Altona Prognostic Index: A New Prognostic Index for ER-Positive and Her2-Negative Breast Cancer of No Special Type

Breast cancer is a heterogeneous disease representing a number of different histopathologic and molecular types which should be taken into consideration if prognostic or predictive models are to be developed. The aim of the present study was to demonstrate the validity of the long-known Nottingham prognostic index (NPI) in a large retrospective study (n = 6654 women with a first primary unilateral and unifocal invasive breast cancer diagnosed and treated between April 1996 and October 2018; median follow-up time of breast cancer cases was 15.5 years [14.9–16.8]) from a single pathological institution. Furthermore, it was intended to develop an even superior risk stratification model considering an additional variable, namely the patient’s age at the time of diagnosis. Heterogeneity of these cases was addressed by focusing on estrogen receptor-positive as well as Her2-negative cases and taking the WHO-defined different tumor types into account. Calculating progression free survival Cox-regression and CART-analysis revealed significantly superior iAUC as well as concordance values in comparison to the NPI based stratification, leading to an alternative, namely the Altona prognostic index (API). The importance of the histopathological tumor type was corroborated by the fact that when calculated separately and in contrast to the most frequent so-called “No Special Type” (NST) carcinomas, neither NPI nor API could show valid prognostic stratification.

Recurrence Rate of Carcinoma Breast patients Undergoing Mastectomy at Gulab Devi Hospital Lahore

Aim: To determine recurrence rate of carcinoma breast after mastectomy in our population and to determine various risk factors associated with local recurrence which would help in management of new carcinoma breast patients in future. Methods: It was a descriptive study conducted on patients of carcinoma breast with stage II and III undergoing modified radical mastectomy with negative resection margins at Gulab Devi Hospital, Lahore. Total of 59 patients were recruited in study using purposive sampling technique. Results: Mean age was 51.61±11.52 years with range from 26 to 78 year. Female 58(98.31%) predominated over the 1(1.69%) male. Recurrence rate was seen only in 5 (8.47%) female patients Conclusion: Proper surgical technique results in less chances of carcinoma breast recurrence. Menopause, positive axillary lymphnodes, lymphovascular invasion and necrosis on histology are associated factors of recurrence. MeSH: Carcinoma breast, recurrence, Nottingham Prognostic Index (NPI)

CLIP4 Shows Putative Tumor Suppressor Characteristics in Breast Cancer: An Integrated Analysis

Background: CAP-Gly domain containing linker protein family member 4 (CLIP4) plays an important role in cancers. However, its expression, prognostic value, and biological effect in breast cancer remain unclear.Methods: Data on patients diagnosed with breast cancer were retrieved from the TCGA-BRCA and other public omics databases. The expression profile of CLIP4 was analyzed using Oncomine, bc-GenExMiner, and TCGA. The prognostic value of CLIP4 was determined by Kaplan-Meier Plotter and Human Protein Atlas. Identification of genes co-expressed with CLIP4 and potential mechanism analyses were performed using UALCAN, STRING, Metascape, and GSEA. The epigenetic characteristics of CLIP4 were determined by DiseaseMeth and MEXPRESS.Results: CLIP4 was downregulated and its expression was negatively correlated with estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor type 2 (HER2) status, Nottingham prognostic index (NPI), and Scarff-Bloom-Richardson (SBR) grade in breast cancer, whereas it was positively linked to basal-like and triple negative breast cancer status. Ectopic expression of CLIP4 was related with poor prognosis. In the analysis of genes co-expressed with CLIP4, GSEA showed that the Hedgehog (Hh), JAK-STAT, ERBB, Wnt signaling pathway, cell adhesion molecules, and pathways in cancer were dissimilarly enriched in the CLIP4 expression high phenotype. Analysis of the genetics and epigenetics of CLIP4 indicated that its expression was negatively correlated with DNA methylation.Conclusion: Methylated CLIP4 may be a novel prognostic and therapeutic biomarker for breast cancer.

