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Neuroimaging may predict cognitive decline after chemotherapy for breast cancer
“Cognitive decline is frequently observed after chemotherapy,” according to Michiel B. de Ruiter, PhD, a research scientist with the Netherlands Cancer Institute in Amsterdam. He specializes in cognitive neuroscience and was the lead author of a study published online Sept. 30, 2021, in the Journal of Clinical Oncology. Dr. de Ruiter and colleagues found that fractional anisotropy may demonstrate a low brain white-matter reserve which could be a risk factor for cognitive decline after chemotherapy for breast cancer treatment.
Cognitive decline after chemotherapy has been reported in 20%-40% of patients with cancer affecting quality of life and daily living skills. Studies have suggested that genetic makeup, advanced age, fatigue, and premorbid intelligence quotient are risk factors for chemotherapy-associated cognitive decline. Changes in the microstructure of brain white matter, known as brain reserve, have been reported after exposure to chemotherapy, but its link to cognitive decline is understudied. Several studies outside of oncology have used MRI to derive fractional anisotropy as a measure for brain reserve.
In the new JCO study, researchers examined fractional anisotropy, as measured by MRI, before chemotherapy. The analysis included 49 patients who underwent neuropsychological tests before treatment with anthracycline-based chemotherapy, then again at 6 months and 2 years after chemotherapy.
The results were compared with those of patients with breast cancer who did not receive systemic therapy and then with a control group consisting of patients without cancer.
A low fractional anisotropy score suggested cognitive decline more than 3 years after receiving chemotherapy treatment. The finding was independent of age, premorbid intelligence quotient, baseline fatigue and baseline cognitive complaints. And, having low premorbid intelligence quotient was an independent risk factor for chemotherapy-associated cognitive decline, which the authors said is in line with previous findings.
Fractional anisotropy did not predict cognitive decline in patients who did not receive systemic therapy, as well as patients in the control group.
The findings could possibly lead to the development a pretreatment assessment to screen for patients who may at risk for cognitive decline, the authors wrote. “Clinically validated assessments of white-matter reserve as assessed with an MRI scan may be part of a pretreatment screening. This could also aid in early identification of cognitive decline after chemotherapy, allowing targeted and early interventions to improve cognitive problems,” such as psychoeducation and cognitive rehabilitation.
No potential conflicts of interest were reported.
“Cognitive decline is frequently observed after chemotherapy,” according to Michiel B. de Ruiter, PhD, a research scientist with the Netherlands Cancer Institute in Amsterdam. He specializes in cognitive neuroscience and was the lead author of a study published online Sept. 30, 2021, in the Journal of Clinical Oncology. Dr. de Ruiter and colleagues found that fractional anisotropy may demonstrate a low brain white-matter reserve which could be a risk factor for cognitive decline after chemotherapy for breast cancer treatment.
Cognitive decline after chemotherapy has been reported in 20%-40% of patients with cancer affecting quality of life and daily living skills. Studies have suggested that genetic makeup, advanced age, fatigue, and premorbid intelligence quotient are risk factors for chemotherapy-associated cognitive decline. Changes in the microstructure of brain white matter, known as brain reserve, have been reported after exposure to chemotherapy, but its link to cognitive decline is understudied. Several studies outside of oncology have used MRI to derive fractional anisotropy as a measure for brain reserve.
In the new JCO study, researchers examined fractional anisotropy, as measured by MRI, before chemotherapy. The analysis included 49 patients who underwent neuropsychological tests before treatment with anthracycline-based chemotherapy, then again at 6 months and 2 years after chemotherapy.
The results were compared with those of patients with breast cancer who did not receive systemic therapy and then with a control group consisting of patients without cancer.
A low fractional anisotropy score suggested cognitive decline more than 3 years after receiving chemotherapy treatment. The finding was independent of age, premorbid intelligence quotient, baseline fatigue and baseline cognitive complaints. And, having low premorbid intelligence quotient was an independent risk factor for chemotherapy-associated cognitive decline, which the authors said is in line with previous findings.
Fractional anisotropy did not predict cognitive decline in patients who did not receive systemic therapy, as well as patients in the control group.
The findings could possibly lead to the development a pretreatment assessment to screen for patients who may at risk for cognitive decline, the authors wrote. “Clinically validated assessments of white-matter reserve as assessed with an MRI scan may be part of a pretreatment screening. This could also aid in early identification of cognitive decline after chemotherapy, allowing targeted and early interventions to improve cognitive problems,” such as psychoeducation and cognitive rehabilitation.
No potential conflicts of interest were reported.
“Cognitive decline is frequently observed after chemotherapy,” according to Michiel B. de Ruiter, PhD, a research scientist with the Netherlands Cancer Institute in Amsterdam. He specializes in cognitive neuroscience and was the lead author of a study published online Sept. 30, 2021, in the Journal of Clinical Oncology. Dr. de Ruiter and colleagues found that fractional anisotropy may demonstrate a low brain white-matter reserve which could be a risk factor for cognitive decline after chemotherapy for breast cancer treatment.
Cognitive decline after chemotherapy has been reported in 20%-40% of patients with cancer affecting quality of life and daily living skills. Studies have suggested that genetic makeup, advanced age, fatigue, and premorbid intelligence quotient are risk factors for chemotherapy-associated cognitive decline. Changes in the microstructure of brain white matter, known as brain reserve, have been reported after exposure to chemotherapy, but its link to cognitive decline is understudied. Several studies outside of oncology have used MRI to derive fractional anisotropy as a measure for brain reserve.
In the new JCO study, researchers examined fractional anisotropy, as measured by MRI, before chemotherapy. The analysis included 49 patients who underwent neuropsychological tests before treatment with anthracycline-based chemotherapy, then again at 6 months and 2 years after chemotherapy.
The results were compared with those of patients with breast cancer who did not receive systemic therapy and then with a control group consisting of patients without cancer.
A low fractional anisotropy score suggested cognitive decline more than 3 years after receiving chemotherapy treatment. The finding was independent of age, premorbid intelligence quotient, baseline fatigue and baseline cognitive complaints. And, having low premorbid intelligence quotient was an independent risk factor for chemotherapy-associated cognitive decline, which the authors said is in line with previous findings.
Fractional anisotropy did not predict cognitive decline in patients who did not receive systemic therapy, as well as patients in the control group.
The findings could possibly lead to the development a pretreatment assessment to screen for patients who may at risk for cognitive decline, the authors wrote. “Clinically validated assessments of white-matter reserve as assessed with an MRI scan may be part of a pretreatment screening. This could also aid in early identification of cognitive decline after chemotherapy, allowing targeted and early interventions to improve cognitive problems,” such as psychoeducation and cognitive rehabilitation.
No potential conflicts of interest were reported.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Biomarker testing in metastatic breast cancer management: ‘Essential’
Identifying biomarkers in metastatic breast cancer (MBC) has become an integral part of choosing treatments and understanding disease progression. The American Society of Clinical Oncology Clinical Practice Guideline, published in 2015, recommends an initial biopsy to confirm estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) status as well as repeat biopsies to watch for receptor status changes over time.
“Decisions concerning the initiation of systemic therapy or selection of systemic therapy for metastatic breast cancer should be guided by ER, PR, and HER2 status in conjunction with clinical evaluation, judgment, and the patient’s goals for care,” according to the guideline authors.This news organization reached out to Kelly McCann, MD, PhD, a hematologist and oncologist in the department of medicine at the David Geffen School of Medicine, University of California, Los Angeles, to explore the role biomarker testing plays in managing MBC.
Question: How important is biomarker testing in guiding MBC treatments? Is there a standard or recommended process?
Dr. McCann: Biomarker testing is essential to breast cancer treatment and the development of targeted therapies. Oncologists typically identify a tumor’s canonical biomarkers — ER, PR, and HER2 — using immunohistochemistry or fluorescence in situ hybridization (FISH) testing and then try to match the tumor biology to drugs that target that subtype.
For tumors that lack canonical biomarkers — for example, triple-negative breast cancer (TNBC) — I send the tumor tissue for next-generation sequencing at the time of metastatic diagnosis to identify a wider range of potential targets or oncogenic drivers, such as somatic or germline mutations in homologous recombination repair genes ( BRCA1, BRCA2, and PALB2 ) or mutations in the PI3K/AKT/mTOR pathway.
In our attempts to define tumor biology and design a treatment strategy, two additional issues quickly arise. First, tumors are heterogeneous from the start. Second, tumors evolve.
Let’s start with how we define or subtype a tumor. Would you walk us through this process?
Defining a breast tumor can be tricky because these cancers often don’t fit neatly into predefined categories. Let’s take the estrogen receptor. In clinical trials, we need to define the cutoff for what constitutes ER-positive MBC or TNBC. Some trials define ER-positive as 1% or greater, others define it as 10% or greater.
But is a PR- and HER2-negative tumor with 1% or even 5% ER expression really ER-positive in the biological or prognostic sense? Probably not. A tumor with less than 10% ER expression, for instance, will actually behave like a triple-negative tumor. Instead of choosing a regimen targeting the ER-positive cells, I’ll lean more toward cytotoxic chemotherapy, the standard treatment for TNBC.
Tumors may have multiple drivers as well. What are some aberrations in addition to the main subtypes?
Tumors also often harbor more than one targetable driver. For instance, PIK3CA gene mutations are present in about 40% of hormone receptor–positive, HER2-negative tumors. Activating mutations in ESR1 develop in anywhere from 10% to 50% of MBCs as a resistance mechanism to estrogen deprivation therapy, conferring estrogen independence to the cells. Activating mutations in ERBB2, which essentially turns HER2 into an active receptor, are found in 2%-4% of breast cancers, including ER-positive, HER2-mutant breast cancers, and are enriched in lobular breast cancers, which are typically ER positive, HER2 negative.
What about tumor evolution, given the growing body of evidence that biomarker status in MBC can change over time?
Patients with MBC often have several active areas of cancer, and these areas will evolve differently. During each line of treatment, some metastases will develop resistance and others won’t. For instance, if my patient’s liver metastases start to grow, I will change therapy immediately. If, however, a single bone metastasis begins to grow and the liver metastases have responded well, I might consider local therapy — such as radiation — to target that bone metastasis, though this particular approach hasn’t been formally studied.
Ultimately, we can expect tumors to change over time as they become more biologically aggressive or resistant to current therapy. The most common biomarker change is probably loss of ER or PR expression, but the frequency of ER, PR, or HER2 biomarker changes is still not well understood.
Resistance mutations can also happen. When, for instance, activating mutations in ESR1 occur, the estrogen receptor becomes independent of estrogen and tumors then develop resistance to endocrine therapies. We see a similar problem arise in metastatic prostate cancer. With chronic testosterone deprivation, eventually the androgen receptor evolves to become independent of testosterone in a stage known as castrate-resistant prostate cancer.
Which biomarkers or combinations of biomarkers can be paired with an approved treatment?
We have a range of treatments targeting ER-positive and HER2-positive MBC in particular. For tumors harboring additional targetable mutations, preliminary data suggest that HER2-targeted tyrosine kinase inhibitors (TKIs), such as tucatinib and neratinib, are effective against activating mutations in ERBB2.
The PI3K inhibitor alpelisib in combination with fulvestrant has been approved for patients with ER-positive, HER2-negative MBC and mutations in PIK3CA. The mTOR inhibitor everolimus plus exemestane is an option for patients with ER-positive, HER2-negative. And for those with activating mutations in ESR1, I switch patients to a selective estrogen receptor degrader, such as fulvestrant.
PARP inhibitors, including olaparib or talazoparib, target metastatic HR-positive disease or TNBC with deleterious germline BRCA1 or BRCA2 mutations. Sacituzumab govitecan has been approved for treating metastatic TNBC and targets the cell surface protein TROP2, expressed in almost 90% of TNBC tumors.
What targets, on the other hand, are less informative for treatment choice?
When we order next-generation sequencing, we also will get a list of possible targets for which there are currently no therapeutic options, but there may be in the future. I find this knowledge is helpful. For example, an activating mutation in KRAS tells me that the cancer has a very strong oncogenic driver that I won›t be able to target. I know that activating KRAS mutations in lung cancer and colon cancer portend a poorer prognosis, which helps me to prepare the patient and family.
Atezolizumab in combination with paclitaxel has been FDA-approved for PD-L1 TNBC in the first-line setting, though data show that immune checkpoint inhibitors may be effective even without PD-L1 expression. Although cell surface protein TROP2 has emerged as a target in recent years, its expression is so common in TNBC that confirmatory testing for TROP2 expression is not required to prescribe sacituzumab govitecan.
What factors do you weigh when selecting among the large number of tests available for tumor testing?
We have many biomarker tests available, but the National Comprehensive Cancer Network does not have guidelines for tumor genetics testing in breast cancer. That means insurance does not have to cover the cost, and many companies don’t. Ultimately, though, drug companies and some testing companies have an incentive to cover the cost themselves because a companion diagnostic might be linked to their drug — therascreen PIK3CA RGQ PCR kit for alpelisib, for instance.
I tend not to use a companion diagnostic test because I want more information with a wider panel. The tumor tests I often use are FoundationOne CDx, Caris Molecular Intelligence, and Tempus. I use Tempus because their financial aid is very generous and almost all of my patients qualify to be tested for less than $100. For germline genetic testing, Invitae, Myriad, and Color are also options. Invitae and Color are about $250 out of pocket without insurance. Many academic centers have their own gene panels as well.
How far have we come in identifying biomarkers in MBC?
Targeted treatment for breast cancer has advanced significantly since doing my PhD research in cancer biology about 15 years ago. Of course, targeted therapies for ER-positive and HER2-amplified cancers were available at that point, but many more have been developed. The most significant advance has been the development of efficient and affordable genome sequencing, which has led to these large panels and identification of therapeutic targets. We’ve also expanded our knowledge of genetic predispositions for breast cancer beyond BRCA1 and BRCA2, which not only allows us to preemptively advise patients and their families about cancer risks and recommendations for cancer screening, but also to select a therapy to target a cancer’s DNA repair deficits.
I feel that we are in an exciting discovery phase in oncology. We currently rely on biomarkers to manage MBC and will continue to refine our strategies and develop more effective drug therapies as we identify more oncogenic drivers, tumor-specific proteins, and cancer cell vulnerabilities.
Identifying biomarkers in metastatic breast cancer (MBC) has become an integral part of choosing treatments and understanding disease progression. The American Society of Clinical Oncology Clinical Practice Guideline, published in 2015, recommends an initial biopsy to confirm estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) status as well as repeat biopsies to watch for receptor status changes over time.
