User login
Despite standard blood monitoring and routine imaging, patients with colorectal cancer (CRC) tend to have multiple, incurable metastases when relapse occurs.
A new study indicates that postsurgical circulating tumor DNA (ctDNA) testing may improve our ability to predict relapse in patients with stage I-III CRC.
ctDNA testing outperformed carcinoembryonic antigen (CEA) testing in predicting relapse-free survival, and ctDNA was detected about 8 months prior to relapse detection via CT.
Tenna V. Henriksen, of Aarhus University in Denmark, presented these results at the 2021 Gastrointestinal Cancers Symposium (abstract 11).
The multi-institutional study included 260 patients with CRC – 4 with stage I disease, 90 with stage II, and 166 with stage III disease.
Patients were monitored with plasma ctDNA testing within 2 months of primary surgery. Some patients were monitored with follow-up ctDNA sampling every 3 months for an additional 3 years.
Individual tumors and matched germline DNA were interrogated with whole-exome sequencing, and somatic single nucleotide variants were identified. Personalized multiplex PCR assays were developed to track tumor-specific single nucleotide variants via the Signatera® ctDNA assay.
The researchers retrospectively assessed ctDNA’s performance in:
- Stratifying the postoperative risk of relapse.
- Quantifying the benefit of adjuvant chemotherapy in patients who had or did not have ctDNA in plasma.
- Efficiently detecting relapse, in comparison with standard surveillance tests.
Surveillance CT scans were performed at 12 and 36 months but not at the frequency recommended in NCCN guidelines.
In all, 165 patients received adjuvant chemotherapy. The decision to give chemotherapy was made on a clinical basis by treating physicians who were blinded to the results of ctDNA testing.
Results
Of the 260 patients analyzed, 48 relapsed. The median follow-up was 28.4 months overall and 29.9 months in the nonrelapse cases.
The researchers assessed postoperative ctDNA status prior to adjuvant chemotherapy in 218 patients and after adjuvant chemotherapy in 108 patients.
In the prechemotherapy group, 20 patients were ctDNA positive, and 80% of them relapsed. In contrast, 13% of the 198 ctDNA-negative patients relapsed. The hazard ratio (HR) for relapse-free survival was 11 (95% confidence interval, 5.9-21; P < .0001).
After adjuvant chemotherapy, 12.5% of the ctDNA-negative patients relapsed, compared with 83.3% of the ctDNA-positive patients. The HR for relapse-free survival was 12 (95% CI, 4.9-27; P < .0001).
[embed:render:related:node:200627]
Results from longitudinal ctDNA testing in 202 patients suggested that serial sampling is more useful than sampling at a single point in time. The recurrence rate was 3.4% among patients who remained persistently ctDNA negative, compared with 89.3% in patients who were ctDNA positive. The HR for relapse-free survival was 51 (95% CI, 20-125; P < .0001).
In a subgroup of 29 patients with clinical recurrence detected by CT imaging, ctDNA detection occurred a median of 8.1 months earlier than radiologic relapse.
Among the 197 patients who had serial CEA and ctDNA measurements, longitudinal CEA testing correlated with relapse-free survival (HR, 4.9; 95% CI, 3.2-15, P < .0001) but not nearly as well as ctDNA testing (HR, 95.7; 95% CI, 28-322, P < .0001) in a univariable analysis.
In a multivariable analysis, the HR for relapse-free survival was 1.8 (95% CI, 0.77-4.0; P = .184) for longitudinal CEA and 80.55 (95% CI, 23.1-281; P < .0001) for longitudinal ctDNA.
“[W]hen we pit them against each other in a multivariable analysis, we can see that all the predictive power is in the ctDNA samples,” Ms. Henriksen said. “This indicates that ctDNA is a stronger biomarker compared to CEA, at least with relapse-free survival.”
Availability is not actionability
Study discussant Michael J. Overman, MD, of MD Anderson Cancer Center in Houston, acknowledged that this research substantiates the ability of postoperative ctDNA detection to risk stratify patients with stage III CRC, the predominant stage of participants in the study.
The current results reinforce the researchers’ previously published work (JAMA Oncol. 2019;5[8]:1124-31) and affirm similar findings by other groups (JAMA Oncol. 2019;5[12]:1710-17 and JAMA Oncol. 2019;5[8]:1118-23).
However, Dr. Overman cautioned that “availability is not the same as actionability.”