The ITIM-Containing Receptor: Leukocyte-Associated Immunoglobulin-Like Receptor-1 (LAIR-1) Modulates Immune Response and Confers Poor Prognosis in Invasive Breast Carcinoma

Background: The leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) plays a role in immune response homeostasis, extracellular matrix remodelling and it is overexpressed in many high-grade cancers. This study aimed to elucidate the biological and prognostic role of LAIR-1 in invasive breast cancer (BC). Methods: The biological and prognostic effect of LAIR-1 was evaluated at the mRNA and protein levels using well-characterised multiple BC cohorts. Related signalling pathways were evaluated using in silico differential gene expression and siRNA knockdown were used for functional analyses. Results: High LAIR-1 expression either in mRNA or protein levels were associated with high tumour grade, poor Nottingham Prognostic Index, hormone receptor negativity, immune cell infiltrates and extracellular matrix remodelling elements. High LAIR-1 protein expression was an independent predictor of shorter BC-specific survival and distant metastasis-free survival in the entire BC cohort and human epidermal growth factor receptor 2 (HER2)+ subtype. Pathway analysis highlights LAIR-1 association with extracellular matrix remodelling-receptor interaction, and cellular proliferation. Depletion of LAIR-1 using siRNA significantly reduced cell proliferation and invasion capability in HER2+ BC cell lines. Conclusion: High expression of LAIR-1 is associated with poor clinical outcome in BC. Association with immune cells and immune checkpoint markers warrant further studies to assess the underlying mechanistic roles.

Bioinformatic analysis of the expression and prognostic value of chromobox family proteins in human breast cancer

Chromobox (CBX) family proteins control chromatin structure and gene expression. However, the functions of CBXs in cancer progression, especially breast cancer, are inadequately studied. We assessed the significance of eight CBX proteins in breast cancer. We performed immunohistochemistry and bioinformatic analysis of data from Oncomine, GEPIA Dataset, bcGenExMiner, Kaplan–Meier Plotter, and cBioPortal. We compared mRNA and protein expression levels of eight CBX proteins between breast tumor and normal tissue. The expression difference of CBX7 was the greatest, and CBX7 was downregulated in breast cancer tissues compared with normal breast tissues. The expression of CBX2 was strongly associated with tumor stage. We further analyzed the association between the eight CBX proteins and the following clinicopathological features: menopause age, estrogen receptor (ER), progesterone receptor (PR) and HER-2 receptor status, nodal status, P53 status, triple-negative status, and the Scarff–Bloom–Richardson grade (SBR) and Nottingham prognostic index (NPI). Survival analysis in the Kaplan–Meier Plotter database showed that the eight CBX proteins were significantly associated with prognosis. Moreover, CBX genes in breast cancer patients had a high net alteration frequency of 57%. There were significant co-expression correlations between the following CBX protein pairs: CBX4 positively with CBX8, CBX6 positively with CBX7, and CBX2 negatively with CBX7. We also analyzed the Gene Ontology enrichment of the CBX proteins, including biological processes, cellular components, and molecular functions. CBX 1/2/3/5/8 may be oncogenes for breast cancer, whereas CBX 6 and 7 may be tumor suppressors for breast cancer. All eight CBX proteins may be predictive for prognosis. Clinical trials are needed to confirm the significance of the eight CBX proteins in breast cancer.

Genomic testing in early breast cancer (EBC) for low middle income countries (LMIC): Is it worth the cost?