“Decisions concerning the initiation of systemic therapy or selection of systemic therapy for metastatic breast cancer should be guided by ER, PR, and HER2 status in conjunction with clinical evaluation, judgment, and the patient’s goals for care,” according to the guideline authors.This news organization reached out to Kelly McCann, MD, PhD, a hematologist and oncologist in the department of medicine at the David Geffen School of Medicine, University of California, Los Angeles, to explore the role biomarker testing plays in managing MBC.
Question: How important is biomarker testing in guiding MBC treatments? Is there a standard or recommended process?
Dr. McCann: Biomarker testing is essential to breast cancer treatment and the development of targeted therapies. Oncologists typically identify a tumor’s canonical biomarkers — ER, PR, and HER2 — using immunohistochemistry or fluorescence in situ hybridization (FISH) testing and then try to match the tumor biology to drugs that target that subtype.
For tumors that lack canonical biomarkers — for example, triple-negative breast cancer (TNBC) — I send the tumor tissue for next-generation sequencing at the time of metastatic diagnosis to identify a wider range of potential targets or oncogenic drivers, such as somatic or germline mutations in homologous recombination repair genes ( BRCA1, BRCA2, and PALB2 ) or mutations in the PI3K/AKT/mTOR pathway.
In our attempts to define tumor biology and design a treatment strategy, two additional issues quickly arise. First, tumors are heterogeneous from the start. Second, tumors evolve.
Let’s start with how we define or subtype a tumor. Would you walk us through this process?
Defining a breast tumor can be tricky because these cancers often don’t fit neatly into predefined categories. Let’s take the estrogen receptor. In clinical trials, we need to define the cutoff for what constitutes ER-positive MBC or TNBC. Some trials define ER-positive as 1% or greater, others define it as 10% or greater.
But is a PR- and HER2-negative tumor with 1% or even 5% ER expression really ER-positive in the biological or prognostic sense? Probably not. A tumor with less than 10% ER expression, for instance, will actually behave like a triple-negative tumor. Instead of choosing a regimen targeting the ER-positive cells, I’ll lean more toward cytotoxic chemotherapy, the standard treatment for TNBC.
Tumors may have multiple drivers as well. What are some aberrations in addition to the main subtypes?
Tumors also often harbor more than one targetable driver. For instance, PIK3CA gene mutations are present in about 40% of hormone receptor–positive, HER2-negative tumors. Activating mutations in ESR1 develop in anywhere from 10% to 50% of MBCs as a resistance mechanism to estrogen deprivation therapy, conferring estrogen independence to the cells. Activating mutations in ERBB2, which essentially turns HER2 into an active receptor, are found in 2%-4% of breast cancers, including ER-positive, HER2-mutant breast cancers, and are enriched in lobular breast cancers, which are typically ER positive, HER2 negative.
What about tumor evolution, given the growing body of evidence that biomarker status in MBC can change over time?
Patients with MBC often have several active areas of cancer, and these areas will evolve differently. During each line of treatment, some metastases will develop resistance and others won’t. For instance, if my patient’s liver metastases start to grow, I will change therapy immediately. If, however, a single bone metastasis begins to grow and the liver metastases have responded well, I might consider local therapy — such as radiation — to target that bone metastasis, though this particular approach hasn’t been formally studied.
Ultimately, we can expect tumors to change over time as they become more biologically aggressive or resistant to current therapy. The most common biomarker change is probably loss of ER or PR expression, but the frequency of ER, PR, or HER2 biomarker changes is still not well understood.
Resistance mutations can also happen. When, for instance, activating mutations in ESR1 occur, the estrogen receptor becomes independent of estrogen and tumors then develop resistance to endocrine therapies. We see a similar problem arise in metastatic prostate cancer. With chronic testosterone deprivation, eventually the androgen receptor evolves to become independent of testosterone in a stage known as castrate-resistant prostate cancer.
Which biomarkers or combinations of biomarkers can be paired with an approved treatment?
We have a range of treatments targeting ER-positive and HER2-positive MBC in particular. For tumors harboring additional targetable mutations, preliminary data suggest that HER2-targeted tyrosine kinase inhibitors (TKIs), such as tucatinib and neratinib, are effective against activating mutations in ERBB2.
The PI3K inhibitor alpelisib in combination with fulvestrant has been approved for patients with ER-positive, HER2-negative MBC and mutations in PIK3CA. The mTOR inhibitor everolimus plus exemestane is an option for patients with ER-positive, HER2-negative. And for those with activating mutations in ESR1, I switch patients to a selective estrogen receptor degrader, such as fulvestrant.
PARP inhibitors, including olaparib or talazoparib, target metastatic HR-positive disease or TNBC with deleterious germline BRCA1 or BRCA2 mutations. Sacituzumab govitecan has been approved for treating metastatic TNBC and targets the cell surface protein TROP2, expressed in almost 90% of TNBC tumors.
What targets, on the other hand, are less informative for treatment choice?
When we order next-generation sequencing, we also will get a list of possible targets for which there are currently no therapeutic options, but there may be in the future. I find this knowledge is helpful. For example, an activating mutation in KRAS tells me that the cancer has a very strong oncogenic driver that I won›t be able to target. I know that activating KRAS mutations in lung cancer and colon cancer portend a poorer prognosis, which helps me to prepare the patient and family.
Atezolizumab in combination with paclitaxel has been FDA-approved for PD-L1 TNBC in the first-line setting, though data show that immune checkpoint inhibitors may be effective even without PD-L1 expression. Although cell surface protein TROP2 has emerged as a target in recent years, its expression is so common in TNBC that confirmatory testing for TROP2 expression is not required to prescribe sacituzumab govitecan.
What factors do you weigh when selecting among the large number of tests available for tumor testing?
We have many biomarker tests available, but the National Comprehensive Cancer Network does not have guidelines for tumor genetics testing in breast cancer. That means insurance does not have to cover the cost, and many companies don’t. Ultimately, though, drug companies and some testing companies have an incentive to cover the cost themselves because a companion diagnostic might be linked to their drug — therascreen PIK3CA RGQ PCR kit for alpelisib, for instance.
I tend not to use a companion diagnostic test because I want more information with a wider panel. The tumor tests I often use are FoundationOne CDx, Caris Molecular Intelligence, and Tempus. I use Tempus because their financial aid is very generous and almost all of my patients qualify to be tested for less than $100. For germline genetic testing, Invitae, Myriad, and Color are also options. Invitae and Color are about $250 out of pocket without insurance. Many academic centers have their own gene panels as well.
How far have we come in identifying biomarkers in MBC?
Targeted treatment for breast cancer has advanced significantly since doing my PhD research in cancer biology about 15 years ago. Of course, targeted therapies for ER-positive and HER2-amplified cancers were available at that point, but many more have been developed. The most significant advance has been the development of efficient and affordable genome sequencing, which has led to these large panels and identification of therapeutic targets. We’ve also expanded our knowledge of genetic predispositions for breast cancer beyond BRCA1 and BRCA2, which not only allows us to preemptively advise patients and their families about cancer risks and recommendations for cancer screening, but also to select a therapy to target a cancer’s DNA repair deficits.
I feel that we are in an exciting discovery phase in oncology. We currently rely on biomarkers to manage MBC and will continue to refine our strategies and develop more effective drug therapies as we identify more oncogenic drivers, tumor-specific proteins, and cancer cell vulnerabilities.
Identifying biomarkers in metastatic breast cancer (MBC) has become an integral part of choosing treatments and understanding disease progression. The American Society of Clinical Oncology Clinical Practice Guideline, published in 2015, recommends an initial biopsy to confirm estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) status as well as repeat biopsies to watch for receptor status changes over time.
“Decisions concerning the initiation of systemic therapy or selection of systemic therapy for metastatic breast cancer should be guided by ER, PR, and HER2 status in conjunction with clinical evaluation, judgment, and the patient’s goals for care,” according to the guideline authors.This news organization reached out to Kelly McCann, MD, PhD, a hematologist and oncologist in the department of medicine at the David Geffen School of Medicine, University of California, Los Angeles, to explore the role biomarker testing plays in managing MBC.
Question: How important is biomarker testing in guiding MBC treatments? Is there a standard or recommended process?
Dr. McCann: Biomarker testing is essential to breast cancer treatment and the development of targeted therapies. Oncologists typically identify a tumor’s canonical biomarkers — ER, PR, and HER2 — using immunohistochemistry or fluorescence in situ hybridization (FISH) testing and then try to match the tumor biology to drugs that target that subtype.
For tumors that lack canonical biomarkers — for example, triple-negative breast cancer (TNBC) — I send the tumor tissue for next-generation sequencing at the time of metastatic diagnosis to identify a wider range of potential targets or oncogenic drivers, such as somatic or germline mutations in homologous recombination repair genes ( BRCA1, BRCA2, and PALB2 ) or mutations in the PI3K/AKT/mTOR pathway.
In our attempts to define tumor biology and design a treatment strategy, two additional issues quickly arise. First, tumors are heterogeneous from the start. Second, tumors evolve.
Let’s start with how we define or subtype a tumor. Would you walk us through this process?
Defining a breast tumor can be tricky because these cancers often don’t fit neatly into predefined categories. Let’s take the estrogen receptor. In clinical trials, we need to define the cutoff for what constitutes ER-positive MBC or TNBC. Some trials define ER-positive as 1% or greater, others define it as 10% or greater.
But is a PR- and HER2-negative tumor with 1% or even 5% ER expression really ER-positive in the biological or prognostic sense? Probably not. A tumor with less than 10% ER expression, for instance, will actually behave like a triple-negative tumor. Instead of choosing a regimen targeting the ER-positive cells, I’ll lean more toward cytotoxic chemotherapy, the standard treatment for TNBC.
Tumors may have multiple drivers as well. What are some aberrations in addition to the main subtypes?
Tumors also often harbor more than one targetable driver. For instance, PIK3CA gene mutations are present in about 40% of hormone receptor–positive, HER2-negative tumors. Activating mutations in ESR1 develop in anywhere from 10% to 50% of MBCs as a resistance mechanism to estrogen deprivation therapy, conferring estrogen independence to the cells. Activating mutations in ERBB2, which essentially turns HER2 into an active receptor, are found in 2%-4% of breast cancers, including ER-positive, HER2-mutant breast cancers, and are enriched in lobular breast cancers, which are typically ER positive, HER2 negative.
What about tumor evolution, given the growing body of evidence that biomarker status in MBC can change over time?
Patients with MBC often have several active areas of cancer, and these areas will evolve differently. During each line of treatment, some metastases will develop resistance and others won’t. For instance, if my patient’s liver metastases start to grow, I will change therapy immediately. If, however, a single bone metastasis begins to grow and the liver metastases have responded well, I might consider local therapy — such as radiation — to target that bone metastasis, though this particular approach hasn’t been formally studied.
Ultimately, we can expect tumors to change over time as they become more biologically aggressive or resistant to current therapy. The most common biomarker change is probably loss of ER or PR expression, but the frequency of ER, PR, or HER2 biomarker changes is still not well understood.
Resistance mutations can also happen. When, for instance, activating mutations in ESR1 occur, the estrogen receptor becomes independent of estrogen and tumors then develop resistance to endocrine therapies. We see a similar problem arise in metastatic prostate cancer. With chronic testosterone deprivation, eventually the androgen receptor evolves to become independent of testosterone in a stage known as castrate-resistant prostate cancer.
Which biomarkers or combinations of biomarkers can be paired with an approved treatment?
We have a range of treatments targeting ER-positive and HER2-positive MBC in particular. For tumors harboring additional targetable mutations, preliminary data suggest that HER2-targeted tyrosine kinase inhibitors (TKIs), such as tucatinib and neratinib, are effective against activating mutations in ERBB2.
The PI3K inhibitor alpelisib in combination with fulvestrant has been approved for patients with ER-positive, HER2-negative MBC and mutations in PIK3CA. The mTOR inhibitor everolimus plus exemestane is an option for patients with ER-positive, HER2-negative. And for those with activating mutations in ESR1, I switch patients to a selective estrogen receptor degrader, such as fulvestrant.
PARP inhibitors, including olaparib or talazoparib, target metastatic HR-positive disease or TNBC with deleterious germline BRCA1 or BRCA2 mutations. Sacituzumab govitecan has been approved for treating metastatic TNBC and targets the cell surface protein TROP2, expressed in almost 90% of TNBC tumors.
What targets, on the other hand, are less informative for treatment choice?
When we order next-generation sequencing, we also will get a list of possible targets for which there are currently no therapeutic options, but there may be in the future. I find this knowledge is helpful. For example, an activating mutation in KRAS tells me that the cancer has a very strong oncogenic driver that I won›t be able to target. I know that activating KRAS mutations in lung cancer and colon cancer portend a poorer prognosis, which helps me to prepare the patient and family.
Atezolizumab in combination with paclitaxel has been FDA-approved for PD-L1 TNBC in the first-line setting, though data show that immune checkpoint inhibitors may be effective even without PD-L1 expression. Although cell surface protein TROP2 has emerged as a target in recent years, its expression is so common in TNBC that confirmatory testing for TROP2 expression is not required to prescribe sacituzumab govitecan.
What factors do you weigh when selecting among the large number of tests available for tumor testing?
We have many biomarker tests available, but the National Comprehensive Cancer Network does not have guidelines for tumor genetics testing in breast cancer. That means insurance does not have to cover the cost, and many companies don’t. Ultimately, though, drug companies and some testing companies have an incentive to cover the cost themselves because a companion diagnostic might be linked to their drug — therascreen PIK3CA RGQ PCR kit for alpelisib, for instance.
I tend not to use a companion diagnostic test because I want more information with a wider panel. The tumor tests I often use are FoundationOne CDx, Caris Molecular Intelligence, and Tempus. I use Tempus because their financial aid is very generous and almost all of my patients qualify to be tested for less than $100. For germline genetic testing, Invitae, Myriad, and Color are also options. Invitae and Color are about $250 out of pocket without insurance. Many academic centers have their own gene panels as well.
How far have we come in identifying biomarkers in MBC?
Targeted treatment for breast cancer has advanced significantly since doing my PhD research in cancer biology about 15 years ago. Of course, targeted therapies for ER-positive and HER2-amplified cancers were available at that point, but many more have been developed. The most significant advance has been the development of efficient and affordable genome sequencing, which has led to these large panels and identification of therapeutic targets. We’ve also expanded our knowledge of genetic predispositions for breast cancer beyond BRCA1 and BRCA2, which not only allows us to preemptively advise patients and their families about cancer risks and recommendations for cancer screening, but also to select a therapy to target a cancer’s DNA repair deficits.
I feel that we are in an exciting discovery phase in oncology. We currently rely on biomarkers to manage MBC and will continue to refine our strategies and develop more effective drug therapies as we identify more oncogenic drivers, tumor-specific proteins, and cancer cell vulnerabilities.
