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CHICAGO – , according to “absolutely practice changing” findings from a prospective analysis of more than 15,000 tumor samples.
“The impact of these findings cannot be understated,” ASCO expert Shannon N. Westin, MD, said during a discussion of the findings presented by Zsofia K. Stadler, MD, at a press briefing at the annual meeting of the American Society of Clinical Oncology.
Lynch Syndrome (LS), an autosomal dominant inherited cancer predisposition syndrome caused by germline mutation in the DNA mismatch repair genes, is responsible for about 3% of colorectal and endometrial cancers; universal testing for tumor markers of LS is recommended in all patients with these types of cancers, said Dr. Stadler, director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center, New York.
“This is usually done either via MSI analysis or immunohistochemical staining for the DNA mismatch repair proteins,” she said, noting that genetic testing and counseling is recommended in patients with tumors suggestive of LS, and increased surveillance and/or risk-reducing surgery is recommended in those recognized as having LS.
MSI-high is a hallmark of LS-associated cancers and has recently been implicated as a marker for response to immunotherapy. This has led to increased MSI testing in metastatic cancer regardless of cancer type.
However, the prevalence of germline mutations in the DNA mismatch repair genes diagnostic of LS across all MSI-high tumors is unknown, she said.
In 15,045 tumor samples across more than 50 cancer types, germline mutations were analyzed across tumor types and according to MSI status.
As expected, the highest level of MSI-high was seen in small bowel cancer (25%), followed by endometrial, colorectal, and gastric cancer (16%, 14%, and 6%, respectively), Dr. Stadler said.
“High frequency MSI was also seen in a number of other tumors as suggested by other papers previously,” she noted.
LS was present in 16.3% of MSI-high tumors vs. 1.9% of MSI-indeterminate (moderate MSI level) tumors, and 0.3% of microsatellite stable (MSS) tumors, she added.
Additional tumor evaluations, including immunohistochemical staining for the mismatch repair genes, were also performed.
“Our analysis corroborated the finding that in these Lynch patients, the MSI-high and MSI-indeterminate tumors were caused by Lynch Syndrome. This is in contrast to our Lynch Syndrome patients with microsatellite stable tumors; their tumor signature suggested that the Lynch Syndrome did not cause these cancers,” she said. “In fact, the prevalence of Lynch Syndrome in the MSS cohort of 0.3% is equivalent to the presence of Lynch Syndrome in the general at-large population.”
Of note, 50% of LS patients with MSI-high and indeterminate tumors had cancers other than colorectal or endometrial cancer, including prostate, sarcoma, mesothelioma, adrenocortical carcinoma, and ovarian germ cell carcinoma, which have been rarely or not previously associated with LS, and 45% of those patients did not meet clinical testing criteria for LS and would not have undergone LS testing.
This finding underscores the previously unknown heterogeneity of the phenotype.
“Our study supports that MSI-high is predictive of LS across tumor types...and also supports that the spectrum of cancers associated with Lynch Syndrome seems to be much broader that previously thought, she said, concluding that “MSI-high tumor signature, regardless of cancer subtype and irrespective of the family cancer history, should prompt germline genetic assessment for the evaluation of Lynch [Syndrome].
“This will result in an increased ability to recognize Lynch Syndrome not only in cancer patients, but also in at-risk family members who will benefit from genetic testing for Lynch [Syndrome] and subsequent enhanced cancer surveillance and risk reduction measures.”
In emphasizing the practice-changing nature of these findings, Dr. Westin, a gynecologic oncologist at MD Anderson Cancer Center, Houston, said that with the rise of precision medicine, increasing numbers of patients are undergoing testing for microsatellite instability, mainly to determine if their tumor can be affected by an-approved therapy.
“What we’ve learned is that MSI not only has therapeutic implications, it also has cancer prevention implications,” she said. “We’ve only been testing the tip of the iceberg of patients who are affected by Lynch Syndrome, and what we now know is that under the surface there is a larger number of patients with specific cancer types that should be tested for Lynch Syndrome.”
She added that this is “a straightforward testing strategy which can be immediately implemented to impact not only the patients themselves and their risk of cancer, but also their family members and their risk of cancer.”
This study was funded by Romeo Milio Lynch Syndrome Foundation, the Marie-Josee and Henry R. Kravis Center for Molecular Oncology, the Robert and Kate Niehaus Center for Inherited Cancer Genomics, the Fieldstone Family Fund, Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant and the NIH/NCI Cancer Center Support Grant. Dr. Stadler reported consulting or advisory roles on the part of an immediate family member for Allergan, Genentech/Roche, Regeneron, Optos, and Adverum.
SOURCE: Schwark A et al., ASCO 2018 LBA1509.
CHICAGO – , according to “absolutely practice changing” findings from a prospective analysis of more than 15,000 tumor samples.
“The impact of these findings cannot be understated,” ASCO expert Shannon N. Westin, MD, said during a discussion of the findings presented by Zsofia K. Stadler, MD, at a press briefing at the annual meeting of the American Society of Clinical Oncology.
