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A case is building for personalized, genome-based radiation dosing
A team of researchers from the Cleveland Clinic, the Moffitt Cancer Center in Tampa, and Case Western Reserve University in Cleveland is zeroing in on a way to personalize radiation therapy for cancer patients based on genomic profile, much as genomics is used to tailor oncologic drug therapy.
It’s called “genomic-adjusted radiation dose” (GARD), a dose tailored to a person’s radiosensitivity as determined by the expression of 10 genes, known as the radiosensitivity index (RSI), combined with a linear quadratic model to yield GARD, a prediction of risk and benefit at various radiation doses for a particular patient.
A recent report in The Lancet Oncology validated GARD in 1,615 patients with seven cancer types from 11 study cohorts. If it holds up in clinical trials set to start later this year, GARD should “allow us to predict the benefit of radiation for an individual patient and adjust their treatment strategy,” wrote the authors of an editorial that accompanied the study. “The efforts need to be applauded worldwide, because radiotherapy is considerably lagging, compared with the enormous progress done in the field of personalized medicine,” Orit Kaidar-Person, MD, a radiation oncologist at Sheba Medical Center in Ramat Gan, Israel, and colleagues wrote.
GARD was associated with time to first recurrence and overall survival for patients receiving radiotherapy and predicted radiotherapy benefit, while physical dose did not. The team found a relative 2% reduction in risk of first recurrence for each unit increase of GARD (P = .0017) and a relative 3% increase in overall survival for each unit increase in GARD (P = .0007), among those who got radiotherapy. Values of GARD run from 0 to over 100, with higher scores meaning more radiation benefit.
The radiosensitivity index, which was derived from genomic studies of cancer cell lines exposed to radiation, was previously validated by the team and other groups across several tumor types.
Currently, radiation dosing is generally uniform for a given disease site and stage, based on the assumption that a given dose of radiation results in the same clinical effect across patients. In fact, the biological effect of a given dose varies widely between individual patients. “Patients we treat uniformly do not have a uniform response” which is why a more personalized approach would help, said lead investigator and Cleveland Clinic radiation oncologist Jacob Scott, MD, DPhil.
One patient with a given tumor might benefit from 2 extra fractions, while the next might need an extra 15 for the same benefit. “You need to know about [a patient’s] tumor genomics to know how hard you have to work,” he said.
Dr. Scott and colleagues are working with a genomics company to commercialize the approach. The vision for now is that physicians would ship in biopsy samples to be analyzed; RSI and GARD would be calculated, and then a decision support report would be sent back to the treatment team outlining the risks and benefits of various doses for the patient.
Dr. Scott, who holds proprietary rights on the approach, is bullish. When asked if he anticipates GARD dosing to be standard of care in 10 years, he said that “I can’t imagine another world. Everything else in cancer is personalized. Why aren’t we? It just makes sense. I know there’s a better way” to prescribe radiation, “and I’m excited for the future when I can use it.”
When asked for comment, Brian Marples, PhD, a radiation oncology professor at the University of Rochester (N.Y.), said the data so far for GARD “seem very solid. I’m very excited by the concept.”
It’s been “the holy grail” of radiation researchers to find a biologic marker that predicts what dosages patients need and what can be given safely. “This strategy is a good way of doing that. Other groups are proposing similar strategies, but I think this group is ahead. I can see [GARD] being readily applied to the clinic because patients are [already] getting their tumors genomically characterized as part of care,” Dr. Marples said.
But many questions remain. For instance, the editorial writers questioned how GARD is “affected by tumor heterogeneity, response to systemic therapy, and changes in the tumor microenvironment.” Also, the approach is based on conventional 2 Gy fractions, but other fractionation regimens are becoming more common.
For Dr. Marples, the big caveat is that most cancer patients are treated with both radiation and chemotherapy. He said he would like to see GARD validated in patients who receive both.
They seven tumor types in the study included breast cancer, head and neck cancer, non–small cell lung cancer, pancreatic cancer, endometrial cancer, melanoma, and glioma. The majority of the subjects were treated with radiation, and each had the genomic data needed to calculate GARD.
Dr. Scott, senior author and Moffitt Center radiation oncologist Javier Torres-Roca, MD, and a third author hold intellectual property rights on RSI, GARD, and prescription dose base on RSI, plus equity in Cvergenx, a company that seeks to commercialize the approach. Dr. Torres-Roca and another author are cofounders. The editorial writers and Dr. Marples did not have any relevant disclosures.
A team of researchers from the Cleveland Clinic, the Moffitt Cancer Center in Tampa, and Case Western Reserve University in Cleveland is zeroing in on a way to personalize radiation therapy for cancer patients based on genomic profile, much as genomics is used to tailor oncologic drug therapy.
It’s called “genomic-adjusted radiation dose” (GARD), a dose tailored to a person’s radiosensitivity as determined by the expression of 10 genes, known as the radiosensitivity index (RSI), combined with a linear quadratic model to yield GARD, a prediction of risk and benefit at various radiation doses for a particular patient.
A recent report in The Lancet Oncology validated GARD in 1,615 patients with seven cancer types from 11 study cohorts. If it holds up in clinical trials set to start later this year, GARD should “allow us to predict the benefit of radiation for an individual patient and adjust their treatment strategy,” wrote the authors of an editorial that accompanied the study. “The efforts need to be applauded worldwide, because radiotherapy is considerably lagging, compared with the enormous progress done in the field of personalized medicine,” Orit Kaidar-Person, MD, a radiation oncologist at Sheba Medical Center in Ramat Gan, Israel, and colleagues wrote.
GARD was associated with time to first recurrence and overall survival for patients receiving radiotherapy and predicted radiotherapy benefit, while physical dose did not. The team found a relative 2% reduction in risk of first recurrence for each unit increase of GARD (P = .0017) and a relative 3% increase in overall survival for each unit increase in GARD (P = .0007), among those who got radiotherapy. Values of GARD run from 0 to over 100, with higher scores meaning more radiation benefit.
The radiosensitivity index, which was derived from genomic studies of cancer cell lines exposed to radiation, was previously validated by the team and other groups across several tumor types.
Currently, radiation dosing is generally uniform for a given disease site and stage, based on the assumption that a given dose of radiation results in the same clinical effect across patients. In fact, the biological effect of a given dose varies widely between individual patients. “Patients we treat uniformly do not have a uniform response” which is why a more personalized approach would help, said lead investigator and Cleveland Clinic radiation oncologist Jacob Scott, MD, DPhil.
One patient with a given tumor might benefit from 2 extra fractions, while the next might need an extra 15 for the same benefit. “You need to know about [a patient’s] tumor genomics to know how hard you have to work,” he said.
Dr. Scott and colleagues are working with a genomics company to commercialize the approach. The vision for now is that physicians would ship in biopsy samples to be analyzed; RSI and GARD would be calculated, and then a decision support report would be sent back to the treatment team outlining the risks and benefits of various doses for the patient.
Dr. Scott, who holds proprietary rights on the approach, is bullish. When asked if he anticipates GARD dosing to be standard of care in 10 years, he said that “I can’t imagine another world. Everything else in cancer is personalized. Why aren’t we? It just makes sense. I know there’s a better way” to prescribe radiation, “and I’m excited for the future when I can use it.”
When asked for comment, Brian Marples, PhD, a radiation oncology professor at the University of Rochester (N.Y.), said the data so far for GARD “seem very solid. I’m very excited by the concept.”
It’s been “the holy grail” of radiation researchers to find a biologic marker that predicts what dosages patients need and what can be given safely. “This strategy is a good way of doing that. Other groups are proposing similar strategies, but I think this group is ahead. I can see [GARD] being readily applied to the clinic because patients are [already] getting their tumors genomically characterized as part of care,” Dr. Marples said.
But many questions remain. For instance, the editorial writers questioned how GARD is “affected by tumor heterogeneity, response to systemic therapy, and changes in the tumor microenvironment.” Also, the approach is based on conventional 2 Gy fractions, but other fractionation regimens are becoming more common.
For Dr. Marples, the big caveat is that most cancer patients are treated with both radiation and chemotherapy. He said he would like to see GARD validated in patients who receive both.
They seven tumor types in the study included breast cancer, head and neck cancer, non–small cell lung cancer, pancreatic cancer, endometrial cancer, melanoma, and glioma. The majority of the subjects were treated with radiation, and each had the genomic data needed to calculate GARD.
Dr. Scott, senior author and Moffitt Center radiation oncologist Javier Torres-Roca, MD, and a third author hold intellectual property rights on RSI, GARD, and prescription dose base on RSI, plus equity in Cvergenx, a company that seeks to commercialize the approach. Dr. Torres-Roca and another author are cofounders. The editorial writers and Dr. Marples did not have any relevant disclosures.
A team of researchers from the Cleveland Clinic, the Moffitt Cancer Center in Tampa, and Case Western Reserve University in Cleveland is zeroing in on a way to personalize radiation therapy for cancer patients based on genomic profile, much as genomics is used to tailor oncologic drug therapy.
It’s called “genomic-adjusted radiation dose” (GARD), a dose tailored to a person’s radiosensitivity as determined by the expression of 10 genes, known as the radiosensitivity index (RSI), combined with a linear quadratic model to yield GARD, a prediction of risk and benefit at various radiation doses for a particular patient.
A recent report in The Lancet Oncology validated GARD in 1,615 patients with seven cancer types from 11 study cohorts. If it holds up in clinical trials set to start later this year, GARD should “allow us to predict the benefit of radiation for an individual patient and adjust their treatment strategy,” wrote the authors of an editorial that accompanied the study. “The efforts need to be applauded worldwide, because radiotherapy is considerably lagging, compared with the enormous progress done in the field of personalized medicine,” Orit Kaidar-Person, MD, a radiation oncologist at Sheba Medical Center in Ramat Gan, Israel, and colleagues wrote.
GARD was associated with time to first recurrence and overall survival for patients receiving radiotherapy and predicted radiotherapy benefit, while physical dose did not. The team found a relative 2% reduction in risk of first recurrence for each unit increase of GARD (P = .0017) and a relative 3% increase in overall survival for each unit increase in GARD (P = .0007), among those who got radiotherapy. Values of GARD run from 0 to over 100, with higher scores meaning more radiation benefit.
The radiosensitivity index, which was derived from genomic studies of cancer cell lines exposed to radiation, was previously validated by the team and other groups across several tumor types.
Currently, radiation dosing is generally uniform for a given disease site and stage, based on the assumption that a given dose of radiation results in the same clinical effect across patients. In fact, the biological effect of a given dose varies widely between individual patients. “Patients we treat uniformly do not have a uniform response” which is why a more personalized approach would help, said lead investigator and Cleveland Clinic radiation oncologist Jacob Scott, MD, DPhil.
One patient with a given tumor might benefit from 2 extra fractions, while the next might need an extra 15 for the same benefit. “You need to know about [a patient’s] tumor genomics to know how hard you have to work,” he said.
Dr. Scott and colleagues are working with a genomics company to commercialize the approach. The vision for now is that physicians would ship in biopsy samples to be analyzed; RSI and GARD would be calculated, and then a decision support report would be sent back to the treatment team outlining the risks and benefits of various doses for the patient.
Dr. Scott, who holds proprietary rights on the approach, is bullish. When asked if he anticipates GARD dosing to be standard of care in 10 years, he said that “I can’t imagine another world. Everything else in cancer is personalized. Why aren’t we? It just makes sense. I know there’s a better way” to prescribe radiation, “and I’m excited for the future when I can use it.”
When asked for comment, Brian Marples, PhD, a radiation oncology professor at the University of Rochester (N.Y.), said the data so far for GARD “seem very solid. I’m very excited by the concept.”
It’s been “the holy grail” of radiation researchers to find a biologic marker that predicts what dosages patients need and what can be given safely. “This strategy is a good way of doing that. Other groups are proposing similar strategies, but I think this group is ahead. I can see [GARD] being readily applied to the clinic because patients are [already] getting their tumors genomically characterized as part of care,” Dr. Marples said.
But many questions remain. For instance, the editorial writers questioned how GARD is “affected by tumor heterogeneity, response to systemic therapy, and changes in the tumor microenvironment.” Also, the approach is based on conventional 2 Gy fractions, but other fractionation regimens are becoming more common.
For Dr. Marples, the big caveat is that most cancer patients are treated with both radiation and chemotherapy. He said he would like to see GARD validated in patients who receive both.
They seven tumor types in the study included breast cancer, head and neck cancer, non–small cell lung cancer, pancreatic cancer, endometrial cancer, melanoma, and glioma. The majority of the subjects were treated with radiation, and each had the genomic data needed to calculate GARD.
Dr. Scott, senior author and Moffitt Center radiation oncologist Javier Torres-Roca, MD, and a third author hold intellectual property rights on RSI, GARD, and prescription dose base on RSI, plus equity in Cvergenx, a company that seeks to commercialize the approach. Dr. Torres-Roca and another author are cofounders. The editorial writers and Dr. Marples did not have any relevant disclosures.
FROM LANCET ONCOLOGY
Polygenic breast cancer risk scores strive to overcome racial bias
The potential of polygenic risk scores (PRSs) to become key components in the assessment of individual risk for disease in the clinical setting is inching closer to fruition; however, the technology is plagued by one glaring omission of most existing PRSs – the lack of applicability to those of non-European ancestry.
Polygenic risk scores predict an individual’s risk of disease based on common genetic variants identified in large genomewide association studies (GWASs). They have gained ground in research, as well as in the unregulated realm of the direct-to-consumer market where they are sold as add-ons to DNA ancestry kits such as 23andMe and MyHeritage.com.
While the risk scores show strong validation in estimating risk among people of European descent, their striking caveat is the lack of applicability to other ancestries, particularly African, and their use in practice outside of clinical trials is discouraged in National Comprehensive Cancer Network guidelines.
Study underscores need for ethnically diverse datasets
In a recent study published in JAMA Network Open, researchers evaluated the use of polygenic risk scores’ models in a clinical setting. Researchers tested 7 PRSs models for breast cancer risk against the medical records data of 39,591 women of European, African, and Latinx ancestry.
The PRSs models – all used only for research purposes – included three models involving European ancestry cohorts, two from Latinx cohorts, and two from women African descent.
After adjusting for factors including age, breast cancer family history, and ancestry, the PRSs from women with European ancestry highly corresponded to breast cancer risk, with a mean odds ratio of 1.46 per standard deviation increase in the score.
PRSs were also generalized relatively well among women of Latinx ancestry with a mean OR of 1.31. The authors noted that association is likely caused by Latinx individuals in the United States having a greater proportion of European ancestry than individuals with African ancestry. Importantly, however, the effect size was lower for women of African ancestry with a highest OR of 1.19 per standard deviation.
In the highest percentiles of breast cancer risk, women of European descent had odds ratio as high as 2.19-2.48, suggesting a statistically significant association with overall breast cancer risk. No statistically significant associations were found among women of Latinx and African-ancestry.
The PRSs models were smaller for women of non-European ancestry and included fewer genetic variants for women of non-European ancestry were notably smaller and hence reflected fewer genetic variants. Of the two risk scores involving African ancestry, the Women’s Health Initiative for Women with African ancestry risk score had just 75 variants, while the African diaspora study (ROOT) had 34 variants, compared with 3,820 and 5,218 in the two largest European ancestry PRSs, the Breast Cancer Association Consortium and the UK Biobank, respectively.
“These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts,” the authors wrote.
First author, Cong Liu, PhD, of Columbia University Irving Medical Center, New York, said that efforts are underway to improve the inclusivity in the Electronic Medical Records and Genomics network data set used in this study.
“Until well-developed and validated PRSs for women with non-European ancestry become available, the current PRSs based on cohorts with European ancestry could be adapted for Latinx women, but not women with African ancestry until additional data sets become available in this important and high-risk group,” Dr. Liu and colleagues wrote.
In a commentary published with the study, Payal D. Shah, MD, of the Basser Center for BRCA at the University of Pennsylvania, Philadelphia, said that PRSs are “disproportionately applicable to patients with European ancestry and are insufficiently vetted and developed in other populations. If an instrument exists that has clinical utility in informing effective cancer risk mitigation strategies, then we must strive to ensure that it is available and applicable to all.”
Higher morality among African American women
While American Cancer Society data shows women with African ancestry generally have incidence rates of breast cancer similar to White women, they have significantly higher mortality from the disease in part because of later-stage diagnosis and health care barriers.
Anne Marie McCarthy, PhD, of the University of Pennsylvania, and Katrina Armstrong, MD, of Harvard Medical School, Boston, wrote in the Journal of the National Cancer Institute that African American women “have 42% higher breast cancer mortality than white women, despite having lower disease incidence, and are more likely to be diagnosed with triple-negative breast cancer, which has poorer prognosis than other molecular subtypes.”
Dr. McCarthy and Dr. Armstrong wrote that African American women are chronically underrepresented in breast cancer studies. And as such, it is impossible to know the extent of the prevalence of mutations and risk.
Failing to address the lack of diversity in genomic studies may worsen health disparities for women with African ancestry, Dr. Liu and colleagues wrote. The higher mortality “underscores the urgent need to increase diversity in genomic studies so that future clinical applications of the PRS do not exacerbate existing health disparities. These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts.”
Potential PRS benefits underscore need to eliminate bias
The potentially important benefits of PRSs as risk prediction tools used in combination with family history, reproductive history and other factors, should provide strong incentive to push for improvement, Dr. Shah wrote.
For instance, if an individual is estrogen receptor positive and shows elevations in breast cancer risk on a reliable PRS, “this may inform antiestrogen chemoprevention strategies,” she wrote.
A risk score could furthermore influence the age at which breast cancer screening should begin or factor into whether a patient should also receive surveillance breast MRI.
Importantly, PRSs could also add to other risk factors to provide more precise risk estimates and inform management of women with a pathogenic variant in a breast cancer risk predisposition gene, Dr. Shah wrote.
Confluence project
Among the most promising developments in research is the National Cancer Institute’s Confluence Project, a large research resource aiming to include approximately 300,000 breast cancer cases and 300,000 controls of different races/ethnicities, utilizing the confluence of existing GWAS and new genomewide genotyping data.
Having started enrollment in 2018, the project is approaching implementation, said Montserrat García-Closas, MD, MPH, DrPH, deputy director of cancer epidemiology and genetics with the National Cancer Institute.
“We expect genotyping to be completed by the end of 2022 and for the data to be made available to the research community soon after that,” she said.
Among the project’s key objectives are the development of PRSs to be integrated with known risk factors to provide a personalized risk assessment for breast cancer, overall and by ancestral subtype.
“We plan to apply novel methods to derive multiancestry PRS that will account for differences and similarities in genetic architecture across ethnic/racial groups to develop breast cancer PRSs that can be applied in multiethnic/racial populations,” she said.
NCI is working with investigators in Africa, Central and South America, and Asia, and reaching out to non-European organizations such as AORTIC for studies of African populations.
Direct-to-consumer global PRS
In the commercial PRS market, efforts to address diversity shortcomings are also gaining momentum, with Myriad Genetics touting a first-of-its kind “global PRS.”
The PRS, a recalibrated version the company’s riskScore PRS, sold as part of its Myriad myRisk Hereditary Cancer test, will reportedly apply to all ethnicities in estimating an individual’s 5-year and lifetime risk of breast cancer.
A study presented in June at the American Society of Clinical Oncology meeting, describes the development of the model with the use of three large ancestry-specific PRSs based on African American, Asian, and European cohorts, with the system including a total of 149 single-nucleotide polymorphisms, including 93 well established for breast cancer and 56 that are ancestry specific.
