physicians. In summary, all patients fitting the study criteria with low (
These landmark and practice changing results mean that each year about 60,000 women in the United States will be spared the side effects of toxic drugs. These 10,273 study volunteers are true heroes to the women who will be diagnosed with breast cancer in coming years.

In the field of lung cancer, many new trial results using immunotherapy were presented, with the most talked about being single-agent pembrolizumab, a PD1 inhibitor, improving survival over traditional chemotherapy in patients with PD-L1 positive tumors, which comprise the majority of squamous cell and adenocarcinomas of the lung. Also in the plenary, Dr Gilberto Lopes of the Sylvester Cancer Center at the University of Miami, presented these results from the KEYNOTE-042 study. In patients with PD-L1 tumor proportion score (TPS) of >1%, the benefit in overall survival (OS) of pembrolizumab compared with chemotherapy was 16.7 versus 12.1 months, respectively (HR, 0.81). In those patients with a TPS of >20%, the OS benefit was 17.7 versus 1.0 months (HR, 0.77), and in the group with a TPS of >50%, the benefit was 20.0 versus 12.2 months (HR, 0.69). Overall, the quality of life and the occurrence of side effects were substantially better for those patients receiving immunotherapy alone. Other findings presented at the meeting demonstrated the benefit of adding immunotherapy to chemotherapy and of treating with combination immunotherapy (PD-1 and CTLA-4 inhibitors). Many options now exist, much work remains to be done, and accrual to clinical trials is more important than ever.

Another plenary session trial evaluated the benefit of performing a nephrectomy in patients with advanced or metastatic renal cell carcinoma (RCC), a long-held and practiced standard of care. Dr Arnaud Mejean of Paris Descartes University presented findings from the CARMENA trial, which randomized 450 patients with metastatic clear cell RCC to receive cytoreductive nephrectomy followed by sunitinib, or sunitinib alone. The OS results of 18.4 versus 13.9 months, respectively (HR, 0.89) favored sunitinib alone in this noninferiority analysis. Other endpoints lined up in favor of not removing the cancerous kidney, and the presenter and discussants were united in their opinion of the results and the resulting change in doing less surgery in these patients.

In a step away from less therapy, the European Pediatric Soft Tissue Sarcoma Study showed that adding 6 months of low-dose maintenance chemotherapy after standard intensive therapy improves survival in children with high-risk rhabdomyosarcoma. The addition of a vinorelbine and cyclophosphamide low-dose regimen improved 5-year disease-free survival from 69.8% to 77.6% (HR, 0.68) and OS from 73.7% to 86.5% (HR, 0.52) as presented by Dr Gianni Bisogno, University of Padovani, Italy. The maintenance regimen showed no increase in toxicity and actually fewer infections were noted.

In the area of molecular profiling, multiple studies at the meeting demonstrated the importance of assessing cancers for mutations as outstanding results were seen with therapies for NTRK, RET, ROS, and MSI-high driven tumors. In a debate on the role of molecular profiling, I had the opportunity to declare and support our position at Sarah Cannon that all patients with relapsed or metastatic cancers should have this testing performed. It will be through better understanding of the biology of these cancers that we will advance the field for all patients while sometimes finding a target or mutation that will dramatically change the life of a patient.

In keeping with the meeting’s theme, Delivering Discoveries: Expanding the Reach of Precision Medicine, the presentations and the discussions clearly demonstrated that through the use of precision medicine techniques such as prognostic gene assays and molecular profiling, patients can receive the best therapy, even “tailored” therapy, which may often actually be less therapy. It is an exciting time in cancer research, and I have never been more optimistic about the future of cancer treatment for our patients.

A record-setting 40,000-plus oncology professionals attended this year’s annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago. The outstanding education and scientific program, with the theme of Delivering Discoveries: Expanding the Reach of Precision Medicine, was planned and led by ASCO President Dr Bruce Johnson, professor and director of Thoracic Oncology at the Dana Farber Cancer Institute in Boston, and chaired by Sarah Cannon’s Dr David Spigel and Harvard’s Dr Ann Partridge. A recurring finding throughout the meeting was that “less is more” in several key areas of cancer therapy. From small molecules targeting driver mutations across various tumors to the application of immunotherapy in subsets of common cancers, it is clear that more patients are experiencing dramatic results from novel approaches.

A featured plenary session trial was TAILORx, a study of 10,273 women with hormone-receptor–positive, surgically resected breast cancer that had not spread to the lymph nodes, was less than 5 cm, and was not positive for the HER2 gene amplification. This clinical trial was sponsored by the NCI and initiated in 2006. It used the OncotypeDX genetic test to stratify patients into groups of low, intermediate, or high risk for recurrence. The low-risk patients received only hormonal therapy, and the high-risk patients were treated with hormonal therapy plus chemotherapy.

Dr Joseph Sparano, professor of Medicine and Women’s Health at the Albert Einstein College of Medicine in New York, presented the results from the group of 6,700 intermediate risk women who were randomized to receive hormonal therapy alone or in combination with chemotherapy. After 9 years of follow-up, 83.3% of the volunteers, as Dr Sparano appropriately referred to them, who were treated with hormonal therapy were still cancer free, compared with 84.3% of those who also received chemotherapy, demonstrating no statistical benefit for the addition of chemotherapy. Of note, breast cancer experts discussing the trial, including Dr Lisa Carey, professor of Breast Cancer Research at the UNC Lineberger Cancer Institute in Chapel Hill, urged that younger women, under the age of 50, with recurrence scores (RS) toward the higher end of the intermediate risk group (RS, 16-25) should still discuss and consider chemotherapy with their physicians. In summary, all patients fitting the study criteria with low (
These landmark and practice changing results mean that each year about 60,000 women in the United States will be spared the side effects of toxic drugs. These 10,273 study volunteers are true heroes to the women who will be diagnosed with breast cancer in coming years.

In the field of lung cancer, many new trial results using immunotherapy were presented, with the most talked about being single-agent pembrolizumab, a PD1 inhibitor, improving survival over traditional chemotherapy in patients with PD-L1 positive tumors, which comprise the majority of squamous cell and adenocarcinomas of the lung. Also in the plenary, Dr Gilberto Lopes of the Sylvester Cancer Center at the University of Miami, presented these results from the KEYNOTE-042 study. In patients with PD-L1 tumor proportion score (TPS) of >1%, the benefit in overall survival (OS) of pembrolizumab compared with chemotherapy was 16.7 versus 12.1 months, respectively (HR, 0.81). In those patients with a TPS of >20%, the OS benefit was 17.7 versus 1.0 months (HR, 0.77), and in the group with a TPS of >50%, the benefit was 20.0 versus 12.2 months (HR, 0.69). Overall, the quality of life and the occurrence of side effects were substantially better for those patients receiving immunotherapy alone. Other findings presented at the meeting demonstrated the benefit of adding immunotherapy to chemotherapy and of treating with combination immunotherapy (PD-1 and CTLA-4 inhibitors). Many options now exist, much work remains to be done, and accrual to clinical trials is more important than ever.

Another plenary session trial evaluated the benefit of performing a nephrectomy in patients with advanced or metastatic renal cell carcinoma (RCC), a long-held and practiced standard of care. Dr Arnaud Mejean of Paris Descartes University presented findings from the CARMENA trial, which randomized 450 patients with metastatic clear cell RCC to receive cytoreductive nephrectomy followed by sunitinib, or sunitinib alone. The OS results of 18.4 versus 13.9 months, respectively (HR, 0.89) favored sunitinib alone in this noninferiority analysis. Other endpoints lined up in favor of not removing the cancerous kidney, and the presenter and discussants were united in their opinion of the results and the resulting change in doing less surgery in these patients.

In a step away from less therapy, the European Pediatric Soft Tissue Sarcoma Study showed that adding 6 months of low-dose maintenance chemotherapy after standard intensive therapy improves survival in children with high-risk rhabdomyosarcoma. The addition of a vinorelbine and cyclophosphamide low-dose regimen improved 5-year disease-free survival from 69.8% to 77.6% (HR, 0.68) and OS from 73.7% to 86.5% (HR, 0.52) as presented by Dr Gianni Bisogno, University of Padovani, Italy. The maintenance regimen showed no increase in toxicity and actually fewer infections were noted.