Lynch Syndrome (LS), an autosomal dominant inherited cancer predisposition syndrome caused by germline mutation in the DNA mismatch repair genes, is responsible for about 3% of colorectal and endometrial cancers; universal testing for tumor markers of LS is recommended in all patients with these types of cancers, said Dr. Stadler, director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center, New York.
“This is usually done either via MSI analysis or immunohistochemical staining for the DNA mismatch repair proteins,” she said, noting that genetic testing and counseling is recommended in patients with tumors suggestive of LS, and increased surveillance and/or risk-reducing surgery is recommended in those recognized as having LS.
MSI-high is a hallmark of LS-associated cancers and has recently been implicated as a marker for response to immunotherapy. This has led to increased MSI testing in metastatic cancer regardless of cancer type.
However, the prevalence of germline mutations in the DNA mismatch repair genes diagnostic of LS across all MSI-high tumors is unknown, she said.
In 15,045 tumor samples across more than 50 cancer types, germline mutations were analyzed across tumor types and according to MSI status.
As expected, the highest level of MSI-high was seen in small bowel cancer (25%), followed by endometrial, colorectal, and gastric cancer (16%, 14%, and 6%, respectively), Dr. Stadler said.
“High frequency MSI was also seen in a number of other tumors as suggested by other papers previously,” she noted.
LS was present in 16.3% of MSI-high tumors vs. 1.9% of MSI-indeterminate (moderate MSI level) tumors, and 0.3% of microsatellite stable (MSS) tumors, she added.
Additional tumor evaluations, including immunohistochemical staining for the mismatch repair genes, were also performed.
“Our analysis corroborated the finding that in these Lynch patients, the MSI-high and MSI-indeterminate tumors were caused by Lynch Syndrome. This is in contrast to our Lynch Syndrome patients with microsatellite stable tumors; their tumor signature suggested that the Lynch Syndrome did not cause these cancers,” she said. “In fact, the prevalence of Lynch Syndrome in the MSS cohort of 0.3% is equivalent to the presence of Lynch Syndrome in the general at-large population.”
Of note, 50% of LS patients with MSI-high and indeterminate tumors had cancers other than colorectal or endometrial cancer, including prostate, sarcoma, mesothelioma, adrenocortical carcinoma, and ovarian germ cell carcinoma, which have been rarely or not previously associated with LS, and 45% of those patients did not meet clinical testing criteria for LS and would not have undergone LS testing.
This finding underscores the previously unknown heterogeneity of the phenotype.
“Our study supports that MSI-high is predictive of LS across tumor types...and also supports that the spectrum of cancers associated with Lynch Syndrome seems to be much broader that previously thought, she said, concluding that “MSI-high tumor signature, regardless of cancer subtype and irrespective of the family cancer history, should prompt germline genetic assessment for the evaluation of Lynch [Syndrome].
“This will result in an increased ability to recognize Lynch Syndrome not only in cancer patients, but also in at-risk family members who will benefit from genetic testing for Lynch [Syndrome] and subsequent enhanced cancer surveillance and risk reduction measures.”
In emphasizing the practice-changing nature of these findings, Dr. Westin, a gynecologic oncologist at MD Anderson Cancer Center, Houston, said that with the rise of precision medicine, increasing numbers of patients are undergoing testing for microsatellite instability, mainly to determine if their tumor can be affected by an-approved therapy.
“What we’ve learned is that MSI not only has therapeutic implications, it also has cancer prevention implications,” she said. “We’ve only been testing the tip of the iceberg of patients who are affected by Lynch Syndrome, and what we now know is that under the surface there is a larger number of patients with specific cancer types that should be tested for Lynch Syndrome.”
She added that this is “a straightforward testing strategy which can be immediately implemented to impact not only the patients themselves and their risk of cancer, but also their family members and their risk of cancer.”
This study was funded by Romeo Milio Lynch Syndrome Foundation, the Marie-Josee and Henry R. Kravis Center for Molecular Oncology, the Robert and Kate Niehaus Center for Inherited Cancer Genomics, the Fieldstone Family Fund, Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant and the NIH/NCI Cancer Center Support Grant. Dr. Stadler reported consulting or advisory roles on the part of an immediate family member for Allergan, Genentech/Roche, Regeneron, Optos, and Adverum.
SOURCE: Schwark A et al., ASCO 2018 LBA1509.
CHICAGO – , according to “absolutely practice changing” findings from a prospective analysis of more than 15,000 tumor samples.
“The impact of these findings cannot be understated,” ASCO expert Shannon N. Westin, MD, said during a discussion of the findings presented by Zsofia K. Stadler, MD, at a press briefing at the annual meeting of the American Society of Clinical Oncology.
Lynch Syndrome (LS), an autosomal dominant inherited cancer predisposition syndrome caused by germline mutation in the DNA mismatch repair genes, is responsible for about 3% of colorectal and endometrial cancers; universal testing for tumor markers of LS is recommended in all patients with these types of cancers, said Dr. Stadler, director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center, New York.