In validation of the data in an independent cohort of 62,707 individuals, the global PRS was strongly associated with breast cancer in the full combined validation cohort as well as in all three of the ancestry subcohorts.
However, the effect size among women with African ancestry was still the lowest of all of the groups, with a mean OR of 1.24 per standard deviation, versus the highest rate of mixed ancestry (OR, 1.59).
According to senior author Holly Pederson, MD, director of medical breast services at the Cleveland Clinic, the applicability of the PRS to women with African ancestry is expected to further improve as additional data become available.
“The discriminatory power in women of African descent was significantly improved but still suboptimal,” she said. “The need for more data, particularly in Black women, is challenging not only because there is likely more diversity in the genomic landscape of women of African descent, but also because the barriers created by historical, cultural, institutional and interpersonal dynamics result in the paucity of this data.”
“We must be committed to ending bias resulting in health care disparities,” Dr. Pederson said. She noted that the global PRS is nevertheless “still clinically useful in Black women,” and recommended that clinicians be up front with patients on the status of the research challenges.
“As with any clinical shared decision-making conversation between a patient and her provider, it is important for Black women to know that data is limited in the African American population, particularly given the vast genomic diversity of the African continent,” she said. “This model, as models that have gone before it, will improve with additional data, particularly in this population.”
Commercial PRSs may benefit research
While the commercial marketing of PRSs in a direct-to-consumer fashion have raised some concerns, such as how individuals respond to their risk scores, there could be important benefits as well, commented Megan C. Roberts, PhD.
“There may be an opportunity to learn from these companies about how to engage diverse communities in genomic testing,” said Dr. Roberts, an assistant professor and director of implementation science in precision health and society at the University of North Carolina at Chapel Hill. “Moreover, the data they collect from their customers often can be used for research purposes as well.”
In a recent perspective, Dr. Roberts and colleagues addressed the role of health disparities in PRSs. She’ll be joining international precision public health researchers in October in hosting a free virtual conference at UNC on the topic.
“There is a huge need to improve racial and ethnic diversity in our genomic datasets,” Dr. Roberts said. “Without this, we will not be able to return on the promise of precision medicine and prevention for improving the health of our whole population.”
Dr. Pederson disclosed that she is a consultant for Myriad Genetics.
The potential of polygenic risk scores (PRSs) to become key components in the assessment of individual risk for disease in the clinical setting is inching closer to fruition; however, the technology is plagued by one glaring omission of most existing PRSs – the lack of applicability to those of non-European ancestry.
Polygenic risk scores predict an individual’s risk of disease based on common genetic variants identified in large genomewide association studies (GWASs). They have gained ground in research, as well as in the unregulated realm of the direct-to-consumer market where they are sold as add-ons to DNA ancestry kits such as 23andMe and MyHeritage.com.
While the risk scores show strong validation in estimating risk among people of European descent, their striking caveat is the lack of applicability to other ancestries, particularly African, and their use in practice outside of clinical trials is discouraged in National Comprehensive Cancer Network guidelines.
Study underscores need for ethnically diverse datasets
In a recent study published in JAMA Network Open, researchers evaluated the use of polygenic risk scores’ models in a clinical setting. Researchers tested 7 PRSs models for breast cancer risk against the medical records data of 39,591 women of European, African, and Latinx ancestry.
The PRSs models – all used only for research purposes – included three models involving European ancestry cohorts, two from Latinx cohorts, and two from women African descent.
After adjusting for factors including age, breast cancer family history, and ancestry, the PRSs from women with European ancestry highly corresponded to breast cancer risk, with a mean odds ratio of 1.46 per standard deviation increase in the score.
PRSs were also generalized relatively well among women of Latinx ancestry with a mean OR of 1.31. The authors noted that association is likely caused by Latinx individuals in the United States having a greater proportion of European ancestry than individuals with African ancestry. Importantly, however, the effect size was lower for women of African ancestry with a highest OR of 1.19 per standard deviation.
In the highest percentiles of breast cancer risk, women of European descent had odds ratio as high as 2.19-2.48, suggesting a statistically significant association with overall breast cancer risk. No statistically significant associations were found among women of Latinx and African-ancestry.
The PRSs models were smaller for women of non-European ancestry and included fewer genetic variants for women of non-European ancestry were notably smaller and hence reflected fewer genetic variants. Of the two risk scores involving African ancestry, the Women’s Health Initiative for Women with African ancestry risk score had just 75 variants, while the African diaspora study (ROOT) had 34 variants, compared with 3,820 and 5,218 in the two largest European ancestry PRSs, the Breast Cancer Association Consortium and the UK Biobank, respectively.
“These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts,” the authors wrote.
First author, Cong Liu, PhD, of Columbia University Irving Medical Center, New York, said that efforts are underway to improve the inclusivity in the Electronic Medical Records and Genomics network data set used in this study.
“Until well-developed and validated PRSs for women with non-European ancestry become available, the current PRSs based on cohorts with European ancestry could be adapted for Latinx women, but not women with African ancestry until additional data sets become available in this important and high-risk group,” Dr. Liu and colleagues wrote.
In a commentary published with the study, Payal D. Shah, MD, of the Basser Center for BRCA at the University of Pennsylvania, Philadelphia, said that PRSs are “disproportionately applicable to patients with European ancestry and are insufficiently vetted and developed in other populations. If an instrument exists that has clinical utility in informing effective cancer risk mitigation strategies, then we must strive to ensure that it is available and applicable to all.”
Higher morality among African American women
While American Cancer Society data shows women with African ancestry generally have incidence rates of breast cancer similar to White women, they have significantly higher mortality from the disease in part because of later-stage diagnosis and health care barriers.
Anne Marie McCarthy, PhD, of the University of Pennsylvania, and Katrina Armstrong, MD, of Harvard Medical School, Boston, wrote in the Journal of the National Cancer Institute that African American women “have 42% higher breast cancer mortality than white women, despite having lower disease incidence, and are more likely to be diagnosed with triple-negative breast cancer, which has poorer prognosis than other molecular subtypes.”
Dr. McCarthy and Dr. Armstrong wrote that African American women are chronically underrepresented in breast cancer studies. And as such, it is impossible to know the extent of the prevalence of mutations and risk.
Failing to address the lack of diversity in genomic studies may worsen health disparities for women with African ancestry, Dr. Liu and colleagues wrote. The higher mortality “underscores the urgent need to increase diversity in genomic studies so that future clinical applications of the PRS do not exacerbate existing health disparities. These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts.”
Potential PRS benefits underscore need to eliminate bias
The potentially important benefits of PRSs as risk prediction tools used in combination with family history, reproductive history and other factors, should provide strong incentive to push for improvement, Dr. Shah wrote.
For instance, if an individual is estrogen receptor positive and shows elevations in breast cancer risk on a reliable PRS, “this may inform antiestrogen chemoprevention strategies,” she wrote.
A risk score could furthermore influence the age at which breast cancer screening should begin or factor into whether a patient should also receive surveillance breast MRI.
Importantly, PRSs could also add to other risk factors to provide more precise risk estimates and inform management of women with a pathogenic variant in a breast cancer risk predisposition gene, Dr. Shah wrote.
Confluence project
Among the most promising developments in research is the National Cancer Institute’s Confluence Project, a large research resource aiming to include approximately 300,000 breast cancer cases and 300,000 controls of different races/ethnicities, utilizing the confluence of existing GWAS and new genomewide genotyping data.
Having started enrollment in 2018, the project is approaching implementation, said Montserrat García-Closas, MD, MPH, DrPH, deputy director of cancer epidemiology and genetics with the National Cancer Institute.
“We expect genotyping to be completed by the end of 2022 and for the data to be made available to the research community soon after that,” she said.
Among the project’s key objectives are the development of PRSs to be integrated with known risk factors to provide a personalized risk assessment for breast cancer, overall and by ancestral subtype.
“We plan to apply novel methods to derive multiancestry PRS that will account for differences and similarities in genetic architecture across ethnic/racial groups to develop breast cancer PRSs that can be applied in multiethnic/racial populations,” she said.
NCI is working with investigators in Africa, Central and South America, and Asia, and reaching out to non-European organizations such as AORTIC for studies of African populations.
Direct-to-consumer global PRS
In the commercial PRS market, efforts to address diversity shortcomings are also gaining momentum, with Myriad Genetics touting a first-of-its kind “global PRS.”
The PRS, a recalibrated version the company’s riskScore PRS, sold as part of its Myriad myRisk Hereditary Cancer test, will reportedly apply to all ethnicities in estimating an individual’s 5-year and lifetime risk of breast cancer.
A study presented in June at the American Society of Clinical Oncology meeting, describes the development of the model with the use of three large ancestry-specific PRSs based on African American, Asian, and European cohorts, with the system including a total of 149 single-nucleotide polymorphisms, including 93 well established for breast cancer and 56 that are ancestry specific.
In validation of the data in an independent cohort of 62,707 individuals, the global PRS was strongly associated with breast cancer in the full combined validation cohort as well as in all three of the ancestry subcohorts.
However, the effect size among women with African ancestry was still the lowest of all of the groups, with a mean OR of 1.24 per standard deviation, versus the highest rate of mixed ancestry (OR, 1.59).
According to senior author Holly Pederson, MD, director of medical breast services at the Cleveland Clinic, the applicability of the PRS to women with African ancestry is expected to further improve as additional data become available.
“The discriminatory power in women of African descent was significantly improved but still suboptimal,” she said. “The need for more data, particularly in Black women, is challenging not only because there is likely more diversity in the genomic landscape of women of African descent, but also because the barriers created by historical, cultural, institutional and interpersonal dynamics result in the paucity of this data.”
“We must be committed to ending bias resulting in health care disparities,” Dr. Pederson said. She noted that the global PRS is nevertheless “still clinically useful in Black women,” and recommended that clinicians be up front with patients on the status of the research challenges.
“As with any clinical shared decision-making conversation between a patient and her provider, it is important for Black women to know that data is limited in the African American population, particularly given the vast genomic diversity of the African continent,” she said. “This model, as models that have gone before it, will improve with additional data, particularly in this population.”
Commercial PRSs may benefit research
While the commercial marketing of PRSs in a direct-to-consumer fashion have raised some concerns, such as how individuals respond to their risk scores, there could be important benefits as well, commented Megan C. Roberts, PhD.
“There may be an opportunity to learn from these companies about how to engage diverse communities in genomic testing,” said Dr. Roberts, an assistant professor and director of implementation science in precision health and society at the University of North Carolina at Chapel Hill. “Moreover, the data they collect from their customers often can be used for research purposes as well.”
In a recent perspective, Dr. Roberts and colleagues addressed the role of health disparities in PRSs. She’ll be joining international precision public health researchers in October in hosting a free virtual conference at UNC on the topic.
“There is a huge need to improve racial and ethnic diversity in our genomic datasets,” Dr. Roberts said. “Without this, we will not be able to return on the promise of precision medicine and prevention for improving the health of our whole population.”
Dr. Pederson disclosed that she is a consultant for Myriad Genetics.
The potential of polygenic risk scores (PRSs) to become key components in the assessment of individual risk for disease in the clinical setting is inching closer to fruition; however, the technology is plagued by one glaring omission of most existing PRSs – the lack of applicability to those of non-European ancestry.
Polygenic risk scores predict an individual’s risk of disease based on common genetic variants identified in large genomewide association studies (GWASs). They have gained ground in research, as well as in the unregulated realm of the direct-to-consumer market where they are sold as add-ons to DNA ancestry kits such as 23andMe and MyHeritage.com.
While the risk scores show strong validation in estimating risk among people of European descent, their striking caveat is the lack of applicability to other ancestries, particularly African, and their use in practice outside of clinical trials is discouraged in National Comprehensive Cancer Network guidelines.
Study underscores need for ethnically diverse datasets
In a recent study published in JAMA Network Open, researchers evaluated the use of polygenic risk scores’ models in a clinical setting. Researchers tested 7 PRSs models for breast cancer risk against the medical records data of 39,591 women of European, African, and Latinx ancestry.
The PRSs models – all used only for research purposes – included three models involving European ancestry cohorts, two from Latinx cohorts, and two from women African descent.
After adjusting for factors including age, breast cancer family history, and ancestry, the PRSs from women with European ancestry highly corresponded to breast cancer risk, with a mean odds ratio of 1.46 per standard deviation increase in the score.
PRSs were also generalized relatively well among women of Latinx ancestry with a mean OR of 1.31. The authors noted that association is likely caused by Latinx individuals in the United States having a greater proportion of European ancestry than individuals with African ancestry. Importantly, however, the effect size was lower for women of African ancestry with a highest OR of 1.19 per standard deviation.
In the highest percentiles of breast cancer risk, women of European descent had odds ratio as high as 2.19-2.48, suggesting a statistically significant association with overall breast cancer risk. No statistically significant associations were found among women of Latinx and African-ancestry.
The PRSs models were smaller for women of non-European ancestry and included fewer genetic variants for women of non-European ancestry were notably smaller and hence reflected fewer genetic variants. Of the two risk scores involving African ancestry, the Women’s Health Initiative for Women with African ancestry risk score had just 75 variants, while the African diaspora study (ROOT) had 34 variants, compared with 3,820 and 5,218 in the two largest European ancestry PRSs, the Breast Cancer Association Consortium and the UK Biobank, respectively.
“These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts,” the authors wrote.
First author, Cong Liu, PhD, of Columbia University Irving Medical Center, New York, said that efforts are underway to improve the inclusivity in the Electronic Medical Records and Genomics network data set used in this study.
“Until well-developed and validated PRSs for women with non-European ancestry become available, the current PRSs based on cohorts with European ancestry could be adapted for Latinx women, but not women with African ancestry until additional data sets become available in this important and high-risk group,” Dr. Liu and colleagues wrote.
In a commentary published with the study, Payal D. Shah, MD, of the Basser Center for BRCA at the University of Pennsylvania, Philadelphia, said that PRSs are “disproportionately applicable to patients with European ancestry and are insufficiently vetted and developed in other populations. If an instrument exists that has clinical utility in informing effective cancer risk mitigation strategies, then we must strive to ensure that it is available and applicable to all.”
Higher morality among African American women
While American Cancer Society data shows women with African ancestry generally have incidence rates of breast cancer similar to White women, they have significantly higher mortality from the disease in part because of later-stage diagnosis and health care barriers.
Anne Marie McCarthy, PhD, of the University of Pennsylvania, and Katrina Armstrong, MD, of Harvard Medical School, Boston, wrote in the Journal of the National Cancer Institute that African American women “have 42% higher breast cancer mortality than white women, despite having lower disease incidence, and are more likely to be diagnosed with triple-negative breast cancer, which has poorer prognosis than other molecular subtypes.”
Dr. McCarthy and Dr. Armstrong wrote that African American women are chronically underrepresented in breast cancer studies. And as such, it is impossible to know the extent of the prevalence of mutations and risk.
Failing to address the lack of diversity in genomic studies may worsen health disparities for women with African ancestry, Dr. Liu and colleagues wrote. The higher mortality “underscores the urgent need to increase diversity in genomic studies so that future clinical applications of the PRS do not exacerbate existing health disparities. These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts.”
Potential PRS benefits underscore need to eliminate bias
The potentially important benefits of PRSs as risk prediction tools used in combination with family history, reproductive history and other factors, should provide strong incentive to push for improvement, Dr. Shah wrote.
For instance, if an individual is estrogen receptor positive and shows elevations in breast cancer risk on a reliable PRS, “this may inform antiestrogen chemoprevention strategies,” she wrote.
A risk score could furthermore influence the age at which breast cancer screening should begin or factor into whether a patient should also receive surveillance breast MRI.
Importantly, PRSs could also add to other risk factors to provide more precise risk estimates and inform management of women with a pathogenic variant in a breast cancer risk predisposition gene, Dr. Shah wrote.
Confluence project
Among the most promising developments in research is the National Cancer Institute’s Confluence Project, a large research resource aiming to include approximately 300,000 breast cancer cases and 300,000 controls of different races/ethnicities, utilizing the confluence of existing GWAS and new genomewide genotyping data.
Having started enrollment in 2018, the project is approaching implementation, said Montserrat García-Closas, MD, MPH, DrPH, deputy director of cancer epidemiology and genetics with the National Cancer Institute.
“We expect genotyping to be completed by the end of 2022 and for the data to be made available to the research community soon after that,” she said.
Among the project’s key objectives are the development of PRSs to be integrated with known risk factors to provide a personalized risk assessment for breast cancer, overall and by ancestral subtype.
“We plan to apply novel methods to derive multiancestry PRS that will account for differences and similarities in genetic architecture across ethnic/racial groups to develop breast cancer PRSs that can be applied in multiethnic/racial populations,” she said.
NCI is working with investigators in Africa, Central and South America, and Asia, and reaching out to non-European organizations such as AORTIC for studies of African populations.
Direct-to-consumer global PRS
In the commercial PRS market, efforts to address diversity shortcomings are also gaining momentum, with Myriad Genetics touting a first-of-its kind “global PRS.”
The PRS, a recalibrated version the company’s riskScore PRS, sold as part of its Myriad myRisk Hereditary Cancer test, will reportedly apply to all ethnicities in estimating an individual’s 5-year and lifetime risk of breast cancer.
A study presented in June at the American Society of Clinical Oncology meeting, describes the development of the model with the use of three large ancestry-specific PRSs based on African American, Asian, and European cohorts, with the system including a total of 149 single-nucleotide polymorphisms, including 93 well established for breast cancer and 56 that are ancestry specific.
In validation of the data in an independent cohort of 62,707 individuals, the global PRS was strongly associated with breast cancer in the full combined validation cohort as well as in all three of the ancestry subcohorts.
However, the effect size among women with African ancestry was still the lowest of all of the groups, with a mean OR of 1.24 per standard deviation, versus the highest rate of mixed ancestry (OR, 1.59).
According to senior author Holly Pederson, MD, director of medical breast services at the Cleveland Clinic, the applicability of the PRS to women with African ancestry is expected to further improve as additional data become available.
“The discriminatory power in women of African descent was significantly improved but still suboptimal,” she said. “The need for more data, particularly in Black women, is challenging not only because there is likely more diversity in the genomic landscape of women of African descent, but also because the barriers created by historical, cultural, institutional and interpersonal dynamics result in the paucity of this data.”
“We must be committed to ending bias resulting in health care disparities,” Dr. Pederson said. She noted that the global PRS is nevertheless “still clinically useful in Black women,” and recommended that clinicians be up front with patients on the status of the research challenges.
“As with any clinical shared decision-making conversation between a patient and her provider, it is important for Black women to know that data is limited in the African American population, particularly given the vast genomic diversity of the African continent,” she said. “This model, as models that have gone before it, will improve with additional data, particularly in this population.”
Commercial PRSs may benefit research
While the commercial marketing of PRSs in a direct-to-consumer fashion have raised some concerns, such as how individuals respond to their risk scores, there could be important benefits as well, commented Megan C. Roberts, PhD.
“There may be an opportunity to learn from these companies about how to engage diverse communities in genomic testing,” said Dr. Roberts, an assistant professor and director of implementation science in precision health and society at the University of North Carolina at Chapel Hill. “Moreover, the data they collect from their customers often can be used for research purposes as well.”
In a recent perspective, Dr. Roberts and colleagues addressed the role of health disparities in PRSs. She’ll be joining international precision public health researchers in October in hosting a free virtual conference at UNC on the topic.
“There is a huge need to improve racial and ethnic diversity in our genomic datasets,” Dr. Roberts said. “Without this, we will not be able to return on the promise of precision medicine and prevention for improving the health of our whole population.”
Dr. Pederson disclosed that she is a consultant for Myriad Genetics.
