Transcription factor loss linked to worse colorectal cancer outcomes

BOSTON– Colorectal cancers arising in the hindgut are more likely to have loss or mutation of the transcription factor SMAD4 than are tumors arising in the proximal two-thirds of the colon, and that loss is associated with significantly worse patient outcomes, investigators reported.

A study of data on nearly 600 patients with colorectal cancer in the Cancer Genome Atlas (TCGA) database showed that loss of SMAD4, which codes for a cell-signaling protein in the transforming growth factor beta pathway, was detected in 87% of tumors originating in the hindgut (including the splenic flexure, descending colon, sigmoid colon, and rectum), compared with 50% of tumors arising in the midgut (small intestine, ascending colon, and transverse colon), reported Dr. Jesse Joshua Smith from Memorial Sloan Kettering Cancer Center, New York.

In a separate analysis of 388 patients with colorectal cancer treated at Dr. Smith’s center, loss of SMAD4 in patients with cancers in the hindgut was associated with significantly shorter recurrence-free survival: 47 months, compared with 231 months for patients with hindgut cancers that retained SMAD4.

“These data indicate that embryologic origin related to SMAD4 status in colorectal cancer may be important in patient outcomes, and could potentially inform individualized treatment options for patients,” Dr. Smith said at the AACR/NCI)/EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Previous studies have suggested that alteration (mutation or loss) of SMAD4 may be more common in cancers of the rectum and other portions of the hindgut, he said.

A recent analysis of 113 patients with locally advanced rectal cancer treated at Memorial Sloan showed that 66% of the tumors evaluated by the MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutational Profile of Actionable Targets) platform had SMAD4 copy number losses, he noted.

The investigators hypothesized that SMAD4 loss is more common in hindgut vs. midgut tumors. To test that, they looked at TCGA data on 595 patients with colorectal cancer to determine copy number loss and diploid status, and compared SMAD4 copy number loss to the mutational status of genes encoding for adenomatous polyposis coli (APC) and tumor protein p53 (TP53), as well as mismatch repair status and KRAS amplification.

They found that SMAD4 copy number loss was significantly more common in hindgut tumors (295 vs. 44 diploid, P < .0001) than in midgut tumors (127 vs. 129 diploid, P = nonsignificant). In addition, mutations in both APC and TP53 were significantly associated with SMAD4 copy number loss – and when adjusting for mismatch repair status, SMDA4 copy number loss remained significantly associated with tumors originating in the hindgut and with TP53 mutations.

Similarly, immunohistochemical analysis showed that SMAD4 staining was lower in hindgut vs. midgut tumors, and lower levels of staining were associated with more advanced tumor and nodal stage (P < .05).

As noted, SMAD4 copy number loss in patients with hindgut-derived tumors was associated with worse recurrence-free survival, compared with similar patients with retained SMAD4: median, 47 months, compared with 231 months.

A similar pattern was seen among patients with hindgut tumors with SMAD4 loss but no mutations in DNA mismatch repair genes, with respective median recurrence-free survival of 36 months vs. not yet reached at 140 months.

Dr. Smith and his colleagues plan to enroll 100 additional patients and prospectively collect tumor samples to help determine whether there is an association between embryologic origins of tumors according to SMAD4 status and poor treatment response. They also hope to determine whether there is a similar association in tumors that metastasize to the liver or the lungs.

There is evidence from mouse models to suggest that loss of SMAD4 may confer to tumors resistance to therapeutic regimens based on 5-fluorouracil, Dr. Smith said.

In an interview, he noted that there are also preliminary data to suggest that when SMAD4 is lost or mutated, other pathways, such as the vascular endothelial growth factor (VEGF) pathway, may be upregulated, suggesting that this subset of patients might respond to a VEGF inhibitor.

The findings suggest that in addition to considering somatic mutations in the development of colorectal cancer, investigators may wish to explore whether lineage-dependent mechanisms or embryologic origin play a role in disease severity, observed Dr. Levi A. Garraway, of the Dana-Farber Cancer Institute, Boston, who was not involved in the study.

Dr. Garraway moderated the briefing at which Dr. Smith presented his data.

The Howard Hughes Medical Institute supported the study. Dr. Smith and Dr. Garraway reported no relevant disclosures.