Many patients, doctors unaware of advancements in cancer care
This is the main finding from two studies presented at the 2021 European Society for Medical Oncology Congress.
The survey of patients found that most don’t understand how immunotherapy works, and the survey of doctors found that many working outside of the cancer field are using information on survival that is wildly out of date.
When a patient is first told they have cancer, counseling is usually done by a surgeon or general medical doctor and not an oncologist, said Conleth Murphy, MD, of Bon Secours Hospital Cork, Ireland, and coauthor of the second study.
Noncancer doctors often grossly underestimate patients’ chances of survival, Dr. Murphy’s study found. This suggests that doctors who practice outside of cancer care may be working with the same information they learned in medical school, he said.
“These patients must be spared the traumatic effects of being handed a death sentence that no longer reflects the current reality,” Dr. Murphy said.
After receiving a diagnosis of cancer, “patients often immediately have pressing questions about what it means for their future,” he noted. A common question is: “How long do I have left?”
Nononcologists should refrain from answering patients’ questions with numbers, Dr. Murphy said.
Family doctors are likely to be influenced by the experience they have had with specific cancer patients in their practice, said Cyril Bonin, MD, a general practitioner in Usson-du-Poitou, France, who has 900 patients in his practice.
He sees about 10 patients with a new diagnosis of cancer each year. In addition, about 50 of his patients are in active treatment for cancer or have finished treatment and are considered cancer survivors.
“It is not entirely realistic for us to expect practitioners who deal with hundreds of different diseases to keep up with every facet of a rapidly changing oncology landscape,” said Marco Donia, MD, an expert in immunotherapy from the University of Copenhagen.
That landscape has changed dramatically in recent years, particularly since immunotherapy was added to the arsenal. Immunotherapy is a way to fine-tune your immune system to fight cancer.
For example, in the past, patients with metastatic melanoma would have an average survival of about 1 year. But now, some patients who have responded to immunotherapy are still alive 10 years later.
Findings from the patient survey
It is important that patients stay well informed because immunotherapy is a “complex treatment that is too often mistaken for a miracle cure,” said Paris Kosmidis, MD, the co-author of the patient survey.
“The more patients know about it, the better the communication with their medical team and thus the better their outcomes are likely to be,” said Dr. Kosmidis, who is co-founder and chief medical officer of CareAcross, an online service that provides personalized education for cancer patients
The survey was of 5,589 patients with cancer who were recruited from CareAcross clients from the United Kingdom, France, Italy, Spain, and Germany.
The survey asked them about how immunotherapy works, what it costs, and its side effects.
Almost half responded “not sure/do not know,” but about a third correctly answered that immunotherapy “activates the immune system to kill cancer cells.”
Similarly, more than half thought that immunotherapy started working right away, while only 20% correctly answered that it takes several weeks to become effective.
“This is important because patients need to start their therapy with realistic expectations, for example to avoid disappointment when their symptoms take some time to disappear,” Dr. Kosmidis said.
A small group of 24 patients with lung cancer who had been treated with immunotherapy got many correct answers, but they overestimated the intensity of side effects, compared with other therapies.
“Well-informed patients who know what to expect can do 90% of the job of preventing side effects from becoming severe by having them treated early,” said Dr. Donia, of the University of Copenhagen.
Most cancer patients were also unaware of the cost of immunotherapy, which can exceed $100,000 a year, Dr. Kosmidis said.
Results of the doctor survey
The other survey presented at the meeting looked at how much doctors know about survival for 12 of the most common cancers.
Dr. Murphy and colleagues asked 301 noncancer doctors and 46 cancer specialists to estimate the percentage of patients who could be expected to live for 5 years after diagnosis (a measure known as the 5-year survival rate).
Answers from the two groups were compared and graded according to cancer survival statistics from the National Cancer Registry of Ireland.
Both groups of doctors had a hard time estimating the survival of common cancers.
Nononcologists accurately predicted 5-year survival for just two of the cancer types, while the cancer specialists got it right for four cancer types.
However, the noncancer doctors had a more pessimistic outlook on cancer survival generally and severely underestimated the chances of survival in specific cancers, particularly stage IV breast cancer. The survival for this cancer has “evolved considerably over time and now reaches 40% in Ireland,” Dr. Murphy pointed out.
“These results are in line with what we had expected because most physicians’ knowledge of oncology dates back to whatever education they received during their years of training, so their perceptions of cancer prognosis are likely to lag behind the major survival gains achieved in the recent past,” Dr. Murphy said.
A version of this article first appeared on Medscape.com.
This is the main finding from two studies presented at the 2021 European Society for Medical Oncology Congress.
The survey of patients found that most don’t understand how immunotherapy works, and the survey of doctors found that many working outside of the cancer field are using information on survival that is wildly out of date.
When a patient is first told they have cancer, counseling is usually done by a surgeon or general medical doctor and not an oncologist, said Conleth Murphy, MD, of Bon Secours Hospital Cork, Ireland, and coauthor of the second study.
Noncancer doctors often grossly underestimate patients’ chances of survival, Dr. Murphy’s study found. This suggests that doctors who practice outside of cancer care may be working with the same information they learned in medical school, he said.
“These patients must be spared the traumatic effects of being handed a death sentence that no longer reflects the current reality,” Dr. Murphy said.
After receiving a diagnosis of cancer, “patients often immediately have pressing questions about what it means for their future,” he noted. A common question is: “How long do I have left?”
Nononcologists should refrain from answering patients’ questions with numbers, Dr. Murphy said.
Family doctors are likely to be influenced by the experience they have had with specific cancer patients in their practice, said Cyril Bonin, MD, a general practitioner in Usson-du-Poitou, France, who has 900 patients in his practice.
He sees about 10 patients with a new diagnosis of cancer each year. In addition, about 50 of his patients are in active treatment for cancer or have finished treatment and are considered cancer survivors.
“It is not entirely realistic for us to expect practitioners who deal with hundreds of different diseases to keep up with every facet of a rapidly changing oncology landscape,” said Marco Donia, MD, an expert in immunotherapy from the University of Copenhagen.
That landscape has changed dramatically in recent years, particularly since immunotherapy was added to the arsenal. Immunotherapy is a way to fine-tune your immune system to fight cancer.
For example, in the past, patients with metastatic melanoma would have an average survival of about 1 year. But now, some patients who have responded to immunotherapy are still alive 10 years later.
Findings from the patient survey
It is important that patients stay well informed because immunotherapy is a “complex treatment that is too often mistaken for a miracle cure,” said Paris Kosmidis, MD, the co-author of the patient survey.
“The more patients know about it, the better the communication with their medical team and thus the better their outcomes are likely to be,” said Dr. Kosmidis, who is co-founder and chief medical officer of CareAcross, an online service that provides personalized education for cancer patients
The survey was of 5,589 patients with cancer who were recruited from CareAcross clients from the United Kingdom, France, Italy, Spain, and Germany.
The survey asked them about how immunotherapy works, what it costs, and its side effects.
Almost half responded “not sure/do not know,” but about a third correctly answered that immunotherapy “activates the immune system to kill cancer cells.”
Similarly, more than half thought that immunotherapy started working right away, while only 20% correctly answered that it takes several weeks to become effective.
“This is important because patients need to start their therapy with realistic expectations, for example to avoid disappointment when their symptoms take some time to disappear,” Dr. Kosmidis said.
A small group of 24 patients with lung cancer who had been treated with immunotherapy got many correct answers, but they overestimated the intensity of side effects, compared with other therapies.
“Well-informed patients who know what to expect can do 90% of the job of preventing side effects from becoming severe by having them treated early,” said Dr. Donia, of the University of Copenhagen.
Most cancer patients were also unaware of the cost of immunotherapy, which can exceed $100,000 a year, Dr. Kosmidis said.
Results of the doctor survey
The other survey presented at the meeting looked at how much doctors know about survival for 12 of the most common cancers.
Dr. Murphy and colleagues asked 301 noncancer doctors and 46 cancer specialists to estimate the percentage of patients who could be expected to live for 5 years after diagnosis (a measure known as the 5-year survival rate).
Answers from the two groups were compared and graded according to cancer survival statistics from the National Cancer Registry of Ireland.
Both groups of doctors had a hard time estimating the survival of common cancers.
Nononcologists accurately predicted 5-year survival for just two of the cancer types, while the cancer specialists got it right for four cancer types.
However, the noncancer doctors had a more pessimistic outlook on cancer survival generally and severely underestimated the chances of survival in specific cancers, particularly stage IV breast cancer. The survival for this cancer has “evolved considerably over time and now reaches 40% in Ireland,” Dr. Murphy pointed out.
“These results are in line with what we had expected because most physicians’ knowledge of oncology dates back to whatever education they received during their years of training, so their perceptions of cancer prognosis are likely to lag behind the major survival gains achieved in the recent past,” Dr. Murphy said.
A version of this article first appeared on Medscape.com.
This is the main finding from two studies presented at the 2021 European Society for Medical Oncology Congress.
The survey of patients found that most don’t understand how immunotherapy works, and the survey of doctors found that many working outside of the cancer field are using information on survival that is wildly out of date.
When a patient is first told they have cancer, counseling is usually done by a surgeon or general medical doctor and not an oncologist, said Conleth Murphy, MD, of Bon Secours Hospital Cork, Ireland, and coauthor of the second study.
Noncancer doctors often grossly underestimate patients’ chances of survival, Dr. Murphy’s study found. This suggests that doctors who practice outside of cancer care may be working with the same information they learned in medical school, he said.
“These patients must be spared the traumatic effects of being handed a death sentence that no longer reflects the current reality,” Dr. Murphy said.
After receiving a diagnosis of cancer, “patients often immediately have pressing questions about what it means for their future,” he noted. A common question is: “How long do I have left?”
Nononcologists should refrain from answering patients’ questions with numbers, Dr. Murphy said.
Family doctors are likely to be influenced by the experience they have had with specific cancer patients in their practice, said Cyril Bonin, MD, a general practitioner in Usson-du-Poitou, France, who has 900 patients in his practice.
He sees about 10 patients with a new diagnosis of cancer each year. In addition, about 50 of his patients are in active treatment for cancer or have finished treatment and are considered cancer survivors.
“It is not entirely realistic for us to expect practitioners who deal with hundreds of different diseases to keep up with every facet of a rapidly changing oncology landscape,” said Marco Donia, MD, an expert in immunotherapy from the University of Copenhagen.
That landscape has changed dramatically in recent years, particularly since immunotherapy was added to the arsenal. Immunotherapy is a way to fine-tune your immune system to fight cancer.
For example, in the past, patients with metastatic melanoma would have an average survival of about 1 year. But now, some patients who have responded to immunotherapy are still alive 10 years later.
Findings from the patient survey
It is important that patients stay well informed because immunotherapy is a “complex treatment that is too often mistaken for a miracle cure,” said Paris Kosmidis, MD, the co-author of the patient survey.
“The more patients know about it, the better the communication with their medical team and thus the better their outcomes are likely to be,” said Dr. Kosmidis, who is co-founder and chief medical officer of CareAcross, an online service that provides personalized education for cancer patients
The survey was of 5,589 patients with cancer who were recruited from CareAcross clients from the United Kingdom, France, Italy, Spain, and Germany.
The survey asked them about how immunotherapy works, what it costs, and its side effects.
Almost half responded “not sure/do not know,” but about a third correctly answered that immunotherapy “activates the immune system to kill cancer cells.”
Similarly, more than half thought that immunotherapy started working right away, while only 20% correctly answered that it takes several weeks to become effective.
“This is important because patients need to start their therapy with realistic expectations, for example to avoid disappointment when their symptoms take some time to disappear,” Dr. Kosmidis said.
A small group of 24 patients with lung cancer who had been treated with immunotherapy got many correct answers, but they overestimated the intensity of side effects, compared with other therapies.
“Well-informed patients who know what to expect can do 90% of the job of preventing side effects from becoming severe by having them treated early,” said Dr. Donia, of the University of Copenhagen.
Most cancer patients were also unaware of the cost of immunotherapy, which can exceed $100,000 a year, Dr. Kosmidis said.
Results of the doctor survey
The other survey presented at the meeting looked at how much doctors know about survival for 12 of the most common cancers.
Dr. Murphy and colleagues asked 301 noncancer doctors and 46 cancer specialists to estimate the percentage of patients who could be expected to live for 5 years after diagnosis (a measure known as the 5-year survival rate).
Answers from the two groups were compared and graded according to cancer survival statistics from the National Cancer Registry of Ireland.
Both groups of doctors had a hard time estimating the survival of common cancers.
Nononcologists accurately predicted 5-year survival for just two of the cancer types, while the cancer specialists got it right for four cancer types.
However, the noncancer doctors had a more pessimistic outlook on cancer survival generally and severely underestimated the chances of survival in specific cancers, particularly stage IV breast cancer. The survival for this cancer has “evolved considerably over time and now reaches 40% in Ireland,” Dr. Murphy pointed out.
“These results are in line with what we had expected because most physicians’ knowledge of oncology dates back to whatever education they received during their years of training, so their perceptions of cancer prognosis are likely to lag behind the major survival gains achieved in the recent past,” Dr. Murphy said.
A version of this article first appeared on Medscape.com.
Novel trastuzumab duocarmazine significantly improved survival in advanced HER2-positive breast cancer
Based on significant progression-free survival (PFS) benefits shown in the phase 3 TULIP trial, trastuzumab duocarmazine (SYD985) may provide a new treatment option among HER2-positive metastatic breast cancer patients, according to Cristina Saura, MD, head of the breast cancer program at Vall d’Hebron University Hospital, Barcelona. Dr. Saura presented the results of the TULIP trial (abstract LBA15) on Sept. 19 at the 2021 European Society for Medical Oncology Congress.
Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate that consists of trastuzumab and a drug containing duocarmycin. Its three-way mechanism of action includes uptake of the antibody-drug conjugate by internalization and intracellular release of duocarmycin with two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.
While one physician described the results as encouraging, another said the treatment is not nearly ready for primetime.
“It is encouraging to observe clinically meaningful and potentially practice changing progression-free survival improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, Massachusetts General Hospital, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years including T-DXd, neratinib, tucatinib, and margetuximab. Trastuzumab duocarmazine could eventually be another option.”
Fatima Cardoso, MD, director of the breast cancer unit at the Breast Cancer Research Foundation, New York, said: “At this time there is only a minor 2-month difference in progression-free survival and a nonsignificant overall difference. With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
Two or more prior therapies for metastatic breast cancer
TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to trastuzumab duocarmazine (1.2 mg/kg every 21 days, 291 patients) or physician’s choice (146 patients) of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.