FROM JAMA NETWORK OPEN
Therapeutic Approaches in Advanced Breast Cancer
More than 280,000 women in the United States will be diagnosed with invasive breast cancer this year. For those with metastatic breast cancer with distant spread, the 5-year survival rate is approximately 28%. Whether advanced disease is discovered at initial diagnosis or in relapsed disease, it is imperative to understand the molecular characteristics of the metastatic tumor.
Dr Susan Domchek, from the University of Pennsylvania, discusses the importance of retesting for estrogen receptor, progesterone receptor, and HER2/neu on a metastatic tumor focus in order to identify potential discordance between the primary cancer and metastatic disease.
Additionally, Dr Domchek discusses the importance of molecular testing for targetable mutations, including P13K and germline BRCA1/2, for which approved therapies have shown survival benefit.
The list of targetable mutations in breast cancer continues to expand. In the tumor-agnostic studies, pembrolizumab has shown survival benefit in tumors that have mismatch repair deficiency and microsatellite instability, and TRK inhibitors have shown efficacy in tumors positive for NTRK fusions. Numerous clinical trials are available looking at additional molecular-based therapies.
--
Susan M. Domchek, MD, Basser Professor, Department of Oncology; Executive Director, Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia.
Susan M. Domchek, MD, has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from: AstraZeneca; Clovis; Bristol Myers Squibb.
More than 280,000 women in the United States will be diagnosed with invasive breast cancer this year. For those with metastatic breast cancer with distant spread, the 5-year survival rate is approximately 28%. Whether advanced disease is discovered at initial diagnosis or in relapsed disease, it is imperative to understand the molecular characteristics of the metastatic tumor.
Dr Susan Domchek, from the University of Pennsylvania, discusses the importance of retesting for estrogen receptor, progesterone receptor, and HER2/neu on a metastatic tumor focus in order to identify potential discordance between the primary cancer and metastatic disease.
Additionally, Dr Domchek discusses the importance of molecular testing for targetable mutations, including P13K and germline BRCA1/2, for which approved therapies have shown survival benefit.
The list of targetable mutations in breast cancer continues to expand. In the tumor-agnostic studies, pembrolizumab has shown survival benefit in tumors that have mismatch repair deficiency and microsatellite instability, and TRK inhibitors have shown efficacy in tumors positive for NTRK fusions. Numerous clinical trials are available looking at additional molecular-based therapies.
--
Susan M. Domchek, MD, Basser Professor, Department of Oncology; Executive Director, Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia.
Susan M. Domchek, MD, has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from: AstraZeneca; Clovis; Bristol Myers Squibb.
More than 280,000 women in the United States will be diagnosed with invasive breast cancer this year. For those with metastatic breast cancer with distant spread, the 5-year survival rate is approximately 28%. Whether advanced disease is discovered at initial diagnosis or in relapsed disease, it is imperative to understand the molecular characteristics of the metastatic tumor.
Dr Susan Domchek, from the University of Pennsylvania, discusses the importance of retesting for estrogen receptor, progesterone receptor, and HER2/neu on a metastatic tumor focus in order to identify potential discordance between the primary cancer and metastatic disease.
Additionally, Dr Domchek discusses the importance of molecular testing for targetable mutations, including P13K and germline BRCA1/2, for which approved therapies have shown survival benefit.
The list of targetable mutations in breast cancer continues to expand. In the tumor-agnostic studies, pembrolizumab has shown survival benefit in tumors that have mismatch repair deficiency and microsatellite instability, and TRK inhibitors have shown efficacy in tumors positive for NTRK fusions. Numerous clinical trials are available looking at additional molecular-based therapies.
--
Susan M. Domchek, MD, Basser Professor, Department of Oncology; Executive Director, Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia.
Susan M. Domchek, MD, has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from: AstraZeneca; Clovis; Bristol Myers Squibb.
Key strategies for managing breast cancer brain metastases
Brain metastases remain a frequent and often fatal consequence of metastatic breast cancer (MBC). MBC carries a median survival of about 3 years, but that rate drops significantly when cancer cells move to the brain. A recent analysis estimates median survival in patients with brain metastases ranges from 6 months in triple-negative breast cancer (TNBC) to 21 months in human epidermal growth factor receptor 2 (HER2)–positive disease.
This news organization spoke to Kevin M. Kalinsky, MD, acting associate professor in the department of hematology and medical oncology at Emory University School of Medicine in Atlanta and director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University, about the risk for brain metastases in patients with MBC, strategies for screening and treatment, and the work being done to achieve a better understanding of the disease.
Question: Before we dig into strategies to manage MBC brain metastasis, let’s talk about the risks. When and how often do brain metastases present in patients with MBC? What factors increase the likelihood of developing brain metastasis?
Dr. Kalinsky: The biggest risk factor for MBC spreading to the central nervous system (CNS), which includes the brain and spine, is breast cancer subtype. For patients with metastatic TNBC, the risk for brain metastasis can be more than 50%. For patients with HER2-positive disease, the risk may be slightly lower, with estimates in the range of 25%-50%, whereas the likelihood of brain metastasis in patients with hormone receptor–positive MBC is significantly lower at close to 14%. In addition, patients with metastatic TNBC may have brain metastases a little earlier in their disease progression compared with patients with HER2-positive or estrogen receptor–positive breast cancers, where brain metastases generally develop a little later in the disease course.
At what point is it recommended to screen patients with MBC for brain metastasis?
Current guidelines suggest that we scan for brain metastasis in the presence of new neurologic symptoms, such as headache, dizziness, or weakness in the arms or legs. MRI, in particular, is useful for evaluating brain metastasis, especially for smaller lesions, but lesions are sometimes detected through CT imaging of the head, too.
That’s where the guidelines are now. But as our systemic agents improve, there’s always the possibility these recommendations will be revisited and potentially include imaging as screening tools in asymptomatic patients, as well.
How do you assess which patients with MBC should receive local therapy?
Increasingly, because our systemic therapies in breast cancer are getting better in terms of crossing the blood-brain barrier, we think about local therapy on a case-by-case basis. We think about it with the question of whether we delay surgery or radiation — whole brain radiation, in particular — given concerns surrounding the side effects of these modalities, namely cognitive dysfunction for radiation and increased risk of bleeding and infection for surgery.
Giving a patient-directed local therapy, such as Gamma Knife radiosurgery or whole-brain radiotherapy, ultimately depends on the burden of brain metastasis, the status of systemic disease outside of the brain, and the number and size of the lesions seen on imaging. If, for instance, a patient has a large lesion that will immediately impact their neurologic status, we may opt to resect the lesion. If there are innumerable lesions, some of which are large, we may do whole-brain radiotherapy. If, however, a patient has systemic disease that is largely under control but is experiencing local progression in the brain, we may use local radiotherapy while continuing systemic therapy.
What about systemic therapies that cross the blood-brain barrier? What’s available now and how do you choose among the options?The subtype of breast cancer informs treatment with systemic therapies. For instance, patients with HER2-positive disease may receive oral tyrosine kinase inhibitors, such as tucatinib, neratinib, and lapatinib, which have strong CNS penetration. For patients with estrogen receptor–positive, HER2-negative MBC, estrogen therapies including aromatase inhibitors, as well as targeted therapies such as the mTOR inhibitor everolimus, have good CNS penetration. For patients with metastatic TNBC, we have chemotherapies that cross the blood-brain barrier, such as capecitabine and platinum-based chemotherapy.
Evidence suggests that tumors in the brain may harbor different genetic abnormalities from tumors in the breast. How do you consider the potential genetic heterogeneity in CNS tumors vs. the primary breast tumor?When a patient’s disease has spread to the brain, we may preferentially use agents we know cross the blood-brain barrier, so we can obtain systemic control both intracranially and extracranially. If we have already resected or biopsied cancerous brain tissue, it’s good to check the tumor’s estrogen receptor, progesterone receptor, and HER2 status and do next-generation sequencing to see if the tumor has any other targetable mutations, such as PIK3CA mutations.
But when a patient has multiple lesions, we don’t go in and biopsy all of them to check for heterogeneity. We have to make decisions based on samples we have. In cases where we start systemic therapy and notice one lesion is not responding to these agents while others are, the nonresponsive lesion may be an outlier in terms of its biologic characteristics. It may be worth targeting that lesion for biopsy and further sequencing to determine the next best systemic approach.
How do quality of life considerations factor into the management of patients with MBC brain metastases?
We use a multidisciplinary approach when treating patients. This means patient care involves a team of experts, which can include medical oncologists, radiation oncologists, and neuro-oncologists who help determine a treatment plan that takes factors such as survival and quality of life into account.
This is why, for example, we try to delay whole brain radiotherapy when we can. The HER2CLIMB study, which led to the approval of tucatinib as a treatment option for patients with HER2-positive MBC, showed us that patients with treated or untreated brain metastases receiving systemic therapy before local therapy could benefit from the combination of tucatinib, trastuzumab, and capecitabine. These patients exhibited a median progression-free survival of 7.6 months compared with 5.4 months in the placebo group.
HER2CLIMB has been practice changing because it showed us that tucatinib has good CNS activity in patients with brain metastases. The HER2CLIMB findings raise an important question: As our systemic therapies improve, how aggressive do we need to be with local therapy? Can we push off modalities like whole-brain radiotherapy, which are associated with toxicity?
This study also highlights how important it is for patients with metastatic disease to seek clinical trials. Although some trials exclude patients with brain metastases and others may have criteria that require the stability of brain metastasis for a certain amount of time, the knowledge gained can be invaluable.
Where are some of the main gaps in our understanding of brain metastases in patients with MBC?
One issue is our understanding of tropism to the brain. In other words, why does MBC spread to the brain? Once we understand this key piece, we can work on developing more effective therapies and therapeutic combinations to block brain metastasis.
For hormone receptor–positive disease, in particular, a central question is whether the current antiestrogen therapies — such as selective estrogen receptor degraders like fulvestrant, as well as targeted AKT inhibitors — have the potential to affect brain tumor activity. The same holds true for TNBC, where antibody drug conjugates and immunotherapies are being evaluated for treatment of brain tumors. For patients with HER2-positive MBC that has spread to the brain, understanding the continued role for tyrosine kinase inhibitors, such as tucatinib and neratinib, as well as whether antibody drug conjugates, including trastuzumab deruxtecan and trastuzumab emtansine, have CNS activity are important areas to explore further.
The CompassHER2 trial, going on now, is randomizing patients with residual HER2-positive disease after neoadjuvant chemotherapy and HER2-targeted therapy to receive trastuzumab emtansine with or without tucatinib. One of the core questions of this study is whether trastuzumab emtansine/tucatinib lowers the rate of brain metastasis and the incidence of systemic metastasis.
Another area in MBC that requires greater scrutiny is patients who develop leptomeningeal disease, which is when cancer cells spread to the cerebrospinal fluid. These patients have a particularly poor prognosis, and it would be helpful to evaluate the efficacy of existing therapies, but these patients are often excluded from clinical trials.
Overall, the ultimate goal in these endeavors is to decrease the rate of metastasis to the brain and improve survival and quality of life in patients with MBC who do experience brain metastases.
A version of this article first appeared on Medscape.com.
Brain metastases remain a frequent and often fatal consequence of metastatic breast cancer (MBC). MBC carries a median survival of about 3 years, but that rate drops significantly when cancer cells move to the brain. A recent analysis estimates median survival in patients with brain metastases ranges from 6 months in triple-negative breast cancer (TNBC) to 21 months in human epidermal growth factor receptor 2 (HER2)–positive disease.
This news organization spoke to Kevin M. Kalinsky, MD, acting associate professor in the department of hematology and medical oncology at Emory University School of Medicine in Atlanta and director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University, about the risk for brain metastases in patients with MBC, strategies for screening and treatment, and the work being done to achieve a better understanding of the disease.
Question: Before we dig into strategies to manage MBC brain metastasis, let’s talk about the risks. When and how often do brain metastases present in patients with MBC? What factors increase the likelihood of developing brain metastasis?
Dr. Kalinsky: The biggest risk factor for MBC spreading to the central nervous system (CNS), which includes the brain and spine, is breast cancer subtype. For patients with metastatic TNBC, the risk for brain metastasis can be more than 50%. For patients with HER2-positive disease, the risk may be slightly lower, with estimates in the range of 25%-50%, whereas the likelihood of brain metastasis in patients with hormone receptor–positive MBC is significantly lower at close to 14%. In addition, patients with metastatic TNBC may have brain metastases a little earlier in their disease progression compared with patients with HER2-positive or estrogen receptor–positive breast cancers, where brain metastases generally develop a little later in the disease course.
At what point is it recommended to screen patients with MBC for brain metastasis?
Current guidelines suggest that we scan for brain metastasis in the presence of new neurologic symptoms, such as headache, dizziness, or weakness in the arms or legs. MRI, in particular, is useful for evaluating brain metastasis, especially for smaller lesions, but lesions are sometimes detected through CT imaging of the head, too.
That’s where the guidelines are now. But as our systemic agents improve, there’s always the possibility these recommendations will be revisited and potentially include imaging as screening tools in asymptomatic patients, as well.
How do you assess which patients with MBC should receive local therapy?
Increasingly, because our systemic therapies in breast cancer are getting better in terms of crossing the blood-brain barrier, we think about local therapy on a case-by-case basis. We think about it with the question of whether we delay surgery or radiation — whole brain radiation, in particular — given concerns surrounding the side effects of these modalities, namely cognitive dysfunction for radiation and increased risk of bleeding and infection for surgery.
Giving a patient-directed local therapy, such as Gamma Knife radiosurgery or whole-brain radiotherapy, ultimately depends on the burden of brain metastasis, the status of systemic disease outside of the brain, and the number and size of the lesions seen on imaging. If, for instance, a patient has a large lesion that will immediately impact their neurologic status, we may opt to resect the lesion. If there are innumerable lesions, some of which are large, we may do whole-brain radiotherapy. If, however, a patient has systemic disease that is largely under control but is experiencing local progression in the brain, we may use local radiotherapy while continuing systemic therapy.
What about systemic therapies that cross the blood-brain barrier? What’s available now and how do you choose among the options?The subtype of breast cancer informs treatment with systemic therapies. For instance, patients with HER2-positive disease may receive oral tyrosine kinase inhibitors, such as tucatinib, neratinib, and lapatinib, which have strong CNS penetration. For patients with estrogen receptor–positive, HER2-negative MBC, estrogen therapies including aromatase inhibitors, as well as targeted therapies such as the mTOR inhibitor everolimus, have good CNS penetration. For patients with metastatic TNBC, we have chemotherapies that cross the blood-brain barrier, such as capecitabine and platinum-based chemotherapy.
Evidence suggests that tumors in the brain may harbor different genetic abnormalities from tumors in the breast. How do you consider the potential genetic heterogeneity in CNS tumors vs. the primary breast tumor?When a patient’s disease has spread to the brain, we may preferentially use agents we know cross the blood-brain barrier, so we can obtain systemic control both intracranially and extracranially. If we have already resected or biopsied cancerous brain tissue, it’s good to check the tumor’s estrogen receptor, progesterone receptor, and HER2 status and do next-generation sequencing to see if the tumor has any other targetable mutations, such as PIK3CA mutations.
But when a patient has multiple lesions, we don’t go in and biopsy all of them to check for heterogeneity. We have to make decisions based on samples we have. In cases where we start systemic therapy and notice one lesion is not responding to these agents while others are, the nonresponsive lesion may be an outlier in terms of its biologic characteristics. It may be worth targeting that lesion for biopsy and further sequencing to determine the next best systemic approach.
How do quality of life considerations factor into the management of patients with MBC brain metastases?
We use a multidisciplinary approach when treating patients. This means patient care involves a team of experts, which can include medical oncologists, radiation oncologists, and neuro-oncologists who help determine a treatment plan that takes factors such as survival and quality of life into account.
This is why, for example, we try to delay whole brain radiotherapy when we can. The HER2CLIMB study, which led to the approval of tucatinib as a treatment option for patients with HER2-positive MBC, showed us that patients with treated or untreated brain metastases receiving systemic therapy before local therapy could benefit from the combination of tucatinib, trastuzumab, and capecitabine. These patients exhibited a median progression-free survival of 7.6 months compared with 5.4 months in the placebo group.
HER2CLIMB has been practice changing because it showed us that tucatinib has good CNS activity in patients with brain metastases. The HER2CLIMB findings raise an important question: As our systemic therapies improve, how aggressive do we need to be with local therapy? Can we push off modalities like whole-brain radiotherapy, which are associated with toxicity?
This study also highlights how important it is for patients with metastatic disease to seek clinical trials. Although some trials exclude patients with brain metastases and others may have criteria that require the stability of brain metastasis for a certain amount of time, the knowledge gained can be invaluable.
Where are some of the main gaps in our understanding of brain metastases in patients with MBC?
One issue is our understanding of tropism to the brain. In other words, why does MBC spread to the brain? Once we understand this key piece, we can work on developing more effective therapies and therapeutic combinations to block brain metastasis.
For hormone receptor–positive disease, in particular, a central question is whether the current antiestrogen therapies — such as selective estrogen receptor degraders like fulvestrant, as well as targeted AKT inhibitors — have the potential to affect brain tumor activity. The same holds true for TNBC, where antibody drug conjugates and immunotherapies are being evaluated for treatment of brain tumors. For patients with HER2-positive MBC that has spread to the brain, understanding the continued role for tyrosine kinase inhibitors, such as tucatinib and neratinib, as well as whether antibody drug conjugates, including trastuzumab deruxtecan and trastuzumab emtansine, have CNS activity are important areas to explore further.
The CompassHER2 trial, going on now, is randomizing patients with residual HER2-positive disease after neoadjuvant chemotherapy and HER2-targeted therapy to receive trastuzumab emtansine with or without tucatinib. One of the core questions of this study is whether trastuzumab emtansine/tucatinib lowers the rate of brain metastasis and the incidence of systemic metastasis.
Another area in MBC that requires greater scrutiny is patients who develop leptomeningeal disease, which is when cancer cells spread to the cerebrospinal fluid. These patients have a particularly poor prognosis, and it would be helpful to evaluate the efficacy of existing therapies, but these patients are often excluded from clinical trials.
Overall, the ultimate goal in these endeavors is to decrease the rate of metastasis to the brain and improve survival and quality of life in patients with MBC who do experience brain metastases.
A version of this article first appeared on Medscape.com.
Brain metastases remain a frequent and often fatal consequence of metastatic breast cancer (MBC). MBC carries a median survival of about 3 years, but that rate drops significantly when cancer cells move to the brain. A recent analysis estimates median survival in patients with brain metastases ranges from 6 months in triple-negative breast cancer (TNBC) to 21 months in human epidermal growth factor receptor 2 (HER2)–positive disease.
This news organization spoke to Kevin M. Kalinsky, MD, acting associate professor in the department of hematology and medical oncology at Emory University School of Medicine in Atlanta and director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University, about the risk for brain metastases in patients with MBC, strategies for screening and treatment, and the work being done to achieve a better understanding of the disease.
Question: Before we dig into strategies to manage MBC brain metastasis, let’s talk about the risks. When and how often do brain metastases present in patients with MBC? What factors increase the likelihood of developing brain metastasis?
Dr. Kalinsky: The biggest risk factor for MBC spreading to the central nervous system (CNS), which includes the brain and spine, is breast cancer subtype. For patients with metastatic TNBC, the risk for brain metastasis can be more than 50%. For patients with HER2-positive disease, the risk may be slightly lower, with estimates in the range of 25%-50%, whereas the likelihood of brain metastasis in patients with hormone receptor–positive MBC is significantly lower at close to 14%. In addition, patients with metastatic TNBC may have brain metastases a little earlier in their disease progression compared with patients with HER2-positive or estrogen receptor–positive breast cancers, where brain metastases generally develop a little later in the disease course.