In the area of molecular profiling, multiple studies at the meeting demonstrated the importance of assessing cancers for mutations as outstanding results were seen with therapies for NTRK, RET, ROS, and MSI-high driven tumors. In a debate on the role of molecular profiling, I had the opportunity to declare and support our position at Sarah Cannon that all patients with relapsed or metastatic cancers should have this testing performed. It will be through better understanding of the biology of these cancers that we will advance the field for all patients while sometimes finding a target or mutation that will dramatically change the life of a patient.

In keeping with the meeting’s theme, Delivering Discoveries: Expanding the Reach of Precision Medicine, the presentations and the discussions clearly demonstrated that through the use of precision medicine techniques such as prognostic gene assays and molecular profiling, patients can receive the best therapy, even “tailored” therapy, which may often actually be less therapy. It is an exciting time in cancer research, and I have never been more optimistic about the future of cancer treatment for our patients.

A record-setting 40,000-plus oncology professionals attended this year’s annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago. The outstanding education and scientific program, with the theme of Delivering Discoveries: Expanding the Reach of Precision Medicine, was planned and led by ASCO President Dr Bruce Johnson, professor and director of Thoracic Oncology at the Dana Farber Cancer Institute in Boston, and chaired by Sarah Cannon’s Dr David Spigel and Harvard’s Dr Ann Partridge. A recurring finding throughout the meeting was that “less is more” in several key areas of cancer therapy. From small molecules targeting driver mutations across various tumors to the application of immunotherapy in subsets of common cancers, it is clear that more patients are experiencing dramatic results from novel approaches.

A featured plenary session trial was TAILORx, a study of 10,273 women with hormone-receptor–positive, surgically resected breast cancer that had not spread to the lymph nodes, was less than 5 cm, and was not positive for the HER2 gene amplification. This clinical trial was sponsored by the NCI and initiated in 2006. It used the OncotypeDX genetic test to stratify patients into groups of low, intermediate, or high risk for recurrence. The low-risk patients received only hormonal therapy, and the high-risk patients were treated with hormonal therapy plus chemotherapy.

Dr Joseph Sparano, professor of Medicine and Women’s Health at the Albert Einstein College of Medicine in New York, presented the results from the group of 6,700 intermediate risk women who were randomized to receive hormonal therapy alone or in combination with chemotherapy. After 9 years of follow-up, 83.3% of the volunteers, as Dr Sparano appropriately referred to them, who were treated with hormonal therapy were still cancer free, compared with 84.3% of those who also received chemotherapy, demonstrating no statistical benefit for the addition of chemotherapy. Of note, breast cancer experts discussing the trial, including Dr Lisa Carey, professor of Breast Cancer Research at the UNC Lineberger Cancer Institute in Chapel Hill, urged that younger women, under the age of 50, with recurrence scores (RS) toward the higher end of the intermediate risk group (RS, 16-25) should still discuss and consider chemotherapy with their physicians. In summary, all patients fitting the study criteria with low (
These landmark and practice changing results mean that each year about 60,000 women in the United States will be spared the side effects of toxic drugs. These 10,273 study volunteers are true heroes to the women who will be diagnosed with breast cancer in coming years.

In the field of lung cancer, many new trial results using immunotherapy were presented, with the most talked about being single-agent pembrolizumab, a PD1 inhibitor, improving survival over traditional chemotherapy in patients with PD-L1 positive tumors, which comprise the majority of squamous cell and adenocarcinomas of the lung. Also in the plenary, Dr Gilberto Lopes of the Sylvester Cancer Center at the University of Miami, presented these results from the KEYNOTE-042 study. In patients with PD-L1 tumor proportion score (TPS) of >1%, the benefit in overall survival (OS) of pembrolizumab compared with chemotherapy was 16.7 versus 12.1 months, respectively (HR, 0.81). In those patients with a TPS of >20%, the OS benefit was 17.7 versus 1.0 months (HR, 0.77), and in the group with a TPS of >50%, the benefit was 20.0 versus 12.2 months (HR, 0.69). Overall, the quality of life and the occurrence of side effects were substantially better for those patients receiving immunotherapy alone. Other findings presented at the meeting demonstrated the benefit of adding immunotherapy to chemotherapy and of treating with combination immunotherapy (PD-1 and CTLA-4 inhibitors). Many options now exist, much work remains to be done, and accrual to clinical trials is more important than ever.

Another plenary session trial evaluated the benefit of performing a nephrectomy in patients with advanced or metastatic renal cell carcinoma (RCC), a long-held and practiced standard of care. Dr Arnaud Mejean of Paris Descartes University presented findings from the CARMENA trial, which randomized 450 patients with metastatic clear cell RCC to receive cytoreductive nephrectomy followed by sunitinib, or sunitinib alone. The OS results of 18.4 versus 13.9 months, respectively (HR, 0.89) favored sunitinib alone in this noninferiority analysis. Other endpoints lined up in favor of not removing the cancerous kidney, and the presenter and discussants were united in their opinion of the results and the resulting change in doing less surgery in these patients.

In a step away from less therapy, the European Pediatric Soft Tissue Sarcoma Study showed that adding 6 months of low-dose maintenance chemotherapy after standard intensive therapy improves survival in children with high-risk rhabdomyosarcoma. The addition of a vinorelbine and cyclophosphamide low-dose regimen improved 5-year disease-free survival from 69.8% to 77.6% (HR, 0.68) and OS from 73.7% to 86.5% (HR, 0.52) as presented by Dr Gianni Bisogno, University of Padovani, Italy. The maintenance regimen showed no increase in toxicity and actually fewer infections were noted.

In the area of molecular profiling, multiple studies at the meeting demonstrated the importance of assessing cancers for mutations as outstanding results were seen with therapies for NTRK, RET, ROS, and MSI-high driven tumors. In a debate on the role of molecular profiling, I had the opportunity to declare and support our position at Sarah Cannon that all patients with relapsed or metastatic cancers should have this testing performed. It will be through better understanding of the biology of these cancers that we will advance the field for all patients while sometimes finding a target or mutation that will dramatically change the life of a patient.

In keeping with the meeting’s theme, Delivering Discoveries: Expanding the Reach of Precision Medicine, the presentations and the discussions clearly demonstrated that through the use of precision medicine techniques such as prognostic gene assays and molecular profiling, patients can receive the best therapy, even “tailored” therapy, which may often actually be less therapy. It is an exciting time in cancer research, and I have never been more optimistic about the future of cancer treatment for our patients.

A major challenge to effective cancer treatment is the astounding level of heterogeneity that tumors display on many different fronts. Here, we discuss how a deeper appreciation of this heterogeneity and its impact is driving research efforts to better understand and tackle it and a radical rethink of treatment paradigms.

A complex and dynamic disease

The nonuniformity of cancer has long been appreciated, reflected most visibly in the variation of response to the same treatment across patients with the same type of tumor (inter-tumor heterogeneity). The extent of tumor heterogeneity is being fully realized only now, with the advent of next-generation sequencing technologies. Even within the same tumor, there can be significant heterogeneity from cell to cell (intra-tumor heterogeneity), yielding substantial complexity in cancer.

Heterogeneity reveals itself on many different levels. Histologically speaking, tumors are composed of a nonhomogenous mass of cells that vary in type and number. In terms of their molecular make-up, there is substantial variation in the types of molecular alterations observed, all the way down to the single cell level. In even more abstract terms, beyond the cancer itself, the microenvironment in which it resides can be highly heterogeneous, composed of a plethora of different supportive and tumor-infiltrating normal cells.

Heterogeneity can manifest spatially, reflecting differences in the composition of the primary tumor and tumors at secondary sites or across regions of the same tumor mass and temporally, at different time points across a tumor’s natural history. Evocative of the second law of thermodynamics, cancers generally become more diverse and complex over time.^1-3
 

A tale of 2 models

It is widely accepted that the transformation of a normal cell into a malignant one occurs with the acquisition of certain “hallmark” abilities, but there are myriad ways in which these can be attained.

