Adjunction of immune response into the TNM classification system improves the prediction of colon cancer (CC) prognosis. However, immune response measurements have not been used as robust biomarkers of pathology in clinical practice until the introduction of Immunoscore (IS), a standardized assay based on automated artificial intelligence assisted digital pathology. The strong prognostic impact of the immune response, as assessed by IS, has been widely validated and IS can help to refine treatment decision making in early CC. In this study, we compared pathologist visual scoring to IS. Four pathologists evaluated tumor specimens from 50 early-stage CC patients and classified the CD3+ and CD8+ T-cell densities at the tumor site (T-score) into 2 (High/Low) categories. Individual and overall pathologist scoring of immune response (before and after training for immune response assessment) were compared to the reference IS (High/Low). Pathologists’ disagreement with the reference IS was observed in almost half of the cases (48%) and training only slightly improved the accuracy of pathologists’ classification. Agreement among pathologists was minimal with a Kappa of 0.34 and 0.57 before and after training, respectively. The standardized IS assay outperformed expert pathologist assessment in the clinical setting.
Conclusions: Neoadjuvant nivolumab in CC pts is feasible, do not compromise surgery and leads to an increase of T lymphocytes immune infiltration of the tumor. Nivolumab could represent a backbone of preoperative treatments in pMMR early stage CC.
(1) Background—The five-year overall survival (OS) of muscle-invasive bladder cancer (MIBC) with neoadjuvant chemotherapy and cystectomy is around 50%. There is no validated biomarker to guide the treatment decision. We investigated whether the Immunoscore (IS) could predict the pathologic response to neoadjuvant chemotherapy and survival outcomes. (2) Methods—This retrospective study evaluated the IS in 117 patients treated using neoadjuvant chemotherapy for localized MIBC from six centers (France and Greece). Pre-treatment tumor samples were immunostained for CD3+ and CD8+ T cells and quantified to determine the IS. The results were associated with the response to neoadjuvant chemotherapy, time to recurrence (TTR), and OS. (3) Results—Low (IS-0), intermediate (IS-1–2), and high (IS-3–4) ISs were observed in 36.5, 43.7, and 19.8% of the cohort, respectively. IS was positively associated with a pathologic complete response (pCR; p-value = 0.0096). A high IS was found in 35.7% of patients with a pCR, whereas it was found in 11.3% of patients without a pCR. A low IS was observed in 48.4% of patients with no pCR and in 21.4% of patients with a pCR. Low-, intermediate-, and high-IS patients had five-year recurrence-free rates of 37.2%, 36.5%, and 72.6%, respectively. In the multivariable analysis, a high IS was associated with a prolonged TTR (high vs. low: p = 0.0134) and OS (high vs. low: p = 0.011). (4) Conclusions—This study showed the significant prognostic and predictive roles of IS regarding localized MIBC.
Background: The absolute benefit of 5-fluorouracil-based adjuvant chemotherapy in stage II CRC is only 3-4%. The identification of biomarkers through deep molecular profiling could provide information about diagnosis, prognosis, but especially to identify those patients who will benefit more from adjuvant chemotherapy.Methods: This is a single-institution retrospective analysis that has examined formalin-fixed paraffin-embedded (FFPE) tissue blocks retrieved from surgical resection, from patients affected by refractory stage II CRC, who underwent surgery from 2009 to 2015 and whose comprehensive genomic profiling of tumors was conducted through next-generation sequencing (NGS) via Roche-FoundationOne © .