BOSTON– Colorectal cancers arising in the hindgut are more likely to have loss or mutation of the transcription factor SMAD4 than are tumors arising in the proximal two-thirds of the colon, and that loss is associated with significantly worse patient outcomes, investigators reported.

A study of data on nearly 600 patients with colorectal cancer in the Cancer Genome Atlas (TCGA) database showed that loss of SMAD4, which codes for a cell-signaling protein in the transforming growth factor beta pathway, was detected in 87% of tumors originating in the hindgut (including the splenic flexure, descending colon, sigmoid colon, and rectum), compared with 50% of tumors arising in the midgut (small intestine, ascending colon, and transverse colon), reported Dr. Jesse Joshua Smith from Memorial Sloan Kettering Cancer Center, New York.

In a separate analysis of 388 patients with colorectal cancer treated at Dr. Smith’s center, loss of SMAD4 in patients with cancers in the hindgut was associated with significantly shorter recurrence-free survival: 47 months, compared with 231 months for patients with hindgut cancers that retained SMAD4.

“These data indicate that embryologic origin related to SMAD4 status in colorectal cancer may be important in patient outcomes, and could potentially inform individualized treatment options for patients,” Dr. Smith said at the AACR/NCI)/EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Previous studies have suggested that alteration (mutation or loss) of SMAD4 may be more common in cancers of the rectum and other portions of the hindgut, he said.

A recent analysis of 113 patients with locally advanced rectal cancer treated at Memorial Sloan showed that 66% of the tumors evaluated by the MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutational Profile of Actionable Targets) platform had SMAD4 copy number losses, he noted.

The investigators hypothesized that SMAD4 loss is more common in hindgut vs. midgut tumors. To test that, they looked at TCGA data on 595 patients with colorectal cancer to determine copy number loss and diploid status, and compared SMAD4 copy number loss to the mutational status of genes encoding for adenomatous polyposis coli (APC) and tumor protein p53 (TP53), as well as mismatch repair status and KRAS amplification.

They found that SMAD4 copy number loss was significantly more common in hindgut tumors (295 vs. 44 diploid, P < .0001) than in midgut tumors (127 vs. 129 diploid, P = nonsignificant). In addition, mutations in both APC and TP53 were significantly associated with SMAD4 copy number loss – and when adjusting for mismatch repair status, SMDA4 copy number loss remained significantly associated with tumors originating in the hindgut and with TP53 mutations.

Similarly, immunohistochemical analysis showed that SMAD4 staining was lower in hindgut vs. midgut tumors, and lower levels of staining were associated with more advanced tumor and nodal stage (P < .05).

As noted, SMAD4 copy number loss in patients with hindgut-derived tumors was associated with worse recurrence-free survival, compared with similar patients with retained SMAD4: median, 47 months, compared with 231 months.

A similar pattern was seen among patients with hindgut tumors with SMAD4 loss but no mutations in DNA mismatch repair genes, with respective median recurrence-free survival of 36 months vs. not yet reached at 140 months.

Dr. Smith and his colleagues plan to enroll 100 additional patients and prospectively collect tumor samples to help determine whether there is an association between embryologic origins of tumors according to SMAD4 status and poor treatment response. They also hope to determine whether there is a similar association in tumors that metastasize to the liver or the lungs.

There is evidence from mouse models to suggest that loss of SMAD4 may confer to tumors resistance to therapeutic regimens based on 5-fluorouracil, Dr. Smith said.

In an interview, he noted that there are also preliminary data to suggest that when SMAD4 is lost or mutated, other pathways, such as the vascular endothelial growth factor (VEGF) pathway, may be upregulated, suggesting that this subset of patients might respond to a VEGF inhibitor.

The findings suggest that in addition to considering somatic mutations in the development of colorectal cancer, investigators may wish to explore whether lineage-dependent mechanisms or embryologic origin play a role in disease severity, observed Dr. Levi A. Garraway, of the Dana-Farber Cancer Institute, Boston, who was not involved in the study.

Dr. Garraway moderated the briefing at which Dr. Smith presented his data.

The Howard Hughes Medical Institute supported the study. Dr. Smith and Dr. Garraway reported no relevant disclosures.

