‘Improving clinical management of colon cancer through CONNECTION, a nation-wide Colon Cancer Registry and Stratification effort.’

Colorectal cancer is the third most common cancer in the Netherlands with an incidence around 14,500 patients in 2017. Patients with high-risk stage II (defined as T4N0) or III colon cancer routinely undergo surgery with curative intent and are being offered adjuvant chemotherapy to reduce the chance of recurrence of disease, when fit for treatment. Despite this intensive treatment, 20% of the patients with high risk stage II and 30-35% of the patients with stage III colon cancer will still develop metastatic disease. In addition, on estimate, 50% of the patients with high-risk stage II and stage III colon cancer would never develop metastases after surgery and are therefore over-treated with adjuvant chemotherapy. Unfortunately, it is currently not possible to predict and identify the patients who will develop recurrence of disease without adjuvant therapy after surgery and therefore it is not feasible to perform optimal patient selection for adjuvant chemotherapy. The consensus molecular subtypes (CMS) in colorectal cancer, consisting of four molecular subtypes, is currently considered the most robust classification of colorectal cancers with clear distinctive biological features. Although the available evidence does not clearly delineate the predictive and prognostic value of CMS, the biological features of the subtypes and the scarce literature available provide some handles.
First, CMS1 tumours, which are generally MSI and hypermutated, show high response to immunotherapy in metastatic disease. It is quite evident that survival of patients with an MSI tumour is much better compared to patients with MSS tumours and it has also been observed that MSI predicts lack of response to conventional chemotherapy. Therefore, according to the new recommendations of the “Dutch Association of Medical Oncology” (NVMO), the advice is to refrain from adjuvant chemotherapy in patients with an MSI tumour staged as high-risk stage II given that for these patients adjuvant chemotherapy has no clinically relevant benefit. Second, CMS4 tumours, characterized by a mesenchymal phenotype, seem to have a worse prognosis when compared to CMS1-3. This may be due to biological features resulting in more metastatic potential and/or a poor response to chemotherapy. Roepman et al showed a similar overall survival for patients treated with and without adjuvant chemotherapy for patients with colorectal cancer classified as a mesenchymal phenotype. Last, CMS2 and CMS3 remain subtypes for which the response to chemotherapy is unknown. Recent data indicate that in the adjuvant setting the benefit of oxaliplatin is only observed in a proportion of colon cancers, which predominantly belong to the CMS2 subtype. Combined, these observations provide further support for the idea that subtypes may be used to predict response to therapy. A solid response monitoring per subtype is hard to obtain because differences in prognosis and response to therapy are difficult to segregate in these patients.
The FOxTROT Collaborative Group (2012) was the first to set up a trial with neoadjuvant chemotherapy in patients with locally advanced resectable colon cancer and concluded that preoperative chemotherapy is feasible with acceptable toxicity and perioperative morbidity. These observations lead us to propose a study to investigate the role of subtypes on therapy response in a novel neoadjuvant setting that allows to determine therapy efficacy in individual patients and in the different early stage colon cancer subtypes.

CMC subtypes matter in the therapy response to systemic chemotherapy for patients with high risk stage II and stage III colon cancer

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neoadjuvant CAPOX