BackgroundThe presence of high levels of stromal tumor infiltrating lymphocytes (TILs) has been associated with better prognosis in early triple-negative breast cancer (TNBC). The Immunoscore® (IS) is a prognostic tool, which categorizes the densities of spatially positioned CD3 and CD8 cells in both invasive margins (IM) and the center of the tumor (CT), yielding a five-tiered classification (0–4). High IS values have been reported to predict improved outcomes in colorectal cancer.MethodsThe cohort consisted of 52 TNBC patients (pts) who previously received neo-adjuvant anthracycline and taxane based chemotherapy. Quantitative analysis of the immune cells was carried out using a computer-assisted image analysis in different tumor locations for CD3 and CD8 T-cell markers. Additionally, we measured stromal TILs according to the internationals TILs working group. Pre-treatment tumor samples were immune-stained for CD3 and CD8 T-cell markers and stromal TILs. The relationship between various clinical pathological factors including tumor size, glands, stage and immune factors were analyzed by Chi2 and Fischer exact test. The logrank test and the Kaplan Meyer methods were used to estimate relapse free survival.ResultsThe median age of the patients was 50 years (27–84 years). Tumor sizes were categorised as T1 = 9 patients (17%), T2 = 41 patients (77%) and T3 = 3 patients (6%). Patients with positive glands = 19 (36%) patients and patients without gland involvement = 34 (64%). Stage grouping included stage 1 = 5 (9%), stage IIA = 33 (63%) patients, stage IIB = 9 (17%) patients, stage III = 6 (11%) patients. The median Ki-67 was 45% (5 – 90%). The median density of CD3 CT cells = 1190 mm² (range 34 – 4614), CD3 IM = 1855 mm² (range 57 – 6190), CD8 CT 508 mm² (range 17 – 2486) and CD8 IM 805 mm² (range 90 – 3156). The median percentage of stromal TIL’s was 5% (0 – 60%). Patient with an IS of 0 = 4 patients (8%), IS 1 = 3 (5%), IS 2 = 20 patients (38%), IS 3 = 24 patients (45%) and IS 4 = 2 patients (4%). The pathological complete response (pCR) rate of the entire cohort was 62%. A positive correlation was found between TILs and CD3 CT (R = 0.641, p < 0.0000), CD8 CT (R = 0.5623, p < 0.0000), CD3 IM (R = 0.6099, p < 0.0000), and CD8 IM. (R = 0.5010, p < 0.0010). TILs correlated with immunoscore (R = 0,3603, p < 0.0087). There was no correlation between TILs and Ki-67 (R = 0.1497, p < 0.2943). On univariate analysis, factors associated with higher pCR included nodal status (positive = 42,11% vs negative = 73,53% (p<0,02362) and Ki67 <40%= 33,33% vs =40% = 76,47% (p<0,00235). A high density of CD3 (> than 1100 mm2) and CD8 (> than 400 mm2) positive T-cells in the CT was associated with higher pCR (CD3 CT: 30% vs 70%, p=0.00489 and CD8 CT: 30% vs 70%, p=0.03344). Analysis of CD3 (> than 1200 mm2) (CD3 IM: 12% vs 88%, p=0.0.02367) and CD8 in the IM (> than 550 mm2) was also significant for an association with pCR (CD8 IM:23% vs 77%, p=0.03). High IS (3+4= 73%) vs intermediate (2=55%) vs low (0+1=43%) showed a numerical difference, however, did not reach a statistical significance with pCR (p=0.111). Analysis of TILs = 20% showed a pCR of 76% compared to patients with TILs < 20% with a pCR of 54% (p < 0.12295). A Ki67 =40% was associated with pCR of 76% compared to patients with Ki67 < 40% with a pCR 33% (p < 0.00235).The median time to progression of the patients not attaining a pCR was 1600 days, compared to patients who did attain a pCR with a median PFS not reached yet, but exceeds 1800 days. The median time to progression of patients with Ki67 < 40% was 1700 days while the patients with Ki67 =40% has not been reached yet (p < 0.03). At 1800 days, 95% of patients with CD3 > 1100 mm2 did not relapse, compared to 75% patients with CD3 = 1100 (p < 0.03).ConclusionsThis exploratory study shows that analysing CD3 and CD8 in the centre of the tumor and invasive margin might be more sensitive than examination of TILs in TNBC patients.Ethics ApprovalThe study was approved by Pharma-Ethics - (Institution’s Ethics Board), approval number 170516563.
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