“This is usually done either via MSI analysis or immunohistochemical staining for the DNA mismatch repair proteins,” she said, noting that genetic testing and counseling is recommended in patients with tumors suggestive of LS, and increased surveillance and/or risk-reducing surgery is recommended in those recognized as having LS.
MSI-high is a hallmark of LS-associated cancers and has recently been implicated as a marker for response to immunotherapy. This has led to increased MSI testing in metastatic cancer regardless of cancer type.
However, the prevalence of germline mutations in the DNA mismatch repair genes diagnostic of LS across all MSI-high tumors is unknown, she said.
In 15,045 tumor samples across more than 50 cancer types, germline mutations were analyzed across tumor types and according to MSI status.
As expected, the highest level of MSI-high was seen in small bowel cancer (25%), followed by endometrial, colorectal, and gastric cancer (16%, 14%, and 6%, respectively), Dr. Stadler said.
“High frequency MSI was also seen in a number of other tumors as suggested by other papers previously,” she noted.
LS was present in 16.3% of MSI-high tumors vs. 1.9% of MSI-indeterminate (moderate MSI level) tumors, and 0.3% of microsatellite stable (MSS) tumors, she added.
Additional tumor evaluations, including immunohistochemical staining for the mismatch repair genes, were also performed.
“Our analysis corroborated the finding that in these Lynch patients, the MSI-high and MSI-indeterminate tumors were caused by Lynch Syndrome. This is in contrast to our Lynch Syndrome patients with microsatellite stable tumors; their tumor signature suggested that the Lynch Syndrome did not cause these cancers,” she said. “In fact, the prevalence of Lynch Syndrome in the MSS cohort of 0.3% is equivalent to the presence of Lynch Syndrome in the general at-large population.”
Of note, 50% of LS patients with MSI-high and indeterminate tumors had cancers other than colorectal or endometrial cancer, including prostate, sarcoma, mesothelioma, adrenocortical carcinoma, and ovarian germ cell carcinoma, which have been rarely or not previously associated with LS, and 45% of those patients did not meet clinical testing criteria for LS and would not have undergone LS testing.
This finding underscores the previously unknown heterogeneity of the phenotype.
“Our study supports that MSI-high is predictive of LS across tumor types...and also supports that the spectrum of cancers associated with Lynch Syndrome seems to be much broader that previously thought, she said, concluding that “MSI-high tumor signature, regardless of cancer subtype and irrespective of the family cancer history, should prompt germline genetic assessment for the evaluation of Lynch [Syndrome].
“This will result in an increased ability to recognize Lynch Syndrome not only in cancer patients, but also in at-risk family members who will benefit from genetic testing for Lynch [Syndrome] and subsequent enhanced cancer surveillance and risk reduction measures.”
In emphasizing the practice-changing nature of these findings, Dr. Westin, a gynecologic oncologist at MD Anderson Cancer Center, Houston, said that with the rise of precision medicine, increasing numbers of patients are undergoing testing for microsatellite instability, mainly to determine if their tumor can be affected by an-approved therapy.
“What we’ve learned is that MSI not only has therapeutic implications, it also has cancer prevention implications,” she said. “We’ve only been testing the tip of the iceberg of patients who are affected by Lynch Syndrome, and what we now know is that under the surface there is a larger number of patients with specific cancer types that should be tested for Lynch Syndrome.”
She added that this is “a straightforward testing strategy which can be immediately implemented to impact not only the patients themselves and their risk of cancer, but also their family members and their risk of cancer.”
This study was funded by Romeo Milio Lynch Syndrome Foundation, the Marie-Josee and Henry R. Kravis Center for Molecular Oncology, the Robert and Kate Niehaus Center for Inherited Cancer Genomics, the Fieldstone Family Fund, Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant and the NIH/NCI Cancer Center Support Grant. Dr. Stadler reported consulting or advisory roles on the part of an immediate family member for Allergan, Genentech/Roche, Regeneron, Optos, and Adverum.
SOURCE: Schwark A et al., ASCO 2018 LBA1509.
REPORTING FROM ASCO 2018
Key clinical point: All MSI-high patients should be tested for LS regardless of cancer type or family history.
Major finding: LS was present in 16.3% of MSI-high tumors vs. 1.9% and 0.3% of MSI-indeterminate and stable tumors, respectively.
Study details: An analysis of 15,045 tumor samples.
Disclosures: This study was funded by Romeo Milio Lynch Syndrome Foundation, the Marie-Josee and Henry R. Kravis Center for Molecular Oncology, the Robert and Kate Niehaus Center for Inherited Cancer Genomics, the Fieldstone Family Fund, Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant, and the NIH/NCI Cancer Center Support Grant. Dr. Stadler reported consulting or advisory roles on the part of an immediate family member for Allergan, Genentech/Roche, Regeneron, Optos, and Adverum.
Source: Schwark A et al. ASCO 2018 LBA 1509.