At what point is it recommended to screen patients with MBC for brain metastasis?
Current guidelines suggest that we scan for brain metastasis in the presence of new neurologic symptoms, such as headache, dizziness, or weakness in the arms or legs. MRI, in particular, is useful for evaluating brain metastasis, especially for smaller lesions, but lesions are sometimes detected through CT imaging of the head, too.
That’s where the guidelines are now. But as our systemic agents improve, there’s always the possibility these recommendations will be revisited and potentially include imaging as screening tools in asymptomatic patients, as well.
How do you assess which patients with MBC should receive local therapy?
Increasingly, because our systemic therapies in breast cancer are getting better in terms of crossing the blood-brain barrier, we think about local therapy on a case-by-case basis. We think about it with the question of whether we delay surgery or radiation — whole brain radiation, in particular — given concerns surrounding the side effects of these modalities, namely cognitive dysfunction for radiation and increased risk of bleeding and infection for surgery.
Giving a patient-directed local therapy, such as Gamma Knife radiosurgery or whole-brain radiotherapy, ultimately depends on the burden of brain metastasis, the status of systemic disease outside of the brain, and the number and size of the lesions seen on imaging. If, for instance, a patient has a large lesion that will immediately impact their neurologic status, we may opt to resect the lesion. If there are innumerable lesions, some of which are large, we may do whole-brain radiotherapy. If, however, a patient has systemic disease that is largely under control but is experiencing local progression in the brain, we may use local radiotherapy while continuing systemic therapy.
What about systemic therapies that cross the blood-brain barrier? What’s available now and how do you choose among the options?The subtype of breast cancer informs treatment with systemic therapies. For instance, patients with HER2-positive disease may receive oral tyrosine kinase inhibitors, such as tucatinib, neratinib, and lapatinib, which have strong CNS penetration. For patients with estrogen receptor–positive, HER2-negative MBC, estrogen therapies including aromatase inhibitors, as well as targeted therapies such as the mTOR inhibitor everolimus, have good CNS penetration. For patients with metastatic TNBC, we have chemotherapies that cross the blood-brain barrier, such as capecitabine and platinum-based chemotherapy.
Evidence suggests that tumors in the brain may harbor different genetic abnormalities from tumors in the breast. How do you consider the potential genetic heterogeneity in CNS tumors vs. the primary breast tumor?When a patient’s disease has spread to the brain, we may preferentially use agents we know cross the blood-brain barrier, so we can obtain systemic control both intracranially and extracranially. If we have already resected or biopsied cancerous brain tissue, it’s good to check the tumor’s estrogen receptor, progesterone receptor, and HER2 status and do next-generation sequencing to see if the tumor has any other targetable mutations, such as PIK3CA mutations.
But when a patient has multiple lesions, we don’t go in and biopsy all of them to check for heterogeneity. We have to make decisions based on samples we have. In cases where we start systemic therapy and notice one lesion is not responding to these agents while others are, the nonresponsive lesion may be an outlier in terms of its biologic characteristics. It may be worth targeting that lesion for biopsy and further sequencing to determine the next best systemic approach.
How do quality of life considerations factor into the management of patients with MBC brain metastases?
We use a multidisciplinary approach when treating patients. This means patient care involves a team of experts, which can include medical oncologists, radiation oncologists, and neuro-oncologists who help determine a treatment plan that takes factors such as survival and quality of life into account.
This is why, for example, we try to delay whole brain radiotherapy when we can. The HER2CLIMB study, which led to the approval of tucatinib as a treatment option for patients with HER2-positive MBC, showed us that patients with treated or untreated brain metastases receiving systemic therapy before local therapy could benefit from the combination of tucatinib, trastuzumab, and capecitabine. These patients exhibited a median progression-free survival of 7.6 months compared with 5.4 months in the placebo group.
HER2CLIMB has been practice changing because it showed us that tucatinib has good CNS activity in patients with brain metastases. The HER2CLIMB findings raise an important question: As our systemic therapies improve, how aggressive do we need to be with local therapy? Can we push off modalities like whole-brain radiotherapy, which are associated with toxicity?
This study also highlights how important it is for patients with metastatic disease to seek clinical trials. Although some trials exclude patients with brain metastases and others may have criteria that require the stability of brain metastasis for a certain amount of time, the knowledge gained can be invaluable.
Where are some of the main gaps in our understanding of brain metastases in patients with MBC?
One issue is our understanding of tropism to the brain. In other words, why does MBC spread to the brain? Once we understand this key piece, we can work on developing more effective therapies and therapeutic combinations to block brain metastasis.
For hormone receptor–positive disease, in particular, a central question is whether the current antiestrogen therapies — such as selective estrogen receptor degraders like fulvestrant, as well as targeted AKT inhibitors — have the potential to affect brain tumor activity. The same holds true for TNBC, where antibody drug conjugates and immunotherapies are being evaluated for treatment of brain tumors. For patients with HER2-positive MBC that has spread to the brain, understanding the continued role for tyrosine kinase inhibitors, such as tucatinib and neratinib, as well as whether antibody drug conjugates, including trastuzumab deruxtecan and trastuzumab emtansine, have CNS activity are important areas to explore further.
The CompassHER2 trial, going on now, is randomizing patients with residual HER2-positive disease after neoadjuvant chemotherapy and HER2-targeted therapy to receive trastuzumab emtansine with or without tucatinib. One of the core questions of this study is whether trastuzumab emtansine/tucatinib lowers the rate of brain metastasis and the incidence of systemic metastasis.
Another area in MBC that requires greater scrutiny is patients who develop leptomeningeal disease, which is when cancer cells spread to the cerebrospinal fluid. These patients have a particularly poor prognosis, and it would be helpful to evaluate the efficacy of existing therapies, but these patients are often excluded from clinical trials.
Overall, the ultimate goal in these endeavors is to decrease the rate of metastasis to the brain and improve survival and quality of life in patients with MBC who do experience brain metastases.
A version of this article first appeared on Medscape.com.
CONCERT: Better QoL but not survival with cabazitaxel in metastatic HER2– breast cancer
For patients with HER2-negative metastatic breast cancer, first line chemotherapy with cabazitaxel (Jevtana) every 3 weeks offers efficacy comparable to that of once-weekly paclitaxel, but with lower risk for peripheral neuropathy and better patient-reported quality of life, investigators in the multicenter CONCERT trial found.
In an open-label clinical trial of 158 patients from 14 hospitals in the United Kingdom, there was no difference in the primary endpoint of progression-free survival (PFS) or a secondary overall survival endpoint between patients randomly assigned to initial chemotherapy with cabazitaxel every 3 weeks or weekly paclitaxel, reported Amit Bahl, MD, of University Hospital Bristol, England, and colleagues.
“Cabazitaxel is safe and well tolerated for metastatic breast cancer and requires fewer hospital visits than weekly paclitaxel, which is very important for patients and health care providers, but more so in the current situation,” he said in an oral abstract session at the American Society of Clinical Oncology annual meeting (Abstract 1008).
Cabazitaxel is currently approved in the United States and Europe in combination with prednisone for treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen. It is not currently approved for the treatment of metastatic breast cancer, but has been explored for this indication in clinical trials.
“In the metastatic setting, where patients continue on treatment pretty much indefinitely until disease progression or unacceptable toxicity, the use of an every-3-week regimen could be attractive, because it means less visits for the patients, and it appears that this drug has lower toxicity in terms of peripheral neuropathy,” said breast cancer specialist Aditya Bardia, MD, MPH, who was not involved in the study.
Dr. Bardia, of Mass General Cancer Center in Boston, commented on the study in an interview.
Although paclitaxel is commonly used as first-line chemotherapy for HER2-negative metastatic breast cancer, it is associated with only modest response rates, ranging from 21.5% to 53.7% and carries significant risk of peripheral neuropathy, Dr. Bahl and colleagues noted.
“There is an unmet need for an alternative first-line cytotoxic chemotherapy agent, and cabazitaxel is a taxoid agent which has showed promising results in phase 2 trial of metastatic breast cancer patients in the second-line setting, even those with taxane resistance,” he said.
Open-label trial
To see whether cabazitaxel could meet those requirements, the investigators conducted a phase 2 randomized trial in which patients with HER2-negative metastatic breast cancer not previously treated with cytotoxic chemotherapy were assigned, 79 in each arm, to receive cabazitaxel 25 mg/m2 every 3 weeks, or paclitaxel 80 mg/m2 weekly.
The median patient age was 56 years in the cabazitaxel group and 61 years in the paclitaxel group. Roughly two-thirds of patients in each arm had Eastern Cooperative Oncology Group performance status 0, and the remainder had ECOG performance status 1.
In each arm, the median time on treatment was 15 weeks, but treatment delays and dose reductions were more common among patients on paclitaxel than cabazitaxel (61% vs. 39%, and 37% vs. 24%, respectively).
There were 149 PFS events at the time of the analysis. The median PFS with cabazitaxel was 6.7 months vs. 5.8 months with paclitaxel. This difference was not statistically significant. Median overall survival was 20.6 months in the cabazitaxel arm, vs. 18.2 months 20.0 months, respectively.
Similarly, there were no significant differences in either the overall response rates (42% vs. 37%), or time to response.
There were no complete responses with cabazitaxel vs. two (2.5%) with paclitaxel. The respective partial response rates were 41.8% vs. 34.2%.
In a subgroup analysis of PFS, there were no significant between-arm differences, except for an improved PFS in patients 65 and older with cabazitaxel (hazard ratio 0.45, 95% confidence interval, 0.25-0.80).
Quality of life favors cabazitaxel
Grade 3 or greater adverse events occurred in 42% of patients on cabazitaxel vs. 51% on paclitaxel. Diarrhea, febrile neutropenia, and nausea were the most common grade 3 or greater events in the cabazitaxel arm, whereas grade 3 or greater lung infection and peripheral neuropathy were more common with paclitaxel.
Sensory peripheral neuropathy of any grade occurred in 16% of patients assigned to cabazitaxel, compared with 54% assigned to paclitaxel. The respective rates of alopecia were 27% and 42%.
Over the course of treatment, the mean EuroQuol EQ-5D-5L single index utility score and visual analogue scale score were higher with cabazitaxel arm compared to paclitaxel, suggesting better patient quality of life with cabazitaxel.
In addition, throughout treatment patients in the cabazitaxel arm reported significantly better scores on The Functional Assessment of Cancer Therapy – Breast (FACT-B) breast cancer subscale, Dr. Bahl said.
Second-line may be better
ASCO invited discussant Marleen Kok, MD, PhD, from the Netherlands Cancer Institute in Amsterdam, pointed out that in the phase 2 GENEVIEVE trial comparing the efficacy and safety of cabazitaxel versus weekly paclitaxel as neoadjuvant treatment in patients with triple negative or luminal B/HER2 normal breast cancer the pathologic complete response rate with cabazitaxel was 1.2%, compared with 11% with paclitaxel.
“This GENEVIEVE trial, together with the CONCERT trial, suggests that there is not a big role for cabazitaxel to be used upfront before other taxanes,” she said.
However, in a phase 2 study of cabazitaxel as second-line therapy in patients with HER2-negative metastatic breast cancer who had previously been treated with taxanes, the overall response rate was 23%, “which is still of interest and importance for our patients,” she added.
Dr. Kok did not address quality of life differences between the regimens, however.
In a side note, Dr. Bardia said that “if there were an oral form of paclitaxel, that would certainly be very welcome, in that an oral drug is more convenient for patients, and would require fewer visits to the hospital.”
The CONCERT trial was funded by an investigator-sponsored study grant from Sanofi. Dr. Bahl disclosed honoraria and institutional research funding from Sanofi/Aventis and others, and travel expenses from Bayer and Roche. Dr. Kok disclosed a consulting or advisory role for Bristol Myers Squibb/Medarex, and institutional research funding from that company and others. Dr. Bardia disclosed a consulting or advisory role and research funding to his institution from multiple companies.
For patients with HER2-negative metastatic breast cancer, first line chemotherapy with cabazitaxel (Jevtana) every 3 weeks offers efficacy comparable to that of once-weekly paclitaxel, but with lower risk for peripheral neuropathy and better patient-reported quality of life, investigators in the multicenter CONCERT trial found.
In an open-label clinical trial of 158 patients from 14 hospitals in the United Kingdom, there was no difference in the primary endpoint of progression-free survival (PFS) or a secondary overall survival endpoint between patients randomly assigned to initial chemotherapy with cabazitaxel every 3 weeks or weekly paclitaxel, reported Amit Bahl, MD, of University Hospital Bristol, England, and colleagues.
“Cabazitaxel is safe and well tolerated for metastatic breast cancer and requires fewer hospital visits than weekly paclitaxel, which is very important for patients and health care providers, but more so in the current situation,” he said in an oral abstract session at the American Society of Clinical Oncology annual meeting (Abstract 1008).
Cabazitaxel is currently approved in the United States and Europe in combination with prednisone for treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen. It is not currently approved for the treatment of metastatic breast cancer, but has been explored for this indication in clinical trials.
“In the metastatic setting, where patients continue on treatment pretty much indefinitely until disease progression or unacceptable toxicity, the use of an every-3-week regimen could be attractive, because it means less visits for the patients, and it appears that this drug has lower toxicity in terms of peripheral neuropathy,” said breast cancer specialist Aditya Bardia, MD, MPH, who was not involved in the study.
Dr. Bardia, of Mass General Cancer Center in Boston, commented on the study in an interview.
Although paclitaxel is commonly used as first-line chemotherapy for HER2-negative metastatic breast cancer, it is associated with only modest response rates, ranging from 21.5% to 53.7% and carries significant risk of peripheral neuropathy, Dr. Bahl and colleagues noted.
“There is an unmet need for an alternative first-line cytotoxic chemotherapy agent, and cabazitaxel is a taxoid agent which has showed promising results in phase 2 trial of metastatic breast cancer patients in the second-line setting, even those with taxane resistance,” he said.
Open-label trial
To see whether cabazitaxel could meet those requirements, the investigators conducted a phase 2 randomized trial in which patients with HER2-negative metastatic breast cancer not previously treated with cytotoxic chemotherapy were assigned, 79 in each arm, to receive cabazitaxel 25 mg/m2 every 3 weeks, or paclitaxel 80 mg/m2 weekly.
The median patient age was 56 years in the cabazitaxel group and 61 years in the paclitaxel group. Roughly two-thirds of patients in each arm had Eastern Cooperative Oncology Group performance status 0, and the remainder had ECOG performance status 1.
In each arm, the median time on treatment was 15 weeks, but treatment delays and dose reductions were more common among patients on paclitaxel than cabazitaxel (61% vs. 39%, and 37% vs. 24%, respectively).
There were 149 PFS events at the time of the analysis. The median PFS with cabazitaxel was 6.7 months vs. 5.8 months with paclitaxel. This difference was not statistically significant. Median overall survival was 20.6 months in the cabazitaxel arm, vs. 18.2 months 20.0 months, respectively.
Similarly, there were no significant differences in either the overall response rates (42% vs. 37%), or time to response.
There were no complete responses with cabazitaxel vs. two (2.5%) with paclitaxel. The respective partial response rates were 41.8% vs. 34.2%.
In a subgroup analysis of PFS, there were no significant between-arm differences, except for an improved PFS in patients 65 and older with cabazitaxel (hazard ratio 0.45, 95% confidence interval, 0.25-0.80).
Quality of life favors cabazitaxel
Grade 3 or greater adverse events occurred in 42% of patients on cabazitaxel vs. 51% on paclitaxel. Diarrhea, febrile neutropenia, and nausea were the most common grade 3 or greater events in the cabazitaxel arm, whereas grade 3 or greater lung infection and peripheral neuropathy were more common with paclitaxel.
Sensory peripheral neuropathy of any grade occurred in 16% of patients assigned to cabazitaxel, compared with 54% assigned to paclitaxel. The respective rates of alopecia were 27% and 42%.
Over the course of treatment, the mean EuroQuol EQ-5D-5L single index utility score and visual analogue scale score were higher with cabazitaxel arm compared to paclitaxel, suggesting better patient quality of life with cabazitaxel.
In addition, throughout treatment patients in the cabazitaxel arm reported significantly better scores on The Functional Assessment of Cancer Therapy – Breast (FACT-B) breast cancer subscale, Dr. Bahl said.
Second-line may be better
ASCO invited discussant Marleen Kok, MD, PhD, from the Netherlands Cancer Institute in Amsterdam, pointed out that in the phase 2 GENEVIEVE trial comparing the efficacy and safety of cabazitaxel versus weekly paclitaxel as neoadjuvant treatment in patients with triple negative or luminal B/HER2 normal breast cancer the pathologic complete response rate with cabazitaxel was 1.2%, compared with 11% with paclitaxel.
“This GENEVIEVE trial, together with the CONCERT trial, suggests that there is not a big role for cabazitaxel to be used upfront before other taxanes,” she said.
However, in a phase 2 study of cabazitaxel as second-line therapy in patients with HER2-negative metastatic breast cancer who had previously been treated with taxanes, the overall response rate was 23%, “which is still of interest and importance for our patients,” she added.
Dr. Kok did not address quality of life differences between the regimens, however.
In a side note, Dr. Bardia said that “if there were an oral form of paclitaxel, that would certainly be very welcome, in that an oral drug is more convenient for patients, and would require fewer visits to the hospital.”
The CONCERT trial was funded by an investigator-sponsored study grant from Sanofi. Dr. Bahl disclosed honoraria and institutional research funding from Sanofi/Aventis and others, and travel expenses from Bayer and Roche. Dr. Kok disclosed a consulting or advisory role for Bristol Myers Squibb/Medarex, and institutional research funding from that company and others. Dr. Bardia disclosed a consulting or advisory role and research funding to his institution from multiple companies.
For patients with HER2-negative metastatic breast cancer, first line chemotherapy with cabazitaxel (Jevtana) every 3 weeks offers efficacy comparable to that of once-weekly paclitaxel, but with lower risk for peripheral neuropathy and better patient-reported quality of life, investigators in the multicenter CONCERT trial found.
In an open-label clinical trial of 158 patients from 14 hospitals in the United Kingdom, there was no difference in the primary endpoint of progression-free survival (PFS) or a secondary overall survival endpoint between patients randomly assigned to initial chemotherapy with cabazitaxel every 3 weeks or weekly paclitaxel, reported Amit Bahl, MD, of University Hospital Bristol, England, and colleagues.
“Cabazitaxel is safe and well tolerated for metastatic breast cancer and requires fewer hospital visits than weekly paclitaxel, which is very important for patients and health care providers, but more so in the current situation,” he said in an oral abstract session at the American Society of Clinical Oncology annual meeting (Abstract 1008).
Cabazitaxel is currently approved in the United States and Europe in combination with prednisone for treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen. It is not currently approved for the treatment of metastatic breast cancer, but has been explored for this indication in clinical trials.
“In the metastatic setting, where patients continue on treatment pretty much indefinitely until disease progression or unacceptable toxicity, the use of an every-3-week regimen could be attractive, because it means less visits for the patients, and it appears that this drug has lower toxicity in terms of peripheral neuropathy,” said breast cancer specialist Aditya Bardia, MD, MPH, who was not involved in the study.
Dr. Bardia, of Mass General Cancer Center in Boston, commented on the study in an interview.