Longer PFS with trastuzumab duocarmazine
Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed PFS was significantly longer in the trastuzumab duocarmazine group at 7.0 months versus 4.9 months for physicians choice treatment (hazard ratio, 0.64; 95% confidence interval, 0.49-0.84; P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for trastuzumab duocarmazine over physician’s choice across all categories (except for Eastern Cooperative Oncology Group status 2). Analysis of PFS by investigators showed a similar benefit for trastuzumab duocarmazine (6.9 months vs. 4.6 months; HR, 0.60; P < .001).
A first look at median overall survival showed a nonsignificant advantage for trastuzumab duocarmazine (20.4 months vs. 16.3 months (HR, 0.83; 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for trastuzumab duocarmazine and 29.5% for physician’s choice with reductions in target lesion measurement at 70.2% and 32.2% for trastuzumab duocarmazine and physician’s choice, respectively. The clinical benefit rates were 38.5% for trastuzumab duocarmazine and 32.2% for physician’s choice.
Ocular toxicity
Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for trastuzumab duocarmazine were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%) and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with trastuzumab duocarmazine, including two grade 5 events.
Eye toxicity led to discontinuations in 20.8% of trastuzumab duocarmazine patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of trastuzumab duocarmazine patients. Six fatalities (2.1%) were reported in the trastuzumab duocarmazine group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.
Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.
TULIP was funded by Byondis. Dr. Saura disclosed numerous financial interests including support from AstraZeneca and Daiichi Sankyo.
Based on significant progression-free survival (PFS) benefits shown in the phase 3 TULIP trial, trastuzumab duocarmazine (SYD985) may provide a new treatment option among HER2-positive metastatic breast cancer patients, according to Cristina Saura, MD, head of the breast cancer program at Vall d’Hebron University Hospital, Barcelona. Dr. Saura presented the results of the TULIP trial (abstract LBA15) on Sept. 19 at the 2021 European Society for Medical Oncology Congress.
Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate that consists of trastuzumab and a drug containing duocarmycin. Its three-way mechanism of action includes uptake of the antibody-drug conjugate by internalization and intracellular release of duocarmycin with two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.
While one physician described the results as encouraging, another said the treatment is not nearly ready for primetime.
“It is encouraging to observe clinically meaningful and potentially practice changing progression-free survival improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, Massachusetts General Hospital, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years including T-DXd, neratinib, tucatinib, and margetuximab. Trastuzumab duocarmazine could eventually be another option.”
Fatima Cardoso, MD, director of the breast cancer unit at the Breast Cancer Research Foundation, New York, said: “At this time there is only a minor 2-month difference in progression-free survival and a nonsignificant overall difference. With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
Two or more prior therapies for metastatic breast cancer
TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to trastuzumab duocarmazine (1.2 mg/kg every 21 days, 291 patients) or physician’s choice (146 patients) of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.
Longer PFS with trastuzumab duocarmazine
Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed PFS was significantly longer in the trastuzumab duocarmazine group at 7.0 months versus 4.9 months for physicians choice treatment (hazard ratio, 0.64; 95% confidence interval, 0.49-0.84; P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for trastuzumab duocarmazine over physician’s choice across all categories (except for Eastern Cooperative Oncology Group status 2). Analysis of PFS by investigators showed a similar benefit for trastuzumab duocarmazine (6.9 months vs. 4.6 months; HR, 0.60; P < .001).
A first look at median overall survival showed a nonsignificant advantage for trastuzumab duocarmazine (20.4 months vs. 16.3 months (HR, 0.83; 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for trastuzumab duocarmazine and 29.5% for physician’s choice with reductions in target lesion measurement at 70.2% and 32.2% for trastuzumab duocarmazine and physician’s choice, respectively. The clinical benefit rates were 38.5% for trastuzumab duocarmazine and 32.2% for physician’s choice.
Ocular toxicity
Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for trastuzumab duocarmazine were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%) and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with trastuzumab duocarmazine, including two grade 5 events.
Eye toxicity led to discontinuations in 20.8% of trastuzumab duocarmazine patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of trastuzumab duocarmazine patients. Six fatalities (2.1%) were reported in the trastuzumab duocarmazine group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.
Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.
TULIP was funded by Byondis. Dr. Saura disclosed numerous financial interests including support from AstraZeneca and Daiichi Sankyo.
Based on significant progression-free survival (PFS) benefits shown in the phase 3 TULIP trial, trastuzumab duocarmazine (SYD985) may provide a new treatment option among HER2-positive metastatic breast cancer patients, according to Cristina Saura, MD, head of the breast cancer program at Vall d’Hebron University Hospital, Barcelona. Dr. Saura presented the results of the TULIP trial (abstract LBA15) on Sept. 19 at the 2021 European Society for Medical Oncology Congress.
Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate that consists of trastuzumab and a drug containing duocarmycin. Its three-way mechanism of action includes uptake of the antibody-drug conjugate by internalization and intracellular release of duocarmycin with two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.
While one physician described the results as encouraging, another said the treatment is not nearly ready for primetime.
“It is encouraging to observe clinically meaningful and potentially practice changing progression-free survival improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, Massachusetts General Hospital, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years including T-DXd, neratinib, tucatinib, and margetuximab. Trastuzumab duocarmazine could eventually be another option.”
Fatima Cardoso, MD, director of the breast cancer unit at the Breast Cancer Research Foundation, New York, said: “At this time there is only a minor 2-month difference in progression-free survival and a nonsignificant overall difference. With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
Two or more prior therapies for metastatic breast cancer
TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to trastuzumab duocarmazine (1.2 mg/kg every 21 days, 291 patients) or physician’s choice (146 patients) of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.
Longer PFS with trastuzumab duocarmazine
Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed PFS was significantly longer in the trastuzumab duocarmazine group at 7.0 months versus 4.9 months for physicians choice treatment (hazard ratio, 0.64; 95% confidence interval, 0.49-0.84; P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for trastuzumab duocarmazine over physician’s choice across all categories (except for Eastern Cooperative Oncology Group status 2). Analysis of PFS by investigators showed a similar benefit for trastuzumab duocarmazine (6.9 months vs. 4.6 months; HR, 0.60; P < .001).
A first look at median overall survival showed a nonsignificant advantage for trastuzumab duocarmazine (20.4 months vs. 16.3 months (HR, 0.83; 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for trastuzumab duocarmazine and 29.5% for physician’s choice with reductions in target lesion measurement at 70.2% and 32.2% for trastuzumab duocarmazine and physician’s choice, respectively. The clinical benefit rates were 38.5% for trastuzumab duocarmazine and 32.2% for physician’s choice.
Ocular toxicity
Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for trastuzumab duocarmazine were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%) and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with trastuzumab duocarmazine, including two grade 5 events.
Eye toxicity led to discontinuations in 20.8% of trastuzumab duocarmazine patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of trastuzumab duocarmazine patients. Six fatalities (2.1%) were reported in the trastuzumab duocarmazine group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.
Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.
TULIP was funded by Byondis. Dr. Saura disclosed numerous financial interests including support from AstraZeneca and Daiichi Sankyo.
FROM ESMO 2021
Treatment shows 'important improvements' in triple-negative breast cancer
But as a subanalysis of data from the randomized, phase 3 study showed, sacituzumab govitecan was associated with significantly better progression-free survival (PFS) and overall survival among patients without an initial TNBC diagnosis, with efficacy similar to that seen in the overall study population and in patients without known brain metastases, reported Joyce O’Shaughnessy, MD, at the 2021 European Society for Medical Oncology Congress. In her presentation (abstract 258P), Dr. O’Shaughnessy, who is an oncologist with the Texas Oncology–Baylor Charles A. Sammons Cancer Center in Dallas, said that it’s not uncommon to see acquired triple-negative breast cancer in patients who have hormone receptor–positive disease initially and then later on, develop triple-negative breast cancer.
“That is why at the time of metastatic diagnosis we always say that patients should have repeat receptor [testing], because it’s been well described that a subset of hormone receptor–positive breast can become triple negative under pressure from endocrine therapy,” said ASCENT coinvestigator Aditya Bardia, MD, MPH, Massachusetts General Hospital, Boston, in an interview
Coinvestigator Kevine Punie, MD, from University Hospitals Leuven (Belgium), said that “triple-negative breast cancer is a diagnosis of exclusion. This is a heterogenous disease where several biological subsets are merged.”
“It was important to perform this subgroup analysis to reassure us that the treatment effect we see from [sacituzumab govitecan] in the overall population is also observed in this specific subgroup of patients where biologically we’re treating a different disease,” he said in an interview.
Antibody-drug conjugate
Sacituzumab govitecan consists of an antibody targeted to the trophoblast antigen 2 cell surface receptor found on most breast cancer cells, plus the topoisomerase-1 inhibitor SN-38 as its toxic payload.
In the primary intent-to-treat (ITT) analysis of ASCENT, sacituzumab significantly prolonged PFS with a median of 4.8 versus 1.7 months for patients treated with the physician’s choice of either capecitabine, eribulin, vinorelbine, or gemcitabine. The difference translated into an HR for progression with the antibody-drug conjugate of 0.41 (P < .00001).
The subgroup analysis looked at outcomes for 70 patients randomized to sacituzumab govitecan and 78 randomized to single-agent chemotherapy who did not have an initial diagnosis of TNBC.
In all, 27% of patients in this subgroup in the sacituzumab arm and 29% in the chemotherapy arm had received a prior line of treatment with a CDK4/6 inhibitor.
At the time of data cutoff in March 2020, four patients (6%) in the sacituzumab arm remained on treatment versus no patient in the chemotherapy arm. The most common reason for treatment discontinuation was disease progression, which occurred in 84% and 72% of patients, respectively.
The median treatment duration was 5.1 months in the sacituzumab and 1.2 months in the chemotherapy arm. The median duration of follow-up was 10.6 and 6.1 months, respectively.
Progression-free survival, overall survival results
For all patients without an initial TNBC diagnosis, the median PFS was 4.6 months with sacituzumab versus 2.3 months with chemotherapy, which translated into a hazard ratio for progression of 0.48 (95% confidence interval, 0.32-0.72). The progression-free benefit with the antibody-drug conjugate was similar to that seen in the intent-to-treat population, as noted before, and among the overall population of patients in the study with no known brain metastases (HR, 5.6 vs. 1.7, respectively; P < .001).
The objective response rates were 21% in the sacituzumab and 5% in the chemotherapy arm. Objective responses were not affected by the prior use of CDK 4/6 inhibitors.
Median overall survival in this subgroup was 12.4 months with the antibody-drug conjugate versus 6.7 months with chemotherapy (95% CI, 0.30-0.64).
The investigators reported that the safety profile was manageable in this subgroup of patients, with a low rate of treatment discontinuations because of adverse events (5%) and no treatment-related deaths with sacituzumab govitecan.
Health-related quality of life
In a separate poster (abstract 257P) presented at the meeting, the ASCENT investigators reported health-related quality of life results in the overall population.
The mean European Organization for the Research and Treatment of Cancer quality of life questionnaire subscale scores at baseline were similar between treatment arms.
For the major domains of global health status, physical and emotional functioning as well as lower symptomatic impact of fatigue, pain, dyspnea, and insomnia, sacituzumab govitecan showed “significantly and meaningfully greater improvement” than the physician’s choice of chemotherapy, the investigators found.
Of individual symptoms, only diarrhea was worse with the antibody-drug conjugate.
“These were important improvements,” Dr. Punie said, “because we saw improvements in the primary health-related quality of life domains such as global health status. We also saw that the time to clinically meaningful deterioration of quality of life domains were significantly longer for patients treated with [sacituzumab govitecan].”
“Patients who received sacituzumab govitecan had better health-related quality of life as compared to the control arm, and that’s a very important result, because in the metastatic setting our goal is twofold: We want to prolong survival, and we want patients to have improved quality of life,” Dr. Bardia said.
The Ascent trial is sponsored by Gilead Sciences. Dr. Punie disclosed relationships with multiple companies/organizations, not including Gilead. Dr. Bardia disclosed contracted research for Gilead and others, as well as other relationships.
But as a subanalysis of data from the randomized, phase 3 study showed, sacituzumab govitecan was associated with significantly better progression-free survival (PFS) and overall survival among patients without an initial TNBC diagnosis, with efficacy similar to that seen in the overall study population and in patients without known brain metastases, reported Joyce O’Shaughnessy, MD, at the 2021 European Society for Medical Oncology Congress. In her presentation (abstract 258P), Dr. O’Shaughnessy, who is an oncologist with the Texas Oncology–Baylor Charles A. Sammons Cancer Center in Dallas, said that it’s not uncommon to see acquired triple-negative breast cancer in patients who have hormone receptor–positive disease initially and then later on, develop triple-negative breast cancer.
“That is why at the time of metastatic diagnosis we always say that patients should have repeat receptor [testing], because it’s been well described that a subset of hormone receptor–positive breast can become triple negative under pressure from endocrine therapy,” said ASCENT coinvestigator Aditya Bardia, MD, MPH, Massachusetts General Hospital, Boston, in an interview
Coinvestigator Kevine Punie, MD, from University Hospitals Leuven (Belgium), said that “triple-negative breast cancer is a diagnosis of exclusion. This is a heterogenous disease where several biological subsets are merged.”
“It was important to perform this subgroup analysis to reassure us that the treatment effect we see from [sacituzumab govitecan] in the overall population is also observed in this specific subgroup of patients where biologically we’re treating a different disease,” he said in an interview.
Antibody-drug conjugate
Sacituzumab govitecan consists of an antibody targeted to the trophoblast antigen 2 cell surface receptor found on most breast cancer cells, plus the topoisomerase-1 inhibitor SN-38 as its toxic payload.
In the primary intent-to-treat (ITT) analysis of ASCENT, sacituzumab significantly prolonged PFS with a median of 4.8 versus 1.7 months for patients treated with the physician’s choice of either capecitabine, eribulin, vinorelbine, or gemcitabine. The difference translated into an HR for progression with the antibody-drug conjugate of 0.41 (P < .00001).
The subgroup analysis looked at outcomes for 70 patients randomized to sacituzumab govitecan and 78 randomized to single-agent chemotherapy who did not have an initial diagnosis of TNBC.
In all, 27% of patients in this subgroup in the sacituzumab arm and 29% in the chemotherapy arm had received a prior line of treatment with a CDK4/6 inhibitor.
At the time of data cutoff in March 2020, four patients (6%) in the sacituzumab arm remained on treatment versus no patient in the chemotherapy arm. The most common reason for treatment discontinuation was disease progression, which occurred in 84% and 72% of patients, respectively.
