by Pam Harrison –
MSI status has clear prognostic value in stage II CRC
Julien Taieb, MD, PhD, University of Paris Descartes, Paris, France
Microsatellite instability (MSI), a molecular marker of defective DNA mismatch repair (dMMR), should be determined in all patients 60 years of age and under with colorectal cancer (CRC) as it has clear prognostic value in those with stage II CRC as well as in patients with Lynch syndrome.
Julien Taieb reviewed evidence on the prognostic implications of new biomarkers, such as MSI, in determining outcome following surgical resection as well as certain adjuvant chemotherapy regimens. In one study reviewed by Dr. Taieb, almost twice as many patients with dMMR stage II and III tumors treated with surgery alone were alive and free of disease progression at 5 years compared to patients with proficient MMR (pMMR) tumors.
A systematic review of a number of studies also indicated that patients with dMMR tumors have a more favourable, stage-adjusted prognosis than patients with pMMR tumors. For example, in one study carried out in stage III patients receiving adjuvant FOLFOX, investigators found patients with MSI tumors were significantly more likely to be alive and free of disease at 6 years than patients with microsatellite stable (MSS) tumors (Hazard Ratio (HR)=2.11, p=0.037).
On the other hand, findings from the recent MOSAIC study suggested that determination of MSI status made no difference to disease-free or overall survival (OS) in stage III patients treated with adjuvant FOLFOX, the regimen being as efficient in MSI or MSS stage III tumours. Dr. Taieb suggested that oxaliplatin component of the FOLFOX regimen may be able to overcome resistance to 5-FU seen with MSI tumours.
To determine if colon cancer patients should be considered for chemotherapy or not, Dr. Taieb suggested stage II tumors be tested for MSI or MSS status. If stage II patients have MSI tumors, they already have a good prognosis and they are likely to be resistant to 5-FU so they should not receive chemotherapy. For stage II CRC patients with MSS tumours, chemotherapy may be discussed based on the presence of other prognostic factors including patient preference to undergo chemotherapy
For stage III patients, no MSI determination is needed, as FOLFOX chemotherapy is already offered as standard-of-care following surgical resection.
CRC highly heterogeneous and so are treatment responses
Sabine Tejpar, MD, PhD, University Hospital Gashuisberg, Leuven
Colorectal cancer (CRC) is a highly heterogeneous cancer and depending on what marker is used to identify different subgroups, responses to therapy may be significantly different than those seen in the overall cohort, according to experts here.
Sabine Tejpar reviewed several examples of clinical trials where subgroup stratification markedly affected interpretation of how effective the drug regimen in question was. For example, in unselected patients, progression-free survival (PFS) in CRC patients receiving cetuximab was significantly better than best supportive care at 12 months follow-up in an earlier pivotal study.
However, when the cohort was stratified by KRAS mutational status, only patients with KRAS wild-type (WT) mutations responded better to cetuximab than supportive care. Furthermore, the location of the primary tumour on either the right or the left side of the colon was highly predictive of benefit from cetuximab among the same KRAS WT subset. Proximal and distal colon tumors are also distinct biological entities, as Dr. Tejpar noted.
Pathways giving rise to tumors are also quite different based on which side of the gut they occur. While survival results may be identical during a treatment trial regardless of tumour location, at least one study cited by Dr. Tejpar showed that survival following relapse was significantly in favor of patients with left-sided lesions. These findings indicate that tumour site is highly influential in the metastatic setting, as she noted.
“When we look at the data, the markers – molecular, histological or clinical – are going to separate your curves and it’s very hard to predict in what way,” Dr. Tejpar said. In an effort to improve on predictability of treatment response, groups are working towards a consensus of gene-expression based subtyping of CRC. At ASCO this year, for example, a new diagnostic classification system was reported in which CRC was broken down into 3 completely different subtypes based on tumour gene expression patterns. These tumour subtypes were associated with different responses to adjuvant chemotherapy and thus different prognoses.
It is anticipated that broad molecular classification of CRC will help clinicians select which treatment would be best for individual patients.
Drug targets being actively explored in early and late CRC
Josep Tabernero, MD, PhD, Vall d’Hebron University Hospital, Barcelona
Numerous new drug targets in colorectal cancer (CRC) are being actively explored in an effort to improve overall outcomes for patients with early and late-stage disease.
Josep Tabernero provided a broad overview of the different pathways researchers are exploring in search of more effective drugs. “The first concept is to try and get more efficient EGFR inhibition,” Dr. Tabernero noted.
Another approach would rely on a mixture of monoclonal antibodies that target different epitopes of the EGFR receptor, the aim being to induce synergistic therapeutic effects. Monoclonals are also being developed that target other members of the HER family including HER-3, which has been associated with tumor resistance in CRC. Indeed, a clinical trial is already underway evaluating two anti-HER 2 monoclonals in a HER-2 enriched CRC cohort, as Dr. Tabernero noted.
A number of trials are also evaluating BRAF V600E inhibitors in combination with anti-EGFR inhibitors in a BRAF V600E mutant CRC population. “These 2 inhibitors are very active and I’m completely sure this concept is going to work,” Dr. Tabernero said. Integrin-mediated interactions in turn play a critical role in regulating cell proliferation, migration and survival, as he also noted, and several strategies are underway to interrupt angiogenesis promoted by the integrins.
“Immune activation may also produce favourable responses,” Dr. Tabernero added. Activity induced by PD-1 and PD-L1 immunotherapy is already being reported in a number of cancers, including CRC.
Choosing adjuvant chemotherapy in stage III CRC
Aimery de Gramont, MD, PhD, professor of oncology, Hopital Sainte-Antoine, Paris, France
Based on the best clinical trial evidence to date, a leading expert in colorectal cancer (CRC) has developed an algorithm to help clinicians match adjuvant chemotherapy to risk in stage III CRC.
“Most patients want to be treated if they can have an absolute survival benefit of more than 3%,” Aimery de Gramont told delegates here. Based on best clinical trial evidence to date, Dr. de Gramont proposed the following algorithm to best match the various risk categories for stage III disease. For stage III A disease, the best adjuvant treatment option is 5-FU.
For intermediate risk stage IIIB patients, either FOLFOX or XELOX regimens may be considered. FOLFOX or XELOX are again well suited for high-risk patients, including those with stage IIIC and elderly males <75 years of age and elderly females <80.
For those with pre-existing neuropathy; frail patients, or elderly males >75 years and elderly females >80, it is best to revert back to 5-FU.