Tumor ‘Sidedness’ in Colon Cancer: Studies Look for Explanations


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“Further work is needed to determine the mechanism by which sidedness remains an independent prognostic variable.”
— Alan P. Venook, MD

TUMOR “SIDEDNESS” in colon cancer has become a topic of great interest, after right-sided tumors were shown to have a worse prognosis than left-sided ones and biologics were found to differ in efficacy based on side. At the 2017 ASCO Annual Meeting, studies explored why this might be so. 

Three years ago, the landmark Cancer and Leukemia Group B and Southwest Oncology Group (CALGB/SWOG) 80405 trial of 1,137 patients with advanced or metastatic adenocarcinoma of the colon or rectum showed that cetuximab (Erbitux) and bevacizumab (Avastin), when added to chemotherapy, yielded similar outcomes.1 Since that report, the CALGB/SWOG 80405 investigators have been milling the data for more information. 

Findings that emerged were “rather surprising,” according to lead investigator Alan P. Venook, MD, of the University of California, San Francisco. Median overall survival was 14 months lower for patients with right-sided tumors (19.4 vs 33.3 months; hazard ratio [HR] = 1.55; P < .0001), and an interaction was shown between sidedness and biologic treatment.2 

Left-sided tumors had a better median survival with cetuximab than bevacizumab (36.0 vs 31.4 months), and overall survival was worst when right-sided tumors were treated with cetuximab (16.7 months), Dr. Venook reported at the 2016 ASCO Annual Meeting. The study only addressed the outcomes with the first-line use of these agents and did not address subsequent usage. 

Based on additional supportive findings, the concept that sidedness is both prognostic and predictive is “not in doubt,” Dr. Venook said. 

Deciphering the Meaning of Sidedness 

THE NEXT STEP was to determine the meaning of this “sidedness,” he said at this year’s ASCO Annual Meeting. “It can’t just be right vs left. What other factors may be important?” 

TUMOR SIDEDNESS IN COLON CANCER

  • The landmark CALGB/SWOG 80405 study found that overall survival was 14 months better for patients with left-sided tumors, vs right-sided ones.
  • In an additional analysis, sidedness remained an independent prognostic factor.
  • Other studies have confirmed the prognostic and predictive power of tumor sidedness, with some showing an interplay with mutational status.
  • An analysis of the PETACC-8 trial showed that the effect of sidedness was only pronounced after recurrence. Right-sided tumors were associated with a shorter disease-free survival in patients with BRAF and RAS wild-type tumors but a longer disease-free interval in mutated tumors.
  • In the NSABP/NRG C-07 trial, sidedness was not associated with recurrence-free survival or with treatment benefit from oxaliplatin in stage III patients, except in patients with enterocyte tumors and left-sided tumors, who had more benefit from oxaliplatin.

To this end, the CALGB/SWOG 80405 investigators delved further into the clinical records and molecular characteristics of the biospecimens, aiming “to identify biomarkers that could replace right-vs-left and individualize care,” he said.3 “We asked whether we could assign the difference to a molecular, not a sidedness, feature.” 

In a multivariate analysis that included age, race, gender, synchronous vs metachronous metastases, consensus molecular subtypes, and mutational events (microsatellite instability [MSI], BRAF, NRAS, KRAS, and HRAS alterations), sidedness remained an independent prognostic factor for survival (HR = 1.392; P = .031), Dr. Venook reported. 

To determine whether this is a result of greater tumor burden in the right side of the colon, the researchers examined volume, number, sites, and resection of metastases; level of lactate dehydrogenase (LDH); blood tumor markers; and more but found no evidence for this as an explanation. The working hypothesis is that differences in tumor biology are responsible, Dr. Venook said. 

This could simply reflect embryology, he proposed: The right side of the colon is derived from the midgut, whereas the left comes from the hind gut—two structures with different cells of origin. Further DNA and RNA sequencing, along with factors yet to be explored, such as the microbiome, immune environment, and the contribution of cancer stem cells, could prove influential. 

“Further work is needed to determine the mechanism by which sidedness remains an independent prognostic variable,” Dr. Venook concluded. 

Sidedness and Prognosis After Relapse 

EUROPEAN INVESTIGATORS also reported an association between sidedness and prognosis, especially after relapse, in an analysis of 1,869 patients in the PETACC-8 trial.4 The study evaluated cetuximab in patients with stage III colon cancer and found no benefit. By sidedness, the current analysis showed that when patients experienced a recurrence, survival was worse for those with right-sided cancers. The status of RAS and RAF was also a factor. 