The median treatment duration was 5.1 months in the sacituzumab and 1.2 months in the chemotherapy arm. The median duration of follow-up was 10.6 and 6.1 months, respectively.
Progression-free survival, overall survival results
For all patients without an initial TNBC diagnosis, the median PFS was 4.6 months with sacituzumab versus 2.3 months with chemotherapy, which translated into a hazard ratio for progression of 0.48 (95% confidence interval, 0.32-0.72). The progression-free benefit with the antibody-drug conjugate was similar to that seen in the intent-to-treat population, as noted before, and among the overall population of patients in the study with no known brain metastases (HR, 5.6 vs. 1.7, respectively; P < .001).
The objective response rates were 21% in the sacituzumab and 5% in the chemotherapy arm. Objective responses were not affected by the prior use of CDK 4/6 inhibitors.
Median overall survival in this subgroup was 12.4 months with the antibody-drug conjugate versus 6.7 months with chemotherapy (95% CI, 0.30-0.64).
The investigators reported that the safety profile was manageable in this subgroup of patients, with a low rate of treatment discontinuations because of adverse events (5%) and no treatment-related deaths with sacituzumab govitecan.
Health-related quality of life
In a separate poster (abstract 257P) presented at the meeting, the ASCENT investigators reported health-related quality of life results in the overall population.
The mean European Organization for the Research and Treatment of Cancer quality of life questionnaire subscale scores at baseline were similar between treatment arms.
For the major domains of global health status, physical and emotional functioning as well as lower symptomatic impact of fatigue, pain, dyspnea, and insomnia, sacituzumab govitecan showed “significantly and meaningfully greater improvement” than the physician’s choice of chemotherapy, the investigators found.
Of individual symptoms, only diarrhea was worse with the antibody-drug conjugate.
“These were important improvements,” Dr. Punie said, “because we saw improvements in the primary health-related quality of life domains such as global health status. We also saw that the time to clinically meaningful deterioration of quality of life domains were significantly longer for patients treated with [sacituzumab govitecan].”
“Patients who received sacituzumab govitecan had better health-related quality of life as compared to the control arm, and that’s a very important result, because in the metastatic setting our goal is twofold: We want to prolong survival, and we want patients to have improved quality of life,” Dr. Bardia said.
The Ascent trial is sponsored by Gilead Sciences. Dr. Punie disclosed relationships with multiple companies/organizations, not including Gilead. Dr. Bardia disclosed contracted research for Gilead and others, as well as other relationships.
But as a subanalysis of data from the randomized, phase 3 study showed, sacituzumab govitecan was associated with significantly better progression-free survival (PFS) and overall survival among patients without an initial TNBC diagnosis, with efficacy similar to that seen in the overall study population and in patients without known brain metastases, reported Joyce O’Shaughnessy, MD, at the 2021 European Society for Medical Oncology Congress. In her presentation (abstract 258P), Dr. O’Shaughnessy, who is an oncologist with the Texas Oncology–Baylor Charles A. Sammons Cancer Center in Dallas, said that it’s not uncommon to see acquired triple-negative breast cancer in patients who have hormone receptor–positive disease initially and then later on, develop triple-negative breast cancer.
“That is why at the time of metastatic diagnosis we always say that patients should have repeat receptor [testing], because it’s been well described that a subset of hormone receptor–positive breast can become triple negative under pressure from endocrine therapy,” said ASCENT coinvestigator Aditya Bardia, MD, MPH, Massachusetts General Hospital, Boston, in an interview
Coinvestigator Kevine Punie, MD, from University Hospitals Leuven (Belgium), said that “triple-negative breast cancer is a diagnosis of exclusion. This is a heterogenous disease where several biological subsets are merged.”
“It was important to perform this subgroup analysis to reassure us that the treatment effect we see from [sacituzumab govitecan] in the overall population is also observed in this specific subgroup of patients where biologically we’re treating a different disease,” he said in an interview.
Antibody-drug conjugate
Sacituzumab govitecan consists of an antibody targeted to the trophoblast antigen 2 cell surface receptor found on most breast cancer cells, plus the topoisomerase-1 inhibitor SN-38 as its toxic payload.
In the primary intent-to-treat (ITT) analysis of ASCENT, sacituzumab significantly prolonged PFS with a median of 4.8 versus 1.7 months for patients treated with the physician’s choice of either capecitabine, eribulin, vinorelbine, or gemcitabine. The difference translated into an HR for progression with the antibody-drug conjugate of 0.41 (P < .00001).
The subgroup analysis looked at outcomes for 70 patients randomized to sacituzumab govitecan and 78 randomized to single-agent chemotherapy who did not have an initial diagnosis of TNBC.
In all, 27% of patients in this subgroup in the sacituzumab arm and 29% in the chemotherapy arm had received a prior line of treatment with a CDK4/6 inhibitor.
At the time of data cutoff in March 2020, four patients (6%) in the sacituzumab arm remained on treatment versus no patient in the chemotherapy arm. The most common reason for treatment discontinuation was disease progression, which occurred in 84% and 72% of patients, respectively.
The median treatment duration was 5.1 months in the sacituzumab and 1.2 months in the chemotherapy arm. The median duration of follow-up was 10.6 and 6.1 months, respectively.
Progression-free survival, overall survival results
For all patients without an initial TNBC diagnosis, the median PFS was 4.6 months with sacituzumab versus 2.3 months with chemotherapy, which translated into a hazard ratio for progression of 0.48 (95% confidence interval, 0.32-0.72). The progression-free benefit with the antibody-drug conjugate was similar to that seen in the intent-to-treat population, as noted before, and among the overall population of patients in the study with no known brain metastases (HR, 5.6 vs. 1.7, respectively; P < .001).
The objective response rates were 21% in the sacituzumab and 5% in the chemotherapy arm. Objective responses were not affected by the prior use of CDK 4/6 inhibitors.
Median overall survival in this subgroup was 12.4 months with the antibody-drug conjugate versus 6.7 months with chemotherapy (95% CI, 0.30-0.64).
The investigators reported that the safety profile was manageable in this subgroup of patients, with a low rate of treatment discontinuations because of adverse events (5%) and no treatment-related deaths with sacituzumab govitecan.
Health-related quality of life
In a separate poster (abstract 257P) presented at the meeting, the ASCENT investigators reported health-related quality of life results in the overall population.
The mean European Organization for the Research and Treatment of Cancer quality of life questionnaire subscale scores at baseline were similar between treatment arms.
For the major domains of global health status, physical and emotional functioning as well as lower symptomatic impact of fatigue, pain, dyspnea, and insomnia, sacituzumab govitecan showed “significantly and meaningfully greater improvement” than the physician’s choice of chemotherapy, the investigators found.
Of individual symptoms, only diarrhea was worse with the antibody-drug conjugate.
“These were important improvements,” Dr. Punie said, “because we saw improvements in the primary health-related quality of life domains such as global health status. We also saw that the time to clinically meaningful deterioration of quality of life domains were significantly longer for patients treated with [sacituzumab govitecan].”
“Patients who received sacituzumab govitecan had better health-related quality of life as compared to the control arm, and that’s a very important result, because in the metastatic setting our goal is twofold: We want to prolong survival, and we want patients to have improved quality of life,” Dr. Bardia said.
The Ascent trial is sponsored by Gilead Sciences. Dr. Punie disclosed relationships with multiple companies/organizations, not including Gilead. Dr. Bardia disclosed contracted research for Gilead and others, as well as other relationships.
FROM ESMO 2021
Better survival with extended letrozole in early-stage breast cancer
The approach “should be considered among the optimal standard endocrine treatments for postmenopausal patients with hormone receptor–positive breast cancer, regardless of the nodal status at diagnosis,” concluded investigators led by Lucia Del Mastro, MD, a medical oncologist at the University of Genoa, Italy.
Clinical practice guidelines recommend an individualized approach to decide the duration of treatment based on relapse risk and tolerability because no study until now has shown an overall survival benefit with extended aromatase inhibitor therapy. Based on “our results ... this statement is no longer supported by the evidence and should be updated,” they wrote.
The optimal duration or type of endocrine therapy has been uncertain; the team sought to bring more clarity to the issue.
Following 2-3 years of adjuvant tamoxifen, they randomized evenly 2,056 women at 69 hospitals in Italy to either 2-3 years or letrozole 2.5 mg once daily – the usual care control group – or 5 years. Women in the trial, dubbed GIM4, had stage I-III histologically proven and operable invasive cancer, with no signs of disease recurrence.
Twelve-year overall survival was 88% with extended letrozole, but 84% in the control arm (HR 0.77, 95% confidence interval, 0.60-0.98; P = 0.036).
Twelve-year disease-free survival was 67% in the extended group versus 62% in the control arm (HR 0.78, 95% CI, 0.65-0.93; P = 0.0064).
At a median follow-up of 11.7 years, disease-free survival (DFS) events occurred in 25.4% of control patients, but only 20.7% with extended aromatase inhibitor treatment.
It took 9.5 years for the survival curves to separate, suggesting “that the effect of letrozole takes several years to be seen,” the investigators said.
With the disease-free survival benefits shown in earlier trials and now better overall survival as well, it’s looking like “7-8 years of adjuvant therapy, including at least 5 years with an aromatase inhibitor, could be the optimal duration of adjuvant endocrine therapy in postmenopausal patients with breast cancer.” It probably represents “the best compromise between efficacy and side-effects,” they said.
Breast cancer oncologists Rachel L. Yung, MD, and Nancy E. Davidson, MD, both of the Fred Hutchinson Cancer Research Center, Seattle, agreed in an editorial.
For now, “the currently available data seem to recommend 5 years of aromatase inhibitor for postmenopausal women who have already completed 2-3 years of tamoxifen,” they said.
However, with 19.5% of control patients and 37.1% in the extended stopping treatment early, “GIM4 highlights that early therapy discontinuation remains a crucial issue ... better ways to promote adherence are sorely needed. Another area of focus is the identification of biomarkers that could [better] inform the optimal duration of therapy,” they said.
Longer duration of letrozole was associated with an increased incidence of arthralgia, myalgia, hypertension, and osteoporosis; however, there was no difference in the incidence of bone fractures.
There was also a slightly higher number of cardiovascular events (1% in the extended group, but fewer in the control arm) which is a known issue with aromatase inhibitors. There were three serious treatment-related adverse events in the control arm and eight in the extended group, but no deaths. The Italian investigators noted that because they enrolled only patients free of recurrence after 2-3 years of tamoxifen, the population with early relapse who were likely to be node-positive, was excluded, leaving only patients with a better prognosis. “On the other hand, patients with node-negative disease relapse later and are therefore captured by this trial with a long follow-up.”
The work was funded by Novartis and the Italian Ministry of Health. The investigators had numerous industry ties, including Dr. Del Mastro, who reported honoraria and nonfinancial support from Novartis, Roche, Pfizer, and others. The editorialists didn’t have any competing interests.
The approach “should be considered among the optimal standard endocrine treatments for postmenopausal patients with hormone receptor–positive breast cancer, regardless of the nodal status at diagnosis,” concluded investigators led by Lucia Del Mastro, MD, a medical oncologist at the University of Genoa, Italy.
Clinical practice guidelines recommend an individualized approach to decide the duration of treatment based on relapse risk and tolerability because no study until now has shown an overall survival benefit with extended aromatase inhibitor therapy. Based on “our results ... this statement is no longer supported by the evidence and should be updated,” they wrote.
The optimal duration or type of endocrine therapy has been uncertain; the team sought to bring more clarity to the issue.
Following 2-3 years of adjuvant tamoxifen, they randomized evenly 2,056 women at 69 hospitals in Italy to either 2-3 years or letrozole 2.5 mg once daily – the usual care control group – or 5 years. Women in the trial, dubbed GIM4, had stage I-III histologically proven and operable invasive cancer, with no signs of disease recurrence.
Twelve-year overall survival was 88% with extended letrozole, but 84% in the control arm (HR 0.77, 95% confidence interval, 0.60-0.98; P = 0.036).
Twelve-year disease-free survival was 67% in the extended group versus 62% in the control arm (HR 0.78, 95% CI, 0.65-0.93; P = 0.0064).
At a median follow-up of 11.7 years, disease-free survival (DFS) events occurred in 25.4% of control patients, but only 20.7% with extended aromatase inhibitor treatment.
It took 9.5 years for the survival curves to separate, suggesting “that the effect of letrozole takes several years to be seen,” the investigators said.
With the disease-free survival benefits shown in earlier trials and now better overall survival as well, it’s looking like “7-8 years of adjuvant therapy, including at least 5 years with an aromatase inhibitor, could be the optimal duration of adjuvant endocrine therapy in postmenopausal patients with breast cancer.” It probably represents “the best compromise between efficacy and side-effects,” they said.
Breast cancer oncologists Rachel L. Yung, MD, and Nancy E. Davidson, MD, both of the Fred Hutchinson Cancer Research Center, Seattle, agreed in an editorial.
For now, “the currently available data seem to recommend 5 years of aromatase inhibitor for postmenopausal women who have already completed 2-3 years of tamoxifen,” they said.
However, with 19.5% of control patients and 37.1% in the extended stopping treatment early, “GIM4 highlights that early therapy discontinuation remains a crucial issue ... better ways to promote adherence are sorely needed. Another area of focus is the identification of biomarkers that could [better] inform the optimal duration of therapy,” they said.
Longer duration of letrozole was associated with an increased incidence of arthralgia, myalgia, hypertension, and osteoporosis; however, there was no difference in the incidence of bone fractures.
There was also a slightly higher number of cardiovascular events (1% in the extended group, but fewer in the control arm) which is a known issue with aromatase inhibitors. There were three serious treatment-related adverse events in the control arm and eight in the extended group, but no deaths. The Italian investigators noted that because they enrolled only patients free of recurrence after 2-3 years of tamoxifen, the population with early relapse who were likely to be node-positive, was excluded, leaving only patients with a better prognosis. “On the other hand, patients with node-negative disease relapse later and are therefore captured by this trial with a long follow-up.”
The work was funded by Novartis and the Italian Ministry of Health. The investigators had numerous industry ties, including Dr. Del Mastro, who reported honoraria and nonfinancial support from Novartis, Roche, Pfizer, and others. The editorialists didn’t have any competing interests.
The approach “should be considered among the optimal standard endocrine treatments for postmenopausal patients with hormone receptor–positive breast cancer, regardless of the nodal status at diagnosis,” concluded investigators led by Lucia Del Mastro, MD, a medical oncologist at the University of Genoa, Italy.