He also said the “tumor-informed mutation” approach utilized in the Signatera assay differs from the simpler “panel-based” approach, which is also undergoing clinical testing and offers the additional opportunity to test potentially actionable epigenetic targets such as DNA methylation.
Furthermore, the practicality of integrating the tumor-informed mutation approach into the time constraints required in clinical practice was not evaluated in the current analysis.
Dr. Overman pointed out that 16 of the 20 ctDNA-positive patients who received adjuvant chemotherapy sustained a recurrence, so the chemotherapy benefit was lower than expected.
Finally, although ctDNA outperformed CEA in detecting relapse, the greatest impact of ctDNA is its potential to inform the clinician’s decision to escalate and deescalate treatment with impact on survival – a potential that remains unfulfilled.
[embed:render:related:node:215785]
Next steps
Ms. Henriksen closed her presentation with the perspective that, for serial ctDNA monitoring to be implemented in clinical settings, testing in randomized clinical trials will be needed.
In Denmark, the IMPROVE-IT study is enrolling patients with stage I or low-risk stage II CRC. In this trial, ctDNA-positive patients will receive adjuvant chemotherapy, and ctDNA-negative patients will have longitudinal ctDNA testing but no adjuvant chemotherapy.
A second study, IMPROVE-IT2, will assess the value of ctDNA to direct intensified radiologic surveillance to improve the application of potentially curative treatment for patients with stage II (high-risk) or stage III CRC. Patients with negative ctDNA tests will be followed with longitudinal ctDNA testing only.
In his talk, Dr. Overman highlighted several prospective studies assessing the value of ctDNA testing.
One of these is the ongoing COBRA study (NRG-GI-005), which uses a ctDNA assay (Guardant Lunar-1) for patients with stage IIA CRC for whom standard adjuvant chemotherapy is not indicated.
The patients in COBRA are randomized to active surveillance or assay-directed therapy. Patients assigned to assay-directed therapy have samples analyzed for ctDNA, which would guide the decision about adjuvant chemotherapy. If the postoperative sample is ctDNA positive and the patient accepts adjuvant chemotherapy, the patient could receive one of two standard adjuvant chemotherapy regimens. If ctDNA negative, the patient would be followed with active surveillance alone.
Dr. Overman also highlighted the planned CIRCULATE US trial (NRG-GI008). The aim of this trial is to test intensified adjuvant treatment for stage III CRC patients with positive ctDNA tests. It will employ the Signatera assay.
Ideally, these ongoing trials will provide the evidence base needed for clinicians to optimize adjuvant therapy and surveillance using ctDNA technology.
The current study was sponsored by the Danish Council for Independent Research, The Novo Nordisk Foundation, The Danish Cancer Society, and Natera Inc. Ms. Henriksen disclosed no conflicts of interest. Dr. Overman disclosed relationships with Array BioPharma, Bristol-Myers Squibb, Gritstone Oncology, Janssen, MedImmune, Merck, Novartis, Pfizer, Promega, Roche/Genentech, and Spectrum Pharmaceuticals.
The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
Despite standard blood monitoring and routine imaging, patients with colorectal cancer (CRC) tend to have multiple, incurable metastases when relapse occurs.
A new study indicates that postsurgical circulating tumor DNA (ctDNA) testing may improve our ability to predict relapse in patients with stage I-III CRC.
ctDNA testing outperformed carcinoembryonic antigen (CEA) testing in predicting relapse-free survival, and ctDNA was detected about 8 months prior to relapse detection via CT.
Tenna V. Henriksen, of Aarhus University in Denmark, presented these results at the 2021 Gastrointestinal Cancers Symposium (abstract 11).
The multi-institutional study included 260 patients with CRC – 4 with stage I disease, 90 with stage II, and 166 with stage III disease.
Patients were monitored with plasma ctDNA testing within 2 months of primary surgery. Some patients were monitored with follow-up ctDNA sampling every 3 months for an additional 3 years.
Individual tumors and matched germline DNA were interrogated with whole-exome sequencing, and somatic single nucleotide variants were identified. Personalized multiplex PCR assays were developed to track tumor-specific single nucleotide variants via the Signatera® ctDNA assay.
The researchers retrospectively assessed ctDNA’s performance in:
- Stratifying the postoperative risk of relapse.
- Quantifying the benefit of adjuvant chemotherapy in patients who had or did not have ctDNA in plasma.
- Efficiently detecting relapse, in comparison with standard surveillance tests.
Surveillance CT scans were performed at 12 and 36 months but not at the frequency recommended in NCCN guidelines.