The clonal evolution model

As cells divide, they randomly acquire mutations as a result of DNA damage. The clonal evolution model posits that cancer develops as the result of a multistep accumulation of a series of “driver” mutations that confer a promalignant advantage to the cell and ultimately fuel a cancerous hallmark.

This evolution can occur in a linear fashion, whereby the emergence of a new driver mutation conveys such a potent evolutionary advantage that it outcompetes all previous clones. There is limited evidence for linear evolution in most advanced human cancers; instead, they are thought to evolve predominantly through a process of branching evolution, in which multiple clones can diverge in parallel from a common ancestor through the acquisition of different driver mutations. This results in common clonal mutations that form the trunk of the cancer’s evolutionary tree and are shared by all cells and subclonal mutations, which make up the branches and differ from cell to cell.

More recently, several other mechanisms of clonal evolution have been proposed, including neutral evolution, a type of branching evolution in which there are no selective pressures and evolution occurs by random mutations occurring over time that lead to genetic drift, and punctuated evolution, in which there are short evolutionary bursts of hypermutation.^4,5
 

The CSC model

This model posits that the ability to form and sustain a cancer is restricted to a single cell type – the cancer stem cells – which have the unique capacity for self-renewal and differentiation. Although the forces of evolution are still involved in this model, they act on a hierarchy of cells, with stem cells sitting at the top. A tumor is derived from a single stem cell that has acquired a mutation, and the heterogeneity observed results both from the differentiation and the accumulation of mutations in CSCs.

Accumulated experimental evidence suggests that these models are not mutually exclusive and that they can all contribute to heterogeneity in varied amounts across different tumor types. What is clear is that heterogeneity and evolution are intricately intertwined in cancer development.^1,2,6
 

An unstable genome

Heterogeneity and evolution are fueled by genomic alterations and the genome instability that they foster. This genome instability can range from single base pair substitutions to a doubling of the entire genome and results from both exposure to exogenous mutagens (eg, chemicals and ultraviolet radiation) and genomic alterations that have an impact on important cellular processes (eg, DNA repair or replication).

Among the most common causes of genome instability are mutations in the DNA mismatch repair pathway proteins or in the proofreading polymerase enzymes. Genome instability is often associated with unique mutational signatures – characteristic combinations of mutations that arose as the result of the specific biological processes underlying them.⁷

Genome-wide analyses have begun to reveal these mutational signatures across the spectrum of human cancers. The Wellcome Sanger Institute’s Catalogue of Somatic Mutations in Cancer (COSMIC) database has generated a set of 30 mutational signatures based on analysis of almost 11,000 exomes and more than 1,000 whole genomes spanning 40 different cancer types, some of which have been linked with specific mutagenic processes, such as tobacco, UV radiation, and DNA repair deficiency (Table 1).⁸

Fueling resistance

Arguably, heterogeneity presents one of the most significant barriers to effective cancer therapy, and this has become increasingly true in the era of personalized medicine in which targeted therapies take aim at specific molecular abnormalities.

It is vital that drugs target the truncal alterations that are present in all cancer cells to ensure that the entire cancer is eradicated. However, it is not always possible to target these alterations, for example, at the present time tumor suppressor proteins like p53 are not druggable.

Even when truncal alterations have been targeted successfully, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) chromosomal rearrangements in non–small-cell lung cancer (NSCLC) and BRAF mutations in melanoma, the long-term efficacy of these drugs is almost invariably limited by the development of resistance.

Tumor heterogeneity and the clonal evolution it fuels are central drivers of resistance. Because tumors are dynamic and continue to evolve, anticancer treatments can act as a strong selective pressure and drive the emergence of drug-resistant subclones that allow the tumor to persist. In fact, study findings have revealed that small populations of resistant cells may be present before treatment. Thus, resistance may also occur as a result of the outgrowth of preexisting treatment-resistant cells that suddenly find that they acquire a survival advantage in the presence of a drug.^1,6
 

Tackling heterogeneity

Despite extensive clinical documentation of the existence of heterogeneity and its underlying mechanisms across a range of tumor types, the development of novel clinical trial designs and therapeutic strategies that account for its effects have only recently begun to be explored.

For the most part, this was because of a lack of effective methods for evaluating intratumor heterogeneity. Multiregion biopsies, in which tissue derived from multiple different regions of a single tumor mass or from distinct cancerous lesions within the same patient, give a snapshot of tumor heterogeneity at a single point in time. The repeated longitudinal sampling required to gain a deeper appreciation of tumor heterogeneity over the course of tumor evolution is often not possible because of the morbidity associated with repeated surgical procedures.

Liquid biopsies, in which DNA sequencing can be performed on tumor components that are found circulating in the blood of cancer patients (including circulating tumor cells and cell-free circulating tumor DNA) have rapidly gained traction in the past several decades and offer an unprecedented opportunity for real-time assessment of evolving tumor heterogeneity.

They have proved to be highly sensitive and specific, with a high degree of concordance with tissue biopsy, they can identify both clonal and subclonal mutations, and they can detect resistance substantially earlier than radiographic imaging, which could permit earlier intervention.^10,11 The first liquid biopsy-based companion diagnostic test was approved by the US Food and Drug Administration in 2016, for the detection of EGFR mutations associated with NSCLC.

Yet, even liquid biopsy alone is not able to fully dissect the extent of tumor heterogeneity, especially because it is limited in its ability to assess spatial heterogeneity. Truly effective assessment of tumor heterogeneity is likely to require a combination of liquid biopsy, carefully selected tumor tissue biopsies, imaging diagnostics, and biomarkers.

The ongoing TRACERx (Tracking cancer evolution through therapy [Rx]) trials are evaluating a combination of approaches to follow tumor evolution across the course of treatment. The study in NSCLC began in 2014 with a target enrollment of 842 patients and will follow patients over 6 years. Preliminary data from the first 100 patients were recently published and demonstrated that increased intratumor heterogeneity correlated with increased risk of recurrence or death.¹²

If patients consent, the TRACERx trials also feed into the PEACE (Posthumous evaluation of advanced cancer environment) trials, which are collecting postmortem biopsies to further evaluate tumor heterogeneity and evolution. TRACERx trials in several other cancer types are now also underway.
 

Cutting off the source

The main therapeutic strategies for overcoming tumor heterogeneity are focused on the mechanisms of resistance that it drives. It is becoming increasingly apparent that rationally designed combinations of drugs are likely to be required and might need to be administered early in the course of disease to prevent resistance.

However, according to mathematical modeling studies, combinations of at least 3 drugs may be necessary.¹³ In many cases, this is unlikely to be feasible owing to the unavailability of drugs for certain targets and issues of toxicity, as well as the high cost.

An alternative strategy is to use immunotherapy, because a single treatment can target multiple neoantigens simultaneously. Although immunotherapy has proved to be a highly effective treatment paradigm in multiple tumor types, resistance still arises through varied mechanisms with tumor heterogeneity at their core.^14,15

A promising avenue for drug development is to cut off the source of tumor heterogeneity – genomic instability and the mutagenic processes that foster it (Table 2). This is exemplified by the success of poly(ADP-ribose) polymerase (PARP) inhibitors in patients with breast cancer susceptibility (BRCA1/2) gene mutations.

A new paradigm

Treatment of a tumor is one of the major selective pressures that shapes its evolution and recent evidence has emerged that these selective pressures can be highly dynamic. Study findings have shown that there is a cost associated with evolution of resistant subclones and, if the selective pressure of therapy is removed, that cost may become too high, such that resistant subclones are then outcompeted by drug-sensitive ones. There have been reports of reversal of drug resistance when drug treatment is interrupted.

The current treatment paradigm is to try to eliminate tumors by hitting them hard and fast with the maximum tolerated dose (MTD) of a drug. However, there is increasing appreciation that this may be inadvertently fostering more rapid disease progression because it selects for the emergence of resistant cells and eliminates all their competitors (Figure 2).