Although paclitaxel is commonly used as first-line chemotherapy for HER2-negative metastatic breast cancer, it is associated with only modest response rates, ranging from 21.5% to 53.7% and carries significant risk of peripheral neuropathy, Dr. Bahl and colleagues noted.
“There is an unmet need for an alternative first-line cytotoxic chemotherapy agent, and cabazitaxel is a taxoid agent which has showed promising results in phase 2 trial of metastatic breast cancer patients in the second-line setting, even those with taxane resistance,” he said.
Open-label trial
To see whether cabazitaxel could meet those requirements, the investigators conducted a phase 2 randomized trial in which patients with HER2-negative metastatic breast cancer not previously treated with cytotoxic chemotherapy were assigned, 79 in each arm, to receive cabazitaxel 25 mg/m2 every 3 weeks, or paclitaxel 80 mg/m2 weekly.
The median patient age was 56 years in the cabazitaxel group and 61 years in the paclitaxel group. Roughly two-thirds of patients in each arm had Eastern Cooperative Oncology Group performance status 0, and the remainder had ECOG performance status 1.
In each arm, the median time on treatment was 15 weeks, but treatment delays and dose reductions were more common among patients on paclitaxel than cabazitaxel (61% vs. 39%, and 37% vs. 24%, respectively).
There were 149 PFS events at the time of the analysis. The median PFS with cabazitaxel was 6.7 months vs. 5.8 months with paclitaxel. This difference was not statistically significant. Median overall survival was 20.6 months in the cabazitaxel arm, vs. 18.2 months 20.0 months, respectively.
Similarly, there were no significant differences in either the overall response rates (42% vs. 37%), or time to response.
There were no complete responses with cabazitaxel vs. two (2.5%) with paclitaxel. The respective partial response rates were 41.8% vs. 34.2%.
In a subgroup analysis of PFS, there were no significant between-arm differences, except for an improved PFS in patients 65 and older with cabazitaxel (hazard ratio 0.45, 95% confidence interval, 0.25-0.80).
Quality of life favors cabazitaxel
Grade 3 or greater adverse events occurred in 42% of patients on cabazitaxel vs. 51% on paclitaxel. Diarrhea, febrile neutropenia, and nausea were the most common grade 3 or greater events in the cabazitaxel arm, whereas grade 3 or greater lung infection and peripheral neuropathy were more common with paclitaxel.
Sensory peripheral neuropathy of any grade occurred in 16% of patients assigned to cabazitaxel, compared with 54% assigned to paclitaxel. The respective rates of alopecia were 27% and 42%.
Over the course of treatment, the mean EuroQuol EQ-5D-5L single index utility score and visual analogue scale score were higher with cabazitaxel arm compared to paclitaxel, suggesting better patient quality of life with cabazitaxel.
In addition, throughout treatment patients in the cabazitaxel arm reported significantly better scores on The Functional Assessment of Cancer Therapy – Breast (FACT-B) breast cancer subscale, Dr. Bahl said.
Second-line may be better
ASCO invited discussant Marleen Kok, MD, PhD, from the Netherlands Cancer Institute in Amsterdam, pointed out that in the phase 2 GENEVIEVE trial comparing the efficacy and safety of cabazitaxel versus weekly paclitaxel as neoadjuvant treatment in patients with triple negative or luminal B/HER2 normal breast cancer the pathologic complete response rate with cabazitaxel was 1.2%, compared with 11% with paclitaxel.
“This GENEVIEVE trial, together with the CONCERT trial, suggests that there is not a big role for cabazitaxel to be used upfront before other taxanes,” she said.
However, in a phase 2 study of cabazitaxel as second-line therapy in patients with HER2-negative metastatic breast cancer who had previously been treated with taxanes, the overall response rate was 23%, “which is still of interest and importance for our patients,” she added.
Dr. Kok did not address quality of life differences between the regimens, however.
In a side note, Dr. Bardia said that “if there were an oral form of paclitaxel, that would certainly be very welcome, in that an oral drug is more convenient for patients, and would require fewer visits to the hospital.”
The CONCERT trial was funded by an investigator-sponsored study grant from Sanofi. Dr. Bahl disclosed honoraria and institutional research funding from Sanofi/Aventis and others, and travel expenses from Bayer and Roche. Dr. Kok disclosed a consulting or advisory role for Bristol Myers Squibb/Medarex, and institutional research funding from that company and others. Dr. Bardia disclosed a consulting or advisory role and research funding to his institution from multiple companies.
FROM ASCO 2021
ASCO 2021: Breast cancer sessions not to miss
This transcript has been edited for clarity.
Hello. It’s Dr. Kathy Miller from Indiana University.
I have to admit that time has snuck up on me this year. It is already time for the American Society of Clinical Oncology Annual Meeting.
I found it hard to keep track of time this year with the pandemic. Many of the things that help mark the passage of time haven’t happened, have happened at different times of the year than is typical, or have happened in different ways that just haven’t had the same impact in my brain.
Just recently, I was taking a look through the breast cancer program at ASCO and there is a special clinical science symposium that I want to make sure you know about and tune into. It’s the sort of session that might not otherwise reach you.
This has been a year of incredible turmoil and critical thinking about issues of race, ethnicity, justice, and how we can make sure that the medical care we’re providing is inclusive and equitable. How we can make sure we are giving the best outcome to all of our patients.
This special clinical science symposium this year includes several presentations that will delve into how genetically determined ancestry and socially determined race might impact the outcome of our patients. This is a tangled web that is difficult to unpack and separate, but there are clear distinctions here: The genes we inherit do affect how we metabolize drugs, what side effects we might have from drugs, and what drugs might be the best choices for us.
Our socially determined race affects how the world interacts with us. Those biases, be they conscious or unconscious, can affect where we live, where we go to school, how people treat us, what opportunities we have, and how the medical system treats us. They’re related, but they’re not the same. Tune into that clinical science symposium to begin thinking about those differences and how we can make sure we give our patients the best care.
There are other high-profile presentations that you’re going to want to see as well, looking at how we can optimize therapy in patients with HER2-positive disease and beginning to think about who might not need chemotherapy to have an excellent outcome in early-stage disease.
Also, we will be thinking about those patients with triple-negative disease who have residual disease after neoadjuvant chemotherapy. We were all caught off guard with the results of the CREATE-X trial, quite frankly, several years ago.
This year we will hear the results of a postneoadjuvant trial coordinated by the Eastern Cooperative Oncology Group comparing platinum therapy with capecitabine. Tune in to think more about whether capecitabine really should be the standard of care in this population.
As always, I’m interested in your thoughts before or after ASCO. What stood out for you this year in breast cancer? Drop us a comment and let us know about these sessions and what else you found worthwhile.
Dr. Miller is associate director of clinical research and codirector of the breast cancer program at the Melvin and Bren Simon Cancer Center at Indiana University, Indianapolis. Her career has combined both laboratory and clinical research in breast cancer.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Hello. It’s Dr. Kathy Miller from Indiana University.
I have to admit that time has snuck up on me this year. It is already time for the American Society of Clinical Oncology Annual Meeting.
I found it hard to keep track of time this year with the pandemic. Many of the things that help mark the passage of time haven’t happened, have happened at different times of the year than is typical, or have happened in different ways that just haven’t had the same impact in my brain.
Just recently, I was taking a look through the breast cancer program at ASCO and there is a special clinical science symposium that I want to make sure you know about and tune into. It’s the sort of session that might not otherwise reach you.
This has been a year of incredible turmoil and critical thinking about issues of race, ethnicity, justice, and how we can make sure that the medical care we’re providing is inclusive and equitable. How we can make sure we are giving the best outcome to all of our patients.
This special clinical science symposium this year includes several presentations that will delve into how genetically determined ancestry and socially determined race might impact the outcome of our patients. This is a tangled web that is difficult to unpack and separate, but there are clear distinctions here: The genes we inherit do affect how we metabolize drugs, what side effects we might have from drugs, and what drugs might be the best choices for us.
Our socially determined race affects how the world interacts with us. Those biases, be they conscious or unconscious, can affect where we live, where we go to school, how people treat us, what opportunities we have, and how the medical system treats us. They’re related, but they’re not the same. Tune into that clinical science symposium to begin thinking about those differences and how we can make sure we give our patients the best care.
There are other high-profile presentations that you’re going to want to see as well, looking at how we can optimize therapy in patients with HER2-positive disease and beginning to think about who might not need chemotherapy to have an excellent outcome in early-stage disease.
Also, we will be thinking about those patients with triple-negative disease who have residual disease after neoadjuvant chemotherapy. We were all caught off guard with the results of the CREATE-X trial, quite frankly, several years ago.
This year we will hear the results of a postneoadjuvant trial coordinated by the Eastern Cooperative Oncology Group comparing platinum therapy with capecitabine. Tune in to think more about whether capecitabine really should be the standard of care in this population.
As always, I’m interested in your thoughts before or after ASCO. What stood out for you this year in breast cancer? Drop us a comment and let us know about these sessions and what else you found worthwhile.
Dr. Miller is associate director of clinical research and codirector of the breast cancer program at the Melvin and Bren Simon Cancer Center at Indiana University, Indianapolis. Her career has combined both laboratory and clinical research in breast cancer.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Hello. It’s Dr. Kathy Miller from Indiana University.
I have to admit that time has snuck up on me this year. It is already time for the American Society of Clinical Oncology Annual Meeting.
I found it hard to keep track of time this year with the pandemic. Many of the things that help mark the passage of time haven’t happened, have happened at different times of the year than is typical, or have happened in different ways that just haven’t had the same impact in my brain.
Just recently, I was taking a look through the breast cancer program at ASCO and there is a special clinical science symposium that I want to make sure you know about and tune into. It’s the sort of session that might not otherwise reach you.
This has been a year of incredible turmoil and critical thinking about issues of race, ethnicity, justice, and how we can make sure that the medical care we’re providing is inclusive and equitable. How we can make sure we are giving the best outcome to all of our patients.
This special clinical science symposium this year includes several presentations that will delve into how genetically determined ancestry and socially determined race might impact the outcome of our patients. This is a tangled web that is difficult to unpack and separate, but there are clear distinctions here: The genes we inherit do affect how we metabolize drugs, what side effects we might have from drugs, and what drugs might be the best choices for us.
Our socially determined race affects how the world interacts with us. Those biases, be they conscious or unconscious, can affect where we live, where we go to school, how people treat us, what opportunities we have, and how the medical system treats us. They’re related, but they’re not the same. Tune into that clinical science symposium to begin thinking about those differences and how we can make sure we give our patients the best care.
There are other high-profile presentations that you’re going to want to see as well, looking at how we can optimize therapy in patients with HER2-positive disease and beginning to think about who might not need chemotherapy to have an excellent outcome in early-stage disease.
Also, we will be thinking about those patients with triple-negative disease who have residual disease after neoadjuvant chemotherapy. We were all caught off guard with the results of the CREATE-X trial, quite frankly, several years ago.
This year we will hear the results of a postneoadjuvant trial coordinated by the Eastern Cooperative Oncology Group comparing platinum therapy with capecitabine. Tune in to think more about whether capecitabine really should be the standard of care in this population.
As always, I’m interested in your thoughts before or after ASCO. What stood out for you this year in breast cancer? Drop us a comment and let us know about these sessions and what else you found worthwhile.
Dr. Miller is associate director of clinical research and codirector of the breast cancer program at the Melvin and Bren Simon Cancer Center at Indiana University, Indianapolis. Her career has combined both laboratory and clinical research in breast cancer.
A version of this article first appeared on Medscape.com.
IL-6 levels predict distant breast cancer recurrence
The inflammatory cytokine interleukin 6 may be a biomarker for distant recurrence of breast cancer among patients treated for stage II-III HER2-negative disease, investigators have found.
In a case-control study of 498 women with breast cancer treated with surgery and adjuvant chemotherapy, as well as endocrine therapy for women with estrogen receptor (ER)–positive tumors, those with higher serum levels of IL-6 at diagnosis had a significantly greater risk for disease recurrence than women with lower levels of the cytokine, Joseph A. Sparano, MD, from the Albert Einstein College of Medicine and Montefiore Medical Center, New York, and colleagues reported.
“This analysis provides level 1B evidence indicating that higher levels of the cytokine IL-6 at diagnosis are associated with a significantly higher distant recurrence risk in high-risk stage II-III breast cancer despite optimal adjuvant systemic therapy,” they wrote in a study presented in a poster discussion session at the American Society of Clinical Oncology Annual Meeting.(Abstract 520)
In an interview, Dr. Sparano said that their findings first need to be validated in a larger study.
“When validated, I think the other key issue is to try to understand what the best cut point for identifying high risk is, “ he said.
If further studies confirm that higher IL-6 levels are prognostic for worse outcomes, it might be possible to use levels of the cytokine as a biomarker to predict for therapies targeting the IL-6/Janus kinase/STAT3 pathway.
“There are trials ongoing testing IL-6 antibodies in combination chemotherapy, and this could be a rational biomarker to identify which patients would be more likely to benefit from that approach,” he said.
Systemic inflammation
Systemic inflammation is suspected as a contributing factor to cancer progression and disease recurrence, Dr. Sparano and colleagues noted.
To test their hypothesis that inflammatory cytokines and/or chemokines could be associated with distant recurrence, they conducted a case-control study with 249 matched pairs of patients enrolled in a phase 3 trial of adjuvant chemotherapy for lymph-node positive and high-risk lymph-node negative breast cancer (NCT00433511).
The patients all had surgery and adjuvant chemotherapy with doxorubicin, cyclophosphamide, and paclitaxel with or without bevacizumab, and endocrine therapy for patients whose tumors were ER positive.
They used propensity score matching to pair each patient with distant recurrence to one without, with covariates including post versus premenopausal or perimenopausal status, estrogen and/or progesterone receptor positivity, tumor size (less than 2 cm, greater than 2-5 cm, or greater than 5 cm) nodal status, and grade.
The only biomarker that met the prespecified boundary for statistical significance (P < .0014) was IL-6, with a hazard ratio for distant recurrence of 1.37 (P = .0006).
The median and mean values for IL-6 were 0.95 and 7.5 pg/mL, respectively
Other substances associated with distant recurrence (with a two-sided P value < .05) were macrophage-derived chemokine/CCL22 (HR, 1.90; P = .0098), IL-17A, a T-helper cell inflammatory cytokine (HR, 1.36; P = .0052), and the cytokine vascular endothelial growth factor A (VEGF-A, HR, 1.13; P = 0.037).
There was no statistical interaction between VEGF-A levels and the benefit of bevacizumab.
Prognostic value, not clinical utility
“This is a nice abstract. It looks at inflammatory cytokines and provides evidence that inflammatory cytokines, particularly IL-6, could have a prognostic role in predicting risk of recurrence in HER2-negative disease, and the team did a very nice job in multivariate analysis looking at different factors,” said Aditya Bardia, MD, MPH, from the Mass General Cancer Center in Boston, the invited discussant for the study.*
In an interview, Dr. Bardia said that the finding “provides prognostic value, but does not provide clinical utility. It’s unclear if we used this assay and it identified that a patient was at high risk of recurrence whether we could change that. Is there any intervention that could be done to potentially alter the course of disease, alter the natural history? That’s unknown.”
He agreed with Dr. Sparano and colleagues that validation of the finding was still needed, ideally in a prospective or retrospective cohort study.
The study was supported by grants from the National Cancer Institute, Komen Foundation, and Breast Cancer Research Foundation. Dr. Sparano disclosed relationships with multiple companies. Dr. Bardia disclosed a consulting or advisory role and research funding to his institution from multiple companies.
*Correction, 6/4/21: An earlier version of this article misstated Dr. Bardia's name.
The inflammatory cytokine interleukin 6 may be a biomarker for distant recurrence of breast cancer among patients treated for stage II-III HER2-negative disease, investigators have found.
In a case-control study of 498 women with breast cancer treated with surgery and adjuvant chemotherapy, as well as endocrine therapy for women with estrogen receptor (ER)–positive tumors, those with higher serum levels of IL-6 at diagnosis had a significantly greater risk for disease recurrence than women with lower levels of the cytokine, Joseph A. Sparano, MD, from the Albert Einstein College of Medicine and Montefiore Medical Center, New York, and colleagues reported.
“This analysis provides level 1B evidence indicating that higher levels of the cytokine IL-6 at diagnosis are associated with a significantly higher distant recurrence risk in high-risk stage II-III breast cancer despite optimal adjuvant systemic therapy,” they wrote in a study presented in a poster discussion session at the American Society of Clinical Oncology Annual Meeting.(Abstract 520)
In an interview, Dr. Sparano said that their findings first need to be validated in a larger study.
“When validated, I think the other key issue is to try to understand what the best cut point for identifying high risk is, “ he said.
If further studies confirm that higher IL-6 levels are prognostic for worse outcomes, it might be possible to use levels of the cytokine as a biomarker to predict for therapies targeting the IL-6/Janus kinase/STAT3 pathway.
“There are trials ongoing testing IL-6 antibodies in combination chemotherapy, and this could be a rational biomarker to identify which patients would be more likely to benefit from that approach,” he said.
Systemic inflammation
Systemic inflammation is suspected as a contributing factor to cancer progression and disease recurrence, Dr. Sparano and colleagues noted.
To test their hypothesis that inflammatory cytokines and/or chemokines could be associated with distant recurrence, they conducted a case-control study with 249 matched pairs of patients enrolled in a phase 3 trial of adjuvant chemotherapy for lymph-node positive and high-risk lymph-node negative breast cancer (NCT00433511).
The patients all had surgery and adjuvant chemotherapy with doxorubicin, cyclophosphamide, and paclitaxel with or without bevacizumab, and endocrine therapy for patients whose tumors were ER positive.
They used propensity score matching to pair each patient with distant recurrence to one without, with covariates including post versus premenopausal or perimenopausal status, estrogen and/or progesterone receptor positivity, tumor size (less than 2 cm, greater than 2-5 cm, or greater than 5 cm) nodal status, and grade.
The only biomarker that met the prespecified boundary for statistical significance (P < .0014) was IL-6, with a hazard ratio for distant recurrence of 1.37 (P = .0006).
The median and mean values for IL-6 were 0.95 and 7.5 pg/mL, respectively
Other substances associated with distant recurrence (with a two-sided P value < .05) were macrophage-derived chemokine/CCL22 (HR, 1.90; P = .0098), IL-17A, a T-helper cell inflammatory cytokine (HR, 1.36; P = .0052), and the cytokine vascular endothelial growth factor A (VEGF-A, HR, 1.13; P = 0.037).
There was no statistical interaction between VEGF-A levels and the benefit of bevacizumab.
Prognostic value, not clinical utility
“This is a nice abstract. It looks at inflammatory cytokines and provides evidence that inflammatory cytokines, particularly IL-6, could have a prognostic role in predicting risk of recurrence in HER2-negative disease, and the team did a very nice job in multivariate analysis looking at different factors,” said Aditya Bardia, MD, MPH, from the Mass General Cancer Center in Boston, the invited discussant for the study.*
In an interview, Dr. Bardia said that the finding “provides prognostic value, but does not provide clinical utility. It’s unclear if we used this assay and it identified that a patient was at high risk of recurrence whether we could change that. Is there any intervention that could be done to potentially alter the course of disease, alter the natural history? That’s unknown.”
He agreed with Dr. Sparano and colleagues that validation of the finding was still needed, ideally in a prospective or retrospective cohort study.
The study was supported by grants from the National Cancer Institute, Komen Foundation, and Breast Cancer Research Foundation. Dr. Sparano disclosed relationships with multiple companies. Dr. Bardia disclosed a consulting or advisory role and research funding to his institution from multiple companies.
*Correction, 6/4/21: An earlier version of this article misstated Dr. Bardia's name.