Clinical practice guidelines recommend an individualized approach to decide the duration of treatment based on relapse risk and tolerability because no study until now has shown an overall survival benefit with extended aromatase inhibitor therapy. Based on “our results ... this statement is no longer supported by the evidence and should be updated,” they wrote.
The optimal duration or type of endocrine therapy has been uncertain; the team sought to bring more clarity to the issue.
Following 2-3 years of adjuvant tamoxifen, they randomized evenly 2,056 women at 69 hospitals in Italy to either 2-3 years or letrozole 2.5 mg once daily – the usual care control group – or 5 years. Women in the trial, dubbed GIM4, had stage I-III histologically proven and operable invasive cancer, with no signs of disease recurrence.
Twelve-year overall survival was 88% with extended letrozole, but 84% in the control arm (HR 0.77, 95% confidence interval, 0.60-0.98; P = 0.036).
Twelve-year disease-free survival was 67% in the extended group versus 62% in the control arm (HR 0.78, 95% CI, 0.65-0.93; P = 0.0064).
At a median follow-up of 11.7 years, disease-free survival (DFS) events occurred in 25.4% of control patients, but only 20.7% with extended aromatase inhibitor treatment.
It took 9.5 years for the survival curves to separate, suggesting “that the effect of letrozole takes several years to be seen,” the investigators said.
With the disease-free survival benefits shown in earlier trials and now better overall survival as well, it’s looking like “7-8 years of adjuvant therapy, including at least 5 years with an aromatase inhibitor, could be the optimal duration of adjuvant endocrine therapy in postmenopausal patients with breast cancer.” It probably represents “the best compromise between efficacy and side-effects,” they said.
Breast cancer oncologists Rachel L. Yung, MD, and Nancy E. Davidson, MD, both of the Fred Hutchinson Cancer Research Center, Seattle, agreed in an editorial.
For now, “the currently available data seem to recommend 5 years of aromatase inhibitor for postmenopausal women who have already completed 2-3 years of tamoxifen,” they said.
However, with 19.5% of control patients and 37.1% in the extended stopping treatment early, “GIM4 highlights that early therapy discontinuation remains a crucial issue ... better ways to promote adherence are sorely needed. Another area of focus is the identification of biomarkers that could [better] inform the optimal duration of therapy,” they said.
Longer duration of letrozole was associated with an increased incidence of arthralgia, myalgia, hypertension, and osteoporosis; however, there was no difference in the incidence of bone fractures.
There was also a slightly higher number of cardiovascular events (1% in the extended group, but fewer in the control arm) which is a known issue with aromatase inhibitors. There were three serious treatment-related adverse events in the control arm and eight in the extended group, but no deaths. The Italian investigators noted that because they enrolled only patients free of recurrence after 2-3 years of tamoxifen, the population with early relapse who were likely to be node-positive, was excluded, leaving only patients with a better prognosis. “On the other hand, patients with node-negative disease relapse later and are therefore captured by this trial with a long follow-up.”
The work was funded by Novartis and the Italian Ministry of Health. The investigators had numerous industry ties, including Dr. Del Mastro, who reported honoraria and nonfinancial support from Novartis, Roche, Pfizer, and others. The editorialists didn’t have any competing interests.
FROM THE LANCET ONCOLOGY
Most community-based oncologists skip biomarker testing
A recent survey shows that fewer than half of community oncologists use biomarker testing to guide patient discussions about treatment, which compares with 73% of academic clinicians.
The findings, reported at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021, highlight the potential for unequal application of the latest advances in cancer genomics and targeted therapies throughout the health care system, which could worsen existing disparities in underserved populations, according to Leigh Boehmer, PharmD, medical director for the Association of Community Cancer Centers, Rockville, Md.
The survey – a mixed-methods approach for assessing practice patterns, attitudes, barriers, and resource needs related to biomarker testing among clinicians – was developed by the ACCC in partnership with the LUNGevity Foundation and administered to clinicians caring for patients with non–small cell lung cancer who are uninsured or covered by Medicaid.
Of 99 respondents, more than 85% were physicians and 68% worked in a community setting. Only 40% indicated they were very familiar or extremely familiar with 2018 Molecular Testing Guidelines for Lung Cancer from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.
Clinicians were most confident about selecting appropriate tests to use, interpreting test results, and prognosticating based on test results, with 77%, 74%, and 74%, respectively, saying they are very confident or extremely confident in those areas. They were less confident about determining when to order testing and in coordinating care across the multidisciplinary team, with 59% and 64%, respectively, saying they were very confident or extremely confident in those areas, Dr. Boehmer reported at the conference.
The shortcomings with respect to communication across teams were echoed in two focus groups convened to further validate the survey results, he noted.
As for the reasons why clinicians ordered biomarker testing, 88% and 82% of community and academic clinicians, respectively, said they did so to help make targeted treatment decisions.
“Only 48% of community clinicians indicated that they use biomarker testing to guide patient discussions, compared to 73% of academic clinicians,” he said. “That finding was considered statistically significant.”
With respect to decision-making about biomarker testing, 41% said they prefer to share the responsibility with patients, whereas 52% said they prefer to make the final decision.
“Shedding further light on this situation, focus group participants expressed that patients lacked comprehension and interest about what testing entails and what testing means for their treatment options,” Dr. Boehmer noted.
In order to make more informed decisions about biomarker testing, respondents said they need more information on financial resources for patient assistance (26%) and education around both published guidelines and practical implications of the clinical data (21%).
When asked about patients’ information needs, 23% said their patients need psychosocial support, 22% said they need financial assistance, and 9% said their patients have no additional resource needs.
However, only 27% said they provide patients with resources related to psychosocial support services, and only 44% share financial assistance information, he said.
Further, the fact that 9% said their patients need no additional resources represents “a disconnect” from the findings of the survey and focus groups, he added.
“We believe that this study identifies key areas of ongoing clinician need related to biomarker testing, including things like increased guideline familiarity, practical applications of guideline-concordant testing, and … how to optimally coordinate multidisciplinary care delivery,” Dr. Boehmer said. “Professional organizations … in partnership with patient advocacy organizations or groups should focus on developing those patient education materials … and tools for improving patient-clinician discussions about biomarker testing.”
The ACCC will be working with the LUNGevity Foundation and the Center for Business Models in Healthcare to develop an intervention to ensure that such discussions are “easily integrated into the care process for every patient,” he noted.
Such efforts are important for ensuring that clinicians are informed about the value of biomarker testing and about guidelines for testing so that patients receive the best possible care, said invited discussant Joshua Sabari, MD, of New York University Langone Health’s Perlmutter Cancer Center.
“I know that, in clinic, when meeting a new patient with non–small cell lung cancer, it’s critical to understand the driver alteration, not only for prognosis, but also for goals-of-care discussion, as well as potential treatment option,” Dr. Sabari said.
Dr. Boehmer reported consulting for Pfizer. Dr. Sabari reported consulting and advisory board membership for multiple pharmaceutical companies.
A recent survey shows that fewer than half of community oncologists use biomarker testing to guide patient discussions about treatment, which compares with 73% of academic clinicians.
The findings, reported at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021, highlight the potential for unequal application of the latest advances in cancer genomics and targeted therapies throughout the health care system, which could worsen existing disparities in underserved populations, according to Leigh Boehmer, PharmD, medical director for the Association of Community Cancer Centers, Rockville, Md.
The survey – a mixed-methods approach for assessing practice patterns, attitudes, barriers, and resource needs related to biomarker testing among clinicians – was developed by the ACCC in partnership with the LUNGevity Foundation and administered to clinicians caring for patients with non–small cell lung cancer who are uninsured or covered by Medicaid.
Of 99 respondents, more than 85% were physicians and 68% worked in a community setting. Only 40% indicated they were very familiar or extremely familiar with 2018 Molecular Testing Guidelines for Lung Cancer from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.
Clinicians were most confident about selecting appropriate tests to use, interpreting test results, and prognosticating based on test results, with 77%, 74%, and 74%, respectively, saying they are very confident or extremely confident in those areas. They were less confident about determining when to order testing and in coordinating care across the multidisciplinary team, with 59% and 64%, respectively, saying they were very confident or extremely confident in those areas, Dr. Boehmer reported at the conference.
The shortcomings with respect to communication across teams were echoed in two focus groups convened to further validate the survey results, he noted.
As for the reasons why clinicians ordered biomarker testing, 88% and 82% of community and academic clinicians, respectively, said they did so to help make targeted treatment decisions.
“Only 48% of community clinicians indicated that they use biomarker testing to guide patient discussions, compared to 73% of academic clinicians,” he said. “That finding was considered statistically significant.”
With respect to decision-making about biomarker testing, 41% said they prefer to share the responsibility with patients, whereas 52% said they prefer to make the final decision.
“Shedding further light on this situation, focus group participants expressed that patients lacked comprehension and interest about what testing entails and what testing means for their treatment options,” Dr. Boehmer noted.
In order to make more informed decisions about biomarker testing, respondents said they need more information on financial resources for patient assistance (26%) and education around both published guidelines and practical implications of the clinical data (21%).
When asked about patients’ information needs, 23% said their patients need psychosocial support, 22% said they need financial assistance, and 9% said their patients have no additional resource needs.
However, only 27% said they provide patients with resources related to psychosocial support services, and only 44% share financial assistance information, he said.
Further, the fact that 9% said their patients need no additional resources represents “a disconnect” from the findings of the survey and focus groups, he added.
“We believe that this study identifies key areas of ongoing clinician need related to biomarker testing, including things like increased guideline familiarity, practical applications of guideline-concordant testing, and … how to optimally coordinate multidisciplinary care delivery,” Dr. Boehmer said. “Professional organizations … in partnership with patient advocacy organizations or groups should focus on developing those patient education materials … and tools for improving patient-clinician discussions about biomarker testing.”
The ACCC will be working with the LUNGevity Foundation and the Center for Business Models in Healthcare to develop an intervention to ensure that such discussions are “easily integrated into the care process for every patient,” he noted.
Such efforts are important for ensuring that clinicians are informed about the value of biomarker testing and about guidelines for testing so that patients receive the best possible care, said invited discussant Joshua Sabari, MD, of New York University Langone Health’s Perlmutter Cancer Center.
“I know that, in clinic, when meeting a new patient with non–small cell lung cancer, it’s critical to understand the driver alteration, not only for prognosis, but also for goals-of-care discussion, as well as potential treatment option,” Dr. Sabari said.
Dr. Boehmer reported consulting for Pfizer. Dr. Sabari reported consulting and advisory board membership for multiple pharmaceutical companies.
A recent survey shows that fewer than half of community oncologists use biomarker testing to guide patient discussions about treatment, which compares with 73% of academic clinicians.
The findings, reported at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021, highlight the potential for unequal application of the latest advances in cancer genomics and targeted therapies throughout the health care system, which could worsen existing disparities in underserved populations, according to Leigh Boehmer, PharmD, medical director for the Association of Community Cancer Centers, Rockville, Md.
The survey – a mixed-methods approach for assessing practice patterns, attitudes, barriers, and resource needs related to biomarker testing among clinicians – was developed by the ACCC in partnership with the LUNGevity Foundation and administered to clinicians caring for patients with non–small cell lung cancer who are uninsured or covered by Medicaid.
Of 99 respondents, more than 85% were physicians and 68% worked in a community setting. Only 40% indicated they were very familiar or extremely familiar with 2018 Molecular Testing Guidelines for Lung Cancer from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.
Clinicians were most confident about selecting appropriate tests to use, interpreting test results, and prognosticating based on test results, with 77%, 74%, and 74%, respectively, saying they are very confident or extremely confident in those areas. They were less confident about determining when to order testing and in coordinating care across the multidisciplinary team, with 59% and 64%, respectively, saying they were very confident or extremely confident in those areas, Dr. Boehmer reported at the conference.
The shortcomings with respect to communication across teams were echoed in two focus groups convened to further validate the survey results, he noted.
As for the reasons why clinicians ordered biomarker testing, 88% and 82% of community and academic clinicians, respectively, said they did so to help make targeted treatment decisions.
“Only 48% of community clinicians indicated that they use biomarker testing to guide patient discussions, compared to 73% of academic clinicians,” he said. “That finding was considered statistically significant.”
With respect to decision-making about biomarker testing, 41% said they prefer to share the responsibility with patients, whereas 52% said they prefer to make the final decision.
“Shedding further light on this situation, focus group participants expressed that patients lacked comprehension and interest about what testing entails and what testing means for their treatment options,” Dr. Boehmer noted.
In order to make more informed decisions about biomarker testing, respondents said they need more information on financial resources for patient assistance (26%) and education around both published guidelines and practical implications of the clinical data (21%).
When asked about patients’ information needs, 23% said their patients need psychosocial support, 22% said they need financial assistance, and 9% said their patients have no additional resource needs.
However, only 27% said they provide patients with resources related to psychosocial support services, and only 44% share financial assistance information, he said.
Further, the fact that 9% said their patients need no additional resources represents “a disconnect” from the findings of the survey and focus groups, he added.
“We believe that this study identifies key areas of ongoing clinician need related to biomarker testing, including things like increased guideline familiarity, practical applications of guideline-concordant testing, and … how to optimally coordinate multidisciplinary care delivery,” Dr. Boehmer said. “Professional organizations … in partnership with patient advocacy organizations or groups should focus on developing those patient education materials … and tools for improving patient-clinician discussions about biomarker testing.”
The ACCC will be working with the LUNGevity Foundation and the Center for Business Models in Healthcare to develop an intervention to ensure that such discussions are “easily integrated into the care process for every patient,” he noted.
Such efforts are important for ensuring that clinicians are informed about the value of biomarker testing and about guidelines for testing so that patients receive the best possible care, said invited discussant Joshua Sabari, MD, of New York University Langone Health’s Perlmutter Cancer Center.
“I know that, in clinic, when meeting a new patient with non–small cell lung cancer, it’s critical to understand the driver alteration, not only for prognosis, but also for goals-of-care discussion, as well as potential treatment option,” Dr. Sabari said.
Dr. Boehmer reported consulting for Pfizer. Dr. Sabari reported consulting and advisory board membership for multiple pharmaceutical companies.
REPORTING FROM WCLC 2020
Twelve-month overall survival benefit with ribociclib for metastatic breast cancer
“Based on these results, ribociclib and letrozole should be considered the preferred treatment option,” said lead investigator Gabriel N. Hortobagyi, MD, a breast cancer medical oncologist at the University of Texas MD Anderson Cancer Center, Houston.
He presented the definitive overall survival results from MONALESSA-2 which randomized 668 patients equally and in the first line to either ribociclib or placebo on a background of standard dose letrozole.
At a median follow up of 6.6 years, median overall survival with ribociclib was 63.9 months versus 51.4 months in the placebo arm, a 24% reduction in the relative risk of death (P = .004).