A major challenge to effective cancer treatment is the astounding level of heterogeneity that tumors display on many different fronts. Here, we discuss how a deeper appreciation of this heterogeneity and its impact is driving research efforts to better understand and tackle it and a radical rethink of treatment paradigms.

A complex and dynamic disease

The nonuniformity of cancer has long been appreciated, reflected most visibly in the variation of response to the same treatment across patients with the same type of tumor (inter-tumor heterogeneity). The extent of tumor heterogeneity is being fully realized only now, with the advent of next-generation sequencing technologies. Even within the same tumor, there can be significant heterogeneity from cell to cell (intra-tumor heterogeneity), yielding substantial complexity in cancer.

Heterogeneity reveals itself on many different levels. Histologically speaking, tumors are composed of a nonhomogenous mass of cells that vary in type and number. In terms of their molecular make-up, there is substantial variation in the types of molecular alterations observed, all the way down to the single cell level. In even more abstract terms, beyond the cancer itself, the microenvironment in which it resides can be highly heterogeneous, composed of a plethora of different supportive and tumor-infiltrating normal cells.

Heterogeneity can manifest spatially, reflecting differences in the composition of the primary tumor and tumors at secondary sites or across regions of the same tumor mass and temporally, at different time points across a tumor’s natural history. Evocative of the second law of thermodynamics, cancers generally become more diverse and complex over time.^1-3
 

A tale of 2 models

It is widely accepted that the transformation of a normal cell into a malignant one occurs with the acquisition of certain “hallmark” abilities, but there are myriad ways in which these can be attained.

The clonal evolution model

As cells divide, they randomly acquire mutations as a result of DNA damage. The clonal evolution model posits that cancer develops as the result of a multistep accumulation of a series of “driver” mutations that confer a promalignant advantage to the cell and ultimately fuel a cancerous hallmark.

This evolution can occur in a linear fashion, whereby the emergence of a new driver mutation conveys such a potent evolutionary advantage that it outcompetes all previous clones. There is limited evidence for linear evolution in most advanced human cancers; instead, they are thought to evolve predominantly through a process of branching evolution, in which multiple clones can diverge in parallel from a common ancestor through the acquisition of different driver mutations. This results in common clonal mutations that form the trunk of the cancer’s evolutionary tree and are shared by all cells and subclonal mutations, which make up the branches and differ from cell to cell.

More recently, several other mechanisms of clonal evolution have been proposed, including neutral evolution, a type of branching evolution in which there are no selective pressures and evolution occurs by random mutations occurring over time that lead to genetic drift, and punctuated evolution, in which there are short evolutionary bursts of hypermutation.^4,5
 

The CSC model

This model posits that the ability to form and sustain a cancer is restricted to a single cell type – the cancer stem cells – which have the unique capacity for self-renewal and differentiation. Although the forces of evolution are still involved in this model, they act on a hierarchy of cells, with stem cells sitting at the top. A tumor is derived from a single stem cell that has acquired a mutation, and the heterogeneity observed results both from the differentiation and the accumulation of mutations in CSCs.

Accumulated experimental evidence suggests that these models are not mutually exclusive and that they can all contribute to heterogeneity in varied amounts across different tumor types. What is clear is that heterogeneity and evolution are intricately intertwined in cancer development.^1,2,6
 

An unstable genome

Heterogeneity and evolution are fueled by genomic alterations and the genome instability that they foster. This genome instability can range from single base pair substitutions to a doubling of the entire genome and results from both exposure to exogenous mutagens (eg, chemicals and ultraviolet radiation) and genomic alterations that have an impact on important cellular processes (eg, DNA repair or replication).

Among the most common causes of genome instability are mutations in the DNA mismatch repair pathway proteins or in the proofreading polymerase enzymes. Genome instability is often associated with unique mutational signatures – characteristic combinations of mutations that arose as the result of the specific biological processes underlying them.⁷

Genome-wide analyses have begun to reveal these mutational signatures across the spectrum of human cancers. The Wellcome Sanger Institute’s Catalogue of Somatic Mutations in Cancer (COSMIC) database has generated a set of 30 mutational signatures based on analysis of almost 11,000 exomes and more than 1,000 whole genomes spanning 40 different cancer types, some of which have been linked with specific mutagenic processes, such as tobacco, UV radiation, and DNA repair deficiency (Table 1).⁸

Fueling resistance

Arguably, heterogeneity presents one of the most significant barriers to effective cancer therapy, and this has become increasingly true in the era of personalized medicine in which targeted therapies take aim at specific molecular abnormalities.

It is vital that drugs target the truncal alterations that are present in all cancer cells to ensure that the entire cancer is eradicated. However, it is not always possible to target these alterations, for example, at the present time tumor suppressor proteins like p53 are not druggable.

Even when truncal alterations have been targeted successfully, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) chromosomal rearrangements in non–small-cell lung cancer (NSCLC) and BRAF mutations in melanoma, the long-term efficacy of these drugs is almost invariably limited by the development of resistance.

Tumor heterogeneity and the clonal evolution it fuels are central drivers of resistance. Because tumors are dynamic and continue to evolve, anticancer treatments can act as a strong selective pressure and drive the emergence of drug-resistant subclones that allow the tumor to persist. In fact, study findings have revealed that small populations of resistant cells may be present before treatment. Thus, resistance may also occur as a result of the outgrowth of preexisting treatment-resistant cells that suddenly find that they acquire a survival advantage in the presence of a drug.^1,6
 

Tackling heterogeneity

Despite extensive clinical documentation of the existence of heterogeneity and its underlying mechanisms across a range of tumor types, the development of novel clinical trial designs and therapeutic strategies that account for its effects have only recently begun to be explored.

For the most part, this was because of a lack of effective methods for evaluating intratumor heterogeneity. Multiregion biopsies, in which tissue derived from multiple different regions of a single tumor mass or from distinct cancerous lesions within the same patient, give a snapshot of tumor heterogeneity at a single point in time. The repeated longitudinal sampling required to gain a deeper appreciation of tumor heterogeneity over the course of tumor evolution is often not possible because of the morbidity associated with repeated surgical procedures.

Liquid biopsies, in which DNA sequencing can be performed on tumor components that are found circulating in the blood of cancer patients (including circulating tumor cells and cell-free circulating tumor DNA) have rapidly gained traction in the past several decades and offer an unprecedented opportunity for real-time assessment of evolving tumor heterogeneity.

They have proved to be highly sensitive and specific, with a high degree of concordance with tissue biopsy, they can identify both clonal and subclonal mutations, and they can detect resistance substantially earlier than radiographic imaging, which could permit earlier intervention.^10,11 The first liquid biopsy-based companion diagnostic test was approved by the US Food and Drug Administration in 2016, for the detection of EGFR mutations associated with NSCLC.

Yet, even liquid biopsy alone is not able to fully dissect the extent of tumor heterogeneity, especially because it is limited in its ability to assess spatial heterogeneity. Truly effective assessment of tumor heterogeneity is likely to require a combination of liquid biopsy, carefully selected tumor tissue biopsies, imaging diagnostics, and biomarkers.

The ongoing TRACERx (Tracking cancer evolution through therapy [Rx]) trials are evaluating a combination of approaches to follow tumor evolution across the course of treatment. The study in NSCLC began in 2014 with a target enrollment of 842 patients and will follow patients over 6 years. Preliminary data from the first 100 patients were recently published and demonstrated that increased intratumor heterogeneity correlated with increased risk of recurrence or death.¹²

If patients consent, the TRACERx trials also feed into the PEACE (Posthumous evaluation of advanced cancer environment) trials, which are collecting postmortem biopsies to further evaluate tumor heterogeneity and evolution. TRACERx trials in several other cancer types are now also underway.
 

Cutting off the source

The main therapeutic strategies for overcoming tumor heterogeneity are focused on the mechanisms of resistance that it drives. It is becoming increasingly apparent that rationally designed combinations of drugs are likely to be required and might need to be administered early in the course of disease to prevent resistance.