In all, 165 patients received adjuvant chemotherapy. The decision to give chemotherapy was made on a clinical basis by treating physicians who were blinded to the results of ctDNA testing.
Results
Of the 260 patients analyzed, 48 relapsed. The median follow-up was 28.4 months overall and 29.9 months in the nonrelapse cases.
The researchers assessed postoperative ctDNA status prior to adjuvant chemotherapy in 218 patients and after adjuvant chemotherapy in 108 patients.
In the prechemotherapy group, 20 patients were ctDNA positive, and 80% of them relapsed. In contrast, 13% of the 198 ctDNA-negative patients relapsed. The hazard ratio (HR) for relapse-free survival was 11 (95% confidence interval, 5.9-21; P < .0001).
After adjuvant chemotherapy, 12.5% of the ctDNA-negative patients relapsed, compared with 83.3% of the ctDNA-positive patients. The HR for relapse-free survival was 12 (95% CI, 4.9-27; P < .0001).
[embed:render:related:node:200627]
Results from longitudinal ctDNA testing in 202 patients suggested that serial sampling is more useful than sampling at a single point in time. The recurrence rate was 3.4% among patients who remained persistently ctDNA negative, compared with 89.3% in patients who were ctDNA positive. The HR for relapse-free survival was 51 (95% CI, 20-125; P < .0001).
In a subgroup of 29 patients with clinical recurrence detected by CT imaging, ctDNA detection occurred a median of 8.1 months earlier than radiologic relapse.
Among the 197 patients who had serial CEA and ctDNA measurements, longitudinal CEA testing correlated with relapse-free survival (HR, 4.9; 95% CI, 3.2-15, P < .0001) but not nearly as well as ctDNA testing (HR, 95.7; 95% CI, 28-322, P < .0001) in a univariable analysis.
In a multivariable analysis, the HR for relapse-free survival was 1.8 (95% CI, 0.77-4.0; P = .184) for longitudinal CEA and 80.55 (95% CI, 23.1-281; P < .0001) for longitudinal ctDNA.
“[W]hen we pit them against each other in a multivariable analysis, we can see that all the predictive power is in the ctDNA samples,” Ms. Henriksen said. “This indicates that ctDNA is a stronger biomarker compared to CEA, at least with relapse-free survival.”
Availability is not actionability
Study discussant Michael J. Overman, MD, of MD Anderson Cancer Center in Houston, acknowledged that this research substantiates the ability of postoperative ctDNA detection to risk stratify patients with stage III CRC, the predominant stage of participants in the study.
The current results reinforce the researchers’ previously published work (JAMA Oncol. 2019;5[8]:1124-31) and affirm similar findings by other groups (JAMA Oncol. 2019;5[12]:1710-17 and JAMA Oncol. 2019;5[8]:1118-23).
However, Dr. Overman cautioned that “availability is not the same as actionability.”
He also said the “tumor-informed mutation” approach utilized in the Signatera assay differs from the simpler “panel-based” approach, which is also undergoing clinical testing and offers the additional opportunity to test potentially actionable epigenetic targets such as DNA methylation.
Furthermore, the practicality of integrating the tumor-informed mutation approach into the time constraints required in clinical practice was not evaluated in the current analysis.
Dr. Overman pointed out that 16 of the 20 ctDNA-positive patients who received adjuvant chemotherapy sustained a recurrence, so the chemotherapy benefit was lower than expected.
Finally, although ctDNA outperformed CEA in detecting relapse, the greatest impact of ctDNA is its potential to inform the clinician’s decision to escalate and deescalate treatment with impact on survival – a potential that remains unfulfilled.
[embed:render:related:node:215785]
Next steps
Ms. Henriksen closed her presentation with the perspective that, for serial ctDNA monitoring to be implemented in clinical settings, testing in randomized clinical trials will be needed.
In Denmark, the IMPROVE-IT study is enrolling patients with stage I or low-risk stage II CRC. In this trial, ctDNA-positive patients will receive adjuvant chemotherapy, and ctDNA-negative patients will have longitudinal ctDNA testing but no adjuvant chemotherapy.
A second study, IMPROVE-IT2, will assess the value of ctDNA to direct intensified radiologic surveillance to improve the application of potentially curative treatment for patients with stage II (high-risk) or stage III CRC. Patients with negative ctDNA tests will be followed with longitudinal ctDNA testing only.
In his talk, Dr. Overman highlighted several prospective studies assessing the value of ctDNA testing.