BOSTON– Colorectal cancers arising in the hindgut are more likely to have loss or mutation of the transcription factor SMAD4 than are tumors arising in the proximal two-thirds of the colon, and that loss is associated with significantly worse patient outcomes, investigators reported.

A study of data on nearly 600 patients with colorectal cancer in the Cancer Genome Atlas (TCGA) database showed that loss of SMAD4, which codes for a cell-signaling protein in the transforming growth factor beta pathway, was detected in 87% of tumors originating in the hindgut (including the splenic flexure, descending colon, sigmoid colon, and rectum), compared with 50% of tumors arising in the midgut (small intestine, ascending colon, and transverse colon), reported Dr. Jesse Joshua Smith from Memorial Sloan Kettering Cancer Center, New York.

In a separate analysis of 388 patients with colorectal cancer treated at Dr. Smith’s center, loss of SMAD4 in patients with cancers in the hindgut was associated with significantly shorter recurrence-free survival: 47 months, compared with 231 months for patients with hindgut cancers that retained SMAD4.

“These data indicate that embryologic origin related to SMAD4 status in colorectal cancer may be important in patient outcomes, and could potentially inform individualized treatment options for patients,” Dr. Smith said at the AACR/NCI)/EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Previous studies have suggested that alteration (mutation or loss) of SMAD4 may be more common in cancers of the rectum and other portions of the hindgut, he said.

A recent analysis of 113 patients with locally advanced rectal cancer treated at Memorial Sloan showed that 66% of the tumors evaluated by the MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutational Profile of Actionable Targets) platform had SMAD4 copy number losses, he noted.

The investigators hypothesized that SMAD4 loss is more common in hindgut vs. midgut tumors. To test that, they looked at TCGA data on 595 patients with colorectal cancer to determine copy number loss and diploid status, and compared SMAD4 copy number loss to the mutational status of genes encoding for adenomatous polyposis coli (APC) and tumor protein p53 (TP53), as well as mismatch repair status and KRAS amplification.

They found that SMAD4 copy number loss was significantly more common in hindgut tumors (295 vs. 44 diploid, P < .0001) than in midgut tumors (127 vs. 129 diploid, P = nonsignificant). In addition, mutations in both APC and TP53 were significantly associated with SMAD4 copy number loss – and when adjusting for mismatch repair status, SMDA4 copy number loss remained significantly associated with tumors originating in the hindgut and with TP53 mutations.

Similarly, immunohistochemical analysis showed that SMAD4 staining was lower in hindgut vs. midgut tumors, and lower levels of staining were associated with more advanced tumor and nodal stage (P < .05).

As noted, SMAD4 copy number loss in patients with hindgut-derived tumors was associated with worse recurrence-free survival, compared with similar patients with retained SMAD4: median, 47 months, compared with 231 months.

A similar pattern was seen among patients with hindgut tumors with SMAD4 loss but no mutations in DNA mismatch repair genes, with respective median recurrence-free survival of 36 months vs. not yet reached at 140 months.

Dr. Smith and his colleagues plan to enroll 100 additional patients and prospectively collect tumor samples to help determine whether there is an association between embryologic origins of tumors according to SMAD4 status and poor treatment response. They also hope to determine whether there is a similar association in tumors that metastasize to the liver or the lungs.

There is evidence from mouse models to suggest that loss of SMAD4 may confer to tumors resistance to therapeutic regimens based on 5-fluorouracil, Dr. Smith said.

In an interview, he noted that there are also preliminary data to suggest that when SMAD4 is lost or mutated, other pathways, such as the vascular endothelial growth factor (VEGF) pathway, may be upregulated, suggesting that this subset of patients might respond to a VEGF inhibitor.

The findings suggest that in addition to considering somatic mutations in the development of colorectal cancer, investigators may wish to explore whether lineage-dependent mechanisms or embryologic origin play a role in disease severity, observed Dr. Levi A. Garraway, of the Dana-Farber Cancer Institute, Boston, who was not involved in the study.

Dr. Garraway moderated the briefing at which Dr. Smith presented his data.

The Howard Hughes Medical Institute supported the study. Dr. Smith and Dr. Garraway reported no relevant disclosures.