However, according to mathematical modeling studies, combinations of at least 3 drugs may be necessary.¹³ In many cases, this is unlikely to be feasible owing to the unavailability of drugs for certain targets and issues of toxicity, as well as the high cost.

An alternative strategy is to use immunotherapy, because a single treatment can target multiple neoantigens simultaneously. Although immunotherapy has proved to be a highly effective treatment paradigm in multiple tumor types, resistance still arises through varied mechanisms with tumor heterogeneity at their core.^14,15

A promising avenue for drug development is to cut off the source of tumor heterogeneity – genomic instability and the mutagenic processes that foster it (Table 2). This is exemplified by the success of poly(ADP-ribose) polymerase (PARP) inhibitors in patients with breast cancer susceptibility (BRCA1/2) gene mutations.

A new paradigm

Treatment of a tumor is one of the major selective pressures that shapes its evolution and recent evidence has emerged that these selective pressures can be highly dynamic. Study findings have shown that there is a cost associated with evolution of resistant subclones and, if the selective pressure of therapy is removed, that cost may become too high, such that resistant subclones are then outcompeted by drug-sensitive ones. There have been reports of reversal of drug resistance when drug treatment is interrupted.

The current treatment paradigm is to try to eliminate tumors by hitting them hard and fast with the maximum tolerated dose (MTD) of a drug. However, there is increasing appreciation that this may be inadvertently fostering more rapid disease progression because it selects for the emergence of resistant cells and eliminates all their competitors (Figure 2).

A major challenge to effective cancer treatment is the astounding level of heterogeneity that tumors display on many different fronts. Here, we discuss how a deeper appreciation of this heterogeneity and its impact is driving research efforts to better understand and tackle it and a radical rethink of treatment paradigms.

A complex and dynamic disease

The nonuniformity of cancer has long been appreciated, reflected most visibly in the variation of response to the same treatment across patients with the same type of tumor (inter-tumor heterogeneity). The extent of tumor heterogeneity is being fully realized only now, with the advent of next-generation sequencing technologies. Even within the same tumor, there can be significant heterogeneity from cell to cell (intra-tumor heterogeneity), yielding substantial complexity in cancer.

Heterogeneity reveals itself on many different levels. Histologically speaking, tumors are composed of a nonhomogenous mass of cells that vary in type and number. In terms of their molecular make-up, there is substantial variation in the types of molecular alterations observed, all the way down to the single cell level. In even more abstract terms, beyond the cancer itself, the microenvironment in which it resides can be highly heterogeneous, composed of a plethora of different supportive and tumor-infiltrating normal cells.

Heterogeneity can manifest spatially, reflecting differences in the composition of the primary tumor and tumors at secondary sites or across regions of the same tumor mass and temporally, at different time points across a tumor’s natural history. Evocative of the second law of thermodynamics, cancers generally become more diverse and complex over time.^1-3
 

A tale of 2 models

It is widely accepted that the transformation of a normal cell into a malignant one occurs with the acquisition of certain “hallmark” abilities, but there are myriad ways in which these can be attained.

The clonal evolution model

As cells divide, they randomly acquire mutations as a result of DNA damage. The clonal evolution model posits that cancer develops as the result of a multistep accumulation of a series of “driver” mutations that confer a promalignant advantage to the cell and ultimately fuel a cancerous hallmark.

This evolution can occur in a linear fashion, whereby the emergence of a new driver mutation conveys such a potent evolutionary advantage that it outcompetes all previous clones. There is limited evidence for linear evolution in most advanced human cancers; instead, they are thought to evolve predominantly through a process of branching evolution, in which multiple clones can diverge in parallel from a common ancestor through the acquisition of different driver mutations. This results in common clonal mutations that form the trunk of the cancer’s evolutionary tree and are shared by all cells and subclonal mutations, which make up the branches and differ from cell to cell.

More recently, several other mechanisms of clonal evolution have been proposed, including neutral evolution, a type of branching evolution in which there are no selective pressures and evolution occurs by random mutations occurring over time that lead to genetic drift, and punctuated evolution, in which there are short evolutionary bursts of hypermutation.^4,5
 

The CSC model

This model posits that the ability to form and sustain a cancer is restricted to a single cell type – the cancer stem cells – which have the unique capacity for self-renewal and differentiation. Although the forces of evolution are still involved in this model, they act on a hierarchy of cells, with stem cells sitting at the top. A tumor is derived from a single stem cell that has acquired a mutation, and the heterogeneity observed results both from the differentiation and the accumulation of mutations in CSCs.

Accumulated experimental evidence suggests that these models are not mutually exclusive and that they can all contribute to heterogeneity in varied amounts across different tumor types. What is clear is that heterogeneity and evolution are intricately intertwined in cancer development.^1,2,6
 

An unstable genome

Heterogeneity and evolution are fueled by genomic alterations and the genome instability that they foster. This genome instability can range from single base pair substitutions to a doubling of the entire genome and results from both exposure to exogenous mutagens (eg, chemicals and ultraviolet radiation) and genomic alterations that have an impact on important cellular processes (eg, DNA repair or replication).

Among the most common causes of genome instability are mutations in the DNA mismatch repair pathway proteins or in the proofreading polymerase enzymes. Genome instability is often associated with unique mutational signatures – characteristic combinations of mutations that arose as the result of the specific biological processes underlying them.⁷

Genome-wide analyses have begun to reveal these mutational signatures across the spectrum of human cancers. The Wellcome Sanger Institute’s Catalogue of Somatic Mutations in Cancer (COSMIC) database has generated a set of 30 mutational signatures based on analysis of almost 11,000 exomes and more than 1,000 whole genomes spanning 40 different cancer types, some of which have been linked with specific mutagenic processes, such as tobacco, UV radiation, and DNA repair deficiency (Table 1).⁸

Fueling resistance

Arguably, heterogeneity presents one of the most significant barriers to effective cancer therapy, and this has become increasingly true in the era of personalized medicine in which targeted therapies take aim at specific molecular abnormalities.

It is vital that drugs target the truncal alterations that are present in all cancer cells to ensure that the entire cancer is eradicated. However, it is not always possible to target these alterations, for example, at the present time tumor suppressor proteins like p53 are not druggable.

Even when truncal alterations have been targeted successfully, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) chromosomal rearrangements in non–small-cell lung cancer (NSCLC) and BRAF mutations in melanoma, the long-term efficacy of these drugs is almost invariably limited by the development of resistance.

Tumor heterogeneity and the clonal evolution it fuels are central drivers of resistance. Because tumors are dynamic and continue to evolve, anticancer treatments can act as a strong selective pressure and drive the emergence of drug-resistant subclones that allow the tumor to persist. In fact, study findings have revealed that small populations of resistant cells may be present before treatment. Thus, resistance may also occur as a result of the outgrowth of preexisting treatment-resistant cells that suddenly find that they acquire a survival advantage in the presence of a drug.^1,6
 

Tackling heterogeneity

Despite extensive clinical documentation of the existence of heterogeneity and its underlying mechanisms across a range of tumor types, the development of novel clinical trial designs and therapeutic strategies that account for its effects have only recently begun to be explored.

For the most part, this was because of a lack of effective methods for evaluating intratumor heterogeneity. Multiregion biopsies, in which tissue derived from multiple different regions of a single tumor mass or from distinct cancerous lesions within the same patient, give a snapshot of tumor heterogeneity at a single point in time. The repeated longitudinal sampling required to gain a deeper appreciation of tumor heterogeneity over the course of tumor evolution is often not possible because of the morbidity associated with repeated surgical procedures.

Liquid biopsies, in which DNA sequencing can be performed on tumor components that are found circulating in the blood of cancer patients (including circulating tumor cells and cell-free circulating tumor DNA) have rapidly gained traction in the past several decades and offer an unprecedented opportunity for real-time assessment of evolving tumor heterogeneity.

They have proved to be highly sensitive and specific, with a high degree of concordance with tissue biopsy, they can identify both clonal and subclonal mutations, and they can detect resistance substantially earlier than radiographic imaging, which could permit earlier intervention.^10,11 The first liquid biopsy-based companion diagnostic test was approved by the US Food and Drug Administration in 2016, for the detection of EGFR mutations associated with NSCLC.

