New Studies Offer Insight Into Implications of Left- Versus Right-Sided Primary Tumor Location in CRC

New Studies Offer Insight Into Implications of Left- Versus Right-Sided Primary Tumor Location in CRC

To begin to tease apart the marked heterogeneity of colorectal cancer (CRC), recent efforts have focused on the “sidedness” of disease. Transformative evidence from a retrospective analysis of the phase III CALGB/SWOG 80405 clinical trial revealed that the anatomic location of the primary tumor within the colon correlates with different survival outcomes among patients with metastatic disease.1 More specifically, cancers originating on the left side of the colon—that is, the splenic flexure, descending colon, sigmoid colon, and rectum—are tied to superior survival as compared with cancers that present on the right side—that is, the cecum and ascending colon.

New analyses are now building on this work, both in metastatic and earlier-stage disease, to provide greater insight into the sidedness issue.

Left-Sided CRCs Vary Molecularly Depending on Location

Dr. Mohamed E. Salem
The CALGB/SWOG 80405 data, in addition to showing that left-sided location is linked to prolonged survival, also indicated that left-sided lesions respond differently to biologic therapy in comparison with right-sided lesions, presumably owing to molecular differences. As noted, tumors from multiple locations were bucketed as “left-sided” in this analysis, but it remains to be determined whether all tumors left of the transverse colon share the same molecular features, particularly those in the colon versus the rectum.

To explore this issue, Mohamed E. Salem, MD, of the Georgetown Lombardi Comprehensive Cancer Center, and colleagues sought to compare and contrast the molecular profile of three subgroups of left-sided primary tumors: (1) those of the descending colon, including the splenic flexure, (2) those of the sigmoid colon, and (3) those of the rectum (Abstract 522).

A large bank of CRC tumors profiled by Caris Life Sciences between 2009 and 2016 were utilized for the study. A total of 1,457 left-sided primary tumors, as well as 273 right-sided tumors, were profiled using immunohistochemistry, microsatellite instability assays, in situ hybridization techniques, and next-generation sequencing.

The findings revealed that the different subgroups of left-sided tumors harbor different molecular alterations when compared with each other. Most notably:

  • The incidence of microsatellite instability significantly decreased when moving from the descending colon (7%) to the sigmoid (4%) and on to the rectum (1%; p = 0.015).
  • MGMT and TOPO1 protein expression was significantly lower in descending and sigmoid colon tumors versus rectal tumors, whereas TOP2A expression was significantly higher (p < 0.05 for all comparisons).
  • Comparison of descending colon tumors versus rectal tumors showed that PIK3CA, BRAF, HNF1A, CTNNB1, and GNAS mutations were significantly more common in the former, whereas TP53 and APC mutations were more common in the latter (p < 0.05 for all comparisons).
  • Comparison of descending colon tumors versus sigmoid tumors showed that BRAF and HNF1A mutations were significantly more common in the former, whereas APC mutations were more common in the latter (p < 0.05 for all comparisons).
  • No mutations occurred significantly more or less often between sigmoid colon and rectal tumors.
  • The proportion of tumors carrying 17 or more mutations per megabase, defined as the tumor mutation load, was higher among descending colon tumors as compared with sigmoid and rectal tumors (8.8%, 1.6%, and 4.2%, respectively).
  • In all three tumor subgroups, tumor mutation burden correlated with microsatellite instability.

Comparisons of right-sided lesions versus left-sided lesions in the colon or rectum also revealed molecular variation between groups:

  • Striking differences in the incidence of microsatellite instability emerged when starting at the right colon (22%) and moving to the descending colon (7%) and then the rectum (1%) (p < 0.0001 between right colon and rectum).
  • Whereas no differences in HER2 overexpression and amplification were observed among the left-sided tumor subgroups, HER2 amplification was significantly more common among rectal tumors versus right-sided colon tumors (5.4% vs. 1.3%; p = 0.0328).
  • MGMT, TOPO1, and TUBB3 protein expression was significantly higher in rectal tumors versus right-sided tumors, whereas EGFR, TS, and PD-1 expression was significantly lower (p < 0.05 for all comparisons).
  • Comparison of rectal tumors versus right-sided tumors showed that TP53 and APC mutations were significantly more common in the former, whereas PIK3CA, BRAF, CTNNB1, BRCA1, PTEN, and ATM mutations were more common in the latter (p < 0.05 for all comparisons).