One of these is the ongoing COBRA study (NRG-GI-005), which uses a ctDNA assay (Guardant Lunar-1) for patients with stage IIA CRC for whom standard adjuvant chemotherapy is not indicated.
The patients in COBRA are randomized to active surveillance or assay-directed therapy. Patients assigned to assay-directed therapy have samples analyzed for ctDNA, which would guide the decision about adjuvant chemotherapy. If the postoperative sample is ctDNA positive and the patient accepts adjuvant chemotherapy, the patient could receive one of two standard adjuvant chemotherapy regimens. If ctDNA negative, the patient would be followed with active surveillance alone.
Dr. Overman also highlighted the planned CIRCULATE US trial (NRG-GI008). The aim of this trial is to test intensified adjuvant treatment for stage III CRC patients with positive ctDNA tests. It will employ the Signatera assay.
Ideally, these ongoing trials will provide the evidence base needed for clinicians to optimize adjuvant therapy and surveillance using ctDNA technology.
The current study was sponsored by the Danish Council for Independent Research, The Novo Nordisk Foundation, The Danish Cancer Society, and Natera Inc. Ms. Henriksen disclosed no conflicts of interest. Dr. Overman disclosed relationships with Array BioPharma, Bristol-Myers Squibb, Gritstone Oncology, Janssen, MedImmune, Merck, Novartis, Pfizer, Promega, Roche/Genentech, and Spectrum Pharmaceuticals.
The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
Despite standard blood monitoring and routine imaging, patients with colorectal cancer (CRC) tend to have multiple, incurable metastases when relapse occurs.
A new study indicates that postsurgical circulating tumor DNA (ctDNA) testing may improve our ability to predict relapse in patients with stage I-III CRC.
ctDNA testing outperformed carcinoembryonic antigen (CEA) testing in predicting relapse-free survival, and ctDNA was detected about 8 months prior to relapse detection via CT.
Tenna V. Henriksen, of Aarhus University in Denmark, presented these results at the 2021 Gastrointestinal Cancers Symposium (abstract 11).
The multi-institutional study included 260 patients with CRC – 4 with stage I disease, 90 with stage II, and 166 with stage III disease.
Patients were monitored with plasma ctDNA testing within 2 months of primary surgery. Some patients were monitored with follow-up ctDNA sampling every 3 months for an additional 3 years.
Individual tumors and matched germline DNA were interrogated with whole-exome sequencing, and somatic single nucleotide variants were identified. Personalized multiplex PCR assays were developed to track tumor-specific single nucleotide variants via the Signatera® ctDNA assay.
The researchers retrospectively assessed ctDNA’s performance in:
- Stratifying the postoperative risk of relapse.
- Quantifying the benefit of adjuvant chemotherapy in patients who had or did not have ctDNA in plasma.
- Efficiently detecting relapse, in comparison with standard surveillance tests.
Surveillance CT scans were performed at 12 and 36 months but not at the frequency recommended in NCCN guidelines.
In all, 165 patients received adjuvant chemotherapy. The decision to give chemotherapy was made on a clinical basis by treating physicians who were blinded to the results of ctDNA testing.
Results
Of the 260 patients analyzed, 48 relapsed. The median follow-up was 28.4 months overall and 29.9 months in the nonrelapse cases.
The researchers assessed postoperative ctDNA status prior to adjuvant chemotherapy in 218 patients and after adjuvant chemotherapy in 108 patients.
In the prechemotherapy group, 20 patients were ctDNA positive, and 80% of them relapsed. In contrast, 13% of the 198 ctDNA-negative patients relapsed. The hazard ratio (HR) for relapse-free survival was 11 (95% confidence interval, 5.9-21; P < .0001).
After adjuvant chemotherapy, 12.5% of the ctDNA-negative patients relapsed, compared with 83.3% of the ctDNA-positive patients. The HR for relapse-free survival was 12 (95% CI, 4.9-27; P < .0001).
[embed:render:related:node:200627]
Results from longitudinal ctDNA testing in 202 patients suggested that serial sampling is more useful than sampling at a single point in time. The recurrence rate was 3.4% among patients who remained persistently ctDNA negative, compared with 89.3% in patients who were ctDNA positive. The HR for relapse-free survival was 51 (95% CI, 20-125; P < .0001).
In a subgroup of 29 patients with clinical recurrence detected by CT imaging, ctDNA detection occurred a median of 8.1 months earlier than radiologic relapse.