Yet, even liquid biopsy alone is not able to fully dissect the extent of tumor heterogeneity, especially because it is limited in its ability to assess spatial heterogeneity. Truly effective assessment of tumor heterogeneity is likely to require a combination of liquid biopsy, carefully selected tumor tissue biopsies, imaging diagnostics, and biomarkers.

The ongoing TRACERx (Tracking cancer evolution through therapy [Rx]) trials are evaluating a combination of approaches to follow tumor evolution across the course of treatment. The study in NSCLC began in 2014 with a target enrollment of 842 patients and will follow patients over 6 years. Preliminary data from the first 100 patients were recently published and demonstrated that increased intratumor heterogeneity correlated with increased risk of recurrence or death.¹²

If patients consent, the TRACERx trials also feed into the PEACE (Posthumous evaluation of advanced cancer environment) trials, which are collecting postmortem biopsies to further evaluate tumor heterogeneity and evolution. TRACERx trials in several other cancer types are now also underway.
 

Cutting off the source

The main therapeutic strategies for overcoming tumor heterogeneity are focused on the mechanisms of resistance that it drives. It is becoming increasingly apparent that rationally designed combinations of drugs are likely to be required and might need to be administered early in the course of disease to prevent resistance.

However, according to mathematical modeling studies, combinations of at least 3 drugs may be necessary.¹³ In many cases, this is unlikely to be feasible owing to the unavailability of drugs for certain targets and issues of toxicity, as well as the high cost.

An alternative strategy is to use immunotherapy, because a single treatment can target multiple neoantigens simultaneously. Although immunotherapy has proved to be a highly effective treatment paradigm in multiple tumor types, resistance still arises through varied mechanisms with tumor heterogeneity at their core.^14,15

A promising avenue for drug development is to cut off the source of tumor heterogeneity – genomic instability and the mutagenic processes that foster it (Table 2). This is exemplified by the success of poly(ADP-ribose) polymerase (PARP) inhibitors in patients with breast cancer susceptibility (BRCA1/2) gene mutations.

A new paradigm

Treatment of a tumor is one of the major selective pressures that shapes its evolution and recent evidence has emerged that these selective pressures can be highly dynamic. Study findings have shown that there is a cost associated with evolution of resistant subclones and, if the selective pressure of therapy is removed, that cost may become too high, such that resistant subclones are then outcompeted by drug-sensitive ones. There have been reports of reversal of drug resistance when drug treatment is interrupted.

The current treatment paradigm is to try to eliminate tumors by hitting them hard and fast with the maximum tolerated dose (MTD) of a drug. However, there is increasing appreciation that this may be inadvertently fostering more rapid disease progression because it selects for the emergence of resistant cells and eliminates all their competitors (Figure 2).

Vitamin D status does not appear to have any effect on the risk of gestational hypertension or preeclampsia, regardless of a woman’s genetic risk profile for vitamin D deficiency.

Writing in the June 21 online edition of the BMJ, researchers reported the results of one- and two-sample mendelian randomization analyses of two pregnancy cohort studies and two case-control studies.

Overall, 7,389 women were included in the one-sample mendelian randomization analysis – 751 with gestational hypertension and 135 with preeclampsia. The two-sample analysis included 3,388 women with preeclampsia and 6,059 controls.

In a conventional multivariable analysis, researchers saw a 3% increase in the relative risk of preeclampsia for each 10% decrease in 25-hydroxyvitamin D levels. However, there was a doubling of risk in women whose 25-hydroxyvitamin D levels were below 25 nmol/L, compared with those with levels at or above 75 nmol/L, but no effect seen for gestational hypertension.

However, in the one-sample mendelian randomization analysis – using genetic risk score as an instrument – the authors saw no clear sign of a linear relationship between 25-hydroxyvitamin D levels and the risk of gestational hypertension or preeclampsia.

The two-sample mendelian randomization analysis showed an odds ratio for preeclampsia of 0.98 per 10% decrease in 25-hydroxyvitamin D level.

“We explored the association between the genetic instruments and intake of vitamin D supplements because, if women with lower genetically predicted 25-hydroxyvitamin D levels are more likely to take supplements, this could theoretically distort our findings,” wrote Maria C. Magnus, PhD, of the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (England) and her coauthors.

They noted that the proportion of women taking vitamin D supplements during pregnancy differed between the two cohorts, which may have reflected cultural, socioeconomic, or policy difference.

The U.S. Institute of Medicine currently recommends that pregnant and lactating women have a dietary intake of 600 IU (15 mcg) of vitamin D per day.

While this study found no strong evidence to support a causal effect of vitamin D status on the risk of gestational hypertension or preeclampsia, the study’s authors suggested similar studies with larger numbers of women with preeclampsia were still needed to definitely establish this.

The study was supported by the European Union and the Research Council of Norway. One author declared funding from the pharmaceutical industry for unrelated research, and several authors declared funding from other institutions. No conflicts of interest were declared.

SOURCE: Magnus MC et al. BMJ. 2018 Jun 21. doi: 10.1136/bmj.k2167.

Vitamin D status does not appear to have any effect on the risk of gestational hypertension or preeclampsia, regardless of a woman’s genetic risk profile for vitamin D deficiency.

Writing in the June 21 online edition of the BMJ, researchers reported the results of one- and two-sample mendelian randomization analyses of two pregnancy cohort studies and two case-control studies.

Overall, 7,389 women were included in the one-sample mendelian randomization analysis – 751 with gestational hypertension and 135 with preeclampsia. The two-sample analysis included 3,388 women with preeclampsia and 6,059 controls.

In a conventional multivariable analysis, researchers saw a 3% increase in the relative risk of preeclampsia for each 10% decrease in 25-hydroxyvitamin D levels. However, there was a doubling of risk in women whose 25-hydroxyvitamin D levels were below 25 nmol/L, compared with those with levels at or above 75 nmol/L, but no effect seen for gestational hypertension.

However, in the one-sample mendelian randomization analysis – using genetic risk score as an instrument – the authors saw no clear sign of a linear relationship between 25-hydroxyvitamin D levels and the risk of gestational hypertension or preeclampsia.

The two-sample mendelian randomization analysis showed an odds ratio for preeclampsia of 0.98 per 10% decrease in 25-hydroxyvitamin D level.

“We explored the association between the genetic instruments and intake of vitamin D supplements because, if women with lower genetically predicted 25-hydroxyvitamin D levels are more likely to take supplements, this could theoretically distort our findings,” wrote Maria C. Magnus, PhD, of the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (England) and her coauthors.

They noted that the proportion of women taking vitamin D supplements during pregnancy differed between the two cohorts, which may have reflected cultural, socioeconomic, or policy difference.

The U.S. Institute of Medicine currently recommends that pregnant and lactating women have a dietary intake of 600 IU (15 mcg) of vitamin D per day.

While this study found no strong evidence to support a causal effect of vitamin D status on the risk of gestational hypertension or preeclampsia, the study’s authors suggested similar studies with larger numbers of women with preeclampsia were still needed to definitely establish this.

The study was supported by the European Union and the Research Council of Norway. One author declared funding from the pharmaceutical industry for unrelated research, and several authors declared funding from other institutions. No conflicts of interest were declared.

SOURCE: Magnus MC et al. BMJ. 2018 Jun 21. doi: 10.1136/bmj.k2167.

Vitamin D status does not appear to have any effect on the risk of gestational hypertension or preeclampsia, regardless of a woman’s genetic risk profile for vitamin D deficiency.

Writing in the June 21 online edition of the BMJ, researchers reported the results of one- and two-sample mendelian randomization analyses of two pregnancy cohort studies and two case-control studies.

Overall, 7,389 women were included in the one-sample mendelian randomization analysis – 751 with gestational hypertension and 135 with preeclampsia. The two-sample analysis included 3,388 women with preeclampsia and 6,059 controls.