Julien Taieb, MD

Julien Taieb, MD

“Sidedness seems to be associated with disease recurrence differently in RAS/BRAF wild-type and mutated patients,” said Julien Taieb, MD, of the Université Paris Descartes in France. 

Right-sided tumors were associated with a shorter disease-free survival in patients with double–wild-type colon cancer (HR = 1.39; P = .04) but with longer disease-free survival in patients with RAS/BRAF-mutated disease (HR = 0.77; P = .01). The results were independent of the treatment received; cetuximab exerted no benefit on outcomes in left-sided tumors, Dr. Taieb reported. He noted that this is in contrast to the benefit shown in left-sided metastatic tumors in CALGB/SWOG 80405. 

Molecular Subtypes and Sidedness 

THE QUESTION of the influence of molecular subtype was explored in a study reported by S. Rim Kim, MD, of the National Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology, in Pittsburgh.5 The analysis showed the proportion of subtypes did vary significantly between the right and the left sides of the colon. The data came from 1,603 patients in the NSABP/NRG C-07 trial, in which the molecular classifiers were the Colorectal Cancer Assigner (CRCA), Colon Cancer Subtypes (CCS), and Consensus Molecular Subtypes (CMS). 

S. Rim Kim, MD

S. Rim Kim, MD

The predominant subtypes among right-sided tumors were goblet-like, inflammatory, CMS1 (immune), CMS3 (metabolic), and CCS2. Predominant types in the left side of the colon were enterocyte, transit-amplifying, CCS1, and CMS2 (canonical). Stem-like/ CMS4 (mesenchymal) subtypes, which are associated with a poor prognosis, had a similar distribution. 

“Sidedness was not associated with recurrence-free survival in NSABP/NRG C-07 or with treatment benefit from oxaliplatin,” Dr. Kim reported. This was true for the entire cohort and for patients with stage III disease, except for those with stage III enterocyte tumors and left-sided tumors, who did benefit from oxaliplatin. “This remained significant even after adjusting for other clinical and molecular variables, including tumor sidedness (P = .005),” Dr. Kim reported. 

Prognosis was poor for patients with stage III stem-like/CCS3/ CMS4 (mesenchymal) subtypes, who did not derive a benefit from oxaliplatin. ■

DISCLOSURE: Dr. Venook has received honoraria from Gilead Sciences; has served as a consultant or advisor for Gilead and Merrimack; and has received travel expenses from Bristol-Myers Squibb, Genentech, Merck Serono, Merrimack, Roche, and Taiho Pharmaceuticals. Dr. Taieb has had a consulting or advisory role for Amgen, Baxalta, Celgene, Lilly, Merck KGaA, Roche, and Servier and has served on speakers bureaus for Amgen, Baxalta, Lilly, Merck, Roche/Genentech, Sanofi, and Servier. Dr. Kim reported no conflicts of interest. 

REFERENCES 

1. Venook AP, Niedzwiecki D, Lenz H-J, et al: CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab or cetuximab for patients with KRAS wild-type untreated metastatic adenocarcinoma of the colon or rectum. 2014 ASCO Annual Meeting. Abstract LBA3. Presented June 1, 2014. 

2. Venook AP, Niedzwiecki D, Innocenti F, et al: Impact of primary tumor location on overall survival and progression-free survival in patients with metastatic colorectal cancer: Analysis of CALGB/SWOG 80405 (Alliance). 2016 ASCO Annual Meeting. Abstract 3504. Presented at a press briefing May 19, 2016. 

3. Venook AP, Ou F, Lenz H, et al: Primary tumor location as an independent prognostic marker from molecular features for overall survival in patients with metastatic colorectal cancer: Analysis of CALGB/SWOG 80405 (Alliance). 2017 ASCO Annual Meeting. Abstract 3503. Presented June 5, 2017. 

4. Taieb J, Kourie HR, Emile JF, et al: Association of prognostic value of primary tumor location in stage III colon cancer with RAS and BRAF mutational status. 2017 ASCO Annual Meeting. Abstract 3515. Presented June 3, 2017. 

5. Kim S, Song N, Yothers G, et al: Tumor sidedness and intrinsic subtypes in patients with stage II/III colon cancer: Analysis of NSABP C-07 (NRG Oncology). 2017 ASCO Annual Meeting. Abstract 3514. Presented June 3, 2017.


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