Among the 197 patients who had serial CEA and ctDNA measurements, longitudinal CEA testing correlated with relapse-free survival (HR, 4.9; 95% CI, 3.2-15, P < .0001) but not nearly as well as ctDNA testing (HR, 95.7; 95% CI, 28-322, P < .0001) in a univariable analysis.
In a multivariable analysis, the HR for relapse-free survival was 1.8 (95% CI, 0.77-4.0; P = .184) for longitudinal CEA and 80.55 (95% CI, 23.1-281; P < .0001) for longitudinal ctDNA.
“[W]hen we pit them against each other in a multivariable analysis, we can see that all the predictive power is in the ctDNA samples,” Ms. Henriksen said. “This indicates that ctDNA is a stronger biomarker compared to CEA, at least with relapse-free survival.”
Availability is not actionability
Study discussant Michael J. Overman, MD, of MD Anderson Cancer Center in Houston, acknowledged that this research substantiates the ability of postoperative ctDNA detection to risk stratify patients with stage III CRC, the predominant stage of participants in the study.
The current results reinforce the researchers’ previously published work (JAMA Oncol. 2019;5[8]:1124-31) and affirm similar findings by other groups (JAMA Oncol. 2019;5[12]:1710-17 and JAMA Oncol. 2019;5[8]:1118-23).
However, Dr. Overman cautioned that “availability is not the same as actionability.”
He also said the “tumor-informed mutation” approach utilized in the Signatera assay differs from the simpler “panel-based” approach, which is also undergoing clinical testing and offers the additional opportunity to test potentially actionable epigenetic targets such as DNA methylation.
Furthermore, the practicality of integrating the tumor-informed mutation approach into the time constraints required in clinical practice was not evaluated in the current analysis.
Dr. Overman pointed out that 16 of the 20 ctDNA-positive patients who received adjuvant chemotherapy sustained a recurrence, so the chemotherapy benefit was lower than expected.
Finally, although ctDNA outperformed CEA in detecting relapse, the greatest impact of ctDNA is its potential to inform the clinician’s decision to escalate and deescalate treatment with impact on survival – a potential that remains unfulfilled.
[embed:render:related:node:215785]
Next steps
Ms. Henriksen closed her presentation with the perspective that, for serial ctDNA monitoring to be implemented in clinical settings, testing in randomized clinical trials will be needed.
In Denmark, the IMPROVE-IT study is enrolling patients with stage I or low-risk stage II CRC. In this trial, ctDNA-positive patients will receive adjuvant chemotherapy, and ctDNA-negative patients will have longitudinal ctDNA testing but no adjuvant chemotherapy.
A second study, IMPROVE-IT2, will assess the value of ctDNA to direct intensified radiologic surveillance to improve the application of potentially curative treatment for patients with stage II (high-risk) or stage III CRC. Patients with negative ctDNA tests will be followed with longitudinal ctDNA testing only.
In his talk, Dr. Overman highlighted several prospective studies assessing the value of ctDNA testing.
One of these is the ongoing COBRA study (NRG-GI-005), which uses a ctDNA assay (Guardant Lunar-1) for patients with stage IIA CRC for whom standard adjuvant chemotherapy is not indicated.
The patients in COBRA are randomized to active surveillance or assay-directed therapy. Patients assigned to assay-directed therapy have samples analyzed for ctDNA, which would guide the decision about adjuvant chemotherapy. If the postoperative sample is ctDNA positive and the patient accepts adjuvant chemotherapy, the patient could receive one of two standard adjuvant chemotherapy regimens. If ctDNA negative, the patient would be followed with active surveillance alone.
Dr. Overman also highlighted the planned CIRCULATE US trial (NRG-GI008). The aim of this trial is to test intensified adjuvant treatment for stage III CRC patients with positive ctDNA tests. It will employ the Signatera assay.
Ideally, these ongoing trials will provide the evidence base needed for clinicians to optimize adjuvant therapy and surveillance using ctDNA technology.
The current study was sponsored by the Danish Council for Independent Research, The Novo Nordisk Foundation, The Danish Cancer Society, and Natera Inc. Ms. Henriksen disclosed no conflicts of interest. Dr. Overman disclosed relationships with Array BioPharma, Bristol-Myers Squibb, Gritstone Oncology, Janssen, MedImmune, Merck, Novartis, Pfizer, Promega, Roche/Genentech, and Spectrum Pharmaceuticals.
The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
FROM GI Cancers Symposium 2021