In a conventional multivariable analysis, researchers saw a 3% increase in the relative risk of preeclampsia for each 10% decrease in 25-hydroxyvitamin D levels. However, there was a doubling of risk in women whose 25-hydroxyvitamin D levels were below 25 nmol/L, compared with those with levels at or above 75 nmol/L, but no effect seen for gestational hypertension.

However, in the one-sample mendelian randomization analysis – using genetic risk score as an instrument – the authors saw no clear sign of a linear relationship between 25-hydroxyvitamin D levels and the risk of gestational hypertension or preeclampsia.

The two-sample mendelian randomization analysis showed an odds ratio for preeclampsia of 0.98 per 10% decrease in 25-hydroxyvitamin D level.

“We explored the association between the genetic instruments and intake of vitamin D supplements because, if women with lower genetically predicted 25-hydroxyvitamin D levels are more likely to take supplements, this could theoretically distort our findings,” wrote Maria C. Magnus, PhD, of the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (England) and her coauthors.

They noted that the proportion of women taking vitamin D supplements during pregnancy differed between the two cohorts, which may have reflected cultural, socioeconomic, or policy difference.

The U.S. Institute of Medicine currently recommends that pregnant and lactating women have a dietary intake of 600 IU (15 mcg) of vitamin D per day.

While this study found no strong evidence to support a causal effect of vitamin D status on the risk of gestational hypertension or preeclampsia, the study’s authors suggested similar studies with larger numbers of women with preeclampsia were still needed to definitely establish this.

The study was supported by the European Union and the Research Council of Norway. One author declared funding from the pharmaceutical industry for unrelated research, and several authors declared funding from other institutions. No conflicts of interest were declared.

SOURCE: Magnus MC et al. BMJ. 2018 Jun 21. doi: 10.1136/bmj.k2167.

The Food and Drug Administration has approved a fully implantable glucose sensor that works with mobile technology to transmit continuous information about blood glucose levels for people with diabetes.

The sensor-mobile app combo, called the Eversense Continuous Glucose Monitoring (CGM) system, is designed to supplant the need for frequent blood sampling to monitor blood glucose levels.

[email protected]

The Food and Drug Administration has approved a fully implantable glucose sensor that works with mobile technology to transmit continuous information about blood glucose levels for people with diabetes.

The sensor-mobile app combo, called the Eversense Continuous Glucose Monitoring (CGM) system, is designed to supplant the need for frequent blood sampling to monitor blood glucose levels.

[email protected]

The Food and Drug Administration has approved a fully implantable glucose sensor that works with mobile technology to transmit continuous information about blood glucose levels for people with diabetes.

The sensor-mobile app combo, called the Eversense Continuous Glucose Monitoring (CGM) system, is designed to supplant the need for frequent blood sampling to monitor blood glucose levels.

[email protected]

The Trump policy of separating children and teenagers from their parents after crossing the U.S. border has been called un-American, immoral, cruel, and inhumane. The policy thankfully has been reversed or at least subject to delay. However, as I write today, 2,300 children and their parents are separated, not in contact, lost to each other, and with no clear plan on reunification. The ultimate outcome of immigration legislation and policy is unknown and mired in partisan politics. The policy hopefully has changed permanently, but what are the harms that will persist?

U.S. Customs and Border Control

1. Many if not all of the 2,300 children taken from their parents to institutional settings will have suffered acute anxiety and despair. Following data gathered by René Spitz and John Bowlby 80 years ago, children forced to separate from their parents for long hospitalizations with limited visitation went through phases of protest, despair, and if repeated or lengthy separations, “detachment” that impaired their ability to form relationships.¹

2. Many of these children have suffered traumas in their country of origin and through the journey to the U.S. border. Some of this traumatic experience was mitigated by being in the presence of their parent(s). Very likely some children have psychiatric and physical disorders that will add to the level of risk. The current trauma, forcible separation by armed guards into restrictive facilities, will compound or intensify the previous traumas without the benefit of parental support.

3. Will the harms persist? Likely this level of trauma has such a strong neurologic and psychological impact that many of the children will suffer from nightmares, depression, and persistent anxiety about trusting the safety of their setting. These harms will impact their health, their ability to learn, their relationships, and may increase the risk of self-medication through use of substances.²

4. The parents who are jailed, have had their children removed, and do not know where they are and aren’t able to talk to them have suffered a massive trauma. We all have lost sight of a child for a minute or two in a store or on the beach. Our anxiety is immediate, and if the separation is longer, we may remember those frightening minutes for the rest of our lives. How many immigrant parents will develop depression and posttraumatic stress disorder?

5. Guards were ordered to be the front-line implementers of the policy and must have been torn between their sworn duty and their inner knowledge that what they are doing is wrong. Hearing the children crying and calling for their parents must have elicited painful feelings of what it would have been like to have their own children taken away with no way to reach them or knowing where they were taken. Implementing this policy dehumanized them, and I believe made them feel guilty or unworthy.

6. Millions of immigrants – whether lawful, dreamers, or undocumented – must have felt fearful, powerless, and angry about this policy. Millions of their children must have been worried and lost a little bit of faith in their parents and in the United States.

7. Did U.S. citizens, many from immigrant roots, wonder if this could happen to them? How many children felt a little less secure? Was the anxiety higher for descendants of the U.S. citizens remembering the trauma of the World War II Japanese internment camps? Other descendants (like me) will remember quite vividly their mother’s story of being on the St. Louis steam ship and being turned away from the United States to face a high likelihood of death in Nazi Germany. A bit of fear will replace trust in and loyalty to the United States.

Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email him at [email protected].
 

References:

1. Dev Psychol. 1992;28:759-75.

2. www.cdc.gov/violenceprevention/acestudy/index.html

The Trump policy of separating children and teenagers from their parents after crossing the U.S. border has been called un-American, immoral, cruel, and inhumane. The policy thankfully has been reversed or at least subject to delay. However, as I write today, 2,300 children and their parents are separated, not in contact, lost to each other, and with no clear plan on reunification. The ultimate outcome of immigration legislation and policy is unknown and mired in partisan politics. The policy hopefully has changed permanently, but what are the harms that will persist?

U.S. Customs and Border Control

1. Many if not all of the 2,300 children taken from their parents to institutional settings will have suffered acute anxiety and despair. Following data gathered by René Spitz and John Bowlby 80 years ago, children forced to separate from their parents for long hospitalizations with limited visitation went through phases of protest, despair, and if repeated or lengthy separations, “detachment” that impaired their ability to form relationships.¹

2. Many of these children have suffered traumas in their country of origin and through the journey to the U.S. border. Some of this traumatic experience was mitigated by being in the presence of their parent(s). Very likely some children have psychiatric and physical disorders that will add to the level of risk. The current trauma, forcible separation by armed guards into restrictive facilities, will compound or intensify the previous traumas without the benefit of parental support.

3. Will the harms persist? Likely this level of trauma has such a strong neurologic and psychological impact that many of the children will suffer from nightmares, depression, and persistent anxiety about trusting the safety of their setting. These harms will impact their health, their ability to learn, their relationships, and may increase the risk of self-medication through use of substances.²

4. The parents who are jailed, have had their children removed, and do not know where they are and aren’t able to talk to them have suffered a massive trauma. We all have lost sight of a child for a minute or two in a store or on the beach. Our anxiety is immediate, and if the separation is longer, we may remember those frightening minutes for the rest of our lives. How many immigrant parents will develop depression and posttraumatic stress disorder?

5. Guards were ordered to be the front-line implementers of the policy and must have been torn between their sworn duty and their inner knowledge that what they are doing is wrong. Hearing the children crying and calling for their parents must have elicited painful feelings of what it would have been like to have their own children taken away with no way to reach them or knowing where they were taken. Implementing this policy dehumanized them, and I believe made them feel guilty or unworthy.

6. Millions of immigrants – whether lawful, dreamers, or undocumented – must have felt fearful, powerless, and angry about this policy. Millions of their children must have been worried and lost a little bit of faith in their parents and in the United States.

