In a presentation at the 33<sup>rd</sup> Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cance, Dr. Galon discussed the definition of the immune contexture of Immunoscore, its international validation for the risk-classification of stage I-III colon cancer, and the potential value of Immunoscore in stage IV metastatic disease.
Jerome Galon, PhD
The immunoscore diagnostic assay has robust prognostic value in the management of patients with colon cancer stages I-III and also may be helpful in predicting the risk of recurrence in patients with stage IV cancer, according to Jérôme Galon, PhD, research director and head of the Laboratory of Integrative Cancer Immunology in Paris, France. In a presentation at the 33rdAnnual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2018), Dr. Galon discussed the definition of the immune contexture of Immunoscore, its international validation for the risk-classification of stage I-III colon cancer, and the potential value of Immunoscore in stage IV metastatic disease.
Immunoscore Colon is a validated test that predicts the risk of relapse in early-stage and locally advanced colon cancer by measuring the host immune response at the tumor site. This risk-assessment tool provides independent and superior prognostic value, compared with the usual tumor risk parameters, and is intended to be used as an adjunct to the TNM classification to guide patients’ management.
“Risk assessment is particularly important in order to decide when to propose an adjuvant treatment to an individual patient with early colon cancer,” Dr. Galon said. “Better risk stratification could improve adjuvant treatment selection to help patients avoid unnecessary toxicities without compromising outcomes.”
According to Dr. Galon, adjuvant treatment is generally recommended for patients with stage III and high-risk stage II disease. Patients with stage II colon cancer are considered at high risk if they present with at least one of the following clinical features: lymph nodes sampling < 12, poorly differentiated tumor, vascular or lymphatic or perineural invasion, and tumor presentation with obstruction or tumor perforation and pT4 stage. However, this does not apply directly to patients with stage III disease.
Results from the international IDEA trial led to more refined risk stratification data for patients with stage III disease. The investigators determined that many patients with low-risk stage III colon cancer can receive three months of therapy instead of the standard six months.1This could allow some patients to receive a shorter duration of adjuvant therapy, leading to fewer toxicities and adverse events.
However, determining who is at high or low risk can be challenging, and there are still unmet medical needs to improve the estimation of risk-of-recurrence of patients with colon cancer. “[There is] especially the need to identify patients in stage II who need treatment [and] patients in stage III who would be harmed by reducing treatment duration based primarily on tumor and node staging,” Dr. Galon said.
This is in part because survival is not directly correlated to TNM stage, and clinical outcomes can vary significantly among patients within the same histological tumor stage due to other clinical and pathologic features. Therefore, patients at high risk must be identified more accurately than what is currently accomplished with TNM alone, and there is a need for a better risk-factor staging system to improve patient prognostication and optimize decisions about adjuvant therapy.
Additionally, five-year survival rates after surgical resection range widely. Patients with stage I colon cancer have about a 92 percent five-year survival rate; stage II, between 65 percent and 87 percent; stage III, between 72 percent and 53 percent; and stage IV, about 12 percent.2“The wide ranges reflect major differences in prognosis depending upon the stage subset, tumor grading, and the other biological characteristics,” Dr. Galon said.
The Immunoscore test could be a better way to stratify these patients accurately and assess each patient’s needor lack thereof—for adjuvant therapy, improving survival outcomes. A large SITC-led validation study confirmed that there is a strong prognostic value in the Immunoscore assay in early-stage colon cancer.
Immunoscore demonstrated a high level of reproducibility between observers and centers (P< 0.0001). In the training set of the study, patients with a high Immunoscore had the lowest risk of recurrence at five years (14 [8 percent] patients with a high Immunoscore, 65 [19 percent] patients with an intermediate Immunoscore, and 51 [32 percent] patients with a low Immunoscore; HR for high vs. low Immunoscore, 0.20; 95 percent CI, 0.10-0.38;P< .0001).3
Immunoscore had the highest relative contribution to identify the risk of all clinical parameters, including the TNM classification system. Immunoscore’s ability to predict overall survival (OS) was superior to that of existing tumor risk parameters such as grade of differentiation; microsatellite instability (MSI) status; mucinous colloid type; sidedness; and venous emboli, lymphatic invasion, and perineural invasion criteria.
Additionally, Dr. Galon noted that patients with a high Immunoscore had a prolonged disease-free survival (DFS) rate regardless of their MSI status. In the training set, a significant difference in time to recurrence was also found between patients with high and intermediate Immunoscores (unadjusted HR, 0.38; 95 percent CI, 0.21-0.70;P= 0.0011), OS (P= .035), and DFS (P= .0050).
OS at five years was achieved for 155 (82 percent) patients with a high Immunoscore, 274 (77 percent) patients with an intermediate Immunoscore, and 94 (62 percent) patients with a low Immunoscore (unadjusted HR for high vs. low Immunoscore, 0.53; 95 percent CI, 0.38-0.75;P= 0.0004).
“These results validate the reliability of Immunoscore Colon in identifying patients with a high risk of recurrence, independently of the TNM staging system,” Dr. Galon said. “Prognostication by the TNM staging was improved by Immunoscore, supporting its implementation as a new component of a TNM-Immune classification of cancer.”
In a phase III study of patients treated with adjuvant FOLFOX (folinic acid [leucovorin], fluorouracil, and oxaliplatin), the Immunoscore and CD3+ invasive margin tests were each significantly discriminant for prognosis for patients with stage III colon cancer in low-risk (T1-3N1) and high-risk (T4 or N2) subsets. When using a prior Immunoscore risk classification, higher results were associated with significantly better DFS (HR, 0.59; 95 percent CI, 0.43-0.82;P= 0.0013). A high versus low Immunoscore was also significantly associated with better three-year DFS rates among T1-3N1 patients (91percent vs. 77percent) and T4 or N2 patients (68 percent vs. 54 percent).4
The study authors concluded that the Immunoscore test is prognostic in patients with stage III colon cancer and is strongly prognostic within low- and high-risk T and N subsets as defined in the IDEA study. The data underscore the limitations of TNM staging and demonstrate the prognostic potential of immune biomarkers (TABLE).
However, the Immunoscore test is not without its limits. The test is proposed from a central laboratory (HalioDx CLIA Lab) and validated only for colon cancer. However, Immunoscore could be useful in many other indications, and according to Dr. Galon, further studies are ongoing. For example, the test’s usefulness in patients with advanced melanoma has been demonstrated, with continuing research efforts to correlate marker expression profile with clinical outcomes. The score could also serve as a useful prognostic marker in patients with rectal cancer who have undergone primary surgery. Another study examined a multivariable suppression index scoring system in patients with oral squamous cell carcinoma. The cumulative index evaluates both the tumor and stromal microcompartments at the invasive margin and incorporates those findings into the Immunoscore, providing accurate stratification, independent of stage or tumor classification.
Additionally, the proportion of patients with metastatic colon cancer who are eligible for inflammatory cell infiltration could be refined and extended by the characterization of their primary tumor immune infiltrate based on Immunoscore status. To validate the Immunoscore’s predictive value for this use, interventional trials are needed.