The inflammatory cytokine interleukin 6 may be a biomarker for distant recurrence of breast cancer among patients treated for stage II-III HER2-negative disease, investigators have found.
In a case-control study of 498 women with breast cancer treated with surgery and adjuvant chemotherapy, as well as endocrine therapy for women with estrogen receptor (ER)–positive tumors, those with higher serum levels of IL-6 at diagnosis had a significantly greater risk for disease recurrence than women with lower levels of the cytokine, Joseph A. Sparano, MD, from the Albert Einstein College of Medicine and Montefiore Medical Center, New York, and colleagues reported.
“This analysis provides level 1B evidence indicating that higher levels of the cytokine IL-6 at diagnosis are associated with a significantly higher distant recurrence risk in high-risk stage II-III breast cancer despite optimal adjuvant systemic therapy,” they wrote in a study presented in a poster discussion session at the American Society of Clinical Oncology Annual Meeting.(Abstract 520)
In an interview, Dr. Sparano said that their findings first need to be validated in a larger study.
“When validated, I think the other key issue is to try to understand what the best cut point for identifying high risk is, “ he said.
If further studies confirm that higher IL-6 levels are prognostic for worse outcomes, it might be possible to use levels of the cytokine as a biomarker to predict for therapies targeting the IL-6/Janus kinase/STAT3 pathway.
“There are trials ongoing testing IL-6 antibodies in combination chemotherapy, and this could be a rational biomarker to identify which patients would be more likely to benefit from that approach,” he said.
Systemic inflammation
Systemic inflammation is suspected as a contributing factor to cancer progression and disease recurrence, Dr. Sparano and colleagues noted.
To test their hypothesis that inflammatory cytokines and/or chemokines could be associated with distant recurrence, they conducted a case-control study with 249 matched pairs of patients enrolled in a phase 3 trial of adjuvant chemotherapy for lymph-node positive and high-risk lymph-node negative breast cancer (NCT00433511).
The patients all had surgery and adjuvant chemotherapy with doxorubicin, cyclophosphamide, and paclitaxel with or without bevacizumab, and endocrine therapy for patients whose tumors were ER positive.
They used propensity score matching to pair each patient with distant recurrence to one without, with covariates including post versus premenopausal or perimenopausal status, estrogen and/or progesterone receptor positivity, tumor size (less than 2 cm, greater than 2-5 cm, or greater than 5 cm) nodal status, and grade.
The only biomarker that met the prespecified boundary for statistical significance (P < .0014) was IL-6, with a hazard ratio for distant recurrence of 1.37 (P = .0006).
The median and mean values for IL-6 were 0.95 and 7.5 pg/mL, respectively
Other substances associated with distant recurrence (with a two-sided P value < .05) were macrophage-derived chemokine/CCL22 (HR, 1.90; P = .0098), IL-17A, a T-helper cell inflammatory cytokine (HR, 1.36; P = .0052), and the cytokine vascular endothelial growth factor A (VEGF-A, HR, 1.13; P = 0.037).
There was no statistical interaction between VEGF-A levels and the benefit of bevacizumab.
Prognostic value, not clinical utility
“This is a nice abstract. It looks at inflammatory cytokines and provides evidence that inflammatory cytokines, particularly IL-6, could have a prognostic role in predicting risk of recurrence in HER2-negative disease, and the team did a very nice job in multivariate analysis looking at different factors,” said Aditya Bardia, MD, MPH, from the Mass General Cancer Center in Boston, the invited discussant for the study.*
In an interview, Dr. Bardia said that the finding “provides prognostic value, but does not provide clinical utility. It’s unclear if we used this assay and it identified that a patient was at high risk of recurrence whether we could change that. Is there any intervention that could be done to potentially alter the course of disease, alter the natural history? That’s unknown.”
He agreed with Dr. Sparano and colleagues that validation of the finding was still needed, ideally in a prospective or retrospective cohort study.
The study was supported by grants from the National Cancer Institute, Komen Foundation, and Breast Cancer Research Foundation. Dr. Sparano disclosed relationships with multiple companies. Dr. Bardia disclosed a consulting or advisory role and research funding to his institution from multiple companies.
*Correction, 6/4/21: An earlier version of this article misstated Dr. Bardia's name.
FROM ASCO 2021
Trastuzumab deruxtecan-related lung disease in MBC patients can occur anytime in first year
Although rates are generally low, interstitial lung disease (ILD) can occur at any point in the first year of treatment with trastuzumab deruxtecan (T-DXd) for HER2-positive metastatic breast cancer (MBC).
That’s according to a pooled analysis of three early clinical trials with the drug that was reported at the European Society for Medical Oncology (ESMO): Breast Cancer virtual meeting.
Over a 5-year analysis period, the rate of any grade of ILD was 15.5%. The majority (79%) of those events were grade 1 or 2, observed pulmonologist Charles A. Powell, MD, of Icahn School of Medicine at Mount Sinai in New York, who presented the findings.
Of the 245 patients who were included in the analysis, 38 had an ILD event deemed related to treatment. A respective 9 (3.7%) and 21 (8.6%) had events graded as 1 or 2, 1 patient each (0.4%) had a grade 3 or 4 event, and 6 (2.4%) patients had a grade 5 event.
The timing of the first identified ILD event varied from 1.1 months to 20.8 months, given a median of 5.6 months overall. “This highlights an opportunity for more timely detection of ILD,” Dr. Powell suggested. He added that in almost all (97%) cases, ILD occurred before 12 months and the risk may even decrease over time “suggesting that the risk is not cumulative.”
He cautioned, however: “It is important to note that this analysis is exploratory and hypothesis generating in nature.”
ILD occurs with other cancer drugs
ILD is not just associated with T-DXd treatment, said the invited discussant for the trial, Harold J. Burstein, MD, PhD, of the Dana-Farber Cancer Institute in Boston.
“It’s important for clinicians to remember that ILD/pneumonitis is an uncommon, but potentially very serious side effect that affects many breast cancer treatments,” he said.
That not only includes T-DXd, but other newer drugs such the cyclin dependent kinase (CDK) 4/6 inhibitors and immune checkpoint inhibitors, as well as other older more established drugs including taxanes, cyclophosphamide and even the mTOR inhibitor everolimus.
“Both clinicians and patients need to be aware of this risk. It’s part of the differential diagnosis for any patient who develops either ground glass changes or other infiltrates on a CT scan, or who has symptoms,” Dr. Burstein added.
Investigating ILD in T-DXd trials
T-DXd (Enhertu) is an anti-HER2-antibody drug conjugate that contains a humanized anti-HER2 IgG1 monoclonal antibody akin to trastuzumab that is linked to DXd, a topoisomerase I inhibitor that is a derivative of exatecan.
It has been approved for use in patients with HER2-positive metastatic breast cancer after two other HER2 treatments fail in the United States and Europe, and after chemotherapy in Japan, noted Dr. Powell. This is largely due to the results from the phase 2, open-label DESTINY-Breast01 trial.
“In breast cancer, T-DXd continues to demonstrate clinically meaningful efficacy with a median duration of response of more than 20 months in a heavily pretreated population,” he said. Objective response rates seen in the DESTINY-Breast01 trial were around 60%, and the median progression-free survival was a little over 19 months.
To look at the issue of drug-related ILD events in patients treated with T-DXd for HER2-positive MBC, an independent adjudication committee was formed to look at all the imaging and clinical data from the DESTINY-Breast01 trial and two single-arm phase 1 trials (NCT02564900 and NCT03383692).
In all, data on 245 patients who had been treated with T-DXd at the approved dose of 5.4 mg/kg in those trials between August 2015 and June 2020 were analyzed.
Dealing with lung toxicity
“We are getting new drugs to improve the treatment of cancer, but they always come with a price in terms of toxicity,” observed David Cameron, MD, professor of medical oncology at Edinburgh University in Scotland. Dr. Cameron chaired the session.
“Several measures were taken to identify and mitigate ILD,” across all the T-DXd studies, Dr. Powell explained. As well as the independent adjudication committee, available guidelines were followed and updated on how to diagnose and treat drug-induced lung injuries, and a “safe use” campaign was run in 2019.
Many patients in the early MBC studies were recruited before these measures were in place, such as the use of systemic steroids to manage low-grade events.
The bottom line, however, is that if a patient develops ILD then treatment should be stopped, Dr. Powell said. “Patients with grade 1 events may restart once the ILD has resolved, but those with grade 2 to 4 events must discontinue treatment.”
Dr. Powell concluded: “The overall clinical data support the positive risk-benefit profile of T-DXd. Phase 3 randomized controlled trials in breast cancer are ongoing.”
ILD also seen in monarchE trial with abemaciclib
Data on ILD events seen in the phase 3 monarchE trial were also reported separately at the ESMO Breast Cancer virtual meeting. The analysis population included 2,971 patients who had been treated with the CDK 4/6 inhibitor abemaciclib (Verzenio) together with endocrine therapy and 2,800 who had received endocrine therapy alone in the early-stage, adjuvant advanced breast cancer setting.
Most ILD (97%) events that occurred were single occurrences, with any grade of ILD occurring in a higher percentage of patients treated with abemaciclib with endocrine therapy than endocrine therapy alone (2.9% vs. 1.2%). Grade 3 events occurred in a respective 0.4% and 0.0% of patients.
So who’s at risk?
The risk factors for ILD and pneumonitis are not well characterized with either of the two drugs discussed, Dr. Burstein observed.
“In the abemaciclib experience, it looked like obesity might be a predisposing factor, with trastuzumab deruxtecan, it looked like patients of Asian ancestry were greater risk, but we need more data to really understand who’s at jeopardy.”
Dr. Burstein observed: “This is something patients need to be aware of as they’re contemplating this treatment.”
While data to prove the benefit of the drug need to mature, Dr. Burstein “would likely discontinue therapy” if a patient were to develop ILD or pneumonitis and treat accordingly.
As for T-DXd, he said: “It’s important that patients know that lung disease is a potentially severe side effect of treatment and that any respiratory symptoms need to be jumped on quickly.”
While prospective studies are now needed, and the phase 3 data should help to better understand the risk of ILD with T-DXd, Dr. Burstein believes it will be important to develop algorithms to ensure the safe administration of the drug.
These algorithms should include “appropriate surveillance and monitoring, especially as we think about trying to move this drug forward into the early stage setting where we’re using it in women who have favorable prognosis, and potentially curative situations for breast cancer.”
The trastuzumab deruxtecan trials were cosponsored by Daiichi Sankyo and AstraZeneca. The monarchE trial was supported by Eli Lilly.
Dr. Powell acknowledged receiving personal fees for acting as an advisory or consultant to both companies as well as to Voluntis. Dr. Burstein had nothing to disclose, and Dr. Cameron had no relevant financial interests in the data being presented.
Although rates are generally low, interstitial lung disease (ILD) can occur at any point in the first year of treatment with trastuzumab deruxtecan (T-DXd) for HER2-positive metastatic breast cancer (MBC).
That’s according to a pooled analysis of three early clinical trials with the drug that was reported at the European Society for Medical Oncology (ESMO): Breast Cancer virtual meeting.
Over a 5-year analysis period, the rate of any grade of ILD was 15.5%. The majority (79%) of those events were grade 1 or 2, observed pulmonologist Charles A. Powell, MD, of Icahn School of Medicine at Mount Sinai in New York, who presented the findings.
Of the 245 patients who were included in the analysis, 38 had an ILD event deemed related to treatment. A respective 9 (3.7%) and 21 (8.6%) had events graded as 1 or 2, 1 patient each (0.4%) had a grade 3 or 4 event, and 6 (2.4%) patients had a grade 5 event.
The timing of the first identified ILD event varied from 1.1 months to 20.8 months, given a median of 5.6 months overall. “This highlights an opportunity for more timely detection of ILD,” Dr. Powell suggested. He added that in almost all (97%) cases, ILD occurred before 12 months and the risk may even decrease over time “suggesting that the risk is not cumulative.”
He cautioned, however: “It is important to note that this analysis is exploratory and hypothesis generating in nature.”
ILD occurs with other cancer drugs
ILD is not just associated with T-DXd treatment, said the invited discussant for the trial, Harold J. Burstein, MD, PhD, of the Dana-Farber Cancer Institute in Boston.
“It’s important for clinicians to remember that ILD/pneumonitis is an uncommon, but potentially very serious side effect that affects many breast cancer treatments,” he said.
That not only includes T-DXd, but other newer drugs such the cyclin dependent kinase (CDK) 4/6 inhibitors and immune checkpoint inhibitors, as well as other older more established drugs including taxanes, cyclophosphamide and even the mTOR inhibitor everolimus.
“Both clinicians and patients need to be aware of this risk. It’s part of the differential diagnosis for any patient who develops either ground glass changes or other infiltrates on a CT scan, or who has symptoms,” Dr. Burstein added.
Investigating ILD in T-DXd trials
T-DXd (Enhertu) is an anti-HER2-antibody drug conjugate that contains a humanized anti-HER2 IgG1 monoclonal antibody akin to trastuzumab that is linked to DXd, a topoisomerase I inhibitor that is a derivative of exatecan.
It has been approved for use in patients with HER2-positive metastatic breast cancer after two other HER2 treatments fail in the United States and Europe, and after chemotherapy in Japan, noted Dr. Powell. This is largely due to the results from the phase 2, open-label DESTINY-Breast01 trial.
“In breast cancer, T-DXd continues to demonstrate clinically meaningful efficacy with a median duration of response of more than 20 months in a heavily pretreated population,” he said. Objective response rates seen in the DESTINY-Breast01 trial were around 60%, and the median progression-free survival was a little over 19 months.
To look at the issue of drug-related ILD events in patients treated with T-DXd for HER2-positive MBC, an independent adjudication committee was formed to look at all the imaging and clinical data from the DESTINY-Breast01 trial and two single-arm phase 1 trials (NCT02564900 and NCT03383692).
In all, data on 245 patients who had been treated with T-DXd at the approved dose of 5.4 mg/kg in those trials between August 2015 and June 2020 were analyzed.
Dealing with lung toxicity
“We are getting new drugs to improve the treatment of cancer, but they always come with a price in terms of toxicity,” observed David Cameron, MD, professor of medical oncology at Edinburgh University in Scotland. Dr. Cameron chaired the session.
“Several measures were taken to identify and mitigate ILD,” across all the T-DXd studies, Dr. Powell explained. As well as the independent adjudication committee, available guidelines were followed and updated on how to diagnose and treat drug-induced lung injuries, and a “safe use” campaign was run in 2019.
Many patients in the early MBC studies were recruited before these measures were in place, such as the use of systemic steroids to manage low-grade events.
The bottom line, however, is that if a patient develops ILD then treatment should be stopped, Dr. Powell said. “Patients with grade 1 events may restart once the ILD has resolved, but those with grade 2 to 4 events must discontinue treatment.”
Dr. Powell concluded: “The overall clinical data support the positive risk-benefit profile of T-DXd. Phase 3 randomized controlled trials in breast cancer are ongoing.”
ILD also seen in monarchE trial with abemaciclib
Data on ILD events seen in the phase 3 monarchE trial were also reported separately at the ESMO Breast Cancer virtual meeting. The analysis population included 2,971 patients who had been treated with the CDK 4/6 inhibitor abemaciclib (Verzenio) together with endocrine therapy and 2,800 who had received endocrine therapy alone in the early-stage, adjuvant advanced breast cancer setting.
Most ILD (97%) events that occurred were single occurrences, with any grade of ILD occurring in a higher percentage of patients treated with abemaciclib with endocrine therapy than endocrine therapy alone (2.9% vs. 1.2%). Grade 3 events occurred in a respective 0.4% and 0.0% of patients.
So who’s at risk?
The risk factors for ILD and pneumonitis are not well characterized with either of the two drugs discussed, Dr. Burstein observed.
“In the abemaciclib experience, it looked like obesity might be a predisposing factor, with trastuzumab deruxtecan, it looked like patients of Asian ancestry were greater risk, but we need more data to really understand who’s at jeopardy.”
Dr. Burstein observed: “This is something patients need to be aware of as they’re contemplating this treatment.”
While data to prove the benefit of the drug need to mature, Dr. Burstein “would likely discontinue therapy” if a patient were to develop ILD or pneumonitis and treat accordingly.
As for T-DXd, he said: “It’s important that patients know that lung disease is a potentially severe side effect of treatment and that any respiratory symptoms need to be jumped on quickly.”
While prospective studies are now needed, and the phase 3 data should help to better understand the risk of ILD with T-DXd, Dr. Burstein believes it will be important to develop algorithms to ensure the safe administration of the drug.
These algorithms should include “appropriate surveillance and monitoring, especially as we think about trying to move this drug forward into the early stage setting where we’re using it in women who have favorable prognosis, and potentially curative situations for breast cancer.”
The trastuzumab deruxtecan trials were cosponsored by Daiichi Sankyo and AstraZeneca. The monarchE trial was supported by Eli Lilly.
Dr. Powell acknowledged receiving personal fees for acting as an advisory or consultant to both companies as well as to Voluntis. Dr. Burstein had nothing to disclose, and Dr. Cameron had no relevant financial interests in the data being presented.
Although rates are generally low, interstitial lung disease (ILD) can occur at any point in the first year of treatment with trastuzumab deruxtecan (T-DXd) for HER2-positive metastatic breast cancer (MBC).
That’s according to a pooled analysis of three early clinical trials with the drug that was reported at the European Society for Medical Oncology (ESMO): Breast Cancer virtual meeting.
Over a 5-year analysis period, the rate of any grade of ILD was 15.5%. The majority (79%) of those events were grade 1 or 2, observed pulmonologist Charles A. Powell, MD, of Icahn School of Medicine at Mount Sinai in New York, who presented the findings.
Of the 245 patients who were included in the analysis, 38 had an ILD event deemed related to treatment. A respective 9 (3.7%) and 21 (8.6%) had events graded as 1 or 2, 1 patient each (0.4%) had a grade 3 or 4 event, and 6 (2.4%) patients had a grade 5 event.
The timing of the first identified ILD event varied from 1.1 months to 20.8 months, given a median of 5.6 months overall. “This highlights an opportunity for more timely detection of ILD,” Dr. Powell suggested. He added that in almost all (97%) cases, ILD occurred before 12 months and the risk may even decrease over time “suggesting that the risk is not cumulative.”
He cautioned, however: “It is important to note that this analysis is exploratory and hypothesis generating in nature.”
ILD occurs with other cancer drugs
ILD is not just associated with T-DXd treatment, said the invited discussant for the trial, Harold J. Burstein, MD, PhD, of the Dana-Farber Cancer Institute in Boston.
“It’s important for clinicians to remember that ILD/pneumonitis is an uncommon, but potentially very serious side effect that affects many breast cancer treatments,” he said.
That not only includes T-DXd, but other newer drugs such the cyclin dependent kinase (CDK) 4/6 inhibitors and immune checkpoint inhibitors, as well as other older more established drugs including taxanes, cyclophosphamide and even the mTOR inhibitor everolimus.
“Both clinicians and patients need to be aware of this risk. It’s part of the differential diagnosis for any patient who develops either ground glass changes or other infiltrates on a CT scan, or who has symptoms,” Dr. Burstein added.
Investigating ILD in T-DXd trials
T-DXd (Enhertu) is an anti-HER2-antibody drug conjugate that contains a humanized anti-HER2 IgG1 monoclonal antibody akin to trastuzumab that is linked to DXd, a topoisomerase I inhibitor that is a derivative of exatecan.