Dr. Sabine Tejpar
“Our study indicates that rectal cancers have molecular features that are different from left-sided colon tumors,” Dr. Salem said. Based on this and other findings, he suggested that clinical trials should stratify patients based on the location of the primary tumor—namely, right versus left—as well as molecular features. However, he noted that the findings do not support further stratification by rectum versus left-sided colon tumors at the present time.

“In conclusion, CRCs, it seems … carry a continuum of molecular alterations from right to left, rather than having a sharp, clear-cut distinction,” Dr. Salem said.

Discussant Sabine Tejpar, MD, PhD, of the University Hospital Leuven, in Belgium, agreed with Dr. Salem’s statement, saying, “It is an important finding.”

To confirm and further explore the molecular variances noted between different portions of the left-sided tumors (e.g., the descending colon and rectum), Dr. Tejpar suggested that the investigators draw on data from The Cancer Genome Atlas 2012 initiative, which provides comprehensive molecular characterization of 276 CRCs, with all the data publically available.

Stage II Right-Sided Tumors More Strongly Associated With Markers of Recurrence Versus Left-Sided Tumors

Dr. Irit Ben-Aharon
In other work, it appears that the sidedness issue also pertains to earlier-stage CRC. As seen in metastatic CRC, right-sided tumors may display worse outcomes compared with left-sided tumors in select patients with stage II disease based on two prognostic markers (Abstract 523). More specifically, sidedness may correlate with recurrence risk and may signal the need to strongly consider adjuvant treatment, the utility of which remains controversial, according to study presenter Irit Ben-Aharon, MD, PhD, of the Institute of Oncology, Davidoff Cancer Center, in Israel.

These findings are based on a retrospective cohort analysis of 1,159 patients with T3 mismatch repair proficient (MMR-P) stage II CRC in whom the 12-gene Oncotype DX score and CDX2 immunostaining were performed. Oncotype DX is a clinically validated predictor of recurrence risk, and lack of CDX2 tumor expression has also recently been shown to predict recurrence given its ties to high levels of ALCAM expression, high pathological grade, and a more aggressive natural history.

When the Oncotype DX recurrence score was matched up with the primary tumor location from the pathologic report, strong links became evident. The recurrence score was significantly higher for colon tumors on the right versus the left (mean score: 27.72 vs. 25.79; p = 0.002). A closer look showed that the recurrence score gradually decreased when moving from right to left across the colon from the cecum (mean score: 29.75) to the hepatic flexure (mean score: 27.76) to the sigmoid colon (mean score: 24.49; p = 0.014 for trend).

Examination of the other prognostic marker revealed that CDX2-negative tumors were more common in patients with right-sided lesions as opposed to left-sided lesions (35.8% vs. 16.1%; p = 0.029). As expected, the Oncotype DX recurrence risk score was higher in CDX2-negative versus -positive tumors (mean score: 32.00 vs. 24.42; p = 0.020).

Additional data from a smaller group of 132 patients with stage III CRC revealed that recurrence scores were also higher in right- versus left-sided tumors (mean score: 31.15 vs. 24.60; p = 0.001). In addition, stage II or III tumors in the rectum had higher recurrence scores compared with stage II or III tumors in the left colon (mean scores: 27.06 to 27.15 vs. 24.60 to 25.79; p ≤ 0.05).

“Further recurrence analysis should be performed to indicate whether primary tumor location may actually serve as a prognostic factor,” Dr. Ben-Aharon concluded. She also said, “Further studies are warranted to confirm the role of tumor location as a predictive factor to adjuvant chemotherapy.”

Dr. Tejpar’s take on the findings was that although this study did demonstrate that the Oncotype DX score and CDX2 status correlate with primary tumor location, the findings do not adequately address whether tumor location, per se, reflects differential prognosis in stage II CRC. Before this study has any clinical impact, this issue needs to be better defined, along with how to use the prognostic markers and tumor location together in the clinic.

–Kara Nyberg, PhD