7. Did U.S. citizens, many from immigrant roots, wonder if this could happen to them? How many children felt a little less secure? Was the anxiety higher for descendants of the U.S. citizens remembering the trauma of the World War II Japanese internment camps? Other descendants (like me) will remember quite vividly their mother’s story of being on the St. Louis steam ship and being turned away from the United States to face a high likelihood of death in Nazi Germany. A bit of fear will replace trust in and loyalty to the United States.

Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email him at [email protected].
 

References:

1. Dev Psychol. 1992;28:759-75.

2. www.cdc.gov/violenceprevention/acestudy/index.html

The Trump policy of separating children and teenagers from their parents after crossing the U.S. border has been called un-American, immoral, cruel, and inhumane. The policy thankfully has been reversed or at least subject to delay. However, as I write today, 2,300 children and their parents are separated, not in contact, lost to each other, and with no clear plan on reunification. The ultimate outcome of immigration legislation and policy is unknown and mired in partisan politics. The policy hopefully has changed permanently, but what are the harms that will persist?

U.S. Customs and Border Control

1. Many if not all of the 2,300 children taken from their parents to institutional settings will have suffered acute anxiety and despair. Following data gathered by René Spitz and John Bowlby 80 years ago, children forced to separate from their parents for long hospitalizations with limited visitation went through phases of protest, despair, and if repeated or lengthy separations, “detachment” that impaired their ability to form relationships.¹

2. Many of these children have suffered traumas in their country of origin and through the journey to the U.S. border. Some of this traumatic experience was mitigated by being in the presence of their parent(s). Very likely some children have psychiatric and physical disorders that will add to the level of risk. The current trauma, forcible separation by armed guards into restrictive facilities, will compound or intensify the previous traumas without the benefit of parental support.

3. Will the harms persist? Likely this level of trauma has such a strong neurologic and psychological impact that many of the children will suffer from nightmares, depression, and persistent anxiety about trusting the safety of their setting. These harms will impact their health, their ability to learn, their relationships, and may increase the risk of self-medication through use of substances.²

4. The parents who are jailed, have had their children removed, and do not know where they are and aren’t able to talk to them have suffered a massive trauma. We all have lost sight of a child for a minute or two in a store or on the beach. Our anxiety is immediate, and if the separation is longer, we may remember those frightening minutes for the rest of our lives. How many immigrant parents will develop depression and posttraumatic stress disorder?

5. Guards were ordered to be the front-line implementers of the policy and must have been torn between their sworn duty and their inner knowledge that what they are doing is wrong. Hearing the children crying and calling for their parents must have elicited painful feelings of what it would have been like to have their own children taken away with no way to reach them or knowing where they were taken. Implementing this policy dehumanized them, and I believe made them feel guilty or unworthy.

6. Millions of immigrants – whether lawful, dreamers, or undocumented – must have felt fearful, powerless, and angry about this policy. Millions of their children must have been worried and lost a little bit of faith in their parents and in the United States.

7. Did U.S. citizens, many from immigrant roots, wonder if this could happen to them? How many children felt a little less secure? Was the anxiety higher for descendants of the U.S. citizens remembering the trauma of the World War II Japanese internment camps? Other descendants (like me) will remember quite vividly their mother’s story of being on the St. Louis steam ship and being turned away from the United States to face a high likelihood of death in Nazi Germany. A bit of fear will replace trust in and loyalty to the United States.

Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email him at [email protected].
 

References:

1. Dev Psychol. 1992;28:759-75.

2. www.cdc.gov/violenceprevention/acestudy/index.html

Quality, not quantity, is what Department of Health & Human Services Secretary Alex M. Azar II is looking for when it comes to physicians being paid through a value-based payment arrangement.

“I am not sure that simply being in an alternative payment model, which was the metric the Obama administration used, is the one that I would find to be substantive and real in terms of transformation of our health care system,” Mr. Azar said June 20 at a forum hosted by the Washington Post.

Wikimedia Commons/WWsgConnect/CC-SA 4.0

The previous administration set a goal of having at least 50% of physician Medicare payments tied to quality by the end of this year. It’s first milestone of 30% by the end of 2016 was reached in March of that year.

The current administration may have had a tough time meeting the 50% goal because of changes it made to the Quality Payment Program exempted two-thirds of eligible clinicians from the Merit-Based Incentive Payment System track in 2018.

Mr. Azar said that he is working with the team at the Centers for Medicare & Medicaid Services to come up with a better way to determine whether paying for quality is effective.

“What I don’t want to do is have an approach where it’s a tag the base, hit a scorecard number,” he said. “We genuinely want to revolutionize how health care is paid for in this country in an outcome-based, health-based, non-procedure-, non-sickness-based way. We are working on that. We want to get to real concrete metrics.”

Mr. Azar also noted that the agency is working on “the concrete strategy for the Center for Medicare & Medicaid Innovation. That will also have dimensions for what we are doing within the fee-for-service program and Medicare Advantage around moving toward value-based payment arrangements.”

He praised the efforts of the Bush Administration and the Obama Administration as providing a good foundation for the transition to paying for quality and “we will build on that.”

[email protected]

Quality, not quantity, is what Department of Health & Human Services Secretary Alex M. Azar II is looking for when it comes to physicians being paid through a value-based payment arrangement.

“I am not sure that simply being in an alternative payment model, which was the metric the Obama administration used, is the one that I would find to be substantive and real in terms of transformation of our health care system,” Mr. Azar said June 20 at a forum hosted by the Washington Post.

Wikimedia Commons/WWsgConnect/CC-SA 4.0

The previous administration set a goal of having at least 50% of physician Medicare payments tied to quality by the end of this year. It’s first milestone of 30% by the end of 2016 was reached in March of that year.

The current administration may have had a tough time meeting the 50% goal because of changes it made to the Quality Payment Program exempted two-thirds of eligible clinicians from the Merit-Based Incentive Payment System track in 2018.

Mr. Azar said that he is working with the team at the Centers for Medicare & Medicaid Services to come up with a better way to determine whether paying for quality is effective.

“What I don’t want to do is have an approach where it’s a tag the base, hit a scorecard number,” he said. “We genuinely want to revolutionize how health care is paid for in this country in an outcome-based, health-based, non-procedure-, non-sickness-based way. We are working on that. We want to get to real concrete metrics.”

Mr. Azar also noted that the agency is working on “the concrete strategy for the Center for Medicare & Medicaid Innovation. That will also have dimensions for what we are doing within the fee-for-service program and Medicare Advantage around moving toward value-based payment arrangements.”

He praised the efforts of the Bush Administration and the Obama Administration as providing a good foundation for the transition to paying for quality and “we will build on that.”

[email protected]

Quality, not quantity, is what Department of Health & Human Services Secretary Alex M. Azar II is looking for when it comes to physicians being paid through a value-based payment arrangement.

“I am not sure that simply being in an alternative payment model, which was the metric the Obama administration used, is the one that I would find to be substantive and real in terms of transformation of our health care system,” Mr. Azar said June 20 at a forum hosted by the Washington Post.

Wikimedia Commons/WWsgConnect/CC-SA 4.0

The previous administration set a goal of having at least 50% of physician Medicare payments tied to quality by the end of this year. It’s first milestone of 30% by the end of 2016 was reached in March of that year.

The current administration may have had a tough time meeting the 50% goal because of changes it made to the Quality Payment Program exempted two-thirds of eligible clinicians from the Merit-Based Incentive Payment System track in 2018.

Mr. Azar said that he is working with the team at the Centers for Medicare & Medicaid Services to come up with a better way to determine whether paying for quality is effective.

“What I don’t want to do is have an approach where it’s a tag the base, hit a scorecard number,” he said. “We genuinely want to revolutionize how health care is paid for in this country in an outcome-based, health-based, non-procedure-, non-sickness-based way. We are working on that. We want to get to real concrete metrics.”

Mr. Azar also noted that the agency is working on “the concrete strategy for the Center for Medicare & Medicaid Innovation. That will also have dimensions for what we are doing within the fee-for-service program and Medicare Advantage around moving toward value-based payment arrangements.”

He praised the efforts of the Bush Administration and the Obama Administration as providing a good foundation for the transition to paying for quality and “we will build on that.”

[email protected]