It has been approved for use in patients with HER2-positive metastatic breast cancer after two other HER2 treatments fail in the United States and Europe, and after chemotherapy in Japan, noted Dr. Powell. This is largely due to the results from the phase 2, open-label DESTINY-Breast01 trial.
“In breast cancer, T-DXd continues to demonstrate clinically meaningful efficacy with a median duration of response of more than 20 months in a heavily pretreated population,” he said. Objective response rates seen in the DESTINY-Breast01 trial were around 60%, and the median progression-free survival was a little over 19 months.
To look at the issue of drug-related ILD events in patients treated with T-DXd for HER2-positive MBC, an independent adjudication committee was formed to look at all the imaging and clinical data from the DESTINY-Breast01 trial and two single-arm phase 1 trials (NCT02564900 and NCT03383692).
In all, data on 245 patients who had been treated with T-DXd at the approved dose of 5.4 mg/kg in those trials between August 2015 and June 2020 were analyzed.
Dealing with lung toxicity
“We are getting new drugs to improve the treatment of cancer, but they always come with a price in terms of toxicity,” observed David Cameron, MD, professor of medical oncology at Edinburgh University in Scotland. Dr. Cameron chaired the session.
“Several measures were taken to identify and mitigate ILD,” across all the T-DXd studies, Dr. Powell explained. As well as the independent adjudication committee, available guidelines were followed and updated on how to diagnose and treat drug-induced lung injuries, and a “safe use” campaign was run in 2019.
Many patients in the early MBC studies were recruited before these measures were in place, such as the use of systemic steroids to manage low-grade events.
The bottom line, however, is that if a patient develops ILD then treatment should be stopped, Dr. Powell said. “Patients with grade 1 events may restart once the ILD has resolved, but those with grade 2 to 4 events must discontinue treatment.”
Dr. Powell concluded: “The overall clinical data support the positive risk-benefit profile of T-DXd. Phase 3 randomized controlled trials in breast cancer are ongoing.”
ILD also seen in monarchE trial with abemaciclib
Data on ILD events seen in the phase 3 monarchE trial were also reported separately at the ESMO Breast Cancer virtual meeting. The analysis population included 2,971 patients who had been treated with the CDK 4/6 inhibitor abemaciclib (Verzenio) together with endocrine therapy and 2,800 who had received endocrine therapy alone in the early-stage, adjuvant advanced breast cancer setting.
Most ILD (97%) events that occurred were single occurrences, with any grade of ILD occurring in a higher percentage of patients treated with abemaciclib with endocrine therapy than endocrine therapy alone (2.9% vs. 1.2%). Grade 3 events occurred in a respective 0.4% and 0.0% of patients.
So who’s at risk?
The risk factors for ILD and pneumonitis are not well characterized with either of the two drugs discussed, Dr. Burstein observed.
“In the abemaciclib experience, it looked like obesity might be a predisposing factor, with trastuzumab deruxtecan, it looked like patients of Asian ancestry were greater risk, but we need more data to really understand who’s at jeopardy.”
Dr. Burstein observed: “This is something patients need to be aware of as they’re contemplating this treatment.”
While data to prove the benefit of the drug need to mature, Dr. Burstein “would likely discontinue therapy” if a patient were to develop ILD or pneumonitis and treat accordingly.
As for T-DXd, he said: “It’s important that patients know that lung disease is a potentially severe side effect of treatment and that any respiratory symptoms need to be jumped on quickly.”
While prospective studies are now needed, and the phase 3 data should help to better understand the risk of ILD with T-DXd, Dr. Burstein believes it will be important to develop algorithms to ensure the safe administration of the drug.
These algorithms should include “appropriate surveillance and monitoring, especially as we think about trying to move this drug forward into the early stage setting where we’re using it in women who have favorable prognosis, and potentially curative situations for breast cancer.”
The trastuzumab deruxtecan trials were cosponsored by Daiichi Sankyo and AstraZeneca. The monarchE trial was supported by Eli Lilly.
Dr. Powell acknowledged receiving personal fees for acting as an advisory or consultant to both companies as well as to Voluntis. Dr. Burstein had nothing to disclose, and Dr. Cameron had no relevant financial interests in the data being presented.
FROM ESMO BREAST CANCER 2021
Endocrine therapy benefits in premenopausal breast cancer differ by molecular risk
The long-term benefits of endocrine therapy in premenopausal breast cancer appear to differ according to whether patients are categorized as high or low molecular risk using the 70-gene signature (MammaPrint).
Based upon data from patients who had participated in the Stockholm tamoxifen (STO-5) trial, high-risk patients significantly benefited from goserelin treatment, whereas low-risk patients benefited more from tamoxifen treatment when compared with no endocrine therapy.
“Goserelin, tamoxifen, and the combination of the two, reduced the 20-year risk of distant occurrences and fatal breast cancer, compared to no endocrine therapy,” Annelie Johansson, MSc, said at the European Society for Medical Oncology: Breast Cancer virtual meeting.
“Our findings indicate that the long-term endocrine therapy benefit in premenopausal patients is influenced by molecular risk classification and thus tumor characteristics,” she added.
Ms. Johansson, a postdoctoral researcher in genomic breast cancer at the Karolinska Institutet in Stockholm, reported the results of the analysis as a late-breaking abstract at the meeting.
“I think this is an innovative translational study trying to use the multigene assay results to look at differential endocrine therapy effects,” said Prudence Francis, MD, the invited discussant for study.
However, there are relatively few patients in the various subgroups being tested, she added. “We’ve also got short duration of tamoxifen, only 2 years, we’ve got prior chemotherapy in some patients and absence of HER2 therapy, all of which might influence outcomes.”
As a result, Dr. Francis, who is head of medical oncology at the Peter MacCallum Cancer Centre and a consultant Medical Oncologist at St. Vincent’s Hospital Melbourne, called the findings purely “hypothesis generating.”
Study details and results
The analysis was based on data from the STO-5 trial, which had recruited just over 900 patients between 1990 and 1997. Patients were stratified according to their lymph node status and some received chemotherapy with or without locoregional radiotherapy before being randomized to one of four study arms: goserelin alone, tamoxifen alone, the combination of the two, or no endocrine therapy.
Ms. Johansson noted that they were able to obtain the primary tumor blocks from 729 patients in the past year, of whom 610 were estrogen receptor positive. The analysis according to the 70-gene signature was then based on data from 465 patients: 131 had been treated with goserelin, 105 with tamoxifen, 120 with both, and 109 had received no endocrine treatment.
We have complete 20-year follow-up from high-quality Swedish National registries,” Ms. Johansson said, observing that the median age in the trial was 46 years.
Before stratifying patients into high and low risk using the 70-gene signature, the risk for having a distant recurrence, compared with no endocrine therapy was reduced by 52% with goserelin (hazard ratio, .48), 41% with tamoxifen (HR, 0.59), and 33% with both in combination (HR, 0.67).
After stratification, however, goserelin was associated with a 78% reduction of distant recurrence versus no endocrine treatment in high-risk patients (HR, 0.22) and a 20% reduction in low-risk patients (HR, 0.80).
Results in high- and low-risk patients with tamoxifen versus no endocrine treatment were a respective 31% reduction (HR, 0.69) and 62% reduction (HR, 0.38), and a respective 36% (HR, 0.64) and 28% (HR, 0.72) for the combination.
A further analysis was performed to compare between the active treatment arms, and this suggested a greater benefit of goserelin in patients at high risk when compared with both tamoxifen (HR, 0.30) and the combination (HR, 0.33).
Dr. Francis commented: “it is a bit surprising to find that goserelin appeared to be also better than the combination,” and it is something that the research team is looking into.
“One hypothesis might be if you look how the different treatments are working,” Ms. Johansson said. “Goserelin is very efficient in lowering the estrogen levels in premenopausal patients, suppressing the ovarian production of estrogen whereas tamoxifen can act both as an antagonist and agonist.
“So, we are thinking that maybe the addition of tamoxifen, with the agonistic properties of tamoxifen, might then make the goserelin not as efficient. But that’s of course, just a hypothesis right now and we need to look into this further,” she said.
The work was funded by The Swedish Research Council (Vetenskapsrådet), The Swedish Research Council for Health, Working life and Welfare, and the Swedish Cancer Society (Cancerfonden). Ms. Johansson had no personal disclosures; one of the coauthors was a coinventor of MammaPrint. Dr. Francis disclosed receiving travel support for overseas lectures from Ipsen and Novartis and acting as a medical oncology editor for Elsevier.
The long-term benefits of endocrine therapy in premenopausal breast cancer appear to differ according to whether patients are categorized as high or low molecular risk using the 70-gene signature (MammaPrint).
Based upon data from patients who had participated in the Stockholm tamoxifen (STO-5) trial, high-risk patients significantly benefited from goserelin treatment, whereas low-risk patients benefited more from tamoxifen treatment when compared with no endocrine therapy.
“Goserelin, tamoxifen, and the combination of the two, reduced the 20-year risk of distant occurrences and fatal breast cancer, compared to no endocrine therapy,” Annelie Johansson, MSc, said at the European Society for Medical Oncology: Breast Cancer virtual meeting.
“Our findings indicate that the long-term endocrine therapy benefit in premenopausal patients is influenced by molecular risk classification and thus tumor characteristics,” she added.
Ms. Johansson, a postdoctoral researcher in genomic breast cancer at the Karolinska Institutet in Stockholm, reported the results of the analysis as a late-breaking abstract at the meeting.
“I think this is an innovative translational study trying to use the multigene assay results to look at differential endocrine therapy effects,” said Prudence Francis, MD, the invited discussant for study.
However, there are relatively few patients in the various subgroups being tested, she added. “We’ve also got short duration of tamoxifen, only 2 years, we’ve got prior chemotherapy in some patients and absence of HER2 therapy, all of which might influence outcomes.”
As a result, Dr. Francis, who is head of medical oncology at the Peter MacCallum Cancer Centre and a consultant Medical Oncologist at St. Vincent’s Hospital Melbourne, called the findings purely “hypothesis generating.”
Study details and results
The analysis was based on data from the STO-5 trial, which had recruited just over 900 patients between 1990 and 1997. Patients were stratified according to their lymph node status and some received chemotherapy with or without locoregional radiotherapy before being randomized to one of four study arms: goserelin alone, tamoxifen alone, the combination of the two, or no endocrine therapy.
Ms. Johansson noted that they were able to obtain the primary tumor blocks from 729 patients in the past year, of whom 610 were estrogen receptor positive. The analysis according to the 70-gene signature was then based on data from 465 patients: 131 had been treated with goserelin, 105 with tamoxifen, 120 with both, and 109 had received no endocrine treatment.
We have complete 20-year follow-up from high-quality Swedish National registries,” Ms. Johansson said, observing that the median age in the trial was 46 years.
Before stratifying patients into high and low risk using the 70-gene signature, the risk for having a distant recurrence, compared with no endocrine therapy was reduced by 52% with goserelin (hazard ratio, .48), 41% with tamoxifen (HR, 0.59), and 33% with both in combination (HR, 0.67).
After stratification, however, goserelin was associated with a 78% reduction of distant recurrence versus no endocrine treatment in high-risk patients (HR, 0.22) and a 20% reduction in low-risk patients (HR, 0.80).
Results in high- and low-risk patients with tamoxifen versus no endocrine treatment were a respective 31% reduction (HR, 0.69) and 62% reduction (HR, 0.38), and a respective 36% (HR, 0.64) and 28% (HR, 0.72) for the combination.
A further analysis was performed to compare between the active treatment arms, and this suggested a greater benefit of goserelin in patients at high risk when compared with both tamoxifen (HR, 0.30) and the combination (HR, 0.33).
Dr. Francis commented: “it is a bit surprising to find that goserelin appeared to be also better than the combination,” and it is something that the research team is looking into.
“One hypothesis might be if you look how the different treatments are working,” Ms. Johansson said. “Goserelin is very efficient in lowering the estrogen levels in premenopausal patients, suppressing the ovarian production of estrogen whereas tamoxifen can act both as an antagonist and agonist.
“So, we are thinking that maybe the addition of tamoxifen, with the agonistic properties of tamoxifen, might then make the goserelin not as efficient. But that’s of course, just a hypothesis right now and we need to look into this further,” she said.
The work was funded by The Swedish Research Council (Vetenskapsrådet), The Swedish Research Council for Health, Working life and Welfare, and the Swedish Cancer Society (Cancerfonden). Ms. Johansson had no personal disclosures; one of the coauthors was a coinventor of MammaPrint. Dr. Francis disclosed receiving travel support for overseas lectures from Ipsen and Novartis and acting as a medical oncology editor for Elsevier.
The long-term benefits of endocrine therapy in premenopausal breast cancer appear to differ according to whether patients are categorized as high or low molecular risk using the 70-gene signature (MammaPrint).
Based upon data from patients who had participated in the Stockholm tamoxifen (STO-5) trial, high-risk patients significantly benefited from goserelin treatment, whereas low-risk patients benefited more from tamoxifen treatment when compared with no endocrine therapy.
“Goserelin, tamoxifen, and the combination of the two, reduced the 20-year risk of distant occurrences and fatal breast cancer, compared to no endocrine therapy,” Annelie Johansson, MSc, said at the European Society for Medical Oncology: Breast Cancer virtual meeting.
“Our findings indicate that the long-term endocrine therapy benefit in premenopausal patients is influenced by molecular risk classification and thus tumor characteristics,” she added.
Ms. Johansson, a postdoctoral researcher in genomic breast cancer at the Karolinska Institutet in Stockholm, reported the results of the analysis as a late-breaking abstract at the meeting.
“I think this is an innovative translational study trying to use the multigene assay results to look at differential endocrine therapy effects,” said Prudence Francis, MD, the invited discussant for study.
However, there are relatively few patients in the various subgroups being tested, she added. “We’ve also got short duration of tamoxifen, only 2 years, we’ve got prior chemotherapy in some patients and absence of HER2 therapy, all of which might influence outcomes.”
As a result, Dr. Francis, who is head of medical oncology at the Peter MacCallum Cancer Centre and a consultant Medical Oncologist at St. Vincent’s Hospital Melbourne, called the findings purely “hypothesis generating.”
Study details and results
The analysis was based on data from the STO-5 trial, which had recruited just over 900 patients between 1990 and 1997. Patients were stratified according to their lymph node status and some received chemotherapy with or without locoregional radiotherapy before being randomized to one of four study arms: goserelin alone, tamoxifen alone, the combination of the two, or no endocrine therapy.
Ms. Johansson noted that they were able to obtain the primary tumor blocks from 729 patients in the past year, of whom 610 were estrogen receptor positive. The analysis according to the 70-gene signature was then based on data from 465 patients: 131 had been treated with goserelin, 105 with tamoxifen, 120 with both, and 109 had received no endocrine treatment.
We have complete 20-year follow-up from high-quality Swedish National registries,” Ms. Johansson said, observing that the median age in the trial was 46 years.
Before stratifying patients into high and low risk using the 70-gene signature, the risk for having a distant recurrence, compared with no endocrine therapy was reduced by 52% with goserelin (hazard ratio, .48), 41% with tamoxifen (HR, 0.59), and 33% with both in combination (HR, 0.67).
After stratification, however, goserelin was associated with a 78% reduction of distant recurrence versus no endocrine treatment in high-risk patients (HR, 0.22) and a 20% reduction in low-risk patients (HR, 0.80).
Results in high- and low-risk patients with tamoxifen versus no endocrine treatment were a respective 31% reduction (HR, 0.69) and 62% reduction (HR, 0.38), and a respective 36% (HR, 0.64) and 28% (HR, 0.72) for the combination.
A further analysis was performed to compare between the active treatment arms, and this suggested a greater benefit of goserelin in patients at high risk when compared with both tamoxifen (HR, 0.30) and the combination (HR, 0.33).
Dr. Francis commented: “it is a bit surprising to find that goserelin appeared to be also better than the combination,” and it is something that the research team is looking into.
“One hypothesis might be if you look how the different treatments are working,” Ms. Johansson said. “Goserelin is very efficient in lowering the estrogen levels in premenopausal patients, suppressing the ovarian production of estrogen whereas tamoxifen can act both as an antagonist and agonist.
“So, we are thinking that maybe the addition of tamoxifen, with the agonistic properties of tamoxifen, might then make the goserelin not as efficient. But that’s of course, just a hypothesis right now and we need to look into this further,” she said.
The work was funded by The Swedish Research Council (Vetenskapsrådet), The Swedish Research Council for Health, Working life and Welfare, and the Swedish Cancer Society (Cancerfonden). Ms. Johansson had no personal disclosures; one of the coauthors was a coinventor of MammaPrint. Dr. Francis disclosed receiving travel support for overseas lectures from Ipsen and Novartis and acting as a medical oncology editor for Elsevier.
FROM ESMO BREAST CANCER 2021
Evolving strategies in sequencing for HER2+ MBC therapy
The landscape for therapies targeting HER2-positive metastatic breast cancer (MBC) has evolved rapidly in the past few years. In a 12-month window, the U.S. Food and Drug Administration approved four agents targeting human epidermal growth factor 2 (HER2)–positive MBC, starting with trastuzumab deruxtecan in December 2019, followed by neratinib and tucatinib a few months later, and margetuximab last December.
Although first-line therapy for the majority of patients continues to be the CLEOPATRA regimen — the monoclonal antibodies trastuzumab and pertuzumab plus a taxane, such as docetaxel or paclitaxel — .
“We have been really fortunate to see a number of highly effective new therapies approved for HER2-positive MBC in the past year, and this has given us even more options to offer our patients,” remarked Rita Nanda, MD, director of the Breast Oncology Program and associate professor of medicine at University of Chicago Medicine.
What considerations do experts weigh when sequencing HER2-positive MBC?
For Kelly McCann, MD, PhD, the order largely depends on balancing two factors: regimens that will provide the best efficacy in terms of patient survival and quality of life. “In the metastatic setting, I know I’m going to end up using all of the available medications one after the other, so the order that allows patients to continue living their best life for as long as possible is essential,” commented Dr. McCann, a hematologist/oncologist in the department of medicine at the David Geffen School of Medicine, University of California, Los Angeles.
A new second-line option?
Before the wave of drug approvals for metastatic HER2-positive disease last year, oncologists routinely looked to trastuzumab emtansine (T-DM1) as second-line therapy.
But tucatinib may also now be considered in the second-line setting, after results from the HER2CLIMB trial. The decision between tucatinib and T-DM1 largely comes down to the presence or absence of brain metastases.
“T-DM1 is well-tolerated, so it’s still my go-to in the second-line setting unless my patient has a brain metastasis, in which case I opt for tucatinib,” Dr. McCann noted, adding that the HER2-specific oral tyrosine kinase inhibitor (TKI) not only crosses the blood-brain barrier but is also effective in patients with untreated brain metastases.
In HER2CLIMB, tucatinib exhibited strong efficacy in patients with advanced HER2-positive disease, including those with previously treated or untreated brain metastases. The randomized controlled trial, which paired tucatinib with trastuzumab and capecitabine, showed median progression-free survival of 7.8 months in 410 patients with HER2-positive MBC compared with 5.6 months in the 202 patients receiving the placebo regimen. The tucatinib cohort showed an overall survival advantage compared with the placebo group (21.9 vs 17.4 months).
Perhaps the most notable finding occurred in patients with brain or central nervous system (CNS) involvement, which develops in as many as half of patients with HER-positive MBC and is associated with shorter survival. In the HER2CLIMB trial, median progression-free survival was 7.6 months in patients with brain metastases compared with 5.4 months in the placebo group.
