High PI3K expression is associated with CRC metastasis. PI3K inhibitor induced apoptosis in CRC cells and displayed strong cytotoxicity for highly metastatic cells. PI3K inhibition may be an effective treatment for CRC.
BackgroundKi67 labeling index (LI) is used as a predictive marker and is associated with prognosis in breast cancer. However, standardised methodologies for measurement are lacking which has limited its application in clinical practice. In this study, we evaluated the interobserver concordance of visual assessment of Ki67 LI in breast cancer.MethodsKi67- immunostained slides of 160 cases of primary invasive breast cancer were visual assessed by five breast pathologists with two different methods to choose the scoring fields: (1) hot-spot score, (2) average score. Proportions of positive invasive tumor cells at 10 % intervals were scored. The intra-class correlation coefficient (ICC) was used to assess the interobserver reproducibility.Results(1) A perfect concordance of Ki67 LI was demonstrated according to both score methods (P<0.0001). Average score method (ICC, 0.904) demonstrated a better correlation than hot-spot score method (ICC, 0.894). (2) By respective means according to two score methods, all cases were classified into three groups (≤10%, 11%-30% and >30% Ki-67 LI). The concordance was relatively low in intermediate Ki67 LI group compared with low and high Ki67 LI groups. (3) All cases were classified into three groups by paired-difference (d) between means of hot-spot score and average score (d<5, 5≤d<10, d≥10). The consistency was observed to decrease with increasing paired-difference according to both methods.ConclusionsVisual assessment of Ki67 LI at 10 % intervals is a candidate for a standard method in breast cancer clinical practice. Average score and hot-spot score of visual assessment both demonstrated a perfect concordance, and an overall average assessment across the whole section including hot spots may be a better method. Interobserver concordance of intermediate Ki67 LI in which most cutoffs are located for making clinical decisions was relatively low.
BackgroundTriple-negative breast cancers (TNBCs) are a group of heterogeneous diseases with various morphology, prognosis, and treatment response. Therefore, it is important to identify valuable biomarkers to predict the therapeutic response and prognosis for TNBCs. Tumor-infiltrating lymphocytes (TILs) may have predictive value to pathological complete response (pCR) in neoadjuvant treated TNBCs. However, absence of standardized methodologies for TILs measurement has limited its evaluation and application in practice. In 2014, the International TILs Working Group formulated the recommendations of pathologic evaluation for TILs in breast cancers.MethodsTo evaluate the predictive value of TILs scored by methods recommended by International TILs Working Group 2014, we performed a retrospective study of TILs in 166 core needle biopsy specimens of primary invasive TNBCs with neoadjuvant chemotherapy (NAC) in a Chinese population. Intratumoral TILs (iTILs) and stromal TILs (sTILs) were scored respectively. The associations between TILs and pCR were analyzed.ResultsBoth sTILs (p = 0.0001) and iTILs (P = 0.001) were associated with pCR in univariate logistic regression analysis. Multivariate logistic regression analysis indicated that both sTILs (P = 0.006) and iTILs (P = 0.04) were independent predictors for pCR. Receiver operating characteristics (ROC) curve analysis was used to identify the optimal thresholds of TILs. TNBCs with more than 20% sTILs (P = 0.001) or with more than 10% iTILs (P = 0.003) were associated with higher pCR rates in univariate analysis. Multivariate analysis showed that a 20% threshold of sTILs (P = 0.005) was an independent predictive factor for pCR.ConclusionsOur study indicated that TILs scored by recommendations of International TILs Working Group 2014 in pre-NAC core needle biopsy specimens was significantly correlated with pCR in TNBCs, higher TILs scores predicting higher pCR rate. Both sTILs and iTILs were independent predictors for pCR in TNBCs. A 20% threshold for sTILs may be feasible to predict pCR to NAC in TNBCs.
Background:Expert consensus on BRCA1/2 genetic testing and clinical application in Chinese breast cancer patients recommends that BRCA1/2 testing should be performed in those with clinical risk factors, such as an early onset, triple-negative breast cancer (TNBC) or family history of cancer. With the increasing application of multigene panels, testing for genes beyond BRCA1/2 has become more prevalent. However, the non-BRCA mutation status of Chinese high-risk breast cancer patients has not been fully explored.Methods: A total of 230 high-risk breast cancer patients from Fudan University Shanghai Cancer Center who had undergone peripheral blood germline 72 genes next-generation sequencing (NGS) from June 2018 to June 2020 were enrolled for retrospective analysis. The 72 genes include common hereditary breast cancer genes, such as homologous recombination repair (HRR) genes and other DNA damage repair genes. High-risk factors included: 1) TNBC; 2) male breast cancer; 3) primary bilateral breast cancer; 4) diagnosed with breast cancer at age less than or equal to 40 years; or 5) at least one first- and/or second-degree relative with BRCA-related cancer (breast or ovarian or prostate or pancreatic cancer).Results: The germline pathogenic or likely pathogenic mutation rate was 29.6% (68/230) in high-risk breast cancer patients. Among them, 44 (19.1%, 44/230) were identified as harboring BRCA1/2 mutation, and 28 (12.2%, 28/230) patients carried non-BRCA germline variants. Variants were detected in 16 non-BRCA genes, including PALB2 (5, 2.2%), ATM (4, 1.7%), RAD51D (3, 1.3%), TP53 (3, 1.3%), CHEK2 (2, 0.9%), FANCA (2, 0.9%) and ATR, BARD1, BRIP1, ERCC3, HOXB13, MLH1, MRE11, PMS2, RAD51C, RAD54L (1, 0.4%). Besides, 22 (9.6%, 22/230) patients were non-BRCA HRR gene mutation (including ATM, ATR, BARD1, BRIP1, CHEK2, FANCA, MRE11, PALB2, RAD51C RAD51D and RAD54L) carriers. Among high-risk factors, family history showed a correlation with both BRCA (p = 0.005) and non-BRCA HRR gene mutation status (p = 0.036). In addition, TNBC showed a correlation with BRCA1 gene mutation status (p = 0.038). However, other high-risk factors have not shown significantly related to BRCA1/2, non-BRCA genes and non-BRCA HRR gene mutations (p > 0.05). In addition, 312 unique variants of uncertain significance (VUS) were identified among 175 (76.1%, 175/230) patients and 65 different genes.Conclusions: Non-BRCA gene mutations are frequently identified in breast cancer patients with high risk factors. Family history showed a correlation with both BRCA (p = 0.005) and non-BRCA HRR gene mutation status (p = 0.036), so we strongly suggest that breast cancer patients with a BRCA-related family history receive comprehensive gene mutation testing in China, especially HRR genes, which are not only related to high risk of breast cancer, but also potentially related to poly ADP ribose polymerase inhibitor (PARPi) targeted therapy. The exact relationship of rare gene mutations to breast cancer predisposition and the pathogenicity of VUS need to be further investigated.
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