e12521 Background: Chemotherapy is crucial for EBC management but has toxicities. Attempts are made to identify patients where chemotherapy can be safely skipped. Genomic testing offers advantage over clinico-pathological tools but given the cost, its utility in clinical practise, especially in LMIC remains questionable. Methods: 50 EBC patients who underwent risk stratification by oncotypeDX were retrospectively studied. Their clinico-pathological characteristics, Nottingham prognostic index (NPI) and PREDICT recommendation (v 2.1) were recorded. Tumor board(TB) made treatment recommendations based on age and histopathology, blinded to recurrence score(RS). The results were compared. Results: 32% patients were < 50 years, 68% were > 50 years. 32% and 68% patients were pre and post menopausal respectively. On pathological examination, T1, T2 & T3 comprised 26%, 70% and 4% respectively. 96% were node negative, 2% node positive, 2% had unknown nodal status. Tumors had Grade 1, 2 and 3 in 8%, 88% and 4% respectively. 4% had unknown estrogen receptor (ER), progesterone receptor (PR) score. ER and PR were low (Allred 3-5) in 2% and 12% respectively. NPI was low ( < 3.4) in 96% and intermediate (3.5- 5.4) in 4%. On PREDICT, all showed low benefit of chemotherapy ( < 3% at 10 years). TB prescribed chemotherapy in 58% and hormonal therapy (HT) in 42% patients. RS was low, intermediate and high in 66%, 26% and 8% patients respectively. Patients with low and high RS were supposed to receive HT and chemotherapy respectively. In the intermediate group, 4% patients were recommended HT as per age. 22% patients could not be assigned a treatment based on RS alone. In remaining 78%, TB’s decision matched RS recommendation in 38% (19) patients. In 2% (1), TB recommended HT while OncotypeDX showed high RS. In 38% (19) patients, TB recommended chemotherapy while OncotypeDX showed low RS. Despite all having low/intermediate NPI with < 3% chemotherapy benefit on PREDICT, 8% showed chemotherapy benefit on OncotypeDX. In 40%, OncotypeDX recommendation deferred from TB. In more than one third patients, when TB recommended chemotherapy, RS came low. In these patients we could avoid chemotherapy, saving ~900 USD treatment costs. As 68% patients were elderly ( > 50), genomic testing avoided chemotherapy in this subgroup, likely to suffer treatment toxicities. Conclusions: In LMIC where all patients don’t have access to hospitals with adequate infrastructure for chemotherapy administration, genomic testing has significant implications. We recommend using it more in clinical practise.

Correlation of OncotypeDx Recurrence Score, Nottingham Prognostic Index, and Ki67

Objective: To identify the correlation between the OncotypeDx Recurrence score, Nottingham Prognostic Index (NPI), and Ki67. Material & Methods: A retrospective study was conducted at Liaquat National Hospital where medical records of early-stage breast cancer patients, who had OncotypeDx RS done were reviewed from 2008-2019. The patient’s age, Histopathology type, tumor grade, size, No. of nodes involved, ER, PR, Her neu and Ki67 were collected. OncotypeDx RS, NPI, and Ki67 were categorized into 3 groups and statistical analysis was done to find a correlation between OncotypeDx RS, NPI and Ki67. Result: Total 76 patient’s records were reviewed. The average age of study participants was 56.40 ± 10.32 years. Oncotype-Dx method categorized 34 (44.74%), 26 (34.21%) and 16 (21.05%) patients as low, moderate and high risk respectively. 18(23.68%), 56(73.68) and 2(2.63%) were classified as low, moderate and high-risk patients by the NPI method correspondingly. According to Ki67, 26(40.63%), 21(32.81%) and 17(26.56%) patients were low, moderate and high risk respectively. Statistically significant fair agreement was only observed between Oncotype-Dx& Ki67 (k=0.33, p<0.001) with weak positive correlation (r=0.44, p<0.001). Further on age-stratification, it was observed that significant fair agreement (k=0.36, p<0.001) and weak positive correlation (r=0.45, p<0.001) between Oncotype-Dx& Ki67 risk assessment categories was for age group >50 years. On age stratification, moderate agreement (k=0.45, 0.002) and moderate correlation (r=0.57, p=0.005) were also observed between OncotypeDx& NPI risk categories for age group ≤50 years. Conclusion: No statistically significant strong agreement and correlation were observed among three risk assessment methods. Further investigations should be conducted with a larger sample size to assess agreement among these risk classification methods.