A follow-up exploratory analysis, which focused on 291 patients with brain metastases, found that adding tucatinib reduced the risk for intracranial progression by two thirds and death by almost half. In patients with active brain metastases, median progression-free survival reached 9.5 months vs 4.1 months in the placebo group. Those with stable metastases also benefited from tucatinib, with median progression-free survival of 13.9 vs 5.6 months in the placebo group.
On the basis of the results, the authors concluded that this randomized trial was the first to demonstrate improvements in both CNS progression–free survival and overall survival in patients with HER2-positive MBC and brain metastases.
Evolving options in the third-line setting and after
For third-line therapy and beyond, oncologists have an array of newer agents to choose from alongside longer-standing options — which include trastuzumab plus lapatinib, trastuzumab or lapatinib plus capecitabine, as well as T-DM1, if not given as second-line therapy.
According to Dr. McCann, the antibody-drug conjugate trastuzumab deruxtecan has been a particularly exciting addition to third-line treatment. In the phase 2 DESTINY-01 trial, more than 60% of a heavily pretreated population showed an objective response to trastuzumab deruxtecan, with a median response duration of almost 15 months and a median progression-free survival of 16.4 months. Longer-term follow-up results, presented in December at the 2020 San Antonio Breast Cancer Symposium, revealed progression-free survival of 19.4 months and preliminary median overall survival of 24.6 months.
Neratinib, the second TKI to bridge the blood-brain barrier in HER2-positive disease, was also approved for third-line use; however, Sayeh Lavasani, MD, MS, said she is more likely to consider this agent later in the sequence, potentially in the fourth-line setting and beyond, given the more robust outcomes observed in the HER2CLIMB tucatinib trial.
“Neratinib improved progression-free survival and time to intervention for CNS metastasis but, unlike tucatinib, did not demonstrate an overall survival benefit,” remarked Dr. Lavasani, a medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.
More specifically, the phase 3 NALA trial, which randomly assigned patients to receive neratinib plus capecitabine or lapatinib plus capecitabine, reported progression-free survival of 8.8 months in the neratinib group compared with 6.6 months in the control arm but no significant gains in overall survival (hazard ratio, 0.88; P = .2098).
The fourth recently approved drug, margetuximab, has not yet made a significant mark on sequencing decisions for Dr. McCann.
“Margetuximab could have been a potential game changer, but clinical trial results were underwhelming,” she said.
In the phase 3 randomized clinical SOPHIA trial, margetuximab plus chemotherapy prolonged median progression-free survival by just over 1 month compared with trastuzumab plus chemotherapy. Preliminary overall survival data showed a slight, but not significant, benefit in the margetuximab group (21.6 vs 19.8 months).
For Dr. Lavasani, the presence of brain metastases is the most important consideration when weighing sequencing options. “For some of my patients with HER2-positive MBC, it’s ultimately disease progression in the brain that takes their life,” she said.
Aside from CNS metastases, specific sequencing choices may vary on the basis of drug-related tolerance as well as patient preferences. “It is critical to get a patient’s input in treatment selection,” Dr. Nanda remarked. “Given the number of effective treatments for HER2-positive MBC and the lack of data to guide how to sequence these regimens, it is important to ask patients what their preferences are.”
Dr. McCann agreed, noting that “a patient with HER2-positive MBC typically has a life expectancy measured in years, which is also why sequencing should be influenced by quality of life considerations.”
Convenience, side-effect profile, and financial toxicity should factor into clinical decision-making, according to Dr. Nanda. Some patients may, for instance, prefer a combination of tucatinib, capecitabine, and trastuzumab over trastuzumab deruxtecan to avoid hair loss and the risk for interstitial lung disease, which has been reported in more than 13% of patients, whereas others may prefer trastuzumab deruxtecan to avoid the possibility of diarrhea.
Taxanes come with a high risk for infusion reactions — which occur in about 30% of patients — and can cause neuropathy as well as hair loss and severe gastrointestinal side effects. In first-line care, Dr. McCann typically stops the taxane at some point for toxicity reasons and continues with trastuzumab plus pertuzumab until disease progression.
Even with an array of new options for treating metastatic HER2-positive disease, ultimately drug resistance does occur, Dr. Lavasani cautioned. Several ongoing trials are exploring new combinations of existing drugs to see whether those variations move the needle on survival outcomes. The HER2CLIMB-04 trial, for instance, is pairing tucatinib with trastuzumab deruxtecan, whereas HER2CLIMB-02 is pairing tucatinib with T-DM1.
But given progress in drug development in just the past few years, Lisa A. Carey, MD, deputy director of Clinical Sciences at the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, sees a promising future for treating metastatic HER2-positive disease. “There is so much going on in the HER2-positive MBC therapeutics space that almost every 6 months, oncologists have to regroup and reevaluate treatment and sequencing, which is a great position to be in,” Dr. Carey noted.
A version of this article first appeared on Medscape.com .
The landscape for therapies targeting HER2-positive metastatic breast cancer (MBC) has evolved rapidly in the past few years. In a 12-month window, the U.S. Food and Drug Administration approved four agents targeting human epidermal growth factor 2 (HER2)–positive MBC, starting with trastuzumab deruxtecan in December 2019, followed by neratinib and tucatinib a few months later, and margetuximab last December.
Although first-line therapy for the majority of patients continues to be the CLEOPATRA regimen — the monoclonal antibodies trastuzumab and pertuzumab plus a taxane, such as docetaxel or paclitaxel — .
“We have been really fortunate to see a number of highly effective new therapies approved for HER2-positive MBC in the past year, and this has given us even more options to offer our patients,” remarked Rita Nanda, MD, director of the Breast Oncology Program and associate professor of medicine at University of Chicago Medicine.
What considerations do experts weigh when sequencing HER2-positive MBC?
For Kelly McCann, MD, PhD, the order largely depends on balancing two factors: regimens that will provide the best efficacy in terms of patient survival and quality of life. “In the metastatic setting, I know I’m going to end up using all of the available medications one after the other, so the order that allows patients to continue living their best life for as long as possible is essential,” commented Dr. McCann, a hematologist/oncologist in the department of medicine at the David Geffen School of Medicine, University of California, Los Angeles.
A new second-line option?
Before the wave of drug approvals for metastatic HER2-positive disease last year, oncologists routinely looked to trastuzumab emtansine (T-DM1) as second-line therapy.
But tucatinib may also now be considered in the second-line setting, after results from the HER2CLIMB trial. The decision between tucatinib and T-DM1 largely comes down to the presence or absence of brain metastases.
“T-DM1 is well-tolerated, so it’s still my go-to in the second-line setting unless my patient has a brain metastasis, in which case I opt for tucatinib,” Dr. McCann noted, adding that the HER2-specific oral tyrosine kinase inhibitor (TKI) not only crosses the blood-brain barrier but is also effective in patients with untreated brain metastases.
In HER2CLIMB, tucatinib exhibited strong efficacy in patients with advanced HER2-positive disease, including those with previously treated or untreated brain metastases. The randomized controlled trial, which paired tucatinib with trastuzumab and capecitabine, showed median progression-free survival of 7.8 months in 410 patients with HER2-positive MBC compared with 5.6 months in the 202 patients receiving the placebo regimen. The tucatinib cohort showed an overall survival advantage compared with the placebo group (21.9 vs 17.4 months).
Perhaps the most notable finding occurred in patients with brain or central nervous system (CNS) involvement, which develops in as many as half of patients with HER-positive MBC and is associated with shorter survival. In the HER2CLIMB trial, median progression-free survival was 7.6 months in patients with brain metastases compared with 5.4 months in the placebo group.
A follow-up exploratory analysis, which focused on 291 patients with brain metastases, found that adding tucatinib reduced the risk for intracranial progression by two thirds and death by almost half. In patients with active brain metastases, median progression-free survival reached 9.5 months vs 4.1 months in the placebo group. Those with stable metastases also benefited from tucatinib, with median progression-free survival of 13.9 vs 5.6 months in the placebo group.
On the basis of the results, the authors concluded that this randomized trial was the first to demonstrate improvements in both CNS progression–free survival and overall survival in patients with HER2-positive MBC and brain metastases.
Evolving options in the third-line setting and after
For third-line therapy and beyond, oncologists have an array of newer agents to choose from alongside longer-standing options — which include trastuzumab plus lapatinib, trastuzumab or lapatinib plus capecitabine, as well as T-DM1, if not given as second-line therapy.
According to Dr. McCann, the antibody-drug conjugate trastuzumab deruxtecan has been a particularly exciting addition to third-line treatment. In the phase 2 DESTINY-01 trial, more than 60% of a heavily pretreated population showed an objective response to trastuzumab deruxtecan, with a median response duration of almost 15 months and a median progression-free survival of 16.4 months. Longer-term follow-up results, presented in December at the 2020 San Antonio Breast Cancer Symposium, revealed progression-free survival of 19.4 months and preliminary median overall survival of 24.6 months.
Neratinib, the second TKI to bridge the blood-brain barrier in HER2-positive disease, was also approved for third-line use; however, Sayeh Lavasani, MD, MS, said she is more likely to consider this agent later in the sequence, potentially in the fourth-line setting and beyond, given the more robust outcomes observed in the HER2CLIMB tucatinib trial.
“Neratinib improved progression-free survival and time to intervention for CNS metastasis but, unlike tucatinib, did not demonstrate an overall survival benefit,” remarked Dr. Lavasani, a medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.
More specifically, the phase 3 NALA trial, which randomly assigned patients to receive neratinib plus capecitabine or lapatinib plus capecitabine, reported progression-free survival of 8.8 months in the neratinib group compared with 6.6 months in the control arm but no significant gains in overall survival (hazard ratio, 0.88; P = .2098).
The fourth recently approved drug, margetuximab, has not yet made a significant mark on sequencing decisions for Dr. McCann.
“Margetuximab could have been a potential game changer, but clinical trial results were underwhelming,” she said.
In the phase 3 randomized clinical SOPHIA trial, margetuximab plus chemotherapy prolonged median progression-free survival by just over 1 month compared with trastuzumab plus chemotherapy. Preliminary overall survival data showed a slight, but not significant, benefit in the margetuximab group (21.6 vs 19.8 months).
For Dr. Lavasani, the presence of brain metastases is the most important consideration when weighing sequencing options. “For some of my patients with HER2-positive MBC, it’s ultimately disease progression in the brain that takes their life,” she said.
Aside from CNS metastases, specific sequencing choices may vary on the basis of drug-related tolerance as well as patient preferences. “It is critical to get a patient’s input in treatment selection,” Dr. Nanda remarked. “Given the number of effective treatments for HER2-positive MBC and the lack of data to guide how to sequence these regimens, it is important to ask patients what their preferences are.”
Dr. McCann agreed, noting that “a patient with HER2-positive MBC typically has a life expectancy measured in years, which is also why sequencing should be influenced by quality of life considerations.”
Convenience, side-effect profile, and financial toxicity should factor into clinical decision-making, according to Dr. Nanda. Some patients may, for instance, prefer a combination of tucatinib, capecitabine, and trastuzumab over trastuzumab deruxtecan to avoid hair loss and the risk for interstitial lung disease, which has been reported in more than 13% of patients, whereas others may prefer trastuzumab deruxtecan to avoid the possibility of diarrhea.
Taxanes come with a high risk for infusion reactions — which occur in about 30% of patients — and can cause neuropathy as well as hair loss and severe gastrointestinal side effects. In first-line care, Dr. McCann typically stops the taxane at some point for toxicity reasons and continues with trastuzumab plus pertuzumab until disease progression.
Even with an array of new options for treating metastatic HER2-positive disease, ultimately drug resistance does occur, Dr. Lavasani cautioned. Several ongoing trials are exploring new combinations of existing drugs to see whether those variations move the needle on survival outcomes. The HER2CLIMB-04 trial, for instance, is pairing tucatinib with trastuzumab deruxtecan, whereas HER2CLIMB-02 is pairing tucatinib with T-DM1.
But given progress in drug development in just the past few years, Lisa A. Carey, MD, deputy director of Clinical Sciences at the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, sees a promising future for treating metastatic HER2-positive disease. “There is so much going on in the HER2-positive MBC therapeutics space that almost every 6 months, oncologists have to regroup and reevaluate treatment and sequencing, which is a great position to be in,” Dr. Carey noted.
A version of this article first appeared on Medscape.com .
The landscape for therapies targeting HER2-positive metastatic breast cancer (MBC) has evolved rapidly in the past few years. In a 12-month window, the U.S. Food and Drug Administration approved four agents targeting human epidermal growth factor 2 (HER2)–positive MBC, starting with trastuzumab deruxtecan in December 2019, followed by neratinib and tucatinib a few months later, and margetuximab last December.
Although first-line therapy for the majority of patients continues to be the CLEOPATRA regimen — the monoclonal antibodies trastuzumab and pertuzumab plus a taxane, such as docetaxel or paclitaxel — .
“We have been really fortunate to see a number of highly effective new therapies approved for HER2-positive MBC in the past year, and this has given us even more options to offer our patients,” remarked Rita Nanda, MD, director of the Breast Oncology Program and associate professor of medicine at University of Chicago Medicine.
What considerations do experts weigh when sequencing HER2-positive MBC?
For Kelly McCann, MD, PhD, the order largely depends on balancing two factors: regimens that will provide the best efficacy in terms of patient survival and quality of life. “In the metastatic setting, I know I’m going to end up using all of the available medications one after the other, so the order that allows patients to continue living their best life for as long as possible is essential,” commented Dr. McCann, a hematologist/oncologist in the department of medicine at the David Geffen School of Medicine, University of California, Los Angeles.
A new second-line option?
Before the wave of drug approvals for metastatic HER2-positive disease last year, oncologists routinely looked to trastuzumab emtansine (T-DM1) as second-line therapy.
But tucatinib may also now be considered in the second-line setting, after results from the HER2CLIMB trial. The decision between tucatinib and T-DM1 largely comes down to the presence or absence of brain metastases.
“T-DM1 is well-tolerated, so it’s still my go-to in the second-line setting unless my patient has a brain metastasis, in which case I opt for tucatinib,” Dr. McCann noted, adding that the HER2-specific oral tyrosine kinase inhibitor (TKI) not only crosses the blood-brain barrier but is also effective in patients with untreated brain metastases.
In HER2CLIMB, tucatinib exhibited strong efficacy in patients with advanced HER2-positive disease, including those with previously treated or untreated brain metastases. The randomized controlled trial, which paired tucatinib with trastuzumab and capecitabine, showed median progression-free survival of 7.8 months in 410 patients with HER2-positive MBC compared with 5.6 months in the 202 patients receiving the placebo regimen. The tucatinib cohort showed an overall survival advantage compared with the placebo group (21.9 vs 17.4 months).
Perhaps the most notable finding occurred in patients with brain or central nervous system (CNS) involvement, which develops in as many as half of patients with HER-positive MBC and is associated with shorter survival. In the HER2CLIMB trial, median progression-free survival was 7.6 months in patients with brain metastases compared with 5.4 months in the placebo group.
A follow-up exploratory analysis, which focused on 291 patients with brain metastases, found that adding tucatinib reduced the risk for intracranial progression by two thirds and death by almost half. In patients with active brain metastases, median progression-free survival reached 9.5 months vs 4.1 months in the placebo group. Those with stable metastases also benefited from tucatinib, with median progression-free survival of 13.9 vs 5.6 months in the placebo group.
On the basis of the results, the authors concluded that this randomized trial was the first to demonstrate improvements in both CNS progression–free survival and overall survival in patients with HER2-positive MBC and brain metastases.
Evolving options in the third-line setting and after
For third-line therapy and beyond, oncologists have an array of newer agents to choose from alongside longer-standing options — which include trastuzumab plus lapatinib, trastuzumab or lapatinib plus capecitabine, as well as T-DM1, if not given as second-line therapy.
According to Dr. McCann, the antibody-drug conjugate trastuzumab deruxtecan has been a particularly exciting addition to third-line treatment. In the phase 2 DESTINY-01 trial, more than 60% of a heavily pretreated population showed an objective response to trastuzumab deruxtecan, with a median response duration of almost 15 months and a median progression-free survival of 16.4 months. Longer-term follow-up results, presented in December at the 2020 San Antonio Breast Cancer Symposium, revealed progression-free survival of 19.4 months and preliminary median overall survival of 24.6 months.
Neratinib, the second TKI to bridge the blood-brain barrier in HER2-positive disease, was also approved for third-line use; however, Sayeh Lavasani, MD, MS, said she is more likely to consider this agent later in the sequence, potentially in the fourth-line setting and beyond, given the more robust outcomes observed in the HER2CLIMB tucatinib trial.
“Neratinib improved progression-free survival and time to intervention for CNS metastasis but, unlike tucatinib, did not demonstrate an overall survival benefit,” remarked Dr. Lavasani, a medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.
More specifically, the phase 3 NALA trial, which randomly assigned patients to receive neratinib plus capecitabine or lapatinib plus capecitabine, reported progression-free survival of 8.8 months in the neratinib group compared with 6.6 months in the control arm but no significant gains in overall survival (hazard ratio, 0.88; P = .2098).
The fourth recently approved drug, margetuximab, has not yet made a significant mark on sequencing decisions for Dr. McCann.
“Margetuximab could have been a potential game changer, but clinical trial results were underwhelming,” she said.
In the phase 3 randomized clinical SOPHIA trial, margetuximab plus chemotherapy prolonged median progression-free survival by just over 1 month compared with trastuzumab plus chemotherapy. Preliminary overall survival data showed a slight, but not significant, benefit in the margetuximab group (21.6 vs 19.8 months).
For Dr. Lavasani, the presence of brain metastases is the most important consideration when weighing sequencing options. “For some of my patients with HER2-positive MBC, it’s ultimately disease progression in the brain that takes their life,” she said.
Aside from CNS metastases, specific sequencing choices may vary on the basis of drug-related tolerance as well as patient preferences. “It is critical to get a patient’s input in treatment selection,” Dr. Nanda remarked. “Given the number of effective treatments for HER2-positive MBC and the lack of data to guide how to sequence these regimens, it is important to ask patients what their preferences are.”
Dr. McCann agreed, noting that “a patient with HER2-positive MBC typically has a life expectancy measured in years, which is also why sequencing should be influenced by quality of life considerations.”
Convenience, side-effect profile, and financial toxicity should factor into clinical decision-making, according to Dr. Nanda. Some patients may, for instance, prefer a combination of tucatinib, capecitabine, and trastuzumab over trastuzumab deruxtecan to avoid hair loss and the risk for interstitial lung disease, which has been reported in more than 13% of patients, whereas others may prefer trastuzumab deruxtecan to avoid the possibility of diarrhea.
Taxanes come with a high risk for infusion reactions — which occur in about 30% of patients — and can cause neuropathy as well as hair loss and severe gastrointestinal side effects. In first-line care, Dr. McCann typically stops the taxane at some point for toxicity reasons and continues with trastuzumab plus pertuzumab until disease progression.
Even with an array of new options for treating metastatic HER2-positive disease, ultimately drug resistance does occur, Dr. Lavasani cautioned. Several ongoing trials are exploring new combinations of existing drugs to see whether those variations move the needle on survival outcomes. The HER2CLIMB-04 trial, for instance, is pairing tucatinib with trastuzumab deruxtecan, whereas HER2CLIMB-02 is pairing tucatinib with T-DM1.
But given progress in drug development in just the past few years, Lisa A. Carey, MD, deputy director of Clinical Sciences at the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, sees a promising future for treating metastatic HER2-positive disease. “There is so much going on in the HER2-positive MBC therapeutics space that almost every 6 months, oncologists have to regroup and reevaluate treatment and sequencing, which is a great position to be in,” Dr. Carey noted.
A version of this article first appeared on Medscape.com .