It was the first report of a median overall survival (OS) exceeding 5 years in a phase 3 trial for advanced breast cancer. The estimated 6-year OS rate was 44.2% for ribociclib versus 32.0% with placebo.
“These are really impressive results” and support the use of CDK 4/6 inhibitors in the front-line setting,” said study discussant Gonzalo Gomez Abuin, MD, a medical oncologist at Hospital Alemán in Bueno Aires.
Ribociclib and other CDK 4/6 inhibitors have shown consistent progression-free survival benefit for metastatic disease, but ribociclib is the first of the major phase 3 trials with definitive overall survival results. They have “been long awaited,” Dr. Abuin said.
The overall survival benefit in MONALESSA-2 began to emerge at around 20 months and continued to increase over time.
Women had no prior CDK4/6 inhibitor treatment, chemotherapy, or endocrine therapy for metastatic disease. “They represented a pure first-line population,” Dr. Hortobagyi said.
Among other benefits, the time to first chemotherapy was a median of 50.6 months with ribociclib versus 38.9 months with placebo, so patients “had an extra year of delay before chemotherapy was utilized,” he said.
In general, Dr. Abuin said, we “see a consistent benefit with CDK 4/6 inhibitors in metastatic breast cancer across different settings.”
However, “it’s a little intriguing” that in a subgroup analysis of non–de novo disease, the overall survival benefit with ribociclib had a hazard ratio of 0.91, whereas the progression-free survival benefit was robust and statistically significant in an earlier report.
“This has been an important question, but I would caution all of us not to make too much out of the forest plot,” Dr. Hortobagyi said.
“There are a number of hypotheses one could come up with that could explain why the de novo and non–de novo populations faired differently in overall survival as opposed to progression-free survival, but there is also the simple possibility that this is a statistical fluke,” he said.
“We are in the process of analyzing this particular observation. In the meantime, I think we should just take the overall survival results of the entire population as the lead answer, and not follow the subgroup analysis until further information is available,” Dr. Hortobagyi said.
No new ribociclib safety signals were observed in the trial. The most common adverse events were neutropenia and liver function abnormalities, but they were “largely asymptomatic laboratory findings and completely reversible,” he said.
Twice as many patients treated with ribociclib developed prolonged QT intervals, but again, “no clinical consequences of this EKG finding were detected,” Dr. Hortobagyi said.
Less than 1% of patients in the ribociclib arm developed interstitial lung disease. The majority of safety events occurred in the first 12 months of treatment.
The work was funded by Novartis, maker of both ribociclib and letrozole. Dr. Hortobagyi reported receiving an institutional grant from the company and personal fees related to the trial. Other investigators disclosed ties to Novartis. Dr. Abuin reported relationships with many companies, including Novartis.
This article was updated 9/24/21.
“Based on these results, ribociclib and letrozole should be considered the preferred treatment option,” said lead investigator Gabriel N. Hortobagyi, MD, a breast cancer medical oncologist at the University of Texas MD Anderson Cancer Center, Houston.
He presented the definitive overall survival results from MONALESSA-2 which randomized 668 patients equally and in the first line to either ribociclib or placebo on a background of standard dose letrozole.
At a median follow up of 6.6 years, median overall survival with ribociclib was 63.9 months versus 51.4 months in the placebo arm, a 24% reduction in the relative risk of death (P = .004).
It was the first report of a median overall survival (OS) exceeding 5 years in a phase 3 trial for advanced breast cancer. The estimated 6-year OS rate was 44.2% for ribociclib versus 32.0% with placebo.
“These are really impressive results” and support the use of CDK 4/6 inhibitors in the front-line setting,” said study discussant Gonzalo Gomez Abuin, MD, a medical oncologist at Hospital Alemán in Bueno Aires.
Ribociclib and other CDK 4/6 inhibitors have shown consistent progression-free survival benefit for metastatic disease, but ribociclib is the first of the major phase 3 trials with definitive overall survival results. They have “been long awaited,” Dr. Abuin said.
The overall survival benefit in MONALESSA-2 began to emerge at around 20 months and continued to increase over time.
Women had no prior CDK4/6 inhibitor treatment, chemotherapy, or endocrine therapy for metastatic disease. “They represented a pure first-line population,” Dr. Hortobagyi said.
Among other benefits, the time to first chemotherapy was a median of 50.6 months with ribociclib versus 38.9 months with placebo, so patients “had an extra year of delay before chemotherapy was utilized,” he said.
In general, Dr. Abuin said, we “see a consistent benefit with CDK 4/6 inhibitors in metastatic breast cancer across different settings.”
However, “it’s a little intriguing” that in a subgroup analysis of non–de novo disease, the overall survival benefit with ribociclib had a hazard ratio of 0.91, whereas the progression-free survival benefit was robust and statistically significant in an earlier report.
“This has been an important question, but I would caution all of us not to make too much out of the forest plot,” Dr. Hortobagyi said.
“There are a number of hypotheses one could come up with that could explain why the de novo and non–de novo populations faired differently in overall survival as opposed to progression-free survival, but there is also the simple possibility that this is a statistical fluke,” he said.
“We are in the process of analyzing this particular observation. In the meantime, I think we should just take the overall survival results of the entire population as the lead answer, and not follow the subgroup analysis until further information is available,” Dr. Hortobagyi said.
No new ribociclib safety signals were observed in the trial. The most common adverse events were neutropenia and liver function abnormalities, but they were “largely asymptomatic laboratory findings and completely reversible,” he said.
Twice as many patients treated with ribociclib developed prolonged QT intervals, but again, “no clinical consequences of this EKG finding were detected,” Dr. Hortobagyi said.
Less than 1% of patients in the ribociclib arm developed interstitial lung disease. The majority of safety events occurred in the first 12 months of treatment.
The work was funded by Novartis, maker of both ribociclib and letrozole. Dr. Hortobagyi reported receiving an institutional grant from the company and personal fees related to the trial. Other investigators disclosed ties to Novartis. Dr. Abuin reported relationships with many companies, including Novartis.
This article was updated 9/24/21.
“Based on these results, ribociclib and letrozole should be considered the preferred treatment option,” said lead investigator Gabriel N. Hortobagyi, MD, a breast cancer medical oncologist at the University of Texas MD Anderson Cancer Center, Houston.
He presented the definitive overall survival results from MONALESSA-2 which randomized 668 patients equally and in the first line to either ribociclib or placebo on a background of standard dose letrozole.
At a median follow up of 6.6 years, median overall survival with ribociclib was 63.9 months versus 51.4 months in the placebo arm, a 24% reduction in the relative risk of death (P = .004).
It was the first report of a median overall survival (OS) exceeding 5 years in a phase 3 trial for advanced breast cancer. The estimated 6-year OS rate was 44.2% for ribociclib versus 32.0% with placebo.
“These are really impressive results” and support the use of CDK 4/6 inhibitors in the front-line setting,” said study discussant Gonzalo Gomez Abuin, MD, a medical oncologist at Hospital Alemán in Bueno Aires.
Ribociclib and other CDK 4/6 inhibitors have shown consistent progression-free survival benefit for metastatic disease, but ribociclib is the first of the major phase 3 trials with definitive overall survival results. They have “been long awaited,” Dr. Abuin said.
The overall survival benefit in MONALESSA-2 began to emerge at around 20 months and continued to increase over time.
Women had no prior CDK4/6 inhibitor treatment, chemotherapy, or endocrine therapy for metastatic disease. “They represented a pure first-line population,” Dr. Hortobagyi said.
Among other benefits, the time to first chemotherapy was a median of 50.6 months with ribociclib versus 38.9 months with placebo, so patients “had an extra year of delay before chemotherapy was utilized,” he said.
In general, Dr. Abuin said, we “see a consistent benefit with CDK 4/6 inhibitors in metastatic breast cancer across different settings.”
However, “it’s a little intriguing” that in a subgroup analysis of non–de novo disease, the overall survival benefit with ribociclib had a hazard ratio of 0.91, whereas the progression-free survival benefit was robust and statistically significant in an earlier report.
“This has been an important question, but I would caution all of us not to make too much out of the forest plot,” Dr. Hortobagyi said.
“There are a number of hypotheses one could come up with that could explain why the de novo and non–de novo populations faired differently in overall survival as opposed to progression-free survival, but there is also the simple possibility that this is a statistical fluke,” he said.
“We are in the process of analyzing this particular observation. In the meantime, I think we should just take the overall survival results of the entire population as the lead answer, and not follow the subgroup analysis until further information is available,” Dr. Hortobagyi said.
No new ribociclib safety signals were observed in the trial. The most common adverse events were neutropenia and liver function abnormalities, but they were “largely asymptomatic laboratory findings and completely reversible,” he said.
Twice as many patients treated with ribociclib developed prolonged QT intervals, but again, “no clinical consequences of this EKG finding were detected,” Dr. Hortobagyi said.
Less than 1% of patients in the ribociclib arm developed interstitial lung disease. The majority of safety events occurred in the first 12 months of treatment.
The work was funded by Novartis, maker of both ribociclib and letrozole. Dr. Hortobagyi reported receiving an institutional grant from the company and personal fees related to the trial. Other investigators disclosed ties to Novartis. Dr. Abuin reported relationships with many companies, including Novartis.
This article was updated 9/24/21.
FROM ESMO 2021
Flurry of cancer drug endorsements from EU panel
The CHMP recommended the granting of a conditional marketing authorization for pralsetinib (Gavreto) for the treatment of non–small cell lung cancer (NSCLC).
Specifically, pralsetinib is indicated as monotherapy for the treatment of adult patients with rearranged during transfection (RET) fusion-positive advanced NSCLC not previously treated with a RET inhibitor.
Available as 100 mg capsules, pralsetinib is a RET-receptor tyrosine kinase inhibitor, targeting oncogenic RET fusion proteins (KIF5B-RET and CCDC6-RET).
Pralsetinib’s benefits are its objective response rate and response duration in patients with RET-fusion positive NSCLC, as observed in a pivotal phase 1/2, open-label, multi-cohort, single-arm study.
The most common side effects are anemia, increased aspartate aminotransferase, neutropenia, constipation, musculoskeletal pain, fatigue, leukopenia, increased alanine aminotransferase, and hypertension.
CHMP also recommended ripretinib (Qinlock) for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with three or more kinase inhibitors, including imatinib (Gleevec).
Available as 50 mg tablets, ripretinib is a protein kinase inhibitor designed to selectively block the oncogenic KIT and PDGFRA kinases by inhibiting their active conformation.
Ripretinib improved progression-free survival in patients with GIST.
The most common side effects are fatigue, alopecia, nausea, myalgia, constipation, diarrhea, palmar-plantar erythrodysesthesia syndrome, weight loss, and vomiting.
The third drug recommended for approval was zanubrutinib (Brukinsa) for the treatment of adult patients with Waldenström’s macroglobulinemia who have received at least one prior therapy or who are to receive the drug as first-line treatment (and are unsuitable for chemo-immunotherapy).
Available as 80 mg capsules, zanubrutinib is a Bruton’s tyrosine kinase inhibitor that blocks the activity of BTK, inactivating the pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.
Zanubrutinib has demonstrated a clinically meaningful rate of very good partial response and/or complete response.
The most common side effects are neutropenia, thrombocytopenia, upper respiratory tract infection, hemorrhage/hematoma, rash, bruising, anemia, musculoskeletal pain, diarrhea, pneumonia, and cough.
Two new indications for already marketed drugs
CHMP also recommended an extension of the indications for two immunotherapies.
Pembrolizumab (Keytruda) will now also have an indication for use in combination with chemotherapy for the treatment of locally recurrent unresectable or metastatic triple negative breast cancer in adults whose tumors express PD-L1 with a CPS greater than or equal to 10 and who have not received prior chemotherapy for metastatic disease
Nivolumab (Opdivo) received an extension of indication to include use, in combination with fluoropyrimidine- and platinum-based combination chemotherapy, in the firstline treatment of adult patients with HER2 negative advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma whose tumors express PD-L1 with a combined positive score (CPS) greater than or equal to 5.
A version of this article first appeared on Medscape.com.
The CHMP recommended the granting of a conditional marketing authorization for pralsetinib (Gavreto) for the treatment of non–small cell lung cancer (NSCLC).
Specifically, pralsetinib is indicated as monotherapy for the treatment of adult patients with rearranged during transfection (RET) fusion-positive advanced NSCLC not previously treated with a RET inhibitor.
Available as 100 mg capsules, pralsetinib is a RET-receptor tyrosine kinase inhibitor, targeting oncogenic RET fusion proteins (KIF5B-RET and CCDC6-RET).
Pralsetinib’s benefits are its objective response rate and response duration in patients with RET-fusion positive NSCLC, as observed in a pivotal phase 1/2, open-label, multi-cohort, single-arm study.
The most common side effects are anemia, increased aspartate aminotransferase, neutropenia, constipation, musculoskeletal pain, fatigue, leukopenia, increased alanine aminotransferase, and hypertension.
CHMP also recommended ripretinib (Qinlock) for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with three or more kinase inhibitors, including imatinib (Gleevec).
Available as 50 mg tablets, ripretinib is a protein kinase inhibitor designed to selectively block the oncogenic KIT and PDGFRA kinases by inhibiting their active conformation.
Ripretinib improved progression-free survival in patients with GIST.
The most common side effects are fatigue, alopecia, nausea, myalgia, constipation, diarrhea, palmar-plantar erythrodysesthesia syndrome, weight loss, and vomiting.
The third drug recommended for approval was zanubrutinib (Brukinsa) for the treatment of adult patients with Waldenström’s macroglobulinemia who have received at least one prior therapy or who are to receive the drug as first-line treatment (and are unsuitable for chemo-immunotherapy).
Available as 80 mg capsules, zanubrutinib is a Bruton’s tyrosine kinase inhibitor that blocks the activity of BTK, inactivating the pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.
Zanubrutinib has demonstrated a clinically meaningful rate of very good partial response and/or complete response.
The most common side effects are neutropenia, thrombocytopenia, upper respiratory tract infection, hemorrhage/hematoma, rash, bruising, anemia, musculoskeletal pain, diarrhea, pneumonia, and cough.
Two new indications for already marketed drugs
CHMP also recommended an extension of the indications for two immunotherapies.
Pembrolizumab (Keytruda) will now also have an indication for use in combination with chemotherapy for the treatment of locally recurrent unresectable or metastatic triple negative breast cancer in adults whose tumors express PD-L1 with a CPS greater than or equal to 10 and who have not received prior chemotherapy for metastatic disease
Nivolumab (Opdivo) received an extension of indication to include use, in combination with fluoropyrimidine- and platinum-based combination chemotherapy, in the firstline treatment of adult patients with HER2 negative advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma whose tumors express PD-L1 with a combined positive score (CPS) greater than or equal to 5.
A version of this article first appeared on Medscape.com.
The CHMP recommended the granting of a conditional marketing authorization for pralsetinib (Gavreto) for the treatment of non–small cell lung cancer (NSCLC).
Specifically, pralsetinib is indicated as monotherapy for the treatment of adult patients with rearranged during transfection (RET) fusion-positive advanced NSCLC not previously treated with a RET inhibitor.
Available as 100 mg capsules, pralsetinib is a RET-receptor tyrosine kinase inhibitor, targeting oncogenic RET fusion proteins (KIF5B-RET and CCDC6-RET).
Pralsetinib’s benefits are its objective response rate and response duration in patients with RET-fusion positive NSCLC, as observed in a pivotal phase 1/2, open-label, multi-cohort, single-arm study.
The most common side effects are anemia, increased aspartate aminotransferase, neutropenia, constipation, musculoskeletal pain, fatigue, leukopenia, increased alanine aminotransferase, and hypertension.
CHMP also recommended ripretinib (Qinlock) for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with three or more kinase inhibitors, including imatinib (Gleevec).
Available as 50 mg tablets, ripretinib is a protein kinase inhibitor designed to selectively block the oncogenic KIT and PDGFRA kinases by inhibiting their active conformation.
Ripretinib improved progression-free survival in patients with GIST.
The most common side effects are fatigue, alopecia, nausea, myalgia, constipation, diarrhea, palmar-plantar erythrodysesthesia syndrome, weight loss, and vomiting.
The third drug recommended for approval was zanubrutinib (Brukinsa) for the treatment of adult patients with Waldenström’s macroglobulinemia who have received at least one prior therapy or who are to receive the drug as first-line treatment (and are unsuitable for chemo-immunotherapy).
Available as 80 mg capsules, zanubrutinib is a Bruton’s tyrosine kinase inhibitor that blocks the activity of BTK, inactivating the pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.
Zanubrutinib has demonstrated a clinically meaningful rate of very good partial response and/or complete response.
The most common side effects are neutropenia, thrombocytopenia, upper respiratory tract infection, hemorrhage/hematoma, rash, bruising, anemia, musculoskeletal pain, diarrhea, pneumonia, and cough.
Two new indications for already marketed drugs
CHMP also recommended an extension of the indications for two immunotherapies.
Pembrolizumab (Keytruda) will now also have an indication for use in combination with chemotherapy for the treatment of locally recurrent unresectable or metastatic triple negative breast cancer in adults whose tumors express PD-L1 with a CPS greater than or equal to 10 and who have not received prior chemotherapy for metastatic disease
Nivolumab (Opdivo) received an extension of indication to include use, in combination with fluoropyrimidine- and platinum-based combination chemotherapy, in the firstline treatment of adult patients with HER2 negative advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma whose tumors express PD-L1 with a combined positive score (CPS) greater than or equal to 5.
A version of this article first appeared on Medscape.com.
Immunotherapy for cancer patients with poor PS needs a rethink
The findings have prompted an expert to argue against the use of immunotherapy for such patients, who may have little time left and very little chance of benefiting.
“It is quite clear from clinical practice that most patients with limited PS do very poorly and do not benefit from immune check point inhibitors (ICI),” Jason Luke, MD, UPMC Hillman Cancer Center and the University of Pittsburgh, said in an email.
“So, my strong opinion is that patients should not be getting an immunotherapy just because it might not cause as many side effects as chemotherapy,” he added.
“Instead of giving an immunotherapy with little chance of success, patients and families deserve to have a direct conversation about what realistic expectations [might be] and how we as the oncology community can support them to achieve whatever their personal goals are in the time that they have left,” he emphasized.
Dr. Luke was the lead author of an editorial in which he commented on the study. Both the study and the editorial were published online in JCO Oncology Practice.
Variety of cancers
The study was conducted by Mridula Krishnan, MD, Nebraska Medicine Fred and Pamela Buffett Cancer Center, Omaha, Nebraska, and colleagues.
The team reviewed 257 patients who had been treated with either a programmed cell death protein–1 inhibitor or programmed cell death–ligand-1 inhibitor for a variety of advanced cancers. The drugs included pembrolizumab (Keytruda), nivolumab (Opdivo), atezolizumab (Tecentique), durvalumab (Imfinzi), and avelumab (Bavencio).
Most of the patients (71%) had good PS, with an Eastern Cooperative Oncology Group (ECOG) PS of 0-1 on initiation of immunotherapy; 29% of patients had poor PS, with an ECOG PS of greater than or equal to 2.
“The primary outcome was OS stratified by ECOG PS 0-1 versus ≥2,” note the authors. Across all tumor types, OS was superior for patients in the ECOG 0-1 PS group, the investigators note. The median OS was 12.6 months, compared with only 3.1 months for patients in the ECOG greater than or equal to 2 group (P < .001).
Moreover, overall response rates for patients with a poor PS were low. Only 8%, or 6 of 75 patients with an ECOG PS of greater than or equal to 2, achieved an objective response by RECIST criteria.
This compared to an overall response rate of 23% for patients with an ECOG PS of 0-1, the investigators note (P = .005).
Interestingly, the hospice referral rate for patients with a poor PS (67%) was similar to that of patients with a PS of 1-2 (61.9%), Dr. Krishnan and colleagues observe.
Those with a poor PS were more like to die in-hospital (28.6%) than were patients with a good PS (15.1%; P = .035). The authors point out that it is well known that outcomes with chemotherapy are worse among patients who experience a decline in functional reserve, owing to increased susceptibility to toxicity and complications.
“Regardless of age, patients with ECOG PS >2 usually have poor tolerability to chemotherapy, and this correlates with worse survival outcome,” they emphasize. There is as yet no clear guidance regarding the impact of PS on ICI treatment response, although “there should be,” Dr. Luke believes.
“In a patient with declining performance status, especially ECOG PS 3-4 but potentially 2 as well, there is little likelihood that the functional and immune reserve of the patient will be adequate to mount a robust antitumor response,” he elaborated.
“It’s not impossible, but trying for it should not come at the expense of engaging about end-of-life care and maximizing the palliative opportunities that many only have a short window of time in which to pursue,” he added.
Again, Dr. Luke strongly believes that just giving an ICI without engaging in a frank conversation with the patient and their families – which happens all too often, he feels – is absolutely not the way to go when treating patients with a poor PS and little time left.
“Patients and families might be better served by having a more direct and frank conversation about what the likelihood [is] that ICI therapy will actually do,” Dr. Luke stressed.
In their editorial, Dr. Luke and colleagues write: “Overall, we as an oncology community need to improve our communication with patients regarding goals of care and end-of-life considerations as opposed to reflexive treatment initiation,” he writes.
“Our duty, first and foremost, should focus on the person sitting in front of us – taking a step back may be the best way to move forward with compassionate care,” they add.
The authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The findings have prompted an expert to argue against the use of immunotherapy for such patients, who may have little time left and very little chance of benefiting.
“It is quite clear from clinical practice that most patients with limited PS do very poorly and do not benefit from immune check point inhibitors (ICI),” Jason Luke, MD, UPMC Hillman Cancer Center and the University of Pittsburgh, said in an email.
“So, my strong opinion is that patients should not be getting an immunotherapy just because it might not cause as many side effects as chemotherapy,” he added.
“Instead of giving an immunotherapy with little chance of success, patients and families deserve to have a direct conversation about what realistic expectations [might be] and how we as the oncology community can support them to achieve whatever their personal goals are in the time that they have left,” he emphasized.
Dr. Luke was the lead author of an editorial in which he commented on the study. Both the study and the editorial were published online in JCO Oncology Practice.
Variety of cancers
The study was conducted by Mridula Krishnan, MD, Nebraska Medicine Fred and Pamela Buffett Cancer Center, Omaha, Nebraska, and colleagues.
The team reviewed 257 patients who had been treated with either a programmed cell death protein–1 inhibitor or programmed cell death–ligand-1 inhibitor for a variety of advanced cancers. The drugs included pembrolizumab (Keytruda), nivolumab (Opdivo), atezolizumab (Tecentique), durvalumab (Imfinzi), and avelumab (Bavencio).
Most of the patients (71%) had good PS, with an Eastern Cooperative Oncology Group (ECOG) PS of 0-1 on initiation of immunotherapy; 29% of patients had poor PS, with an ECOG PS of greater than or equal to 2.
“The primary outcome was OS stratified by ECOG PS 0-1 versus ≥2,” note the authors. Across all tumor types, OS was superior for patients in the ECOG 0-1 PS group, the investigators note. The median OS was 12.6 months, compared with only 3.1 months for patients in the ECOG greater than or equal to 2 group (P < .001).
Moreover, overall response rates for patients with a poor PS were low. Only 8%, or 6 of 75 patients with an ECOG PS of greater than or equal to 2, achieved an objective response by RECIST criteria.
This compared to an overall response rate of 23% for patients with an ECOG PS of 0-1, the investigators note (P = .005).
Interestingly, the hospice referral rate for patients with a poor PS (67%) was similar to that of patients with a PS of 1-2 (61.9%), Dr. Krishnan and colleagues observe.
Those with a poor PS were more like to die in-hospital (28.6%) than were patients with a good PS (15.1%; P = .035). The authors point out that it is well known that outcomes with chemotherapy are worse among patients who experience a decline in functional reserve, owing to increased susceptibility to toxicity and complications.
“Regardless of age, patients with ECOG PS >2 usually have poor tolerability to chemotherapy, and this correlates with worse survival outcome,” they emphasize. There is as yet no clear guidance regarding the impact of PS on ICI treatment response, although “there should be,” Dr. Luke believes.
“In a patient with declining performance status, especially ECOG PS 3-4 but potentially 2 as well, there is little likelihood that the functional and immune reserve of the patient will be adequate to mount a robust antitumor response,” he elaborated.
“It’s not impossible, but trying for it should not come at the expense of engaging about end-of-life care and maximizing the palliative opportunities that many only have a short window of time in which to pursue,” he added.
Again, Dr. Luke strongly believes that just giving an ICI without engaging in a frank conversation with the patient and their families – which happens all too often, he feels – is absolutely not the way to go when treating patients with a poor PS and little time left.
“Patients and families might be better served by having a more direct and frank conversation about what the likelihood [is] that ICI therapy will actually do,” Dr. Luke stressed.
In their editorial, Dr. Luke and colleagues write: “Overall, we as an oncology community need to improve our communication with patients regarding goals of care and end-of-life considerations as opposed to reflexive treatment initiation,” he writes.
“Our duty, first and foremost, should focus on the person sitting in front of us – taking a step back may be the best way to move forward with compassionate care,” they add.
The authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The findings have prompted an expert to argue against the use of immunotherapy for such patients, who may have little time left and very little chance of benefiting.
“It is quite clear from clinical practice that most patients with limited PS do very poorly and do not benefit from immune check point inhibitors (ICI),” Jason Luke, MD, UPMC Hillman Cancer Center and the University of Pittsburgh, said in an email.
“So, my strong opinion is that patients should not be getting an immunotherapy just because it might not cause as many side effects as chemotherapy,” he added.
“Instead of giving an immunotherapy with little chance of success, patients and families deserve to have a direct conversation about what realistic expectations [might be] and how we as the oncology community can support them to achieve whatever their personal goals are in the time that they have left,” he emphasized.
Dr. Luke was the lead author of an editorial in which he commented on the study. Both the study and the editorial were published online in JCO Oncology Practice.
Variety of cancers
The study was conducted by Mridula Krishnan, MD, Nebraska Medicine Fred and Pamela Buffett Cancer Center, Omaha, Nebraska, and colleagues.
The team reviewed 257 patients who had been treated with either a programmed cell death protein–1 inhibitor or programmed cell death–ligand-1 inhibitor for a variety of advanced cancers. The drugs included pembrolizumab (Keytruda), nivolumab (Opdivo), atezolizumab (Tecentique), durvalumab (Imfinzi), and avelumab (Bavencio).
Most of the patients (71%) had good PS, with an Eastern Cooperative Oncology Group (ECOG) PS of 0-1 on initiation of immunotherapy; 29% of patients had poor PS, with an ECOG PS of greater than or equal to 2.
“The primary outcome was OS stratified by ECOG PS 0-1 versus ≥2,” note the authors. Across all tumor types, OS was superior for patients in the ECOG 0-1 PS group, the investigators note. The median OS was 12.6 months, compared with only 3.1 months for patients in the ECOG greater than or equal to 2 group (P < .001).
Moreover, overall response rates for patients with a poor PS were low. Only 8%, or 6 of 75 patients with an ECOG PS of greater than or equal to 2, achieved an objective response by RECIST criteria.
This compared to an overall response rate of 23% for patients with an ECOG PS of 0-1, the investigators note (P = .005).
Interestingly, the hospice referral rate for patients with a poor PS (67%) was similar to that of patients with a PS of 1-2 (61.9%), Dr. Krishnan and colleagues observe.
Those with a poor PS were more like to die in-hospital (28.6%) than were patients with a good PS (15.1%; P = .035). The authors point out that it is well known that outcomes with chemotherapy are worse among patients who experience a decline in functional reserve, owing to increased susceptibility to toxicity and complications.
“Regardless of age, patients with ECOG PS >2 usually have poor tolerability to chemotherapy, and this correlates with worse survival outcome,” they emphasize. There is as yet no clear guidance regarding the impact of PS on ICI treatment response, although “there should be,” Dr. Luke believes.
“In a patient with declining performance status, especially ECOG PS 3-4 but potentially 2 as well, there is little likelihood that the functional and immune reserve of the patient will be adequate to mount a robust antitumor response,” he elaborated.
“It’s not impossible, but trying for it should not come at the expense of engaging about end-of-life care and maximizing the palliative opportunities that many only have a short window of time in which to pursue,” he added.
Again, Dr. Luke strongly believes that just giving an ICI without engaging in a frank conversation with the patient and their families – which happens all too often, he feels – is absolutely not the way to go when treating patients with a poor PS and little time left.
“Patients and families might be better served by having a more direct and frank conversation about what the likelihood [is] that ICI therapy will actually do,” Dr. Luke stressed.
In their editorial, Dr. Luke and colleagues write: “Overall, we as an oncology community need to improve our communication with patients regarding goals of care and end-of-life considerations as opposed to reflexive treatment initiation,” he writes.
“Our duty, first and foremost, should focus on the person sitting in front of us – taking a step back may be the best way to move forward with compassionate care,” they add.
The authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.